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PINK BOOK 3

Sebacic Acid/Dicarboxylic Acids

CIR EXPERT PANEL MEETING

AUGUST 30-31, 2010

Memorandum

To: CIR Expert Panel Members and Liaisons From: Monice M. Fiume MMF Senior Scientific Analyst/Writer Bart A. Heldreth, Ph.D. BAH

Chemist Date: July 30, 2010 Subject: Draft Report on Dicarboxylic Acids (previously called Diisopropyl Sebacate) The draft report on dicarboxylic acids was last reviewed in December 2009, under the title Diisopropyl Sebacate. At that time, the report was tabled for reorganization. Also at that time, it was determined that oxalic acid would not be part of the safety assessment. The entire report has been reorganized and rewritten. It will be obvious that the Chemistry section is now prepared in a way that allows you to view the dicarboxylic acids in order of increasing chain length. Also included are charts demonstrating the relationship between molecular weight and the log octanol – water partitioning coefficient. Additionally, the report, from the General Biology section on, is now divided into two sections, as was suggested by the Panel in December. The first section addresses dicarboxylic acids and their salts, while the second part addresses esters of dicarboxylic acids. These two subsets of ingredients have different functions in cosmetics, and this will allow the Panel to view the data on each subset separately. In addition to the reorganization, the report has change greatly in the extent of data included. A complete new search of the literature has been performed, and a substantial amount of new data has been added. A great deal of the information included in this report has come from summary documents, such as HPV robust summaries, that cite unpublished sources. Whatever details were available have been included, but often the summaries were brief. Additional unpublished data received from Council, including concentration of use data, have been added. Also included are summaries of information from the 1984 Final Assessment of Dioctyl Adipate and Diisopropyl Adipate and from the 2006 Amended Final Report on the Safety Assessment of Dibutyl Adipate as Used in Cosmetics. (Dioctyl adipate is now correctly named diethylhexyl adipate.) These reports have been included for your use. The diesters have been shown to metabolize. Accordingly, data on esterase metabolites have been included as support information. For your ease in use of this data, an Appendix to the report, that

CIR Panel Book Page 1

summarizes these data, immediately follows the reference section. When applicable, these data are also included in the appropriate tables. There are many aspects for discussion in this report, and we have tried to present it to you as cohesively as possible. The following are included as paper copy:

1. Final report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate; 2. Amended Final Report on the Safety Assessment of Dibutyl Adipate as Used in Cosmetics; 3. Updated concentration of use data – dated February 25, 2010; 4. Unpublished data on Diethylhexyl Succinate, Diisobutyl Adipate, Diisocetyl Adipate,

Diisodecyl Adipate, Dioctyldodecyl Adipate, Diethylhexyl Sebacate and Diisopropyl Sebacate; submitted January 27, 2010. (One in French has not yet been translated, so is not included in text.);

5. Unpublished data on Diisostearyl Adipate, Diisocetyl Dodecanedioate, and Dioctyldodecyl Dodecanedioate; submitted January 15, 2010; and

6. Unpublished data - Physical/Chemical Properties on Dibutyl Octyl Sebacate, Dihexyldecyl Sebacate, and Dioctyldodecyl Sebacate; dated February 15, 2010


REPORT HISTORY: DICARBOXYLIC ACID AND THEIR SALTS AND ESTERS July 10, 2009: SLR was issued September 2009 Panel meeting Initial review of the draft report. The recommendation was made to add 5 additional dicarboxylic acids – oxalic, malonic, succinic, glutaric, and adipic – and their salts and esters December 2009 Panel meeting The report was tabled for reorganization into (1) acids and salts and (2) esters. It was also agreed that oxalic acid should be removed. It was also felt that more data should be available. August 2010 Panel meeting The report has been completely reorganized. A new search was done and the text was updated with much new data.


Sebacates Search Update June 2010 Toxline NTP HPV EU/SCCP EPA IARC OTC SIDS

Sebacic Acid 0 0 NR/NS 0 0 Dibutyl Sebacate 0 0 NR/NS 0 0 Dibutyloctyl Sebacate 0 0 NR/NS 0 0 Dicapryl/Capryl Sebacate 0 0 NR/NS 0 0 Diethyl Sebacate 0 x NR/NS 0 0 Diethylhexyl Sebacate G 0 NR/NS 0 0 Dihexyldecyl Sebacate 0 0 NR/NS 0 0 Diisooctyl Sebacate 0 0 NR/NS 0 0 Diisopropyl Sebacate 0 0 NR/NS 0 0 Diisostearyl Sebacate 0 0 NR/NS 0 0 Dioctyldodecyl Sebacate 0 0 NR/NS 0 0 Disodium Sebacate 0 0 NR/NS 0 0 Isostearyl Sebacate 0 0 NR/NS 0 0 Malonic Acid G 0 NR/NS 0 0 Diethyl Malonate 0 0 NR/NS 0 0 Succinic Acid 0 x NR/NS 0 0 Sodium Succinate 0 0 NR/NS 0 0 Disodium Succinate 0 0 NR/NS 0 0 x Dimethyl Succinate G x NR/NS 0 0 Diethyl Succinate 0 0 NR/NS 0 0 Diethylhexyl Succinate 0 0 NR/NS 0 0 Decyl Succinate 0 0 NR/NS 0 0 Dicapryl Succinate 0 0 NR/NS 0 0 Dicetearyl Succinate 0 0 NR/NS 0 0 Diisobutyl Succinate 0 0 NR/NS 0 0 Glutaric Acid G x NR/NS 0 0 Dimethyl Glutarate G x NR/NS 0 0 Diisostearyl Glutarate 0 0 NR/NS 0 0 Diisobutyl Glutarate 0 0 NR/NS 0 0 Adipic Acid G x NR/NS 0 0 x Dimethyl Adipate G x NR/NS 0 0 Diethyl Adipate 0 0 NR/NS 0 0 Diethylhexyl Adipate C,G x NR/NS x 2 0 x Dipropyl Adipate 0 0 NR/NS 0 0 Dibutyl Adipate 0 x NR/NS 0 0 x Di-C12-15 Alkyl Adipate 0 0 NR/NS 0 0 Dicapryl Adipate 0 0 NR/NS 0 0 Dicetyl Adipate 0 0 NR/NS 0 0 Diheptylundecyl Adipate 0 0 NR/NS 0 0 Dihexyl Adipate 0 0 NR/NS 0 0 Dihexyldecyl Adipate 0 0 NR/NS 0 0 Diisobutyl Adipate 0 0 NR/NS 0 0 Diisocetyl Adipate 0 0 NR/NS 0 0 Diisodecyl Adipate 0 x NR/NS x 0 0 Diisononyl Adipate 0 x NR/NS x 0 0 Diisooctyl Adipate 0 x NR/NS x 0 0 Diisopropyl Adipate 0 0 NR/NS 0 0 Diisostearyl Adipate 0 0 NR/NS 0 0 Dioctyldodecyl Adipate 0 0 NR/NS 0 0 Ditridecyl Adipate 0 x NR/NS x 0 0 Azelaic Acid 0 0 NR/NS 0 0 Dipotassium Azelate 0 0 NR/NS 0 0 Disodium Azelate 0 0 NR/NS 0 0 Dodecanedioic Acid 0 x NR/NS 0 0 x Diisocetyl Dodecanedioate 0 0 NR/NS 0 0 Dioctyldodecyl Dodecanedioate 0 0 NR/NS 0 0 Totals 2744


Toxline - searched 6-10-10; included Medline NTP - searched 6-20-10; G - genotoxicity, C - carcinogenicity HPV - searched 6-20&21-10; x - listed in HPV database EU - searched 6-20-10; NR - no restrictions; NS - no SCCP opinion IARC - searched 6-21-10 OTC - searched 6-22-10 (April 7, 2010 update) EPA - searched 7-8-10 found updated Robust Summaries for HPV items

TOXNET Search Strategy: Sebacic 06-11-10 306 hits 111-20-6 OR 184706-97-6 OR 109-43-3 OR 110-40-7 OR 122-62-3 OR 359073-59-9 OR 10340-41-7 OR 7491-02-3 OR 69275-01-0 OR 17265-14-4 OR 478273-24-4 OR (DICAPRYL AND CAPRYL AND SEBACATE) OR (DIISOSTEARYL AND SEBACATE) Malonic-Succinic-Glutaric 06-10-10 2511 hits 141-82-2 OR 105-53-3 OR 110-15-6 OR 2922-54-5 OR 150-90-3 OR 106-65-0 OR 123-25-1 OR 2915-57-3 OR 2530-33-8 OR 14491-66-8 OR 93280-98-9 OR 925-06-4 OR 110-94-1 OR 1119-40-0 OR 71195-64-7 OR (DIISOSTEARYL AND GLUTARATE) Adipic 06-10-10 1167 hits 124-04-9 OR 627-93-0 OR 141-28-6 OR 103-23-1 OR 106-19-4 OR 105-99-7 OR 105-97-5 OR 26720-21-8 OR 155613-91-5 OR 110-33-8 OR 141-04-8 OR 57533-90-1 OR 58262-41-2 OR 59686-69-0 OR 27178-16-1 OR 33703-08-1 OR 108-63-4 OR 6938-94-9 OR 62479-36-1 OR 155613-91-5 OR 85117-94-8 OR 16958-92-2 OR (ALKYL AND ADIPATE) OR (DIHEXYLDECYL AND ADIPATE) Azelaic-Dodecanedioic 06-10-10 208 hits 123-99-9 OR 9619-43-3 OR 52457-54-2 OR 17265-13-3 OR 27825-99-6 OR 132499-85-5 OR 693-23-2 OR 131252-83-0 OR 129423-55-8 Combined files minus existing references – 2744 June 21, 2010 – 47 published papers ordered July 8, 2010 - 20 additional papers ordered July 15, 2010 – 10 additional papers ordered *Metabolite alcohols and monoesters were searched for supplemental information in TOXLINE and RTECS, via STN. CAS Registry files were used to search in each of the databases. 55 published papers were ordered. Numerous other references on metabolite alcohols were available from prior safety assessments.


Transcripts/ Minutes

CIR Meeting day 2 Page: 40

Anderson Court Reporting -- 703-519-7180 -- www.andersonreporting.net

1 isononanoates and all that -- those parts. And,

2 hopefully, we can have our -- you know, at the

3 next meeting, have a good discussion on whether

4 these are long shots or not, in other words, if

5 they're lipophilic, probably really concerned and

6 so forth, because I'd hate to pull --

7 unnecessarily pull ingredients off the list when

8 there's a good reason to believe that it's not a

9 problem.

10 DR. BERGFELD: Well, thank you for that

11 clarification of who does what.

12 All right. Well, then we move on.

13 We're moving on to the second ingredient under the

14 reports advancing and that's sebacates by Dr.

15 Marks.

16 DR. MARKS: So, this is the second time

17 we've looked at the sebacates. In the September

18 2009 meeting we decided to table these ingredients

19 so that we could expand the number and I have a

20 feeling we're going to have a discussion again

21 procedurally how to go. Our team felt that we

22 should continue to table these ingredients with

ANDERSON COURT REPORTING 706 Duke Street, Suite 100

PANEL - DEC 2009 CIR Meeting day 2 Page: 41


1 the aim of splitting the acids and salts into one

2 group -- they are used as pH adjusters -- and then

3 the esters into another group, rather than having

4 them all mixed in as is in the present document.

5 That could either be, as we discussed,

6 whether this should be two separate documents or

7 one document and just have the document organized

8 so these ingredients were split, and we felt that

9 we could proceed with one document. And then we

10 also felt that within this list, that we should

11 reopen three of the esters that have already been

12 determined to be safe by the CIR panel, and that's

13 the diethylhexyl adipate, the dibutyl adipate, and

14 the diisopropyl adipate. So, we felt some more

15 work needed to be done on the document and,

16 therefore, recommend to table it.

17 DR. BERGFELD: Is there a second to

18 table?

19 SPEAKER: Second.

20 DR. BERGFELD: Second. There's no

21 discussion on the table. Motion, all those in

22 favor of tabling, please indicate by raising your




1 hand?

2 DR. BELSITO: Any discussion?

3 DR. BERGFELD: No discussion on the

4 table. It's four against four? So, the chair has

5 to vote. I'll vote to table. So, this particular

6 ingredient has been tabled and let's go over why

7 it's being tabled again.

8 DR. MARKS: Well, the first is that we

9 felt the document could be reorganized and that

10 really by uses, so the acids and the salts are

11 used as pH adjusters and then the esters had other

12 uses. And so the document would be split to

13 discuss those two groups together, and that we, as

14 part of this document, reopened three esters which

15 had previously been determined by the CIR as all

16 are safe to be included in this new amended.

17 DR. BERGFELD: May I ask, Alan, is this

18 really editorial or is this truly -- does it truly

19 have a need for being tabled?

20 DR. ANDERSON: Yes, I would have said

21 that was an editorial change. It's just a matter

22 of reorganizing the document, whether it is split




1 into two or split into two pieces in one document.

2 We have lots of experience with both approaches.

3 It's simply a question of approach. It doesn't

4 address the question of any real additional data

5 needs. So, I'm not sure there's a benefit to

6 tabling from that standpoint.

7 DR. BERGFELD: How about the addition of

8 the other previously approved ingredients?

9 DR. ANDERSON: I think --

10 DR. BERGFELD: Does that fit with the

11 first comment?

12 DR. ANDERSON: There is -- there are

13 data that are available in the other safety

14 assessments that previously the panel has

15 completed. To the extent that you want those data

16 incorporated, tabling it to do that step is, I

17 think, a valid thing to do because clearly they're

18 not in there now.

19 DR. BERGFELD: Don? Comment?

20 DR. BELSITO: Well, I mean, we obviously

21 didn't vote to table, but some comments. First,

22 yes, I mean, I think the other three should be



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FULL PANEL - DEC 2009



1 included. Jim, I think you said dibutyl, you mean

2 dioctyl.

3 DR. MARKS: Okay. Thank you, Don.

4 DR. BELSITO: The biggest discussion we

5 had revolving around this was oxalic acid, which

6 did not -- I mean, all of the safety data on that

7 specific acid, particularly in terms of causing

8 renal calculi, was not in this document. And we

9 actually thought since we didn't see it listed as

10 having any cosmetic uses, that unless there were

11 cosmetic uses for oxalic acid or its esters that

12 it be dropped from this family because of those

13 issues with renal toxicity.

14 DR. BERGFELD: So, your recommendation

15 under the conditions that we were tabling this is

16 to reconsider the inclusion of oxalic acid?

17 DR. BELSITO: Well, to first of all

18 confirm whether, in fact, it's used -- currently

19 being used, and, if not, then our recommendation

20 would be to remove it from this family because of

21 those issues that were being countered and because

22 of the huge amount of data that we'd have to




1 review and grapple with.

2 DR. LIEBLER: If I could just elaborate

3 on that.

4 DR. BERGFELD: Don?

5 DR. LIEBLER: Yeah, I think the idea of

6 including the smaller diacids and their esters and

7 salts was mainly to expand the chemical space to

8 things that are possibly relevant. But in getting

9 down to oxalic acid, you run into some unique

10 toxicology that's very well documented, very

11 prominent, and quite problematic, and we don't

12 even know if this is used as a cosmetic

13 ingredient. So, rather than get tangled up in all

14 of that, it's worth considering deleting the

15 oxalic acid from this report.

16 DR. BERGFELD: John Bailey?

17 MR. BAILEY: Yeah, I think we didn't

18 have time in getting these additional ingredients

19 to survey -- do our usual survey of use and use

20 levels, so we can't answer definitively whether

21 that's the situation or not, so I think we need

22 some more information. I would point out that in




1 Europe, oxalic acid is on annex 3 for hair dyes,

2 so presumably, you know, that may be a use. And

3 we haven't done the research necessary to get more

4 information about how it got there and use levels

5 and so forth. So, I would say, certainly oxalic

6 acid is in the textbooks. We all know about it,

7 but there may be some additional information that

8 would be relevant that we simply, you know, didn't

9 have time to get.

10 DR. BERGFELD: So, that's a promise to

11 get?

12 MR. BAILEY: Certainly, yeah. We'll do

13 our usual survey of --

14 DR. BERGFELD: Okay. Any further

15 discussion? Don?

16 DR. BELSITO: Yeah, I guess, just to

17 follow up on Dan's point, there is such a

18 voluminous amount of literature on oxalic acid

19 that even if it's used in cosmetics, do we want to

20 get bogged down dealing with why that is going to

21 be safe in a cosmetic product and reviewing all of

22 that literature on oxalic acid? Or would it be




1 better simply to keep all the ingredients, which

2 is a large number of ingredients we have right

3 now, get rid of oxalic acid and, in fact, if it's

4 used, we can always look at oxalic acid

5 specifically rather than as a member of this

6 group? Because I just think we're going to get

7 hugely bogged down even if it's used in trying to

8 explain why it'd say brief discontinuous use on

9 the hair, no absorption, yadda, yadda, yadda. But

10 we're going to have to look at all the data

11 anyway.

12 MR. BAILEY: Yeah, I concur.

13 DR. BERGFELD: So, we might entertain a

14 motion at this time to delete oxalic acid from the

15 list.

16 DR. BELSITO: I would like to make that

17 motion.

18 DR. BERGFELD: Is there a second?

19 Second. Is there a discussion of that

20 recommendation?

21 Curt?

22 DR. KLAASSEN: No problem.





1 DR. BERGFELD: Paul? Dan? Ron?

2 That's okay.

3 DR. HILL: I have no problem with that.

4 DR. BERGFELD: Okay, we'll call for the

5 vote to delete oxalic acid from the list of

6 ingredients. All those in favor? Unanimous, with

7 the intent of taking it up as a separate

8 ingredient at some time in the future when it's

9 been declared how it's used and how frequent it's

10 used.

11 MR. BAILEY: To that end, we'll include

12 that in our survey just so we'll have that

13 information.

14 DR. BERGFELD: Thank you. Ron?

15 DR. HILL: Yeah, in our discussions

16 yesterday our starting point was really a

17 suggestion that Ron Shank made to separate into

18 two documents, and then we talked about two sort

19 of separate sections of the main document because

20 in the consideration of the diacids, they're

21 pretty much -- their uses are as pH adjusters and

22 then similar like that. There are a lot of esters




1 here. You'd have to pull out that list, Ron, that

2 you had where we would seem to be depending on

3 read-across data for things like genotoxicity,

4 tumor-promoting potential, and even sensitization.

5 Am I mistaken there? We have direct data on the

6 sebacates, some of the adipates, and a number of

7 the others we don't. Isn't that correct?

8 DR. SHANK: That's correct.

9 DR. HILL: So, we're looking at a pretty

10 high number of read-across, which was another

11 reason, I think, basis, for why we had suggested

12 the tabling idea, so that we had the time to

13 really better assess those gaps.

14 DR. BERGFELD: We need to record your

15 response, Ron.

16 DR. SHANK: I agree with Dr. Hill that

17 we have some information on the esters, but the

18 esters are used quite differently from the acids

19 and salts. And that's why I had suggested that we

20 split them, either two reports or within the same

21 report, make it very clear that the acids and

22 their salts are -- can be handled one way and the




1 esters will have to be handled a different way.

2 DR. ANDERSON: Yeah, I really don't

3 think that that's a problem in terms of overall

4 strategy. It provides the opportunity to be a lot

5 clearer to the reader, that we understand the

6 fundamental difference between how these chemicals

7 are used in cosmetics. So I think we'll simply do

8 that.

9 Now, I am concerned about the suggestion

10 that read-across may be problematic. I would ask

11 the panel to reserve that, to focus on the data,

12 where the data gaps are, and what your comfort

13 level is going to be with the ability to use data

14 on one chain length ester of dicarboxylic acid to

15 inform your decision about another chain length,

16 all other things being equal. So, having all data

17 on all ingredients is not the norm. So, I think

18 there needs to be a comfort level with some degree

19 of read-across as you evaluate these data. Only

20 you folks on the panel can reach that level of

21 comfort, but I would ask you not to veto it a

22 priori.




1 DR. HILL: Well, I'm relatively new,

2 but, you know, I mean, I still have the same

3 issues. There's some of the alcohols that we just

4 talked about in the pelargonate section that show

5 up again here. And if there's no reason to

6 believe that there's any significant generation of

7 those alcohols in the skin, if there's no reason

8 to believe that those alcohols would lead to

9 sensitization in the skin, then there's probably

10 -- and there's no reason to believe that either

11 the alcohols or, in fact, these esters that we

12 have no data on could promote tumor development in

13 skin, then we don't have a problem. But I'd like

14 to know, when I make a final vote, that I'm

15 comfortable whether that is valid scientifically,

16 and that's really the only concern I have is that

17 it's scientifically valid to make that conclusion.

18 DR. ANDERSON: Point well taken.

19 DR. BERGFELD: Thank you. So we're

20 going to be tabling the sebacates and we've had

21 the discussion and we're going to reorganize the

22 document, and we're going to get some more





1 information on some of the ingredients. Is that

2 correct?

3 DR. ANDERSON: Mm-hmm.

4 DR. BERGFELD: All right.

5 DR. ANDERSON: And we're deleting oxalic

6 acid --

7 DR. BERGFELD: And we're deleting oxalic

8 acid, thank you.

9 DR. ANDERSON: Deleting oxalic acid.

10 Nobody has specifically said it, but let me say

11 it, we're also going to delete the oxalic acid

12 esters.

13 DR. BERGFELD: Correct. All right.

14 It's time to move on to the next ingredient, the

15 PEGs. Dr. Belsito.

16 DR. BELSITO: Yes. At our September

17 meeting, we reviewed results from industry

18 essentially done on tape- stripped skin as a

19 method of looking at PEG toxicity on damaged skin

20 because previously we had a conclusion that

21 restricted the use of PEGs on damaged skin. We

22 had a chance to look at what would be absorbed.



Cosmetic Ingredient Review Panel December 8, 2009 Page: 143


1 Sebacate? Sebacate?

2 SPEAKER: You asked that last time.

3 DR. BELSITO: Sebacates. Sebaceous.

4 Okay, so we're going to go to the --

5 SPEAKER: Sebacates.

6 DR. BELSITO: Dicarboxylic Acid Salts

7 and Ester Report. That, I know how to pronounce.

8 Okay. And I guess as part of the

9 add-ins now, we've been provided with a final

10 report that we did on dioctyl and diisopropyl

11 adipate. And we're back in December. We tabled

12 this to look at a whole bunch of related

13 dicarboxylic acids that we agreed to incorporate

14 into this report. And we've gone out and got

15 information on azelaic acid as used in topical

16 drugs. And we've got some new unpublished data

17 that we saw briefly at the September meeting but

18 didn't really have time to digest. And so now

19 we've got this tentative safety assessment and all

20 of the information in it is in here, short of a

21 discussion and a conclusion, so.

22 Then we've heard a little bit from Bob




1 this morning on dermal penetration. We don't have

2 a lot of genotox and carcinogenicity here. But we

3 do for the azelaic acid, which is used as a

4 topical, have some information. So if there is a

5 concern about that, I guess we still have Bob here

6 and he can tell us what he would think about the

7 absorption of these.

8 So with that as an intro, the question

9 is do we have enough here for this group of

10 dicarboxylic acids, which now will contain azelaic

11 acid, malonic, succinic, glutaric, adipic, and

12 sebacic acid and their salts and esters that are

13 listed in the Cosmetic Dictionary to go with a

14 safe as used conclusion?

15 SPEAKER: We have, to date, not received

16 use data.

17 MS. ROBINSON: It's forthcoming. Carol

18 (inaudible) by the next --

19 SPEAKER: Mic, please.

20 MS. ROBINSON: The use information is

21 forthcoming. Carol has said that it may be here

22 by the next meeting.




1 DR. BELSITO: But how can we --

2 SPEAKER: By the next meeting? April?

3 DR. ANDERSON: We don't have it.

4 DR. LIEBLER: Can I get a clarification

5 of that? Were these the data that were from the

6 American Chemistry Council?

7 MR. ANSELL: That data has been

8 included. This is the use concentration on all

9 the add-ons, which came to us in too short a time

10 to turnaround between these.

11 DR. LIEBLER: Okay, so we did -- last

12 time we did talk about the American Chemistry

13 Council data that we thought would be useful. And

14 there was a question of whether or not we joined

15 -- or CIR joined in or somehow got access to that.

16 So I see some of the data in this report. And

17 just, I'm curious, how do we get that?

18 MS. ROBINSON: Well, to date, we haven't

19 received any additional data from the last

20 meeting, from the reports. So what you see in the

21 report is essentially the same that we saw at the

22 last meeting.




1 DR. BELSITO: Okay. And one comment I

2 have is are the impurities sufficient? We have

3 impurities only for dimethyl malonate and

4 diethylmalonate and diethylhexyl adipate. We

5 don't have impurities for the other compounds

6 we're reviewing.

7 So I just, you know, sort of throw that

8 out as an aside, to get the sense of chemists

9 looking at the way these are manufactured as to

10 whether they would be concerned about that.

11 DR. LIEBLER: I'd like to see data that

12 describes the impurities, at least the types of

13 compounds that would be present as impurities and

14 their approximate ranges of concentrations.

15 DR. BELSITO: And then in terms of

16 concentrations of use, I mean, we do have some

17 information here if we go to Table 4, particularly

18 for the sebacic acid groups we have. We have some

19 for the succinate. We have some for adipic acid

20 and its groups, and then we have azelaic acid. So

21 we have some concentrations of use. And we have

22 that standard, you know, asterisk boilerplate that



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Typewritten Text

BELSITO TEAM - DEC 2009



1 if where we're not giving a concentration of use,

2 we assume it's being used in the same

3 concentration as the other groups.

4 So I'm not sure -- I mean, it would be

5 nice to get updated information, and there are

6 lots and lots of blanks here, I agree. But I

7 think the issue that bothered me the most was the

8 lack of impurities in all these groups that we're

9 adding in.

10 And then, of course, we're relying on

11 azelaic acid and the data from the Finacea and the

12 Azelex cream to support a lot of our systemic or

13 lack thereof of systemic toxicity. So again, I

14 just throw out is there any concern here about

15 absorption of the other molecules? Because for --

16 and again, it's back to Dan whether you can. You

17 know, is the systemic toxicity going to be

18 generalizable across all these dicarboxylic acids

19 or are there any that you would be concerned

20 about?

21 DR. LIEBLER: Aside from parameters that

22 would affect absorption and distribution, I'm not




1 aware of any sort of pharmacodynamic reasons why

2 different chain length dicarboxylates would have

3 different toxicological effects.

4 DR. BELSITO: Curt?

5 DR. KLAASSEN: I agree.

6 DR. SNYDER: And the overall toxicity is

7 relatively low. Pretty high OB50s.

8 SPEAKER: Okay.

9 DR. BRONAUGH: I guess there was an

10 absorption study in guinea pig skin of the diethyl

11 -- what is it? -- the diethylhexyl sebacate, which

12 the molecular weight looks to be under 500. You

13 know, sometimes, if you have a large family of

14 ingredients, it might be useful if we could know

15 what the molecular weight is, what the logP is, so

16 you could look through and have a better sense.

17 But, you know, this data is in a

18 hairless guinea pig -- or the guinea pig, anyway,

19 that was given to us, where they said it was

20 readily absorbed. But I would imagine some of

21 these molecules are absorbed. But, you know, it's

22 really kind of hard to say without, you know, how




1 to compare them without knowing a little bit more

2 about their chemistry.

3 DR. KLAASSEN: One would think that

4 these would be extremely water soluble and not be

5 absorbed so well, right?

6 SPEAKER: (inaudible) the mic.

7 DR. KLAASSEN: Yeah.

8 SPEAKER: Sometimes I -- if it --

9 DR. KLAASSEN: You know, in regard to

10 these dicarboxylic acids, I guess it'd be my

11 impression that they'd be so water soluble that

12 they probably wouldn't be absorbed. I think it

13 would be nice to see some partition coefficients,

14 etcetera.

15 DR. BRONAUGH: It would take a little

16 extra time, but maybe it'd be worthwhile if -- I

17 mean, this data could be calculated in a family

18 like this and we'd have a better idea.

19 DR. KLAASSEN: And in your talk this

20 morning didn't you say that there was some EPA or

21 FDA website that had a lot of that data on there.

22 DR. BRONAUGH: It has the software where




1 you can calculate logP and water solubility just

2 knowing the SMILES code of any ingredient. And

3 again, the SMILES codes are available on the NIH

4 site, for many compounds.

5 So it might be useful to have that

6 sometimes.

7 DR. KLAASSEN: Yeah, I agree 100

8 percent.

9 DR. BELSITO: But if the toxicity is the

10 same, at least systemic toxicity is, that was the

11 reason I asked the question. And we have use that

12 looks like it's not going to above 10 percent in

13 cosmetics. And then we have Azelex cream, which

14 has been looked at by FDA, that's 20 percent for

15 treatment of acne. Then I think I'm okay as long

16 as I don't see cosmetic products coming out above

17 10 percent or certainly over the 20 percent in

18 terms of, you know, okay, you know, is there

19 absorption, you know, and what are slight

20 differences in absorption.

21 But I agree in principle with what Bob

22 is saying. As we create these superfamilies, it





1 would be nice if CIR would go to that website and

2 provide us with a list of molecular weights and

3 logPs. You know, particularly when it comes to

4 picking, you know, if there is an issue about

5 absorption, what ingredient do we want as the

6 model ingredient to assure the safety for the

7 entire family. Well, it would be the one that we

8 would predict from these various parameters would

9 be most likely to be absorbed. So I think it

10 would be helpful.

11 MR. ANSELL: To the discussion on

12 systemic safety, we would like to point out that

13 CIR has already conducted and found safe as used

14 three of the adipates, including diethylhexyl,

15 dibutyl, and diisopropyl. And that the

16 diethylhexyl has already gone through a complete

17 NTP screen through carcinogenicity.

18 DR. ANDERSON: I think the, excuse me,

19 Table 2 already includes many of the data you're

20 talking about. Admittedly they are buried in

21 amongst all of the other chemical and physical

22 properties. But the American Chemistry Council




1 report, in fact, did use the EPA program to

2 calculate logPs, and these are included. So for

3 dimethyl sebacate, it's 3.4 for a logP; for

4 diethylhexyl sebacate, it's 3.74 there. Just

5 outside, if you will, of the -1 to 3 range that

6 would suggest penetration, but not far enough

7 outside so that I'd be comfortable for giving them

8 a free ride. I think you'd have to presume there

9 is some absorption of these things. Then the

10 question becomes what's the toxicity, which is

11 rather low. And I wouldn't kiss them off on the

12 basis of dermal penetration.

13 SPEAKER: Yeah.

14 DR. ANDERSON: But I take your point

15 that a table that presents just molecular weight

16 and logP, if those data are available, paints an

17 interesting picture that you'd like to see.

18 DR. BRONAUGH: Yeah, I forgot about that

19 data. I don't have a copy. Linda has our copy of

20 the book. I forgot that that was done for this

21 series of compounds. And I think it was very

22 useful. There were some gaps in there that maybe




1 could have been filled in, but I think that's

2 useful.

3 SPEAKER: That's good to know.

4 DR. LIEBLER: You could represent the

5 calculated logP values in a plot, like the plot

6 for the phenyls that Bob showed during his talk,

7 in which you'd number, instead of just using round

8 dots as the points, you actually use numbers as

9 the points. And the numbers could refer back to

10 the compounds in a table. And what that would

11 allow us to do is see much better which compounds

12 are within the range or close to the range that's

13 typically associated with the potential for

14 absorption.

15 DR. ANDERSON: That raises an

16 interesting idea of what would that plot look like

17 since we have calculated logP values on one axis

18 as a function of molecular weight on another.

19 DR. KLAASSEN: Well, those are two of

20 the more important characteristics of chemicals

21 that are important to us. And, you know, a lot of

22 these that we have, you know, like boiling point,




1 vapor pressure, density even, we have all of these

2 other things. It's kind of like the important

3 data gets lost in the minutiae.

4 SPEAKER: Yep, the --

5 DR. LIEBLER: With the Henry's Law

6 constant, you're saying.

7 DR. ANDERSON: I take your point. Just,

8 we need a good chemist on staff.

9 DR. BELSITO: Now, were the data from --

10 all of the data from this dioctyl and diisopropyl

11 adipate report incorporated into this report?

12 Because it seems like they have not been.

13 And did I understand, Jay, from your

14 comment, that there is another adipate that we've

15 also previously reviewed out there?

16 MR. ANSELL: Yeah, we have three

17 adipates that were CIR reviewed, which have not

18 been included. These were diethylhexyl, dibutyl,

19 and diisopropyl adipate.

20 DR. BELSITO: Okay. So then there's the

21 diethylhexyl has also not been incorporated into

22 this at this point?





1 MS. ROBINSON: If it was from the

2 original report, it has not been incorporated.

3 But an updated search was performed, so anything

4 outside of that is in the report.

5 DR. BELSITO: Okay. So we have one

6 other report, other than this one, that needs to

7 be incorporated into this document, as well?

8 SPEAKER: (inaudible)

9 DR. BELSITO: Okay.

10 MR. ANSELL: We also -- the NTP study,

11 we don't believe has been incorporated on a whole

12 series of materials. I'm also unclear as to

13 whether the -- we did obtain from ACC robust

14 summaries that we were requested to -- and the

15 cover letter suggests they were included, but

16 Valerie's suggesting they're not. So I think

17 there's some data that needs to be included.

18 MS. ROBINSON: The robust summaries from

19 ACC were incorporated, but we haven't received any

20 additional information that we asked for prior.

21 MR. ANSELL: The data which was

22 requested of us in September, though, I think was




1 Dan's question. And we did find robust summaries,

2 and I do believe they have been incorporated.

3 DR. LIEBLER: I couldn't tell what was

4 different. I guess I didn't have the previous

5 book, so. I saw some references to the American

6 Chemistry Council HPV summaries. Is that what

7 you're referring to, Jay?

8 MR. ANSELL: Yeah.

9 MS. ROBINSON: Yes, those are new.

10 DR. LIEBLER: Those are new.

11 MS. ROBINSON: Yes.

12 DR. LIEBLER: Since September.

13 DR. ANDERSON: That's correct. Those

14 were not in the document.

15 DR. LIEBLER: Okay.

16 DR. ANDERSON: And the only issue from

17 the panel's perspective is that now that you

18 understand dicarboxylic acids were in the American

19 Chemistry Council report, there is a couple of

20 points of overlap with this safety assessment, and

21 is that enough?

22 DR. BELSITO: Okay. Where do we get the




1 information as to what was in the American

2 Chemical report? How do we divine that from this

3 document?

4 DR. ANDERSON: Well, if you go to page

5 34, for example, for the question, really, of the

6 genotoxicity data, then there's specific mention,

7 you know: Mammalian cell gene mutation assay.

8 Two ingredients in this assessment were included

9 in the ACC report and were negative in the mouse

10 lymphoma assay.

11 DR. BELSITO: Okay, so you're talking

12 about the mutagenicity studies, in particular.

13 DR. ANDERSON: Yes.


15 DR. ANDERSON: Yeah, that was the --

16 DR. BELSITO: Wasn't clear where you

17 were.

18 DR. ANDERSON: Yeah, I'm sorry. That

19 was the major gap. Without those data, the

20 genotoxicity section was really quite bleak.

21 DR. BELSITO: Okay. So where are we

22 with this? Are we going insufficient for




1 impurities? Are we going insufficient for more

2 concentration of use? Are we going safe as used

3 when we add in the NTP summaries and the

4 information from the dioctyl, diisopropyl,

5 diethylhexyl adipate documents that were

6 previously published?

7 Paul, where are you?

8 DR. SNYDER: Sounding an awful lot like

9 insufficient. I mean, Dan's comment to the

10 impurities issue, he's not comfortable with the

11 absence of additional impurities data.

12 DR. LIEBLER: So I'd be happy with

13 representative data for some of these compounds

14 for impurities. I mean, we have a wide range of

15 things from small dicarboxylates to big,

16 long-chain esters, which are going to result from

17 different processes and are going to have

18 different impurities. We may not have impurity

19 data for every compound in the table, but I'd like

20 to see representative impurity data from compounds

21 that represent the processes that go into these

22 products.





1 And I was struck, in concentrations and

2 frequency of use, that it seemed like they were

3 inversely related. The compounds with recorded

4 significant frequencies of use had almost no

5 concentration data and the compounds with bigger

6 numbers for frequency of use tended to have no

7 concentration data.

8 Talking about Table 4.

9 DR. ANDERSON: Yeah, and that's very

10 likely an artifact of the late addition of many of

11 the compounds.

12 DR. LIEBLER: Do you think the

13 information's available and we just haven't gotten

14 it into a table yet?

15 DR. ANDERSON: I think that's the case.

16 DR. BELSITO: That's what we're told,

17 that Carol --

18 DR. LIEBLER: I see, okay.

19 DR. BELSITO: So then what we're looking

20 at is Dan would like some representative impurity

21 data. Would you like to mention any specific ones

22 you'd like or just leave it open-ended back to the




1 council and industry for some representative

2 impurity data?

3 DR. LIEBLER: I'd like to see impurity

4 data on the dicarboxylates.

5 DR. BELSITO: But which ones? Any

6 specific one that you're concerned about, or?

7 DR. LIEBLER: How about sebacate.


9 DR. LIEBLER: As representative. And

10 then how about succinate as -- or malonate as

11 representative? So you get a longer one and a

12 shorter one.


14 DR. LIEBLER: And then how about the

15 impurity data on short esters of both of those and

16 long esters of both of those? I think that

17 represents the chemical space reasonably well.

18 DR. BELSITO: Okay. So then what we're

19 suggesting is that we are going insufficient for

20 impurities. And we would like to see something on

21 the sebacates or sebacic acid, and either malonic

22 or succinic acid, and then whatever two you




1 choose, some impurity data on short- and a

2 long-chain ester of each of those acids. And we

3 would appreciate getting updated concentration of

4 use, particularly for those ingredients that have

5 considerable use. And assuming that that data

6 looks clear, I am guessing that we would be going

7 safe as used for these dicarboxylic acids.

8 DR. BERGFELD: So are you going out

9 insufficient or are you tabling it?

10 DR. BELSITO: No, insufficient. I mean,

11 it's only -- it's at a pink stage.

12 MR. ANSELL: But there's so much data

13 which was not included in the report, and so many

14 added after, it would be possible for us to have

15 provided the data. We would prefer it be tabled

16 to include CIR's reports, to include the NTP

17 study, to include the actual concentrations of

18 use.

19 DR. BELSITO: But I guess, Jay, I don't

20 see how tabling it versus us telling you what we

21 find is insufficient in the current report really

22 changes things since it's at a pink stage. I




1 mean, it's not like it's going out for a final.

2 And if we were going out for a final, it was going

3 to be, you know, we're saying it's insufficient,

4 and you're going to get the data for us before the

5 next meeting. But, I mean, if anything, I mean,

6 PC has been --

7 DR. BERGFELD: Are you asking for an

8 announcement?

9 DR. BELSITO: -- after us to expedite

10 the process. Well, this expedites the process.

11 It moves it up to the next stage and it tells you

12 where we're at.

13 DR. BERGFELD: Are you going out for

14 insufficient data announcement or --

15 DR. BELSITO: Yeah.

16 DR. BERGFELD: -- insufficient final

17 announcement?

18 DR. BELSITO: No, this is not even a

19 final. This is pink, Wilma.

20 DR. BERGFELD: No, no, I know, but I'm

21 --

22 DR. BELSITO: We haven't even gotten --





1 DR. BERGFELD: I know, but we had jumped

2 over the announcement part in our new progression.

3 But you're going to input in this one

4 announcement, insufficient data announcement.

5 DR. BELSITO: Right.

6 DR. BERGFELD: It's different than a

7 final.

8 DR. BELSITO: It's not a final, it's

9 just a --

10 DR. BERGFELD: No, no, I know that. But

11 we had done away with announcements. We've done a

12 few of them, but we've done away with that process

13 a little bit. Haven't we? Alan? We were trying

14 to expediate the flow.

15 DR. ANDERSON: Yeah. I think in terms

16 of process, at the last meeting the panel agreed

17 to move forward to prepare a draft report which in

18 our judgment, given your comments, would be ready

19 to be issued as a tentative report. There were a

20 couple of oopses in that process in that a couple

21 of background reports prepared by the panel didn't

22 get captured. The other oops is that the panel




1 flagged these very long list of additions too late

2 for the council to in any way be expected to

3 respond with use concentration data. So those are

4 -- there's some serious gaps in those data.

5 But it is at a stage when you would be

6 expected to do one of two things: Issue an

7 insufficient data announcement or issue a

8 tentative report. And you flag that there are

9 clearly data that you want. In our expedited

10 process of keep it moving, this is ready for an

11 insufficient data announcement. That's,

12 processwise, that's where it is.

13 There is the issue of the couple of

14 oopses. And I wouldn't be upset if you used that

15 as a basis for saying, look, we got to fix these

16 gaps. We've got the reports from previous safety

17 assessments that weren't captured. You need to do

18 that. And arguably that would allow enough time

19 for the use data to come in. And I don't see any

20 difficulty in tabling it. I would write in the

21 post-meeting announcement that part of tabling it

22 is the expectation for the impurities data that




1 Dan has outlined.

2 The risk of that is that we get to April

3 and those data don't show up.

4 DR. BELSITO: Exactly.

5 DR. ANDERSON: And that's --

6 DR. BERGFELD: However, the document is

7 cleaned up and all of the --

8 DR. ANDERSON: Yeah, but you just

9 delayed it --

10 DR. BELSITO: But cleaning up the

11 document is not -- I mean, if all of the

12 information we needed was in the oops documents

13 that didn't get in and an update in the

14 concentration of use, then I would be very happy

15 tabling it. But I'm just concerned that if we

16 want the impurities data and, you know, Dan is the

17 man I go to to tell me if we need that, and we

18 just table it, even if Alan says, oh, by the way,

19 you know, I don't think, based upon past

20 performance of industry, we're going to get it.

21 And then we're going to be sitting at the April

22 meeting where we were at the December meeting.




1 So, I mean, it's -- we go insufficient, we list

2 what we need, clean up the document, update

3 concentration of use, give us some impurities,

4 then I think it's very clear what we're looking at

5 for safety. And that's what I would -- I mean,

6 that's my argument. In the spirit of trying to

7 expedite getting these documents done, I think the

8 best way to expedite it is to be very upfront as

9 to where we are.

10 SPEAKER: Well said.

11 DR. KLAASSEN: There's one additional

12 comment I'd like to make. And that is one major

13 group of chemicals in this larger class is oxalic

14 acid and its various compounds. And the toxicity

15 of oxalic acid is well known, if it gets absorbed,

16 in that it's quite -- produces kidney injury.

17 And, in fact, that's the toxicity from ethylene

18 glycol, is that it's metabolized oxalic acid and

19 it causes severe kidney injury. And while I don't

20 think we're probably getting enough absorbed here

21 to be a problem, there's really not much data in

22 this entire document on oxalic acid. And I just





1 want to make sure people are aware of that.

2 DR. BELSITO: There's a lot of

3 literature on it.

4 DR. KLAASSEN: There's a lot of

5 literature, but it's not in here.

6 DR. BELSITO: Yeah, I know.

7 DR. KLAASSEN: And I think somehow we

8 need to at least address oxalic acid in a

9 discussion or something, if there is good reasons

10 why we haven't kind of paid special attention to

11 it. And, in fact, it's -- yes, there's a lot of

12 information out there. In fact, it's -- also, a

13 lot of plants contain oxalic acid and -- so,

14 anyhow, it needs to be somehow addressed.

15 DR. LIEBLER: I didn't see oxalic acid

16 listed in Table 4, or any of its derivatives

17 listed in Table 4. Is it used in cosmetic

18 products? Oxalic acid or oxalate esters?

19 MR. HAVERY: We don't have any reported

20 uses for oxalic acid.

21 DR. LIEBLER: So I think that -- my

22 recollection is that last time we met, in




1 September, this category was expanded at Ron

2 Shank's suggestion based on incorporating the

3 greater range of chemistries. But I think the

4 rationale was going across the chemical space as

5 opposed to the cosmetic ingredient space, and we

6 might have picked up some unnecessary compounds in

7 doing so; oxalic acid and its esters being

8 representative of that.

9 DR. BELSITO: But they're in the

10 dictionary. And we thought we could cover them in

11 this report. One of the things that we get

12 criticized for by groups such as the Environmental

13 Working Group is that there are X-number of

14 thousands of chemicals in the dictionary and we

15 have looked at only a certain small percentage of

16 them. And so that was the whole purpose for

17 grouping these. And so if oxalic acid is in the

18 dictionary and the functions are similar to the

19 other dicarboxylic acids, and we feel that the

20 safety can adequately be reviewed, you know, we do

21 it. And then there's that footnote at the end

22 saying, well, you know, oxalic acid and its esters




1 aren't being used, but if they were to be used,

2 we're assuming that they would have the same

3 function and the same concentration as everything

4 else in this report.

5 SPEAKER: (inaudible) review.

6 DR. LIEBLER: They may just -- and

7 oxalic acid may be somewhat unrepresentative of

8 this class of compounds. I mean, in the case of

9 oxalic acid in the kidney, it forms these very

10 insoluble crystals with calcium, calcium oxalate,

11 very insoluble. So it's kind of the --

12 mechanistically, it's an outlier.

13 DR. KLAASSEN: And it is at the end of

14 the chain that we're talking about. I mean, it is

15 the smallest one.

16 DR. BELSITO: Well, if mechanistically

17 it's an outlier, and if that's the issue, and then

18 if you're concerned about absorption, then we

19 could easily delete it by saying that it is an

20 outlier. You know, that we cannot group this

21 specific dicarboxylic acid with the others. On

22 the other hand, if you're not concerned about the




1 level of absorption from a cosmetic product, I

2 mean, if it's a true no-brainer, then we should

3 add it. If it's not a true no- brainer, then we

4 shouldn't. And I guess that's a point that, I

5 mean, if you want to raise tomorrow, we can

6 certainly do that.

7 DR. LIEBLER: Yeah, I just don't know

8 what the data are on absorption of oxalic acid in

9 a use that would be consistent with a cosmetic

10 product, oxalic acid or oxalic acid derived from

11 oxalate esters.

12 So if it's insignificant, yeah, then I'm

13 not worried. If it's likely to be more

14 significant, then I would worry.

15 DR. BELSITO: Well, 10 percent would the

16 highest concentration, at least from the limited

17 use data we have right now, in a cosmetic product.

18 Bob, what is your sense for absorption

19 of oxalic acid versus a shorter chain acid?

20 DR. BRONAUGH: I don't know. It's

21 really hard to say. Oh, excuse me. It's really

22 hard to say. I guess, and not being a chemist, I





1 don't automatically know solubility properties. I

2 mean, it's certainly an acid; it's going to be

3 water soluble. I don't know to the extent that it

4 would penetrate through the stratum corneum if it

5 has no lipid solubility. But it depends. I don't

6 know the pKa of oxalic acid. I'm not sure what

7 that is.

8 DR. BELSITO: Well, we have in, let's

9 see, the table, the solubility is 1 gram per 7 mls

10 of water. And --

11 SPEAKER: That's very soluble.

12 DR. BELSITO: -- that's it.

13 DR. KLAASSEN: But then you have the --

14 DR. BELSITO: We don't have a --

15 DR. KLAASSEN: That's the dibutyl

16 oxalate.

17 DR. BRONAUGH: Right. Now there you

18 would start expecting some penetration.

19 DR. KLAASSEN: Yeah.

20 DR. BRONAUGH: In lipophilicity.

21 DR. KLAASSEN: I guess the point is this

22 is not a no-brainer. I mean, there's enough doubt




1 here, or at least in my mind.

2 DR. SNYDER: I guess my question goes to

3 why didn't the scientific literature review then

4 identify some of this information regarding the

5 renal toxicity? So did you search under the term,

6 all of those terms?

7 MS. ROBINSON: Mm-hmm. Yes, I did.

8 Yes, I did the search on the terms. And a couple

9 of the studies Halyna and I took out because there

10 wasn't enough information in the published report.

11 I can actually bring those back in.

12 DR. BELSITO: Well, what I'm hearing is

13 that, at least from both Dan and Curt, is that

14 they have enough concern that, again, the add-ons

15 are supposed to be no- brainers, and we've now

16 spent at least 10 minutes discussing whether

17 oxalic acid actually fits into this report, and

18 we're not seeing any evident cosmetic use of it.

19 So the no- brainer, you know, swore it would say

20 that we should eliminate oxalic acid and its

21 esters from this report.

22 DR. KLAASSEN: I agree. And just to put




1 this in perspective, some people, like myself, and

2 maybe us around this table have a job because of

3 the toxicity of oxalic acid. So in the 1930s, to

4 get a drug on the market what you had to do was to

5 show that it was effective. But then in the

6 1930s, when the sulphonamides came out, they

7 dissolved the sulphonamides in ethylene glycol.

8 And then we had a number of people that died,

9 especially children, from kidney injury. And the

10 toxicity really was due to the ethylene glycol

11 being metabolized oxalic acid. And as a result of

12 that, the FDA, Congress changed the laws for FDA

13 to get a drug on the market. You not only had to

14 show that it was effective, but that it was not

15 toxic. So this whole business around oxalic acid

16 is kind of, like, no small story in the history of

17 toxicology, for whatever that's worth.

18 MR. ANSELL: And, you know, I certainly

19 agree with these comments. I just want to throw

20 out that I can't actually find the reference for

21 it, but apparently it's used as a pH adjuster to a

22 concentration of about 5 percent in hair products.




1 So we'll follow up on that and see whether that

2 would have any bearing on that conclusion.

3 DR. BELSITO: So, to recap. We are

4 suggesting that the addition of oxalic acid to

5 this group is not a no-brainer and that we would

6 recommend that oxalic acid and the esters be

7 removed. Once that is done, if it's done, we find

8 this group to be insufficient for impurities, and

9 we would like impurities on a representative short

10 and long chain. The suggested ones were sebacate

11 and malonic or succinic acid. And then

12 subdividing those, we would like short- and long-

13 chain esters of a short- and long-chain acid,

14 impurities for those representative ones. And

15 then concentration of use. And the assumption,

16 also, is that when this document comes back to us,

17 that the NTP summary and that the information on

18 the dioctyl, diisopropyl, and diethylhexyl adipate

19 studies will be included in this report.

20 Is that where we're at?

21 SPEAKER: Mm-hmm.

22 DR. BERGFELD: Well, and use, because





1 they promised you use.

2 DR. BELSITO: I said that.

3 DR. BERGFELD: Did you say that?


5 DR. BERGFELD: Okay.

6 DR. SNYDER: Unless we're provided data

7 on oxalic acid regarding dermal absorption

8 toxicity.

9 DR. BELSITO: Yeah, I suppose that could

10 be done. But again, the boilerplate that we've

11 had for the decision to go ahead with additions

12 has been that it be a no-brainer. And that we

13 wouldn't need that additional data; that the data

14 was already there. I don't know.

15 DR. ANDERSON: I think the option would

16 always exist for any interested party to provide

17 data.

18 DR. BELSITO: Yeah, if there was data

19 provided on lack of absorption, then I guess that

20 the no-brainer part of it is if it gets absorbed,

21 how much and what would it do to the kidney. If

22 we see information that, you know, it's used




1 at.001 percent in a hairspray and it's not going

2 to get absorbed, then, you know, we might change

3 our minds. So I guess that we're considering

4 deleting oxalic acid unless we get information on

5 absorption and concentration of use in products

6 that it would be used in. But if it's open-ended

7 and we assume that it's going to be used in all

8 the same type of products as these other

9 dicarboxylic acids in concentrations up to 10

10 percent, we don't have any information, we'll

11 probably just remove it from the report.

12 SPEAKER: Lunchtime.

13 DR. BELSITO: It is 12:10. Be back at

14 1:10.

15 (Recess)

16 DR. BELSITO: Okay, welcome back. So,

17 we're back here at the PEGS. And at the last

18 meeting, as you know, the issue here is to reopen

19 it to get rid of this damaged skin restriction in

20 the conclusion. At the last meeting we had a

21 wonderful presentation on transepidermal water

22 loss and various skin diseases, including atopic



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TEAM MEETING MINUTES ON SEBACATES DR. BELSITO’S TEAM

7 DR. BELSITO: If you could do that, let

8 us know because then it would help. I mean, I

9 don't think we're going to reopen the report. The

10 question is how to wordsmith the discussion

11 regarding this.

12 Okay. Anything else on the bromates?

13 Okay. So we're moving to the sebacates. How do

14 you pronounce that?

15 DR. ANDERSEN: We had a short discussion

16 on the other team and nobody knew how to pronounce

17 it.

18 SPEAKERS: Sebacates.

19 DR. BELSITO: Sebacates.

20 SPEAKER: What color?

21 DR. BELSITO: Green. It's with the

22 kojic acid.

ANDERSON COURT REPORTING

706 Duke Street, Suite 100

Alexandria, VA 22314

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1 SPEAKER: Green one.

2 DR. BELSITO: Okay. Okay, so this is a

3 first for us. A SLR, so it's in green along with

4 kojic acid.

5 And we've gotten some new data. And

6 again, this was one of the reports, like kojic

7 acid, that was sort of formulated in, hopefully,

8 the new CIR approach to doing documents, which I

9 think we already discussed with kojic acid that we

10 liked. And so now we're just looking at this data

11 and deciding what we need.

12 On Table 1 on page 42 and 43, there were

13 just a couple that I thought needed to be

14 amplified like dioctyl sebacate is an organic

15 compound. That's the definition. See Structure.

16 DR. LIEBLER: The middle of page 32

17 you're talking about?

18 DR. BELSITO: No, top.

19 MS. BECKER: Top of page.

20 DR. BELSITO: And then on page 33, the

21 same thing with dodecanedioic acid is an organic

22 compound.




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1 DR. ANDERSEN: Coagula extract is an

2 extract of coagulum.


4 DR. ANDERSEN: This is the dictionary

5 we're talking about.


7 DR. ANDERSEN: It is what it is.

8 DR. BELSITO: So straight out of the

9 dictionary?

10 DR. ANDERSEN: Yes.

11 DR. BELSITO: Because all the others say

12 it's the diester of isostearyl alcohol and sebacic

13 acid.

14 Okay. Just questioning.

15 DR. LIEBLER: You know, the structures

16 in this table, I realize it's tough, but the

17 structures are just about unreadable. And I think

18 -- I don't exactly know how you do these, but if

19 you can perhaps paste in better quality structures

20 from something like ChemDraw or ChemOffice.

21 MS. BECKER: Yeah, these were done in

22 ChemDraw.




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1 DR. LIEBLER: Well, you've got the

2 world's tallest carbonyls.

3 MS. BECKER: I don't have steady hands.

4 DR. LIEBLER: There's a bug, so if you

5 did it in ChemDraw and it looked right, then

6 there's a problem with cutting and pasting or

7 something. But that just needs to be fixed

8 because they're unreadable.

9 MS. BECKER: Okay. Okay.

10 DR. ANDERSEN: All right. And this is a

11 perfect opportunity to get some feedback from you

12 on -- flip back to the kojic acid report, since

13 it's in the same document, real quick. My own

14 personal preference, which hasn't succeeding in

15 posing yet, my own personal preference is that you

16 get more out of showing the stick figures.

17 DR. SNYDER: Yes.

18 DR. ANDERSEN: A better understanding of

19 what the heck this molecule really looks like in

20 its length, especially if your eyes aren't good

21 enough to figure out if that's an 11 or a 17 in

22 the little side script in the "formula." So




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Typewritten Text

BELSITO TEAM - SEPT 2009

201

1 that's the direction that I would like to go.

2 And frankly, since that looks hugely

3 awkward when you try to put it in tables, I'd pull

4 it out of the table.

5 DR. BELSITO: Right, as in figure 7.

6 Right.

7 DR. LIEBLER: The figure is fine and

8 these figures for the kojic acid compounds look

9 just fine.

10 SPEAKER: What page is that on?

11 DR. LIEBLER: 55.

12 MS. BECKER: 55.

13 SPEAKER: (off mike) the kojic ones.

14 DR. SEIDMAN: Alan, what are you

15 suggesting gets pulled out of the table?

16 DR. ANDERSEN: The figures.

17 SPEAKER: So all the figures.

18 DR. BELSITO: The figures. Do it as a

19 figure.

20 SPEAKER: They don't fit.

21 SPEAKER: So do it as a separate (off

22 mike)?




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1 DR. BELSITO: Yes.

2 SPEAKER: Okay.

3 DR. SEIDMAN: Which, I might point out,

4 is how Valerie had it in the first place.

5 SPEAKER: (off mike) acid.

6 DR. SNYDER: What are we going to title

7 it?

8 DR. BELSITO: Basic acids and salts and

9 esters as used in cosmetic products. So basic

10 acids and other related dicarboxylic acids and

11 their salts and esters as used in cosmetic

12 products. You don't like that sound?

13 DR. SNYDER: No, I'm just curious.

14 MR. RE: If you would like to see the

15 stick figures, just turn to the HPB.

16 DR. BELSITO: Yeah. Okay. On page 3,

17 this West Germany reference. First of all,

18 there's not even a reference. It just says

19 amongst Germany that's got to be at least 20 years

20 old. So I would say that unless we have some

21 update from the EU or from the current German

22 state, we delete that.




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1 Page 4, the azelaic acid, 20 percent is

2 approved by the FDA. It's a topical cream for the

3 treatment of mild to moderate acne. There is also

4 a 15 percent gel for the treatment of rosacea.

5 DR. SNYDER: And along those lines,

6 that's not -- transillic acid is not listed in the

7 use table.

8 SPEAKER: I thought it was.

9 MS. ROBINSON: It is. It should be.

10 DR. SNYDER: I thought it was at the

11 very end.

12 MS. ROBINSON: Yes. It's on page 39,

13 all the way at the bottom it starts.

14 DR. SNYDER: I'm looking at the new use

15 (off mike).

16 MS. ROBINSON: Oh, it's in the actual

17 tables.

18 DR. BELSITO: Page 39.

19 MS. ROBINSON: Yeah, at the end of the

20 actual document.

21 SPEAKER: At the bottom.

22 DR. BELSITO: Azelaic acid shaving care.




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1 DR. SNYDER: Oh, okay. I was looking at

2 (off mike).

3 DR. BELSITO: No.

4 DR. SNYDER: Okay. Never mind.

5 DR. BELSITO: Page 7, under Acute

6 Toxicity, the dibutyl and sebacate and azelaic

7 acid. I thought that the last couple of sentences

8 in both of those paragraphs -- while dibutyl is

9 not currently used, it would unlikely cause acute

10 toxicity, and the rest of that paragraph. And

11 then these data indicate that azelaic acid is not

12 highly toxic (off mike) oral. Shouldn't those be

13 in the discussion rather than here? Or are we

14 making -- again, I guess we're changing the format

15 so this -- is it likely renal?

16 MS. ROBINSON: I can move it to the

17 discussion if it's an easier read. But what do

18 you think, Brenda?

19 DR. ANDERSEN: I think what we've been

20 doing is trying to calibrate how it is we handle

21 giving the reader a sense of the import of the

22 section.




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2 DR. ANDERSEN: This goes much further

3 than we did in the examples for kojic acid. So

4 the question is what's your level of comfort with

5 that? Kojic acid was more of an attempt simply to

6 summarize what data you'll find in the following

7 paragraphs. This says these data are gone because

8 they are. But if you want to reserve any such

9 statements for the discussion, we can do that. We

10 wanted to push the envelope a little bit and see

11 what your reaction was.

12 DR. SNYDER: I like it better in the old

13 report where it was italicized right up front

14 rather than here it's kind of --

15 DR. BELSITO: Buried.

16 DR. SNYDER: -- buried at the summary

17 statement or discussion-like statement instead of

18 being a summary-like statement there.

19 DR. SEIDMAN: May I suggest something?

20 I think revisit this in just a few minutes when

21 you get to the tables. The new tables we're

22 throwing out there as floaters or trial balloons,




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1 so you might want to just consider this. Revisit

2 it in just a few minutes when you look at the

3 summary tables because you might want to think

4 about putting summary tables in the individual

5 sections instead of a summary statement or you

6 might want a combination. So you can discuss this

7 further, of course, now. But you might just want

8 to think of shelving it for just a few minutes

9 until you see the tables in 5 (off mike).

10 DR. BELSITO: Okay. We can do that.

11 Page 10.

12 DR. SNYDER: Well, in that same area, I

13 prefer to say the studies that reported NOEL are

14 less than 4,000 milligrams rather than "CIR

15 concluded." We had a couple things CIR concluded,

16 CIR determinate. I think we (off mike).

17 MS. ROBINSON: What paragraph?

18 DR. SNYDER: On page 7, (off mike). The

19 third line in the first paragraph there where it

20 says, "CIR concluded that the study supported (off

21 mike)." Say, "The study supported NOEL."

22 MS. ROBINSON: Okay.




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1 DR. SNYDER: And then down at the next

2 one under azelaic acid with rat and rabbit, CIR

3 determined the maximum tolerated dose. It should

4 just say, "Based on the reported endpoints of

5 animal deaths, the maximum tolerated dose (off

6 mike)."

7 DR. BELSITO: On page 10 on the Mingrone

8 Study 1083, were the ends given? There were no

9 ends.

10 DR. ANDERSEN: A perfect segue to let's

11 talk tables. What Brenda was referring to earlier

12 was that there had originally been captured Table

13 5 that summarized at least one study. And not to

14 put words in Brenda's mouth, but the idea of

15 having a full picture of which species, what dose

16 levels, how many animals, is what she would like

17 to see. So she went ahead and made tables for

18 both Smith in '53 and Mingrone in whatever year.

19 And those tables 5A and B or whatever --

20 DR. SEIDMAN: 5D and C.

21 DR. BELSITO: 5C.

22 DR. ANDERSEN: D and C show how we would




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1 maybe like to communicate with you about what

2 details are actually available in these tox of

3 studies. Now, maybe the acute tox aren't the most

4 important studies on earth, but in getting ready

5 for this meeting that's what we had time to play

6 with.

7 And I think that there is a prevailing

8 sentiment that those tables have more information

9 content than any of the verbiage that we can

10 write. At a glance you can see what it is you

11 see.

12 DR. BELSITO: So we would get rid of all

13 the verbiage. These paragraphs would disappear

14 and under Acute Toxicity it would just say --

15 DR. SEIDMAN: I think that's on the

16 table. And it's on the table for different

17 endpoints. You might not want verbiage for acute,

18 but you might want it for subacute or chronic.


20 DR. SEIDMAN: Because I think that's

21 going to be a case-by-case depending on the

22 endpoint.




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1 SPEAKER: But it's up for discussion.

2 DR. BELSITO: No, I mean, I think

3 certainly for the acute. I mean, we all know what

4 an acute study is. And, you know, basically we're

5 looking at, you know, the --

6 DR. SNYDER: The most important thing

7 for an acute study is the LD50.

8 DR. SEIDMAN: If it's reported. We

9 don't always get an LD50.

10 DR. SNYDER: Right, but that kind of

11 goes to (off mike).

12 DR. ANDERSEN: It's two animals. We're

13 not very interested anymore.

14 DR. SNYDER: But under the Acute section

15 we have basically, at least I can count, four or

16 five different summary statements where we could

17 have just put that all in one saying there was low

18 toxicity based upon LD50s and an oral (off mike)

19 and --

20 DR. ANDERSEN: As shown in tables.

21 DR. SNYDER: Exactly.

22 SPEAKER: Right.




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1 SPEAKER: (off mike)

2 DR. SEIDMAN: And (off mike) the summary

3 statement and address that in the text.

4 DR. SNYDER: Yeah, up front.

5 DR. SEIDMAN: And then up front in the

6 table.

7 MS. ROBINSON: Like the kojic acid.

8 DR. SNYDER: Yeah, like kojic acid,

9 right up front.

10 MS. ROBINSON: Okay.

11 DR. SNYDER: There's three or four (off

12 mike) around that.

13 DR. BELSITO: Then no verbiage. Just

14 your summary statement, no verbiage, and a

15 referral to the tables.

16 DR. SEIDMAN: That's what I would prefer

17 (off mike).

18 DR. ANDERSEN: Yeah, definitely.

19 SPEAKER: Really shortened this stuff.

20 And that's certainly a case for a lot of the

21 animal tox studies.





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1 DR. SEIDMAN: Well, there's a third

2 wrinkle on this, if I can just raise the issue,

3 because it came up in the other group (off mike)

4 has to do with editorializing a bit. So like

5 under Azelaic Acid, I put -- this was how I

6 summarized this particular study, given the low

7 toxicity for azelaic acid by the oral and (off

8 mike) routes of exposure and as (off mike) dermal

9 route of exposure in concentration used in

10 cosmetics, because azelaic acid presents a very

11 low risk of causing acute toxicity (off mike).

12 Now, in the -- when Jay brought up the

13 -- he mentioned that he'd prefer no conclusion on

14 the data, but we always are considering dose. So

15 here we -- well, we are considering dose of, you

16 know, use in cosmetics, and that's what we always

17 are comparing our data to in the literature. So

18 we're just editorializing what we put in the

19 beginning and end, you know, summarizing the data

20 and then editorializing.

21 Where does one begin and the other end?

22 MR. ANSELL: I think it was our position




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1 that when they start drawing conclusions from the

2 data, that deserved to be in the discussion

3 section. They really didn't go to whether the

4 staff should be doing conclusions or not but

5 rather where they should be included, particularly

6 because if we start parsing it too finely we'll

7 end up drawing conclusions about energenicity and

8 outside of the entire scope of evidence that might

9 be relevant to a conclusion of carcinogenicity.

10 So we thought within the data section it

11 was appropriate to have summaries of the data, but

12 that when you went the further step and said so

13 I'm concluding that this presents a low risk, that

14 that should not be in the data section; that

15 should be in the discussion section.

16 DR. LIEBLER: I agree with that.


18 DR. SNYDER: I think we should just

19 stick to summarizing the data, not interpreting

20 the data.

21 DR. BELSITO: Mm-hmm.

22 DR. SEIDMAN: In the individual




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1 sections.

2 DR. BELSITO: In the individual

3 sections.

4 DR. SEIDMAN: Let's discuss the

5 discussion section then at the end of the

6 document. Do we consider -- in the CIR, is it

7 appropriate to consider, which I think it is,

8 concentration of use relative to the data?

9 DR. BELSITO: We always do.

10 SPEAKER: Absolutely.

11 DR. SEIDMAN: Okay, so that's fair

12 enough.


14 DR. SEIDMAN: Just let me get a feel for

15 that. Okay.

16 DR. ANDERSEN: Yeah. And I think if I

17 can take that one step further. Even at this

18 early stage of the document -- let's say that this

19 is now December and we got this and we had this

20 discussion back in September -- that language that

21 Brenda developed in the front end relating to

22 azelaic acid, I'm not sure I would be




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1 uncomfortable in preloading the discussion section

2 with that information for your consideration.

3 It's a toxicologist's review of the information.

4 It sure looks that way and then you guys get to

5 look at it.

6 DR. SNYDER: Well, when we make a

7 comment on kojic acid it makes writing the summary

8 very easy because you just basically merge all

9 those summaries (off mike) flow in a summary

10 statement.

11 DR. ANDERSEN: You bet. So I think we

12 have in the past not touched anything relating to

13 the discussion section until we have a couple of

14 panel discussions under our belt. But I'm

15 wondering whether we may not be able to just be

16 able to prime it a little bit. If you disagree,

17 you're not going to be reluctant to say so. If

18 you agree and say attaboy, then you will have

19 accomplished something. But I think, you know,

20 Jay's message -- the reinforcement to the other

21 group that to the extent that we possibly can,

22 those are discussion elements.




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1 SPEAKER: Message received.

2 DR. BELSITO: On page 11, the Leong

3 Study, I don't think it belongs there, but I don't

4 know really where to place it other than perhaps

5 to eliminate it completely. It says the

6 biocompatibility of bioerodible polyanhydrides and

7 the toxicology of the polymer breakdown products.

8 That certainly doesn't belong under chronic

9 toxicity, I don't think.

10 SPEAKER: We'd be comfortable removing

11 it.

12 DR. BELSITO: Yeah. I don't think it

13 adds anything to the document at all.

14 DR. SNYDER: I agree. There's lots of

15 stuff related to designating time versus

16 short-term studies in that section. And also on

17 that same page right above it, that looks like

18 aminotricity acids (off mike) that should go back

19 to the genotox section.

20 MS. ROBINSON: I'm sorry. Which page?

21 DR. SNYDER: On page 11. The (off mike)

22 toxicity and mutagenicity of the degradation




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1 products were driven by a forward mutation (off

2 mike). That's not in the right place.

3 That's got to go.

4 MS. ROBINSON: That's part of the Leong

5 Study.

6 DR. BELSITO: That's part of what we're

7 deleting. We're deleting that whole thing.

8 Leong. We're deleting the whole bottom two-thirds

9 of page 11.

10 DR. SNYDER: Okay. Right.

11 DR. BELSITO: And the top part of page

12 12. And Table 6, it says summary of mammalian

13 effects.

14 And then under Genotoxicity it has

15 negative aims, so that's not mammalian. So do we

16 want to get rid of mammalian and just say summary

17 of effects?

18 DR. ANDERSEN: Very advanced salmonella.

19 (Laughter)

20 DR. BELSITO: Point well taken. Page

21 20, that's just typos.





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1 DR. BELSITO: On page 26, the third

2 paragraph up from the bottom, it says basic acid

3 did not show any teratogenic effect on fetal

4 toxicity. Is that redundant, did not show any

5 fetal toxicity?

6 DR. LIEBLER: So just remove any

7 teratogenic effect.

8 DR. BELSITO: Right. Just any fetal

9 toxicity. Did not show fetal toxicity.

10 DR. ANDERSEN: You know, I think

11 actually, Curt, checking on this I'm not sure what

12 the truth is, but those are two separate

13 endpoints. I mean, I could have either yes or no

14 for fetal toxicity and still have some increased

15 incidence in birth defects, so.

16 DR. BELSITO: So did not show

17 teratogenicity?

18 SPEAKER: (off mike) in developmental

19 studies that separate out the two.

20 DR. ANDERSEN: So what should be done

21 there is take out the word "teratogenic effects

22 in."




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1 DR. BELSITO: Right. It just did not

2 show fetal toxicity, teratogenicity, and neonatal

3 toxicity in rabbit studies.

4 SPEAKER: Right.

5 DR. ANDERSEN: (off mike) did not cause

6 fetal toxicity (off mike).

7 SPEAKER: Yeah, "did not cause" would be

8 better to show --

9 DR. BELSITO: And "separate?"

10 SPEAKER: Yes.

11 DR. ANDERSEN: And that should be "or"

12 instead of "and."

13 DR. BELSITO: A question that I had

14 throughout this report is that we've already

15 looked at some other aliphatic diesters, for

16 instance, maleic acid. And did we want to bring

17 in at least a summary of any of that data into

18 this report to help us out in terms of the safety

19 assessment or --

20 DR. ANDERSEN: I forget. What's the

21 (off mike)?

22 DR. LIEBLER: Maleic acid is two carbons




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1 with two carboxins with a double bond between (off

2 mike) three carbons.

3 DR. ANDERSEN: So it's about as short as

4 you can get.

5 DR. LIEBLER: Yeah.

6 DR. ANDERSEN: And these are a bit

7 longer. It's got eight carbons including the two.

8 I'm not sure --

9 DR. LIEBLER: You've got adipic acid

10 (off mike) I don't know if that's used.

11 DR. ANDERSEN: -- how instructive it is.

12 DR. BELSITO: Okay. So I'll strike that

13 question. Okay. And I guess the only new data we

14 got were 2 additional sensitization studies at 1.2

15 percent. Is that -- I'm trying to look at what we

16 sent as new. That's the only thing I picked up.

17 It was sent by e-mail or some fashion,

18 some additional studies, and I just made a note

19 that there were -- in addition to what we have

20 here in the document, there were two additional

21 sensitization studies done at 1.2 percent, which

22 doesn't really help us since it's used at a higher




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1 concentration.

2 SPEAKER: (off mike) I thought it was a

3 2.2 negative (off mike).

4 DR. BELSITO: It may be already in the

5 document. I didn't see it.

6 DR. ANDERSEN: No, the new thing that

7 was sent out was September 18th. I had it dated

8 when the council provided it. It isn't in the

9 book.

10 DR. BELSITO: Right. Okay.

11 DR. SNYDER: August 18th and September

12 24th. There's a memo from John Bailey on August

13 18th that we got prior to coming to the meeting.

14 For this meeting we got one on 9-16 to 9-18.

15 DR. BELSITO: Yeah. And then we got

16 another one September 16th that I guess was handed

17 out today. Is that right?

18 MS. ROBINSON: Yes.

19 DR. BELSITO: And 18th. So the 16th is

20 7.8 percent --

21 SPEAKER: Two.

22 DR. BELSITO: 7.2 (off mike). And then




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1 it was a human repeat in self patch testing.

2 SPEAKER: Yes.

3 DR. BELSITO: Fifty-one subjects

4 completed. And then --

5 SPEAKER: And they all take (off mike).

6 DR. BELSITO: Another study, Primary

7 Skin Irritation, and this is 100 percent diethyl

8 and 30 percent diethyl, and 8 male Japanese White

9 Strain rabbits. At that high concentration there

10 were some allergic reactions.

11 SPEAKER: (off mike) 100 percent.

12 DR. BELSITO: A hundred percent, yeah.

13 And then case reports. What is (off mike)? Oh,

14 (off mike) motion, okay.

15 DR. ANDERSEN: That chart is also

16 something we put together that basically

17 summarizes what's in the report. Again, it takes

18 a long time to read through the case literature.

19 Again, we're wondering whether a table that shows

20 it -- in this case shows that there were some

21 positive reactions in the case literature. You

22 can do what you will with it, but it's -- at a




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1 glance you can see that there are positive

2 reactions. You don't have to dig for it.

3 DR. BELSITO: Yeah. Well --

4 DR. SEIDMAN: I'm going to pass out this

5 table. (off mike) I don't think you're going to

6 find it of value, but I'm going to pass it out.

7 This is case reports.

8 DR. LIEBLER: I think they've got them.

9 DR. BELSITO: We've got them, yeah.

10 DR. SEIDMAN: Okay, I'm sorry. It's

11 really not -- it's not for induction --


13 DR. SEIDMAN: -- so I think this has a

14 policy and the (off mike) do not.

15 DR. BELSITO: Well, looking at what we

16 have for these and the new data that we got, we

17 don't have impurities.

18 We don't have UV absorption. But

19 looking at the structure, there are no rings.

20 They're not likely to absorb. We have a negative

21 Ames but no mammalian genotoxicity. And then do

22 we have sufficient carcinogenicity? No.




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1 If we have sufficient carcinogenicity

2 and you don't feel we need mammalian genotoxicity

3 and we have negative repro tox, then do we really

4 need impurities? Because presumably whatever

5 impurities were there were tested and weren't

6 giving problems, so.

7 DR. SNYDER: We only really have one

8 carcinogenicity study.


10 DR. SNYDER: The other one is actually

11 renal processing (off mike).

12 DR. LIEBLER: Is the one you're talking

13 about called the BIBRA 96 reference?

14 DR. SNYDER: Yes.

15 DR. LIEBLER: Which has very little

16 information provided, right?

17 DR. SNYDER: 10 milligrams per kilogram

18 for (off mike).

19 DR. LIEBLER: And the only other one is

20 around liver phocyte tests.

21 SPEAKER: In the (off mike) in the test

22 plan, someplace in here a whole bunch of data on




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1 genotoxicity.


3 SPEAKER: All we have so far are (off

4 mike), but the American Chemistry Council has

5 provided us with data before. So if you wanted

6 these expanded, it's page 15 in the (off mike) HPB

7 test plan that was provided by the council in one

8 of their submissions. It's kind of like that

9 page, a quarter of an inch.

10 SPEAKER: (off mike) looks like a lot

11 that they have. There was a 13-week -- or the 90

12 days thing.

13 SPEAKER: Well, those should probably be

14 summarized.

15 SPEAKER: Yeah. Yeah, we need to bring

16 those in.


18 SPEAKER: Yeah, I think the question the

19 other group had related to is this enough or do

20 you want to see the real studies? They were

21 inclined to see the real studies, but I'll leave

22 it up to you as to what your comfort level is.




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1 DR. BELSITO: Well, I think we'd

2 probably want to see the real studies, but the

3 question is I'm assuming since this is being put

4 together for HPV and REACH, that these are

5 accurate summaries or statements of what was

6 found. And assuming that's the case, is this safe

7 as used? And do we have enough information?

8 Assuming that, in fact, when we get the real

9 studies they confirm the summary.

10 DR. SEIDMAN: Are you proposing that we

11 get the real studies?

12 DR. BELSITO: I think it's always been,

13 I mean, you know, they're not studies that are my

14 area of expertise.

15 So, you know, from my standpoint, I

16 would read them, but I'd be relying on my

17 colleagues to guide me. I think it's always been

18 the policy of the panel, particularly maybe in

19 this case where we don't have impurities and we're

20 going to be assuming that these are -- we don't

21 need the impurities because whatever the

22 impurities are, they were studied. We'd want to




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1 see in more detail exactly what was done in the

2 studies. I'm assuming, but let me let Curt, Paul,

3 and Dan discuss that.

4 DR. SNYDER: It's always a case-by-case

5 basis. So if we have 10 chronic studies, even

6 with low numbers of animals, you get a lot more

7 confidence than if you have one study. So if you

8 only have one study, you'd like to have pretty

9 good information to make sure the methodology and

10 the valuations and things like that were

11 appropriate. So I think on a case-by-case basis

12 it's when there is minimal data, I want to see

13 more. When there's minimal data I want to see

14 more data. And when there's lots of data, I don't

15 need to see lots of data, so to speak, of how it's

16 done.

17 DR. SEIDMAN: And so lots of data --

18 lots of data coming from one source, is that

19 right? I haven't reviewed this document.

20 MR. ANSELL: No, no, it's a consortium

21 of producers that come together.

22 DR. SEIDMAN: It's a summary from that




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1 consortium and there are no original data which

2 were published or which were available to CIR?

3 MR. ANSELL: You'd have to look at the

4 data area because they tried to minimize animal

5 testing, so they uses confrontational methods,

6 they used all sorts of things. But I think if you

7 were to identify what particular effect you're

8 concerned about, we can see if we could get

9 additional data.

10 The package itself goes into, you know,

11 an entire analysis of toxicity and carcinogenicity

12 and chronic toxicity. So, I think getting the

13 full package would be --

14 DR. BELSITO: I don't think we need the

15 full package. In my assessment, what we're

16 lacking right now are impurities and

17 genotoxicity/carcinogenicity. And therefore, we

18 would be relying on, you know, if we don't get

19 impurities that's fine because we, you know, again

20 we can say in the discussion, you know, whatever

21 the impurities are they didn't result to any

22 reproductive or teratogenic effects and they




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1 didn't result in mutagenic or genotoxic effects or

2 carcinogenic effects if we have that data. So

3 that the data that we're missing right now are the

4 mammalian, genotoxin, carcinogenicity. And then

5 the question becomes are these summaries adequate

6 for my colleagues or do my colleagues want to see

7 the actual studies. And I leave that up to them

8 to comment.

9 MR. RE: Just to note the actual study

10 reports that went to ZIAM and OECD programs (off

11 mike) letting your (off mike). I'm not certain

12 that we could obtain them (off mike).

13 DR. KLAASSEN: Apparently there's not a

14 whole lot of carcinogenicity studies that have

15 been done according to their document either. So,

16 I guess it would be nice to know is that one the

17 only one that's been done? And that one that has

18 been done should have more data. Definitely look

19 at that data. Did they use two mice?

20 MR. ANSELL: You know, if you look in

21 the report, you know, page 14, 15, the results

22 from (off mike) genotoxicity material, mammalian,




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1 in vitro chromosome, in vivo chromosome, so I

2 think the question is highly relevant.

3 And let us see what data responsive to

4 that question we can get. But it's unlikely to be

5 the entire package (off mike).

6 DR. LIEBLER: We may not need the whole

7 package. In fact, the compound space -- chemical

8 space that this is describing is larger than what

9 we're considering in these ingredients any way.

10 There are a lot of shorter chain things here.

11 There's some unsaturated things that might have

12 different properties.

13 I just feel it sounds like there are

14 data out there that we're not getting. I don't

15 think it's appropriate for us to just decide that

16 we shouldn't look at any of it. So, I think we

17 need to see if we can get some of this. It sounds

18 like from looking at this Table 3, at the end of

19 the HPV report, I don't see any references for

20 anything. This looks like it's stuff that's been

21 done and not published.

22 MR. ANSELL: Yeah, I mean, those are all




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1 important questions.

2 DR. LIEBLER: And if that's, you know --

3 SPEAKER: And at this stage in the

4 review, (off mike).

5 DR. LIEBLER: It may be, you know, many

6 yards of data or whatever you said, but, on the

7 other hand, it may be something that we can get

8 our hands on and look at and we should at least

9 try to do that.

10 DR. SNYDER: And when there's a NOEL or

11 a NOAEL, it's always nice to know what it was

12 based on rather than just -- because these all

13 just say there was a NOAEL, but they don't say

14 what was the basis. Was it decreased weight gain

15 or was it some, you know, toxicity endpoint that

16 might pop up that we can look at someplace else.

17 So, again, we just need a little bit more

18 information than what's in this summary.

19 DR. BELSITO: So, where are we going?

20 Are we saying insufficient for impurities,

21 genotox, carcinogenicity?

22 Are we tabling to get more information




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1 from the summary reports that we see here in the

2 diester HPV test plan? Where do we want to go?

3 This is the first time we're seeing this document.

4 DR. SNYDER: I prefer tabling it and

5 asking for the additional data that we know

6 exists. We're going to get it.


8 DR. SNYDER: I think that's a more

9 logical (off mike).

10 DR. BELSITO: So we're going to table it

11 and ask for additional genotoxin carcinogenicity

12 data that appears to be from the diester HPV test

13 plan available to us. And if it's linear feet or

14 data, send it electronically and let us shift

15 through it.

16 MS. ROBINSON: Do we need impurities?

17 No? Impurities?

18 DR. BELSITO: I mean, if they have

19 impurities, that would be great, but, again, I

20 think we can handle -- I mean, we handle

21 reproductive toxicity. You know, we can handle

22 impurities by saying we didn't have impurities,




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1 but whatever impurities were there didn't result

2 in problems in the genotox, carcinogenicity, and

3 reproductive studies. We've done that before.

4 SPEAKER: That's a wonderfully empirical

5 approach --


7 SPEAKER: -- resolving (off mike).

8 DR. BRESLAWEC: May I ask your opinion

9 on one format matter here? If you look at page 21

10 and 22 and 23 and the top of section 24, it

11 summarizes what are called "skin treatments."

12 These are essentially efficacy studies involving

13 one or more of these components. In the past

14 we've summarized them. An alternate way of

15 dealing with these studies is presented in italics

16 in the middle of page 24 and we'd like your

17 opinion on that.

18 DR. ANDERSEN: It takes much less space.

19 (Laughter)

20 DR. BELSITO: I think when you're

21 dealing with something like azelaic acid that also

22 has a drug use, you know, you're, I think,




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1 summarizing it as you did in the alternate skin

2 study section -- is fine. I don't think we need

3 all of the details as to whether they wanted to

4 treat acne with minocycline plus azelaic acid and

5 whether there was a difference in those two

6 treatment groups. I mean, that's not --

7 DR. BRESLAWEC: We have the same issue

8 in things like botanicals where there are

9 thousands of studies done on a variety of

10 conditions from growing hair to losing hair. And

11 we prefer not to deal with the effectiveness

12 question.

13 DR. BELSITO: Yeah. Right.

14 DR. BRESLAWEC: Great. Thanks.

15 MR. RE: Just getting back to the

16 availability for a moment, would the CIR entertain

17 the idea of joining the aliphatic esters panel?

18 Because that is the usual mechanism on which you

19 gain access to this data (off mike). So if you'd

20 like to go that way, that would be the traditional

21 way of gaining access to these data (off mike) --

22 SPEAKER: Never done it.




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1 MR. RE: -- (off mike) part of the (off

2 mike).

3 MR. ANSELL: You know, that's all true.

4 Let us look first and then we will come back and

5 say if there's a problem or not. You know, I

6 expect that there are robust summaries available

7 (off mike). Let us look first.

8 SPEAKER: You know, we pay for ASTM

9 standards, IOC standards (off mike), so we'll need

10 to do that.

11 DR. BELSITO: Okay. So --

12 DR. SNYDER: I have one more question.

13 On page 25, there's a chronic toxicity study in 40

14 rats and 40 rabbits. Do you see it there?

15 MS. ROBINSON: Oh, yeah.

16 DR. SNYDER: They present the results of

17 the rabbits, but there are no rats. Is it in the

18 table there?

19 SPEAKER: (off mike)? I'm sorry.

20 DR. SNYDER: The chronic toxicity was

21 investigated in 40 rats and 40 rabbits. And then

22 we go on to say that chronic toxicity (off mike)




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1 no significant difference in (off mike) and

2 rabbits, but we don't get any data results for

3 rats.

4 DR. SEIDMAN: Oh.

5 SPEAKERS: Oops.

6 DR. SEIDMAN: Yeah, oops.

7 DR. SNYDER: I didn't look in the table,

8 (off mike) to the table then.

9 DR. SEIDMAN: The two tables I prepared

10 (off mike).

11 DR. BELSITO: Okay. That's what I

12 thought. Okay.

13 DR. SEIDMAN: So I didn't touch this.


15 DR. SEIDMAN: But that's kind of why I

16 think we do need tables because sometimes the

17 reviewers have a lot to do and they might not get

18 all the information. If we have a table, then

19 we're sure to get it.

20 DR. KLAASSEN: That needs to say Table 3

21 right there if it's going to be in Table 3, so you

22 don't have to guess.




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1 DR. SEIDMAN: If we put it in a table,

2 we'd have to say, of course, reference the table.

3 DR. KLAASSEN: Yeah, right.

4 DR. BELSITO: Any other comments? Okay.

5 Why don't we take a 10-minute break before we move

6 to PEGs, get some coffee, relieve our bladders.

7 (Recess)


TEAM MEETING MINUTES ON SEBACATES – DR. MARKS’S TEAM

14 DR. MARKS: It will be quick, Alan. Is

15 everybody fine with that, Ron, Ron and Tom?

16 Table. Next we're to the sebacates or sebacates?

17 Which is it?

18 DR. ANDERSEN: Is there a linguist in

19 the house?

20 DR. BERGFELD: It's in the Green Book.

21 DR. MARKS: This is the first time that

22 the panel has seen this report, and obviously with

127

1 that, one of the things is do we want to group all

2 these ingredients together, should we delete some

3 of them, and then obviously move on to data needs?

4 And Ron Hill and Ron Shank also, how do you like

5 Acute Toxicity Tables 5-B, 5-C? Was that helpful?

6 We'll open it up for discussion.

7 DR. SHANK: I guess I'll start. I would

8 go as insufficient data. We need genotoxicity

9 data for microbial and mammalian. However, Table

10 3 from the American Chemistry Council report

11 indicates that there may be some data, but it's

12 not in our report other than the table. Maybe

13 it's already there. My second comment is that

14 there are five other dicarboxyl acids listed in

15 the dictionary. Why are they not included? And

16 the rest are just editorial. You did ask about

17 Tables 5-A, 5-B and 5-C. There's nothing much in

18 those tables, so I would just convert that

19 information to text and delete the tables.

20 DR. MARKS: Ron, did you feel the

21 impurities were okay in that section? Did we have

22 any needs in the impurities?




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1 DR. SHANK: I don't have that marked.

2 DR. MARKS: There are no impurities, so

3 I guess would that be a need we have to move as

4 insufficient?

5 DR. BERGFELD: Ron?

6 DR. MARKS: Ron?

7 DR. SHANK: I don't have any concerns,

8 but maybe others do.

9 DR. SLAGA: I don't have any concerns

10 here, but mutagenicity in the new data in the back

11 there is some mammalian genotoxicity, so there is

12 genotoxicity, both bacterial as well as mammalian.

13 DR. SHANK: But it's not in the report,

14 so do we actually have the studies or is this just

15 a quotation from some report?

16 DR. HILL: Which specific compounds are

17 in that report?

18 DR. MARKS: We'll want to go over that

19 and make sure because Ron Shank raised the issue

20 of should there be five more ingredients listed

21 and are the ingredients that are already in the

22 report ones that we want to include. Why don't we




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1 do that and we'll go over it? So far we have the

2 needs, although the table indicates mutagenicity

3 data and genotox data, that doesn't appear in the

4 report itself. Shall we assume that that's going

5 to appear in the report and not put that out as an

6 insufficient at this point?

7 DR. SLAGA: It's in the data in the

8 back.

9 DR. MARKS: So it's in the data in the

10 back.

11 DR. ANDERSEN: I'm not finding it.

12 DR. BERGFELD: It's in the additions

13 behind everything there.

14 DR. SHANK: That is a page 15, diesters.

15 There's the high production volume. There is a

16 report called "Diesters: High Production Volume

17 Test Plan" in the back of the book and on pages 14

18 and 15. It gives mutagenicity data which

19 apparently the American Chemistry Council has

20 those data. So if those data are there, can they

21 be made available to us?

22 DR. ANDERSEN: I got you now. So




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mmf

Typewritten Text

MARKS TEAM - SEPT 2009

130

1 there's a whole series of studies that are

2 described on pages 14 and 15, the details of

3 which, were they captured and put in the document

4 could resolve the concerns.

5 DR. MARKS: Rachel?

6 MS. WEINTRAUB: In terms of a lack of

7 data, I just wanted to make sure that we consider

8 that there's no phototoxocity data and no

9 subchronic toxicity data. So the question is do

10 you think we need that kind of data? Another

11 comment that I had is that on page 24 under the

12 Alternate Skin Study section, there are a few

13 studies mentioned, but then it says, "The safety

14 information from the studies was not provided, or

15 provided in a manner that was not conducive to

16 evaluation." Why include it if it provides

17 absolutely no information? Page 24.

18 MS. ROBINSON: The Alternate Skin

19 Studies?

20 MS. WEINTRAUB: Yes.

21 MS. ROBINSON: With these studies there

22 were limited details, so we just included it




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1 anyway. But if the panel decides that it's

2 irrelevant, then we'll take it out, but there were

3 very limited details described by the authors.

4 MS. WEINTRAUB: I was wondering if there

5 was some reason to include it just to make clear

6 that we've seen them but find it inclusive.

7 DR. ANSELL: We support that comment.

8 The study goes to the drug efficacy and doesn't

9 really report on safety.

10 DR. MARKS: Correct. Actually starting

11 with page 21. Is that where you started, Rachel?

12 Eliminate everything from 21 to 24, so Skin

13 Treatments all the way to the Alternative Skin

14 Study section because it all relates to the

15 efficacy of these drugs and acne. Valerie, I'll

16 give you two printouts here, once on Azelex, the

17 package insert which isn't very helpful, but

18 there's a much better one on Finacea.

19 Interestingly, I had the same concerns about

20 phototox data, and they have a number of

21 irritations, sensitization, photosensitization and

22 phototox studies on Finacea which is the 15




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1 percent azelaic acid preparation, so that I'm

2 going to give these to you. The references are in

3 there even though I think that's helpful data in

4 terms of the safety for this group. The rest of

5 these I had concern about no photo absorption, but

6 then again that would speak to the safety. What's

7 your feeling, Ron?

8 DR. SHANK: I don't think these

9 compounds would absorb in the important areas of

10 UV for skin toxicity.

11 DR. MARKS: Under the Clinical

12 Assessments, the diisopropyl sebacate is fine. I

13 had there were a number of severe case reports of

14 allergic contact dermatitis to diethyl sebacate.

15 What was reassuring was they had a RIPT of this

16 compound with a 1.5 percent concentration of

17 diethyl sebacate, and I would suggest that we put

18 a limit on that particular ingredient to that

19 concentration because of the alerts for these

20 multiple cases of severe allergic contact

21 dermatitis.

22 DR. ANDERSEN: What would a good number




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1 be?

2 DR. MARKS: The 1.5 percent. That's

3 what was found in the cream which they did an RIPT

4 on, so we have that data that we know at that

5 limit that it was safe in that cream.

6 MS. SEIDMAN: The 1.5 percent?

7 DR. MARKS: Yes.

8 MS. SEIDMAN: If you look at the table

9 that I prepared, I prepared a table on the diethyl

10 sebacate allergic contact case reports. So if you

11 look down there, there is a 1 percent diethyl

12 sebacate -- positive. I think there is something

13 less than that. But just look down that table and

14 see what you think.

15 DR. MARKS: Which page?

16 MS. SEIDMAN: This is separate. It's a

17 handout.

18 DR. MARKS: The handout?

19 MS. SEIDMAN: Yes.

20 DR. MARKS: Thank you.

21 MS. SEIDMAN: You're welcome.

22 DR. SLAGA: So these are case report




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1 individuals? Is that correct?

2 MS. SEIDMAN: Yes.

3 DR. MARKS: So your conclusion from

4 these? Take me through it. These were mostly

5 medications as I read the case reports, hence some

6 had, yes, very high concentrations which isn't

7 surprising that they would sensitize at those

8 concentrations.

9 MS. SEIDMAN: I think there was a.1.

10 DR. MARKS: Was that for patch testing

11 though? It went down. For actually patch testing

12 they went down as I recollect to.01, but that to

13 me just is a little bit different than what

14 concentration could you feel safe going

15 prospectively and not sensitize individuals, not

16 if they've already become sensitized. So that's

17 why I thought the 1.5 percent cream from the

18 maximization test, and that was probably one of

19 these added at the end.

20 MS. SEIDMAN: You're just talking about

21 induction.

22 DR. MARKS: Yes. That was from the PCPC




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1 memorandum from John Bailey dated August 18 and

2 you'll see in the fourth study down, KGL 2003, a

3 cream containing 1.5 percent diethyl sebacate in

4 human skin by means of the maximization assay was

5 okay. So that's why I thought that that would be

6 safe in light of having this alert from the case

7 reports.

8 DR. ANSELL: You will also see a report

9 dated September 18 for diethyl.

10 DR. MARKS: What does that add, Jay?

11 DR. ANSELL: Just that it was induced at

12 higher percents than that.

13 DR. MARKS: This was with?

14 DR. ANSELL: Diethyl.

15 DR. MARKS: Diethyl. Then I guess you

16 have the contradiction of which limit level are

17 you going to use.

18 DR. ANSELL: Yes.

19 DR. MARKS: I think I'd like to err to

20 that lower concentration. Are there any other

21 comments? Ron Shank, going back to the original,

22 do you think if we have all this data included in




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1 the body and not just in the tables that we could

2 move forward without insufficient data conclusion?

3 DR. SHANK: Yes. I assume you have

4 those data, it's just not a quote from a review or

5 something, but if the mutagenicity data are

6 available, then they should be included into the

7 report.

8 DR. ANDERSEN: The American Chemistry

9 Council has provided the data whenever we've asked

10 for it in the past, so I don't anticipate that

11 that's a glitch. In a sense, I'm thinking that

12 tabling this to allow those data to be gathered

13 makes sense. I'm also concerned about the idea

14 that there are four other dicarboxyl acids that we

15 didn't capture, I think potentially do that

16 homework as well if this were tabled.

17 DR. SHANK: The dictionary lists five,

18 phthalic acid, malonic acid, succinic acid,

19 glutaric acid and adipic acid.

20 DR. ANDERSEN: I see what you're saying.

21 DR. SHANK: It's just you take the alkyl

22 group, and we start with butyl dicarbonyl where




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1 there are four CH2 groups, or I think we start

2 with five. So if you look at the alkyl with four

3 and three, two, one and zero, all of those are

4 listed in the dictionary as pH adjusters and

5 fragrance. So if we're including all of the

6 larger ones, is there a reason that we're not

7 including those smaller ones? And I couldn't find

8 that they had been reviewed before.

9 DR. HILL: Could I respond to that

10 briefly? The major issue in my mind with lumping

11 these compounds as a class, the salts to me were

12 no-brainer additions, but these's a fair amount of

13 read-across data or by analogy data that I think

14 makes the implicit assumptions that the starting

15 point in all of the biological handling of these

16 compounds if they're absorbed is ester hydrolysis,

17 actually twice, and so at least in terms of the

18 ones that were already there and these others that

19 are not added, for example, oxalic acid, there are

20 no carbons between the carbonyls, and maleic acid

21 ones, I don't think that's on your list but that's

22 in the table here, there are just two carbons in




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1 between. So the ester hydrolysis could go very

2 differently there, and I haven't had a chance to

3 digest it because even in the HPV report there's

4 quite a bit of listed read-across data and I'm not

5 sure how read across that data actually is until I

6 have a matter since to map, and since we just got

7 this a short time ago, I didn't have access to

8 that information because if there's penetration of

9 the diester or even monoesters into dermal layers

10 where there are potentially precancerous cells,

11 then that changes everything in my mind in terms

12 of what you can lump together as a class so that

13 then you need information about the biological

14 handling of that to know.

15 DR. BERGFELD: May I get a point of

16 clarification? Alan, you're urging tabling for

17 all the needs that we're assessing and these are

18 needs for further staff work as I see it. Is that

19 official that we would table or we would just hold

20 this to the next time to clarify those? Do we

21 have to officially table this? I mean, we can.

22 DR. HILL: No, you don't have to




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1 officially table it.

2 DR. BERGFELD: Can just hold it for that

3 information. I'm not sure there's a difference,

4 but when we table things they've been a little bit

5 more worrisome or waiting for a piece of industry

6 rather than in-house sort of clarifications.

7 DR. HILL: We have our marching orders,

8 so I know what it is we're going to do and I guess

9 from that standpoint it doesn't matter what we

10 call it, just postponing further discussion until

11 these data and the question of the further

12 expansion can be resolved is what we're going to

13 do, whether it's tabled or not. Just in terms of

14 the expansion, simply that there may be a place

15 where the line has to be drawn in terms how far

16 apart the dicarboxylic acids groups are on these,

17 and there may be a reason why these are there and

18 the others are not.

19 DR. ANDERSEN: I think that's the answer

20 to the question, but without getting down and

21 dirty and having all of the staff talk that

22 through, I didn't want to commit to that.




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1 DR. HILL: Then furthermore, if that is

2 the case and there is significant absorption in

3 the toxicology of the resultant alcoholics that

4 come from the ester hydrolysis in some cases come

5 into play and there's data for some of these

6 compounds that are pretty comfortable for not for

7 all if the class is expanded the way it's given,

8 but then again my digestion of the HPV information

9 is still limited. I haven't had enough time with

10 it.

11 DR. MARKS: So I think if I understand

12 where we're going with this, it is the idea to

13 table it or postpone it or however you want to

14 talk about this first look at these cosmetic

15 ingredients, and I guess are we still going to use

16 sebacic acid as our lead ingredient on this, then

17 as it was put in the memo related dicarboxylic

18 acids and their salts and simple esters? We need

19 a genotox carcinogenicity, the primary references,

20 and get that into the document itself, and then

21 the second big issue is to firm up which

22 ingredients we're really going to include in this




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1 going to include in this report. Are those the

2 two things? And then Valerie, just capture also

3 in there the concerns I had about the sensitivity

4 and potentially having a maximum with a diethyl

5 sebacate concentration of 2.5 percent.

6 DR. HILL: From my perception, this is a

7 fairly complex class as expanded even without

8 adding the others, and just to make sure that

9 Valerie gets the support she needs to wade her way

10 through all of those complexities.

11 DR. ANDERSEN: In looking at the, if you

12 will, parent compound and focusing on the fact

13 that there was an 8 carbon chain between the two

14 carboxylic acid groups, I think part of the logic

15 was that would give us a certain family depending

16 on whether people are comfortable with the esters

17 that are on the list. It begged the question how

18 different is azelaic acid? It's 7, not that

19 different from 8. We would have included one with

20 9 except that's not a cosmetic ingredient, and

21 then we upped it to 10 on the high side. We can

22 certainly examine the question of can we go a




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1 little lower and can we go a little bit higher

2 with that trepidation of how distance is going to

3 start to matter depending on what you're doing.

4 DR. HILL: And I would also remind you

5 that the biologic handling of even-chain and

6 odd-chain carboxylic acids and I think also

7 dicarboxylic acids ends up quite differently, and

8 actually there are steps that are different, so

9 that probably also needs to be recognized and

10 accounted for.

11 DR. ANDERSEN: So 7 may be more

12 different from 8.

13 DR. HILL: Than 6 is or 10 is.

14 MS. SEIDMAN: Excuse me, handling in

15 what respect?

16 DR. HILL: If you look at the biological

17 handling of fatty acids, and I think the analogy

18 here of carboxylic acids, even chain and odd chain

19 are handled very differently by biologically and

20 double bonds also have some nuances of handling.

21 MS. SEIDMAN: You're talking about

22 metabolism?




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143

1 DR. HILL: I'm talking about

2 chain-shortening metabolism, yes. So there's the

3 parent dicaroxylic acid and then assuming the

4 esters are hydrolyzed which there's a lot of

5 implicit assumption that that is the case, where

6 does that happen and when? Does it happen in skin

7 so that nothing systemic leaves other than

8 dicarboxylic acid in each case? Or we have

9 monoesters? Or we have diesters making it into

10 other tissues? Then if you liberate the alcohols,

11 and that happens immediately and fast wherever the

12 compound is dosed, then the toxicology of the

13 alcohols comes into play depending on how much

14 dermal penetration if it's dermal.

15 DR. MARKS: I think, Valerie, when the

16 nuances start as we decide on what ingredients

17 that we include in this report, we're going to

18 have to catch those nuances that Dr. Hill

19 mentioned. Ron Shank, going back, and one of the

20 questions was Table 5 and Table 5-B and 5-C. I

21 don't think you found them particularly helpful.

22 Could you help clarify that so they could be




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144

1 improved in the future?

2 DR. SHANK: There's not enough

3 information in my opinion in those three tables to

4 warrant the space of the tables, so I would just

5 include that information in the text.

6 MS. SEIDMAN: I tried to do a table here

7 just because I personally am frustrated as a

8 toxicologist in going through text because I

9 cannot compare doses, I cannot compare species, I

10 can't get a quick read on the data. So personally

11 I felt it was really useful to put things in

12 tables. This table might not have a lot, so you

13 might say for acute maybe we can just do text.

14 Still, for me I find it useful because I can see

15 the doses readily and the species readily and the

16 numbers of animals used. It's all right there.

17 But think about it maybe more for the longer- term

18 studies if you're not happy with it for acute. I

19 think most toxicologists find it very useful to

20 put things in tables.

21 DR. HILL: I would echo the benefits of

22 tables for me for the same exact reasons you said,




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145

1 unless there's just really not much data at all.

2 Even if there are two data lines, still you can

3 compare numbers of animals, doses, route of

4 administration, all those things you mentioned.

5 MS. SEIDMAN: We think alike.

6 DR. MARKS: Ron Shank, what more would

7 you liked to have seen?

8 DR. SHANK: I don't put that much

9 importance on acute toxicity tests when we're

10 talking about cosmetics products. We never have a

11 problem with acute toxicity. So to put that

12 information in a table, yes, it makes it easier to

13 read. It's good to have, but I don't use it in my

14 safety evaluation for a cosmetic product because

15 we never get to acute toxicity problems.

16 MS. SEIDMAN: So the relevance of the

17 acute for cosmetic products is not important.

18 That I can accept. But think about other end

19 points as you go through this. This is just a

20 trial balloon, so for other end points that might

21 be more relevant to cosmetic products.

22 DR. SHANK: Absolutely, yes.




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146

1 DR. MARKS: I think the conclusion is

2 that we will recommend tabling this. Actually

3 it's the Belsito team which will report first, but

4 we will recommend tabling it to get the genotox

5 and carcinogenicity data in the text and also to

6 firm up what ingredients are actually going to

7 appear in this report. Are there any other

8 comments?

9 DR. ANDERSEN: I think in terms of some

10 of the lessons for this, I want to make sure it

11 gets captured in terms of the data that had been

12 in the back of the report on all of the clinical

13 testing, the skin treatments. You're reaffirming

14 that those, to the extent that they describe the

15 clinical effectiveness, have no place in a safety

16 assessment and if there were safety data such as

17 may be gleaned from what you've provided, Valerie,

18 those will stand on their own.

19 DR. MARKS: Correct.

20 DR. ANDERSEN: So we can really shorten

21 that section down to almost zero.

22 DR. MARKS: Yes. I have it deleted.




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147

1 Correct.

2 DR. ANDERSEN: Thank you. Halyna will

3 be pleased.

4 DR. MARKS: Shall we take a break for

5 lunch? Do you think we'll be able to do kojic

6 acid in 5 minutes?

7 DR. BERGFELD: No.

8 DR. ANDERSEN: The audience is on their

9 own for lunch. The panel will be going downstairs

10 to the lobby, make a left, go past the desk, down

11 to the end to the Carleton Room for lunch.

12 (Recess)


Report

Draft Report

Dicarboxylic Acids and Their Salts as Used in Cosmetics Esters of Dicarboxylic Acids as Used in Cosmetics

August 30, 2010 The 2010 Cosmetic Ingredient Review Expert Panel members are: Chairman, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; Ronald A Hill, Ph.D. James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is F. Alan Andersen, Ph.D. This report was prepared by Monice M. Fiume, Scientific Analyst/Writer, and Bart A. Heldreth, Ph.D., Chemist.

© Cosmetic Ingredient Review 1101 17th Street, NW, Suite 412 " Washington, DC 20036-4702 " ph 202.331.0651 " fax 202.331.0088 "

[email protected]


ii

TABLE OF CONTENTS

Introduction.................................................................................................................................................................................. 1

Chemistry ..................................................................................................................................................................................... 1

Definition, Structure and Manufacture .................................................................................................................................... 1

Physical and Chemical Properties ........................................................................................................................................... 2

Analytical Methods ................................................................................................................................................................. 3

Impurities ................................................................................................................................................................................ 3

Ultraviolet Absorption ............................................................................................................................................................ 4

Use ............................................................................................................................................................................................... 4

Cosmetic ................................................................................................................................................................................. 4

Non-Cosmetic ......................................................................................................................................................................... 5

DICARBOXYLIC ACIDS AND THEIR SALTS ....................................................................................................................... 6

General Biology ........................................................................................................................................................................... 6

Absorption, Distribution, Metabolism, and Excretion ............................................................................................................ 6

Percutaneous Absorption ...................................................................................................................................................... 10

Peroxisome Proliferation....................................................................................................................................................... 11

Cellular Effects ..................................................................................................................................................................... 11

Animal Toxicology .................................................................................................................................................................... 12

Acute Toxicity ...................................................................................................................................................................... 12

Short-Term Oral Toxicity ..................................................................................................................................................... 12

Short-Term Inhalation Toxicity ............................................................................................................................................ 12

Subchronic Oral Toxicity ...................................................................................................................................................... 13

Subchronic Inhalation Toxicity ............................................................................................................................................. 13

Chronic Oral Toxicity ........................................................................................................................................................... 14

Ocular Irritation .................................................................................................................................................................... 14

Dermal Irritation/Sensitization .............................................................................................................................................. 15

Mucosal Irritation.................................................................................................................................................................. 16

Reproductive and Developmental Toxicity ................................................................................................................................ 16

Genotoxicity............................................................................................................................................................................... 18

In Vitro .................................................................................................................................................................................. 18

In Vivo .................................................................................................................................................................................. 19

Carcinogenicity .......................................................................................................................................................................... 19

Tumor Promotion .................................................................................................................................................................. 19

Clinical Assessment of Safety .................................................................................................................................................... 20

Dermal Irritation ................................................................................................................................................................... 20

Case Reports ......................................................................................................................................................................... 21

ESTERS OF DICARBOXYLIC ACIDS ................................................................................................................................... 22

General Biology ......................................................................................................................................................................... 22

Absorption, Distribution, Metabolism, and Excretion .......................................................................................................... 22

Penetration Enhancement ...................................................................................................................................................... 26

Peroxisome Proliferation....................................................................................................................................................... 26

Mechanism ....................................................................................................................................................................... 27

DNA Binding/DNA Synthesis .............................................................................................................................................. 29

Hepatic Lipid Metabolism .................................................................................................................................................... 30

Cellular Effects ..................................................................................................................................................................... 30

Animal Toxicology .................................................................................................................................................................... 30

Acute Toxicity ...................................................................................................................................................................... 30

Short-Term Oral Toxicity ..................................................................................................................................................... 31

Short-Term Dermal Toxicity ................................................................................................................................................. 32

Subchronic Oral Toxicity ...................................................................................................................................................... 33

Subchronic Dermal Toxicity ................................................................................................................................................. 34

Subchronic Inhalation Toxicity ............................................................................................................................................. 34

Chronic Oral Toxicity ........................................................................................................................................................... 34

Inhalation Toxicity ................................................................................................................................................................ 35


Dermal Irritation ................................................................................................................................................................... 36

Dermal Sensitization ............................................................................................................................................................. 38


iii

Phototoxicity ......................................................................................................................................................................... 38

Mucous Membrane Irritation ................................................................................................................................................ 38

Reproductive and Developmental Toxicity ................................................................................................................................ 39

Endocrine Disruption ............................................................................................................................................................ 44

Genotoxicity............................................................................................................................................................................... 44

Carcinogenicity .......................................................................................................................................................................... 46

Tumor Promotion .................................................................................................................................................................. 47

Clinical Assessment of Safety .................................................................................................................................................... 47

Human Exposure ................................................................................................................................................................... 47

Dermal Irritation and Sensitization ....................................................................................................................................... 47

Phototoxicity and Photosensitization .................................................................................................................................... 49


Comedogenicity .................................................................................................................................................................... 50

Case Reports ......................................................................................................................................................................... 50

Risk Assessment .................................................................................................................................................................... 50

Summary .................................................................................................................................................................................... 51

Discussion .................................................................................................................................................................................. 56

Conclusion ................................................................................................................................................................................. 56

References .................................................................................................................................................................................. 57


1

INTRODUCTION

This safety assessment includes sebacic acid and other alkyl α,ω-dicarboxylic acids, salts, monoesters and diesters.

The dicarboxylic acids are terminally functionalized straight alkyl chains characterized by a separation between the acid

functional groups of one to 10 carbons (1 carbon = malonic acid; 2 carbons = succinic acid; 3 carbons = glutaric acid; 4

carbons = adipic acid; 5-6 carbons = no representative cosmetic ingredients; 7 carbons = azelaic acid; 8 carbons = sebacic

acid; 9 carbons = no representative cosmetic ingredients; and 10 carbons = dodecanedioic acid). The simple alkyl di-esters

are the result of the condensation of alkyl dicarboxylic acids and two equivalents of alkyl alcohols. These ingredients can be

metabolized via hydrolysis back to the parent alcohol, the mono-ester, and the parent dicarboxylic acid (Figure 1). The

simple alkyl esters (mono- and di-) of these dicarboxylic acids have straight or branched side chains ranging in length from

one to 18 carbons. Throughout this report, the data are presented by order of acid chain length (i.e., beginning with malonic

acid and ending with dodecanedioic acid; beginning with dimethyl malate and ending with diisocetyl dodecanedioate).

Accordingly, this draft report presents available information pertinent to the safety of 56 cosmetic ingredients in two

groups, first, the 12 alkyl dicarboxylic acids/salts and, second, the 44 corresponding esters (mono- and di-). The alkyl dicar-

boxylic acids and salts include:

malonic acid

succinic acid

sodium succinate

disodium succinate

glutaric acid

adipic acid

azelaic acid

dipotassium azelate

disodium azelate

sebacic acid

disodium sebacate

dodecanedioic acid.

The esters include:

diethyl malonate

decyl succinate

dimethyl succinate

diethyl succinate

dicapryl succinate

dicetearyl succinate

diisobutyl succinate

diethylhexyl succinate

dimethyl glutarate

dibutyl glutarate

diisostearyl glutarate

dimethyl adipate

diethyl adipate

dipropyl adipate

dibutyl adipate

dihexyl adipate

dicapryl adipate

di-C12-15 alkyl adipate

ditridecyl adipate

dicetyl adipate

diisopropyl adipate

diisobutyl adipate

diethylhexyl adipate

diisooctyl adipate

diisononyl adipate

diisodecyl adipate

dihexyldecyl adipate

diheptylundecyl adipate

dioctyldodecyl adipate

diisocetyl adipate

diisostearyl adipate

isostearyl sebacate

diethyl sebacate

dibutyl sebacate

dicaprylyl/capryl sebacate

diisopropyl sebacate

diethylhexyl sebacate

dibutyloctyl sebacate

diisooctyl sebacate

dihexyldecyl sebacate

dioctyldodecyl sebacate

isostearyl sebacate

dioctyldodecyl dodecanedioate

diisocetyl dodecanedioate


1

The structures and functions of these ingredients are presented in Table 1.

A safety assessment of diethylhexyl adipate (often inaccurately named dioctyl adipate)1 and diisopropyl adipate was

published in 1984 with the conclusion that these ingredients are safe as used in cosmetics.2 The safety of these ingredients

was reviewed and confirmed in 20053 and 2006.4 Additionally, dibutyl adipate was previously reviewed in 1996 and the

available data were found insufficient to support the safety of dibutyl adipate in cosmetic formulations. When re-reviewed in

2006, additional data were made available to address the needs identified by the CIR Expert Panel, and an amended

conclusion was issued stating that dibutyl adipate is safe for use in cosmetic formulations.5

The ingredients in this report function in cosmetics as pH-adjusters, fragrance ingredients, plasticizers, skin-

conditioning agents and/or solvents and corrosion inhibitors.

CHEMISTRY

Definition, Structure and Manufacture

The CAS numbers, definitions, structures and functions for the alkyl dicarboxylic acid, salt and ester ingredients

included in this report are given in Table 1.

Alkyl Dicarboxylic Acids

While many of the alkyl dicarboxylic acids are natural products, commercial production of these acids has historical-

ly occurred via alkali pyrolysis of lipids.6 For example, when castor oil (a lipid which is comprised of approximately 84%

ricinoleic acid-sidechain bearing triglycerides) is pyrolyzed with sodium hydroxide, some of the major products are sebacic

acid and 2-octanol (Figure 2).6 Sodium and potassium salts of the alkyl dicarboxylic acids are readily prepared via addition to

the appropriate stoichiometric equivalent(s) of sodium hydroxide or potassium hydroxide, respectively.

Malonic Acid (C3)

Malonic acid, first prepared by malic acid oxidation, is commonly manufactured by more recent methods including

the ozonolysis of cyclopentadiene or the air oxidation of 1,3-propanediol.7

Succinic Acid (C4)

Succinic acid is an intermediate of the citric acid cycle and is found in almost all plant and animals cells, although at

very low concentrations.8 Succinic acid is commonly produced synthetically by catalytic (e.g., nickel or palladium catalyst)

hydrogenation of maleic anhydride.

Glutaric (C5) and Adipic(C6) Acids

Although glutaric acid is often encountered in nature, adipic acid is not commonly encountered in nature. Glutaric

and adipic acids were first synthesized by oxidation of castor oil with nitric acid. However, adipic acid is now more common-

ly manufactured by oxidation of cyclohexane, cyclohexanol, or cyclohexanone, and glutaric acid may be manufactured by

ozonolysis of cyclopentene.9

Azelaic Acid (C9)

Azelaic acid, first detected in rancid fats, was originally produced via nitric acid oxidation of oleic acid. 10 Azelaic

acid is a naturally-occurring dicarboxylic acid that can be found in dietary sources, such as whole grains.11 Azelaic acid is

commonly manufactured by oxidative cleavage of oleic acid (obtained from grease or tallow) with chromic acid, nitric acid or

by ozonolysis.10,7

Sebacic Acid (C10)

Sebacic acid was originally isolated from distillation products of beef tallow. More recently, however, sebacic acid

has been manufactured via alkali pyrolysis of castor oil, as mentioned above and drawn in Figure 2, or by alkali pyrolysis of


2

ricinoleic acid.12,7

Dodecanedioic Acid (C12)

Dodecanedioic acid can be manufactured by fermentation of long-chain alkanes with a specific strain of Candida

tropicalis.13 Another method of manufacture involves the nitric acid oxidation of a mixture of cyclododecanone and

cyclododecanol.7

Alkyl Dicarboxylic Acid Esters

The alkyl dicarboxylic acids are easily esterified with the appropriate alcohol, with our without acid or metal catalyst

(Fischer esterification).9 For example, diethylhexyl adipate can be manufactured from adipic acid and ethylhexanol with an

acid catalyst (Figure 3).

Diethyl Malonate

Malonic acid esters can be produced either by cobalt-catalyzed alkoxycarbonylation of chloroacetates with carbon

monoxide in the presence of the appropriate alcohol, or by hydrolysis of cyanoacetic acid followed by esterification with the

respective alcohol.14 Diethyl malonate is prepared from chloroacetic acid and sodium cyanide followed by esterification with

ethanol and sulfuric acid.15

Diisopropyl Adipate

Diisopropyl adipate is produced by esterification of adipic acid with an excess of isopropanol. The excess alcohol is removed by vacuum stripping and the ester is then alkali-refined and filtered. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2

Dibutyl Adipate

Adipic acid is esterified with butyl alcohol by a continuous distillation process.16

Diethylhexyl Adipate

Diethylhexyl adipate can be prepared by the reaction of adipic acid and 2-ethylhexanol in the presence of an esterifi-

cation catalyst such as sulfuric acid or para-toluenesulfonic acid (Figure 3).17 Purification of the reaction product includes

removal of the catalyst, alkali refining, and stripping.2

Alkyl Succinates

Succinic anhydride reacts readily with alcohols to give monoesters of succinic acid (e.g., decyl succinate from

decanol), which are readily further esterified to the diesters by Fischer methods.7 Dimethyl succinate can be produced from

methanol and succinic anhydride or succinic acid, or by hydrogenation of dimethyl maleate. Diethyl succinate can be

prepared by the same methods (from ethanol or diethyl maleate).

Physical and Chemical Properties

Tables 2a lists physical and chemical properties of the dicarboxylic acids and salts and Table 2b lists the properties

of the esters. Charts 1a, 1b, and 2 demonstrate the relationship between molecular weight and the log octanol – water

partioning coefficient.

Dicarboxylic Acids - General

The alkyl dicarboxylic acids vary considerably in their physical properties. The shorter chain (malonic, succinic, and

glutaric) members are crystalline solids, very water-soluble and have limited solubility in organic solvents. As the chain

length increases through adipic to dodecanedioic, water solubility decreases sharply (although still soluble in hot water). In

other words, the water solubility of these acids is inversely proportional to their chain length. There is a marked alternation in

melting point with changes in carbon number from even to odd.7 Odd members (e.g., malonic acid and glutaric acid) exhibit


3

lower melting points and higher solubility than even carbon number alkyl dicarboxylic acids (e.g., succinic acid and adipic

acid). These alternating effects are believed to be the result of the inability of odd carbon number compounds to assume an

in-plane orientation of both carboxyl groups with respect to the hydrocarbon chain.

Dicarboxylic acids react with Brønsted-Lowry bases (e.g., sodium hydroxide) to form carboxylate salts (e.g., sodium

succinate or disodium succinate). Dicarboxylic acids also react with alcohols to give mono- and di-esters, such as those in

this report.

Esters

The diesters, in contrast, are much more lipid soluble and more difficult to dissolve in water. The mono-esters, by

definition, are hybrids of the acids and diesters, but their physical properties are much more closely related to the diesters.

The short-chain alkyl (i.e., methyl, isopropyl, and butyl) mono- and diesters are more soluble in water, less lipo-

philic, and relatively more volatile than the corresponding longer-chain alkyl (i.e., C8-C13 alcohol) esters.18 Most esters with

molecular weights greater than 340 have boiling points greater than 300°C and are relatively non-volatile and lipophilic (log

Kow >7).

Analytical Methods

Succinic Acid

Methods used to analyze succinic acid include acidimetric titration for acidity; comparison with Pt-Co standard

calibrated solutions for color; oxidation with potassium permanganate for detection of unsaturated compounds; atomic

absorption or plasma spectroscopy for metals; and titration with silver nitrate or barium chloride for chloride or sulfate

detection, respectively.7 Small concentrations of succinic acid can be detected by common instrumentation such as gas/liquid

chromatography and polarography.

Adipic Acid

Adipic acid can be extracted from a water sample and analyzed by gas chromatography/mass spectrometry.17

Sebacic Acid

Gas chromatography can be used to identify sebacic acid in air.19

Diisopropyl Adipate and Diethylhexyl Adipate

Diisopropyl adipate and diethylhexyl adipate can be identified through standard infrared (IR) spectroscopy. Gas-liquid chromatography (GLC), liquid-liquid extraction, mass spectrometry, and high-pressure liquid chromatography (HPLC) are also methods of analysis for the adipates. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2

Impurities

Diethyl Malonate

Diethyl malonate is a colorless organic liquid with an ester like odor.14 The purity is typically > 99 %. Impurities

from the production process include ethanol (ca. 0.1 % w/w), ethyl acetate (ca. 0.05 % w/w), and ethyl methyl malonate (ca.

0.05 % w/w).

Dibutyl Adipate

Impurities are generally not found due to the manufacturing process, but available data demonstrate that arsenic

levels are below a detection limit of 1 ppm, heavy metals (as lead) are below a detection limit of 10 ppm, and sulfated ash is

below a detection limit of 0.1%.16

Diisopropyl Adipate and Diethylhexyl Adipate

Diisopropyl adipate and diethylhexyl adipate are considered stable; however, hydrolysis of the ester groupings may occur in the presence of aqueous acids or bases. No known impurities occur in either


4

diisopropyl adipate or diethylhexyl adipate, although the acid values imply the presence of adipic acid or of the monoester in both. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2 Diethylhexyl adipate is commercially available with the following specifications: purity – 99 to 99.9%; acidity – 0.25

µg/100g max; moisture – 0.05 to 0.10% max.17

Diisopropyl Sebacate

A supplier reported that the expected impurities in diisopropyl sebacate are the starting material sebacic acid, <0.3%,

and isopropyl alcohol, <0.2%.20

Ultraviolet Absorption

Absorption of ultraviolet (UV) radiation was not detected in the 280 - 500 nm range.21

USE

Cosmetic

The ingredients included in this safety assessment have a variety of functions in cosmetics.22 The majority of the

dicarboxylic acids function in cosmetics as pH adjusters and fragrance ingredients. The functions of most of the salts are not

reported, but it is stated that sodium succinate functions as a buffering agent and pH adjuster. For the esters, some of the

common functions include skin conditioning agents, fragrance ingredients, plasticizers, solvents, and emollients. The

functions of all ingredients are listed in Table 1.

Six of the 12 dicarboxylic acids and their salts and 24 of the 44 esters included in this safety assessment are reported

to be used in cosmetic formulations. The frequency of use of the acids and salts, as supplied to the Food and Drug Admini-

stration (FDA) by industry as part of the Voluntary Cosmetic Registration Program (VCRP),23 and the concentration of use, as

supplied by industry in response to a Personal Care Products Council (Council) survey, are found in Table 3a. The frequency

and concentration of use of the esters, with the exception of dibutyl, diisopropyl, and diethylhexyl adipate, which have

previously been reviewed, are found in Table 3b. The current and historical use data for the 3 previously reviewed esters are

found in Table 3c. The 6 acids and salts and 20 esters not currently reported to be used are listed in Table 3d.

For the dicarboxylic acids and their salts, disodium succinate has the greatest number of reported uses, with a total

of 45. The acid with the greatest concentration of use is succinic acid, 26%; use at this concentration is in rinse-off products.

The greatest leave-on concentration is 0.4%, disodium succinate, with dermal contact exposure.

For the esters, diisopropyl adipate has the greatest number of uses, with 70 reported. The concentration of use is

greatest for dimethyl glutarate, 15% in a dermal rinse-off product. The ingredients with the greatest leave-on use concentra-

tions, which are all dermal contact exposures, are diethylhexyl adipate, 14%, diisostearyl adipate, 10%, and diisopropyl

sebacate, 10%.

A few of the ingredients are applied around the eye, can possibly be ingested, or involve mucous membrane expo-

sure, and some are used in underarm deodorant. None are reported to be used in baby products.

Dicapryl and diethylhexyl succinate, dibutyl, dicapryl, diisopropyl, diisobutyl, and diethylhexyl adipate, diisopropyl,

diethylhexyl, and dioctyldodecyl sebacate, and dioctyldodecyl and diisocetyl dodecanedioate are used in hair sprays, and

effects on the lungs that may be induced by aerosolized products containing this ingredient, are of concern.

The aerosol properties that determine deposition in the respiratory system are particle size and density. The para-

meter most closely associated with deposition is the aerodynamic diameter, da, defined as the diameter of a sphere of unit

density possessing the same terminal settling velocity as the particle in question. In humans, particles with an aerodynamic

diameter of ≤ 10µm are respirable. Particles with a da from 0.1 - 10µm settle in the upper respiratory tract and particles with a


5

da < 0.1 µm settle in the lower respiratory tract 24,25

Particle diameters of 60-80 µm and ≥80 µm have been reported for anhydrous hair sprays and pump hairsprays,

respectively.26 In practice, aerosols should have at least 99% of their particle diameters in the 10 – 110 µm range and the

mean particle diameter in a typical aerosol spray has been reported as ~38 µm.27 Therefore, most aerosol particles are

deposited in the nasopharyngeal region and are not respirable.

With the exception of dipotassium azelate, disodium sebacate, and di-C12-15 alkyl adipate, the dicarboxylic acids

and their salts and esters are listed for use by the European Union (EU) without restriction.28 Adipic acid is on the EU

Dangerous Substances List; it is classified as Xi (irritant) and R36 (irritating to eyes).

Non-Cosmetic

Many of the dicarboxylic, their salts, and their esters are used in many foods as direct or indirect food additives. The

alkyl dicarboxylic acids are unusually versatile because of their two carboxyl groups.9 This enables many additional types of

useful reactions, particularly the manufacture of polymers (e.g., nylon). The most common uses include functions as plastici-

zers, lubricants and building blocks in the manufacture of polyesters, polyamides and other plastics. The alkyl dicarboxylic

acid salts are used to synthesize cyclic ketones, including commercially used macrocyclic musk compounds.29 The diesters

have widespread use as lubricants, plasticizers, and solvents.30

Malonic Acid

Malonic acid is a useful intermediate in the manufacture of barbiturates.31

Succinic Acid

Succinic acid is listed by the FDA as a food additive that is Generally Recognized as Safe (GRAS).32 Succinic acid

is also utilized in detergents, pigments, toners, cement additives, soldering fluxes and as an intermediate in the synthesis of a

number of pharmaceutical products.7

Adipic Acid

Adipic acid is listed as a GRAS food additives by the FDA.33 Adipic acid has several industrial uses in the

production of adhesives, plasticizers, gelatinizing agents, hydraulic fluids, lubricants, emollients, polyurethane foams, leather

tanning, and urethane.7 However, the bulk of the industrial production of adipic acid is driven by its usefulness in the

manufacture of nylon-6,6 (in combination with 1,6-hexanediamine).

Azelaic Acid

FDA has approved azelaic acid for use in treating acne and rosacea. A skin cream containing 20% (w/w) azelaic

acid, is indicated for the topical treatment of mild-to-moderate inflammatory acne vulgaris,34 and a gel containing 15% azelaic

acid is approved for treating rosacea.35 These drugs are available by prescription only.

Azelaic acid is used in the manufacture of plasticizers, lubricants, and greases. Azelaic acid was identified as a

molecule that accumulated at elevated levels in some parts of plants and was shown to be able to enhance the resistance of

plants to infections.36

Sebacic Acid

Sebacic acid was widely used in the U.S. as an aromatic in food before 1973.37

Sebacic acid is used in resorbable polymer systems that deliver chemotherapeutic agents (e.g. cisplatin, carboplatin)

that are implanted at the site of tumors to provide for sustained release of the drugs.38 Sebacic acid and its derivatives have a

variety of industrial uses as plasticizers, lubricants, diffusion pump oils, candles and as intermediates in the synthesis of

polyamides and various alkyd resins.7


6

Dodecanedioic Acid

Dodecanedioic acid is used in the production of nylon (nylon-6,12), polyamides, coatings, adhesives, greases,

polyesters, dyestuffs, detergents, flame retardants, and fragrances.

Diethyl Malonate

Diethyl malonate finds great utility as the starting material in Malonic Ester Synthesis, a classic organic chemistry

reaction wherein a very wide variety of esters can be synthesized.29

Diisobutyl Adipate

The FDA has included diisobutyl adipate in Part 181 of Title 21 of the Code of Federal Regulations (CFR) – Prior-

Sanctioned Food Ingredients, Subpart B--Specific Prior-Sanctioned Food Ingredients includes Sec. 181.27, Plasticizers. In

this section, “substances classified as plasticizers, when migrating from food-packaging material shall include...diisobutyl

adipate...” (21 CFR § 181.27).


Diethylhexyl adipate is used as a plasticizer for polyvinyl chloride (PVC) plastics.39

Diethyl Sebacate

Diethyl sebacate was widely used in the U.S. as an aromatic in food before 1973.37

Dibutyl Sebacate

Dibutyl sebacate is a component of PVC.40

DICARBOXYLIC ACIDS AND THEIR SALTS

Much of the information on the dicarboxylic acids was obtained from summary documents that mostly contained

unpublished data. The summary documents are therefore listed as the citation, and, when there are numerous studies

described, will only be cited at the beginning of that section.

GENERAL BIOLOGY

Absorption, Distribution, Metabolism, and Excretion

Dicarboxylic acids are natural metabolic products of the ω-oxidation of monocarboxylic acids when the β-oxidation

of free fatty acids is impaired.41 Under normal physiological conditions, dicarboxylic acids are rapidly β-oxidized, resulting

in very low cellular concentrations and practically non-detectable concentrations in the plasma.42 Medium-chain dicarboxylic

acids (up to 12 carbon atoms) are β-oxidized in mitochondria and peroxisomes. Oxidation of odd- and even-numbered chains

proceeds to different end points. Odd-chain dicarboxylic acids are β-oxidized, giving acetyl Co-A and malonic acid (C3).

Oxidation can then go no further, and malonic acid is the starter of fatty acid synthesis. Even-chain carboxylic acids are com-

pletely oxidized and produce succynil-CoA, a gluconeogenic substrate, as an intermediate metabolite.

Dicarboxylic acids are more polar than their esters, therefore they will diffuse less readily through normal cell

membranes.43

Malonic Acid

Malonic acid can be activated to malonyl-CoA and undergoes decarboxylation to acetyl-CoA by various mammalian

tissues.14

Adipic Acid

In animals, after oral dosing with adipic acid, 70% of the dose was exhaled as carbon dioxide. Adipic acid and a number of metabolites was recovered in the urine, while very little radioactivity was found in the tissues. After oral dosing in conjunction with i.p. sodium malonate, the presence of radioactive adipic and succinic acid was an indication of β-oxidation. Oral studies have reported recovering 53-67% unchanged adipic acid in the urine,


7

while 59-71% was recovered in the urine following i.v. dosing and 61% was recovered following s.c. dosing, with an increase in urinary oxalic acid. In humans, 6.76-61% of the dose was recovered unchanged following oral dosing with adipic acid.

A summary document on adipic acid contained a number of excretion and metabolism studies that were performed

between 1918-1960.44 These studies are described below.

Animal Adipic acid metabolism was studied using fasted male albino rats. In one study, in which the rats were dosed orally,

by gavage, with 50 mg radioactive adipic acid (labeled on C1 or C2), 70% of the dosed was exhaled as carbon dioxide.

Adipic acid and the metabolites urea, glutamic acid, lactic acid, β-ketoadipic acid, and citric acid, were recovered in the urine.

Very little radioactivity was found in the tissues. Fasted male rats were also given a solution containing 50 mg radioactive

adipic acid (labeled on C1), by gavage, in conjunction with 2 ml of 0.5 M sodium malonate, given by intraperitoneal (i.p.)

injection. Both radioactive adipic acid and succinic acid were found in the urine, an indication that adipic acid underwent

β-oxidation. By feeding rats 25 mg radioactive adipic acid (labeled on C1) and 100 mg γ-phenyl-α-aminobutyric acid, it was

determined that acetate is a metabolite of adipic acid. Finally, rats were given radioactive sodium bicarbonate with non-

radioactive adipic acid. Radioactive citric acid was formed, which suggested that carbon dioxide interacted with a metabolite

of adipic acid.

Two rats were dosed orally by gavage with 2.43 g/kg partially neutralized adipic acid for 28 days. In the urine, 67%

of the dose was recovered unchanged. There was no change in excretion pattern over time during the study.

Rabbits were dosed orally by gavage (n=4) or by intravenous (i.v.) administration (n=2) with 2.43 g/kg partially

neutralized adipic acid for 2 days. Following oral administration, 53-61% of the dose was recovered unchanged in the urine.

With i.v. administration, 59-71% was recovered unchanged in the urine. In another study using rabbits, animals were given a

subcutaneous (s.c.) dose of 2000 mg adipic acid; 3 rabbits were given a single dose, one was dosed on days 1 and 5, and one

was dosed on days 1, 5, 9, 13, and 15. On average, 61% of the dose was recovered unchanged in the urine. There was an

increase in urinary oxalic acid concentrations.

A female dog was fed either 150 mg/kg adipic acid (in 2 feedings) for 5 days or 750 mg/kg (in 2 feedings) for 7

days. In the urine, 18% and 63.6% of the low and high doses were recovered unchanged.

Rabbits (number not stated) were given up to 4 s.c. injections of ≤2000 mg sodium adipate.45 An average of 61% of

the dose was recovered unchanged in the urine. Oxalic acid was increased in the urine.

Human In a study in which one subject was given 33 mg/kg sodium adipate, orally, for 5 days (10 g total), 6.76% of the

dose was recovered in the urine. In another study in which one person was given 100 mg/kg adipic acid for 10 days (70 g

total), 61% of the dose was recovered in the urine. Administration of 19.0 g adipic acid over 5 days or 23.4 g over 6 or 9

days (1 subject per dose) resulted in 53% of the administered dose recovered in the urine.

C9 to C12 Dicarboxylic Acids

For rats dosed orally with azelaic, sebacic, undecanedioic, and dodecanedioic acid, 2.5, 2.1, 1.8, and 1.6% of the respective acid was found in the urine unchanged. In humans the amount recovered decreased with increasing chain length. After oral dosing, 60, 17, 5, and 0.1% of azelaic, sebacic, decanedioic, and undecanedioic acids, respectively, were recovered unchanged in the urine. In the plasma of both animals and humans, dicarboxylic acid catabolites that were 2-, 4-, or 6- carbons shorter than the corresponding dicarboxylic acid were found.

Animal Groups of 30 male Wistar rats were dosed orally, by gavage, with azelaic (C9), sebacic (C10), undecanedioic (C11),


8

or dodecanedioic (C12) acid.46 Ten rats in each group were dosed with 20, 50, or 100 mg of the respective acid. Blood,

urine, and feces from the treated rats were analyzed and compared to the blank control obtained from untreated rats. (None of

the C9-C12 acids were found in the blank controls.) In urine, approximately 2.5% of azelaic, 2.1% of sebacic, 1.8% of unde-

canedioic, and 1.6% of dodecanedioic acid was recovered after 5 days; the amount recovered was not affected by dosage.

The dicarboxylic acids were not excreted in conjugated form. None of the C9-C12 dicarboxylic acids were recovered in the

feces. In the plasma, dicarboxylic acid catabolites that were 2-, 4-, or 6-carbons shorter than the corresponding dicarboxylic

acid were detected.

Human Groups of 3 male and 2 female subjects were also dosed with C9-C12 acids orally, in gelatin capsules, once a wk for

5 wks.46 The dose administered increased each week, from 0.5 g at wk 1 to 5.0 g at wk 5. None of the C9-C12 acids were

found in the blank control samples of blood, urine, and feces obtained from non-treated humans. In urine, approximately 60%

of azelaic, 17% of sebacic, 5% of undecanedioic, and 0.1% of dodecanedioic acid was recovered after 12 h; the amount re-

covered was not affected by dosage. At 24 h, the amounts recovered were not much increased. Initially, undecanedioic and

dodecanedioic acid administration raised the urinary pH to a value of 7.4-8.5; the pH returned to normal with 3-6 h. The

di-carboxylic acids were not excreted in conjugated form. None of the C9-C12 dicarboxylic acids were recovered in the

feces. In the plasma, dicarboxylic acid catabolites that were 2-, 4-, or 6-carbons shorter than the corresponding dicarboxylic

acid were detected. Plasma levels of azelaic acid peaked at 2 h, while the levels of the other three acids peaked at 3 h.

Recovery in the plasma was greatest for azelaic acid, 74.6 µg/ml with the 5 g dose, and the amount detected decreased with

increasing chain length.

Azelaic Acid

In animals, after oral dosing with azelaic acid, 40% of the radioactivity was recovered in the urine over 5 days, and 14.5% was found in expired carbon dioxide at 48 h. Mostly dicarboxylic acid metabolites were found in the blood for up to 72 h after dosing. Radioactivity was found in all tissues, with the greatest levels in the liver, lungs, and kidneys; levels then decreased in all organs, except the adipose tissue for which an increase continued. In humans, the dermal and oral administration of a 20% azelaic acid cream was compared. A total of 2.2% of the dose was recovered in the urine after dermal administration, as compared to 61.2% following oral administration. The calculated percutaneous absorption was determined to be 3.6%.

Azelaic acid is a dietary constituent found in whole grain cereals and animal products.47 It can be formed

endogenously from longer-chain dicarboxylic acids, metabolism of oleic acid, and ψ-oxidation of monocarboxylic acids.48

Endogenous plasma concentration and daily urinary excretion of azelaic acid are highly dependent on dietary intake. Azelaic

acid crosses the blood-brain barrier.49

Animal A group of 25 male Wistar rats were dosed orally, by gavage, with 100 µCi of [1,9-14C]azelaic acid, and the animals

were killed at various intervals 1-96 h after dosing.46 After 12 and 48 h, 13 and 14.5% of the radioactivity was found in

expired carbon dioxide, respectively. Approximately 40% of the radioactivity was recovered in the urine over 5 days. The

C7 and C5 dicarboxylic acid metabolites were found in the urine up to 72 h after dosing. Very little was recovered in the

feces. Labeled dicarboxylic acids were present in the blood for up to 72 h, and consisted mainly of dicarboxylic acid

metabolites. Radioactivity was found in all tissues, with the highest levels present in the liver, lungs, and kidneys after 12 h.

Tissue radioactivity levels then decreased slowly in all organs except adipose tissue, in which case increasing levels were still

seen at 96 h. Approximately 90% of the radioactivity found in the tissues was present in the lipids, and it was essentially

localized in the fatty acid portion of the triglycerides and of the phospholipids. Traces of C9, C5, and C7 dicarboxylic acids

were detected in the first 24 h.


9

Human The percutaneous absorption of azelaic acid was determined using 6 male subjects. A total of 5 g of a cream

containing 20% azelaic acid was applied to the face (1 g), chest (2 g) and upper back (2 g) of each subject, giving an area

dose of approx 5 mg cream/cm2 skin. The test areas were covered 1 h after dosing with cotton tissues, and washed 24 h after

dosing. After 1 wk, 100 ml of an aq. microcrystalline suspension containing 1 g azelaic acid was given orally to each subject

Urinary excretion of unchanged azelaic acid was measured after each dose. Following dermal application, 1.29% of the dose

was recovered unchanged in the urine in 24 h, and a total of 2.2% was recovered by day 3. Following oral administration,

61.2% of the dose was recovered within 4 h; excretion was complete at this point. Assuming similar rates and pathways in

biotransformation following both routes of exposure, percutaneous absorption of azelaic acid was determined to be 3.6% of

the dermally applied dose.50

Sebacic Acid

Sebacic acid is oxidized to water and carbon dioxide, passing through acetyl-CoA and succinyl-CoA formation.51

Disodium Sebacate

In rat, following i.v. administration of disodium sebacate, 34.6% of the dose of the dose was recovered in the urine as sebacate and 5% was recovered as suberic acid. A total of 25% of the sebacate was recovered in expired carbon dioxide. No appreciable radioactivity was found in the body. Following i.p. administration, sebacate renal clearance was a concentration-independent function. With oral administration, the relative bioavailability was 69%. In humans given a steady infusion of disodium sebacate, less than 15% of the dose was recovered in the urine. The percent oxidation of sebacate was 6.14%

Animal Disodium sebacate, 80 and 160 mg with 25 µCi of (1,10)14C sebacic acid tracer, was administered by i.v. injection

to 14 male Wistar rats, and blood samples were obtained at various intervals 5-320 min after dosing.51 The plasma half-life of

radioactive disodium sebacate was 37.86 and 39.82 min for the 80 and 160 mg dose groups, respectively. The apparent

volume of distribution was 2.65 ml/100 g body wt.

In a second experiment, a group of 4 male Wistar rats were given 160 mg disodium sebacate with 25 µCi sebacic

acid tracer by i.v. injection, and expired carbon dioxide, urine, and feces were collected. The carbon dioxide half-life for

radioactive sebacate was 93.64 min; 25% of the administered dose was expired in carbon dioxide. A total of 34.6% of

sebacate was recovered in the urine in 24 h, while 5.08% suberic acid (C8) was recovered in the same time frame. Most of

the excretion occurred in the first 24 h. Radioactivity was not found in the feces.

In the third experiment, groups of 10 male Wistar rats were also given 160 mg disodium sebacate with 25 µCi

sebacic acid tracer by i.v. injection, and the animals were sacrificed at various intervals from 30-360 min after dosing and the

amount of radioactivity in various organs was analyzed. No appreciable radioactivity was found in the body. Sebacate

appeared to be in an absorption phase in fat 1 h after dosing, but no radioactivity was found in the body after 24 h.

The pharmacokinetics of disodium sebacate was studied in male and female Wistar rats.52 Sebacate was admini-

stered either i.p., 6 doses o f 10-320 mg, or orally, 2 doses of 80 or 60 mg. Plasma concentrations of sebacate and urinary

concentrations of sebacate and its products of β-oxidation (suberic and adipic acids) were measured using GLC/mass

spectrometry. Both renal and non-renal elimination parameters were obtained. The sebacate half-life was 31.5 min. The tissue

elimination rate was 0.0122 min-1, and the overall volume of distribution was 26.817 ml/100 g. The renal clearance was

0.291 ml/min/100 g, which was much less than the value of the glomerular filtration rate (GFR) of approximately 1

ml/min/100g reported elsewhere, suggesting the presence of sebacate reabsorption from the ultrafiltrate. Sebacate renal

clearance was found to be a concentration-independent function, suggesting the presence of a passive back-diffusion. The

relative bioavailability of the oral route compared to the i.p. route was 69.09%, showing an extensive absorption of the


10

compound.

Human The metabolism and excretion of disodium sebacate was studied in 7 fasting male subjects that were given a

continuous steady infusion of 20 g unlabeled disodium sebacate over 480 min.53 At 240 min into the infusion,

(1,10)[C14]-sebacic acid was infused simultaneously as a tracer (sp. act. 0.416 µCi/min). The was a gradual increase in the

amount of sebacate expired in carbon dioxide for the first 300 min; the value remained elevated for an additional 120 min

before declining. At 24 h, 11.38 mmol sebacate was recovered in the urine, as well as 2.04 mmol suberic acid and 1.11 mmol

adipic acid, which was less than 15% of the dose administered. The serum concentration of unlabeled sebacate reached a

plateau after 270 min of infusion. Ten to 15% of serum radioactivity was found in the aq. fraction of serum extracts. The

renal clearance rate was 5.67 ml/min. The overall tissue uptake of unlabeled sebacate was 180 µmol/min, and the apparent

distribution volume was 12.46 l. The percent oxidation of sebacate was 6.14%.

The pharmacokinetic profile of disodium sebacate during a short-time infusion (5 h at 10 g/h) was also studied in 7

male subjects .54 Sebacate in serum and urine was measured by HPLC. The apparent volume of distribution of sebacate was

8.39 l, and the plasma fractional removal rate constant was 0.0086 min-1.

Six male subjects were given a single i.v. bolus of 1 g disodium sebacate, while another 6 received 10 g of sebacate

in 500 ml of distilled water, i.v., at a rate of 3.33 g/h over 3 h.55 For the group given a bolus dose, the distribution phase had

a short half-life, 0.34 h, and a rapid elimination, 2.045 h-1. For the group given the 3 h infusion, 12% of the dose was excreted

as sebacic acid in 24 h; suberic acid (C8) and adipic acid were also present in the urine.

Dodecanedioic Acid

Approximately 50% of an oral dose of dodecanedioic acid was recovered in the urine of rats, and the C10, C8, and C6 metabolites were found up to 72 h after dosing. Labeled dicarboxylic acid was found in the blood for up to 72 h after dosing, mainly as the dicarboxylic acid metabolites. Radioactivity was found in all tissues, with the highest levels in the liver, lungs, and kidneys; after 24 h, the levels declined in all tissues except adipose.

A group of 25 male Wistar rats were dosed orally, by gavage, with 100 µCi of [10,11-3H]dodecanedioic acid, and

the animals were killed at various intervals 1-96 h after dosing.46 Approximately 50% of the radioactivity was recovered in

the urine over 5 days. The C10, C8, and C6 dicarboxylic acid metabolites were found up to 72 h after dosing. Only 2% of

the radioactivity was recovered in the feces. Labeled dicarboxylic acids were present in the blood for up to 72 h, and

consisted mainly of dicarboxylic acid metabolites. Radioactivity was found in all tissues, with the highest levels present in the

liver, lungs, and kidneys after 24 h. Tissue radioactivity levels then decreased slowly in all organs except adipose tissue, in

which case an increase in radioactivity was still seen at 96 h. Radioactivity levels were 20-40% lower in the lipid extracts of

the tissues than in the residual matter. 3H was distributed in the whole molecule, not only the fatty acid portion, of the

phospholipid and triglyceride fractions. Traces of C12, C10, C8,and C6 dicarboxylic acids were detected in the first 24 h.

Male Wistar rats were given an i.v. bolus of 800 µmol/kg disodium dodecanedioic acid.56 The apparent volume of

distribution was 0.248 l/kg, and the plasma half-life was 12.47 min. The renal clearance was 0.00051 l/kg/min, while

systemic clearance was 0.0138 l/kg/min. Only 3-5% of the dose was recovered in the urine.

Percutaneous Absorption

Azelaic Acid

Vehicle affects the absorption of azelaic acid.43 After a 12 h period, absorption from a 15% azelaic gel was 8%,

while absorption from a water-soluble polyethylene glycol ointment base was only 3%. (Species and details not given.)

The in vitro percutaneous absorption of a 15% azelaic acid gel, prior to or after the application of three different

moisturizer formulations, was determined.57 All doses were applied as 5 µl/cm2. The second dose was applied 15 min after


11

the first. [14C]Azelaic acid had a finite dose absorption profile, with a rise to peak penetration followed by a slow but steady

decline. In vitro, 70% of the azelaic acid diffused into the reservoir solution. The application of a moisturizer, and whether it

was applied prior to or following azelaic acid administration, did not have a statistically significant effect on the penetration

of azelaic acid. However, there was a trend toward greater percutaneous penetration and mass distribution with the

application of a moisturizer lotion prior to the azelaic acid gel.

Peroxisome Proliferation

Adipic Acid

The effect of adipic acid on hepatic peroxisome proliferation was evaluated in an in vivo study in which 4 male F344

rats were fed chow containing 2% adipic acid dissolved in alcohol.58 After 3 wks of dosing, the animals were killed. Adipic

acid did not induce peroxisome proliferation and did not affect relative liver weight.

Cellular Effects

Dicarboxylic acids have a cytotoxic effect on the abnormally hyperactive and malignant epidermal melanocyte.

Dicarboxylic acids, C8to C13, have been shown to inhibit mitochondrial oxidoreductases,59 and they have been show to

reversibly inhibit microsomal NADPH and cytochrome P450 reductase.60 Medium chain length dicarboxylic acids are also

competitive inhibitors of tyrosinase in vitro.

Adipic Acid

The effect of adipic acid on primary keratinocyte cultures was evaluated using epidermal cells from neonatal NMRI

mice.61 Concentrations of ≤30 mM did not inhibit 3H-thymidine incorporation or affect DNA synthesis, while 40 and 50 mM

inhibited both of these parameters. No effect on labeling indices was observed with 1-30 mM adipic acid.

Azelaic Acid

Azelaic acid, a naturally occurring competitive inhibitor of tyrosinase, has a cytotoxic effect on malignant

melanocytes .62 Azelaic acid is also a competitive inhibitor of a number of oxidoreductive enzymes, enzymes involved in

DNA synthesis, and of oxidoreductases of the respiratory chain.63 In vitro, azelaic acid is a scavenger of toxic oxygen

species, inhibits oxyradical activity in cell cultures, and inhibits generation of reactive oxygen species by neutrophils. It has

been reported that, in vitro, azelaic acid has time- and dose-dependent, reversible, and anti-proliferative and cytotoxic effects

on a number of tumoral cell lines. Azelaic acid had no effect on normal cell lines.

Disodium Azelate

Disodium azelate inhibited cell proliferation and affected viability of Cloudman and Harding-Passey murine

melanomata at concentrations ≥10-2 M when incubated over a 3 day period.59 The mitochondria were the prime target of

action.

The effect of disodium azelate on primary keratinocyte cultures was evaluated using epidermal cells from neonatal

NMRI mice.61 A dose-dependent inhibition of 3H-thymidine incorporation into DNA, ranging from 50% inhibition with

20mM to 90% inhibition with 50mM disodium azelate, was observed following a 12 h incubation period. Concentrations of 1

and 10 mM did not affect DNA synthesis, but a marked reduction was seen with 20-50 mM. The effects on DNA synthesis

were time-dependent, with the maximum inhibitory effect observed at 4 h; this effect was reversible. RNA and protein

synthesis were also inhibited during the first 4 h of incubation with 50 mM disodium azelate. Cellular structure was altered

upon incubation with disodium azelate, primarily affecting mitochondria, and the rough endoplasmic reticulum. These effects

were also reversible.

Dodecanedioic Acid

The disodium salt of dodecanedioic acid inhibited cell proliferation and affected viability of Cloudman and Harding-


12

Passey murine melanomata at concentrations ≥10-2 M when incubated over a 3 day period.59 The mitochondria was the prime

target of action.

ANIMAL TOXICOLOGY

Acute Toxicity

The oral LD50 values of the dicarboxylic acids for rats ranged from 0.94 g/kg adipic acid to ≥4 g/kg azelaic acid (although most reported values were >5 g/kg). The reported dermal LD50 values ranged from >6 g/kg dodecanedioic acid to >10 g/kg glutaric acid.

The acute oral, dermal, inhalation, and parenteral toxicity of the dicarboxylic acids and some of the salts are

summarized in Table 4.44,64-69

Short-Term Oral Toxicity

In short-term oral toxicity studies, ≤3000 mg/kg/day adipic acid did not produce significant toxicological effects in rats. Signs of toxicity were seen at >3600 mg/kg/day. No toxicity was observed with guinea pigs fed 400-600 mg/day azelaic acid.

Adipic Acid

Groups of 6 male Sprague-Dawley rats were dosed orally (method not specified) with 3600-5600 mg/kg adipic acid

as an 18.6-24.9% solution in saline for 14 days.44 Three animals of the 3600 mg/kg group, 5 of the 4000 mg/kg group, and all

of the 4500-5600 mg/kg groups died prior to study termination. Signs of toxicity included depressed activity, labored

respiration, ataxia, and convulsions. No gross findings were noted at necropsy at study termination.

Groups of 5 rats were dosed with 0 or 3000 mg/kg of a neutralized 20% adipic acid solution orally, by gavage, for 4

wks. A non-significant decrease in body weight gain was observed. In a 4 wk study in which a group of 3 rats was dosed

orally, by gavage, with 2400 mg/kg adipic acid, no significant toxicological effects were noted.

In a 4-wk dietary study in which groups of 17-20 female rats were fed 0-40 mg/day (0-435 mg/kg/day) adipic acid,

no effects were reported. The no-observable adverse effect level (NOAEL) was >435 mg/kg/day. In a 5-wk dietary study in

which groups of 15-18 male rats were fed 0-800 mg/day (0-13,333 mg/kg/day) decreased body weight gains, an unkempt

appearance, and diarrhea were observed for the animals fed 800 mg/day the first 3 wks. In another 5-wk dietary study in

which groups of 4 rats, gender not specified, were fed 100 or 200 mg/day (310-922 mg/kg/day) of a 20% adipic acid solution

in ethanol, 5 days/wk, no signs of toxicity were observed.

Ten rats were dosed orally, method not specified, with 199 mg/day (638-1332 mg/kg/day) sodium adipate, 5 days/wk

for 9 wks. No toxicological effects were observed.

A group of 5 guinea pigs, gender not specified, were dosed orally using capsules with 400 mg/day (682-942

mg/kg/day) adipic acid for 5 days, followed by dosing with 600 mg/day (1032-1739 mg/kg/day), 5 days/wk for 5 wks. No

signs of toxicity were observed.

No toxicity was observed in a study in which pigs were fed 1% adipic acid in the diet for 7 days.

Short-Term Inhalation Toxicity

Short-term inhalation exposure to 126 mg/m3 adipic acid to rats did not produce signs of toxicity, but exposure of mice to 460 mg/m3 did.


13

Adipic Acid

Mice, gender and number per group not specified, were exposed to 460 mg/m3 adipic acid for 1.5 mos.44 (Details of

exposure were not specified.) Decreased weight gain, altered oxidase activity, and upper respiratory tract, liver, kidney, and

central nervous system effects were observed. (Details were not given.)

Two male and 2 female rats were exposed to 126 mg/m3 adipic acid for 15 days, 6 h/day. No signs of toxicity were

observed, and no gross or microscopic findings were noted at necropsy.

Subchronic Oral Toxicity

In a subchronic oral study, 10 male and 10 female rats exposed to 10% sodium succinate in the drinking water died, but no compound-related lesions were found. Body weights were decreased in rats given ≥2.5% sodium succinate for 13 wks, but toxicological treatment-related changes were not observed. Glutaric acid ad a low degree of toxicity to rats (at 2%) and dogs (concentration not specified) when given in the drinking water. Dietary administration of ≤3400 mg/kg/day adipic acid for 19 wks produced slight effects in the liver of male rats; the NOAEL was 3333 mg/kg. A mixture of adipic, glutaric, and succinic acids had a low degree of toxicity in rats when tested at 3% for 90-days.

Sodium Succinate

The oral toxicity of sodium succinate was evaluated using F344 rats.68 Groups of 10 males and 10 females were

given 0, 0.3, 0.6, 1.25, 2.5, 5 or 10% sodium succinate in the drinking water for 13 wks. All animals were killed at the

termination of dosing. Body weight gains of animals of the 10% group were significantly decreased, and all animals of this

group died by wk 4. These animals were extremely emaciated; however, no compound-related microscopic lesions were

found. Body weight gains were decreased in animals given ≥2.5% sodium succinate, as compared to controls. No toxicologi-

cal treatment-related effects were observed.

Glutaric Acid

The oral toxicity of 1-2% glutaric acid was evaluated in a 90-day study using rats.65 Glutaric acid had a low degree

of toxicity at ≤2%; decreased weight gains were seen with higher concentrations. No specific target organs were identified.

(Additional details, including the method of oral administration, were not given.) A low degree of toxicity was also reported

in a 90-day oral toxicity study using dogs. (Details were not provided.)

Adipic Acid

Groups of 8-10 male rats were given 0, 420, 840, 1700, or 3400 mg/kg/day sodium adipate for 19 wks in a protein

deficient diet.67 Animals were killed after either 7 wks or at study termination. For unexplained reasons, only 5-7

animals/group survived until study termination. Rats of the 3400 mg/kg/day group had decreased body weight gains and

decreased body weights. (Statistical significance not stated.) Slight effects were seen in the liver, and the NOAEL was 3333

mg/kg.

Adipic/Glutaric/Succinic Acid Mixture

The oral toxicity of a mixture of adipic, glutaric, and succinic acids, tested at 3%, was evaluated in a 90-day study.65

The mixture had a low degree of toxicity at this dose. Higher concentrations caused decreased weight gain. No specific

target organs were identified. (Additional details, including the method of oral administration and percentage of acids in the

mixture, were not given.)

Subchronic Inhalation Toxicity

Signs of toxicity were reported in a subchronic inhalation study in which mice were exposed to 13 or 120 mg/m3 adipic acid.


14

Adipic Acid

Mice, gender and number per group not specified, were exposed to 13 or 120 mg/m3 adipic acid for 4 mos.44

(Details of exposure were not specified.) Decreased weight gain, altered oxidase activity, and upper respiratory tract, liver,

kidney, and central nervous system effects were observed.

Chronic Oral Toxicity

A low degree of toxicity to sodium succinate was observed in a 2 yr oral study using rats. Slight effects were seen in the livers of rats fed ≤3200 mg/kg/day adipic acid for 33 wks, and the NOAEL for rats fed a diet containing adipic acid for 2 yrs was 1%; no significant toxicological effects were seen at concentrations of ≤5%. No significant toxicological effects were observed for mice fed ≤280 mg/kg or rabbits fed ≤400 mg/kg azelaic acid for 180 days. Disodium sebacate was not toxic to rats or rabbits fed up to 1000 mg/kg for 6 mos.

Sodium Succinate

The oral toxicity of 1% sodium succinate was evaluated in rats in a 2-year study.65 A low degree of toxicity was

observed with this dose. Higher concentrations caused decreased weight gain. No specific target organs were identified.

(Additional details, including the method of oral administration, were not given.)

Adipic Acid

Groups of 13-15 male and female rats were fed a diet containing 0, 1600, or 3200 mg/kg/day adipic acid for 33

wks.44 Rats were killed at various intervals throughout the study. Ten of 14 rats fed 3200 mg/kg/day died during wks 0-4;

surviving rats had decreased weight gains during this time. However, at study termination, body weights were for surviving

animals of this group were similar to controls. Slight effects were seen in the liver. (Statistical significance not stated.)

In a 2-yr study, groups of 20 male rats were fed a diet containing 0, 0.1, 1, 3, and 5% adipic acid (equiv. to 0, 75,

750, 2250, and 3750 mg/kg/day), and a groups of 10 and 19 females were fed 0 and 1% adipic acid, respectively. Weight

gains of male rats fed 3 and 5% adipic acid were significantly less than controls. There were no significant toxicological

findings upon gross or microscopic observation. The NOAEL was 1% adipic acid for male and female rats.

Azelaic Acid

Groups of 15 male and 15 female Wistar rats were fed a diet containing 140 or 280 mg/kg azelaic acid for 180 days,

and a control group of 10 males and 10 females was given untreated feed.69 No significant toxicological effects were

observed. Growth was similar between test and control groups, as were the microscopic examinations and clinical chemistry

parameters. The researchers found similar, negative, results when groups of 10 male and 10 female New Zealand rabbits

were fed diets containing 0, 200, or 400 mg/kg azelaic acid for 180 days.

Disodium Sebacate

Groups of 10 male and 10 female Wistar rats were fed a diet containing 0, 500, or 1000 mg/kg disodium sebacate

for 6 mos, after which time they were killed and necropsied.64 Growth was similar between test and control groups, as were

the microscopic examinations and clinical chemistry parameters. The researchers found similar, negative, results when

groups of 10 male and 10 female New Zealand rabbits were fed diets containing 0, 750, or 1000 mg/kg disodium sebacate for

6 mos.

Ocular Irritation

For the dicarboxylic acids, the severity of ocular irritation seems to decrease with increasing carbon number. Succinic acid was a severe ocular irritant, glutaric acid was moderately irritating, and dodecanedioic acid was a slight irritant. Ocular irritation produced by adipic acid was dose-dependent.


15

Succinic Acid

Succinic acid was severely irritating in an ocular irritation study.65 Details were not provided.

Glutaric Acid

Glutaric acid was a moderate ocular irritant.65 Details were not provided.

Adipic Acid

The ocular irritation of adipic acid was evaluated using groups of 2 albino rabbits.65 Ten or 57.1 mg of adipic acid

was placed in the eye of each rabbit, and the eye of 1 animal in each group was rinsed. Using 10 mg, no irritation was seen in

the rinsed eye, and the test article was minimally irritating to the unrinsed eye. With 57.1 mg adipic acid, mild to moderate

irritation was seen in both the rinsed and unrinsed eyes. Severe irritation was seen upon instillation of 0.1 ml, 100 mg, and 50

mg into the eyes of 6, 3, and 2 rabbits, respectively.44 The irritation had not cleared after 8 days.

Dodecanedioic Acid

In studies using rabbits that evaluated the ocular irritation of dodecanedioic acid, slight irritation was reported in one

study, with a primary irritation index (PII) of 11.96/110, and small areas of corneal opacity and mild conjunctival irritation

were seen in the other.66 Details were not provided.

Ocular irritation studies are summarized in Table 5.

Dermal Irritation/Sensitization

Slight to mild dermal irritation was observed for succinic, glutaric, and adipic acid. Adipic acid, dodecanedioic acid, and a mixture of succinic, glutaric, and adipic acids are not sensitizers.

Succinic Acid

Succinic acid was a slight to mild irritant to rabbit skin.65 Details were not provided.

Glutaric Acid

Glutaric acid was a slight irritant to rabbit skin.65 Details were not provided.

Adipic Acid

A dermal irritation study was performed in which 500 mg of 50% aq. adipic acid was applied under an occlusive

patch to a 5 cm x 5 cm area of intact and abraded skin of 6 rabbits for 24 h.44 With intact skin, an erythema score of 2-3/4

was reported, with clearing by day 3. With abraded skin, mild to severe erythema and edema were reported, which cleared by

day 7.

Adipic acid, undiluted or as an 80% aq. paste, was applied occlusively to the backs or ears of rabbits for 24 h. Two

rabbits were used per group. No irritation was observed on the backs of animals. Erythema was observed on the ear, with

clearing by 72 h. In another study in which adipic acid was applied occlusively for 24 h, irritation was not observed. Details

were not provided.

A semi-occlusive application of 500 mg of a paste of 50% adipic acid in propylene glycol to 6 rabbits produced

slight to mild irritation in 3 of the rabbits. A semi-occlusive application of undiluted adipic acid was not corrosive. Using 10

guinea pigs, 50% adipic acid in propylene glycol was not irritating.

The sensitization potential of adipic acid was evaluated using groups of 10 guinea pigs. For induction, 0.1 ml of 1%

aq. adipic acid was given as a sacral intradermal injection, once a week for 4 wks. After a 2-wk non-treatment period, the

dermal challenge was performed with 0.05 ml of 50 and 25% adipic acid in propylene glycol. Adipic acid produced very

mild or no irritation, and it was not a sensitizer.


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Succinic/Glutaric/Adipic Acids Mixture

A mixture of succinic, glutaric, and adipic acid (percentages not specified) was evaluated for irritation and for sensi-

tization using guinea pigs.67 The mixture produced mild or no irritation, and it was not a sensitizer. Details were not

provided.

Dodecanedioic Acid

Dodecanedioic acid was not a sensitizer in a 4-h exposure study or upon application of 0.5 g.66 In a maximization

study using female guinea pigs, 0.5% dodecanedioic acid was injected intracutaneously at induction and 25 and 50% was used

for the dermal challenge. Dodecanedioic acid was not a sensitizer.

Dermal irritation and sensitization studies are summarized in Table 6.

Mucosal Irritation

Succinic Acid

Succinic acid has been considered to be an exacerbating factor in ulcerative colitis, therefore its influence on rat co-

lonic mucosa in terms of mucosal blood flow and superoxide generation was investigated.70 The left side of the colon of 5

male and 5 female rats was exposed, and 0.9-5% succinic acid in physiological saline was instilled into the colonic lumen. A

segment of the colon was then ligated as to not include the mesenteric blood vessel. Mucosal blood flow decreased with all

dose levels. Microscopically, the higher the concentration of succinic acid, the greater was the erosion formation in the colon-

ic mucosa. Significant polymorphonuclear cell infiltration superoxide generation from colon tissue was observed with 0.01%

succinic acid, as compared to higher or lower concentrations. Succinic acid, at fecal concentrations found in active stage

ulcerative colitis, appears to be implicated in mucosal injury, mediated by a decrease in colonic mucosal blood flow and infil-

tration of superoxide-generating polymorphonuclear cells into the mucosa.70

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

Reproductive and developmental effects were not seen upon oral dosing with the dicarboxylic acids or disodium sebacate. Malonic acid has a spermicidal effect on human spermatozoa. Glutaric acid was tested at doses of ≤1300 mg/kg in rats and 500 mg/kg in rabbits, adipic acid at doses of ≤263 mg/kg in mice, 288 mg/kg in rats, 205 mg/kg in hamsters, or 250 mg/kg in rabbits, azelaic acid at doses of ≤140 mg/kg in rats and 200 mg/kg in rabbits, disodium sebacate at 500 mg/kg in rats and 1000 mg/kg in rabbits, and dodecanedioic acid was tested at ≤1000 mg/kg using rats. Embryotoxic effects were reported for in a reproductive study of 2500 mg/kg/day azelaic acid using rats and in reproductive studies with ≤500 mg/kg/day azelaic acid using rabbits and monkey. Sodium salts of some dicarboxylic acid had a specific inhibitory effect on the uterine horn, and this effect progressively increased with chain length.

Malonic Acid

Malonic acid, 0.1%, reduced the pH of sperm suspensions to 4.-5.5 and rendered human spermatozoa immotile

within 30 min.71 A concentration of 1.0% reduced the pH to 1.5-3.0 and was almost instantaneously spermicidal.

Succinic Acid

Subcutaneous injections of 31 mg/kg/day succinic acid for 3 wks did not change the typical diestrous vaginal smears

in 2 mos old ovariectomized rats.72

Glutaric Acid

The reproductive toxicity of glutaric acid was evaluated. Rats were dosed with 125, 400, or 1300 mg/kg and rabbits

with 40, 160, or 500 mg/kg. No reproductive, embryotoxic or teratogenic effects were observed. No other details were

provided.73

Adipic Acid

Groups of 20-24 gravid albino CD-1 mice were dosed orally, by gavage, with 0, 2.6, 12, 56, or 263 mg/kg adipic


17

acid on days 6-15 of gestation.44 All animals were killed on day 17 of gestation. No reproductive, developmental, or

maternal effects were observed, and the NOAEL for maternal and developmental toxicity was 263 mg/kg. Similar results

were obtained in a study in which gravid Wistar rats were dosed orally, by gavage, with 0, 2.9, 13, 62, or 288 mg/kg adipic

acid on days 6-15 of gestation. The NOAEL for maternal and developmental toxicity was 288 mg/kg.

Groups of 21-24 gravid hamsters were dosed orally, by gavage, with 0, 2.9, 5, 44, or 205 mg/kg adipic acid on days

6-10 of gestation. A significant increase in resorption per implant site was observed with 205 mg/kg adipic acid, resulting in a

decreased number of live fetuses. (This decrease was not evaluated statistically.) No other effects were reported.

Groups of 10-14 gravid Dutch-belted rabbits were dosed by oral intubation with 0, 2.5, 12, 54, or 250 mg/kg adipic

acid on days 6-18 of gestation. No reproductive, developmental, or maternal effects were observed. The NOAEL for mater-

nal toxicity was ≥250 mg/kg and for developmental toxicity was 250 mg/kg.

Azelaic Acid

Reproductive and teratogenic effects of azelaic acid were evaluated using Wistar rats and New Zealand rabbits.69 A

group of 20 gravid rats was fed a diet containing 140 mg/kg/day azelaic acid, and a control group of 10 gravid rats was given

untreated feed. Half of each group was killed and necropsied on day 19 of gestation, and the remaining animals continued

dosing for 3 mos. The day of gestation that dosing started is not clear. No gross or microscopic lesions were observed for the

uteri, placentas, or ovaries. There were no differences in reproductive, teratogenic, or developmental effects between treated

and control groups, nor were there any differences in fetal weights of the live fetuses. Similar results were seen using groups

of 20 gravid rabbits fed 200 mg/kg/day azelaic acid; 10 untreated gravid rabbits were used as a negative control group.

Embryotoxic effects were observed in oral studies with rats receiving 2500 mg/kg/day of azelaic acid.48 Similar

effects were observed in studies in rabbits given 150 to 500 mg/kg/day and in monkeys given 500 mg/kg/day. The doses at

which these effects were noted were all within toxic dose ranges for the dams. No teratogenic effects were observed. (Details

were not provided.)

Disodium Sebacate

Reproductive, teratogenic, and developmental effects of disodium sebacate were evaluated using Wistar rats and

New Zealand rabbits.69 Groups of 20 gravid rats were fed a diet containing 0 or 500 mg/kg/day disodium sebacate, and

groups of 20 gravid rabbits were fed 0 or 1000 mg/kg. Half of each group was killed and necropsied on day 19 of gestation,

and the remaining animals continued dosing for 3 mos. The day of gestation that dosing started is not clear. No gross or

microscopic lesions were observed for the uteri, placentas, or ovaries. There were no differences in reproductive or

developmental effects between treated and control groups, nor were there any differences in fetal weights of the live fetuses.

Dodecanedioic Acid

The reproductive toxicity of 0-1000 mg/kg dodecanedioic acid was evaluated using male and female Crl:CD:BR

rats.66 The no-observable effect level (NOEL) for reproductive and developmental toxicity was 1000 mg/kg. The NOELs for

toxicity of male and female rats were 100 and 500 mg/kg, respectively. The NOAEL for both male and female rats was 1000

mg/kg. (No other details were provided.)

Sodium Salt of Adipic, Azelaic, Sebacic, and Dodecanedioic Acids

The influence of the sodium salt of some dicarboxylic acids (adipic acid, azelaic acid, sebacic acid, dodecanedioic

acid) on both spontaneous and evoked muscle activity of the uterine horns of 35 female Wistar rats (250-300g) has been

studied in vitro.74 Spontaneous activity of uterine muscle was inhibited by dicarboxylic salts causing the total abolition of

mechanical events at concentrations of 24,, 32, 40, and 64 x 10-3 M. Dicarboxylic salts antagonized the maximal isometric

contraction of the uterine horn induced by administration of acetylcholine, oxytocin or prostaglandins (PGF2-α). The amount


18

of antagonism was dependent upon the concentration of dicarboxylic salt used. Dicarboxylic salts had an specific inhibitory

effect on the uterine horn which progressively increased with their chain length. The results suggested that the inhibitory

effects of dicarboxylic salts on smooth muscle could be due to a cellular membrane hyperpolarization.

GENOTOXICITY

The dicarboxylic acids are not genotoxic, and consistently were not mutagenic in Ames tests. Positive results were seen in a transformation assay on glutaric acid using Balb/c-3T3 cells, both with and without metabolic activation. The results of a mouse lymphoma assay, with and without metabolic activation, on glutaric acid was pH-dependent. Equivocal results were obtained in an in vitro chromosomal aberration assay of ≤15 mg/mg disodium succinate using Chinese hamster fibroblast cells. The dicarboxylic acids were not genotoxic in in vivo assays.

In Vitro

Malonic Acid

Malonic acid, 3333 µg/plate, was not mutagenic in a National Toxicology Program (NTP) preincubation assay, with

or without metabolic activation.75

Succinic Acid

The genotoxic potential of succinic acid was evaluated in an Ames test and in a chromosomal aberration study using

a Chinese hamster fibroblast cell line.76 Succinic acid, at a concentration of ≤5.0 mg/plate in phosphate buffer, was not muta-

genic in the Ames test. (Whether metabolic activation was used is not stated.) Concentrations of ≤1.0 mg/ml in saline were

not genotoxic in the chromosomal aberration assay. Sodium succinate, ≤10 /plate, was negative in an Ames test, with and

without metabolic activation.77

Disodium Succinate

The genotoxic potential of disodium succinate was evaluated in an Ames test and in a chromosomal aberration study

using a Chinese hamster fibroblast cell line.76 In the Ames test, disodium succinate was not mutagenic at concentration up to

5.0 mg/plate in phosphate buffer. (Whether metabolic activation was used is not stated.) Equivocal genotoxic results were

obtained in the chromosome aberration assay using concentrations of ≤15.0 mg/ml disodium succinate in saline.

Glutaric Acid

Glutaric acid was evaluated in vitro in a standard Ames assay, the L5178Y/TK ± mouse lymphoma assay with and

without metabolic activation, and the mammalian in vitro Balb/c-3T3 cell transformation assay with and without metabolic

activation.73 The Ames tests were negative. However, the cell transformation assay was positive both in the presence and

absence of metabolic activation and the results in the mouse lymphoma assay were dependent upon pH of the culture medium.

The researchers stated that the variable response in the mouse lymphoma assay and the positive effect in the cell transforma-

tion assay may have been an indirect effect of other factors (such as the pH or osmolarity of the media in which the cells were

exposed), rather than a direct effect of glutaric acid.

Adipic Acid

Adipic acid was evaluated in a number of Ames assays using Salmonella typhimurium and Escherichia coli; results

were negative, with or without metabolic activation, at concentrations as high as 10,000 mg/plate.44,78,79 Negative results were

also obtained in an Ames test with 0-200 mg/l adipic acid using S. typhimurium TA1530 and G-46 without metabolic activa-

tion44. Results were negative in a yeast gene mutation assay using Saccharomyces cerevisiae without metabolic activation at

concentrations ≤200 mg/l. A mouse lymphoma assay using L5178Y/TK ± cells was negative with and without metabolic acti-

vation at concentrations of ≤2000 µg/plate,79 as was a cytogenetic assay using human embryonic lung fibroblast cells with

≤200 mg/l adipic acid.44 In a viral enhanced cell transformation assay using Syrian hamster embryo cells at dosed of 62-1000


19

µg/ml adipic acid, results were negative.

Azelaic Acid

Azelaic acid, 20%, was not mutagenic or genotoxic in an Ames assay, HGPRT test in Chinese hamster ovary cells,

or human lymphocyte test.48 Details were not provided.

Dodecanedioic Acid

Dodecanedioic acid was not mutagenic in an Ames assay at concentrations of ≤5000 µg/plate, with and without

metabolic activation.66 Toxicity occurred at ≥500 µg/plate.

In Vivo

Glutaric Acid

Glutaric acid was evaluated in a mammalian micronucleus cytogenetic assay in mice.73 Glutaric acid was not

genotoxic in this assay. (Details not specified.)

Adipic Acid

Adipic acid was not genotoxic in in vivo cytogenetic assays using chromosomes from rats dosed orally, by gavage,

with a single dose of 5000 mg/kg or daily for 5 days with 2500 mg/kg.44 Adipic acid was also not genotoxic in dominant

lethal studies with doses up to 5000 mg/kg..

Azelaic Acid

Azelaic acid was not genotoxic in a dominant lethal assay in mice.48 (Details not specified.)

Dodecanedioic Acid

Dodecanedioic acid, at concentrations of ≤5000 mg/kg, was not mutagenic in a micronucleus assay using mice.66

Available details for the genotoxicity studies are summarized in Table 7.

CARCINOGENICITY

Carcinogenic results were not seen in rats given up to 2% sodium succinate in the drinking water or 5% adipic acid in feed for 2 yrs. An increase in the incidence of C-cell adenoma/carcinoma of the thyroid in females given 2% sodium succinate, and a positive trend in the occurrence of this tumor, was considered a function of experimental variability and not related to dosing.

Sodium Succinate

Groups of 50 male and 50 female F344 rats were given drinking water containing 0, 1, or 2% sodium succinate for 2

yrs, and the carcinogenic potential was determined.68 Dosing was discontinued after 104 wks, and, after a 9-wk recovery

period, the rats were killed at wk 113. Body weights of the high dose animals were decreased by 10% as compared to con-

trols. There were no statistically significant differences in overall tumor incidence or mean survival time between treated and

control animals. An increase in the incidence of C-cell adenoma/carcinoma of the thyroid in females of the 2% group, and a

positive trend in the occurrence of this tumor, was considered a function of experimental variability and not related to dosing.

Sodium succinate was not toxic or carcinogenic to male or female F344 rats when given in the drinking water for 2 yrs.

Adipic Acid

Adipic acid was not carcinogenic in the 2-yr chronic oral toxicity study (described previously) in which groups of 20

male rats were fed diets containing 0, 0.1, 1, 3, and 5% adipic acid, and groups of 10 and 19 females were fed 0 and 1%

adipic acid, respectively.67

Tumor Promotion

Succinic Acid, Sodium Succinate, Disodium Succinate

The promotion of urinary bladder carcinogenesis by sodium succinate was evaluated using male F344 rats.80 Groups


20

of 16 male F344 rats were given 5% succinic acid, sodium succinate, or disodium succinate with 0.05% N-butyl-N- (4-

hydroxybutyl)nitrosamine (BBN) in the drinking water for 4 wks, followed by dietary administration of 5% of the respective

test article without BBN for 32 wks. Negative controls were given water with BBN only and untreated feed. Groups of 8

male F344 rats followed the same protocol without the addition of BBN to the drinking water, as did a group of non-BBN-

treated negative controls. The animals were killed at wk 37.

In the BBN-pretreated groups, many rats given sodium or disodium succinate developed hematuria towards the end

of the study. There were no statistically significant differences in body or organ weights between the control and test groups.

(Information on organ and body weights was not provided for the non-BBN groups.) Large tumors were found on the urinary

bladders of the BBN-pretreated animals given sodium and disodium succinate; tiny lesions were found in the control or

succinic acid BBN-pretreated animals. The incidence and number of urinary bladder carcinomas and papillomas and of papil-

lary or nodular hyperplasia (preneoplastic lesions) were statistically significantly increased in the sodium and disodium

succinate BBN-pretreated groups as compared to the succinic acid and control BBN-pretreated groups. The incidence and

numbers observed in the sodium and disodium succinate groups were not statistically significantly different from each other.

An association between tumor area and sodium intake was noted. Urinary bladder lesions were not observed in any of the

animals that were not pretreated with BBN. Urinary pH and electrolyte concentrations were affected by dosing with sodium

or disodium succinate with BBN, as compared to the control and succinic acid groups, and statistically significant differences

between these two groups were observed as well.

The researchers also evaluated cell proliferation and DNA synthesis in the urinary bladder epithelium. Groups of 20

male F344 rats were given 5% succinic acid, sodium succinate, or disodium succinate in the feed, without BBN pretreatment

for 8 wks. Negative controls were given basal diet. Five rats per group were given an i.p. injection of 50 mg/kg 5-bromo-2’-

deoxyuridine (BrdU) 1 h prior to being killed. Compared to control values, BrdU uptake was statistically significantly

increased by increased disodium succinate and was increased, but not in a statistically significant manner, by sodium

succinate. Succinic acid did not have any effect on DNA synthesis. Microscopically, simple hyperplasia was observed in the

urinary bladders of animals given sodium and disodium succinate. The appearance of the urinary bladder epithelial surface

was altered by sodium and disodium succinate. Spermidine/spermine N1-acetyltransferase activity in the urinary bladder epi-

thelium was increased for disodium succinate, but not sodium succinate, when compared to controls. Urinary pH and

electrolyte concentrations were affected as described previously.

CLINICAL ASSESSMENT OF SAFETY

In a cumulative irritancy test, the cumulative irritation of a 15% azelaic acid gel increased with successive patching. It is not known if the vehicle played a role in the irritation scores. Daily application of a 20% azelaic cream causes erythema and irritation.

Dermal Irritation

Azelaic Acid

The cumulative irritation potential of a 15% azelaic acid gel (prescription formulation; vehicle not identified) was

determined in a study using 31 female and 2 male subjects.81 (During the study, 1 subject withdrew for personal reasons.)

White petrolatum was used as a negative control. Azelaic acid and petrolatum, 0.2 g of each, were applied under occlusion to

2 cm x 2 cm sites on the back of each subject 3 times per week for 3 wks. Weekday patches were removed after 24 h, while

the patches applied on Fridays were removed after 72 h. The test sites were evaluated 15-30 min after removal of the patch,

and then a new patch was applied. Application was discontinued if severe irritation, which was designated by a maximum

erythema score of 3, was observed. A 15% azelaic acid gel was statistically significantly more irritating than the negative


21

control, with a mean cumulative irritancy index of 1.05/3. Individual reaction scores for the test article ranged from 0 to 3,

and 5 subjects discontinued patching with azelaic acid due to an irritation score ≥3. Cumulative irritancy increased with suc-

cessive patching. The researchers noted that since the vehicle used for azelaic acid was not tested, there was uncertainty as to

whether the vehicle components affected the irritation scores.

Twice daily application of a cream containing 20% azelaic acid has been reported to cause erythema, irritation,

pruritus, dryness, scaling, and burning.82

Case Reports

Adipic Acid

In two case reports with industrial exposure to adipic acid, positive sensitization reactions were reported with follow-

up testing.44


22

ESTERS OF DICARBOXYLIC ACIDS

Much of the information on the esters of dicarboxylic acids was obtained from summary documents that mostly

contained unpublished data. The summary documents are therefore listed as the citation, and, when there are numerous

studies described, will only be cited at the beginning of that section. Data on esterase metabolites other than the parent

dicarboxylic acid (i.e. parent alcohol and monoester) are summarized in Appendix I, immediately following the reference

section. It is important to note that this is merely for support and not for review as ingredients themselves.

GENERAL BIOLOGY

Absorption, Distribution, Metabolism, and Excretion

Metabolism of diesters in animals is expected to occur, initially, via enzymatic hydrolysis, leading to the correspond-

ing dicarboxylic acids and the corresponding linear or branched alcohol.83 These dicarboxylic acids and alcohols can be fur-

ther metabolized or conjugated to polar products that are excreted in urine. However, other studies have shown that enzy-

matic hydrolysis of at least some diesters may be incomplete and result, instead, in the production of monoesters.84

Diethyl Malonate

In in vitro absorption studies using pig skin, 8.8 and 3% of undiluted diethyl malonate was found in the skin and receptor fluid, respectively. Absorption was enhances when diethyl malonate was diluted with ethanol and reduced when diluted in acetone Using human skin, 16% of the applied diethyl malonate penetrated. In vivo, absorption of diethyl malonate, estimated from urinary and fecal recovery, was 15% in nude mice, 4 % in human skin grafted to nude mice, 6% in pig skin grafted to nude mice, 2.5% in pigs, and 4% in dogs.

Diethyl malonate is hydrolyzed via a two-step reaction to malonic acid and the corresponding alcohol, ethanol.14

Dimethyl malonate, which is not listed in the International Cosmetic Ingredient Dictionary, has similar physico-

chemical properties and hydrolyzes in the same manner to malonic acid and methanol. Because of this similarity, data on

dimethyl malonate will be included in this safety assessment to provide read-across data.

Distribution of diethyl malonate (and dimethyl malonate) is likely to occur in the water compartments, and

accumulation in fat is unlikely based on physical and chemical properties. Both esters are likely to be metabolized by

unspecific (serine-) esterases of different tissues, in particular, in the liver to the monoesters and then to malonic acid and

ethanol (or methanol). The hydrolysis product is likely to be metabolized via physiological pathways, such as the tricarboxylic

acid cycle, as they are part of the normal intermediate metabolism. Both are assumed to readily absorb via mucous

membranes.

In Vitro - Animal The percutaneous absorption of radiolabeled diethyl malonate was determined in vitro using skin from Yorkshire

pigs. [2-14C]Diethyl malonate was applied either undiluted (100 µg/cm2) or diluted in ethanol at 12.5 mg/ml with an applied

dose of 100 µg/cm2 or as 0.5 mg/ml with an applied dose of 4 µg/cm2. At 50 h, with undiluted diethyl malonate, 8.8% of the

radioactivity was found in the skin and 3% was in the receptor fluid. With 100 µg in ethanol, 13% of the radioactivity was

found in the skin and 6% in the receptor fluid and with 4 µg in ethanol, 30% was found in the skin and 10% in the receptor

fluid. Absorption appeared to be enhanced with ethanol.

The percutaneous absorption of 1 mg/cm2 [2-14C]diethyl malonate in 10 µl acetone was determined in vitro also

using skin from Yorkshire pigs. At 24 h, 0.2-1.6% of the diethyl malonate was found in the receptor fluid, 0.2-0.9% was

found in the skin, and 0.6-0.7% was found on the skin surface. Skin mediated hydrolysis amounted to 15-35% of the applied

dose. In the receptor fluid, 20-21% of the applied dose was present as hydrolysis products. In the skin and on the skin

surface, 3-5% and 2-4%, respectively, of the applied dose was present as hydrolysis products.


23

In Vivo - Animal The percutaneous penetration of radiolabeled diethyl malonate was studied in vivo in the following animal models:

athymic nude mouse, human, and pig skin grafted to athymic nude mice, in weanling pigs, and in hairless dogs. [2-14C]Diethyl

malonate was applied at a dose of 0.1 mg/cm2 for 24 h to a 1.27 cm2 area of mouse skin or for 48 h to a 25 cm2 area of pigs

and hairless dogs using non-occluded applications. Absorption, estimated using urinary and fecal recovery after s.c.

administration, was 15% in nude mice, 4 % in human skin grafted to nude mice, 6% in pig skin grafted to nude mice, 2.5% in

pigs, and 4% in dogs.

In Vitro - Human An in vitro skin absorption study was performed using diethyl malonate, no vehicle given. Human cadaver split

thickness skin was used in flow through cells. Diethyl malonate (4 µl) was applied to the skin samples. After 24 h, 16% of

the applied dose had penetrated through the skin. The maximum flux rate was reached after 5 h and amounted to 280 µg/h

(350 µg/cm2/h); the mean penetration rate was 99 µg/h (120 µg/cm2/h). Much of the test substance, 45 to 50%, evaporated

from the skin, and 34 to 39% remained on the skin.

Ditridecyl Adipate

Approximately 11% of ditridecyl adipate was absorbed through the skin of rats; 5.5-7.4% of the applied dose was found in the tissues, 3.5-4.7%was found in the urine, and 0.4-0.7% was found in the feces. Prior dosing with ditridecyl adipate did not significantly affect absorption.

The percutaneous absorption of [14C]ditridecyl adipate was determined using groups of 10 male and 10 female

Sprague-Dawley rats that were untreated or that had previously been exposed to unoccluded dermal applications of 0 or 2000

mg/kg ditridecyl adipate, 5 days/wk for 13 wks.85 (This study is described in the section on ‘Subchronic Dermal Toxicity’.)

A single 58 µl dose of 2000 mg/kg [14C]ditridecyl adipate was applied topically (size of test site not specified), and urine and

feces were collected for 4 days. In the previously untreated rats, a total of 11.6 and 10.6% of the [14C] solution was absorbed

by male and female rats, respectively, over 4 days. Approximately 63 and 52% of the absorbed dose (7.4 and 5.5% of the

applied dose, respectively) was found in the tissues of males and females, respectively. A total of 3.5-4.7% of the applied

dose was recovered in the urine and 0.4-0.7% in the feces of previously untreated rats. The values for the animals previously

dosed with 2000 mg/kg ditridecyl adipate were not statistically significantly different from the controls. In the previously

dosed animals, a total of 10.8 and 9.1% of the dose was absorbed by males and females, respectively, over the 4 days, with

approximately 87 and 81% of the absorbed dose (9.4 and 7.4% of the applied dose, respectively) found in the tissues of the

male and female rats, respectively. A total of 0.7-1.3% of the [14C] was recovered in the urine and 0.4-0.6% in the feces.

Based on the radioactivity recovered in the urine, the bioavailability of ditridecyl adipate was 2-6%, and previous dosing did

not significantly affect absorption.


In vitro, diethylhexyl adipate was readily hydrolyzed to MEHA or adipic acid in rat liver, pancreas, and small intestine tissue preparations. In animals, diethylhexyl adipate is hydrolyzed to adipic acid and 2-ethylhexanol or MEHA. 2-Ethylhexanol is converted to 2-ethylhexanoic acid, which may form a glucuronide conjugate or may be subjected to ω- and (ω-1)-oxidation and further metabolism. In rats, carbonyl-labeled diethylhexyl adipate rapidly hydrolyzed to adipic acid and MEHA. More than 98% of orally administered diethylhexyl adipate was excreted in 48 h; 21-45% of the radioactivity was expired in carbon dioxide and 34-52% was excreted in the urine. Metabolism studies have shown that excretion in the urine is not as unchanged diethylhexyl adipate; mostly adipic acid is found. In body tissues, the highest levels of radioactivity were found in the liver, kidneys, blood, muscle, and adipose tissue; elimination from the tissues was rapid, with no affinity for a specific organ. In the tissues, diethylhexyl adipate, adipic acid, and/or MEHA were found. When comparing distribution with labeling on the acid versus the alcohol, radioactivity was observed in the ovaries of gravid mice and some fetal tissues following dosing with [carbonyl-14C]diethylhexyl adipate, but none was detected in the ovaries of gravid mice after dosing with [2-ethylhexyl-1-14C]diethylhexyl adipate, and very little


24

radioactivity was seen in fetal tissues. Vehicle affects absorption, but not urinary excretion. In humans dosed orally with diethylhexyl adipate labeled on the ethyl side chains, unconjugated 2-ethylhexanoic acid was the only measurable compound in plasma, and the rate of elimination was rapid. In urine, 2-ethylhexanoic acid was again the principal metabolite, and was probably eliminated in the conjugated form. Peak urinary elimination of all metabolites occurred within 8 h of dosing.

In Vitro The in vitro hydrolysis of diethylhexyl adipate (and mono-(2-ethylheyxl) adipate [MEHA]) using tissue preparations

from the liver, pancreas, and small intestine of 2 rats was examined, as were the effects of diethylhexyl adipate on serum and

hepatic enzymatic activities in vitro.86 Diethylhexyl adipate was readily hydrolyzed to MEHA or adipic acid by each tissue

preparation. The formation of adipic acid was rapid and approximately the same for all three tissues, while the formation of

MEHA was rapid only in pancreatic tissue and was negligible in the intestine. The rate of hydrolysis from MEHA to adipic

acid was greater that than from diethylhexyl adipate and the highest activity was found in intestinal tissue. In examining the

effects on serum and hepatic enzymes, only N-demethylase activity was considerably inhibited by diethylhexyl adipate.

In Vivo - Animal The elimination, distribution, and metabolism of diethylhexyl adipate was investigated using male Wistar rats.86 In

these studies, diethylhexyl adipate was labeled at the carbonyl carbon. In elimination studies, 2 rats were dosed by gavage

with 500 mg/kg [14C]diethylhexyl adipate (1.26 µCi/rat) as a saturated solution in dimethyl sulfoxide (DMSO), and respired

carbon dioxide, urine, and feces were collected for 2 days. At 24 h after dosing, 86% of the administered dose was excreted,

and at 48 h, more than 98% of the dose was excreted. In one animal, 44.8% of the dose was excreted in expired carbon

dioxide and 33.9% in the urine at the 48 h measurement, while in the other rat, 21.1% and of the dose was excreted in expired

carbon dioxide and 52.2% in the urine. Little (1.4 or 5% of the dose) was excreted in the feces.

In the distribution study, 3 rats per group were given a single dose as described above. The animals were killed at

various intervals, and blood, organ, and tissue samples were collected. Not taking into account the stomach and intestines, the

greatest levels of radioactivity, as a percent of dose administered, were found in the liver, kidney, blood, muscle, and adipose

tissue. These values ranged from 0.34-8.21% at 6 h, with the greatest percentage found in the adipose tissue, and from 0.54-

3.44% at 12 h, with the greatest percentage found in the muscle. In most tissues, the amount of residual radioactivity reached

a peak by 6 h, except for the liver, kidneys, testicles, and muscle, which reached a peak at 12 h. The researchers stated that

the elimination of radioactivity from the tissues and organs was very rapid, and there was no specific organ affinity.

The metabolism of diethylhexyl adipate was examined in rats dosed orally, by gavage, with 100 mg of non-labeled

diethylhexyl adipate as a 5% solution in DMSO. A control group was dosed with vehicle only. The rats were killed 1, 3, or 6

h after dosing. The metabolites were determined using GLC. Diethylhexyl adipate was rapidly hydrolyzed to adipic acid, the

main intermediate metabolite, and MEHA. In the urine, adipic acid was detected at 1 h, and excretion as adipic acid in the

urine reached 20-30% at 6 h. Diethylhexyl adipate and MEHA were not detected in the urine. Adipic acid only also was de-

tected in the blood and the liver, with constant excretion of 0.5-0.7% of the dose in the blood and excretion in the liver in-

creasing with time, with 2-3.3% excreted in the liver at 6 h. In the stomach, diethylhexyl adipate, adipic acid, and MEHA

were found. The concentrations of diethylhexyl adipate declined rapidly, while the levels of adipic acid (9-10%) and MEHA

(6-11.5%) peaked at 3 h. Adipic acid, but not MEHA, was found in the intestine and increased with time, reaching 19% at 6

h.

The absorption, distribution, and elimination of diethylhexyl adipate was examined using radioactive labeling on the

acid [carbonyl-14C] (specific activity 39.5 mCi/mmol) or the alcohol [2-ethylhexyl-1-14C] (44.1 mCi/mmol).39 The research-

ers used both DMSO and commercial corn oil as vehicles for all tests. (DMSO is an active penetrant and carrier of other


25

substances through tissue membranes; a fat-soluble substance, such as diethylhexyl adipate, is more realistically studied dis-

solved in corn oil.) The following groups of animals were dosed with 84.3 µg (9 µCi) [carbonyl 14C]diethylhexyl adipate or

84.3 µg (10 µCi) [2-ethylhexyl-1-14C]diethylhexyl adipate in both vehicles: 12 male NMRI mice were dosed i.v. and killed at

intervals from 5 min to 4 days after dosing; 10 male NMRI mice were dosed intragastrically (i.g.) and killed at intervals from

20 min to 4 days after dosing; 12 gravid NMRI mice were dosed i.v. or i.g. on day 17 of gestation and killed at intervals from

20 min to 24 h. Six male rats were dosed i.g. with 843 µg (90 µCi) [carbonyl 14C]diethylhexyl adipate or 843 µg (100 µCi)

[2-ethylhexyl-1-14C]diethylhexyl adipate and killed at intervals from 20 min to 4 h. Whole body autoradiography was used to

determine tissue distribution.

Following dosing with [carbonyl-14C]diethylhexyl adipate, distribution was similar in male mice, male rats, and

gravid mice. The amount of radioactivity in the tissues peaked at a later time following i.g. dosing as compared to i.v. dosing.

The presence of radioactivity in the gastrointestinal tract following i.v dosing indicated biliary excretion. Four h following

both i.v. and i.g. dosing, the greatest uptake of radioactivity was found in the liver, bone marrow, brown fat, adrenal cortex,

kidneys, and a few other tissues. At 24 h after i.g. dosing, significant levels of radioactivity remained in several tissues,

including the liver, of both rats and mice. In gravid mice, a “remarkable strong uptake” of radioactivity in the corpora lutea of

the ovary was observed at all time intervals with both i.v. and i.g. dosing, and some radioactivity was found in the fetal

intestine, liver, and bone marrow.

Similar distribution patterns were seen following dosing with [2-ethylhexyl-1-14C]diethylhexyl adipate as were seen

with [carbonyl-14C]diethylhexyl adipate. Following i.g. dosing, the appearance of radioactivity was lessened and not as great

as it was with i.v. dosing. Very high radioactivity levels were seen in the liver and kidney at 5 min-1 h after i.v. dosing and at

20 min-4 h after i.g. dosing. The radioactivity in the liver was still high at 24 h after i.g. dosing in mice and rats.

Radioactivity was also seen in the intestinal contents at 1-4 h after i.v. dosing, again indicating biliary excretion. At longer

intervals after i.v. injection, 4 h-4 days, radioactivity was detected in the bronchi of mice. While radioactivity was observed

in the ovaries of gravid mice and some fetal tissues following dosing with [carbonyl-14C]diethylhexyl adipate, none was

detected in the ovaries of gravid mice after dosing with [2-ethylhexyl-1-14C]diethylhexyl adipate, and very little radioactivity

was seen in some fetal tissues.

The effect of vehicle on the absorption and biliary and urinary excretion of diethylhexyl adipate was also examined

using rats in a gavage study with [14C]diethylhexyl adipate. Radioactivity was measured every 30 min for 7.5 h. The times

and extent of absorption were different for all four preparations of [14C]diethylhexyl adipate. Radioactivity levels in the blood

increased faster and were greater with DMSO as the vehicle, as compared to corn oil. The highest blood radioactivity levels

were found with [carbonyl-14C]diethylhexyl adipate in DMSO. Biliary excretion of [14C]diethylhexyl adipate was greatly

affected by vehicle; with DMSO, 41% of the dose was detected in the bile, while only 10% of the dose was found with the

corn oil vehicle. This difference was not seen with [carbonyl-14C]diethylhexyl adipate. Finally, vehicle did not have much

influence on urinary excretion. However, unlike the results reported by the previous researchers, little radioactivity was

excreted in the urine. The researchers hypothesized that since the study duration was only 7.5 h, urinary excretion may not

have been complete.

The metabolism of diethylhexyl adipate was examined in vivo using male Wistar rats and compared to in vitro

metabolism using hepatocytes.87 In vivo, rats were dosed with 0.665 or 1.5 g/kg diethylhexyl adipate in corn oil by gavage for

5 days, and the controls were given vehicle only. Urine was collected daily. Diethylhexyl adipate was not recovered in the

urine after 24 h. Adipic acid was the main metabolite of diethylhexyl adipate. In vitro, the first hydrolysis of diethylhexyl


26

adipate appears to be a rate-limiting step. In vivo, it was thought that this hydrolysis probably occurs in the gastrointestinal

tract. Metabolic pathways (ω and ω-1oxidations, glucuronidation) seemed to prove that transformations of diethylhexyl

adipate are localized mainly in the liver.

Oral administration of diethylhexyl adipate to cynomolgus monkeys results in rapid elimination, with 47-57% of the

dose excreted in the urine.17 Unchanged diethylhexyl adipate is absorbed from the gastrointestinal tract, and the glucuronide

of MEHA and traces of unchanged diethylhexyl adipate were found in the urine. (Details were not provided.)

In Vivo - Human The pharmacokinetics of [2H10]diethylhexyl adipate, labeled on the ethyl side-chains, were examined using 6 male

subjects.88 A dose of 46 mg [2H10]diethylhexyl adipate in corn oil, for a total volume of 0.5 cm3, was administered orally in a

gelatin capsule. Blood samples were taken for up to 31 h after dosing, and urine samples were taken at intervals for up to 96

h after dosing. In the plasma, unconjugated [2H5]2-ethylhexanoic acid was the only measurable diethylhexyl adipate-related

compound. This compound appeared rapidly in the plasma, and the peak concentrations (1.6 ±0.5 µg/cm3) occurred between

1 and 2 h. [2H5]2-Ethylhexanol was detected, but it was below the limit of quantification. The rate of formation was calcu-

lated, since there was no evidence of diethylhexyl adipate absorption, as 1.63 ± 1.19 hr-1. The rate of elimination from the

plasma was also rapid and estimated to be 0.42 ± 0.15 h-1., which corresponded to an elimination half-life of 1.65 h.

Although there were inter-individual differences in the rate and extent of [2H5]2-ethylhexanoic acid formation, it was below

the limit of detection in all subjects by 31 h.

In the urine, [2H5]2-ethylhexanoic acid was again the principal metabolite, and it was probably eliminated as a

conjugated product. This conjugated form, most likely the glucuronide, accounted for up to 99% of the total [2H5]2-ethyl-

hexanoic acid measured. Conjugation of the other urinary metabolites was minimal. Peak urinary elimination of the

measured metabolites occurred within 8 h of dosing, and no metabolites were detected in the urine after 36 h. The rates of

elimination were similar for all metabolites, with a mean elimination half-life of 1.5 h. The measured urinary metabolites

accounted for 12.1% of the dose, with the majority being eliminated in 24 h. Fecal analysis determined that a minor portion

of the dose was present as diethylhexyl adipate (0.43%) and [2H5]MEHA (0.27%). The researchers noted that recovery of the

administered dose was incomplete and hypothesized that it was most probably due to further systemic metabolism.

Diethylhexyl Sebacate

Diethylhexyl sebacate is not readily absorbed through the skin of guinea pigs (no further details were provided).1 It

was noted that the metabolism of diethylhexyl sebacate in rodents and humans may follow partially common pathways,.

Penetration Enhancement

Diethyl Sebacate

The addition of diethyl sebacate to an antifungal agent (ME1401) increased its in vivo antifungal activity and its

penetration.89

Peroxisome Proliferation

Peroxisome proliferation causes an increase in liver weights and can induce hepatocarcinogenicity in rats and mice. Diethylhexyl adipate is a peroxisome proliferator requiring extensive phase I metabolism to produce the proximate peroxisome proliferator, which in both mice and rats appears to be 2-ethylhexanoic acid. Studies conducted to explain the species difference in liver tumors seen in mice, but not rats, in the NTP carcinogenicity study on diethylhexyl adipate, suggested that diethylhexyl adipate-induced cell replication, rather than hepatic peroxisome proliferation, provided a better correlation with tumor formation. Diethylhexyl adipate is not as potent a proliferator as diethylhexyl phthalate. Peroxisome proliferation is not believed to pose the risk of inducing hepatocarcinogenesis in humans.


27

Mechanism

Peroxisomes, single membrane-limited cytoplasmic organelles present in cells, have several important functions in

intermediary metabolism.90 Peroxisome proliferators can induce hepatocarcinogenicity in mice and rats, and may also pro-

duce tumors in other organs, such as the testes and pancreas, of these species. Some compounds require extensive phase I

metabolism to produce the proximate peroxisome proliferator.

Rat liver peroxisomes contain both catalase, which destroys hydrogen peroxide, and a number of hydrogen peroxide-

generating oxidase enzymes. Liver peroxisomes contain a complete fatty acid β-oxidation cycle. The stimulation of micro-

somal fatty acid-oxidizing enzymes is caused by the induction of cytochrome P450 isoenzymes in the CYP4A subfamily.

Good correlations have been reported for rat livers between the induction of peroxisomal fatty acid β-oxidation and organelle

proliferation, as well as between the induction of peroxisomal and microsomal fatty acid-oxidizing activities.

Peroxisome proliferators can stimulate DNA synthesis in rat hepatocytes, but do not bind covalently to DNA and are

not considered to be genotoxic carcinogens. Proposed mechanisms of liver tumor formation include induction of sustained

oxidative stress, a role for enhanced cell replication, and the promotion of spontaneous preneoplastic lesions. Sustained oxi-

dative stress does not appear to be solely responsible for peroxisome proliferator-induced hepatocarcinogenesis. In general,

there is a poor quantitative correlation between markers of oxidative stress and compound potency to produce tumors.

The administration of peroxisome proliferators in rodents results in marked increases in liver weights, which is

associated with both morphological and biochemical changes. Liver enlargement is due to both hepatocyte hyperplasia and

hypertrophy. Morphologically, the size and the number of peroxisomes increase. Although potent peroxisome proliferators

are more likely to produce tumors, the magnitude of proliferation does not always correlate with tumor formation. Peroxi-

some proliferators that produce a sustained stimulation of cell replication produce tumors more rapidly than other agents that

produce a similar magnitude of proliferation but do not produce sustained stimulation of cell replication.

Transformation of hepatocytes, by either oxidative stress or alternative mechanisms, may cause initiated cells to be

promoted and progress to tumors by enhanced cell replication. Both peroxisome proliferation and cell replication are impor-

tant biomarkers of peroxisome proliferator-induced tumor formation in rodent livers.

A species difference in response to peroxisome proliferators exists. Humans do not react to peroxisome proliferators

in the manner that rodents do, and peroxisome proliferators do not appear to pose any serious hazard for humans. There

seems to be a lack of effect on organelle proliferation and induction of peroxisomal and microsomal fatty acid-oxidizing

enzymes in species other than rats and mice, and it is suggested that other species are not susceptible to peroxisome prolifera-

tor-induced liver tumor formations.


In male rats fed 2% diethylhexyl adipate in the feed for 3 wks, hepatic peroxisome proliferation, an increase in liver size, and an increase in two hepatic activities of peroxisome-associated enzymes, catalase and carnitine acetyl transferase, were observed. It was postulated that a metabolite, 2-ethylhexyl alcohol, may be responsible for the induction of hepatic peroxisome proliferation. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2 Cultured hepatocytes from male Swiss mice and Wistar rats were used to identify the proximate peroxisome prolif-

erator derived from diethylhexyl adipate.91 Diethylhexyl adipate did not induce peroxisome proliferation in mouse or rat

hepatocyte cultures. However, the primary metabolites of diethylhexyl adipate, MEHA and 2-ethylhexanol, produced similar

results in both mouse and rat hepatocyte cultures, with a 5-fold induction of peroxisomal β-oxidation (measured as cyanide-

insensitive palmitoyl CoA oxidase [PCO] activity) in mouse hepatocytes and a 4-5-fold increase in rat hepatocytes at concen-

trations of 0.5 mM. The most potent peroxisome proliferation occurred in cultured mouse hepatocytes with the secondary


28

metabolite of diethylhexyl adipate, 2-ethylhexanoic acid, which resulted in a 25-fold induction at a concentration of 1 mM. In

cultured rat hepatocytes, 2-ethylhexanoic acid again induced the greatest stimulation of PCO, but only a 9-fold increase was

observed with a concentration of 1 mM. 2-Ethyl-5-hydroxyhexan-1-oic acid, at a concentration of 2mM, stimulated PCO

approximately 5-fold. (Higher concentrations of these agents were cytotoxic.) In both mice and rats, 2-ethylhexanoic acid

was the proximate peroxisome proliferator, but mouse hepatocytes were approximately twice as sensitive as rat hepatocytes.

The effects of diethylhexyl adipate and its metabolites on cultured guinea pig and marmoset hepatocytes were also

examined. Unlike mouse and rat hepatocytes cultures, neither diethylhexyl adipate nor it metabolites, at concentrations up to

2 mM, stimulated PCO.

In another study investigating the effect of diethylhexyl adipate on PCO induction, 2-ethylhexanoic acid was again

found to be the proximate peroxisome proliferator.92 In this in vivo study, male and female Wistar rats and male and female

Swiss mice, 5 per gender per group, were dosed orally by gavage with 0-2.5 g/kg (0-6.74 mmol/kg) diethylhexyl adipate, 0-

1.75 g/kg (0-13.49 mmol/kg) 2-ethylhexanol, or 0-1.0 g/kg (0-13.49 mmol/kg) 2-ethylhexanoic acid in corn oil for 14 days.

The animals were killed 24 h after the final dose and the livers excised. Relative liver weights were increased in a dose-

dependent manner for rats and mice. On a molar basis, diethylhexyl adipate was approximately twice as potent as 2-ethylhex-

anol or 2-ethylhexanoic acid. Diethylhexyl adipate, 2-ethylhexanol, and 2-ethylhexanoic acid induced peroxisomal β-oxida-

tion in a linear dose-response manner in F344 rats and Swiss mice. PCO was stimulated to the greatest extent in male mice.

In an attempt to explain the species difference in an NTP study93 that used these strains of rat and mouse, the peroxi-

some proliferation induced by diethylhexyl adipate was examined, with the same dosing scheme, using male and female F344

rats and male and female B6C3F1 mice 92 (The NTP study found that diethylhexyl adipate induced hepatocellular tumors, and

was carcinogenic, in mice but not rats.) In contrast to the expected results, it was found that PCO activity was increased to the

greatest extent, up to 15-fold, in male F344 rats. However, catalase activity was statistically significantly increased in male

and female mice at all doses, but this was not seen in rats at any dose. Using electron microscopy, a dose-related peroxisome

proliferation was observed for rats and mice. This increase was statistically significant at all dose levels for male rats, and all

but the lowest dose level for female rats and male and female mice. Relative liver weights were increased in a dose-dependent

manner for rats and mice.

Another in vivo study was performed in which the species difference on the hepatic effects of diethylhexyl adipate

was evaluated using female F344 rats and female B6C3F1 mice.94 Groups of 5-8 rats were fed diets containing 0-4.0% di-

ethylhexyl adipate for 1, 4, or 13 wks, and 5-8 mice were fed diets containing 0-2.5% for the same time periods. Marked

dose-dependent increases in relative liver weights were reported for rats given 1.2-4.0% and mice given 0.6-2.5% diethyl-

hexyl adipate for 1 and 4 wks and for rats given 0.6-4.0% and mice given 1.2 and 2.5% diethylhexyl adipate for 13 wks. Di-

ethylhexyl adipate markedly increased PCO induction in rats and mice at all 3 time periods, and microsomal lauric acid 11-

and 12-hydroxylase activities were also increased. Diethylhexyl adipate had little effect on microsomal cytochrome activity

in the rat, but significant increases were observed in mice given 1.2 and 2.5% diethylhexyl adipate for 1 and 4 wks and those

given 0.6-2.5% for 13 wks. Replicative DNA synthesis was determined using 5-bromo-2’-deoxyuridine. Diethylhexyl

adipate produced a sustained stimulation of replicative DNA synthesis in mice given 1.2 and 2.5%, but this effect was not

seen in rats. The researchers suggested that diethylhexyl adipate-induced cell replication, rather than hepatic peroxisome

proliferation, provided a better correlation with tumor formation (in the NTP study). Toxic effects are described in “Short-

Term Oral Toxicity” for the 1 and 4 wk studies and “Subchronic Oral Toxicity” for the 13 wk study.

The effect of diethylhexyl adipate on in vitro steady-state levels of hydrogen peroxide was also evaluated as an


29

attempt to explain the species diference.95 Groups of 5 male F344 rats and female B6C3F1 mice were dosed with 5 ml/kg of 0

or 2 g/kg diethylhexyl adipate daily for 14 days. (Route of dosing not specified.) Statistically significant increases in PCO

and catalase activity, but not glutathione peroxidase activity, were observed for both rats and mice. As compared to controls,

a 5-fold increase was seen in PCO activity with rats, and a 4-fold increase with mice. Catalase activity, as compared to

controls, was 2-times greater in both rats and mice. Steady-state hydrogen peroxide concentrations, determined by measuring

rates of hydrogen peroxide production from palmitoyl CoA oxidation, was also increased 2-fold for male rats and female

mice. However, absolute values for steady-state hydrogen peroxide concentrations were greater in the livers of treated mice,

compared to rats. The researchers stated the difference in the absolute concentration may be important and possibly a

contributing factor to the species difference.

The extent of peroxisome proliferation induced by diethylhexyl adipate was compared to the proliferative effects of

diethylhexyl phthalate and ciprofibrate, a very effective peroxisome proliferator.96 Groups of 3-4 male F344 rats were fed a

diet containing 0.25-2% diethylhexyl adipate, 0.25-2% diethylhexyl phthalate, or 0.001-0.02% ciprofibrate for 30 days. With

diethylhexyl adipate, a statistically significant increase in liver weight was seen at the 2% dose level, but not at lower dose

levels. Dose-dependent increases in liver weight were seen at all dose levels with the other two test compounds, and the

hepatomegalic potencies of diethylhexyl phthalate and ciprofibrate were approximately 200 and 1000-fold greater than di-

ethylhexyl adipate, respectively. The researchers found a close relationship between hepatomegalic and peroxisome prolifera-

tive effects. Diethylhexyl adipate induced a moderate degree of peroxisome proliferation at the 2% concentration, but not at

lower dose levels, where as a greater induction in peroxisome proliferation was observed with diethylhexyl phthalate, and a

much greater induction with ciprofibrate. The researchers also stated that the degree of peroxisome proliferation also

corresponded with hepatocarcinogenic potential in rodents.

Peroxisome induction by diethylhexyl adipate was again determined and compared to a number of phthalate esters,

including diethylhexyl phthalate.97 When groups of 2 male and female rats were fed a diet containing ≤2.5% diethylhexyl

adipate for 21 days, a marked increase in peroxisome proliferation was observed for males and a moderate increase for

females of the 2.5% group. Overall, however, diethylhexyl adipate consistently showed weak activity. The peroxisome

proliferation was analyzed using multivariate analysis.98 Diethylhexyl adipate ranked lower than diethylhexyl phthalate,

di(isodecyl)phthalate, di(isononyl)- phthalate, and di(n-butyl)phthalate, but greater than di(undecyl)phthalate, butyl benzyl

phthalate, di(heptyl, nonyl, undecyl) phthalate, and di(n-hexyl, n-octyl, n-decyl) phthalate. However, in terms of 99.9%

statistically predicted dose, diethylhexyl adipate was the least potent, presumably due to a threshold effect. Histological

findings of reduced basophilia or increased eosinophilia were highly correlated with peroxisome proliferation.


The effect of diethylhexyl sebacate on hepatic peroxisome proliferation was evaluated in an in vivo study in which 4

male F344 rats were fed chow containing 2% diethylhexyl adipate.58 After 3 wks of dosing, the animals were killed. Hepatic

peroxisome proliferation was found, as evidenced by an increase in liver size, hepatic activities of peroxisome-associated

enzymes, and hypolipidemia. Relative liver weights were statistically significantly increased in test animals compared to con-

trols. (The conclusion regarding the involvement of 2-ethylhexyl alcohol is described earlier under ‘Diethylhexyl Adipate’.)

DNA Binding/DNA Synthesis

Diethylhexyl adipate did not bind covalently to hepatic DNA in mice. It did stimulate DNA synthesis in livers of rats. In another study, a significant increase in 8-OH-dG was seen in rat liver, but not kidney DNA. The IARC remarked that the weight of evidence for diethylhexyl adipate demonstrated that rodent, peroxisome proliferators do not act as direct DNA-damaging agents.


30


The potential of diethylhexyl adipate to bind to liver DNA of female NMRI mice was evaluated by administering a

solution of 119 mg diethylhexyl adipate/ml with 3.85 mCi/ml of [14C]diethylhexyl adipate (labeled at C1 of the alcohol

moiety) and 27.7 mCi/ml of [3H]diethylhexyl adipate (tritiated at positions 2 and 3 of the alcohol moiety) in olive oil.99 The

animals were dosed by gavage, and the livers were excised 16 h after dosing. Some animals were pretreated with 10 g/kg of

unlabeled dietary diethylhexyl adipate for 4 wks. Diethylhexyl adipate did not covalently bind to hepatic DNA in mice. Pre-

treatment with diethylhexyl adipate caused an increase in liver weight, but no increase in DNA binding. The researchers

stated that tumorigenicity of diethylhexyl adipate must be due to an activity other than DNA binding.

The ability of diethylhexyl adipate to stimulate liver DNA synthesis in male F344 rats was investigated using radio-

labeled thymidine.100 Contrary to expected results, diethylhexyl adipate did stimulate DNA synthesis. The stimulation factor,

which is indicated by the ratio of the thymidine incorporation in treated animals compared to controls, was 10.5 and the

doubling dose, which is the dose that produced a doubling of the control level DNA synthesis, was 0.7 mmol/kg.

The effect of dosing with diethylhexyl adipate on 8-hydroxydeoxyguanosine (8-OH-dG) in liver and kidney DNA of

rats was examined.101 Groups of 10 male F344 rats were fed a diet containing 0 or 2.5 diethylhexyl adipate. Five animals per

group were killed after 1 wk, and the other 5 after 2 wks of dosing. Relative liver weights were statistically significantly

increased after 1 and 2 weeks of dosing, and the relative kidney weights were statistically significantly increased only after 2

wks. A statistically significant increase in 8-OH-dG was increased in the liver DNA, but not the kidney DNA, at wk 1 and 2.

The IARC remarked that the weight of evidence for diethylhexyl adipate, and other rodent peroxisome proliferators

in general, demonstrated that rodent peroxisome proliferators do not act as direct DNA-damaging agents.17

Hepatic Lipid Metabolism


Dietary administration of diethylhexyl adipate affects hepatic lipid metabolism.17 Hepatic fatty acid-binding protein

and microsomal stearoyl-CoA desaturation were increased in Wistar rats fed 2% diethylhexyl adipate for 7 days.102,103 When

fed to rats for 14 days, an increase in hepatic phospholipid levels and a decrease in phosphatidylcholine:phosphatidylethanol-

amine ratio was reported.104 In male NZB mice fed 2% diethylhexyl adipate for 5 days, an induction of fatty acid translocase,

fatty acid transporter protein, and fatty acid binding protein in the liver was reported.105

Cellular Effects

Dibutyl Adipate

Dibutyl adipate was tested for cytotoxicity in the metabolic inhibition test. A dilution series of dibutyl adipate was suspended in HeLa cells. Dibutyl adipate had no acute toxicity to the cells, which was attributed to its insolubility in water. From the Amended Final Report on Dibutyl Adipate5

Dibutyl Sebacate

The toxic effects of dibutyl sebacate on cultures of human KB cells, monkey Vero cells, and dog MDKC cells was

examined.40 Dibutyl sebacate, in ethyl alcohol and diluted in Eagle’s minimum essential medium, caused a dose-dependent

inhibition of growth in all three cell types.

ANIMAL TOXICOLOGY

Acute Toxicity

The oral and dermal LD50 values are greater than 2 g/kg. Mostly, acute exposure via inhalation to diethyl malonate, dibutyl adipate, and diethylhexyl sebacate did not result in death of rats.

Acute toxicity data on esters of dicarboxylic acids are presented in Table 8.1,14,40,85,106-117 Data from the original


31

safety assessments on dibutyl, diisopropyl and diethylhexyl adipate are included in italics.2,5 The acute toxicity of esterase

metabolites are also summarized in this table.118,119

Short-Term Oral Toxicity

Oral administration of ≤1000 mg/kg dibutyl adipate for 28 days was not toxic effects in rats. In short-term oral dosing with diethylhexyl adipate, decreased weight gain was reported for rats and mice. The NOELs for rats and mice were 2 and 0.63%, respectively, in feed; administration of 10% in feed killed 5/5 female mice. In 2- and 4-wk studies of diethylhexyl adipate, the oral NOAEL for ovarian toxicity was 200 mg/kg in rats; an increase in atresia of the large follicle and a decrease in currently formed corpora lutea were seen in females dosed with 1000 and 2000 mg/kg diethylhexyl adipate.

Dibutyl Adipate

Male and female Crj:CD(SD) rats, number per group not specified, were dosed orally, by gavage, with 0, 20, 140, or

1000 mg/kg dibutyl adipate in olive oil daily for 28 days.106 No clinical, hematological, or microscopic test-article related

changes were observed.


In a 14-day dietary study, groups of 5 male rats and mice were given ≤50,000 ppm and groups of 5 female rats and mice were given ≤100,000 ppm diethylhexyl adipate. Male rats and mice fed 50,000 ppm and female rats and mice fed ≥25,000 ppm had decreased weight gains or weight loss. (It is not specified whether the results were statistically significant.) One female rat and all female mice of the 100,000 ppm group died. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2

Groups of 5 male and 5 female F344 rats were fed a diet containing 0-5.0% (males) or 0-10% (females) diethylhexyl

adipate for 14 days, after which time they were killed for necropsy.117 One female of the 10% group died. Weight gain was

decreased for male rats of the 5% group and female rats of the 2.5 and 5% groups. Feed consumption was decreased for the

animals of the 5 and 10% groups. Females of the 10% group were lethargic, and piloerection, wetness of hair, and ataxia

were observed. Microscopically, gray-white casts were observed in the livers one female of both the 2.5 and 5% groups and

for 2 females of the 10% group, and atrophy of the spleen in one female of the 10% group. These findings were not

considered test-article related. The NOEL was 2.5% and the lowest observable effect level (LOEL) was 5% diethylhexyl

adipate.

Groups of 5 male and 5 female B6C3F1 mice were dosed following the same protocol, with the same dose

concentrations, as described above. All females of the 10% dose group died, and all animals were lethargic and emaciated

prior to death. Feed consumption was decreased in this group. Weight loss was observed for males of the 5% group and

female of the 2.5% group. No compound-related microscopic effects were found. The NOEL was 0.63% and the LOEL was

2.5% diethylhexyl adipate.

In the 14-day study described in the section on “Peroxisome Proliferation” in which 5 male and 5 female Wistar and

F344 rats and Swiss and B6C3F1 mice were dosed with 0-2.5 g/kg diethylhexyl adipate in corn oil for 14 days, diethylhexyl

adipate was toxic to female B6C3F1 mice, causing mortality, at a dose level of 2.5 g/kg.92 The toxicity of two metabolites of

diethylhexyl adipate, 2-ethylhexanol and 2-ethylhexanoic acid, was also examined using Wistar rats and Swiss mice. 2-Ethyl-

hexanol was toxic to male and female rats, with mortality reported at doses >1.05 g/kg in male and female rats. 2-Ethylhexa-

noic acid was toxic to female rats, with mortality reported at doses ≥1.9 g/kg; mortality was not reported for male rats.. These

effects were not reported in mice.

In a 1 and 4-wk dietary study described in the section on “Peroxisome Proliferation” in which groups of 5-8 rats and

mice were fed diets containing 0-4.0% and 0-2.5% diethylhexyl adipate, respectively, feed consumption by rats was decreased

in the 4.0% group at 1 wk and in the 2.5 and 4.0% dose groups at 4 wks.94 Body weights were significantly reduced in these


32

groups. Feed consumption by mice was not affected, but a significant decrease in body weights was seen in the 1.2 and 2.5%

dose groups at 4 wks.

Toxicity was evaluated in a study in which groups of 10 female Crl:CD(SD) rats were dosed, by gavage, with 5

ml/kg of 0, 200, 1000, or 2000 mg/kg diethylhexyl adipate in corn oil for 2 or 4 wks.120 All animals survived until study

termination. In the 2-wk study, no statistically significant findings were observed for the animals dosed with 200 mg/kg, and

the only statistically significant finding in the 1000 mg/kg dose group was an increase in relative liver weight. In the 2000

mg/kg dose group, there was staining around the perineum, statistically significant increases in relative liver and kidney

weights, and a statistically significant decrease in the relative weight of the left ovary. Microscopically, abnormal findings

were reported for both the ovary and kidney. In the ovary, an increase in atresia of the large follicle and a decrease in current-

ly formed corpora lutea were seen in animals dosed with 1000 and 2000 mg/kg, and in the 2000 mg/kg group, an increase in

follicular cysts was observed. In the kidney, an eosinophilic change of the proximal tubule was observed for the 2000 mg/kg

dose group. The NOAEL was 200 mg/kg.

In the rats dosed for 4 wks, similar observations were made. There was staining around the perineum of animals

dosed with 1000 and 2000 mg/kg diethylhexyl adipate, and final body weights of animals dosed with 2000 mg/kg were

statistically significantly decreased. The relative kidney weights were statistically significantly increased in animals at all

dose levels, and liver weights were statistically significantly increased in animals of the 1000 and 2000 mg/kg dose groups.

The mean estrous cycle length was statistically significantly decreased in the 200 mg/kg dose group, but this was not

considered treatment-related since a dose-response was not seen. The same microscopic abnormalities reported in the 2 wk

study were seen in the ovaries and kidneys of the animals dosed with 1000 and 2000 mg/kg in the 4-wk study. As in the 2-wk

study, the NOAEL for ovarian toxicity was 200 mg/kg.

Short-Term Dermal Toxicity

In a short-term dermal study in which 10 rabbits were dosed dermally with 0.5 or 1.0 ml/kg of a 20% dispersion of dibutyl adipate for 6 wks, there was a significant reduction in body weights in the high dose group, and renal lesions in one animal of each group. There were no signs of toxicity in guinea pigs in an immersion study with 20.75% diisopropyl adipate, diluted to an actual concentration of 0.10% adipate. Dermal administration of diethylhexyl adipate to rabbits for 2 wks resulted in slight to moderate erythema at the test site, but toxic effects were not reported for most of the animals.

Dibutyl Adipate

Groups of 10 rabbits were dosed dermally with 0.5 or 1.0 ml/kg/day of a 20% dispersion of dibutyl adipate, 5x/wk for 6 wks. A significant reduction in body weight gain was seen for animals of the 1.0 ml/kg/day group, and renal lesions were seen in one animal of each group. From the Amended Final Report on Dibutyl Adipate5

Diisopropyl Adipate

An immersion study was performed using guinea pigs in which a product containing 20.75% diisopropyl adipate was diluted, giving an actual adipate concentration of 0.10%. The animals were immersed 4 h/day for 3 days. There were no signs of systemic toxicity, and the degree of dermal irritation was considered minimal. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2


Diethylhexyl adipate, 410 or 2060 mg/kg, was applied to the shaved abdomen of male rabbits, 4 per group, 5 days

per wk for 2 wks.117 Mineral oil was applied in the same manner to a group of 4 rabbits as a negative control. A collar was

used to restrict ingestion. One animal in the 410 mg/kg group died during wk 2 of the study. All other animals in this group

appeared normal. Slight to moderate erythema was observed at the test site. No animals of the 2060 mg/kg group died, but 3


33

of the 4 did not gain weight, and they had labored breathing and were lethargic during wk 2. Moderate erythema was

observed in this group. Microscopically, one animal of the 2060 mg/kg group had altered cytology of the liver parenchymal

cells. No other microscopic lesions were noted.


No deaths occurred when 4 rats, 2 guinea pigs, 2 rabbits and 1 cat were exposed to 400 mg diethylhexyl sebacate/m3,

7 hrs/day, for 10 days.1 Details were not provided.

Subchronic Oral Toxicity

In a subchronic oral toxicity study using rats, the NOEL for diethyl malonate was 1000 mg/kg/day. Dietary administration of ≤2.5% di-C7-9 branched and linear alkyl esters of adipic acid (approx. 1500 and 1900 mg/kg/day for males and females, respectively) for 90 days did not result in systemic toxicity. The NOAELS for male and female rats were 1500 and 1950 mg/kg/day, respectively. Subchronic oral administration of diethyl-hexyl adipate to rats caused significant decreases in body weight gains and increases in liver and kidney weights. The dietary NOEL for rats in a 90-day study was 610 mg/kg. In mice, no lesions were induced by dietary administration of ≤25,000 ppm diethylhexyl adipate for 13 wks. A decrease in body weights was seen in mice fed a diet with 1.2 and 2.5% diethylhexyl adipate. For diisononyl adipate, dietary administration of up to 500 mg/kg for 13 wks, a statistically significant increase in relative kidney weights was reported, but there were not toxicological findings. With dogs, 3.0% dietary diisononyl adipate resulted in a decrease in body weights, testes weight, and feed consumption, increased liver weight, elevated enzyme levels, liver and kidney discolora-tion, and microscopic changes in the liver, testes, spleen, and kidneys.

Diethyl Malonate

Groups of 10-16 male and female CD rats were fed diets containing either 0, 36 (males) or 41 mg/kg/day (females)

diethyl malonate.14 No treatment related effects were observed, and the NOEL was 1000 mg/kg/day.

Di-C7-9 Branched and Linear Alkyl Esters of Adipic Acid

Groups of 15 male and 15 female Sprague-Dawley rats were fed a diet containing 0, 0.1, 0.5, or 2.5% di-C7-9

branched and linear alkyl esters of adipic acid for 90 days, corresponding to approximately 1500 mg/kg/day for high dose

males and 1900 mg/kg/day for high dose females.85 All rats were killed for necropsy at study termination. No systemic

toxicity was reported. Small, but significant, increases in absolute and relative kidney weights reported for females of the

2.5% dose group were not considered treatment-related. The NOAELs for male and female rats were 1500 and 1950

mg/kg/day, respectively.


In a 13-wk dietary study, groups of 10 rats and 10 mice were fed ≤25,000 ppm diethylhexyl adipate. With the exception of decreased weight gain for some of the groups, no compound-related toxicologic effects were observed. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2

In a 90-day dietary study, groups of 10 rats per group were fed 0-4740 mg/kg diethylhexyl adipate for 90 days.117

Mortality occurred in the 4740 mg/kg group, but the number of deaths was not specified. Decreased growth and feed con-

sumption was reported for animals fed 2920 mg/kg. Changes in kidney and liver weights were noted, but no details were

given. The NOEL was 610 mg/kg, and the LOEL was 2920 mg/kg diethylhexyl adipate.

Groups of 10 male and 10 female F344 rats and B6C3F1 mice were fed a diet containing 0-25,000 ppm for 13 wks,

after which time the surviving animals were necropsied.121 No compound-related deaths occurred. No lesions were induced

by administration of ≤25,000 ppm diethylhexyl adipate.

Groups of 15 male and 15 female Sprague Dawley rats were fed 0 or 2.5% diethylhexyl adipate for 90 days.85 At

study termination, all animals were killed for necropsy. Body weight gains were statistically significantly decreased for

treated males and females, and relative kidney and liver weights were statistically significantly increased for treated females,


34

when compared to controls.

In a 13-wk dietary study described in the section on “Peroxisome Proliferation” in which groups of 5-8 rats and

mice were fed diets containing 0-4.0% and 0-2.5% diethylhexyl adipate, feed consumption by rats was decreased in the 2.5

and 4.0% dose groups, and body weights were significantly reduced in these groups.94 Feed consumption by mice was not

affected, but a significant decrease in body weights was seen in the 1.2 and 2.5% dose groups

Diisononyl Adipate

Groups of 10 male and 10 female rats were fed 0, 50, 150, or 500 mg/kg diisononyl adipate for 13 wks.85 A

statistically significant increase in relative kidney weights was reported for males and females given 500 mg/kg, but absolute

kidney weights were not affected and no significant microscopic effects were seen. Microscopic changes in any of the organs,

including the testes and epididymis of males and ovaries of females, were not observed. There were not significant

toxicological findings, and the NOAEL was 500 mg/kg/day.

In another 13-wk study, groups of 4 male and 4 female beagle dogs were fed 0, 0.3, 1.0, or 3.0% diisononyl adipate;

the high dose was increased to 6% during wks 9-13. No significant findings were reported for the 0.3 or 1.0% groups. In the

high dose group, decreased body weight, testes weight, and feed consumption, increased liver weight, elevated enzyme levels,

liver and kidney discoloration, and microscopic changes in the liver, testes, spleen, and kidneys were reported. The dietary

NOAEL for diisononyl adipate was 1.0%.

Subchronic Dermal Toxicity

No adverse effects were reported with whole-body application of an 6.25% emulsion of dibutyl adipate to dogs for 3 mos. Unoccluded dermal application of up to 2000 mg/kg ditridecyl adipate for 13 wks to rats produced slight erythema, but no systemic toxicity.

Dibutyl Adipate

No adverse effects were reported in a study using 4 dogs in which entire-body applications of an emulsion containing 6.25% dibutyl adipate were made 2x/wk for 3 mos. From the Amended Final Report on Dibutyl Adipate5

Ditridecyl Adipate

Ditridecyl adipate, 0, 800, or 2000 mg/kg, was applied to the backs of groups of 10 male and 10 female Sprague-

Dawley rats, 5 days/wk for 13 wks.85 The test sites were not occluded, but the animals wore Elizabethan collars. Slight

erythema and flaking of the skin was observed in the treated groups, with hyperplasia of the sebaceous glands in the dermis,

but otherwise no significant differences were observed between test and control animals. Differences in relative organ

weights were not statistically significant, and ditridecyl adipate did not appear to cause systemic toxicity.

Subchronic Inhalation Toxicity


Groups of 12 F344 rats, gender not specified, were exposed 4 h/day, 5 days/wk, to 25 or 250 mg/m3 diethylhexyl

sebacate for ≤13 wks.85 No adverse systemic or lung effects were observed.

Chronic Oral Toxicity

In a 6-mos study in which rats were dosed intragastrically with ≤2.0 g/kg diethylhexyl adipate, hepatic detoxification appeared depressed at the beginning of the study, while in a 10-mos study, a decrease in central nervous system excitability was noted. Dietary administration of ≤1.25% dibutyl sebacate for 1 yr or ≤6.25% for 2 yrs did not have an effect on growth


Intragastric doses of ≤2.0 g/kg diethylhexyl adipate to rats (number not stated) for 6 mos produced no enzy-matic changes, but levels of sulphydryl compounds in the blood were increased. Hepatic detoxification


35

appeared depressed at the onset of the study, but it was accelerated after 6 mos. Administration of 0.1 g/kg for 10 mos decreased central nervous system excitability. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2

Dibutyl Sebacate

Groups of 5 male and 5 female Sprague-Dawley rats were fed a diet containing 0, 0.01, 0.05, 0.25, or 1.25% dibutyl

sebacate for 1 yr.116 Necropsies were performed whenever rats exhibited significant weight losses or other evidences of

severe concurrent infection. Dibutyl sebacate had no effect on growth or well-being.

The researches then fed groups of 16 male Sprague Dawley rats a diet containing 0.01, 0.05, 0.25, 1.25, or 6.25%

dibutyl sebacate for 2 yrs.116 Two control groups were given untreated feed. Necropsies were performed on 3 rats from each

group after 1yr, and the experiment was terminated at the end of the 2-year feeding period. Interim, animals were killed

whenever they became moribund. In such instances the rats usually had incapacitating tumors or severe intercurrent infec-

tions. Dibutyl sebacate did not adversely affect growth or survival, and it did not produce significant hematological changes

in peripheral blood. As the rats increased in age, slight changes in distribution of leukocytes were found, but these trends

occurred in both the control and treatment groups.

Inhalation Toxicity

In a 4-hr inhalation toxicity study of 5.9 mg/l of a mixture of 66.0% dimethyl glutarate, 16.5% dimethyl succinate, and 17.0% dimethyl adipate, the anterior and posterior nasal passageways were affected. Regeneration of damaged olfactory epithelium was related to the severity of the initial tissue damage.

Dimethyl Glutarate/Dimethyl Succinate/Dimethyl Adipate Mixture

Male Crl:Cd/BR rats were used to study the development of nasal lesions upon exposure to a solvent mixture of

66.0% dimethyl glutarate, 16.5% dimethyl succinate, and 17.0% dimethyl adipate, termed dibasic esters.122 A group of 42

rats were exposed, nose-only, to dibasic esters at an aerosol concentration of 5.9 mg/l for 4 hr, and a negative control group of

24 rats was exposed to air only. The mean dibasic esters aerosol concentration was 5900 mg/m3, and the mass median aero-

dynamic diameter was 3.9 µm. Seven test animals and 4 controls were killed at 1, 4, 7, 14, 21, or 42 days post-exposure.

Three test and 3 control animals were injected i.p. with BrdU 2 h prior to being killed. Both the anterior and posterior nasal

passages were affected. Nasal lesions were distributed along major inspiratory airflow routes, and the lesions were markedly

less severe in the posterior nasal cavity. Regeneration of damaged olfactory epithelium was related to the severity of the

initial tissue damage, with extensively damaged epithelium failing to regain a normal structure at 6 wks. Numerous mitotic

figures and BrdU labeling were found in the regenerating basal cells, stem cells, and sustentacular cells at 4 and 7 days.

Ocular Irritation

Ocular irritation appeared to lessen in severity as chain length of the dicarboxylic acid esters increased. Diethyl malonate was slightly to moderately irritating to rabbit eyes. Dibutyl, diisopropyl, and diethylhexyl adipate were non- or minimal ocular irritants. Diisopropyl sebacate was minimally irritating, while diethylhexyl sebacate was non-irritating to rabbit eyes. Dioctyldodecyl and diisocetyl dodecanedioate were not irritating to rabbit eyes.

Ocular irritation data on esters of dicarboxylic acids are presented in Table 9. Data from the original safety assess-

ments on dibutyl, diisopropyl and diethylhexyl adipate are included in italics. The available ocular irritation data on esterase

metabolites are also summarized in this table.

Diethyl Malonate

The ocular irritation potential of diethyl malonate was evaluated using rabbits, number and gender not specified.14

A volume of 0.1 ml was instilled into the conjunctival sac of one eye, which was not rinsed, and the contralateral eye was

untreated and served as the negative control. Diethyl malonate produced slight to moderate irritation.


36

Dimethyl Malonate

In a similar study as described above, undiluted dimethyl malonate produced slight to moderate irritation in rabbit

eyes.14 All signs of irritation were cleared by day 8.

Dibutyl Adipate

Undiluted dibutyl adipate was minimally irritating to they eyes of rabbits, and 0.1% in olive oil was non-irritating. From the Amended Final Report on Dibutyl Adipate5

Diisopropyl Adipate

The ocular irritation potential of 2 lots of undiluted diisopropyl adipate was evaluated using rabbits. One caused negligible irritation, while the other was non-irritating. A formulation containing 0.7% diisopropyl adipate produced some corneal stippling in rabbit eyes, while a formulation containing 5.0% and one containing 20.75% were non-irritating to rabbit eyes. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2 The ocular irritation of undiluted diisopropyl adipate was evaluated using 3 albino rabbits.114 A volume of 0.1 ml

was instilled into the conjunctival sac of one eye, which was not rinsed. The contralateral eye was untreated and served as the

negative control. Diisopropyl adipate was not irritating.


Undiluted diethylhexyl adipate was non-irritating to rabbit eyes and a formulation containing 0.0175 was, at most, a mild transient irritant. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2


A primary ocular irritation study was performed using 6 New Zealand white to determine the ocular irritation

potential of diisopropyl sebacate.123 A volume o f 0.1 ml was applied to one eye of each animal, which was not rinsed, and

the contralateral eye of each animal served as the control. The average Draize scores were 2.0 at 24 and 48 h, 0.3 at 72 h, and

0.0 at 4 days. Diisopropyl sebacate was a minimal ocular irritant.


The ocular irritation o f a cream containing 1.2% diethylhexyl sebacate was evaluated using the in vitro EpiOcular

MTT viability assay .124 The tissue samples were exposed to undiluted test material for 64 min, 256 min, or 1200 min.

Following treatment, the viability of those tissues were calculated. The ET50 (time for tissue viability to be reduced by 50%)

was 484.9 min, and diethylhexyl sebacate was considered to be non-irritating.

Dioctyldodecyl Dodecanedioate

The primary eye irritation of dioctyldodecyl dodecanedioate was evaluated using 6 albino rabbits.125 A volume of

0.1 ml was applied to one eye of each animal, which was not rinsed. and the contralateral eye served as a negative control.

They eyes were evaluated at 24, 48, and 72 h. At 24 h, the maximum mean total score (MMTS) was 0.00, and dioctyldodecyl

dodecanedioate was considered not irritating.

Diisocetyl Dodecanedioate

The primary eye irritation of diisocetyl dodecanedioate was evaluated using the procedure described above.126 The

MMTS was 0.00, and diisocetyl dodecanedioate was considered not irritating to the eyes of rabbits.

Dermal Irritation

The esters of dicarboxylic acids were mostly non or mildly irritating to rabbits. Some minimal irritation was seen with diisopropyl adipate, undiluted or at 5-20.75% in formulation, and moderate erythema was reported with undiluted dibutyl adipate.


37

Diethyl Malonate

The dermal irritation potential of diethyl malonate was evaluated using a 24 h occlusive application.14 Diethyl

malonate was slightly irritating to rabbit skin.

Dimethyl Malonate Dimethyl malonate was applied undiluted to rabbit skin for 4 h under a semi-occlusive patch.14 Slight erythema was

observed only at 30-60 min after patch removal, and dimethyl malonate was considered non-irritating to rabbit skin.

Dibutyl Adipate

Application of undiluted butyl adipate to rabbit skin resulted in a primary irritation score of 2/8. Undiluted dibutyl adipate caused moderate erythema in rabbits following repeated dermal exposure. However, material impregnated with dibutyl adipate was not irritating to the skin of rabbits. Application of dibutyl adipate at 10% in acetone produced no observable adverse effect when applied to rabbit ears, and no dermal reaction was observed following twice daily application for 14 days to the backs of hairless mice Two perfume formulations containing 1.1% diisopropyl adipate were not primary dermal irritants using rabbits. From the Amended Final Report on Dibutyl Adipate5

Diisopropyl Adipate

Draize tests of undiluted diisopropyl adipate resulted in, at most, mild irritation of rabbit skin. In Draize tests with formulations containing 5.0% or 20.75% diisopropyl adipate, minimal irritation was reported with both formulations. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2


Undiluted diethylhexyl adipate was a very mild irritant when applied under occlusion to intact and abraded rabbit skin). A formulation containing 0.175% diethylhexyl adipate had an irritation index of 1.6/4. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2

Diisodecyl Adipate

The dermal irritation potential of diisodecyl adipate was determined using 3 albino rabbits.112 Undiluted test

material was applied to the skin for 4 h under a semi-occlusive patch. The erythema scores were 0-1 during 1-72 h, and the

edema scores were 0. Diisodecyl adipate was considered non-irritating to rabbit skin.

Dioctyldodecyl Adipate

The dermal irritation of dioctyldodecyl adipate was evaluated using the same procedure.113 The erythema scores

were 0-2 during 1-72 h, and the edema scores were 0-1. Dioctyldodecyl adipate was considered non-irritating to rabbit skin.

Diisocetyl Adipate

The dermal irritation of diisocetyl adipate was evaluated using the same procedure.111 The erythema scores were 0-2

during 1-72 h, and the edema scores were 0-1. Diisocetyl adipate was considered non-irritating to rabbit skin.

Diethyl Sebacate

Undiluted diethyl sebacate and 30% diethyl sebacate in ethanol were tested on 8 male Japanese White strain rabbits

(gender not specified).127 The flank of the animals was clipped free of hair 1 day prior to application of test substance. The

skin of 4 animals abraded. The test substance, 0.3 ml, was applied occlusively to the back of all animals for 24 h. The skin

reactions were evaluated at 24 h and 72 h. The primary irritation score was 0.0 (none to weak irritant) in undiluted diethyl

sebacate and 0.3 (none to weak irritant) in 30% diethyl sebacate. These results suggest that 100% diethyl sebacate has no

primary skin irritation under these test conditions.


A primary dermal irritation study on diisopropyl sebacate was performed using 6 New Zealand white rabbits.123 A

dermal application of 0.5 ml of undiluted test material was applied to an abraded and an intact site on each animal. The test


38

sites were occluded for 24 h and observed individually for erythema, edema, and other effects 24 and 72 h after application.

Mean scores from the 24 and 72 h reading were averaged to give a primary irritation index (PII) of 2.88. Diisopropyl sebacate

was not considered a primary dermal irritant.

The dermal irritation potential of diisopropyl sebacate was determined using 3 albino rabbits.128 Undiluted test

material was applied to the skin for 4 h under a semi-occlusive patch. The erythema scores were 1 during 1-72 h, and the

edema scores were 0-1. Diisopropyl sebacate was considered non-irritating to rabbit skin.


The dermal irritation potential of diethylhexyl sebacate was evaluated using the same procedure.110 The erythema

scores were 1 during 1-72 h, and the edema scores were 0. Diethylhexyl sebacate was considered non-irritating to rabbit skin.

Patch tests with diethylhexyl sebacate (neat; 48-hr occluded) did not irritate the skin of 2-4 rabbits.1 It was also

reported that diethylhexyl sebacate was non-irritating to the skin of guinea pigs. No further study details were provided

Dermal Sensitization

Dimethyl malonate, dibutyl and diethylhexyl adipate, diethylhexyl sebacate, and dioctyldodecyl dodecanedioate were not sensitizers in guinea pigs or rabbits.

Dimethyl Malonate

Dimethyl malonate was not a sensitizer in a Buehler guinea pig sensitization test.14 Details were not provided.

Dibutyl Adipate

Dibutyl adipate was not a dermal sensitizer in guinea pigs when tested at 25% in a maximization test. From the Amended Final Report on Dibutyl Adipate5


Diethylhexyl adipate, 0.1%, was not a sensitizer in a maximization study using guinea pigs. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2


A limited attempt was made to sensitize a group of 2-4 rabbits by applying diethylhexyl sebacate using occlusive

patches.1 No reactions were seen in an occlusive challenge with the undiluted test article 2 weeks later. Details were not

provided.


A maximization test was performed to evaluate the sensitization potential of dioctyldodecyl dodecanedioate.129 Ten

female guinea pigs were used. The dose used at intradermal injection was 0.1 ml, and 0.5 ml was used for the topical

challenge. Slight erythema was observed at induction, but a sensitization reaction was not observed.

Dermal irritation and sensitization data on esters of dicarboxylic acids are presented in Table 10. Data from the

original safety assessments on dibutyl, diisopropyl and diethylhexyl adipate are included in italics. The available dermal

irritation and sensitization data on esterase metabolites are also summarized in this table.

Phototoxicity

Diisopropyl Adipate

Two perfume formulations containing 1.1% diisopropyl adipate were not phototoxic using rabbits. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2

Mucous Membrane Irritation


A product containing 0.175% diethylhexyl adipate did not produce mucous membrane irritation in rabbits.


39

From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

Oral administration of up to 1000 mg/kg dimethyl malonate did not have an effect on fertility, and no development toxicity was reported. The NOAEL was 300 mg/kg for repeated dose and maternal toxicity and 1000 mg/kg for fertility and developmental toxicity. Oral administration of up to 100 mg/kg dibutyl adipate did not cause any reproductive effects, and the NOEL for parental and offspring toxicity was 300 mg/kg/day and for reproductive toxicity was 100 mg/kg/day. Oral administration of ≤7000 mg/kg di-C7-9 branched and linear alkyl esters of adipic acid branched and linear alkyl esters of adipic acid did not result in developmental toxicity. Dietary administration of up to 1.2% diethylhexyl adipate did not affect fertility when fed to rats prior to mating. Fetal weight, total litter weight, and litter size were reduced with 1.2% diethylhexyl adipate. In a study in which gravid rats were fed the same doses during gestation, no significant effects on fetal weight or litter size were reported. An increased incidence of minor skeletal abnormalities was attributed to fetotoxicity. . In a study in which diethylhexyl adipate was given orally to rats from day 7 of gestation until post-natal day 17, antiandrogenic effects were not observed, although some increase in post-natal death were observed. Administration of up to 2000 mg/kg diethylhexyl adipate prior to dosing and through day 7 of gestation did have an effect on the mean estrus cycle length at a dose of 1000 and 2000 mg/kg, and did appear to disturb ovulation. Significant decreases were also seen in implantation rate and number of live embryos, as well as an increase in pre-implantation loss. Diethylhexyl adipate did not produce testicular toxic effects when fed at up to 25,000 ppm in the diet for 4 wks. Dietary administration of 6.25% dibutyl sebacate to male and female for 10 wks prior to mating had no adverse effects on fertility, litter size, or survival of offspring. Diethylhexyl sebacate, 200 ppm in the diet, did not produce reproductive or developmental effects.

Dermal applications of up to 2000 mg/kg ditridecyl adipate affected mean fetal body weights and crown-rump lengths. Ditridecyl adipate, 2000 mg/kg, did not have an effect on sperm morphology. Some visceral anomalies were reported. The NOAELs for maternal toxicity and developmental and reproductive effects were 2000 and 800 mg/kg/day, respectively.

Dimethyl, diethyl, dipropyl dibutyl, diisobutyl, and diethylhexyl adipate were evaluated for fetotoxic and terato-genic effects in rats when administered i.p. at 1/3 – 1/30 of the i.p. LD50 values. Some effect on resorptions and abnormalities were seen with all but diethyl adipate.

Inhalation by rats of up to 1.0 mg/l of a mixture of dimethyl glutarate, dimethyl succinate, and dimethyl adipate on days 7-16 of gestation or for 14 days prior to mating, during mating and gestation, and lactation, produced no observed adverse developmental or reproductive effects. The only exception was a statistically significant decrease in pup weight at birth and day 21.

Dimethyl Malonate

The reproductive and developmental toxicity of dimethyl malonate was evaluated using groups of 10 male and 10

female Wistar rats.14 The animals were dosed with 0, 100, 300, or 1000 mg/kg dimethyl malonate orally, by gavage. Males

were dosed for 2 wks prior to mating, during mating, and 2 wks after mating, for a total of 39 doses. Females were dosed 2

weeks prior to mating, during mating, and through day 4 of lactation. A recovery group of 5 male and 5 female high dose

animals were observed for 14 days after the termination of dosing. Microscopically, the incidence of treatment-related

hepatocellular hypertrophy of the liver was observed for males and females given 1000 mg/kg dimethyl malonate. This effect

was not observed in the recovery animals or in the other test groups. No other significant toxicological effects were observed.

Performance in a functional observation battery was similar for test and control animals. There was no effect on fertility. An

increase in post-implantation loss was increased in the 100 mg/kg group, resulting in a statistically significant decrease in the

number of live pups. This effect was not considered treatment related, and no developmental toxicity was reported. The

NOAEL was 300 mg/kg for repeated dose and maternal toxicity and 1000 mg/kg for fertility and developmental toxicity.

Dimethyl Adipate

The fetotoxic and teratogenic effects of dimethyl adipate were evaluated in a study in which groups of 5 gravid

Sprague Dawley rats were dosed i.p. with 0.0603-0.6028 ml/kg (1/30, 1/10, 1/5, and 1/3 of the i.p. LD50 value) on days 5, 10,

and 15 of gestation.115 A pooled volume control consisted of animals dosed with 10 ml/kg distilled water, saline, or cotton-


40

seed oil. A positive control group was not used. All animals were killed and examined on day 20 of gestation. The mean

fetal weights and the numbers of live fetuses were not statistically significantly different between treated and blunt-needle

control groups. Resorptions in animals dosed with 0.1809 ml/kg were statistically significantly increased when compared to

the pooled controls, but not the blunt-needle controls. Gross and skeletal abnormalities, but not visceral, were statistically

significantly increased in fetuses of the 0.3617 and 0.6028 ml/kg groups.

Diethyl Adipate

The fetotoxic and teratogenic effects of diethyl adipate were evaluated following the same procedure described

above.115 These rats were dosed i.p. with 0.0837-0.8373 ml/kg diethyl adipate. The mean fetal weight and the number of live

fetuses were not statistically significantly different between treated and blunt-needle control groups, and the number of resorp-

tions was similar between treated animals and both the blunt needle and pooled controls. There were no differences in the

incidences of gross, skeletal, or visceral abnormalities in fetuses of the treated groups compared to pooled controls.

Dipropyl Adipate

The fetotoxic and teratogenic effects of dipropyl adipate were evaluated following the same procedure described

earlier.115 These rats were dosed i.p. with 0.1262-1.2619 ml/kg dipropyl adipate. The numbers of live and dead fetuses were

not statistically significantly different between treated and blunt-needle control groups, but there was a statistically significant

decrease in the mean fetal weight of the 0.7572 ml/kg group. Resorptions in animals dosed with 1.2619 ml/kg were statisti-

cally significantly increased when compared to the pooled controls, but not the blunt-needle controls. Gross abnormalities,

but not skeletal or visceral, were statistically significantly increased in fetuses of the 1.2619 ml/kg group.

Dibutyl Adipate

A reproductive toxicity study was performed in which groups of 5 gravid Sprague Dawley rats were dosed i.p. with 0.1748-1.7480 ml/kg dibutyl adipate on days 5, 10, and 15 of gestation. The incidence of gross abnormalities was only statistically significantly increased in the high dose group when compared to pooled controls. From the Amended Final Report on Dibutyl Adipate5 The reproductive toxicity of dibutyl adipate was evaluated in a study Sprague-Dawley rats.106 Groups of 13 males

and 13 female’s rats were dosed with 0, 100, 300, or 1000 mg/kg dibutyl adipate orally, by gavage, for 14 days prior to

mating through parturition; males were dosed for a total of 42 days and female dams were dosed until day 3 of lactation. The

test article had no effect on fertility. Body weight gains of males of the 1000 mg/kg group were slightly decreased. Kidney

weights of the high dose males and females sere increased compared to controls. No gross or microscopic effects were noted

at necropsy, and the internal genitalia were normal. Dosing with dibutyl adipate did not produce any reproductive effects.

The only effect on the offspring was a decrease in pup weight on post-natal days 0 and 4 and in viability on post-natal day 4.

The NOEL for parental and offspring toxicity was 300 mg/kg/day. The reproductive NOEL was 1000 mg/kg/day.


Groups of 24 gravid Sprague Dawley rats were dosed orally by gavage with 0, 1000, 4000, or 7000 mg/kg/day di-

C7-9 branched and linear alkyl esters of adipic acid on days 6-19 of gestation, and all animals were killed and examined on

day 20.85 All dams survived until study termination. Body weights were significantly decreased for dams of the 7000 mg/kg

group. Weights of male and female fetuses of the 7000 mg/kg group were slightly, but not statistically significantly,

decreased compared to the other groups. A greater incidence of rudimentary structures was observed for high dose fetuses as

compared to the other groups in this study, but the incidence was within the range of historical controls. There was no

evidence of developmental toxicity at any dose tested.


41

Ditridecyl Adipate

The reproductive and developmental toxicity of ditridecyl adipate was evaluated using groups of 15 mated female

Sprague-Dawley rats.85 Doses of 0, 800, and 2000 mg/kg were applied dermally without occlusion on days 0-19 of gestation,

and the dams were killed on day 20. Mild skin irritation consisting of erythema and flaking were observed at the test sites of

the treated animals. No maternal mortality was reported. Weight gains were statistically significantly decreased for the 2000

mg/kg group during days 0-3 and 16-20 of gestation. Weight gain was statistically significantly decreased in the 800 mg/kg

group during days 0-3 of gestation. Mean fetal body weights and crown-rump lengths were affected exposure to the test

article. No differences in skeletal anomalies were observed, but there were some differences in visceral anomalies, including

increased incidence of levocardia at 2000 mg/kg. These anomalies were not considered treatment-related. The NOAEL for

maternal toxicity was 2000 mg/kg/day, and for developmental and reproductive effects it was 800 mg/kg/day.

Groups of 25 mated female rats were dosed dermally with 0 and 2000 mg/kg ditridecyl adipate following the same

study protocol as above. Again, there were no signs of maternal toxicity. No developmental toxicity was reported, and there

were no visceral anomalies.

Tridecyl adipate, 2000 mg/kg, was applied, unoccluded, to groups of 10 male Sprague-Dawley rats, 5 days/wk for

13 wks, and the effect on sperm morphology was evaluated.85 (The 'Subchronic Dermal Toxicity’ study was described

earlier.) No differences in sperm morphology were observed between control and test animals.

Diisobutyl Adipate

The fetotoxic and teratogenic effects of diisobutyl adipate were evaluated following the procedure described in the

earlier i.p. study.115 These rats were dosed i.p. with 0.1983-1.9833 ml/kg diisobutyl adipate. The numbers of live and dead

fetuses were not statistically significantly different between treated and blunt-needle control groups, but there was a statistical-

ly significant decrease in the mean fetal weight of the 1.1900 and 0.9833ml/kg dose groups. The number of resorptions was

similar between treated animals and both the blunt needle and pooled controls. Gross abnormalities, but not skeletal or vis-

ceral, were statistically significantly increased in fetuses of the 0.5950 and 1.9833 ml/kg groups.


The reproductive effects of diethylhexyl adipate were studied in Swiss mice. Groups of 10 male mice were dosed i.p. with ≤9.3 g/kg and then mated with undosed females. A reduction in the number of gravid females was considered an anti-fertility effect, and the dominant lethal mutation was determined directly from the dose-dependent increase in the number of early fetal deaths and indirectly from the dose- and time-dependent decrease in implantations. There were no test article-related changes in the incidence of late fetal deaths. It was noted that the experimental design and interpretation have been questioned by some. Diethylhexyl adipate, ≤9.3 g/kg, was administered by i.p. injection to groups of 5 gravid Sprague Dawley rats on day 5, 10, and 15 of gestation. Resorption rates were similar to controls. A decrease in the mean fetal body weight and a significant increase in gross fetal abnormalities at the high dose were observed when compared to pooled control values. However teratogenic effects were not observed when compared to concurrent controls. It was stated that the lack of historical and positive controls affected the validity of the results. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2 Groups of 15 male and 30 female Wistar rats were fed a diet containing 0, 0.03, 0.18, or 1.2% diethylhexyl adipate

(calculated as 28, 170, or 1080 mg/kg/day) for 10 weeks prior to mating.85 Dosing was terminated, and the animals were

mated. (A different source indicated that dosing continued throughout the study.130) A reduction in body weight gain was

reported during gestation for the dams of the 1.2% group. No test article-related effects on fertility were observed. Fetal

weight, total litter weight, and litter size were reduced in the 1.2% group, but the number of pups born live, or their survival,

was not affected. The NOAEL was 170 mg/kg/day and the LOAEL was 1080 mg/kg/day.


42

In another study in which gravid females were fed the same doses as above on days 1-22 of gestation, maternal body

weight and feed consumption were statistically decreased in the 1.2% group. No significant effects on fetal weight or litter

size were reported. Animals of the 0.18 and 1.2% groups had slightly increased incidences of minor skeletal abnormalities;

this increase was attributed to fetotoxicity. The NOEL for maternal toxicity was 170 mg/kg/day. The NOAELs for develop-

mental toxicity and fetotoxicity were 170 and 28 mg/kg/day, respectively. The LOAEL was 1080 mg/kg day.

A dose-range finding study was performed using groups of 8 gravid Wistar rats that were dosed by gavage with 2

ml/kg of 0, 800, or 1200 mg/day diethylhexyl adipate, in peanut oil, from day 7 of gestation until day 17 after parturition.131

No signs of toxicity were reported in any of the groups. In the 800 mg/kg group, the only statistically significant observation

made was decreased body weights of male and female pups on day 3. In the 1200 mg/kg group, statistically significant effects

were observed for a number of parameters, including decreased maternal weight gain during days 7-21 of gestation, increased

length of gestation (by 1 day), decreased pup body weights at birth and day 3, and an increase in perinatal loss per litter.

(Perinatal loss was 42% in the 1200 mg/kg groups, as compared to 4.6% in controls.)

Based on the results of the dose-range finding study, groups of 20 gravid Wistar rats were dosed with 2 ml/kg of 0,

200, 400, or 800 mg/kg diethylhexyl adipate, in peanut oil, from day 7 of gestation until post-natal day 17. At postnatal day

21, all dams and pups were killed, with the exception that one male and one female pup per litter was kept for further evalua-

tion. No signs of toxicity were reported in any of the groups. No significant effects were observed in the 200 mg/kg group.

In the 400 mg/kg dose groups, the number of postnatal deaths per number of pups was statistically significant increased. In

the 800 mg/kg group, statistically significant effects were observed for a number of parameters, including increased length of

gestation (by 1 day), decreased pup body weights at birth and days 3 and 13, increased mean number of postnatal deaths, and

an increase in postnatal death per number of pups. The percentage of perinatal loss per litter was twice as high in the 400 and

800 mg/kg groups (23%) as compared to controls (11%), but the change was not statistically significant. Testicular testoster-

one levels were unaffected in any of the pups that were killed on postnatal day 21 or the adult male offspring, and all other

hormones that were measured were similar to controls. None of the sperm parameters that were evaluated were affected by

dosing. The only statistically significant effects, noted in the 800 mg/kg group, were increased relative liver weights in male

pups on day 21 and increased body weights and decreased adrenal weights in adult male offspring. Diethylhexyl adipate did

not produce any antiandrogenic effects in the study. Fetal steroidogenesis was not evaluated. NOAEL was 200 mg/kg.

Groups of 10 female Crl:CD(SD) rats were dosed with 5 ml/kg, by gavage, of 0, 200, 1000, or 2000 mg/kg diethyl-

hexyl adipate in corn oil for 2 wks prior to mating with undosed males, throughout mating, and until day 7 of gestation day.120

The dams were killed on day 14 of gestation. All animals survived until study termination. Body weights and body weight

gains were significantly decreased in the 2000 mg/kg dose group prior to mating. Staining around the perineum was observed

in the 1000 and 2000 mg/kg dose groups. No statistically significant differences were observed for the 200 mg/kg group

compared to controls. The mean estrus cycle length was statistically significantly increased in the 1000 and 2000 mg/kg

groups, and the post-implantation loss rate was also statistically significantly increased in these groups. Additionally, in the

2000 mg/kg group, there was a significant decrease in implantation rate, and the number of live embryos was statistically

significantly decreased and the pre-implantation loss rate statistically significantly increased. The researchers stated that the

effects observed in this fertility study, in conjunction with the ovarian effects described earlier in the repeated dose study,

suggest that diethylhexyl adipate disturbed ovulation. This correlated with the effect on estrus cycle length.

The testicular toxicity of diethylhexyl adipate was examined using male F344 rats.132 Groups of six rats were fed a

diet containing 6000 or 25,000 ppm diethylhexyl adipate for 4 wks, and the controls were given untreated feed. Some groups


43

were dosed i.p. with 200 mg/kg thioacetamide, 3x/wk for 4 wks, and prior to dosing with diethylhexyl adipate to evaluate

whether liver disease enhanced testicular effects. (There was a 1-wk rest period prior to dosing with diethylhexyl adipate.)

The final body weights of animals given 25,000 ppm diethylhexyl adipate, with and without prior administration of thioceta-

mide, were statistically significantly decreased compared to their respective controls. The relative liver weights of these

animals were statistically significantly increased. No significant effect on the relative weights of the testes or epididymis were

seen for any of the test groups. Diethylhexyl adipate did not have any testicular toxic effects, with or without the induction of

hepatic damage.

Dibutyl Sebacate

A test group of 20 male and 20 female Sprague-Dawley rats was fed a diet containing 6.25% dibutyl sebacate for 10

wks, while a control group of 12 male and 12 female rats were fed the basal diet, and then animals of each group were then

mated.116 The dams were allowed to deliver their litters, and at weaning, 24 male and 24 female offspring were randomly

chosen, fed the test diet for 21 days, and then killed for necropsy. The study results indicated that ingestion of a diet contain-

ing 6.25% dibutyl sebacate had no adverse effect on fertility, litter size, or survival of offspring. Growth was decreased dur-

ing the pre-weaning and post-weaning periods. However, no gross pathological changes were found among young rats killed

at the end of the 21-day post-weaning period.


Reproduction, suckling and growth were normal in a four-generation study of rats fed a diet containing 200 ppm

diethylhexyl sebacate (~10 mg/kg/day).1 No reproductive or developmental toxicity was observed.

Dimethyl Glutarate/Dimethyl Succinate/Dimethyl Adipate Mixture

The developmental toxicity produced by the inhalation of dibasic esters (mixture of 65.1% dimethyl glutarate, 17.8%

dimethyl succinate, and 16.8% dimethyl adipate) was evaluated in rats.133 Groups of 24 gravid Crl:CD rats were exposed for

6 h/day to 0, 0.16, 0.4, or 1.0 mg/l dibasic esters, by whole body inhalation, on days 7-16 of gestation. The aerosol particle

size in the 1.0 mg/l chamber was 5.3-5.4 µm, with 72-74% of the aerosol <10 µm. The animals were killed on day 21 of

gestation. All animals survived until study termination. Body weight gains were statistically significantly decreased in the 0.4

and 1.0 mg/l groups. Feed consumption by these groups was reduced during the first 6 exposures; statistical significance was

not given. Statistically significant differences in absolute and relative liver weights were not observed, but there was a

significant trend of decreased absolute, but not relative, liver weights. The only significant clinical signs observed were

perinasal staining and wet fur of rats in the 1.0 mg/l group. Reproductive and developmental effects were not observed, and

dibasic esters was not a developmental toxicant in rats following inhalation of ≤1.0 mg/l.

Groups of 20 Crl:CD(SD)BR rats/gender were exposed for 6 h/day, 5 days/wk, to 0, 0.16, 0.40, or 1.0 mg/l dibasic

esters by whole body inhalation for 14 wks prior to mating, and then 7 days/wk for 8 wks of mating, gestation, and lactation. 134 The mean aerosol particle size in the 1.0 mg/l chamber was 6.2 µm, with 69% of the aerosol <10 µm. Exposure was

discontinued from day 109 of gestation through day 3 post-partum. All parental rats and 10 pups/gender were killed and

necropsied on day 21 post-partum. The remaining pups were not necropsied. Maternal body weights in the 0.40 mg/l group

were decreased during the last week of the study, while body weights of male and female rats of the 1.0 mg/l group were

slightly decreased from wk 7 on. Relative liver weights were slightly, but not significantly, decreased in the 0.4 and 1.0 mg/l

groups. Other differences in organ weights were not considered dose-related. With the exception of a statistically significant

decrease in pup body weights at birth and day 21, no reproductive or developmental effects were observed. The only

microscopic findings were squamous metaplasia in the olfactory epithelium of all treated parental rats. This effect was


44

minimal in the 0.16 mg/l group and mild to moderate in the 0.4 and 1.0 mg/ml groups. The NOEL for reproductive

parameters was 1.0 mg/l.

Endocrine Disruption

Diethylhexyl adipate appeared to have endocrine-mediated effects in a 28-day oral study; however, it was stated that the findings may be attributable to the disturbance ovarian function according to the hypothalamic-pituitary-gonad axis.


A 28-day repeated-dose toxicity study was performed to determine whether diethylhexyl adipate has endocrine-

mediated activities.135 Groups of 10 male and 10 female Crj:CD (SD) rats were dosed orally by gavage with 0, 40, 200, or

1000 mg/kg diethylhexyl adipate in corn oil, at a volume of 10 ml/kg, for a minimum of 28 days. In addition to clinical

observations, a functional observation battery was performed during wk 4, estrous cycling was assessed from day 22,

hormone analysis was measured at the end of the test period, and sperm morphology and sperm count were examined. Male

animals were killed and necropsied on day 29, while females were killed and necropsied on days 30-34 when in diestrous.

Signs of toxicity were not observed, and no clinical chemistry or hematological findings were recorded. Hormonal and

spermatological analyses were normal. Statistically significant increased were seen in relative kidney weights in males of the

200 and 1000 mg/kg groups, relative liver weights of males in the 1000 mg/kg group, and in relative liver, kidney, and

adrenal weights in females of the 1000 mg/kg group. Microscopically, increased eosinophilic bodies and hyaline droplets

were seen in the kidneys of male rats of the 1000 mg/kg group. Ovarian follicle atresia was observed in 4 females of the 1000

mg/kg group, accompanied by a prolonged estrous cycle in 2 of these rats. A change in the estrous cycle is an important

endpoint for determination of endocrine-mediated effects in the enhanced TG 407 assay. The researchers stated that this

effect, in conjunction with the microscopic findings, appears to be related to endocrine-mediated effects of diethylhexyl

adipate. However, it was also stated that these finding may be attributable to the disturbance of ovarian function according to

the hypothalamic-pituitary-gonad axis. The changes in relative organ weights were considered toxic effects, and the NOEL

was 40 mg/kg/day.

The effect of diethylhexyl adipate on estrogen receptor and thyroid hormone (TH) functions was also examined.136

The TH-like activity was assessed using the rat pituitary tumor cell line Gh3 expressing intracellular TH and estrogen

receptors and responding to physiological concentration of TH by proliferation. At low potency, diethylhexyl adipate

stimulated the TH- dependent rat pituitary GH3 cell proliferation in a concentration-dependent manner. Cotreatment of GH3

cells with diethylhexyl adipate potentiated the L-3,5,3’-triiodothyronine (T3)-EC50 potentiated the T3-induced GH3 cell

proliferation.

Diisononyl Adipate

In a subchronic dietary study described earlier, groups of male and female beagle dogs were fed 0, 0.3, 1.0, or 3.0%

(wks 1-8) and 6.0% (wks 9-13) diisononyl adipate for 13 wks.85 Reproductive tissues were evaluated. No significant findings

were reported for the 0.3 and 1.0% groups. In the high dose group, testes weight was decreased. At microscopic examina-

tion, it was found that the epididymal ducts were devoid of spermatozoa, the seminiferous tubules were composed of sertoli

cells and spermatogonia, spermatocytes and spermatids were not evident, and there was almost total aspermatogenesis.

Ovaries were not weighed at necropsy. There were no gross or microscopic changes in any of the test groups upon compari-

son to controls.

GENOTOXICITY

The esters of dicarboxylic acids are not mutagenic or genotoxic a battery of in vitro and in vivo tests. The only


45

non-negative results reported were equivocal results in a sister-chromatid exchange assay with ≤400 µg/ml diethylhexyl adipate in the presence of metabolic activation and a dose-dependent inhibition of 3H-thymidine into replicating DNA, with a dose-dependent increase in the ratio of acid-incorporated 3H-thymidine with ≤0.01 M diethylhexyl adipate.. (The same effect was seen in the 3H-thymidine assay with 2-ethylhexanol.)

Diethyl Malonate

Diethyl malonate was not mutagenic in an Ames test or a cytogenetic assay using human peripheral lymphocytes at

concentrations ≤5000 µg/plate.14

Dimethyl Malonate Dimethyl malonate was not mutagenic in an Ames test at concentrations ≤5000 µg/plate.14

Dimethyl Succinate

Dimethyl succinate was not mutagenic in an Ames tests with concentrations of ≤ 20,000 µg/plate137 or in a

preincubation assay with concentrations of ≤10,000 µg/plate.138

Dimethyl Glutarate

Dimethyl glutarate was not mutagenic in a preincubation assay with concentrations of ≤10,000 µg/plate.139

Dimethyl Adipate

Dimethyl adipate was not mutagenic in a preincubation assay with concentrations of ≤10,000 µg/plate.140

Dibutyl Adipate

Dibutyl adipate was mutagenic in an Ames test at concentrations of ≤5000 µg/plate. It was not genotoxic in an in vivo mouse micronucleus assay in which the animals were dosed with ≤2000 mg/kg. From the Amended Final Report on Dibutyl Adipate5


Di-C7-9 branched and linear alkyl esters of adipic acid were not mutagenic in an Ames test at concentrations of

≤10.0 µl/plate.85

Ditridecyl Adipate

Ditridecyl adipate was not mutagenic in an Ames test at concentrations of 0-10 µl/plate, and it was not clastogenic in

an in vivo micronucleus assay using rats dosed dermally with 0, 800, or 2000 mg/kg ditridecyl adipate.85


Diethylhexyl adipate was not mutagenic in an Ames. (The specific concentrations tested were not provided.) From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2 Diethylhexyl adipate was not mutagenic in a number of genotoxicity studies. In vitro, negative results were reported

in Ames tests at concentrations ranging from ≤150 -10,000 µg/plate,85,141-143 in an NTP preincubation assay,144 in a liquid

suspension assay,145 and in a forward mutation assay using L5178Y cells at concentrations ≤1000 µg/ml .146 In an assay for

sister chromatid exchanges and chromosomal aberrations using concentrations of ≤200 µg/plate, results were negative,147

while in another assay with ≤400 µl/plate, results were negative without, but equivocal with, metabolic activation in the sister

chromatid exchange assay and there was some evidence of genotoxicity without, but none with, metabolic activation in the

chromosomal aberration assay.148 In a 3H-thymidine assay, there was a dose-dependent inhibition of 3H-thymidine into repli-

cating DNA, with a dose-dependent increase in the ratio of acid-soluble DNA-incorporated 3H-thymidine.142 In vivo, results

were negative in micronucleus tests85,149 and chromosomal aberration assays.150,151

An Ames test was performed on urine of rats dosed with diethylhexyl adipate to assess whether mutagenic substances

occur in the urine following diethylhexyl adipate adminstration.152 Groups of ≥6 male Sprague-Dawley rats were dosed orally

by gavage with 0 or 2000 mg/kg diethylhexyl adipate in corn oil for 15 days. Urine was collected daily. The urine was not


46

mutagenic in the Ames test, indicating that it is not converted to metabolic urinary metabolites. The urine of rats dosed with

1000 mg/kg 2-ethylhexanol by gavage for 15 days was also tested in an Ames assay. The urine of these rats also was not

mutagenic. Urine from rats that were dosed with a known mutagen gave a positive response in an Ames test.

Diisononyl Adipate

Diisononyl adipate was not mutagenic in an Ames assay at ≤1000 µg/plate, and it was not genotoxic in a mouse

lymphoma assay, a transformation assay, or a BALB/3t3 assay at concentrations of ≤100, 1000, or 1.3 µg/ml, respectively.153

Diethyl Sebacate

Diethyl sebacate was non-mutagenic in an Escherichia coli Sd-4-73 reversion (streptomycin dependence to

independence) assay.154

Dibutyl Sebacate

Dibutyl sebacate, ≤10,000 µg/plate, was not mutagenic in the Ames assay.155,156


Diethylhexyl sebacate was not mutagenic in an Ames assay at concentrations of ≤10,000 µg/plate.141,157 In the rat

liver foci test, diethylhexyl sebacate demonstrated no evidence of activity when administered orally at 500 mg/kg 3x/wk for

11 wks, following a single oral treatment with a known carcinogen.158

Details of the genotoxicity studies on esters of dicarboxylic acids are described in Table 11. Data from the original

safety assessments on dibutyl and diethylhexyl adipate are included in italics. Details of the available genotoxicity data on

esterase metabolites are also summarized in this table.

CARCINOGENICITY

In a 2-yr NTP study, ≤2.5% diethylhexyl adipate did not produce tumors in male or female rats, but it did increase the incidence of hepatocellular adenoma and carcinoma in male and female mice. Diethylhexyl adipate did not cause skin tumors with weekly application of 10 mg to the back of mice in a lifetime study. Other compounds with a 2-ethylhexyl group that have been evaluated for carcinogenicity had some evidence of hepatocarcinogenicity, ranging from very strong to equivocal, in rodents. The IARC has stated that diethylhexyl adipate is not classifiable as to its carcinogenicity in humans. However, feeding of diethylhexyl sebacate to rats for 19mos did not result in carcinogenic effects.


In an NTP carcinogenicity study, administration of ≤25,000 ppm diethylhexyl adipate to rats for 103 wks did not produce carcinogenic effects. However, mice fed the same amount for 103 wks had dose-related body weight reductions and a higher incidence of hepatocellular adenoma and carcinoma than the controls. In another study in which rats were fed ≤2.5% diethylhexyl adipate for 2 yrs, tumor incidence for the test animals was similar to that of controls. The same researchers found no tumors in dogs fed up to 0.2% diethylhexyl adipate for 1 yr. A single 10 mg dose of diethylhexyl adipate given by s.c.. injection was not carcinogenic in mice. In a lifetime study, diethylhexyl adipate caused no skin tumors when 10 mg was applied weekly to the back skin of mice. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2

Research has shown that other compounds with a 2-ethylhexyl group that have been evaluated for carcinogenicity

had some evidence of hepatocarcinogenicity, ranging from very strong to equivocal, in rodents. 121

In an evaluation of the carcinogenic risk of diethylhexyl adipate, the IARC stated that there was limited evidence in

experimental animals for the carcinogenicity of diethylhexyl adipate.17 Therefore, the overall evaluation of diethylhexyl

adipate was not classifiable as to its carcinogenicity to humans (Group 3).


No evidence of carcinogenicity was observed in an unspecified number of rats fed a diet providing about 10 mg

diethylhexyl sebacate/kg/day for up to 19 months.1 No further study details were provided.


47

Tumor Promotion


A group of 14 male F344 rats were used to assess the carcinogenic potential of diethylhexyl adipate in a medium-

term liver bioassay.159 The rats were given a single i.p. dose of diethylnitrosamine, and 2 wks later they were given 20,000

ppm diethylhexyl adipate in the diet. At wk 3, a partial hepatectomy was performed. Positive results for carcinogenic

potential were indicated by a significant increase in GST-P positive foci. Diethylhexyl adipate did not have an enhancing

effect on the development of GST-P-positive foci.

CLINICAL ASSESSMENT OF SAFETY

Human Exposure


Diethylhexyl adipate can migrate into food, and it is most marked when plasticized PVC film comes in direct contact

with fatty foods.88 Using the analyses of a range of typical food, a maximum intake of 16 mg/person/day for diethylhexyl

adipate was estimated. The amount of diethylhexyl adipate used in PVC films was reduced, and the estimate was revised to

8.2 mg/day.

Dibutyl Sebacate

Dibutyl sebacate, a component of PVC, can pass from the packing films to the enclosed food.40

Dermal Irritation and Sensitization

In a number of irritation and sensitization studies, the diesters of dicarboxylic acids are not irritants or sensitizers. The only exception noted was that undiluted diisopropyl adipate was moderately irritating in one cumulative irritancy test, and some slight irritation was seen with formulations containing diethylhexyl adipate.

Dimethyl Malonate

The sensitization potential of 8% dimethyl malonate in petrolatum was evaluated in a maximization test using 25

subjects.14 Dimethyl malonate was not a sensitizer.

Dibutyl Adipate

Undiluted dibutyl adipate was not irritating in a 24-hr clinical patch test with 10 subjects. Slight reactions (not defined) were reported for 4 of 18 subjects in a 24-h patch test with dibutyl adipate, 20% in alcohol. From the Amended Final Report on Dibutyl Adipate5

Diisopropyl Adipate

The dermal irritation and sensitization o f diisopropyl adipate was evaluated in a number of studies. Undiluted diisopropyl adipate produced no irritation in 4 h patch tests, but was moderately irritating in a 21-day cumulative irritancy test. Formulations containing 0.26-20.75% diisopropyl adipate caused minimal to mild irritation, but no sensitization. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2


The dermal irritation and sensitization o f diethylhexyl adipate was evaluated in a number of studies. Clini-cal assessment of diethylhexyl adipate at concentrations of 0.01-9.0% in formulation showed, at most, erythema and papules when applied under occlusion for extended periods of time. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2

Diisostearyl Adipate

A human repeat insult patch test (HRIPT) using 50 subjects was used to evaluate the irritation and sensitization

potential of diisostearyl adipate.160 Two-tenths ml was applied neat to the back of each subject under an occlusive patch for

24 h, after which time the subject removed the patch. This procedure was performed 3 times per wk for 3 wks, for a total of 9


48

induction patches. Following a 10-14 day non-treatment period, a 24 h challenge patch was applied to a previously untreated

site, and reactions were scored at 24 and 48 h. No adverse reactions were observed, and diisostearyl adipate was not a

primary irritant or a sensitizer.

Diethyl Sebacate

A single insult occlusive patch test (SIOPT) was performed using 20 subjects to determine the irritation potential of

a body cream containing 1.5% diethyl sebacate.161 The test patch was applied for 24 h. The PII was 0.00, and the body

cream containing 1.5% diethyl sebacate was non-irritating.

The sensitization potential of a body cream containing 1.5% diethyl sebacate was evaluated in a maximization

study.162 During induction, 0.05 ml of 0.25% aq. sodium lauryl sulfate (SLS) was applied under an occlusive patch for 24 h.

At that time, the patch was removed and 0.05 ml of the test material was applied to the same site under an occlusive patch for

48-72 h. If no irritation was present at the test site upon patch removal, an occlusive patch with 0.25% aq. SLS was applied

for 24 h, followed by a patch of the test material. This sequence was used for 5 induction patches. If irritation developed

during induction, the SLS patch was eliminated. After a 10-day non-treatment period, a challenge was performed at a pre-

viously untreated site. The challenge site was pretreated with 0.05 ml of 5.0% aq. SLS under an occlusive patch for 1 h,

followed by an occlusive patch of the test material for 48 h. Twenty-five subjects completed the study. No reactions were

seen at challenge, and a body cream containing 1.5% diethyl sebacate did not have contact-sensitizing potential.


An SIOPT was performed using 20 subjects to determine the irritation potential of a foundation containing 1.8%

diisopropyl sebacate.163 The patch was applied for 24 h. The foundation containing 1.8% diisopropyl sebacate was not

irritating.

The irritation and sensitization potential of diisopropyl sebacate was evaluated in a patch test that consisted of four

24-h applications of diisopropyl sebacate as supplied (approximately 100%) during weeks 1, 2, 3, and 6 on a 2 cm x2 cm

area of skin on the right upper arm of each subject.164 Examinations were performed immediately after patch removal. The

induction phase was performed during wks 1-4 using 107 subjects. No clinically significant effects were detected on any of

the subjects during this phase. During wk 6, the challenge phase was conducted on 105 subjects. No clinically significant

effects were noted in any of the subjects during this phase. Diisopropyl sebacate was not observed to have any significant

skin-irritating or sensitizing activity under the conditions of this study.

A maximization assay was performed, using a modified protocol of the maximization assay procedure described

earlier, to determine the contact-sensitization potential of a foundation containing 2.2% diisopropyl sebacate.165 In this study,

the test material was allowed to volatilize for 30 min before the occlusive patch was applied. Twenty-five subjects completed

the study. No reactions were seen at challenge, and a foundation containing 2.2% diisopropyl sebacate did not have contact-

sensitizing potential.

Two heat protection hair spray products containing 1% diisopropyl sebacate were tested using a modified Draize

HRIPT procedure to determine the potential of those products to induce irritation and contact sensitization.166 The products

were tested neat and allowed to volatilize prior to patch application. Samples were patched under semi-occlusive conditions.

Approximately 0.2ml was used in each patch. One hundred ten subjects completed the study. Generally transient, barely

perceptible (0.5-level) to mild (1-level) patch test responses on 22 test subjects for one formulation and only barely per-

ceptible (0.5-level) patch test response on 15 test subjects with the other formulation during the induction and/or challenge

phases of the study were reported. Both products were considered to be non-irritating and non-sensitizing.


49

A heat protection hair spray product containing 7.2% diisopropyl sebacate was tested using an HRIPT to determine

the potential of this product to induce irritation and contact sensitization.167 The product was tested neat under semi-occlusive

conditions. Approximately 0.2 ml sample was used in each patch. Fifty-one subjects completed the study. No skin reactivity

was observed in any of the test subjects during the course of the study.


Diethylhexyl sebacate was applied neat using occlusive patches to the skin of 15-30 subjects (sex not specified) for

48-h.1 No local reactions were observed in the challenge phase (48-h covered contact with neat liquid) that was carried out 2

weeks later, presumably due to limited induction.


An HRIPT with 50 subjects was performed to evaluate the irritation and sensitization potential of dioctyldodecyl

dodecanedioate.160 Two-tenths ml was applied to the back of each subject under an occlusive patch for 24 h, after which time

the subject removed the patch. This procedure was performed 3 times per wk for 3 wks, for a total of 9 induction patches.

Following a 10-14 day non-treatment period, a 24 h challenge patch was applied to a previously untreated site, and reactions

were scored at 24 and 48 h. No adverse reactions were observed, and dioctyldodecyl dodecanedioate was not a primary

irritant or a sensitizer.


An HRIPT with 50 subjects was performed as described above to evaluate the irritation and sensitization potential of

diisocetyl dodecanedioate.160 No adverse reactions were observed, and diisocetyl dodecanedioate was not a primary irritant

or a sensitizer.

Clinical dermal irritation and sensitization data on esters of dicarboxylic acids are presented in Table 12. Data from

the original safety assessments on dibutyl, diisopropyl and diethylhexyl adipate are included in italics. The available dermal

irritation and sensitization data on esterase metabolites are also summarized in this table.

Phototoxicity and Photosensitization

A 10% dilution of dibutyl adipate and formulations containing 0.7-17% diisopropyl adipate and 9% diethylhexyl adipate were not phototoxic.

Dibutyl Adipate

Dibutyl adipate, as a 10% dilution in liquid paraffin, was not phototoxic in a clinical study.5

Diisopropyl Adipate

In photopatch test studies, formulations containing 0.7-17.0% diisopropyl adipate were not phototoxic, primary irritants, or sensitizers. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2


In a photopatch test with 9.0% diethylhexyl adipate, no phototoxic or photoallergic reactions were observed. From the Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate2

Ocular Irritation

Dibutyl Adipate

Dibutyl adipate, 0.1% in paraffin oil, was not an ocular irritant in two subjects. From the Amended Final Report on Dibutyl Adipate5


50

Comedogenicity

Dibutyl Adipate

Dibutyl adipate, 10-100% (vehicle not stated), was not comedogenic in clinical testing. From the Amended Final Report on Dibutyl Adipate5

Case Reports

A number of investigators have reported cases of allergic contact dermatitis in response to diethyl sebacate-contain-

ing products, and have demonstrated diethyl sebacate to be the substance, or one of several substances in the products, elicit-

ing the dermatitis.37,168-172 Two case studies were reported of allergic reactions to lotion containing diisopropyl sebacate.173,174

In a case study where one patient was sensitized to other sebacate esters, diethylhexyl sebacate was not irritating.173 For

stearyl alcohol, a metabolite of distearyl succinate, contact sensitization was reported in 3 individuals.175 These case reports

are described in Table 13.

Risk Assessment


According to the Integrated Risk Information System of the EPA, the weight-of-evidence classification for diethyl-

hexyl adipate was “possible human carcinogen”.130 The classification was based on an absence of human data and increased

liver tumors in female mice. The only genotoxic effect was a positive dominant lethal assay. It was noted that diethylhexyl

adipate exhibits structural relationships to other non-genotoxic compounds that are classified as probable and possible

carcinogens.


51

SUMMARY

This safety assessment includes sebacic acid and other alkyl α,ω-dicarboxylic acids, salts, monoesters and diesters,

for a total of 56 ingredients. The dicarboxylic acids are terminally functionalized straight alkyl chains characterized by a

separation between the acid functional groups of one to 10 carbons. The simple alkyl di-esters are the result of the condensa-

tion of alkyl dicarboxylic acids and two equivalents of alkyl alcohols. These ingredients can be metabolized via hydrolysis

back to the parent alcohol, the mono-ester, and the parent dicarboxylic acid. The simple alkyl esters (mono- and di-) of these

dicarboxylic acids have straight or branched side chains ranging in length from one to 18 carbons. This safety assessment is

divided into two parts – (1) the dicarboxylic acids and their salts and (2) esters of dicarboxylic acids

A safety assessment of diethylhexyl adipate and diisopropyl adipate was published in 1984 with the conclusion that

these ingredients are safe as used in cosmetics. Additionally, dibutyl adipate was previously reviewed in 1996 and the avail-

able data were found insufficient to support the safety of dibutyl adipate in cosmetic formulations. When re-reviewed in

2006, additional data were made available to address the needs identified by the CIR Expert Panel, and an amended conclu-

sion was issued stating that dibutyl adipate is safe for use in cosmetic formulations.

While many of the alkyl dicarboxylic acids are natural products, commercial production of these acids has historical-

ly occurred via alkali pyrolysis of lipids.

A relationship exists between the molecular weight and the log octanol – water partioning coefficient. Physical

properties change as chain length increases, and the water solubility of these acids is inversely proportional to their chain

length. Odd versus even chain length also plays a role. The alternating effects are believed to be the result of the inability of

odd carbon number compounds to assume an in-plane orientation of both carboxyl groups with respect to the hydrocarbon

chain. The diesters, in contrast, are much more lipid soluble and more difficult to dissolve in water. The short-chain alkyl

mono- and diesters are more soluble in water, less lipophilic, and relatively more volatile than the corresponding longer-chain

alkyl esters.

The ingredients in this report function in cosmetics as pH-adjusters, fragrance ingredients, plasticizers, skin-condi-

tioning agents and/or solvents and corrosion inhibitors. The majority of the dicarboxylic acids function in cosmetics as pH

adjusters and fragrance ingredients. Six of the 12 dicarboxylic acids and their salts and 24 of the 44 esters included in this

safety assessment are reported to be used in cosmetic formulations. For the dicarboxylic acids and their salts, disodium succi-

nate has the greatest number of reported uses, with a total of 45. The acid with the greatest concentration of use is succinic

acid, 26%; use at this concentration is in rinse-off products. The greatest leave-on concentration is 0.4%, disodium succinate,

with dermal contact exposure. For the esters, diisopropyl adipate has the greatest number of uses, with 70 reported. The con-

centration of use is greatest for dimethyl glutarate, 15% in a dermal rinse-off product. The ingredients with the greatest leave-

on use concentrations, which are all dermal contact exposures, are diethylhexyl adipate, 14%, diisostearyl adipate, 10%, and

diisopropyl sebacate, 10%. With the exception of dipotassium azelate, disodium sebacate, and di-C12-15 alkyl adipate, the

dicarboxylic acids and their salts and esters are listed for use by the European Union (EU) without restriction.

Dicarboxylic Acids and Their Salts Dicarboxylic acids are natural metabolic products of the ω-oxidation of monocarboxylic acids when the β-oxidation

of free fatty acids is impaired. Under normal physiological conditions, dicarboxylic acids are rapidly β-oxidized, resulting in

very low cellular concentrations and practically non-detectable concentrations in the plasma. Oxidation of odd- and even-

numbered chains proceeds to different end points; even chains are completely, while odd-number chains are not completely

oxidized.


52

Unchanged dicarboxylic acid was found in the urine of rats. With oral dosing, approximately 53-67% adipic acid,

40% azelaic acid, and 50% dodecanedioate was recovered with the respective acid. With i.v. dosing, 59-71% adipic acid

and 35% sebacate was recovered. In humans, 6.76-61 adipic acid, and 61% azelaic acid were found in the urine after dosing

with the respective acid. With azelaic acid and dodecanedioic acid, radioactivity was found in all tissues, and it decreased

after 24 h in all tissues except adipose tissue. Radioactivity was found in expired carbon dioxide following dosing adipic acid

(70%), azelaic acid (14.5%), and disodium sebacate (25%). For rats dosed orally with azelaic, sebacic, undecanedioic, and

dodecanedioic acid, 2.5, 2.1, 1.8, and 1.6% of the respective acid was found in the urine unchanged. The amount recovered

decreased with increasing chain length. After oral dosing, 60, 17, 5, and 0.1% of azelaic, sebacic, decanedioic, and undecane-

dioic acids, respectively, were recovered unchanged in the urine. In the plasma of both animals and humans, dicarboxylic

acid catabolites that were 2-, 4-, or 6- carbons shorter than the corresponding dicarboxylic acid were found.

Adipic acid did not induce peroxisome proliferation. Dicarboxylic acids did have some cellular effects and inhibited

mitochondrial oxidoreductases, reversibly inhibited microsomal NADPH and cytochrome P450 reductase ,and competitively

inhibited tyrosinase in vitro.

The oral LD50 values of the dicarboxylic acids for rats ranged from 0.94 g/kg adipic acid (although most reported

values were >5 g/kg) to ≥4 g/kg azelaic acid. The reported dermal LD50 values ranged from >6 g/kg dodecanedioic acid to

>10 g/kg glutaric acid.

In short-term oral toxicity studies, ≤3000 mg/kg/day adipic acid did not produce significant toxicological effects in

rats. Signs of toxicity were seen at >3600 mg/kg/day. No toxicity was observed with guinea pigs fed 400-600 mg/day azelaic

acid. Short-term inhalation exposure to 126 mg/m3 adipic acid to rats did not produce signs of toxicity, but exposure of mice

to 460 mg/m3 did.

In a subchronic oral study, 10 male and 10 female rats exposed to 10% sodium succinate in the drinking water died,

but no compound-related lesions were found. Body weights were decreased in rats given ≥2.5% sodium succinate for 13 wks,

but toxicological treatment-related changes were not observed. Glutaric acid ad a low degree of toxicity to rats (at 2%) and

dogs (concentration not specified) when given in the drinking water. Dietary administration of ≤3400 mg/kg/day adipic acid

for 19 wks produced slight effects in the liver of male rats; the NOAEL was 3333 mg/kg. A mixture of adipic, glutaric, and

succinic acids had a low degree of toxicity in rats when tested at 3% for 90-days. Signs of toxicity were reported in a sub-

chronic inhalation study in which mice were exposed to 13 or 120 mg/m3 adipic acid.

A low degree of toxicity to sodium succinate was observed in a 2 yr oral study using rats. Slight effects were seen in

the livers of rats fed ≤3200 mg/kg/day adipic acid for 33 wks, and the NOAEL for rats fed a diet containing adipic acid for 2

yrs was 1%; no significant toxicological effects were seen at concentrations of ≤5%. No significant toxicological effects were

observed for mice fed ≤280 mg/kg or rabbits fed ≤400 mg/kg azelaic acid for 180 days. Disodium sebacate was not not toxic

to rats or rabbits fed up to 1000 mg/kg for 6 mos.

For the dicarboxylic acids, the severity of ocular irritation seems to decrease with increasing carbon number. Suc-

cinic acid was a severe ocular irritant, glutaric acid was moderately irritating, and dodecanedioic acid was a slight irritant.

Ocular irritation produced by adipic acid was dose-dependent. Slight to mild dermal irritation was observed for the succinic,

glutaric, and adipic acid. Adipic acid, dodecanedioic acid, and a mixture of succinic, glutaric, and adipic acids are not

sensitizers.

Reproductive and developmental effects were not seen upon oral dosing with the dicarboxylic acids or disodium

sebacate. Malonic acid has a spermicidal effect on human spermatozoa. Glutaric acid was tested at doses of ≤1300 mg/kg in


53

rats and 500 mg/kg in rabbits, adipic acid at doses of ≤263 mg/kg in mice, 288 mg/kg in rats, 205 mg/kg in hamsters, or 250

mg/kg in rabbits, azelaic acid at doses of ≤140 mg/kg in rats and 200 mg/kg in rabbits, disodium sebacate at 500 mg/kg in rats

and 1000 mg/kg in rabbits, and dodecanedioic acid was tested at ≤1000 mg/kg using rats. Embryotoxic effects were reported

for in a reproductive study of 2500 mg/kg/day azelaic acid using rats and in reproductive studies with ≤500 mg/kg/day azelaic

acid using rabbits and monkey. Sodium salts of some dicarboxylic acid had a specific inhibitory effect on the uterine horn,

and this effect progressively increased with chain length.

The dicarboxylic acids are not genotoxic, and consistently were not mutagenic in Ames tests. Positive result were

seen in a transformation assay on glutaric acid using Balb/c-3T3 cells, both with and without metabolic activation. The

results of a mouse lymphoma assay, with and without metabolic activation, on glutaric acid was pH-dependent. Equivocal

results were obtained in an in vitro chromosomal aberration assay of ≤15 mg/mg disodium succinate using Chinese hamster

fibroblast cells. The dicarboxylic acids were not genotoxic in in vivo assays.

Carcinogenic results were not seen in rats given up to 2% sodium succinate in the drinking water or 5% adipic acid

in feed for 2 yrs. An increase in the incidence of C-cell adenoma/carcinoma of the thyroid in females given 2% sodium

succinate, and a positive trend in the occurrence of this tumor, was considered a function of experimental variability and not

related to dosing.

In a cumulative irritancy test, the cumulative irritation of a 15% azelaic acid gel increased with successive patching.

It is not known if the vehicle played a role in the irritation scores. Daily application of a 20% azelaic cream causes erythema

and irritation.

Esters of Dicarboxylic Acids

The metabolism of diesters in animals is expected to occur, initially, via enzymatic hydrolysis, leading to the corre-

sponding dicarboxylic acids and the corresponding linear or branched alcohol. These dicarboxylic acids and alcohols can be

further metabolized or conjugated to polar products that are excreted in urine, or, the enzymatic hydrolysis may be

incomplete and result, at least for some diesters, in the production of monoesters.

In vitro using pig skin, 8.8 and 3% of undiluted diethyl malonate was found in the skin and receptor fluid, respective-

ly, 30 and 10% of diethyl malonate in ethanol was found in the skin and receptor fluid, respectively, and 0.2-0.9 and 0.2-1.6%

diethyl malonate in acetone was found in the skin are receptor fluid, respectively. Using human skin, 16% of the applied di-

ethyl malonate penetrated. In vivo, absorption of diethyl malonate, estimated from urinary and fecal recovery, was 15% in

nude mice, 4 % in human skin grafted to nude mice, 6% in pig skin grafted to nude mice, 2.5% in pigs, and 4% in dogs.

Approximately 11% of ditridecyl adipate was absorbed through the skin of rats; 5.5-7.4% of the applied dose was

found in the tissues, 3.5-4.7%was found in the urine, and 0.4-0.7% was found in the feces. Prior dosing with ditridecyl

adipate did not significantly affect absorption.

In vitro, diethylhexyl adipate was readily hydrolyzed to MEHA or adipic acid in rat liver, pancreas, and small

intestine tissue preparations. In animals, diethylhexyl adipate is hydrolyzed to adipic acid and 2-ethylhexanol or MEHA. 2-

Ethylhexanol is converted to 2-ethylhexanoic acid, which may form a glucuronide conjugate or may be subjected to ω- and

(ω-1)-oxidation and further metabolism. More than 98% of diethylhexyl adipate administered orally to rats was excreted in

48 h; 21-45% of the radioactivity was expired in carbon dioxide and 34-52% was excreted in the urine. Diethylhexyl adipate

and MEHA are not found in the blood or urine; diethylhexyl adipate or the metabolites are recovered in the tissues. Metabo-

lism studies have shown that excretion in the urine is not as unchanged diethylhexyl adipate; mostly adipic acid is found. In

humans, peak urinary elimination of all metabolites occurred within 8 h of dosing.


54

Diethylhexyl sebacate is not readily absorbed through the skin of guinea pigs. Metabolism in rodents and humans

may follow partially common pathways, producing 2-ethylhexanol as an intermediary metabolite.

Peroxisome proliferation causes an increase in liver weights and can induce hepatocarcinogenicity in rats and mice.

Diethylhexyl adipate is a peroxisome proliferator requiring extensive phase I metabolism to produce the proximate peroxi-

some proliferator, which in both mice and rats appears to be 2-ethylhexanoic acid. Studies conducted to explain the species

difference in liver tumors seen in mice, but not rats, in the NTP carcinogenicity study on diethylhexyl adipate suggested that

diethylhexyl adipate-induce cell replication, rather than hepatic peroxisome proliferation, provided a better correlation with

tumor formation. Diethylhexyl adipate is not as potent a proliferator as diethylhexyl phthalate. Peroxisome proliferation is

not believed to pose the risk of inducing hepatocarcinogenesis in humans.

Diethylhexyl adipate did not bind covalently to hepatic DNA in mice. It did stimulate DNA synthesis in livers of

rats. In another study, a significant increase in 8-OH-dG was seen in rat liver, but not kidney DNA. The IARC remarked that

the weight of evidence for diethylhexyl adipate demonstrated that rodent, peroxisome proliferators do not act as direct DNA-

damaging agents.

The oral and dermal LD50 values of esters of dicarboxylic acids are greater than 2 g/kg. Mostly, acute exposure via

inhalation to diethyl malonate, dibutyl adipate, and diethylhexyl sebacate did not result in death of rats

Oral administration of ≤1000 mg/kg dibutyl adipate for 28 days was not toxic effects in rats. In short-term oral dos-

ing with diethylhexyl adipate, decreased weight gain was reported for rats and mice. The NOELs for rats and mice were 2

and 0.63%, respectively, in feed; administration of 10% in feed killed 5/5 female mice. In 2- and 4-wk studies of diethylhexyl

adipate, the oral NOAEL for ovarian toxicity was 200 mg/kg in rats; an increase in atresia of the large follicle and a decrease

in currently formed corpora lutea were seen in females dosed with 1000 and 2000 mg/kg diethylhexyl adipate.

In a short-term dermal study in which 10 rabbits were dosed dermally with 0.5 or 1.0 ml/kg of a 20% dispersion of

dibutyl adipate for 6 wks, there was a significant reduction in body weights in the high dose group, and renal lesions in one

animal of each group. There were no signs of toxicity in guinea pigs in an immersion study with 20.75% diisopropyl adipate,

diluted to an actual concentration of 0.10% adipate. Dermal administration of diethylhexyl adipate to rabbits for 2 wks

resulted in slight to moderate erythema at the test site, but toxic effects were not reported for most of the animals.

In a subchronic oral toxicity study using rats, the NOEL for diethyl malonate was 1000 mg/kg/day. Dietary admini-

stration of ≤2.5% di-C7-9 branched and linear alkyl esters of adipic (approx. 1500 and 1900 mg/kg/day for males and

females, respectively) for 90 days did not result in systemic toxicity. The NOAELS for male and female rats were 1500 and

1950 mg/kg/day, respectively. Subchronic oral administration of diethylhexyl adipate to rats caused significant decreases in

body weight gains and increases in liver and kidney weights. The dietary NOEL for rats in a 90-day study was 610 mg/kg. In

mice, no lesions were induced by dietary administration of ≤25,000 ppm diethylhexyl adipate for 13 wks. A decrease in body

weights was seen in mice fed a diet with 1.2 and 2.5% diethylhexyl adipate. For diisononyl adipate, dietary administration of

up to 500 mg/kg for 13 wks, a statistically significant increase in relative kidney weights was reported, but there were not

toxicological findings. With dogs, 3.0% dietary diisononyl adipate resulted in a decrease in body weights, testes weight, and

feed consumption, increased liver weight, elevated enzyme levels, liver and kidney discoloration, and microscopic changes in

the liver, testes, spleen, and kidneys.

No adverse effects were reported with whole-body application of an 6.25% emulsion of dibutyl adipate to dogs for 3

mos. Unoccluded dermal application of up to 2000 mg/kg ditridecyl adipate for 13 wks to rats produced slight erythema, but

no systemic toxicity.


55

In a 6-mos study in which rats were dosed intragastrically with diethylhexyl adipate, hepatic detoxification appeared

depressed at the beginning of the study, while in a 10-mos study, a decrease in central nervous system excitability was noted.

Dietary administration of ≤1.25% dibutyl sebacate for 1 yr or ≤6.25% for 2 yrs did not have an effect on growth

In a 4-hr inhalation toxicity study of 5.9 mg/l of a mixture of 66.0% dimethyl glutarate, 16.5% dimethyl succinate,

and 17.0% dimethyl adipate, the anterior and posterior nasal passageways were affected. Regeneration of damaged olfactory

epithelium was related to the severity of the initial tissue damage. In a 13-wk study with ≤250 mg/m3 diethylhexyl sebacate,

no systemic or lung effects were observed.

Ocular irritation appeared to lessen in severity as chain length of the dicarboxylic acid esters increased. Diethyl

malonate was slightly to moderately irritating to rabbit eyes. Dibutyl, diisopropyl, and diethylhexyl adipate were non- or min-

imal ocular irritants. Diisopropyl sebacate was minimally irritating, while diethylhexyl sebacate was non-irritating to rabbit

eyes. Dioctyldodecyl and diisocetyl dodecanedioate were not irritating to rabbit eyes.

The esters of dicarboxylic acids were mostly non or mildly irritating to rabbits. Some minimal irritation was seen

with diisopropyl adipate, undiluted or at 5-20.75% in formulation, and moderate erythema was reported with undiluted dibutyl

adipate. Dimethyl malonate, dibutyl and diethylhexyl adipate, diethylhexyl sebacate, and dioctyldodecyl dodecanedioate

were not sensitizers in guinea pigs or rabbits. Perfume formulations containing 1.1% diisopropyl adipate were not phototoxic.

Oral administration of up to 1000 mg/kg dimethyl malonate did not have an effect on fertility, and no development

toxicity was reported. The NOAEL was 300 mg/kg for repeated dose and maternal toxicity and 1000 mg/kg for fertility and

developmental toxicity. Oral administration of up to 100 mg/kg dibutyl adipate did not cause any reproductive effects, and

the NOEL for parental and offspring toxicity was 300 mg/kg/day and for reproductive toxicity was 100 mg/kg/day. Oral

administration of ≤7000 mg/kg di-C7-9 branched and linear alkyl esters of adipic acid branched and linear alkyl esters of

adipic acid did not result in developmental toxicity. Dietary administration of up to 1.2% diethylhexyl adipate did not affect

fertility when fed to rats prior to mating. Fetal weight, total litter weight, and litter size were reduced with 1.2% diethylhexyl

adipate. In a study in which gravid rats were fed the same doses during gestation, no significant effects on fetal weight or

litter size were reported. An increased incidence of minor skeletal abnormalities was attributed to fetotoxicity. . In a study in

which diethylhexyl adipate was given orally to rats from day 7 of gestation until post-natal day 17, antiandrogenic effects

were not observed, although some increase in post-natal death were observed. Administration of up to 2000 mg/kg diethyl-

hexyl adipate prior to dosing and through day 7 of gestation did have an effect on the mean estrus cycle length at a dose of

1000 and 2000 mg/kg, and did appear to disturb ovulation. Significant decreases were also seen in implantation rate and

number of live embryos, as well as an increase in pre-implantation loss. Diethylhexyl adipate did not produce testicular toxic

effects when fed at up to 25,000 ppm in the diet for 4 wks. Dietary administration of 6.25% dibutyl sebacate to male and fe-

male for 10 wks prior to mating had no adverse effects on fertility, litter size, or survival of offspring. Diethylhexyl sebacate,

200 ppm in the diet, did not produce reproductive or developmental effects.

Dermal applications of up to 2000 mg/kg ditridecyl adipate affected mean fetal body weights and crown-rump

lengths. Ditridecyl adipate, 2000 mg/kg, did not have an effect on sperm morphology. Some visceral anomalies were

reported. The NOAELs for maternal toxicity and developmental and reproductive effects were 2000 and 800 mg/kg/day,

respectively.

Dimethyl, diethyl, dipropyl dibutyl, diisobutyl, and diethylhexyl adipate were evaluated for fetotoxic and teratogenic

effects in rats when administered i.p. at 1/3 – 1/30 of the i.p. LD50 values. Some effect on resorptions and abnormalities were

seen with all but diethyl adipate.


56

Inhalation by rats of ≤1.0 mg/l of a mixture of dimethyl glutarate, dimethyl succinate, and dimethyl adipate on days

7-16 of gestation or for 14 days prior to mating, during mating and gestation, and lactation, no adverse developmental or re-

productive effects were observed. The only exception was a statistically significant decrease in pup weight at birth and day

21.

Diethylhexyl adipate appeared to have endocrine-mediated effects in a 28-day oral study; however, it was stated that

the findings may be attributable to the disturbance ovarian function according to the hypothalamic-pituitary-gonad axis.

The esters of dicarboxylic acids are not mutagenic or genotoxic a battery of in vitro and in vivo tests. The only non-

negative results reported were equivocal results in a sister-chromatid exchange assay with ≤400 µg/ml diethylhexyl adipate in

the presence of metabolic activation and a dose-dependent inhibition of 3H-thymidine into replicating DNA, with a dose-

dependent increase in the ratio of acid-incorporated 3H-thymidine with ≤0.01 M diethylhexyl adipate.. (The same effect was

seen in the 3H-thymidine assay with 2-ethylhexanol.)

In a 2-yr NTP study, ≤2.5% diethylhexyl adipate did not produce tumors in male or female rats, but it did increase

the incidence of hepatocellular adenoma and carcinoma in male and female mice. Diethylhexyl adipate did not cause skin

tumors with weekly application of 10 mg to the back of mice in a lifetime study. Other compounds with a 2-ethylhexyl group

that have been evaluated for carcinogenicity had some evidence of hepatocarcinogenicity, ranging from very strong to

equivocal, in rodents. The IARC has sated that diethylhexyl adipate is not classifiable as to its carcinogenicity in humans.

However, feeding of diethylhexyl sebacate to rats for 19mos did not result in carcinogenic effects.

In a number of irritation and sensitization studies, the diesters of dicarboxylic acids are not irritants or sensitizers.

The only exception noted was that undiluted diisopropyl adipate was moderately irritating in one cumulative irritancy test, and

some slight irritation was seen with formulations containing diethylhexyl adipate. A 10% dilution of dibutyl adipate and

formulations containing 0.7-17% diisopropyl adipate and 9% diethylhexyl adipate were not phototoxic.

Cases of allergic contact dermatitis in response to diethyl sebacate-containing products have been reported, and it

has been demonstrated diethyl sebacate was the substance, or one of several substances in the products, eliciting the derma-

titis. Two case studies were reported of allergic reactions to lotion containing diisopropyl sebacate.

According to the Integrated Risk Information System of the EPA, the weight-of-evidence classification for diethyl-

hexyl adipate was “possible human carcinogen”. The classification was based on an absence of human data and increased

liver tumors in female mice.

DISCUSSION

To be determined at the meeting.

CONCLUSION

To be determined at the meeting.


57

REFERENCES

1. BIBRA Working Group. 1996. Diethylhexyl Sebacate Toxicity Profile. 6 pages.

2. Elder RL,ed. Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate. J Am Coll Toxicol. 1984;3:(3):101-129.

3. Andersen FA (ed). Annual review of Cosmetic Ingredient Safey Assessments - 2002/2003. Int J Toxicol. 2005;24:(Suppl 1):1-102.

4. Andersen FA (ed). Annual review of Cosmetic Ingredient Safety Assessments - 2004/2005. Int J Toxicol. 2006;25:(Suppl 1):1-89.

5. Andersen FA,ed. Amended final report of the safety assessment of dibutyl adipate as used in cosmetics. Int J Toxicol. 2006;25:(Suppl 1):129-134.

6. Vasihtha, A. K, Trivedi, R. K., and Das, G. Sebacic Acid and 2-Octanol from Castor Oil. Journal of the American Oil Chemists' Society. 1990;67:(5):333-337.

7. Editor: Kroschwitz, J. Concise Encyclopedia od Chemical Technology. 4th ed. 2001.

8. Nghiem NP, Davison BH, and Thomspon JE. Effect of biotin on the production of succinic acid by anaerobiospirillum succinicproducents. Gov't Reports Announcements & Index. Appl.Biochem.Biotechnol. 1995;633:57-58.

9. Kadesch, Richard G. Dibasic Acids. Journal of the American Oil Chemists' Society. 1954;31:568-573.

10. Breathnach, A. S. Azelaic Acid - Biological Activities and Therapeutic Applications. Drugs of Today. 1989;25:(7):463-472.

11. Aditya K.Gupta, Melissa D. Gover. Azelaic acid (15% gel) in the treatment of acne rosacea. International Journal of Dermatology. 2007;46:(5):533-538.

12. Kadesch, Richard G. Dibasic Acids. Journal of the American Oil Chemists' Society. 1954;31:(11):568-573.

13. Ayorinde et al. Synthesis of Dodecanedioic Acid from Vernonia galamensis Oil. Jounal of the American Oil Chemists' Society. 1989;66:(5):690.

14. Organisation for Economic Co-Operation and Development.SIDS Initial Assessment for SIAM 22 -Malonic Acid Diesters, Dimethylmalonate, 108-59-8, and Diethylmalonate, 105-53-3. 2005. http://www.chem.unep.ch/irptc/sids/OECDSIDS/Malonates.pdf. Accessed 7-29-2010.

15. Gattermann, T. Wieland. Praxis des Organischen Chemikers. 40th ed. 1961.

16. Cognis Deutchsland GmbH & Co. 2002. Data Profile: Cetiol® B. 4 pages.

17. International Agency for Research on Cancer (IARC). Di(2-ethylhexyl) adipate. IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans. 2000;77:149-175.

18. American Chemistry Council Aliphatic Esters Diesters Task Group.High Production Volume (HPV) Chemical Challenge Program test plan for th diesters category of the aliphatic esters chemicals. Dated June 2, 2010. 6-28-2010. http://www.epa.gov/oppt/chemrtk/pubs/summaries/alipestr/c13466rt8.pdf. Accessed 7-8-0010.

19. Kvatadze MK. The gas-chromatographic detection of Sebacic Acid in the air. Gig.Tr.Prof.Zabol. 1989;9:45-46.

20. Hokoku Corporation. Impurity data on diisopropyl sebacate. Unpublished data submitted by the Personal Care Products Council (1 p). 2010.

21. Cognis Deutchsland GmbH & Co. 2002. Cetiol® B Toxicological Evaluation. 8 pages.


58

22. Gottschalck TE and Bailey J, eds. International Cosmetic Ingredient Dictionary and Handbook. 2010. 13:(1-3):Washington DC: Personal Care Products Council.2977.

23. Food and Drug Administration.Frequency of use of cosmetic ingredients. 2010.

24. James, A. C., Stahlhofen, W, Rudolf, G, Kobrich, R, Briant, J. K., Egan, M. J., Nixon, W, and Birchall, A. Annexe D. Deposition of inhaled particles. Annals of the ICRP. 1994;24:(1-3):231-2.

25. Oberdorster, G, Oberdorster, E, and Oberdorster, J. Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles. Environmental Health Perspectives. 2005;113:(7):823-839.

26. Bower, D. 1999. Unpublished information on hair spray particle sizes provided at the September 9, 1999 CIR Expert Panel meeting.

27. Johnson, M. A. The Influence of Particle Size. Spray Technology and Marketing. 2004;November:24-27.

28. European Commission.Cosing database on cosmetic ingredient and substances. 2010. http://ec.europa.eu/consumers/cosmetics/cosing/. Accessed 7-27-2010.

29. Dekker. Ingredients. The Chemistry and Manufacture of Cosmetics. 1999. III:(2):


31. The Merck Index. 2009. http://themerckindex.cambridgesoft.com/TheMerckIndex/index.asp. Accessed 10-20-2009.

32. Food and Drug Administration.GRAS status sof succinic acid. 10-31-2006. http://www.accessdata.fda.gov/scripts/fcn/fcnDetailNavigation.cfm?rpt=scogsListing&id=339. Accessed 7-28-2010.

33. Food and Drug Administration.GRAS status of adipic acid. 10-31-2006. http://www.accessdata.fda.gov/scripts/fcn/fcnDetailNavigation.cfm?rpt=scogsListing&id=9.

34. Food and Drug Administration.Azelaic Acid 20% Cream – Drug Approval Label. 1999. http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/20428slr016_azelex_lbl.pdf.

35. Food and Drug Administration.Azelaic Acid 15% Gel – Drug Approval Label. 2003. http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021470s003lbl.pdf.

36. Jung, H. W., Tschaplinski, T. J., Wang, L., Glazebrook, J., and Greenberg, J. T. Priming in Systemic Plant Immunity. Science. 2009;324:(5923):89-91.

37. Schneider KW. Contact dermatitis due to diethyl sebacate. Cont.Derm. 1980;6:506-507.

38. Shikani AH, Eisele DW, and Domb AJ. Polymer delivery of chemotherapy for squamous cell carcinoma of the head and neck. Arch.Otolaryngol.Head and Neck Surg. 1994;120:1242-1247.

39. Bergman K and Albanus L. Di-(2-ethylhexyl) adipate: absorption, autoradiographic distribution and elimination in mice and rats. Fd Chem Toxicol. 1987;25:(4):309-316.

40. Mochida K, Gomyoda M, and Fujita T. Acetyl tributyl citrate and Dibutyl Sebacate inhibit the growth of cultured mammalian cells. Bulletin of Environ.Contamin.and Toxicol. 1996;56:635-637.

41. Greco AV and Mingrone G. Dicarboxylic acids, an alternate fuel substrate in parental nutrition: an update. Clin.Nutr. 1995;14:143-148.

42. Bertuzzi A, Gandolfi A, Salinari S, Mingrone G, and Greco AV. Pharmacokinetics of dicarboxylic acids in man. Engng Med Biol. 1994;13:472-478.


59

43. Nguyen, Q. H. and Bui, T. P. Azelaic acid: pharmacokinetic and pharmacodynamic properties and its therapeutic role in hyperpigmentary disorders and acne. Int.J.Dermatol. 1995;34:(2):75-84.

44. Organisation for Economic Co-Operation and Development.IUCLID Data Set for Adipic Acid. 2-15-2006. http://www.chem.unep.ch/irptc/sids/OECDSIDS/124049.pdf. Accessed 7-29-2010.

45. Kennedy GL. Toxicity of adipic acid. Drug.Chem.Toxicol. 2002;25:191-202.

46. Passi S, Nazzaro-Porro M, Picardo M, Mingrone G, and Fasella P. Metabolism of straight saturated medium chain length (C9 to C12) dicarboxylic acids. J Lipid Res. 1983;24:1140-1147.

47. Akhavan A and Bershad S. Topical acne drugs: review of clinical properties, systemic exposure, and safety. Am.J.Clin.Dermatol. 2003;4:473-492.

48. Allergan Inc. 2004. Package Insert: AZELEX – Azelaic Acid cream (20%).

49. Passi S. Pharmacology and pharmacokinetics of azelaic acid. (Secondary reference in Breathnach 1999). Rev Comtemp Pharmacother. 1993;4:441-447.

50. Täuber U, Weiss C, and Matthes H. Percutaneous absorption of azelaic acid in humans. Exp Dermatol. 1992;1:176-179.

51. Tataranni PA, Mingrone G, DeGaetano A, Raguso C, and Greco AV. Tracer study of metabolism and tissue distributon of sebacic acid in rats. Ann Mutr Metab. 1992;36:296-303.

52. Favuzzi AM, Mingrone G, Bertuzzi A, and et al. Pharmacokinetics of Sebacic Acid in rats. Eur Rev Med Pharmacol Sci. 1999;3:119-125.

53. Mingrone G, Greco AV, Castegneto M, De Gaetano A, Raguso C, and et al. Tissue uptake and oxdation of Disodium Sebacate in man. J.Parenter.Enteral.Nutr. 1991;15:(4):454-459.

54. Greco AV, Mingrone G, Raguso C, and et al. Metabolic effects and disposition of sebacate, an laternate dicarboxylic fuel substrate. Ann.Nutr.Metab. 1992;36:1-11.

55. Mingrone, G., Tacchino, R. M., Castagneto, M., Finotti, E., and Greco, A. V. Use of even-numbered carbon atom dicarboxylic salts in parenteral nutrition as fuel substrate. JPEN J.Parenter.Enteral Nutr. 1992;16:32-38.

56. Mingrone G, Greco AV, Tataranni PA, DeGaetano A, and Castagneto M. Pharmacokinetic profile of dodecanedioic acid, a proposed alternative fuel substrate. JPEN. 1994;18:225-230.

57. Del Rosso, J. Q., Lehman, P. A., and Raney, S. G. Impact of order of application of moisturizers on percutaneous absorption kinetics: evaluation of sequential application of moisturizer lotions and azelaic acid gel 15% using a human skin model. Cutis. 2009;83:119-124.

58. Moody DE and Reddy, J. K. Hepatic peroxisome (microbody) proliferation in rats fed plasticizers and related compounds. Toxicol Appl Pharmacol. 1978;45:497-504.

59. Robins, E. J., Breathnach, A. S., Ward, B. J., Bhasin, Y. P., Ethridge, L., Nazzaro-Porro, M., Passi, S., and Picardo, M. Effect of dicarboxylic acids on Harding-Passey and Cloudman S91 melanoma cells in tissue culture. J.Invest Dermatol. 1985;85:(3):216-221.

60. Passi S, Picardo M, Mingrone G, Breathnach AS, and Navarro-Porro M.Azelaic Acid - biochemistry and metabolism. 1989.

61. Detmar, M., Mayer-da-Silva, A., Stadler, R., and Orfanos, C. E. Effects of azelaic acid on proliferation and ultrastructure of mouse keratinocytes in vitro. J.Invest Dermatol. 1989;93:(1):70-74.

62. Nazzaro-Porro, M., Passi, S., Zina, G., Bernengo, A., and Breathnach, A. Effect of azelaic acid on human malignant melanoma. Lancet. 1980;1:1109-1111.


60

63. Breathnach, A. S. Azelaic acid: potential as a general antitumoural agent. Med.Hypotheses. 1999;52:(3):221-226.

64. Greco AV, Mingrone G, Arcieri Mastromattei E, Finotti E, and Castegneto M. Toxicity of Disodium Sebacate. Drug Exp.Clin.Res. 1990;16:531-536.

65. Environmental Protection Agency.Robust summary for dicarboxylic acid category. 7-10-2001. http://www.epa.gov/HPV/pubs/summaries/dicarbx/c13108.pdf. Accessed 7-19-2010.

66. Organisation for Economic Co-Operation and Development.SIDS report on Dodecanedioic Acid, CAS No. 693-23-2. 1994. http://www.chem.unep.ch/irptc/sids/OECDSIDS/693232.pdf. Accessed 7-29-2010.

67. Organisation for Economic Co-Operation and Development.SIDS Initial Report for SIAM 18 - Adipic Acid, CAS No. 124-04-9. 2004. http://www.chem.unep.ch/irptc/sids/OECDSIDS/124049.pdf. Accessed 7-29-2010.

68. Maekawa, A., Todate, A., Onodera, H., Matsushima, Y., Nagaoka, T., Shibutani, M., Ogasawara, H., Kodama, Y., and Hayashi, Y. Lack of toxicity/carcinogenicity of monosodium succinate in F344 rats. Food Chem.Toxicol. 1990;28:(4):235-241.

69. Mingrone G, Greco AV, Navarro-Porro M, and Passi S. Toxicity of Azelaic Acid. Drugs Exp.Clin.Res. 1983;9:447-455.

70. Fukui S, Shimoyama T, Tamura K, Yamamura M, and Satomi M. Mucosal blood flow and generation of superoxide in rat experimental colitis induced by Succinic Acid. J.Gastroenterol. 1997;32:464-471.

71. Brown-Woodman PD, Post EJ, Chow PY, and White IG. Effects of malonic, citric and caffeic acids on the motility of human sperm and penetration of cervical mucous. Int.J.Fertil. 1985;30:38-44.

72. Organisation for Economic Co-Operation and Development.SIDS Initial Assessment for SIAM 16 - Disodium Succinate, CAS No. 150-90-3. 2003. http://www.chem.unep.ch/irptc/sids/OECDSIDS/150903.pdf. Accessed 7-29-2010.

73. Bradford JC, Brown GL, Caldwell JA, and Drobeck HP. Teratology and mutagenicity studies with glutaric acid. Teratol. 1984;29:19A.

74. Mingrone G, Manicelli R, and Metro D. Influence of sodium salts of saturated medium chain length C6, C9, C10 and C12 dicarboxylic acids on the uterine horn of rat in vitro. Q.J.Exp.Physiol. 1988;73:153-162.

75. National Toxicology Program.Salmonella assayon malonic acid. Study ID: 228078. 1989. http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=salmonella.salmonellaData&endpointlist=SA&study%5Fno=228078&cas%5Fno=141%2D82%2D2&activetab=detail. Accessed 7-26-2010.

76. Ishidate M Jr, Sofuni T, Yoshikawa K, Hayaski M, Nohmi T, Sawada M, and MAtsouka A. Primary mutagenicity screening of food additives currently used in Japan. Food Chem Toxicol. 1984;22:(8):623-636.

77. TOXNET.CCRIS database - Sodium Succinate. CAS No. 2292-54-5. 2-14-1997. Accessed 7-26-2010.

78. National Toxicology Program.Salmonella assay on adipic acid. Study ID: A86767. 1997. http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=salmonella.salmonellaData&endpointlist=SA&study%5Fno=A86767&cas%5Fno=124%2D04%2D9&activetab=detail. Accessed 7-26-2010.

79. TOXNET.CCRIS database - Adipic acid. CAS No. 124-04-9. 10-1-2009. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~vDEUtx:1.

80. Otoshi T, Iwata H, Yamamoto S, Murai T, Yamaguchi S, Matsui-Yuasa I, Otani S, and Fukushima S. Severity of promotion by sodium salts of succinic acid in rat urinary bladder carcinogenesis correlates with sodium ion concentration under conditions of equal urinary pH. Carcinogenesis. 1993;14:(11):2277-2281.

81. Ziel, K., Yelverton, C. B., Balkrishnan, R., and Feldman, S. R. Cumulative irritation potential of metronidazole gel compared to azelaic acid gel after repeated applications to healthy skin. J.Drugs Dermatol. 2005;4:(6):727-


61

731.

82. Feldman, S., Careccia, R. E., Barham, K. L., and Hancox, J. Diagnosis and treatment of acne. Am.Fam.Physician. 2004;69:(9):2123-2130.


84. Dirven, H. A., Theuws, J. L., Jongeneelen, F. J., and Bos, R. P. Non-mutagenicity of 4 metabolites of di(2-ethylhexyl)phthalate (DEHP) and 3 structurally related derivatives of di(2-ethylhexyl)adipate (DEHA) in the Salmonella mutagenicity assay. Mutat.Res. 1991;260:(1):121-130.

85. Environmental Protection Agency.Robust summaries for substances in the HPV test plan for the diesters category of the aliphatic esters chemicals. 6-2-2010. http://www.epa.gov/oppt/chemrtk/pubs/summaries/alipestr/c13466rr8.pdf. Accessed 7-8-2010.

86. Takahashi T, Tanaka A, and Yamaha T. Elimination, distribution, and metabolsim of di-(2-ethylhexyl)adipate (DEHA) in rats. Toxicology. 1981;22:223-233.

87. Cornu, M. C., Keith, Y., Elcombe, C. R., and Lhuguenot, J. C. In vivo and in vitro metabolism of di-(2-ethylhexyl) adipate a peroxisome proliferator, in the rat. Arch.Toxicol. 1988;Suppl 12:265-268.

88. Loftus, N. J., Laird, W. J., Steel, G. T., Wilks, M. F., and Woollen, B. H. Metabolism and pharmacokinetics of deuterium-labelled di-2-(ethylhexyl) adipate (DEHA) in humans. Food Chem.Toxicol. 1993;31:(9):609-614.

89. Fukuyasu H, Orikasa Y, Kai F, Inouye S, Yamaguchi H, and et al. In vivo activity and metabolic fate of 2-(2,3,3-triiodoallyl)tetrazole (ME1401), a novel antifungal agent. Drugs Exp.Clin.Res. 1989;15:(8):335-347.

90. Lake BG. Mechanisms of hepatocarcinogenicity of peroxisome-proliferating drugs and chemicals. Annu Rev Pharmacol Toxicol. 1995;35:483-507.

91. Cornu, M. C., Lhuguenot, J. C., Brady, A. M., Moore, R., and Elcombe, C. R. Identification of the proximate proliferator(s) derived from di (2-ethylhexyl) adipate and species differences in response. Biochem Pharmacol. 1992;43:(10):2129-2134.

92. Keith, Y., Cornu, M. C., Canning, P. M., Foster, J., Lhuguenot, J. C., and Elcombe, C. R. Peroxisome proliferation due to di (2-ethylhexyl) adipate, 2-ethylhexanol and 2-ethylhexanoic acid. Arch.Toxicol. 1992;66:(5):321-326.

93. National Toxicology Program.Carcinogenesis bioassay of di(2-ethylhexyl)adipate (CAS No. 103-23-1). F344 and B6C3F1 mice. (Feed study). 1982. http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr212.pdf. Accessed 6-20-2010.

94. Lake, B. G., Price, R. J., Cunninghame, M. E., and Walters, D. G. Comparison of the effects of di-(2-ethylhexyl)adipate on hepatic peroxisome proliferation and cell replication in the rat and mouse. Toxicology. 1997;123:(3):217-226.

95. Tomaszewski, K. E., Agarwal, D. K., and Melnick, R. L. Invitro steady-state levels of hydrogen eroxide after exposure of male F344 rats and female B6C3F1 mice to hepatic peroxisome proliferators. Carcinogenesis. 1986;7:(11):1871-1876.

96. Reddy, J. K., Reddy, M. K., Usman, M. I., Lalwani, N. D., and Rao, M. S. Comparison of hepatic peroxisome proliferative effect and its implication for hepatocarcinogenicity of phthalate esters, di(2-ethylhexyl) phthalate, and di(2-ethylhexyl) adipate with a hypolipidemic drug. Environ.Health Perspect. 1986;65:317-327.

97. Barber, E. D., Astill, B. D., Moran, E. J., Schneider, B. F., Gray, T. J., Lake, B. G., and Evans, J. G. Peroxisome


62

induction studies on seven phthalate esters. Toxicol.Ind.Health. 1987;3:7-22.

98. Lin, L. I. The use of multivariate analysis to compare peroxisome induction data on phthalate esters in rats. Toxicol.Ind.Health. 1987;3:(2):25-48.

99. von Däniken A., Lutz, W. K., Jâckh, R., and Schlatter, C. Investigation of the potential for binding of di(2-ethylhexyl) phthalate and di(2-ethylhexyl) adipate to liver DNA in vivo. Toxicol Appl Pharmacol. 1984;73:(3):373-387.

100. Büsser, M.-T. and Lutz, W. K. Stimulation of DNA Synthesis in Rat and Mouse Liver by Various Tumor Promoters. Carcinogenesis. 1987;8:(10):1433-1437.

101. Takagi, A., Sai, K., Umemura, T., Hasegawa, R., and Kurokawa, Y. Significant increase of 8-hydroxydeoxyguanosine in liver DNA of rats following short-term exposure to the peroxisome proliferators di(2-ethylhexyl)phthalate and di(2-ethylhexyl)adipate. Jpn.J.Cancer Res. 1990;81:213-215.

102. Kawashima, Y., Hanioka, N., Matsumura, M., and Kozuka, H. Induction of microsomal stearoyl-CoA desaturation by the administration of various peroxisome proliferators. (Secondary reference in IARC 2000). Biochim.Biophys.Acta. 1983;752:259-264.

103. Kawashima Y, Nakagawa S, Tachibana Y, and Kozuka H. Effects of peroxisome proliferators on fatty acid-binding protein in rat liver. (Secondary reference in IARC 2000). Biochim Biophys Acta. 1983;754:21-27.

104. Yanagita T., Satoh M., Nomura H., Enomoto N., and Sugano M. Alteration of hepatic phospholipids in rats and mice by feeding di-(2-ethylhexyl)adipate and di-(2-ethylhexyl)phthalate. (Secondary reference in IARC 2000.). Lipids. 1987;22:572-577.

105. Motojima, K., Passilly, P., Peters, J. M., Gonzalez, F. J., and Latruffe, N. Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. (Secondary reference in IARC 2000). J.Biol.Chem. 1998;273:16710-16714.

106. Organisation for Economic Co-Operation and Development.SIDS Initial Report for Siam 4 - Dibutyl Adipate CAS No. 105-99-7. 1996. http://www.chem.unep.ch/irptc/sids/OECDSIDS/105997.pdf. Accessed 7-29-2010.

107. AMA Laboratories. Acute oral toxicity of Liquiwax DIADD (Dioctyldodecyl Dodecanedioate). AMA Ref No. WPAT90-59/OT5982.II. Unpublished data submitted by the Council (3 pp). 12-13-1990.

108. AMA Laboratories. Acute oral toxicity of Liquiwax DICDD (Diisocetyl Dodecanedioate). AMA Ref No: WPAT90-59/OT6098.II Unpublished data submitted by the Council (3 pp). 1-3-1991.

109. AMA Laboratories. Acute dermal toxicity - limit test - Liquiiwax DIADD (Dioctyldedecyl Dodecanediaote). AMA Ref No. WPAT93-155/AD1076.BII. Unpublished data submitted by Council (4 pp). 6-14-1993.

110. EviC-CEBA. Attestation of biological significance (acute oral toxicity and dermal irritation) on diethylhexyl sebacate. Study ref. T 207/4072. Unpublished data submitted by the Council (2 pp). 4-7-1994.

111. EviC-CEBA. Attestation of biological significance (acute oral toxicity and dermal irritation) on diisocetyl adipate. Study ref. T 207/4073. Unpublished data submitted by the Council (2 pp). 4-7-1994.

112. EviC-CEBA. Attestation of biological test (acute oral toxicity and dermal irritation) on diisodecyl adipate. Study ref. T 207/4076. Unpublished data submitted by the Council (2 pp). 5-9-1994.

113. EviC-CEBA. Attestation of biological significance (acute oral toxicity and dermal irritation) on dioctyldodecyl adipate. Study ref. T 207/4071. Unpublished data submitted by the Council (2 pp). 5-9-1994.

114. EviC-CEBA. Study of acute toxicity and local tolerance (acute oral, acute dermal, and ocular irritation) on diisopropyl adipate. Study report: Te 297/98-1589 and Te 298/98-1589. Unpublished data submitted by the Council (4 pp). 5-27-1998.


63

115. Singh AR, Lawrence WH, and Autian J. Embryonic-fetal toxicity and teratogenic effects of adipic acid esters in rats. J Pharm Sci. 1973;62:(10):1596-1600.

116. Smith CC. Toxicity of butyl stearate, dibutyl sebacate, dibutyl phthalate, and methoxyethyl oleate. AMA Arch.Ind.Hyg.Occup.Med. 1953;7:310-318.

117. Organisation for Economic Co-Operation and Development.SIDS Initial Report for SIAM 10 - Bis(2-ethylhexyl) Adipate (DEHA), CAS No. 103-23-1. 2000. http://www.chem.unep.ch/irptc/sids/OECDSIDS/103231.pdf. Accessed 7-29-2010.

118. ExxonMobil Chemical Company.High Production Volume (HPV) Chemical Challenge Program. Test plan for the alkyl alcohols C6-C13 Category. 2-5-2002. http://www.epa.gov/HPV/pubs/summaries/alkal613/c13590rs.pdf. Accessed 2010.

119. Smyth HF, Carpenter CP, and Weil CS. Range-finding toxicity data: List IV. AMA Arch.Ind.Hyg.Occup.Med. 1949;4:119-122.

120. Wato, E., Asahiyama, M., Suzuki, A., Funyu, S., and Amano, Y. Collaborative work on evaluation of ovarian toxicity. 9) Effects of 2- or 4-week repeated dose studies and fertility study of di(2-ethylhexyl)adipate (DEHA) in female rats. J.Toxicol.Sci. 2009;34:(Special Issue I):SP101-SP109.

121. Kluwe, W. M. Carcinogenic potential of phthalic acid esters and related compounds: structure-activity relationships. Environ.Health Perspect. 1986;65:271-278.

122. Lee, K. P., Valentine, R., and Bogdanffy, M. S. Nasal lesion development and reversibility in rats exposed to aerosols of dibasic esters. Toxicol.Pathol. 1992;20:(3 Part 1):376-393.

123. Consumer Product Testing. 1991. Primary dermal irritation in rabbits, primary ocular irritation in rabbits of Schermcemol DIS (Diisopropyl Sebacate). Experiment Reference Number: 91055. (Material tested as supplied - approx. 100%). 3 pages.

124. MB Research Laboratories. 2003. EpiOcular MTT viability assay of a cream containing 1.2% Diethylhexyl Sebacate. 10 pages.

125. AMA Laboratories. Primary eye irritation of liquiwax DIADD (Dioctyldodecyl Dodecanedioate). AMA Lab No. WPAT90-59/PE5982.II. Unpublished data submitted by theCouncil (5 pp). 12-3-1990.

126. AMA Laboratories. Primary eye irritation of liquiwax DICDD (Diisocetyl Dodecanedioate). AMA Ref No: WPAT90-59/PE6098.II. Unpublished data submitted by the Council (3 pp). 12-22-1990.

127. Personal Care Products Council. 1989. Summary of safety data on Diethyl Sebacate (primary skin irritation, cumulative skin irritation, contact allergenicity). 8 pages.

128. EviC-CEBA. Attestation of biological significance (acute oral toxicity and dermal irritation) on diisopropyl sebacate. Study ref. T 207/4078. Unpublished data submitted by the Council (2 pp). 4-7-1998.

129. AMA Laboratories. Guinea pig maximization test (Kligman) on liquiwax DIADD (Dioctyldodecyl Dodecanedioate). AMA Ref No: WPAT93-GPMB1076.BII. Unpublished data submitted by the Council (6 pp). 6-14-1993.

130. Environmental Protection Agency.Integrated Risk Information System. Di(2-ethylhexyl)adipate. (CASRN 103-23-1). 3-6-2010. N:\CIR\DicarboxylicAcids\DatabaseSearchResults\EPA\IRIS-searched7-8-10_updatred3-16-10.mht. Accessed 7-8-2010.

131. Dalgaard, M., Hass, U., Vinggaard, A. M., Jarfelt, K., Lam, H. R., rensen, I. K., Sommer, H. M., and Ladefoged, O. Di(2-ethylhexyl) adipate (DEHA) induced developmental toxicity but not antiandrogenic effects in pre- and postnatally exposed Wistar rats. Reprod.Toxicol. 2003;17:(2):163-170.

132. Kang, J. S., Morimura, K., Toda, C., Wanibuchi, H., Wei, M., Kojima, N., and Fukushima, S. Testicular toxicity of DEHP, but not DEHA, is elevated under conditions of thioacetamide-induced liver damage.


64

Reprod.Toxicol. 2006;21:253-259.

133. Alvarez, L., Driscoll, C., Kelly, D. P., Staples, R. E., Chromey, N. C., and Kennedy, G. L., Jr. Developmental toxicity of dibasic esters by inhalation in the rat. Drug Chem.Toxicol. 1995;189:(4):295-314.

134. Kelly, D. P., Kennedy, G. L., Jr., and KEENAN, C. M. Reproduction study with dibasic esters following inhalation in the rat. Drug Chem.Toxicol. 1998;21:(3):253-267.

135. Miyata, K., Shiraishi, K., Houshuyama, S., Imatanaka, N., Umano, T., Minobe, Y., and Yamasaki, K. Subacute oral toxicity study of di(2-ethylhexyl)adipate based on the draft protocol for the "Enhanced OECD Test Guideline no. 407". Arch.Toxicol. 2006;80:181-186.

136. Ghisari, M. and Bonefeld-Jorgensen, E. C. Effects of plasticizers and their mixtures on estrogen receptor and thyroid hormone functions. Toxicol.Lett. 2009;189:(1):67-77.

137. Andersen, P. H. and Jensen, N. J. Mutagenic investigation of flavourings: dimethyl succinate, ethyl pyruvate and aconitic acid are negative in the Salmonella/mammalian-microsome test. Food Addit.Contam. 1984;1:(3):283-288.

138. National Toxicology Program.Salmonella assay on dimethyl succinate. Study ID: 947738. 1988. http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=salmonella.salmonellaData&endpointlist=SA&study%5Fno=947738&cas%5Fno=106%2D65%2D0&activetab=detail. Accessed 7-26-2010.

139. National Toxicology Program.Salmonella assay on dimethyl glutarate. Study ID A20348. 1995. http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=salmonella.salmonellaData&endpointlist=SA&study%5Fno=A20348&cas%5Fno=1119%2D40%2D0&activetab=detail. Accessed 7-26-2010.

140. National Toxicology Program.Salmonella assay on dimethyl adipate. Study ID: A45330. 1994. http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=salmonella.salmonellaData&endpointlist=SA&study%5Fno=A45330&cas%5Fno=627%2D93%2D0&activetab=detail. Accessed 7-26-2010.

141. Zeiger E, Haworth E, Mortelmans S, and et al. Mutagenicity testing of di(2-ethylhexyl) phthalate and related chemicals in Salmonella. Environ Mutagen. 1985;7:213-232.

142. Warren JR, Lalwani, N. D., and Reddy, J. K. Phthalate esters as peroxisome proliferator carcinogens. Environ.Health Perspect. 1982;45:35-40.

143. Simmon VF, Kauhanen K, and Tardiff R.G. Mutagenic activity of chemicals identified in drinking water. Dev Toxicol Environ Sci. 1977;2:249-258.

144. National Toxicology Program.Salmonella assay eith diethylhexyl adipate. Study ID: 963935. 1988. http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=salmonella.salmonellaData&endpointlist=SA&study%5Fno=963935&cas%5Fno=103%2D23%2D1&activetab=detail. Accessed 7-26-2010.

145. Seed JL. Mutagenic activity of phthalate estes in bacterial seed liquid suspension assays. Environ.Health Perspect. 1982;45:111-114.

146. McGregor, D. B., Brown, A., Cattanach, P., Edwards, I., McBride, D., Riach, C., and Caspary, W. J. Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay: III. 72 coded chemicals. (Secondary reference in IARC 2000). Environ.Mol.Mutagen. 1988;12:(1):85-154.

147. Reisenbichler, H. and Eckl, P. M. Genotoxic effects of selected peroxisome proliferators. (Secondary reference in IARC 2000). Mutat.Res. 1993;286:135-144.

148. Galloway SM, Armstrong MJ, Rueben C, Colman S, Brown B, CAnnon C, Bloom AD, Nakamura F, Ahmed M, Duk S, Rimpo J, Margolin BH, REsnick MA, Anderson B, and Zeiger E. Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells: Evaluation of 108 chemicals. Environ Mol Mutagen. 1987;10:(Suppl 10):1-175.


65

149. Shelby, MD, Erexson GL, Hook GH, and Tice RR. Evaluation of a three-exposure mouse bone marrow micronucleus protocol: Results with 49 chemicals. Environ Mol Mutagen. 1993;21:160-179.

150. Shelby, MD and Witt, KL. Comparison of results from mouse bone marrow chromosome aberration and micronucleus tests. Environ Mol Mutagen. 1995;25:302-313.

151. National Toxicology Program.Chromosome aberration assay of diethylhexyl adipate. Study ID: 959525. 1988. http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=invivoca.casummary&study_no=959525&cas_no=103%2D23%2D1&endpointlist=CA. Accessed 7-26-2010.

152. DiVincenzo, G. D., Hamilton, M. L., Mueller, K. R., Donish, W. H., and Barber, E. D. Bacterial mutagenicity testing of urine from rats dosed with 2-ethylhexanol derived plasticizers. Toxicology. 1985;34:(3):247-259.

153. McKee, R. H., Lington, A. W., and Traul, K. A. An evaluation of the genotoxic potential of di-isononyl adipate. Environ.Mutagen. 1986;8:(6):817-827.

154. Szybalski W. Special microbiological systems - Observations on chemical mutagenesis in microorganisms. Ann.NY Acad.Sci. 1958;76:475-489.

155. Wild, D., King, M. T., Gocke, E., and Eckhardt, K. Study of artificial flavoring substances for mutagenicity in the salmonella/microsome, basc and micronucleus tests. Fd Chem Toxicol. 1983;21:707-719.

156. TOXNET.CCRIS database - Dibutyl Sebacate. CAS No. 109-43-3. 2-12-2001. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~LfAk2H:2. Accessed 7-26-2010.

157. TOXNET.CCRIS database - Diethylhexyl Sebacate. CAS NO. 122-62-3. 6-2-2010. http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~J98xpD:1. Accessed 7-26-2010.

158. Osterle D and Deml E. Promoting activity of di(2-ethylhexyl)phthalate in rat liver foci bioassay. J.Cancer Res.Clin.Oncol. 1988;114:(2):133-136.

159. Hasegawa R and Ito N. Liver medium-term bioassay in rats for screening of carcinogenesis and modifying factors in hepatocarcinogenesis. Fd Chem Toxicol. 1992;30:(11):979-992.

160. AMA Laboratories. 50 Human subject repeat insult patch test skin irritation/sensitization evaluation on Liquiwax DISA (Diisostearyl Adipate), DICDD (Diisocetyl Dodecanedioate), and DIADD (Dioctyldodecyl Dodecanedioate). AMA Ref No: WP96-BERN1-18/RIPT4618.BII. Unpublished data submitted by the Council. 4-11-1996.

161. Anonymous. Clinical evaluation report: human patch test of a body cream containing 1.5% diethyl sebacate. Unpublished data submittd by the Personal Care Products Council. 2003.

162. KGL Inc. 2003. An evaluation of the contact-sensitization potential of a topical coded product (body cream containing 1.5% diethyl sebacate) in human skin by means of the maximization assay. 10 pages.

163. Anonymous. Clinical evaluation report: human patch test of a foundation containing 1.8% diisopropyl sebacate. Unpublished data submitted by the Council.. 2000.

164. Product Investigations Inc. 2005. Determination of the irritating and sensitizing propensities of Schercemol DIS (Diisopropyl Sebacate) on human skin. Report: PII No. 19745. (Material tested as supplied - approx. 100%). 12 pages.

165. KGL Inc. 2006. An evaluation of the contact-sensitization potential of a topical coded product (foundation containing 2.2% diisopropyl sebacate) in human skin by means of the maximization assay. 10 pages.

166. Reliance Clinical Testing Services. 2007. Summary of HRIPT of two heat protection hair sprays containing 1% Diisopropyl Sebacate. 1 pages.


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167. Essex Testing Clinic Inc. 2007. Summary of HRIPT of a heat protection hair spray containing 7.2% Diisopropyl Sebacate.

168. Kimura M and Kawada A. Contact dermatitis due to Diethyl Sebacate. Contact Dermatitis. 1999;40:48-49.

169. Narita T, Oiso N, Ota T, Kawara S, and Kawada A. Allergic contact dermatitis due to Diethyl Sebacate in a hand cream. Contact Dermatitis. 2006;55:117.

170. Sasaki E, Hata M, Aramaki J, and Honda M. Allergic contact dermatitis due to Diethyl Sebacate. Contact Dermatitis. 1997;36:172.

171. Soga F, Katoh N, and Kishimoto S. Contact dermatitis due to lanoconazole, cetyl alcohol and Diethyl Sebacate in lanoconazole cream. Contact Dermatitis. 2004;50:49-50.

172. Tanaka M, Kobayashi S, Murata T, Tanikawa A, and Nishikawa T. Allergic contact dermatitis from Diethyl Sebacate in lanoconazole cream. Contact Dermatitis. 2000;43:233-234.

173. De Groot AC, Conemans JM, and Schutte T. Contact allergy to Diisopropyl Sebacate in Zineryt lotion. Contact Dermatitis. 1991;25:260-261.

174. Dooms-Goossens A, De Veyhlder H, De Boulle K, and Maertens M. Allergic contact dermatitis due to Diisopropyl Sebacate. Contact Dermatitis. 1986;15:192.

175. Elder RL (ed). Final Report on the Safety Assessment of Stearyl Alcohol, Oleyl Alcohol, and Octyl Dodecanol. Journal of the American College of Toxicology. 1985;4:(5):1-29.

176. Opdyke, D. L. J. Fragrance Raw Materials Monographs - Supplement to Earlier Monographs on Fragrance Materials. 1973. 1079

177. Andersen, F. A. Final Report on the Safety Assessment of Formic Acid. International Journal of Toxicology. 1997;16:(3).

178. International Programme on Chemical Safety.Methanol: Poisons Information Monograph 335. 2009. http://www.inchem.org/documents/pims/chemical/pim335.htm. Accessed 10-20-2009.

179. D'Alessandro, A., Osterloh, J. D., Chuwers, P., Quinlan, P. J., Kelly, T. J., and Becker, C. E. Formate in serum and urine after controlled methanol exposure at the threshold limit value. Environ.Health Perspect. 1994;102:(2):178-181.

180. Heldreth BA. Final report on Methyl Acetate, Simple Alkyl Acetate Estes and Related Alcohols (Draft). Report in progress. Available from the Cosmetic Ingredient Review. 2010.

181. Andersen, F. A. Final Report on the Safety Assessment of Methyl Alcohol. International Journal of Toxicology. 2001;20:((Suppl. 1)):57-85.

182. American Chemistry Council and Oxo Process Panel. Screening Information Data Set (SIDS) Initial Assessment Report for SIDS Initial Assessment Meeting (SIAM) 27: n-Propyl Acetate. OECD. 2008.

183. Nelson BK, Brightwell WS, Taylor BJ, Khan A, Burg JR, Kreig EF Jr, and Massari VJ. Behavioral teratology investigatoi of 1-propanol administered by inhalation to rats. Neurotoxicol Teratol. 1989;11:(2):153-159.

184. Stillman MA, Maiback HI, and Shalita AR. Relative irritancy of free fatty acids of different chain length. Contact Derm. 1975;1:65-69.

185. Wahlberg JE and MAibach HI. Nonanoic acid irrigation: A positive control at routine patch testing? Contact Derm. 1980;6:(2):128-130.

186. Agner, T. and Serup J. Skin reactions to irritants assessed by polysulfide rubber replica. Contact Dermatitis. 1987. 17:(4):205-211.


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187. Agner T and Serup J. Nonanoic acid irrigation: A positive contorl at routine patch testing? Contact Derm. 1987;17:(4):20-211.

188. Willis CM, Stephens JM, and Wilkinson JD. Experimentally-induced irritant contact dermatitis. Determination of optimum irritant concentrations. Contact Derm. 2010;1:20-24.

189. Agner T and Serup J. Seasonal variation ofskin resistance to irritants. Br J Dermatol. 2010;121:(3):323-328.

190. Elder RL (ed). Final Report on the Safety Assessment of Cetearyl Alcohol, Cetyl Alcohol, lsostearyl Alcohol, Myristyl Alcohol, and Behenyl Alcohol. Journal of the American College of Toxicology. 1988;7:(3):359-413.

191. Martinez, T. T., Jaeger, R. W., deCastro, F. J., Thompson, M. W., and Hamilton, M. F. A comparison of the absorption and metabolism of isopropyl alcohol by oral, dermal and inhalation routes. Vet Hum Toxicol. 1986;28:(3):233-236.

192. Burleight-Flayer H, Garman R, Neptun D, Bevan C, Gardiner T, Kapp R, Tyler T, and Wright G. Isopropanol vapor inhalaiton oncogenicity study in Fischer 344 rats and CD-1 mice. Fund Appl Toxicol. 1997;36:(2):95-111.

193. International Programme on Chemical Safety.Isopropyl Alcohol: Poisons Information Monograph 290. 2009. http://www.inchem.org/documents/pims/chemical/pim290.htm. Accessed 10-12-2009.

194. Tyl, R. W., Masten, L. W., Marr, M. C., Myers, C. B., Slauter, R. W., Gardiner, T. H., Strother, D. E., McKee, R. H., and Tyler, T. R. Developmental toxicity evaluation of isopropanol by gavage in rats and rabbits. Fundam.Appl Toxicol. 1994;22:(1):139-151.

195. Damato JM, Martin DM, and Fehn PA. Allergic contact sensitization test of a spray concentrate containining 80.74% isopropyl alcohol. 1979.

196. Anonymous. Final Report Repeated Insult Patch Test of a Hair Dye Base (3373) Containing 2.85% Isopropyl Alcohol and 1.95% Isopropyl Acetate. Unpublished data submitted by teh Council. 2010.

197. Suihko C and Serup J. Fluorescence confocal laser scanning microscopy for in vivo imaging of epidermal reactions to two experimental irritants. Skin Res Technol. 2008;14:(4):498-503.

198. High Production Volume (HPV) Chemical Challenge Program. Test Plan for the Alkyl Alcohols C6 - C13 Category. 2002.

199. International Program on Chemical Safety.Butyl acetates. 2005. http://www.inchem.org/documents/cicads/cicad64.htm. Accessed 11-20-2009.

200. Kawaguchi, M., Yamazaki, T., and Nakazawa, H. Biological effects of di(2-ethylhexyl)adipate. Environmental.Sciences.: an.International.Journal of Environmental.Physiology.and Toxicology. 2002;9:(2-3):198.


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APPENDIX I – ESTEARSE METABOLITE SUMMARY DATA Decyl Alcohol – metabolite of Decyl Succinate Clinical Irritation and Sensitization Tested in at a concentration of 3% in petrolatum, decyl alcohol produced no irritation in a 48 h closed-patch test in 25 human subjects.176 Methanol – metabolite of Dimethyl Succinate, Dimethyl Glutarate, Dimethyl Adipate Absorption, Distribution, Metabolism, and Excretion

Methanol is further metabolized to formaldehyde and then to formic acid. The CIR Expert Panel concluded that formic acid is safe where used in cosmetic formulations as a pH adjustor with a 64 ppm limit for the free acid.177 The main toxicological risks in humans are severe metabolic acidosis with increased anion gap, typically following oral exposure resulting in > 100 mg/L of formate in the urine.178 The acidosis and the formic acid metabolite are believed to play a central role in both the central nervous system toxicity and the ocular toxicity. A study to determine the formate levels that resulted from exposure of human volunteers to 200 ppm of methanol for 4 h was conducted. Human volunteers (n=27; age 20-55 y) were exposed to 200 ppm methanol (the Occupational Safety and Health Administration [OSHA] Permissible Exposure Limit) for 4 h and to water vapor for 4 h in a double-blind, random study.179 Urine samples were collected at 0, 4 and 8 h and blood samples were collected from the subjects before they entered the chamber, every 15 min for the first hour, every 30 min from the first to the third hour and at 4 h. Urine and serum samples were analyzed for formate (LOD 0.5 mg/L). Twenty-six of 27 enrolled subjects completed the study (11 females and 15 males). The researchers did not find any statistically significant differences in serum or urine formate levels between the two exposure conditions at any time point. At the end of the 4 h methanol exposure, formate concentrations of 14.28 ± 8.90 and 7.14 ± 5.17 mg/L were measured in serum and urine, respectively. Under control conditions, formate concentrations of 12.68 ± 6.43 (p=0.38; n=26) and 6.64 ± 4.26 (p=0.59; n=25) mg/L were measured in serum and urine respectively. After 8 h (4 h of no exposure) the serum concentrations were not statistically different with 12.38 ± 6.53 mg/L under methanol exposure conditions and 12.95 ± 8.01 (P=0.6; n=26) under control conditions. Urine formate concentrations after 8 h were 6.08 ± 3.49 and 5.64 ±3.70 mg/L (p=0.6; n=25) in exposed and control conditions, respectively, and were not statistically significantly different. From CIR Final Report on Methyl Acetate180

Clinical Irritation and Sensitization

Methyl Alcohol caused primary irritation to the skin; prolonged and repeated contact with Methyl Alcohol resulted in de-fatting and dermatitis. In one occupational study, 3.2% of 274 metalworkers with dermatitis had positive results to a patch test of 30% Methyl Alcohol. Typical allergic responses observed after contact with alcohols were eczematous eruption and wheal and flare at the exposure sites. Eczema and erythema were reported after the consumption of alcoholic beverages by persons sensitized to ethyl alcohol. Five percent Methyl Alcohol caused a slight positive (+) reaction in a closed patch test for allergic contact dermatitis, and concentrations of 7% and 70% caused (+++) reactions. From the CIR final report on methyl alcohol181

Clinical Assessment of Safety

Clinical data show that Methyl Alcohol can cause severe metabolic acidosis, blindness, and death: toxicity was manifested earlier and at a lower dose compared to ethyl alcohol, but the comparative fatal dose was the same for both alcohols. All routes of exposure were toxicologically equivalent, as the alcohol distributed readily and uniformly throughout all tissues and organs. Individual susceptibilities to Methyl Alcohol varied, but typically, the ingestion of 80 to 150 ml of 80% Methyl Alcohol was fatal. Symptoms of Methyl Alcohol intoxication after ingestion were delayed for 12 to 18 hours; afterwards, the symptoms included headache, anorexia, weakness, fatigue, leg cramps, and/or pain and vertigo. Severe gastrointestinal pain, nausea, vomiting, diarrhea, mania, failed vision, and convulsions could occur. Chronic exposure to Methyl Alcohol could cause edema, granular degeneration, and necrosis of heart muscle fibers, as well as fatty degeneration of the heart muscle; sudden cardiac failure was associated with Methyl Alcohol intoxication. The liver and kidneys often had parenchymatous degeneration, and the liver had focal necrosis and fatty infiltration. Severe acidosis was necessary for the development of blindness. Similar symptoms were observed after percutaneous or inhalation exposure to Methyl Alcohol. From the CIR final report on methyl alcohol181


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Propyl Alcohol – metabolite of Dipropyl Adipate Absorption, Distribution, Metabolism, and Excretion

Rats (strain/sex/number not specified) were exposed via inhalation to 2,000 ppm (8360 mg/m3) for 90 min.182 Propyl acetate was rapidly hydrolyzed to propyl alcohol. During the 90 min exposure period, blood levels of propyl alcohol were between 2.6 and 7.7 fold greater than propyl acetate. From the CIR final report on Methyl Acetate180

Reproductive and Developmental Toxicity

The effects of propyl alcohol on fertility were investigated by exposing male Sprague-Dawley rats (18/group) to 0, 3500 or 7000 ppm (0, 8.61 or 17.2 mg/L) propyl alcohol vapor via inhalation 7 h/day, 7days/week for 62 days, prior to mating with unexposed virgin females.183 Female Sprague-Dawley rats (15/group) were similarly exposed and mated with unexposed males. Following parturition, litters were culled to 4/sex and the pups fostered by unexposed dams. The pups were weaned on post natal day (PND) 25 and weighed on PND’s 7, 14, 21, 28 and 35. Male rats exposed to 7000 ppm exhibited a decrease in mating success with 2/16 producing a litter (1 male died as a result of a cage fight and 1 male did not mate). Mating success was not affected in 3500 ppm exposed males or in females. Six males from the 7000 ppm group were retained to determine if this effect was reversible. All 6 males successfully mated 15 weeks after exposure. The authors reported that weight gain was not affected in 7000 ppm exposed females (data not shown), but feed intake was decreased in this treatment group. Crooked tails were observed in 2-3 offspring in 2 of 15 litters from the 7000 ppm maternally exposed group. No other effects on female fertility were reported. No significant differences resulted between offspring of the 7000 ppm group and controls on several behavioral toxicology measures including the Ascent test, Rotorod test, Open Field test, activity test, running wheel activity, avoidance conditioning, and operant conditioning. Activity measures were significantly different between offspring of the 3500 ppm exposure group and controls. From the CIR final report on Methyl Acetate180


A cumulative irritation study was conducted involving 20 male subjects, where the relative irritancy of free fatty acids of different chain lengths was evaluated.184 Equimolar concentrations (0.5 M and 1.0 M) of even- and odd-numbered - straight chain saturated fatty acids were dissolved in propanol. Each Al-test® patch containing a fatty acid (0.5 M) was applied to the interscapular area of 10 subjects, and, similarly, each fatty acid was applied at a higher concentration (1.0 M) to the remaining 10 subjects. A control patch containing propanol was also applied to each subject. Patches remained in place for 24 h and reactions were scored 30 minutes after patch removal. This procedure was repeated daily for a total of 10 applications. In both groups of 10 subjects, there were no reactions to propanol. In an irritation study, wherein 116 healthy male subjects (21 to 55 years old) were patch tested with pelargonic acid at concentrations of 5%, 10%, 20%, and 39.9% in propanol, a propanol-treated control patch was used.185 Dose response curves were developed. Patches (Al-test® discs) were saturated with 0.04 ml of a test solution and applied to the upper back for 48 h. Reactions were scored at 48 h and 96 h post-application. There were no reactions to propanol. In an another irritation study, wherein 16 volunteers (10 females, 6 males; median age of 29.5 years) were patch tested (closed patches, Finn chambers) with 20% pelargonic acid in propanol (pH of 4.3), propanol was one of the controls used.186 Patches were applied to the anterolateral surface of both upper arms for 24 h. Reactions were scored at 24, 48, and 96 h post-application according to the following scale: 0 (no reaction) to 3 (strong positive reaction: marked erythema, infiltration, possibly vesicles, bullae, pustules and/or pronounced crusting). There were no reactions to propanol. A skin irritation study was conducted using 42 healthy, non-atopic male volunteers (mean age = 34 years; skin types: II [20 subjects], III [17 subjects], and IV [5 subjects]).187 Pelargonic acid was patch-tested (Finn chambers, volar forearm) at the following concentrations (in propanol): 40% (12 subjects), 60% (32 subjects), 70% (32 subjects), and 80% (28 subjects), and propanol was used as a control. Each subject received between 3 and 10 patch tests. The patches remained in place for 48 h, and reactions were scored 1 h later according to the following scale: - (no visible reaction) to 4+ (intense erythema with bullous formation). There were no reactions to propanol. In an irritation study, wherein 16 healthy subjects (ages not stated) were patch tested with pelargonic acid (20% in


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propanol), propanol was used as a control.188 Closed patches (Finn chambers) containing the test substance were applied to the anterolateral surface of both upper arms. The patches were removed at 24 h post-application and reactions were scored at 24 h and 96 h post-application. There were no reactions to propanol. In study conducted to investigate a possible seasonal variation in the skin response to pelargonic acid during the winter and summer, propanol was used as a control.189 The study was conducted using 17 healthy volunteers (10 males, 7 females; mean age = 27 years). The test substance was applied (closed patch, Finn chamber) to each arm for 24 h. Reactions were scored at 30 min post-removal. Reactions were not observed at sites treated with propanol, water, or to which an empty chamber was applied. From CIR final report on Methyl Acetate180

Cetyl Alcohol – metabolite of Dicetyl Succinate and Dicetyl Adipate Clinical Irritation and Sensitization

A topical tolerance study involving an 11.5% Cetyl Alcohol cream base was conducted with 80 male subjects, ranging in age from 21 to 52 years and in weight from 120 to 220 pounds. The preparations were applied five times daily (every 3 hours) for 10 days. One subject had erythema, folliculitis, and pustule formation (forearm site). A formulation containing 6.0% Cetyl Alcohol was tested for its skin irritation potential in 20 subjects according to the protocol stated above. The product did not induce skin irritation. In another study, the skin irritation potential of a cream containing 6.0% Cetyl Alcohol was evaluated in 12 female subjects (18-60 years old). The total irritation score (all panelists) for the 21 applications was 418, indicating mild cumulative irritation. The skin irritation and sensitization potential of a product containing 8.4% Cetyl Alcohol was evaluated in 110 female subjects. Fourteen days after scoring of the tenth application site, a challenge patch was applied to each subject and removed after 48 h; sites were scored after patch removal. The product did not induce primary irritation or sensitization. The sensitization potential of a cream containing 3.0% Cetearyl Alcohol was evaluated in 25 subjects (18-25 years old). Following a 10-day non-treatment period, occlusive challenge patches were applied to new sites and removed after 48 h. Sensitization reactions were not observed in any of the subjects. From the CIR final report on cetyl alcohol190

Photosensitization

The photosensitization potential of a lipstick product containing 4.0% Cetyl Alcohol was evaluated in 52 subjects. The experimental procedure was not stated. Photosensitization reactions were not noted in any of the subjects. In another study, a skin care preparation containing 1.0% Cetyl Alcohol did not induce photosensitization in the 407 subjects tested. The experimental procedure was not stated. From CIR final report on cetyl alcohol190

Isopropyl Alcohol – metabolite of Diisopropyl Adipate and Diisopropyl Sebacate Absorption, Distribution, Metabolism, and Excretion

Male rabbits (3/group; strain not specified) were treated by different routes of exposure to compare the absorption and metabolism of isopropyl alcohol.191 Groups 1 and 2 were treated via gavage with the equivalent of 2 and 4 ml/kg absolute isopropyl alcohol, respectively, as a 35% isopropanol/water solution. Groups 3 and 4 were treated via whole-body inhalation for 4 h (towels soaked with isopropyl alcohol were place in the inhalation chamber and replenished at ½ hour intervals to maintained a saturated environment; no exact concentration given), with Group 3 animals receiving an additional dermal exposure in the form of a towel soaked with 70% isopropyl alcohol applied to the animals’ chests and Group 4 animals having plastic barriers on their chests and towels prepared the same way as in Group 3 applied on top of the plastic barriers. The alcohol on the towels was replenished at half hour intervals throughout the duration of the experiment. Blood samples were taken at 0, 1, 2, 3 and 4 h. Samples were analyzed for isopropyl alcohol and the metabolite acetone. Following gavage exposure to 2 or 4 ml/kg, maximum blood levels of 147 and 282 mg/dl, respectively, of isopropyl alcohol were measured. Concentrations of acetone rose steadily over the 4 h period and were 74 and 73 mg/dl


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following exposure to 2 or 4 ml/kg, respectively. The authors stated that the maximum levels of isopropyl alcohol observed in this experiment, correlated with inebriation and near coma in the animals. Following inhalation and dermal exposure, the concentration of isopropyl alcohol in the blood continued to rise and was 112 mg/dl at 4 h while the concentration of acetone was 19 at 4 h. Inhalation exposure with a plastic barrier between the soaked towel and the chest resulted in isopropyl alcohol and acetone blood levels of <10 mg/dl. The researchers concluded that isopropyl alcohol is absorbed by the dermal route but that prolonged dermal exposure (i.e. repeated sponging or soaking for several hours) would be required to produce significant toxicity. From CIR final report on Methyl Acetate180

Subchronic Inhalation Toxicity Fischer 344 rats and CD-1 mice (10/sex/group) were exposed via inhalation to 0, 100, 500, 1500, or 5000 ppm (0, 246, 1230, 3690, or 12,300 mg/m3) isopropyl alcohol for 6 h/day, 5 days/wk for 13 weeks.192 Ataxia, narcosis, hypoactivity and the lack of a startle reflex were observed during exposure at 5000 ppm. Hypoactivity was observed in animals exposed to 1500 ppm isopropyl alcohol. At 13 weeks, no gross lesions were observed. Microscopic examination of control and 5000 ppm exposed animal tissues showed hyaline droplets within the kidneys of male rats only. The size and frequency of the droplets was increased in the treated group. The authors concluded that the NOAEL for this study was 500 ppm and the lowest-observable adverse effect level (LOAEL) was 1500 ppm based upon clinical signs and changes in hematology at 6 weeks. To evaluate the neurobehavioral effects of isopropanol exposure, an additional 15 rats/sex were exposed (via inhalation) to 0, 500, 1500, or 5000 ppm (0, 1230, 3690, or 12,300 mg/m3) for 6 h/day, 5 days/wk for 13 weeks. Isopropyl alcohol did not produce any changes to the parameters of the functional observations battery which was conducted at 1, 2, 4, 9 and 13 weeks. Clinical signs observed in mice, during the exposure, included ataxia, narcosis, hypoactivity and lack of a startle reflex at 5000 ppm. Narcosis, ataxia and hypoactivity were observed in animals exposed to 1500 ppm isopropyl alcohol. At 5000 ppm, increased body weight and increased rate of weight gain were observed in female mice. At 13 weeks, no gross lesions were observed and no treatment-related microscopic changes were observed. A 10% and 21% increase in relative liver weight was observed in female mice at 1500 and 5000 ppm, respectively. The authors concluded that the NOAEL for this study was 500 ppm and the LOAEL was 1500 ppm based on clinical signs and increased liver weights. Ocular Irritation

Isopropyl alcohol has been labeled a severe ocular irritant based on rabbit ocular irritation tests.193 From CIR final report on Methyl Acetate180


Female Sprague-Dawley rats (25/group) were exposed to 0, 400, 800, or 1200 mg/kg/day isopropyl alcohol via gavage on gestational days (GD) 6 through 15.194 Female New Zealand white rabbits (15/group) were exposed to 0, 120, 240, or 480 mg/kg/day isopropyl alcohol via gavage on GD 6 through 18. Animals were observed for body weight, clinical effects and feed consumption and the fetuses examined for body weight, sex and visceral and skeletal alterations at GD 20 for rats and GD 30 for rabbits. In rats, 2 dams died at the 1200 mg/kg dose and 1 dam died at the 800 mg/kg dose. Maternal gestational weight gain was reduced at the highest dose tested. No other effects were observed on maternal reproductive health. Fetal body weights at the two highest doses were decreased statistically. No evidence of teratogenicity was observed at any dose. In rabbits, four does died at the 480 mg/kg dose. Treatment related clinical signs of toxicity were observed at the 480 mg/kg dose and included, cyanosis, lethargy, labored respiration and diarrhea. No treatment related findings were observed at GD 30. Decreased feed consumption and maternal body weights, at 480 mg/kg, were statistically significant. No other effects were observed on maternal reproductive health. No evidence of teratogenicity was observed in the rabbits at any dose. The authors determined NOAEL’s for both maternal and developmental toxicity of 400 mg/kg, each, in rats and 240 and 480 mg/kg, respectively, in rabbits. From CIR final report on Methyl Acetate180

Carcinogenicity

Fischer 344 rats and CD-1 mice (65/rats/sex/group; 55/mice/sex/group) were treated via inhalation with 0, 500, 2500, or 5000 ppm (0, 1230, 6150, or 12,300 mg/m3) isopropyl alcohol for 6 h/day, 5 days/wk for 104 weeks in rats and 78 weeks in mice.192 An additional 10/animals/sex/species were treated with these same concentrations of isopropyl alcohol for 6 h/day, 5 days/wk for 72 weeks in rats and 54 weeks in mice and underwent an interim evaluation. Another 10 mice/sex/group were treated according to the paradigm described above for 54 weeks and then allowed to recover before being killed at 78 weeks. Animals were observed and evaluated for body and organ weights, ophthalmology, and clinical and anatomic pathology. In rats, increased mortality due to chronic renal disease was observed at 5000 ppm (both sexes) and at 2500 ppm (males only). Hypoactivity and lack of startle reflex were observed in 2500 ppm treated rats and hypoactivity, lack of startle


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reflex and narcosis were observed in 5000 ppm treated rats. With the exception of the ataxia, the clinical signs were transient and ceased when the exposure ended. Increases in body weight, body weight gain, and liver weights were observed in 2500 and 5000 ppm treated rats. Chronic renal disease was exacerbated in rats treated with isopropyl alcohol. Male rats had a concentration related increase in absolute and relative testes weights. At the interim euthanasia (after 72 weeks) male rats treated with 5000 ppm had an increased frequency of testicular seminiferous tubule atrophy upon microscopic evaluation. At the terminal euthanasia (104 weeks), male rats had a concentration dependent increase in the incidence of interstitial (Leydig) cell adenomas of the testes at all administered doses. No other tumor types were increased in rats under these treatment conditions as compared to controls. In mice, no differences in mortality were observed between control and treated animals. Hypoactivity, lack of a startle reflex, narcosis, ataxia, and prostration were observed in 5000 ppm treated mice. Hypoactivity, lack of startle reflex and narcosis were observed in 2500 ppm treated mice. Increases in body weight, body weight gain, and liver weights were observed in 2500 and 5000 ppm treated mice. Male mice in all treatment groups had a decrease in relative testes weights, and female mice exposed to 5000 ppm isopropyl alcohol exhibited decreases in absolute and relative brain weights. At the terminal euthanasia (78 weeks) an increased incidence of minimal to mild renal tubular proteinosis was observed in males and females in all treatment groups. Male mice exposed to 2500 and 5000 ppm exhibited an increased incidence of dilation of the seminal vesicles. No neoplastic lesions were observed in male or female mice. The authors reported a NOAEL for toxic effects of 500 ppm for both rats and mice based on kidney and testicular effects.

IARC (International Agency for Research on Cancer) has determined that isopropyl alcohol is not classifiable as to its carcinogenicity to humans (Group 3). From the CIR final report on Methyl Acetate180


According to unpublished data, a 80.74% spray concentrate caused did not exhibit any potential for dermal sensitization in 9 human subjects.195 According to unpublished HRIPT study on 109 test subjects, a 2.85% hair dye base formulation of isopropyl alcohol and a 1.95% isopropyl acetate caused no dermal sensitization in humans.196 The applicability of fluorescence confocal laser scanning microscopy for in situ imaging of irritant contact dermatitis caused by pelargonic acid using 12 healthy individuals (8 males, 4 males; 18 to 64 years old) was studied.197 Using Finn chambers (occlusive patches), the flexor side of the right and left forearm was exposed to 60 µl of 10% (w/v) pelargonic acid in isopropanol solution and isopropanol vehicle. Isopropanol was used as a control. The Finn chambers were removed at 24 h post-application and reactions were scored according to the following scale: 0 (no visible reaction) to 4+ (intense erythema with bullous formation). Reactions were not observed at sites treated with isopropanol. From the CIR final report on Methyl Acetate180

Hexyl Alcohol – metabolite of Dihexyl Adipate Ocular Irritation Undiluted hexyl alcohol has been labeled as highly irritating on rabbit ocular irritation tests.198 Dermal Sensitization In a maximization test using guinea pigs, hexyl alcohol was not a sensitizer at 1% in petrolatum.198 Caprylic Alcohol – metabolite of Dicapryl Succinate, Dicapryl Adipate and Dicaprylyl/Capryl Sebacate Dermal Irritation – Animals Caprylic alcohol applied full strength to intact or abraded rabbit skin produced a mild irritation.176 Clinical Irritation and Sensitization Tested in at a concentration of 2% in petrolatum, caprylic alcohol produced no irritation in a 48 h closed-patch test in 25 human subjects.176


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Isobutyl Alcohol – metabolite of Diisopropyl Adipate and Diisopropyl Sebacate Subchronic Inhalation Toxicity

Rats (10/sex/group) were exposed via inhalation to isobutyl alcohol vapor concentrations of approximately 0, 770, 3100, or 7700 mg/m3, for 6 h/day, 5 days/week, for 14 weeks.199 The functional observational battery was conducted along with endpoints of motor activity, neuropathology and scheduled-controlled operant behavior. A slight reduction in responsiveness to external stimuli was observed in all treated groups during exposure. This effect resolved upon cessation of exposure to isobutyl alcohol. From the CIR final report on Methyl Acetate180

Ethylhexyl Alcohol – metabolite of Diethylhexyl Succinate, Diethylhexyl Adipate and Diethylhexyl Sebacate Ocular Irritation Instillation of 20 µg of ethylhexyl alcohol into the conjunctival sac of rabbits caused moderately severe irritation of the cornea.198 Dermal Irritation – Animals Ethylhexyl alcohol was applied under occlusion to the skin of 3 male rabbits for 4 hours and found to be irritating.198 In another study with rabbits, 0.5 ml of ethylhexyl alcohol was applied under occlusion on intact skin for 1, 2, 4, and 24 hours. Irritation was considered high, and effects seen after 7 days were not reversible. Reproductive and Developmental Toxicity A group of female rats was exposed for 7 h per day to 850 mg/m3 of ethylhexyl alcohol on gestation days 1-19.198 Dams were sacrificed at day twenty. Ethylhexyl alcohol reduced maternal feed intake, but did not produce any malformations. The estrogenic activity of 2-ethylhexanoic acid was examined using an E-SCREEN assay using T47D human breast cancer cells.200 Weak estrogenic activity was observed. (Additional details were not provided.) Genotoxicity In vitro, ethylhexyl alcohol was negative in a number of Ames assays, a liquid suspension assay, mouse lymphoma assay, and unscheduled DNA synthesis assay.118,141,142,145,153 In a 3H-thymidine assay, there was a dose-dependent inhibition of 3H-thymi-dine into replicating DNA, with a dose-dependent increase in the ratio of acid-soluble DNA incorporated into the thymidine.142 The urine of rats dosed orally with 1000 mg/kg ethylhexyl alcohol was not mutagenic.152 In vivo, ethylhexyl alcohol was not genotoxic in a mouse micronucleus test or a transformation assay.153 MEHA, Mono-(2-Ethyl-5-Hydroxyhexyl)Adipate,Mono-(2-Ethyl-5-Oxohexyl)Adipate - metabolites of Diethylhexyl Adipate Genotoxicity MEHA was not mutagenic in an Ames assay at concentrations of ≤100084 or 10,000 µg/plate.141 Mono-2(ethyl-5- hydroxy-hexyl)adipate and mono-(2-ethyl-5-oxohexyl)adipate, were not mutagenic in an Ames assay at concentrations of ≤1000 µg/plate.84 Isooctyl Alcohol – metabolite of Diisooctyl Adipate and Diisooctyl Sebacate Subchronic Oral Toxicity In a subchronic gavage toxicity study of a mixture of C7-9, branched alkyl alcohols in rats, a NOEL of 125 mg/kg/day and a lowest-observed effect level of 250 mg/kg/day were determined.118 Reproductive and Developmental Toxicity In an oral gavage developmental toxicity study of a mixture of C7-9, branched alkyl alcohols in rats, a maternal NOAEL of 500 mg/kg and a fetal NOAEL of 1000 mg/kg were reported.198 Genotoxicity A mixture of C7-9, branched alkyl alcohols were not mutagenic in in vitro bacterial and mammalian cell assays.198 Carcinogenicity


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Ethylhexyl alcohol was not oncogenic in rats dosed, via gavage, with 0, 50, 150, or 500 mg/kg, in an aqueous vehicle with 0.005% Cremophor EL.198 Nonyl Alcohol – metabolite of Diisononyl Adipate Reproductive and Developmental Toxicity In an oral gavage developmental toxicity study of a mixture of C8-10, branched alkyl alcohols in rats, maternal and fetal NOAEL values were each reported to be 144 mg/kg. 198 Isodecyl Alcohol – metabolite of Diisodecyl Adipate Reproductive and Developmental Toxicity In an oral gavage developmental toxicity study of a mixture of C9-11, branched alkyl alcohols in rats, a maternal NOAEL of 158 mg/kg and a fetal NOAEL of 790 mg/kg were reported. 198 Isostearyl Alcohol – metabolite of Diisostearyl Glutarate, Diisostearyl Adipate and Isostearyl Sebacate Clinical Irritation and Sensitization

The skin irritation potential of lsostearyl Alcohol was evaluated in 19 male and female subjects (18-65 years old) at a concentration of 25.0% in petrolatum. The test substance did not induce skin irritation in any of the subjects (Primary Irritation Index = 0.05). In three similar studies, three different lipstick products containing 25.0, 27.0, and 28.0% Isostearyl Alcohol, respectively, were tested according to the same protocol. The three products did not induce skin irritation. The irritation and sensitization potential of Isostearyl Alcohol (25% v/v in 95.0% isopropyl alcohol) was evaluated in 12 male subjects (21-60 years old). Challenge applications were made to original and adjacent sites 2 weeks after removal of the last induction patch. Three of 12 subjects had slight erythema during induction, and there was no evidence of sensitization. The sensitization potential of a pump spray antiperspirant containing 5.0% Isostearyl Alcohol was evaluated using 148 male and female subjects. The product was applied via an occlusive patch to the upper arm for a total of nine induction applications (3 times/week for 3 weeks). Each patch remained for 24 h, and sites were scored immediately before subsequent applications. During the challenge phase, a patch was applied to the induction site and to a new site on the opposite arm of each subject. Reactions were scored 48 and 96 h after application. Ten of the twelve subjects with reactions suggestive of sensitization were re-challenged with the product 2 months later. Patches remained for 24 h, and sites were scored at 48 and 96 h post-application. Six subjects had reactions during the re-challenge. Four of the six subjects were then tested with 5.0% Isostearyl Alcohol in solution with ethanol 6 weeks after scoring of the first rechallenge; all had positive responses. Negative responses were reported when the product (without lsostearyl Alcohol) and 100.0% ethanol each were tested. In a second study, the same product was applied to 60 male and female subjects (same protocol). Five of the subjects had positive responses after the first challenge. One of the five was re-challenged with 5.0% Isostearyl Alcohol in ethanol solution, and a positive reaction was observed. From the CIR final report on Isostearyl Alcohol190

Isopropanol Comedogencity An LDLo of 2-4 ml/kg of isopropyl alcohol has been reported in adults and 6 ml/kg (9 ml/kg 70% isopropyl alcohol) was reported to induce coma in children.


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APPENDIX I – ESTEARSE METABOLITE SUMMARY DATA Decyl Alcohol – metabolite of Decyl Succinate Clinical Irritation and Sensitization Tested in at a concentration of 3% in petrolatum, decyl alcohol produced no irritation in a 48 h closed-patch test in 25 human subjects.177 Methanol – metabolite of Dimethyl Succinate, Dimethyl Glutarate, Dimethyl Adipate Absorption, Distribution, Metabolism, and Excretion

Methanol is further metabolized to formaldehyde and then to formic acid. The CIR Expert Panel concluded that formic acid is safe where used in cosmetic formulations as a pH adjustor with a 64 ppm limit for the free acid.178 The main toxicological risks in humans are severe metabolic acidosis with increased anion gap, typically following oral exposure resulting in > 100 mg/L of formate in the urine.179 The acidosis and the formic acid metabolite are believed to play a central role in both the central nervous system toxicity and the ocular toxicity. A study to determine the formate levels that resulted from exposure of human volunteers to 200 ppm of methanol for 4 h was conducted. Human volunteers (n=27; age 20-55 y) were exposed to 200 ppm methanol (the Occupational Safety and Health Administration [OSHA] Permissible Exposure Limit) for 4 h and to water vapor for 4 h in a double-blind, random study.180 Urine samples were collected at 0, 4 and 8 h and blood samples were collected from the subjects before they entered the chamber, every 15 min for the first hour, every 30 min from the first to the third hour and at 4 h. Urine and serum samples were analyzed for formate (LOD 0.5 mg/L). Twenty-six of 27 enrolled subjects completed the study (11 females and 15 males). The researchers did not find any statistically significant differences in serum or urine formate levels between the two exposure conditions at any time point. At the end of the 4 h methanol exposure, formate concentrations of 14.28 ± 8.90 and 7.14 ± 5.17 mg/L were measured in serum and urine, respectively. Under control conditions, formate concentrations of 12.68 ± 6.43 (p=0.38; n=26) and 6.64 ± 4.26 (p=0.59; n=25) mg/L were measured in serum and urine respectively. After 8 h (4 h of no exposure) the serum concentrations were not statistically different with 12.38 ± 6.53 mg/L under methanol exposure conditions and 12.95 ± 8.01 (P=0.6; n=26) under control conditions. Urine formate concentrations after 8 h were 6.08 ± 3.49 and 5.64 ±3.70 mg/L (p=0.6; n=25) in exposed and control conditions, respectively, and were not statistically significantly different. From CIR Final Report on Methyl Acetate181


Methyl Alcohol caused primary irritation to the skin; prolonged and repeated contact with Methyl Alcohol resulted in de-fatting and dermatitis. In one occupational study, 3.2% of 274 metalworkers with dermatitis had positive results to a patch test of 30% Methyl Alcohol. Typical allergic responses observed after contact with alcohols were eczematous eruption and wheal and flare at the exposure sites. Eczema and erythema were reported after the consumption of alcoholic beverages by persons sensitized to ethyl alcohol. Five percent Methyl Alcohol caused a slight positive (+) reaction in a closed patch test for allergic contact dermatitis, and concentrations of 7% and 70% caused (+++) reactions. From the CIR final report on methyl alcohol182


Clinical data show that Methyl Alcohol can cause severe metabolic acidosis, blindness, and death: toxicity was manifested earlier and at a lower dose compared to ethyl alcohol, but the comparative fatal dose was the same for both alcohols. All routes of exposure were toxicologically equivalent, as the alcohol distributed readily and uniformly throughout all tissues and organs. Individual susceptibilities to Methyl Alcohol varied, but typically, the ingestion of 80 to 150 ml of 80% Methyl Alcohol was fatal. Symptoms of Methyl Alcohol intoxication after ingestion were delayed for 12 to 18 hours; afterwards, the symptoms included headache, anorexia, weakness, fatigue, leg cramps, and/or pain and vertigo. Severe gastrointestinal pain, nausea, vomiting, diarrhea, mania, failed vision, and convulsions could occur. Chronic exposure to Methyl Alcohol could cause edema, granular degeneration, and necrosis of heart muscle fibers, as well as fatty degeneration of the heart muscle; sudden cardiac failure was associated with Methyl Alcohol intoxication. The liver and kidneys often had parenchymatous degeneration, and the liver had focal necrosis and fatty infiltration. Severe acidosis was necessary for the development of blindness. Similar symptoms were observed after percutaneous or inhalation exposure to Methyl Alcohol. From the CIR final report on methyl alcohol182


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Propyl Alcohol – metabolite of Dipropyl Adipate Absorption, Distribution, Metabolism, and Excretion

Rats (strain/sex/number not specified) were exposed via inhalation to 2,000 ppm (8360 mg/m3) for 90 min.183 Propyl acetate was rapidly hydrolyzed to propyl alcohol. During the 90 min exposure period, blood levels of propyl alcohol were between 2.6 and 7.7 fold greater than propyl acetate. From the CIR final report on Methyl Acetate181


The effects of propyl alcohol on fertility were investigated by exposing male Sprague-Dawley rats (18/group) to 0, 3500 or 7000 ppm (0, 8.61 or 17.2 mg/L) propyl alcohol vapor via inhalation 7 h/day, 7days/week for 62 days, prior to mating with unexposed virgin females.184 Female Sprague-Dawley rats (15/group) were similarly exposed and mated with unexposed males. Following parturition, litters were culled to 4/sex and the pups fostered by unexposed dams. The pups were weaned on post natal day (PND) 25 and weighed on PND’s 7, 14, 21, 28 and 35. Male rats exposed to 7000 ppm exhibited a decrease in mating success with 2/16 producing a litter (1 male died as a result of a cage fight and 1 male did not mate). Mating success was not affected in 3500 ppm exposed males or in females. Six males from the 7000 ppm group were retained to determine if this effect was reversible. All 6 males successfully mated 15 weeks after exposure. The authors reported that weight gain was not affected in 7000 ppm exposed females (data not shown), but feed intake was decreased in this treatment group. Crooked tails were observed in 2-3 offspring in 2 of 15 litters from the 7000 ppm maternally exposed group. No other effects on female fertility were reported. No significant differences resulted between offspring of the 7000 ppm group and controls on several behavioral toxicology measures including the Ascent test, Rotorod test, Open Field test, activity test, running wheel activity, avoidance conditioning, and operant conditioning. Activity measures were significantly different between offspring of the 3500 ppm exposure group and controls. From the CIR final report on Methyl Acetate181


A cumulative irritation study was conducted involving 20 male subjects, where the relative irritancy of free fatty acids of different chain lengths was evaluated.185 Equimolar concentrations (0.5 M and 1.0 M) of even- and odd-numbered - straight chain saturated fatty acids were dissolved in propanol. Each Al-test® patch containing a fatty acid (0.5 M) was applied to the interscapular area of 10 subjects, and, similarly, each fatty acid was applied at a higher concentration (1.0 M) to the remaining 10 subjects. A control patch containing propanol was also applied to each subject. Patches remained in place for 24 h and reactions were scored 30 minutes after patch removal. This procedure was repeated daily for a total of 10 applications. In both groups of 10 subjects, there were no reactions to propanol. In an irritation study, wherein 116 healthy male subjects (21 to 55 years old) were patch tested with pelargonic acid at concentrations of 5%, 10%, 20%, and 39.9% in propanol, a propanol-treated control patch was used.186 Dose response curves were developed. Patches (Al-test® discs) were saturated with 0.04 ml of a test solution and applied to the upper back for 48 h. Reactions were scored at 48 h and 96 h post-application. There were no reactions to propanol. In an another irritation study, wherein 16 volunteers (10 females, 6 males; median age of 29.5 years) were patch tested (closed patches, Finn chambers) with 20% pelargonic acid in propanol (pH of 4.3), propanol was one of the controls used.187 Patches were applied to the anterolateral surface of both upper arms for 24 h. Reactions were scored at 24, 48, and 96 h post-application according to the following scale: 0 (no reaction) to 3 (strong positive reaction: marked erythema, infiltration, possibly vesicles, bullae, pustules and/or pronounced crusting). There were no reactions to propanol. A skin irritation study was conducted using 42 healthy, non-atopic male volunteers (mean age = 34 years; skin types: II [20 subjects], III [17 subjects], and IV [5 subjects]).188 Pelargonic acid was patch-tested (Finn chambers, volar forearm) at the following concentrations (in propanol): 40% (12 subjects), 60% (32 subjects), 70% (32 subjects), and 80% (28 subjects), and propanol was used as a control. Each subject received between 3 and 10 patch tests. The patches remained in place for 48 h, and reactions were scored 1 h later according to the following scale: - (no visible reaction) to 4+ (intense erythema with bullous formation). There were no reactions to propanol. In an irritation study, wherein 16 healthy subjects (ages not stated) were patch tested with pelargonic acid (20% in


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propanol), propanol was used as a control.189 Closed patches (Finn chambers) containing the test substance were applied to the anterolateral surface of both upper arms. The patches were removed at 24 h post-application and reactions were scored at 24 h and 96 h post-application. There were no reactions to propanol. In study conducted to investigate a possible seasonal variation in the skin response to pelargonic acid during the winter and summer, propanol was used as a control.190 The study was conducted using 17 healthy volunteers (10 males, 7 females; mean age = 27 years). The test substance was applied (closed patch, Finn chamber) to each arm for 24 h. Reactions were scored at 30 min post-removal. Reactions were not observed at sites treated with propanol, water, or to which an empty chamber was applied. From CIR final report on Methyl Acetate181

Cetyl Alcohol – metabolite of Dicetyl Succinate and Dicetyl Adipate Clinical Irritation and Sensitization

A topical tolerance study involving an 11.5% Cetyl Alcohol cream base was conducted with 80 male subjects, ranging in age from 21 to 52 years and in weight from 120 to 220 pounds. The preparations were applied five times daily (every 3 hours) for 10 days. One subject had erythema, folliculitis, and pustule formation (forearm site). A formulation containing 6.0% Cetyl Alcohol was tested for its skin irritation potential in 20 subjects according to the protocol stated above. The product did not induce skin irritation. In another study, the skin irritation potential of a cream containing 6.0% Cetyl Alcohol was evaluated in 12 female subjects (18-60 years old). The total irritation score (all panelists) for the 21 applications was 418, indicating mild cumulative irritation. The skin irritation and sensitization potential of a product containing 8.4% Cetyl Alcohol was evaluated in 110 female subjects. Fourteen days after scoring of the tenth application site, a challenge patch was applied to each subject and removed after 48 h; sites were scored after patch removal. The product did not induce primary irritation or sensitization. The sensitization potential of a cream containing 3.0% Cetearyl Alcohol was evaluated in 25 subjects (18-25 years old). Following a 10-day non-treatment period, occlusive challenge patches were applied to new sites and removed after 48 h. Sensitization reactions were not observed in any of the subjects. From the CIR final report on cetyl alcohol191

Photosensitization

The photosensitization potential of a lipstick product containing 4.0% Cetyl Alcohol was evaluated in 52 subjects. The experimental procedure was not stated. Photosensitization reactions were not noted in any of the subjects. In another study, a skin care preparation containing 1.0% Cetyl Alcohol did not induce photosensitization in the 407 subjects tested. The experimental procedure was not stated. From CIR final report on cetyl alcohol191

Isopropyl Alcohol – metabolite of Diisopropyl Adipate and Diisopropyl Sebacate Absorption, Distribution, Metabolism, and Excretion

Male rabbits (3/group; strain not specified) were treated by different routes of exposure to compare the absorption and metabolism of isopropyl alcohol.192 Groups 1 and 2 were treated via gavage with the equivalent of 2 and 4 ml/kg absolute isopropyl alcohol, respectively, as a 35% isopropanol/water solution. Groups 3 and 4 were treated via whole-body inhalation for 4 h (towels soaked with isopropyl alcohol were place in the inhalation chamber and replenished at ½ hour intervals to maintained a saturated environment; no exact concentration given), with Group 3 animals receiving an additional dermal exposure in the form of a towel soaked with 70% isopropyl alcohol applied to the animals’ chests and Group 4 animals having plastic barriers on their chests and towels prepared the same way as in Group 3 applied on top of the plastic barriers. The alcohol on the towels was replenished at half hour intervals throughout the duration of the experiment. Blood samples were taken at 0, 1, 2, 3 and 4 h. Samples were analyzed for isopropyl alcohol and the metabolite acetone. Following gavage exposure to 2 or 4 ml/kg, maximum blood levels of 147 and 282 mg/dl, respectively, of isopropyl alcohol were measured. Concentrations of acetone rose steadily over the 4 h period and were 74 and 73 mg/dl


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following exposure to 2 or 4 ml/kg, respectively. The authors stated that the maximum levels of isopropyl alcohol observed in this experiment, correlated with inebriation and near coma in the animals. Following inhalation and dermal exposure, the concentration of isopropyl alcohol in the blood continued to rise and was 112 mg/dl at 4 h while the concentration of acetone was 19 at 4 h. Inhalation exposure with a plastic barrier between the soaked towel and the chest resulted in isopropyl alcohol and acetone blood levels of <10 mg/dl. The researchers concluded that isopropyl alcohol is absorbed by the dermal route but that prolonged dermal exposure (i.e. repeated sponging or soaking for several hours) would be required to produce significant toxicity. From CIR final report on Methyl Acetate181

Subchronic Inhalation Toxicity Fischer 344 rats and CD-1 mice (10/sex/group) were exposed via inhalation to 0, 100, 500, 1500, or 5000 ppm (0, 246, 1230, 3690, or 12,300 mg/m3) isopropyl alcohol for 6 h/day, 5 days/wk for 13 weeks.193 Ataxia, narcosis, hypoactivity and the lack of a startle reflex were observed during exposure at 5000 ppm. Hypoactivity was observed in animals exposed to 1500 ppm isopropyl alcohol. At 13 weeks, no gross lesions were observed. Microscopic examination of control and 5000 ppm exposed animal tissues showed hyaline droplets within the kidneys of male rats only. The size and frequency of the droplets was increased in the treated group. The authors concluded that the NOAEL for this study was 500 ppm and the lowest-observable adverse effect level (LOAEL) was 1500 ppm based upon clinical signs and changes in hematology at 6 weeks. To evaluate the neurobehavioral effects of isopropanol exposure, an additional 15 rats/sex were exposed (via inhalation) to 0, 500, 1500, or 5000 ppm (0, 1230, 3690, or 12,300 mg/m3) for 6 h/day, 5 days/wk for 13 weeks. Isopropyl alcohol did not produce any changes to the parameters of the functional observations battery which was conducted at 1, 2, 4, 9 and 13 weeks. Clinical signs observed in mice, during the exposure, included ataxia, narcosis, hypoactivity and lack of a startle reflex at 5000 ppm. Narcosis, ataxia and hypoactivity were observed in animals exposed to 1500 ppm isopropyl alcohol. At 5000 ppm, increased body weight and increased rate of weight gain were observed in female mice. At 13 weeks, no gross lesions were observed and no treatment-related microscopic changes were observed. A 10% and 21% increase in relative liver weight was observed in female mice at 1500 and 5000 ppm, respectively. The authors concluded that the NOAEL for this study was 500 ppm and the LOAEL was 1500 ppm based on clinical signs and increased liver weights. Ocular Irritation

Isopropyl alcohol has been labeled a severe ocular irritant based on rabbit ocular irritation tests.194 From CIR final report on Methyl Acetate181


Female Sprague-Dawley rats (25/group) were exposed to 0, 400, 800, or 1200 mg/kg/day isopropyl alcohol via gavage on gestational days (GD) 6 through 15.195 Female New Zealand white rabbits (15/group) were exposed to 0, 120, 240, or 480 mg/kg/day isopropyl alcohol via gavage on GD 6 through 18. Animals were observed for body weight, clinical effects and feed consumption and the fetuses examined for body weight, sex and visceral and skeletal alterations at GD 20 for rats and GD 30 for rabbits. In rats, 2 dams died at the 1200 mg/kg dose and 1 dam died at the 800 mg/kg dose. Maternal gestational weight gain was reduced at the highest dose tested. No other effects were observed on maternal reproductive health. Fetal body weights at the two highest doses were decreased statistically. No evidence of teratogenicity was observed at any dose. In rabbits, four does died at the 480 mg/kg dose. Treatment related clinical signs of toxicity were observed at the 480 mg/kg dose and included, cyanosis, lethargy, labored respiration and diarrhea. No treatment related findings were observed at GD 30. Decreased feed consumption and maternal body weights, at 480 mg/kg, were statistically significant. No other effects were observed on maternal reproductive health. No evidence of teratogenicity was observed in the rabbits at any dose. The authors determined NOAEL’s for both maternal and developmental toxicity of 400 mg/kg, each, in rats and 240 and 480 mg/kg, respectively, in rabbits. From CIR final report on Methyl Acetate181

Carcinogenicity

Fischer 344 rats and CD-1 mice (65/rats/sex/group; 55/mice/sex/group) were treated via inhalation with 0, 500, 2500, or 5000 ppm (0, 1230, 6150, or 12,300 mg/m3) isopropyl alcohol for 6 h/day, 5 days/wk for 104 weeks in rats and 78 weeks in mice.193 An additional 10/animals/sex/species were treated with these same concentrations of isopropyl alcohol for 6 h/day, 5 days/wk for 72 weeks in rats and 54 weeks in mice and underwent an interim evaluation. Another 10 mice/sex/group were treated according to the paradigm described above for 54 weeks and then allowed to recover before being killed at 78 weeks. Animals were observed and evaluated for body and organ weights, ophthalmology, and clinical and anatomic pathology. In rats, increased mortality due to chronic renal disease was observed at 5000 ppm (both sexes) and at 2500 ppm (males only). Hypoactivity and lack of startle reflex were observed in 2500 ppm treated rats and hypoactivity, lack of startle


72

reflex and narcosis were observed in 5000 ppm treated rats. With the exception of the ataxia, the clinical signs were transient and ceased when the exposure ended. Increases in body weight, body weight gain, and liver weights were observed in 2500 and 5000 ppm treated rats. Chronic renal disease was exacerbated in rats treated with isopropyl alcohol. Male rats had a concentration related increase in absolute and relative testes weights. At the interim euthanasia (after 72 weeks) male rats treated with 5000 ppm had an increased frequency of testicular seminiferous tubule atrophy upon microscopic evaluation. At the terminal euthanasia (104 weeks), male rats had a concentration dependent increase in the incidence of interstitial (Leydig) cell adenomas of the testes at all administered doses. No other tumor types were increased in rats under these treatment conditions as compared to controls. In mice, no differences in mortality were observed between control and treated animals. Hypoactivity, lack of a startle reflex, narcosis, ataxia, and prostration were observed in 5000 ppm treated mice. Hypoactivity, lack of startle reflex and narcosis were observed in 2500 ppm treated mice. Increases in body weight, body weight gain, and liver weights were observed in 2500 and 5000 ppm treated mice. Male mice in all treatment groups had a decrease in relative testes weights, and female mice exposed to 5000 ppm isopropyl alcohol exhibited decreases in absolute and relative brain weights. At the terminal euthanasia (78 weeks) an increased incidence of minimal to mild renal tubular proteinosis was observed in males and females in all treatment groups. Male mice exposed to 2500 and 5000 ppm exhibited an increased incidence of dilation of the seminal vesicles. No neoplastic lesions were observed in male or female mice. The authors reported a NOAEL for toxic effects of 500 ppm for both rats and mice based on kidney and testicular effects.

IARC (International Agency for Research on Cancer) has determined that isopropyl alcohol is not classifiable as to its carcinogenicity to humans (Group 3). From the CIR final report on Methyl Acetate181


According to unpublished data, a 80.74% spray concentrate caused did not exhibit any potential for dermal sensitization in 9 human subjects.196 According to unpublished HRIPT study on 109 test subjects, a 2.85% hair dye base formulation of isopropyl alcohol and a 1.95% isopropyl acetate caused no dermal sensitization in humans.197 The applicability of fluorescence confocal laser scanning microscopy for in situ imaging of irritant contact dermatitis caused by pelargonic acid using 12 healthy individuals (8 males, 4 males; 18 to 64 years old) was studied.198 Using Finn chambers (occlusive patches), the flexor side of the right and left forearm was exposed to 60 µl of 10% (w/v) pelargonic acid in isopropanol solution and isopropanol vehicle. Isopropanol was used as a control. The Finn chambers were removed at 24 h post-application and reactions were scored according to the following scale: 0 (no visible reaction) to 4+ (intense erythema with bullous formation). Reactions were not observed at sites treated with isopropanol. From the CIR final report on Methyl Acetate181

Hexyl Alcohol – metabolite of Dihexyl Adipate Ocular Irritation Undiluted hexyl alcohol has been labeled as highly irritating on rabbit ocular irritation tests.199 Dermal Sensitization In a maximization test using guinea pigs, hexyl alcohol was not a sensitizer at 1% in petrolatum.199 Caprylic Alcohol – metabolite of Dicapryl Succinate, Dicapryl Adipate and Dicaprylyl/Capryl Sebacate Dermal Irritation – Animals Caprylic alcohol applied full strength to intact or abraded rabbit skin produced a mild irritation.177 Clinical Irritation and Sensitization Tested in at a concentration of 2% in petrolatum, caprylic alcohol produced no irritation in a 48 h closed-patch test in 25 human subjects.177


73

Isobutyl Alcohol – metabolite of Diisopropyl Adipate and Diisopropyl Sebacate Subchronic Inhalation Toxicity

Rats (10/sex/group) were exposed via inhalation to isobutyl alcohol vapor concentrations of approximately 0, 770, 3100, or 7700 mg/m3, for 6 h/day, 5 days/week, for 14 weeks.200 The functional observational battery was conducted along with endpoints of motor activity, neuropathology and scheduled-controlled operant behavior. A slight reduction in responsiveness to external stimuli was observed in all treated groups during exposure. This effect resolved upon cessation of exposure to isobutyl alcohol. From the CIR final report on Methyl Acetate181

Ethylhexyl Alcohol – metabolite of Diethylhexyl Succinate, Diethylhexyl Adipate and Diethylhexyl Sebacate Ocular Irritation Instillation of 20 µg of ethylhexyl alcohol into the conjunctival sac of rabbits caused moderately severe irritation of the cornea.199 Dermal Irritation – Animals Ethylhexyl alcohol was applied under occlusion to the skin of 3 male rabbits for 4 hours and found to be irritating.199 In another study with rabbits, 0.5 ml of ethylhexyl alcohol was applied under occlusion on intact skin for 1, 2, 4, and 24 hours. Irritation was considered high, and effects seen after 7 days were not reversible. Reproductive and Developmental Toxicity A group of female rats was exposed for 7 h per day to 850 mg/m3 of ethylhexyl alcohol on gestation days 1-19.199 Dams were sacrificed at day twenty. Ethylhexyl alcohol reduced maternal feed intake, but did not produce any malformations. The estrogenic activity of 2-ethylhexanoic acid was examined using an E-SCREEN assay using T47D human breast cancer cells.137 Weak estrogenic activity was observed. (Additional details were not provided.) Genotoxicity In vitro, ethylhexyl alcohol was negative in a number of Ames assays, a liquid suspension assay, mouse lymphoma assay, and unscheduled DNA synthesis assay.118,142,143,146,154 In a 3H-thymidine assay, there was a dose-dependent inhibition of 3H-thymi-dine into replicating DNA, with a dose-dependent increase in the ratio of acid-soluble DNA incorporated into the thymidine.143 The urine of rats dosed orally with 1000 mg/kg ethylhexyl alcohol was not mutagenic.153 In vivo, ethylhexyl alcohol was not genotoxic in a mouse micronucleus test or a transformation assay.154 MEHA, Mono-(2-Ethyl-5-Hydroxyhexyl)Adipate,Mono-(2-Ethyl-5-Oxohexyl)Adipate - metabolites of Diethylhexyl Adipate Genotoxicity MEHA was not mutagenic in an Ames assay at concentrations of ≤100084 or 10,000 µg/plate.142 Mono-2(ethyl-5- hydroxy-hexyl)adipate and mono-(2-ethyl-5-oxohexyl)adipate, were not mutagenic in an Ames assay at concentrations of ≤1000 µg/plate.84 Isooctyl Alcohol – metabolite of Diisooctyl Adipate and Diisooctyl Sebacate Subchronic Oral Toxicity In a subchronic gavage toxicity study of a mixture of C7-9, branched alkyl alcohols in rats, a NOEL of 125 mg/kg/day and a lowest-observed effect level of 250 mg/kg/day were determined.118 Reproductive and Developmental Toxicity In an oral gavage developmental toxicity study of a mixture of C7-9, branched alkyl alcohols in rats, a maternal NOAEL of 500 mg/kg and a fetal NOAEL of 1000 mg/kg were reported.199 Genotoxicity A mixture of C7-9, branched alkyl alcohols were not mutagenic in in vitro bacterial and mammalian cell assays.199 Carcinogenicity


74

Ethylhexyl alcohol was not oncogenic in rats dosed, via gavage, with 0, 50, 150, or 500 mg/kg, in an aqueous vehicle with 0.005% Cremophor EL.199 Nonyl Alcohol – metabolite of Diisononyl Adipate Reproductive and Developmental Toxicity In an oral gavage developmental toxicity study of a mixture of C8-10, branched alkyl alcohols in rats, maternal and fetal NOAEL values were each reported to be 144 mg/kg. 199 Isodecyl Alcohol – metabolite of Diisodecyl Adipate Reproductive and Developmental Toxicity In an oral gavage developmental toxicity study of a mixture of C9-11, branched alkyl alcohols in rats, a maternal NOAEL of 158 mg/kg and a fetal NOAEL of 790 mg/kg were reported. 199 Isostearyl Alcohol – metabolite of Diisostearyl Glutarate, Diisostearyl Adipate and Isostearyl Sebacate Clinical Irritation and Sensitization

The skin irritation potential of lsostearyl Alcohol was evaluated in 19 male and female subjects (18-65 years old) at a concentration of 25.0% in petrolatum. The test substance did not induce skin irritation in any of the subjects (Primary Irritation Index = 0.05). In three similar studies, three different lipstick products containing 25.0, 27.0, and 28.0% Isostearyl Alcohol, respectively, were tested according to the same protocol. The three products did not induce skin irritation. The irritation and sensitization potential of Isostearyl Alcohol (25% v/v in 95.0% isopropyl alcohol) was evaluated in 12 male subjects (21-60 years old). Challenge applications were made to original and adjacent sites 2 weeks after removal of the last induction patch. Three of 12 subjects had slight erythema during induction, and there was no evidence of sensitization. The sensitization potential of a pump spray antiperspirant containing 5.0% Isostearyl Alcohol was evaluated using 148 male and female subjects. The product was applied via an occlusive patch to the upper arm for a total of nine induction applications (3 times/week for 3 weeks). Each patch remained for 24 h, and sites were scored immediately before subsequent applications. During the challenge phase, a patch was applied to the induction site and to a new site on the opposite arm of each subject. Reactions were scored 48 and 96 h after application. Ten of the twelve subjects with reactions suggestive of sensitization were re-challenged with the product 2 months later. Patches remained for 24 h, and sites were scored at 48 and 96 h post-application. Six subjects had reactions during the re-challenge. Four of the six subjects were then tested with 5.0% Isostearyl Alcohol in solution with ethanol 6 weeks after scoring of the first rechallenge; all had positive responses. Negative responses were reported when the product (without lsostearyl Alcohol) and 100.0% ethanol each were tested. In a second study, the same product was applied to 60 male and female subjects (same protocol). Five of the subjects had positive responses after the first challenge. One of the five was re-challenged with 5.0% Isostearyl Alcohol in ethanol solution, and a positive reaction was observed. From the CIR final report on Isostearyl Alcohol191

Isopropanol Comedogencity An LDLo of 2-4 ml/kg of isopropyl alcohol has been reported in adults and 6 ml/kg (9 ml/kg 70% isopropyl alcohol) was reported to induce coma in children.


Figure 1. Map of the ester ingredients in this assessment, and associated esterase metabolites.



Adipic Acid

O

HO

HO CH3Methyl alcohol

HO CH3

Ethyl alcohol

Caprylic alcoholCH3HO

CH3OH Cetyl alcohol

OH

O

O

O O

OCH3H3C

Dimethyl Adipate

O

O O

ODiethyl Adipate

HO

Propyl alcohol

O

O O

ODipropyl Adipate

CH3

CH3H3C

H3C CH3

HOButyl alcohol

O

O O

ODibutyl AdipateCH3

H3C CH3

HOHexyl alcohol

O

O O

O(CH2)5CH3CH3(CH2)5

Dihexyl AdipateCH3

O

O O

O(CH2)7CH3CH3(CH2)7

Dicapryl Adipate

O

O O

O(CH2)15CH3CH3(CH2)15

Dicetyl Adipate

Lauryl alcoholHO

O

O O

O(CH2)nCH3CH3(CH2)n

Di-C12-15 Alkyl AdipateCH3

Tridecyl alcoholHO CH3

Myristyl alcoholHO CH3

HO CH3Heptadecyl alcohol

O

O O

O(CH2)12CH3CH3(CH2)12

Ditridecyl Adipate

n = 11-14

Methyl Adipate*

Ethyl Adipate*

Propyl Adipate*

Butyl Adipate*

Hexyl Adipate*

Caprylic Adipate*

C12-15 Alkyl Adipate*

Tridecyl Adipate*

Cetyl Adipate*

O

O OH

O

H3C

O

O OH

OH3C

O

O OH

O

H3C

O

O OH

OH3C

O

O OH

O

CH3(CH2)5

O

O OH

O

CH3(CH2)7

O

O OH

O

CH3(CH2)n n = 11-14

O

O OH

O

CH3(CH2)12

O

O OH

O

CH3(CH2)15

*



H3C

CH3OH

Isobutyl alcohol *

Ethylhexyl alcohol

OH

H3C

H3C

O

O O

O

H3C

CH3CH3

CH3

Diisobutyl Adipate

H3C OH

CH3Isopropyl alcohol

O

O O

OH3C CH3

Diisopropyl AdipateCH3

CH3

O

O O

O

CH3(CH2)3(CH2)3CH3

Diethylhexyl Adipate (DEHA)H3C

CH3

Adipic Acid

O

HO OH

O

O

OO

O(CH2)5(CH2)5

H3C

H3C CH3

CH3

Diisooctyl AdipateIsooctanol

H3C OH

O

OO

O(CH2)6(CH2)6

H3C

H3C CH3

CH3

Diisononyl AdipateIsononyl alcohol *

OHH3C

CH3

O

OO

O(CH2)7(CH2)7

H3C

H3C CH3

CH3

Diisodecyl Adipate

H3C OH

CH3

CH3

Isodecyl alcohol *

O

OO

O (CH2)7CH3CH3(CH2)7

CH3(CH2)4

(CH2)4CH3

H3C OHH3C

Hexyldecanol Dihexyldecyl Adipate

O

OO


CH3(CH2)5

(CH2)5CH3

Diheptylundecyl AdipateHeptylundecanol

H3C OHH3C

O

OO


CH3(CH2)6

(CH2)6CH3

Dioctyldodecyl AdipateOctyldodecanolH3C OH

H3C

O

OO

O(CH2)13(CH2)13

H3C

H3C CH3

CH3

Diisocetyl Adipate

CH3OH Isocetyl alcohol

O

OO

O(CH2)15(CH2)15

H3C

H3C CH3

CH3


OHIsostearyl alcohol

CH3

Isopropyl Adipate*

Isobutyl Adipate*

monoester

*

Isooctyl Adipate*

Isononyl Adipate*

Isodecyl Adipate*

Hexyldecyl Adipate*

Heptylundecyl Adipate*

Octyldodecyl Adipate*

Isocetyl Adipate*

Isostearyl Adipate*

(Branched esters)

O

O OH

OH3C

CH3

O

O OH

O

H3C

CH3

O

O OH

O

CH3(CH2)3

H3CEthylhexyl Adipate

O

OO

OH(CH2)5H3C

H3C

*

O

OO

OH(CH2)6H3C

H3C

O

OO

OH(CH2)7H3C

H3C

O

OO

OHCH3(CH2)7

CH3(CH2)4

O

OO

OHCH3(CH2)8

CH3(CH2)5

O

OO

OHCH3(CH2)9

CH3(CH2)6

O

OO

OH(CH2)13H3C

H3C

O

OO

OH(CH2)15H3C

H3C

CH3

CH3



HO CH3

Ethyl alcohol

Decyl alcoholCH3HO

HOButyl alcohol

CH3

HO

Caprylic alcohol

O

HO OH

OSebacic Acid

O

OO

OH3C CH3

O

OO

OCH3(CH2)3(CH2)3CH3

O

OO

OCH3(CH2)n(CH2)nCH3

O

HOO

O (CH2)15

CH3

CH3

O

OO

OH3C CH3CH3

CH3

O

OO

OCH3(CH2)3(CH2)3CH3

CH3

H3C

O

OO

OCH3(CH2)5(CH2)5CH3

(CH2)2CH3

CH3(CH2)2

O

OO

O (CH2)5

CH3

CH3(CH2)5

H3C

H3C

O

OO

OCH3(CH2)7(CH2)7CH3

(CH2)4CH3

CH3(CH2)4

O

OO

OCH3(CH2)9(CH2)9CH3

(CH2)6CH3

CH3(CH2)6

O

OO

O (CH2)15

CH3

CH3(CH2)15

H3C

H3C

Ethyl Sebacate*

Butyl Sebacate*

Caprylyl/Capryl Sebacate*

Diethyl Sebacate

Dibutyl Sebacate

n = 7 or 9

Dicaprylyl/Capryl Sebacate

Isostearyl Sebacate

Isopropyl Sebacate*

Ethylhexyl Sebacate*

Butyloctyl Sebacate*

Isooctyl Sebacate*

Hexyldecyl Sebacate*

Octyldodecyl Sebacate*

H3C OH

CH3Isopropyl alcohol

CH3

Ethylhexyl alcohol *

OH

H3C

H3C

H3C OH

H3C

Butyloctanol

H3C OHCH3

Isooctanol

H3C OHH3C

Hexyldecanol

OctyldodecanolH3C OH

H3C

H3C O H

CH3 Isostearyl alcohol



Dibutyloctyl Sebacate

Diisooctyl Sebacate

Dihexyldecyl Sebacate

Dioctyldodecyl Sebacate

Diisostearyl Sebacate

O

OO

OHH3C

O

OO

OHCH3(CH2)3

O

OO

OHCH3(CH2)n

O

OO

OHH3C

CH3

O

OO

OHCH3(CH2)3

H3C

O

OO

OHCH3(CH2)5

CH3(CH2)2

O

OO

OH(CH2)5H3C

H3C

+

O

OO

OHCH3(CH2)7

CH3(CH2)4+

O

OO

OHCH3(CH2)9

CH3(CH2)6+

n = 7 or 9


Figure 2. Sebacic acid synthesis from castor oil.


Figure 3. Diethylhexyl adipate synthesis from adipic acid.


Chart 1. Log Kow vs Molecular Weight: Alkyl Dicarboxylic Acids


Chart 2. Log Kow vs Molecular Weight: Alkyl Dicarboxylic Acids and Salts


Chart 3. Log Kow vs Molecular Weight: Esters of Alkyl Dicarboxylic Acids


Table 1. Definitions, functions and structures of dicarboxylic acid, salt and ester ingredients in this safety assessment.

Ingredient CAS No.

Definition Function(s) Formula/structure

Dicarboxylic Acids and Metal Salts Malonic Acid 141-82-2

Malonic Acid is a three carbon, straight-chain alkyl dicarboxylic acid.

Fragrance Ingredients; pH Adjusters

Succinic Acid 110-15-6

Succinic Acid is a four carbon, straight-chain alkyl dicarboxylic acid.


O

HOO

OH

Sodium Succinate 2922-54-5

Sodium Succinate is the monosodium salt of succinic acid.

Buffering Agents; pH Adjusters

Disodium Succinate 150-90-3

Disodium Succinate is the disodium salt of succinic acid.

Fragrance Ingredients; Not Reported

Glutaric Acid 110-94-1

Glutaric Acid is a five carbon, straight-chain alkyl dicarboxylic acid.


Adipic Acid 124-04-9

Adipic Acid is a six carbon, straight-chain alkyl dicarboxylic acid.


Azelaic Acid 123-99-9

Azelaic Acid is an eight carbon, straight-chain alkyl dicarboxylic acid.


Disodium Azelate 17265-13-3

Disodium Azelate is the disodium salt of azelaic acid.

Not Reported

Dipotassium Azelate 19619-43-3

Dipotassium Azelate is the dipotassium salt of azelaic acid.

Not Reported

Sebacic Acid 111-20-6

Sebacic Acid is a ten carbon, straight-chain alkyl dicarboxylic acid.

pH Adjusters

Disodium Sebacate 17265-14-4

Disodium Sebacate is the disodium salt of sebacic acid.

Not Reported

Dodecanedioic Acid 693-23-2

Dodecanedioic Acid is a twelve carbon, straight-chain alkyl dicarboxylic acid.

Skin-Conditioning Agents - Miscellaneous

Malonic Diester Ingredient Diethyl Malonate 105-53-3

Diethyl Malonate is the diester of ethanol and malonic acid.

Fragrance Ingredients

Succinic Ester Ingredients Monoester Decyl Succinate 54482-22-3 (wrong CAS No. 2530-33-8)

Decyl Succinate is the monoester of decyl alcohol and succinic acid.

Skin-Conditioning Agents - Emollient

Diesters Dimethyl Succinate 106-65-0

Dimethyl Succinate is the diester of methyl alcohol and succinic acid.

Nail Polish and Enamel Removers

Diethyl Succinate 123-25-1

Diethyl Succinate is the diester of ethyl alcohol and succinic acid.

Fragrance Ingredients; Plasticizers; Solvents



Ingredient CAS No.


Dicapryl Succinate 14491-66-8

Dicapryl Succinate is the diester of caprylic alcohol and succinic acid.

Film Formers; Hair Conditioning Agents; Nail Conditioning Agents; Plasticizers; Skin-Conditioning Agents - Emollient

Dicetearyl Succinate 93280-98-9

Dicetearyl Succinate is the diester of cetearyl alcohol and succinic acid.

Skin-Conditioning Agents - Miscellaneous wherein n=15 or 17

Branched Diisobutyl Succinate 925-06-4

Diisobutyl Succinate is the diester of isobutyl alcohol and succinic acid.

Plasticizers

Diethylhexyl Succinate 2915-57-3

Diethylhexyl Succinate is the diester of 2-ethylhexyl alcohol and succinic acid.

Plasticizers; Skin-Conditioning Agents - Emollient; Solvents

Glutaric Ester Ingredients Dimethyl Glutarate 1119-40-0

Dimethyl Glutarate is the diester of methyl alcohol and glutaric acid.

Nail Polish and Enamel Removers

Branched Diisobutyl Glutarate 71195-64-7

Diisobutyl Glutarate is the diester of isobutyl alcohol and glutaric acid.

Plasticizers

Diisostearyl Glutarate No CAS No.

Diisostearyl Glutarate is the diester of isostearyl alcohol and glutaric acid.


One example of an “iso”

Adipic Ester Ingredients Dimethyl Adipate 627-93-0

Dimethyl Adipate is the diester of methyl alcohol and adipic acid.


Diethyl Adipate 141-28-6

Diethyl Adipate is the diester of ethyl alcohol and adipic acid.

Fragrance Ingredients; Skin-Conditioning Agents - Emollient

Dipropyl Adipate 106-19-4

Dipropyl Adipate is the diester of propyl alcohol and adipic acid.

Skin-Conditioning Agents - Emollient; Solvents

Dibutyl Adipate 105-99-7

Dibutyl Adipate is the diester of butyl alcohol and adipic acid.

Nail Polish and Enamels; Suntan Gels, Creams, and Liquids

Dihexyl Adipate 110-33-8

Dihexyl Adipate is the diester of hexyl alcohol and adipic acid.




Ingredient CAS No.


Dicapryl Adipate 105-97-5

Dicapryl Adipate is the diester of capryl alcohol and adipic acid.

Plasticizers

Di-C12-15 Alkyl Adipate No CAS No.

Di-C12-15 Alkyl Adipate is the diester of C12-15 alcohols and adipic acid.

Skin-Conditioning Agents - Emollient wherein n=11, 12, 13 or 14

Ditridecyl Adipate 16958-92-2

Ditridecyl Adipate is the diester of tridecyl alcohol and adipic acid.


Dicetyl Adipate 26720-21-8

Dicetyl Adipate is the diester of cetyl alcohol and adipic acid.


Branched Diisopropyl Adipate 6938-94-9

Diisopropyl Adipate is the diester of isopropyl alcohol and adipic acid.

Fragrance Ingredients; Plasticizers; Skin-Conditioning Agents - Emollient; Solvents

Diisobutyl Adipate 141-04-8

Diisobutyl Adipate is the diester of isobutyl alcohol and adipic acid.


Diethylhexyl Adipate 103-23-1

Diethylhexyl Adipate is the diester of a 2-ethylhexyl alcohol and adipic acid.


Diisooctyl Adipate 108-63-4

Diisooctyl Adipate is the diester of isooctyl alcohol and adipic acid.



Diisononyl Adipate 33703-08-1

Diisononyl Adipate is the diester of isononyl alcohol and adipic acid.



Diisodecyl Adipate 27178-16-1

Diisodecyl Adipate is the diester of isodecyl alcohol and adipic acid.



Dihexyldecyl Adipate 57533-90-1

Dihexyldecyl Adipate is the diester of hexyldecanol and adipic acid.


Diheptylundecyl Adipate 155613-91-5

Diheptylundecyl Adipate is the diester of heptylundecanol and adipic acid.




Ingredient CAS No.


Dioctyldodecyl Adipate 85117-94-8

Dioctyldodecyl Adipate is the diester of octyldodecanol and adipic acid.

Plasticizers; Skin-Conditioning Agents - Emollient

Diisocetyl Adipate 59686-69-0 sec: 58262-41-2

Diisocetyl Adipate is the diester of hexadecyl alcohol and adipic acid.



Diisostearyl Adipate 62479-36-1

Diisostearyl Adipate is the diester of isostearyl alcohol and adipic acid.

Plasticizers; Skin-Conditioning Agents - Emollient


Sebacic Ester Ingredients Diethyl Sebacate 110-40-7

Diethyl Sebacate is the diester of ethyl alcohol and sebacic acid.


Dibutyl Sebacate 109-43-3

Dibutyl Sebacate is the diester of butyl alcohol and sebacic acid.


Dicaprylyl/ Capryl Sebacate No CAS. No.

Dicaprylyl/Capryl Sebacate the diester of caprylic and capryl alcohol, and sebacic acid.


wherein n=7 or 9

Branched Monoester Isostearyl Sebacate 478273-24-4

Isostearyl Sebacate is the monoester of isostearyl alcohol and sebacic acid.

Skin-Conditioning Agents - Miscellaneous


Branched Disesters Diisopropyl Sebacate 7491-02-3

Diisopropyl Sebacate is the diester of isopropyl alcohol and sebacic acid.


Diethylhexyl Sebacate 122-62-3

Diethylhexyl Sebacate is the diester of 2-ethylhexyl alcohol and sebacic acid.

Fragrance Ingredients; Plasticizers; Solvents

Dibutyloctyl Sebacate 184706-97-6

Dibutyloctyl Sebacate is the diester of butyloctyl alcohol and sebacic acid.




Ingredient CAS No.


Diisooctyl Sebacate 10340-41-7

Diisooctyl Sebacate is the diester of isooctyl alcohol and sebacic acid.

Antioxidants; Plasticizers; Skin-Conditioning Agents - Emollient


Dihexyldecyl Sebacate 359073-59-9

Dihexyldecyl Sebacate is the diester of hexyldecyl alcohol and sebacic acid.


Dioctyldodecyl Sebacate 69275-01-0

Dioctyldodecyl Sebacate is the diester of octyldodecanol and sebacic acid.


Diisostearyl Sebacate No CAS No.

Diisostearyl Sebacate is the diester of isostearyl alcohol and sebacic acid.



Dodecanoic Ester Ingredients Dioctyldodecyl Dodecanedioate 129423-55-8

Dioctyldodecyl Dodecanedioate is the diester of octyldodecanol and dodecanedioic acid.

Hair Conditioning Agents; Skin-Conditioning Agents - Miscellaneous

Diisocetyl Dodecanedioate 131252-83-0

Diisocetyl Dodecanedioate is the diester of octyldodecanol and dodecanedioic acid.

Skin-Conditioning Agents - Emollient; Surfactants - Emulsifying Agents



Table 2a. Physical and Chemical properties of the alkyl dicarboxylic acid and salt ingredients. INCI Name Malonic

Acid Succinic

Acid Sodium

Succinate Disodium Succinate

Glutaric Acid

Adipic Acid

Appearance small crystals

colorless prisms

crystalline crystalline large monoclinic

prisms

white, monoclinic

prisms

Molecular Weight (g/mol)

104.06 118.09 140.07 162.05 132.11 146.14

Melting/Boiling Point (°C)

135 (dec.)/ 264 (est.)

185-187/ 235

206 (est.)/ 486 (est.)

156 (est.)/ 426 (est.)

97.5-98/ 302-304

152/265

Density (g/cm3) 1.63 1.56 -- -- 1.429 1.360

Vapor pressure (mm Hg @ 25°C)

0.001 (est.) 0.0000002 7.3 E-10 (est.) 8.7 E-8 (est.)

0.000003 0.07

Solubility (g/L water @ 25°C)

1520 83 1000 (est.) 31 (est.) 639 30

Log Kow -0.81 -0.59 -3.98 (est.) -3.98 (est.) -0.29 0.08

INCI Name Azelaic Acid

Disodium Azelate

Dipotassium Azelate

Sebacic Acid

Disodium Sebacate

Dodecanedioic Acid

Appearance monoclinic prismatic needles

crystalline crystalline Monoclinic prismatic

tablets

crystalline --


188.22 238.18 264.40 202.25 246.21 230.31


106.5/ 286.5

186 (est.)/ 484 (est.)

186 (est.)/ 484 (est.)

134.5/ 294.5

194/496 (est.)

128/383 (est.)

Density (g/cm3) 1.0291 -- -- 1.207 -- 1.16


0.00002 (est.)

1.4 E-9 (est.)

1.4 E-9 (est.) 0.000007 (est.)

5.9 E-10 (est.)

0.000002 (est.)


2.4 1000 (est.) 1000 (est.) 1.0 1000 (est.) 0.040

Log Kow 1.57 -3.56 (est.) -3.56 (est.) 2.19 (est.) -3.01 (est.) 3.17 (est.)


Table 2b. Physical and Chemical properties of the mono- and di-carboxylic acid esters. INCI Name Diethyl

Malonate Decyl

Succinate Dimethyl Succinate

Diethyl Succinate

Dicapryl Succinate

Dicetearyl Succinate

Diisobutyl Succinate

Appearance colorless liquid

-- -- liquid -- -- liquid


160.17 258.35 146.14 174.19 342.51 566-623 230.30


-50/ 198-199

96/377 (est.)

19.5/196.1 -21.3/217.7 14 (est.)/ 375 (est.)

--/-- -48 (est.)/ 216

Density (g/cm3) 1.055 1.002 (est.)

1.1 1.04 0.94 (est.) -- 0.967


0.269 0.000001 (est.)

0.4 (est.) 0.126 0.000008 (est.)

-- 0.019 (est.)


20 20 (est.) 50 (est.) 10 (est.) 0.0015 (est.)

-- 0.60 (est.)

Log Kow 0.96 4.57 (est.) 0.26 (est.) 1.28 (est.) 7.39 (est.) -- 3.00 (est.) INCI Name Diethylhexyl

Succinate Dimethyl Glutarate

Diisobutyl Glutarate

Diisostearyl Glutarate

Dimethyl Adipate

Diethyl Adipate

Dipropyl Adipate

Appearance -- liquid -- -- -- -- --


342.51 160.17 244.33 637.07 174.19 202.25 230.30


-12 (est.)/ 359 (est.)

-42.5/ 214.2

-38 (est.)/ 237

212 (est.)/ 600 (est.)

210/229 (est.)

24-26/ 248-249

-15.7/ 274 (est.)

Density (g/cm3) 0.933 1.0876 0.97 (est.) -- 1.062 1.08 0.98


0.00002 0.185 (est.)

0.008 (est.)

7.8 E-13 (est.)

0.073 (est.)

0.027 (est.)

0.0055 (est.)


0.002 (est.) 27 (est.) 0.29 (est.) 1.16 E-16 (est.)

14 (est.) 2.8 (est.)

0.62 (est.)

Log Kow 7.08 (est.) 0.57 (est.) 3.44 (est.) 17.5 (est.) 0.95 (est.)

1.97 (est.)

2.99 (est.)


INCI Name Dibutyl Adipate

Dihexyl Adipate

Dicapryl Adipate

Di-C12-15 Alkyl Adipate

Ditridecyl Adipate

Dicetyl Adipate

Diisopropyl Adipate

Appearance -- liquid -- -- -- -- liquid


258.35 314.46 426.67 482-567 510.83 594.99 230.30


37.5/300 (est.)

-8/351 (est.)

26.5-27.1/ 442 (est.)

--/-- 45.9/503 (est.)

56.5-57/ 559 (est.)

-1.1/253 (est.)

Density (g/cm3) 0.96 0.95 (est.)

0.92 (est.) -- 0.91 (est.) 0.897 (est.) 0.982 (est.)


0.0011 (est.)

0.00004 (est.)

0.00000005 (est.)

-- 3.0 E-10

(est.) 1.5 E-12 (est.)

0.0192 (est.)


0.14 (est.) 0.0082 (est.)

0.000041 (est.)

-- 0.0000011 (est.)

0.00000005 (est.)

0.78 (est.)

Log Kow 4.0 (est.) 6.0 (est.) 10.1 (est.) -- 13.8 (est.) 17 (est.) 2.68 (est.)

INCI Name Diisobutyl

Adipate Diethylhexyl

Adipate Diisooctyl Adipate

Diisononyl Adipate

Diisodecyl Adipate

Dihexyldecyl Adipate

Appearance liquid liquid -- -- -- --


258.35 370.57 370.57 398.62 426.67 594.99


-20/278-280 -67.8/390 9 (est.)/ 382 (est.)

56 (est.)/ 230

51 (est.)/ 426 (est.)

181 (est.)/ 548 (est.)

Density (g/cm3) 0.95 0.925 0.93 (est.) -- -- 0.896 (est.)


0.0036 (est.)

0.0000009 0.000004 (est.)

3.3 E-6 (est.)

1.9 E-6 (est.)

4.6 E-12 (est.)


0.18 0.00078 0.00067 (est.)

4.0 E-5 (est.)

5.2 E-6 (est.)

0.00000006 (est.)

Log Kow 3.70 (est.) 6.11 7.77 (est.) 9.24 (est.) 10.1 (est.) 16.6 (est.)


INCI Name Diheptylundecyl Adipate

Dioctyldodecyl Adipate

Diisocetyl Adipate


Diethyl Sebacate

Dibutyl Sebacate

Appearance -- -- -- -- liquid liquid


651.10 707.20 594.99 651.10 258.35 314.46


229 (est.)/ 584 (est.)

267 (est.)/ 619 (est.)

181 (est.)/ 565 (est.)

229 (est.)/ 611 (est.)

5/298 -10/ 344-345

Density (g/cm3) 0.892 (est.) 0.888 (est.) 0.896 (est.)

-- 0.969 (est.)

0.94


1.26 E-13 (est.) 3.17 E-15 (est.) 1.4 E-11 (est.)

2.4 E-13 (est.)

0.00054 (est.)

0.00004 (est.)


9.8 E-9 (est.) 2.1 E-9 (est.) 4.0 E-12 (est.)

3.6 E-14 (est.)

0.15 (est.)

0.0085 (est.)


5.96 (est.)

INCI Name Dicaprylyl/

capryl Sebacate

Isostearyl Sebacate



Dibutyloctyl Sebacate

Diisooctyl Sebacate

Appearance -- -- -- -- -- --


426-482 454.73 286.41 426.67 538.89 426.67


--/-- 215 (est.)/ 545 (est.)

-7 (est.)/ 308 (est.)

-48/436 (est.)

135 (est.)/ 510 (est.)

51 (est.)/ 428 (est.)

Density (g/cm3) -- 0.929 (est.) 0.953 (est.) 0.91 0.901 (est.) 0.916 (est.)


-- 2.5 E-13 (est.)

0.0007 (est.)

8.7 E-8 (est.) 1.6 E-10 (est.) 1.6 E-7 (est.)


-- 0.0013 (est.)

0.046 0.00006 (est.)

0.0000006 (est.)

0.00006 (est.)

Log Kow -- 11.2 (est.) 4.63 (est.) 9.72 (est.) 14.1 (est.) 9.72 (est.)


Table 2b. Physical and Chemical properties of the mono- and di-carboxylic acid esters. (continued)

INCI Name Dihexyldecyl Sebacate

Dioctyldodecyl Sebacate

Diisostearyl Sebacate



Appearance -- -- -- -- --


651.10 763.31 707.20 791.36 679.15


229 (est.)/ 584 (est.)

299 (est.)/ 652 (est.)

268 (est.)/ 568 (est.)

314 (est.)/ 668 (est.)

247 (est.)/ 635 (est.)

Density (g/cm3) 0.892 (est.) 0.885 (est.) -- 0.884 (est.) --


1.3 E-13 (est.) 7.4 E-17 (est.) 4.8 E-15 (est.)

1.1 E-17 (est.) 3.6 E-14 (est.)


0.0000001 (est.)

6.8 E-10 (est.) 3.2 E-16 (est.)

3.6 E-10 (est.) 3.4 E-15 (est.)


“(est.)” = estimated value by EPI Suite “(dec.)” = some decomposition occured “--“ = Value not found “E-13” = divided by 1013


24

Table 3a. Frequency and concentration of use by duration and exposure - Dicarboxylic Acids and Their Salts

2010 Uses (VCRP)

2010 Conc. of Use (%) (Council)

2010 Uses (VCRP)


2010 Uses (VCRP)


Succinic Acid Sodium Succinate Disodium SuccinateTotals 4 0.001-26 7 NR 45 0.0005-0.4Duration of UseLeave-On 2 0.001-0.2 3 NR 38 0.005-0.4Rinse Off 2 0.001-26 4 NR 7 0.0005Exposure TypeEye Area NR NR NR NR 4 NRPossible Ingestion NR NR NR NR NR NRInhalation NR NR NR NR NR NRDermal Contact 2 0.01-26 5 NR 40 0.0005-0.4Deodorant (Underarm) NR NR NR NR NR NRHair, Non-Coloring 2 0.001-0.2 2 NR 5 NRHair, Coloring NR NR NR NR NR NRNail NR NR NR NR NR NRMucous Membrane NR 0.2 1 NR NR NRBath Products NR 26 1 NR NR NRBaby Products NR NR NR NR NR NR

Adipic Acid Azelaic Acid Sebacic AcidTotals 25 0.000001-18 9 0.007-10 12 0.0009-1Duration of UseLeave-On 2 0.000001 7 0.007-0.3 9 0.0009-0.03Rinse Off 23 0.5-18 2 10 3 0.001-1Exposure TypeEye Area NR 0.000001 NR NR NR NRPossible Ingestion NR 0.000001 NR NR NR NRInhalation NR NR NR NR NR NRDermal Contact 1 0.000001-18 25 0.007-10 12 0.0009-1Deodorant (Underarm) NR NR NR NR NR 0.0009H i N C l iHair, Non-Coloring 24 0 50.5 NRNR NRNR NRNR NRNRHair, Coloring NR NR NR NR NR NRNail NR NR NR NR NR NRMucous Membrane - NR NR NR 1 0.04Bath Products 1 15-18 NR NR NR NRBaby Products NR NR NR NR NR NR


Dio

ctyl

dode

cyl A

dipa

te

Dim

ethy

l Adi

pate

1N

R38

NR

220

001

31

NR

NR

63

NR

Tab

le 3

b. F

requ

ency

and

con

cent

ratio

n of

use

by

dura

tion

and

expo

sure

- E

ster

s of D

icar

boxy

lic A

cids

2010

U(V

CR

ses

P)

2010

CU

se(C

ou

onc.

of

(%)

ncil)

2010

Use

s (V

CRP

)

2010

Con

c. o

fU

se (%

) (C

ounc

il)

20

10 U

ses

(VC

RP)

20

10 C

of U

se

(Cou

nonc.

(%

) ci

l)20

10 U

(VC

Rse

s P)

2010

U

s(C

oCon

c. o

f e

(%)

unci

l)20

10 U

ses

(VC

RP)

2010

Con

c. o

f U

se (%

) (C

ounc

il)20

10 U

ses

(VC

RP)

2010

Con

c.

of U

se (%

) (C

ounc

il)D

ieth

yl M

alon

aD

imet

hyl S

teuc

cina

teD

ieth

Dic

apry

l Suc

cina

teyl

hexy

l Suc

cina

teD

imet

hyl G

luta

rate

Tot

als

NR

0.00

4-0.

0212

0.00

2-5

12 N

R38

0.02

-613

0.5-

1512

0.2

Dur

atio

n of

Use

Leav

e-O

nN

R0.

02N

R0.

002

9N

R34

0.02

-6N

RN

RN

RN

RRi

nse

Off

NR

0.00

4-0.

0112

0.2-

5N

RN

R4

3-5

130.

5-15

120.

2E

xpos

ure

Type

Eye

Are

aN

RN

RN

R0.

002

NR

NR

1N

RN

RN

RN

RN

RPo

ssib

le In

gest

ion

NR

NR

NR

NR

NR

NR

NR

3N

RN

RN

RN

RIn

hala

tion

NR

NR

NR

NR

1N

RN

R1

NR

NR

NR

NR

Der

mal

Con

tact

NR

0.00

4-0.

02N

R0.

002-

58

NR

341-

6N

R15

NR

NR

Deo

dora

nt (U

nder

arm

)N

RN

RN

RN

RN

RN

RN

RN

RN

RN

RN

RN

RH

air,

Non

-Col

orin

gN

RN

RN

RN

R1

NR

40.

02-5

NR

NR

NR

NR

Hai

r, C

olor

ing

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Nai

lN

RN

R12

0.2

NR

NR

NR

NR

130.

512

0.2

Muc

ous M

embr

ane

NR

NR

NR

NR

2N

R1

NR

NR

NR

NR

NR

Bat

h Pr

oduc

tsN

RN

RN

RN

RN

RN

RN

RN

RN

RN

RN

RN

RB

aby

Prod

ucts

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Dih

exyl

Adi

pate

Diis

obu

Dic

apry

l Adi

pate

tyl A

dipa

teD

iisod

ecyl

Adi

pate

Dih

epty

lund

ecyl

Adi

pate

Tot

als

13

43N

R22

0.00

1-3

1N

RN

R6

3N

RD

urat

ion

of U

seLe

ave

On

Leav

e-O

n1

NR

38N

R22

000

1.

31

-N

RN

R6

3N

RRi

nse

Off

NR

35

NR

NR

0.00

2-0.

5N

RN

RN

RN

RN

RN

RE

xpos

ure

Type

Eye

Are

aN

R3

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Poss

ible

Inge

stio

nN

RN

RN

RN

RN

RN

RN

RN

RN

RN

R3

NR

Inha

latio

nN

RN

R1

NR

50.

05-3

NR

NR

NR

NR

NR

NR

Der

mal

Con

tact

13

43N

R8

0.00

2-3

1N

RN

R6

3N

RD

eodo

rant

(Und

erar

m)

NR

NR

30N

RN

RN

RN

RN

RN

RN

RN

RN

RH

air,

Non

-Col

orin

gN

RN

RN

RN

R5

0.05

-0.2

NR

NR

NR

NR

NR

NR

Hai

r, C

olor

ing

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Nai

lN

RN

RN

RN

R9

0.00

1-0.

7N

RN

RN

RN

RN

RN

RM

ucou

s Mem

bran

eN

RN

RN

RN

RN

R0.

009

NR

NR

NR

NR

NR

NR

Bat

h Pr

oduc

tsN

RN

R5

NR

NR

0.5

NR

NR

NR

NR

NR

NR

Bab

y Pr

oduc

tsN

RN

RN

RN

RN

RN

RN

RN

RN

RN

RN

RN

R


Diis

ooct

yl S

ebac

ate

Tab

le 3

b. F

requ

ency

and

con

cent

ratio

n of

use

by

dura

tion

and

expo

sure

- E

ster

s of D

icar

boxy

lic A

cids

(con

tinue

d)

2010

U(V

CR

ses

P)

2010

CU

se(C

ou

onc.

of

(%)

ncil)

2010

Use

s (V

CRP

)

2010

Con

c. o

fU

se (%

) (C

ounc

il)

20

10 U

ses

(VC

RP)

20

10 C

of U

se

(Cou

nonc.

(%

) ci

l)20

10 U

(VC

Rse

s P)

2010

U

s(C

oCon

c. o

f e

(%)

unci

l)20

10 U

ses

(VC

RP)

2010

Con

c. o

f U

se (%

) (C

ounc

il)20

10 U

ses

(VC

RP)

2010

Con

c.

of U

se (%

) (C

ounc

il)D

iisos

tear

yl A

diD

ieth

yl S

epa

teba

cate

Diis

Isos

tear

yl S

ebac

ate

opro

pyl S

ebac

ate

Die

thyl

hexy

l Seb

acat

eT

otal

s6

3-10

NR

1.5

NR

0.00

5-0.

730

0.06

-10

130.

5-5

NR

1-3

Dur

atio

n of

Use

Leav

e-O

n4

10N

R1.

5N

R0.

005-

0.7

290.

06-1

013

0.5-

5N

R1-

3Ri

nse

Off

23

NR

NR

NR

NR

12

NR

1N

RN

RE

xpos

ure

Type

Eye

Are

aN

RN

RN

RN

RN

RN

R1

NR

4N

RN

RN

RPo

ssib

le In

gest

ion

410

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Inha

latio

nN

RN

RN

RN

RN

RN

R1

NR

NR

1N

RN

RD

erm

al C

onta

ct6

3-10

NR

1.5

NR

0.00

5-0.

723

0.06

-10

110.

5-5

NR

1-3

Deo

dora

nt (U

nder

arm

)N

RN

RN

RN

RN

RN

R4

1N

R0.

5N

RN

RH

air,

Non

-Col

orin

gN

RN

RN

RN

RN

RN

R6

82

NR

NR

NR

Hai

r, C

olor

ing

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Nai

lN

RN

RN

RN

RN

RN

R1

0.08

NR

NR

NR

NR

Muc

ous M

embr

ane

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Bat

h Pr

oduc

tsN

RN

RN

RN

RN

RN

RN

RN

RN

RN

RN

RN

RB

aby

Prod

ucts

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Dio

ctyl

dode

cyl S

ebac

ate

Dio

ctyl

doD

odec

ane

Diis

ocet

yl

decy

l di

oate

Dod

ecan

edio

ate

Tot

als

NR

3-8

56

20.

9-7

Dur

atio

n of

Use

Leav

e-O

nN

R3-

85

62

0.9-

7Ri

nse

Off

NR

NR

NR

NR

NR

NR

Exp

osur

e Ty

peEy

e A

rea

NR

NR

NR

NR

NR

NR

Poss

ible

Inge

stio

nN

R8

16

NR

NR

Inha

latio

nN

R3-

52

NR

NR

0.9-

3D

erm

al C

onta

ctN

R3-

85

62

0.9-

7D

eodo

rant

(Und

erar

m)

NR

NR

NR

NR

NR

NR

Hai

r, N

on-C

olor

ing

NR

NR

NR

NR

NR

NR

Hai

r, C

olor

ing

NR

NR

NR

NR

NR

NR

Nai

lN

RN

RN

RN

RN

RN

RM

ucou

s Mem

bran

eN

RN

RN

RN

RN

RN

RB

ath

Prod

ucts

NR

NR

NR

NR

NR

NR

Bab

y Pr

oduc

tsN

RN

RN

RN

RN

RN

R

NR

- no

ne re

porte

d


Tabl

e 3c

. C

urre

nt a

nd h

isto

rical

freq

uenc

y an

d co

ncen

tratio

n of

use

acc

ordi

ng to

dur

atio

n an

d ty

pe o

f exp

osur

e -

prev

ious

ly re

view

ed e

ster

s

# of

Use

sC

onc.

of U

se (%

)#

of U

ses

Con

c. o

f Use

(%)

# of

Use

sC

onc.

of U

se (%

)D

ibut

yl A

dipa

teD

iisop

ropy

l Adi

pate

Die

thyl

hexy

l Adi

pate

data

yea

r20

0220

1020

0220

1019

8120

1019

8120

1019

8120

1019

8120

10T

otal

sN

R6

5-8

NR

112

70≤0

.1-2

50.

005-

827

48≤0

.1-2

50.

6-14

Dur

atio

n of

Use

Leav

e-O

nN

R6

5-8

NR

9264

≤0.1

-25

0.00

5-8

2139

≤0.1

-10

0.9-

14Ri

nse

Off

NR

0N

RN

R20

6≤0

.1-2

62-

76

91-

250.

6Ex

posu

re T

ype

Eye

Are

aN

R2

NR

NR

22

1-25

1N

R3

NR

NR

Poss

ible

Inge

stio

nN

RN

RN

RN

RN

R1

NR

NR

51

1-5

NR

Inha

latio

nN

R2

NR

NR

4721

0.1-

250.

005-

86

51-

5N

RD

erm

al C

onta

ctN

R3

8N

R10

250

≤0.1

-25

0.00

5-8

2543

≤0.1

-25

0.6-

14D

eodo

rant

(und

erar

m)

NR

NR

NR

NR

NR

6N

RN

R1

NR

0.1-

10.

9H

air -

Non

-Col

orin

gN

RN

RN

RN

R10

17≤0

.1-5

0.5-

3N

R1

NR

NR

Hai

r-C

olor

ing

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Nai

lN

R1

5N

RN

RN

RN

RN

R2

41-

52-

3M

ucou

s Mem

bran

eN

RN

RN

RN

R1

NR

0.1-

1N

RN

R1

NR

NR

Bat

h Pr

oduc

tsN

RN

RN

RN

R8

11-

252

4N

R10

-25

NR

Bab

y Pr

oduc

tsN

RN

RN

RN

RN

RN

RN

RN

RN

R1

NR

NR

NR

- no

t rep

orte

d to

the

VC

RP

or th

e C

ounc

il


Table 3d. Ingredients not reported to be used Dicarboxylic Acids and Their Salts Malonic Acid Glutaric Acid Disodium Azelate Dipotassium Azelate Disodium Sebacate Dodecanedioic Acid Esters of Dicarboxylic Acids Decyl Succinate Diethyl Succinate Dicetearyl Succinate Diisobutyl Succinate Diisobutyl Glutarate Diisostearyl Glutarate Diethyl Glutarate Dipropyl Glutarate Di-C 12-15 Alkyl Adipate Ditridecyl Adipate Dicetyl Adipate Diisooctyl Adipate Diisononyl Adipate Dihexyldecyl Adipate Diisocetyl Adipate Dibutyl Sebacate Dicaprylyl/Capryl Sebacate Dibutyloctyl Sebacate Dihexyldecyl Sebacate Diisostearyl Sebacate


Animals No./Gender/Group Dose median lethal dose/conc. Reference

Succinic Acidrats not specified not specified 2750 mg/kg EPA 2001rats not specified not specified 2260 mg/kg OECD 2003Sodium Succinaterats 4 males, 4 females 0.5-8 g/kg 8000 mg/kg Maekawa et al 1990Glutaric Acidrats not specified not specified 2260 mg/kg EPA 2001

mice 13 males 1500-2500 mg/kg of a 6% suspension in 0.5% methyl cellulose

1900 mg/kg OECD 2006

mice not specified not specified 4175 mg/kg OECD 2006mice not specified not specified 4200 mg/kg OECD 2006rats not specified not specified 5050 mg/kg EPA 2001rats 5 or 10 males 100-3000 mg/kg (n=5) or 5000 mg/kg (n=10) adipic

acid in 0.85% saline940 mg/kg OECD 2006

Wistar rats not specified not specified approx. 3600 mg/kg OECD 2006rats 10 males 5000 mg/kg of a 33.3% suspension in 0.85% saline >5000 mg/kg OECD 2006

rats 5 males, 5 females 14.7-10,000 mg/kg as a 14.7-50% suspension in carboxymethyl cellulose (CMC)

5560 mg/kg OECD 2006

rats not specified 10,000 mg/kg >10,000 mg/kg OECD 2006rat and rabbit not specified not specified >11,000 mg/kg OECD 2006rabbits not specified 2430 or 4860 mg/kg of a 20% partially neutralized

soln (75% sodium adipate)>2430 and <4860 mg/kg OECD 2006

Adipic/Glutaric/Succinic Mixture (percentages not given)rats not specified not specified 6829 mg/kg EPA 2001

Wistar rats 6 males 6 females 500-4000 mg/kg ≥4000 mg/kg Mingrone et al 1983New Zealand rabbits

6 males 6 females 500-4000 mg/kg ≥4000 mg/kg Mingrone et al 1983

Disodium Sebacate

Table 4. Acute toxicity - Dicarboxylic Acids and Their Salts

Adipic Acid

ORAL

Azelaic Acid

Wistar rats 4 males, 4 females 0-5000 mg/kg >5000 mg/kg Greco et al 1990New Zealand rabbits

4 males, 4 females 0-6000 mg/kg >6000 mg/kg Greco et al 1990

Dodecanedioic Acidrats m/f; no. not specified not specified >3000 mg/kg OECD 1994

rabbits not specified not specified >10,000 mg/kg EPA 2001Adipic Acidrabbits 1- 2/group; male and

female5010 (n=1) or 7940 mg/kg (n=2) 40% adipic acid in corn oil, with occlusion

>7940 mg/kg OECD 2006

Adipic/Glutaric/Succinic Mixture (percentages not given)rabbits not specified not specified >7940 mg/kg EPA 2001Dodecanedioic Acidalbino rabbits males; no. not specified not specified >6000 mg/kg OECD 1994

Adipic Acidrats 20/group; males and

females5.4 or 7.7 mg/l; head/nose-only exposure; MMAD50

<3.5 µm>7700 mg/m3 OECD 2004

Adipic/Glutaric/Succinic Mixture (percentages not given)rats not specified not specified >0.03 mg/l EPA 2001

Disodium Succinatemice not specified i.v. 4500 mg/kg OECD 2003Adipic Acidmouse not specified i.p., 0.681-50% solution in 0.5% CMC approx. 170 mg/kg OECD 2006

mouse not specified i.p., 600 and 900 mg/kg aq. 600 mg/kg OECD 2006mouse not specified i.p. admin 4000 mg/kg OECD 2006rats 7 males i.p., 200-350 mg/kg 275 mg/kg OECD 2006

PARENTERAL

INHALATION

Glutaric AcidDERMAL


Animals No./Gender/Group Dose median lethal dose/conc. Reference

Table 4. Acute toxicity - Dicarboxylic Acids and Their Salts

mouse not specified i.v., 650-700 mg/kg 2% solution 680 mg/kg OECD 2006rabbit not specified i.v., 2430 mg/kg 20% soln, partially neutralized 2430 mg/kg OECD 2006

Disodium Azelaterats 6 males, 6 females i.p., 0-1198 mg/kg >1198 mg/kg Mingrone et al 1983rabbits 6 males, 6 females i.p., 0-1198 mg/kg >1198 mg/kg Mingrone et al 1983Disodium SebacateWistar rats 4 males, 4 females i.p., 0-7000 mg/kg 5500 mg/kg; dehydration and

ascites formation was notedGreco et al. 1990

New Zealand rabbits

4 males, 4 females i.p., 0-8000 mg/kg 6000 mg/kg; dehydration and ascites formation was noted

Greco et al 1990

Wistar rats 10 i.v. , 0-1000 mg/kg 560 mg/kg; dehydration and ascites formation was noted

Greco et al 1990

New Zealand rabbits

10 i.v., 0-1800 mg/kg 1400 mg/kg; dehydration and ascites formation was noted

Greco et al 1990


Con

cent

ratio

nA

nim

als

Proc

edur

eR

esul

tsR

efer

ence

not s

peci

fied

not s

peci

fied

ocul

ar ir

ritat

ion

stud

y (d

etai

ls n

ot sp

ecifi

ed)

seve

re o

cula

r irri

tant

EPA

200

1

not s

peci

fied

not s

peci

fied

ocul

ar ir

ritat

ion

stud

y (d

etai

ls n

ot sp

ecifi

ed)

mod

erat

e oc

ular

irrit

ant

EPA

200

1A

dipi

c A

cid

undi

lute

d2

albi

no ra

bbits

10 o

r 57.

1 m

g pl

aced

in e

ye; e

ye o

f 1 a

nim

al ri

nsed

10 m

g: n

o irr

itatio

n in

rins

ed e

ye, m

inim

al in

unr

inse

d ey

e;

57.1

mg:

mild

to m

oder

ate

irrita

tion

in ri

nsed

and

unr

inse

d ey

es

EPA

200

1

undi

lute

d6

rabb

its; g

ende

r not

spec

ified

0.1

ml i

nstil

led

into

the

eye;

eye

s wer

e no

t rin

sed

seve

rely

irrit

atin

g - p

rimar

y irr

itatio

n in

dex

of 4

1.5/

110;

irr

itate

d co

njun

ctiv

a an

d sc

ar fo

rmat

ion,

incr

ease

d co

rnea

l op

acity

and

irid

al in

flam

mat

ion;

not

cle

ared

by

day

8

OEC

D 2

006

undi

lute

d3

rabb

its; g

ende

r not

spec

ified

100m

g in

still

ed fo

llow

ing

GLP

; acu

te e

ye

irrita

tion/

corr

osio

n te

stse

vere

irrit

atio

n; c

orne

al o

paci

ty a

nd ir

idal

irrit

atio

n; c

lear

ed

with

in 1

6 da

ysO

ECD

200

6

undi

lute

d2

rabb

its; g

ende

r not

spec

ified

50 m

g pl

aced

in e

ye; e

yes w

ere

not r

inse

dse

vere

ly ir

ritat

ing;

cor

neal

opa

city

still

pre

sent

at d

ay 8

OEC

D 2

006

Dod

ecan

edio

ic A

cid

not s

peci

fied

mal

e ra

bbits

, no.

not

spec

ified

ocul

ar ir

ritat

ion

stud

y (G

LP; d

etai

ls n

ot p

rovi

ded)

slig

ht ir

ritan

t; irr

itatio

n in

dex

11.9

6/11

0O

ECD

199

4no

t spe

cifie

dra

bbits

; no.

/gen

der n

ot sp

ecifi

edoc

ular

irrit

atio

n st

udy

(det

ails

not

pro

vide

d)sm

all a

rea

of c

orne

al o

paci

ty a

nd m

ild c

onju

nctiv

al ir

ritat

ion;

cl

eare

d w

ithin

7 d

ays

OEC

D 1

994

Tabl

e 5.

Ocu

lar I

rrita

tion

- Dic

arbo

xylic

Aci

d an

d Th

eir E

ster

s

Succ

inic

Aci

d

Glu

tari

c A

cid


Dos

e/C

onc.

.A

nim

als

Proc

edur

eR

esul

tsR

efer

ence

not s

peci

fied

rabb

its, n

o./g

ende

r not

spec

ified

irrita

tion

stud

ies (

deta

ils n

ot p

rovi

ded)

slig

ht to

mild

irrit

atio

nEP

A 2

001

Glu

tari

c A

cid

not s

peci

fied

rabb

its, n

o./g

ende

r not

spec

ified

irrita

tion

stud

ies (

deta

ils n

ot p

rovi

ded)

slig

ht ir

ritat

ion

EPA

200

1A

dipi

c A

cid

500

mg

of 5

0% a

q.6

rabb

itsoc

clus

ive

appl

icat

ion

to a

5 c

m x

5 c

m a

rea

of

abra

ded

or in

tact

skin

for 2

4 h

inta

ct sk

in: e

ryth

ema

(sco

re 2

-3/4

), cl

eare

dby

day

3; a

brad

ed sk

in:

mild

to se

vere

ery

them

a an

d ed

ema

(2/4

at 2

4 h;

0-2

at 7

2 h)

, cl

eare

d by

day

7

OEC

D 2

006

undi

lute

d or

80%

aq.

pas

te2

rabb

its/g

roup

occl

usiv

e ap

plic

atio

n to

inta

ct sk

in o

n th

e ba

ck a

nd

the

ear f

or 2

0 h

no ir

ritat

ion

on th

e ba

ck; e

ryth

ema

on th

e ea

r at 2

4 h

(sco

re o

f 2/4

), w

ith c

lear

ing

by 7

2 h

OEC

D 2

006

not s

peci

fied

rabb

its, n

o./g

ende

r not

spec

ified

occl

usiv

e ap

plic

atio

n fo

r 24

hno

t irri

tatin

gO

ECD

200

6

undi

lute

d or

50%

pas

te in

pr

opyl

ene

glyc

ol (P

G)

6 ra

bbits

sem

i-occ

lusi

ve a

pplic

atio

n of

500

mg

for 2

4 h

slig

ht to

mild

irrit

atio

n in

3/6

rabb

its w

ith 5

0%; n

o co

rrosi

on w

ith

undi

lute

d te

st m

ater

ial

OEC

D 2

006

50%

in P

G10

gui

nea

pigs

, gen

der n

ot sp

ecifi

edap

plie

d to

inta

ct sk

inno

irrit

atio

nO

ECD

200

6Su

ccin

ic/G

luta

ric/

Adi

pic

Aci

ds M

ixtu

re (p

erce

ntag

es n

ot sp

ecifi

ed)

not g

iven

guin

ea p

igs,

no./g

ende

r not

spec

ified

irrita

tion

stud

y (d

etai

ls n

ot p

rovi

ded)

no to

mild

irrit

atio

nO

ECD

200

4D

odec

aned

ioic

Aci

dno

t spe

cifie

dm

ale

rabb

its, n

o. n

ot sp

ecifi

edirr

itatio

n st

udy;

4 h

exp

osur

e (G

LP; d

etai

ls n

ot

prov

ided

)no

t an

irrita

nt; i

rrita

tion

inde

x 0/

8O

ECD

199

4

0.5

gm

ale

rabb

its, n

o. n

ot sp

ecifi

edFH

SA p

roce

dure

sno

t an

irrita

ntO

ECD

199

4

Succ

inic

Aci

d

Tabl

e 6.

Der

mal

irrit

atio

n an

d se

nsiti

zatio

n - D

icar

boxy

lic A

cids

and

The

ir Sa

lts

IRR

ITA

TIO

N

SEN

SIT

IZA

TIO

NA

dipi

c A

cid

indu

ctio

n: 0

.1 m

l of 1

.0%

aq.

so

ln; c

halle

nge:

0.0

5 m

l of 5

0 an

d 25

% in

PG

10 g

uine

a pi

gs/g

roup

indu

ctio

n: 4

sacr

al in

trade

rmal

inje

ctio

ns, 1

/wk;

ch

alle

nge:

der

mal

app

licat

ion

afte

r a 2

wk

rest

per

iod

very

mild

to n

o irr

itatio

n; n

o se

nsiti

zatio

n O

ECD

200

6

Succ

inic

/Glu

tari

c/A

dipi

c A

cids

Mix

ture

(per

cent

ages

not

spec

ified

)no

t giv

engu

inea

pig

s, no

./gen

der n

ot sp

ecifi

edse

nsiti

zatio

n st

udy

(det

ails

not

pro

vide

d)no

t a se

nsiti

zer

OEC

D 2

004

Dod

ecan

edio

ic A

cid

indu

ctio

n: 0

.5%

; cha

lleng

e: 2

5 an

d 50

%fe

mal

e gu

inea

pig

s, no

. not

spec

ified

Mag

nuss

on-K

ligm

an m

axim

izat

ion

test

(in

tracu

tane

ous a

dmin

at i

nduc

tion;

der

mal

adm

in a

t ch

alle

nge)

not a

sens

itize

rO

ECD

199

4

SEN

SIT

IZA

TIO

N


Tabl

e 7.

Gen

otox

icity

stud

ies -

Dic

arbo

xylic

Aci

ds a

nd T

heir

Salts

Con

cent

ratio

nV

ehic

lePr

oced

ure

Tes

t Sys

tem

Res

ults

Ref

eren

ce

Mal

onic

Aci

d≤3

333

µg/p

late

wat

erN

TP p

rein

cuba

tion

assa

y, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A100

, TA1

535,

TA9

7, T

A98

nega

tive

NTP

198

9 ID

: 228

078

Succ

inic

Aci

d≤5

mg/

plat

eph

osph

ate

buff

erA

mes

test

S. ty

phim

uriu

m T

A92

, TA

1535

, TA

100,

TA

1537

, TA

94, T

A98

nega

tive

Ishi

date

et a

l. 19

84

≤1.0

mg/

ml

salin

ech

rom

osom

al a

berr

atio

n as

say

Chi

nese

ham

ster

fibr

obla

sts c

ells

nega

tive

Ishi

date

et a

l. 19

84So

dium

Suc

cina

te≤1

0 µg

/pla

tedi

still

ed w

ater

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A97,

TA1

02ne

gativ

eTO

XN

ET 1

997

Dis

odiu

m S

ucci

nate

≤5 m

g/pl

ate

phos

phat

e bu

ffer

Am

es te

stS.

typh

imur

ium

TA9

2, T

A153

5, T

A100

, TA1

537,

TA9

4, T

A98

nega

tive

Ishi

date

et a

l. 19

84≤1

0,00

0 µg

/pla

tedi

still

ed w

ater

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A97

, TA

102

nega

tive

OEC

D 2

003

≤15.

0 m

g/m

lsa

line

chro

mos

omal

abe

rrat

ion

assa

yC

hine

se h

amst

er fi

brob

last

s cel

lseq

uivo

cal

Ishi

date

et a

l. 19

84G

luta

ric

Aci

dno

t spe

cifie

dno

t spe

cifie

dA

mes

test

, +/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

, stra

ins n

ot sp

ecifi

edne

gativ

eB

radf

ord

1984

not s

peci

fied

not s

peci

fied

mou

se ly

mph

oma

assa

y, +

/- m

etab

olic

act

ivat

ion

L517

8Y/T

K ±

cel

ls

depe

nden

t on

cultu

re p

HB

radf

ord

1984

not s

peci

fied

not s

peci

fied

trans

form

atio

n as

say,

+/-

met

abol

ic a

ctiv

atio

n B

alb/

c-3T

3 ce

llspo

sitiv

e, +

/- ac

tivat

ion

Bra

dfor

d 19

84

≤10,

000

µg/p

late

wat

erN

TP p

rein

cuba

tion

assa

y, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A100

, TA1

535,

TA9

7, T

A98

nega

tive

NTP

198

9 ID

: 994

718

Adi

pic

Aci

d≤1

0,00

0 µg

/pla

teD

MSO

NTP

pre

incu

batio

n as

say,

+/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA1

00, T

A153

5, T

A97,

TA9

8ne

gativ

eN

TP 1

997

ID: A

8676

7

≤10

mg/

plat

eno

t spe

cifie

dA

mes

test

, +/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA

1535

, TA

1537

, TA

1538

, TA

98, T

A10

0;

E.

coli

WP2

nega

tive

OEC

D 2

006

IN V

ITR

O

coli

WP2

≤5 m

g/pl

ate

not s

peci

fied

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A15

35, T

A15

37, T

A15

38, T

A98

, TA

100;

E.

co

li W

P2uv

rAne

gativ

eO

ECD

200

6

≤200

mg/

lno

t spe

cifie

dA

mes

test

, with

out m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A15

30, G

-46

nega

tive

OEC

D 2

006

≤200

mg/

lno

t spe

cifie

dye

ast g

ene

mut

atio

n as

say,

with

out m

etab

olic

ac

tivat

ion

S. c

erev

isia

e D

-3ne

gativ

eO

ECD

200

6

≤200

0 µg

/pla

teD

MSO

mou

se ly

mph

oma

assa

y, +

/- m

etab

olic

act

ivat

ion

L517

8Y/T

K ±

cel

ls

nega

tive

TOX

NET

200

9≤2

00 m

g/l

not s

peci

fied

cyto

gene

tic a

ssay

, with

out m

etab

olic

act

ivat

ion

hum

an e

mbr

yoni

c lu

ng fi

brob

last

sne

gativ

eO

ECD

200

6≤1

000

µg/m

lno

t spe

cifie

dvi

ral e

nhan

ced

cell

trans

form

atio

n as

say

Syria

n ha

mst

er o

vary

cel

lsne

gativ

eO

ECD

200

6A

zela

ic A

cid

20%

crea

mA

mes

test

; no

deta

ilsno

t spe

cifie

dne

gativ

eA

llega

n 20

0420

%cr

eam

HG

RPT

test

; no

deta

ilsC

hine

se h

amst

er o

vary

cel

lsne

gativ

eA

llega

n 20

0420

%cr

eam

hum

an ly

mph

ocyt

e te

st, n

o de

tails

hum

an ly

mph

ocyt

esne

gativ

eA

llega

n 20

04Se

baci

c A

cid

≤500

0 µg

/pla

teD

MSO

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A15

35, T

A15

37, T

A15

38, T

A98

, TA

100;

E.

co

li W

P2ne

gativ

eTO

XN

ET 1

990

Dod

ecan

edio

ic A

cid

10-5

000

µg/p

late

not s

peci

fied

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A15

35, T

A15

37, T

A15

38, T

A98

, TA

100

nega

tive

OEC

D 1

994


Tabl

e 7.

Gen

otox

icity

stud

ies -

Dic

arbo

xylic

Aci

ds a

nd T

heir

Salts

Con

cent

ratio

nV

ehic

lePr

oced

ure

Tes

t Sys

tem

Res

ults

Ref

eren

ce

Glu

tari

c A

cid

not s

peci

fied

not s

peci

fied

mic

ronu

cleu

s ass

aym

ice

nega

tive

Bra

dfor

d 19

84A

dipi

c A

cid

≤375

mg/

kg; 1

or 5

dos

esno

t spe

cifie

dcy

toge

netic

ass

ay; a

nim

als d

osed

ora

lly b

y ga

vage

mal

e ra

tsne

gativ

eO

ECD

200

6

5000

mg/

kg (1

dos

e);

2500

mg/

kg (5

dos

es)

not s

peci

fied

cyto

gene

tic a

ssay

; ani

mal

s dos

ed o

rally

by

gava

gem

ale

rats

nega

tive

OEC

D 2

006

≤375

mg/

kg; 1

or 5

dos

esno

t spe

cifie

ddo

min

ant l

etha

l ass

ay; a

nim

als d

osed

ora

lly b

y ga

vage

mal

e ra

tsne

gativ

eO

ECD

200

6

5000

mg/

kg (1

dos

e);

2500

mg/

kg (5

dos

es)

not s

peci

fied

dom

inan

t let

hal a

ssay

; ani

mal

s dos

ed o

rally

by

gava

gem

ale

rats

nega

tive

OEC

D 2

006

Aze

laic

Aci

d20

%cr

eam

dom

inan

t let

hal a

ssay

mic

ene

gativ

eA

llerg

an 2

004

Dod

ecan

edio

ic A

cid

≤500

0 m

g/kg

not s

peci

fied

mic

ronu

cleu

s ass

ayC

rl:C

D-1

(CR

)BR

mic

ene

gativ

eO

ECD

199

4

IN V

IVO


Animals No./Gender/Group Dose median lethal dose/concentration, or result Reference

Diethyl Malonaterats not specified not specified 15,000 mg/kg OECD 2005Dimethyl Malonaterats not specified not specified >2000 mg/kg OECD 2005Diethyl Succinaterats not specified not specified 8530 mg/kg Smyth et al.1949

rats not specified 20% dispersion 11,260-12,900 mg/kg Andersen 2006rats not specified undiluted 1520 mg/kg Andersen 2006rats not specified not specified 1290 mg/kg OECD1996rats not specified undiluted 12,900 mg/kg EPA 2010Di-C7-9 Branched and Linear Alkyl Esters of Adipic AcidSprague-Dawley 5-10; males/females 2000-15,800 mg/kg, undiluted >15,800 mg/kg EPA 2010Ditridecyl AdipateSherman Wistar 5/gender 16,000 mg/kg >16,000 mg/kg EPA 2010Wistar rats 5/gender 15,000 mg/kg >15,000 mg/kg EPA 2010Diisopropyl AdipateSprague-Dawley 5 males/5 females formulation containing 1.08% 1 female died Elder 1984Sprague-Dawley 5 males/5 females formulation containing 1.08% no animals died Elder 1984Sprague-Dawley 5 males/5 females formulation containing 5% no animals died Elder 1984rats 5 males/f5 females formulation containing 0.7% >76,800 mg/kg Elder 1984rats not specified formulation containing 20.75% >15,ooo mg/kg Elder 1984Diisobutyl AdipateNMRI mice 5 males 2000 mg/kg >2000 mg/kg EvicCEBA 1998Diethylhexyl Adipatemice 5 males/5 females ≤20,000 mg/kg in corn oil males: 15,000 mg/kg; females: 24,600 mg/kg Elder 1984rats 5 males/5 females ≤20,000 mg/kg, undiluted 2 males of the 10,000 mg/kg group died; 1 male and 1

female of the 20,000 mg/kg group diedElder 1984

albino rats 5 males/5 femals 7400 mg/kg 1 animal died Elder 1984

rats not specified not specified single oral toxic dose - 9.11 g/kg Elder 1984rats not specified not specified no-effect dose: 6000 mg/kg; central nervous system

ff hi h iElder 1984

Table 8. Acute toxicity - Esters of Dicarboxylic Acids

Dibutyl Adipate

ORAL

effects seen at higher concentrationsHarlan-Wistar rats 5 males/5 females formulations containing 0.175% >6500 mg/kg Elder 1984

rats not specified not specified 9110 mg/kg OECD 2000

rats 5 males/females 7380 mg/kg, undiluted >7300 mg/kg EPA 2010rats not specified not specified 9.1 g/kg EPA 2010Diisooctyl Adipaterats 5/group 2000-64,000 mg/kg, undiluted >64,000 mg/kg EPA 2010guinea pigs not specified not specified >5 ml/kg EPA 2010Diisononyl Adipaterats 5/group 0.0346-10 g/kg, undiluted >10,000 mg/kg EPA 2010Diisodecyl AdipateNMRI mice 5 male 2000 mg/kg >2000 mg/kg EviC-CEBA 1994rats not specified undiluted 20,500 mg/kg EPA 2010Dioctyldodecyl AdipateNMRI mice 5 female 2000 mg/kg >2000 mg/kg EvicC-CEBA1994rats not specified not specified NOAEL <4000 mg/kg Mochida et al 1996Diisocetyl AdipateNMRI mice 5 males 2000 mg/kg >2000 mg/kg EviC-CEBA 1994Diisopropyl SebacateNMRI mice 5 female 2000 mg/kg >2000 mg/kg EvicC-CEBA1994Diethylhexyl SebacateNMRI mice 5 female 2000 mg/kg >2000 mg/kg EviC-CEBA 1994mice not specified undiluted 9.5 g/kg EPA 2010rats not specified undiluted 5.0 cc/kg EPA 2010rats not specified undiluted 12.8 g/kg EPA 2010rats not specified undiluted 17 g/kg EPA 2010Dioctyldodecyl DodecanedioateWistar rats 5 male/5 female 5000 mg/kg >5000 mg/kg AMA 1990




Diisocetyl DodecanedioateWistar rats 5 male/5 female 5000 mg/kg >5000 mg/kg AMA 1991Esterase MetabolitesEthylhexyl Alcohol (metabolite of diethylhexyl succinate, diethylhexyl adipate, and diethylhexyl sebacate)rats 1516-7000 mg/kg ExxonMobil 2002mice 2500-3768 mg/kg ExxonMobil 2002Hexyl Alcohol (metabolite of diehexyl adipate)rats 3131-4900 mg/kg ExxonMobil 2002mice 103-1950 mg/kg ExxonMobil 2002Butyloctanol (metabolite of dibutyloctyl sebacate)rats 12,900 mg/kg Smyth et al 1949Decyl Alcohol (metabolite of decyl succinate )rats 9800 mg/kg Smyth et al 1949Isooctyl Alcohol (metabolite of diisooctyl adipate and diisoctyl sebacate)rats mixture of C7-9 branched alkyl >2000 mg/kg ExxonMobil 2002Nonyl Alcohol (metabolite of diisononyl adipate)rats mixture of C8-10 branched alkyl 3000 mg/kg ExxonMobil 2002Isodecyl Alcohol (metabolite of diisodecyl adipate)rats mixture of C9-11 branched alkyl 4600 mg/kg ExxonMobil 2002

Diethyl Malonaterabbits not specified not specified 16,700 mg/kg OECD 2005Dibutyl Adipaterabbits not specified 96% 20 ml/kg Andersen 2006rats not specified i.m. NOAEL >8000 mg/kg Smith 1953Ditridecyl Adipaterabbits 3 2000 mg/kg >2000 mg/kg EPA 2010rabbits 10 5000 m/kg to abraded skin; semi-

occlusive>5000 mg/kg EPA 2010

Diethylhexyl Adipaterabbits 8 ≤8700 m/kg to abraded skin;

occlusivemild irritation; no systemic toxic effects Elder 1984

rabbits 1 male/1 female ≤8660 mg/kg for 24 h occcluded 1 >8670 mg/kg OECD 2000

DERMAL

rabbits 1 male/1 female ≤8660 mg/kg for 24 h, occcluded, 1 intact and 1 abraded site

>8670 mg/kg OECD 2000

Diisononyl Adipate

rabbits 4/group 50-3160 mg/kg to abraded skin >3160 mg/kg EPA 2010

Diethylhexyl Sebacateguinea pigs not specified not specified <10,000 mg/kg BIBRA 1996Dioctyldodecyl DodecanedioateNZW rabbits 5 male/5 female 2000 mg/kg, intact skin, 24 h >2000 mg/kg AMA 1993

Esterase MetabolitesEthylhexyl Alcohol (metabolite of diethylhexyl succinate, diethylhexyl adipate, and diethylhexyl sebacate)rats >3000 mg/kg ExxonMobil 2002rabbits 1980-2600 mg/kg ExxonMobil 2002Hexyl Alcohol (metabolite of diehexyl adipate)rats 1500 mg/kg ExxonMobil 2002rabbits 1500 - >500 mg/kg ExxonMobil 2002Butyloctanol (metabolite of dibutyloctyl sebacate)rabbits 3.36 ml/kg Smyth et al 1949Decyl Alcohol (metabolite of decyl succinate )rabbits 3.5 ml/kg Smyth et al 1949Isooctyl Alcohol (metabolite of diisooctyl adipate and diisoctyl sebacate)rats mixture of C7-9 branched alkyl >2600 mg/kg ExxonMobil 2002Nonyl Alcohol (metabolite of diisononyl adipate)rats mixture of C8-10 branched alkyl 3160 mg/kg ExxonMobil 2002Isodecyl Alcohol (metabolite of diisodecyl adipate)rats mixture of C9-11 branched alkyl >2600 mg/kg ExxonMobil 2002




Diethyl Malonaterats not specified concentrated vapors for 8 h no deaths OECD 2005Diethyl Succinaterats not specified concentrated vapors for 8 h no deaths Smyth et al.1949Dibutyl Adipatealbino rats 6 male flowing stream of saturated air, 8 h no mortality Elder 1984Dethylhexyl Adipaterats not specified concentrated vapors for 8 h no deaths Smyth et al.1949Diethylhexyl Sebacaterats not specified 250 mg/m3 for 4 h no effect on lung or liver BIBRA 1996rats 3 saturated vapor, 6 h no lung toxicity BIBRA 1996rats 4 940 mg/m3, 7 h 3 rats died, may be attributable to thermal decomp BIBRA 1996guinea pigs 2 940 mg/m3, 7 h no animals died BIBRA 1996rabbits 4 940 mg/m3, 7 h 2 rabbits died, may be attributable to thermal decomp BIBRA 1996

Esterase MetabolitesEthylhexyl Alcohol (metabolite of diethylhexyl succinate, diethylhexyl adipate, and diethylhexyl sebacate)rats 3 males/3 females vapor conc. of 0.89 mg/l or aerosol/

vapor conc of 5.3 mg/l, 4 h0.89 mg/l: all animals survived; 5.3 mg/l: all animals died ExxonMobil 2002

mice, rats, and guinea pigs

10 227 ppm, 6 h all animals survived ExxonMobil 2002

Hexyl Alcohol (metabolite of diehexyl adipate)rats 21 mg/l, 1 h >21 mg/l ExxonMobil 2002Butyloctanol (metabolite of dibutyloctyl sebacate)rats concentrated vapors for 8 h no deaths Smyth et al 1949Decyl Alcohol (metabolite of decyl succinate )rats concentrated vapors for 8 h no deaths Smyth et al 1949

Dimethyl AdipateSprague-Dawley not specified i.p. 1.8 ml/kg Singh et al 1973Diethyl AdipateSprague-Dawley not specified i.p. 2.5 ml/kg Singh et al 1973

PARENTERAL

INHALATION

Sprague Dawley not specified i.p. 2.5 ml/kg Singh et al 1973Dipropyl AdipateSprague-Dawley not specified i.p. 3.8 ml/kg Singh et al 1973Dibutyl Adipaterats not specified i.p. 5.2 ml/kg Andersen 2006Diisopropyl Adipaterats not specified i.v. 640 mg/kg Elder 1984Diethylhexyl Adipaterats not specified i.v. 900 mg/kg Elder 1984rabbits not specified i.v. 540 mg/kg Elder 1984Sprague-Dawley not specified i.p. >50 ml/kg Singh et al 1973


Concentration Animals Procedure Results Reference

Diethyl Malonateundiluted rabbits, no./gender not specified 0.1 ml slight to moderate irritation OECD 2005Dimethyl Malonateundiluted rabbits, no./gender not specified 0.1 ml ,unrinsed slight to moderate irritation;

cleared by day 8OECD 2005

Dibutyl Adipateundiluted rabbits, no. not specified unrinsed minimally irritating Andersen 2006undiluted 2 New Zealand rabbits unrinsed slight irritation Andersen 20060.1% in olive oil rabbits unrinsed non-irritating Andersen 2006

Diisopropyl Adipateundiluted 6 albino rabbits 0.1 ml, unrinsed negligible irritation Elder 1984

undiluted 6 albino rabbits 0.1 ml, unrinsed non-irritating Elder 19840.7% in formulation 9 albino rabbits 0.1 mi, undiluted, rinsed some corneal stippling Elder 1984

5% in formulation 6 albino rabbits not specified non-irritating Elder 198420.75% in formulation 6 albino rabbits not specified non-irritating Elder 1984undiluted 3 albino rabbits 0.1 ml, unrinsed non-irritating EviC-CEBA 1998

Diethylhexyl Adipateundiluted 6 albino rabbits 0.1 ml, unrinsed non-irritating Elder 19840.01% in formulation 6 albino rabbits 0.1 ml, unrinsed non-irritating Elder 19840.175% in formulation 6 albino rabbits 0.1 ml, unrinsed mild transient irritant Elder 1984

Diisopropyl Sebacate6 rabbits 0.1 ml, unrinsed minimally irritating Consumer Product Testing Co 1991

Diethylhexyl Sebacate1.2% in formulation undiluted EpiOcular MTT viability

assaynon-irritating MB Research Laboratories 2003

Dioctyldodecyl Dodecanedioateundiluted 6 rabbits 0.1 ml, unrinsed MMTS = 0.0; non-irritating AMA 1990

Diisocetyl Dodecanedioatedil t d 6 bbit 0 1 l i d MMTS 0 0 i it ti AMA 1990

Table 9. Ocular Irritation - Esters of Dicarboxylic Acids

undiluted 6 rabbits 0.1 ml, unrinsed MMTS = 0.0; non-irritating AMA 1990Esterase MetabolitesEthylhexyl Alcohol (metabolite of diethylhexyl succinate, diethylhexyl adipate, and diethylhexyl sebacate)

rabbits 20 μg moderately severe corneal irritation

ExxonMobil 2002

Isopropyl Alcohol (metabolite of diisopropyl adipate and diisopropyl sebacate)rabbits severely irritatiting Inchem 2009

Hexyl Alcohol (metabolite of dihexyl adipate)rabbits highly irritative ExxonMobli 2002


Dos

e/C

onc.

Ani

mal

sPr

oced

ure

Res

ults

Ref

eren

ce

Die

thyl

Mal

onat

eno

t spe

cifie

dra

bbits

occl

usiv

e ap

plic

atio

n; 4

hsl

ight

ly ir

ritat

ing

OEC

D 2

005

Dim

ethy

l Mal

onat

eno

t spe

cifie

dra

bbits

sem

i-occ

lusi

ve a

pplic

atio

n; 4

hno

t irri

tatin

g; sl

ight

ery

them

a at

30-

60 m

in a

fter p

atch

rem

oval

OEC

D 2

005

Dib

utyl

Adi

pate

undi

lute

dra

bbits

appl

ied

to b

elly

PII o

f 2/8

Ande

rsen

200

6un

dilu

ted

5 al

bino

rabb

its0.

1 m

l, ap

plie

d 8x

in 4

hm

oder

ate

eryt

hem

a at

24

h

undi

lute

d3

rabb

itsim

preg

nate

d ba

nds,

3 d

appl

icat

ion,

3 w

ksm

oder

ate

eryt

hem

aAn

ders

en 2

006

undi

lute

d5

rabb

itsim

preg

nate

d ba

nds,

appl

ied

2w/w

k fo

r 6

liti

no p

rogr

essi

ve sk

in d

amag

eAn

ders

en 2

006

undi

lute

d3

rabb

its0.

025

ml t

o in

tact

and

abr

aded

skin

, 3

appl

icat

ions

at 3

h in

terv

als f

or 3

day

ser

ythe

ma

and

capi

llary

inje

ctio

n du

ring

the

stud

y; d

esqu

amat

ion

was

obs

erve

dAn

ders

en 2

006

10%

in a

ceto

ne5

hair

less

mic

eap

plie

d to

ear

, 1x/

day,

10

days

no a

dver

se e

ffect

Ande

rsen

200

610

% in

ace

tone

mic

eap

plic

atio

n to

bac

ks, 2

x/da

y, 1

4 da

ysno

adv

erse

effe

ctAn

ders

en 2

006

Diis

opro

pyl A

dipa

teun

dilu

ted

9 al

bino

rabb

its24

h, 0

.1 m

l, oc

clus

ive

PII o

f 1.6

/4; m

ild ir

rita

ntEl

der 1

984

undi

lute

d9

albi

no ra

bbits

24 h

, 0.1

ml,

occl

usiv

ePI

I of 1

.3/4

; mild

irri

tant

Elde

r 198

4

undi

lute

d9

albi

no ra

bbits

24 h

, 0.1

ml,

occl

usiv

ePI

I of 0

.06/

4; m

inim

ally

irri

tatin

gEl

der 1

984

5% in

form

ulat

ion

9 al

bino

rabb

its24

h, 0

.1 m

l, oc

clus

ive

PII o

f 0.3

3; m

inim

ally

irri

tatin

gEl

der 1

984

20.7

5% in

form

ulat

ion

9 al

bino

rabb

its24

h, 0

.1 m

l, oc

clus

ive

PII o

f 0.1

1; m

inim

ally

irri

tatin

gEl

der 1

984

undi

lute

d3

albi

no ra

bbits

sem

i-occ

lusi

ve a

pplic

atio

n; 4

h, u

ndilu

ted

non-

irrita

ting

EviC

-CEB

A 1

998

Die

thyl

hexy

l Adi

pate

DE

RM

AL

IRR

ITA

TIO

N

Tabl

e 10

. Der

mal

irrit

atio

n an

d se

nsiti

zatio

n - E

ster

s of D

icar

boxy

lic A

cids

Die

thyl

hexy

l Adi

pate

undi

lute

d6

albi

no ra

bbits

inta

ct a

nd a

brad

ed sk

in, 0

.5 m

l, 24

h, o

cclu

sive

very

mild

irri

tant

Elde

r 198

4

0.17

5% in

form

ulat

ion

3 al

bino

rabb

its4,

0.5

ml a

pplic

atio

nsir

rita

tion

inde

x of

1.6

/4El

der 1

984

Diis

odec

yl A

dipa

teun

dilu

ted

3 al

bino

rabb

itsse

mi-o

cclu

sive

app

licat

ion,

4 h

, und

ilute

dno

n-irr

itatin

g; sc

ores

of 0

-1 fo

r ery

them

a an

d 0

for e

dem

a at

1-7

2 h;

reve

rsib

leEv

iC-C

EBA

199

4D

ioct

yldo

decy

l Adi

pate

undi

lute

d3

albi

no ra

bbits

sem

i-occ

lusi

ve a

pplic

atio

n, 4

h, u

ndilu

ted

non-

irrita

ting;

scor

es o

f 0-1

for e

ryth

ema

and

0 or

1 fo

r ede

ma

at 2

4-72

h; r

ever

sibl

eEv

iC-C

EBA

199

4D

iisoc

etyl

Adi

pate

undi

lute

d3

albi

no ra

bbits

sem

i-occ

lusi

ve a

pplic

atio

n, 4

h, u

ndilu

ted

non-

irrita

ting;

scor

es o

f 0-2

for e

ryth

ema

and

0 or

1 fo

r ede

ma

at 1

-72

h; re

vers

ible

EviC

-CEB

A 1

994

Die

thyl

Seb

acat

eun

dilu

ted

8 ra

bbits

inta

ct a

nd a

brad

ed sk

in, o

cclu

sive

, 0.3

ml

PII o

f 0.0

Cou

ncil

1989

30%

in e

than

ol8

rabb

itsin

tact

and

abr

aded

skin

, occ

lusi

ve, 0

.3 m

lPI

I of 0

.3

Cou

ncil

1989

Diis

opro

pyl

Seba

cate

undi

lute

d6

rabb

itsin

tact

and

abr

aded

skin

, occ

lusi

ve, 0

.5 m

lPI

I of 2

.88;

not

a p

rimar

y irr

itant

Con

sum

er P

rodu

ct

Test

ing

1991

undi

lute

d3

albi

no ra

bbits

sem

i-occ

lusi

ve a

pplic

atio

n, 4

h, u

ndilu

ted

non-

irrita

ting;

scor

es o

f 1 fo

r ery

them

a, w

ith a

2 a

t 24

h, a

nd 0

or 1

for e

dem

a at

1-7

2 h;

re

vers

ible

EviC

-CEB

A 1

994


Dos

e/C

onc.

Ani

mal

sPr

oced

ure

Res

ults

Ref

eren

ceTa

ble

10. D

erm

al ir

ritat

ion

and

sens

itiza

tion

- Est

ers o

f Dic

arbo

xylic

Aci

ds

Die

thyl

hexy

l Seb

acat

eun

dilu

ted

3 al

bino

rabb

itsse

mi-o

cclu

sive

app

licat

ion,

4 h

, und

ilute

dno

n-irr

itatin

g; sc

ores

of 1

for e

ryth

ema

and

0 fo

r ede

ma

at 1

-72

h; re

vers

ible

EviC

-CEB

A 1

994

undi

lute

d2-

4 ra

bbits

occl

usiv

e ap

plic

atio

n; 4

8 h

not i

rrita

ting

BIB

RA

199

6D

ioct

yldo

decy

l Dod

ecan

edio

ate

undi

lute

d6

NZW

rabb

itsoc

clus

ive

appl

icat

ion,

24

h, 0

.5 m

lPI

I = 0

; not

a p

rimar

y irr

itant

AM

A 1

990

Diis

ocet

yl D

odec

aned

ioat

eun

dilu

ted

6 N

ZW ra

bbits

occl

usiv

e ap

plic

atio

n, 2

4 h,

0.5

ml

PII =

0; n

ot a

prim

ary

irrita

ntA

MA

199

0E

ster

ase

Met

abol

ites

Ethy

lhex

yl A

lcoh

ol (m

etab

olite

of d

ieth

ylhe

xyl a

dipa

te a

nd d

ieth

ylhe

xyl s

ebac

ate)

3 m

ale

rabb

itsoc

clui

sion

, 4 h

irrita

ting

Exxo

nMob

il 20

02ra

bbits

occl

usiv

e, 0

.5 m

lhi

ghly

irrit

atin

g; n

ot re

vers

ible

Exxo

nMob

il 20

02C

apry

lic A

lcoh

ol (m

etab

olite

of d

icap

ryl s

ucci

nate

, dic

apry

l adi

pate

, and

dic

apry

lyl/c

apry

l seb

acat

e)un

dilu

ted

rabb

itsm

ild ir

ritat

ion

Dim

ethy

l Mal

onat

eno

t spe

cifie

dgu

inea

pig

sB

uehl

er m

etho

dno

t sen

sitiz

ing

OEC

D 2

005

Dib

utyl

Adi

pate

25%

5 gu

inea

pig

sm

axim

izat

ion

test

not s

ensi

tizin

gAn

ders

en 2

006

Die

thyl

hexy

l Adi

pate

0.1%

in o

live

oil

10 m

ale

guin

ea

pigs

indu

ctio

n: 1

0 in

ject

ions

; 2 w

k no

n-tr

eatm

ent

pd; c

halle

nge:

0.0

5 m

l inj

ectio

nno

t sen

sitiz

ing

Elde

r 198

4

Die

thyl

hexy

l Seb

acat

eun

dilu

ted

rabb

itsoc

clus

ive

patc

hes,

deta

ils n

ot p

rovi

ded

no re

actio

nsB

IBR

A 1

996

Di

tld

dlD

ddi

t

SEN

SIT

IZA

TIO

N

Dio

ctyl

dode

cyl D

odec

aned

ioat

e0.

1 m

l for

intra

derm

in

duct

ion;

0.5

ml t

op.

indu

ctio

n /c

halle

nge

10 fe

mal

e gu

inea

pi

gsm

axim

izat

ion

test

not s

ensi

tizin

g; sl

ight

ery

them

a at

indu

ctio

nA

MA

199

3

Est

eras

e M

etab

olite

sH

exyl

Alc

ohol

(met

abol

ite o

f dih

exyl

adi

pate

)1%

in p

etro

latu

mgu

inea

pig

sm

axim

izat

ion

test

not s

ensi

tizin

gEx

xonM

obil

2002


Tabl

e 11

. Gen

otox

icity

stud

ies -

Est

ers o

f Dic

arbo

xylic

Aci

ds

Con

cent

ratio

nV

ehic

lePr

oced

ure

Tes

t Sys

tem

Res

ults

Ref

eren

ce

Die

thyl

Mal

onat

e≤5

000

µg/p

late

not s

peci

fied

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A15

35, T

A15

37, T

A98

, TA

100

nega

tive

OEC

D 2

005

≤500

0 µg

/pla

teno

t spe

cifie

dcy

toge

netic

ass

ay, +

/- m

etab

olic

act

ivat

ion

hum

an p

erip

hera

l lym

phoc

ytes

nega

tive;

cyt

otox

ic a

t 500

0 µg

/pla

teO

ECD

200

5

Dim

ethy

l Mal

onat

e≤5

000

µg/p

late

not s

peci

fied

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A15

35, T

A15

37, T

A98

, TA

100

nega

tive;

cyt

otox

ic a

t ≥10

00

µg/p

late

OEC

D 2

005

Dim

ethy

l Suc

cina

te20

,000

µg/

plat

eD

MSO

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A15

35, T

A15

37, T

A98

, TA

100

nega

tive

And

erse

n an

d Je

nsen

198

4

≤10,

000

µg/p

late

wat

erN

TP p

rein

cuba

tion

assa

y, +

/- m

etab

olic

ac

tivat

ion

S. ty

phim

uriu

m T

A100

, TA1

535,

TA9

7, T

A98

nega

tive

NTP

1988

ID: 9

4773

8

Dim

ethy

l Glu

tara

te

≤10,

000

µg/p

late

DM

SON

TP p

rein

cuba

tion

assa

y, +

/- m

etab

olic

ac

tivat

ion

S. ty

phim

uriu

m T

A100

, TA1

535,

TA9

7, T

A98

nega

tive

NTP

1995

ID: A

2034

8

Dim

ethy

l Adi

pate

≤10,

000

µg/p

late

DM

SON

TP p

rein

cuba

tion

assa

y, +

/- m

etab

olic

ac

tivat

ion

S. ty

phim

uriu

m T

A100

, TA1

535,

TA9

7, T

A98

nega

tive

NTP

1994

ID: A

4533

0

Dib

utyl

Adi

pate

≤500

0 µg

/pla

teAm

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A98,

TA1

00, T

A153

5, T

A153

7,

TA15

38ne

gativ

eAn

ders

en 2

006

Di-C

7-9

Bra

nche

d an

d Li

near

Alk

yl E

ster

s of A

dipi

c A

cid

≤10.

0 µl

/pla

teno

t spe

cifie

dA

mes

test

, +/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA15

35, T

A15

37, T

A98

, TA

100

nega

tive

EPA

201

0

IN V

ITR

O

≤10.

0 µl

/pla

teno

t spe

cifie

dA

mes

test

, +/

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA15

35, T

A15

37, T

A98

, TA

100

nega

tive

EPA

201

0D

itrid

ecyl

Adi

pate

≤10

µl/p

late

DM

SOA

mes

test

, +/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA

1535

, TA

1537

, TA

1538

, TA

98,

TA10

0ne

gativ

eEP

A 2

010

Diis

obut

yl A

dipa

te≤1

0,00

0 µg

/pla

teD

MSO

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A98

, TA

100,

TA

102,

TA

97, T

A98

, E.

col

i w

p2ne

gativ

eTO

XN

ET 2

001

Die

thyl

hexy

l Adi

pate

≤5 m

g/pl

ate

not s

peci

fied

Ames

test

, +/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA1

535,

TA1

537,

TA1

538,

TA9

8,

TA10

0ne

gativ

eEl

der 1

984

5000

µg/

plat

eno

t spe

cifie

dA

mes

test

, +/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA

1535

, TA

1537

, TA

1538

, TA

98,

TA10

0ne

gativ

eSi

mm

on e

t al 1

977

≤0.0

1 M

not s

peci

fied

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

mTA

98, T

A10

0ne

gativ

eW

arre

n et

al 1

982

10,0

00 µ

g/pl

ate

DM

SOA

mes

test

, +/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA

1535

, TA

1537

,. TA

98, T

A10

0ne

gativ

eZe

iger

et a

l 198

510

,000

µg/

plat

e95

% e

than

olA

mes

test

, +/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA

1535

, TA

1537

,. TA

98, T

A10

0ne

gativ

eZe

iger

et a

l 198

510

,000

µg/

plat

eac

eton

eN

TP p

rein

cuba

tion

assa

y, +

/- m

etab

olic

ac

tivat

ion

S. ty

phim

uriu

m T

A100

, TA1

535,

TA9

7, T

A98

nega

tive

NTP

1988

ID: 9

6393

5

≤150

µg/

plat

eno

t spe

cifie

dA

mes

test

, +/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA

1535

, TA

1537

, TA

1538

, TA

98,

nega

tive

EPA

201

0no

t spe

cifie

dD

MSO

liqui

d su

spen

sion

ass

ayS.

typh

imur

ium

TA1

00ne

gativ

eSe

ed 1

982


Tabl

e 11

. Gen

otox

icity

stud

ies -

Est

ers o

f Dic

arbo

xylic

Aci

ds

Con

cent

ratio

nV

ehic

lePr

oced

ure

Tes

t Sys

tem

Res

ults

Ref

eren

ce≤4

00 µ

g/m

lno

t spe

cifie

dsi

ster

chr

omat

id e

xcha

nge

assa

y, +

/- m

etab

olic

act

ivat

ion

Chi

nese

ham

ster

ova

ry c

ells

nega

tive

w/o

ut a

ctiv

atio

n;

equi

voca

l w/a

ctiv

atio

nG

allo

way

et a

l 198

7

≤200

µg/p

late

, 3 o

r 51

hD

MSO

sist

er c

hrom

atid

exc

hang

e as

say

fem

ale

F344

rat h

epat

ocyt

esne

gativ

eR

eise

nbic

hler

and

Eck

l 199

3≤4

00 µ

g/m

lno

t spe

cifie

dch

rom

osom

al a

berr

atio

n as

say,

+/-

met

abol

ic

activ

atio

nC

hine

se h

amst

er o

vary

cel

lsso

me

evid

ence

w/o

ut a

ctiv

atio

n;

nega

tive

w/a

ctiv

atio

nG

allo

way

et a

l 198

7

≤200

µg/p

late

, 3 o

r 51

hD

MSO

chro

mos

omal

abe

rratio

n as

say

fem

ale

F344

rat h

epat

ocyt

esne

gativ

eR

eise

nbic

hler

and

Eck

l 199

3≤0

.01

Mno

t spe

cifie

d3 H

-thym

idin

e as

say,

+/-

met

abol

ic a

ctiv

atio

nsp

leni

c ly

mph

oid

cells

dose

-dep

ende

nt in

hibi

tion

of 3 H

-th

ymid

ine

into

repl

icat

ing

DN

A, w

/a d

ose-

depe

nden

t in

crea

se in

the

ratio

of a

cid-

solu

ble

to D

NA

-inco

rpor

ated

3 H-

thym

idin

e

War

ren

et a

l 198

2

≤100

0 µg

/pla

tefo

rwar

d m

utat

ion

assa

y, +

/- m

etab

olic

act

.L5

178Y

cel

lsne

gativ

eM

cGre

gor e

t al 1

988

urin

e of

rats

dos

ed w

ith 2

000

mg/

kg d

ieth

ylhe

xyl a

dipa

te

corn

oil

Am

es te

stne

gativ

eD

iVin

cenz

o et

al 1

986

Diis

onon

yl A

dipa

te≤1

000

µg/p

late

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A98

, TA

100,

TA

1535

, TA

1537

, TA

1538

nega

tive

McK

ee e

t al 1

986

≤100

µg/

ml

lym

phom

a as

say,

+/-

met

abol

ic a

ctiv

atio

nm

ouse

lym

phom

a L5

178Y

cel

lsne

gativ

eM

cKee

et a

l 198

6

≤100

0 µg

/ml

trans

form

atio

n as

say

Syria

n ha

mst

er e

mbr

yo c

ells

nega

tive

McK

ee e

t al 1

986

≤1.3

µ/m

lB

ALB

/3T3

ass

ayne

gativ

eM

cKee

et a

l 198

6D

ieth

yl S

ebac

ate

yre

vers

ion

assa

yE.

col

i Sd

-4-7

3ne

gativ

eSz

ybal

ski 1

958

Dib

utyl

Seb

acat

eno

t spe

cifie

dno

t spe

cifie

dA

mes

test

S, ty

phim

uriu

m T

A98

, TA

100,

TA

1535

, TA

1537

, TA

1538

nega

tive

Wild

et a

l 198

3

≤10,

000

µg/p

late

DM

SO &

Tw

een

80A

mes

test

, +/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA

98, T

A10

0, T

A15

35, T

A15

37;

E. c

oli w

p2 u

vrA

nega

tive

TOX

NET

200

1

Die

thyl

hexy

l Seb

acat

e≤1

0,00

0 µg

/pla

teD

MSO

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

S. ty

phim

uriu

m T

A98,

TA1

00, T

A153

5, T

A153

7ne

gativ

eZe

iger

et a

l 198

5≤5

000

µg/p

late

DM

SOA

mes

test

, +/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA

98, T

A10

0, T

A15

35, T

A15

37;

E. c

oli w

p2 u

vrA

nega

tive

TOX

NET

201

0

Est

eras

e M

etab

olite

sEt

hylh

exyl

Alc

ohol

(met

abol

ite o

f die

thyl

hexy

l suc

cina

te, d

ieth

ylhe

xyl a

dipa

te, a

nd d

ieth

ylhe

xyl s

ebac

ate)

10,0

00 µ

g/pl

ate

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

nega

tive

Zeig

er e

t al 1

985

Am

es te

stne

gativ

eM

cKee

et a

l 198

6≤0

.01

Mno

t spe

cifie

dA

mes

test

, +/-

met

abol

ic a

ctiv

atio

nS.

typh

imur

ium

TA98

, TA

100

nega

tive

War

ren

et a

l 198

2≤5

000 μg

/pla

teno

t spe

cifie

dA

mes

test

, +/-

met

abol

ic a

ctiv

atio

nne

gativ

eEx

xonM

obil

2002

0-1.

5 m

MD

MSO

liqui

d su

spen

sion

ass

ayS,

. typ

him

uriu

m T

A10

0ne

gativ

eSe

ed 1

982

not s

peci

fied

not s

peci

fied

mou

se ly

mph

oma

assa

yne

gativ

eM

cKee

et a

l 198

6no

t spe

cifie

dno

t spe

cifie

dun

sche

dule

d D

NA

synt

hesi

sne

gativ

eM

cKee

et a

l 198

6


Tabl

e 11

. Gen

otox

icity

stud

ies -

Est

ers o

f Dic

arbo

xylic

Aci

ds

Con

cent

ratio

nV

ehic

lePr

oced

ure

Tes

t Sys

tem

Res

ults

Ref

eren

ce≤0

.01

Mno

t spe

cifie

d3 H

-thym

idin

e as

say,

+/-

met

abol

ic a

ctiv

atio

nsp

leni

c ly

mph

oid

cells

dose

-dep

ende

nt in

hibi

tion

of 3 H

-th

ymid

ine

into

repl

icat

ing

DN

A, w

/a d

ose-

depe

nden

t in

crea

se in

the

ratio

of a

cid-

solu

ble

to D

NA

-inco

rpor

ated

3 H-

thym

idin

e

War

ren

et a

l 198

2

1000

mg/

kgco

rn o

ilA

mes

test

per

form

ed o

n ur

ine

from

rats

do

sed

oral

ly fo

r 15

days

nega

tive

DiV

ince

nzo

et a

l 198

6

MEH

A (m

etab

olite

of d

ieth

ylhe

xyl a

dipa

te)

10,0

00 µ

g/pl

ate

Am

es te

st, +

/- m

etab

olic

act

ivat

ion

nega

tive

Zeig

er e

t al 1

985

≤100

0 µg

/pla

teA

mes

test

nega

tive

Dirv

en e

t al 1

991

Mon

o-(2

-Eth

yl-5

-Hyd

roxy

hexy

l)Adi

pate

(met

abol

ite o

f die

thyl

hexy

l adi

pate

)≤1

000

µg/p

late

Am

es te

stne

gativ

eD

irven

et a

l 199

1M

ono-

(2-E

thyl

-5-O

xohe

xyl)A

dipa

te (m

etab

olite

of d

ieth

ylhe

xyl a

dipa

te)

≤100

0 µg

/pla

teA

mes

test

nega

tive

Dirv

en e

t al 1

991

Prop

yl a

nd Is

opro

pyl A

lcoh

ol (m

etab

olite

of d

ipro

pyl a

dipa

te, d

iisop

ropy

l adi

pate

, and

diis

opro

pyl s

ebac

ate)

bact

eria

l and

mam

mal

ian

cell

assa

ysne

gativ

eH

eldr

eth

2010

Isoo

ctyl

Alc

ohol

(met

abol

ite o

f diis

ooct

yl a

dipa

te a

nd d

iisoo

ctyl

seba

cate

)C

7-9

bran

ched

alk

yl

bact

eria

l and

mam

mal

ian

cell

assa

ysne

gativ

eEx

xonM

obil

2002

Dim

ethy

l Suc

cina

te≥1

250

mg/

kgco

rn o

ilm

icro

nucl

eus t

est,

i.p.

mal

e F3

44 ra

tsne

gativ

eN

TP 1

996

ID:A

7100

6D

imet

hyl G

luta

rate

≥125

0 m

g/kg

corn

oil

mic

ronu

cleu

s tes

t, i.p

.m

ale

F344

rats

nega

tive

NTP

199

5 ID

: A36

863

IN V

IVO

≥125

0 m

g/kg

corn

oil

mic

ronu

cleu

s tes

t, i.p

.m

ale

F344

rats

nega

tive

NTP

199

5 ID

: A36

863

Dib

utyl

Adi

pate

≤200

0 m

g/kg

oliv

e oi

lm

ouse

mic

ronu

cleu

s tes

tm

ice

nega

tive

Ande

rsen

200

6≥7

24 m

g/kg

corn

oil

mic

ronu

cleu

s tes

t, i.p

.m

ale

F344

rats

nega

tive

NTP

199

4 ID

: A86

146

Ditr

idec

yl A

dipa

te≤2

000

mg/

kgno

nem

icro

nucl

eus t

est;

dose

d de

rmal

ly fo

r 13

wks

grou

ps o

f 10

mal

e an

d 10

fem

ale

Spra

gue

Daw

ley

rats

nega

tive

EPA

201

0

Die

thyl

hexy

l Adi

pate

2000

mg/

kgco

rn o

ilm

icro

nucl

eus t

est;

dose

d i.p

. for

3 d

ays

5 m

ale

B3C

3F1 m

ice

nega

tive

Shel

by e

t al 1

993

≤500

0 m

g/kg

corn

oil

chro

mos

omal

abe

rratio

n as

say

8 m

ale

B3C

3F1 m

ice

nega

tive

NTP

198

8 ID

:959

525

not s

peci

fied

corn

oil

chr

omos

omal

abe

rratio

n as

say

8 B

6C3F

1 mic

ene

gativ

eSh

elby

and

Witt

199

550

00 m

g/kg

corn

oil

mic

ronu

cleu

s tes

t sin

gle

i.p. d

ose

6 m

ale/

6 fe

mal

e B

3C3F

1 m

ice

nega

tive

EPA

201

0D

ibut

yl S

ebac

ate

943-

2829

mg/

kgol

ive

oil

mic

ronu

cleu

s tes

t, i.p

.m

icro

nucl

eus t

est

nega

tive

Wild

et a

l 198

3D

ieth

ylhe

xyl S

ebac

ate

500

mg/

kgno

t spe

cifie

dra

t liv

er fo

ci te

stsi

ngle

dos

e of

kno

wn

carc

inog

en, t

he d

osin

g 3x

/wk

for 1

1 w

ksno

act

ivity

Ost

erle

and

Dem

l 198

8


Tabl

e 11

. Gen

otox

icity

stud

ies -

Est

ers o

f Dic

arbo

xylic

Aci

ds

Con

cent

ratio

nV

ehic

lePr

oced

ure

Tes

t Sys

tem

Res

ults

Ref

eren

ceE

ster

ase

Met

abol

ites

Ethy

lhex

yl A

lcoh

ol (m

etab

olite

of d

ieth

ylhe

xyl s

ucci

nate

, die

thyl

hexy

l adi

pate

, and

die

thyl

hexy

l seb

acat

e)no

t spe

cifie

dno

t spe

cifie

dm

icro

nucl

eus t

est

mic

ene

gativ

eM

cKee

et a

l 198

6no

t spe

cifie

dno

t spe

cifie

dtra

nsfo

rmat

ion

assa

yB

ALB

/3T3

nega

tive

McK

ee e

t al 1

986

Prop

yl a

nd Is

opro

pyl A

lcoh

ol (m

etab

olite

of d

ipro

pyl a

dipa

te, d

iisop

ropy

l adi

pate

, and

diis

opro

pyl s

ebac

ate)

C7-

9 br

anch

ed a

lkyl

m

icro

nucl

eus t

est

nega

tive

Hel

dret

h 20

10


Tabl

e 12

. C

linic

al d

erm

al ir

ritat

ion

and

sens

itiza

tion

- Est

ers o

f Dic

arbo

xylic

Aci

ds

Tes

t Mat

eria

lN

o. o

f Su

b jec

tsPr

oced

ure

Res

ults

Ref

eren

ce

Dim

ethy

l Mal

onat

e8%

in p

etro

latu

m25

max

imiz

atio

n te

stno

t a se

nsiti

zer

OEC

D 2

005

Dib

utyl

Adi

pate

undi

lute

d10

24 h

pat

ch te

stno

irri

tatio

n at

24

or 4

8 h

Ande

rsen

200

620

% in

alc

ohol

1024

h o

cclu

sive

pat

ch te

stsl

ight

reac

tions

in 4

subj

ects

Ande

rsen

200

6D

iisop

ropy

l Adi

pate

undi

lute

d19

24 h

occ

lusi

ve p

atch

, 0.1

ml

no ir

rita

tion

Elde

r 198

4un

dilu

ted

1924

h o

cclu

sive

pat

ch, 0

.1 m

lno

irri

tatio

nEl

der 1

984

undi

lute

d15

24 h

occ

lusi

ve p

atch

, 0.1

ml

no ir

rita

tion

Elde

r 198

4un

dilu

ted

1524

h o

cclu

sive

pat

ch, 0

.1 m

lno

irri

tatio

nEl

der 1

984

undi

lute

d16

cum

ulat

ive

irri

tanc

y te

st m

oder

atel

y ir

rita

ting;

scor

e of

395

/945

; irr

itatio

n in

14/

16 su

bjec

ts

Elde

r 198

40.

7% in

form

ulat

ion

13cu

mul

ativ

e ir

rita

ncy

test

non-

irri

tatin

g; sc

ore

of 2

/630

Elde

r 198

41.

1% in

form

ulat

ion

17cu

mul

ativ

e ir

rita

ncy

test

low

pot

entia

l for

haz

ard

to c

onsu

mer

; sco

re o

f 0.2

9/84

Elde

r 198

41.

1% in

form

ulat

ion

17cu

mul

ativ

e ir

rita

ncy

test

low

pot

entia

l for

haz

ard

to c

onsu

mer

; sco

re o

f 0.2

4/84

Elde

r 198

420

.75%

in a

bat

h oi

l7

cum

ulat

ive

irri

tanc

y te

stsc

ore

of 8

/84

Elde

r 198

420

.75%

in fo

rmul

atio

n di

lute

d to

1.2

5%19

24 h

occ

lusi

ve p

atch

, 0.1

ml

min

imal

irri

tatio

nEl

der 1

984

5.0%

in fo

rmul

atio

n19

24 h

occ

lusi

ve p

atch

, 0.1

ml

no ir

rita

tion

Elde

r 198

41.

08%

in fo

rmul

atio

n23

5H

RIPT

no se

nsiti

zatio

n; sl

ight

hyp

erpi

gmen

tatio

nEl

der 1

984

3.0%

in fo

rmul

atio

n50

HRI

PTno

irri

tatio

n or

sens

itiza

tion

Elde

r 198

45.

0% in

form

ulat

ion

108

HRI

PTno

irri

tatio

n or

sens

itiza

tion

Elde

r 198

45.

0% a

q. d

ispe

rsio

n of

a p

rodu

ct

cont

aini

ng 2

0.75

%11

6H

RIPT

min

imal

, fai

nt e

ryth

ema

prod

uced

thro

ugho

ut th

e st

udy

Elde

r 198

4

0.7%

in fo

rmul

atio

n25

max

imiz

atio

n te

stno

con

tact

sens

itiza

tion

pote

ntia

lEl

der 1

984

Di

hlh

lAdi

Die

thyl

hexy

l Adi

pate

0.17

5% in

form

ulat

ion

11cu

mul

ativ

e ir

rita

ncy

test

slig

htly

irri

tatin

g; sc

ore

of 7

2/63

0El

der 1

984

0.01

% in

form

ulat

ion

100

Schw

artz

-Pec

k pr

ophe

tic p

atch

test

not a

n ir

rita

nt o

r a se

nsiti

zer

Elde

r 198

40.

01%

in fo

rmul

atio

n49

Shel

ansk

i and

She

lans

ki H

RIPT

wea

k re

actio

ns in

up

to 4

subj

ects

and

stro

ng re

actio

ns in

1 su

bjec

tEl

der 1

984

9.0%

in fo

rmul

atio

n20

9m

odifi

ed D

raiz

e-Sh

elan

ski p

atch

test

3 st

rong

reac

tions

and

1 fa

int r

eact

ion

at 2

nd c

halle

nge

Elde

r 198

49.

0% in

form

ulat

ion

151

mod

ified

Dra

ize-

Shel

ansk

i pat

ch te

stir

rita

nt re

actio

ns in

2 su

bjec

ts; n

o se

nsiti

zatio

nEl

der 1

984

prod

uct c

onta

inin

g 0.

7% o

f a 2

5%

not g

iven

Shel

ansk

i-Jor

dan

RIPT

1-2

subj

ects

had

reac

tions

dur

ing

the

stud

yEl

der 1

984

Diis

oste

aryl

Adi

pate

undi

lute

d50

HR

IPT

not a

prim

ary

irrita

nt o

r sen

sitiz

erA

MA

Lab

orat

orie

s 199

61.

5% in

form

ulat

ion

20SI

OPT

not i

rrita

ting

Ano

nym

ous 2

003

1.5%

in fo

rmul

atio

n25

max

imiz

atio

n te

stno

con

tact

sens

itiza

tion

pote

ntia

lK

GL

Inc

2003

Diis

opro

pyl S

ebac

ate

1.8%

in fo

rmul

atio

n20

SIO

PTno

t irr

itatin

gA

nony

mou

s 200

0un

dilu

ted

105

patc

h te

stno

irrit

atio

n or

sens

itiza

tion

Prod

uct I

nves

tigat

ions

Inc.

200

52.

2% in

form

ulat

ion

27m

axim

izat

ion

test

no ir

ritat

ion

or se

nsiti

zatio

nK

GL

Inc

2006

1% in

form

ulat

ion

110

mod

ified

HR

IPT,

sem

i-occ

lusi

veno

t an

irrita

nt o

r a se

nsiti

zer

Rel

ianc

e C

linic

al T

estin

g 20

071%

in fo

rmul

atio

n11

0m

odifi

ed H

RIP

T, se

mi-o

cclu

sive

not a

n irr

itant

or a

sens

itize

rR

elia

nce

Clin

ical

Tes

ting

2007

7.2%

in fo

rmul

atio

n51

HR

IPT,

sem

i-occ

lusi

veno

skin

reac

tivity

obs

erve

dEs

sex

Test

ing

Clin

ic 2

007

Die

thyl

hexy

l Seb

acat

eun

dilu

ted

15-3

0oc

clus

ive

patc

hes

no re

actio

nsB

IBR

A 1

996

Dio

ctyl

dode

cyl D

odec

aned

ioat

eun

dilu

ted

50H

RIP

Tno

t a p

rimar

y irr

itant

or s

ensi

tizer

AM

A L

abor

ator

ies 1

996


Tabl

e 12

. C

linic

al d

erm

al ir

ritat

ion

and

sens

itiza

tion

- Est

ers o

f Dic

arbo

xylic

Aci

ds

Tes

t Mat

eria

lN

o. o

f Su

b jec

tsPr

oced

ure

Res

ults

Ref

eren

ce

Diis

ocet

yl D

odec

aned

ioat

eun

dilu

ted

50H

RIP

Tno

t a p

rimar

y irr

itant

or s

ensi

tizer

AM

A L

abor

ator

ies 1

996

Est

eras

e M

etab

olite

sM

etha

nol (

met

abol

ite o

f dim

ethy

l suc

cina

te, d

imet

hyl g

luta

rate

, and

dim

ethy

l adi

pate

prim

ary

irrita

tion

of th

e sk

inA

nder

sen

2001

3.2%

274

prov

ocat

ive

occu

patio

nal s

tudy

posi

tive

resu

ltsA

nder

sen

2001

5%cl

osed

pat

ch te

stsl

ight

pos

itive

reac

tion

(+)

And

erse

n 20

017

and

70%

clos

ed p

atch

test

+++

reac

tions

And

erse

n 20

01Pr

opyl

Alc

ohol

undi

lute

d20

24 h

pat

ch te

stno

reac

tions

Still

man

et a

l. 19

75un

dilu

ted

116

48 h

pat

ch te

stno

reac

tions

Wah

lber

g an

d M

aiba

ch 1

980

undi

lute

d16

24 h

pat

ch te

stno

reac

tions

Agn

er a

nd S

erup

198

7un

dilu

ted

4248

h p

atch

test

no re

actio

nsW

illis

et a

l 198

8un

dilu

ted

1624

h p

atch

test

no re

actio

nsA

gner

and

Set

up 1

988

undi

lute

d7

24 h

pat

ch te

stno

reac

tions

Agn

er a

nd S

etup

201

0Is

opro

pyl A

lcoh

ol (m

etab

olite

of d

iisop

ropy

l alc

ohol

and

diis

opro

pyl s

ebac

ate)

80.7

4% sp

ray

conc

entra

tion

9no

sens

itiza

tion

pote

ntia

lD

amat

o et

al 1

979

2.85

% in

form

ulat

ion

109

HR

IPT

no se

nsiti

zatio

nA

nony

mou

s 201

0un

dilu

ted

1224

h p

atch

test

no re

actio

nsSu

ihko

and

Ser

up 2

008

Cet

yl A

lcoh

ol (m

etab

olite

of d

icet

yl su

ccin

ate

and

dice

tyl a

dipa

te)

11.5

% in

form

ulat

ion

80to

pica

l tol

eran

ce st

udy

reac

tion

in 1

subj

ect

Elde

r 198

86.

0% in

form

ulat

ion

12cu

mul

ativ

e irr

itanc

y te

stm

ild c

umul

ativ

e irr

itatio

nEl

der 1

988

8.4%

in fo

rmul

atio

n11

0H

RIP

Tno

t a p

rimar

y irr

itant

or s

ensi

tizer

Elde

r 198

83

0%in

form

ulat

ion

25H

RIP

Tno

tase

nsiti

zer

Elde

r198

83.

0% in

form

ulat

ion

25H

RIP

Tno

t a se

nsiti

zer

Elde

r 198

8M

yris

tyl A

lcoh

ol (m

etab

olite

of d

imyr

isty

l adi

pate

)0.

80%

in fo

rmul

atio

n53

4 w

k ap

plic

atio

nno

irrit

atio

nEl

der 1

988

0.25

% in

form

ulat

ion

514

wk

appl

icat

ion

1 re

actio

n by

1 su

bjec

tEl

der 1

988

0.25

% in

form

ulat

ion

229

10 -

24 h

occ

lusi

ve p

atch

not a

n irr

itant

or a

n al

lerg

enEl

der 1

988

Stea

ryl A

lcoh

ol ((

met

abol

ite o

f dis

tear

yl su

ccin

ate)

undi

lute

dSI

OPT

mild

irrit

atio

nEl

der 1

985

Isos

tear

yl A

lcoh

ol (m

etab

olite

of d

iisos

tear

yl g

luta

rate

, diis

oste

aryl

adi

pate

, or d

iisos

tear

yl se

baca

te)

25%

in p

etro

latu

m19

no ir

ritat

ion

Elde

r 198

825

.0%

in fo

rmul

atio

nno

irrit

atio

nEl

der 1

988

27.0

% in

form

ulat

ion

no ir

ritat

ion

Elde

r 198

828

.0%

in fo

rmul

atio

nno

irrit

atio

nEl

der 1

988

25%

in 9

5% is

opro

pyl a

lcoh

ol12

HR

IPT

3 su

bjec

t slig

ht e

ryth

ema

at in

duct

ion;

no

sens

itiza

tion

Elde

r 198

85%

in fo

rmul

atio

n14

8H

RIP

T, w

ith re

chal

leng

e fo

r rea

ctor

s;

add'

l cha

lleng

e w

ith 5

% in

eth

anol

12 su

bjec

ts h

ad p

ossi

ble

sens

itiza

tion

reac

tions

at 1

st c

halle

nge;

6

reac

ted

at re

chal

leng

e; a

ll 6

had

posi

tive

reac

tions

to 5

% in

alc

ohol

Elde

r 198

8

5% in

form

ulat

ion

60H

RIP

T, re

chal

leng

e of

5%

in e

than

ol

for r

eact

ors

5 su

bjec

ts re

acte

d at

1 c

halle

nge1

/5 re

chal

leng

ed re

acte

dEl

der 1

988

Cap

rylic

Alc

ohol

(met

abol

ite o

f dic

apry

l suc

cina

te, d

icap

ryl a

dipa

te, a

nd d

icap

ryly

l/cap

ryl s

ebac

ate)

2% in

pet

rola

tum

2548

h c

lose

d pa

tch

no ir

ritat

ion

Opd

yke

1973

Dec

yl A

lcoh

ol (m

etab

olite

of d

ecyl

succ

inat

e an

d di

decy

l seb

acat

e)3%

in p

etro

latu

m25

48 h

clo

sed

patc

hno

irrit

atio

nO

pdyk

e 19

73


Tabl

e 13

. Cas

e re

port

- Est

ers o

f Dic

arbo

xylic

Aci

ds

Sub j

ect

Pres

enta

tion

Follo

w-U

p T

estin

g/D

iscu

ssio

nR

efer

ence

Die

thyl

Seb

acat

e1

subj

ect

seve

re c

onta

ct d

erm

atiti

s afte

r 7 d

ays o

f tre

atm

ent w

ith a

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985


Personal Care Products CouncilCommitted to Safety,Quality & Innovation

Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CR)

FROM: John Bailey, Ph.D.Industry Liaison to the CR Expert Panel

DATE: February 25, 2010

SUBJECT: Concentration of Use Dicarboxylic Acid and their Salts and Esters

Updated concentration of use table on Sebacic Acid and related ingredients

Concentration of use additions to the Sebacic Acid report

11011 7th Street, N.W., Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org CIR Panel Book Page 173

Concentration of Use - Additions to the Sebacic Acid and Related Ingredients ReportMalonic Acid, Diethyl Malonate, Succinic Acid, Decyl Succinate, Dicapryl Succinate,Dicetearyl Succinate, Diethyihexyl Succinate, Diethyl Succinate, Dimethyl Succinate,

Disodium Succinate, Sodium Succinate, Glutaric Acid, Diisostearyl Glutarate, DimethylGlutarate, Adipic Acid, Dibutyl Adipate, Di-C12-15 Alkyl Adipate, Dicapryl Adipate,

Dicetyl Adipate, Diethyl Adipate, Diethyihexyl Adipate, Diheptylundecyl Adipate, DihexylAdipate, Dihexyldecyl Adipate, Dilsobutyl Adipate, Diisocetyl Adipate, Dhlsodecyl Adipate,

Diisononyl Adipate, Dihsooctyl Adipate, Dhlsopropyl Adipate, Diisostearyl Adipate,Dimethyl Adipate, Dioctyldodecyl Adipate, Dipropyl Adipate and Ditridecyl Adipate*

Ingredient Product Category Concentrationof Use

Diethyl Malonate Skin cleansing (cold creams, cleansing 0.0 1%lotions, liquids and pads)

Diethyl Malonate Night creams, lotions and powders 0.02%

Diethyl Malonate Other skin care products 0.004%

Succinic Acid Bath oils, tablets and salts 26%

Succinic Acid Hair conditioners 0.2%

Succinic Acid Hair straighteners 0.001%

Succinic Acid Rinses (noncoloring) 0.01%

Succinic Acid Foundations 0.01%

Succinic Acid Makeup bases 0.01%

Succinic Acid Bath soaps and detergents 0.2%

Succinic Acid Face and neck creams, lotions and powders 0.2%

Succinic Acid Moisturizing creams, lotions and powders 0.1%

Diethyihexyl Succinate Colognes and toilet waters 1%

Diethyihexyl Succinate Hair conditioners 5%

Diethyihexyl Succinate Hair sprays (aerosol fixatives 0.02-0.3%

Diethyihexyl Succinate Permanent waves 3%

Diethylhexyl Succinate Tonics, dressings and other hair grooming 4%aids

Page 1 of 4


Diethyihexyl Succinate Face powders 3%

Diethyihexyl Succinate Foundations 3%

Diethyihexyl Succinate Lipstick 3%

Diethyihexyl Succinate Preshave lotions (all types) 4%

Diethyihexyl Succinate Face and neck creams, lotions and powders 4-5%

Diethylhexyl Succinate Body and hand creams, lotions and 4-6%powders

Diethylhexyl Succinate Moisturizing creams, lotions and powders 3%

Diethylhexyl Succinate Other skincare preparations 4%

Diethylhexyl Succinate Suntan gels, creams and liquids 3-4%

Diethylhexyl Succinate Indoor tanning preparations 4%

Dimethyl Succinate Nail polish and enamel removers 0.2%

Dimethyl Succinate Skin cleansing (cold creams, cleansing 5%lotions, liquids and pads)

Dimethyl Succinate Eye lotion 0.002%

Disodium Succinate Foundations 0.0005%

Disodium Succinate Skin cleansing (cold creams, cleansing 0.0005%lotions liquids and pads)

Disodium Succinate Face and neck creams, lotions and powders 0.0 1-0.4%

Disodium Succinate Night creams, lotions and powders 0.02%

Disodium Succinate Skin fresheners 0.0005%

Dimethyl Glutarate Nail polish and enamel removers 0.5%

Dimethyl Glutarate Skin cleansing (cold creams, cleansing 15%lotions, liquids and pads)

Adipic Acid Bath oils, tablets and salts 15-18%

Adipic Acid Mascara 0.000001%

Adipic Acid Permanent waves 0.5%

Adipic Acid Lipstick 0.000001%

Page 2 of 4


Diethyihexyl Adipate Blushers (all types) 14%

Diethylhexyl Adipate Foundations 0.9%

Diethylhexyl Adipate Makeup bases 1%

Diethylhexyl Adipate Nail extenders 3%

Diethyihexyl Adipate Nail polish and enamel 2%

Diethyihexyl Adipate Deodorants (underarm) 0.9%

Diethyihexyl Adipate Aftershave lotions 4%

Diethylhexyl Adipate Shaving cream (aerosol, brushless and 0.6%lather)

Diethylhexyl Adipate Face and neck creams, lotions and powders 3%

Diheptylundecyl Adipate Moisturizing creams, lotions and powders 6%

Dihexyl Adipate Eye makeup remover 3%

Diisobutyl Adipate Bath oils, tablets and salts 0.5%

Diisobutyl Adipate Colognes and toilet waters 0.6%

Diisobutyl Adipate Perfumes 3%

Diisobutyl Adipate Hair conditioners 0.2%

Diisobutyl Adipate Hair sprays (aerosol fixatives) 0.05-0.2%

Diisobutyl Adipate Tonics, dressings and other hair grooming 0.2%aids

Diisobutyl Adipate Basecoats and undercoats (manicuring 0.001-0.7%preparations)

Diisobutyl Adipate Cuticle softeners 0.5%

Diisobutyl Adipate Nail polish and enamel 0.009-0.7%

Diisobutyl Adipate Bath soaps and detergents 0.009%

Diisobutyl Adipate Face and neck creams, lotions and powders 0.003%

Diisobutyl Adipate Body and hand creams, lotions and 0.8%powders

Diisobutyl Adipate Moisturizing creams, lotions and powders 0.03%

Page 3 of 4


Diisobutyl Adipate Paste masks (mud packs) 0.002%

Diisobutyl Adipate Suntan gels, creams and liquids 0.003%

Diisopropyl Adipate Bubble baths 2%

Diisopropyl Adipate Mascara 1%

Diisopropyl Adipate Perfumes 0.005-8%

Diisopropyl Adipate Other fragrance preparations 0.07-7%

Diisopropyl Adipate Tonics, dressings and other hair grooming 0.5-3%aids

Diisopropyl Adipate Blushers (all types) 0.02%

Diisopropyl Adipate Foundations 0.02%

Diisopropyl Adipate Aftershave lotions 0.009%

Diisopropyl Adipate Skin cleansing (cold creams, cleansing 7%lotions, liquids and pads)

Diisopropyl Adipate Face and neck creams, lotions and powders 3%

Diisopropyl Adipate Body and hand creams, lotions and 2%powders

Diisopropyl Adipate Body and hand sprays 2%

Diisopropyl Adipate Skin fresheners 1%

Diisostearyl Adipate Lipstick 10%

Diisostearyl Adipate Skin cleansing (cold creams, cleansing 3%lotions, liquids and pads)

Dimethyl Adipate Nail polish and enamel removers 0.2%*Ingredients found in the title of the table but not found in the table were included in theconcentration of use survey, but no uses were reported.

Information collected in 2010Table prepared February 24, 2010

Page 4 of 4


Confidential data removed

Personal Care Products CouncilCommitted to Safety,Quality & Innovation

Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)

FROM: John Bailey, Ph.D.Industry Liaison to the CIR Expert Panel

DATE: January 15, 2010 (revised summaries submitted July 26, 2010)

SUBJECT: Unpublished data on Diisostearyl Adipate, Diisocetyl Dodecandedioate andDioctyldodecyl Dodecanedioate

For each ingredient there is a toxicological summary sheet (signed by Lisa Bouldin), followed by thestudies on that compound. Please note that the AMA Laboratories, Inc. (1996) HRIPT includes allthree compounds, and that a copy of this study is included following each summary sheet.

Bouldin L. Toxicological summary Liquiwax DISA (Diisostearyl Adipate)

AMA Laboratories, Inc. 1996. 50 human subject repeat insult patch test skin irritation/sensitizationevaluation of several substances (including Liquiwax DISA [Diisostearyl Adipate]).

Bouldin L. Toxicological summary Liquiwax DICDD (Diisocetyl Dodecanedioate)

AMA Laboratories, Inc. 1996. 50 human subject repeat insult patch test skin irritation/sensitizationevaluation of several substances (including Liquiwax DICDD [Diisocetyl Dodecanedioate]).

AMA Laboratories, Inc. 1991. Acute oral toxicity Liquiwax DICDD (Diisocetyl Dodecanedioate).

AMA Laboratories, Inc. 1990. Primary skin irritation Liquiwax DICDD (Diisocetyl Dodecanedioate).

AMA Laboratories, Inc. 1990. Primary eye irritation Liquiwax DICDD (Diisocetyl Dodecanedioate).

Bouldin L. Toxicological summary Liquiwax DIADD (Dioctyldodecyl Dodecanedioate)

AMA Laboratories, Inc. 1996. 50 human subject repeat insult patch test skin irritationlsensitizationevaluation of several substances (including Liquiwax DIADD [DioctyldodecylDodecanedioate]).

1101 17th Street, N.W., Suite 3OO Washington, D.C. 20036-4702 202.331.1770 I 202.331.1969 (fax) www.personalcarecouncil.org CIR Panel Book Page 197

AMA Laboratories, Inc. 1990. Acute oral toxicity Liquiwax DIADD (DioctyldodecylDodecanedioate).

AMA Laboratories, Inc. 1990. Primary skin irritation Liquiwax DLkDD (DioctyldodecylDodecanedioate).

AMA Laboratories, Inc. 1990. Primary eye irritation Liquiwax DJADD (DioctyldodecylDodecandioate).

AMA Laboratories, Inc. 1993. Guinea pig maximization test Liquiwax DIADD (DioctyldodecylDodecanedioate).

2


Persona Care Products CounciCommitted to Safety,Quality & Innovation

Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CW)

FROM: John I}(OIndustry Liaison to the CIR Expert Panel

DATE: February 15, 2010

SUBJECT: Physical Chemical Properties Sebacates

Hokoku Corporation. 2010. Physical/Chemical Properties Dibutyl Octyl Sebacate, DihexyldecylSebacate and Dioctyldodecyl Sebacate.

Another supplier reports that the expected impurities in Diisopropyl Sebacate are the starting materialsSebacic Acid <0.3% and Isopropyl Alcohol <0.2%.

11011 7th Street, N.W., Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncfl.org CIR Panel Book Page 260

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SEBACIC ACID 11A - Aftershave Lotion 1

SEBACIC ACID 12A - Cleansing 3

SEBACIC ACID 12D - Body and Hand (exc shave) 1

SEBACIC ACID 12F - Moisturizing 7

DIETHYLHEXYL SEBACATE 03F - Mascara 4

DIETHYLHEXYL SEBACATE 05I - Other Hair Preparations 2

DIETHYLHEXYL SEBACATE 11A - Aftershave Lotion 7

DIMETHYL SEBACATE 10B - Deodorants (underarm) 1 ??

DIISOPROPYL SEBACATE 03D - Eye Lotion 1

DIISOPROPYL SEBACATE 04A - Cologne and Toilet waters 1

DIISOPROPYL SEBACATE 05A - Hair Conditioner 1

DIISOPROPYL SEBACATE 05G - Tonics, Dressings, and Other Hair Grooming Aids5

DIISOPROPYL SEBACATE 07I - Other Makeup Preparations 1

DIISOPROPYL SEBACATE 08A - Basecoats and Undercoats 1

DIISOPROPYL SEBACATE 10B - Deodorants (underarm) 4

DIISOPROPYL SEBACATE 11A - Aftershave Lotion 1

DIISOPROPYL SEBACATE 12C - Face and Neck (exc shave) 3

DIISOPROPYL SEBACATE 12D - Body and Hand (exc shave) 2

DIISOPROPYL SEBACATE 12F - Moisturizing 3

DIISOPROPYL SEBACATE 12J - Other Skin Care Preps 2

DIISOPROPYL SEBACATE 13B - Indoor Tanning Preparations 5

DIMETHYL SEBACATE 10B - Deodorants (underarm) 1 ??

SUCCINIC ACID 05C - Hair Straighteners 2

SUCCINIC ACID 12F - Moisturizing 2

SODIUM SUCCINATE 02B - Bubble Baths 1

SODIUM SUCCINATE 05F - Shampoos (non-coloring) 2

SODIUM SUCCINATE 10A - Bath Soaps and Detergents 1

SODIUM SUCCINATE 12F - Moisturizing 3

DISODIUM SUCCINATE 03D - Eye Lotion 2

DISODIUM SUCCINATE 03G - Other Eye Makeup Preparations 2

DISODIUM SUCCINATE 05A - Hair Conditioner 1

DISODIUM SUCCINATE 05E - Rinses (non-coloring) 1

DISODIUM SUCCINATE 05F - Shampoos (non-coloring) 1

DISODIUM SUCCINATE 05I - Other Hair Preparations 2

DISODIUM SUCCINATE 07C - Foundations 1

DISODIUM SUCCINATE 07F - Makeup Bases 1

DISODIUM SUCCINATE 12A - Cleansing 4

DISODIUM SUCCINATE 12C - Face and Neck (exc shave) 9

DISODIUM SUCCINATE 12D - Body and Hand (exc shave) 2

DISODIUM SUCCINATE 12F - Moisturizing 9

DISODIUM SUCCINATE 12G - Night 5

DISODIUM SUCCINATE 12I - Skin Fresheners 1

DISODIUM SUCCINATE 12J - Other Skin Care Preps 4

DIMETHYL SUCCINATE 08F - Nail Polish and Enamel Removers 12

DIETHYLHEXYL SUCCINATE 03D - Eye Lotion 1

DIETHYLHEXYL SUCCINATE 05A - Hair Conditioner 1

DIETHYLHEXYL SUCCINATE 05G - Tonics, Dressings, and Other Hair Grooming Aids2


DIETHYLHEXYL SUCCINATE 05I - Other Hair Preparations 1

DIETHYLHEXYL SUCCINATE 07A - Blushers (all types) 1

DIETHYLHEXYL SUCCINATE 07C - Foundations 1

DIETHYLHEXYL SUCCINATE 10E - Other Personal Cleanliness Products1

DIETHYLHEXYL SUCCINATE 11A - Aftershave Lotion 1

DIETHYLHEXYL SUCCINATE 12A - Cleansing 2

DIETHYLHEXYL SUCCINATE 12C - Face and Neck (exc shave) 2

DIETHYLHEXYL SUCCINATE 12D - Body and Hand (exc shave) 9

DIETHYLHEXYL SUCCINATE 12F - Moisturizing 8

DIETHYLHEXYL SUCCINATE 12G - Night 2

DIETHYLHEXYL SUCCINATE 12J - Other Skin Care Preps 3

DIETHYLHEXYL SUCCINATE 13B - Indoor Tanning Preparations 3

DIOCTYL SUCCINATE 05B - Hair Spray (aerosol fixatives) 1 actually Dicapryl

DIOCTYL SUCCINATE 12C - Face and Neck (exc shave) 2

DIOCTYL SUCCINATE 12D - Body and Hand (exc shave) 1

DIOCTYL SUCCINATE 12F - Moisturizing 3

DIOCTYL SUCCINATE 12G - Night 1

DIOCTYL SUCCINATE 13C - Other Suntan Preparations 1

DIMETHYL GLUTARATE 08F - Nail Polish and Enamel Removers 13

ADIPIC ACID 02A - Bath Oils, Tablets, and Salts 1

ADIPIC ACID 05A - Hair Conditioner 8

ADIPIC ACID 05D - Permanent Waves 6

ADIPIC ACID 05F - Shampoos (non-coloring) 8

ADIPIC ACID 05G - Tonics, Dressings, and Other Hair Grooming Aids2

DIMETHYL ADIPATE 08F - Nail Polish and Enamel Removers 12

DIETHYLHEXYL ADIPATE 01B - Baby Lotions, Oils, Powders, and Creams1

DIETHYLHEXYL ADIPATE 03C - Eye Shadow 1

DIETHYLHEXYL ADIPATE 03D - Eye Lotion 1

DIETHYLHEXYL ADIPATE 03G - Other Eye Makeup Preparations 1

DIETHYLHEXYL ADIPATE 04E - Other Fragrance Preparation 5

DIETHYLHEXYL ADIPATE 05G - Tonics, Dressings, and Other Hair Grooming Aids1

DIETHYLHEXYL ADIPATE 07A - Blushers (all types) 1

DIETHYLHEXYL ADIPATE 07C - Foundations 5

DIETHYLHEXYL ADIPATE 07E - Lipstick 1

DIETHYLHEXYL ADIPATE 07F - Makeup Bases 3

DIETHYLHEXYL ADIPATE 07I - Other Makeup Preparations 1

DIETHYLHEXYL ADIPATE 08A - Basecoats and Undercoats 1

DIETHYLHEXYL ADIPATE 08E - Nail Polish and Enamel 3

DIETHYLHEXYL ADIPATE 10E - Other Personal Cleanliness Products1

DIETHYLHEXYL ADIPATE 11E - Shaving Cream 4

DIETHYLHEXYL ADIPATE 12A - Cleansing 2

DIETHYLHEXYL ADIPATE 12C - Face and Neck (exc shave) 6

DIETHYLHEXYL ADIPATE 12D - Body and Hand (exc shave) 1

DIETHYLHEXYL ADIPATE 12F - Moisturizing 2

DIETHYLHEXYL ADIPATE 12G - Night 2

DIETHYLHEXYL ADIPATE 12H - Paste Masks (mud packs) 2

DIETHYLHEXYL ADIPATE 12J - Other Skin Care Preps 2

DIETHYLHEXYL ADIPATE 13A - Suntan Gels, Creams, and Liquids 1

DIBUTYL ADIPATE 03F - Mascara 2

DIBUTYL ADIPATE 04E - Other Fragrance Preparation 2

DIBUTYL ADIPATE 08E - Nail Polish and Enamel 1

DIBUTYL ADIPATE 12F - Moisturizing 1


DICAPRYL ADIPATE 02A - Bath Oils, Tablets, and Salts 5

DICAPRYL ADIPATE 04E - Other Fragrance Preparation 1

DICAPRYL ADIPATE 10B - Deodorants (underarm) 30

DICAPRYL ADIPATE 12D - Body and Hand (exc shave) 7

DIHEXYL ADIPATE 12D - Body and Hand (exc shave) 1

DIISOBUTYL ADIPATE 05B - Hair Spray (aerosol fixatives) 5

DIISOBUTYL ADIPATE 08A - Basecoats and Undercoats 2

DIISOBUTYL ADIPATE 08E - Nail Polish and Enamel 7

DIISOBUTYL ADIPATE 11A - Aftershave Lotion 2

DIISOBUTYL ADIPATE 12D - Body and Hand (exc shave) 5

DIISOBUTYL ADIPATE 12F - Moisturizing 1

DIISODECYL ADIPATE 12G - Night 1

DIISOPROPYL ADIPATE 02A - Bath Oils, Tablets, and Salts 1

DIISOPROPYL ADIPATE 02D - Other Bath Preparations 1

DIISOPROPYL ADIPATE 03F - Mascara 2

DIISOPROPYL ADIPATE 04A - Cologne and Toilet waters 8

DIISOPROPYL ADIPATE 04B - Perfumes 6

DIISOPROPYL ADIPATE 04E - Other Fragrance Preparation 7

DIISOPROPYL ADIPATE 05G - Tonics, Dressings, and Other Hair Grooming Aids10

DIISOPROPYL ADIPATE 05H - Wave Sets 2

DIISOPROPYL ADIPATE 05I - Other Hair Preparations 5

DIISOPROPYL ADIPATE 07E - Lipstick 1

DIISOPROPYL ADIPATE 08F - Nail Polish and Enamel Removers 1

DIISOPROPYL ADIPATE 10B - Deodorants (underarm) 6

DIISOPROPYL ADIPATE 11A - Aftershave Lotion 11

DIISOPROPYL ADIPATE 12A - Cleansing 1

DIISOPROPYL ADIPATE 12D - Body and Hand (exc shave) 2

DIISOPROPYL ADIPATE 12F - Moisturizing 2

DIISOPROPYL ADIPATE 12J - Other Skin Care Preps 2

DIISOPROPYL ADIPATE 13A - Suntan Gels, Creams, and Liquids 1

DIISOPROPYL ADIPATE 13C - Other Suntan Preparations 1

DIISOSTEARYL ADIPATE 07E - Lipstick 4

DIISOSTEARYL ADIPATE 12A - Cleansing 2

DIOCTYLDODECYL ADIPATE 07E - Lipstick 3

DI-N-OCTYL ADIPATE 07C - Foundations 2 ???

DI-N-OCTYL ADIPATE 10E - Other Personal Cleanliness Products1

OCTYL ADIPATE 12C - Face and Neck (exc shave) 1 ??

AZELAIC ACID 11G - Other Shaving Preparation Products1

AZELAIC ACID 12C - Face and Neck (exc shave) 6

AZELAIC ACID 12H - Paste Masks (mud packs) 1

AZELAIC ACID 12J - Other Skin Care Preps 1

DIISOCETYL DODECANEDIOATE07I - Other Makeup Preparations 1

DIISOCETYL DODECANEDIOATE13B - Indoor Tanning Preparations 1


DIOCTYLDODECYL DODECANEDIOATE04E - Other Fragrance Preparation 2

DIOCTYLDODECYL DODECANEDIOATE07E - Lipstick 1

DIOCTYLDODECYL DODECANEDIOATE12D - Body and Hand (exc shave) 2


JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY

Volume 3, Number 3, 19&Q Mary Ann Liebert, Inc., Publishers

3

Final Report on the Safety

Assessment of Dioctyl Adipate and

Diisopropyl Adipate

Dioctyl Adipate, the diester of octyl alcohol and adipic acid, and Diisopropyl Adipate, the diester of isopropyl alcohol, are used in cosmetics as emollients and bases. These two ingredients have a low acute oral and percutaneous toxicity. Undiluted Dioctyl Adipate and Diisopropyl Adipate were, at most, only very mild, transient eye irritants. Primary dermal irritation tests indicated that Dioctyl Adipate was a very mild irritant and Diisopropyl Adipate was minimally irritating. Dioctyl Adipate was not a skin sensitizer in guinea pigs.

An Ames test for the mutagenic potential of Dioctyl Adipate was negative. An assay of the carcinogenic potential of Dioctyl Adipate produced no untoward effects and was noncarcinogenic to rats. Mice studies indicated a dose- related body weight reduction and a higher incidence of hepatocellular adenoma and carcinoma than controls. In a lifetime study Dioctyl Adipate caused no skin tumors when 10 mg was applied weekly to the back skin of mice. The teratogenicity potential of Dioctyl Adipate is reviewed.

Clinical assessment of Dioctyl Adipate in formulations showed, at most, minimal erythema and papules when applied under occlusion. No UV sensitization occurred. Undiluted Diisopropyl Adipate produced no irritation in 24 h patch tests, but was moderately irritating in a 21-day cumulative irritancy test. Formulations containing up to 20°h Diisopropyl Adipate caused minimal to mild irritation, no sensitization and no photosensitization. On the basis of available data, it is concluded that Dioctyl Adipate and Diisopropyl Adipate are safe as presently used in cosmetics.

INTRODUCTION

D ioctyl Adipate and Diisopropyl Adipate are common plasticizers and emollient esters. In cosmetics they are used as emollients and as the base of many

different types of products.“-3)

CHEMICAL AND PHYSICAL PROPERTIES

Structure

1. Dioctyl Adipate is the diester of octyl alcohol and adipic acid. It conforms generally to the formula:

101


102 COSMETIC INGREDIENT REVIEW

0 II y2H5

HgCa-CH-CH2-0-C-(CH2)4-C-0-CH2-CH-C4Hg

CAS Number: 103-23-l Synonyms include: Di-(2-Ethylhexyl)Adipate and Wickenol 1 58.(3)

2. Diispropyl Adipate is the diester of isopropyl alcohol and adipic acid. It conforms generally to the formula:

0 0 II II

(CHj)2CH-O-C-(CH2),-C-O-CH(CH3)2

CAS Number 6938-94-9 Other names include:

Beta DIA Ceraphyl 230 Crodamol DA I so-Ad i pate 2/043 700 Prod i pate Schercemol DIA Standamul DIPA Tegester 504-D Wickenol 11 6.(3’

Production

Dioctyl Adipate is produced by the reaction of adipic acid and 2-ethylhexanol in the presence of an esterification catalyst such as sulfuric acid, p-toluenesulfonic acid or a proprietary catalyst. Purification of the reaction product includes removal of the catalyst, alkali refining and stripping. (4.5) Diisopropyl Adipate is produced by esterification of adipic acid with an excess of isopropanol. The excess alcohol is removed by vacuum stripping and the ester is then alkali-refined and filtered.(6)

Properties

Dioctyl Adipate and Diisopropyl Adipate are clear, colorless to light yellow viscous liquids with an aromatic odor. They are soluble in most organic solvents and insoluble in water. For other properties, see Table 1.

Analytical Methods

Diisopropyl Adipate and Dioctyl Adipate can be identified through standard Infrared (IR) spectroscopy. (‘I Gas-liquid chromatography, liquid-liquid extraction, mass spectrometry, and high-pressure liquid chromatography are also methods of analysis for the Adipates.“-lo)

Reactivity/Stability

Dioctyl Adipate and Diisopropyl Adipate are considered stable; however,


ASSESSMENT: DIOCTYL ADIPATE AND DIISOPROPYL ADIPATE 103

TABLE 1. Properties of Dioctyl and Diisopropyl Adipate.

Dioctyl Property Adipate Ref.

Diisopropyl

Adipate Ref.

Form Oily liquid 2 Oily liquid 7 Color Colorless to 2,4 Colorless, clear 7

light yellow Boiling point (“C) 417 2 - -

Specific gravity 0.9268 2 0.950 to 0.965 7

(20/20%) Flash point, T, (“F) 204.4 (400) 11 - - Melting point (“C) -67.8 4 - -

Molecular weight 370.56 11 230.34 4 Refractive index at 20°C 1.4474 11 1.4200-l .4245 7 Acid value 1 .O (max.) 5 2.0 (max.) 7 Saponification value 298-308 5 465-500 7 Iodine value 0.5 (max.) 5 1 .O (max.) 5 Viscosity (20°C) 13.7 cps - - Vapor pressure 0 200% 2.4 mm Hg - - - Soluble in: Alcohol 4 - -

Ether

Acetone

Acetic acid

Most organic solvents Insoluble in: Water 2,4 - -

Glycerin and glycols

hydrolysis of the ester groupings may occur in the presence of aqueous acids or bases.‘5a6)

Impurities

No known minor impurities occur in either Dioctyl Adipate or Diisopropyl Adipate, although the acid values imply the presence of adipic acid or of the monoester in both.(5*6)

USE

Non-Cosmetic Uses

The Adipates are used primarily as plasticizers in food wraps, vinyl blood bags and hemodialysis bags. Adipates are also used as solvents and aircraft Iubes.(‘.2.4,‘2.13) Dioctyl Adipate has Indirect Food Additive (IFA) Status for use in food wrapping.(14)

Cosmetic Use

The Adipates are used as components of cosmetic bases and as solvents and emollients in other cream-type skin preparations. (I) They are also used to modify the tactile and flow properties of emollient blends, especially in bath products.(‘5)

The cosmetic product formulation computer printout which is made available by the Food and Drug Administration (FDA) is compiled through voluntary filing of such data in accordance with Title 21 part 720.4 of the Code of



Federal Regulations. (14) Ingredients are listed in prescribed concentration ranges under specific product type categories. Since certain cosmetic ingredients are supplied by the manufacturer at less than 100% concentration, the value reported by the cosmetic formulator may not necessarily reflect the true, actual concentration found in the finished product; the actual concentration in such a case would be a fraction of that reported to the FDA. Since data are submitted only within the framework of preset concentration ranges; this presents the opportunity for overestimation of the actual concentration of an ingredient in a particular product. An entry at the lowest end of a concentration range is considered the same as one entered at the highest end of that range, thus, introducing the possibility of a two- to lo-fold error in the assumed ingredient concentration.

According to the industry’s 1981 submission of product formulation data to the FDA, Dioctyl Adipate was used in 27 products in concentrations of I 0.1 Oh-1 % in some facial makeup, and up to lo%-25% in bath preparations(16) (see Table 2).

Diisopropyl Adipate was used in 112 cosmetic formulations according to the 1981 FDA product formulation data. Its concentrations of use ranged from less than 0.1% up to 25%‘16) (see Table 2).

Surfaces to Which Commonly Applied and Frequency of Application

Dioctyl and Diisopropyl Adipates are found in cosmetics which may come in contact with the skin of the face, hands, and the general body surface, the mucous membranes, nails, scalp, and hair. Thus, cosmetics containing Adipates may be applied to the body once every few days to several times daily(16) (see Table 2).

TABLE 2. Product Formulation Data.a

Product categoryb

Total no. No. of product formulations within each concentration

containing range (% j b

ingredient >JO-25 >5-10 >J-5 >O. J-J s0.J

Dioctyl Adipate

Bath oils, tablets, and salts

Colognes and toilet waters

Blushers (all types)

Makeup foundations

Lipstick

Other makeup preparations

(not eye)

Nail polish and enamel

remover

Deodorants (underarm)

Aftershave lotions

Face, body, and hand skin

1

2

1

1

4 - - - -

- - 6 - -

- - - - 1

- 2 1 1 -

- - 5 - -

- - 1 - -

- - 2 - - - - - 1 - - - 1 - -

care preparations (excluding

shaving preparations) 1 - - 1 - -

Other suntan preparations 1 - - - 1 -

198 1 TOTALS 27 4 2 17 3 1


ASSESSMENT: DIOCTYL ADIPATE AND DIISOPROPYL ADIPATE

TABLE 2. (Continued.)

105

Product categoryb

Total no.

containing

ingredient

No. of product formulations within each concentration

range (%) b

> JO-25 >5-JO >J-5 >O.J-7 s0.J

Diisopropyl Adipate

Bath oils, tablets, and salts

Bubble baths

Eyeliner

Eye shadow

Colognes and toilet waters

Perfumes

Sachets

Other fragrance preparations

Hair conditioners

Hair sprays (aerosol fixatives)

Tonics, dressings, and other

hair grooming aids

Wave sets

Blushers (all types)

Face powders

Makeup foundations

Other personal cleanliness

products

Aftershave lotions

Preshave lotions (all types)

Skin cleansing preparations

(cold creams, lotions,

liquids, and pads)

Foot powders and sprays

Moisturizing skin care

preparations

Night skin care preparations

Skin fresheners

Other skin care preparations

Suntan gels, creams, and

liquids

Indoor tanning preparations

7

1

1

1

15

20

1

9

3

1

1

16 1

5

1

2

1

11

2

2

2

1 - - -

- - -

-

- -

- -

- -

-

- - 1

- -

-

1

3

1

2 -

1 - 1 - 1 -

- - 12 3

4 -

- -

6 1 - 1

1 -

4

1

1

1 -

-

9 -

-

-

1 -

-

1

-

2

-

1 -

-

1

1

7 -

5

1

1 -

6 -

-

-

- - - - - - -

2 -

-

-

-

-

-

-

-

-

-

-

-

-

2 -

-

-

1981 TOTALS 112 11 23 46 28 4

a Data from Ref. 16.

bPreset product categories and concentration ranges in accordance with federal filing regulations (21 CFR

720.4).

BIOLOGICAL PROPERTIES

General Studies

Subcellular and Enzyme Effects

Dioctyl Adipate was fed to male rats in a dietary concentration of 2% for three weeks. Effects included hepatic peroxisome proliferation, increased size of the liver, and increase in the hepatic activities of the peroxisome-associated enzymes catalase and carnitine acetyl transferase. Hypolipidemia and a decrease



in serum lipids were also observed in Dioctyl Adipate-treated animals. The authors postulated that the active portion of the compound, in the induction of hepatic peroxisome proliferation, may be the metabolite 2-ethylhexyl alcohol.(“)

Effect on Cultured Cells

When contracting chick embryo heart cells were maintained in tissue culture and exposed to Dioctyl Adipate at a level of 1.5 pglml (4 km), the number of cardiac contracting cells was reduced to 50% of control levels.(18) In cultures of human diploid cells of the WI38 strain, the IDso (dose that inhibits cell growth to 50% of the control culture) for Dioctyl Adipate was 32 pM.‘l’)

Animal Toxicology

Acute Toxicity

Oral

Dioctyl Adipate was administered by gavage to nine groups of five male and five female F344 rats at doses of 0.08, 0.16, 0.31, 0.63, 1.25, 2.5, 5.0, 10, or 20 g/kg of the substance in corn oil. Two of five males of the 10 g/kg group died and one male and one female of the 20 g/kg group died.(‘O)

Five groups of five male and five female mice were given Dioctyl Adipate in corn oil in single doses of 1.25, 2.5, 5.0, 10.0, or 20.0 g/kg. Mortality observations were: one male of the 1.25 g/kg group died “accidentally,” two males of the 10.0 g/kg group, three at the 20.0 g/kg group, one female of the 20 g/kg group. The estimated LDso for male mice was 15.0 g/kg, and for females it was 24.6 g/kg.(‘O)

In an acute oral toxicity study using rats, Andreeva(z1) reported a no effect dose of Dioctyl Adipate in rats of 6 g/kg. Doses greater than this resulted in central nervous system (CNS) stimulation followed by depression which lasted for the five- to seven-day observation period.

The single oral toxic dose of Dioctyl Adipate for the rat over an observation period of 14 days was 9.11 g/kg.(22)

A group of five male and five female albino rats was fasted overnight, intubated with a dose of 7.4 g/kg Dioctyl Adipate, and then observed daily for 14 days. One animal died on Day 14, but other observations were not recorded.(23)

A product containing 0.175% Dioctyl Adipate was administered in a single undiluted 6.5 g/kg dose to five male and five female Harlan Wistar rats. During the seven observation days, no signs of toxicity were observed and body weight gains were normal.(24)

A face cream containing 0.7% Diisopropyl Adipate was intubated into groups of five male and five female Wistar rats per dose concentration. Animals were observed for 14 days; one male rat of the highest dose group (76.8 g/kg of the formulation) died on Day 4 of observation. At necropsy of this animal, the findings included urinary staining of the abdomen, prominent serosal blood vessels in the stomach, cecum and intestines, and red fluid in the intestines. No other deaths or abnormal findings were reported.‘25)

A perfume containing 1.08% Diisopropyl Adipate was administered in a single 5 g/kg dose of the preparation to five male and five female Sprague- Dawley rats. The animals were observed for 14 days; one female died on Day 2.


ASSESSMENT: DIOCTYLADIPATE AND DIISOPROPYLADIPATE 107

Necropsy findings of this animal were dark and mottled lungs and liver, reddened pylorus, and gas-filled GI tract. Other surviving animals showed signs of decreased activity, ataxia, diarrhea, gasping, and urinary incontinence.(26)

In a similar study a perfume. containing 1.08% Diisopropyl Adipate was studied. Five male and five female Sprague-Dawley rats were given by oral intubation a single 5 g/kg dose of the formulation; animals were observed for 14 days. No animals died, but three males and five females had decreased activity and ataxia.r2”

A product containing 5% Diisopropyl Adipate was administered as a single 5 g/kg dose of the formulation by intubation to five female albino rats; the animals were observed for seven days. No deaths or abnormal behavior were observed.‘2*)

A dose of 15 g/kg of a product containing 20.75% Diisopropyl Adipate was administered orally by stomach tube to five female rats. After seven observation days, no deaths or abnormal responses were observed and the LDso was > 15 g/kg dose’29) (see Table 3).

74-day oral study

A 14-day repeated dose study of Dioctyl Adipate was conducted using six groups of five male and five female F344 rats and of the same number of B6C3Fl mice. Dosages of 0 (control), 3,100, 6,300, 12,500, 25,000, and 50,000 ppm in the diet were fed to male rats and mice for 14 days. Female rats and mice were fed 0 (control), 6,300, 12,500, 25,000, 50,000, and 100,000 ppm Dioctyl Adipate in the diet. Weight gain was depressed in male rats fed 50,000 ppm and in female rats fed 25,000 ppm or more. Females fed 100,000 ppm lost weight and one died. All female mice receiving 100,000 ppm died, and males at 50,000 ppm and females at 25,000 or more lost weight.‘20’

Intravenous

The intravenous LDso of Dioctyl Adipate to rats and rabbits was 900 mglkg and 540 mglkg, respectively.‘30)

The acute intravenous LDso of Diisopropyl Adipate to rats was 640 mg/kg.‘30)

Percutaneous

The acute dermal toxicity of Dioctyl Adipate was tested using eight albino rabbits. The trunk of each animal was clipped of all hair and half of the rabbits received longitudinal epidermal abrasions over the clipped area. The rabbits were immobilized and plastic sleeves were slipped over the shaved areas. The animals were placed into groups of two each and received doses of 0 (control), 3.6, 5.6, and 8.7 g/kg of pure Dioctyl Adipate under the sleeve. After 24 h, the sleeves were removed, the volume of unabsorbed material was cleaned from each animal and measured, and skin reactions were evaluated. The animals were observed for signs of toxicity for two weeks. Daily observation included body weights, food consumption, and behavior. Urinalysis, hematologic features, and skin changes were also observed and skin changes were rated according to standard Draize scores. The animals had only slight erythema which increased in duration with increasing concentration. However, all irritation disappeared several days before the end of the observation period. Weight gain, feed consumption, urine and hematologic values, as well as behavior were normal in all animals. Dioctyl Adipate produced mild irritation, but no systemic toxic effects. (23)

-


TAB

LE

3.

Ac

ute

O

ral

Toxi

city

.

Ing

red

ient

Spe

cies

an

d N

o.

Ing.

C

ont.

of

An

ima

ls 66

) D

ose/

kg

L D

sdkg

Ob

serv

atio

n

perio

d C

omm

ents

R

ef.

Dio

cty

l A

dip

ate

Ing

red

ient

F3

44

rats

-

0.08

-20.

0 g

45

ma

le,

45

fem

ale

B6C

3Fl

mic

e

25

ma

le,

25

fem

ale

- 1.

25-2

0.0

g

rats

-

6g

5 m

ale

ra

ts

- -

5 m

ale

, 5

fem

ale

ra

ts

- 7.

4 g

45.0

g

fo

r

ma

le9

26.0

g

fo

r

fem

ale

?

15.0

g

fo

r

ma

le9

24.6

g

fo

r

fem

ale

9

-

9.11

g

(7.2

8-l

1.4)

-

14

da

ys

15 d

ays

7 d

ays

14 d

ays

14

da

ys

2 o

f 5

ma

les

die

d

in t

he

10

g/k

g d

ose

gro

up;

1 o

f 5

ma

les

an

d

1 o

f

5 fe

ma

les

die

d

in t

he

20

g/k

g d

ose

gro

up.

2 o

f 5

ma

les

die

d

in t

he

10

g/k

g d

ose

gro

up;

3 m

ale

s a

nd

1 o

f 5

fem

ale

s

die

d

in t

he

20

g/k

g g

roup

.

6 g

/kg

=

“N

o

eff

ec

t le

vel.”

G

rea

ter

do

ses

ca

use

CN

S d

istur

ba

nce

. -

On

e

an

ima

l d

ied

on

Da

y 14

.

20

20

21

22

23

6.5

g

- 7

da

ys

No

o

f w

eig

ht

signs

to

xic

ity;

ga

ins

24

norm

al.

up

to

76

.8

g

- 14

d

ays

O

ne

m

ale

ra

t a

t th

e

80

ml/

kg

leve

l 25

die

d

on

Da

y 4

of

ob

serv

atio

n.

5.0

g

- 14

da

ys

On

D

ay

2 o

f o

bse

rva

tion,

o

ne

26

an

ima

l d

ied

. N

ec

rop

sy

sho

we

d

red

, m

ott

led

lu

ngs

an

d l

ive

r, g

as-

fille

d

C.1

. tr

ac

t.

5.0

g

14 d

ays

3

ma

les

an

d 5

fe

ma

les

sho

we

d

27

de

cre

ase

d

ac

tivity

a

nd

ata

xia

.

No

d

ea

ths.

15.0

g

-

7 d

ays

N

o

de

ath

s o

cc

urre

d

an

d a

ll a

nim

als

28

ap

pe

are

d

norm

al.

15.0

g

-

7 d

ays

N

o

de

ath

s o

cc

urre

d

an

d a

ll a

nim

als

29

ap

pe

are

d

norm

al.

Form

ula

tion

5

ma

le,

5 fe

ma

le

Wist

ar

rats

Diis

op

rop

yl

Ad

ipa

te

Form

ula

tion

5

ma

le,

5 fe

ma

le

Wist

ar

alb

ino

rats

p

er

do

sag

e

5 m

ale

, 5

fem

ale

Sp

rag

ue

-Da

wle

y

rats

5 m

ale

, 5

fem

ale

Sp

rag

ue

-Da

wle

y

rats

5 fe

ma

le

alb

ino

ra

ts

5 fe

ma

le

alb

ino

ra

ts

(0.1

75)

0.7

1.08

1.08

5.0

20.7

5

a Ex

tra

po

late

d

by

aut

hor.



Immersion test

A product containing 20.75% Diisopropyl Adipate was tested for dermal irritation and percutaneous toxicity- in a whole-body immersion test using six albino guinea pigs. The product was diluted to 0.5% w/v with water so that the actual concentration of the Adipate was 0.10%. The animals were clipped of all abdominal hair and placed in restraining cylinders. The lower parts of the body were immersed in the 37°C test solution for 4 h per day for three consecutive days. Forty-eight hours after the last exposure, the skin of the abdomen was graded according to a scale from 10 (normal) to 1 (moribund as determined by skin in- juries). Clinical signs were recorded daily, and products with a score less than seven are considered potential irritants. On observation, four animals were normal (score = 10) and two had a “first hint of scaling” (score = 9). There were no signs of systemic toxicity and the degree of skin irritation was considered minimal.(31r

Ocular

Undiluted Dioctyl Adipate (0.1 ml) was instilled into one eye of each of six albino rabbits. The untreated eye served as control. The eyes were graded at 24, 48, and 72 h on a scale of 0 (normal) to 4 (cornea1 opacity, iridial destruction, red conjunctivae, and swelling). No irritation (all scores = 0) was found at any of the observation periods.(23)

Each of six albino rabbits was treated in one eye with 0.1 ml of a cosmetic moisturizer containing 0.175% Dioctyl Adipate. The animals were observed up to seven days following instillation. After 1 h, slight conjunctival redness was observed, but it had disappeared after 24 h. No other effects were noted.‘24)

A 0.1 ml sample of a rouge product containing 0.01% Dioctyl Adipate was instilled into one eye of each of six albino rabbits. The untreated eye served as the control and all eyes were graded after 24,48, and 72 h. This product produced no conjunctival redness or chemosis, keratitis, or iritis and it was considered nonirritating.(32)

Two lots of undiluted Diisopropyl Adipate were tested for ocular irritation using six albino rabbits per lot. One eye of each animal received 0.1 ml of the ingredient and examinations for irritation were made daily until all scores were negative or up to seven days. One lot caused neligible irritation on Day 1, which disappeared by Day 2. No irritation was caused by the second lot.(33’

A face cream formulation containing 0.7% Diisopropyl Adipate was tested on nine albino rabbits for ocular irritation. One-tenth milliliter of the undiluted test material was placed in one eye of each animal; the other eye served as the control. Thirty seconds after instillation, the treated eyes of three rabbits were rinsed with 20 ml of deionized water. Observations for ocular reactions were made at 24, 48, and 72 h, and four and seven days after administration. In rabbits with unwashed eyes, two had conjunctival redness for 72 h and one had some presence of cornea1 stippling for 48 h. No other reactions were noted. The washed eyes of two rabbits had some cornea1 stippling up to Day 4; no other reactions were noted.(34)

Two products, one containing 5.0% Diisopropyl Adipate and one containing 20.75%, were each tested for ocular irritation using six albino rabbits. The products were instilled into one eye of each animal; the untreated eye served as the control. Observations were made until all eyes were negative for up to seven



days. The 5.0% product produced minimal irritation (score = 6 out of 110) on Day 1 and the irritation had disappeared by Day 2.(35’ The second product produced minimal irritation (score = 2 out of 110) on Day 1 and the irritation had disappeared by Day 2(36) (see Table 4).

Primary skin irritation

The primary cutaneous irritation of undiluted Dioctyl Adipate was studied using six albino rabbits. An intact and an abraded site on each rabbit received 0.5 ml of the Adipate under an occluded patch. After 24 h of exposure, the patches were removed and the sites evaluated for irritation according to the Draize method. A second observation was made 48 h after patch removal. Only very slight, barely perceptible erythema was observed in all animals at 24 h. After 72 h, the irritation had decreased in severity in all animals and had disappeared in one. The Primary Irritation Index (PII) was 0.83, indicating that Dioctyl Adipate was a very mild irritant.‘13’

The primary skin irritation of a moisturizing cream containing 0.175% Dioc- tyl Adipate was tested using three albino rabbits. The formulation was applied in four single daily 0.5 ml applications to the shaved backs of the animals and observations were made for seven days. After 24 h, slight erythema was observed which persisted throughout the seven-day period. One animal had well defined erythema with edema, and mild desquamation was seen on day seven. The irritation index was 1 .6.(24)

The primary skin irritation of three lots of Diisopropyl Adipate was investigated according to the Draize method. In each experiment, 0.1 ml of the undiluted product was applied under occlusion to the clipped back skin of nine albino rabbits. After 24 h of contact, the dressing was removed and the sites scored on a Primary Skin Irritation (PSI) scale of 0 (no effect) to 4 (severe erythema with or without edema). The PII was the average score of the total number of test subjects. The first lot had a PII of 1.6 and the second, 1.3. These scores indicated that the material was a mild irritant.“‘) The third lot caused no irritation in eight rabbits and only barely perceptible erythema in one. The PII score of 0.06 indicated that this compound was minimally irritating.(3B1

Two products containing Diisopropyl Adipate at 5.0% and 20.75% were tested by the Draize technique. The undiluted product (0.1 ml) was applied under occlusion to the shaved skin of nine albino rabbits for 24 h. Observations were made 24 and 72 h after contact. The product with 5.0% Diisopropyl Adipate had a PII of 0.33, indicating that the product was minimally irritating.(39) The product with 20.75% Diisopropyl Adipate had a PII of 0.11 and was minimally ir- ritatingC40) (see Table 5).

Sensitization

The skin sensitizing potential of Dioctyl Adipate was studied using 10 white male guinea pigs. An area on the backs and flanks, clipped free from hair, was injected intracutaneously with 0.1% Dioctyl Adipate in olive oil. Injections were made every other day, three times weekly, until 10 had been given. The first injection was 0.05 ml and all subsequent ones were 0.1 ml each. Two weeks after the last injection, a challenge dose of 0.05 ml was injected. Observations were made 24 h after each injection as to area, height, and color of reaction. The retest or challenge injection reaction was compared with an average of-the scores taken after the original 10 doses. The area and height of the retest area was


TABL

E 4.

O

cul

ar

Irrita

tion

.

ingr

edie

nt

Spe

cie

s a

nd

no.

C

ont.

of

anim

als

(%)

Ap

plie

d

am

oun

t

(ml)

Ob

serv

atio

n

pe

riod

irrita

tion

sc

ore

Ma

x.

scor

e C

omm

ents

R

ef.

Dio

ctyl

A

dipa

te

Ing

red

ient

6

alb

ino

ra

bb

its

100

0.1

72

h

o/4

N

oni

rrita

ting

to

ra

bb

it e

ves.

23

Form

ula

tion

Form

ula

tion

6 a

lbin

o

rab

bits

0.

175

0.1

7 d

ays

-

Slig

ht

co

nju

nc

tiva

l re

dne

ss

aft

er

1 h;

24

cle

are

d

aft

er

24

h.

6 a

lbin

o

rab

bits

0.

01

0.1

72

h

- N

o

irrita

tion.

32

Diis

opro

pyl

Adi

pate

Ing

red

ient

Lot

75

6 a

lbin

o

rab

bits

Lot

76

6 a

lbin

o

rab

bits

Form

ula

tion

9

alb

ino

ra

bb

its

(6 u

nw

ash

ed

e

yes)

(3 w

ash

ed

e

yes)

6 a

lbin

o

rab

bits

6 a

lbin

o

rab

bits

100

100

0.1

0.1

72

h

72

h

l/11

0

O/l

10

Ne

glig

ibly

irr

itatin

g

on

Da

y 1.

Irr

itatio

n

disa

pp

ea

red

o

n D

ay

2.

No

nirri

tatin

g.

33

33

0.7

0.1

7 d

ays

-

5.0

0.1

2 d

ays

6/

l 10

20.7

5 0.

1 2

da

ys

2/l

10

Un

wa

she

d

eye

s;

2 sh

ow

ed

c

on

jun

ctiv

al

red

ness

fo

r 72

h,

1

ha

d c

orn

ea

1

stip

plin

g

for

48

h. W

ash

ed

e

yes;

2

sho

we

d

co

rne

a1

stip

plin

g

to

Da

y 4.

M

inim

al

irrita

tion

o

cc

urre

d

on

Da

y 1

an

d d

isap

pe

are

d

on

Da

y 2.

M

inim

al

irrita

tion

o

cc

urre

d

on

Da

y 1

an

d d

isap

pe

are

d

on

Da

y 2.

34

35

36


TAB

LE

5.

Prim

ary

D

erm

al

Irrita

tion.

App

lied

Tim

e In

gr.

Con

t. a

mo

unt

Spe

cie

s a

nd

no.

Ingr

edie

nt

6)

(ml)

of

anim

als

Con

tact

O

bser

v.

P///

Max

. C

omm

ents

R

ef.

Dio

ctyl

A

dipa

te

Ing

red

ient

10

0 0.

5 6

alb

ino

ra

bb

its

24

h

48 h

0.

83ia

.o

Ve

ry

slig

ht,

ba

rely

p

erc

ep

tible

23

ery

the

ma

in

all

an

ima

ls.

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

----

Pro

duc

t-m

oist

uriz

er

0.17

5 0.

5 3

alb

ino

ra

bb

its

4 d

ays

7

da

ys

1.61

40

Aft

er

24

h,

slig

ht

ery

the

ma

24

pe

rsist

ing

to

D

ay

7 w

ith

de

squa

ma

tion.

Diis

opro

pyl

Adi

pate

Ing

red

ient

10

0 0.

1 9

alb

ino

ra

bb

its

24h

- 1.

6l4.

0 M

ild

irrita

nt.

37

100

0.1

9 a

lbin

o

rab

bits

24

h -

1.31

4.0

Mild

irr

itant

. 37

loo

0.

1 9

alb

ino

ra

bb

its

24h

- 0.

06/4

.0

Min

ima

lly

irrita

ting

. 38

Pro

duc

ts

5.0

0.1

9 a

lbin

o

rab

bits

24

h

72

h

0.

3314

.0

Min

ima

lly

irrita

ting

. 39

20.7

5 0.

1 9

alb

ino

ra

bb

its

24

h

72

h

0.11

/4.0

M

inim

ally

irr

itatin

g.

40



smaller and lower than the average induction reactions; therefore, Dioctyl Adipate was not a sensitizer.(23)

P hototoxici ty

Primary dermal phototoxic irritation studies were conducted on two perfumes both containing 1.1% Diisopropyl Adipate. Four male and three female New Zealand white rabbits were clipped of all back hair and 200 mg of the undiluted product was applied to gauze patches which were then affixed to the shaved areas. Six patches were applied to the back of each test rabbit and one rabbit received two positive control patches. After a 2 h exposure, the patches on the right-hand side of each animal were removed and the skin irradiated for 15 min with four F40BLB bulbs (wavelength of 320-420 nm, peaking at approximately 360 nm), 24 in from the skin. The left-hand side was not irradiated. The patches were replaced on the right side and sealed with an occlusive wrap. All patches were removed 48 h after the initial application and 1 h after removal, sites were scored according to the Draize criteria. Scores were again recorded 72 and 96 h postdose. Both perfumes scored 0 (no irritation) for primary dermal irritation as well as primary dermal phototoxic irritation.(41’42)

Mucous membrane irritation

Six female albino rabbits were used to test the mucous membrane irritancy of a product containing 0.175% Dioctyl Adipate. The animals were given a single 0.1 ml topical application of the product to the genital mucosa. During the seven- day observation period, no irritation was noted.(24’

Subchronic Toxicity

Oral

Diets containing 0, 1,600, 3,100, 6,300, 12,500, or 25,000 ppm Dioctyl Adipate were fed for 13 weeks to six groups of ten F344 rats and ten B6C3Fl mice of both sexes. Observations were made twice daily and animals were weighed weekly. After 91 days, all survivors were sacrificed, necropsy was performed, and tissues were examined histopathologically. Weight gain was depressed for male rats at the 12,500 and 25,000 ppm dosage levels. No other compound-related abnormalities were found. Weight gain depression occurred in male mice fed 3,100 ppm or more and in female mice fed 6,000 or 25,000 ppm. No other compound- related abnormalities occurred.(20)

Chronic Toxicity

Oral

lntragastric doses of Dioctyl Adipate of 0.4, 1 .O or 2.0 g/kg given for six months to rats caused no enzymatic changes, but did increase the level of sulphydryl compounds in the blood. Hepatic detoxification appeared depressed at the onset of the study, but it was accelerated after six months. Administration of 0.1 g/kg for 10 months decreased CNS excitability. (21) (See Carcinogenesis Section of this report for additional chronic test results.)(20)


114

Mutagenesis

COSMETIC INGREDIENT REVIEW

Special Studies

Dioctyl Adipate (5 mg/plate or the dose which gave a toxic response, whichever was lower), was tested in the Ames Salmone//a/microsome assay. The compound was nonmutagenic when S. typhimurium strains TA1535, TA1537, TA1538, TA98, and TAlOO were exposed to the chemical with and without metabolic activation systems from rat livers.‘43)

Carcinogenesis

Oral administration

Groups of 50 male and 50 female F344 rats and 50 male and 50 female B6C3Fl mice were fed diets containing 12,000 or 25,000 ppm Dioctyl Adipate for 103 weeks. Fifty untreated rats and mice of both sexes were used as controls, and all surviving animals were sacrificed at 104-107 weeks. In rats, mean body weights of the 25,000 ppm group were lower than those of the controls. Males had survival rates of 68% in both the control and low-dose (12,000 ppm) group and 80% in the high-dosed (25,000 ppm) group. In females, 58% of controls, 78% of the low-dose group, and 88% of the high-dose group survived the study. Neoplastic and nonneoplastic lesions were seen with equal frequency in treated and control groups and none appeared related to administration of the compound. Dioctyl Adipate was not carcinogenic in F344 rats.(20)

In the prechronic studies a dose level of 12,500 ppm and 25,000 ppm caused a weight change in male mice, relative to controls, of minus 15% and minus 25%, respectively. In female mice, the same low and high dose concentrations caused a plus 5.6% and minus 13% weight loss, respectively. In three of these four dose concentrations, the weight loss exceeded the criteria for selecting the Maximum Tolerated Dose.(44)

In treated mice, mean body weights of either sex were lower than those of controls. Males had survival rates of 72% in controls, 64% in the low-dose group, and 82% in the high-dose group. In females, 84% of controls, 78% of the low- dose group, and 73% of the high-dose group survived. Incidence of hepatocellular adenomas in male mice were dose-related and statistically significant in the high- dose group. The incidence of hepatocellular carcinomas in male mice was higher in dosed groups, but was not statistically significantly increased. In female mice, there was a significant, dose-related trend and significantly higher incidence of hepatocellular adenomas or carcinomas in each of the dosed groups than in the control group (see Table 6). Since hepatocellular tumors were induced in this bioassay, Dioctyl Adipate was considered carcinogenic in B6C3Fl mice.(20)

Hodge and associates (45) fed rats a diet containing O%, O.l%, 0.5%, or 2.5% Dioctyl Adipate for two years. A total of 33 tumors were found which were mainly lymphomas and adenomas; one fibroma occurred. Also two carcinomas of the mammary gland and one carcinoma of the kidney were found, but the incidence of these tumors was not different from controls and not related to dietary treatment. They concluded the compound was not carcinogenic.

No tumors were found when dogs were maintained for one year on diets containing O%, 0.07%, 0.15%, or 0.2% Dioctyl Adipate.r45)



TABLE 6. Hepatocelhlar Tumors in Mice.a

Tumor Dose @pm)

Time to first observed tumor

(weeks)

F M

incidence (%)

F M

Adenoma 0 12,000 25,000

Carcinoma 0 12,000 25,000


106 46 4 12

103 37 10 16 a4 101 12 31

106 86 2 14

a5 68 28 24 79 65 24 24

Subcutaneous and skin application

Dioctyl Adipate was included in a study which tested the carcinogenic potency of six chemicals by subcutaneous implantation and by repeated skin application. Three compounds, aminotriazole, Aramite [2-(p-tert-butylphenoxy) isopropyl 2-chloroethyl oulfite] and Flectol H (a polymer of 1,2,dihydro-2, 2,4trimethylquinoline) were chosen as carcinogens or suspected carcinogens. Two additional reported noncarcinogenic compounds, butylated hydroxyanisole and dioctyl adipate, were included in the study. Groups of 50 male and 50 female C3HIAnF strain mice were used for each chemical and for each dosing method and dose concentration. A single 10 mg subcutaneous injection dose was used for one group of animals. A weekly application of either 0.1 or 10 mg of each chemical in acetone was applied for life to the clipped skin of the back in two separate groups of animals. All animals were observed for life. No significant adverse treatment-related effects were reported, nor were any of the compounds tested considered to be carcinogenic by the test methods used. The authors con-

cluded that methods used are not substitutes for tests by other routes of administration.(45)

Teratogenesis/Dominant lethal Study

Dioctyl Adipate was injected i.p. to each of 10 male albino Swiss strain mice at doses of 0.47, 0.93, 4.7, or 9.3 g/kg. Two groups of controls were injected with distilled water. Immediately after injection, two virgin female mice were caged with each male mouse. Females were replaced weekly for eight weeks. Pregnant mice were sacrificed on Day 15 ( f 2) of gestation and necropsy was performed to determine the number of corpora lutea, implantations, preimplantation losses, early and late fetal deaths, and viable fetuses. The antifertility effect was considered a function of the reduction in the number of pregnancies; the dominant lethal mutation was determined directly from the number of early fetal deaths in individual females and indirectly from the number of implantations. The results indicated no compound-related changes in the incidence of late fetal deaths. The 10 ml/kg dose of Dioctyl Adipate reduced the number of pregnancies, but the lower doses had values comparable to controls. The compound caused a dose- dependent and time-dependent decrease in implants per pregnancy, and there was a dose-related increase in early fetal death, a direct measure of dominant lethal mutation. A dose- and time-related decrease in the number of live fetuses



TABLE 7. Embryonic-Fetal Toxicity of Dioctyl Adipate on Rat Fetuses.=fb

Number

Dose of Number of live

in jetted corpora resorptions Dead fetuses

Treatment groups b’k) lutea (percent) fetuses Cpercen t)

Mean weight

of fetuses (g)’

Blunt needle (injection)

Distilled water

Normal saline Control

Cottonseed oil

Di-2-ethylhexyl adipate

-

10.00

10.00

9.2

0.93

4.7

9.3

69

59

62

71

62

65

60

4t6.0)

4C6.8)

7f11.5)

S(7.5)

3f5.3)

2f3.1)

4f7.0)

63 (94.0) 3.91 f 0.02

55 (93.2) 4.40 f 0.33

54 (88.5) 4.10 f 0.13

62 (92.5) 3.89 f 0.09

54 (94.7) 3.90 f 0.09

63 (96.9) 3.83 f 0.03~

53 (93.0) 3.49 f 0.14d


b Five pregnant female rats were injected in each group on Days 5, 10, and 15 of pregnancy.

CNumbers represent the average values (g) f the standard error of the mean for each group.

dp S 0.05.

occurred in groups treated with Dioctyl Adipate. The authors concluded that the mutational effects occurred mainly during the postmeiotic stage of sper- matogenesis. (46) A comment received on this study questioned the author’s conclusions, noting that additional data on the number of pregnancies per treated male were required. It was also suggested the number of corpora lutea was necessary if one is to determine whether the differences in implantations per pregnancy are associated with male infertility or are a dominant lethal effect. The comment also stressed the need for historical control data on the test species, as well as the need to have included a positive control in the experiment.(47’

Singh et al.“” studied the embryonic-fetal toxicity and teratogenic effect of Dioctyl Adipate in rats. The compound was administered i.p. at 0.93, 4.7, and 9.3 g/kg to pregnant rats on the 5th, lOth, and 15th days of gestation. The diluents at each dose level were water, saline and cottonseed oil, respectively. Animals were sacrificed on Day 20. Resorption rates were 5.3%, 3.1 O/O, and 7.0% for each increasing dose; each control had similar or greater rates (Tables 7 and 8). One

TABLE 8. Gross, Skeletal, and Visceral Malformationsa

Dose

injected Resorptionsb Abnormalities

Treatment groups (g/kg) f%o) CrossC ske/etald Viscera/e

Blunt needle (injection) - 4f6.0) 0 1(3.0%) 0 Distilled Water 10.00 4f6.8) 0 0 -

Normal saline 10.00 7Ul.5) 1(1.9%) 4(14.3%) -

Cottonseed oil 10.00 5f7.5) 1(1.6%) 2(6.3%) 0

Di-2-ethylhexyl adipate 0.93 3f5.3) 0 1(3.6%) 0

4.7 2(3.1) 1(1.6%) 3(9.4%) 1(3.2%)

9.3 4(7.0) 2(3.8%)’ 2(7.1%) 1(4.0%)


bPercent resorptions are based on total number of resorptions and dead and live fetuses.

c Percent gross abnormalities are based on total number of fetuses.

d Percent skeletal abnormalities are based on total number of stained fetuses (50% of total fetuses).

ePercent visceral abnormalities are based on total number of unstained fetuses,

‘Values greater than the 95% confidence interval of the “pooled volume control.”



malformed fetus occurred at the 4.7 g/kg dose and two at the 9.3 g/kg dose. The equivalent control had one abnormality. Skeletal abnormalities occurred at rates of 3.6%, 9.4%, and 7.1% as compared with 6.3% in the control. Visceral abnormalities of O%, 3.2%, and 4.0% were observed for each increasing dose. No similar results were seen in the control. The investigator concluded that Dioctyl Adipate depressed the mean body weight of the developing fetus. Further, there was a significant increase of gross fetal abnormalities in the high-dose group as compared with the pooled controls. However, the available data did not indicate teratogenic effect when the same results were compared to control groups for each dose concentration. The lack of data on historical controls, and the failure to include a positive control in the study, make it difficult to accept the validity of the statistical procedures used and the conclusions made by the investigator.


Dioctyl Adipate

Patch tests

A Schwartz-Peck prophetic patch test was used to assess the irritation and

sensitization potential of a rouge product containing 0.01% Dioctyl Adipate. A 48 h patch impregnated with the formulation was applied under occlusion to the cleansed upper backs of 100 panelists. Simultaneously, an open patch was affixed for 48 h to the inside of the right upper arm and after the allotted time, the sites were scored. After a 1Cday rest, a second open and closed insult was applied and graded 48 h later. The sites on the backs were then irradiated for 1 min at a distance of 12 in with a UV source (Hanovia Tanette Mark I Lamp) at a wavelength of 360 nm. These sites were read 48 h after irradiation. Two of the 100 subjects had a weak erythematous reaction at the open patch site after the first patch and one individual had a strong edematous or vesicular reaction after the second open patch. No reactions occurred after the UV exposure. The investigators concluded the product was nonirritating, nonsensitizing and nonphotosensitizing.(49)

A Shelanski and Shelanski repeated insult patch test was conducted on the same rouge product discussed above. A series of 10 successive 24 h open and closed patches was applied to the skin of 49 panelists and each site was graded after patch removal. After a two- to three-week rest, an 11 th challenge patch was applied for 48 h and read after patch removal. Ultraviolet light sensitization was evaluated after removal of patch numbers 1, 4, 7, 10, and 11 by irradiating the sites for 1 min at a distance of 12 in with a Hanovia Tanette Mark I Lamp. No photosensitivity was indicated by this test, but weak reactions were produced in three, one, and four panelists, after the fourth, fifth, and tenth open patch exposures, respectively. Strong reactions occurred in one panelist after the sixth open patch, and in another after the 1 lth (challenge) open patch.(49)

A liquid makeup product containing 9.0% Dioctyl Adipate was assayed in a Modified Draize-Shelanski patch test on 209 men and women. The undiluted product was applied under occlusion to sites on the upper back on Monday, Wednesday, and Friday for three consecutive weeks. Patches were removed and sites scored on the next patch replacement day. After a two-week rest, two consecutive 48 h challenge patches were applied to adjacent sites on the back and these areas were scored 48 and 96 h after application. Three subjects had moderate to strong erythematous reactions, with or without infiltration and



vesicles, and one subject had a macular faint erythema over 25% of the test area after the second challenge.‘50’

Another makeup product containing 9.0% Dioctyl Adipate was tested as above in a Modified Draize-Shelanski patch test. The product caused irritant reactions in two of the 151 men and women tested, but no significant sensitization or primary irritation occurred.(S”

A Shelanski-Jordan repeated insult procedure was used to evaluate primary irritation and allergic sensitivity of a moisturizing product containing 0.7% of a 25% solution of Dioctyl Adipate (0.175% actual concentration). Patches containing the material were affixed to the cleansed back for 24 h on each Monday, Wednesday, and Friday for 3% consecutive weeks for 10 insults. A lo- to 14-day rest followed removal of the 10th insult, at which time a 48 h challenge patch was applied. The challenge site was scored and seven to 10 days later, a second 48 h challenge patch was applied and graded immediately and 24 h after patch removal. One subject had erythema and papules on the test site after the ninth and tenth inductions. The second challenge patch caused erythema and papules in one subject. No other reactions were noted.(52)

Cumulative irritancy test

A similar moisturizing product containing 0.175% Dioctyl Adipate was tested in a 21-day cumulative irritation assay. The product, 0.2 ml, was applied under cotton patches to the backs of 11 female panelists for 21 consecutive days. The patches were removed 23 h after application and the sites were scored 1 h after patch removal. New patches were applied immediately. The cumulative irritation score for this product was 72 out of a possible 630. This product was slightly irritating.(53)

Photopatch test

A photopatch test was conducted using a formulation containing 9.0% Dioc- tyl Adipate. Each of 25 panelists received patches containing 0.1 ml of the product. Twenty-four hours later, the patches were removed and the sites were irradiated with a Xenon Arc Solar Simulator (150 W) with a continuous emission in the UVA and UVB range (290-400 nm). Forty-eight hours later, the irradiated sites were scored for irritation. This entire procedure was repeated twice weekly for a total of six exposures. After a lo-day rest, a challenge patch was applied for 24 h and then irradiated for 3 min. This site was then scored 0.25, 24, 48, and 72 h after irradiation. Two control sites, one with the test product with no irradiation, and a second receiving irradiation but no product, were included in the test program. None of the 25 individuals had phototoxic or photoallergic reactions(54) (see Table 9).

Diispropyl Adipate

24-hour patch tests

Diisopropyl Adipate, alone and in a formulation, was assayed for skin irritation potential in 24 h patch tests. Occlusive patches containing 0.1 ml of the substance were affixed to the volar surface of the forearm and/or the medial aspect of arm. The patches were removed 24 h later, and the sites read 2 and 24 h later. The sites were scored on a scale of 0 (no irritation) to 4 (severe deep red


TAB

LE

9.

Clin

ica

l A

sse

ssm

ent

o

f Sa

fety

.

ing

red

ient

Te

st

App

lied

Tim

e Ir

rit.

scor

e N

o.

of

Con

t. am

ount

sub

jec

ts

(%)

(ml)

C

ont

ac

t O

bser

v.

Ma

x.

Com

men

ts

Ref

.

Dio

ctyl

A

dip

ate

Form

ula

tion

Sc

hw

art

z-Pe

ck

pro

phe

tic

pa

tch

100

M,F

0.

01

- 2

24-h

Form

ula

tion

Sh

ela

nsk

i- 49

M

,F

0.01

-

11

24-h

She

lan

ski

RIPT

+

u

v

Form

ula

tion

M

od

ifie

d

Dra

ize

-

She

lan

ski

RIPT

209

M,F

9.

0 -

See

co

mm

ent

s

48

h

-

48,

96

h

Mo

difi

ed

D

raiz

e-

151

M,F

9.

0 -

See

48

, 96

h

She

lan

ski

RIPT

c

om

me

nts

- Tw

o

pa

ne

lists

sh

ow

ed

a

mild

re

ac

tion

49

aft

er

the

fir

st

op

en

pa

tch.

1

pa

ne

list

sho

we

d

a s

tro

ng

rea

ctio

n a

fte

r th

e

2nd

o

pe

n p

atc

h.

- Te

n in

duc

tion

p

atc

hes;

14

-da

y re

st;

49

ch

alle

ng

e

pa

tch

(1 lt

h).

UV

irr

ad

iatio

n

aft

er

pa

tch

nos.

1,

4,7,

10,1

1.

We

ak

rea

ctio

n in

3/

49

aft

er

pa

tch

4;

in

l/49

a

fte

r p

atc

h 5;

in

4/4

9 a

fte

r

pa

tch

10.

-

Stro

ng

rea

ctio

n in

l/

49

aft

er

pa

tch

6;

in

l/49

a

fte

r p

atc

h 11

. N

o

UV

rea

ctio

n.

Nin

e

48

h i

nduc

tions

; 14

-da

y re

st;

50

one

48

h

ch

alle

ng

e.

Thre

e

mo

de

rate

to s

tro

ng

ery

the

ma

tous

re

ac

tions

dur

ing

in

duc

tion

. O

ne

fa

int

ery

the

ma

tous

re

ac

tion

from

ch

alle

ng

e

pa

tch.

N

ot

a s

ens

itize

r o

r

irrita

nt.

Nin

e

48

h i

nduc

tions

; 14

-da

y re

st;

one

48

h

ch

alle

ng

e.

Two

su

bje

cts

ha

d i

rrita

nt

rea

ctio

ns;

no

sens

itiza

tion.

51


TABL

E 9.

(C

ont

inue

d.)

hgre

dien

t T

est

Ap

plie

d

Tim

e In

it.

sco

re

No.

of

C

ont.

am

oun

t

sub

jec

ts

(%)

(ml)

Co

nta

ct

Obs

erv.

M

ax.

Co

mm

ent

s R

ef.

Form

ula

tion

Sh

ela

nsk

i-Jo

rda

n

210

M,F

0.

225

- Se

e

See

-

Ten

24

h i

nduc

tions

; 14

-da

y re

st;

one

52

RIPT

c

om

me

nts

co

mm

ent

s 48

h

ch

alle

ng

e;

7- t

o

lo-d

ay

rest

an

d 2

nd

48

h c

ha

llen

ge

.

Resu

lts:

Insu

lts

l-8

ca

use

d

no

rea

ctio

n.

Insu

lts

9,10

c

aus

ed

e

ryth

em

a,

pa

pu

les

in 2

/210

.

Ch

alle

ng

e

1 c

aus

ed

no

re

ac

tion.

Ch

alle

ng

e

2 c

aus

ed

e

ryth

em

a,

pa

pu

les

in

l/21

0 a

fte

r 72

h.

Form

ula

tion

21

-da

y c

um

ula

tive

11

F

0.17

5 0.

2 21

23

-h

- 72

1630

Si

tes

sco

red

1

h a

fte

r p

atc

h re

mo

val.

53

irrita

nt

test

M

axi

mum

irr

itatio

n

oc

cur

red

in

3

pa

ne

lists

a

fte

r in

sults

3,

7,18

; sli

ght

irrita

tion

o

cc

urre

d

in

1 a

fte

r

pa

tch

16.

Form

ula

tion

Ph

oto

pa

tch

test

25

M

,F

9.0

0.1

See

-

- Si

x 24

h

pa

tche

s (t

wic

e

we

ekl

y fo

r 54

co

mm

ent

s 3

we

eks

).

Site

s irr

ad

iate

d

(Xe

no

n

UV

lam

p)

on

pa

tch

rem

ova

l a

nd

re

ad

48

h l

ate

r; lo

-da

y re

st;

one

24

h

pa

tch

to

ne

w s

ite;

irra

dia

tion

a

fte

r

pa

tch

rem

ova

l; re

ad

ing

s ta

ken

0.25

,

24,

48,

an

d 7

2 h

aft

er

irra

dia

tion

.

Resu

lts:

No

p

hoto

toxi

city

o

r p

hoto

-

alle

rge

nic

ity.

Diis

op

rop

yl

Ad

ipa

te

Ing

red

ient

24

h

pa

tch

24

h p

atc

h

24

h p

atc

h

24

h p

atc

h

19

M,F

10

0 0.

1 24

h

2,

24

h

o

/4

No

irr

itatio

n.

55

19

M,F

10

0 0.

1 24

h

2,

24

h

o

/4

No

irr

itatio

n.

55

15

M,F

10

0 0.

1 24

h

2,

24

h

o

/4

No

irr

itatio

n

56

15

M,F

10

0 0.

1 24

h

2,

24

h

o

/4

No

irr

itatio

n.

56


Form

ula

tion

24

h

pa

tch

19

M,F

24

h p

atc

h 19

M

,F

Form

ula

tion

M

aib

ac

h-M

arz

ulli

23

5 M

,F

RIPT

Form

ula

tion

RI

PT

50

M,F

Mo

difi

ed

D

raiz

e

108

M,F

RIPT

RIPT

11

6 M

.F

Form

ula

tion

Kl

igm

an

ma

xim

iza

tion

test

25

M,F

0.

7

0.26

0.

1 24

h

2.

24

h

5.0

1.08

0.1

24

h

2,

24

h

0.5

See

-

co

mm

ent

s

3.0

5.0

1.04

- Se

e

See

co

mm

ent

s c

om

me

nts

0.4

See

Se

e

co

mm

ent

s c

om

me

nts

0.1

See

Se

e

co

mm

ent

s c

om

me

nts

- Se

e

See

co

mm

ent

s c

om

me

nts

- N

ine

24

h

in

duc

tion

p

atc

hes;

14

-da

y

rest

; o

ne

24

h c

ha

llen

ge

re

ad

48

an

d 9

6 h

aft

er

ap

plic

atio

n.

No

irrita

tion

w

as

see

n in

a

ny

pa

ne

list.

61

F $ 0 x 62

0 2 0 s 6 z 4

- N

ine

24

h

ind

uctio

ns,

3-w

ee

k re

st,

one

24

h

ch

alle

ng

e

sco

red

24

a

nd

48

h a

fte

r re

mo

val.

If a

ch

alle

ng

e

rea

ctio

n o

cc

urre

d,

a 2

nd

24

h

ch

alle

ng

e

wa

s a

pp

lied

.

Resu

lts:

Ind

uctio

n N

o.

l-fa

int

ery

the

ma

in

2/l

16

; m

ild

ery

the

ma

in

l/

l 16

.

Ind

uctio

n N

o.

2-fa

int

ery

the

ma

in 4

1116

; in

duc

tion

s 3

an

d 5

-

fain

t e

ryth

em

a

in

l/l

16;

an

d

ind

uctio

n

4-m

ild

ery

the

ma

in

l/l

16.

Ch

alle

ng

e

pro

duc

ed

fa

int

ery

the

ma

in

21

116.

No

p

ote

ntia

l fo

r a

llerg

ic

sens

itiza

tion.

-

Five

48

h

in

duc

tion

p

atc

hes;

e

ight

63

lo-d

ay

rest

; 1

h p

retr

ea

tme

nt

with

SLS;

48

h

ch

alle

ng

e

pa

tch

rea

d a

t

pa

tch

rem

ova

l a

nd

aft

er

24

an

d

48

h.

No

c

ont

ac

t se

nsiti

zatio

n

oc

cur

red

.

0.16

14.0

13

su

bje

cts

h

ad

no

irri

tatio

n;

6 h

ad

57

ba

rely

p

erc

ep

tible

e

ryth

em

a.

i?i

i4

Min

ima

l irr

itatio

n.

No

irr

itatio

n.

w

o/4

58

3

- Te

n 48

h

pa

tche

s;

14-d

ay

rest

; O

ne

59

48

h p

atc

h.

Eryt

hem

a

oc

cur

red

in

T

one

p

ers

on

aft

er

ind

uctio

n.

Hyp

er-

6

pig

me

nta

tion

oc

cur

red

in

17

1235

,

but

no

se

nsiti

zatio

n re

ac

tions

K

oc

cur

red

. 2

- Te

n 24

h

pa

tche

s,

7-d

ay

rest

, o

ne

24

h

60

ch

alle

ng

e

an

d o

bse

rva

tion

aft

er

24

an

d 4

8 h.

N

o

irrita

tion

o

r

sens

itiza

tion

rea

ctio

ns.

d

I:


TABL

E 9.

(C

ont

inue

d.)

Ap

plie

d

Tim

e Ir

rit.

scor

e N

o.

of

Co

nt.

am

oun

t

ing

red

ient

Te

st

sub

jec

ts

(%)

(ml)

Co

nta

ct

Ob

serv

. M

ax.

C

om

me

nts

Ref.

Ing

red

ient

21

-da

y c

um

ula

tive

16

M,F

10

0 0.

3 21

22

-h

- 26

.33/

630

All

but

one

p

an

elis

t sh

ow

ed

e

ryth

em

a.

64

irrita

tion

te

st

pa

tche

s In

gre

die

nt

is

“mo

de

rate

ly

irrita

ting

.”

Form

ula

tion

21

-da

y c

um

ula

tive

10

F

0.7

0.3

21

23-h

-

2163

0

irrita

tion

te

st

pa

tche

s

21-d

ay

cu

mu

lativ

e

irrita

tion

te

st

17F

1.08

0.

5 Se

e

co

mm

ent

s

- 0.

2918

4

21-d

ay

cu

mu

lativ

e

17

F 1.

08

0.5

See

-

irrita

tion

te

st

co

mm

ent

s

21 -

da

y c

um

ula

tive

7

M,F

20

.75

- 21

24

-h

-

irrita

tion

te

st

pa

tche

s

Form

ula

tion

Sc

hw

art

z-Pe

ck

98

M,F

0.

7 -

2 24

-h

48

h

pro

phe

tic

pa

tch

+

uv

+

uv

0.24

184

8184

-

On

e

pa

ne

list

sho

we

d

min

ima

l 65

ery

the

ma

a

fte

r p

atc

h no

. 18

. Pr

od

uct

is

“ess

en

tially

no

nirri

tatin

g.”

Ap

plic

atio

n

of

ma

teria

l w

as

ma

de

on

66

5 c

ons

ec

utiv

e

da

ys d

urin

g

3 c

ons

ec

utiv

e

we

eks

. C

ont

inuo

us

co

nta

ct

wa

s m

ad

e o

n Sa

t./Su

n.

to

allo

w

for

21-d

ay

co

ntin

uous

exp

osu

re.

Two

p

an

elis

ts

ha

d

que

stio

na

ble

e

ryth

em

a,

one

h

ad

vesic

ula

tion

. Lo

w

irrita

tion.

Pro

ce

dur

e

as

ab

ove

. O

ne

p

an

elis

t h

ad

66

que

stio

na

ble

e

ryth

em

a,

2 h

ad

de

finite

e

ryth

em

a.

Low

irr

itatio

n.

- 67

All

pa

tch

test

s w

ere

ne

ga

tive

. U

V

test

68

wa

s ne

ga

tive

.


Form

ula

tion

D

raiz

e-S

he

lan

ski

RIPT

+

U

V

Form

ula

tion

M

od

ifie

d

ma

xim

iza

tion

+

uv

Mo

difi

ed

ma

xim

iza

tion

+

uv

Mo

difi

ed

ma

xim

iza

tion

+

uv

Mo

difi

ed

ma

xim

iza

tion

+

uv

49

F 0.

7 -

See

co

mm

ent

s

50

M,F

3.

0 -

See

co

mm

ent

s

49

M,F

3.

0 -

See

co

mm

ent

s

50

M,F

17

.0

See

co

mm

ent

s

50

M,F

17

.0

See

co

mm

ent

s

48

h

- Te

n 48

h

ind

uctio

ns;

14-d

ay

rest

; o

ne

48

h c

ha

llen

ge

. U

V

irra

dia

tion

a

fte

r

pa

tch

nos.

1,

4,7,

10,1

1.

All

pa

tch

test

s +

U

V

test

s w

ere

ne

ga

tive

. -

Patc

h te

st

site

s p

retr

ea

ted

w

ith

5%

aq

.

SLS

for

30

min

. Si

x to

8

h l

ate

r, th

e

first

te

st

pa

tch

wa

s a

pp

lied

a

nd

re

ad

48

h l

ate

r. A

se

co

nd

48

h p

atc

h w

as

the

n a

pp

lied

. Th

is p

roc

ed

ure

w

as

rep

ea

ted

tw

ice

a

nd

fo

llow

ed

b

y a

5-d

ay

rest

. A

n SL

S p

retr

ea

tme

nt

pre

ce

de

d t

he

48

h c

ha

llen

ge

p

atc

h.

Dup

lica

te

site

s w

ere

e

xpo

sed

to

a

Ha

no

via

U

V

Lam

p

aft

er

pa

tche

s

1,3,

5,

an

d 7

(c

ha

llen

ge

) a

nd

re

ad

48

h l

ate

r. N

o

ph

oto

alle

rgic

resp

ons

es

oc

cur

red

. -

- Te

st

pe

rfo

rme

d

as

dire

ctly

a

bo

ve.

Pro

duc

t is

no

t a

pho

tose

nsiti

zer

or

pho

toto

xic

. -

- Te

st

pe

rfo

rme

d

as

dire

ctly

a

bo

ve.

Pro

duc

t is

no

t a

ph

oto

alle

rgic

sens

itize

r. -

- Te

st

pe

rfo

rme

d

as

dire

ctly

a

bo

ve

Pro

duc

t is

no

t a

ph

oto

alle

rgic

sens

itize

r o

r a

prim

ary

irr

itant

.

68

>

M

Ii 52

69

T 0 70

=

5 2 71

0 3

72

G

zj

m



erythema, vesiculation). Two different lots of the undiluted ingredient were tested on 15 men and women. Neither product caused irritation.(55) Additionally, 19 individuals were tested with two different lots of the undiluted ingredient. None of the 19 had signs of irritation.‘55*56)

Product formulations containing Diisopropyl Adipate were tested as discussed in the preceding paragraph. One formulation containing the ingredient at 20.75% was diluted to 1.25% in water (actual ingredient concentration = 0.26%) and tested on 19 individuals. Thirteen subjects had no irritation and six had minimal faint erythema. The PII was 0.16 (possible score of 4.0).‘57’ Another formulation containing 5.0% Diisopropyl Adipate was tested undiluted on 19 panelists and produced no irritation.(5B)

Repeated insult patch tests

A Marzulli-Maibach repeat insult sensitization study was performed using a perfume containing 1.08% Diisopropyl Adipate (18% of a 6% solution). The perfume (0.5 ml) was applied under occlusion to the skin of the upper backs of 235 women for 48 h (72 h on weekends). The sites. were scored on a scale of 0 (no reaction) to 5 (erythema with induration and bullae). New patches were applied to the same sites; this procedure was repeated for a total of 10 applications. A two-week rest was followed by a challenge patch applied to an adjacent, untreated site for 48 h. During the induction series, one individual had erythema covering the entire test site and one had erythema with induration and vesiculation. This patient had no reaction when challenged. Seventeen subjects had slight hyperpigmentation, but no sensitization reaction occurred in any of the 235 volunteers.r59) A similar test was conducted using a suntan lotion containing 3.0% Diisopropyl Adipate. No reactions were produced in the 50 men and women panelists. The product was neither a sensitizer nor a contact irritant.‘60’ A hair grooming preparation containing 5.0% Diisopropyl Adipate was tested as above on 108 men and women. This product caused no reactions and gave no evidence of sensitization.‘61) A 5.0% aqueous dispersion of a bath oil containing 20.75% Diisopropyl Adipate was tested as above on 116 men and women. The first insult produced minimal faint to pink erythema in four panelists. Minimal faint erythema occurred in four panelists after insult 2, in one after insult 3, and in one after insult 5. Pink, uniform erythema occurred in one person after insult 4. The challenge patch produced minimal, faint erythema in two persons after 24 h, and no reactions occurred after 48 h.(62)

Maximization test

A facial cream containing 0.7% Diisopropyl Adipate was evaluated for contact-sensitization potential in a maximization test. The material was applied under occlusion to the skin of the volar forearm or back of 25 subjects for five consecutive 48 h periods. The patch site was then treated with 2.5% sodium lauryl sulfate for 24 h under occlusion. A challenge.patch was then applied for 48 h and the site read immediately after patch removal and 24 h later. The product produced no reactions indicative of contact-sensitization.‘6J,

Cumulative irritancy test

Twenty-one day cumulative irritancy tests were performed on Diisopropyl Adipate alone and in a formulation. The undiluted ingredient was tested on 16 men and women. No irritation was observed until after the sixth patch was ap-


ASSESSMENT: DlOCTYL ADIPATE AND DIISOPROPYL ADIPATE 125

plied (sixth day). After this time, irritation was reported in 14 of 16 panelists

where erythema and papules were the most severe reaction. The undiluted ingredient had a total irritation score of 395 out of a possible 945; it was classified by the authors as “moderately irritating.” The formulation, a face cream product containing 0.7% Diisopropyl Adipate, was tested on 13 individuals. Minimal erythema occurred in one person after the third patch (third day), and in one person after patch 18 (18th day). This product had a score of 2 out of a possible 630; the product was classified as nonirritating.‘64*65)

A cumulative irritancy test of two products containing 1.1% Diisopropyl Adipate was tested on 17 subjects using procedures similar to that previously noted for Dioctyl Adipate. cs3) The first product had a score of 0.5 (questionable

erythema) in two subjects, T.0 (definite erythema) in one, and 3.0 (vesiculation) in one. The mean score was 0.29 (possible 84). The second product had a score of 0.5 in one person, 1 .O in two people, and 1.5 (definite erythema and possible induration) in one person. The mean score for this product was 0.24 (possible 84). These product scores indicate a low potential for hazard to the consumer.(66) In a similar test, a bath oil containing 20.75% Diisopropyl Adipate was tested on seven patients. The bath oil caused an average score of 8 (possible 84).(57’

Photopatch tests

A face cream containing 0.7% Diisopropyl Adipate was evaluated for irritation potential by a Schwartz-Peck prophetic patch test followed by UV exposure and by the Draize-Shelanski repeated insult patch test which was also followed by UV exposure. In the Schwartz-Peck Procedure, 98 panelists were patch tested with the product on the back and on the volar surface of the right arm for 48 h. A second patch was applied 12-14 days later and graded 48 h after application. After the patch site was scored, the same site was irradiated with a UV source (Hanovia Tanette Mark I Lamp) at 12 in for 1 min. The site was graded 48 h after exposure. Reactions were not observed at the induction patch, the challenge patch, or the irradiation sites.(6s) In the Draize-Shelanski test, 10 consecutive 48 h inductions were applied for 48 h to each of 49 panelists and an 11 th challenge patch was applied for 48 h approximately 14 days later. Skin sites which received patches 1, 4, 7, 10, and 11 also were exposed to UV radiation (Hanovia Tanette Mark I Lamp) at 12 in for 1 min. These light-exposed sites were graded 48 h after irradiation. No reactions occurred after any induction patch, challenge patch, or UV exposure. The product was neither a primary irritant nor a sensitizer.‘68)

Several products were used in modified maximization tests with UV exposure. The procedures followed were: on Day 1 of the test (Monday), patch test sites were pretreated for 30 min with 0.5 ml of 5.0% aqueous sodium lauryl sulfate. The test material was then applied to the test site 6-8 h later for a period of 48 h. On Wednesday, the sites were graded immediately after patch removal, and a new patch was then applied for 48 h. On Friday, this site was graded and left untreated over the weekend. This regimen was repeated for two more weeks. After the last induction patch was graded (Friday of the third week), a five-day nontreatment period followed and a patch of sodium lauryl sulfate was again applied for 30 min. After 6-8 h, a challenge test patch was applied and graded 48 h later. A control site was treated with sodium lauryl sulfate, but no test material was applied to it. To assess UV sensitization, skin sites which received patches 1, 3, 5, and 7 were also exposed to a UV source (Hanovia Tanette Mark I Lamp) at 12 in for 1 min. Sites were graded 48 h later. A suntan product containing 3.0%



Diisopropyl Adipate was tested on 50 people. There were no reactions and the product was not a photoallergic sensitizer. (6g) A sunburn lotion containing 3.0% Diisopropyl Adipate was similarly tested on 49 individuals. No reaction occurred and the product was not a photosensitizer or a phototoxic agent.“‘) Two sunburn foam bases, each containing 17.0% Diisopropyl Adipate, were tested on two panels of 50 subjects. Neither material caused any reaction and the products were not photoallergic sensitizers or primary irritants’71.72’ (see Table 9).

SUMMARY

Dioctyl Adipate, the diester of octyl alcohol and adipic acid, and Diisopropyl Adipate, the diester of isopropyl alcohol and adipic acid, are plasticizers and emollients. They are produced by the esterification of adipic acid and the appropriate alcohol in the presence of an esterification catalyst. Both Adipates are clear, colorless to light yellow viscous liquids, with an aromatic odor.

In noncosmetic products, the two Adipates are used in plastic food wraps, blood and hemodialysis bags, solvents, and lubricants. Dioctyl Adipate has In- direct Food Additive status for use in food wrapping materials. The Adipates are used in cosmetics as emollients and bases. Dioctyl Adipate is used in 27 products in concentrations of I O.l%-25%, and Diisopropyl Adipate is used in 112 formulations, ranging in concentration from I O.l%-25%.

Dioctyl Adipate had low acute oral toxicity, with the LDso ranging from 9.11 g/kg to 45.0 g/kg (estimated). Likewise, Diisopropyl Adipate had low oral toxicity. Estimated LDSOs ranged from greater than 5 g/kg to greater than 76.8 g/kg. In a 14-day study, rats and mice fed up to 50,000 ppm (for males) and 100,000 ppm (females) had weight loss and weight gain reduction at the highest concentrations. Females fed the 100,000 ppm diet died. The intravenous LDso of Dioctyl Adipate to rats and rabbits was 900 mglkg and 540 mg/kg, respectively. Diisopropyl Adipate had an intravenous LDso of 640 mg/kg for rats. A percutaneous absorption test on rabbits showed that Dioctyl Adipate had an LDso of 16 g/kg, but up to 8.7 g/kg for 24 h was not toxic to rabbits in another test. An immersion test of a formulation containing Diisopropyl Adipate (20.75%) indicated no toxicity to guinea pigs. The intraperitoneal LDso of Dioctyl Adipate in mice was 1 .O g/kg; in rats, 47.0 g/kg; and 38.0 g/kg in rabbits.

In ocular irritation studies, undiluted Dioctyl Adipate was nonirritating; formulations containing up to 0.175% of the ingredient were, at most, mild, transient irritants. Undiluted Diisopropyl Adipate was a very mild, transient irritant; formulations containing the ingredient produced minimal irritation. The results of primary dermal irritation tests indicated that Dioctyl Adipate, when administered alone and in formulations, was a very mild irritant and Diisopropyl Adipate was minimally irritating. Dioctyl Adipate was not a skin sensitizer in guinea pigs. Two perfumes containing 0.108% Diisopropyl Adipate were neither irritating nor phototoxic to rabbits and a product with 0.175% Dioctyl Adipate caused no mucous membrane irritation in rabbits.

Mice and rats fed up to 25,000 ppm Dioctyl Adipate for 91 days had weight gain depression, but no other abnormalities.

An Ames test for the mutagenic potential of Dioctyl Adipate was negative. An assay of the carcinogenic potential of Dioctyl Adipate showed that administration


ASSESSMENT: 9lOCTYL ADIPATE AND DIISOPROPYL ADIPATE 127

of up to 25,000 ppm of the compound for 103 weeks produced no untoward effects and was noncarcinogenic to rats. Mice fed the same amount for 103 weeks had dose-related body-weight reductions and a higher incidence of hepatocellular adenoma and carcinoma than controls. Hodge and associates reported that rats fed up to 2.5 Dioctyl Adipate for two years had a tumor incidence similar to that of the control group. They also found no tumors in dogs fed up to 0.2% Dioctyl Adipate for one year. A single 10 mg dose of Dioctyl Adipate given by subcutaneous injection was not carcinogenic in mice. In a lifetime study Dioctyl Adipate caused no skin tumors when 10 mg was applied weekly to the back skin of mice.

The teratogenicity of Dioctyl Adipate was studied in mice. According to the author, intraperitoneal injection of up to 9.3 g/kg of the ingredient to male mice caused antifertility effects in females to which they were mated. lntraperitoneal injections of up to 9.3 g/kg Dioctyl Adipate were administered to pregnant rats on the 5th, lOth, and 15th days of gestation. The investigator reported that resorption rates were similar; however, there was a greater incidence of skeletal and visceral abnormalities. The experimental design and interpretation have been questioned by some.

Clinical assessment of Dioctyl Adipate at concentrations of O.Ol%-9.0% in formulation showed, at most, erythema and papules when applied under occlusion for extended periods of time. No UV sensitization occurred. Undiluted Diisopropyl Adipate produced no irritation in 24 h patch tests, but was moderately irritating in a 21-day cumulative irritancy test. Formulations containing concentrations of 0.26%-20.75% Diisopropyl Adipate caused minimal to mild irritation, no sensitization and no photosensitization.

DISCUSSION

The Expert Panel, in reviewing the animal and human test data on Dioctyl Adipate and Diisopropyl Adipate, found them adequate to evaluate the safety of these ingredients as used in cosmetic products. No human data were available for Dioctyl Adipate as a pure ingredient; however, data were available on formulations up to a concentration of 9.0%. These data, plus animal test data at a concentration of 100% of the ingredient, indicated Dioctyl Adipate is, at most, a weak irritant. Sensitization and phototoxicity tests were negative. In a formulation Diisopropyl Adipate at a concentration of 0.1% was neither an irritant or phototoxic agent to rabbits.

Two studies by the same investigator, one which reported on fetal toxicity and teratogenic effects, and the second on mutation and antifertility effects of Dioctyl Adipate, were reviewed. The author concluded a statistically significant effect in each study, but there were several deficiencies noted in each study which made the author’s conclusions questionable.

Several carcinogenic studies have been reported. All but one were negative; one oral feeding study conducted by the National Toxicology Program indicated that Dioctyl Adipate was carcinogenic in female mice and was probably carcinogenic in male mice. The Expert Panel noted that the Maximum Tolerated Dose was significantly exceeded in this chronic study; thus, these test data may not be relevant in a safety assessment for humans.


128

CONCLUSION

COSMETIC INGREDIENT REVIEW

On the basis of available data, the Panel concludes that Dioctyl Adipate and Diisopropyl Adipate are safe as presently used in cosmetics.

ACKNOWLEDGMENT

Ms. Anne Moore, Scientific Analyst and writer, prepared the literature review used by the Expert Panel in developing this report.

REFERENCES

1. BALSAM, M.S. and SAGARIN, E. (ed.). (1972). Cosmetics: Science and Technology. New York, NY: Wiley

Interscience.

2. HAWLEY, G.G. (ed.). (1971). The Condensed Chemical Dictionary, 8th ed. New York, NY: Van Nostrand

Reinhold Co.

3. ESTRIN, N.F., CROSLEY, P., and HAYNES, C. (ed.). (1982). CTFA Cosmetic Ingredient Dictionary, 3rd ed.

Washington, DC: Cosmetic, Toiletry and Fragrance Assoc.

4. NATIONAL LIBRARY OF MEDICINE (NLM). (1981). Toxicology database; computer database.

5. CTFA. (Oct. 9, 1981). Submission of data of CTFA. Cosmetic ingredient chemical description for Dioctyl

Adipate.*

6. CTFA. (Oct. 9, 1981). Submission of data by CTFA. Cosmetic ingredient chemical description for

Diisopropyl Adipate.’

7. CTFA. (1972). Specifications. Washington, DC.

8. RAMSEY, JO., LEE, T.D., OSSELTON, M.D., and MOFFAT, A.C. (1980). Gas liquid chromatographic reten-

tion indices of 296 nondrug substances on SE-30 or OV-1 likely to be encountered in toxicological analyses.

J. Chromatogr. 184(2), 185-206.

9. JANARDAN, K.G., SCHAEFFER, D.)., and SOMANI, S.M. (1980). Efficiencies of liquid-liquid extraction car-

bon and XAD-2 absorption in isolating organic compounds from environmental sources. Bull. Environ,

Contam. Toxicol. 24(l), 145-51.

10. THRUSTON, Jr., A.D. (1978). High pressure liquid chromatography techniques for the isolation and iden-

tification of organics in drinking water extracts. 1. Chromatogr. Sci. 16(6), 254-9.

11. CLAYTON, C.D. and CLAYTON, F.E. (eds.). (1978). Patty’s fndustrial Hygiene and Toxicology, 3rd rev. ed.,

vol. ZA, Toxicology. New York, NY: Wiley-lnterscience Publication.

12. VANDERVORT, R. and BROOKS, S.M. (1977). Polyvinyl chloride fils thermal decomposition products as an

occupational illness: I. Environmental exposures and toxicology. 1. Occup. Med. 19(3), 188-91.

13. BAXTER TRAVENOL LABS. (May 7, 1980). Japan Kokai Tokkyo Koho Patent No. 80 60459.

14. CODE OF FEDERAL REGULATIONS (CFR). Title 21, Parts 175.105; 177.1200; 177.1210; 177.2600;

178.3740.

15. SOCIETY OF COSMETIC CHEMISTS (SCC). (March 5, 1982). Submission of data by CTFA. Personal com-

munication.

16. FOOD AND DRUG ADMINISTRATION (FDA). (Dec. 22, 1981). Cosmetic product formulation data. Com-

puter printout. Washington, DC.

17. MOODY, D.E. and REDDY, J.K. (1978). Hepatic peroxisome (microbody) proliferation in rats fed

plasticizers and related compounds. Toxicol. Appl. Pharmacol. 45(2), 497-504.

18. RUBIN, R.]. and JAEGER, R.J. (1973). Some pharmacologic and toxicologic effects of di-2-ethylhexyl

phthalate (DEHP) and other plasticizers. Environ. Health Perspect. 1973(3), 53-9.

19. NAPIER, Jr., E.A. (1976). Accumulation, toxicity and metabolism of common plasticizers in humans, U.S.N.T.I.S. PB 260406.

20. NATIONAL TOXICOLOGY PROGRAM (NTP). (March 1982). Carcinogenesis bioassay of Di(2&hylhexyl)- adipate. NTP report series No. 212, NIH Publication No. 81-l 768.

*Available on request: Administrator, Cosmetic Ingredient Review, Suite 810, 11 10 Vermont Ave., NW,

Washington, DC 20005.



21. ANDREEVA, G.A. (1971). Gig. Primen. Toksikol. Pestits. Klin. 9, 373.

22. SMYTH, H.F., CARPENTER, C.P., and WEIL, C.S. (1951). Range-findingtoxicitydata: list IV. Arch. Ind. Hyg.

4,119-22. 23. CTFA. (Aug. 1967). Submission of data by CTFA. Unpublished primary skin irritation, primary irritation of

eye mucous membrane, acute oral toxicity, acute dermal toxicity, and skin sensitization study of Dioctyl

Adipate.* 24. CTFA. (March 18, 1982). Submission of data by CTFA. Unpublished acute oral, dermal, ocular, and mucous

membrane testing of a moisturizing product containing 0.7 percent of a 25 percent solution of Dioctyl

Adipate (0.175 percent).* 25. BIODYNAMICS, INC. (BI). (Jan. 16, 1976). Submission of data by CTFA. Unpublished acute oral toxicity in

rats of a face cream containing 0.7 percent Diisopropyl Adipate.’

26. FOOD AND DRUG RESEARCH LABS (FDRL). (June 20, 1980). Submission of data by CTFA. Unpublished

acute oral toxicity in rats of Diisopropyl Adipate (18 percent of a 6 percent solution in perfume [1.08 per-

cent]).*

27. FDRL (May 1, 1979). Submission of data by CTFA. Unpublished acute oral toxicity in rats of Diisopropyl Adipate (18 percent of a 6 percent solution in perfume [1.08 percent]).*

28. CTFA. (Feb. 21, 1975). Submission of data by CTFA. Unpublished acute oral toxicity test of a product con-

taining 5.0 percent Diisopropyl Adipate.* 29. CTFA. (Nov. 9, 1978). Submission of data by CTFA. Unpublished acute oral toxicity test of a product con-

taining 20.75 percent Diisopropyl Adipate.* 30. NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH (NIOSH). (1977). Registry of Toxic

Effects and Chemical Substances, vols, I and II. Cincinnati, OH.

31. CTFA. (Nov. 9, 1978). Submission of data by CTFA. Unpublished immersion test of a product containing

20.75 percent Diisopropyl Adipate.’ 32. CTFA (1975). Submission of data by CTFA. Unpublished ocular irritation test summary of a product contain-

ing 0.01 percent Dioctyl Adipate.*

33. CTFA. (May 28, 1973). Submission of data by CTFA. Unpublished eye irritation test of Diisopropyl

Adipate.’

34. BI. (Dec. 29, 1975). Submission of data by CTFA. Unpublished rabbit eye irritation study of a face cream

containing 0.7 percent Diisopropyl Adipate.’

35. CTFA. (Feb. 21, 1975). Submission of data by CTFA. Unpublished eye irritation test of a product containing

5.0 percent Diisopropyl Adipate.’

36. CTFA. (Nov. 9, 1978). Submission of data by CTFA. Unpublished eye irritation test of a product containing

20.75 percent Diisopropyl Adipate.*

37. CTFA. (Feb. 2, 1973). Submission of data by CTFA. Unpublished primary skin irritation study of Diisopropyl

Adipate.*

38. CTFA. (Nov. 2, 1978). Submission of data by CTFA. Unpublished primary skin irritation test of Diisopropyl

Adipate.’

39. CTFA. (Feb. 21, 1975). Submission of data by CTFA. Unpublished primary skin irritation study of a product

containing 5 percent Diisopropyl Adipate.*

40. CTFA. (Nov. 9, 1978). Submission of data by CTFA. Unpublished primary skin irritation test of a product

containing 20.75 percent Diisopropyl Adipate.*

41. FDRL. (July 21, 1980). Submission of data by CTFA. Unpublished primary dermal phototoxic irritation study

of Diisopropyl Adipate (18 percent of a 6 percent solution in perfume [1.08 percent]).*

42. FDRL. (July 21, 1980). Submission of data by CTFA. Unpublished primary dermal phototoxic irritation study

with Diisopropyl Adipate (18 percent of a 6 percent solution in perfume [1.08 percent]).*

43. SIMMON, V.F., KAUHANEN, K., and TARDIFF, R.G. (1977). Mutagenic activity of chemicals identified in

drinking water. Dev. Toxicol. Environ. Sci. Prog. Genet. Toxicol. 2, 249-58.

44. SONTAG, J.M., PAGE, N.P., and SAFFIOTTI. (Feb. 1976). National Cancer Institute. PB-264-061.

45. HODGE, H.C., MAYNARD, E.A., DOWNS, W.L., ASHTON, J.K., and SALERNO, L.L. (1966). Tests on mice

for evaluating carcinogenicity. Toxicol. Appl. Pharmacol. 9(3), 583-96.

46. SINGH, A.R., LAWRENCE, W.H., and AUTIAN, J. (1975). Dominant lethal mutations and antifertility effect

of di-2-ethylhexyl adipate and diethyl adipate in male mice. Toxicol. Appl. Pharmacol. 32(3), 566-76.

47. NORTHUP, S. (March 9, 1982). Comment received on the CIR Scientific Literature Review on Dioctyl

Adipate and Diisopropyl Adipate.*

48. SINGH, A.R., LAWRENCE, W.H., and AUTIAN, J. (1973). Embryonic fetal toxicity and teratogenic effects of

adipic acid esters in rats. J. Pharm. Sci. 62(10), 1596-600.

49. CTFA. (1977). Submission of data by CTFA. Unpublished human prophetic patch test and repeated insult

patch test of a product containing 0.01 percent Dioctyl Adipate.*

50. CTFA. (March 10, 1978). Submission of data by CTFA. Unpublished human modified Draize-Shelanski-Jor-

dan patch test of a product containing 9 percent Dioctyl Adipate.’



51. CTFA. (Sept. 22, 1976). Submission of data by CTFA. Unpublished human modified Draize-Shelanski test

of a product containing 9 percent Dioctyl Adipate.*

52. LEO WINTER ASSOCIATES (LWA). (Sept. 1978). Submission of data by CTFA. Unpublished human Shelan-

ski-Jordan repeated insult procedure of a product containing 0.175 percent Dioctyl Adipate.* 53. HILL TOP RESEARCH (HTR). (Oct. 6, 1978). Submission of data by CTFA. Unpublished human cumulative

irritancy test of a product containing 0.175 percent Dioctyl Adipate.* 54. CTFA. (March 10, 1978). Submissiion of data by CTFA. Unpublished human photopatch test of a product

containing 9 percent Dioctyl Adipate.* 55. CTFA. (Jan. 24, 1973). Submission of data by CTFA. Unpublished human skin irritation test of Diisopropyl

Adipate.*

56. CTFA. (May 18, 1973). Submission of data by CTFA. Unpublished human skin irritation of Diisopropyl

Adipate.* 57. CTFA. (Oct. 26, 1978). Submission of data by CTFA. Unpublished human skin irritancy test of a product

containing 20.75 percent Diisopropyl Adipate.*

58. CTFA. (Feb. 12, 1975). Submission of data by CTFA. Unpublished human skin irritation of a product con-

taining 5 percent Diisopropyl Adipate.*

59. CONCORDIA RESEARCH LABORATORIES (CRL). (Oct. 29, 1980). Submission of data by CTFA. Unpublished

human repeated insult patch test of a product containing 1.08 percent Diisopropyl Adipate.*

60. CTFA. (March 5, 1974). Submission of data by CTFA. Unpublished human repeated insult patch test of a

product containing 3.0 percent Diisopropyl Adipate.*

61. HTR. (Nov. 3, 1976). Submission of data by CTFA. Unpublished human repeated insult patch test of a

product containing 5 percent Diisopropyl Adipate.*

62. CTFA. (Feb. 1, 1982). Submission of data by CTFA. Unpublished human allergic contact sensitizatron test of

a product containing 20.75 percent Diisopropyl Adipate.*

63. IVY RESEARCH LABORATORIES (IRL). (Feb. 17, 1976). Submission of data by CTFA. Unpublished human

maximization test of a product containing 0.7 percent Diisopropyl Adipate.’

64. HTR. (March 30, 1976). Submission of data by CTFA. Unpublished human cumulative irritancy test of

Diisopropyl Adipate.*

65. HTR. (Feb. 18, 1976). Submission of data by CTFA. Unpublished human cumulative irritancy test of a

product containing 0.7 percent Diisopropyl Adipate.’

66. CRL. (June 9, 1980). Submission of data by CTFA. Human 21-day cumulative irritation test of a product con-

taining 1.08 percent Diisopropyl Adipate.*

67. CTFA. I(May 11, 1978). Submission of data by CTFA. Unpublished human 21.day cumulative irritancy test

of a product containing 20.75 percent Diisopropyl Adipate.*

68. RESEARCH TESTING LABORATORIES (RTL). (March 4, 1976). Submission of data by CTFA. Unpublished

human prophetic patch test of a product containing 0.7 percent Diisopropyl Adipate.’

69. CTFA. (June 21, 1974). Submission of data by CTFA. Unpublished human modified maximization test of a


70. CTFA. (March 3, 1975). Submission of data by CTFA. Unpublished human modified maximization test of a

product containing 3.0 percent Diisopropyl Adipate.*

71. CTFA. (June 21, 1974). Submission of data by CTFA. Unpublished human photopatch test of a product con-

taining 17.0 percent Diisopropyl Adipate.*

72. CTFA. (June 21, 1974). Submission of data by CTFA. Unpublished human modified maximization test of a



Persona Care’ Products CounciCommitted to Safety,Quaity & nnovation

Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (C]R)

FROM: John Bailey, Ph.DZ E__3 I . I 2Industry Liaison to the Cifi Expert Panel

DATE: December 1, 2009

SUBJECT: Comments on the Draft Report on the Dicarboxylic Acids and their Salts and Estersprepared for the December 7-8, 2009 CIR Expert Panel meeting

General Comment - This report is still very incomplete. Diethyihexyl Adipate, Dibutyl Adipate andDiisopropyl Adipate, have already been reviewed by CIR and found safe as used. This reportfails to mention these earlier CIR reviews, and this report does not include the information thatwas summarized in these original CW reports, including an NTP bioassay on DiethyhexylAdipate.

Looking only at the Safety/Regulatory Information for the added ingredients on the On-Line,the following items are missing from this report.

Oxalic Acid: listed in EU Annex ifi; NTP continuous breeding study; NTP testednegative in Salmonella (Haworth et al. 1983)

Malonic Acid: NTP tested negative in SalmonellaDimethyl Succinate: NTP micronucleus test in male rats, negative; NTP tested negative

in Salmonella (Zeiger et al. 1992)Glutaric Acid: NTP tested negative in SalmonellaDimethyl Glutarate: NTP micronucleus test in male rats, equivocal; NTP tested negative

in SalmonellaAdipic Acid: NTP tested negative in SalmonellaDimethyl Adipate: NTP has selected Dimethyl Adipate for further study; there is a

nomination background report that includes information that is not in the CIRreport; NTP tested negative in Salmonella

Diethylhexyl Adipate - IARC unclassifiable; CIR report; NTP carcinogenicity study(includes 14-day, 90-day and 2-year studies); NTP battery of genotoxicity assays

Report organization - Generally CW reports are organized by duration of exposure, route of exposure,then compound. It is not clear how this report is organized. There are very few route ofexposure section headings. Inhalation exposure is its own section, not under any duration ofexposure. The Introduction states “the data are presented by order of carbon chain length,beginning with Oxalic Acid.” This is a good idea, but it is not how the report is organized.

11011 7th Street, N.W., Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331 .1969 (fax) www.personalcarecouncil.org CIR Panel Book Page 295

Most sections start with information on Sebacic Acid and the Sebacates. Both the text (eachsection) and all the tables should be presented by order of carbon chain length as indicated inthe Introduction.

p.1 - Only the esters of the dicarboxylic acids have side chains between 1-18 carbons (not the salts).p.1 - In the introduction, it should be mentioned that Diethyihexyl Adipate, Dibutyl Adipate and

Diisopropyl Adipate have previously been reviewed by CW and found safe for use.p.2 - Please delete the sentence concerning the name of Sodium Oxalate. If you search on ChemlD for

Sodium Oxalate, the compound found has two sodium atoms, a compound with one sodium isnot found.

p.2 - In the second paragraph under the heading Dicarboxylic Acids - General, it would be helpful toadd some of the additional ingredients that have been added to this report.

p.3, 4, 49 - Anonymous (2000b) should be changed to IARC (2000).p.4 - Ingredients in addition to the sebacates should be mentioned in the first paragraph of the Cosmetic

use section.p.5 - As the ingredients added to this report since the September meeting have not yet been included in

a Council concentration of use survey, it is likely that the results will not be available untilsometime in March. Please look at the VCRP again to be sure all of the ingredients included inthe report were found. Searching the VCRP for adipate revealed 2 uses of Dimethyl Adipate, 2uses of Dibutyl Adipate and 41 uses of Diethylhexyl Adipate that are not included in the Cifireport. The uses of Diethyihexyl Adipate, Dibutyl Adipate and Diisopropyl Adipate from theold reports (and re-reviews) should also be mentioned in this report

p.6 - Please change “setting” to “settling”. How did Lehman-McKeeman (2008) define nanoparticles?p.6 - Information about how these ingredients are regulated in Europe should be added to the cosmetic

use section.p.9 - In the last paragraph of this page, what is meant by “both substances”?p.10, 25, 44, 45 - The INCI names for diethylmalonate and dimethylmalonate includes a space (Diethyl

Malonate, Dimethyl Malonate).p.10 - The following is not a complete sentence: “Tyrode’s solution as receptor fluid.”p.12 - Please delete the last sentence on p.12 (“According to Lubrizol (2000), Diisopropyl Sebacate is

rapidly absorbed and is fast-spreading, but no supporting data were provided.”), as it does notadd any useful information.

p.13 - What is meant by “the same oxidative stress parameters”? Please define TAR the first time it isused.

p.13 - It is not clear what is meant by “the study supported a NOAEL of 4000 mg/kg for the oral routeand 8000 mg/kg”. Was 4000 mg/kg the highest dose tested and some effects were observed,and was 8000 mg/kg the highest dose tested and no effects observed?

p.14 - What were the i.v. doses given to rabbits? Currently, it states “from 300 to 1800 mg” should thisbe mg/kg b.w.?

p.14 - The information on Diethylhexyl Sebacate in Table 5 is also presented in Table 7.p.15 - Please delete “in repeat dose studies, and no effects in teratologic evaluations” from the Acute

Exposure section. There is no information about acute studies in Table 9. Please provide areference for “A similar relationship existed for ocular irritation, where severity of responsedecreases with increasing carbon number.”

2


p.15 - If route subheadings are going to be used, they should be used throughout the report.p.15 - It is not clear what is meant by “Smyth et al. (1969) reported an acute oral toxicity in rats of

DEM of 15,794 mg/kg bw (SIDS 2005)”. If Smyth et al. (1969) did the study, why is there alsoa citation to SIDS (2005)? Smyth et al. (1969) is not in the reference section.

p.15 - What is “Gemini surfactant (AGS) mixture”?p.16 - Please delete the second paragraph under Short-Term Exposure as it presents the same

information as in the first paragraph of this section.p.17 - The 3-day rat study should not be presented in the Subchronic Exposure section.p.17-18 - The protocol of the Mingrone et al. (1983) study of Azelaic Acid is not clear. Animals were

fed for 90 days. Was there also a recovery group that was kept for about 90 days after exposureended?

p.18 - What compound were the beagle dogs fed for 90 days (American Chemistry Council, 2003)?p.19 - The three week study of Diethyihexyl Sebacate should not be in the Subchronic Exposure

section.p.19, 45 - Why is 2-ethylhexyl adipate considered a surrogate diester? 2-Ethyihexyl adipate is

Diethylhexyl Adipate, a cosmetic ingredient being reviewed in this report, and previouslyreviewed by CIR and found safe for use in cosmetics.

p.19, 31 - Why is Ditridecyl Adipate included in the Diesters subsection? As it is an ingredientincluded in this report, it should have its own subsection.

p.20 - The 90-day studies should not be discussed in the Chronic Exposure section.p.21, 26 - It is not necessary to present the information on butyl stearate for the Smith (1953) study.p.22 - The inhalation exposure studies are usually presented under the various duration subheadings.p.25 - The Magnussen Kligman test of Dodecanedioic Acid (SIDS 1994) should be moved to the

Dermal Sensitization section.p.26 - There are no additional details of the BIBRA (1996) reproductive study in TableS (the same

information is presented in Table 7).p.27 - The acute exposure studies cited to Greco et al. (1990) should not be in the Reproductive and

Developmental Toxicity section.p.27 - Please clarify what days of gestation the ewes were treated in the Scheifer et al. (1976) study.p.27 - Were reproductive outcomes studied in the Goldman et al. (1977) study of Oxalic Acid? Did

they look for testicular effects?p.27-28 - The protocol of the Lamb et al. (1997) study is not clear. Is this the NTP continuous breeding

study?p.28 - Please change “life” to “live”p.29 - What route of exposure was used in the Bradford et a!. (1984) study? When during gestation

were the rats and rabbits treated?p.29 - When during gestation were the rats treated with the seven adipates?p.29 - When during gestation were the rats and rabbits treated in the Mingrone et al. (1983) study?

Were the rabbits really sacrificed on gestation day 19?p.30 - In the last paragraph of the Azelaic Acid subsection, please change “rams” to “dams”.p.31 - Please delete the following sentence, as this study has already been presented (more than once).

“No adverse reproductive , suckling and growth affects were evident in a four-generation studyin rats fed a diet containing 200 ppm Diethylhexyl Sebacate (BIBRA 1996).”

3


p.32 - The BII3RA (1996) study is mentioned again at the top of p.32 and should be deleted.p.33 - In the first sentence under the heading Bacterial Gene Mutation Assay, what is meant by “in this

assessment:?p.40 - Did De Groot et al. (1991) really use PEG-300? Or is this PEG-6 (a PEG with an average

molecular weight of 300)?p.43 - Please check the VCRP again for additional adipate ingredients.p.4-7 - The following sentence should be moved with the rest of the genotoxicity information. “In the

HPV report on diesters, mutagenicity nor clastogenicity were exhibited by those diesters citedin vivo or in vitro tests, with or without metabolic activation.” What is meant by those diesters?Please change “cited” to “studied”.

p.48 - There is no mention of the cancer studies in the Summary.Table section - The table section is missing page numbers.Table 1- This table should be organized as stated on the first page of the report (from smallest to largest

dicarboxylic acid). The title of the table needs to be change to reflect all of the ingredientsincluded in the report. For those ingredients for which the definition is based on the structure,the table should refer to the figure in which the structure is shown. Please delete “q.v.” fromthe table or define it at the end of the table. Other names that are the same as the INCI name,with another group designation, e.g., Diisobutyl Adipate (RIFM) should be deleted from thereport. If these names are left in the report the group, e.g., RIFM, should be defined.

Table 2 - The title of Table 2 should indicate the types of compounds included in the table. The tableshould be organized as stated on the first page of the report (from smallest to largestdicarboxylic acid). On the second page of the table, what does “*“ and “**“ mean? Please usethe INCI name, Diethylhexyl Adipate rather than Di(2-Ethylhexyl) Adipate. Please use theINCI names for Dimethylmalonate and Dimethylmalonate. Some units in this table arepresented in the first column, some are presented in the second column; please be consistent.

Table 3 - The title of the table should include more that just Sebacates. Please organize this table asstated on the first page of the report (from smallest to largest dicarboxylic acid).

Table 4 - The title of the table needs to be changed to include the ingredients that have been added tothe report. When the Council concentration of use survey for the other ingredients is complete,the concentration of use for Diethyl Sebacate will be revised to 1.5% (it was rounded to 2%).Please check the VCRP to be sure all the ingredients in this report were identified. The VCRPalso has 2 uses for Dimethyl Adipate, 2 uses for Dibutyl Adipate and 41 uses for DiethylhexylAdipate. Consider adding old concentration of use information for the ingredients alreadyreviewed (and re-reviewed) by CIR. The total uses for Diisobutyl Adipate is listed as DicaprylAdipate. The total uses for Diisopropyl Adipate is listed as Diisostearyl Adipate. The footnote“Ingredients not found in the table were included in the concentration of use survey, but no useswere reported.” is not correct as the Council concentration of use survey on the ingredientsadded to this report has not yet been sent out.

Table 5- Since Diethyihexyl Sebacate is the only ingredient included in this table, the first column canbe deleted. Please consider deleting this complete table as all this information is also presentedin the last row of Table 7.

Table 6 - The heading of column 3 needs to be changed as it includes more than just LD50 values. Inthe route column, please change “skin” to “dermal”. It is not clear what is meant by the NOELs

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of 100 mg/kg (males), 500 mg/kg (females) and then in the next row a NOEL for males andfemales of 1000 mg/kg is given. Are the first values adult NOELs and the last value a NOELfor developmental effects?

Table 7 -The Summary table of Diesters Toxicity is misleading as it does not include all of the data oneach ingredient. If it is left in the report, it should include al the data on each ingredient withappropriate references, not just the information as presented by the American ChemistryCouncil (2003).

Table 8- Please identify what was in the Dicarboxylic Acid Mixture. In what species were the dermaland eye irritation tests completed?

Table 9 - What route of exposure was used for these studies? The doses provided are actuallyconcentrations. What do they represent - concentration in the diet? What species were tested inthe developmental and reproductive toxicity studies? What doses were used in thedevelopmental and reproductive toxicity studies?

Table 10 - In the title of this table, please indicate which ingredient was studied.

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pink book 3 sebacic acid/dicarboxylic acids · · 2017-07-12pink book 3 sebacic acid/dicarboxylic...

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