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Caprylohydroxamic Acid (CAS #7377-03-9) GreenScreen® for Safer Chemicals

(GreenScreen®) Assessment

Prepared for:

Environmental Defense Fund

February 1, 2016

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TABLE OF CONTENTS

GreenScreen® Executive Summary for Caprylohydroxamic Acid (CAS #7377-03-9) .......................... i

Chemical Name ...................................................................................................................................... 1

GreenScreen® Summary Rating for Caprylohydroxamic Acid ............................................................. 2

Transformation Products and Ratings .................................................................................................... 3

Introduction ............................................................................................................................................ 3

GreenScreen® List Translator Screening Results ................................................................................... 5

PhysicoChemical Properties of Caprylohydroxamic Acid .................................................................... 5

Group I Human Health Effects (Group I Human) ................................................................................. 6

Carcinogenicity (C) Score .................................................................................................................. 6

Mutagenicity/Genotoxicity (M) Score ............................................................................................... 6

Reproductive Toxicity (R) Score ........................................................................................................ 7

Developmental Toxicity incl. Developmental Neurotoxicity (D) Score ............................................ 8

Endocrine Activity (E) Score ............................................................................................................. 8

Group II and II* Human Health Effects (Group II and II* Human) ...................................................... 9

Acute Mammalian Toxicity (AT) Group II Score .............................................................................. 9

Systemic Toxicity/Organ Effects incl. Immunotoxicity (ST) ............................................................ 9

Group II Score (single dose) ........................................................................................................... 9

Group II* Score (repeated dose) ..................................................................................................... 9

Neurotoxicity (N) ............................................................................................................................. 10

Group II Score (single dose) ......................................................................................................... 10

Group II* Score (repeated dose) ................................................................................................... 10

Skin Sensitization (SnS) Group II* Score ........................................................................................ 11

Respiratory Sensitization (SnR) Group II* Score ............................................................................ 11

Skin Irritation/Corrosivity (IrS) Group II Score ............................................................................... 12

Eye Irritation/Corrosivity (IrE) Group II Score ................................................................................ 12

Ecotoxicity (Ecotox) ............................................................................................................................ 13

Acute Aquatic Toxicity (AA) Score ................................................................................................. 13

Chronic Aquatic Toxicity (CA) Score .............................................................................................. 14

Environmental Fate (Fate) ................................................................................................................... 14

Persistence (P) Score ........................................................................................................................ 14

Bioaccumulation (B) Score .............................................................................................................. 15

Physical Hazards (Physical) ................................................................................................................. 15

Reactivity (Rx) Score ....................................................................................................................... 15

Flammability (F) Score..................................................................................................................... 16

References ............................................................................................................................................ 17

APPENDIX A: Hazard Benchmark Acronyms ................................................................................... 20

APPENDIX B: Results of Automated GreenScreen® Score Calculation for Caprylohydroxamic

Acid (CAS #7377-03-9) ................................................................................................................ 21





APPENDIX C: Pharos Output for Caprylohydroxamic Acid (CAS #7377-03-9) ............................... 22

APPENDIX D: Toxtree Carcinogenicity Results for Caprylohydroxamic Acid

(CAS #7377-03-9) ......................................................................................................................... 23

APPENDIX E: Toxtree Genotoxicity Results for Caprylohydroxamic Acid (CAS #7377-03-9) ....... 24

APPENDIX F: Known Structural Alerts for Skin Sensitization .......................................................... 25

APPENDIX G: Toxtree Skin Sensitization Results for Caprylohydroxamic Acid

(CAS #7377-03-9) ......................................................................................................................... 26

APPENDIX H: ECOSAR Modeling Results for Caprylohydroxamic Acid (CAS #7377-03-9) ........ 27

APPENDIX I: EPISuite Modeling Results for Caprylohydroxamic Acid (CAS #7377-03-9) ........... 30

Licensed GreenScreen® Profilers ......................................................................................................... 32

TABLE OF FIGURES

Figure 1: GreenScreen® Hazard Ratings for Caprylohydroxamic Acid ................................................ 3

TABLE OF TABLES

Table 1: Physical and Chemical Properties of Caprylohydroxamic Acid (CAS #7377-03-9) .............. 5




and distribution are expressly prohibited. Page i

GreenScreen® Executive Summary for Caprylohydroxamic Acid (CAS #7377-03-9)

Caprylohydroxamic acid is a chemical that functions as a chelating agent in personal care products.

Caprylohydroxamic acid was assigned a GreenScreen Benchmark™ Score of U (“Benchmark

Unspecified-Due to Data Gaps”). Prior to the data gap analysis, it was assigned a preliminary score

of 3. This preliminary score is based on the following hazard score combinations:

Benchmark 3b

o High Ecotoxicity (acute aquatic-AA and chronic aquatic-CA)

Benchmark 3c

o Moderate Group II* Human Toxicity (repeated dose systemic toxicity-STr*)

o High Group II Human Toxicity (eye irritation-IrE)

Data gaps (DG) exist for carcinogenicity-C, reproductive toxicity-R, endocrine activity-E,

neurotoxicity-Ns and Nr*, and respiratory sensitization-SnR*. As outlined in CPA (2013) Section

12.2 (Step 8 – Conduct a Data Gap Analysis to assign a final Benchmark score), caprylohydroxamic

acid does not meet requirements for a GreenScreen® Benchmark Score of 3 due to the hazard data

gaps. In addition, it does not meet requirements for a GreenScreen® Benchmark Score of 2 due to

the hazard data gaps. Therefore it was assigned a GreenScreen® Benchmark Score of U. In a worst-

case scenario, if caprylohydroxamic acid were assigned a High score for the data gaps C, R or E, it

would be categorized as a Benchmark 1 Chemical.

GreenScreen® Benchmark Score for Relevant Route of Exposure:

As a standard approach for GreenScreen® evaluations, all exposure routes (oral, dermal and

inhalation) were evaluated together, so the GreenScreen® Benchmark Score of U (“Benchmark

Unspecified-Due to Data Gaps”) is applicable for all routes of exposure.

GreenScreen® Hazard Ratings for Caprylohydroxamic Acid

C M R D E AT SnS* SnR* IrS IrE AA CA P B Rx F

single repeated* single repeated*

DG L DG L DG L DG M DG DG L DG L H H H vL vL L L

Fate Physical

ST N

Group I Human Group II and II* Human Ecotox

Note: Hazard levels (Very High (vH), High (H), Moderate (M), Low (L), Very Low (vL)) in italics reflect estimated

(modeled) values, authoritative B lists, screening lists, weak analogues, and lower confidence. Hazard levels in

BOLD font are used with good quality data, authoritative A lists, or strong analogues. Group II Human Health

endpoints differ from Group II* Human Health endpoints in that they have four hazard scores (i.e., vH, H, M, and L)

instead of three (i.e., H, M, and L), and are based on single exposures instead of repeated exposures. Please see

Appendix A for a glossary of hazard acronyms.




and distribution are expressly prohibited. Page 1 of 32

GreenScreen® Assessment for Caprylohydroxamic Acid (CAS #7377-03-9)

Method Version: GreenScreen® Version 1.21

Assessment Type2: Certified

Chemical Name: Caprylohydroxamic acid

CAS Number: 7377-03-9

GreenScreen® Assessment Prepared By:

Quality Control Performed By:

Name: Jennifer Rutkiewicz, Ph.D. Name: Bingxuan Wang, Ph.D., D.A.B.T.,

Title: Toxicologist Title: Toxicologist

Organization: ToxServices LLC Organization: ToxServices LLC

Date: March 9, 2015 Date: May 13, 2015, Dec 4, 2015, Feb 1, 2016

Assessor Type: Licensed GreenScreen® Profiler Assessor Type: Licensed GreenScreen® Profiler

Name: Jennifer Rutkiewicz, Ph.D.

Title: Toxicologist

Organization: ToxServices LLC

Update Date: December 3, 2015

Assessor Type: Licensed GreenScreen® Profiler

Confirm application of the de minimus rule3: N/A (this assessment was conducted for the

theoretically pure substance). No hazardous impurities, additives or adjuvants are identified in

commercial preparations of caprylohydroxamic acid, which has a reported purity of >99% (NICNAS

2012).

Chemical Structure(s):

`

Also called: Octanohydroxamic acid; N-Hydroxyoctanamide; Octanoylhydroxamic acid; N-

Hydroxyoctanamide; Octanamide, N-hydroxy- (ChemIDplus 2015); N-hydroxy-caprylohydroxamic

acid; Capryloylhydroxamic acid; CHA (NICNAS 2012)

Chemical Structure(s) of Chemical Surrogates Used in the GreenScreen®:

In the absence of available data for the chemical of interest, ToxServices searched for a suitable

analog or class of analogs using guidance in the U.S. EPA’s procedure for identifying analogs (U.S.

EPA 2010), ECHA’s read across assessment framework (ECHA 2015a) and OECD’s guidance on

1 Use GreenScreen® Assessment Procedure (Guidance) V1.2 2 GreenScreen® reports are either “UNACCREDITED” (by unaccredited person), “AUTHORIZED” (by Authorized

GreenScreen® Practitioner), “CERTIFIED” (by Licensed GreenScreen® Profiler or equivalent) or “CERTIFIED WITH

VERIFICATION” (Certified or Authorized assessment that has passed GreenScreen® Verification Program) 3 Every chemical in a material or formulation should be assessed if it is:

1. intentionally added and/or

2. present at greater than or equal to 100 ppm





grouping of chemicals (OECD 2014). Resources used for the surrogate search included the

ChemIDplus structural similarity search, OECD Toolbox, U.S. EPA’s Analog Identification

Methodology (AIM), and U.S. EPA’s Chemical Assessment Clustering Engine (ChemACE).

Surrogates were considered to be appropriate if they resemble the target in terms of molecular

structure and size, contain a substructure of functional group that may play a critical toxicological

role, share similar physicochemical properties (e.g. water solubility, partition coefficient), or have

common or similar precursors, metabolites, or breakdown products. Where surrogates are used to fill

data gaps or as supporting evidence, the use of a surrogate is clearly indicated for that endpoint.

Data for acetohydroxamic acid were used to supplement the available genotoxicity dataset for

caprylohydroxamic acid. As both are hydroxamic acids, caprylohydroxamic acid and

acetohydroxamic acid have a shared functional group that is expected to be responsible for potential

toxicological effects. As acetohydroxamic acid is much smaller than caprylohydroxamic acid (C2 vs.

C8) and is expected to be better able to interact with DNA, it is likely to be a conservative surrogate

and is not likely to underestimate the genotoxic potential of caprylohydroxamic acid. ToxServices

did not use acetohydroxamic acid as a surrogate for other endpoints due to the lack of sufficient data

to fill data gaps and because the impact of the presence of the long alkyl chain length on

toxicological activity is uncertain. No suitable surrogates with data were identified in order to fill

remaining data gaps.

Acetohydroxamic acid (CAS# 546-88-3)

Identify Applications/Functional Uses: (NICNAS 2012)

1. Chelating agent in cosmetics and personal care products at concentrations up to 0.5%

GreenScreen® Summary Rating for Caprylohydroxamic Acid4: Caprylohydroxamic acid was

assigned a GreenScreen Benchmark™ Score of U (“Benchmark Unspecified-Due to Data Gaps”)

(CPA 2014). Prior to the data gap analysis, it was assigned a preliminary score of 3. This

preliminary score is based on the following hazard score combinations:

Benchmark 3b

o High Ecotoxicity (acute aquatic-AA and chronic aquatic-CA)

Benchmark 3c

o Moderate Group II* Human Toxicity (repeated dose systemic toxicity-STr*)

o High Group II Human Toxicity (eye irritation-IrE)

Data gaps (DG) exist for carcinogenicity-C, reproductive toxicity-R, endocrine activity-E,

neurotoxicity-Ns and Nr*, and respiratory sensitization-SnR*. As outlined in CPA (2013) Section

12.2 (Step 8 – Conduct a Data Gap Analysis to assign a final Benchmark score), caprylohydroxamic

acid does not meet requirements for a GreenScreen® Benchmark Score of 3 due to the hazard data

gaps. In addition, it does not meet requirements for a GreenScreen® Benchmark Score of 2 due to

4 For inorganic chemicals with low human and ecotoxicity across all hazard endpoints and low bioaccumulation potential,

persistence alone will not be deemed problematic. Inorganic chemicals that are only persistent will be evaluated under the

criteria for Benchmark 4.





the hazard data gaps. Therefore it was assigned a GreenScreen® Benchmark Score of U. In a worst-

case scenario, if caprylohydroxamic acid were assigned a High score for the data gaps C, R or E, it

would be categorized as a Benchmark 1 Chemical.

Figure 1: GreenScreen® Hazard Ratings for Caprylohydroxamic Acid

C M R D E AT SnS* SnR* IrS IrE AA CA P B Rx F

single repeated* single repeated*

DG L DG L DG L DG M DG DG L DG L H H H vL vL L L

Fate Physical

ST N

Group I Human Group II and II* Human Ecotox

Note: Hazard levels (Very High (vH), High (H), Moderate (M), Low (L), Very Low (vL)) in italics reflect estimated

(modeled) values, authoritative B lists, screening lists, weak analogues, and lower confidence. Hazard levels in

BOLD font are used with good quality data, authoritative A lists, or strong analogues. Group II Human Health

endpoints differ from Group II* Human Health endpoints in that they have four hazard scores (i.e., vH, H, M, and L)

instead of three (i.e., H, M, and L), and are based on single exposures instead of repeated exposures. Please see

Appendix A for a glossary of hazard acronyms.

Transformation Products and Ratings:

Identify feasible and relevant fate and transformation products (i.e., dissociation products,

transformation products, valence states) and/or moieties of concern5. Caprylohydroxamic acid may

hydrolyze under alkaline or acidic conditions to form octanoic acid and hydroxylamine (NICNAS

2012). Because these conditions are not environmentally relevant, the hydrolysis products are not

feasible. Biodegradation products have not been measured, but because caprylohydroxamic acid is

readily biodegradable (see details in the section for persistence below), none of its biodegradation

products are expected to be relevant because they will be transient as the substance is fully

mineralized (CPA 2013).

Introduction

Caprylohydroxamic acid is used as a chelating agent in personal care products (NICNAS 2012).

The safety of Caprylohydroxamic acid in cosmetics has not been evaluated by the CIR Expert Panel.

Caprylhydroxamic acid is not listed as a prohibited ingredient in Annex II of EC Regulation No.

1223/2009 (EU 2009).

ToxServices assessed caprylohydroxamic acid against GreenScreen® Version 1.2 (CPA 2013)

following procedures outlined in ToxServices’ SOP 1.37 (GreenScreen® Hazard Assessment)

(ToxServices 2013).

Preservative Spectrum of Effect:

As summarized below, caprylohydroxamic acid displays a good preservative spectrum of effect

against gram-positive and gram-negative bacteria, as well as yeast and molds. Caprylohydroxamic

acid is able to inhibit growth of microorganism via various mechanisms. Antimicrobial activity of

acyclic hydroxamic acids such as caprylohydroxamic acid has been associated with the specific

inhibition of microbial urease. Urease inhibition may be attributed to interaction of hydroxamic

acids with the metal ion at the active site of the enzyme (Bravo and Lazo 1993). Although the

5 A moiety is a discrete chemical entity that is a constituent part or component of a substance. A moiety of concern is often the

parent substance itself for organic compounds. For inorganic compounds, the moiety of concern is typically a dissociated

component of the substance or a transformation product.





hydroxamic acid function is necessary for urease inhibition, alkyl group and its length also play a

role in preservative effectiveness (Hase et al. 1971). Additionally, hydroxamic acids have strong

chelating and H-bond forming capabilities. This allows them to act as potent inhibitors of any

enzyme that contains metal ions and residues able to act as hydrogen bond donors or acceptors

(Gupta and Sharma 2013).

Studies on the antimicrobial activity of hydroxamic acids are detailed below.

Caprylohydroxamic Acid’s Preservative Spectrum of Effect

Microorganism Spectrum of Effect Reference

Gram-positive bacteria Good Hase et al. 1971 Ammendola

et al. 2009 Bravo and Lazo

1993

Gram-negative bacteria Good Hase and Kobashi 1966 Hase

et al. 1971 Ammendola et al.

2009 Bravo and Lazo 1993

Yeasts/Molds Good Hase et al. 1971 Ammendola

et al. 2009 Bravo and Lazo

1993

Hase and Kobashi (1966) investigated caprylohydroxamic acids inhibitory effect on the urease

extracted from Proteus vulgaris and that on the ureolytic activity of it intact cell. Urease activity was

inhibited by caprylohydroxamic acid with an apparent I50 value of 5.6 µmoles/vessel (stated by

authors as 8.0 x 10-7 M in a final concentration). The inhibition was progressive with time and

affected by reaction temperature. Caprylohydroxamic acid was also found to strongly inhibit the

ureolytic activity of the cell suspension, at one order of magnitude higher than that for the cell free

system. Caprylohydroxamic acid had activity over a broad range of pH values (8.0-9.5), however,

outside of this range activity decreased sharply. Additionally caprylohydroxamic acid was the most

potent inhibitor compared to acetohydroxamic acid and benzohydroxamic acid, suggesting increase

in carbon number leads to optimal inhibition up to C8, followed by a decrease in inhibitory action

(Hase and Kobashi 1966).

The antibacterial and antifungal activity of hydroxamic acids were evaluated against Escherichia coli

O-55, Shigella flexneri 2a, Shigella flexneri EW_10, Salmonella typhi S-57, and Staphylococcus

aureus 209 for antibacterial activity, and Candida albicans, Saccharomyces sake, Microsporium

gypseum, Aspergillus oryzae, and Trichophyton interdigitale for antifungal activity. Against all the

test-bacteria, the hydroxamic acids were almost ineffective up to concentrations of 320 µg/mL, the

highest dose tested. Caprylohydroxamic acid, specifically, had the following MICs against fungi:

320 µg/mL for C. albicans, 100 µg/mL for S. sake, 32 µg/mL for M. gypseum, 320 µg/mL for A.

oryzae, and 32 µg/mL for T. interdigitale (Hase et al. 1971).

A study on structurally similar 10-undecanhydroxamic acid demonstrate the strong antimicrobial

activity of hydroxamic acids relies on their ability to interfere with iron homeostasis. The effect of

10-undecanhydroxamic acid was tested on Escherichia coli, Salmonella typhimurium, Enterococcus

faecalis, Candida albicans, Aspergillus niger and Chaetomium globosum. 10-Undecanhydroxamic

acid caused dose dependent growth inhibition in all strains, susceptibility was dependent on the

microorganism, with C. albicans displaying the highest susceptibility and E. faecalis showing the

highest resistance. Growth of the microorganisms were inhibited at the following concentrations: 0.2





mM for E. coli, 0.4 mM for S. typhimurium, 1.5 mM for E. faecalis, 0.08 mM for C. albicans, and

0.5 mM for both A. niger and C. globosum. Analysis of intracellular concentration of protein

involved in iron transport in Salmonella enterica serovar typhimurium suggests that its antimicrobial

effect actually relies on the ability to chelate iron ions, providing an efficient mechanism to interfere

with microbial growth (Ammendola et al. 2009).

Bravo and Lazo (1993) investigated antibacterial and antifungal activity of hydroxamic acid

aglucones and their derivatives. Hydroxamic acid aglucones and their derivatives are derived from

2,4-dihydroxy-1,4-benzoxazin-3-one, and are therefore cyclic with two highly reactive centers: (1)

the hydroxamic acid function and (2) the hemiacetal function at C2. However, the authors state the

opening of the hemiacetal at C2 to form acyclic hydroxamic acids is not necessary for activity, and

suggests that antimicrobial activity may be related to the hydroxamic acid function. All hydroxamic

acid aglucones and derivatives tested showed moderate activity against the test microorganisms, with

minimum inhibitory concentrations (MIC) of 166-1,500 µg/mL in Staphylococcus aureus, 500-1,500

µg/mL in Escherichia coli, and 333-1,500 µg/mL in Candida albicans. The range of MICs identified

were in the range of non-cyclic hydroxamic acids, supporting the hypothesis that the hydroxamic

acid function is responsible for antimicrobial activity. Additionally, the results suggest the rigidity of

the hydroxamic acid function in the heterocyclic ring does not significantly affect activity (Bravo and

Lazo 1993).

GreenScreen® List Translator Screening Results

The GreenScreen® List Translator identifies specific authoritative or screening lists that should be

searched to identify GreenScreen® benchmark 1 chemicals (CPA 2012a). Pharos (Pharos 2015) is an

online list-searching tool that is used to screen chemicals against the List Translator electronically. It

checks all of the lists in the List Translator with the exception of the U.S. Department of

Transportation (U.S. DOT) lists (U.S. DOT 2008a,b) and these should be checked separately in

conjunction with running the Pharos query. The output indicates benchmark or possible benchmark

scores for each human health and environmental endpoint. The output for caprylohydroxamic acid

can be found in Appendix C and a summary of the results can be found below:

Caprylohydroxamic acid is not present in the Pharos database.

Physicochemical Properties of Caprylohydroxamic Acid

Caprylohydroxamic acid is a solid at room temperature. Its estimated vapor pressure of 5.6 x 10-6

mmHg indicates that it is not likely to form a gas. It is highly soluble in water (1.55 g/L) and its

estimated log Kow of 1.66 indicates that it is hydrophilic and has a low potential for bioaccumulation.

Table 1: Physical and Chemical Properties of Caprylohydroxamic Acid (CAS #7377-03-9)

Property Value Reference

Molecular formula C8-H17-N-O2 ChemIDplus 2015

SMILES Notation C(CC(NO)=O)CCCCC ChemIDplus 2015

Molecular weight 159.227 ChemIDplus 2015

Physical state Solid NICNAS 2012

Appearance White to tan crystalline solid NICNAS 2012

Melting point 78.75°C

81°C

ChemIDplus 2015

NICNAS 2012

Vapor pressure 3.33 × 10-7 kPa (5.6 x 10-6 mmHg) at 25°C (est.) NICNAS 2012

Water solubility 1.55 g/L at 23°C NICNAS 2012

Dissociation constant pKa ~ 9 (est.) NICNAS 2012





Table 1: Physical and Chemical Properties of Caprylohydroxamic Acid (CAS #7377-03-9)

Property Value Reference

Density/specific gravity 341.3 kg/m3 at 25°C NICNAS 2012

Partition coefficient log Kow = 1.66 (est.) ChemIDplus 2015

NICNAS 2012

Hazard Classification Summary Section6:

Group I Human Health Effects (Group I Human)

Carcinogenicity (C) Score (H, M, or L): DG

Caprylohydroxamic acid was assigned a score of Data Gap for carcinogenicity based on a lack of

adequate data for this endpoint (CPA 2012b).

Authoritative and Screening Lists

o Authoritative: Not present on any authoritative lists

o Screening: Not present on any screening lists

Toxtree 2014

o Toxtree did not identify structural alerts for genotoxic or nongenotoxic carcinogenicity

(Appendix D).

Based on the weight of evidence, a Data Gap was assigned. Modeling was attempted with

OncoLogic, but the compound does not fall into any of the chemical classes included in the

program. Modeling was also attempted with VEGA (2012), but the compound is out of the

model applicability domain. A lack of structural alerts was not considered to be sufficient for a

Low score, and therefore a Data Gap was assigned in the absence of data for caprylohydroxamic

acid or a suitable surrogate.

Mutagenicity/Genotoxicity (M) Score (H, M, or L): L

Caprylohydroxamic acid was assigned a score of Low for mutagenicity/genotoxicity based on

negative results in bacterial mutagenicity assays for caprylohydroxamic acid and negative results in

an in vitro chromosome aberration test for the surrogate hydroxamic acid, acetohydroxamic acid.

GreenScreen® criteria classify chemicals as a Low hazard for mutagenicity/genotoxicity when

adequate data are available and are negative, and the chemical is not present on authoritative or

screening lists (CPA 2012b). Confidence in the score is reduced due to the lack of experimental

details and the lack of mutation data in mammalian cells.




NICNAS 2012

o Caprylohydroxamic acid (purity not reported) was negative in a bacterial mutagenicity

assay that was conducted according to U.S. FDA 21 CFR Part 48 Guidelines (GLP status

not reported) in S. typhimurium strains TA1535, TA98, TA100, TA102, and TA97a.

Cells were tested using plate incorporation procedures at concentrations of 0, 16, 50, 160,

500, 1,600, or 5,000 µg/plate with and without metabolic activation (rat liver S9).

Cytotoxicity was seen at doses > 500 µg/plate. There was no dose-related increase in

6 When original study reports were not available, ToxServices summarized study methodology, results, and study author

conclusions as reported in secondary sources. In cases where conclusions were not reported or where ToxServices interpreted the

results differently based on the information presented in the study summary, ToxServices’ conclusions are clearly stated.





mutations and there were no increases in mutations (> 2-fold) at any dose tested.

NICNAS concluded that the substance is not mutagenic in this assay.

o Caprylohydroxamic acid (purity not reported) was weakly positive in a bacterial

mutagenicity test (similar to OECD Guideline 471) in S. typhimurium strains TA1538,

TA1535, TA1537, TA98, and TA100 and E. coli WP2 hcr trp. Cells were tested using

plate incorporation procedures at doses of 0 – 2,000 µg/plate. There was a very weak but

clear dose-dependent increase in mutagenicity for E. coli WP2 hcr trp but not for any of

the S. typhimurium strains. NICNAS reports that the methodology and results were

reported only briefly for this study.

o Caprylohydroxamic acid (purity not reported) was negative in a Bacillus subtilis rec

assay test that was conducted in B. subtilis H17 Rec+ and M45 Rec-. Cultures were

streaked on an agar plate and a paper disk soaked with 0.02 mL of a solution of the test

substance (concentration not reported) was placed on the streaks, and the growth

inhibition zone was measured after 1-2 days. No additional study details were provided,

and NICNAS reports that methodology and results were reported only briefly.

Caprylohydroxamic acid was negative in this assay, and NICNAS concluded that it is not

a DNA-damaging agent under the conditions of the assay.

Toxtree 2014

o Toxtree identified one positive structural alert for the in vivo micronucleus assay (H-

acceptor-path3-H-acceptor) (Appendix E).

Surrogate: Acetohydroxamic acid (CAS# 546-88-3)

Gene-Tox 1991

o Acetohydroxamic acid was negative in an in vitro chromosome aberration assay in

human lymphocytes. No additional details were provided.

Based on the weight of evidence, a score of Low was assigned. Overall, bacterial mutagenicity

assays indicate that caprylohydroxamic acid is not likely to produce gene mutations. In its

review of caprylohydroxamic acid, NICNAS reported that the available data do not raise a strong

suspicion for genotoxicity, but due to the limited availability of data and lack of a study on

clastogenic effects, the potential for genotoxicity cannot be ruled out. Toxtree identified a

structural alert for the in vivo micronucleus assay. However, ToxServices identified negative in

vitro chromosome aberration data for a structurally similar hydroxamic acid, acetohydroxamic

acid, in the Gene-Tox database. Although acetohydroxamic acid is much smaller than

caprylohydroxamic acid, it contains the same functional group associated with the structural alert

and the alkyl chain is not expected to contribute to the genotoxicity potential of

caprylohydroxamic acid. Therefore ToxServices considered it to be a suitable surrogate to

determine the clastogenicity potential for caprylohydroxamic acid based on the hydroxamic acid

moiety, and a score of Low was assigned. Confidence in the score is reduced due to the lack of

experimental details for the chromosome aberration study and the lack of mutation data in

mammalian cells.

Reproductive Toxicity (R) Score (H, M, or L): DG

Caprylohydroxamic acid was assigned a score of Data Gap for reproductive toxicity based on a lack

of data for this endpoint.




No data were identified.





Developmental Toxicity incl. Developmental Neurotoxicity (D) Score (H, M, or L): L

Caprylohydroxamic acid was assigned a score of Low for developmental toxicity based on a lack of

specific developmental toxicity even at maternally toxic dose in a rat study and the conclusion drawn

by NICNAS. GreenScreen® criteria classify chemicals as a Low hazard for developmental toxicity

when adequate data are available and negative, there are no structural alerts, and they are not

classified under GHS (CPA 2012b). Confidence level was reduced as limited details were provided

in the only study available.




NICNAS 2012

o Caprylohydroxamic acid was tested in a prenatal developmental toxicity test in 18 female

Wistar rats that were administered 0, 50, 250, or 500 mg/kg/day of a 10% solution of

caprylohydroxamic acid (0, 5, 25, or 50 mg/kg/day active ingredient7) in a 5% gum

arabic solution via gavage on gestation days 9-14. Twelve dams were sacrificed on

gestation day 20 and the remaining were allowed to deliver to monitor neonatal viability

and postnatal development. Body weight gain and food intake were decreased in dams at

the mid and high doses. Statistical significance was not specified, but body weight gain

and food intake were reported by NICNAS to be “a little lower than those of the control”.

Fetal body weights and ossification were also decreased at these doses. Magnitude of

effects and statistical significance were not specified. There were no skeletal

abnormalities or functional differences in offspring. No additional details were provided.

NICNAS reported that growth retardation was secondary to decreased maternal body

weight and food consumption, and concluded that the 10% solution of

caprylohydroxamic acid was not a developmental toxicant.

Based on the weight of evidence, a score of Low was assigned. Treatment with up to 50

mg/kg/day caprylohydroxamic acid produced slight maternal toxicity, seen as reduced body

weight gain, and effects on fetal weight and ossification that NICNAS attributed to maternal

toxicity. Based on the lack of specific developmental toxicity at maternally toxic dose,

ToxServices assigned a score for Low for this endpoint. The confidence in this score is reduced

because limited study details were available in the English translation of the summary, and the

original study was in Japanese language and therefore could not be reviewed by ToxServices.

Endocrine Activity (E) Score (H, M, or L): DG

Caprylohydroxamic acid was assigned a score of Data Gap for endocrine activity based on a lack of

data for this endpoint.




Not listed as a potential endocrine disruptor on the EU Priority List of Suspected Endocrine

Disruptors.

Not listed as a potential endocrine disruptor on the OSPAR List of Chemicals of Possible

Concern.


7 500 mg/kg/day * 10% = 50 mg/kg/day





Group II and II* Human Health Effects (Group II and II* Human)

Note: Group II and Group II* endpoints are distinguished in the v 1.2 Benchmark system. For

Systemic Toxicity and Neurotoxicity, Group II and II* are considered sub-endpoints and test data

for single or repeated exposures may be used. If data exist for single OR repeated exposures, then

the endpoint is not considered a data gap. If data are available for both single and repeated

exposures, then the more conservative value is used.

Acute Mammalian Toxicity (AT) Group II Score (vH, H, M, or L): L

Caprylohydroxamic acid was assigned a score of Low for acute toxicity based on oral LD50 values of

10,700 mg/kg in rats and 8,820 mg/kg in mice. GreenScreen® criteria classify chemicals as a Low

hazard for acute toxicity when oral LD50 values are greater than 2,000 mg/kg (CPA 2012b).

Confidence in this score is reduced due to the lack of experimental details for the acute toxicity

studies.




RTECS 1996

o Oral: LD50 (rat, sex and strain not specified) = 10,700 mg/kg

o Oral: LD50 (mouse, sex and strain not specified) = 8,820 mg/kg

Systemic Toxicity/Organ Effects incl. Immunotoxicity (ST)

Group II Score (single dose) (vH, H, M, or L): DG

Caprylohydroxamic acid was assigned a score of Data Gap for systemic toxicity (single dose) based

on a lack of data for this endpoint.





Group II* Score (repeated dose) (H, M, or L): M

Caprylohydroxamic acid was assigned a score of Moderate for systemic toxicity (repeated dose)

based on a NOAEL of 50 mg/kg/day in a 91-day oral toxicity study in rats. GreenScreen® criteria

classify chemicals as a Moderate hazard for systemic toxicity (repeated dose) when systemic toxicity

is seen between the guidance values of 10 and 100 mg/kg/day in an oral study (CPA 2012b).




NICNAS 2012

o In a subchronic oral toxicity study in male and female Wistar rats, animals (10/sex/dose)

were administered 10% solution of caprylohydroxamic acid (purity not reported) in

lactose via gavage at doses of 0, 100, 500, or 2,500 mg/kg/day (0, 10, 50, or 250

mg/kg/day caprylohydroxamic acid) 7 days/week for 91 days. Animals were evaluated

for clinical signs of toxicity, organ weight, clinical chemistry, hematology, and urinalysis.

In males at the high dose, there was a significant decrease in alanine amino transferase,

glucose, and potassium levels. There was a significant increase in leukocyte count, and

significant decreases in erythrocyte, hematocrit, and hemoglobin counts at the high dose

in both sexes. The spleen weights were significantly increased at the high dose, and mild

atrophy of the epithelial cells of the glomeruli in the kidney and deposits of blood





pigment in the spleen were seen. NICNAS identified a NOAEL and LOAEL of 500 and

2,500 mg/kg/day of the 10% solution (50 and 250 mg/kg/day caprylohydroxamic acid)

based on effects on blood count and spleen and concluded that the NOAEL for

caprylohydroxamic acid is expected to be 50 mg/kg/day. NICNAS noted that effects

were consistent with those expected to occur with hydroxylamine derivatives.

o In a previously-described developmental toxicity study, a 10% solution of

caprylohydroxamic acid was tested in in 18 female Wistar rats that were administered 0,

50, 250, or 500 mg/kg/day of a 10% solution of caprylohydroxamic acid (0, 5, 25, or 50

mg/kg/day active ingredient8, purity not reported) in a 5% gum arabic solution via gavage

on gestation days 9-14. Twelve dams were sacrificed on gestation day 20 and the

remaining were allowed to deliver to monitor neonatal viability and postnatal

development. Body weight gain and food intake were decreased in dams at the mid and

high doses. Statistical significance was not specified, but was reported by NICNAS to be

“a little lower than those of the control”. ToxServices did not identify the

NOAEL/LOAEL for maternal toxicity for this study due to lack of study details on the

extent and statistical significance of the maternal effects observed (decreased body

weight gain and food intake).

Based on the weight of evidence, a conservative score of Moderate was assigned. Although no

effects were seen below the guidance value of 100 mg/kg/day, due to dose spacing it is not

possible to determine conclusively if effects seen at the LOAEL of 250 mg/kg/day would have

been seen between the NOAEL of 50 mg/kg/day and the guidance value. Effects were seen in

both sexes and included hematological, organ weight, and histopathological changes. The

magnitude of effects was not reported. As noted by NICNAS, effects are consistent with

hematological effects of hydroxylamine derivatives, which can oxidize hemoglobin to

methemoglobin. Slightly reduced food consumption and weight gain were observed in dams

exposed during gestation at 25 and 50 mg/kg/day, indicating that the LOAEL for systemic effects

may be lower than the threshold of 100 mg/kg/day. ToxServices assigned a score of Moderate

under the conservative assumption that effects may be seen between 50 and 100 mg/kg/day, but

confidence in this score is reduced because the true NOAEL and LOAEL cannot be identified

based on dose spacing in this study.

Neurotoxicity (N)

Group II Score (single dose) (vH, H, M, or L): DG

Caprylohydroxamic acid was assigned a score of Data Gap for neurotoxicity (single dose) based on a

lack of data for this endpoint.





Group II* Score (repeated dose) (H, M, or L): DG

Caprylohydroxamic acid was assigned a score of Data Gap for neurotoxicity (repeated dose) based

on a lack of data for this endpoint.




8 500 mg/kg/day * 10% = 50 mg/kg/day






Skin Sensitization (SnS) Group II* Score (H, M, or L): L

Caprylohydroxamic acid was assigned a score of Low for skin sensitization based on negative results

in an HRIPT test of neat caprylohydroxamic acid with support from a lack of structural and reactivity

alerts. GreenScreen® criteria classify chemicals as a Low hazard for skin sensitization when

adequate data are available and are negative, there are no structural alerts, and the chemical is not

present on authoritative or screening lists (CPA 2012b). Confidence in the score is reduced because

the HRIPT may not detect a very low frequency of responses due to the sample size and due to the

reliance on modeling for support.




NICNAS 2012

o The sensitization potential of caprylohydroxamic acid was tested in a human repeated

insult patch test (HRIPT) in 56 volunteers. Individuals were dermally administered neat

caprylohydroxamic acid (purity and volume not reported) directly to the upper back

(under semiocclusive patches) for 24 hours three times/week for a total of 9 applications.

After a 14 day rest period, challenge patches were applied to previously untreated sites on

the back for 24 hours. Four individuals did not complete the study for reasons unrelated

to treatment with the test substance, and the 52 remaining volunteers were evaluated for

sensitization responses at 24, 48, and 72 hours after application of the challenge patch.

There was no evidence of sensitization.

Payne and Walsh 1994

o Caprylohydroxamic acid is not predicted to be a skin sensitizer based on the absence of

structural alerts identified by Payne and Walsh. See Appendix F for complete list of

structural alerts.

Toxtree 2014

o Caprylohydroxamic acid is predicted to not be a skin sensitizer using the Toxtree model

using decision tree methodology. This chemical has not been identified as a substrate for

any of the 5 electrophilic mechanisms known to produce a skin sensitization reaction

(Appendix G).

Based on the weight of evidence, a score of Low was assigned. No animal data are available, but

caprylohydroxamic acid was negative in a well conducted and reported HRIPT in human

volunteers when tested neat. Because the sample size of 56 individuals indicates that the test

may not be able to detect a low frequency of occurrence, ToxServices performed supportive

modeling and examined the structure for alerts. A lack of structural alerts and skin sensitization

reactivity domain alerts by Toxtree also supports a low potential for sensitization. Confidence in

this score is reduced due to the relatively small sample size for the HRIPT.

Respiratory Sensitization (SnR) Group II* Score (H, M, or L): DG

Caprylohydroxamic acid was assigned a score of Data Gap for respiratory sensitization based on a

lack of data for this endpoint.









Skin Irritation/Corrosivity (IrS) Group II Score (vH, H, M, or L): L

Caprylohydroxamic acid was assigned a score of Low for skin irritation/corrosivity based on a lack

of dermal irritation in an HRIPT test in human volunteers. GreenScreen® criteria classify chemicals

as a Low hazard for skin irritation/corrosivity when adequate data are available and are negative for

irritation, and the chemical is not present on authoritative or screening lists (CPA 2012b).

Confidence in the score is high because it is based on experimental data in humans.




NICNAS 2012

o In the HRIPT described above for skin sensitization, 56 individuals were dermally

administered neat caprylohydroxamic acid (purity and volume not reported) directly to

the upper back (under semiocclusive patches) for 24 hours three times/week for a total of

9 applications. After a 14 day rest period, challenge patches were applied to previously

untreated sites on the back for 24 hours. Four individuals did not complete the study for

reasons unrelated to treatment with the test substance, and the 52 remaining volunteers

were evaluated for irritation responses at 24, 48, and 72 hours after application of the

challenge patch. Caprylohydroxamic was not dermally irritating.

Based on the weight of evidence, a score of Low was assigned. No guideline studies in animals

are available, but caprylohydroxamic acid was not dermally irritating in human volunteers when

administered repeatedly under semiocclusion for 24 hours/application. As the guideline studies

upon which GHS classifications are determined involve only a single 4 hour exposure, the lack of

irritation in humans following repeated 24 hour exposures indicates a low potential for irritation.

Confidence in the score is high because it is based on experimental data in humans.

Eye Irritation/Corrosivity (IrE) Group II Score (vH, H, M, or L): H

Caprylohydroxamic acid was assigned a score of High for eye irritation/corrosivity based on

evidence of potential eye irritation in an in vitro BCOP test. GreenScreen® criteria classify

chemicals as a High hazard for eye irritation/corrosivity when available data indicate that GHS

Category 2A classification is warranted (CPA 2012b). Confidence in this score is reduced due to the

lack of in vivo ocular irritation studies and because the in vitro study results do not correspond

directly to GHS classification criteria.




NICNAS 2012

o Caprylohydroxamic acid was evaluated in an in vitro bovine corneal opacity and

permeability test (BCOP) designed to identify corrosive and severely irritating chemicals.

Bovine corneas were exposed to a 0.75 mL of a 20% solution of caprylohydroxamic acid

(purity not reported) for 4 hours followed by a 180 minute incubation period. Opacity

measurements and fluorescein staining were performed on each corneal. Permeability

was evaluated through measurements of the OD490 using a spectrophotometer, and

values were compared to those of the negative control (MEM). NICNAS notes that

concurrent positive controls were not included in the experiments. Caprylohydroxamic

acid demonstrated some evidence of eye irritation but was not considered to be a severe

ocular irritant based on test results, as the in vitro score of 12.12 did not reach the

threshold of > 55.1 to be classified as corrosive or a severe irritant. No additional details

were provided. Based on this study, NICNAS concluded that caprylohydroxamic acid is





not expected to be a severe ocular irritant but that it cannot be considered to be a non-

irritant.

o A 100% solution of caprylohydroxamic acid (>99% purity) was tested in an in vitro

ocular irritation test using the EpiOcular Tissue Model (MTT viability assay). Tissue

was treated for 16, 64, or 256 minutes with undiluted test substance and viability was

measured using MTT uptake and reduction and was presented as a percentage of the

negative (water) control viability. An ET50 value, which corresponds to the time at which

viability was 50% that of the negative control, was 130.8 minutes. The positive control

(Triton X-100) had an ET50 of 31.5 minutes. NICNAS concluded that based on results of

this assay, caprylohydroxamic acid is predicted to be non-irritating to the eye.

ECHA 2015b

o Caprylohydroxamic acid is self-classified to H319 (causes serious eye irritation) by 4/4

notifiers to ECHA.

Based on the weight of evidence, a conservative score of High was assigned. There are no

experimental eye irritation data in animals for caprylohydroxamic acid. The EpiOcular irritation

test predicted that it is not an irritant, while the BCOP showed some evidence of eye irritation but

did not indicate that it is likely to be corrosive or a severe irritant. Neither of these in vitro tests

is designed to allow for GHS Category 2A or 2B classification, but the results indicate that

caprylohydroxamic acid is not a Category 1 (corrosive) eye irritant. However, the BCOP results

do indicate that the potential for eye irritation cannot be excluded. Therefore ToxServices

conservatively classified this chemical to GHS Category 2. Because the reversibility and severity

of effects with relation to GHS classification criteria cannot be determined based on the results of

the in vitro tests, ToxServices assigned the more conservative score of High (GHS Category 2A).

This is consistent with the self-classification to H319 in the ECHA C&L database. Confidence in

the score is reduced because there are no in vivo studies available and because the in vitro study

results do not correspond directly to GHS classification criteria.

Ecotoxicity (Ecotox)

Acute Aquatic Toxicity (AA) Score (vH, H, M, or L): H

Caprylohydroxamic acid was assigned a score of High for acute aquatic toxicity based on an

extrapolated LC50 of 2.6 mg/L in fish, an experimental EC50 of 10 mg/L in shrimp, and a modeled

EC50 of 2.432 mg/L in algae. GreenScreen® criteria classify chemicals as a High hazard for acute

aquatic toxicity when acute toxicity values are between 1 and 10 mg/L (CPA 2012b). Confidence is

reduced due to the use of extrapolated or modeled data and poorly reported studies in non-standard

species.




NICNAS 2012

o 96-hour EC50 (Salmo salar, salmon) = 2.6 mg/L (extrapolated from 24-hour values using

regression equation)

ECOTOX 2015

o 48-hour EC50 (Artemia salina, brine shrimp) = 10 mg/L

U.S. EPA 2012a

o Caprylohydroxamic acid is designated to the amides and neutral organics ECOSAR

chemical classes. The most conservative predicted LC/EC50 values are 83.21 mg/L in





fish (96-hr), 107.134 mg/L in daphnia (48-hr), and 2.432 mg/L in green algae (96-hr)

(Appendix H).

Based on the weight of evidence, a score of High was assigned. Very limited experimental data

are available. NICNAS extrapolated 96-hour LC50 of 2.6 mg/L in salmon based on an

experimental 24-hour LC50. This value corresponds to a score of High. An experimental EC50 of

10 mg/L in brine shrimp also corresponds to a High, as does a modeled EC50 of 2.432 mg/L in

algae. Therefore the score of High was based on LC/EC50 values in all three trophic levels, but

confidence is reduced due to the use of extrapolated or modeled data and poorly reported studies

in non-standard species.

Chronic Aquatic Toxicity (CA) Score (vH, H, M, or L): H

Caprylohydroxamic acid was assigned a score of High for chronic aquatic toxicity based on a

modeled ChV of 0.1 mg/L in fish. GreenScreen® criteria classify chemicals as a High hazard for

chronic aquatic toxicity when the most conservative chronic aquatic toxicity values are between 0.1

and 1.0 mg/L (CPA 2012b).




U.S. EPA 2012a

o Caprylohydroxamic acid is designated to the amides and neutral organics ECOSAR

chemical classes. The most conservative predicted ChV values are 0.17 mg/L in fish,

4.802 mg/L in daphnia, and 1.979 mg/L in green algae (Appendix H).

No experimental data were identified for this endpoint. Based on modeled data, a score of High

was assigned based on the most conservative ChV of 0.17 mg/L in fish. Confidence in the score

is reduced because it is based on modeled data.

Environmental Fate (Fate)

Persistence (P) Score (vH, H, M, L, or vL): vL

Caprylohydroxamic acid was assigned a score of Very Low for persistence based on being classified

as readily biodegradable in an OECD Guideline 301A DOC Die-Away Test. GreenScreen® criteria

classify chemicals as a Very Low hazard for persistence when the chemical meets the 10-day

biodegradation window if the dominant compartment is soil or water (CPA 2012b). Confidence in

the score is high because it is based on experimental data from a well conducted study.




NICNAS 2012

o Caprylohydroxamic acid (purity not reported) was readily biodegradable in a ready

biodegradation test that was conducted according to OECD Guideline 301A (DOC Die-

Away Test; GLP-status not reported) using aerobic activated domestic sludge inoculum

(adaptation not specified). NICNAS reports that there were no deviations from the

guideline protocol, and that all validity criteria were met. Caprylohydroxamic acid

achieved 90% biodegradation in 3 days, 99.4% in 7 days, 97.6% in 14 days, and 98.2% in

28 days. NICNAS concluded that the substance is readily biodegradable.

U.S. EPA 2012b

o The BIOWIN modeling Ready Biodegradable Predictor indicates that caprylohydroxamic

acid is expected to be readily biodegradable. Fugacity modeling predicts 82.2% will





partition to soil with a half-life of 30 days, 17.7% will partition to water with a half-life

of 15 days, and 0.18% will partition to sediment with a half-life of 135 days (Appendix

I).

Based on the weight of evidence, a score of Very Low was assigned because caprylohydroxamic

acid was readily biodegradable, achieving 90% biodegradation in just 3 days, in a test conducted

according to OECD guidelines. Modeling predicts that this compound partitions primarily to soil

and water, and GreenScreen criteria specify a score of Very Low for compounds that meet the

10-day biodegradation window if the dominant compartment is soil or water. Confidence in this

score is high because it is based in experimental data from a well conducted study.

Bioaccumulation (B) Score (vH, H, M, L, or vL): vL

Caprylohydroxamic acid was assigned a score of Very Low for bioaccumulation based on a modeled

BCF of 4.456. GreenScreen® criteria classify chemicals as a Very Low hazard for bioaccumulation

when the BCF is less than 100 (CPA 2012b). Confidence in the score is reduced because it is based

on modeled data.




U.S. EPA 2012b

o BCFBAF predicts a BCF of 4.456 based on a log Kow of 1.66, indicating this chemical is

not likely to bioaccumulate because the BCF is less than 100 based on a log Kow less than

5 (Appendix I).

No experimental data are available, but modeling predicts a BCF of 4.456 which corresponds to a

score of Very Low. This is consistent with the estimated log Kow of 1.66 and high water

solubility, which also indicate that caprylohydroxamic acid is unlikely to bioaccumulate.

Confidence in the score is reduced because it is based on modeled data.

Physical Hazards (Physical)

Reactivity (Rx) Score (vH, H, M, or L): L

Caprylohydroxamic acid was assigned a score of Low for reactivity based on an HMIS rating of 0 for

physical hazards. GreenScreen® criteria classify chemicals as a Low hazard for reactivity when the

chemical is not explosive, self-reactive, or otherwise reactive, and the chemical is not present on

authoritative or screening lists (CPA 2012b).




NICNAS 2012

o Caprylohydroxamic acid does not contain structural groups associated with explosive

properties.

o Caprylohydroxamic acid is stable under normal environmental and usage conditions.

TCI America 2013

o Caprylohydroxamic acid received an HMIS rating of 0 for physical hazards, which

corresponds to “Materials that are normally stable, even under fire conditions, and will

NOT react with water, polymerize, decompose, condense, or self-react. Non Explosives”

(Paint.org 2015).





Based on the weight of evidence, a score of Low was assigned because the HMIS rating of 0

indicates that caprylohydroxamic acid is not explosive or self-reactive. Confidence in the score

is reduced because there are no experimental data available.

Flammability (F) Score (vH, H, M, or L): L

Caprylohydroxamic acid was assigned a score of Low for flammability based on an HMIS rating of 0

for flammability. GreenScreen® criteria classify chemicals as a Low hazard for flammability when

available data indicate that GHS classification as a flammable solid is not warranted (CPA 2012b).

Confidence in the score is reduced because there are no experimental data available.




TCI America 2013

o Caprylohydroxamic acid received an HMIS rating of 0 for flammability, which

corresponds to “Materials that will not burn” (Paint.org 2015).

Based on the weight of evidence, a score of Low was assigned because the HMIS rating of 0

indicates that caprylohydroxamic acid does not warrant GHS classification for flammability.

Confidence in the score is reduced because there are no experimental data available.





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http://www.gpo.gov/fdsys/pkg/CFR-2008-title49-vol2/pdf/CFR-2008-title49-vol2-sec172-101.pdf

http://www.ecfr.gov/cgi-bin/text-idx?c=ecfr&tpl=/ecfrbrowse/Title49/49cfr173_main_02.tpl

http://www.ecfr.gov/cgi-bin/text-idx?c=ecfr&tpl=/ecfrbrowse/Title49/49cfr173_main_02.tpl

http://www.epa.gov/oppt/newchems/tools/21ecosar.htm/

http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm




Virtual Models for Evaluating the Properties of Chemicals within a Global Architecture (VEGA).

2012. Predictive Model Platform. Available at: http://www.vega-qsar.eu/index.php.


http://www.vega-qsar.eu/index.php




APPENDIX A: Hazard Benchmark Acronyms

(in alphabetical order)

(AA) Acute Aquatic Toxicity

(AT) Acute Mammalian Toxicity

(B) Bioaccumulation

(C) Carcinogenicity

(CA) Chronic Aquatic Toxicity

(D) Developmental Toxicity

(E) Endocrine Activity

(F) Flammability

(IrE) Eye Irritation/Corrosivity

(IrS) Skin Irritation/Corrosivity

(M) Mutagenicity and Genotoxicity

(N) Neurotoxicity

(P) Persistence

(R) Reproductive Toxicity

(Rx) Reactivity

(SnS) Sensitization- Skin

(SnR) Sensitization- Respiratory

(ST) Systemic/Organ Toxicity



Limited license provided to EDF for posting via EDF’s website at https://www.edf.org/. Further copying, resale, and distribution are expressly prohibited. Page 21 of 32

APPENDIX B: Results of Automated GreenScreen® Score Calculation for Caprylohydroxamic Acid (CAS #7377-03-9)

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Inorganic

Chemical?

Chemical

NameCAS# C M R D E AT STs STr Ns Nr SNS* SNR* IrS IrE AA CA P B Rx F

NoCaprylohydroxam

ic acid3/9/7377 DG L DG L DG L DG M DG DG L DG L H H H vL vL L L

a b c d e f g

No No No No No

No No No No No No No

No Yes Yes No

STOP

a b c d e f g h i j bm4End

Result

No Yes Yes Yes Yes No Yes Yes Yes Yes U

2

3

4

U2

Note: Chemical has not undergone a data gap

assessment. Not a Final GreenScreenTM

Score

After Data gap Assessment

Note: No Data gap Assessment Done if Preliminary

GS Benchmark Score is 1.4

Table 5: Data Gap Assessment Table

Datagap Criteria

3

Caprylohydroxami

c acid

1

Table 6

Benchmark Chemical Name

Preliminary

GreenScreen®

Benchmark Score

Chemical Name

Table 4

Final

GreenScreen®

Benchmark Score

1 Caprylohydroxami

c acid3

GreenScreen® Score Inspector

Table 1: Hazard Table

Group I Human Group II and II* Human Ecotox Fate Physical

Sy

stem

ic T

ox

icit

y

Neu

roto

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ity

Table 2: Chemical Details

Table 3: Hazard Summary Table




APPENDIX C: Pharos Output for Caprylohydroxamic Acid (CAS #7377-03-9)





APPENDIX D: Toxtree Carcinogenicity Results for Caprylohydroxamic Acid (CAS #7377-03-

9)





APPENDIX E: Toxtree Genotoxicity Results for Caprylohydroxamic Acid (CAS #7377-03-9)




APPENDIX F: Known Structural Alerts for Skin Sensitization

Below are known structural alerts for skin sensitizers (Payne and Walsh 1994). Caprylohydroxamic acid does not possess any known

structural alerts.





APPENDIX G: Toxtree Skin Sensitization Results for Caprylohydroxamic Acid (CAS #7377-

03-9)





APPENDIX H: ECOSAR Modeling Results for Caprylohydroxamic Acid (CAS #7377-03-9)

CAS Number: 7377-03-9

SMILES: ONC(=O)CCCCCCC

CHEM:

MOL FOR: C8 H17 N1 O2

MOL WT: 159.23

------------------------------ EPI SUMMARY (v4.11) --------------------------

Physical Property Inputs:

Log Kow (octanol-water): ------

Boiling Point (deg C): ------

Melting Point (deg C): 78.75

Vapor Pressure (mm Hg): ------

Water Solubility (mg/L): 1550

Henry LC (atm-m3/mole): ------

Log Octanol-Water Partition Coef (SRC):

Log Kow (KowWIN v1.68 estimate) = 1.66

Boiling Pt, Melting Pt, Vapor Pressure Estimations (MPBPVP v1.43):

Boiling Pt (deg C): 343.32 (Adapted Stein & Brown method)

Melting Pt (deg C): 110.43 (Mean or Weighted MP)

VP (mm Hg,25 deg C): 2.49E-006 (Modified Grain method)

VP (Pa, 25 deg C): 0.000333 (Modified Grain method)

MP (exp database): 78.75 deg C

Subcooled liquid VP: 8.1E-006 mm Hg (25 deg C, Mod-Grain method)

: 0.00108 Pa (25 deg C, Mod-Grain method)

Water Solubility Estimate from Log Kow (WSKow v1.42):

Water Solubility at 25 deg C (mg/L): 2026

log Kow used: 1.66 (estimated)

melt pt used: 78.75 deg C

Water Sol Estimate from Fragments:

Wat Sol (v1.01 est) = 14000 mg/L

ECOSAR Class Program (ECOSAR v1.11):

Class(es) found:

Amides

Henrys Law Constant (25 deg C) [HENRYWIN v3.20]:

Bond Method: 1.23E-010 atm-m3/mole (1.24E-005 Pa-m3/mole)

Group Method: Incomplete

For Henry LC Comparison Purposes:

User-Entered Henry LC: not entered

Henrys LC [via VP/WSol estimate using User-Entered or Estimated values]:

HLC: 3.366E-010 atm-m3/mole (3.410E-005 Pa-m3/mole)





VP: 2.49E-006 mm Hg (source: MPBPVP)

WS: 1.55E+003 mg/L (source: User-Entered)

Log Octanol-Air Partition Coefficient (25 deg C) [KoaWIN v1.10]:

Log Kow used: 1.66 (KowWin est)

Log Kaw used: -8.299 (HenryWin est)

Log Koa (KoaWIN v1.10 estimate): 9.959

Log Koa (experimental database): None

Probability of Rapid Biodegradation (BIOWIN v4.10):

Biowin1 (Linear Model): 0.7802

Biowin2 (Non-Linear Model): 0.9303

Expert Survey Biodegradation Results:

Biowin3 (Ultimate Survey Model): 3.1456 (weeks)

Biowin4 (Primary Survey Model): 3.8871 (days)

MITI Biodegradation Probability:

Biowin5 (MITI Linear Model): 0.5353

Biowin6 (MITI Non-Linear Model): 0.6284

Anaerobic Biodegradation Probability:

Biowin7 (Anaerobic Linear Model): 0.5947

Ready Biodegradability Prediction: YES

Hydrocarbon Biodegradation (BioHCwin v1.01):

Structure incompatible with current estimation method!

Sorption to aerosols (25 Dec C)[AEROWIN v1.00]:

Vapor pressure (liquid/subcooled): 0.00108 Pa (8.1E-006 mm Hg)

Log Koa (Koawin est): 9.959

Kp (particle/gas partition coef. (m3/µg)):

Mackay model: 0.00278

Octanol/air (Koa) model: 0.00223

Fraction sorbed to airborne particulates (phi):

Junge-Pankow model: 0.0912

Mackay model: 0.182

Octanol/air (Koa) model: 0.152

Atmospheric Oxidation (25 deg C) [AopWin v1.92]:

Hydroxyl Radicals Reaction:

OVERALL OH Rate Constant = 16.3973 E-12 cm3/molecule-sec

Half-Life = 0.652 Days (12-hr day; 1.5E6 OH/cm3)

Half-Life = 7.828 Hrs.

Ozone Reaction:

No Ozone Reaction Estimation

Fraction sorbed to airborne particulates (phi):

0.137 (Junge-Pankow, Mackay avg)

0.152 (Koa method)

Note: the sorbed fraction may be resistant to atmospheric oxidation





Soil Adsorption Coefficient (KocWIN v2.00):

Koc: 218.4 L/kg (MCI method)

Log Koc: 2.339 (MCI method)

Koc: 69.1 L/kg (Kow method)

Log Koc: 1.840 (Kow method)

Aqueous Base/Acid-Catalyzed Hydrolysis (25 deg C) [HYDROWIN v2.00]:

Rate constants can NOT be estimated for this structure!

Bioaccumulation Estimates (BCFBAF v3.01):

Log BCF from regression-based method = 0.763 (BCF = 5.788 L/kg wet-wt)

Log Biotransformation Half-life (HL) = -1.0107 days (HL = 0.09756 days)

Log BCF Arnot-Gobas method (upper trophic) = 0.649 (BCF = 4.456)

Log BAF Arnot-Gobas method (upper trophic) = 0.649 (BAF = 4.456)

log Kow used: 1.66 (estimated)

Volatilization from Water:

Henry LC: 1.23E-010 atm-m3/mole (estimated by Bond SAR Method)

Half-Life from Model River: 6.006E+006 hours (2.503E+005 days)

Half-Life from Model Lake : 6.553E+007 hours (2.73E+006 days)

Removal in Wastewater Treatment:

Total removal: 2.03 percent

Total biodegradation: 0.09 percent

Total sludge adsorption: 1.94 percent

Total to Air: 0.00 percent

(using 10000 hr. Bio P,A,S)

Level III Fugacity Model:

Mass Amount Half-Life Emissions

(percent) (hr.) (kg/hr.)

Air 0.00242 15.7 1000

Water 17.7 360 1000

Soil 82.2 720 1000

Sediment 0.18 3.24e+003 0

Persistence Time: 764 hr.





APPENDIX I: EPISuite Modeling Results for Caprylohydroxamic Acid (CAS #7377-03-9)

ECOSAR Version 1.11 Results Page

SMILES: ONC(=O)CCCCCCC

CHEM:

CAS Num: 007377-03-9

ChemID1:

MOL FOR: C8 H17 N1 O2

MOL WT: 159.23

Log Kow: 1.660 (EPISuite Kowwin v1.68 Estimate)

Log Kow: (User Entered)

Log Kow: (PhysProp DB exp value - for comparison only)

Melt Pt: 78.75 (deg C, User Entered for Wat Sol estimate)

Melt Pt: 78.75 (deg C, PhysProp DB exp value for Wat Sol est)

Wat Sol: 2026 (mg/L, EPISuite WSKowwin v1.43 Estimate)

Wat Sol: 1550 (mg/L, User Entered)

Wat Sol: (PhysProp DB exp value)

--------------------------------------

Values used to Generate ECOSAR Profile

--------------------------------------

Log Kow: 1.660 (EPISuite Kowwin v1.68 Estimate)

Wat Sol: 1550 (mg/L, User Entered)

------------------------------------------------

Available Measured Data from ECOSAR Training Set

------------------------------------------------

No Data Available

--------------------------------------

ECOSAR v1.1 Class-specific Estimations

--------------------------------------

Amides

Predicted

ECOSAR Class Organism Duration End Pt mg/L (ppm)

=========================== ================== ======== ======

==========

Amides : Fish 96-hr. LC50 83.210

Amides : Daphnid 48-hr. LC50 107.134

Amides : Green Algae 96-hr. EC50 2.432

Amides : Fish ChV 0.117

Amides : Daphnid ChV 4.802





Amides : Green Algae ChV 1.979

Amides : Fish (SW) 96-hr. LC50 73.245

Amides : Mysid (SW) 96-hr. LC50 4.162

=========================== ================== ======== ======

==========

Neutral Organic SAR : Fish 96-hr. LC50 264.010

(Baseline Toxicity) : Daphnid 48-hr. LC50 145.279

: Green Algae 96-hr. EC50 95.060

: Fish ChV 24.869

: Daphnid ChV 12.984

: Green Algae ChV 23.215

Note: * = asterisk designates: Chemical may not be soluble enough to

measure this predicted effect. If the effect level exceeds the

water solubility by 10X, typically no effects at saturation (NES)

are reported.

------------------------------

Class Specific LogKow Cut-Offs

------------------------------

If the log Kow of the chemical is greater than the endpoint specific cut-offs

presented below, then no effects at saturation are expected for those endpoints.

Amides :

-------

Maximum LogKow: >8.5 (LC50)

Maximum LogKow: >8.0 (EC50,ChV)

Baseline Toxicity SAR Limitations:

---------------------------------

Maximum LogKow: 5.0 (Fish 96-hr LC50; Daphnid LC50)

Maximum LogKow: 6.4 (Green Algae EC50)

Maximum LogKow: 8.0 (ChV)





Licensed GreenScreen® Profilers

Caprylohydroxamic Acid GreenScreen® Evaluation Prepared by:

Jennifer Rutkiewicz, Ph.D.

Toxicologist

ToxServices LLC

Caprylohydroxamic Acid GreenScreen® Evaluation QC’d by:

Bingxuan Wang, Ph.D.

Toxicologist

ToxServices LLC


caprylohydroxamic acid (cas #7377-03-9) greenscreen for ... · benchmark 3c o moderate group ii*...

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