green amino acidswith the exception of glycine and methionine, the naturally occurring amino acids...

GREEN

Amino Acids

CIR EXPERT PANEL MEETING

MARCH 5-6, 2012

Memorandum

To: CIR Expert Panel Members and Liaisons

From: Christina L. Burnett

Scientific Writer/Analyst

Date: January 23, 2012

Subject: Draft Report on Amino Acids

In September 2011, CIR issued the Scientific Literature Review (SLR) for amino acids. As the strategy was developed for how to approach this safety assessment, the Panel’s recommendation was to rely heavily on the GRAS direct food additive status of many of these common amino acids to demonstrate the absence of significant oral toxicity --- and to do this safety assessment first, as a prelude to considering ingredients that contain amino acids and various protein hydrolysates. That is the approach we have taken. As a result, the draft report for amino acids is limited to the common amino acids and emphasizes available information on adverse reactions to dermal exposures. In the SLR, data were requested on any possible reactions that may occur in individuals with sensitivities to phenylalanine and monosodium glutamate following dermal exposure. No such data were received.

Since the September announcement, the Personal Care Products Council (Council) has provided comments on the report, which have been considered, and method of manufacturing and HRIPT data which have been incorporated. The comments and the data are in the panel book so that you can see what was provided.

According to the FDA’s VCRP database, arginine has the most reported uses in cosmetic and personal care products, with a total of 440; 328 of those uses are in leave-on formulations. Glycine has the second greatest number of overall uses reported, with a total of 323; 221 of those uses are in leave-on formulations. No uses were reported to the VCRP for sodium aspartate, dipotassium aspartate, calcium aspartate, calcium glycinate, or magnesium glycinate. In the Council’s use concentration survey, arginine had a wide maximum use concentration range of 2.0 x 10-5 to 18%, with the 18% reported in paste masks and mud packs. Glycine also had a wide maximum use concentration range of 5.0 x 10-4 to 4%, with the 4% reported in hair dyes and non-spray deodorants. No use concentrations were reported for asparagine, sodium aspartate, dipotassium aspartate, calcium aspartate, sodium glycinate, and magnesium glycinate. If no further data are needed, the Panel should issue a Tentative Report.

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SAFETY ASSESSMENT FLOW CHART

Draft Priority

Draft Priority

iIIiReport

60 day public comment period Draft AmendedTentative Report

Tentative Report Tentative AmendedReport

Final Report

Difft. Conci.

Draft Amended FinalReport

*The CIR Staff notifies of the public of the decision not to re-open the report and prepares a draft statement for review by the Panel. AfterPanel review, the statement Is issued to the Public.* *lf Draft Amended Report (DAR) is available, the Panel may choose to review; if not, CIR staff prepares DAR for Panel Review.Expert Panel Decision

____________

Document for Panel ReviewZZJOption for Re-review

Distributed for comment -- Do not cite or quote

CIR Panel Book Page 1

Amino Acids History September 2011 – Scientific Literature Review announced. Pre-December 2011 – CIR Staff decided not to present the Draft Report to the CIR Panel at the December 2011 Panel Meeting in order to allow the Industry to finish conducting their concentration of use survey.



1

Amino Acids Data Profile* – March 2012 – Writer, Christina Burnett

Rep

orte

d U

se

Chem

ical

Properties

Irri

tati

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Sen

siti

zati

on -

A

nim

al

Irri

tati

on/

Sen

siti

zati

on -

C

lin

ical

Ocular/

Mucousal

Alanine X X X Arginine X X X X X ArginineHCl X X Asparagine X X AsparticAcid X X CalciumAspartate DipotassiumAspartate

MagnesiumAspartate X PotassiumAspartate X SodiumAspartate Cysteine X X X CysteineHCl X X X Cystine X X GlutamicAcid X X X X SodiumGlutamate X Glutamine X X Glycine X X X X CalciumGlycinate X MagnesiumGlycinate SodiumGlycinate X Histidine X X X HistidineHCl X X X Isoleucine X X Leucine X X Lysine X X X LysineHCl X X Methionine X X X X Phenylalanine X X X Proline X X Serine X X X Threonine X X Tryptophan X X Tyrosine X X X Valine X X

*“X” indicates that data were available in a category for the ingredient



SEARCH STRATEGY FOR AMINO ACIDS (Performed by Christina Burnett)

August/September 2011: SCIFINDER search for under the answer set for Amino Acids – GRAS (42 substances): - Initial search for “adverse effect, including toxicity” yielded 24,960 references. - Limited search to books, clinical trials, commentary, conference, editorial, historical, journals,

preprints, reports, and reviews; 23,955 references came back. o Limited search to “irritation”, 127 references came back. o Limited search to “dermal”, 70 references came back.

Search Terms TOXLINE (excluding PUBMED, English only)

PUBMED

Aug/Sept 2011 Amino Acids 25,000 (limit) 759,948 Amino Acids NOT diet 25,000 (limit) 733,770 L-Amino Acids 12,396 2095 Amino Acids AND dermal 225 989 Amino Acids AND irritation 119 212 Alanine AND dermal 15 50 Arginine AND dermal 6 114 Asparagine AND dermal 0 4 Aspartic Acid AND dermal 1 48 Cysteine AND dermal 29 176 Cystine AND dermal 0 3 Glutamic Acid AND dermal 0 29 Glutamine AND dermal 0 16 Glycine AND dermal 16 90 Histidine AND dermal 4 32 Isoleucine AND dermal 0 8 Leucine AND dermal 6 61 Lysine AND dermal 1 135 Methionine AND dermal 4 84 Phenylalanine AND dermal 0 67 Proline AND dermal 6 294 Serine AND dermal 5 288 Threonine AND dermal 1 121 Tryptophan AND dermal 6 48 Tyrosine AND dermal 2 473 Valine AND dermal 4 12

Total references ordered: 44



Rep

ort

Draft Safety Assessment

Amino Acids as Used in Cosmetics

March 5, 2012 All interested persons are provided 60 days from the above date to comment on this Draft Report and to identify additional published data that should be included or provide unpublished data which can be made public and included. Information may be submitted without identifying the source or the trade name of the cosmetic product containing the ingredient. All unpublished data submitted to CIR will be discussed in open meetings, will be available at the CIR office for review by any interested party and may be cited in a peer-reviewed scientific journal. Please submit data, comments, or requests to the CIR Director, Dr. F. Alan Andersen. The 2012 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, 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 Christina L. Burnett, Scientific Analyst/Writer, and Bart Heldreth, Ph.D., Chemist CIR.

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

[email protected]



Table of Contents

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

Chemistry ...................................................................................................................................................... 1

Method of Manufacturing ........................................................................................................................ 2

Impurities .................................................................................................................................................. 2

Use ................................................................................................................................................................ 2

Cosmetic .................................................................................................................................................... 2

Non‐Cosmetic ............................................................................................................................................ 3

Toxicological Studies ..................................................................................................................................... 3

Enzyme Regulation .................................................................................................................................... 3

Irritation and Sensitization ............................................................................................................................ 3

Irritation .................................................................................................................................................... 3

Dermal – Non‐Human ........................................................................................................................... 3

Ocular – Non‐Human ............................................................................................................................ 3

Sensitization .............................................................................................................................................. 3

Dermal – Non‐Human ........................................................................................................................... 3

Dermal – Human ................................................................................................................................... 4

Phototoxicity ............................................................................................................................................. 5

Amino Acid Analogs ...................................................................................................................................... 5

Summary ....................................................................................................................................................... 5

Tables and Figures ........................................................................................................................................ 6

References .................................................................................................................................................. 26



1

INTRODUCTION Amino acids and their salts are widely used as cosmetic ingredients, and function primarily as hair

conditioning agents and skin conditioning agents (humectant and miscellaneous). The 21 most common naturally occurring amino acids also are building blocks to proteins. As such, amino

acids are critical to life and metabolic function. Eight of these amino acids, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine, are both essential and must be obtained through nutrients as they cannot be synthesized. Because amino acids are present in all living organisms and their general biology is well characterized, they are not considered to pose any significant safety concern following oral exposure, except to individuals with certain genetic disorders.. Accordingly, this safety assessment focuses on the basic chemistry, uses as cosmetic ingredients, and, because of the importance for products that will be applied to the skin, addresses all irritation and sensitization data available on these 21 amino acids and their simple salts. . The full list of ingredients in this report is found in Table 1.

With the exception of glycine and methionine, the naturally occurring amino acids are all α-amino acids, with S-stereochemistry (commonly referred to as “L-“) at the α-carbon. The “L-“amino acids are considered Generally Recognized As Safe (GRAS) direct food additives by the Food and Drug Administration (FDA), thus oral toxicity was not a focus for these ingredients in this assessment.

CHEMISTRY The definition and structure of these ingredients are presented in Table 2, and available information on the

physical and chemical properties of amino acids and their salts are presented in Table 3. The generic term “amino acid” is commonly considered shorthand for α-amino acid. This designates a

carboxylic acid with an amine group on the immediately adjacent (α) carbon.

Figure 1. α-amino acids

The “natural” amino acids, those that play an important role in human biochemistry, are all α-amino acids, with S-stereochemistry (commonly referred to as “L-“) at the α-carbon (except glycine and methionine). Glycine is achiral (no stereochemistry). Methionine is the one natural amino acid to also play an important role in human biochemistry with an R-stereogenic carbon (commonly referred to as “D-“). Additionally, all of the natural amino acids contain primary amines (i.e. acids with an NH2 group pendant from the α-carbon), except proline, which is a secondary amine.

NH2

S

H3C

O

OH

NH2

S

H3C

O

OH

OH

O

NH 2o amine Glycine is achiral Methionine is commonly found in the L- and D-forms Proline is a secondary amine

Figure 2. Exceptions in natural amino acid chirality and amine substitution

Cysteine and cystine are related as thiol (mercaptan) and the disulfide (thiol dimer) of said thiol, respectively. These two molecules play major roles in reversible cellular redox chemistry and can serve a similar function in hairdressings, such as permanent waves.



2

Figure 3. Cysteine/Cystine redox chemistry

Method of Manufacturing

In a test sample, L-arginine was produced from the fermentation of unspecified sugars.1 L-glutamic acid is reported to be produced from the fermentation of sugarcane.2 One supplier that reported

the sale of D-glutamic acid to the cosmetics industry states that racemization of L-glutamic acid results in the production of D-glutamic acid.

Impurities A supplier to the cosmetics industry reported that D-glutamic acid has not more than 0.3% methanol.2

USE Cosmetic

The amino acids and the salts discussed in this safety assessment function primarily as hair conditioning agents and skin conditioning agents (humectant and miscellaneous) in cosmetic formulations.3 Additional functions may include the use as oral care agents (arginine), antioxidants (cysteine and cysteine HCl), hair waving/straightening agents (cysteine and cysteine HCl), reducing agents (cysteine and cysteine HCl), fragrance ingredients (cystine), buffering agents (glycine and its calcium and magnesium salts), and pH adjusters (glycine and its calcium and magnesium salts).

Table 4 presents the current product formulation data for amino acids. According to information supplied to the Food and Drug Administration (FDA) by industry as part of the Voluntary Cosmetic Registration Program (VCRP), arginine has the most reported uses in cosmetic and personal care products, with a total of 440; 328 of those uses are in leave-on formulations.4 Glycine has the second greatest number of overall uses reported, with a total of 323; 221 of those uses are in leave-on formulations. No uses were reported to the VCRP for sodium aspartate, dipotassium aspartate, calcium aspartate, calcium glycinate, or magnesium glycinate. In a recent survey of use concentrations, arginine had a maximum use concentration range of 2.0 x 10-5 to 18%, with the 18% reported in paste masks and mud packs.5 Glycine had a maximum use concentration range of 5.0 x 10-4 to 4%, with the 4% reported in hair dyes and non-spray deodorants. No use concentrations were reported for asparagine, sodium aspartate, dipotassium aspartate, calcium aspartate, sodium glycinate, and magnesium glycinate.

Products containing amino acids are reported to be used on baby skin, may be applied to the eye area or mucous membranes, or could be incidentally ingested. Additionally, amino acids are used in cosmetic sprays, including hair, deodorant, and other propellant and pump spray products, and could possibly be inhaled. In practice, 95% to 99% of the droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters >10 µm, with propellant sprays yielding a greater fraction of droplets/particles <10 µm compared with pump sprays.6,7 Therefore, most droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and thoracic regions of the respiratory tract and would not be respirable (ie, able to enter the lungs) to any appreciable amount.8,9 However, the potential for inhalation toxicity is not limited to respirable droplets/particles deposited in the lungs. Inhaled droplets/particles deposited in the nasopharyngeal and thoracic regions may cause toxic effects depending on their chemical and other properties.



3

The European Commission’s Scientific Committee on Consumer Products (SCCP) concluded that the risk

of exposure to viruses, such as avian influenza virus or papillomavirus, is negligible through topical application of cosmetic products containing amino acids that are obtained from hydrolysis of human hair or chicken feathers.10

Non-Cosmetic The FDA approved the use of amino acids as food additives in the free, hydrated or anhydrous forms or as

the hydrochloride, sodium or potassium salts (21 CFR §172.320). In addition to food additives and supplements, amino acids also may be used in the production of

pesticides.11,12

TOXICOLOGICAL STUDIES The amino acids in this assessment are found in the foods we consume daily, and the daily exposure from

food use would result in a much larger systemic dose than that resulting from use in cosmetic products. Numerous studies and reviews have been published in the literature regarding the safety of dietary exposure to amino acids, including a review by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) that summarized studies on oral acute and chronic exposure/carcinogenicity studies and genotoxicity and found no safety concerns with regards to these substances at the amounts they are used in flavoring agents.13 Also, as noted earlier, the “L-“amino acids are considered Generally Recognized As Safe (GRAS) in direct food additives by the FDA. Consequently, the systemic toxicity potential is not addressed further in this report. The safety focus of use of these amino acids as cosmetic ingredients is on the potential for irritation and sensitization.

Enzyme Regulation Because keratinocytes play a role in dermal sensitization reactions, it may be informative that in an in vitro study using human keratinocytes, continuous application of arginine (L-) at concentrations of 10-50 mmol/l was found to increase endogenous intrakeratinocytic urea synthesis through increased activity of keratinocytic arginase.14

IRRITATION AND SENSITIZATION Irritation

Dermal – Non-Human ARGININE In a Draize test in 4 male New Zealand albino rabbits, 5% L-arginine in distilled water was nonirritating.15 CYSTEINE HCL Cysteine HCl up to 500 mM was used as a negative control in an in vitro assay to predict potential skin irritants.16 METHIONINE

Methionine up to 500 mM was used as a negative control in an in vitro assay to predict potential skin irritants.16 Ocular – Non-Human ARGININE L-Arginine at a concentration of 5% in distilled water was determined to be nonirritating to rabbit eyes in a Draize test using 4 male New Zealand albino rabbits.15

Sensitization Dermal – Non-Human ARGININE In an efficacy study of a wound dressing composed of a hyaluronic acid sponge containing 0.2-1.0 g arginine (final concentrations not specified), the amino acid did not produce any adverse effects in Sprague-Dawley rats.17 A maximization test of 5% L-arginine in distilled water was negative for skin sensitization in 10 female Dunkin-Hartley albino guinea pigs.15 CYSTEINE Cysteine up to a concentration of 13% did not produce adverse effects in albino guinea pigs in efficacy studies of this amino acid for the treatment of sesquiterpene lactone-induced acute contact dermatitis.18,19 GLUTAMIC ACID Glutamic acid (concentrations not specified) was used as a negative control in a cell-based in vitro alternative to identify skin sensitizers.20,21



4

GLYCINE Glycine at 1 mmol/l in 50% ethanol, when used as a topical-barrier recovery-accelerator in a mouse skin model for chronic eczematous dermatitis, did not produce adverse effects.22 Dermal – Human ALANINE In a human repeat insult patch test (HRIPT) conducted using 104 subjects, 0.04% alanine in a face and neck product tested at 100% under semi-occlusive conditions did not produce signs of irritation or sensitization.23 ARGININE

In the HRIPT study of a face and neck product described above, 0.15% arginine did not produce signs of irritation or sensitization.23

A HRIPT of the potential of 1.1% arginine to induce contact sensitization was conducted using 105 subjects.24 The subjects received 0.2 g applications of a mascara. Induction applications were made to the infrascapular region of the back with a 1 in2 pad portion of an adhesive dressing. The test sites were semi-occluded. The patches were removed after 24 h and there were 9 consecutive applications. Following a 2 week non-treatment period, the challenge application was applied to a previously untreated site for 24 h, and the site was scored 24 and 72 h after patch removal. No skin reactions were observed in the induction or challenge phases. The study concluded that there was no evidence of sensitization to a mascara containing 1.1% arginine. In a HRIPT conducted using 56 subjects, 1% arginine in a face and neck product tested at 100% under semi-occlusive conditions did not produce signs of irritation or sensitization.23 In another HRIPT of a face and neck product at 100% under semi-occlusive conditions, 0.025% arginine was not an irritant or sensitizer in 102 subjects.23 Arginine at 0.27% in a suntan product tested at 100% under occlusive conditions did not produce signs of irriation or sensitization in 104 subjects.23 GLUTAMIC ACID

In the HRIPT study of 104 subjects using a face and neck product that is described above, 0.01% glutamic acid did not produce signs of irritation or sensitization.23 GLYCINE The potential of 2.784% glycine to induce dermal irritation and contact sensitization was studied in108 subjects.25 The subjects received an unreported amount of an A/P roll-on. Induction applications were made to the infrascapular region of the back and the test sites were semi-occluded. The patches were removed after 24 h and there were 9 consecutive applications. Following 2 week non-treatment period, the challenge application was applied to a previously untreated site for 24 h, and the site was scored 48 and 72 h after application. During the induction phase, several subjects had a single incidence of a + reaction that was not observed in subsequent patches. No reactions were observed in the challenge phase. The study concluded that there was no evidence that the A/P roll-on containing 2.784% glycine elicited dermal irritation or sensitization. In the HRIPT of 102 subjects with a face and neck product that is described above, 0.025% glycine was not an irritant or a sensitizer.23 HISTIDINE

In the HRIPT study of 104 subjects using a face and neck product that is described above, 0.05% histidine did not produce signs of irritation or sensitization.23 HISTIDINE HCL In the study above that describes a HRIPT of a suntan product in 104 subjects, 0.07% histidine HCl did not produce signs of irritation or sensitization.23 LYSINE

In the HRIPT study of 104 subjects using a face and neck product that is described above, 0.01% lysine did not produce signs of irritation or sensitization.23 METHIONINE

In the HRIPT of 102 subjects with a face and neck product that is described above, 0.005% methionine was not an irritant or a sensitizer.23 PHENYLALANINE Phenylalanine at 0.03% in the HRIPT of a suntan product that is described above did not produce signs of irritation or sensitization.23 SERINE

In the HRIPT study of 104 subjects using a face and neck product that is described above, 013% serine did not produce signs of irritation or sensitization.23 TYROSINE



5

Tyrosine at 0.03% in the HRIPT of a suntan product that is described above did not produce signs of irritation or sensitization.23

Phototoxicity

HISTIDINE In several validation studies for in vitro phototoxicity assays, histidine up to a concentration of 10% was used as a negative control.26,27

AMINO ACID ANALOGS

Glyphosate, an aminophosphonic analog of glycine, is a non-selective herbicide that has very low acute dermal toxicity in animals (>2000 mg/kg bw).11 Dermal penetration in in vitro human skin samples and in vivo monkey studies was very low.28 Skin contact can cause irritation and contact dermatitis; however, these effects are probably due to preservatives or co-formulants and not to glyphosate itself.11 Ocular exposure may cause mild conjunctivitis and superficial corneal injury.

SUMMARY

Amino acids are critical to life and metabolic function. Because amino acids are present in all living organisms, they are not considered to pose any significant safety concern following oral exposure, except to individuals with certain genetic disorders, and their general biology is well characterized.

The amino acids and their salts are used primarily as hair conditioning agents and skin conditioning agents in cosmetic formulations. Arginine has the most reported uses in cosmetic and personal care products, with a total of 440. The maximum use concentration range for arginine is 2.0 x 10-5 to 18%. Glycine has the second greatest number of overall uses reported, with a total of 323, and has a maximum use concentration range of 5.0 x 10-4 to 4%. The European Commission’s SCCP concluded that the risk of exposure to viruses, such as avian influenza virus or papillomavirus, is negligible through topical application of cosmetic products containing amino acids that are obtained from hydrolysis of human hair or chicken feathers.

The “L-“amino acids are considered Generally Recognized As Safe (GRAS) in direct food additives by the FDA. In addition to food additives and supplements, amino acids may be used in the production of pesticides. An in vitro study using human keratinocytes found that continuous application of arginine (L-) increased endogenous intrakeratinocytic urea synthesis through increased activity of keratinocytic arginase. Cysteine HCl and methionine were used as negative controls in in vitro assays to predict potential skin irritants. In separate efficacy studies, arginine and cysteine did not produce any adverse effects in rats or guinea pigs. Glutamic acid was used as a negative control in an in vitro study to identify skin sensitizers. Glycine, when used as a topical-barrier recovery-accelerator in a mouse skin model for chronic eczematous dermatitis, did not produce adverse effects. A HRIPT study concluded that there was no evidence of sensitization to a mascara containing 1.1% arginine in 105 subjects. Another HRIPT study concluded that there was no evidence that the A/P roll-on containing 2.784% glycine elicited dermal irritation or sensitization.

In several validation studies for in vitro phototoxicity assays, histidine was used as a negative control. The herbicide glyphosate, an aminophosphonic analog of glycine, has very low acute dermal toxicity in

animals and very low dermal penetration in in vitro human skin samples and in vivo monkey studies was very low. Irritation and contact dermatitis that have been observed in case studies may be due to preservatives or co-formulants in glyphosate products. Ocular exposure may cause mild conjunctivitis and superficial corneal injury.



6

TABLES AND FIGURES Table 1. Amino acids and related simple salts. Alanine Histidine Arginine Histidine HCl Arginine HCl Isoleucine Asparagine Leucine Aspartic Acid Lysine Sodium Aspartate Lysine HCl Potassium Aspartate Methionine Dipotassium Aspartate Phenylalanine Calcium Aspartate Proline Magnesium Aspartate Serine Cysteine Threonine Cysteine HCl Tryptophan Cystine Tyrosine Glutamic Acid Valine Sodium Glutamate Glutamine Glycine Sodium Glycinate Calcium Glycinate Magnesium Glycinate



7

Table 2. Definitions, functions, and idealized structures of alpha-amino acid ingredients in this safety assessment. Although the amino acids are typically zwitter-ionic in situ, the acid and base groups are drawn uncharged for simplicity (except in the case of salts). Ingredient CAS No. Definition Formula/structure Alanine 56-41-7

Alanine is the α-methyl substituted amino acid of proteins.

Arginine 74-79-3

Arginine is the α-guanidinylpropyl substituted amino acid of proteins.

Arginine HCl 1119-34-2

Arginine HCl is the hydrochloride salt of Arginine.

NH3

NH

NH

H2N

O

OH

ClAsparagine 70-47-3 5794-13-8 (monohydrate)

Asparagine is the α-acetamidyl substituted amino acid of proteins.

Aspartic Acid 56-84-8

Aspartic Acid is the α-acetic acid substituted amino acid of proteins.

Sodium Aspartate 5598-53-8

Sodium Aspartate is the monosodium salt of Aspartic Acid.

Potassium Aspartate 1115-63-5

Potassium Aspartate is the monopotassium salt of Aspartic Acid.



8

Table 2. Definitions, functions, and idealized structures of alpha-amino acid ingredients in this safety assessment. Although the amino acids are typically zwitter-ionic in situ, the acid and base groups are drawn uncharged for simplicity (except in the case of salts). Ingredient CAS No. Definition Formula/structure Dipotassium Aspartate 14007-45-5

Dipotassium Aspartate is the dipotassium salt of Aspartic Acid.

Calcium Aspartate 21059-46-1

Calcium Aspartate is the calcium salt of Aspartic Acid.

Magnesium Aspartate 2068-80-6 18962-61-3

Magnesium Aspartate is the magnesium salt of Aspartic Acid.

Cysteine 52-90-4

Cysteine is the α-mercaptomethyl (α-thiomethyl) substituted amino acid of proteins.

Cysteine HCl 52-89-1

Cysteine HCl is the hydrochloride salt of Cysteine.

Cystine 56-89-3

Cystine is the disulfide (thiol dimer) of Cysteine.



9

Table 2. Definitions, functions, and idealized structures of alpha-amino acid ingredients in this safety assessment. Although the amino acids are typically zwitter-ionic in situ, the acid and base groups are drawn uncharged for simplicity (except in the case of salts). Ingredient CAS No. Definition Formula/structure Glutamic Acid 56-86-0

Glutamic Acid is the α-propionic acid substituted amino acid of proteins.

Sodium Glutamate 16177-21-2 142-47-2 6106-04-3 (hydrate)

Sodium Glutamate (MSG) is the monosodium salt of Glutamic Acid.

NH2

O

HO

O

O Na+

Glutamine 56-85-9

Glutamine is the α-propanamidyl substituted amino acid of proteins.

NH2

O

H2N

O

OH

Glycine 56-40-6

Glycine is the α-unsubstituted amino acid of proteins. Glycine is the only α-amino acid of proteins without a stereocenter.

H2N

O

OH

Sodium Glycinate 6000-44-8

Sodium Glycinate is the sodium salt of Glycine.

Na+

H2N

O

O-

Calcium Glycinate 35947-07-0

Calcium Glycinate is the calcium salt of Glycine.

Ca2H2N

O

O-

2Magnesium Glycinate 14783-68-7

Magnesium Glycinate is the magnesium salt of Glycine.

Mg2H2N

O

O-

2



10

Table 2. Definitions, functions, and idealized structures of alpha-amino acid ingredients in this safety assessment. Although the amino acids are typically zwitter-ionic in situ, the acid and base groups are drawn uncharged for simplicity (except in the case of salts). Ingredient CAS No. Definition Formula/structure Histidine 71-00-1

Histidine is the α-imidazolemethyl substituted amino acid of proteins.

NH2HN

N

O

OH

Histidine HCl 645-35-2 5934-29-2 (hydrate)

Histidine HCl is the hydrochloride salt of Histidine.

NH3HN

N

O

OH

Cl

Isoleucine 73-32-5

Isoleucine is the α-((S)-sec-butyl) substituted amino acid of proteins.

NH2CH3

CH3 O

OH

Leucine 61-90-5

Leucine is the α-isobutyl substituted amino acid of proteins.

NH2

H3C

CH3

O

OH

Lysine 56-87-1

Lysine is the α-(4-amino-n-butyl) substituted amino acid of proteins.

OH

O

NH2

H2N

Lysine HCl 657-27-2 10098-89-2

Lysine HCl is the hydrochloride salt of Lysine.

OH

O

NH3

H2N

Cl



11

Table 2. Definitions, functions, and idealized structures of alpha-amino acid ingredients in this safety assessment. Although the amino acids are typically zwitter-ionic in situ, the acid and base groups are drawn uncharged for simplicity (except in the case of salts). Ingredient CAS No. Definition Formula/structure Methionine 59-51-8 (DL) 63-68-3

Methionine is the α-methylmercaptopropyl (α-methylthiopropyl) substituted amino acid of proteins.

Phenylalanine 63-91-2 62056-68-2

Phenylalanine is the α-benzyl substituted amino acid of proteins.

NH2

O

OH

Proline 147-85-3

Proline is the α-pyrrolidine substituted amino acid of proteins. Proline is the only α-amino acid of proteins wherein the α-amine is secondary.

OH

O

NH

Serine 56-45-1

Serine is the α-hydroxymethyl substituted amino acid of proteins.

O

OH

NH2

HO

Threonine 72-19-5

Threonine is the α-((R)-1-hydroxy-1-ethyl) substituted amino acid of proteins.

Tryptophan 73-22-3

Tryptophan is the α-indolemethyl substituted amino acid of proteins.

NH2HN

O

OH



12

Table 2. Definitions, functions, and idealized structures of alpha-amino acid ingredients in this safety assessment. Although the amino acids are typically zwitter-ionic in situ, the acid and base groups are drawn uncharged for simplicity (except in the case of salts). Ingredient CAS No. Definition Formula/structure Tyrosine 60-18-4

Tyrosine is the α-(p-hydroxybenzyl) substituted amino acid of proteins.

NH2

HO

O

OH

Valine 72-18-4

Valine is the α-isopropyl substituted amino acid of proteins.

OH

O

H3C

CH3

NH2



13

Table 3. Physical and chemical properties. Property Value Reference

Alanine

Physical Form Crystals Merck

Molecular Weight g/mol 89.09 Merck

Molecular Volume cm3/mol @ 20 oC & 760 mmHg 76.7 29

Density/Specific Gravity 1.401 Merck

Vapor pressure mmHg @ 25 oC 0.0661 29

Boiling Point oC @760 mmHg 212.9 29

Water Solubility g/L @ 25 oC 166.5 Merck

Other Solubility Insol in ether Merck

log P @ 25 oC -0.574 29

Disassociation constants (pKa, pKb) pK1 2.34; pK2 9.69 Merck

Arginine




Density/Specific Gravity g/cm3 @ 20 oC & 760 mmHg 1.46 29

Vapor pressure mmHg@ 25 oC 2.08E-6 29


Water Solubility Freely sol in water Merck

Other Solubility Sparingly sol in alc. Insol in ether Merck

log P @ 25 oC -1.652 29

Disassociation constants (pKa, pKb) pK1 2.17; pK2 9.04; pK3 12.48 Merck

Arginine HCl

Physical Form Prisms Merck



Other Solubility Slightly sol in hot alc. Merck



14

Table 3. Physical and chemical properties.

Asparagine


Color White Merck




Vapor pressure mmHg @ 25 oC 6.74E-9 29

Melting Point oC 234-235 Merck

Boiling Point oC @ 760 mmHg 438.0 29

Water Solubility Sol in water Merck

Other Solubility Sol in acids and alkalies. Practically insol in methanol, ethanol, ether, benzene

Merck

log P @ 25 oC -1.880 29


Aspartic Acid









Other Solubility Sol in dilute sol of mineral acids, alkalies.. Practically insol in alc and ether

Merck

log P @ 25 oC -1.075 29

Disassociation constants (pKa, pKb pK1 1.88; pK2 3.65; pK3 9.60 Merck

Cysteine




Density/Specific Gravity g?cm3 @ 20 oC & 760 mmHg 1.334 29



Other Solubility

Freely sol in alc., acetic acid, ammonia. Insol in ether, acetone, ethyl acetate, benzene, carbon disulfide, carbon tet.

Merck

log P @ 25 oC 0.085 29




15


Cysteine HCl

Physical Form Crystals or crystalline powder Merck


Water Solubility Sol in water Merck

Other Solubility Sol in alc and acetone. Merck

Cystine




Density/Specific Gravity @ 20 oC & 760 mmHg 1.571 29




Other Solubility g/L @ oC & pH Insol in alc. Merck

log P @ 25 oC 0.773 29

Disassociation constants (pKa, pKb) @ 35 oC pK1 1; pK2 2.1; pK3 8.02; pK4 8.71.

Merck

Glutamic Acid






Melting Point oC 160 Merck



Other Solubility Insol in methanol, ethanol, ether, acetone, glacial acetic acid, and neutral solvents.

Merck

log P @ 25 oC -0.969 29




16


Glutamine



Molecular Volume cm3/mol 20 oC & 760 mmHg 110.5 29




Water Solubility g/L @ 30 oC & pH 48.1 Merck

Other Solubility Practically insol in methanol, ethanol, ether, benzene, acetone, ethyl acetate, chloroform

Merck

log P @ 25 oC -1.576 29


Glycine





Vapor pressure mmHg@ 25 oC 0.0123 29


Water Solubility g/L @ 25 oC 250 Merck

Other Solubility Practically insol in ether Merck

log P @ 25 oC -0.928 29


Histidine








Other Solubility Insol in neutral solvents. Merck

log P @25 oC -1.418 29




17


Histidine HCl



Water Solubility Fairly sol Merck

Other Solubility Insol in alc, ether Merck

Isoleucine




Density/Specific Gravity g/cm3@ 20 oC & 760 mmHg 1.035 Merck



Water Solubility g/L @ 23.7 oC 33.85 Merck

Other Solubility Sparingly sol in hot alc and hot aceteic acid. Insol in ether.

Merck

log P @ 25 oC 0.799 29


Leucine


Color White Merck






Water Solubility g/L @ 25 oC & pH 24.26 Merck

Other Solubility Insol in ether Merck

log P @ 25 oC 0.799 29

Disassociation constants (pKa, pKb) @ 25 oC pK1 2.55; pK2 9.79 29



18


Lysine



Molecular Volume cm3/mol @20 oC & 760 mmHg 129.9 29

Density/Specific Gravity g/cm3@ 20 oC & 760 mmHg 1.125 29



Water Solubility Freely sol Merck


log P @ 25 oC -0.734 29

Disassociation constants (pKa, pKb) pK1 2.18; pK2 8.95; pK310.53 Merck

Lysine HCl




Methionine (L-)








Water Solubility Sol Merck

Other Solubility Insol in ether, benzene, acetone Merck

log P @ 25 oC 0.217 29

Disassociation constants (pKa, pKb) @ 25 oC pK1 2.23; pK2 9.40 29

Methionine (DL-)


Molecular Weight g/mol 149.21 29

Molecular Volume cm3/mol 20 oC & 760 mmHg 123.7 29


Vapor pressure mmHg@ 25oC 1.70E-4 29



Other Solubility Sol in dil acids, alkalies, Slightly sol in alc. Insol in ether.

Merck

log P @ 25 oC 0.217 29




19


Phenylalanine



Molecular Volume cm3/mol @20 oC & 760 mmHg 137.4 29


Vapor pressure mmHg 3.13E-4 29



Other Solubility g/L @ oC & pH Slightly sol in methanol, ethanol Merck

log P @ 25 oC 0.235 29


Proline




Density/Specific Gravity g/cm3@ 20 oC & 760 mmHg 1.186 29



Water Solubility g/L @ 25 oC 1623 Merck

Other Solubility Insol in ether, butanol, isopropanol.

Merck

log P @ 25 oC -0.060 29


Serine





Vapor pressure mmHg@ 25oC 7.17E-8 29


Water Solubility Sol Merck


log P @ 25 oC -1.49 29

Disassociation constants (pKa, pKb) pK1 2.16; pK2 9.10 29



20


Threonine




Density/Specific Gravity g/cm3 @ 20 oC & 760 mmHg oC 1.307 29

Vapor pressure mmHg 3.77E-6 29

Boiling Point oC @ 760 mmHg 345..8 29

Water Solubility Freely sol Merck


log P @ 25 oC -1.136 29

Disassociation constants (pKa, pKb pK1 2.63; pK210.43 Merck

Tryptophan







Water Solubility g/L @ 25 oC & pH 11.36 g/l Merck

Other Solubility g/L @ oC & pH Sol in hot alc and alkali hydroxides. Insol in chloroform.

Merck

log P @ 25 oC 0.704 29

Disassociation constants (pKa, pKb) @oC pK1 2.38; pK2 9.39 Merck

Tyrosine








Other Solubility Sol in alkaline soln. Insol in neutral solvents.

Merck

log P @ 25 oC -0.418 29

Disassociation constants (pKa, pKb) pK1 2.20; pK2 9.11; pK310.07 Merck



21


Valine






Melting Point oC 315 Merck




log P @ 25 oC 0.289 29




22

Table 4. Frequency and concentration of use according to duration and type of exposure4,5 # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) Alaninea Arginine Arginine HCl Totals* 265 3.0x10-7-0.1 440 0.00002-18 69 0.004-0.1 Duration of Use Leave-On 223 3.0x10-7-0.1 328 0.00002-2 45 0.004-0.02 Rinse-Off 42 5.0x10-7-0.06 107 0.00004-18 24 0.004-0.1 Diluted for (Bath) Use NR NR 5 NR NR NR Exposure Type Eye Area 15 0.0004-0.05 36 0.00002-2 4 NR Incidental Ingestion NR 0.00003 1 0.00003-0.001 NR NR

Incidental Inhalation-Spray NR

3.0x10-7; 0.0007 aerosols; 0.001-0.01 pump

sprays

NR 0.2;

0.0001-0.1 aerosols; 0.0003-0.1 pumps

6 NR

Incidental Inhalation-Powder NR NR NR NR NR NR Dermal Contact 234 3.0x10-7-0.1 358 0.00002-18 37 0.02 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 30 5.0x10-7-0.05 72 0.00004-3 32 0.004-0.1 Hair-Coloring NR 0.05 1 0.004-0.8 NR NR Nail NR NR 1 0.5 NR 0.004 Mucous Membrane 2 0.00003 25 0.00003-0.001 NR NR Baby Products NR NR NR NR NR NR

Asparagine Aspartic Acidb Potassium Aspartate Totals* 9 NR 148 0.000005-1 15 0.0003-0.008 Duration of Use Leave-On 4 NR 105 0.000005-0.6 10 0.0003-0.008 Rinse Off 5 NR 43 0.0001-1 5 0.005 Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR 9 0.2 NR NR Incidental Ingestion NR NR NR NR 1 0.001 Incidental Inhalation-Spray NR NR NR 0.003-0.2 aerosols NR NR Incidental Inhalation-Powder NR NR NR NR NR 0.0003 Dermal Contact 3 NR 111 0.000005-0.2 13 0.0003-0.008 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 6 NR 37 0.0001-1 1 0.005 Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR NR 1 0.001 Baby Products NR NR NR NR NR 0.0003-0.005

Magnesium Aspartate Cysteinec Cysteine HCld

Totals* 94 0.00005-0.1 20 0.0001-5 5 0.0001-6 Duration of Use Leave-On 76 0.0003-0.1 17 0.0001-0.05 1 0.0001 Rinse-Off 18 0.00005-0.06 3 0.0001-5 4 0.0001-6 Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area 16 0.005-0.05 NR NR NR NR Incidental Ingestion 1 0.001 NR NR NR NR Incidental Inhalation-Spray NR NR 2 0.001 NR NR Incidental Inhalation-Powder NR 0.0003 NR 0.05 NR NR Dermal Contact 92 0.0003-0.1 8 0.0009-0.05 1 NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 1 0.00005-0.005 8 0.0001-5 3 0.0001-6 Hair-Coloring NR NR NR NR 1 NR Nail NR 0.001 4 NR NR NR Mucous Membrane 2 0.0005-0.003 NR NR NR NR Baby Products NR 0.0003-0.005 NR NR NR NR



23

Table 4. Frequency and concentration of use according to duration and type of exposure4,5 # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%)

Cystine Glutamic Acide Sodium Glutamate Totals 10 0.001-3 274 0.000004-2 19 0.01-2 Duration of Use Leave-On 5 0.001 190 0.000004-0.4 18 0.01-2 Rinse Off 5 0.001-3 84 0.00003-2 1 0.01 Diluted for (Bath) Use NR NR NR 0.1 NR NR Exposure Type Eye Area NR NR 17 0.000004-0.08 1 0.5-2 Incidental Ingestion NR NR NR 0.00003 NR 0.2 Incidental Inhalation-Spray NR NR NR NR NR NR Incidental Inhalation-Aerosol NR NR NR NR NR NR Dermal Contact 3 0.001 184 0.000004-0.2 19 0.01-2 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 7 0.001-3 81 0.00003-2 NR 1 Hair-Coloring NR NR 5 0.01 NR 0.01 Nail NR NR NR NR NR NR Mucous Membrane NR NR 1 0.00003-0.1 1 0.2 Baby Products NR NR NR NR NR NR Glutaminef Glycine Sodium Glycinate Totals* 17 0.002-0.005 323 0.0005-4 15 NR Duration of Use Leave-On 15 0.002 221 0.0007-4 NR NR Rinse-Off 2 0.005 102 0.0005-4 15 NR Diluted for (Bath) Use NR NR NR 0.2-0.4 NR NR Exposure Type Eye Area 1 NR 21 0.001-0.3 NR NR Incidental Ingestion NR NR 1 0.01 NR NR

Incidental Inhalation-Spray NR NR 8 0.3

0.0007 aerosols; 0.01-0.1 pump sprays

NR NR

Incidental Inhalation-Powder NR NR 1 NR NR NR Dermal Contact 15 0.002-0.005 239 0.001-4 NR NR Deodorant (underarm) NR NR 4 0.5-4 (not spray) NR NR Hair - Non-Coloring 2 NR 82 0.0005-2 NR NR Hair-Coloring NR NR NR 0.004-4 15 NR Nail NR NR NR 0.5-1 NR NR Mucous Membrane NR NR 6 0.01-1 NR NR Baby Products NR NR 1 NR NR NR Calcium Glycinate Histidine Histidine HClg Totals* NR 3 59 0.00009-0.05 8 0.00003-0.07 Duration of Use Leave-On NR 3 43 0.00009-0.05 8 0.00003-0.07 Rinse-Off NR NR 16 0.0004-0.0008 NR NR Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR 2 NR 1 0.01 Incidental Ingestion NR NR NR 0.001 NR 0.00003

Incidental Inhalation-Spray NR NR NR 0.00009 aerosols;

0.0003 pump sprays NR NR

Incidental Inhalation-Powder NR NR NR NR NR NR Dermal Contact NR 3 33 0.0003-0.05 8 0.01-0.07 Deodorant (underarm) NR 3 (not spray) NR NR NR NR Hair - Non-Coloring NR NR 26 0.00009-0.0008 NR NR Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR 0.001 NR 0.00003 Baby Products NR NR NR NR NR NR



24

Table 4. Frequency and concentration of use according to duration and type of exposure4,5 # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) Isoleucineh Leucinei Lysinej

Totals* 28 0.0003-0.002 33 0.0009-0.001 132 1.0x10-7-0.7 Duration of Use Leave-On 23 0.0003-0.002 27 0.0009-0.001 119 0.00002-0.7 Rinse-Off 5 0.001-0.002 6 NR 13 1.0x10-7-0.04 Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area 1 NR NR NR 8 0.00002-0.04 Incidental Ingestion NR 0.001 NR 0.001 1 NR Incidental Inhalation-Spray NR 0.0003 aerosols NR NR NR NR Incidental Inhalation-Powder NR NR NR NR NR NR Dermal Contact 24 0.001 27 0.0009 120 1.0x10-7-0.7 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 4 0.0003-0.002 6 NR 11 0.00004 Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR 0.001 NR 0.001 1 NR Baby Products NR NR NR NR NR NR # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%)

Lysine HClk Methioninel Phenylalanine Totals* 46 0.00003-0.6 24 0.0001-0.07 36 0.00009-0.03 Duration of Use Leave-On 30 0.00003-0.6 18 0.0001-0.005 27 0.00009-0.03 Rinse-Off 16 0.0008-0.1 5 0.0001-0.07 9 0.0004-0.0008 Diluted for (Bath) Use NR NR 1 NR NR NR Exposure Type Eye Area 1 0.001 NR NR 2 0.005 Incidental Ingestion 2 0.00003-0.001 NR NR NR NR Incidental Inhalation-Spray 1 NR NR NR NR 0.00009 aerosols Incidental Inhalation-Powder NR NR NR NR NR NR Dermal Contact 11 0.0002-0.6 18 0.001-0.005 26 0.0004-0.03 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 33 0.0008-0.2 6 0.0001-0.07 9 0.00009-0.001 Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane 2 0.00003-0.001 1 NR NR NR Baby Products NR NR NR NR NR NR # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%)

Prolinem Serinen Threonineo Totals* 273 0.00001-2 298 0.00003-2 146 0.00002-0.05 Duration of Use Leave-On 210 0.0001-2 258 0.00003-2 102 0.00003-0.02 Rinse-Off 59 0.00001-1 40 0.0002-1 44 0.00002-0.05 Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area 11 0.0001-0.2 28 0.002-0.3 6 0.0002-0.003 Incidental Ingestion 1 NR NR 0.00003-0.05 NR 0.00003-0.001

Incidental Inhalation-Spray NR 0.0003 aerosols NR 0.08;

0.0005 aerosols NR 0.0003 aerosols

Incidental Inhalation-Powder NR NR 9 NR NR NR Dermal Contact 219 0.0001-1 275 0.002-2 106 0.0001-0.02 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 18 0.00001-0.03 14 0.0002-1 10 0.00002-0.002 Hair-Coloring 29 NR NR NR 29 0.05 Nail 2 2 2 0.004 1 0.004 Mucous Membrane 2 NR 2 0.00003-0.05 1 0.00003-0.001 Baby Products 2 NR 1 NR NR NR



25

Table 4. Frequency and concentration of use according to duration and type of exposure4,5 # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) # of Uses Max Conc of Use (%) Tryptophan Tyrosine Valine Totals* 10 0.0001 54 0.0005-1 31 0.0004-1 Duration of Use Leave-On 8 NR 47 0.0009-1 25 0.0004-0.5 Rinse-Off 2 0.0001 7 0.0005-0.001 6 0.002-1 Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR 3 0.004-1 1 NR Incidental Ingestion NR NR NR NR NR 0.001 Incidental Inhalation-Spray NR NR 9 NR NR 0.0004 aerosols Incidental Inhalation-Powder NR NR NR 0.05 NR NR Dermal Contact 8 NR 45 0.0009-1 27 0.0009-0.02 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 2 0.0001 9 0.0005 4 0.0004-1 Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR NR NR 0.001 Baby Products NR NR NR NR NR NR

* Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types my not equal the sum of total uses. NR – no reported uses a The VCRP listed separate entries for Alanine and L-Alanine, which have been combined in this table. L-Alanine has a total of 18 uses, 9 in rinse-off products and 9 in leave-on products. 12 uses lead to a dermal exposure, and 6 uses are to hair (non-coloring). b The VCRP listed separate entries for Aspartic Acid and L-Aspartic Acid, which have been combined in this table. L-Aspartic Acid has a total of 3 uses, 2 in rinse-off products and 1 in leave-on products. 1 use leads to a dermal exposure, and 2 uses are to hair (non-coloring). c The VCRP listed separate entries for Cysteine and L-Cysteine, which have been combined in this table. L-Cysteine has a total of 3 uses, all in rinse-off products . 1 use leads to a dermal exposure, and 2 uses are to hair (non-coloring). d The VCRP only listed an entry for L-Cysteine HCl. This data has been combined with the concentration of use data for Cysteine HCl. e The VCRP listed separate entries for Glutamic Acid, DL-Glutamic Acid, and L-Glutamic Acid, which have been combined in this table. DL-Glutamic Acid has a total of 2 uses, all in leave-on products. Both uses are a dermal exposure. L-Glutamic Acid has a total of 14 uses, 8 uses in leave-on products and 6 uses in rinse-off products. 8 uses are a dermal exposure, and 6 uses are to hair (non-coloring). f The VCRP only listed an entry for L-Glutamine. This data has been combined with the concentration of use data for Glutamine. g The VCRP only listed an entry for L-Histidine HCl. This data has been combined with the concentration of use data for Histidine HCl. h The VCRP only listed an entry for L-Isoleucine. This data has been combined with the concentration of use data for Isoleucine. i The VCRP only listed an entry for L-Leucine. This data has been combined with the concentration of use data for Leucine. j The VCRP listed separate entries for Lysine, DL-Lysine, and L-Lysine, which have been combined in this table. DL-Lysine has 1 use in a leave-on product with dermal exposure. L-Lysine has a total of 18 uses, 14 uses in leave-on products and 4 uses in rinse-off products. 1 use is in the eye area, 14 uses are a dermal exposure, and 4 uses are to hair (non-coloring). k The VCRP only listed an entry for L-Lysine HCl. This data has been combined with the concentration of use data for Lysine HCl. l The VCRP listed separate entries for Methionine and L-Methionine, which have been combined in this table. L-Methionine has a total of 2 uses, both in leave-on products with a dermal exposure. m The VCRP listed separate entries for Proline and DL-Proline, which have been combined in this table. DL-Proline has a total of 9 uses, 3 in leave-on products and 6 in rinse-off products. 1 use may lead to incidental ingestion, 1 use may be to the mucous membranes, 2 uses are dermal exposures, and 6 uses are to the hair (coloring). n The VCRP listed separate entries for Serine and L-Serine, which have been combined in this table. L-Serine has a total of 49 uses, 38 in leave-on products and 11in rinse-off products. 2 uses are in the eye area, 1 use is in nail products, 43 uses are dermal exposures, and 5 uses are to hair (non-coloring). o The VCRP listed separate entries for Threonine and L-Threonine, which have been combined in this table. L-Threonine has a total of 8 uses, 6 in leave-on products and 2 in rinse-off products. 6 uses are dermal exposures and 2 are to the hair (non-coloring).



26

References

1. AAD. 2011. Manufacturing flow diagram for L-Arginine used for the testing. 1 pages.

2. Personal Care Products Council. 11-1-2011. Method of Manufacture and Impurities: D-Glutamic Acid. 1 pages.

3. Gottschalck TE and Bailey JE. International Cosmetic Ingredient Dictionary and Handbook. 13 ed. Washington, DC: Personal Care Products Council (formerly the Cosmetic, Toiletry, and Fragrance Association.), 2010.

4. Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients. FDA Database. 2011. Washington, DC: FDA.

5. Personal Care Products Council. 1-11-2012. Concentration of use by FDA Product Category: Amino Acids. 17 pages.

6. Johnsen MA. The influence of particle size. Spray Technology and Marketing. 2004;November:24-27.

7. Rothe H. Special Aspects of Cosmetic Spray Evalulation. 9-26-2011.

8. Bremmer HJ, Prud'homme de Lodder LCH, and Engelen JGM. Cosmetics Fact Sheet: To assess the risks for the consumer; Updated version for ConsExpo 4. 2006. Report No. RIVM 320104001/2006. pp. 1-77.

9. Rothe H, Fautz R, Gerber E, Neumann L, Rettinger K, Schuh W, and Gronewold C. Special aspects of cosmetic spray safety evaluations: Principles on inhalation risk assessment. Toxicol Lett. 2011;205(2):97-104.

10. Scientific Committee on Consumer Products (SCCP). Opinion on Amino Acids Obtained by Hydrolysis of Human Hair. European Commission Health & Consumer Protection Directorate-General. 2005. http://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_o_005.pdf. Report No. SCCP/0894/05.

11. Bradberry SM, Proudfoot AT, and Vale JA. Glyphosate Poisoning. Toxicol Rev. 2004;23(3):159-167.

12. Kaloyanova F, Ivanova-Chemishanska L, Zaykov HR, Baynova A, Mihaylova A, Mircheva V, Anton G: Shumkov N, Vergieva T, Halkova ZH, Ilieva P, and Bardarov V. Toxicological evaluation of Agromet (Metalaxyl) preparation. J Hyg Epidemiol Micobiol Immunol. 1991;35(4):375-382.

13. Joint FAO/WHO Expert Committee on Food Additive. Amino Acids and Related Substances. In: Evaluation of certain food additives and contaminants (Sixty-third meeting of the Joint FAO/WHO Expert Committee on Food Additives). Geneva, Switzerland, World Health Organization. 2006. http://whqlibdoc.who.int/publications/2006/9241660546_eng.pdf. Date Accessed 1-12-2012. Report No. 54. pp. 435-486.

14. Wohlrab J, Siemes C, and Marsch WC. The influence of L-arginine on the regulation of epidermal arginase. Skin Pharmacol Appl Skin Physiol. 2002;15:44-54.

15. AAD. 2011. L-Arginine: Safety data summary. 1 pages.



27

16. Reinhardt CA, Pelli DA, and Zbinden G. Interpretation of cell toxicity data for the estimation of potential irritation. Fd Chem Toxic. 1985;23(2):247-252.

17. Matsumoto Y, Arai K, Momose H, and Kuroyanagi Y. Development of a wound dressing composed of a hyaluronic acid sponge containing arginine. J Biomat Sci. 2009;20:993-1004.

18. Picman J and Picman AK. Treatment of dermatitis caused by the sesquiterpene lactone helenin. Pharmazie. 1990;45:57-59.

19. Picman J and Picman AK. Treatment of dermatitis from parthenin. Contact Dermatitis. 1985;13:9-13.

20. Hooyberghs J, Schoeters E, Lambrechts N, Nelissen I, Witters H, Schoeters G, and Van Den Heuvel R. A cell-based in vitro alernative to identify skin sensitizers by gene expression. Toxicology and Applied Phamacology. 2008;231:103-111.

21. Lambrechts N, Verstraelen S, Lodewyckx H, Felicio A, Hooyberghs J, Witters H, Van Tendeloo V, Van Cauwenberge P, Nelissen I, Van Den Heuvel R, and Schoeters G. THP-1 monocytes but not macrophages as a potential alternative for CD34+ dendritic cells to identify chemical skin sensitizers. Toxicology and Applied Phamacology. 2009;236:221-230.

22. Matsunaga Y, Ogura Y, Ehama R, Amano S, Nishiyama T, and Tagami H. Establishment of a mouse skin model of the lichenification in human chronic eczematous dermatitis. Br J Derm. 2007;156:884-891.

23. Personal Care Products Council. 1-23-2012. Summaries of human repeat insult patch tests (HRIPTs) of products containing amino acids.

24. Consumer Product Testing Co. 2008. Repeated insult patch test of a mascara containing 1.1% Arginine. Experiment Reference Number C08-3409.02. 14 pages.

25. Clinical Research Laboratories Inc. 2008. Repeated insult patch test of an A/P roll-on containing 2.784% Glycine. CRL Study Number: CRL83708-12. 14 pages.

26. Bernard FX, Barrault C, Deguercy A, De Wever B, and Rosdy M. Development of a highly sensitive in vitro phototoxicity assay using the SkinEthic reconstructed human epidermis. Cell Biology and Toxicology. 2000;16:391-400.

27. Liebsch M, Doring B, Donelly TA, Logemann P, Rheins LA, and Speilmann H. Application of the human dermal model Skin2 ZK 1350 to phototoxicity and skin corrosivity testing. Toxic.in Vitro. 1995;9(4):557-562.

28. Williams GM, Kroes R, and Munro IC. Safety evaluation and risk assessment of the herbicide Roundup and its active ingredient, glyphosate, for humans. Reg Toxicol Pharmacol. 2000;31:117-165.

29. Advanced Chemistry Development (ACD/Labs). Advanced Chemistry Development software v11.02. 2011.



Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)

FROM: Halyna Breslawec, Ph.D. Industry Liaison to the CIR Expert Panel

DATE: November 1, 2011

SUBJECT: Method of Manufacture and Impurities: D-Glutamic Acid

One supplier indicates that they sell D-Glutamic Acid to the cosmetics industry.

Fermentation from sugarcane is used to produce L-Glutamic Acid. Racemization of the L-GlutamicAcid results in the product of D-Glutamic Acid.

D-Glutamic Acid contains not more than 0.3% methanol.



2011 FDA VCRP Raw Data

03C - Eye Shadow ALANINE 103D - Eye Lotion ALANINE 303F - Mascara ALANINE 103G - Other Eye Makeup Preparations ALANINE 1005A - Hair Conditioner ALANINE 1205C - Hair Straighteners ALANINE 105F - Shampoos (non-coloring) ALANINE 405G - Tonics, Dressings, and Other Hair Grooming Aids ALANINE 605I - Other Hair Preparations ALANINE 107C - Foundations ALANINE 807H - Makeup Fixatives ALANINE 107I - Other Makeup Preparations ALANINE 310E - Other Personal Cleanliness Products ALANINE 211A - Aftershave Lotion ALANINE 211G - Other Shaving Preparation Products ALANINE 112A - Cleansing ALANINE 712C - Face and Neck (exc shave) ALANINE 4212D - Body and Hand (exc shave) ALANINE 3412F - Moisturizing ALANINE 7812G - Night ALANINE 712H - Paste Masks (mud packs) ALANINE 612I - Skin Fresheners ALANINE 412J - Other Skin Care Preps ALANINE 13 05A - Hair Conditioner ALANINE, L- 205D - Permanent Waves ALANINE, L- 105F - Shampoos (non-coloring) ALANINE, L- 205H - Wave Sets ALANINE, L- 107C - Foundations ALANINE, L- 212A - Cleansing ALANINE, L- 212C - Face and Neck (exc shave) ALANINE, L- 212F - Moisturizing ALANINE, L- 512H - Paste Masks (mud packs) ALANINE, L- 1 02B - Bubble Baths ARGININE 503B - Eyeliner ARGININE 203D - Eye Lotion ARGININE 1203E - Eye Makeup Remover ARGININE 203F - Mascara ARGININE 703G - Other Eye Makeup Preparations ARGININE 1305A - Hair Conditioner ARGININE 2205C - Hair Straighteners ARGININE 305E - Rinses (non-coloring) ARGININE 205F - Shampoos (non-coloring) ARGININE 2405G - Tonics, Dressings, and Other Hair Grooming Aids ARGININE 1105I - Other Hair Preparations ARGININE 1006A - Hair Dyes and Colors ARGININE 107C - Foundations ARGININE 507E - Lipstick ARGININE 1



07I - Other Makeup Preparations ARGININE 308B - Cuticle Softeners ARGININE 110A - Bath Soaps and Detergents ARGININE 1610E - Other Personal Cleanliness Products ARGININE 311E - Shaving Cream ARGININE 311G - Other Shaving Preparation Products ARGININE 112A - Cleansing ARGININE 2212C - Face and Neck (exc shave) ARGININE 6512D - Body and Hand (exc shave) ARGININE 1312F - Moisturizing ARGININE 11412G - Night ARGININE 2112H - Paste Masks (mud packs) ARGININE 812I - Skin Fresheners ARGININE 1212J - Other Skin Care Preps ARGININE 38 03D - Eye Lotion

ARGININE HYDROCHLORIDE 4

05A - Hair Conditioner ARGININE HYDROCHLORIDE 9

05F - Shampoos (non-coloring) ARGININE HYDROCHLORIDE 14

05G - Tonics, Dressings, and Other Hair Grooming Aids ARGININE HYDROCHLORIDE 1

05I - Other Hair Preparations ARGININE HYDROCHLORIDE 8

12C - Face and Neck (exc shave) ARGININE HYDROCHLORIDE 15

12F - Moisturizing ARGININE HYDROCHLORIDE 9

12G - Night ARGININE HYDROCHLORIDE 1

12H - Paste Masks (mud packs) ARGININE HYDROCHLORIDE 1

12J - Other Skin Care Preps ARGININE HYDROCHLORIDE 1

13B - Indoor Tanning Preparations ARGININE HYDROCHLORIDE 6

05A - Hair Conditioner ASPARAGINE 205F - Shampoos (non-coloring) ASPARAGINE 305G - Tonics, Dressings, and Other Hair Grooming Aids ASPARAGINE 112J - Other Skin Care Preps ASPARAGINE 3 03C - Eye Shadow ASPARTIC ACID 103D - Eye Lotion ASPARTIC ACID 303G - Other Eye Makeup Preparations ASPARTIC ACID 505A - Hair Conditioner ASPARTIC ACID 3005F - Shampoos (non-coloring) ASPARTIC ACID 405G - Tonics, Dressings, and Other Hair Grooming Aids ASPARTIC ACID 107C - Foundations ASPARTIC ACID 807F - Makeup Bases ASPARTIC ACID 107H - Makeup Fixatives ASPARTIC ACID 111A - Aftershave Lotion ASPARTIC ACID 2



11G - Other Shaving Preparation Products ASPARTIC ACID 112A - Cleansing ASPARTIC ACID 112C - Face and Neck (exc shave) ASPARTIC ACID 2312D - Body and Hand (exc shave) ASPARTIC ACID 1912F - Moisturizing ASPARTIC ACID 2812G - Night ASPARTIC ACID 212H - Paste Masks (mud packs) ASPARTIC ACID 512I - Skin Fresheners ASPARTIC ACID 212J - Other Skin Care Preps ASPARTIC ACID 8 05A - Hair Conditioner ASPARTIC ACID, L- 105D - Permanent Waves ASPARTIC ACID, L- 107C - Foundations ASPARTIC ACID, L- 1 03B - Eyeliner MAGNESIUM ASPARTATE 403D - Eye Lotion MAGNESIUM ASPARTATE 303G - Other Eye Makeup Preparations MAGNESIUM ASPARTATE 905I - Other Hair Preparations MAGNESIUM ASPARTATE 107C - Foundations MAGNESIUM ASPARTATE 107E - Lipstick MAGNESIUM ASPARTATE 110A - Bath Soaps and Detergents MAGNESIUM ASPARTATE 111A - Aftershave Lotion MAGNESIUM ASPARTATE 112A - Cleansing MAGNESIUM ASPARTATE 1012C - Face and Neck (exc shave) MAGNESIUM ASPARTATE 2212D - Body and Hand (exc shave) MAGNESIUM ASPARTATE 112F - Moisturizing MAGNESIUM ASPARTATE 1512G - Night MAGNESIUM ASPARTATE 1012H - Paste Masks (mud packs) MAGNESIUM ASPARTATE 712I - Skin Fresheners MAGNESIUM ASPARTATE 212J - Other Skin Care Preps MAGNESIUM ASPARTATE 6 05I - Other Hair Preparations POTASSIUM ASPARTATE 107C - Foundations POTASSIUM ASPARTATE 107E - Lipstick POTASSIUM ASPARTATE 111A - Aftershave Lotion POTASSIUM ASPARTATE 112A - Cleansing POTASSIUM ASPARTATE 212D - Body and Hand (exc shave) POTASSIUM ASPARTATE 312F - Moisturizing POTASSIUM ASPARTATE 212H - Paste Masks (mud packs) POTASSIUM ASPARTATE 312J - Other Skin Care Preps POTASSIUM ASPARTATE 1 05A - Hair Conditioner CYSTEINE 105B - Hair Spray (aerosol fixatives) CYSTEINE 105F - Shampoos (non-coloring) CYSTEINE 205G - Tonics, Dressings, and Other Hair Grooming Aids CYSTEINE 105I - Other Hair Preparations CYSTEINE 307C - Foundations CYSTEINE 107D - Leg and Body Paints CYSTEINE 107I - Other Makeup Preparations CYSTEINE 1



08A - Basecoats and Undercoats CYSTEINE 208E - Nail Polish and Enamel CYSTEINE 212C - Face and Neck (exc shave) CYSTEINE 312F - Moisturizing CYSTEINE 113B - Indoor Tanning Preparations CYSTEINE 1 05A - Hair Conditioner CYSTEINE, L- 105C - Hair Straighteners CYSTEINE, L- 112H - Paste Masks (mud packs) CYSTEINE, L- 1 05A - Hair Conditioner

CYSTEINE, L-, HYDROCHLORIDE 1

05C - Hair Straighteners CYSTEINE, L-, HYDROCHLORIDE 1

05D - Permanent Waves CYSTEINE, L-, HYDROCHLORIDE 1

06A - Hair Dyes and Colors CYSTEINE, L-, HYDROCHLORIDE 1

12J - Other Skin Care Preps CYSTEINE, L-, HYDROCHLORIDE 1

05A - Hair Conditioner CYSTINE 205F - Shampoos (non-coloring) CYSTINE 305G - Tonics, Dressings, and Other Hair Grooming Aids CYSTINE 212C - Face and Neck (exc shave) CYSTINE 3 03C - Eye Shadow GLUTAMIC ACID 103D - Eye Lotion GLUTAMIC ACID 203F - Mascara GLUTAMIC ACID 403G - Other Eye Makeup Preparations GLUTAMIC ACID 1005A - Hair Conditioner GLUTAMIC ACID 5605C - Hair Straighteners GLUTAMIC ACID 105D - Permanent Waves GLUTAMIC ACID 105E - Rinses (non-coloring) GLUTAMIC ACID 105F - Shampoos (non-coloring) GLUTAMIC ACID 405G - Tonics, Dressings, and Other Hair Grooming Aids GLUTAMIC ACID 405I - Other Hair Preparations GLUTAMIC ACID 806H - Other Hair Coloring Preparation GLUTAMIC ACID 507C - Foundations GLUTAMIC ACID 707H - Makeup Fixatives GLUTAMIC ACID 107I - Other Makeup Preparations GLUTAMIC ACID 310E - Other Personal Cleanliness Products GLUTAMIC ACID 111A - Aftershave Lotion GLUTAMIC ACID 211G - Other Shaving Preparation Products GLUTAMIC ACID 112A - Cleansing GLUTAMIC ACID 512C - Face and Neck (exc shave) GLUTAMIC ACID 4012D - Body and Hand (exc shave) GLUTAMIC ACID 2112F - Moisturizing GLUTAMIC ACID 5712G - Night GLUTAMIC ACID 712H - Paste Masks (mud packs) GLUTAMIC ACID 312I - Skin Fresheners GLUTAMIC ACID 312J - Other Skin Care Preps GLUTAMIC ACID 10



12C - Face and Neck (exc shave) GLUTAMIC ACID, DL- 205A - Hair Conditioner GLUTAMIC ACID, L- 305D - Permanent Waves GLUTAMIC ACID, L- 105F - Shampoos (non-coloring) GLUTAMIC ACID, L- 105G - Tonics, Dressings, and Other Hair Grooming Aids GLUTAMIC ACID, L- 107C - Foundations GLUTAMIC ACID, L- 212C - Face and Neck (exc shave) GLUTAMIC ACID, L- 212F - Moisturizing GLUTAMIC ACID, L- 312H - Paste Masks (mud packs) GLUTAMIC ACID, L- 1 03B - Eyeliner GLUTAMINE, L- 105F - Shampoos (non-coloring) GLUTAMINE, L- 105G - Tonics, Dressings, and Other Hair Grooming Aids GLUTAMINE, L- 112C - Face and Neck (exc shave) GLUTAMINE, L- 112D - Body and Hand (exc shave) GLUTAMINE, L- 412F - Moisturizing GLUTAMINE, L- 312G - Night GLUTAMINE, L- 212H - Paste Masks (mud packs) GLUTAMINE, L- 112I - Skin Fresheners GLUTAMINE, L- 112J - Other Skin Care Preps GLUTAMINE, L- 2 03D - Eye Lotion SODIUM GLUTAMATE 107C - Foundations SODIUM GLUTAMATE 907H - Makeup Fixatives SODIUM GLUTAMATE 210A - Bath Soaps and Detergents SODIUM GLUTAMATE 112C - Face and Neck (exc shave) SODIUM GLUTAMATE 312F - Moisturizing SODIUM GLUTAMATE 212J - Other Skin Care Preps SODIUM GLUTAMATE 1 01B - Baby Lotions, Oils, Powders, and Creams GLYCINE 103B - Eyeliner GLYCINE 903D - Eye Lotion GLYCINE 703F - Mascara GLYCINE 103G - Other Eye Makeup Preparations GLYCINE 404E - Other Fragrance Preparation GLYCINE 105A - Hair Conditioner GLYCINE 3505C - Hair Straighteners GLYCINE 105D - Permanent Waves GLYCINE 205F - Shampoos (non-coloring) GLYCINE 3605G - Tonics, Dressings, and Other Hair Grooming Aids GLYCINE 505H - Wave Sets GLYCINE 105I - Other Hair Preparations GLYCINE 207C - Foundations GLYCINE 107E - Lipstick GLYCINE 107I - Other Makeup Preparations GLYCINE 310A - Bath Soaps and Detergents GLYCINE 110B - Deodorants (underarm) GLYCINE 410E - Other Personal Cleanliness Products GLYCINE 411A - Aftershave Lotion GLYCINE 111G - Other Shaving Preparation Products GLYCINE 1



12A - Cleansing GLYCINE 1312C - Face and Neck (exc shave) GLYCINE 4812D - Body and Hand (exc shave) GLYCINE 2412F - Moisturizing GLYCINE 7312G - Night GLYCINE 712H - Paste Masks (mud packs) GLYCINE 812I - Skin Fresheners GLYCINE 412J - Other Skin Care Preps GLYCINE 2213B - Indoor Tanning Preparations GLYCINE 213C - Other Suntan Preparations GLYCINE 1 06A - Hair Dyes and Colors SODIUM GLYCINATE 15 03D - Eye Lotion HISTIDINE 205A - Hair Conditioner HISTIDINE 905F - Shampoos (non-coloring) HISTIDINE 405G - Tonics, Dressings, and Other Hair Grooming Aids HISTIDINE 1312C - Face and Neck (exc shave) HISTIDINE 612D - Body and Hand (exc shave) HISTIDINE 612F - Moisturizing HISTIDINE 712H - Paste Masks (mud packs) HISTIDINE 312I - Skin Fresheners HISTIDINE 112J - Other Skin Care Preps HISTIDINE 8 03D - Eye Lotion

HISTIDINE, L-, MONOHYDROCHLORIDE 1

12C - Face and Neck (exc shave) HISTIDINE, L-, MONOHYDROCHLORIDE 2

12F - Moisturizing HISTIDINE, L-, MONOHYDROCHLORIDE 4

12G - Night HISTIDINE, L-, MONOHYDROCHLORIDE 1

03D - Eye Lotion ISOLEUCINE, L- 105A - Hair Conditioner ISOLEUCINE, L- 105G - Tonics, Dressings, and Other Hair Grooming Aids ISOLEUCINE, L- 105I - Other Hair Preparations ISOLEUCINE, L- 212C - Face and Neck (exc shave) ISOLEUCINE, L- 612F - Moisturizing ISOLEUCINE, L- 512H - Paste Masks (mud packs) ISOLEUCINE, L- 412I - Skin Fresheners ISOLEUCINE, L- 212J - Other Skin Care Preps ISOLEUCINE, L- 6 05A - Hair Conditioner LEUCINE, L- 105F - Shampoos (non-coloring) LEUCINE, L- 205G - Tonics, Dressings, and Other Hair Grooming Aids LEUCINE, L- 105H - Wave Sets LEUCINE, L- 105I - Other Hair Preparations LEUCINE, L- 107C - Foundations LEUCINE, L- 112C - Face and Neck (exc shave) LEUCINE, L- 1112D - Body and Hand (exc shave) LEUCINE, L- 112G - Night LEUCINE, L- 2



12H - Paste Masks (mud packs) LEUCINE, L- 212I - Skin Fresheners LEUCINE, L- 212J - Other Skin Care Preps LEUCINE, L- 8 03C - Eye Shadow LYSINE 103D - Eye Lotion LYSINE 303G - Other Eye Makeup Preparations LYSINE 305A - Hair Conditioner LYSINE 205C - Hair Straighteners LYSINE 105G - Tonics, Dressings, and Other Hair Grooming Aids LYSINE 305I - Other Hair Preparations LYSINE 107C - Foundations LYSINE 107E - Lipstick LYSINE 107F - Makeup Bases LYSINE 107I - Other Makeup Preparations LYSINE 612A - Cleansing LYSINE 412C - Face and Neck (exc shave) LYSINE 3212D - Body and Hand (exc shave) LYSINE 812F - Moisturizing LYSINE 2812G - Night LYSINE 512H - Paste Masks (mud packs) LYSINE 212I - Skin Fresheners LYSINE 212J - Other Skin Care Preps LYSINE 9 03D - Eye Lotion LYSINE HCL, L- 105A - Hair Conditioner LYSINE HCL, L- 1205F - Shampoos (non-coloring) LYSINE HCL, L- 405G - Tonics, Dressings, and Other Hair Grooming Aids LYSINE HCL, L- 1305I - Other Hair Preparations LYSINE HCL, L- 407E - Lipstick LYSINE HCL, L- 212C - Face and Neck (exc shave) LYSINE HCL, L- 212F - Moisturizing LYSINE HCL, L- 412G - Night LYSINE HCL, L- 112I - Skin Fresheners LYSINE HCL, L- 112J - Other Skin Care Preps LYSINE HCL, L- 113B - Indoor Tanning Preparations LYSINE HCL, L- 1 02B - Bubble Baths METHIONINE 105A - Hair Conditioner METHIONINE 205F - Shampoos (non-coloring) METHIONINE 105G - Tonics, Dressings, and Other Hair Grooming Aids METHIONINE 105I - Other Hair Preparations METHIONINE 212C - Face and Neck (exc shave) METHIONINE 812H - Paste Masks (mud packs) METHIONINE 212I - Skin Fresheners METHIONINE 112J - Other Skin Care Preps METHIONINE 4 12J - Other Skin Care Preps METHIONINE, L- 2 03D - Eye Lotion PHENYLALANINE 103F - Mascara PHENYLALANINE 1



05A - Hair Conditioner PHENYLALANINE 305F - Shampoos (non-coloring) PHENYLALANINE 305G - Tonics, Dressings, and Other Hair Grooming Aids PHENYLALANINE 205I - Other Hair Preparations PHENYLALANINE 112C - Face and Neck (exc shave) PHENYLALANINE 812F - Moisturizing PHENYLALANINE 912H - Paste Masks (mud packs) PHENYLALANINE 312I - Skin Fresheners PHENYLALANINE 212J - Other Skin Care Preps PHENYLALANINE 3 01A - Baby Shampoos PROLINE 203D - Eye Lotion PROLINE 503G - Other Eye Makeup Preparations PROLINE 605A - Hair Conditioner PROLINE 705C - Hair Straighteners PROLINE 105F - Shampoos (non-coloring) PROLINE 205G - Tonics, Dressings, and Other Hair Grooming Aids PROLINE 405I - Other Hair Preparations PROLINE 206A - Hair Dyes and Colors PROLINE 2307C - Foundations PROLINE 207I - Other Makeup Preparations PROLINE 308B - Cuticle Softeners PROLINE 210E - Other Personal Cleanliness Products PROLINE 111A - Aftershave Lotion PROLINE 312A - Cleansing PROLINE 812C - Face and Neck (exc shave) PROLINE 2912D - Body and Hand (exc shave) PROLINE 2612F - Moisturizing PROLINE 7912G - Night PROLINE 1712H - Paste Masks (mud packs) PROLINE 912I - Skin Fresheners PROLINE 612J - Other Skin Care Preps PROLINE 2313A - Suntan Gels, Creams, and Liquids PROLINE 4 06A - Hair Dyes and Colors PROLINE, DL- 607E - Lipstick PROLINE, DL- 112F - Moisturizing PROLINE, DL- 112J - Other Skin Care Preps PROLINE, DL- 1 01B - Baby Lotions, Oils, Powders, and Creams SERINE 103D - Eye Lotion SERINE 703F - Mascara SERINE 703G - Other Eye Makeup Preparations SERINE 1205A - Hair Conditioner SERINE 205C - Hair Straighteners SERINE 105F - Shampoos (non-coloring) SERINE 105G - Tonics, Dressings, and Other Hair Grooming Aids SERINE 405I - Other Hair Preparations SERINE 107B - Face Powders SERINE 807C - Foundations SERINE 107I - Other Makeup Preparations SERINE 3



08B - Cuticle Softeners SERINE 110E - Other Personal Cleanliness Products SERINE 211A - Aftershave Lotion SERINE 212A - Cleansing SERINE 1512C - Face and Neck (exc shave) SERINE 5112D - Body and Hand (exc shave) SERINE 1212F - Moisturizing SERINE 7712G - Night SERINE 912H - Paste Masks (mud packs) SERINE 812I - Skin Fresheners SERINE 312J - Other Skin Care Preps SERINE 21 03D - Eye Lotion SERINE, L- 205A - Hair Conditioner SERINE, L- 205F - Shampoos (non-coloring) SERINE, L- 205H - Wave Sets SERINE, L- 108G - Other Manicuring Preparations SERINE, L- 112A - Cleansing SERINE, L- 512C - Face and Neck (exc shave) SERINE, L- 1012D - Body and Hand (exc shave) SERINE, L- 312F - Moisturizing SERINE, L- 1412G - Night SERINE, L- 112H - Paste Masks (mud packs) SERINE, L- 112I - Skin Fresheners SERINE, L- 212J - Other Skin Care Preps SERINE, L- 5 03D - Eye Lotion THREONINE 203G - Other Eye Makeup Preparations THREONINE 405A - Hair Conditioner THREONINE 205C - Hair Straighteners THREONINE 105F - Shampoos (non-coloring) THREONINE 105G - Tonics, Dressings, and Other Hair Grooming Aids THREONINE 305I - Other Hair Preparations THREONINE 106A - Hair Dyes and Colors THREONINE 2907C - Foundations THREONINE 107I - Other Makeup Preparations THREONINE 308B - Cuticle Softeners THREONINE 110E - Other Personal Cleanliness Products THREONINE 112A - Cleansing THREONINE 412C - Face and Neck (exc shave) THREONINE 2112D - Body and Hand (exc shave) THREONINE 1012F - Moisturizing THREONINE 3712G - Night THREONINE 412H - Paste Masks (mud packs) THREONINE 412I - Skin Fresheners THREONINE 112J - Other Skin Care Preps THREONINE 8 05A - Hair Conditioner THREONINE, L- 105F - Shampoos (non-coloring) THREONINE, L- 112C - Face and Neck (exc shave) THREONINE, L- 112F - Moisturizing THREONINE, L- 4



12I - Skin Fresheners THREONINE, L- 1 05A - Hair Conditioner TRYPTOPHAN 212C - Face and Neck (exc shave) TRYPTOPHAN 612J - Other Skin Care Preps TRYPTOPHAN 2 03D - Eye Lotion TYROSINE 103G - Other Eye Makeup Preparations TYROSINE 205A - Hair Conditioner TYROSINE 305F - Shampoos (non-coloring) TYROSINE 305G - Tonics, Dressings, and Other Hair Grooming Aids TYROSINE 205I - Other Hair Preparations TYROSINE 107C - Foundations TYROSINE 107I - Other Makeup Preparations TYROSINE 112C - Face and Neck (exc shave) TYROSINE 1612D - Body and Hand (exc shave) TYROSINE 212F - Moisturizing TYROSINE 412G - Night TYROSINE 212H - Paste Masks (mud packs) TYROSINE 112I - Skin Fresheners TYROSINE 112J - Other Skin Care Preps TYROSINE 513B - Indoor Tanning Preparations TYROSINE 813C - Other Suntan Preparations TYROSINE 1 03D - Eye Lotion VALINE 105A - Hair Conditioner VALINE 105F - Shampoos (non-coloring) VALINE 105H - Wave Sets VALINE 105I - Other Hair Preparations VALINE 107C - Foundations VALINE 112C - Face and Neck (exc shave) VALINE 812D - Body and Hand (exc shave) VALINE 112F - Moisturizing VALINE 512G - Night VALINE 212H - Paste Masks (mud packs) VALINE 312I - Skin Fresheners VALINE 112J - Other Skin Care Preps VALINE 5



Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)

FROM: Halyna Breslawec, Ph.D. Industry Liaison to the CIR Expert Panel

DATE: October 20, 2011

SUBJECT: Comments on the Scientific Literature Review on Amino Acids as Used in Cosmetics

Key Issues

Concentration of Use Information and Studies of Products Containing Amino AcidsThe concentration of use information for the amino acid ingredients will not be available for the

December 12-13, 2011 CIR Expert Panel meeting. The concentration of use survey needs to becompleted to identify studies, e.g., HRIPTs on products containing the highest useconcentrations of the amino acids.

As it is clear that the CIR Expert Panel cannot reach a conclusion without the concentration ofuse information, please delay the first review of this report until the concentration of use surveycan be completed (March 2012).

Reference Safety Reviews of the Amino AcidsAlthough it is not necessary to include all the safety data on the amino acids, the CIR report should

provide references to reviews of the safety of amino acids. For example, in the Introduction orthe beginning of the Toxicological Studies section it would be helpful to state that JECFAcompleted a review of the amino acids in 2006. This review summarizes numerous studies onthe amino acids including long-term exposure/carcinogenicity studies of Glycine, Histidine andTaurine. This review can be found on the I drive under Shared_Projects/CIRSubmissions/2011_05_2012 Priorities/p-JECFA amino acid review. Leaving this informationout, suggests that there are no studies of the amino acids, when many studies exist. For the CIRreview, it is not necessary to repeat the review of systemic oral studies when it has already beencompleted.



Provide Information About Phenylketonuria and Allergy to MSGIt is not until the Data Needs section that phenylketonuria and allergy to MSG is mentioned. If these

issues are a concern, please find reviews of these topics and explain why they are of concernearlier in the report.

Additional Comments

p.2 - What concentration of Arginine was used in the in vitro study in human keratinocytes (reference5).

p.3 - Please provide the doses or concentrations tested in the studies described under the Irritation,Sensitization and Phototoxicity headings (references 7, 8, 9, 10, 11, 12, 13, 14).

2



green amino acidswith the exception of glycine and methionine, the naturally occurring amino acids...

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