GREEN MEA CIR EXPERT PANEL MEETING SEPTEMBER 26-27, 2011

Transcription

1 GREEN MEA CIR EXPERT PANEL MEETING SEPTEMBER 26-27, 2011

2 Memorandum TO: CIR Expert Panel Members and Liaisons FROM: Monice M. Fiume MMF Senior Scientific Analyst/Writer DATE: September 8, 2011 SUBJECT: Draft Amended Safety Assessment of Part I: Ethanolamine and Ethanolamine-Containing Ingredients; Part II: Ethanolamides Enclosed is the draft amended safety assessment on ethanolamine and ethanolamine-containing ingredients. This is the first time you will be reviewing this document. At the December 2010 Panel meeting, the Panel made the decision to reopen the 1983 safety assessment of Triethanolamine (TEA), Diethanolamine (DEA), and Monoethanolamine (now named Ethanolamine), splitting the report in to three separate documents, and adding related ingredients to each. This is the last of the reports resulting from that split. As each of these split-off reports has been presented, the Panel has been given an exhaustive list of related ingredients and then decided which ingredients were appropriate for inclusion in the safety assessment and which were not. Since the Panel has excluded amides from the re-reviews of DEA and TEA, the draft report you are reviewing has been developed so that monoethanolamine and all ethanolamine-containing ingredients, except the ethanolamides, are presented in the first section of the report, and then the information on the ethanolamides is presented as a second section. The reasoning is that, if the ethanolamides are excluded from this reopened report, we wouldn t want to lose this group entirely. CIR could then break the ethanolamides (total of 49 ingredients) out of this report and add them to a new re-review of the 1995 safety assessment on Isostearmide MEA, Myristamide MEA, and Stearamide MEA at a later date (maybe December). By creating a section that presents only the information on ethanolamides, we are hoping to facilitate such an approach, while leaving it up to the Panel to make the actual decision. As for the first section of the report, there are 21 ingredients being proposed for inclusion in the rereview of ethanolamine 2 inorganic acid salts, 8 organic salts, 2 protein salts, 3 organic-substituted inorganic acid salts, and 6 alkyl substituted ethanolamines. In the review of DEA, the Panel did not find it appropriate to include the alkyl substituted diethanolamines. Since quite a bit of data was available on the alkyl-substituted ethanolamines, rather than summarize and include those data at this stage, it was decided that those data would be added only if the alkyl-substituted ethanolamines were actually included in the re-review of ethanolamine. Some of the ingredients included in this re-review include a component that has been reviewed by the CIR. For example, MEA-Cocoate is the ethanolamine salt of coconut acid; coconut acid has been reviewed by the CIR. Tables 2a and 2b provide the conclusions from the CIR reports on the component ingredients. The data profile indicates the types of data that were available in those reports. The Panel should consider whether read-across data from existing reports can be used.

3 The following unpublished data have been summarized for this draft report, and these papers are included with this report package: 1. Concentration of Use by FDA Product Category: Ethanolamine and Ethanolamine Containing Ingredients. Memo dated July 5, Ethanolamine hydrochloride. Two-generation reproduction toxicity study in Wistar rats; administration via diet. 3. Hepatic choline level in rats after repeated dose feeding of ethanolamine hydrochloride. At this meeting, the Panel should decide which ingredients to include. If the data are sufficient to assure the safety of those ingredients in cosmetics, the Panel should develop a rationale and a tentative conclusion and issue that for public comment. MEA/Page 2

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5 History: Ethanolamine Original Report: In 1983, the Expert Panel determined that TEA, DEA, and MEA were safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin. In products intended for prolonged contact with the skin, the concentration of ethanolamines should not exceed 5%. Ethanolamine (MEA) should be used only in rinse-off products. Triethanolamine (TEA) and diethanolamine (DEA) should not be used in products containing N-nitrosating agents. December 2010: a formal rereview package was presented to the Panel for the report on TEA, DEA, and MEA - the report was split into 3 separate documents DEA, TEA, and MEA, - appropriate new ingredients are to be added to each report September 26-27, 2011: Re-Review Draft Report The Draft Amended Safety Assessment was presented to the Panel. The assessment was divided into two parts. The first part, entitled Ethanolamine and Related Ethanolamine-Containing Ingredients, included 21 ingredients for consideration for inclusion in the re-review of ethanolamine Part II, entitled Ethanolamides, was created so that if the Panel determined that the ethanolamides were not appropriate as part of the re-review of ethanolamine, the Panel could decide that it would be appropriate to re-review isostearamide, myristamide, and stearamide MEA (reviewed in 1995), and included these ethanolamides CIR Panel Book Page 2

6 MEA SEARCH STRATEGY SCIFINDER June 10, Searched all ingredients (except MEA) with CAS #s (38 substances) 18,866 references a. Refined by document type 7091 references b. Refined by removing documents in Chinese 5701 references 2. Searched MEA by CAS # a. Refined by document type references b. Refined by year references 3. Combined results of SS 1 and 2 above references 4. Searched all ingredients without CAS #, refined by document type a. MEA laureth carboxylate 1 b. MEA steareth carboxylate 0 c. MEA talloweth 0 d. MEA hydrolyzed Silk 0 e. MEA hydrolyzed collagen 1 f. MEA distearyl phosphate 0 g. Butylethanolamine 128 h. Stearamidoethyl ethanolamine phosphate - 0 i. Lysophosphatidylethanolamine 1982 j. Azelamide MEA 0 k. Cocamide methyl MEA 0 l. Deoxyphytantriyl Palmitamide MEA 0 m. Hydroxyethyl pantotheamide 0 n. Hydroxylpropyl MEA 227 o. Myristoyl/palmitoyl/oxostearamide/arachamide DEA 0 p. Oatamide MEA 0 q. Palm kernelamide MEA 0 r. Palmamide MEA 0 s. Panthothenamide MEA 0 t. Peanutamide MEA 0 u. PEG Cocamide MEA 0 5. Combined SS 3 and all results of SS references 6. Applied the following qualifiers to SS 5 above a. Carcinogen 593 b. Mutagen 79 c. Teratogen 15 d. Developmental toxicity 56 e. Reproductive toxicity 8 f. Dermal 46 g. Toxicology 728 h. Ocular 164 i. Irritation 86 j. Sensitization 119 k. Photosensitization 59 l. ADME 7 m. Dermal absoroption 4 n. Excretion 70 o. Pharmacokinetics 116 p. Kidney renal 219 q. Choline deficiency 20 r. Nitrosation Combined all of SS references Keep Me Posted Results are received weekly CIR Panel Book Page 3

7 SEARCH STRATEGY TEA/DEA/MEA TOXLINE PUBMED EU Jan DEA not to be used & choline & carcinogen* choline & deficiency & 38 human & cancer TEA & carcinogen* & choline 5 2 MEA Jan 25, OR (downloaded 58) (1980-current) restrictions restrictions UPDATED SEARCH May 31, 2010 ( OR OR ) AND (REPRODUCTI* OR TERATOGEN*) 142 (Toxline); 41 (DART) ( OR OR ) AND (DEVELOPMENT* OR FETOTOX*) 378 (Toxline); 47 (DART) ( OR OR ) AND TOX* ( OR OR ) AND (GENOTOX* OR MUTAGEN* OR CLASTOGEN*) 286 Toxline); 7 (DART); 9 (CCRIS) ( OR OR ) AND (SENSITIZA* OR SENSITIZE* OR SENSITIS* OR IRRIT*) 306 (Toxline); 6 (DART) ( OR OR ) AND (METBOLI* OR ABSORB* OR ABSORP* OR DISTRIBUT* OR EXCRET*) 403 (Toxline); 18 (DART) AND CARCINOGEN* AND CHOLINE - 0 Total Download (most duplicates removed): 1218 UPDATED SEARCH Sept 21, 2010 last 12 mos OR OR hits/1 useful CIR Panel Book Page 4

8 Ethanolamine, Ethanolamine-Ingredients, and Components Data Profile* Sept 2011 Writer, Monice Fiume Previously Reviewed# Reported Use Method of Manufacture Toxicokinetics Animal Tox Acute, Dermal Animal Tox Acute, Oral Animal Tox, Acute, Inhalation Animal Tox Rptd Dose, Dermal Animal Tox, Rptd Dose, Oral Animal Tox Rptd Dose, Inhalation Repro/Dev Tox Genotoxicity Carcinogenicity Dermal Irr/Sens Ocular Irritation Ethanolamine 1983 X X X X X X X X X X X X X Butylethanolamine Dibutyl Ethanolamine Diethyl Ethanolamine Dimethyl MEA Ethanolamine HCl X X X Ethyl Ethanolamine MEA PPG 6 Laureth 7 Carboxylate MEA Benzoate MEA Cocoate X MEA Dicetearyl Phosphate MEA Hydrolyzed Collagen X MEA Hydrolyzed Silk MEA Laureth Sulfate X MEA Laureth 6 Carboxylate MEA Lauryl Sulfate X MEA PPG 8 Steareth 7 Carboxylate MEA Salicylate MEA Sulfite MEA Tallowate X MEA Undecylenate Methylethanolamine COMPONENTS Ammonium & Sodium Lauryl Sulfate 1983 X X X X X X X X X X X Benzoic Acid current X X X X X X X X X X X X X Coconut Ingredients 2008 X X X X X X X X X Hydrolyzed Collagen 1985 X X X X X X Isostearic Acid 1983 X X X X Laureths 2010 X X X X X X X X X X X PPG 2010 X X X X X X Sodium Laureth Sulfate/Sulfated Ethoxylated Alcohols 2010 X X X X X X X X X Steareths 2010 * X indicates that data were available in a category for the ingredient # year the report was published CIR Panel Book Page 5

9 1 Ethaolamides Data Profile* Sept 2011 Writer, Monice Fiume Ocular Irritation Dermal Irr/Sens Carcinogenicity - Dermal Genotoxicity Repro/Dev Tox** Animal Tox, Acute, Inhalation Animal Tox Rptd Dose, Dermal Animal Tox, Rptd Dose, Oral Animal Tox Rptd Dose, Inhalation Animal Tox Acute, Oral Animal Tox Acute, Dermal Toxicokinetics Data log P value Info on Free MEA Content Reported Use CIR Review on Component* Previously Reviewed* Acetamide MEA 1993 x x x x x x x x x Azelamide MEA 2010 Babassuamide MEA 2011 Behenamide MEA x Behenamide MEA C16 22 Acid Amide MEA x Cocamide MEA x x x x x x x Cocamide Methyl MEA 2010 x Cocamidopropyl Betainamide MEA 2010 x Chloride Deoxyphytantriyl Palmitamide MEA Hexyloxodecanamide MEA x Hexyloxodecanamide MEA Phosphate Hydroxyethyl Pantothenamide MEA 1987 Hydroxypropyl Bisisostearamide MEA Hydroxypropyl Bislauramide MEA Hydroxypropyl Bispalmitamide MEA Hydroxypropyl Bisstearaminde MEA Hydroxystearamide MEA 1999 x Isostearamide MEA Lactamide MEA 1998 x Lauramide MEA 1987 x x x x x x Linoleamide MEA x Myristamide MEA x x x Myristoyl/Palmitoyl/Oxostearmide/ x Arachamide MEA Oatamide MEA 2011 x Oleamide MEA 1987 Oliveamide MEA 2011 Palm Kernelamide MEA 2011 Palmamide MEA 2011 Palmitamide MEA 1987 x Pantothenamide MEA 1987 Peanutamide MEA 2001 x Ricinoleamide MEA 2007 x x Stearamide MEA x x x x x x Stearamide MEA Stearate 1987 x x Stearamidoethyl Ethanolamine x CIR Panel Book Page 6

10 Ethaolamides Data Profile* Sept 2011 Writer, Monice Fiume 2 Ocular Irritation Previously Reviewed* CIR Review on Component* Reported Use Info on Free MEA Content log P value Toxicokinetics Data Animal Tox Acute, Dermal Animal Tox Acute, Oral Animal Tox, Acute, Inhalation Animal Tox Rptd Dose, Dermal Animal Tox, Rptd Dose, Oral Animal Tox Rptd Dose, Inhalation Repro/Dev Tox** Genotoxicity Carcinogenicity - Dermal Dermal Irr/Sens Sunfloweramide MEA 2011 Tallowamide MEA Trideceth-2 Carboxamide MEA 2010 x Undecylenamide MEA x x PEG-2 Cocamide 2010 PEG-3 Cocamide 2010 PEG-4 Cocamide 2010 PEG-5 Cocamide x 2010 PEG-6 Cocamide x 2010 PEG-7 Cocamide 2010 PEG-9 Cocamide MEA x 2010 x PEG-11 Cocamide 2010 PEG-20 Cocamide 2010 PEG-20 Cocamide MEA 2010 * X indicates that data were available in a category for the ingredient *year of review is provided **data on the DEA amides were not available; data from previous CIR reports on DEA and fatty acids were summarized CIR Panel Book Page 7

11 Report

12 Draft Amended Report MEA as Used in Cosmetics September 26, 2011 All interested persons are provided 60 days from the above date to comment on this Draft Amended 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 2011 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; Ronald A Hill, Ph.D. James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is F. Alan Andersen, Ph.D. This report was prepared by Monice Fiume, Senior Scientific Analyst/Writer. Cosmetic Ingredient Review th Street, NW, Suite 412 " Washington, DC " ph " fax " cirinfo@cir-safety.org CIR Panel Book Page 8

13 Table of Contents PART I: ETHANOLAMINE and RELATED ETHANOLAMINE CONTAINING INGREDIENTS... 1 Introduction... 1 Chemistry... 2 Method of Manufacture... 3 Impurities... 3 Use... 3 Cosmetic... 3 Non-Cosmetic... 4 Toxicokinetics... 4 In-Vitro... 5 Dermal... 5 Non-Human... 5 Oral... 5 Non-Human... 5 Other... 6 Non-Human... 6 Toxicological Studies... 6 Acute (Single) Dose Toxicity... 6 Dermal... 6 Oral... 6 Inhalation... 7 Other... 7 Repeated Dose Toxicity... 7 Dermal... 7 Oral... 7 Inhalation... 7 Reproductive and developmental Toxicity... 7 Dermal... 7 Oral... 8 Genotoxicity... 9 In Vitro... 9 Irritation and Sensitization... 9 Irritation... 9 Skin... 9 Non-Human... 9 Human... 9 Sensitization Non-Human Human Provocative Testing Ocular Irritation Non-Human In Vitro Occupational ExpoSure Occupational Exposure Limits Miscellaneous Studies Effect on Hepatic Choline Effect on Bronchoconstriction Summary PART II: ETHANOLAMIDES Introduction Chemistry Method of Manufacture Impurities Use Cosmetic Toxicokinetics Toxicological Studies ii CIR Panel Book Page 10

14 Acute (Single) Dose Toxicity Dermal Oral Repeated Dose Toxicity Dermal Oral Reproductive and developmental Toxicity Genotoxicity In Vitro Irritation and Sensitization Irritation Skin Non-Human Human Sensitization Non-Human Human Ocular Irritation Non-Human Summary Tables Table 1a. Definition and structures of ethanolamine and ethanolamine-containing ingredients Table 1b. Definition and structures of ethanolamides Table 2a. Conclusions of previously reviewed ingredients, as pertaining to the ethanolamine and ethanolaminecontaining ingredients Table 2b. Conclusions of previously reviewed ingredients, as pertaining to the ethanolamides Table 3a. Physical and chemical properties Table 3b. Physical and chemical properties of ethanolamides Table 4a. Frequency and concentration of use according to duration and type of exposure Table 4b. Ingredients not reported to be in use Table 4c. Status for use in Europe according to the EC CosIng Database for ethanolamine ingredients Table 5a. Frequency and concentration of use according to duration and type of exposure ethanolamides Table 5b. Ethanolamides not reported to be in use References iii CIR Panel Book Page 11

15 PART I: ETHANOLAMINE AND RELATED ETHANOLAMINE CONTAINING INGREDIENTS INTRODUCTION In 1983, the Cosmetic Ingredient Review (CIR) Expert Panel issued a report on the safety of Triethanolamine, Diethanolamine, and Monoethanolamine. In 2010, the Panel decided to reopen that safety assessment as three separate reports and to include additional related ingredients in each of the new reviews. The International Nomenclature Cosmetic Ingredient (INCI) name for monoethanolamine is now ethanolamine. This assessment addresses ethanolamine and ethanolamine-containing ingredients. The acid salt ingredients (as recited below) would be expected to dissociate into ethanolamine and the corresponding acid, some of which have been reviewed separately. In most cases, this means that the composition of these salts is stoichiometrically half ethanolamine (i.e. as its conjugate acid). In 1983, the Expert Panel concluded that ethanolamine, an ingredient that functions in cosmetics as a ph adjuster, is safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin, and ethanolamine should only be used in rinse-off products. 1 In that review, it was shown that ethanolamine is a skin and eye irritant in animals, and clinical studies with formulations containing ethanolamine indicated that it is a human skin irritant. Also, there was indication that the longer ethanolamine was in contact with the skin, the greater the likelihood of irritation. The following 21 ingredients are being proposed for inclusion in the re-review of ethanolamine: Inorganic Acid Salts Ethanolamine HCl MEA-Sulfite Organic Acid Salts MEA-Benzoate MEA-Salicylate MEA-Cocoate MEA-Tallowate MEA-Undecylenate MEA-Laureth-6 Carboxylate MEA PPG-6 Laureth-7 Carboxylate MEA-PPG-8-Steareth-7 Carboxylate Protein Salts MEA-Hydrolyzed Silk MEA-Hydrolyzed Collagen Organic-Substituted Inorganic Acid Salts MEA-Lauryl Sulfate MEA-Laureth Sulfate MEA-Dicetearyl Phosphate Alkyl Substituted Ethanolamines Methylethanolamine Ethyl Ethanolamine Butylethanolamine Dimethyl MEA Diethyl Ethanolamine Dibutyl Ethanolamine 1 CIR Panel Book Page 12

16 The organic salts and the organic-substituted inorganic salts mostly function as surfactants, with the exception of MEA-benzoate and MEA-salicylate, which are preservatives. Many of the alkyl substituted ethanolamines, as well as ethanolamine HCl, are reported to function as ph adjusters. Other reported functions in this category include anti-static agent, skin conditioning agent, and skin protectant. MEA-sulfite is reported to function as a hair fixative. MEA-salicylate also has been reviewed previously by the CIR Expert Panel. In 2003, the Panel concluded that MEA-salicylate is safe as used when formulated to avoid skin irritation and when formulated to avoid increasing the skin s sun sensitivity, or, when increased sun sensitivity would be expected; directions for use include the daily use of sun protection. 2 The definitions and structures of ethanolamine and the ethanolamine-containing ingredients listed above are provided in Table 1a. Since the ingredients included in this review consist of ethanolamine and one or more components, and the safety of some of these components has been reviewed by the CIR, the conclusions of those relevant ingredients that have been previously reviewed are provided in Table 2a. CHEMISTRY Ethanolamine is an amino alcohol. (Figure 1). Ethanolamine is produced commercially by aminating ethylene oxide with ammonia; the replacement of one hydrogen of ammonia with an ethanol group produces ethanolamine. Ethanolamine typically contains a small amount of diethanolamine (DEA). Figure 1. Eethanolamine Ethanolamine is reactive and bifunctional, combining the properties of alcohols and amines. At temperatures of C, ethanolamine will react with fatty acids to form ethanolamides. Additionally, the reaction of ethanolamines and sulfuric acid produces sulfates, and, under anhydrous conditions, ethanolamine may react with carbon dioxide to form carbamates. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine 1 While many secondary amines and amides are readily nitrosated to form isolatable nitrosamines and nitrosamides, primary amines, such as ethanolamine, ultimately yield diazonium salts instead of nitrosamines. 3 Acid Salts The acid salts (inorganic acid salts, organic acid salts, sulfate salts, and phosphate salt), named above, are ion pairs which freely dissociate in water (e.g., Figure 2). Therefore, these salts are closely related to the corresponding free acids and ethanolamine. In other words, MEA-undecylenate is closely related to undecylenic acid and ethanolamine. Figure 2. MEA-Undecylenate Alkyl Substituted Ethanolamines The alkyl substituted ethanolamines consist of covalent, secondary (and sometimes tertiary) amines, whereby one of the nitrogen substituents is ethanol and the second (and in some cases third) is an alkyl chain (e.g., a four carbon chain is the alkyl substituent on butylethanolamine; Figure 3). These ingredients are not salts, do not readily dissociate in water, and are not readily hydrolyzed. Since some of these ingredients are secondary amines, the conversion (nitrosation) of secondary amines (R 1 -NH-R 2 ), such as butylethanolamine (wherein R 1 is butyl and R 2 is ethanol), into N-nitrosamines that may be carcinogenic is of concern in cosmetics is. 4,5 Of the approximately 209 nitrosamines tested, 85% have been shown to produce cancer in laboratory animals. Nitrosation can occur under physiologic conditions. Depending on the nitrosating 2 CIR Panel Book Page 13

17 agent and the substrate, nitrosation can occur under acidic, neutral, or alkaline conditions. Atmospheric NO 2 may also participate in the nitrosation of amines in aqueous (aq.) solution. Accordingly, alkyl substituted ethanolamines should be formulated to avoid the formation of nitrosamines. Figure 3. Butylethanolamine Chemical and physical properties are summarized in Table 3a. Method of Manufacture Ethanolamine Ethanolamine is produced by reacting 1 mole of ethylene oxide with 1 mole of ammonia. Typically, ethylene oxide is reacted with ammonia in a batch process to produce a crude mixture of approximately one-third each ethanolamine, DEA, and TEA, which are then separated, achieving varying degrees of single component purity. 6 Ethanolamine combines with long-chain fatty acids to produce neutral carboxylates or alkanolamine soaps. 7 Impurities Ethanolamine contains a small amount of DEA. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine 1 USE Cosmetic Ethanolamine is reported to function in cosmetics as a ph adjuster. 8 The organic salts and the organic-substituted inorganic salts mostly function as surfactants, with the exception of MEA-benzoate and MEA-salicylate, which are preservatives. Many of the alkyl substituted ethanolamines, as well as ethanolamine HCl, are reported to function as ph adjusters. Other reported functions in this category include anti-static agent, skin conditioning agent, and skin protectant. MEA-sulfite is reported to function as a hair fixative. In 1981, data provided to the Food and Drug Administration (FDA) Voluntary Cosmetic Registration Program (VCRP) indicated that ethanolamine was used in 51 formulations. 1 All but 2 of those products were rinse-off formulations, and 28 uses were in hair coloring products. Products contained ethanolamine at concentrations of 10%. VCRP data obtained in 2011 indicate that the use of ethanolamine has increased significantly, as it is now reported to be used in 764 formulations. 9 All of the uses, except 1, are rinse-off products, and 750 uses are in hair coloring formulations. 10 A few of the other ethanolamine-containing ingredients are in use, but all of those are reported to be used in less than 15 formulations. According to data submitted by industry in response to a recent survey conducted by the Personal Care Products Council (Council), ethanolamine is used only in rinse-off products, and at concentrations of %. 11 MEA-lauryl sulfate has the highest reported concentration of use, with a concentration of 35% reported in rinse-off formulations. The only leave-on use concentration reported is for MEA-hydrolyzed collagen, with a maximum use concentration of 0.2%. Use data for ethanolamine and all other in-use ethanolamine-containing ingredients are provided in Table 4a. Ethanolamine ingredients not reported to be in use, according to VCRP data and the Council survey, are listed in Table 4b. Monoalkylamines, monoalkanolamines, and their salts are listed by the European Commission in Annex III Part 1: the list of substances which cosmetic products must not contain, except subject to the restrictions and conditions laid down. 12 These restrictions for these ingredients include an allowed maximum secondary amine content of 0.5% in finished product; do not use with nitrosating agents; minimum purity of 99%; maximum secondary amine content of 0.5% for raw materials; 3 CIR Panel Book Page 14

18 maximum nitrosamine content of 50 µg/kg; and must be kept in nitrite-free containers. The ingredients named in this report that have these restrictions are listed in Table 4c. According to data obtained from Health Canada, ethanolamine is used at up to 10%. 13 Most of the uses are rinseoff, but some leave-on type products are reported. For example ethanolamine is reported to be included at 3-10% in an eye make-up. However, other information provided by Health Canada indicate that ethanolamine is used primarily in hair coloring products, with concentrations of use of 30% (Health Canada, personal communication). Ethanolamine is also reported to be used in Canada at concentrations of 30% in non-coloring hair preparations and rinse-off formulations, and at 10% in leave-on formulations; this includes reported use at 0.3-3% in baby products and 3-10% in lipsticks. Non-Cosmetic Ethanolamine is used in the manufacture of emulsifiers and dispersing agents for textile specialties, agricultural chemicals, waxes, mineral and vegetable oils, paraffin, polishes, cutting oils, petroleum demulsifiers, and cement additives. It is an intermediate for resins, plasticizers, and rubber chemicals. It is also used as a lubricant in the textile industry, as a humectant and softening agent for hides, as an alkalizing agent and surfactant in pharmaceuticals, as an absorbent for acid gases, and in organic syntheses. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 Ethanolamine has uses as an indirect food additive; according to 21 CFR ethanolamine is allowed for use as a component of adhecives. 14 Ethanolamine is also used as a rust inhibitor in water-based metalworking fluids. 15 TOXICOKINETICS Ethanolamine is the only naturally occurring ethanolamine in mammals; it occurs in phospholipids known as phosphatides. In an in vitro study, absorption of undiluted and aq. ethanolamine was much greater through mouse skin than it was through human, rat, or rabbit skin; human skin was the least permeable. The cumulative dose absorbed through mouse and human skin was greater with aq. ethanolamine compared to undiluted ethanolamine; 16.92%of the undiluted and 24.79% of the aq. ethanolamine absorbed through mouse skin while 0.61% undiluted and 1.11% aq. ethanolamine absorbed through human skin. In split-thickness pig skin, 5% of the dose of ethanolamine HCl in ethanol penetrated percutaneously. In a metabolism and distribution study, ethanolamine HCl was applied dermally to human skin-grafted and ungrafted athymic nude mice. Radioactivity was recovered in the skin (18.4% recovered in grafted skin; 12.1% in ungrafted skin), liver (~24-26%), and kidneys (~2%). Approximately 5% of the radioactivity was recovered in the urine; 10% of the radioactivity recovered in the urine was unchanged ethanolamine, and the major urinary metabolites were urea and glycine. In an oral study in Wistar rats fed a diet containing mg/kg ethanolamine HCl for 10 wks, plasma ethanolamine concentrations increased in a dose-dependent manner from <3 mg/kg in control animals and <4 mg/kg in low dose animals to mg/kg in high-dose animals. Ethanolamine is the only naturally occurring ethanolamine in mammals, and it is excreted in the urine. Ethanolamine was converted to phosphatidylethanolamine (PE) in the liver, blood, and brain of female rats that were dosed intraperitoneally (i.p.) with radiolabeled ethanolamine. The step-wise methylation of PE that converts it to phosphatidylcholine (PC) did not occur in the brain. Labeled respiratory carbon dioxide has been found in rats after i.p. administration of labeled ethanolamine. A coenzyme-b 12 -dependent ethanolamine deaminase-mediated conversion of ethanolamine to acetaldehyle and ammonia was demonstrated. Intraperitoneal administration of ethanolamine to rats increased blood urea and blood glutamine, and the researchers suggested that ethanolamine was an ammonia source. Additional researchers, upon detection of labeled acetate in the urine of rats fed labeled ethanolamine, suggested that ethanolamine is phosphorylated by ATP in vivo, converted to acetaldehyde, ammonia, and inorganic phosphate, and the acetaldehyde is oxidized to acetate. The researchers further hypothesized that the removal of phosphorylated ethanolamine by its conversion to acetate may exert a regulatory effect on PE biosynthesis. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Ethanolamine. 1 Ethanolamine occurs naturally in phospholipids known as phosphatides. 7 Ethanolamine is a structural component of the phospholipids as part of the headgroups in phospholipid bilayers. In man and other animals, the alcohol group of ethanolamine is phosphorylated, and phosphorylated ethanolamine is transferred to cytidine monophosphate to form cytidine- 5 -diphosphoethanolamine and phospholipids via diacylglycerol. 4 CIR Panel Book Page 15

19 In-Vitro Ethanolamine Three full thickness skin preparations from CD rats, CD-1 mice, and New Zealand White rabbits and 6 samples from female mammoplasty patients were used to compare the dermal penetration of ethanolamine through skin of different species. 16 [ 14 C]ethanolamine (98.8% purity; specific activity [sp. act.] 15.0 mci/mmol) was applied to the skin sample undiluted or as an aq. solution at a dose of 4 mg/cm 2. Dose volumes of 7 µl undiluted [ 14 C]ethanolamine or 32 µl of the aq. solution (22% w/w) were applied to the exposed surface of the skin (1.77 cm 2 ) for 6 h. With undiluted ethanolamine, the cumulative dose absorbed was 5.98, 16.92, 8.66, and 0.61% through rat, mouse, rabbit, and human skin, respectively. With aq. ethanolamine, 1.32, 24.79, 1.87, and 1.11%, was the cumulative dose absorbed through rat, mouse, rabbit, and human skin, respectively. In vitro absorption of undiluted and aq. ethanolamine was much greater through mouse skin than human skin, and human skin was the least permeable of all the skin samples. With human skin samples, the cumulative dose absorbed was greater with aq. ethanolamine as compared to undiluted ethanolamine. The researchers hypothesized that enhanced penetration of aq. ethanolamine may be attributable to elevated skin hydration. Ethanolamine HCl The dermal penetration of [1,2-14 C]ethanolamine HCl was evaluated in vitro using split-thickness skin from weanling Yorkshire pigs. 17 An ethanolic solution was prepared so that a 5 µl application to 0.8 cm 2 of skin gave a chemical dose of 4 µg/cm 2 and a radioactive dose of approximately 0.05 µci. After 50 h, 11% of the dose was lost to evaporation, 5% penetrated percutaneously, and 62% was recovered in the skin residue. Seven to nine times more radioactivity was recovered in the upper 100 µm layer, compared to recovery from the remaining dermis. Dermal Non-Human The distribution and metabolism of ethanolamine was determined using groups of 5 male athymic nude mice with human skin grafts and ungrafted athymic nude mice. 17 [1,2-14 C]Ethanolamine HCl in ethanol was applied at a dose of 4.0 µg (3.6 µci) to a 1.45 cm 2 area of grafted or non-grafted skin. Penetration appeared similar for both groups. Radioactivity in expired carbon dioxide (CO 2 ) appeared 30 min after dosing, and the amount recovered at 30 min was % of the dose for grafted and ungrafted skin, respectively. After 24 h, % of the dose was in expired CO 2. Distribution was also similar for both groups. At 24 h after dosing, % of the dose was recovered in the liver and % in the kidneys. At the application site, 18.4% of the radioactivity was recovered in the grafted skin, and 12.1% was recovered in the ungrafted skin. The amount of radioactivity recovered in the urine was 4.6 and 5.2% for grafted and ungrafted nude mice, respectively. Unchanged ethanolamine comprised 10.2% of the urinary radioactivity. The major urinary metabolites were urea and glycine, comprising 39.9 and 20.4% of the urinary radioactivity. Minor urinary metabolites were serine, uric acid, choline, and unidentified ninhydrin-positive compounds. The radioactivity in proteins and amino acids isolated from the liver, human skin grafts, and mouse skin was determined as an evaluation of the metabolism of ethanolamine. The researchers stated that the appearance of 14 C in skin and hepatic amino acids and proteins, and the incorporation of ethanolamine into phospholipids, was evidence of extensive metabolism of the absorbed ethanolamine. The liver was the most active site of ethanolamine metabolism. Oral Non-Human In a dietary two-generation reproductive toxicity study (described later in the Reproductive and Developmental Toxicity section), blood samples were taken from groups of 10 male and 10 female F 0 and F 1 Wistar rats that were fed 0, 100, 300, or 1000 mg/kg ethanolamine HCl in feed for 10 wks. 18 Plasma levels of ethanolamine, calculated as ethanolamine 5 CIR Panel Book Page 16

20 HCl, increased in a dose-dependent manner. The plasma concentration of ethanolamine was <3 mg/kg for control male and female F 0 and F 1 animals. In the low dose group, the plasma concentration values of ethanolamine were <4 mg/kg, in the mid-dose animals, the levels were 8-11 mg/kg, and in the high dose animals, the plasma ethanolamine levels ranged from mg/kg. Other Non-Human Five male athymic nude mice were dosed intraperitoneally (i.p.) with 4.0 µg (3.6 µci) of [1,2-14C]ethanolamine HCl in ethanol, and the distribution and metabolism were examined following dosing. 7 Radioactivity was detected in expired CO 2, increasing gradually over time. After 24 h, 18% of the radioactivity was detected in expired air. Dermal TOXICOLOGICAL STUDIES Single applications of 5 and 10% ethanolamine were mildly toxic to mouse skin. The dermal LD 50 in rabbits was g/kg ethanolamine. Oral LD 50 values were g/kg in mice and g/kg in rabbits. The inhalation LC 50 of a mixture containing ethanolamine, hydroxylamine, 1-aminopropanolo-2-ol, catechol, and water was 2.48 mg/l. Acute (Single) Dose Toxicity Female C3H mice were used to determine the in vivo and in vitro morphological response of mouse skin exposed to a single application of 1, 5, or 10% ethanolamine in acetone In vivo, ethanolamine was applied to an area of skin 1 inch in diameter, the animals were killed the next day, and the treated skin was removed and processed. In vitro, ethanolamine was applied to a 1-inch diameter mouse skin disc for 1 min, and the skin discs were then cultured for 20 h. No lesions were observed in vitro or in vivo at any concentration tested. Lactate dehydrogenase activity in in vitro samples was statistically significantly elevated with 5 and 10% ethanolamine, suggesting that ethanolamine was mildly toxic to the skin at these concentrations. The dermal LD 50 in rabbits was g/kg ethanolamine. 7 The acute dermal toxicity of a mixture containing ethanolamine (as well as hydroxylamine, diglycolamine, propylene glycol, catechol, and water; percentages not specified) was determined by applying 2g/kg of the mixture to the shaved back of 5 male and 5 female rabbits. 20 The dermal LD 50 of the mixture was >2 g/kg. In a similar study with a formulation containing ethanolamine (and hydroxylamine, diglycolamine, gallic acid, and water; percentages not specified), the LD 50 of the mixture in rabbits was 1.24 g/kg bw. 21 Oral The acute oral toxicity of ethanolamine, concentration not specified, ranged from g/kg for rats. Using rats, 20% aq. ethanolamine had an LD 50 of g/kg, based on results of studies performed over a 10 yr time period. With groups of 10 rats, a hair preparation containing 5.9% ethanolamine had an LD 50 of 14.1 g/kg when diluted and 12.9 ml/kg when undiluted. In a study using guinea pigs, all in the group of 2 or 3 guinea pigs survived oral dosing with 0.6 g/kg ethanolamine, while none survived dosing with 7.0 g/kg. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 In oral studies, the LD 50 of ethanolamine was g/kg in mice and g/kg in rabbits. 7 The acute oral toxicity of a mixture containing ethanolamine (as well as hydroxylamine, diglycolamine, propylene glycol, catechol, glycolic acid and water; percentages not specified) was determined using groups of 5 male and 5 female rats. 22 The oral LD 50 of the mixture was 0.95 g/kg. In a similar study with a formulation containing ethanolamine (and hydroxylamine, diglycolamine, gallic acid, and water; percent in formulation not specified), the oral LD 50 of the mixture was g/kg bw. CIR Panel Book Page 17

21 Inhalation The acute inhalation toxicity of a mixture containing ethanolamine (as well as hydroxylamine, 1-amino-propano-2- ol, catechol, and water; percent of each not specified) was determined using groups of 5 male and 5 female rats. The inhalation LC 50 of the mixture was estimated to be 2.48 mg/l. 22 Other The intraperitoneal (i.p.) LD 50 of ethanolamine was 1.05 g/kg for mice. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 Repeated Dose Toxicity Dermal Percutaneous application of 4 mg/kg/day ethanolamine to rats resulted in nonspecific histological changes in the heart and lung, fatty degeneration of the liver parenchyma, and subsequent focal liver necrosis. The duration of dosing was not specified. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 Oral Groups of 10 rats were fed g/kg/day ethanolamine for 90 days. Heavy livers and kidneys were observed at 0.64 g/kg/day, and deaths and major pathology occurred with 1.25 g/kg/day. In a 2-yr dietary study in which groups of 12 beagle dogs were fed g/kg/day of a hair dye composite that contained 22% ethanolamine, no toxic effects were observed. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 Inhalation The dominant effects of continuous exposure of dogs, guinea pigs, and rats to 5-6 ppm ethanolamine vapor were skin irritation and lethargy. No dogs or rodents exposed to ppm ethanolamine vapor for 90 days died, but mortality was reported in dogs exposed to 102 ppm ethanolamine vapor for 2 days and rodents exposed to ppm ethanolamine vapor for days. Dogs and rodents exposed to ppm ethanolamine vapor had behavioral changes, pulmonary and hepatic inflammation, hepatic and renal damage, and hematological changes. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Dermal developmental toxicity studies were performed using rats and rabbits. In a study in which gravid rats were dosed with mg/kg bw/day ethanolamine on days 6-15 of gestation, the no-observed effect level (NOEL) for maternal toxicity was 75 mg/kg/day and for embryonal/fetal toxicity was 225 mg/kg/day. In rabbits that were dosed with mg/kg bw/day ethanolamine on days 6-18 of gestation, the NOEL for maternal toxicity was 10 mg/kg bw/day and for embryonal/fetal toxicity was 75 mg/kg bw/day. Significant skin irritation was observed in the high dose groups for both rats and rabbits. In a Chernoff-Kavlock post-natal mouse screening assay, oral dosing with 850 mg/kg/day ethanolamine on days 6-15 of gestation resulted in 16% mortality of maternal mice and a reduced number of viable litters. In a study in which Wistar rats were gavaged with mg/kg bw/day aq. ethanolamine on days 6-15 of gestation, the NOEL for maternal toxicity was 120 mg/kg/day and for developmental toxicity was 450 mg/kg/day. In an oral study in which Long-Evans rats were dosed with mg/kg aq. ethanolamine on days 6-15 of gestation, there was no significant maternal toxicity, but embryolethality was increased in the 500 mg/kg group, and more reproductive and developmental effects were observed involving male pups compared to female pups. There was an increase in malformed pups in all dose groups. In a dietary two-generation study in rats with mg/kg bw/day ethanolamine HCl, the no-observed adverse effect level (NOAEL) for systemic toxicity and for reproductive effects was 300 mg/kg bw/day, and the NOAEL for developmental toxicity was 1000 mg/kg bw/day. Dermal The developmental toxicity of dermally-applied aq. ethanolamine was evaluated using groups of gravid Sprague-Dawley rats and 15 gravid New Zealand White rabbits Ethanolamine was applied at doses of 0, 10, 25, 75, and 225 mg/kg bw/day to the backs of rats on days 6-15 of gestation, with a dose volume of 1 ml/kg. Significant skin irritation, consisting of erythema followed by necrosis, scabs, and scar formation, occurred with 225 mg/kg ethanolamine, but not at the other dose levels. No effects on kidney or liver weights were reported. Despite maternal effects in the 225 mg/kg dose group, no effects on reproductive parameters were observed at any dose, and there were no treatment-related increases in the CIR Panel Book Page 18

22 visceral or skeletal malformations. In rats, the no-observed effect level (NOEL) for maternal toxicity was 75 mg/kg/day and for embryonal/fetal toxicity, it was 225 mg/kg/day. In rabbits, 0, 10, 25, and 75 mg/kg bw/day ethanolamine was applied to the back (2 ml/kg) on days 6-18 of gestation. Severe skin irritation at the application site, consisting of necrosis, exfoliation, and crusting, was observed in the 75 mg/kg group, and crusting, transient erythema, and edema were observed in a few rabbits of the 25 mg/kg dose group. No effects on kidney or liver weights were reported. As with the rats, no effects on reproductive parameters were observed at any dose, and there were no treatment-related increases in the visceral or skeletal malformations. In rabbits, the NOEL for maternal toxicity was 10 mg/kg bw/d and for embryonal/fetal toxicity, it was 75 mg/kg/day, the highest dose tested. Oral Ethanolamine No reproductive or developmental effects were observed in groups of gravid rats given a hair dye and base containing 22% ethanolamine in the diet at concentrations 7800 ppm on days 6-15 of gestation. No differences in reproductive or developmental parameters were observed when male rats were fed treated diet for 8 wks prior to and during mating with undosed females or when female rats were fed treated feed for 8 wks prior to dosing until day 21 of lactation. These females were mated with undosed males. Additionally, no teratologic effects were induced by dosing gravid rabbits with 19.5 mg/kg/day of the hair dye and base by gavage on days 6-18 of gestation. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Ethanolamine. 1 The teratogenic potential of ethanolamine was evaluated in a Chernoff-Kavlock postnatal mouse screening assay. 24 Gravid CD-1 mice were dosed orally with 850 mg/kg/day ethanolamine on days 6-15 of gestation, resulting in 16% mortality of maternal mice and reduced numbers of viable litters. Litter size, percentage survival of pups, birth weight, and pup weight gains were not affected. A preliminary study was performed in which gravid Wistar rats were dosed orally with mg/kg by/day aq. ethanolamine; details not provided. 25 Maternal effects were observed in the high dose animals, but no embryonal/fetal effects were observed at any dose. Based on these results, groups of 40 Wistar rats were dosed by gavage with 0, 40, 120, or 450 mg/kg bw/day aq. ethanolamine on days 6-15 of gestation. On day 20 of gestation, 25 dams/group were killed and necropsied, while the remaining 15 were allowed to litter, and then killed on day 21 of lactation. Despite evidence of maternal toxicity in the 450 mg/kg group, as indicated by statistically significant decreases in maternal body weights and feed consumption, no effects on reproductive parameters, incidences of visceral or skeletal malformations, or postnatal growth were observed at any dose. The NOELs for maternal and developmental toxicity were 120 and 450 mg/kg/day, respectively. Groups of 10 gravid Long-Evans rats were dosed by gavage with 50, 300, or 500 mg/kg aq. ethanolamine on days 6-15 of gestation, and a negative control group of 34 gravid rats were dosed with water only. 26 The animals were killed and examined on day 20 of gestation. Significant maternal toxicity was not noted. Embryolethality was significantly increased in the 500 mg/kg group, with male pups affected more than female pups. Male pups were more severely affected than female pups at all dose levels in regards to intrauterine growth retardation and increased gross structural anomalies that were considered indicative of depressed fetal growth. However, pups of either sex who were contiguous to male siblings were more adversely affected that those contiguous to one or more female siblings. Male pups contiguous to male siblings (mmm) were, apparently, resorbed (mrm). The number of malformed pups per dam was significantly increased in animals dosed with 300 mg/kg ethanolamine. The number of malformed pups, when evaluated as a percent of the litter affected, was significantly increased for all 3 dose groups. Ethanolamine HCl Groups of 25 male and 25 female Wistar rats (F 0 parental generation) were fed 0, 100, 300, or 1000 mg/kg bw/d ethanolamine HCl for at least 75 days prior to mating. 18 Twenty-five male and 25 female F 1 pups/group were continued on 8 CIR Panel Book Page 19

23 the test diets of their parents, and then mated, becoming the F 1 parental generation. The study was terminated after the weaning of the F 2 pups. No test substance-related adverse reproductive, developmental, or toxic effects were observed in any of the pups or parental animals of the 100 or 300 mg/kg bw/d groups. In the 1000 mg/kg group, adverse effects on fertility and reproduction were evidenced by statistically significant decreases in absolute and relative weights of the epididymides and cauda epididymidis in male and statistically significant decreased number of implantation sites, increased postimplantation loss, and smaller litters in female F 0 and F 1 parents. Sperm head count in the cauda epididymidis and absolute and relative liver weights were also statistically significantly decreased in male F 0 parents. Body weight gains of both the F 0 and F 1 parental animals were statistically significantly decreased during gestation when compared to controls, as was feed consumption during lactation. There were no test-related signs of developmental toxicity observed in F 1 and F 2 pups of this dose group. The no-observed adverse effect level (NOAEL) for systemic toxicity and for reproductive effects was 300 mg/kg bw/d, and the NOAEL for developmental toxicity was 1000 mg/kg bw/d, which was the highest dose tested. GENOTOXICITY In Vitro ethanolamine, with and without metabolic activation using liver preparations from rats induced with a polychlorinated biphenyl mixture, was not mutagenic to Salmonella typhimurium TA100 or TA1535. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 Ethanolamine was negative in most Ames tests at concentrations 2000 μg/plate; 27,28 however weak mutagenic effects were reported in one study. 29 Ethanolamine, µg/ml, was negative in a cell transformation assay using hamster embryo cells. 30 Ethanolamine was clearly cytotoxic at 500 µg/ml. Ethanolamine did not produce chromosomal aberrations in rat liver cells, 27 but a weak positive response was reported in human lymphocytes. 29 (Concentrations tested were not provided.) Skin IRRITATION AND SENSITIZATION Ethanolamine HCl did not have a sensitizing effect in a local lymph node assay. In a maximization study with intradermal and epicutaneous inductions of 0.6 and 10.3% aq. ethanolamine, respectively, in guinea pigs, positive reactions were observed at challenge. Possible cross-reactions to 5% TEA and 7% DEA were reported. In provocative testing of metalworkers with dermatitis, a higher reaction to ethanolamine was observed for the patients as compared to control subjects. In a study of hairdressers and clients, cosensitization to DEA was reported for 38% of the patients that reacted to ethanolamine. Ethanolamine was classified as a moderate irritant in in vitro studies of ocular irritation potential. Irritation Non-Human Ethanolamine was corrosive to rabbit skin with single semi-occlusive patches of 30, 85 and 100% on intact and abraded skin. When applied to rabbit ears using non-occlusive applications and to shaved skin of the abdomen under semi-occlusive patches, 10% was corrosive, >1% was extremely irritating, and 1% was irritating. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 Human In a study in which a formulation containing 5.9% ethanolamine was applied to the backs of 12 female subjects for 23 h/day for 21 days, the formulation was considered an experimental cumulative irritant. Results observed during the induction phase of a patch test of 165 subjects using a formulation containing 11.47% ethanolamine were interpreted by the Expert Panel as irritation. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 9 CIR Panel Book Page 20

24 Sensitization Non-Human A local lymph node assay was performed to evaluate the sensitization potential of ethanolamine (as the hydrochloride salt). 15,31 Groups of 6 female CBA/Ca mice were treated on the ear with 10, 40, or 70% w/w aq. ethanolamine HCl. Ethanolamine HCl did not have a skin sensitizing effect. In a maximization study using 15 Dunkin-Hartley guinea pigs, intradermal and epicutaneous inductions with 0.6% and 10.3% aq. ethanolamine, respectively, were performed after 10% sodium lauryl sulfate pre-treatment. 15 (Ethanolamine contained less than 0.1% DEA and TEA.) At challenge with 0.41, 2.05, or 4.1% ethanolamine, 3, 2, and 3 animals, respectively, reacted positively after 3 days. Two of the 15 test animals reacted to the vehicle, but none of the control animals reacted to ethanolamine or the vehicle. Possible cross-reactions to 5% TEA occurred in 3 animals, and to 7% DEA in 2 animals. In a second test using the same protocol, no animals reacted to 0.41% ethanolamine, 2 reacted to 2.05% ethanolamine, and 1 reacted to 4.1% ethanolamine. Additionally, 1 animal reacted to 10% TEA and 2 reacted to 7% DEA. The control animals did not react to any of the ethanolamines. Human A formulation containing 5.9% ethanolamine, tested undiluted, and one containing 11.47% ethanolamine, tested at 5% in 25% alcohol, were not sensitizing in clinical studies. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 Provocative Testing Metalworkers that were dermatitis patients were patch tested with 2% ethanolamine in pet. 32 applied for 1-2 days. On day 3, 3 of 155 patients (1.9%) had positive reactions. dermatitis. 33 The patches were Patch testing was performed with 2% ethanolamine in pet. in 199 patients with suspected metalworking fluid contact (All patients were metalworkers.) Patches were applied for 1 or 2 days. On day 3, 40 patients had positive reactions, 16 (?), 19 (+), 4 (++), and 1 (+++). The % positive reactions were 11.6%. A patch test using 2% ethanolamine in petrolatum was performed on 370 patients with suspected dermatitis to ethanolamine-containing metal-working fluids and on 452 control subjects. 34 A 10-fold higher reaction was seen in the patient group, with 12.2% of the patients having positive reactions, as compared to 1.3% in the control group. Over a 3-yr period, 11/595 (1.9%) hairdresser clients and 7/401 (1.8%) female hairdressers reacted positively to 2% ethanolamine pet. 15 In 22 patients with suspected intolerance to oxidative hair dye components, 4 had a positive reaction to 2% ethanolamine pet. Over a 15-yr period, provocative patch testing using ethanolamine was performed on 9602 subjects. There were 363 (3.8%) positive reactions to ethanolamine, and most of the reactions (277; 2.9%) were weak positives. There were 55 (0.6%) irritant reactions reported. Cosensitization was reported; 38% of the patients that reacted to ethanolamine also tested positive to DEA. Occupational sensitization was reported; of 5884 male patients, 2.9% that did not work in the metal industry had positive reactions as opposed to 7.0 and 15.2% of those working in the metal industry and those exposed to water-based metalworking fluids, respectively. Ocular Irritation Non-Human Using 6 rabbits, 30% aq. ethanolamine was moderately irritating to rabbit eyes. Undiluted ethanolamine, instilled as a volume of ml, produced severe injury to rabbit eyes. A hair preparation containing 5.96% ethanolamine had a maximum avg. irritation score of 0.7/110 for rinsed and unrinsed eyes. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine CIR Panel Book Page 21

25 In Vitro Ethanolamine The ocular irritation potential of ethanolamine was evaluated in several in vitro studies. The ocular irritation potential of ethanolamine was evaluated in the rabbit corneal epithelium model at concentrations of 0.05, 0.5, and 1%; ethanolamine was classified as a moderate irritant at these concentrations. 35 OCCUPATIONAL EXPOSURE Ethanolamine inhalation by humans has been reported to cause immediate allergic responses of dyspnea and asthma and clinical symptoms of acute liver damage and chronic hepatitis. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 A case of occupational asthma in an industrial worker exposed to a detergent containing 8% ethanolamine was reported. 36 Since the detergent was used in hot water, release of ethanolamine vapor was greater than if the detergent temperature was lower. Exposure to vapors from ethanolamine in cleaning solutions can irritate the nose, throat, and lungs. 37 Occupational Exposure Limits The Occupational Safety and Health Administration permissible exposure level for ethanolamine is 3 ppm (8 mg/m 3 ) as an 8-hr time-weighted average concentration. 38 The National Institute for Occupational Health and Safety (NIOSH) has a recommended exposure limit (REL) of 3 ppm (8 mg/m 3 ) for a 10 h workday and 40 h work week; the shortterm exposure limit (STEL) is 6 ppm (15 mg/m 3 ), for periods not to exceed 15 min. 39 The threshold limit value set by the American Conference of Governmental Industrial Hygienists is the same as the REL set by NIOSH, and the STEL is also the same. 38 MISCELLANEOUS STUDIES Effect on Hepatic Choline The effects of ethanolamine HCl on hepatic choline was determined in the F 0 and F 1 parental rats from the twogeneration feeding study described earlier in this report. 40 Liver weights were determined for all parental rats at necropsy, and the livers of control and high-dose animals (1000 mg/kg bw/day) were examined microscopically. Feeding ethanolamine HCl to rats did not affect liver weights of any of the animals. No adverse microscopic affects in the livers of high-dose rats were reported. Liver samples of F 1 female rats of the test and control groups were analyzed for choline, phosphocholine, glycerophosphocholine, and phosphatidylcholine. A statistically significant increase in phosphocholine and phosphatidylcholine was observed in the 100 and 300 mg/kg bw/day dose groups, but no other statistically significant difference in choline content were reported. In that there was no dose-response, these effects were not considered dose-related. The researchers concluded that based on the combined hepatic observations, ethanolamine hydrochloride does not affect hepatic choline metabolism in the rat. Effect on Bronchoconstriction The effect of ethanolamine on bronchoconstriction was investigated using a group of 4 anesthetized male Hartley guinea pigs. 41 When an aerosol of 0.1 ml/kg of 3.3% ethanolamine solution was inhaled through a tracheal cannula, bronchoconstriction was observed. The results were compared to those obtained using an aerosol of potassium hydroxide. Bronchoconstriction induced by ethanolamine was greater than that induced by potassium hydroxide. Additional testing suggested that ethanolamine-induced bronchoconstriction may not result from induction of acetylcholine or histamine release, but that they may result partly from an agonistic effect of ethanolamine at the histamine-h 1 receptor and the muscarinic receptor. 11 CIR Panel Book Page 22

26 SUMMARY This report assesses the safety of ethanolamine and ethanolamine-containing ingredients as used in cosmetics. The ethanolamine salts are expected to dissociate into ethanolamine and the corresponding acid. Ethanolamine typically contains a small amount of DEA. Ethanolamine functions in cosmetic formulations as a ph adjuster. The organic salts and the organic-substituted inorganic salts mostly function as surfactants, with the exception of MEA-benzoate and MEA-salicylate, which are preservatives. Many of the alkyl substituted ethanolamines, as well as ethanolamine HCl, are reported to function as ph adjusters. Other reported functions in this category include anti-static agent, skin conditioning agent, and skin protectant. MEA-sulfite is reported to function as a hair fixative. In 2011, ethanolamine was reported to be used in 764 formulations, 750 of which are hair coloring formulations; one use was in a leave-on formulation. Of the ethanolamine-containing ingredients that are in use, none have more than 15 uses. Ethanolamine is reported to be used at concentrations of %. MEA-lauryl sulfate has the highest reported concentration of use at 35% in rinse-off formulations. The only leave-on use concentration reported is for MEA-hydrolyzed collagen, with a maximum use concentration of 0.2%. In Europe, monoalkylamines, monoalkanolamines, and their salts are on the list of substances which must not form part of the composition of cosmetic products, except subject to restrictions and conditions laid down. These restrictions include a maximum secondary amines contaminant content of 0.5% in finished products, a maximum secondary amines content of 0.5% in raw materials, and a maximum nitrosamine content of 50 µg/kg. Ethanolamine is the only naturally occurring ethanolamine in mammals; it occurs in phospholipids known as phosphatides. In an in vitro study, absorption of undiluted and aq. ethanolamine was much greater through mouse skin than it was through human, rat, or rabbit skin; human skin was the least permeable. The cumulative dose absorbed through mouse and human skin was greater with aq. ethanolamine compared to undiluted ethanolamine; 16.92%of the undiluted and 24.79% of the aq. ethanolamine absorbed through mouse skin while 0.61% undiluted and 1.11% aq. ethanolamine absorbed through human skin. In split-thickness pig skin, 5% of the dose of ethanolamine HCl in ethanol penetrated percutaneously. In a metabolism and distribution study, ethanolamine HCl was applied dermally to human skin-grafted and ungrafted athymic nude mice. Radioactivity was recovered in the skin (18.4% recovered in grafted skin; 12.1% in ungrafted skin), liver (~24-26%), and kidneys (~2%). Approximately 5% of the radioactivity was recovered in the urine; 10% of the radioactivity recovered in the urine was unchanged ethanolamine, and the major urinary metabolites were urea and glycine. In an oral study in Wistar rats fed a diet containing mg/kg ethanolamine HCl for 10 wks, plasma ethanolamine concentrations increased in a dose-dependent manner from <3 mg/kg in control animals and <4 mg/kg in low dose animals to mg/kg in high-dose animals. Single applications of 5 and 10% ethanolamine were mildly toxic to mouse skin. The dermal LD 50 in rabbits was g/kg ethanolamine. Oral LD 50 values were g/kg in mice and g/kg in rabbits. The inhalation LC 50 of a mixture containing ethanolamine, hydroxylamine, 1-aminopropanolo-2-ol, catechol, and water was 2.48 mg/l. Percutaneous application of 4 mg/kg/day ethanolamine to rats for an unspecified length of time resulted in nonspecific histological changes in the heart and lung, fatty degeneration of the liver parenchyma, and subsequent focal liver necrosis. In a dietary study in which rats were fed g/kg/day ethanolamine for 90 days, heavy livers and kidneys were observed at 0.64 g/kg/day, and deaths and major pathology occurred with 1.25 g/kg/day. In a 2-yr dietary study in which beagle dogs were fed g/kg/day of a hair dye composite that contained 22% ethanolamine, no toxic effects were observed. In repeated-dose inhalation studies, the dominant effects of continuous exposure of dogs, guinea pigs, and rats to 5-6 ppm ethanolamine vapor were skin irritation and lethargy; mortality was observed in dogs exposed to 102 ppm ethanolamine vapor for 2 days 12 CIR Panel Book Page 23

27 and some rodents exposed to ppm ethanolamine vapor for days. Dogs and rodents exposed to ppm ethanolamine vapor had pulmonary and hepatic inflammation, hepatic and renal damage, and hematological changes. Dermal developmental toxicity studies were performed using rats and rabbits. In a study in which gravid rats were dosed with mg/kg bw/day ethanolamine on days 6-15 of gestation, the no-observed effect level (NOEL) for maternal toxicity was 75 mg/kg/day and for embryonal/fetal toxicity, it was 225 mg/kg/day. In rabbits that were dosed with mg/kg bw/day ethanolamine on days 6-18 of gestation, the NOEL for maternal toxicity was 10 mg/kg bw/day and for embryonal/fetal toxicity, it was 75 mg/kg bw/day. Significant skin irritation was observed in the high dose groups for both rats and rabbits. In a Chernoff-Kavlock post-natal mouse screening assay, oral dosing with 850 mg/kg/day ethanolamine on days 6-15 of gestation resulted in 16% mortality of maternal mice and a reduced number of viable litters. In a study in which Wistar rats were gavaged with mg/kg bw/day aq. ethanolamine on days 6-15 of gestation, the NOEL for maternal toxicity was 120 mg/kg/day and for developmental toxicity was 450 mg/kg/day. In an oral study in which Long-Evans rats were dosed with mg/kg aq. ethanolamine on days 6-15 of gestation, there was no significant maternal toxicity, but embryolethality was increased in the 500 mg/kg group, and more reproductive and developmental effects were observed involving male pups compared to female pups. There was an increase in malformed pups in all dose groups. In a dietary two-generation study in rats with mg/kg bw/day ethanolamine HCl, the no-observed adverse effect level (NOAEL) for systemic toxicity and for reproductive effects was 300 mg/kg bw/day, and the NOAEL for developmental toxicity was 1000 mg/kg bw/day. The effect of ethanolamine HCl on hepatic choline was investigated in the F 0 and F 1 parental rats, and it was concluded that ethanolamine HCl did not affect the hepatic choline metabolism in the rat. Ethanolamine was mostly negative in Ames tests ( 2000 μg/plate). Ethanolamine ( 500 μg/ml) was negative in a cell transformation assay. Ethanolamine did not produce chromosomal aberrations in rat liver cells, but did produce a weak positive response in human lymphocytes. In non-human studies, semi-occlusive application of % ethanolamine was corrosive to rabbit skin. Irritation responses ranging from irritating to corrosive were observed with 1-10% ethanolamine, respectively, applied non-occlusively to rabbit ears and under semi-occlusive patches to rabbit skin. The degree of irritation increased with the concentration applied. In human studies, a formulation containing 5.9% ethanolamine was a cumulative irritant in a 21-day study, and an irritant response was reported during the induction phase of patch test of a formulation containing 11.47% ethanolamine. Ethanolamine did not have a sensitizing effect in a local lymph node assay. In a maximization study with intradermal and epicutaneous inductions of 0.6 and 10.3% aq. ethanolamine, respectively, in guinea pigs, positive reactions were observed at challenge. Possible cross-reactions to 5% TEA and 7% DEA were reported. In provocative testing of metalworkers with dermatitis, a higher reaction to ethanolamine was observed for the patients as compared to control subjects. In a study of hairdressers and clients, cosensitization to DEA was reported for 38% of the patients that reacted to ethanolamine. In ocular irritation studies in rabbits, 30% aq. ethanolamine was moderately irritating to rabbit eyes, and undiluted ethanolamine produced severe injury. A hair preparation containing 5.96% ethanolamine had a maximum average irritation score of 0.7/110 in rinsed and unrinsed eyes. Ethanolamine was classified as a moderate irritant in in vitro studies of ocular irritation potential. An aerosol of 0.1 ml/kg of 3.3% ethanolamine solution induced bronchoconstriction in guinea pigs. Ethanolamineinduced bronchoconstriction may result partly from an agonistic effect of ethanolamine at the histamine-h 1 receptor and the muscarinic receptor. 13 CIR Panel Book Page 24

28 PART II: ETHANOLAMIDES INTRODUCTION Isostearamide MEA, myristamide MEA, and stearamide MEA were reviewed by the CIR Expert Panel in The Panel concluded that these ingredients are safe for use in rinse-off products. In leave-on products, these ingredients are safe for use at concentrations that will limit the release of free ethanolamine to 5%, but with a maximum use concentration of 17% for isostearamide, myristamide, and stearamide MEA. These ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed. The following 49 ingredients are being considered for inclusion of a re-review of isostearamide MEA, myristamide MEA, and stearamide MEA: Acetamide MEA* Azelamide MEA Babassuamide MEA Behenamide MEA C16-22 Acid Amide MEA Cocamide MEA* Cocamide Methyl MEA Cocamidopropyl Betainamide MEA Chloride Deoxyphytantriyl Palmitamide MEA Hexyloxodecanamide MEA Hexyloxodecanamide MEA Phosphate Hydroxyethyl Pantothenamide MEA Hydroxypropyl Bisisostearamide MEA Hydroxypropyl Bislauramide MEA Hydroxypropyl Bispalmitamide MEA Hydroxypropyl Bisstearaminde MEA Hydroxystearamide MEA Isostearamide MEA* Lactamide MEA Lauramide MEA Linoleamide MEA Myristamide MEA* Myristoyl/Palmitoyl/Oxostearmide/Arachamide MEA Oatamide MEA Oleamide MEA Oliveamide MEA Palm Kernelamide MEA Palmamide MEA Palmitamide MEA Pantothenamide MEA Peanutamide MEA Ricinoleamide MEA Stearamide MEA* Stearamide MEA Stearate Stearamidoethyl Ethanolamine Sunfloweramide MEA Tallowamide MEA Trideceth-2 Carboxamide MEA Undecylenamide MEA Glycol Ethers PEG-2 Cocamide PEG-3 Cocamide PEG-4 Cocamide PEG-5 Cocamide PEG-6 Cocamide PEG-7 Cocamide PEG-9 Cocamide MEA PEG-11 Cocamide PEG-20 Cocamide PEG-20 Cocamide MEA The ingredients marked with an asterisk (*) also have been reviewed previously by the CIR Expert Panel. In 1993, the Panel concluded that acetamide MEA is safe as used as a cosmetic ingredient at concentrations not to exceed 7.5% in leave-on products and is safe in the present practices of use in rinse-off products; cosmetic formulations containing acetamide MEA should not contain nitrosating agents or significant amounts of free acetamide. 43 (Acetamide MEA was reported to be used at up to 25% in rinse-off products.) This conclusion was reaffirmed in Cocamide MEA was reviewed in 1999; the Panel concluded that cocamide MEA is safe as used in rinse-off cosmetic products and safe at concentrations up to 10% in leave-on products. 44 (Cocamide MEA was reported to be used at up to 25%, but the types of products, i.e., rinse-off or 14 CIR Panel Book Page 25

29 leave-in, were not specified.) Cocamide MEA should not be used as an ingredient in cosmetic products containing N- nitrosating agents, or in product formulations intended to be aerosolized. The structures of the ethanolamides are provided in Table 1b. The ingredients included in this review consist of ethanolamine and one or more components. The safety of many of these components has been reviewed by the CIR. The conclusions of the previously reviewed ingredients, and of the components that have been reviewed, are provided in Table 2b. CHEMISTRY The ethanolamides consist of covalent, secondary amides, whereby one of the nitrogen substituents is ethanol (or at least an ethanol residue) and the second is a carbonyl attached substituent. For example, myristamide MEA is a secondary amide wherein one of the nitrogen substituents is ethanol and the second is a fourteen carbon, carbonyl attached chain (Figure 4). These ingredients are not salts and do not readily dissociate in water. However, amidases, such as fatty acid amide hydrolase (FAAH) which is known to be present in human skin, could potentially convert these amides to ethanolamine and the corresponding fatty acids. Secondary amides do tend to react with nitrosating agents to form nitrosamides. Figure 4. Myristamide MEA Chemical and physical properties of ethanolamides are summarized in Table 3b. Method of Manufacture Ethanolamine reacts with long-chain fatty acid esters in a 1:1 mole ratio to produce a 90+% pure, crystalline ethanolamide mixture. 7 Two different routes of synthesis of ethanolamides are common: direct acylation with free fatty acids and transacylation using fatty acid esters (often enzymatically). 45,46 Ethanolamides can be produced via enzymatic amidification; monoacylated ethanolamine can be isolated from the reaction mixture. The reaction is carried out using an equimolar ratio of fatty acid and ethanolamine. The enzyme is filtered upon completion of the reaction, and the product is dissolved in a mixture of methanol and chloroform. The solvent is then eliminated by evaporation, and the resulting solid is the amide. Acetamide MEA Acetamide MEA is prepared by the reaction of acetic acid with ethanolamine. Additional methods of production, involving acetamide and ethylene oxide, ethanolamine and acetyl chloride, have been reported. From The Final Report on the Safety Assessment of Acetamide MEA 43 Impurities Acetamide MEA Analysis of 4 lots of acetamide MEA by gas chromatography-mass spectrometry indicated the presence of % ethanolamine and % acetamide. Using high-performance liquid chromatography, N-nitrosodiethanolamine was not detected (limit of detection = ppm) in acetamide MEA. From The Final Report on the Safety Assessment of Acetamide MEA 43 Myristamide MEA The maximum free amine content of myristamide MEA is 1.5%. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA 42 Stearamide MEA Stearamide DEA has 0.8% max. free fatty acids (as stearic acid), % free amine (as ethanolamine), and % total fatty acids (as stearic acid). From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA CIR Panel Book Page 26

30 USE Cosmetic Most of the ethanolamides are reported to function in cosmetics as hair conditioning agents, skin conditioning agents, and surfactant foam boosters; a few are reported to have other uses. 8 In 1995, data provided through to FDA VCRP indicated that isostearamide MEA was used in 1 and stearamide MEA was used in 22 cosmetic formulations. 42 Isostearamide MEA was reported to be used in leave-on products at concentrations of up to 15% and in rinse-off products at up to 6%, and stearamide MEA was reported to be used at concentrations of up to 25%. Myristamide MEA was not reported to be used. VCRP data obtained in 2011 indicate that the use of stearamide MEA has decreased, with only 10 reported uses. 9 Myristamide MEA has one reported use, and isostearamide MEA does not have any uses reported. Other ethanolamides have many more reported uses. Cocamide MEA has the highest frequency of use with 1122 reported uses; only 33 of those uses are in leave-on products. Trideceth-2 carboxamide has 189 reported uses, and acetamide MEA is reported to be used in 148 formulations. The use information for the ethanolamides is summarized in Table 5a. According to data submitted by industry in response to a recent survey conducted by the Personal Care Products Council (Council), cocamide MEA is reported to be used at up to 18% in rinse-off formulations and at up to 5% in leave-on formulations. Stearamide MEA has the highest concentration of use in leave-on formulations at up to 15%. The ethanolamides that are not reported to be in use, according to VCRP data and the Council survey, are listed in Table 5b. Monoalkylamines, monoalkanolamines, and their salts are listed by the European Commission in Annex III Part 1: the list of substances which cosmetic products must not contain, except subject to the restrictions and conditions laid down. 12 These ingredients are allowed a maximum secondary amine content of 0.5% in finished product; are not use to be used with nitrosating agents; must have a minimum purity of 99%; the maximum secondary amine content of 0.5% is allowed for raw materials; maximum nitrosamine content allowed is 50 µg/kg; and must be kept in nitrite-free containers. Acetamide MEA and babassuamide MEA are the only ethanolamides listed in this category. All the other ethanolamides, with the exception of PEG-9 cocamide MEA (which in not an INCI ingredient), are listed in the EU inventory. Dermal TOXICOKINETICS Published toxicokinetic data were not found. TOXICOLOGICAL STUDIES In an acute dermal study in rabbits, the LD 50 for cocamide MEA was > 2g/kg, which was the highest dose tested. In oral studies, the LD 50 of cocamide MEA was >5 g/kg in rats and >10 g/kg in mice. In a 14-day oral study, the NOAEL of cocamide MEA in rats was >750 mg/kg/day, which was the highest dose tested. Acute (Single) Dose Toxicity Acetamide MEA No deaths occurred when rabbits were dosed dermally with 20 ml/kg acetamide MEA. From The Final Report on the Safety Assessment of Acetamide MEA 43 Cocamide MEA The dermal LD 50 of cocamide MEA was >2 g/kg, the highest dose tested, in male and female rabbits. Occlusive patches were applied to abraded and intact skin for 24 h. 47,48 16 CIR Panel Book Page 27

31 Oral Cocamide MEA The acute oral toxicity of cocamide MEA (purity not specified) was evaluated in a number of studies using rats In most studies, the highest dose administered was 5 g/kg or 5 ml/kg; the LD 50 was greater than this dose. In a study in which doses of 1-32 g/kg were used, the LD 50 was reported to be 7.4 g/kg in rats 47,48 cocamide MEA was identified as 3.3 g/kg and >3.125 g/kg, respectively. 49 In two other rat studies, the oral LD 50 of In studies in mice, the oral LD 50 of cocamide MEA was >10 g/kg in most studies. However, a value of g/kg was reported in one study using mice. (Details were not provided.) Acetamide MEA The oral LD 50 of acetamide MEA has been reported as and as g/kg in rats. The acute toxicity of two hair products containing 1.3% acetamide MEA was >16.9 g/kg for one product and >25 ml/kg for the other; these were the highest concentrations tested. From The Final Report on the Safety Assessment of Acetamide MEA 43 Lauramide MEA The oral LD 50 of lauramide MEA was >2 g/kg in rats. 50 Tallowamide MEA (The following is being provided for read-across use.) The oral LD 50 of hydrogenated tallow amide was >5 g/kg bw in male and female rats; 5 g/kg was the highest dose tested. 47 Dermal Repeated Dose Toxicity Acetamide MEA In a 13-wk study, a hair product containing 1.3% acetamide MEA, applied as an aq. solution that was diluted to 50% w/v, was not toxic to rabbits. Slight-to-moderate erythema was observed sporadically at the application site from days of the study. From The Final Report on the Safety Assessment of Acetamide MEA 43 Cocamide MEA Cocamide MEA, 25% in olive oil, was applied to mice twice a day for 1 wk, and the application site was not covered. 49 No dermal reactions were observed. Additional details were not provided. Stearamide MEA The dermal toxicity of a formulation containing 17.0% stearamide MEA was evaluated in a 4-wk study in rabbits. Two g/kg of a 10% aq. solution of the formulation was applied to intact and abraded skin; no gross or microscopic lesions were observed. In a 13-wk dermal study, a formulation containing 5.27% stearamide MEA was not toxic in rats. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA 42 Oral Cocamide MEA Groups of 10 male and 10 female Wistar rats were dosed by gavage with 0, 70, 250, and 750 mg/kg bw/day cocamide MEA in olive oil; the high dose was increased to 1500 mg/kg bw after 14 days The animals were dosed once daily, 5x/wk, for 4 wks. Recovery groups of 5 male and 5 female rats per dose level were included. None of the animals died, and no significant test-article related gross or microscopic lesions were observed. The NOAEL was >750 mg/kg bw/day. REPRODUCTIVE AND DEVELOPMENTAL TOXICITY Data on the reproductive and developmental toxicity of the ethanolamides were not found. Since ethanolamine may be present as an impurity in the ethanolamides, and since amidases in the skin might convert some of the ethanolamide to ethanolamine and the corresponding fatty acid, summary data from the reports on ethanolamine and a few components of these dialkanolamides is being provided. CIR Panel Book Page 28

32 MEA: In a dietary study, ppm of a composite hair dye and base containing 22% ethanolamine was fed to 60 gravid female rats on days 6-15 of gestation, and the rats were killed on day 19 of gestation. No developmental effects were observed. In another dietary study, 30 male rats were fed ppm of the hair for 8 wks prior to mating with female rats that were being fed a basal diet, while a group of 60 female rats were fed ppm of the test substance for 8 wks prior to mating with male rats being fed a basal diet. No effects on reproduction or fertility were observed. In rabbits, no developmental effects were observed when pregnant females were gavaged on days 6-18 of gestation with ml/kg/day of the hair day containing 22% ethanolamine. 1 Arachis Hypogaea (Peanut) Oil Peanut oil was used as the vehicle in a fertility study in rats. It was administered orally for 28 days prior to mating and for 6 days during mating. No unusual findings were noted in the vehicle group. No unusual finding were observed in a teratogenicity study in which rats were injected with a test article, and peanut oil was used as the vehicle. Treatment-related changes were not observed in a study in which rabbits were dosed intramuscularly with 21% peanut oil on day 8 of gestation. However, in a study of the effects of oil vehicles on early embryonic lethality in mice, it was stated that plant oils proved to be unsuitable carriers of test mutagens in female dominant-lethal studies where the route of administration is via the peritoneal cavity. 51 Hydroxystearic Acid The dermal teratogenicity of two formulations containing 7% hydroxystearic acid was evaluated using female rats. No teratogenic effects were observed. (However, dermal irritation was reported.) 52 Palm Oil: Crude palm oil was not a reproductive toxicant in a study in which male and female Wistar/NIN inbred weanling rats were fed a diet containing this ingredient (10%) prior to mating. Mean litter sizes were comparable between test and control groups. No significant changes were found in liver or kidney weight in adult animals. Neither untreated palm oil (15%) nor 15% heated palm oil in the diet induced anomalies with respect to fertility and in utero growth when fed to male and female Sprague-Dawley SPF rats prior to mating. In a study investigating the effects of palm oil on sexual maturation and endocrine function, vaginal opening was observed significantly earlier (compared to 5% corn oil control) in weanling rats fed 20% palm oil in the diet. No significant differences were observed in endocrine function. 53 Palm Kernel Oil: In the second generation resulting from the mating of adult Mongolian gerbils fed a diet containing 8.75% w/w palm kernel oil, no statistically significant differences were found with respect to the following: frequency of litters, mean litter size, total of newborns, and suckling death. Animals receiving a basal diet served as the control. 53 GENOTOXICITY In Vitro Acetamide MEA Acetamide MEA was not mutagenic in an Ames test, and acetamide MEA did not induce unscheduled DNA synthesis in primary rat hepatocytes. From The Final Report on the Safety Assessment of Acetamide MEA 43 Cocamide MEA In an Ames test, cocamide MEA was mutagenic in Salmonella typhimurium TA100 with metabolic activation; it was not mutagenic with S. typhimurium TA98, TA1535, TA1537, or TA1538, with or without metabolic activation using TA100 without metabolic activation. Cocamide MEA was not mutagenic in a plate incorporation assay. From The Final Report on the Safety Assessment of Cocamide MEA 44 The mutagenic potential of cocamide MEA was evaluated in an Ames test using S. typhimurium TA1535, TA1537, TA1538,TA98, and TA100, with and without metabolic activation. 47,48 Cocamide MEA, evaluated at doses of μg/plate, was not mutagenic. The use of controls was not specified. Lauramide MEA The mutagenic potential of lauramide MEA was evaluated in an Ames test with S. typhimurium TA98, TA100, TA1535, TA1537, and TA1538 at doses of μg/plate, with and without metabolic activation. 54 Doses of 3.3 and 10 μg/plate were tested with TA1537 without metabolic activation, and a dose of 10 μg/plate was tested in strains TA100 without metabolic activation. Negative controls were used and gave expected results. Lauramide MEA was not mutagenic in this assay. 18 CIR Panel Book Page 29

33 Skin IRRITATION AND SENSITIZATION Irritation Non-Human Acetamide MEA Acetamide MEA was a mild skin irritant in an open-patch Draize test in 12 rabbits. In another study, acetamide MEA (70% active) was not a primary irritant when applied to the intact and abraded skin of rabbits using a 24-h occlusive patch. From The Final Report on the Safety Assessment of Acetamide MEA 43 Cocamide MEA The irritancy potential of cocamide MEA in petrolatum was evaluated in a 24-h patch test in guinea pigs, rabbits, and hairless mice. Cocamide MEA was slightly irritating to rabbits, but was not irritating to guinea pigs and hairless mice. From The Final Report on the Safety Assessment of Cocamide MEA 44 The irritation potential of cocamide MEA was evaluated in rabbits. 49 rabbits when applied under an occlusive patch for 24 h. (Additional details were not provided.) Lauramide MEA In a Draize study, lauramide MEA was not irritating to rabbit skin. 50 Cocamide MEA, 25%, was not irritating to No details were provided. Stearamide MEA The primary irritation index of a formulation containing 17.0% stearamide MEA was 1.00/8 in a group of 3 rabbits. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA 42 Human Acetamide MEA In a dermal irritation study using 19 female subjects, a formulation containing 0.5% acetamide MEA did not evoke unacceptable clinical irritation and was comparable to the control product From The Final Report on the Safety Assessment of Acetamide MEA 43 Cocamide MEA Cocamide MEA, 50% in petrolatum, was not irritating when a single 24-h patch was applied to the arm of 4 subjects. From The Final Report on the Safety Assessment of Cocamide MEA 44 Stearamide MEA In a single-insult occlusive patch test with 19 subjects, a 1% aq. solution of a formulation containing 17% stearamide MEA, 7 subjects had questionable reactions and 3 subjects had mild reactions. In a 21-day, 14-subject, cumulative irritation study in which 0.2 ml of a formulation containing 5.0% stearamide MEA was applied using occlusive patches, slight irritation was observed, with a composite total score of 156/882. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA 42 Sensitization Non-Human Acetamide MEA Acetamide MEA was not a sensitizer in a maximization study using 10 guinea pigs. Induction included an intradermal injection of 5.0% acetamide MEA in propylene glycol and in Freund s complete adjuvant and a topical application of 10% acetamide MEA. From The Final Report on the Safety Assessment of Acetamide MEA 43 Cocamide MEA Cocamide MEA was not a sensitizer in a guinea pig maximization study. Details were not provided. Human Acetamide MEA In a 50-subject study, an aq. solution of 7.5% acetamide MEA did not cause primary irritation or sensitization. In an RIPT of a hair product containing 1.3% acetamide MEA, completed with 111 subjects, 12 subjects had mild reactions during induction and, and 2 of those subjects had mild reactions during challenge. However, the researchers concluded that a hair product containing 1.3% acetamide MEA was not a sensitizer. From The Final Report on the Safety Assessment of Acetamide MEA CIR Panel Book Page 30

34 Stearamide MEA In a repeated insult patch test (RIPT) using 100 subjects in which 0.1 ml a formulation containing 5.27% stearamide MEA was applied using occlusive patches, the formulation did not produce sensitization. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA 42 Ocular Irritation Non-Human Acetamide MEA Acetamide MEA (70% minimum activity) was practically non-irritation to the eyes of rabbits, and two hair formulations containing 1.3% acetamide MEA were not irritating to rabbit eyes. From The Final Report on the Safety Assessment of Acetamide MEA 43 Lauramide MEA In a Draize ocular irritation study, Lauramide MEA was highly irritating to rabbit eyes. 50 Details were not provided. Stearamide MEA A formulation containing 5.27% stearamide MEA was not irritating to rabbit eyes. Minimal irritation was reported in one study with a formulation containing 17.0% stearamide MEA, while moderate irritation was reported in another.. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA 42 SUMMARY This report assesses the safety of 49 Ethanolamides. This safety assessment originated as a re-review of isostearamide MEA, myristamide MEA, and stearamide MEA, and was expanded to include additional related ingredients. Some of these ingredients have been previously reviewed by the CIR, and are included here to create a report on the complete family of ingredients. Amidases, such as fatty acid amide hydrolase which is known to be present in human skin, could potentially convert the ethanolamides to ethanolamine and the corresponding fatty acids. The yield of ethanolamine from metabolism of ethanolamides in human skin is unknown. Secondary amides do not tend to react with nitrosating agents to form nitrosamides. Impurity data were available for acetamide, myristamide, and stearamide MEA: acetamide MEA contained up to % ethanolamine, % acetamide, and no N-nitrosodiethanolamine; myristamide contained a maximum of 1.5% ethanolamine; and stearamide MEA contained up to 2.0% free amine (as ethanolamine). Most of the ethanolamides are reported to function in cosmetics as hair conditioning agents, skin conditioning agents, and surfactant foam boosters; a few are reported to have other uses. In 2011, stearamide MEA was reported to have only 10 uses, myristamide MEA had one, and isostearamide had none. Cocamide MEA has the highest frequency of use with 1122 reported uses; only 33 of those uses are in leave-on products. Cocamide MEA is reported to be used at up to 18% in rinse-off formulations and at up to 5% in leave-on formulations. Stearamide MEA has the highest concentration of use in leave-on formulations at up to 15%. In Europe, monoalkylamines, monoalkanolamines, and their salts are on the list of substances which must not form part of the composition of cosmetic products, except subject to restrictions and conditions laid down. Acetamide MEA and babassuamide MEA are included in this list. These restrictions include a maximum secondary amines contaminant content of 0.5% in finished products, a maximum secondary amines content of 0.5% in raw materials, and a maximum nitrosamine content of 50 µg/kg. In an acute dermal study in rabbits, the LD 50 for cocamide MEA was > 2g/kg and for acetamide MEA, it was >20 ml/kg; these were the highest doses tested. In oral studies, the LD 50 of cocamide MEA was >5 g/kg in rats and >10 g/kg in mice. The oral LD 50 values in rats for acetamide and lauramide MEA were 27 g/kg and 2 g/kg, respectively. In a 14-day oral study, the NOAEL of cocamide DEA in rats was >750 mg/kg/day, the highest dose tested. 20 CIR Panel Book Page 31

35 No data on the reproductive and developmental toxicity of ethanolamides were found. Available reproductive and developmental toxicity data from previous CIR reports on ethanolamine and some of the component ingredients were summarized, and no significant toxic effects were noted. Cocamide MEA ( 2500 μg/plate) and lauramide MEA ( 3333 μg/plate) were not mutagenic in Ames test with or without metabolic activation. Acetamide MEA was at most a mild skin irritant in rabbits, and in humans, a formulation containing 0.5% acetamide MEA was not an irritant. Cocamide MEA was, at most, slightly irritating to rabbit skin, and it was not irritating to guinea pigs and hairless mice. In clinical testing, 50% cocamide MEA in petrolatum was not irritating. A formulation containing 17% stearamide MEA had a primary irritation score of 1/8 in rabbits; 5% stearamide MEA produced slight irritation in a cumulative irritation study. Acetamide MEA and cocamide MEA were not sensitizers in guinea pigs. In clinical testing, a solution of 7.5% acetamide MEA, a formulation containing 1.3% acetamide MEA, and a formulation containing 5.27% stearamide MEA were not sensitizers. Acetamide MEA (70% minimum activity) was practically non-irritating to rabbit eyes, and formulations containing 1.3% acetamide MEA and 5.27% stearamide MEA were not irritating to rabbit eyes. A formulation containing 17% stearamide MEA was a moderate ocular irritant and lauramide MEA was highly irritating to rabbit eyes. 21 CIR Panel Book Page 32

36 TABLES Table 1a. Definition and structures of ethanolamine and ethanolamine-containing ingredients Ingredient CAS No. Definition Formula/structure MEA and Inorganic Acid Salts Ethanolamine Ethanolamine is a primary amine with one ethanol functional group. Ethanolamine HCl MEA-Sulfite Organic Acid Salts MEA-Benzoate Ethanolamine HCl is the ethanolamine salt of hydrochloric acid. MEA-Sulfite is the ethanolamine salt of hydrogen sulfite. MEA-Benzoate is the ethanolamine salt of benzoic acid. HSO 3 HO NH 3 MEA-Salicylate MEA-Salicylate is the ethanolamine salt of salicylic acid. MEA-Cocoate MEA-Cocoate is the ethanolamine salt of coconut acid. MEA-Tallowate MEA-Tallowate is the ethanolamine salt of tallow acid. MEA-Undecylenate MEA-Undecylenate is the ethanolamine salt of undecylenic acid. MEA-Laureth-6 Carboxylate MEA-Laureth-6 Carboxylate is the ethanolamine salt of laureth-6 carboxylic acid (wherein -6 represents the number ethylene glycol units, including the carboxylate). MEA PPG-6 Laureth-7 Carboxylate MEA PPG-6 Laureth-7 Carboxylate is the ethanolamine salt of PPG-6 laureth-7 carboxylic acid (wherein -7 represents the number ethylene glycol units, including the carboxylate). 22 CIR Panel Book Page 33

37 Table 1a. Definition and structures of ethanolamine and ethanolamine-containing ingredients Ingredient CAS No. Definition Formula/structure O CH 3 CH 3 CH 3 O O O O O O O O O O O O O CH 3 CH 3 CH 3 O CH 3 NH 3 HO MEA-PPG-8-Steareth-7 Carboxylate O O O O O MEA-PPG-8-Steareth-7 Carboxylate is the ethanolamine salt of PPG-8 steareth-7 carboxylic acid (wherein -7 represents the number ethylene glycol units, including the carboxylate). CH 3 O O O O O O CH 3 O CH 3 CH 3 O O CH 3 CH 3 O O CH 3 CH 3 O CH 3 HO NH 3 -Protein Salts MEA-Hydrolyzed Silk MEA-Hydrolyzed Collagen MEA-Lauryl Sulfate MEA-Hydrolyzed Silk is the monoethanolamine salt of Hydrolyzed Silk. Hydrolyzed silk is the substance obtained by acidic, alkaline, or enzymatic hydrolysis of silk worm cocoon, composed primarily of amino acids, peptides, and proteins. MEA- Hydrolyzed Collagen is the monoethanolamine salt of Hydrolyzed Collagen. Hydrolyzed collagen the substance obtained by acidic, alkaline, or enzymatic hydrolysis of collagen, composed primarily of amino acids, peptides, and proteins. Organic-Substituted Inorganic Salts MEA-Lauryl Sulfate is the ethanolamine salt of sulfated lauryl alcohol. MEA-Laureth Sulfate MEA-Dicetearyl Phosphate MEA-Laureth Sulfate is the ethanolamine salt of sulfated, ethoxylated lauryl alcohol (wherein the number of ethylene glycol units ranges from one to four). MEA-Dicetearyl Phosphate is the ethanolamine salt of dicetearyl phosphate. Methylethanolamine Ethyl Ethanolamine Alkyl Substituted Ethanolamines Methylethanolamine is a secondary amine with one N-ethanol functional group and one N-methyl group. Ethyl Ethanolamine is a secondary amine with one N-ethanol functional group and one N-ethyl group. 23 CIR Panel Book Page 34

38 Table 1a. Definition and structures of ethanolamine and ethanolamine-containing ingredients Ingredient CAS No. Definition Formula/structure Butylethanolamine Butylethanolamine is a secondary amine with one N-ethanol functional group and one N-butyl group. Dimethyl MEA Dimethyl MEA is a tertiary amine with one N-ethanol functional group and two N-methyl groups. Diethyl Ethanolamine Dibutyl Ethanolamine Diethyl MEA is a tertiary amine with one N-ethanol functional group and two N-ethyl groups. Dibutyl MEA is a tertiary amine with one N-ethanol functional group and two N-butyl groups. Table 1b. Definition and structures of ethanolamides Ingredient CAS No. Definition Formula/structure Ethanolamides Acetamide MEA Acetamide MEA is the ethanolamide of acetic acid. Myristamide MEA Cocamide MEA Myristamide MEA is the ethanolamide of myristic acid. Cocamide MEA is a mixture of ethanolamides of Cocos Nucifera (Coconut) Acid. Isostearamide MEA Isostearamide MEA is the ethanolamide of Isostearic Acid. one example of an iso Stearamide MEA Stearamide MEA is the ethanolamide of stearic acid. Azelamide MEA Babassuamide MEA Azelamide MEA is the ethanolamide of azelaic acid. Babassuamide MEA is a mixture of ethanolamides of the fatty acids derived from Orbignya Oleifera (Babassu) Oil. 24 CIR Panel Book Page 35

39 Table 1b. Definition and structures of ethanolamides Ingredient CAS No. Definition Formula/structure Behenamide MEA Behenamide MEA is the ethanolamide of Behenic Acid. C16-22 Acid Amide MEA C16-22 Acid Amide MEA is a mixture of ethanolamides of C16-22 fatty acids. Cocamide Methyl MEA Cocamidopropyl Betainamide MEA Chloride Deoxyphytantriyl Palmitamide MEA Cocamide Methyl MEA is a mixture of tertiary, N-methyl ethanolamides of the fatty acids derived from Cocos Nucifera (Coconut) Oil. Cocamidopropyl Betainamide MEA Chloride is a mixture of N -betaine ethanolamides of the fatty acids derived from coconut oil. Deoxyphytantriyl Palmitamide MEA is a multi-branched, polyol derivative of palmitamide MEA. O H 3 C OH CH 3 CH 3 CH 3 H 3 C N CH 3 HO OH Hexyloxodecanamide MEA Hexyloxodecanamide MEA is the hexyl substituted derivative of oxodecanamide MEA. H 3 C O O N H OH Hexyloxodecanamide MEA Phosphate Hexyloxodecanamide MEA Phosphate is the phosphate salt of Hexyloxodecanamide MEA. H 3 C H 3 C H 3 C O O N H OH H 3 PO 4 25 CIR Panel Book Page 36

40 Table 1b. Definition and structures of ethanolamides Ingredient CAS No. Definition Formula/structure Hydroxyethyl O Pantothenamide MEA Hydroxypropyl Bisisostearamide MEA Hydroxyethyl Pantothenamide MEA is the O-monoethyleneglycol substituted derivative Pantothenamide MEA. Hydroxypropyl Bisisostearamide MEA is a 1,3-disubstituted 2-hydroxypropane compound, wherein each substituent is an N-isostearamide MEA. O H 3 C CH 3 HO N H OH one example of an iso O O N H O OH H 3 C N N CH 3 CH 3 HO OH OH CH 3 Hydroxypropyl Bislauramide MEA Hydroxypropyl Bisisostearamide MEA is a 1,3-disubstituted 2-hydroxypropane compound, wherein each substituent is an N-lauramide MEA. O O H 3 C N N CH 3 HO OH OH Hydroxypropyl Bispalmitamide MEA Hydroxypropyl Bisisostearamide MEA is a 1,3-disubstituted 2-hydroxypropane compound, wherein each substituent is an N-palmitamide MEA. O O H 3 C N N CH 3 HO OH OH Hydroxypropyl Bisstearamide MEA Hydroxypropyl Bisisostearamide MEA is a 1,3-disubstituted 2-hydroxypropane compound, wherein each substituent is an N-stearamide MEA. O O H 3 C N HO OH OH N CH 3 Hydroxystearamide MEA Hydroxystearamide MEA is the 12-hydroxy substituted derivative of stearamide MEA. O H 3 C Lactamide MEA OH Lactamide MEA is the ethanolamide of lactic acid H 3 C N H OH O N H OH OH 26 CIR Panel Book Page 37

41 Table 1b. Definition and structures of ethanolamides Ingredient CAS No. Definition Formula/structure Lauramide MEA Lauramide MEA is the ethanolamide of lauric acid H 3 C O N H OH Linoleamide MEA Linoleamide MEA is the ethanolamide of linoleic acid H 3 C CH Myristoyl/Palmitoyl Oxostearamide/Arachamide MEA Oatamide MEA Oleamide MEA CH CH CH Myristoyl/Palmitoyl Oxostearamide/Arachamide MEA is the alkyl substituted derivative of an oxoalkylamide MEA. Oatamide MEA is a mixture of ethanolamides of the fatty acids derived from oat kernel oil. Oleamide MEA is the ethanolamide of oleic acid. H 3 C m O H 3 C O n N H O N H OH wherein m is and n is O OH OH R N H where RCO- represents the fatty acids derived from Avena Sativa (Oat) Kernel Oil H 3 C Oliveamide MEA Palm Kernelamide MEA CH CH Oliveamide MEA is a mixture of ethanolamides of the fatty acids derived from olive oil. Palm Kernelamide MEA is a mixture of ethanolamides of the fatty acids derived from Elaeis Guineensis (Palm) Kernel Oil. O O N H OH OH R N H where RCO- represents the fatty acids derived from olive oil O OH R N H where RCO- represents the fatty acids derived from palm kernel oil Palmamide MEA Palmitamide MEA H 3 C Pantothenamide MEA Peanutamide MEA Palmamide MEA is a mixture of ethanolamides of the fatty acids derived from Elaeis Guineensis (Palm) Oil. Palmitamide MEA is the ethanolamide of palmitic acid. Pantothenamide MEA is the O-monoethyleneglycol substituted derivative Pantothenamide MEA. Peanutamide MEA is a mixture of ethanolamides of the fatty acids derived from Arachis Hypogaea (Peanut) Oil. O O OH R N H where RCO- represents the fatty acids derived from palm oil N H OH H 3 C CH 3 HO O OH O N H OH R N H where RCO- represents the fatty acids derived from peanut oil O N H OH 27 CIR Panel Book Page 38

42 Table 1b. Definition and structures of ethanolamides Ingredient CAS No. Definition Formula/structure Ricinoleamide MEA Ricinoleamide MEA is ethanolamide derived from ricinoleic acid. O H 3 C Stearamide MEA-Stearate H 3 C Stearamidoethyl Ethanolamine HO N H Sunfloweramide MEA Tallowamide MEA NH OH O C H C H Stearamide MEA-Stearate is ethanoate-amide derived from 2 equivalents of stearic acid. O Stearamidoethyl Ethanolamine is the ethylamidoethylamine derived from stearic acid. Sunfloweramide MEA is a mixture of ethanolamides of the fatty acids derived from Helianthus Annuus (Sunflower) Seed Oil. Tallowamide MEA is a mixture of ethanolamides of Tallow Acid. O O NH O N H OH CH 3 OH R N H where RCO- represents the sunflower seed oil fatty acids O R N H OH CH 3 Trideceth-2 Carboxamide MEA NH HO O O Undecylenamide MEA Glycol ethers PEG-2 Cocamide (generic to all ethoxylated deriviatives of Cocamide MEA) PEG-3 Cocamide (generic to all ethoxylated deriviatives of Cocamide MEA) PEG-4 Cocamide (generic to all ethoxylated deriviatives of Cocamide MEA) PEG-5 Cocamide (generic to all ethoxylated deriviatives of Cocamide MEA) PEG-6 Cocamide (generic to all ethoxylated deriviatives of Cocamide MEA) Trideceth-2 Carboxamide MEA is the ethanolamide of Trideceth-2. O Undecylenamide MEA is the ethanolamide of undecylenic acid. PEG-2 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of one ethylene glycol unit. PEG-3 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of two ethylene glycol units. PEG-4 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of three ethylene glycol units. PEG-5 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of four ethylene glycol units. PEG-6 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of five ethylene glycol units. where RCO- represents the fatty acids derived from tallow H 3 C 28 CH 3 O N H OH where RCO- represents the coconut oil fatty acids where RCO- represents the coconut oil fatty acids where RCO- represents the coconut oil fatty acids where RCO- represents the coconut oil fatty acids where RCO- represents the coconut oil fatty acids CIR Panel Book Page 39

43 Table 1b. Definition and structures of ethanolamides Ingredient CAS No. Definition Formula/structure PEG-7 Cocamide (generic to all ethoxylated deriviatives of Cocamide MEA) PEG-7 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of six ethylene PEG-9 Cocamide MEA (generic to all ethoxylated deriviatives of Cocamide MEA) PEG-11 Cocamide (generic to all ethoxylated deriviatives of Cocamide MEA) PEG-20 Cocamide (generic to all ethoxylated deriviatives of Cocamide MEA) glycol units. PEG-9 Cocamide MEA is an ethoxylated derivative of Cocamide MEA, with an average of nine ethylene glycol units. PEG-11 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of ten ethylene glycol units. PEG-20 Cocamide is an ethoxylated derivative of Cocamide MEA, with an average of nineteen ethylene glycol units. where RCO- represents the coconut oil fatty acids where RCO- represents the coconut oil fatty acids where RCO- represents the coconut oil fatty acids where RCO- represents the coconut oil fatty acids PEG-20 Cocamide MEA PEG-20 Cocamide MEA is (generic to all an ethoxylated derivative of ethoxylated deriviatives of Cocamide MEA, with an Cocamide MEA) average of 20 ethylene glycol units. where RCO- represents the coconut oil fatty acids Table 2a. Conclusions of previously reviewed ingredients, as pertaining to the ethanolamine and ethanolamine-containing ingredients Ingredient Conclusion Reference Ethanolamine MEA-Salicylate Ammonium Lauryl Sulfate Sodium Lauryl Sulfate Benzoic Acid PREVIOUSLY REVIEWED INGREDIENTS is safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin, and MEA should only be used in rinse-off products safe as used when formulated to avoid skin irritation and when formulated to avoid increasing the skin s sun sensitivity,.or, when increased sun sensitivity would be expected; directions for use include the daily use of sun protection COMPONENTS safe in formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin; in products intended for prolonged contact with skin, concentrations should not exceed 1% safe as used (currently being reviewed) Coconut Acid safe as used 56 Hydrolyzed Collagen safe as used 57 Laureths safe as used when formulated to be non-irritating 58 PPG safe as used when formulated to be non-irritating 59 Sodium Laureth Sulfate and safe as used when formulated to be non-irritating 60 related salts of ethoxylated alcohols Steareths safe as used when formulated to be non-irritating CIR Panel Book Page 40

44 Table 2b. Conclusions of previously reviewed ingredients, as pertaining to the ethanolamides Ingredient Conclusion Reference Isostearamide MEA Myristamide MEA Stearamide MEA Acetamide MEA Cocamide MEA Ethanolamine (likely an impurity) PREVIOUSLY REVIEWED INGREDIENTS safe for use in rinse-off products; in leave-on products, safe for use at a concentration that will limit the release of free ethanolamines to 5%, with a maximum use concentration of 17% safe for use in rinse-off products; in leave-on products, safe for use at a concentration that will limit the release of free ethanolamines to 5%, with a maximum use concentration of 17% safe for use in rinse-off products; in leave-on products, safe for use at a concentration that will limit the release of free ethanolamines to 5%, with a maximum use concentration of 17% safe as a cosmetic ingredient at concentrations not to exceed 7.5% in leave-on products; safe in the present practices of use in rinse-off products; products containing acetamide MEA should not contain nitrosating agents or significant amounts of acetamide safe as used in rinse-off products; safe at concentrations up to 10% in leave-on products; should not be used as an ingreidnet in products containing N-nitrosating agents, or in product formulations intended to be aerosolized COMPONENTS to be determined at this meeting Arachis Hypogaea (Peanut) Oil safe as used 61 Azelaic Acid safe as used 62 Cocamidopropyl Betaine safe as used when formulated to be non-sensitizing 63 Coconut Acid safe as used 56 Elaeis Guineensis (Palm) Kernel Oil Elaeis Guineensis (Palm) Oil safe as used 53 Helianthus Annuus (Sunflower) Seed Oil safe as used 61 Hydroxystearic Acid safe as used 52 Isostearic Acid safe as used 64 Lactic Acid safe for use in cosmetic products at concentrations 10%, at final formulation ph > 3.5, when formulated to avoid increasing sun sensitivity or when directions for use include the daily use of sun protection. These ingredients are safe for use in salon products at concentrations 30%, at final 65 formulation ph 3.0, in products designed for brief, discontinuous use followed by thorough rinsing from the skin, when applied by trained professionals, and when application is accompanied by directions for the daily use of sun protection Lauric Acid safe as used 66 Myristic Acid safe as used 66 Oat Kernel Oil safe as used 61 Olea Europaea (Olive) Fruit Oil safe as used 61 Oleic Acid safe as used 66 Orbignya Oleifera (Babassu) Oil safe as used 61 Palmitic Acid safe as used 61 Pantothenic Acid safe as used 67 PEGs safe as used 68 Ricinoleic Acid safe as used 69 Stearic Acid safe as used 66 Trideceth-2 safe as used when formulated to be non-irritating CIR Panel Book Page 41

45 Table 3a. Physical and chemical properties Property Value Reference Ethanolamine Physical Form clear viscous liquid 1 Color colorless 1 Odor ammonia-like 1 Molecular Weight Specific Gravity (25 C) 1 Viscosity (25 C) 1 Refractive Index (20 C) 7 Vapor Pressure 0.48 mm Hg (20 C) 1 pk a 9.5 (25 C0 7 Melting Point C 1 Boiling Point 171 C 1 Water Solubility miscible with water 23 Other Solubility miscible with methanol and acetone soluble in alcohol, ethanol, chloroform,glycerol, logroin 23 7 log P ow (estimated) MEA Benzoate Molecular Weight (calculated) 71 pka 8.0 g/cm 3 ( (most basic; 25 C) (calculated) 71 Density g/cm 3 (20 C) (calculated) 71 Boiling Point C (calculated) 71 logp (25 C) (calculated) 71 Table 3b. Physical and chemical properties of ethanolamides Property Value Reference Acetamide MEA Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (25 C) (calculated) 72 Melting Point C 73 Boiling Point C 72 logp (25 C) (calculated) 71 Behenamide MEA Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Boiling Point 74 logp (25 C) (calculated) 71 C16-22 Acid Amide MEA Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Melting Point -2 C 74 Boiling Point 199 C 74 logp (25 C) (calculated) 71 Cocamide MEA Melting Point ~72 C 49 Density ~0.894 g/cm 3 (80 C) 49 partition Coefficient 3.89 (calculated) 49 Solubility not soluble in water 49 Hexyloxodecanamide MEA Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Boiling Point C (calculated) 71 logp (25 C) (calculated) CIR Panel Book Page 42

46 Table 3b. Physical and chemical properties of ethanolamides Property Value Reference Hydroxystearamide MEA Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Melting Point C 75 Boiling Point C (calculated) 71 logp (25 C) (calculated) 71 Lauramide MEA Physical Form solid 48 Molecular Weight pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Melting Point c 76 Boiling Point C (calculated) 71 Water Solubility miscible with water 48 logp (25 C) (calculated) 71 Linoleamide MEA Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Boiling Point C (calculated) 71 logp (25 C) (calculated) 71 Myristamide MEA Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Melting Point C 77 Boiling Point C (calculated) 71 logp (25 C) (calculated) 71 Oleamide MEA Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Melting Point C 76 Boiling Point C (calculated) 71 logp (25 C) (calculated) 71 Palmitamide MEA Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Melting Point 98 C 78 Boiling Point C (calculated) 71 logp (25 C) (calculated) 71 Ricinoleamide MEA Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Melting Point C 75 Boiling Point C (calculated) 71 logp (25 C) (calculated) 71 Stearmide MEA Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Melting Point C 76 Boiling Point C (calculated) 71 logp (25 C) (calculated) 71 Stearamide MEA-Stearate Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Melting Point C 79 Boiling Point C (calculated) CIR Panel Book Page 43

47 Table 3b. Physical and chemical properties of ethanolamides Property Value Reference logp (25 C) (calculated) 71 Stearamidoethyl Ethanolamine Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Melting Point C 80 Boiling Point C (calculated) 71 logp (25 C) (calculated) 71 Undecylenamide MEA Molecular Weight (calculated) 71 pka g/cm 3 (most acidic; 25 C) g/cm 3 (most basic; 25 C) (calculated) Density g/cm 3 (20 C) (calculated) 71 Melting Point C 81 Boiling Point C (calculated) 71 logp (25 C) (calculated) CIR Panel Book Page 44

48 Table 4a. Frequency and concentration of use according to duration and type of exposure # of Uses 9 Conc of Use (%) 11 # of Uses 9 Conc of Use (%) 11 # of Uses 9 Conc of Use (%) 11 Ethanolamine MEA Cocoate MEA-Hydrolyzed Collagen Totals* NR NR Duration of Use Leave-On 1 NR NR NR NR Rinse-Off NR NR Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Spray NR 3 NR NR NR NR Incidental Inhalation-Powder NR NR NR NR NR NR Dermal Contact NR NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR NR 0.06 Hair-Coloring NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR NR Baby Products NR NR NR NR NR NR MEA-Laureth Sulfate MEA-Lauryl Sulfate MEA-Tallowate Totals* 13 NR NR Duration of Use Leave-On NR NR NR NR NR NR Rinse Off 13 NR NR Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Spray NR NR NR NR NR NR Incidental Inhalation-Powder NR NR NR NR NR NR Dermal Contact NR NR 1 NR 6 NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 1 NR 4 5 NR NR Hair-Coloring 12 NR NR 35 NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR NR 6 NR Baby Products NR NR 1 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. a Includes deodorants, in that it is not known whether or not the product is a spray. b Includes suntan products, in that it is not known whether or not the reported product is a spray. NR no reported uses Table 4b. Ingredients not reported to be in use *this table will be created after the Panel finalizes the list of ingredients that will be included in the re-review of ethanolamine Table 4c. Status for use in Europe according to the EC CosIng Database for ethanolamine ingredients Fatty Acid Monoalkylamines, monoalkanolamines,and their salts listed in Annex III restrictions 12 (maximum secondary amine content of 0.5% in the finished product; do not use with nitrosating systems; minimum purity 99%; maximum secondary amine content of 5% for raw materials; maximum nitrosamine content of 50 µg/kg; keep in nitrite free containers) Ethanolamine Ethanolamine HCl MEA PPG-6 Laureth-7 Carboxylate MEA-Benzoate MEA-Biotinate MEA-Cocoate MEA-Dicetearyl Phosphate MEA -Hydrolyzed Collagen 34 MEA -Hydrolyzed Silk MEA -Laureth Sulfate MEA -Laureth-6 Carboxylate MEA -Lauryl Sulfate MEA -Ppg-8-Steareth-7 Carboxylate MEA -Salicylate MEA -Sulfite MEA Undecylenate CIR Panel Book Page 45

49 Table 5a. Frequency and concentration of use according to duration and type of exposure ethanolamides # of Uses 9 Conc of Use (%) 11 # of Uses 9 Conc of Use (%) 11 # of Uses 9 Conc of Use (%) 11 Acetamide MEA Cocamide MEA Cocamide Methyl MEA Totals* NR 5 Duration of Use Leave-On NR NR Rinse-Off NR 5 Diluted for (Bath) Use NR NR NR NR Exposure Type Eye Area NR NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Spray 23 a a 3 b b NR NR Incidental Inhalation-Powder NR NR NR NR NR NR Dermal Contact NR NR Deodorant (underarm) 9 2 NR NR NR NR Hair - Non-Coloring NR 5 Hair-Coloring 1 NR NR NR Nail 1 NR 2 NR NR NR Mucous Membrane NR NR Baby Products NR NR 4 2 NR NR Cocamidopropyl Betainamide MEA Chloride Lactamide MEA Lauramide MEA Totals* Duration of Use Leave-On NR NR Rinse Off Diluted for (Bath) Use NR NR NR Exposure Type Eye Area NR NR 1 NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Spray NR NR Incidental Inhalation-Powder NR NR NR NR NR NR Dermal Contact Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR Hair-Coloring NR NR NR NR 43 3 Nail NR NR 1 NR NR 1 Mucous Membrane Baby Products NR NR NR NR NR 0.5 Myristoyl/Palmitoyl/Oxostearamide Myristamide MEA Peanutamide MEA /Arachamide MEA Totals* NR NR 0.3 Duration of Use Leave-On NR 4 3 NR NR NR Rinse-Off NR NR 0.3 Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Spray NR NR NR NR NR NR Incidental Inhalation-Powder NR NR NR NR NR NR Dermal Contact NR NR 0.3 Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR NR NR NR NR Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane 1 NR NR NR NR NR Baby Products NR NR NR NR NR NR 35 CIR Panel Book Page 46

50 Table 5a. Frequency and concentration of use according to duration and type of exposure ethanolamides # of Uses 9 Conc of Use (%) 11 # of Uses 9 Conc of Use (%) 11 # of Uses 9 Conc of Use (%) 11 Ricinoleamide MEA Stearamide MEA Stearamide MEA-Stearate Totals NR Duration of Use Leave-On NR NR Rinse Off NR NR Diluted for (Bath) Use NR NR NR 17 NR NR Exposure Type Eye Area NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Spray NR NR 2 a 15 a NR NR Incidental Inhalation-Aerosol NR NR NR NR NR NR Dermal Contact NR NR Deodorant (underarm) NR NR 2 15 NR NR Hair - Non-Coloring NR NR NR NR Hair-Coloring NR NR NR NR Nail NR NR NR 2 NR NR Mucous Membrane NR NR NR 17 NR NR Baby Products NR NR NR NR NR NR Trideceth-2 Carboxamide MEA Undecylenamide MEA Totals* NR Duration of Use Leave-On NR 2 2 NR Rinse-Off NR Diluted for (Bath) Use NR NR NR NR Exposure Type Eye Area NR NR NR NR Incidental Ingestion NR NR NR NR Incidental Inhalation-Spray NR NR 2 NR Incidental Inhalation-Powder NR NR NR NR Dermal Contact 1 NR 2 NR Deodorant (underarm) NR NR 1 NR Hair - Non-Coloring 5 2 NR NR Hair-Coloring NR Nail NR NR NR NR Mucous Membrane 1 NR NR NR Baby Products NR NR NR NR PEG-5 Cocamide PEG-6 Cocamide PEG-9 Cocamide Totals* 40 NS 23 NS 1 NR Duration of Use Leave-On NR NS 3 NS NR NR Rinse-Off 40 NS 19 NS 1 NR Diluted for (Bath) Use NR NS 1 NS NR NR Exposure Type Eye Area NR NS NR NS NR NR Incidental Ingestion NR NS NR NS NR NR Incidental Inhalation-Spray NR NS NR NS NR NR Incidental Inhalation-Powder NR NS NR NS NR NR Dermal Contact 24 NS 14 NS NR NR Deodorant (underarm) NR NS NR NS NR NR Hair - Non-Coloring 15 NS 8 NS 1 NR Hair-Coloring 1 NS 1 NS NR NR Nail NR NS NR NS NR NR Mucous Membrane 2 NS 12 NS NR NR Baby Products NR NS NR NS 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 NS -These ingredients have not been included in a Council concentration of use survey 36 CIR Panel Book Page 47

51 Table 5b. Ethanolamides not reported to be in use Azelamide MEA Babassuamide MEA Behenamide MEA C16-22 Acid Amide MEA Deoxyphytantriyl Palmitamide MEA Hexyloxodecanamide MEA Hydroxyethyl Pantothenamide MEA Hydroxypropyl Bisisostearamide MEA Hydroxypropyl Bislauramide MEA Hydroxypropyl Bispalmitamide MEA Hydroxypropyl Bisstearaminde MEA Hydroxystearamide MEA Isostearamide MEA Linoleamide MEA Oatamide MEA Oleamide MEA Oliveamide MEA Palm Kernelamide MEA Palmamide MEA Palmitamide MEA Pantothenamide MEA Stearamidoethyl Ethanolamine Sunfloweramide MEA Tallowamide MEA PEG-2 Cocamide a PEG-3 Cocamide a PEG-4 Cocamide a PEG-7 Cocamide a PEG-11 Cocamide a PEG-20 Cocamide a PEG-20 Cocamide MEA a a These ingredients have not been included in a Council concentration of use survey 37 CIR Panel Book Page 48

52 REFERENCES 1. Elder RE (ed). Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. J Am Coll Toxicol. 1983;2:(7). 2. Andersen FA (ed). Safety assessment of salicylic acid, butyloctyl salicylate, calcium salicylate, C12-15 alkyl salicylate, capryloyl salicylic acid, hexyldodecyl salicylate, isocetyl salicylate, isodecyl salicyalte, magnesium salicylate, MEA-salicylate, ethylhexyl salicylate, potassium salicylate, methyl salicylate, myristyl salicylate, sodium salicylate, TEA-salicylate, and tridecyl salicylate. Int J Toxicol. 2003;22:(Suppl 3): Rostkowska K, Zwierz K, Rózanski A, Moniuszko-Jakoniuk J, and Roszczenko A. Formation and metabolism of nitrosamines. Polish Journal of Environmental Studies. 1998;7:(6): Shank RC and Magee PN. Toxicity and carcinogenicity of N-nitroso compounds. Chapter: 1. Shank RC.In: Mycotoxins and N- Nitroso Compounds:Environmental Risks. Boca Raton, FL: CRC Press, Inc; 1981: Challis BC, Shuker DE, Fine DH, Goff EU, and Hoffman GA. Amine nitration and nitrosation by gaseous nitrogen dioxide. IARC Sci Publ. 1982;41: Dow Chemical Company. The alkanolamines handbook Midland, MI: The Dow Chemical Company.Secondary reference in Knaak et al Knaak JB, Leung H-W, Stott WT, Busch J, and Bilsky J. Toxicology of mono-, di-, and triethanolamine. Review of Environmental Contamination and Toxicology. 1997;149: Gottschalck T.E. and Bailey, J. E. eds. International Cosmetic Ingredient Dictionary and Handbook. Washington, DC: Personal Care Products Council, Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients. FDA Database Washington, DC: FDA.Updated Feb Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients. FDA Database Washington, DC: FDA.Updated May Personal Care Products Council Concentration of Use by FDA Product Category: Ethanolamine, Diethanolamine and Triethanolamine. Unpublished data submitted by Personal Care Products Council. 12. European Commission. European Commission Enterprise and Industry. Cosmetics - Cosing. Annex III/Part 1, 61 - Monoalkylamines, nomoalkanolamines and their salts Date Accessed Heatlh Canada. Cosmetic Ingredient Hotlist Date Accessed Food and Drug Administration. Everything Added to Food in the United States (EAFUS) Date Accessed Lessmann H, Uter W, Schnuch A, and Geier J. Skin sensitizing properties of ethanolamines mono-, di-, and triethanolamine. Data analysis of a multicentre surveillance network (IVDK) and review of literature. Contact Derm. 2009;60: Sun JD, Beskitt JL, Tallant MJ, and Frantz SW. In vitro skin penetration of monoethanolamine and diethanolamine using excised skin from rats, mice, rabbits, and humans. J Toxicol -- Cut & Ocular Toxicol. 1996;15:(2): Klain GC, Reifenrath WG, and Black KE. Distribution and metabolism of topically applied ethanolamine. Fund Appl Toxicol. 1985;5:S127-S BASF. Ethanolamine hydrochloride. Two-generation reproduction toxicity study in Wistar rats - administration via diet Report No. 75R0372/ Unpublished data submitted by the American Chemistry Council. June (32 pp). 19. Helman, R. G., Hall, J. W., and Kao, J. Y. Acute dermal toxicity: in vivo and in vitro comparisons in mice. Fundamental and Applied Toxicology. 1986;7:(1): CIR Panel Book Page 49

53 20. Anonymous. Letter to the Environmental Protection Agency reporting an actue dermal toxcity study of a formulation containing DEA EHQ Anonymous. Letter to the Environmental Protection Agency reporting actue dermal and oral toxcity studies of a formulation containing DEA EHQ Anonymous. Letter to the Environmental Protection Agency reporting an actue inhalaton toxcity studies of a formulation containing DEA EHQ A. 23. Liberacki AB, Neeper-Bradley TL, Breslin WJ, and Zielke GJ. Evaluation of developmental toxicity of dermally applied monoethanolamine in rats and rabbits. Fund Appl Toxicol. 1996;31: Pereira M, Barnwell P, and Bailes W. Screening of priority chemicals for reproductive hazards, monoethanolamine, diethanolamine,, triethanolamine. NIOSH Contract No Environmental Health Research and Testing, Inc. REport No. ETOX Secondary reference in Liberacki et al Hellwig J and Liberacki AB. Short communication. Evaluation of the pre-, peri-, and postnatal toxicity of monothanolamine in rats following repeated oral adminstration during organogenesis. Fund Appl Toxicol. 1997;40: Mankes RF. Studies on the embryopathic effects of ethanolamine in Long-Evans rats: Preferential embryopathy in pups contiguous with male siblings in utero. Teratog.Carcinog Mutagen. 1986;6: Dean BJ, Brooks TM, Hodson-Walker G, and Hutson DH. Genetic toxicology testing of 41 industrial chemicals. Mutat Res. 1985;153: Mortelmans K, Haworth S, Lawlor T, Speck W, Tainer B, and Zeiger E. Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals. Environ Mutagen. 1986;8:(Suppl 7): Arutyunyan RM, Zalinyan RM, Mugnetsyan EG, and Gukasyan LA. Mutagenic action of latex polumerization stabilizers in different test systems. Tsitol Genet : pp Secondary referenc ein Knaak et al Inoue K, Sunakawa T, Okamoto K, and Tanaka Y. Mutagenicity tests and in vitro transformation assays on triethanolamine. Mutat Res. 1982;101: BASF. Ethanolamine hydrochloride Murine Local Lymph Node Assay (LLNA) Unpublished data sumitted by the American Chemistry Council on October 8, (44 pages). 32. Geier, J, Lessmann H, Frosch, PJ., Koch, Patrick, Aschoff, R, Richter, G, Becker, D, Eckert, C, Uter, Wg, Schnuch, A, and Fuchs, T. Patch testing with components of water-based metalworking fluids. Contact Dermatitis. 2003;49:(2): Geier, J, Lessmann, H, Dickel, H, Frosch, PJ., Koch, P, Becker, D, Jappe, U, Aberer, W, Schnuch, A, and Uter, W. Patch test results with the metalworking fluid series of the German Contact Dermatitis Research Group (DKG). Contact Dermatitis. 2004;51:(3): Geier J, Lessmann H, Schnuch A, and Uter W. Diagnostic quality of patch test preparation monoethanolamine 2% pet. Contact Derm. 2005;52: Matsuda S, Hidama M, Shibayama H, Itou N, and Iwaki M. Application of the reconstructed rabbit corneal epithelium model to assess the in vitro eye irritancy test of chemicals. Yakugaku Zasshi. 2009;129:(9): Savonius B, Keskinen H, Tupperainen M, and Kanerva L. Occupational asthma caused by ethanolamines. Allergy. 1994;49: Bello A, Quinn MM, Perry MJ, and Milton DK. Characterization of occupational exposures to cleaning products used for common cleaning tasks - A pilot study of hospital cleaners. Envron Health. 2009;8: Occupational Safety and Health Administration (OSHA). Occupational safety and health guideline for ethanolamine Date Accessed National Institure for Occupational Safety and Health (NIOSH). NIOSH Pocket guide to chemical hazards: ethanolamine Dow Chemical Company. Hepatic choline levels in rats after repeated dose feeding of ethanolamine hydrocholoride Unpublished data submitted by the American Chemistry Council, June (15 pp). 39 CIR Panel Book Page 50

54 41. Kamijo, Y., Hayashi, I., Ide, A., Yoshimura, K., Soma, K., and Majima, M. Effects of inhaled monoethanolamine on bronchoconstriction. Journal of Applied Toxicology. 2009;29:(1): Pang S. Isostearamide DEA & MEA, Myristamide DEA & MEA, Stearmide DEA & MEA Available from the CIR, th Street, NW, Ste 412, Washington DC Andersen FA (ed). Final report on the safety assessment of acetamide MEA. J Am Coll Toxicol. 1993;12:(3): Andersen FA (ed). Final report on the safety assessment of cocamide MEA. Int J Toxicol. 1999;18:(Suppl 2): Fernandez-Perez, M. and Otero, C. Enzymatic synthesis of amide surfactants from ethanolamine. Enzyme and Microbial Technology. 2001;28:(6): Abdul Rahman MB, Yap, C. L., Dzulkefly K., Abdul Rahman RNZ, Salleh, AB, and Basri M. Synthesis of palm kernel oil alkanolamide using lipase. Journal of Oleo Science. 2003;52:(2): Environmental Protection Agency. Appendix 1. Robust summaries. ACC FND Amides Category I - FND Amides Summaries of unpublished data. 48. Environmental Protection Agency. Screening-level hazard characterization, Fatty nitrogen derived (FND) amides category Summaries of unpublished data. 49. European Commission - European Chemicals Bureau. IUCLID dataset. Amides, coco, N-(Hydroxyethyl) Date Accessed European Commission - European Chemicals Bureau. IUCLID Dataset. N-(2-hydroxyethyl)dodecanamide Andersen FA (ed). Final report on the safety assessment of Peanut (Arachis Hypogaea) Oil, Hydrogenated Peanut Oil, Peanut Acid, Peanut Glycerides, and Penaut (Arachis Hypogaea) Flour. Int J Toxicol. 2001;20:(Suppl 2): Andersen FA (ed). Amended final report on the safety assessment of hydroxystearic acid. Int J Toxicol. 1999;18:(Suppl 1): Andersen FA (ed). Final Report on the Safety Assessment of Elaeis Guineensis (Palm) Oil, Elaeis Guineensis (Palm) Kernel Oil, Hydrogenated Palm Oil and Hydrogenated Palm Kernel Oil. Int J Toxicol. 2011;19:(Suppl 2): Zeiger E, Andersen B, Haworth S, Lawlor T, Mortelmans K, and Speck W. Salmonella mutagencitiy tests: III. Results from the testing of 25 chemicals. Environ Mutagen. 1987;9:(Suppl 9): Elder RL (ed). Final report on the safety assessment of sodium lauryl sulfate and ammonium lauryl sulfate. J Am Coll Toxicol. 1983;2:(7): Diamante C, Bergfeld WF, Belsito DV, Klaassen CD, Hill RA, Liebler DC, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Amended Safety Assessment of Cocos Nucifera (Coconut) Oil, Coconut Acid, Hydrogenated Coconut Acid, Hydrogenated Coconut Oil, Ammonium Cocomonoglyceride Sulfate, Butylene Glycol Cocoate, Caprylic/Capric/Coco Glycerides, Cocoglycerides, Coconut Alcohol, Coconut Oil Decyl Esters, Decyl Cocoate, Ethylhexyl Cocoate, Hydrogenated Coco-Glycerides, Isodecyl Cocoate, Lauryl Cocoate, Magnesium Cocoate, Methyl Cocoate, Octyldodecyl Cocoate, Pentaerythrityl Cocoate, Potassium Cocoate, Potassium Hydrogenated Cocoate, Sodium Cocoate, Sodium Cocomonoglyceride Sulfate, Sodium Hydrogenated Cocoate, and Tridecyl Cocoate Available from the CIR, th Street, NW, Ste 412, Washington DC Elder RL (ed). Final report on the safety assessment of hydrolyzed collagen. J Am Coll Toxicol. 1985;4:(5): Fiume MM, Heldreth BA, Bergfeld WF, Belsito DV, Klaassen CD, Liebler DC, Hill RA, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. CIR Expert Panel final amended report on alkyl PEG ethers as used in cosmetics Available from the CIR, th Street, NW, Ste 412, Washington DC Fiume MM, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks A, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final amended report of the Cosmetic Ingredient Review Expert Panel. Safety assessment of propylene glycol, tripropylene glycol, and PPGs as used in cosmetics Available from the CIR, th Street, NW, Ste 412, Washington DC CIR Panel Book Page 51

55 60. Robinson VC, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the amended safety assessment of sodium laureth sulfate and related salts of sulfated ethoxylated alcohols. Int J Toxicol. 2010;29:(Supple 3):151S-161S. 61. Burnett CL, Fiume MM, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks A, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the CIR Expert Panel on the safety of plant-derived fatty acid oils and used in cosmetics Available from the CIR, th Street, NW, Ste 412, Washington DC Fiume MM, Heldreth BA, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG, Shanks RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the safety assessment on dicarboxlic acids and their salts and esters of dicarboxylic acids as used in cosmetics Available from the CIR, th Street, NW, Ste 412, Washington DC Burnett CL, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG, Shanks RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the safety assessment of cocamidopropyl betaine Available from the CIR, th Street, NW, Ste 412, Washington DC Elder RL (ed). Final report on the safety assessment of isostearic acid. J Am Coll Toxicol. 1986;2:(7): Andersen FA (ed). Final report on the safety assessment of glycolic acid, ammonium, calcium, potassium, and sodium glycolates, methyl, ethyl, propyl, and butyl glycolates, and lactic acid, ammonium, calcium, potassium, sodium, and TEA-lactates, methyl, ethyl, isoprpyl, and butyl lactates, and lauryl, myristyl, and cetyl lactates. Int J Toxicol. 1998;17:(Suppl 1): Elder RL (ed). Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, and stearic acid. J Am Coll Toxicol. 1987;6:(3): Elder RL (ed). Final report on the safety assessment of panthenol and pantothenic acid. J Am Coll Toxicol. 1987;6:(1): Andersen FA (ed). Final Report of the CIR Expert Panel - Amended Safety Assessment of Triethylene Glycol and Polyethylene Glycols (PEGs)-4, -6, -7, -8, -9, -10, -12, -14, -16, -18, -20, -32, -33, -40, -45, -55, -60, -75, -80, -90, -100, -135, -150, - 180, -200, -220, -240, -350, -400, -450, -500, -800, -2M, -5M, -7M, -9M, -14M, -20M, -23M, -25M, -45M, -65M, - 90M, -115M, -160M and -180M and any PEGs 4 as used in Cosmetics Available from the CIR, th Street, NW, Ste 412, Washington DC Andersen FA (ed). Final Report on the Safety Assessment of Ricinus Communis (Castor) Seed Oil, Hydrogenated Castor Oil, Glyceryl Ricinoleate, Glyceryl Ricinoleate SE, Ricinoleic Acid, Potassium Ricinoleate, Sodium Ricinoleate, Zinc Ricinoleate, Cetyl Ricinoleate, Ethyl Ricinoleate, Glycol Ricinoleate, Isopropyl Ricinoleate, Methyl Ricinoleate, and Octyldodecyl Ricinoleate. Int J Toxicol. 2011;26:(Suppl 3): Inchem. Ethanolamine Date Accessed ACD/Labs. Advanced Chemistry Development (ACD/Labs) Software (9.02): 72. Wenker H. Synthesis of 2-oxazolines and 2-thiazolines from N-acyl-2-aminoethanols. Journal of the American Chemical Society. 1935;57: Effenberger F and Bessey E. Transacylations with acyl derivatives of 4-pyridone. Chemische Berichte. 1980;113:(6): Syracuse Research Corporation. PhysProp data. 75. Rowe RG and Flower G Jr. Antistatic plastics (US ): 76. Morales-Sanfrutos J, Megia-Fernandez A, Hernandez-Mateo F, Giron-Gonzalez MD, Salto-Gonzalez R, and Santoyo-Gonzalez F. Alkyl sulfonyl derivatized PAMAM-G2 dendrimers as nonviral gene delivery vectors with improved transfection efficiencies. Organic and Biomolecular Chemistry. 2011;9:(3): Kimura C, Kashiwaya K, Murai K, and Suzuki S. Preparation and surface active properties of sodium 2-(N-alkanoylamino)ethyl sulfates. Yukagaku. 1983;32:(11): Roe ET, Miles TD, and Swern D. Fatty acid amides. V. Preparation of N-(2-acetoxyethyl) amides of aliphatic acid. Journal of the American Chemical Society. 1952;74: CIR Panel Book Page 52

56 79. Butler RN, Thornton JD, and O'Regan CB. Rapid synthesis and interconversions of fatty 4,5-dihydroimidazoles and fatty 1,4,5,6- tetrahydropyrimidines. Thermal cyclizations of fatty amides involving phenyl phosphorodiamidate. Journal of the Chemical Society. 1983;9: Bergman CA and Hansen EC. Ampholytic compositions for wet treatment of textiles (US ): 81. Guan L-P, Zhao D-H, Xiu J-H, Sui X, Piao H-R, and Quan Z-S. Synthesis and anticonvulsant activity of N-(2-hydroxyethyl)amide derivatives. Archiv der Pharmazie. 2009;342:(1): CIR Panel Book Page 53

57 Data

58 Personal Care Memorandum Products Council Committed to Safety, Quality & Innovation TO: FROM: DATE: SUBJECT: F. Alan Andersen, Ph.D. Director - COSMETIC INGREDIENT REVIEW (CIR) John Bailey, Ph.D. Industry Liaison to the CW Expert Panel July 5, 2011 Concentration of Use by FDA Product Category: Ethanolamine and Ethanolamine Containing Ingredients Concentration of Use by FDA Product Category: Ethanolamine, Diethanolamine and Triethanolamine (this table has already been provided) Concentration of Use by FDA Product Category: MEA Salts Concentration of Use by FDA Product Category: MEA Ingredients Alkyl and Alkenyl Amides th Street, N.W., Suite 300 Washington, D.C (fax) CIR Panel Book Page 54

59 Concentration of Use by FDA Product Category Ethanolamine, Diethanolaniine and Triethanolamine Ingredient Product Category Concentration of Use Ethanolamine Hair conditioners 4% Ethanolamine Hair straighteners 3% Ethanolamine Permanent waves 4-6% Ethanolamine Shampoos (noncoloring) 0.05% Ethanolamine Hair dyes and colors (all types requiring caution statement and 3-13% patch testing) Ethariolamine Hair color sprays (aerosol) 3% Ethanolamine Hair bleaches 4-18% Ethanolamine Bath soaps and detergents % Ethanolamine Shaving cream (aerosol, brushless and lather) % Ethanolamine Skin cleansine (cold creams, cleansine lotions. liouids and ads % Diethanolamine Shampoos (noncoloring) % Diethanolamine Tonics, dressings and other hair grooming aids 0.008% Diethanolamine Bath soaps and detergents 0.009% Diethanolamine Shaving cream (aerosol, brushless and lather) 0.06% Diethanolamine Moisturizin creams, lotions and nowders 0.06% Triethanolamine Baby lotions, oils, powders and creams 0.2-2% Triethanolamine Bubble baths % Triethanolamine Other bath preparations 1-2% Triethanolamine Eyebrow pencil 1-3% Triethanolamine Eyeliner 0.3-3% Triethanolamine Eye shadow 0.4-3% Triethanolamine Eye lotion 0.2-3% Triethanolamine Eye makeup remover % Triethanolamine Mascara 0.7-4% Triethanolamine Other eye makeup preparations 0.8-3% Triethanolamine Colognes and toilet waters % Page 1 of 3 CIR Panel Book Page 55

60 Triethanolamine Perfumes % Triethanolamine Hair conditioners % Triethanolamine Hair sprays (aerosol fixatives) % Triethanolamine Hair straighteners 3% Triethanolamine Permanent waves 0.01% Triethanolamine Shampoos (noncoloring) % Triethanolamine Tonics, dressings and other hair grooming aids % Triethanolamine Other hair preparations (noncoloring) 0.5-3% Triethanolamine Hair dyes and colors (all types requiring caution statement and 2-13% patch testing) Triethanolamine Hair tints 1% Triethanolamine Hair rinses (coloring) 5% Triethanolamine Other hair coloring preparations 3% Triethanolamine Blushers (all types) % Triethanolamine Face powders 0.06% Triethanolamine Foundations 1-2% Triethanolamine Leg and body paints 6% Triethanolamine Lipstick 0.2-1% Triethanolamine Makeup bases 1-3% Triethanolamine Other makeup preparations 0.7-2% Triethanolamine Basecoats and undercoats (manicuring preparations) 3% Triethanolamine Cuticle softeners 0.5-2% Triethanolamine Nail creams and lotions 0.2-1% Triethanolamine Other manicuring preparations 0.5-2% Triethanolamine Bath soaps and detergents % Triethanolamine Deodorants (underarm) % Triethanolamine Feminine hygiene deodorants 0.1% Triethanolamine Other personal cleanliness products 0.2-3% Triethanolamine Aftershave lotions 0.5-2% Triethanolamine Beard softeners 0.7% Page 2 of 3 CIR Panel Book Page 56

61 Triethanolamine Preshave lotions (all types) 0.3% Triethanolamine Shaving cream (aerosol, brushless and lather) 3-10% Triethanolamine Other shaving preparations 0.3-6% Triethanolamine Skin cleansing (cold creams, cleansing lotions, liquids and pads) % Triethanolamine Depilatories 0.8% Triethanolamine Face and neck creams, lotions and powders 0.4-6% Triethanolamine Face and neck sprays % Triethanolamine Body and hand creams, lotions and powders 0.3-3% Triethanolamine Body and hand sprays % Triethanolamine Foot powders and sprays 0.4-1% Triethanolamine Moisturizing creams, lotions and powders 0.2-3% Triethanolamine Night creams, lotions and powders 0.3-5% Triethanolamine Paste masks (mud packs) 1-3% Triethanolamine ---fl- Skin fresheners 2% Triethanolamine 1 Other skin care preparations 0.4-2%, 7% Triethanolamine Suntan gels, creams and liquids 2% Triethanolamine Indoor tanning preparations 0.3-2% 7% in a rinse-off skin care preparation Information collected in 2010 Table prepared October 13, 2010 Updated November 8, 2010 (Triethanolamine: lowered minimum for Mascara to 0.7; increased maximum Moisturizing to 3%) Page 3 of 3 CIR Panel Book Page 57

62 Concentration of Use By FDA Product Category - MEA Salts Ethanolamine HCI MEA-Laureth Sulfate MEA-Sulfite MEA-Lauryl Sulfate MEA PPG-6 Laureth-7 Carboxylate, MEA-Dicetearyl Phosphate MEA-Cocoate Dibutyl Ethariolamine MEA-Laureth-6 Carboxylate Diethyl Ethanolamine MEA-PPG-8-Steareth-7 Carboxylate Dimethyl MEA MEA-Undecylenate Ethyl Ethanolamirie MEA-Tallowate Methylethanolamine MEA-Benzoate Butylethanolamine, MEA-Salicylate Stearamidoethyl Ethanolamine Phosphate MEA-Hydrolyzed Silk Lysophosphatidylethanolamine* MEA-Hydrolyzed Collagen Ingredient Product Category Concentration of Use MEA-Hydrolyzed Collagen Hair conditioners 0M6% MEA-Hydrolyzed Collagen Skin cleansing (cold creams, cleansing 006% lotions, liquids and pads) MEA-Hydrolyzed Collagen Face and neck creams, lotions and powders 0.1% MEA-Hydrolyzed Collagen Moisturizing creams, lotions and powders 0.2% MEA-Hydrolyzed Collagen Night creams, lotions and powders 0.2% MEA-Hydrolyzed Collagen Paste masks and mud packs 0.03% MEA-Lauryl Sulfate Shampoos 5% MEA-Lauryl Sulfate Hair dyes and colors (all types requiring 35% caution statement and patch test) *Ingredients found in the title of the table but not found in the table were included in the concentration of use survey, but no uses were reported. Information collected in 2011 Table prepared July 5, 2011 Page 1 of 1 CIR Panel Book Page 58

63 Concentration of Use by FDA Product Acetamide MEA Myristamide MBA Cocamide MEA Isostearamide MEA Stearamide MEA Azelamide MEA Babassuamide MEA Behenamide MEA C Acid Amide MEA Cocamide Methyl MBA Cocamidopropyl Betainamide MBA Chloride Deoxyphytantriyl Palmitamide MEA Hexyloxodecanamide MBA Phosphate Hydroxyethyl Pantothenamide MEA Hydroxypropyl Bisisostearamide MEA Hydroxypropyl B islauramide MBA Hydroxypropyl Bispalmitamide MBA Hydroxypropyl Bisstearamide MBA Hydroxystearamide MEA Lactamide MEA Lauramide MEA Category - MEA Ingredients Alkyl and Alkenyl Amides Linoleamide MEA MyristoyllPalmitoyl Oxostearamide/Arachamide MEA Oatamide MEA Oleamide MEA Oliveamide MBA Palm Kernelamide MBA Palmamide MBA Palmitamide MBA Pantothenamide MBA Peanutamide MBA Ricinoleamide MEA Stearamide MEA-Stearate Stearamidoethyl Ethanolamine Sunfloweramide MBA Tallowamide MBA Trideceth-2 Carboxamide MBA Undecylenamide MBA Hexyloxodecanamide MBA PEG-9 Cocamide MEA* Ingredient Product Category Concentration of Use Acetamide MBA Eye lotion 0.5% Acetamide MBA Hair conditioners 0.3-3% Acetamide MBA Hair sprays (aerosol fixatives) % Acetamide MEA Shampoos (noncoloring) 2-3% Acetamide MBA Tonics, dressings and other hair grooming aids 0.3-5% Acetamide MBA Other hair preparations (noncoloring) % Acetamide MEA Bath soaps and detergents 3-4% Acetamide MBA Deodorants (underarm) 2% Acetamide MBA Skin cleansing (cold creams, cleansing lotions, % liquids and pads) Acetamide MBA Face and neck creams, lotions and powders 0.1% Acetamide MBA Moisturizing creams, lotions and powders 0.2% Acetamide MBA Night creams, lotions and powders 0.2-1% Acetamide MBA Paste masks and mud packs 0.03% Page 1 of 4 CIR Panel Book Page 59

64 Myristamide MEA Skin cleansing (cold creams, cleansing lotions, 0.3% liquids and pads) Myristamide MEA Body and hand creams, lotions and powders 4% Cocamide MEA Baby shampoos 2% Cocamide MEA Bubble baths 2-6% Cocamide MEA Other bath preparations 6% Cocamide MEA Other fragrance preparations 1 3% Cocamide MEA Hair conditioners 0.3-2% Cocamide MEA Shampoos (noncoloring) 1-15% Cocamide MEA Tonics, dressings and other hair grooming aids 0.5% Cocamide MEA Hair dyes and colors (all types requiring caution 3-18% statement and patch test) Cocamide MEA Hair rinses (coloring) 3% Cocamide MEA Hair shampoos (coloring) 3% Cocamide MEA Bath soaps and detergents 1-7% Cocamide MEA Other personal cleanliness products % Cocamide MEA Aftershave lotions 1% Cocamide MEA Shaving cream (aerosol, brushless and lather) 0.2-2% V Cocamide MEA Skin cleansing (cold creams, cleansing lotions, 0.3-8% liquids and pads) Cocamide MEA Body and hand creams, lotions and powders 3% Cocamide MEA Foot powders and sprays 1% Cocamide MEA Moisturizing creams, lotions and powders 0.7% Cocamide MEA Other skin care preparations 3-5% Cocamide MEA Other suntan preparations 0.7% Stearamide MEA Other bath preparations 17% Stearamide MEA Eye liner 6% Stearamide MEA Eye shadow 7% Stearamide MEA Hair conditioners 0.07% Stearamide MEA Hair dyes and colors (all types requiring caution 2-6% statement and patch test) Page 2 of 4 CIR Panel Book Page 60

65 Stearamide MEA Blushers (all types) 5% Stearamide MEA Cuticle softeners 2% Stearamide MEA Deodorants (underarm) 15% Stearamide MEA Skin cleansing (cold creams, cleansing lotions, 0.2% liquids and pads) Cocade Methyl MBA bhampoos (noncoloring) Cocamidopropyl Betainamide Bath soaps and detergents 3% MBA Cocamidopropyl Betainamide Other personal cleanliness products 1% MEA Cocamidopropyl Betainamide Skin cleansing (cold creams, cleansing lotions, 1% MBA liquids and pads) Lactamide MEA Bubble baths 2% Lactamide MEA Other bath preparations 2% Lactamide MBA Other fragrance preparations 3 2% Lactamide MBA Hair conditioners 0.2-3% Lactamide MEA Hair sprays (aerosol fixatives) % Lactamide MBA Shampoos (noncoloring) 0.5% Lactamide MBA Tonics, dressings and other hair grooming aids % Lactamide MBA Other hair preparations (noncoloring) 0.3% Lactamide MBA Bath soaps and detergents 3% Lactamide MBA Body and hand creams, lotions and powders 2% Lactamide MBA Paste masks and mud packs 2% Lauramide MEA Other baby products 0.5% Lauramide MBA Bubble baths 2% Lauramide MBA Other bath preparations 2% Lauramide MEA Other fragrance preparations 1% Lauramide MBA Shampoos (noncoloring) 1-3% Lauramide MBA Hair dyes and colors (all types requiring caution 3% statement and patch test) Lauramide MEA Nail creams and lotions 1% Lauramide MBA Bath soaps and detergents 1% Page 3 of 4 CIR Panel Book Page 61

66 Lauramide MEA Other personal cleanliness products 1-3% Lauramide MEA Skin cleansing (cold creams, cleansing lotions, 0.3-2% liquids and pads) Lauramide MEA Body and hand creams, lotions and powders 1-4% Lauramide MEA Foot powders and sprays 1% Peanutamide MEA Paste masks and mud packs 0.3% Ricinoleamide MEA Other personal cleanliness products % Stearamide MEA-Stearate Mascara 3% Trideceth-2 Carboximide MEA Hair conditioners 2% Trideceth-2 Carboximide MEA Hair straighteners 2% Trideceth-2 Carboximide MEA Shampoos (noncoloring) 2% Trideceth-2 Carboximide MEA Tonics, dressings and other hair grooming aids 2% s. Trideceth-2 Carboximide MEA Hair dyes and colors (all types requiring caution 14% statement and patch test) Trideceth-2 Carboximide MEA Hair bleaches 4% *Ingredients included in the title of the table but not found in the table were included in the survey, but no uses were reported. 13% in a rinse-off preparation 202% in foot scrub; 0.9% in a liquid hand soap; 2-10% in shower/body washes 2% in a rinse-off preparation 0.02% in a liquid hand soap Information collected in 2011 Table prepared July 5, 2011 Page 4 of 4 CIR Panel Book Page 62

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