GREEN TEA CIR EXPERT PANEL MEETING JUNE 27-28, 2011

Transcription

1 GREEN TEA CIR EXPERT PANEL MEETING JUNE 27-28, 2011

2 Administrative

3 Memorandum To: From: CIR Expert Panel Members and Liaisons Monice M. Fiume MMF Senior Scientific Analyst/Writer Date: June 3, 2011 Subject: Draft Amended Report of Triethanolamine (TEA) and TEA-containing ingredients In 1983, the Expert Panel published a safety assessment on triethanolamine (TEA), diethanolamine (DEA), and monoethanolamine (MEA) with the conclusion that TEA, DEA, and MEA are 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%. MEA should only be used in products that do not contain N- nitrosating agents. At the December 2010 Panel meeting, the Panel made the decision to reopen the safety assessment of TEA, DEA, and MEA. That decision was based on the need to incorporate new data, but most importantly, on the benefit of separating the ethanolamines and having each of these ingredients be in its own report, with a family of related ingredients created for each. The Draft Amended Report for TEA, listing 93 TEA-containing ingredients as possible add-ons, is being submitted. We are aware that the list of ingredients is extensive and that many may not be appropriate for inclusion in the re-review of TEA. However, the Panel has indicated that they would like to see a complete list, giving them the opportunity to determine the final grouping. Please be aware that the Council has submitted an opinion on the possible add-ons, and it follows this transmittal memo. The safety of 8 of the ingredients included in this re-review, as currently grouped, has been reviewed previously by the CIR. Summary information from the existing safety assessments is included in the current re-review document, and conclusions from the original CIR reports are provided in Table 1 of the report. In most cases, existing information on these ingredients was not substantial. Some of the ingredients included in this re-review include a component that has been reviewed by the CIR. For example, TEA-isostearate is the TEA salt of isostearic acid; isostearic acid has been reviewed by the CIR. Table 1 provides the conclusions from the CIR reports on the component ingredients. The data profile indicates the types of data that were available in those reports. Finally, many of the ingredients are lacking safety data. The Panel should consider whether read-across data from existing reports can be used. To facilitate that determination, full reports on the previously reviewed TEA ingredients are provided at

4 Included in the data tab of this report are: 1. concentration of use data by FDA product category, memo dated May 17, 2011; 2. Council comments on the December version of the TEA document, memo dated Dec 10, 2010; 3. FDA raw data. Once the Panel finalizes the grouping for TEA, and if there are no additional data needs, the Panel should be prepared to formulate a tentative conclusion on the TEA family of ingredients, with the rationale provided in the Discussion of the report. A Tentative Amended Report would then be issued for public comment. If the data are not complete for making a determination of safety, then an Insufficient Data Announcement should be issued listing the additional data that are needed.

5 COSMETIC Personal Care Memorandum Products Council Committed to Safety, Quality & Innovation TO: FROM: F. Alan Andersen, Ph.D. Director - INGREDIENT REVIEW (CIR) CIR Science and Support Committee of the Personal Care Products Council DATE: March 15, 2011 SUBJECT: Comments on the Proposed Ingredient Grouping for the Draft Report on Triethanolamine (TEA) and Related TEA-Containing Ingredients The CR Science and Support Committee (CIR SSC) is highly supportive of scientifically based grouping of ingredients in CR reports. However, the CR SSC is concerned about the grouping of ingredients in the proposed report on Triethanolamine (TEA) and related TEA-containing ingredients that is posted on the CR website at org/current. shtml (short list is attached). It is the Cornniittee s understanding that for re-review reports the information in the original report should support the safety of ingredients added to the report. CR reviews of components of ingredients and related ingredients can also be used to support the safety of ingredients containing the components. The chemical and toxicological properties of many ingredients in the list of ingredients proposed for inclusion in the TEA report are likely to be driven by the other portion of the compound, not TEA. In addition, there are many ingredients included in the proposed list for which the other components have not yet been reviewed by CR. Examples of unreviewed components included among ingredients proposed for inclusion in the TEA review include amino acids (for which the CR SSC has previously requested be reviewed by CR), carrageenan and a number of hydrolyzed proteins. Because a component other than TEA may drive the chemical and toxicological properties, and because of the lack of review of a component, the CR SSC recommends that the following ingredients not be included in the re-review of TEA. TEA-Lauryl Phosphate TEA-C 12-l3Alkyl Phosphate TEA-C12-14 Alkyl Phosphate TEA-Dimethicone PEG-7 Phosphate TEA-Laureth-4 Phosphate TEA-Polyphosphate Di-TEA-Palmitoyl Aspartate TEA-Cocoyl Alaninate TEA-Cocoyl Glutamate TEA-Cocoyl Glutaminate TEA-Cocoyl Glycinate TEA-Hydrogenated Tallowoyl Glutamate th Street, N.W., Suite 300 Washington, D.C (fax)

6 TEA-Lauroyl Glutamate TEA-LauryolfMyristoyl Aspartate TEA-Alginate Sodium/TEA-Lauroyl Collagen Amino Acids Sodium/TEA-Lauroyl Hydrolyzed Keratin Sodium TEA-Lauroyl Keratiri Amino Acids Sodium/TEA-Undecylenoyl Alginate Sodium/TEA-Undecylenoyl Collagen Amino Acids Sodium/TEA-Undecylenoyl Hydrolyzed Soy Protein Sodium/TEA-Undecylenoyl Hydrolyzed Wheat Protein TEA-Cocoyl Hydrolyzed Soy Protein TEA-Lauroyl Collagen Amino Acids TEA-Lauroyl Keratin Amino Acids TEA-Acrylates/Acrylonitrogens Copolymer TEA-Acrylates/Ethylhexyl Copolymer TEA-Diethanolaminoethyl Polyisobutenylsuccinate TEA-Diricinoleate/IPDI Copolymer Triethanolamine Polyoxyethylene Alkylphenylether Phosphate (Japan Trivial Name) The CW Expert Panel has included a number of TEA-containing ingredients in other reports, suggesting that TEA may not be driving potential safety concerns of these ingredients. The CIR SSC recommends that these previously reviewed TEA-containing ingredients not be added to this report as they have been more appropriately reviewed in other reports. Based on a previous dr review, the CIR SSC recommends that the following ingredients not be included in the re-review of TEA. TEA-Laurate TEA-Lactate TEA-Salicylate TEA-EDTA TEA-Lauryl Sulfate TEA-Tridecylbenzenesulfonate TEA-Dodecylbenzenesulfonate TEA-Cocoyl Hydrolyzed Collagen The CIR Expert Panel has reviewed the safety of Sodium Lauraminopropionate (report published in 1997) and found the data insufficient to support safety. The data requested included concentration of use, chemical characterization, chemical and physical properties, method of manufacture, 28-day dermal toxicity, dermal teratogenicity, ocular irritation at concentration of use, dermal irritation and sensitization at concentration of use and two different mammalian genotoxicity studies. Based on this conclusion, the CIR SSC recommends that TEA-Lauraminopropionate be removed from the re-review of TEA. 2

7 List of Potential Additional ingredients to TEA (Triethanolamine ) Report Inorganic Acid Salts TEA-Hydrochloride Organic Acid Salts TEA-U ndecylenate TEA-La urate TEA-La urate/myristate TEA-Myristate TEA-Pa Imitate TEA-Stea rate TEA-Isostea rate Hydroxy Acid Salts TEA-Lactate TEA-Diricinoleate Amine & Amide Acid Salts TEA-EDTA TEA-Myristaminopropion ate TEA-Laura minopropionate Di-TEA Cocamide Diacetate Di-TEA-Palmitoyl Aspartate TEA-Cocamide Diacetate TEA-Cocoyl Alaninate TEA-Cocoyl Glutamate TEA-Cocoyl Glutaminate TEA-Cocoyl Glycinate Ester Acid Salts TEA-Lauroyl Lactylate Organo-Substituted Inorganic Acid Salts Magnesium/TEA-Coco-Sulfate Sodium/TEA C12-13 Pareth-3 Sulfate Di-TEA-Oleamido PEG-2 Sulfosuccinate TEA-Lauryl Sulfate TEA-Laneth-5 Sulfate TEA-Laureth Sulfate TEA-Oleyl Sulfate TEA-C1O-15 Alkyl Sulfate TEA-C11-15 Alkyl Sulfate TEA-C12-13 Alkyl Sulfate TEA-C12-14 Alkyl Sulfate TEA-C12-15 Alkyl Sulfate -Aryl Sulfonate Salts TEA-Tridecylbenzen esu Ifon ate Polysaccharide & Protein Salts TEA-Cocoyl Hydrolyzed Collagen TEA-Algi nate TEA-Sulfate TEA-Sorbate TEA-Oleate TEA-Ca nolate TEA-Cocoate TEA-Hydrogenated Cocoate TEA-Rosinate TEA-Ta I late TEA-Glyceryl Dimaleate TEA-Salicylate TEA-Cocoyl Sarcosinate TEA-Hydrogenated Tallowoyl Glutamate TEA-Lauroyl Glutamate TEA-Lauroyl Methylaminopropionate TEA-Lauroyl/Myristoyl Aspartate TEA-Lauroyl Sarcosinate TEA-Oleoyl Sarcosinate TEA-Palm Kernel Sarcosinate TEA-PCA TEA-PEG-50 Hydrogenated Castor Oil Succinate TEA C14-17 Alkyl Sec Sulfonate TEA-Coco-Su Ifate TEA-C11-15 Pareth Sulfate TEA-C12-13 Pareth-3 Sulfate TEA-PEG-3 Cocamide Sulfate TEA-Lauryl Phosphate TEA-C12-13 Alkyl Phosphate TEA-C12-14 Alkyl Phosphate TEA-Dimethicone PEG-7 Phosphate TEA-Laureth-4 Phosphate TEA-Polyphosph ate TEA- Dodecylenzenesu Ifonate TEA-Isostearoyl Hydrolyzed Collagen Sodium/TEA-Lauroyl Collagen Amino Acids

8 Sodium/TEA-Lauroyl Hydrolyzed Collagen Sodium/TEA-Lauroyl Hydrolyzed Keratin Sodium/TEA-Lauroyl Keratin Amino Acids Sodium/TEA-Undecylenoyl Alginate Sodium/TEA-Undecylenoyl Carrageenan Sodium/TEA-Undecylenoyl Collagen Amino Acids Sodium/TEA-Undecylenoyl Hydrolyzed Collagen Sodium/TEA-Undecylenoyl Hydrolyzed Corn Protein Sodium/TEA-Undecylenoyl Hydrolyzed Soy Protein Sodium/TEA-Undecylenoyl Hydrolyzed Wheat Protein TEA-Abietoyl Hydrolyzed Collagen TEA-Cocoyl Hydrolyzed Soy Protein TEA-Dextrin Octenylsuccinate TEA-Lauroyl Collagen Amino Acids TEA-Lauroyl Hydrolyzed Collagen TEA-Lauroyl Keratin Amino Acids TEA-Myristoyl Hydrolyzed Collagen TEA-Oleoyl Hydrolyzed Collagen TEA-U ndecylenoyl Hydrolyzed Collagen Polymer Salts TEA-Acrylates/Acrylonitrogens Copolymer TEA-Acrylates/Ethylhexyl Acrylate Copolymer TEA-Ca rbomer TEA-Diethanolaminoethyl Polyisobutenylsuccinate TEA-Diricinoleate/l PDI Copolymer Triethanolamine Polyoxyethylene AlkylphenyletherPhosphate

9 Panel Book Page 1

10 History: Triethanolamine Original Report: In 1983, the Expert Panel determined that these ingredients 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 June 2011: the Draft Amended Report for TEA was presented to the Panel, including 93 ingredients for review as possible add-ons Panel Book Page 2

11 April 21, 2011: SCIFINDER search : SEARCH STRATEGY - All ingredients with CAS Nos. were searched using the Search Substances search engine of SciFinder; when applicable, the search was limited to only years since the previous CIR review(2095 hits before refining by document type) - Ingredients without CAS Nos. were searched using the Search References search engine - Combining all search results yielded 1120 hits; 34 references were ordered KeepMe Posted Results are received weekly 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) (DART) ( OR OR ) AND (DEVELOPMENT* OR FETOTOX*) 378 (Toxline); 47 ( 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) Panel Book Page 3

12 ( 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 Panel Book Page 4

13 TEA, TEA-Ingredients, and Components Data Profile* June 2011 Writer, Monice Fiume (updated ) 1 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 TEA 1983 X X X X X X X X X X X X X Di-TEA Cocamide Diacetate Di-TEA-Oleamino PEG-2 Sulfosuccinate Di-TEA Palmitoyl Aspartate X Magnesium/TEA-Coco Sulfate Sodium/TEA C12-13 Pareth-3 Sulfate Sodium/TEA-lauroyl Collagen Amino Acids Sodium/TEA-Lauroyl Hydrolyzed Collagen Sodium/TEA-Lauroyl Hydrolyzed Keratin Sodium/TEA-Lauroyl Keratin Amino Acids Sodium/TEA-Undecylenoyl Alginate Sodium/TEA-Undecylenoyl Carrageenan Sodium/TEA-Undecylenoyl Collagen Amino Acids Sodium/TEA-Undecylenoyl Hydrolyzed Collagen Sodium/TEA-Undecylenoyl Hydrolyzed Corn Protein Sodium/TEA-Undecylenoyl Hydrolyzed Soy Protein Sodium/TEA-Undecylenoyl Hydrolyzed Wheat Protein TEA-Abietoyl Hydrolyzed Collagen X TEA-Acrylates/Acrylonitrogens Copolymer TEA-Acrylates/Ethylhexyl Acrylate Copolymer TEA-Alginate TEA-C12-13 Alkyl Phosphate TEA-C12-14 Alkyl Phosphate TEA-C10-15 Alkyl Sulfate TEA-C11-15 Alkyl Sulfate TEA-C12-13 Alkyl Sulfate TEA-C12-14 Alkyl Sulfate TEA-C12-15 Alkyl Sulfate TEA-C14-17 Alkyl Sec Sulfonate TEA-C11-15 Pareth Sulfate TEA-C12-13 Pareth-3 Sulfate TEA-Canolate TEA Carbomer X TEA-Cocamide Diacetate TEA-Coco Sulfonate Panel Book Page 5

14 TEA, TEA-Ingredients, and Components Data Profile* June 2011 Writer, Monice Fiume (updated ) 2 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 TEA Cocoate X TEA Cocoyl Alaninate X TEA Cocoyl Glutamate X TEA-Cocoyl Glutaminate TEA-Cocoyl Glycinate TEA-Cocoyl Hydrolyzed Collagen 1983 X X x TEA-Cocoyl Hydrolyzed Soy Protein X TEA-Cocoyl Sarcosinate X TEA-Dextrin Octenylsuccinate TEA-Diethanolaminoethyl Polyisobutenylsuccinate TEA-Dimethicone PEG-7 Phosphate TEA-Diricinoleate TEA-Dodecylbenzenesulfonate 2010 X X X X TEA-EDTA 2002 TEA-Glyceryl Dimaleate TEA-Hydrochloride X TEA-Hydrogenated Cocoate TEA-Hydrogenated Tallowyl Glutamate TEA-Isostearate X TEA-Isostearoyl Hydrolyzed Collagen TEA-Lactate 1998 TEA-Laneth-5 Sulfate TEA-Lauraminopropionate TEA-Laurate X X TEA-Laureth-4 Phosphate TEA-Laureth Sulfate X TEA-Laurate/Myristate TEA-Lauroyl Collagen Amino Acids X TEA-Lauroyl Glutamate TEA-Lauroyl Hydrolyzed Collagen TEA-Lauroyl Keratin Amino Acids TEA-Lauroyl Lactylate TEA-Lauroyl Methylaminopropionate TEA-Lauroyl/Myristoyl Aspartate TEA-Lauroyl Sarcosinate Panel Book Page 6

15 TEA, TEA-Ingredients, and Components Data Profile* June 2011 Writer, Monice Fiume (updated ) 3 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 TEA-Lauryl Phosphate TEA-Lauryl Sulfate 1982 X X X X X X X TEA-Myristaminopropionate TEA-Myristate X TEA-Myristoyl Hydrolyzed Collagen TEA-Oleate X TEA-Oleoyl Hydrolyzed Collagen TEA-Oleoyl Sarcosinate TEA-Palm Kernel Sarcosinate TEA_Palmitate X TEA-PEG-3 Cocamide Sulfate TEA=PEG-50 Hydrogenated Castor Oil TEA-PCA X TEA-Polyphosphate TEA-Rosinate X TEA-Salicylate 2003 X X TEA-Sorbate TEA-Stearate 1995 X X TEA-Sulfate X TEA-Tallate TEA-Tridecylbenzenesulfonate 2010 TEA-Undecylenate TEA-Undecylenoyl Hydrolyzed Collagen X COMPONENTS Alkyl PEG Ethers 2010 X X X X X X X X X X X X Ammonium & Sodium Lauryl Sulfate 1983 X X X X X X X X X X X Coconut Ingredients 2008 X X X X X X X X X Cocoyl,Lauroyl,Myristoyl,&Oleoyl Sarcosine/Sarcosinate 2001 X X X X X X X X X Dimethicone Copolyol 1982 X X X X X X X X X X Isostearic Acid 1983 X X X X Lauric Acid 1987 X X X X X X X Myristic Acid 2010 X X X X X X Oleic Acid 1987 X X X X X X X X X X Palmitic Acid 1987 X X X X X X X X X Stearic Acid 1987 X X X X X X X X X X Panel Book Page 7

16 TEA, TEA-Ingredients, and Components Data Profile* June 2011 Writer, Monice Fiume (updated ) 4 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 PCA 1999 X X X X X X X Plant-Derived Fatty Acid Oils 2011 X X X Ricinoleic Acid 2007 X X X X X X Sodium Cetearyl Sulfate and Related Alkyl Sulfates 2010 X X X X X X X X X X Sodium Lauraminopropionate 1997 X X X Sodium Laureth Sulfate/Sulfated Ethoxylated Alcohols 2010 X X X X X X X X X Sorbic Acid 1988 X X X X X X X X X X Tall Oil Acid 2009 X X X X * X indicates that data were available in a category for the ingredient # year the report was published Panel Book Page 8

17 Transcripts

18 FULL PANEL - December 2010 DR. BERGFELD: Thank you. So, the motion's been made to reopen and it's been seconded. Any further discussion? DR. MARKS: And with the intent -- and we'll -- as Paul mentioned earlier, at least for our team the intent was to add methylene glycol, but as we work through the report, we'll decide whether or not we want to continue that. DR. BERGFELD: All right. Call for the question, all those in favor, please indicate by raising your hand? Thank you. Unanimous. Then moving on to the second to the last ingredient which is the MEA/DEA/TEA. Dr. Belsito? DR. BELSITO: Yes, this is a re-review of the document and it's gone through a number of iterations. The initial was 1983, and since that time there have been a number of discussions regarding DEA. However, it's really time that we look at the original report which contained all three. And when we -- when my team looked at the data we really felt that perhaps with the exception of opening it to reassess MEA and changing it to our current way of stating that we had limited it to rinse off products because of irritation, to the current way of stating, could be used in leave-ons if formulated not to be irritating, it was really no reason to open the document. However, the reason to open it would be that there are a number of MEA, DEA, and TEA compounds that could be tagged onto this quite easily that we haven't reviewed. So we are recommending that, A, the report be split into three different reports: An MEA, a DEA, and a TEA report; and that all of the related cosmetic MEAs, DEAs, and TEAs be included in each of those reports. And that's a motion. DR. BERGFELD: Motion to reopen and split it into three different ingredient groups has been made. DR. MARKS: Second. DR. BERGFELD: Second. Any further discussion about reopening? John? DR. BAILEY: Yeah, I agree, but I think that it's really important how these groups are going to be constituted. And I would like to see the proposed group as soon as possible and then we will refer that to our Science and Support Committee just to make sure that they're comfortable with the way the group is put together. You know, there was some, I wouldn't say concern, but some interest in making sure that these groups are as rational and logical as possible, so we would need to get those as soon as we can. DR. BERGFELD: Alan? DR. ANDERSEN: Yeah, we will most certainly get the potential add-ons out ASAP. I see a primary focus of the March meeting on receiving that input from industry, receiving the input from the panel as the panel gets the opportunity to look at those groupings, and negotiating what actually should be done as add-ons. So, I don't know that we're -- I mean, unless we hit the nail perfectly on the head, there's going to be some negotiating in March. DR. BERGFELD: Call for the question then to reopen, all those in favor please indicate by raising your hands? Thank you. It's reopened. And then moving to the last ingredient to be considered this morning, human umbilical extract, Dr. Marks? DR. MARKS: In 2002, the CIR published its final safety assessments in the ingredients derived from human and animal placentas and umbilical cords with a conclusion that the available data were insufficient to support the safety. We recently had correspondence from a company specifically concerning use of human umbilical extract in cosmetic products. They supplied some data, but when you look at our insufficient data needs from the original safety assessment, really those data needs were not met and so our team moves not to reopen this safety assessment. DR. BERGFELD: Second? Is that a second? Comment? Panel Book Page 9

19 BELSITO TEAM - December 2010 CIR Meeting day 1 of 2 (Breakout Session) Page: 14 CIR Meeting day 1 of 2 (Breakout Session) Page: 15 1 the risk assessment pages that you're looking at 2 will substantially make up the summary that you're 3 going to see at the next meeting. 4 DR. BELSITO: Okay, good. Anything else 5 on this? No? Okay. So moving on to the next 6 one, it's the re- review of MEA, DEA, and TEA. 7 And Alan has essentially already stolen my 8 thunder, which is basically how many salts and 9 esters of these can we make into super families? 10 And so I'm thinking we should be reopen it not 11 only to add those in, but I think our conclusion 12 that MEA should not be used in leave-on products 13 is based upon irritation. And we've taken a 14 different step now to say "when formulated not to 15 be irritating," so that conclusion may not be 16 correct either as it stands. So I would say that 17 we reopen the documents and take Alan's, split 18 them into three and add the salts and esters of 19 the MEAs, DEAs, and TEAs so that we get everything 20 that's out there. 21 DR. ANDERSEN: I think with that 22 strategy what you could expect to see at the next Anderson Court Reporting meeting would be three more, three separate and 2 more comprehensive documents that list the Organic 3 Acid Salts that could conceptually be included and 4 then examines the question of going on to, let's 5 see, MEAs, for example, the DEA list. There is 6 yet a second group that takes off on the fact that 7 we've already reviewed cocamide DEA, lauramide 8 DEA, which are not -- may not technically be 9 considered as salts, but we'll look at forming 10 those groups as well. Monice and Bart have 11 already done a great deal of homework on this, and 12 are kind of ready to package that, but we just 13 kind of finished it last week and it seemed 14 disingenuous to dump all of that on the Panel for 15 this meeting. So if for all sorts of reasons, it 16 seems appropriate to reopen these, then we can 17 take the next step at the next meeting. 18 DR. BELSITO: Is everyone in agreement 19 of splitting them into three separate documents 20 when we do that? 21 DR. SNYDER: Yes. 22 DR. LIEBLER: Fine with it. Anderson Court Reporting CIR Meeting day 1 of 2 (Breakout Session) Page: 16 1 DR. BELSITO: Okay, any comments? 2 DR. LIEBLER: I guess I had 3 misinterpreted the cover memo, and I thought that 4 the main reason to discuss these was the 5 appearance of new data on carcinogenicity. So 6 really that's not the main issue here. 7 DR. SNYDER: No. 8 DR. LIEBLER: Okay. 9 MS. FIUME: Originally DR. ANDERSEN: I think, in fact, it's an 11 old issue at this point in terms of DEA 12 carcinogenesis. At this point in time arguably 13 explained process of choline metabolism in mice, 14 and it's not hugely relevant. 15 DR. LIEBLER: Right, so based on all of 16 that, I said don't reopen these, but I agree with 17 the reason now to reopen. 18 DR. BELSITO: Any other comments? Okay, 19 dicarboxylic acid. Okay, so in August we issued a 20 tentative report for the twelve dicarboxylic 21 acids, 44 diesters, finding them safe in present 22 practice of use and concentration. There was one MARKS TEAM - December 2010 CIR Meeting day 1 of 2 ( Main Session) Page: HIV, it put together all sorts of stuff, and we 2 started to separate the two boilerplates out, and 3 some time next year, we will be bringing to the 4 panel all of the boilerplates for boilerplate 5 re-review so we can go through and make sure 6 they're currently up to date. We felt there were 7 more than enough agenda items on this meeting to 8 not do it starting with this meeting. 9 DR. MARKS: Thank you. Okay, onto the 10 next ingredient or ingredients. We're in the MEA, 11 DEA, TEA re- review. There's quite a history of 12 these ingredients, and I think where we're at at 13 this point is do we reopen, do we separate it out 14 into three different reports, do we put them 15 together? And I'll open it up for discussion. 16 And then, also, we should talk about if we reopen, 17 do we reopen it to add salts and simple esters, 18 also? And to further comment, and, Tom, I'd asked 19 you about the nitrosamine formulation concern, and 20 Ron's, where DEA has been banned in the EU and 21 Canada, plus it's salts and MEA and TEA has had 22 restrictions. So, let's go ahead and decide Anderson Court Reporting Panel Book Page 10 Anderson Court Reporting

20 CIR Meeting day 1 of 2 ( Main Session) Page: 148 CIR Meeting day 1 of 2 ( Main Session) Page: whether we're going to reopen and then do we do 2 them together or separate and what do we add? 3 DR. SLAGA: After reading this and 4 trying to compare to three of them, the DEA and 5 TEA and the MEA, so to speak, and with the data 6 related to EU and Canada, it seems to me it would 7 be a good idea to reopen and separate them. 8 In terms of nitrosamines, they all have 9 capabilities, don't they? 10 DR. SHANK: Not MEA. 11 DR. SLAGA: I mean, TEA. 12 DR. SHANK: Yes, TEA. 13 DR. SLAGA: TEA and DEA. 14 DR. HILL: I'm not sure I understand why 15 TEA does actually. I'm a little confused about 16 that. 17 DR. SLAGA: Chemistry. 18 DR. MARKS: So, let's go back. So, I 19 saw nodding of heads, all team members endorse the 20 idea of reopening? 21 DR. SHANK: Yes. 22 DR. MARKS: And to separate into the Anderson Court Reporting mono, di, and tri? 2 DR. SHANK: What do you mean by 3 "separate?" Three reports or three sections of 4 one report? 5 DR. MARKS: That's the question. 6 Because my sense was there was a possibility of 7 doing three separate reports, but we can do -- 8 MS. BRESLAWEC: We could do it 9 administratively anyway. We just noticed that, 10 over the years, keeping them in one report has led 11 to unnecessary confusion. So, we would like to 12 either keep them separately in the same report or 13 put them in three different reports with cross 14 references. 15 DR. HILL: I guess I'd endorse the idea 16 of putting them in three separate reports on the 17 basis that there doesn't seem to be any 18 significant biotransformation, for example, of TEA 19 to DEA. The only relationships I see are in the 20 choline depletion, the ones that have that 21 activity, and I'm wondering, I mean, 22 monoethanolmine is relatively abundant endogenous Anderson Court Reporting CIR Meeting day 1 of 2 ( Main Session) Page: molecules. 2 So, until you get to really, really 3 artificial dose levels, I'm not sure -- so, my 4 personal bias, but I hadn't thought about keeping 5 them in the same report and just considering them 6 separately. My personal bias was to separate them 7 out into three individual reports. That is just 8 my personal bias based on everything I saw there. 9 DR. MARKS: Tom and Ron Shank? Together 10 or as separate? I should together in one report, 11 but separated within that report? 12 DR. SLAGA: I don't know. It seems to 13 me it'd be better in separate reports, not 14 confusing them. 15 DR. SHANK: I don't feel strongly about 16 it. If it were strictly up to me, I'd have one 17 report with three sections. 18 DR. MARKS: Okay. Well it sounds like 19 at least at this point we'll go with separate 20 reports, and we'll see what the Belsito Team's 21 feelings are. 22 Any further comments before we -- CIR Meeting day 1 of 2 ( Main Session) Page: DR. SHANK: Yes, that being the case, 2 then I think TEA and MEA would carry the same 3 conclusion that the report has now, in that the 4 major changes would be in the DEA report. 5 MS. FIUME: Could you clarify what you 6 mean, Dr. Shank? 7 DR. SHANK: Yes, we have a report 8 already with all three ingredients in it. The 9 conclusion for that report would still apply to 10 TEA and MEA, even though you're splitting those 11 reports. And then the major changes would be in 12 the new report on DEA, diethanolamine. 13 MS. BRESLAWEC: Are you suggesting that 14 you would not reopen TEA and MEA? 15 DR. SHANK: You have to reopen it 16 because it's now one report, and now you're going 17 to split it into three. So, I don't see how you 18 can do that without reopening it. And now if 19 you're going to add the other ingredients that 20 pertain to each of those ethanolamines, that's 21 your opportunity to do that. 22 MS. BRESLAWEC: But you can reopen them Anderson Court Reporting Panel Book Page 11 Anderson Court Reporting

21 CIR Meeting day 1 of 2 ( Main Session) Page: 152 CIR Meeting day 1 of 2 ( Main Session) Page: just to add ingredients, which makes it a little 2 more expedient. DEA, it seems you're suggesting 3 to reopen to reconsider the conclusion, perhaps? 4 DR. SHANK: Correct. 5 DR. SLAGA: Yes. 6 DR. SHANK: How do you reopen? You're 7 creating three new reports. So, you're not 8 reopening DEA, you're not reopening the current 9 report. You're splitting it. 10 DR. MARKS: Yes DR. SHANK: How do you do that 12 procedurally? What words you use MS. BRESLAWEC: I think it's something 14 that we would do administratively. 15 DR. MARKS: No, that's a good point, 16 Ron, because in 1983, these were grouped together. 17 So, you're reopening that report, but if we decide 18 to do three separate reports, we're not reopening 19 them in that; we're reopening to separate it. So, 20 I guess administratively, you have to make sure 21 that that's not a problem with the CIR guidelines. 22 But, if there are, it seems to me just as we've Anderson Court Reporting done with other reports; we've had major sections 2 within the report. There will be. Well, the 3 conclusion will just deal with it. 4 DR. BAILEY: And couldn't this also -- 5 in splitting these, wouldn't it be logical to 6 include adding the other alkanolamines within that 7 group, like a diethanol. I mean, it would be 8 dialkonalamines because there are some in the 9 dictionary now. 10 MS. BRESLAWEC: We've actually prepared, 11 and, Bart, maybe you'd like to come up here, as 12 well, but we've started looking at possible 13 add-ons for all there, MEA, DEA, and TEA, and we 14 are approaching it very systematically. There are 15 groups that seem to us to be natural add-ons, like 16 organic acid salts, for example, and then there 17 are groups that are related, but may be a little 18 far out or groups that are related, but probably 19 should be considered on their own. We're not 20 ready to present those groups for discussion right 21 now, but we have started the process, and we have 22 quite a bit of information on it, but it's Anderson Court Reporting CIR Meeting day 1 of 2 ( Main Session) Page: something that warrants more preparation before 2 it's presented to you all for discussion. 3 So, yes, we would like to consider 4 reopening all three reports for the potential of 5 adding new ingredients. 6 DR. MARKS: Halyna, how much do you see 7 in having separate reports that you're now going 8 to have a lot of refer to the other report to 9 support that the safety of the other ingredients. 10 Like Ron says TEA and MEA, the same conclusions. 11 So, does that make sense to separate them out if 12 we're going to be using data from one to support 13 the other? And, I, again, am looking forward in 14 terms of if there's going to be a lot of data 15 that's shared in all three reports, and does it 16 make sense to have there separate reports? 17 DR. BOYER: For each of the three 18 chemicals, there is a lot of chemical-specific 19 information. So, it doesn't need to be a lot of 20 cross-reference and so forth. And DEA actually 21 stands out when you look at that data and the 22 mechanistic information that's been published and CIR Meeting day 1 of 2 ( Main Session) Page: so forth. So, I think from that perspective, it 2 certainly makes sense to separate them. 3 DR. HILL: Excuse me. And in regards to 4 potentially expanding the groups, I would just say 5 that I strongly suspect that there's going to be, 6 particularly with DEA, there's some toxicology 7 issues that might pertain to it that might not 8 pertain to anything even related. Now, amides of 9 DEA at some point, but those are really widely, 10 heavily used for cosmetic ingredients, and I think 11 moving in that direction would be right now with 12 great caution in my estimation because I think 13 there might not be that much to worry about. 14 DR. BOYER: Right. 15 DR. HILL: And, so, if you tag related 16 to something where there clearly is a problem well, I say "clearly is a problem," seems to be a 18 problem. Don't know in humans, but you might be 19 creating a problem where there wasn't one before. 20 DR. MARKS: I think, again, for the 21 stenographers, that was Dr. Boyer who was 22 commenting earlier, correct? Anderson Court Reporting Panel Book Page 12 Anderson Court Reporting

22 CIR Meeting day 1 of 2 ( Main Session) Page: 156 CIR Meeting day 1 of 2 ( Main Session) Page: DR. BOYER: Yes. 2 DR. MARKS: As new member of the CIR 3 support staff. Thank you. 4 To kind of reinforce what you said, Ron 5 Hill, for TEA, there's now am I reading 6 this correctly, 4,015 products that it's used in? 7 DR. ANSELL: The group is potentially 8 enormous depending on where you start drawing your 9 lines. 10 DR. MARKS: Yes. Plus it looks like and, obviously, there are also baby products 12 there, but a huge number of products that contain 13 this ingredient. 14 Okay, so, it looks like I think what 15 we'll find out what the other team moves tomorrow, 16 but, for us, it's to reopen separate reports and 17 to consider add-ons, and we'll see that, I 18 presume, some time in a future meeting. And then 19 we'll start, I suspect, on looking at the add-ons 20 to begin with and then go from there. 21 Does that sound reasonable, team 22 members? Anderson Court Reporting TEAM MEMBERS: (Nodding) 2 DR. MARKS: Anything else we need to 3 discuss about these three at this point? And, Ron 4 Shank, you've given us an insight of where the 5 safety assessments are going to go in the TEA and 6 MEA. It sounds like the same conclusion or 7 similar, and DEA, that I will have some 8 significant changes in the conclusion. 9 MR. SHANK: Okay, so, we're not going to 10 discuss this until we see it in three different 11 reports? Is that what you're saying? 12 DR. MARKS: Well, that's what I 13 suggested, but I guess in discussing it MR. SHANK: Do you want to discuss the 15 mouse carcinogenicity assay? 16 DR. MARKS: Sure. 17 MR. SHANK: Or not? Wait? 18 MS. FIUME: That's fine, because that 19 would be one reason to reopen that portion of the 20 report to separate than just to add. 21 MR. SHANK: Yes. 22 MS. FIUME: So, if there's information Anderson Court Reporting CIR Meeting day 1 of 2 ( Main Session) Page: you want taken care of there, I'd like to discuss 2 that part now. 3 DR. MARKS: Go ahead, Tom. 4 DR. SLAGA: (Off mike) restriction, too. 5 DR. MARKS: This isn't -- 6 DR. SHANK: I think the reason -- 7 DR. MARKS: This is the choline. 8 DR. SHANK: The main reason this was 9 coming up for re-review was there was a cancer 10 bioassay in the mouse on DEA that produced tumors, 11 and I think we need to address that mouse 12 bioassay. But if you want to wait until the 13 reports are split, then we can do it at that time. 14 DR. MARKS: I think that's up to you. 15 DR. SHANK: (Off mike) for three 16 different reports. 17 DR. MARKS: Yes, for Ron and Tom and Ron 18 Hill, there is that, and, also, the nitrosamine 19 formulation, we could discus that, also, at this 20 point and give a nice idea of the direction we're 21 going. Yes. 22 DR. SHANK: That's pretty simple. MEA, CIR Meeting day 1 of 2 ( Main Session) Page: it's a primary amine, and that's not 2 nitro-satiable. DEA and TEA are, and the 3 nitrosation products are in the literature. So, 4 that's not an issue. The issue is how does one 5 interpret the mouse cancer bioassay? 6 MS. DAHLIN: Dr. Marks, Dr. Shank, the 7 report, although under one cover, is in three 8 separate sections, as you've noted. So, we are 9 certainly prepared to hear a discussion on one of 10 the reports to see if you want any additional 11 scientific or safety information incorporated and 12 considered before considering add-ons. 13 DR. SHANK: No, I don't think there's a 14 data need. It's just how do we interpret that 15 assay? 16 MS. FIUME: And, Dr. Shank, I think it 17 was probably after this report was packaged and 18 sent out. We did find some information from I 19 want to say 1999 or the last time it was reviewed 20 where it was discussed and the panel at that time 21 had decided that the problem was it was the 22 choline deficiency causing the problem. It wasn't Anderson Court Reporting Panel Book Page 13 Anderson Court Reporting

23 CIR Meeting day 1 of 2 ( Main Session) Page: 160 CIR Meeting day 1 of 2 ( Main Session) Page: the DEA, it was the choline, and there was a 2 discussion. So, I will capture that, as well, it 3 was just discovered after it came out. But if you 4 don't agree what may have been said at that time, 5 then I'll capture something differently or look 6 for different information. 7 DR. SHANK: Okay, I'd have to read that, 8 but I was on the panel at that time, so, I 9 shouldn't make the same argument all over again. 10 We don't need to discuss that now, and we'll see 11 what we said 11 years ago. 12 DR. MARKS: Well, basically in 2008, the 13 panel agreed that the NTP findings of 14 carcinogenesis in the mouse for DEA and certain 15 DEA fatty acid esters was related to choline 16 (inaudible) and not relevant to human health. 17 Tom, is that your recollection? 18 DR. SLAGA: (Nodding) 19 DR. MARKS: I think that's how we dealt 20 with the mouse carcinogenicity. 21 DR. HILL: But I had a question based on 22 information that was in both presentations at the Anderson Court Reporting meeting. Of course, that was long before my 2 participation. Both Dr. Lehman-McKeeman, I don't 3 know if I'm saying her name right, and Dr. Stott 4 mentioned that DEA is incorporated in ceramides 5 and possibly sphingomyelins, and then in the 6 discussion of DEA, that whole possible mechanism 7 is dropped, and because I guess there's a 8 pharmacologist in our department who's working on 9 that and effects on cancer stem cells and 10 apoptosis, I want to know if that thread of 11 biology has continued or people have just ignored 12 those pieces of information which came from 13 industry source presentations. Whether there's 14 been any follow-up whatsoever on that biology. 15 And that's one of the reasons why I was looking to 16 see this split was because there may be an issue 17 with DEA biology that doesn't show up at all that 18 shouldn't be an issue with TEA, that shouldn't be 19 an issue with monoethanolmine, but it very well 20 might be a big issue with DEA and only DEA. 21 DR. BOYER: Well, that mechanism seems 22 to certainly distinguish DEA from the other two. Anderson Court Reporting CIR Meeting day 1 of 2 ( Main Session) Page: As far as I know, there has been no significant 2 progress in terms of developing information to 3 interpret or to determine the importance of those 4 observations, the observation that DEA seems to be 5 incorporated into possible lipids. And there's a 6 lot of speculation about what could happen and how 7 that mechanism might explain some of the toxic 8 effects not necessarily the carcinogenicity. 9 DR. HILL: Well, ceramides have a strong 10 role to play in regulating apoptotic pathways, as 11 well as proliferative pathways, and these were 12 mentioned in two different presentations by two 13 independent labs. So, I guess I'm raising it now 14 so that in mining the literature, whatever might 15 be out there, you will be attuned to looking for 16 anything. 17 DR. BOYER: Absolutely. 18 DR. HILL: (off mike) 19 DR. BOYER: Right. 20 DR. HILL: And I'm not thinking that 21 this is at all relevant in any of the amides of 22 DEA because I doubt that DEA is significantly CIR Meeting day 1 of 2 ( Main Session) Page: generated from those amides. But I think it might 2 be something specific to DEA, which I guess is 3 really not used much at all at this point. I get 4 the sense. 5 DR. BOYER: Right. 6 DR. HILL: But it would be clean if 7 those three were dealt with separately then in 8 going to -- because I can envision language in 9 something that's reviewed that's structurally 10 similar, like the kinds of ingredients you were 11 suggesting to expand to. The panel has previously 12 reviewed DEA. We note the structural similarity, 13 but the specific toxicological issues pertaining 14 to that compound don't pertain to any of these, 15 and here's why. 16 DR. BOYER: Yes. 17 DR. HILL: And, so, it would be very 18 clean to be able to refer to that single report 19 and not give issue with the other two that I don't 20 think have any same issues at all. 21 DR. MARKS: Would you like to, since 22 there are three separate reports within this Anderson Court Reporting Panel Book Page 14 Anderson Court Reporting

24 CIR Meeting day 1 of 2 ( Main Session) Page: 164 CIR Meeting day 1 of 2 ( Main Session) Page: document, should we, again, sort of have a preview 2 of what's coming down the road, take a look at 3 them individually? I think that the conclusion in it's going to be a little interesting if 5 we keep the same wording. So, his conclusion that 6 TEA, DEA, and MEA are safe for use in cosmetic 7 formulations designed for discontinuous brief use 8 followed by thorough rinsing from the surface of 9 the skin. And products intended for prolonged 10 contact with the skin, the concentration 11 ethanolamines should not exceed 5 percent, MEA 12 should only be used in products that do not 13 contain nitrosating agents. 14 So, I know the TEA and the MEA, Ron, you 15 suggested this same conclusion or something 16 similar is going to be okay. The DEA, there's 17 going to be changes. 18 Do you want to go through these 19 individually now? We dealt with the mouse, I 20 think, where the choline metabolism not relevant 21 to the human. We disused the nitrosamine 22 formulation concern left to deal with the ban in Anderson Court Reporting EU and Canada. Or restricted. 2 DR. SLAGA: Wasn't it suggested to have 3 two reports instead of three? I mean, I thought 4 that's what you were thinking, too. No? 5 DR. SHANK: No, my suggestion was one 6 report with three sections. But we all decided 7 three individual reports. I think. 8 DR. SLAGA: I thought you meant that you 9 wanted to have TEA and MEA combined because they 10 all have the same conclusions. 11 DR. ANDERSEN: I wanted all three 12 combined. One single report with three sections. 13 But that's a minority opinion. 14 DR. HILL: Well, if there's nothing to 15 ceramides and if there's nothing to more than 16 choline deficiency in that particular assay then 17 you could keep them combined. I guess in my mind, 18 it's somewhat dependent on the toxicology here. 19 MS. BRESLAWEC: We really would prefer 20 separating them out in one form or another because 21 it's caused a lot of confusion when we've looked 22 at derivatives or components that contain DEA or Anderson Court Reporting CIR Meeting day 1 of 2 ( Main Session) Page: MEA or TEA. Administratively, it's very difficult 2 to deal with them in the same report. So, whether 3 it's one report with three sections, we're fine 4 with that, or three separate reports, we're fine 5 with that, as long as each of the ingredients are 6 handled separately. 7 DR. MARKS: Well, certainly, if they 8 were all in the same report, we wouldn't be 9 dealing with taking a combined report in 1983 and 10 now re-reviewing it and creating three separate 11 reports. 12 Ron Hill and Tom, does it matter to you 13 whether they all be combined in the one report and 14 three sections or three separate reports? 15 DR. SLAGA: Really, it's the same thing. 16 DR. MARKS: Yes, except we have to know 17 which way we're going to go as we proceed. Should 18 we wait and see what the Belsito Team says? I can 19 see there's not a strong DR. SLAGA: -- (Off mike) six reports. 21 DR. MARKS: Yes, six. I can see there's 22 not a great strong feeling one way or another, as CIR Meeting day 1 of 2 ( Main Session) Page: long as it's separated. So, we'll just say 2 separated in either3 separate reports or within 3 one. 4 Anything more in terms of looking at 5 these individual ones before we come back to this 6 in a future meeting? If there anything else you 7 wanted, Monice, to get any directions? 8 MS. FIUME: I just wanted to make sure 9 so from my understanding, what we will bring back 10 at the next meeting is three reports with what we 11 feel were the proper add-on ingredients that you 12 are more than welcome to take out, but this way, 13 we'd at least have it prepared for you as what we 14 think the next iteration of the reports are. 15 Is that correct? 16 DR. MARKS: Yes. Are there any data 17 needs for these individual ones at this point, and 18 is there enough in this report in terms of the 19 data? Certainly from irritation and 20 sensitization, I thought it was fine. Is there 21 anything else in terms of data needs? 22 Ron, you had mentioned one concern you Anderson Court Reporting Panel Book Page 15 Anderson Court Reporting

25 CIR Meeting day 1 of 2 ( Main Session) Page: had, but -- 2 DR. HILL: It was just an information, 3 sort of see if there's anything out there request. 4 Not a data need. 5 DR. MARKS: So, it sounds like the main 6 thing we're going to do next time is clarify the 7 discussion concerning the mouse and concerning the 8 nitrosamine formation for each of these as 9 separate ingredients, and then decide on the 10 add-ons, but in terms of data, it seems like we're 11 okay at this point. Is that DR. BRESLAWEC: Just to clarify one 13 thing, they'll be draft amended reports that 14 you'll get next time. 15 MS. FIUME: And then the only other 16 thing I was going to say is in Wave 2, you should 17 have received what the original re-review summary 18 was for DEA. So, I will pull from that 19 information, as well, that includes some of your 20 decision-making or conclusion as to why it went 21 the way it did. 22 DR. MARKS: Anything else? Anderson Court Reporting Panel Book Page 16

26 Report

27 Draft Amended Report Triethanolamine (TEA) and TEA-Containing Ingredients as Used in Cosmetics June 27, 2011 The 2011 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Ronald A. Hill, Ph.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; James G. Marks, Jr., M.D.; Ronald C. Shank, Ph.D.; Thomas J. Slaga, Ph.D.; and Paul W. Snyder, D.V.M., Ph.D. The CIR Director is F. Alan Andersen, Ph.D. This report was prepared by Monice Fiume, Senior Scientific Analyst/Writer. Cosmetic Ingredient Review th Street, NW, Suite 412 " Washington, DC " ph " fax " Panel Book Page 17

28 Table of Contents Introduction... 1 Chemistry... 2 Definition and Structure... 4 Method of Manufacture... 4 Stability... 5 Impurities... 5 N-Nitrosodiethanolamine Formation... 5 Use... 5 Cosmetic... 5 Non-Cosmetic... 6 Toxicokinetics... 7 Dermal... 7 In Vitro... 7 Non-Human... 7 Human... 8 Oral... 9 Non-Human... 9 Other... 9 Non-Human... 9 Toxicological Studies... 9 Acute (Single) Dose Toxicity Dermal Oral Other Repeated Dose Toxicity Dermal Oral Inhalation Reproductive and Developmental Studies Dermal Oral Genotoxicity In Vitro In Vivo Carcinogenicity Dermal Oral Possible Mode of Action for Carcinogenic Effects of TEA Carcinogenic Potential in Humans Irritation and Sensitization Irritation Skin In Vitro Non-Human Human Mucosal In Vitro Non-Human Sensitization Non-Human Human Provocative Testing Phototoxicity/Photoallergenicity Non-Human Human ii Panel Book Page 18

29 Clinical Assessment Case Reports Summary Tables Table 1. Conclusions of previously reviewed ingredients and components Table 2. Definitions and structures Table 3. Physical and Chemical Properties Table 4a. Frequency and concentration of use according to duration and type of exposure Table 4b. Ingredients not reported to be used References iii Panel Book Page 19

30 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 add additional related ingredients included in each of the new reviews. This assessment addresses triethanolamine (TEA) and 93 possible add-on cosmetic ingredients containing TEA. TEA, an ingredient that functions as a surfactant or ph adjuster in cosmetic products, has previously been reviewed by the CIR Expert Panel. In 1983, the Expert Panel concluded that TEA is safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin. 1 In products intended for prolonged contact with the skin, the concentration of TEA should not exceed 5%. TEA should not be used with products containing N- nitrosating agents. In the 1983 assessment, data demonstrated that TEA was a mild skin and eye irritant, and that irritation increased with increasing ingredient concentration. The following 93 ingredients are the potential add-ons to the TEA re-review. The ingredients are sorted by chemical class. Most of these ingredients function in cosmetics as surfactants, viscosity increasing agents, skin conditioning agents, or hair conditioning agents. A few ingredients may function as a chelating agent, binder, film former, or emulsion stabilizer. TEA-sorbate functions only as a preservative and TEA-salicylate as a light stabilizer or sunscreen agent. It is almost certain that the Expert Panel will delete some of the ingredients from this list; however, all are being presented, as requested by the Panel. Inorganic salts TEA-Hydrochloride TEA-Sulfate Organic acid salts TEA-Laurate TEA-Laurate/ Myristate TEA-Myristate TEA-Palmitate TEA-Stearate* TEA-Isostearate TEA-Undecylenate Triethanolamine diester TEA-Diricinoleate TEA-Sorbate TEA-Oleate TEA-Canolate TEA-Cocoate TEA-Hydrogenated Cocoate TEA-Rosinate TEA-Tallate TEA-Glyceryl Dimaleate Hydroxy Acid Salts TEA-Lactate* TEA-Salicylate* Amine & Amide Acid Salts TEA-EDTA* TEA-Myristaminopropionate TEA-Lauraminopropionate Di-TEA-Palmitoyl Aspartate TEA-Cocoyl Glycinate TEA-Cocamide Diacetate TEA-Cocoyl Alaninate TEA-Cocoyl Sarcosinate TEA-Hydrogenated Tallowoyl Glutamate TEA-Lauroyl Glutamate TEA-Lauroyl Methylaminopropionate TEA-Lauroyl/Myristoyl Aspartate TEA-Lauroyl Sarcosinate TEA-Oleoyl Sarcosinate TEA-PCA Di-TEA Cocamide Diacetate TEA-Cocoyl Glutamate TEA-Cocoyl Glutaminate TEA-Palm Kernel Sarcosinate 1 Panel Book Page 20

31 Ester Acid Salts TEA-PEG-50 Hydrogenated Castor Oil Succinate TEA-Lauroyl Lactylate Inorganic Acid Salts -Sulfates and Sulfonates Magnesium/TEA-Coco-Sulfate Sodium/TEA C12-13 Pareth-3 Sulfate Di-TEA-Oleamido PEG-2 Sulfosuccinate TEA-Lauryl Sulfate* TEA-Laneth-5 Sulfate TEA-Laureth Sulfate TEA-Oleyl Sulfate TEA-C10-15 Alkyl Sulfate -Phosphates TEA-Lauryl Phosphate TEA-Laureth-4 Phosphate TEA-C12-13 Alkyl Phosphate Polysaccharide & Protein Salts TEA-Cocoyl Hydrolyzed Collagen* TEA-Alginate TEA-Isostearoyl Hydrolyzed Collagen Sodium/TEA-Lauroyl Collagen Amino Acids Sodium/TEA-Lauroyl Hydrolyzed Collagen Sodium/TEA-Lauroyl Hydrolyzed Keratin Sodium/TEA-Lauroyl Keratin Amino Acids Sodium/TEA-Undecylenoyl Alginate Sodium/TEA-Undecylenoyl Carrageenan Sodium/TEA-Undecylenoyl Collagen Amino Acids Sodium/TEA-Undecylenoyl Hydrolyzed Collagen TEA-C11-15 Alkyl Sulfate TEA-C12-13 Alkyl Sulfate TEA-C12-14 Alkyl Sulfate TEA-C12-15 Alkyl Sulfate TEA C14-17 Alkyl Sec Sulfonate TEA-Coco-Sulfate TEA-C11-15 Pareth Sulfate TEA-C12-13 Pareth-3 Sulfate TEA-PEG-3 Cocamide Sulfate TEA-Dodecylbenzenesulfonate* TEA-Tridecylbenzenesulfonate* TEA-C12-14 Alkyl Phosphate TEA-Dimethicone PEG-7 Phosphate TEA-Polyphosphate Sodium/TEA-Undecylenoyl Hydrolyzed Corn Protein Sodium/TEA-Undecylenoyl Hydrolyzed Soy Protein Sodium/TEA-Undecylenoyl Hydrolyzed Wheat Protein TEA-Abietoyl Hydrolyzed Collagen TEA-Cocoyl Hydrolyzed Soy Protein TEA-Dextrin Octenylsuccinate TEA-Lauroyl Collagen Amino Acids TEA-Lauroyl Hydrolyzed Collagen TEA-Lauroyl Keratin Amino Acids TEA-Myristoyl Hydrolyzed Collagen TEA-Oleoyl Hydrolyzed Collagen TEA-Undecylenoyl Hydrolyzed Collagen Polymer Salts TEA-Acrylates/Acrylonitrogens Copolymer TEA-Acrylates/Ethylhexyl Acrylate Copolymer TEA-Carbomer TEA-Diethanolaminoethyl Polyisobutenylsuccinate The ingredients marked with an asterisk have been previously reviewed by the CIR, and the conclusions of the safety assessments of these ingredients are provided in Table 1. CHEMISTRY TEA is an amino alcohol. TEA is produced commercially by aminating ethylene oxide with ammonia. The replacement of three hydrogens of ammonia with ethanol groups produces TEA. (Figure 1). TEA contains small amounts of diethanolamine (DEA) and ethanolamine (MEA). HO N OH OH Figure 1. TEA TEA is reactive and bifunctional, combining the properties of alcohols and amines. The reaction of ethanolamines and sulfuric acid produces sulfates. TEA can act as an antioxidant against the autoxidation of fats of both animal and vegetable origin. TEA can react with nitrite or oxides of nitrogen to form N-nitrosodiethanolamine (NDELA). The optimum ph for nitrosamine formation is between 1 and 6; however the rate of NDELA formation in the ph range of 4-9 is four to six times greater in the presence of formaldehyde. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine 1 2 Panel Book Page 21

32 TEA-cocoyl hydrolyzed collagen is prepared by the hydrolysis of collagen to short-chain polypeptides, followed by the addition of coconut fatty acid, and then neutralization of the terminal carboxyl group of the fatty acid with TEA. Impurities reported in TEA-cocoyl hydrolyzed collagen include coconut fatty acids, hydrolyzed animal protein (collagen), TEA sulfate, sodium chloride, and sodium sulfate. From the Final Report on the Safety Assessment of Triethanolamine-Coco-Hydrolyzed Animal Protein 2 Of concern in cosmetics is the conversion (nitrosation) of secondary amines (R 1 -NH-R 2 ), such as DEA (wherein R 1 and R 2 are each ethanol), into N-nitrosamines that may be carcinogenic. Tertiary alkyl amines (NR 1 R 2 R 3 ), such as TEA (wherein R 1, R 2, and R 3 are each ethanol), however, do not tend to react with nitrosating agents to form nitrosamines directly. However, tertiary amines can act as precursors in nitrosamine formation by undergoing nitrosative cleavage (e.g., one ethanol functional group can be cleaved off of TEA to generate DEA). The resultant secondary amine (i.e. DEA) can then be nitrosated (i.e. to NDELA). Acid Salts The acid salts (inorganic salts, organic acid salts, and hydroxy acid salts), mentioned 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 TEA. In other words, TEA stearate is closely related to stearic acid and TEA. Figure 2. TEA Stearate Amine and Amide Acid Salts The amine and amide acid salts consist of organic acid salts which have the additional functional group of either an amine or an amide (e.g., Figure 3). Therefore, these salts are closely related to the corresponding amine or amide containing free acids and TEA. In other words, TEA-myristaminopropionate is closely related to myristaminopropionic acid and TEA. Figure 3. TEA-Myristaminopropionate Organo-Substituted Inorganic Acid Salts The organo-substituted inorganic acid salts can be segregated into sulfur or phosphorus acids. The sulfates and sulfonates consist of organic acid salts which have the additional functional group of sulfate or sulfonate. For example, TEA lauryl sulfate is a twelve carbon alkyl chain (i.e. lauryl) attached to a sulfate anion, balanced with a triethanolammonium cation (Figure 4). 3 Panel Book Page 22

33 Figure 4. TEA-Myristaminopropionate Protein Salts, Polysaccharide Salts, and Polymer Salts The protein, polysaccharide, and polymer salts consist of natural and synthetic polymers which have at least one carboxylate anion paired with a triethanolammonium cation. For example, TEA-acrylates/acrylonitrogens copolymer is the polymer formed from the partial hydrolysis of polyacrylonitrile, neutralized by TEA (Figure 5). Therein, the acrylonitrile residues are segregated into blocks of 1) untouched, acrylonitrile residues, 2) partial hydrosylate, acrylamide residues, and 3) hydrosylate, acrylate residues (which are later converted to the TEA salt). Figure 5. TEA-Acrylates/Acrylonitrogens Copolymer Some of the acids or salts that comprise these ingredients have been reviewed by the CIR. Conclusions of these reports are provided in Table 1. Definition and Structure The definitions and structures of TEA and the possible add-on ingredients are provided in Table 2. Chemical and physical properties are described in Table 3. Method of Manufacture TEA TEA is produced by reacting 3 moles of ethylene oxide with 1 mole of ammonia; additional ethylene oxide will continue to react to produce higher ethylene oxide adducts of TEA. 3 Typically, ethylene oxide is reacted with ammonia in a batch process to produce a crude mixture of approximately one-third each MEA, DEA, and TEA. The crude mixture is later separated by distillation. TEA-Stearate TEA stearate was produced by mixing partially neutralized stearic acid and TEA at temperatures above 80 C, and then cooling. 4 It was determined that the acid-soap complex at a 2:1 fixed stoichiometric ratio was formed between TEA stearate and stearic acid. TEA-Lauryl Sulfate TEA-lauryl sulfate is manufactured by neutralizing lauryl sulfuric acid with aq. TEA. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 5 4 Panel Book Page 23

34 Commercial alkyl sulfates are produced by the sulfation of primary alcohols using sulfur trioxide or chlorosulfonic acid followed by neutralization with a base to produce the corresponding salt. 6 TEA-Stearate Stability TEA stearate was produced as described previously. On cooling, a lamellar gel phase formed. 7 5 Solid crystals were observed after 5 h. Upon storage, the sample gradually separated into two phases; after a few weeks, a separate liquid phase and a solid-pearly crystalline phase were observed. Impurities TEA Based on unpublished survey data collected by the Food and Drug Administration (FDA), a DEA impurity level of 0.3% was found in TEA samples. 8 TEA Lauryl Sulfate Impurities in TEA-lauryl sulfate may include TEA, TEA-sulfate, unsulfated alcohol, TEA chloride, and formaldehyde (some grades). From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 5 Sodium sulfate and residual alcohols may be present as impurities in commercial alkyl sulfate products. 6 industrial alkyl sulfates contain 1-4% sodium sulfate and % residual alcohol. N-Nitrosodiethanolamine Formation Typically, Nitrosamines are compounds containing the R 1 R 2 N-NO functional group. Nitrosation is the process of converting organic compounds (e.g., alkyl amines) into nitroso derivatives (e.g., nitrosamines) by reaction with nitrosating agents. These agents include nitrous acid (HNO 2 ), oxides of nitrogen (e.g., nitrites), and other compounds capable of generating a nitrosonium ion, NO +. The formation of a specific nitrosamine, NDELA, from reaction of TEA with nitrite was examined in vitro and in vivo. 9 The TEA used in these studies had an impurity content of 0.4% DEA. In an aqueous (aq.) matrix, approximately 3% TEA converted to NDELA at a ph of 4.0 in the presence of acetic acid. At the same ph, in the presence of sulfuric or hydrochloric acid, only about 1% of the TEA was nitrosated. At ph 7, the greatest nitrosation to NDELA, 0.5%, occurred in the presence of sulfuric acid. No conversion of TEA to NDELA was detected at ph 2 or 10. In nutrient broth cultures (neutral ph), 0.08% and 0.68% of the TEA was nitrosated to NDELA in a diluted (high cecal inoculum) and full-strength (low cecal inoculum) media. (The percent nitrosation was determined using values that were corrected for DEA impurity-related NDELA formation). In vivo, female B6C3F1 mice were dosed dermally or orally with 1000 mg/kg TEA, in conjunction with oral exposure to sodium nitrite. 9 Following 7 days of dermal dosing, no NDELA was detected in the blood, ingesta, or urine of test, vehicle control, or sodium nitrite control mice. (The limits of detection for the blood, ingesta, and urine were 0.001, 0.006, and 0.47 µg/ml, respectively). With a single oral dose, the concentrations of NDELA found in the blood and ingesta of mice 2 h post-dosing were ± µg/g and ± µg/g, respectively. USE Cosmetic TEA functions in cosmetics as a surfactant or ph adjuster, and it can be used in fragrances. 10 Most of the other TEA ingredients function in cosmetics as surfactants, viscosity increasing agents, skin conditioning agents, or hair conditioning agents. A few ingredients may function as a chelating agent, binder, film former, or emulsion stabilizer. Notable exceptions Panel Book Page 24

35 are TEA-sorbate, which functions as a preservative, and TEA-salicylate, which functions as a light stabilizer or sunscreen agent. Voluntary Cosmetic Registration Program (VCRP) data obtained from the FDA in 2011 indicate that TEA is used in 3745 formulations; 3023 of those products are leave-on formulations, and 3100 formulations involve dermal exposure. 11 According to data submitted by industry in response to a survey conducted by the Personal Care Products Council (Council), TEA is used at concentrations of %. 12 In leave-on products, the reported use concentrations range from %. The number of leave-on and dermal contact uses have increased substantially since the original 1983 review, and the maximum concentration of use has decreased. The number of non-coloring hair formulations and formulations involving mucous membrane exposure increased greatly since Three other TEA ingredients had greater than 100 uses: TEA-lauryl sulfate (3202 uses), TEA-stearate (130 uses), and TEA-dodecylbenzenesulfonate (116 uses). 11 TEA-lauryl sulfate had the highest concentrations of use, with 40% being reported for rinse-off and 8% for leave-on formulations. 13 The available use data on all in-use ingredients are provided in Table 4a. Ingredients not reported to be in use, according to VCRP data and a Council survey, are listed in Table 4b The dermal exposure of consumers to TEA was estimated assuming 2.5% TEA in cosmetic products (based on the limit set by the European Commission [EC]) and that all TEA is unreacted. 14 Using an EC algorithm method, the dermal exposure of consumers to an eye make-up powder is mg/kg bw/day and to a body lotion is 6.25 mg/kg bw/day. Using a DERMAL program method, the dermal potential dose rate for a bar soap containing 2.5% TEA is mg/day. Products containing TEA may be applied to baby skin, used near the eye area or mucous membranes, or could possibly be ingested or inhaled. Since TEA is reported to be in products that could be inhaled, and effects on the lungs that may be induced by aerosolized products containing these ingredients are of concern. The particle size of aerosol hair sprays and in pump hair sprays is around 38 μm and >80 μm, respectively, and is large compared to respirable particle sizes ( 10 μm). Therefore, because of their size, most aerosol particles are deposited in the nasopharyngeal region and are not respirable. The melting point of TEA is very close to room temperature. Accordingly, depending on storage and application conditions, aerosolized TEA may be a liquid/vapor, instead of a particle. All of the ingredients named in this report are listed by the EC in Annex III Part 1, i.e. the list of substances which cosmetic products must not contain, except subject to the restrictions and conditions laid down. 15 The ingredients reviewed in this safety assessment, trialkylamine, trialkanolamines, and their salts, are allowed at up to 2.5% in non rinse-off products. In leave-on and rinse-off, the following limitations apply: do not use with nitrosating systems; minimum allowable purity is 99%; maximum allowable secondary amine content is 0.5% in raw material; maximum allowable nitrosamine content is 50 µg/kg; must be kept in nitrite-free containers. The following ingredients are listed by the EC for use as preservatives, with the maximum concentration of use based on the free acid: TEA-undecylenate (0.2%). TEA-sorbate (0.6%), and TEAsalicylate (0.5%). 16 According to data obtained from Health Canada, some leave-on type products reportedly use TEA as high 10 and 30%, with some reporting 100% TEA (Health Canada, personal communication). Non-Cosmetic TEA TEA 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 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 6 Panel Book Page 25

36 TEA, TEA-myristate, TEA-palmitate, TEA-oleate, TEA-cocoate, and TEA-tallate have uses as an indirect food additive. 17 TEA is used as a rust inhibitor in water-based metalworking fluids. 18 TEA-salicylate is approved as an ultraviolet filter in sunscreens at concentrations up to 12%. 19 TOXICOKINETICS Dermal absorption studies of TEA were performed using mice and rats. In mice, [14C]TEA in acetone was rapidly absorbed, and absorption increased with increasing dose. The majority of the radioactivity was excreted in the urine, 48-56% in 72 h, primarily as unchanged TEA. TEA was absorbed more slowly and less extensively in rats than mice. Over a 72-h period, 19-28% of the dose was absorbed, and 13-24% of the dose was recovered in the urine, mostly as unchanged TEA. In an oral dosing study with rats, TEA was rapidly absorbed in the gastrointestinal tract and excreted mostly in the form of unchanged TEA. The dermal penetration of salicylate from a formulation containing 10% TEA-salicylate was investigated in vitro and in vivo. In vitro, 1 g of the formulation was applied to full-thickness skin samples from rats and humans. The penetration of salicylate measured as flux was 39.9 µg/cm 2 /h with rat skin and 8.7 µg/cm 2 /h with human skin. With in vivo testing, the formulations were applied to rat skin for intervals of up to 6 h. No salicylate was found in the deep muscle or fat under the application site, and very little salicylate was found in the plasma. In humans there was no evidence of direct tissue penetration of salicylate following dermal application. Dermal In Vitro TEA-Salicylate The dermal penetration of TEA-salicylate was determined using full-thickness skin from male Wistar rats. 20 of a formulation containing 10% TEA-salicylate was applied to a 1.3 cm 2 area for 28 h. Three skin samples were tested. The test site was then wiped and tape stripped one time. The permeability of salicylate measured as flux was 39.9 µg/cm 2 /h, and the permeability coefficient was x 10-3 cm/h. The amount of salicylate absorbed in 24 h was µg/cm 2, and the amount of salicylate remaining in the tissue after the 28-h application was µg/g. Full-thickness human breast skin and epidermal membranes were used in an in vitro study examining the dermal penetration of salicylic acid from TEA-salicylate. 21 Five samples were used. One g of a formulation containing 10% TEAsalicylate was applied to a 1.3 cm 2 area for 24 h. Using full-thickness skin samples, the permeability of salicylic acid as flux was 8.7 µg/cm 2 /h. After removing the top layer of the stratum corneum with a single tape strip, the amount of salicylic acid in 100 mg of the full-thickness human skin sample after exposure to TEA-salicylate was 73.8 µg. In the epidermal membranes exposed to TEA-salicylate, penetration of salicylic acid measured as flux was 26.7 µg/cm 2 /h and the amount of salicylic acid in 100 mg of the sample after exposure was µg. Non-Human TEA The blood kinetics and absorption, distribution, metabolism, and excretion (ADME) of [ 14 C]TEA were determined following dermal application of 2000 mg/kg neat [ 14 C]TEA without occlusion to 24 male C3H/HeJ mice and with occlusion to 3 male mice. 22 (Non-radiolabeled TEA was 99.6% pure; radiochemical purity was 98.6%). TEA was extensively and rapidly absorbed following a single open application of 2000 ml/kg neat [ 14 C]TEA. The majority of the radioactivity, 49-62% of the total dose (~58-72% of the absorbed dose), was excreted in the urine, primarily as unmetabolized TEA. DEA and MEA were not detected in the urine. Approximately 18-28% of the total dose (~20-32% of the absorbed dose) was excreted in the feces. The amount of radioactivity remaining in the body after 48 h ranged from %, and the amount recovered at the application site ranged from % for the open applications and 6-11% for the The National Toxicology Program (NTP) examined the ADME of TEA following dermal administration to B6C3F 1 mice and F344 rats. 23 With mice, groups of 4 females were given a single dose of 79 or 1120 mg/kg [ 14 C]TEA in acetone; 7 Panel Book Page 26 One g

37 the dose contained µci, with the appropriate amount of non-labeled TEA in a volume of 190 µl/dose. (Radiochemical purity of [ 14 C]TEA was 97%; the purity of non-labeled TEA was confirmed, but the purity was not stated). The dose was applied to a 1.44 cm 2 area of clipped skin, and a non-occlusive cover was used. Approximately 60-80% of the dose was absorbed, and absorption increased with increasing dose. In the urine % and 48-56% of the dose was recovered after 24 and 72 h, respectively, and TEA was excreted mostly unchanged. Approximately 5-9 and 8-13% of the dose was recovered in the feces at the same time periods. With rats, groups of 4 females were given a single dermal dose of 68 or 276 mg/kg [ 14 C]TEA in acetone; the dose contained 65 µci, with the appropriate amount of non-labeled TEA in a volume of 190 µl/dose. The dose was applied to a 12 cm 2 area of clipped skin, and a non-occlusive cover was used. Only 19-28% of the dose was absorbed over 72 h; absorption increased with increasing dose, but not significantly. In the urine, 13-24% of the dose was recovered in 72 h as mostly unchanged TEA. The amount recovered in the feces after 72 h was <0.25%. Very little radioactivity, <1%, was present in the tissues; a number of tissues had elevated concentrations of radiolabel relative to blood. TEA-Salicylate In a dermal absorption study in rabbits, 14.59% of a 36.2 mmol/100g dose of TEA-salicylate (applied for 6 h) was excreted in the urine in 48 h. In Beagle dogs 1 h after dermal application of up to 10 g TEA-salicylate, most of the dose was recovered at the application site. More than 82% of a dermal application of 1.5 g of a 10% TEA-salicylate formulation was absorbed in Yorkshire swine. From the Final Report on the Safety Assessment of Salicylic Acid [and Salicylates] 24 The absorption of salicylate from dermally applied TEA-salicylate was determined using groups of 3 male Wistar rats per time point examined. 20 One g of a formulation containing 10% TEA-salicylate was applied to a 9.6 cm 2 area of the abdomen of anesthetized rats. There is no indication that the test site was occluded. Blood samples were taken at 0.5, 1, 2, 4, and 6 h, and the animals were then killed. Tissue samples that included deep muscle and fat were excised at the test site; the epidermis was removed. At 6 h after dosing, 1400, 650, and 200 µg/g total salicylate was found in the dermis, subcutaneous tissue, superficial muscle, respectively. In these three tissues, the salicylate levels rose for the first hour, were decreased at 2 h, and then increased until the end of the study. No salicylate was found in the deep muscle or fat. Very little (approximately 10 µg/ml) salicylate was found in the plasma at any of the time points. TEA-Lauryl Sulfate Skin irritation tests in guinea pigs suggested that TEA-lauryl sulfate may be absorbed in toxic amounts. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 5 Human TEA-Salicylate In dermal absorption studies in arthritic males, only small amounts of salicylate were found in the synovial fluid, blood, and urine. From the Final Report on the Safety Assessment of Salicylic Acid [and Salicylates] 24 Cutaneous microdialysis was performed to determine the penetration of salicylic acid from dermally applied TEAsalicylate. 21 A dermal probe and a subcutaneous probe were inserted superficially into the forearms of 4 subjects. The dermal probe, but not the subcutaneous probe, was inserted in a way that would cause an axon reflex flare. A formulation containing 10% TEA-salicylate was applied to a 16 cm 2 area of skin over the probe tips, 10 mm away from the insertion points, and dialysate samples were collected at min intervals for up to 360 min. The researchers stated that the formulations were reapplied every 2 h during sampling, but the actual dose applied was not given. Two of the subjects applied liberal amounts of the test formulation every 2-3 h, 24 h prior to probe insertion. The levels of salicylate in the dermal and subcutaneous probes were low, near the limits of detection, in both the pre-exposed and non-pre-exposed subjects. The tissue 8 Panel Book Page 27

38 concentration of salicylate ranged from µg/ml in the dermal probe and from µg/ml in the subcutaneous probes. The tissue:plasma ratio following dermal application of 10% TEA-salicylate ranged from with the dermal probes and from with the subcutaneous probes. The researchers stated that the 10% TEA-salicylate formulation showed no evidence of direct tissue penetration following topical application. Oral Non-Human TEA TEA (purity not specified) was administered orally to male and female rats as a single dose or as a repeated dose for 5-6 days. 25 (Dosing details were not described). At 24 h after administration of the single dose, the excretion ratio of unchanged TEA in the urine and feces was 53 and 20% of the dose, respectively. With repeated administration, the excretion ratio per day remained constant. Gender did not affect the ratios. TEA glucuronide was detected, but in a very small amount. (Actual concentration not specified). TEA was rapidly absorbed in the gastrointestinal tract, and excreted mostly in the urine in unchanged form. Other Non-Human TEA A group of 27 male C3H/HeJ mice was given an intravenous (i.v.) injection of 1 mg/kg [ 14 C]TEA as an aq. solution (0.5 mg/ml), and the dose volume was 2 ml/kg. 22 (Non-radiolabeled TEA was 99.6% pure; radiochemical purity was 98.6%). Radioactivity in the blood declined in a biphasic, exponential manner for 24 h, with a relatively rapid initial phase of [ 14 C] elimination, followed by a slower terminal phase. The majority of the radioactivity, approximately 69%, was excreted in the urine, primarily as unmetabolized TEA. DEA and MEA were not detected in the urine. Some of the radioactivity, ~17%, was excreted in the feces. The average amount of radioactivity recovered in the tissues was 3.1%. The NTP examined the ADME of TEA following i.v. administration to B6C3F 1 mice and F344 rats. 23 Groups of 4 female mice and 4 female rats were given a single i.v. dose of 3 mg/kg [ 14 C]TEA in isotonic saline. For mice, the dose contained 6 µci, with the appropriate amount of non-labeled TEA, for a dosing volume of 2 ml/kg. (Radiochemical purity of [ 14 C]TEA was 97%; the purity of non-labeled TEA was confirmed, but the purity was not stated). At 24 h, 26 and 14% of the dose was excreted in the urine and feces, respectively, while at 72 h, these values were 62 and 28%, respectively. TEA was excreted mostly unchanged. Little, <0.5%, was detected in expired carbon dioxide. A number of tissues contained higher concentrations of TEA equivalents relative to blood. For rats, the dose contained 47 µci, with the appropriate amount of non-labeled TEA, for a dosing volume of 1 ml/kg. Much more of the radioactivity was excreted in the urine for rats compared to mice, and excretion was more rapid. Approximately 90% of the dose was recovered in the urine in 24 h, and 98% in 72 h, mostly as unchanged TEA. Like mice, <0.5%, was detected in expired carbon dioxide. Only 0.9% of the radioactivity was detected in the tissues after 72 h. TOXICOLOGICAL STUDIES In 2 and 13-wk repeated dose dermal toxicity studies in mice with mg/kg bw TEA in acetone or 4000 mg/kg bw neat, dermal irritation was observed in the highest dose group, and kidney and liver weights were increased with the higher doses. In rats, mg/kg bw TEA in acetone or mg/kg bw neat was applied to rats for 13 wks, irritation was observed at the dosing site. Kidney weights were increased in males and females of rats dosed with 500 mg/kg TEA, and dosed females had higher incidences of nephropathy. In a 14-day drinking water study, animals given 8%TEA in drinking water were all killed due to severe hydration before study terminations. Treatment-related changes were not observed for animals given 2 or 4^% TEA in their water. 9 Panel Book Page 28

39 Dermal TEA Oral TEA Acute (Single) Dose Toxicity The acute dermal toxicity of TEA was examined using groups of 6 rabbits. Undiluted TEA, 91.8 and 88.1% active, was applied to the intact and abraded skin of 3 rabbits under a 24 h occlusive patch. The exposure to actual TEA was 2 g/kg. None of the animals died. Mild erythema and edema were reported at 24 h. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 The acute oral toxicity of TEA was determined using guinea pigs and rats. In guinea pigs, undiluted TEA has an LD 50 of 8 g/kg, and the LD 50 of TEA in a gum arabic solution was between 1.4 and 7.0 g/kg. Using rats, the oral LD 50 of undiluted TEA ranged from 4.19 g/kg g/kg. The purity ranged from 78.6% TEA (with 8.6% DEA and 1.7% MEA) to unspecified high purity. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine 1 TEA-cocoyl Hydrolyzed Collage was practically non-toxic in rats. From the Final Report on the Safety Assessment of Triethanolamine-Coco-Hydrolyzed Animal Protein 2 TEA-Lauryl Sulfate TEA-lauryl sulfate was moderately to slightly toxic in acute oral studies with rats, LD 50 values ranged from 0.27 > 1.95 g/kg. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 5 The LD 50 of TEA-lauryl sulfate in male and female Wistar rats was >2 g/kg. 26 TEA-Dodecylbenzenesulfonate group. 27 The acute oral toxicity of 10% aq. TEA-dodecylbenzenesulfonate was determined using female albino rats, 5 per Doses of g/kg bw were administered by gavage. The oral LD 50 of TEA-dodecylbenzenesulfonate in rabbits was 1.5 g/kg. Other TEA The intraperitoneal LD 50 of TEA was 1.45 g/kg for mice. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1 Repeated Dose Toxicity Dermal TEA A closed-patch continuous exposure test was performed using 10 guinea pigs in which commercial and high purity TEA, 8 g/kg, was applied daily 5 days/wk. All guinea pigs died by the 17 th application; adrenal, pulmonary, hepatic, and renal damage were observed. In a 13-wk study, 1 mg/kg of a hair dye formulation containing % or 1.5% TEA was applied to the backs of 12 rabbits for 1 h, twice weekly. The test site skin was abraded for half of the animals. No systemic toxicity was observed, and there was no histomorphologic evidence of toxicity. In a 6-mos study in which TEA was applied caudally to rats for 1 h/day, 5 days/wk, no toxic effects were observed with a 6.5% solution. However, using a 13% solution, changes (not specified) were seen in liver and central nervous system function. The addition of 1.4 mg/l TEA to the drinking water of the rats dosed dermally with 13% TEA did not increase the toxic effects. In inhalation studies with TEA in rats and mice, no observations were reported that were indicative of a toxic pulmonary effect. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 In a 2-wk study, undiluted TEA (purity not specified) was applied dermally to B6C3F 1 mice at doses of g/kg and to F344 rats at doses of g/kg, 5 days/wk. 28 Chronic active necrotizing inflammation of the skin at the application site occurred at a greater frequency and severity in rats than in mice. No renal or hepatic lesions were detected with either species. 10 Panel Book Page 29

40 In a 2 wk and a 13-wk dermal study with up to 100% TEA (99.3% pure) in acetone using male and female C3H/HeJ mice, no toxicity or irritation was observed. 29 The only treatment-related effect was a mild thickening of the epidermis. In a 13-wk NTP dermal study using male and female B6C3F 1 mice, application of mg/kg bw TEA in acetone or 4000 mg/kg neat resulted in decreased mean body weights and body weight gains for some male mice. 30 (Purity of TEA was 99%. Functional group titration indicated <0.4% MEA or DEA). Irritation was observed for the highest dose group. Microscopically, inflammation was observed for this dose group and acanthosis was noted for all dose groups, with severity increasing with dose. Absolute kidney and liver weights of males and females of the 4000 mg/kg group and relative kidney to body weights of males dosed with 1000 mg/kg were increased compared to controls. Absolute and relative spleen weights were also significantly increased in high dose female mice compared to controls. In a 13-wk dermal study using male and female F344/N rats, application of mg/kg bw TEA (99% pure) in acetone or 2000 mg/kg neat, resulted in significant decreases of mean body weights and body weight gains in the high dose animals. 30 (Functional group titration indicated <0.4% MEA or DEA present). Irritation was observed at the application site. Microscopic lesions included acanthosis and inflammation. Kidney weights of males and females dosed with 500 mg/kg were increased compared to controls, and dosed females, but not males, had greater incidences of nephropathy, as compared to controls. TEA-Lauryl Sulfate In a 28-day dermal study, application of a diluted shampoo containing 1% TEA-lauryl sulfate to rabbit skin caused erythema, edema, wrinkling, eschar formation, and severe desquamation. In a 13-wk dermal study in rabbits with a diluted shampoo containing 2.4% TEA-lauryl sulfate, mild erythema and dryness were observed. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 5 Oral TEA Oral studies were conducted in which groups of 8-20 rats were dosed with g/kg/day TEA for 60 days to 6 mos, and groups of 8 guinea pigs were dosed with g/kg/day TEA for 60 or 120 doses. Repeated oral ingestion of TEA produced evidence of hepatic and renal damage. Some deaths occurred in groups of rats fed 0.17 g/kg/day TEA. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 Male and female B6C3F 1 mice and F344 rats were given drinking water containing 2-8% TEA (purity not specified) for 14 days. 31,32 Male and female high dose mice, and male and female rats given 4% TEA, had decreased body weights. All but one of the high dose rats were euthanized early due to severe dehydration. No treatment-related changes were observed in mice given 4% TEA or rats given 2% TEA in the drinking water. Inhalation TEA In a 5-day dose-range finding inhalation study, 5 male and 5 female Wistar rats were exposed, nose only, to target concentrations of mg/m 3 TEA (98.9% pure) for 6 h. 33 Concentration-dependent laryngeal inflammation and edema were observed at microscopic examination, and the no observed adverse effect concentration (NOAEC) was 100 mg/m 3. The full, 28 day/20 exposure study used target concentrations of 0, 20, 100, and 500 mg/m 3, and the mass median aerodynamic diameter (MMAD) was µm. A functional observational battery was conducted using 7 rats/sex/group. Minimal to moderate focal inflammation in the submucosa of the larynx was observed; effects were concentration-dependent. No systemic toxicity was observed, and there were no effects on organ weights. There were no indications of neurotoxicological effects. Based on the results of this study, the 90-day NOAEC for local irritation was calculated to be 4.7 mg/m 3. (The extrapolation of the 28-day laryngeal irritation used the calculation of benchmark concentrations for a 5% incidence of mucosal inflammation, without consideration of severity, using a multistage model). 11 Panel Book Page 30

41 In a 14-day inhalation study, B6C3F 1 mice and F344 rats were exposed to mg/m 3 TEA (purity not specified) 6h/day, 5 days/wk, for 2 wks. 34,35 Female mice and male and female rats of the high dose group had decreased body weights, and male mice of the high dose group had increased kidney weights. Increased kidney weights in rats dosed with 500 mg/m 3, and decreased thymus and heart weights in mice at all doses, were not clearly associated with TEA. The only histopathologic observation was a minimal acute inflammation of the laryngeal submucosa in both mice and rats; however, this occurred sporadically and there was no dose-response associated with this lesion. REPRODUCTIVE AND DEVELOPMENTAL STUDIES No adverse reproductive effects were seen in dermal studies in which rats and mice were dosed with TEA in acetone from before mating through lactation or in an oral teratogenicity screening test in mice. Dermal TEA Hair dyes containing % or 1.5% TEA were applied topically to the shaved skin of groups of 20 gravid rats on days, 1, 4, 7, 10, 13, 16, and 19 of gestation, and the rats were killed on day 20 of gestation. No developmental or reproductive effects were observed. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 F344 rats. 36 TEA, 0.5 g/kg in acetone (purity not stated), was applied dermally to clipped skin on the back of male and female A volume of 1.8 ml/kg was applied daily for 10 wks prior to mating, during mating, and through gestation and lactation. No effect on mating or fertility or offspring growth or survival was observed. A similar study was performed in which Swiss CD-1 mice were given daily applications of 2 g/kg TEA at a volume of 3.6 ml/kg. 37 No adverse reproductive effects were observed. Oral TEA A Chernoff-Kavlock teratogenicity screening test was performed using mated female CD-1 mice, in which the animals were dosed by gavage with 1125 mg/kg/day TEA on days 6-15 of gestation. 38 (It was stated that the TEA was the purest grade commercially available ). No adverse reproductive effects were observed. GENOTOXICITY TEA was negative for genotoxic effects in an Ames test with or without metabolic activation, gene conversion assay, rec assay, sister chromatid exchange assay with or without metabolic activation, chromosomal aberration assay, and cell transformation assay. In Vitro TEA Undiluted TEA, at concentrations of 100 mg/plate, was not mutagenic in Salmonella typhimurium with or without metabolic activation. TEA with sodium nitrite, but not TEA alone, was mutagenic in Bacillus subtilis without metabolic activation. NDELA, which is not mutagenic in B. subtilis without metabolic activation, was found in the mixture. In an unscheduled DNA synthesis test in which primary rat hepatocyte cultures were exposed to 10-8 to 10-1 M TEA and [ 3 H]thymidine, simultaneously, TEA did not appear to cause DNA-damage-inducible repair. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 TEA, in distilled water or dimethylsulfoxide, was not mutagenic to Escherichia coli 39 or S. typhimurium, with or without metabolic activation, at doses of 0-20,000 µg/plate Saccharomyces cerevisiae. 40 TEA (88.2% purity) did not cause gene conversion in TEA was negative in a rec assay at doses of µg/disk. No induction of sister chromatid exchanges occurred in Chinese hamster ovary (CHO) cells at µg/ml without metabolic activation or 0-10,100 µg/ml with metabolic activation, 42 and chromosomal aberrations were not induced in cultured rat liver cells 40 or at doses of Panel Book Page 31

42 µg/ml in cultured Chinese hamster cells. 39,42 embryo cells. 39 TEA TEA, µg/ml, was negative in a cell transformation assay using hamster In Vivo A mouse peripheral blood micronucleus test was performed using samples collected from mice that were dosed dermally for 90-days with 0-4 g/kg TEA in an NTP study. 43 Dermal TEA Results were negative in both male and female mice. CARCINOGENICITY In a 2-yr dermal carcinogenicity study of TEA in mice and a 2-yr study in rats, it was concluded that TEA produced equivocal evidence of carcinogenic activity in male mice based on the occurrence of liver hemangiosarcoma, some evidence of carcinogenic activity in female mice based on increased incidences of hepatocellular adenoma, equivocal evidence of carcinogenic activity in male rats based on a marginal increase in the incidence of renal tubule cell adenoma, and no evidence of carcinogenic activity in female rats. In oral carcinogenicity studies in rats and mice, TEA was not carcinogenic to rats or mice, but it was toxic to the kidneys of rats, especially females. It has been speculated that TEA may cause liver tumors in mice via a choline-depletion mode of action. In a series of 3 experiments using a total of 560 CBA x C 57 Bl 6 male mice, the carcinogenic effects of 99%+ pure TEA and 80%+ industrial grade TEA and the cocarcinogenic effect of TEA and syntanol DC-10 (alcohols C10-18 ethoxylated) were examined over a mo timeframe. TEA was not carcinogenic or cocarcinogenic. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 An initial carcinogenicity study of TEA using B6C3F 1 mice performed by the NTP was deemed inadequate due to a Helicobacter hepaticus infection. 30 Therefore, a second 2-yr study was performed in which TEA in acetone was applied dermally at doses of mg/kg/day to male B6C3F 1 mice and at doses of mg/kg/day to female B6C3F 1 mice. 44 (Purity of TEA was 99+%. Using high-performance liquid chromatography/mass spectrometry, 0.491% DEA was detected as an impurity. A slight increase in DEA was seen in acetone and ethanol solutions after 11 days of storage; the dose formulations were prepared approximately every 2 wks). The body weights of high dose males were decreased compared to controls during wks and at the end of the study. Dermal irritation increased with increasing dose, and was more severe in males than in females. At necropsy, treatment-related epidermal hyperplasia, suppurative inflammation, and ulceration and dermal chronic inflammation occurred at the application site in most test groups, and the incidence and severity increased with increasing dose. Lesions were found, and it was concluded that there was equivocal evidence of carcinogenic activity of TEA in male mice, based on the occurrence of liver hemangiosarcoma, and some evidence of carcinogenic activity in female mice, based on increased incidences of hepatocellular adenoma. In a 2-yr NTP dermal carcinogenicity study using F344/N rats, TEA in acetone was applied at doses of mg/kg/day in acetone to males and at doses of mg/kg/day to females. 30 (Purity of TEA was 99%. Functional group titration indicated <0.4% MEA or DEA). Irritation was observed at the application site, and frequency increased with increasing dose. At the interim necropsy, the absolute and relative kidney weights of high dose females were significantly greater than the controls. Microscopically, at the site of application, dermal lesions, including acanthosis, inflammation, and/or ulceration, were observed. It was concluded that there was equivocal evidence of carcinogenic activity in male rats, based on a marginal increase in the incidences of renal tubule cell adenoma, and there was no evidence of carcinogenic activity in female rats. 13 Panel Book Page 32

43 The carcinogenic potential of TEA was evaluated using a Tg AC transgenic mouse model. 45 Groups of female homozygous mice were dosed dermally with 3-30 mg TEA/mouse in acetone, 5x/wk for 20 wks. TEA was inactive in Tg AC mice. Oral TEA Groups of 40 male and 40 female ICR-JCL mice were fed a diet containing 0.01, 0.03, or 0.3% TEA throughout their lifetime. The malignant tumor incidence was 2.8, 27, and 36% for females, respectively, and 2.9, 9.1, and 3.6% for males, respectively. Treated females had a much higher incidence of thymic and non-thymic tumors in lymphoid tissues than treated males. Survival was similar for treated and control animals. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 The oral carcinogenic potential of TEA was examined by administering 1 or 2% TEA in drinking water to groups of male and female B6C3F 1 mice for 82 wks. 46 (DEA was present as an impurity at 1.9 %). Body weights of male mice of the 2% group were decreased during wks 1-20 when compared to controls. No significant changes in organ weights were observed. No dose-related increase of the incidence of any tumors was observed in the treated groups, and there was no evidence of carcinogenic potential of TEA upon oral administration. Drinking water containing 1 or 2% TEA was given to groups of male and female F344 rats for 2 yrs. 47 (DEA was present as an impurity at 1.9%). From wk 69 on, the dose concentrations for females were reduced by half because of associated nephrotoxicity. A dose-related decrease in body weight gain was reported for male and female test group rats, and a dose-dependent increase in mortality, starting at wk 60, was observed. Absolute and relative kidney-to-body weights were significantly increased in males and females, and the increase was dose-related. Severe chronic nephropathy was statistically significantly increased in males of the high dose group and females of both dose groups. No treatment-related effects were found in the liver. There was no increase in the incidence of any tumors in the treated groups compared to controls when using the Chi-square test. Since increased nephrotoxicity appeared to affect the lifespan of the treated animals, especially the females, an age-adjusted statistical analysis was performed on the incidences of main tumors or tumor groups for males and females, and a positive trend was noted in the occurrence of hepatic tumors (neoplastic nodule/hepatocellular carcinoma) in males and of uterine endometrial sarcomas and renal-cell adenomas in females. The researchers stated that, because these tumors have been observed spontaneously in F344 rats, and since their incidences in the control group was lower than that of historical controls, the occurrence of the tumors may not be attributable to TEA. Instead, increased incidence of renal tumors in the high-dose group may have been associated with renal damage. The researchers concluded that TEA was toxic to the kidneys, especially in females, but it was not carcinogenic to F344 rats. Possible Mode of Action for Carcinogenic Effects of TEA It has been reported that choline deficiency induces liver cancer in rodents; 48,49 therefore, the potential of TEA to cause choline deficiency in the liver of female B6C3F 1 mice was investigated as a mode of tumorigenesis. 50 Female mice were dosed dermally with unoccluded applications of mg/kg/day TEA in acetone, 5 days/wk for 3 wks, and female CDF rats were dosed in a similar manner with 250 mg/kg/day TEA. (Purity of TEA was 99+%; DEA impurity levels were 0.04 and 0.45%). No clinical signs of toxicity were noted for mice or rats. Phosphocholine and betaine levels were statistically significantly decreased in the high dose mice, and choline levels were decreased in these mice. The decrease in phosphocholine levels was variable, but dose-related. (More pronounced effects were observed when the TEA having 0.45% DEA impurity was used). In rats, no changes in choline or its metabolites were noted. The potential of TEA to inhibit the uptake of [ 3 H]choline by CHO cells was also investigated, and a dose-related decrease was observed. The researchers concluded that TEA may cause liver tumors in mice via a choline-depletion mode of action, and this effect is likely caused by 14 Panel Book Page 33

44 the inhibition of choline uptake by the cells. The researchers stated that, while DEA impurity may contribute to choline depletion, a choline-deficiency mode of tumorigenesis appears to be a property of TEA, exclusive of any DEA impurity. Carcinogenic Potential in Humans TEA According to an evaluation of TEA by the International Agency for Research on Cancer (IARC) Working Group, there is inadequate evidence in humans, as well as in animals, for the carcinogenicity of TEA. 51 The overall evaluation of the IARC is that TEA is not classifiable as to its carcinogenicity to humans (Group 3). IRRITATION AND SENSITIZATION TEA can be a dermal irritant in both animals and human, but it has not been shown to be a sensitizer. Many of the ingredients in this report are surfactants, which can be irritating to skin and eyes. Skin In Vitro TEA Irritation The dermal irritation potential of TEA was determined in two in vitro assays, and these results were compared to results obtained in the in vivo Draize test and human patch test. 52 The tissues used in the in vitro tests were fully-differentiated three-dimensional reconstituted human epidermal cultures. Each in vitro test was performed in triplicate. In the first test, the in vitro patch test, TEA was applied to the skin samples for 4 h using a 0.95 cm 2 polypropylene chamber. In the second in vitro test, the direct topical application test, 100 µl TEA was applied directly to a 0.63 cm 2 area of the epidermal surface for 4 h. Histology, cell viability determined via 3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) reduction, and interleukin (IL)-1α release endpoints were measured in both tests, and a combination of the outcomes of these endpoints was used to determine the potential for irritation. TEA, which was described as non-classified in the Draize and human patch tests, was classified as a non-irritant in the in vitro patch test and an irritant in the direct topical application test. The irritant classification was based on tissue necrosis and a higher amount of released IL-1α compared to the negative control (water). The concentration of TEA tested for each of the studies was not specified. TEA-Laurate; TEA-Oleate skin. 53 The binding of surfactants to stratum corneum proteins appears to play a role in the harshness of the surfactants to Human stratum corneum samples were used to evaluate the binding of sodium/tea-laurate and sodium/tea-oleate. At low surfactant levels (<20 mm), higher levels of sodium/tea-oleate than sodium/tea-laurate were bound to the stratum corneum 1 min after exposure. TEA-oleate binding stabilized at concentrations of mm, with binding of approximately mg surfactant/mg stratum corneum. With sodium/tea-laurate, binding increased with increasing surfactant concentration; at a concentration of 50 mm sodium,/tea-laurate, binding was approximately mg/mg stratum corneum. Non-Human TEA The primary skin irritation potential of undiluted TEA was determined using rabbits. After 10 open applications of 0.1 ml to rabbit ears and 10 unoccluded applications to the intact skin of the abdomen, and 3 semi-occluded 24-h applications to abraded skin, it was concluded that TEA was slightly to moderately irritating, and prolonged or repeated exposure may be irritating. Twenty-four h occluded patch tests using groups of 8 male rabbits were performed in 22 laboratories; the primary irritation score ranged from 0-5.5/24, and the total score for all 22 laboratories was 27.3/400. In a preliminary study, occlusive dermal applications of % aq. TEA to pairs of guinea pigs resulted in one erythematic reaction to undiluted TEA, and in another preliminary study, no irritation was observed when 5, 10, or 25% TEA was applied to the backs of guinea pigs. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine Panel Book Page 34

45 mice. 54 The irritancy potential of TEA (purity not specified) was evaluated in an ear swelling test using female BALB/c A significant increase in irritancy was observed with 25 and 50% TEA compared to the vehicle (4:1 acetone/olive oil). TEA-Lauryl Sulfate The dermal irritation of TEA-lauryl sulfate ranged from not-irritating to moderately irritating to rabbit skin at concentrations up to 46%. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 5 TEA-Dodecylbenzenesulfonate Albino rabbits (number per group not specified) were used to evaluate the dermal irritation potential of aq. TEAdodecylbenzenesulfonate. 27 Ten applications of 1, 5, or 25% TEA-dodecylbenzenesulfonate were made to intact skin over a 14-day period, and three application were made to abraded skin during the same 14-day period. A 1 cm 2 cotton pad was used to apply 5 ml of the test material, and the test sites were wrapped following dosing. TEA-dodecylbenzenesulfonate was not irritating to very slight irritating at 1%, very slightly to slightly irritating at 5%, and slightly to moderately irritating to rabbit skin at a concentration of 25%. TEA-dodecylbenzenesulfonate was applied to the intact ears of albino rabbits (number per group not specified) using the same application protocol. In rabbit ears, irritation was slight irritation at 1% aq., very slight to slight irritation at 5% aq., and slight to moderate at 25% aq. TEA-dodecylbenzenesulfonate. TEA-Cocoyl Hydrolyzed Collagen TEA-cocoyl hydrolyzed collagen was non-irritating to mildly irritating to rabbit skin at concentrations of 10-50%. From the Final Report on the Safety Assessment of Triethanolamine-Coco-Hydrolyzed Animal Protein 2 Human TEA Clinical studies were performed with formulations containing TEA. In a few studies on formulations containing % TEA, the researchers concluded that no irritation was observed, while short-lived acute irritation was reported for formulations containing % TEA. However, according to the Expert Panel s interpretation of the results of a number of other studies, formulations containing % TEA were irritating. In clinical provocative testing using 5-10 hyper reactors, 100% TEA produced an irritant reaction on non-scarified skin, 10% TEA in ethanol was a marked irritant on scarified skin, while 5% in ethanol was a slight irritant on scarified skin. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 A patch test with TEA (purity not specified) was performed on 20 subjects, and erythema and transepidermal water loss (TEWL) were measured, and the contents of suction blister fluids (SBF) were evaluated for primary proinflammatory mediators. 55 Aq. TEA, %, was applied occlusively for 24 h; µl, concentrated to 20 µl with drying, were applied. The percent of non-responders to 100% TEA was 80%; those that did respond had weak and non-uniform erythema. The incidence was below or about that found with the solvent controls. For the challenge phase, 765 µmol/cm 2 TEA was applied occlusively to 12 subjects for 6-24 h. No increase in TEWL or change in eicosanoid profile of the SBF was observed. TEA was a non-irritant. TEA-Lauryl Sulfate In clinical studies, shampoos containing 10.5% TEA-lauryl sulfate caused no irritation with semi-occlusive patches or use testing, while diluted shampoos containing % produced no to moderate irritation. In an occlusive patch test, a diluted shampoo containing 4.4% TEA-lauryl sulfate was highly irritating in a 21-day cumulative irritation test. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 5 The dermal irritation potential of a 10% solution of TEA-lauryl sulfate (vehicle not identified) at neutral ph was determined using 10 subjects. 56 Duhring chambers were applied to the forearm of each subject for 5 days. A 10% solution of 16 Panel Book Page 35

46 TEA-lauryl sulfate caused intense erythema in nearly all subjects by day 4. Testing was terminated. (Additional details were not provided). TEA-Cocoyl Hydrolyzed Collagen TEA-cocoyl hydrolyzed collagen, 10%, was non-irritating in clinical single insult patch tests. From the Final Report on the Safety Assessment of Triethanolamine-Coco-Hydrolyzed Animal Protein 2 Mucosal In Vitro TEA The ocular irritation potential of TEA was evaluated in two in vitro studies. In the luminescent bacterial toxicity test (i.e. the Microtox test), TEA had an EC 50 of 110 mg/l, corresponding to non/moderate irritant potential. 57 In the EYTEX assay, TEA had an EYTEX/Draize equivalent of 42.1, corresponding to a prediction of severe ocular irritant. 58 Non-Human TEA The ocular irritation potential of ml undiluted TEA was evaluated in a number of studies using rabbits. With high concentrations and long contact time, TEA may be irritating to rabbit eyes. Using rabbits, 10% aq. TEA produced essentially no irritation with or without rinsing. A formulation containing 12.6% TEA, 0.1 ml, was evaluated in a study using 6 rhesus monkeys. Slit lamp examination revealed some corneal effects in 2 monkeys at 24 h and slight positive fluorescein staining in one monkey at 72 h. The vaginal irritation potential of a spermicidal formulation containing 1.92% TEA was evaluated by placing 0.5 ml of the ointment inside the vaginas of 6 rats for 3 days. The formulation was a non-irritant. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 TEA-Lauryl Sulfate The ocular irritation potential of TEA-lauryl sulfate was evaluated in rabbit eyes; irritation ranged from not-irritating to severely irritating at concentrations up to 40%. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 5 TEA-Dodecylbenzenesulfonate The ocular irritation potential of aq. TEA-dodecylbenzenesulfonate was evaluated using albino rabbits (number per group not specified). 27 Two drops of 1, 5, or 25% TEA-dodecylbenzenesulfonate were instilled into the eyes of rabbits. One eye of each rabbit was rinsed after 30 sec, the other eye was not rinsed. Without rinsing, a 1% solution was very slightly irritating, a 5% solution was very slightly to slightly irritating, and a 25% solution was moderately to severely irritating. With rinsing, very slight to slight irritation was observed in the eyes of rabbits dosed with 5 and 25% aq. TEAdodecylbenzenesulfonate. TEA-Cocoyl Hydrolyzed Collagen TEA-cocoyl hydrolyzed collagen was practically non-irritating to mildly irritating at concentrations of % in rabbit eyes. From the Final Report on the Safety Assessment of Triethanolamine-Coco-Hydrolyzed Animal Protein 2 Sensitization TEA was not a sensitizer to guinea pigs when 20 guinea pigs were given dermal applications of undiluted TEA 1x/wk for 3 wks, followed by challenge applications 14 and 21 days after dosing. No sensitization was seen when four lots of TEA were evaluated using groups of 20 guinea pigs; induction applications were applied for up to 6 h, 1x/wk, for 3 wks, and the challenge was performed after 14 days. One of the studies used undiluted TEA during induction, while the other 3 studies used 50% TEA at induction. All four studies used challenge patches with 90% TEA. No sensitization was observed in a similar study in which induction patches contained a 25% active TEA solution, and a challenge patch with the 25% solution was applied after 1 wk of non-treatment. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine Panel Book Page 36

47 Non-Human TEA The sensitization potential of TEA was evaluated in a local lymph node assay (LLNA) performed with groups of 5 BALB/c mice. 54 This study was performed in conjunction with the ear-swelling test described previously. Lymphocyte proliferation increased with dose, but the increases were not statistically significant. TEA was not identified as a sensitizer in the LLNA. The hypersensitivity of mice to TEA (99+% pure) was determined. 59 patients. Many of the patients allergic to TEA were also allergic to other ingredients. 18 TEA, in an acetone:olive oil mixture (4:1) at concentrations of 3%, 10%, or 30%, was applied daily for 5 consecutive days to groups of 8 female B6C3F 1 mice, and the animals were challenged 7 days later with a 30% solution. For some animals, dermabrasion, as well as intradermal injections of Freund s complete adjuvant (FCA), was used. There were no treatment-related effects on survival or body weights. There were no statistically significant or dose-related hypersensitivity responses to TEA observed with a radioisotopic method or in an ear swelling test, with or without FCA. Results were negative in three maximization studies examining the sensitization potential of TEA. 18 In the first test, performed using Pirbright-White guinea pigs, induction consisted of intradermal injections of 2% TEA (98.9% pure) in isotonic saline and epicutaneous application of undiluted TEA, and challenge used 10% TEA in isotonic saline. In the second test using 20 Dunkin-Hartley guinea pigs, intradermal and epicutaneous inductions used 1.5% technical grade TEA and 25% technical grade TEA with 10% sodium lauryl sulfate pre-treatment, respectively, and challenge doses consisted of 1, 5, and 10% technical and analytical grade TEA. In the third study, with 15 animals and the same induction protocol just described (grade of TEA not specified); 2/15 reacted to 10% TEA after 1, but not 3, days. TEA-Cocoyl Hydrolyzed Collagen TEA-cocoyl hydrolyzed collagen was not a sensitizer in guinea-pigs studies. From the Final Report on the Safety Assessment of Triethanolamine-Coco-Hydrolyzed Animal Protein 2 Human TEA In cumulative reports on patch tests conducted over a number of years, TEA, tested at 2% aq, 5% (vehicle not specified), or 5% in petrolatum, had positive reactions for contact dermatitis in 23/500, 9/479, and 2/100 subjects. The Expert Panel interpreted these findings as sensitizing. In a patch test with 64 subjects in which 0.5 ml of 1% TEA (containing 88.6% TEA and 6% DEA) was used, the test solution was not sensitizing. The majority of formulations containing % TEA were not sensitizing, and a formulation containing 20.04% TEA, tested on 26 subjects, was not considered sensitizing when it produced 2 slight reactions upon challenge. However, according to the interpretation of the Expert Panel, there were a few cosmetic formulations containing 2.1 and 2.4% TEA that the Panel determined to be sensitizing. In other studies with cosmetic formulations containing 2.1% TEA, the researchers concluded that reactions observed at challenge were probably due to skin fatigue. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 TEA-Lauryl Sulfate Undiluted shampoo formulations containing 10.5% TEA-lauryl sulfate and dilutions of formulations containing % TEA-lauryl sulfate were not sensitizers in clinical studies. Aq. shampoo formulations containing % TEA-lauryl sulfate were not photosensitizers. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 5 petrolatum. 60 Provocative Testing A group of 737 patients was patch tested with 6 different emulsifiers, including 2.5% TEA (purity not specified) in The patch tests were performed according to International Contact Dermatitis Research Group (ICDRG) recommendations. A total of 39 patients had positive reactions to the emulsifiers, and 20 of those patients, 5 males and 15 females, had positive reactions to TEA. There were 106 irritant reactions reported. The results were clinically relevant in 7 Panel Book Page 37

48 Over a 15-yr period, provocative patch testing using TEA was performed on 85,098 dermatological patients. 18 There were 323 positive reactions to TEA, and most of the reactions (289) were weak positives. The researchers stated that occupational exposure was not a risk factor for TEA contact allergy. Non-Human TEA Human TEA TEA Phototoxicity/Photoallergenicity A formulation containing 1% TEA was applied to the stripped skin of 6 guinea pigs, and each animal was then exposed to ultraviolet A (UVA) light for 2 h. No erythema or edema was observed. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 There were no phototoxicity or photosensitization reactions in clinical studies with a number of formulations containing % TEA, nor were there any reactions with a formulation containing 20.04% TEA. However, in one study with a formulation containing 4.2% TEA, the Expert Panel felt that the formulation was either mildly phototoxic or there was UV enhancement of an irritant response. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 CLINICAL ASSESSMENT Case Reports Eczema of the face of 2 female patients was exacerbated by a cream that contained TEA. 61 Patch testing was performed using the ICDRG standard series, a cosmetic battery, the TEA-containing cream, and TEA at 1%, 2%, and 5% in petrolatum (pet.). Both patients reacted to the TEA-containing cream (+ reaction) and to 5% TEA pet. (++ reaction). One patient reacted to 2% TEA (+ reaction), and neither reacted to 1% TEA pet. Patch tests were negative for all other compounds. In a control group of 50 subjects, patch testing with 5% TEA pet. was negative. Over a 4-yr period, the incidences of positive patch test reactions to the same TEA-containing cream were 69/171 patients in one clinic and 49/191 in another. 62 It was hypothesized that the difference between the clinics was due to differences in sampling methods; the first clinic tested only those patients that had recently used the TEA-containing cream or who had suspected reactions. In follow-up patch testing with a total of 54 subjects from the 2 clinics, 15 of which were controls, 19 subjects had a positive allergic response to the TEA-containing cream, 40 had a positive irritant response, and 13 had negative responses. With % TEA, 6 subjects had a positive response. However, with 5-20% TEA stearate, 8/8 patients and 15/15 controls had a positive irritant response. (TEA stearate was tested because it was demonstrated that TEA stearate was formed from the combination of TEA and stearic acid in formulation). The researchers postulated the reactions were irritant reactions to TEA stearate. (The amount of TEA stearate present in formulation was estimated to be 4.8%, and 6/23 subjects patch tested with 5% TEA stearate had irritant reactions). Two cases of occupational asthma in metal workers exposed to cutting fluid containing TEA were reported. 63 Exposure to TEA at temperatures higher than that of ambient air was a common feature. TEA-PEG-3 Cocamide Sulfate Two patients with a reaction to a shampoo were patch tested with the ICDRG standard series and a 1% aq. solution of the shampoo. 64 Both patients had positive patch results to the shampoo only. Subsequent patch test with 1% aq. TEA- PEG-3 Cocamide DEA (as well as 1% cocamidopropyl betaine) yielded produced positive results in both patients. Twenty eczema patients patch used as controls had negative patch test results to 10% aq. TEA-PEG-3 Cocamide DEA. 19 Panel Book Page 38

49 SUMMARY This report is a re-review of the safety of TEA as used in cosmetics. TEA can function as a surfactant or ph adjuster, and is reported to be used in 3745 cosmetic ingredients at concentrations up to 6% in leave-on formulations, 19% in rinse-off formulations, and 0.7% in products that are diluted for use. TEA may contain DEA as an impurity. The ingredients reviewed in this report, as trialkylamines, trialkanolamines, and their salts, are allowed at up to 2.5% in leave-on-products. There are additional restrictions regarding conditions for use in leave-on and rinse-off products. Dermal absorption studies of TEA were performed using mice and rats. In mice, [ 14 C]TEA in acetone was rapidly absorbed, and absorption increased with increasing dose. The majority of the radioactivity was excreted in the urine, 48-56% in 72 h, primarily as unchanged TEA. TEA was absorbed more slowly and less extensively in rats than mice. Over a 72-h period, 19-28% of the dose was absorbed, and 13-24% of the dose was recovered in the urine, mostly as unchanged TEA. In an oral dosing study with rats, TEA was rapidly absorbed in the gastrointestinal tract and excreted mostly in the form of unchanged TEA. The dermal penetration of salicylate from a formulation containing 10% TEA-salicylate was investigated in vitro and in vivo. In vitro, 1 g of the formulation was applied to full-thickness skin samples from rats and humans. The penetration of salicylate measured as flux was 39.9 µg/cm 2 /h with rat skin and 8.7 µg/cm 2 /h with human skin. With in vivo testing, the formulations were applied to rat skin for intervals of up to 6 h. No salicylate was found in the deep muscle or fat under the application site, and very little salicylate was found in the plasma. In humans there was no evidence of direct tissue penetration of salicylate following dermal application. In 2 and 13-wk repeated dose dermal toxicity studies in mice with mg/kg bw TEA in acetone or 4000 mg/kg bw neat,, dermal irritation was observed in the highest dose group, and kidney and liver weights were increased with the higher doses. In rats, mg/kg bw TEA in acetone or mg/kg bw neat was applied to rats for 13 wks, irritation was observed at the dosing site. Kidney weights were increased in males and females of rats dosed with 500 mg/kg TEA, and dosed females had higher incidences of nephropathy.. In a 14-day drinking water study, animals given 8%TEA in drinking water were all killed due to severe hydration before study terminations. Treatment-related changes were not observed for animals given 2 or 4^% TEA in their water. In inhalation studies with TEA in rats and mice, no observations were reported that were indicative of a toxic pulmonary effect. No adverse reproductive effects were seen in dermal studies in which rats and mice were dosed with TEA in acetone from before mating through lactation or in an oral teratogenicity screening test in mice. TEA was negative for genotoxic effects in an Ames test with or without metabolic activation, gene conversion assay, rec assay, sister chromatid exchange assay with or without metabolic activation, chromosomal aberration assay, and cell transformation assay. In a 2-yr dermal carcinogenicity study of TEA in mice and a 2-yr study in rats, it was concluded that TEA produced equivocal evidence of carcinogenic activity in male mice based on the occurrence of liver hemangiosarcoma, some evidence of carcinogenic activity in female mice based on increased incidences of hepatocellular adenoma, equivocal evidence of carcinogenic activity in male rats based on a marginal increase in the incidence of renal tubule cell adenoma, and no evidence of carcinogenic activity in female rats. In oral carcinogenicity studies in rats and mice, TEA was not carcinogenic to rats or mice, but it was toxic to the kidneys of rats, especially females. It has been speculated that TEA may cause liver tumors in mice via a choline-depletion mode of action. TEA can be a dermal irritant in both animals and human, but it has not been shown to be a sensitizer. Many of the ingredients in this report are surfactants, which can be irritating to skin and eyes. 20 Panel Book Page 39

50 TABLES Table 1. Conclusions of previously reviewed ingredients and components Ingredient Conclusion Reference TEA TEA-Cocoyl Hydrolyzed Collagen TEA Dodecylbenzenesulfonate TEA Tridecylbenzenesulfonate TEA-EDTA PREVIOUSLY REVIEWED INGREDIENTS 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 DEA should not exceed 5%; should not be used with products containing N-nitrosating agents. safe as used safe as used when formulated to be non-irritating safe as used TEA-Lactate TEA-Lauryl Sulfate TEA-Salicylate TEA Stearate Alkyl PEG Ethers Ammonium Lauryl Sulfate Sodium Lauryl Sulfate Coconut Ingredients Cocoyl Sarcosine Lauroyl Sarcosine Oleoyl Sarcosine Dimethicone Copolyol Isostearic Acid Lauric Acid Myristic Acid Oleic Acid Palmitic Acid Stearic Acid PCA Plant-Derived Fatty Acid Oils Ricinoleic Acid Sodium Cetearyl Sulfate and Related Alkyl Sulfates Sodium Lauraminopropionate Sodium Laureth Sulfate and Sulfated Ethoxylated Alcohols Sorbic Acid Tall Oil 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 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 can be used without significant irritation at a final concentration thereof not exceeding 10.5%; greater concentrations may cause irritation, especially if allowed to remain in contact with the skin for significant periods of time 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 safe as used in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing; in products intended for prolonged contact with the skin, the concentration should not exceed 15% in formulation; should not be in products under conditions resulting in N-nitrosation reactions PREVIOUSLY REVIEWED COMPONENTS safe as used when formulated to be non irritating 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 safe as used in rinse-off products, safe for use in leave-on products at concentrations of 5%, and the data were insufficient to determine the safety for use in products where cocoyl sarcosine is likely to be inhaled; should not be used in cosmetic products in which N-nitroso compounds may be formed safe as used safe as used safe as used safe as used; should not be used in products containing nitrosating agents safe as used safe as used safe as used insufficient data (extensive list of data needs) safe as used when formulated to be non-irritating safe as used safe as used , Panel Book Page 40

51 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure Triethanolamine (TEA) and inorganic salts Triethanolamine Triethanolamine is a tertiary amine with three ethanol functional groups. HO N OH OH TEA-Hydrochloride TEA-Hydrochloride is the triethanolamine salt of hydrochloric acid. TEA-Sulfate TEA-Sulfate is the triethanolamine salt of sulfuric acid. HO N OH OH m O HO S OH O n Organic acid salts TEA-Laurate TEA-Laurate is the triethanolamine salt of a twelve carbon fatty acid, lauric acid. TEA-Laurate/ Myristate TEA-Laurate/Myristate is the triethanolamine salt of a mixture of a twelve carbon fatty acid, lauric acid, and a fourteen carbon fatty acid, myristic acid. H 3 C O O OH HO NH OH O H 3 C O OH TEA-Myristate TEA-Myristate is the triethanolamine salt of a fourteen carbon fatty acid, myristic acid. HO NH OH TEA-Palmitate TEA-Palmitate is the triethanolamine salt of a sixteen carbon fatty acid, palmitic acid. TEA-Stearate TEA-Stearate is the triethanolamine salt of an eighteen carbon fatty acid, stearic acid. 22 Panel Book Page 41

52 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-Isostearate TEA-Isostearate is the triethanolamine salt of a branched, eighteen carbon fatty acid, isostearic acid. TEA-Undecylenate TEA-Undecylenate is the triethanolamine salt of a terminally unsaturated, eleven carbon fatty acid, undecylenic acid. one example of an iso TEA-Sorbate TEA-Sorbate is the triethanolamine salt of an α, β, γ, δ-unsaturated six carbon acid, sorbic acid. TEA-Oleate TEA-Oleate is the triethanolamine salt of an eighteen carbon, Ω-9 fatty acid, oleic acid. TEA-Canolate TEA-Canolate is the triethanolamine salt of the fatty acids derived from canola oil. TEA-Cocoate TEA-Cocoate is the triethanolamine salt derived from coconut fatty acids. wherein RC(O)O - = the fatty acid anions derived from Canola Oil TEA-Hydrogenated Cocoate TEA-Hydrogenated Cocoate is the triethanolamine salt of hydrogenated coconut fatty acids wherein RC(O)O - = the fatty acid anions derived from coconut wherein RC(O)O - = the fatty acid anions derived from hydrogenated coconut 23 Panel Book Page 42

53 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-Rosinate TEA-Rosinate is the triethanolamine salt of the acids derived from rosin. TEA-Tallate TEA-Tallate is the triethanolamine salt of tall oil acid. wherein RC(O)O - = the fatty acid anions derived from Rosin TEA-Glyceryl Dimaleate [ ] per CAS Triethanolamine diester TEA-Diricinoleate TEA-Glyceryl Dimaleate is the triethanolamine salt of the diester of glycerin and maleic acid. TEA-Diricinoleate is diester of the Ω-8 hydroxy, Ω-9 unsaturated, eighteen carbon fatty acid, ricinoleic acid. wherein RC(O)O - = the fatty acid anions derived from Tall Oil Acid Not enough information for a structure Hydroxy Acid Salts TEA-Lactate TEA-Lactate is the triethanolamine salt of the three carbon, α-hydroxy acid, lactic acid TEA-Salicylate TEA-Salicylate is the triethanolamine salt of the ß-hydroxy acid, salicylic acid Amine & Amide Acid Salts TEA-EDTA TEA-EDTA is the triethanolamine salt of ethylenediamine-tetraacetic acid (EDTA). 24 Panel Book Page 43

54 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA- Myristaminopropionate TEA-Myristaminopropionate is the triethanolamine salt of myristaminopropionic acid. TEA- Lauraminopropionate TEA-Lauraminopropionate is the triethanolamine salt of N-dodecyl substituted alanine. Di-TEA-Palmitoyl Aspartate Di-TEA-Palmitoyl Aspartate is the triethanolamine salt of the palmitic amide of aspartic acid HO NH OH O O O O O H 3 C N H OH O HO NH O TEA-Cocoyl Glycinate TEA-Cocoyl Glycinate is the triethanolamine salt of the coconut acid amide of acetate. TEA-Cocamide Diacetate TEA-Cocamide Diacetate is the triethanolamine salt of the coconut acid amide of diacetate. wherein RCO- represents the fatty acids derived from coconut acid TEA-Cocoyl Alaninate TEA-Cocoyl Alaninate is the triethanolamine salt of the coconut acid amide of alanine. wherein RCO- represents the fatty acids derived from coconut oil TEA-Cocoyl Sarcosinate TEA-Cocoyl Sarcosinate is the triethanolamine salt of cocoyl sarcosine. wherein RCO- represents the fatty acids derived from coconut acid wherein RCO- represents the fatty acids derived from coconut oil 25 Panel Book Page 44

55 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-Hydrogenated Tallowoyl Glutamate TEA-Hydrogenated Tallowoyl Glutamate is the triethanolamine salt of the hydrogenated tallow acid amide of glutamic acid. TEA-Lauroyl Glutamate TEA-Lauroyl Glutamate is the triethanolamine salt of the lauric acid amide of glutamic acid. wherein RCO- represents the fatty acids derived from hydrogenated tallow TEA-Lauroyl Methylaminopropionate is the triethanolamine salt of the lauric acid amide of N-methylalanine. TEA-Lauroyl Methylaminopropionate TEA- Lauroyl/Myristoyl Aspartate TEA-Lauroyl/Myristoyl Aspartate is the triethanolamine salt of a mixture of the lauric acid amide of glutamic acid and the myristic acid amide or glutamic acid. TEA-Lauroyl Sarcosinate TEA-Lauroyl Sarcosinate is the triethanolamine salt of lauroyl sarcosine TEA-Oleoyl Sarcosinate TEA-Oleoyl Sarcosinate is the triethanolamine salt of oleoyl sarcosine 26 Panel Book Page 45

56 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-PCA TEA-PCA is the triethanolamine salt of pyrrolidone-carboxylic acid (PCA). Di-TEA Cocamide Diacetate Di-TEA Cocamide Diacetate is the triethanolamine salt, w/rcorepresenting fatty acids from coconut oil. TEA-Cocoyl Glutamate TEA-Cocoyl Glutamate is the 1:1 triethanolamine salt of the coconut acid amide of glutamic acid wherein RCO- represents the fatty acids derived from coconut acid TEA-Cocoyl Glutaminate TEA-Cocoyl Glutaminate is the triethanolamine salt of the coconut acid amide of glutamine. wherein RCO- represents the fatty acids derived from coconut acid and R represents hydrogen or a negative charge TEA-Palm Kernel Sarcosinate TEA-Palm Kernel Sarcosinate is the triethanolamine salt of the palm kernel acid amide of sarcosine; RCO- represents the fatty acids derived from palm kernel oil wherein RCO- represents the fatty acids derived from coconut acid Ester Acid Salts TEA-PEG-50 Hydrogenated Castor Oil Succinate TEA-PEG-50 Hydrogenated Castor Oil Succinate is the triethanolamine salt of the hydrogenated castor oil ether of polyethoxylated succinic acid. wherein RCO- represents the fatty acids derived from palm kernel acid wherein R represents the fatty acid residue from hydrogenated castor oil 27 Panel Book Page 46

57 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-Lauroyl Lactylate TEA-Lauroyl Lactylate is the triethanolamine salt of the lauric acid ester of lactyl lactylate. Inorganic Acid Salts -Sulfates and Sulfonates Magnesium/TEA- Magnesium/TEA-Coco-Sulfate is the Coco-Sulfate mixed magnesium and triethanolamine salt of coco-sulfate. wherein R represents the fatty acid residue from hydrogenated castor oil Sodium/TEA C12-13 Pareth-3 Sulfate Sodium/TEA C12-13 Pareth-3 Sulfate is the mixed sodium and triethanolamine salt of the sulfate ester of C12-13 pareth- 3. where R represents the alkyl groups derived from coconut oil Di-TEA-Oleamido PEG-2 Sulfosuccinate Di-TEA-Oleamido PEG-2 Sulfosuccinate is the bis (triethanolamine salt) of the monooleyl amide of the diglycol half ester of sulfosuccinic acid. TEA-Lauryl Sulfate TEA-Lauryl Sulfate is the triethanolamine salt of lauryl sulfuric acid. 28 Panel Book Page 47

58 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-Laneth-5 Sulfate TEA-Laneth-5 Sulfate is the triethanolamine salt of the sulfate ester of laneth-5 TEA-Laureth Sulfate TEA-Laureth Sulfate is the triethanolamine salt of polyethoxylated lauryl sulfate. TEA-Oleyl Sulfate TEA-Oleyl Sulfate is the triethanolamine salt of Ω-9 unsaturated eighteen carbon alkyl sulfate, oleyl sulfate. where n = 1-4 TEA-C10-15 Alkyl Sulfate TEA-C10-15 Alkyl Sulfate is the mixture of 10 to 15 carbon alkyl sulfate triethanolamine salts. 29 Panel Book Page 48

59 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-C11-15 Alkyl Sulfate TEA-C11-15 Alkyl Sulfate is the mixture of 11 to 15 carbon alkyl sulfate triethanolamine salts. TEA-C12-13 Alkyl Sulfate TEA-C12-13 Alkyl Sulfate is the mixture of 12 to 13 carbon alkyl sulfate triethanolamine salts. TEA-C12-14 Alkyl Sulfate TEA-C12-14 Alkyl Sulfate is the mixture of 12 to 14 carbon alkyl sulfate triethanolamine salts. TEA-C12-15 Alkyl Sulfate TEA-C12-15 Alkyl Sulfate is the mixture of 12 to 15 carbon alkyl sulfate triethanolamine salts. 30 Panel Book Page 49

60 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA C14-17 Alkyl Sec Sulfonate TEA C14-17 Alkyl Sec Sulfonate is the mixture of 14 to 17 carbon, alkyl 2-sulfate triethanolamine salts. TEA-Coco-Sulfate TEA-Coco-Sulfate is the triethanolamine salt of sulfated Coconut Alcohol. TEA-C11-15 Pareth Sulfate TEA-C11-15 Pareth Sulfate is the triethanolamine salt of the sulfate ester of a mixture of monoethoxylated, 11 to 15 carbon fatty alcohols. where R represents the alkyl groups derived from coconut oil TEA-C12-13 Pareth-3 Sulfate TEA-C12-13 Pareth-3 Sulfate is the triethanolamine salt of the sulfate ester of a mixture of triethoxylated, 12 to 13 carbon fatty alcohols. 31 Panel Book Page 50

61 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-PEG-3 Cocamide Sulfate TEA-PEG-3 Cocamide Sulfate is the triethanolamine salt of the sulfate ester of triethoxylated cocamide. TEA-Dodecylbenzenesulfonate TEA-Dodecylbenzenesulfonate is the triethanolamine salt of p-dodecyl (i.e. para-12 carbon alkyl chain) substituted benzenesulfonate. where RCO- represents the fatty acids derived from coconut oil TEA-Tridecylbenzenesulfonate TEA-Tridecylbenzenesulfonate is the triethanolamine salt of p-tridecyl (i.e. para-13 carbon alkyl chain) substituted benzenesulfonate. -Phosphates TEA-Lauryl Phosphate [ ] per CAS TEA-Lauryl Phosphate is the triethanolamine salt of a complex mixture of esters of phosphoric acid and a twelve carbon alcohol, lauryl alcohol. TEA-Laureth-4 Phosphate TEA-Laureth-4 Phosphate is the triethanolamine salt of a complex mixture of phosphate esters of Laureth-4. H 3 C O where R represents either hydrogen or a lauryl chain O O O P O O O OR OH HO NH OH where R represents either hydrogen or a laureth-4 chain TEA-C12-13 Alkyl Phosphate TEA-C12-13 Alkyl Phosphate is the triethanolamine salt of a complex mixture of esters of phosphoric acid and twelve to thirteen carbon alcohols. where R represents hydrogen, a 12 carbon alkyl chain or a 13 carbon alkyl chain 32 Panel Book Page 51

62 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-C12-14 Alkyl Phosphate TEA-C12-14 Alkyl Phosphate is the triethanolamine salt of a complex mixture of esters of phosphoric acid and twelve to fourteen carbon alcohols. O H 3 C O P O OR O H 3 C O P O OR O H 3 C O P O OR HO HO HO NH NH NH OH OH OH OH OH OH TEA-Dimethicone PEG-7 Phosphate where R represents hydrogen, a twelve carbon alkyl chain, a 13 carbon alkyl chain or a 14 carbon chain TEA-Dimethicone PEG-7 Phosphate is the triethanolamine salt of a dimethicone terminated polyethylene glycol phosphate. TEA-Polyphosphate TEA-Polyphosphate is triethanolamine salt of polyphosphoric acid. Polysaccharide & Protein Salts TEA-Cocoyl TEA-Cocoyl Hydrolyzed Collagen is the Hydrolyzed Collagen triethanolamine salt of the condensation product of coconut acid chloride and hydrolyzed collagen. TEA-Alginate TEA-Alginate is the triethanolamine salt of alginic acid. (Alginic acid is a linear, anionic polysaccharide consisting of β-dmannuronopyranosyl (M) and α-l-guluronopyranosyl (G) residues, arranged in blocks of repeating M residues (MM blocks), blocks of repeating G residues (GG blocks), and blocks of mixed M and G residues (MG blocks), extracted from various species of brown seaweed, Phaeophyceae.) O OH R' R O NH HO OH where RCO- represents the fatty acids derived from coconut oil and R represents hydrolyzed collagen 33 Panel Book Page 52

63 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-Isostearoyl Hydrolyzed Collagen TEA-Isostearoyl Hydrolyzed Collagen is the triethanolamine salt of the condensation product of isostearic acid chloride and Hydrolyzed Collagen Sodium/TEA-Lauroyl Collagen Amino Acids H 3 C CH 3 Sodium/TEA-Lauroyl Collagen Amino Acids is a mixture of sodium and triethanolamine salts of the condensation product of lauric acid chloride and collagen amino acids O OH R O NH HO OH where R represents hydrolyzed collagen Sodium/TEA-Lauroyl Hydrolyzed Collagen Sodium/TEA-Lauroyl Hydrolyzed Collagen is a mixture of sodium and triethanolamine salt of the condensation product of lauric acid chloride and Hydrolyzed Collagen H 3 C where R represents collagen amino acids Na 2 O OH R O NH HO OH Sodium/TEA-Lauroyl Hydrolyzed Keratin Sodium/TEA-Lauroyl Hydrolyzed Keratin is a mixture of sodium and triethanolamine salts of the condensation product of lauric chloride and Hydrolyzed Keratin where R represents hydrolyzed collagen Sodium/TEA-Lauroyl Keratin Amino Acids Sodium/TEA-Lauroyl Keratin Amino Acids is a mixture of sodium and triethanolamine salts of the condensation product of Lauric Acid and Keratin Amino Acids where R represents hydrolyzed keratin Sodium/TEA- Undecylenoyl Alginate Sodium/TEA-Undecylenoyl Alginate is a mixture of sodium and triethanolamine salts of the condensation product of undecylenic acid chloride and Alginic Acid where R represents keratin amino acids 34 Panel Book Page 53

64 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure Sodium/TEA- Undecylenoyl Carrageenan Sodium/TEA-Undecylenoyl Carrageenan is a mixture of sodium and triethanolamine salts of the condensation product of undecylenic acid chloride and Carrageenan. Carrageenans are a family of sulfated polysaccharides with a linear chain of D-galactose, linked alternately alpha(l 3) and β(l 4). The sulfate groups are present at the 2, 4, or 6 positions. Some of the galactose residues are converted to 3,6-anhydrogalactose by the formation of a bridging bond across the ring between the C-3 and C-6. Sodium/TEA- Undecylenoyl Collagen Amino Acids Sodium/TEA-Undecylenoyl Collagen Amino Acids is a mixture of sodium and triethanolamine salts of the condensation product of undecylenic acid chloride and Collagen Amino Acids H 3 C where R represents hydrogen, sulfate or undecylenoyl and some of the galactose units have been converted to 3,6-anhydrogalactose 2 O R O HO NH Na OH OH Sodium/TEA- Undecylenoyl Hydrolyzed Collagen Sodium/TEA-Undecylenoyl Hydrolyzed Collagen is a mixture of sodium and triethanolamine salts of the condensation product of undecylenic acid chloride and Hydrolyzed Collagen where R represents collagen amino acids Sodium/TEA- Undecylenoyl Hydrolyzed Corn Protein Sodium/TEA-Undecylenoyl Hydrolyzed Corn Protein is a mixture of sodium and triethanolamine salts of the condensation product of undecylenic acid chloride and Hydrolyzed Corn Protein where R represents hydrolyzed collagen Sodium/TEA- Undecylenoyl Hydrolyzed Soy Protein Sodium/TEA-Undecylenoyl Hydrolyzed Soy Protein is a mixture of sodium and triethanolamine salts of the condensation product of undecylenic acid chloride and Hydrolyzed Soy Protein where R represents hydrolyzed corn protein where R represents hydrolyzed soy protein 35 Panel Book Page 54

65 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure Sodium/TEA- Undecylenoyl Hydrolyzed Wheat Protein Sodium/TEA-Undecylenoyl Hydrolyzed Wheat Protein is a mixture of sodium and triethanolamine salts of the condensation product of undecylenic acid chloride and Hydrolyzed Wheat Protein TEA-Abietoyl Hydrolyzed Collagen TEA-Abietoyl Hydrolyzed Collagen is the triethanolamine salt of the condensation product of abietic acid chloride and Hydrolyzed Collagen where R represents hydrolyzed wheat protein TEA-Cocoyl Hydrolyzed Soy Protein TEA-Dextrin Octenylsuccinate TEA-Cocoyl Hydrolyzed Soy Protein is the triethanolamine salt of the condensation product of coconut acid chloride with Hydrolyzed Soy Protein TEA-Dextrin Octenylsuccinate is the triethanolamine salt of the rxn product of octenylsuccinic anhydride with Dextrin. Dextrin is the glucose polysaccharide obtained from partial hydrolysis of starch. where R represents hydrolyzed collagen where RCO- represents the fatty acids derived from coconut oil and R represents hydrolyzed soy protein TEA-Lauroyl Collagen Amino Acids TEA-Lauroyl Collagen Amino Acids is the triethanolamine salt of the condensation product of lauric acid chloride and Collagen Amino Acids where R represents dextrin or a negative charge TEA-Lauroyl Hydrolyzed Collagen TEA-Lauroyl Hydrolyzed Collagen is the triethanolamine salt of the condensation product of Hydrolyzed Collagen and lauric acid chloride where R represents collagen amino acids TEA-Lauroyl Keratin Amino Acids TEA-Lauroyl Keratin Amino Acids is the triethanolamine salt of the condensation product of lauric acid chloride and Keratin Amino Acids where R represents hydrolyzed collagen TEA-Myristoyl Hydrolyzed Collagen TEA-Myristoyl Hydrolyzed Collagen is the triethanolamine salt of the condensation product of myristic acid chloride and Hydrolyzed Collagen where R represents keratin amino acids where R represents hydrolyzed collagen 36 Panel Book Page 55

66 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-Oleoyl Hydrolyzed Collagen TEA-Oleoyl Hydrolyzed Collagen is the triethanolamine salt of the condensation product of oleic acid chloride and hydrolyzed collagen. TEA-Undecylenoyl Hydrolyzed Collagen TEA-Undecylenoyl Hydrolyzed Collagen is the triethanolamine salt of the condensation product of undecylenic acid chloride and Hydrolyzed Collagen where R represents hydrolyzed collagen Polymer Salts TEA-Acrylates/ Acrylonitrogens Copolymer TEA-Acrylates/ Acrylonitrogens Copolymer is the polymer formed from the controlled hydrolysis of polyacrylonitrile neutralized by triethanolamine. where R represents hydrolyzed collagen TEA-Acrylates/ Ethylhexyl Acrylate Copolymer TEA-Acrylates/ Ethylhexyl Acrylate Copolymer is a copolymer of ethylhexyl acrylate and the triethanolamine salt of one or more monomers consisting of acrylic acid, methacrylic acid, or one of their simple esters. Wherein simple esters means esters wherein the alcohol residue is one to 4 carbons long. TEA-Carbomer TEA-Carbomer is the triethanolamine salt of Carbomer. Wherein carbomer is a homopolymer of acrylic acid crosslinked with an allyl ether of pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene. where R represents hydrogen or a methyl group, and R represents hydrogen or an alkyl group, one to four carbons in length. where R is hydrogen during the polymerization, but is then converted to the triethanolammonium 37 Panel Book Page 56

67 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA- Diethanolaminoethyl Polyisobutenylsuccinate TEA-Diethanolaminoethyl Polyisobutenyl-succinate is triethanolamine salt where R represents the polyisobutenyl succinic anhydride moiety. Table 3. Physical and Chemical Properties Property Value Reference Triethanolamine Physical Form clear viscous liquid 1 Color colorless to pale yellow 23 Odor ammonical 1 Molecular Weight Melting Point 21.6 C 23 Boiling Point mm Hg 23 Water Solubility miscible in water 23 Other Solubility insoluble in benzene, ether, and petroleum distillates 1 miscible with methanol or acetone; sparingly soluble in hydrocarbon solvents; readily 86 forms salts with organic and inorganic acids log K ow 20 C 14 pka 25 C 33 Viscosity C 86 TEA-Hydrochloride Melting Point 177 C 87 TEA-Diricinoleate Molecular Weight Boiling Point C 88 Density g/cm 3 (20 C; 7600 Torr) 88 log P (25 C0 88 pka (25 C) (most acidic) (most basic) TEA-Lactate Melting Point C 89 Density g/cm 3 89 TEA Lauryl Sulfate Density approx. 1 g/cm 3 (20 C) 6 38 Panel Book Page 57

68 Table 4a. Frequency and concentration of use according to duration and type of exposure # of Uses 11,90 Conc of Use (%) 12 # of Uses 11,90 Conc of Use (%) 12 # of Uses 11,90 Conc of Use (%) 12 Triethanolamine Di-TEA Palmitoyl Aspartate TEA-Abietoyl Hydrolyzed Collagen Totals* NR Duration of Use Leave-On NR NR NR Rinse-Off NR 0.2 Diluted for Use NR NR NR NR Exposure Type Eye Area NR NR NR 0.3 Possible Ingestion NR NR NR NR Inhalation NR NR NR NR Dermal Contact NR Deodorant (underarm) NR NR NR NR Hair - Non-Coloring NR NR NR Hair-Coloring NR NR NR NR Nail NR NR NR NR Mucous Membrane NR 0.4 NR NR Bath Products NR NR NR NR Baby Products NR NR NR NR TEA-Carbomer TEA-Cocoate TEA Cocoyl Alaninate Totals* 24 NR 2 NR 2 NR Duration of Use Leave-On 21 NR 1 NR 1 NR Rinse Off 3 NR 1 NR 1 NR Diluted for Use NR NR NR NR NR NR Exposure Type Eye Area 1 NR NR NR NR NR Possible Ingestion 1 NR NR NR NR NR Inhalation NR NR NR NR NR NR Dermal Contact 24 NR 2 NR 2 NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 2 NR NR NR NR NR Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR 1 NR 1 NR Bath Products NR NR NR NR NR NR Baby Products NR NR NR NR NR NR TEA Cocoyl Glutamate TEA-Cocoyl Hydrolyzed Collagen TEA Cocoyl Hydrolyzed Soy Protein Totals* Duration of Use Leave-On 8 NR NR NR 2 NR Rinse-Off Diluted for Use NR 3 1 NR NR NR Exposure Type Eye Area NR NR NR NR NR NR Possible Ingestion NR NR NR NR NR NR Inhalation 1 NR NR NR NR NR Dermal Contact NR NR NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring Hair-Coloring NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR Bath Products NR 5 1 NR NR NR Baby Products 1 NR NR NR NR NR 39 Panel Book Page 58

69 Table 4a. Frequency and concentration of use according to duration and type of exposure # of Uses 11,90 Conc of Use (%) 12 # of Uses 11,90 Conc of Use (%) 12 # of Uses 11,90 Conc of Use (%) 12 TEA-Cocoyl Sarcosinate TEA-Dodecylbenzenesulfonate TEA-Hydrochloride Totals NR NR 0.5 Duration of Use Leave-On NR NR NR NR Rinse Off NR NR 0.5R Diluted for Use NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR Possible Ingestion NR NR NR NR NR NR Inhalation NR NR NR NR NR NR Dermal Contact NR NR NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR 0.5 Hair-Coloring NR NR NR 6 NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR Bath Products NR NR NR NR NR NR Baby Products NR NR NR NR NR NR TEA-Isostearate TEA Lactate TEA Laurate Totals* 1 NR NR 8 Duration of Use Leave-On 1 NR 13 NR NR NR Rinse-Off NR NR NR NR NR 8 Diluted for Use NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR Possible Ingestion NR NR NR NR NR NR Inhalation NR NR NR NR NR NR Dermal Contact 1 NR NR 8 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 NR NR NR NR NR NR Bath Products NR NR NR NR NR NR Baby Products NR NR NR NR NR NR TEA-Laureth Sulfate TEA-Lauroyl Collagen Amino Acid TEA-Lauryl Sulfate Totals* Duration of Use Leave-On 2 NR Rinse-Off NR NR Diluted for Use NR 3 NR NR Exposure Type Eye Area NR NR NR NR NR NR Possible Ingestion NR NR NR NR NR NR Inhalation NR NR NR NR NR 8 Dermal Contact NR NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring Hair-Coloring NR 6 NR NR NR 2 Nail NR NR NR NR NR NR Mucous Membrane 1 9 NR NR Bath Products NR 3 NR NR Baby Products NR NR NR NR 2 NR 40 Panel Book Page 59

70 Table 4a. Frequency and concentration of use according to duration and type of exposure # of Uses 11,90 Conc of Use (%) 12 # of Uses 11,90 Conc of Use (%) 12 # of Uses 11,90 Conc of Use (%) 12 TEA-Myristate TEA-Palmitate TEA-PCA Totals* 2 NR 5 14 NR Duration of Use Leave-On NR NR 3 NR NR Rinse-Off 2 NR 2 NR NR NR Diluted for Use NR NR NR NR NR NR Exposure Type Eye Area NR NR 1 NR NR NR Possible Ingestion NR NR NR NR NR NR Inhalation NR NR NR NR NR NR Dermal Contact 2 NR 4 14 NR 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 NR NR NR NR NR NR Bath Products NR NR NR NR NR NR Baby Products NR NR NR NR NR NR TEA-Rosinate TEA-Salicylate TEA-Stearate Totals* 1 NR 3 NR Duration of Use Leave-On NR NR NR NR 108 NR Rinse-Off 1 NR 3 NR 22 NR Diluted for Use NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR 9 NR Possible Ingestion NR NR NR NR 1 NR Inhalation NR NR NR NR 1 NR Dermal Contact 1 NR NR NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR 3 NR 16 NR Hair-Coloring NR NR NR NR 1 NR Nail NR NR NR NR NR NR Mucous Membrane NR NR NR NR 13 NR Bath Products NR NR NR NR NR NR Baby Products NR NR NR NR NR NR TEA-Undecylenoyl Hydrolyzed TEA-Sulfate Animal Protein Totals* NR Duration of Use Leave-On NR NR NR Rinse-Off Diluted for Use NR NR NR0 Exposure Type Eye Area NR NR NR Possible Ingestion NR NR NR Inhalation NR NR NR Dermal Contact NR NR 6 Deodorant (underarm) NR NR NR Hair - Non-Coloring NR Hair-Coloring NR NR NR Nail NR NR NR Mucous Membrane NR NR NR Bath Products NR NR NR Baby Products NR NR NR * Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types my not equal the sum of total uses. NR no reported uses 41 Panel Book Page 60

71 Table 4b. Ingredients not reported to be used Di-TEA Cocamide Diacetate Di-TEA-Oleamido PEG-2 Sulfosuccinate Magnesium/TEA-Coco-Sulfate Sodium/TEA-Lauroyl Hydrolyzed Collagen Sodium/TEA C12-13 Pareth-3 Sulfate Sodium/TEA-Lauroyl Collagen Amino Acids Sodium/TEA-Lauroyl Hydrolyzed Keratin Sodium/TEA-Lauroyl Keratin Amino Acids Sodium/TEA-Undecylenoyl Alginate Sodium/TEA-Undecylenoyl Carrageenan Sodium/TEA-Undecylenoyl Collagen Amino Acids Sodium/TEA-Undecylenoyl Hydrolyzed Collagen Sodium/TEA-Undecylenoyl Hydrolyzed Corn Protein Sodium/TEA-Undecylenoyl Hydrolyzed Soy Protein Sodium/TEA-Undecylenoyl Hydrolyzed Wheat Protein TEA C14-17 Alkyl Sec Sulfonate TEA-Acrylates/ Acrylonitrogens Copolymer TEA-Acrylates/ Ethylhexyl Acrylate Copolymer TEA-Alginate TEA-C10-15 Alkyl Sulfate TEA-C11-15 Alkyl Sulfate TEA-C12-13 Alkyl Sulfate TEA-C12-13 Alkyl Sulfate TEA-C12-14 Alkyl Sulfate TEA-C12-15 Alkyl Sulfate TEA-C12-13 Alkyl Phosphate TEA-C12-14 Alkyl Phosphate TEA-C11-15 Pareth Sulfate TEA-C12-13 Pareth-3 Sulfate TEA-Canolate TEA-Cocamide Diacetate TEA-Coco-Sulfate TEA-Cocoyl Glutaminate TEA-Cocoyl Glycinate TEA-Dextrin Octenylsuccinate TEA-Diethanolaminoethyl Polyisobutenylsuccinate TEA-Dimethicone PEG-7 Phosphate TEA-Diricinoleate TEA-EDTA TEA-Glyceryl Dimaleate TEA-Hydrogenated Cocoate TEA-Hydrogenated Tallowoyl Glutamate TEA-Isostearoyl Hydrolyzed Collagen TEA-Laneth-5 Sulfate TEA-Lauraminopropionate TEA-Laurate/ Myristate TEA-Laureth-4 Phosphate TEA-Lauroyl Glutamate TEA-Lauroyl Hydrolyzed Collagen TEA-Lauroyl Keratin Amino Acids TEA-Lauroyl Lactylate TEA-Lauroyl Methylaminopropionate TEA-Lauroyl Sarcosinate TEA-Lauroyl/Myristoyl Aspartate TEA-Lauryl Phosphate TEA-Myristaminopropionate TEA-Myristoyl Hydrolyzed Collagen TEA-Oleate TEA-Oleoyl Hydrolyzed Collagen TEA-Oleoyl Sarcosinate TEA-Oleyl Sulfate TEA-Palm Kernel Sarcosinate TEA-PEG-3 Cocamide Sulfate TEA-PEG-50 Hydrogenated Castor Oil Succinate TEA-Polyphosphate TEA-Sorbate TEA-Tallate TEA-Tridecylbenzenesulfonate TEA-Undecylenate 42 Panel Book Page 61

72 REFERENCES 1. Elder RE (ed). Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. J Am Coll Toxicol. 1983;2:(7): Elder RE (ed). Final report on the safety assessment of potassium-coco-hydrolyzed animal protein and triethanolamine-cocohydrolyzed animal protein. J Am Coll Toxicol. 1983;2:(7): Dow Chemical Company. The alkanolamines handbook Midland, MI: The Dow Chemical Company.Secondary reference in Knaak et al Zhu, S., Heppenstall-Butler, M., Butler, M. F., Pudney, P. D. A., Ferdinando, D., and Mutch, K. J. Acid Soap and Phase Behavior of Stearic Acid and Triethanolamine Stearate. Journal of Physical Chemistry B. 2005;109:(23): Elder RE (ed). Final report on the safety assessment of TEA-Lauryl Sulfate. J Am Coll Toxicol. 1982;1:(4): Organisation for Economic Co-operation and Development. SIDS Dossier on Chem ID: (TEA-lauryl sulfate) Date Accessed Zhu, S., Pudney, P. D. A., Heppenstall-Butler, M., Butler, M. F., Ferdinando, D., and Kirkland, M. Interaction of the Acid Soap of Triethanolamine Stearate and Stearic Acid with Water. Journal of Physical Chemistry B. 2007;111:(5): Kraeling MEK, Yourick JJ, and Bronaugh RL. In vitro human skin penetration of diethanolamine. Food Chem Toxicol. 2004;42: Saghir SA, Brzak A, Markham DA, Bartels MJ, and Stott WT. Investigation of the formation of N-nitrosodiethanolamine in B6C3F1 mice following topical administration of triethanolamine. REg Toxicol Pharmacol. 2005;43: 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 Personal Care Products Council. Updated concentration of use by FDA product category: TEA-containing ingredients Unpublished data submitted by the Council on May 17, ( 3 pp). 13. Personal Care Products Council. Concentration of use by FDA product category: TEA Containing Ingredients Unpublished data submitted by the Council on March 15, (3 pp). 14. Organisation for Economic Co-operation and Development. SIDS Initial Assessment Report for SIAM 3 (Triethanolamine) Date Accessed European Commission. European Commission Enterprise and Industry. Cosmetics - Cosing. Annex III/1,62 - Trialkylamines, trialkanolamines and their salts Date Accessed European Commission. Cosing Database. Annex V. List of preservatives allowed in cosmetic products; EC Regulation (v.2) 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: Food and Drug Administration. Sunscreen drug products for over-the-counter human use; final rule. Fed Regist ;64: Cross, Sheree E., Megwa, Stella A., Benson, Heather A. E., and Roberts, Michael S. Self promotion of deep tissue penetration and distribution of methylsalicylate after topical application. Pharmaceutical Research. 1999;16:(3): Panel Book Page 62

73 21. Cross, Sheree E., Anderson, Chris, and Roberts, Michael S. Topical penetration of commercial salicylate esters and salts using human isolated skin and clinical microdialysis studies. British Journal of Clinical Pharmacology. 1998;46:(1): Stott WT, Waechter JM, Rick DL, and Mendrala AL. Absorption, distribution, metabolism and excretion of intravenously and dermally administered triethanolamine in mice. Food Chem Toxicol. 2000;38: National Toxicology Program. NTP Technical report on the toxicology and carcinogenesis studies of triethanolamine (CAS No ) in B6C3F 1 mice. (Dermal study). NTP TR Andersen FA (ed). Safety assessment of salicylic acid, butyloctyl salicylate, calcium salicylate, C12-15 alkyl salicylate, capryloyl salicylic acid, hexyldodecyl salicylate, isocetyl salicylate, isodecyl salicylate, magnesium salicylate, MEA-salicyalte, ethylhexyl salicylate, potassium salicylate, methyl salicylate, myristyl salicylate, sodium salicylate, TEA-salicylate, and tridecyl salicylate. Int J Toxicol. 2003;22:(Suppl 3): Kohri N, Matsuda T, Umeniwa K, Miyazaki K, and Arita T. Development of assay method in biological fluids and biological fate of triethanolamine. Yakuzaigaku. 1982;42:(4): Kao Company. Acute oral toxicity test in rats. Fixed dose method (Unpublished Report No. CD-95/4286T) Unpublished data cited in the SIDS Dossier on Chem ID: (TEA-lauryl sulfate), Olson, K. J., Dupree, R. W., Plomer, E. T., and Rowe, V. K. Toxicological properties of several commercially available surfactants. Journal of the Society of Cosmetic Chemists. 1962;13: Melnick R and Hejtmancki M Mezza L Ryan M persing R Peters A. Comparative effects of triethanolamine (TEA) and diethanolamine (DEA) in short-term dermal studies. (Secondary reference in Melnick and Tomaszewski 1990). The Toxiologist. 1988;8: DePass LR, Fowler EH, and Leung H-W. Subchronic dermal toxicity study of triethanolamine in C3H/HeJ mice. Fd Chem Toxicol. 1995;33:(8): National Toxicology Program. Toxicology and carcinogenesis studies of triethanolamine (CAS No ) in F344/N rats and B6C3F 1 mice. (Dermal studies.) TR No Hejtmancik M, Mezza L, Peters AC, and Athey PM. The repeated dose dosed water study of triethanolamine (CAS No ) in Fischer-344 rats Columbus OH: Columbus Division Laboratories.Unpublished data summarized in Knaak et al Hejtmancik M, Mezza L, Peters A, and Athey PM. The repeated dose dosed water study of triethanolamine (CAS No ) in B6C3F 1 mice Columbus Division Laboratories.Unpublished data summarized in Knaak et al Gamer AO, Rossbacher R, Kaufmann W, and van Ravenzwaay B. The inhalation toxicity of di- and triethanolamine upon repeated exposure. Food Chem Toxicol. 2008;46: Mosberg A, McNEill D, Hejtmancik M, Persing RL, and Peters A. The repeated dsoe inhalation study of triethanolamine (CAS No ) in Fischer-344 rats Columbus OH: Battelle Columbus Division Laboratories.Unpublished data summarized in Knaak et al Mosberg A, McNEill D, Hejtmancik M, Persing RL, and Peters A. The repeated dose inhalation study of triethanolamine (CAS No ) in B6C3F 1 mice Columbus OH: Battelle Columbus Division Laboratories.Unpublished data summarized in Knaak et al Battelle Columbus Laboratories. Mating trial dermal study of triethanolamine (CAS No ) in Fischer 344 rats. Final report (NIH Cotnract No. N01-ES-45068). Secondary reference in NTP Battelle Columbus Laboratories. Mating trial dermal study of triethanolamine (CAS No ) in Swiss CD-1 mice. Final report (NIH Cotnract No. N01-ES-45068). Secondary reference in NTP Secondary reference in NTP TR Environmental Protection Agency. High Production Volume (HPV) Challenge Program Revised Test Plan and Robust Summaries for Polyphosphoric Acid Esters of Triethanolamine, Sodium Salts Panel Book Page 63

74 39. Inoue K, Sunakawa T, Okamoto K, and Tanaka Y. Mutagenicity tests and in vitro transformation assays on triethanolamine. Mutat Res. 1982;101: 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): Galloway SM, Armstrong MJ, Reuben, Colman, Brown B, Cannon C, Bloom AD, Nakamura F, Ahmed M, Duk S, Rimpo J, Margolin BH, Resnick MA, Anderson B, and Zeiger E. Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells: Evaluation of 108 chemicals. Environ Mol Mutagen. 1987;10:(Suppl 10): Witt KL, Knapton A, Wehr CM, Hook GJ, Mirsalis J, Shelby MD, and MacGregor JT. Micronucleated erythrocyte frequency in peripheral blood of B6C3F 1 mice from short-term. prechronic, and chronic studies of the NTP carcinogenesis bioassay program. Environ Mol Mutagen. 2000;36: National Toxicology Program. Toxicology and carcinogenesis studies of triethanolamine (CAS NO ) in B6C3F 1 mice. (Dermal study.) NTP TR Report No. NIH Publication NO Tennant RW, French JE, and Spalding JW. Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environ Health Perspect. 1995;103: Konishi, Y., Denda, A., Uchida, K., Emi, Y., Ura, H., Yokose, Y., Shiraiwa, K., and Tsutsumi, M. Chronic toxicity carcinogenicity studies of triethanolamine in B6C3F1, mice. Fundam.Appl Toxicol. 1992;18:(1): Maekawa, A., Onodera, H., Tanigawa, H., Furuta, K., Kanno, J., Matsuoka, C., Ogiu, T., and Hayashi, Y. Lack of carcinogenicity of triethanolamine in F344 rats. J Toxicol Environ Health. 1986;19:(3): Ghoshal AK and Farber E. The induction of liver cancer by dietary deficieny of choline and methionine without added carcinogens. Carcinogenesis. 1984;5:(10): Rogers AE. Methyl donors in the diet and responses to chemical carcinogens. Am J Clin Nutr. 1995;61:(Suppl):659S-665S. 50. Stott WT, Radtke BJ, LinscombeVA, Mar MH, and Zeisel SH. Evaluation of the potential of triethanolamine to alter hepatic choline levels in female B6C3F1 mice. Toxicol Sci. 2004;79:(2): International Agency for Research on Cancer (IARC). Triethanolamine. IARC Monogr Eval.Carcinog Risks Hum. 2000;77: Tornier, Carine, Rosdy, Martin, and Maibach, Howard I. In vitro skin irritation testing on reconstituted human epidermis: Reproducibility for 50 chemicals tested with two protocols. Toxicology in Vitro. 2006;20:(4): Ananthapadmanabhan, K. P., Yu, K. K., Meyers, C. L., and Aronson, M. P. Binding of surfactants to stratum corneum. Journal of the Society of Cosmetic Chemists. 1996;47:(4): Anderson SE, Brown KK, Butterworth LF, Fedorowicz A, Jackson LG, Frasch HF, Beezhold D, Munson AE, and Meade BJ. Evaluation of irritancy and sensitization potential of metalworking fluid mixtures and components. J Immunotoxicol. 2009;6:(1): Müller-Decker K, Heinzelmann T, Fürstenberger G, Kecskes A, Lehmann W-D, and Marks F. Arachidonic acid metabolism in primary irritant dermatitis produced by patch testing of human skin with surfactants. Toxicol Appl Pharmacol. 1998;153: Tavss, Edward A., Eigen, Edward, and Kligman, Albert M. Anionic detergent-induced skin irritation and anionic detergentinduced ph rise of bovine serum albumin. Journal of the Society of Cosmetic Chemists. 1988;39:(4): Bulich AA, Tung K-K, and Scheibner G. The luminescent bacteria toxicity test: Its potential as an in vitro alternative. J Biolumin Chemilumin. 1990;5: Gordon VC. Utilization of biomacromolecular in vitro assay systems in the prediction of in vivo toxic responses. Lens and Eye Toxicity Research. 1992;9:(3&4): Panel Book Page 64

75 59. National Toxicology Program. Abstract for IMM The immunotoxicity of triethanolamine (CAS No ) Date Accessed Tosti A, Morelli R, and Bardazzi F. Prevalence and sources of sensitization to emulsifiers: a clinical study. Contact Derm. 1990;23: Jones SK and Kennedy TC. Contact dermatitis from triethanolamine in E45 cream. Contact Derm. 1988;19:(3): Batten TL, Wakeel RA, Douglas WS, Evans C, White MI, Moody R, and Ormerod AD. Contact dermatitis from the old formula E45 cream. Contact Derm. 1994;30: Savonius B, Keskinen H, Tupperainen M, and Kanerva L. Occupational asthma caused by ethanolamines. Allergy. 1994;49: Andersen, K. E., Roed-Petersen, J., and Kamp, P. Contact allergy related to TEA-PEG-3 cocamide sulfate and cocamidopropyl betaine in a shampoo. Contact Dermatitis. 1984;11:(3): Becker LC, Bergfeld W, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG, Shank RS, Slaga TJ, Snyder PW, and Andersen FA. Amended safety assessment of dodecylbenezenesulfonate, decylbenzenesulfonate, and tridecylbenzenesulfonate salts as used in cosmetics. Int J Toxicol. 2010;29:(Suppl 4):288S-305S. 66. Andersen FA (ed). Final report on the safety assessment of EDTA, calcium disodium EDTA, diammonium EDTA, dipotassium EDTA, disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium EDTA, HEDTA, and trisodium EDTA. Int J Toxicol. 2002;21:(Suppl 2): 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): Andersen FA (ed). Final report on the safety assessment of TEA Stearate. J Am Coll Toxicol. 1995;14:(3): 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 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 Andersen FA (ed). Final report on the safety assessment of cocoyl sarcosine, lauroyl sarcosine, myristoyl sarcosine, oleoyl sarcosin, stearoyl sarcosine, sodium cocoyl sarcosinate, sodium lauroyl sarcosinate, sodium myristoyl sarcosinate, ammonium cocoyl sarcosinate, and ammonium lauroyl sarcosinate. Int J Toxicol. 2001;20:(Suppl 1): Elder RE (ed). Final report on the safety assessment of dimethicone copolyol. J Am Coll Toxicol. 1982;1:(4): Elder RL (ed). Final report on the safety assessment of isostearic acid. J Am Coll Toxicol. 1983;2:(7): 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): Becker LC, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the amended safety assessment of myristic acid and its salts and esters as used in cosmetics. Int J Toxicol. 2010;29:(3):162S-186S. 46 Panel Book Page 65

76 77. Andersen FA (ed). Final safety assessment for PCA and Sodium PCA. Int J Toxicol. 1999;18:(Suppl 2): Burnett CL, Fiume MM, Bergfeld WF, Belsito DV, Klaassen CD, Liebler DC, Hill RA, Marks JG, 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 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. 2007;26:(Suppl 3): Fiume MM, Bergfeld WF, Belsito DV, Klaassen CD, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report on the safety assessment of sodium cetearyl sulfate and related alkyl sulfates as used in cosmetics. Int J Toxicol. 2010;29:(Suppl 2):115S-132S. 81. Andersen FA (ed). Final report on the safety assessment of sodium lauraminopropionate and sodium lauriminodipropionate. Int J Toxicol. 1997;16:(Suppl 1): Robinson VC, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Marks JG, 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:(Suppl 3):151S-161S. 83. Elder RL (ed). Final report on the safety assessment of sodium laureth sulfate and ammonium laureth sulfate. J Am Coll Toxicol. 1983;2:(5): Elder RE (ed). Final report on the safety assessment of sorbic acid and potassium sorbate. J Am Coll Toxicol. 1988;7:(6): Robinson VC, Bergfeld WF, Belsito DV, Klaassen CD, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Amended safety assessment of tall oil acid, sodium tallate, potasstium tallate, and ammonium tallate. Int J Toxicol. 2009;28:(Suppl 3):252S-258S. 86. Melnick RL and Tomaszewski KE. Triethanolamine. Chapter: 7.6. Buhler DR and Reed DJ.In: Ethel Browning's Toxicity and Metabolism of Industrial Solvents. Vol. II: Nitrogen and Phosphorus Solvents. 2nd ed. Amsterdam/New York/Oxford: Elsevier; 1990: Rohmann C and Wischniewski T. Sulfur-containing esters of morpholinoethanol and thiomorpholinoethanol. Archives der Pharmazie und Berichet der Deutschen Pharmazeutischen Gesellschaft. 1959;292: ACD/Labs. Advanced Chemistry Development (ACD/Labs) Software (8.19):As cited in Chemical Abstracts Services Registry. Date Accessed Yuan XL, Jiang S, and Mei X. Hydroxyl ammonium ionic liquids: Synthesis, properties, and solubility of SO2. Jorunal of Chemical & Engineering Data. 2007;52:(2): Personal Care Products Council. Updated concentration of use of triethanolamine Unpublished data submitted by the Council (3 pp). 47 Panel Book Page 66

77 Data

78 What The Where COSMETIC Personal Care Products Council Committed to Safety, Qualify & Innovation Memorandum TO: FROM: F. Alan Andersen, Ph.D. Director - INGREDIENT REVIEW (CIR) John Bailey, Ph.D. Industry Liaison to the CIR Expert Panel DATE: December 10, 2010 SUBJECT: Comments on the Draft Reports on Triethanolamine, Diethanolamine and Ethanolamine Prepared for the December 13-14, 2010 CIR Expert Panel Meeting Memo - Rather than Acute (Single Dose) Toxicity and Repeated Dose Toxicity, the sections should be titled Acute (Single) Dose Exposure and Repeated Dose Exposure. Acute and Repeated Dose describe the exposure rather than toxicity. Triethanolamine p.1 - is missing from the following sentence? The crude is later separated by distillation. p.1 - It would be helpful to indicate where in the report the in vivo studies of NDELA formation are presented. p.2 - The meaning of the following sentence is not clear, Accordingly, depending on storage and application conditions, aerosolized TEA may be a liquidlvapor instead of a particle. Aerosol products will produce aerosols. For compounds that are part of the formulation that have relatively high vapor pressures, the more important exposure will likely be inhalation of a vapor rather than inhalation of the aerosol. p.2 - Where did the information on use from Health Canada come from? The website listed in reference 13 (the Canadian Hotlist) was checked and use information for individual ingredients is not included on this website. p.3 - first two paragraphs of the Absorption, Distribution, Metabolism and Excretion study are describing the same study. Reference 16 is the unpublished version of the dermal study described in reference 17. p.4- - was the TEA-glucuronide found (reference 20)? p.6 - How was the 90-day NOAEC for local irritation calculated, e.g., using safety factors or modeling? p.7 - Searching the internet indicates that syntanol DC-b is CAS alcohols Cb0-18 ethoxylated. p.9 - LLNA s are not in vitro studies. They are considered alternatives because they reduce distress. As LLNAs are useful for quantitative risk assessment., please include the doses used in this study th Street, N.W., Suite 3OO Washington, D.C (fax) Panel Book Page 67

79 As The In Were It The Vehicle It These p.10 - the human studies described in the summary of the original report single patch tests or repeated patch tests? Were the subjects patients or volunteers with no dermal conditions? p.10 - Were the subjects tested in reference 15 patients with dermatological conditions? p.11 - would be helpful if the information on in vivo N-nitrosodiethanolamine formation were presented as a subsection under Absorption, Distribution, Metabolism and Excretion. p.11 - Please present the carcinogenicity mechanism information as a subsection under Carcinogenicity. p.12 - exposure information should be presented in the Cosmetic Use section and the cancer evaluation should be the last item presented in the Carcinogenicity section. p.13, Table 1 - Please provide the references for this Table. p.14, 15 reference 19 and reference 38 - two references are the same. Diethanolamine p.2 - there are inhalation data on Diethanolamine, is the aerosol boilerplate information necessary? p.2-3, It is not clear why the in vitro dermal penetration data is presented in two different subsections. p.4 - Please defined PC and PE the first time they appear. p.s - In the description of reference 20 should 5 mi/kg bw be 5 mg/kg bw as the units for the rest of the doses are mg/kg? p.s - i.v. study described in reference 22 appears to be the same study as that described in reference 20. Please provide the dose used in reference 20. = p.6 - Please change The percutaneous absorption of cosmetic formulations... to The percutaneous absorption of DEA in cosmetic formulations... p.8 - In the description of reference 30, should ppm be mg/kg? The units in the rest of the paragraph are mg/kg. p.9 - the summary of the inhalation data from the original report, please give the duration of the short-term inhalation exposure. p.10 - It would be helpful if the 45-day inhalation study were presented before the 90-day inhalation studies. p.10 - In reference 35, were any dermal effects observed in the male mice treated with Diethanolamine? Were there any effects on the number of offspring? p.11 - not specified is not necessary for reference 40, 41, an inhalation study. p.13 - LLNA s are not in vitro studies. They are considered alternatives because the reduce distress. As LLNAs are useful for quantitative risk assessment, please include the doses used in this study. p.13 - The internet indicates that FORAFAC 1203 is an additive used in portable fire extinguishers. As it is not possible to tell which component resulted in the sensitization, this study is not very helpful and can be deleted. p.14 - would be helpful if the information on in vivo N-nitrosodiethanolamine formation were presented as a subsection under Absorption, Distribution, Metabolism and Excretion. p.16 - Please present the carcinogenicity mechanism information as a subsection under Carcinogenicity. 2 Panel Book Page 68

80 Where LLNA s If The - Please p.17 - the OSHA and ACGIH values are presented, they should be cited to OSHA and ACGIH references, respectively. The NIOSH Safety Card (link from the On-Line) indicates that OSHA does not have a Permissible Exposure limit for Diethanolamine. NIOSH has a recommendation of 3 ppm. p.17 - IARC cancer review should be moved to the end of the Carcinogenicity section. p.18, Table 1 provide references for this table. Ethanolamine p.1 - did the information on use from Health Canada come from? The website listed in reference 5 (the Canadian Hotlist) was checked and use information for individual ingredients is not included on this website. p.6 - are not in vitro studies. They are considered alternatives because the reduce distress. p.6 - Please provide OSHA and ACGIII references for the exposure limits. p.7, Table 1 - Please provide references for this table. 3 Panel Book Page 69

81 COSMETIC Personal Care iproducts Council Committed to Safety, Quality & Innovation Memorandum TO: FROM: DATE: SUBJECT: F. Alan Andersen, Ph.D. Director - NGREDIENT REVIEW (CW) John Bailey, Ph.D. Industry Liaison to the CIR Expert Panel May 17, 2011 Updated Concentration of Use by FDA Product Category: TEA Containing Ingredients th Street, N.W., Suite 3O0 Washington, D.C (fax) Panel Book Page 70

82 Concentration of Use by FDA Product Category TEA-Hydrochloride, TEA-Sulfate, TEA-Undecylenate, TEA-Laurate, TEA-Laurate/Myristate, TEA-Myristate, TEA-Palmitate, TEA-Stearate, TEA-Isostearate, TEA-Sorbate, TEA-Oleate, TEA-Canolate, TEA-Cocoate, TEA-Hydrogenated Cocoate, TEA-Rosinate, TEA-Tallate, TEA-Lactate, TEA-Diricinoleate, TEA-Glyceryl Dimaleate, TEA-Salicylate, TEA-EDTA, TEA-Myristaminopropionate, TEA-Lauraminopropionate, Di-TEA Cocamide Diacetate, Di-TEA-Palmitoyl Aspartate, TEA-Cocamide Diacetate, TEA-Cocoyl Alaninate, TEA-Cocoyl Glutamate, TEA-Cocoyl Glutaminate, TEA-Cocoyl Glycinate, TEA-Cocoyl Sarcosinate, TEA-Hydrogenated Tallowoyl Glutamate, TEA-Lauroyl Glutamate, TEA-Lauroyl Methylaminopropionate, TEA-Lauroyl/Myristoyl Aspartate, TEA-Lauroyl Sarcosinate, TEA-Oleoyl Sarcosinate, TEA-Palm Kernel Sarcosinate, TEA-PCA, TEA-Lauroyl Lactylate, TEA-PEG-50 Hydrogenated Castor Oil Succinate, Magnesium/TEA-Coco-Sulfate, Sodium/TEA C12-13 Pareth-3 Sulfate, Di-TEA-Oleamido PEG-2 Sulfosuccinate, TEA-Lauryl Sulfate, TEA-Laneth-5 Sulfate, TEA-Laureth Sulfate, TEA-Oleyl Sulfate, TEA-C1O-15 Alkyl Sulfate, TEA-C11-15 Alkyl Sulfate, TEA-C12-13 Alkyl Sulfate, TEA-C12-14 Alkyl Sulfate, TEA-C12-15 Alkyl Sulfate, TEA C14-17 Alkyl Sec Sulfonate, TEA-Coco-Sulfate, TEA-C11-15 Pareth Sulfate, TEA-C12-13 Pareth-3 Sulfate, TEA-PEG-3 Cocamide Sulfate, TEA-Lauryl Phosphate, TEA-C12-13 Alkyl Phosphate, TEA-C12-14 Alkyl Phosphate, TEA-Dimethicone PEG-7 Phosphate, TEA-Laureth-4 Phosphate, TEA-Tridecylbenzenesulfonate, TEA-Dodecylbenzenesulfonate, TEA-Cocoyl Hydrolyzed Collagen, TEA-Alginate, TEA-Isostearoyl Hydrolyzed Collagen, Sodium/TEA-Lauroyl Collagen Amino Acids, Sodium/TEA-Lauroyl Hydrolyzed Collagen, SodiumITEA-Lauroyl Hydrolyzed Keratin, Sodiurn/TEA-Lauroyl Keratin Amino Acids, Sodium/TEA-Undecylenoyl Alginate, Sodium/TEA-Undecylenoyl Carrageenan, Sodiuni/TEA-Undecylenoyl Collagen Amino Acids, Sodium/TEA-Undecylenoyl Hydrolyzed Collagen, SodiumJTEA-Undecylenoyl Hydrolyzed Corn Protein, Sodium/TEA-Undecylenoyl Hydrolyzed Soy Protein, Sodium/TEA-Undecylenoyl Hydrolyzed Wheat Protein, TEA-Abietoyl Hydrolyzed Collagen, TEA-Cocoyl Hydrolyzed Soy Protein, TEA-Dextrin Octenylsuccinate, TEA-Lauroyl Collagen Amino Acids, TEA-Lauroyl Hydrolyzed Collagen, TEA-Lauroyl Keratin Amino Acids, TEA-Myristoyl Hydrolyzed Collagen TEA-Oleoyl Hydrolyzed Collagen, TEA-Undecylenoyl Hydrolyzed Collagen, TEA-Acrylates/Acrylonitrogens Copolymer, TEA-Acrylates/Ethylhexyl Acrylate Copolymer, TEA-Carbomer, TEA-Diethanolaminoethyl Polyisobutenylsuccinate, TEA-Diricinoleate/IPDI Copolymer and Triethanolamine Polyoxyethylene Alkylphenylether Phosphate Ingredient Product Category Concentration of Use TEA-Hydrochloride Shampoos (noncoloring) 0.5% TEA-Sulfate Shampoos (noncoloring) 0.2% TEA-Laurate Skin cleansing (cold creams, cleansing lotions, 8% liquids and pads) TEA-Palmitate f Shaving cream (aerosol, brushless and lather) 14% TEA-Stearate Shaving cream (aerosol, brushless and later) 9% TEA-Lactate Face and neck creams, lotions and powders 0.06% Di-TEA-Palmitoyl Aspartate f Other personal cleanliness products 0.4% TEA-Cocoyl Glutamate Bubble baths 3% TEA-Cocoyl Glutamate Other bath preparations 3% TEA-Cocoyl Glutamate Shampoos (noncoloring) 8% Page 1 of 3 Panel Book Page 71

83 - TEA-Cocoyl Glutamate Bath soaps and detergents 5% TEA-Cocoyl Glutamate Other personal cleanliness products % TEA-Cocoyl Glutamate Shaving cream (aerosol, brushless and lather) 4% TEA-Cocoyl Glutamate Skin cleansing (cold creams, cleansing lotions, 2-4% liquids and pads) TEA-Cocoyl Sarconsinate Shampoos (noncoloring) 2% TEA-Cocoyl Sarconsinate Other personal cleanliness products 2 5% TEA-Cocoyl Sarconsinate Shaving cream (aerosol, brushless and lather) 1% TEA-Cocoyl Sarconsinate Skin cleansing (cold creams, cleansing lotions, 4% liquids and pads) TEA-PCA Face and neck creams, lotions and powders 1% TEA-PCA Moisturizing creams, lotions and powders 0.3% TEA-Lauryl Sulfate Bubble baths 12-15%...U; TEA-Lauryl Sulfate Other fragrance preparations 4%.. TEA-Lauryl Sulfate Hair conditioners % TEA Lauryl Sulfate Shampoos (noncoloring) % TEA-Lauryl Sulfate Tonics, dressings and other hair grooming aids % TEA-Lauryl Sulfate Hair dyes and colors (all types requiring caution statement and patch test) 2% TEA-Lauryl Sulfate Bath soaps and detergents 5-30% TEA-Lauryl Sulfate Other personal cleanliness products % TEA-Lauryl Sulfate Shaving cream (aerosol, brushless and lather) 2% TEA-Lauryl Sulfate Skin cleansing (cold creams, cleansing lotions, 2-40% liquids and pads) TEA-Lauryl Sulfate Body and hand creams, lotions and powders 0.3% TEA-Lauryl Sulfate Foot powders and sprays 8% TEA-Lauryl Sulfate Moisturizing creams, lotions and powders 0.2% TEA-Lauryl Sulfate Other skin care preparations 4 6% TEA-Laureth Sulfate Bath oils, tablets and salts 3% TEA-Laureth Sulfate Shampoos (noncoloring) 14% TEA-Laureth Sulfate Hair tints 6% Page 2 of 3 Panel Book Page 72

84 TEA-Laureth Sulfate 5 Other personal cleanliness products 9% TEA-Laureth Sulfate Skin cleansing (cold creams, cleansing lotions, 3% liquids and pads) TEA-Dodecylbenzenesulfonate Hair conditioners % TEA-Dodecylbenzenesulfonate Shampoos (noncoloring) % TEA-Dodecylbenzenesulfonate Tonics, dressings and other hair grooming aids 0.8% TEA-Dodecylbenzenesulfonate Hair tints 6% TEA-Dodecylbenzenesulfonate Bath soaps and detergents % TEA-Dodecylbenzenesulfonate Skin cleansing (cold creams, cleansing lotions, 0.9% liquids and pads) TEA-Cocoyl Hydrolyzed Collagen Hair conditioners 0.3% TEA-Abietoyl Hydrolyzed Collagen Masacara 0.3% TEA-Abietoyl Hydrolyzed Collagen Hair conditioners 0.2% TEA-Abietoyl Hydrolyzed Collagen Shampoos (noncoloring) 0.2% TEA-Abietoyl Hydrolyzed Collagen Tonics, dressings and other hair grooming aids 0.4% TEA-Abietoyl Hydrolyzed Collagen Foundations % TEA-Cocoyl Hydrolyzed Soy Protein TEA-Cocoyl Hydrolyzed Soy Protein Hair conditioners Shampoos (noncoloring) 0.001% % TEA-Cocoyl Hydrolyzed Soy Protein Tonics, dressings and other hair grooming aids 0.005% TEA-Cocoyl Hydrolyzed Soy Protein Hair dyes and colors (all types requiring caution % statement and patch test) TEA-Lauroyl Collagen Amino Acids Tonics, dressings and other hair grooming aids 0.4% *Ingredients included 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. 13% in a body wash and shower gel 25% in a make-up removing mousse 35% in a shower gel; 11% in a body wash 6% in a rinse-off product 59% in a body wash Information collected in 2011 Table prepared March 14, 2011 Table updated May 16, 2011 TEA-Lauryl Sulfate: added hair dyes and colors; TEA-Cocoyl Hydrolyzed Collagen: added ingredient Page 3 of 3 Panel Book Page 73