BLUE TEA CIR EXPERT PANEL MEETING SEPTEMBER 26-27, 2011

Transcription

1 BLUE TEA CIR EXPERT PANEL MEETING SEPTEMBER 26-27, 2011

2 Memorandum To: CIR Expert Panel Members and Liaisons From: Monice M. Fiume MMF Senior Scientific Analyst/Writer Date: September 1, 2011 Subject: Draft Final Amended Safety Assessment on Triethanolamine (TEA) and TEA-Containing Ingredients as Used in Cosmetics Included is the draft Final Amended Safety Assessment on TEA and TEA-Containing Ingredients as Used in Cosmetics. This re-review was opened in December, when TEA was split from the report on TEA, DEA, and MEA. In June, the list of ingredients included in the re-review was narrowed to include only those for which a read-across approach was applicable. Also at that meeting, the Expert Panel issued a Tentative Amended Safety Assessment that concluded the TEA and TEA-containing ingredients are safe when formulated to be non-irritating. The Panel included the caveat that cautions these ingredients should not be used in cosmetic products in which N- nitroso compounds are formed. While not disagreeing in principle, this caveat prompted a comment from the Council. (See the Nitrosamine Formation Boilerplate Language memo.). The Council is concerned that the language used in the June conclusion regarding N-nitroso formation implies that some cosmetic products are formulated to form N-nitroso compounds. The Council has requested that, instead, the wording The Expert Panel cautions that products containing there ingredients should be formulated to avoid the formation of nitrosamines. (This request also applies to the conclusions of the safety assessments that were issued for the DEA and DEA Amides reports.) Since avoiding formation of nitrosamines is the goal, the Panel should again address what language it wants to use to achieve that goal. The Panel also established that TEA and TEA-containing ingredients should not contain DEA at levels above those considered safe in the amended safety assessment of DEA. The Panel purposefully did not name those levels, but stated that the amount of free DEA must be limited to no more than that considered safe by the Panel. The Council commented that, as there is more than one CIR report on DEA, it would be helpful to state which CIR report on DEA the reader should consult for the limit on DEA. In response to this comment, as described in the most current CIR report on DEA has been added to the Discussion. It is expected that the Panel will discuss this comment and issue a Final Amended Safety Assessment at this meeting.

3 CIR Panel Book Page 1

4 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 27-28, 2011: Re-Review Draft Report The RR of TEA was presented to the Panel, including 93 ingredients for review as possible addons The Panel created a list of 32 ingredients to be included in this re-review. A Tentative Amended Safety Assessment was issued on these ingredients with the following conclusion: safe as used when formulated to be non-irritating; were the ingredients not in current use to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group; these ingredients should not be used in cosmetic products in which N-nitroso compounds are formed. September 2011: Draft Final Amended Safety Assessment CIR Panel Book Page 2

5 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, identifying newly posted studies 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) CIR Panel Book Page 3

6 ( OR OR ) AND (METBOLI* OR ABSORB* OR ABSORP* OR DISTRIBUT* OR EXCRET*) 403 (Toxline); 18 (DART) AND CARCINOGEN* AND CHOLINE - 0 Total Download (most duplicates removed): 1218 UPDATED SEARCH Sept 21, 2010 last 12 mos OR OR hits/1 useful CIR Panel Book Page 4

7 TEA, TEA-Ingredients, and Components Data Profile* Sept 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 Magnesium/TEA-Coco Sulfate Sodium/TEA C12-13 Pareth-3 Sulfate TEA-Alginate 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-C11-15 Pareth Sulfate TEA-C12-13 Pareth-3 Sulfate TEA-Canolate TEA-Coco Sulfonate TEA Cocoate X TEA-Glyceryl Dimaleate TEA-Hydrochloride X TEA-Hydrogenated Cocoate TEA-Isostearate X TEA-Lactate 1998 TEA-Laurate X X TEA-Laureth Sulfate X TEA-Laurate/Myristate TEA-Lauryl Sulfate 1982 X X X X X X X TEA-Myristate X TEA-Oleate X TEA_Palmitate X TEA-PEG-3 Cocamide Sulfate TEA-Sorbate TEA-Stearate 1995 X X TEA-Sulfate X TEA-Tallate TEA-Undecylenate CIR Panel Book Page 5

8 TEA, TEA-Ingredients, and Components Data Profile* Sept 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 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 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 Plant-Derived Fatty Acid Oils 2011 X X X Sodium Cetearyl Sulfate and Related Alkyl Sulfates 2010 X X X X X X X 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 CIR Panel Book Page 6

9 Transcripts

10 June 2011 Meeting Belsito Team DR. BELSITO: No, no, that's just part of the discussion. The conclusion is safe as used when formulated to be nonirritating. Anything else on the DEA amides? Okay. Believe it or not, the last one, TEA. Okay. So, again, in December, we agreed to split these all up and this is the TEA report. And basically, at this point it's just everything in the dictionary that had to do with TEA. And where do we want to go with that? The Council has reviewed it and suggested that some things be deleted because they were previously reviewed. And I would disagree with that, so stuff like TEA laurate. Again, I think, you know, if they belong in the family they belong in the family. Let's get them in there and not have to deal with isolated reports in the future. And -- but then the question is, whether the families if we're doing TEA, what belongs under the TEA? So, I would cede to Dan to tell us which of these families -- the inorganic acids, the organic acids, the hydroxides, the amides, et cetera, et cetera -- should be under the TEA family. And I guess I was assuming that the amides and everything else aren't, since we already didn't do it for DEA. But, Dan, tell us what to do. DR. LIEBLER: Okay. So, I guess I hadn't thought about this, but I guess I can accept your reasoning on including things that have been reviewed previously because I got a bunch of flags on this to try and eliminate the things that have been previously reviewed. So, I'm fine with keeping them in. In that case, the rosinate -- TEA rosinate needs to come out because the rosins we don't have much information on. Inorganic acid salts are fine, the other organic acid salts are fine. Those are all fatty acids, except for the rosinate. The hydroxy acid salts, I think, are fine. I'll say perhaps the salicylates -- salicylate has already been -- DR. BELSITO: Reviewed. DR. LIEBLER: Yeah, it's already been reviewed. It's not really that chemically analogous, I suppose. I mean, the salicylate itself has a lot of its own chemistry and biology. So that's one reason I would think that the properties of this compound might be more driven by the salicylate than the TEA piece. DR. BELSITO: Then let's take it out. It's already been reviewed. DR. LIEBLER: Yeah. DR. BELSITO: Okay. DR. LIEBLER: I don't know in the case of the amine and amino acid salts, I think the issue might be that we -- I don't know to what extent the amino acid properties drive these. I tend to look at most of these amino acids; just my gut instinct is that they're pretty innocuous. But we haven't reviewed them, so I can't say that. So, I could say delete the amine and amide acid salts. DR. BELSITO: Okay. DR. LIEBLER: And the -- for the organo- substituted inorganic acid salts, we've got the phosphates I would take out, because they're the -- for the same reason we talked about the alkyl phosphates before. They haven't been reviewed. And also, the polysaccharide and protein salts, I'd probably take out the TEA cocoyl hydrolyzed collagen, TEA alginate, sodium TEA lauryl, collagen amino acids, and TEA isostearoyl hydrolyzed collagen. DR. BELSITO: So we're taking out that entire group? DR. LIEBLER: That whole group, I'm sorry. That whole group, yeah. Next page. Right? DR. BELSITO: The polymer salts, too? I mean, again -- DR. LIEBLER: Yeah. DR. BELSITO: -- these are supposed to be no- brainer issues. DR. LIEBLER: I don't think the polymer salts are no-brainers, either. DR. BELSITO: Okay. So -- and the aryl sulfonate salts? Both of them have already been reviewed? DR. LIEBLER: Right. CIR Panel Book Page 7

11 DR. BELSITO: Do they belong in the family, though? Sounds like from what we said before with DEA, they probably don't. DR. LIEBLER: No. DR. BELSITO: And since they've both been reviewed, get rid of them? DR. LIEBLER: I think so. DR. BELSITO: Okay. So, with the organo- substituted inorganic acids, you're saying get rid of all of the phosphates? DR. LIEBLER: Yes. DR. BELSITO: Okay. Now, the Scientific Committee, for reasons I don't understand -- and maybe Carol can comment -- wanted us to get rid of TEA lauryl sulfate, TEA C12-13 alkyl, TEA C12-14 alkyl, but they didn't say anything about TEA C10-15, 11-15, and 12-15, and And then, TEA dimethicone PEGs -- well, that's a phosphate. But they left other phosphates in. So, Carol, what was driving that? DR. EISENMANN: They probably were just omitted not on purpose. The intent was to get rid of the -- to be consistent with the DEA report, where you removed the phosphates. DR. BELSITO: So, in other words, they made a mistake in their note when they said C12-13 alkyl sulfate? They made alkyl -- they meant alkyl phosphate? Or I made a mistake when I was crossing things out? Yeah, I made the mistake. Sorry. Okay. So we're getting rid of all the phosphates, keeping all of the sulfates. What about the sulfonate, the TEA C14-17 alkyl sulfonate? And the PEG 2 sulfosuccinate? SPEAKER: (inaudible) DR. BELSITO: What? I didn't see that on the SSC list. And -- DR. LIEBLER: To err on the side of caution, I would dump the sulfosuccinate. DR. BELSITO: Okay. DR. LIEBLER: And the sulfonate. DR. BELSITO: Okay. And what about the pareth-3 sulfate? DR. LIEBLER: I think that can probably stay. DR. BELSITO: Okay. So then -- DR. LIEBLER: That's just a substituent position, I think, so. DR. BELSITO: Okay, so, we're keeping the two inorganic salts listed. We're keeping all of the organic acid salts listed, except for the rosinate for reasons that the rosin derives that. We're keeping the hydroxy salts except for the TEA salicylate, which we're getting rid of. And that includes the two that have previously been reviewed in those three categories, the TEA laurate and the TEA lactate we're bringing into the report. We're getting rid of all the amine and amide acid salts -- DR. EISENMANN: One comment on that one. You're getting rid of TEA lauraminopropionate where you left in DEA lauraminopropionate. I just prefer you be consistent, don't you think? DR. BELSITO: We're getting rid of that whole group. DR. EISENMANN: Right, right. DR. BELSITO: This is not the amide. DR. EISENMANN: But you left -- I mean, this is the insufficient data -- I mean, sodium lauraminopropionate is insufficient data. You left DEA lauraminopropionate in the DEA report, where you're going to list the DEA -- all the insufficients -- CIR Panel Book Page 8

12 DR. BELSITO: But that was DEA amides, Carol. DR. EISENMANN: No. DR. BELSITO: Yes. It's not the DEA report -- they -- what we left the DEA lauraminopropionate -- DR. EISENMANN: Is in the DEA report. DR. BELSITO: -- is in the DEA amide report, no. It's in this report. DR. EISENMANN: It's in the DEA report, isn't it? DR. BELSITO: No. There are two reports. There's a DEA report and the DEA amide. MS. FIUME: I think it's in the DEA, because it was actually -- it was a salt. But it's in the DEA. Because this group here is a different combination than just the amides. DR. BELSITO: Okay. Well, then I apologize. So, why is the TEA lauraminopropionate listed under an amide here -- an amine amide? Because it's an amine, of course. Okay, duh. Sorry. DR. LIEBLER: An acid salt, right. DR. BELSITO: It's getting late, folks. DR. LIEBLER: Yes. DR. BELSITO: Well, so then, in the TEA -- then the real issue is, in the DEA report we included DEA amines with DEA. In this report, we are excluding the amines? I mean, they got listed under the same category. DR. LIEBLER: You can't have TEA amides because they're tertiary, so it's chemically not possible. So that's why there's a disconnect. DR. BELSITO: Well, but there's TEA lauraminopropionate. Is that not an amide? DR. LIEBLER: That's where -- lauraminopropionate is the acid part and the TEA is the base part, the salt, to give you the salt. DR. BELSITO: Right. DR. EISENMANN: Does it make sense to leave it in the DEA report and take it out of this one? DR. LIEBLER: So I'm getting punchy. We left it in the DEA report as the salt? DR. EISENMANN: Yes. DR. BELSITO: Yes. DR. LIEBLER: And that's the one where we decided we're going to go insufficient? DR. BELSITO: Right. DR. LIEBLER: Okay. Then, to be consistent we leave it in here and say, insufficient. DR. BELSITO: So then do we include TEA myristaminopropionate? DR. LIEBLER: Yeah, same reason. Probably the same problem, too. DR. BELSITO: So, are there any other aminopropionates here? So, we're including the amine salts but not the acid salts? Okay. The ester acid salts we're not including, and everything else we're not including. Is that correct? Or no, wait a minute. I'm sorry. The ester acid salts, are we keeping those two, TEA lauroyl lactylate and PEG 50 hydrogenated castor oil succinate? CIR Panel Book Page 9

13 DR. LIEBLER: Well, the lauroyl lactylate is probably fine. The hydrogenated castor oil succinate -- DR. BELSITO: Or are these no-brainers? Would the data for TEA support -- and having reviewed constituents -- DR. LIEBLER: No. I would say the hydrogenated castor oil succinate would probably be the tail wagging this particular dog. DR. BELSITO: Okay. And what about the lauroyl lactylate? DR. LIEBLER: I'm not sure what the structure is of that, what the lactylate is. DR. BELSITO: Okay. DR. LIEBLER: Is it a lactic acid derivative? DR. BELSITO: Beyond me. So -- DR. LIEBLER: Let's put a Post-It on that one, I'll come back to it. DR. BELSITO: Okay. DR. LIEBLER: I'll look it up while we're talking. DR. BELSITO: Okay. And then we are keeping in some of the organo-substituted inorganic acids. We're getting rid of all of the phosphates. We're keeping all of the sulfates and we're getting rid of the sulfosuccinate and the sulfonate. Okay. And then all the other groups, we're getting rid of. All the others. DR. BERGFELD: We're getting rid of the alkyl sulfonates, too? DR. BELSITO: We're getting rid of the aryl sulfonates, the polysaccharide and protein salts, and the polymer salts. Yeah, the aryl sulfonates, they've both been reviewed. And the feeling is that the decylbenzenesulfonate groups will be important there and they're not necessarily no-brainers. Plus, they've already both been reviewed. DR. LIEBLER: Carol just showed me the TEA lauroyl lactylate. That's a very large acid component. And again, I think it would be driving the properties of this much more than the TEA is. DR. BELSITO: So we're getting -- DR. LIEBLER: So I would say these two ester acid salts, the hydrogenated castor oil succinate and the lauroyl lactylate can be deleted. DR. BELSITO: Okay. So, we're going ahead with the TEA report. And in addition to TEA, we're doing the two inorganic salts, we're doing all of the organic acid salts listed except for the rosinate, we're doing all of the hydroxy acid salts listed except for the TEA salicylate. Under the amine and amide acid salts, we're doing TEA myristaminopropionate and lauraminopropionate, knowing that they may go insufficient. All of the others, we're not including. We're deleting both ester acid salts listed. We're including some but not all of the organo-substituted inorganic acids. The ones we're not including are any with phosphate, the sulfonate, and the sulfosuccinate. MS. FIUME: Dr. Belsito? So I'm clear, the sulfonate that you're not including is the TEA C DR. BELSITO: Alkyl sec=sulfonate and the sulfosuccinate is the di-tea oleamido PEG 2 sulfosuccinate. MS. FIUME: I believe the alkyl sec-sulfonate were reviewed in the alkyl PEG ethers report. Isn't that correct? I'm pretty sure they were -- DR. BELSITO: If they were, they weren't listed by the Council as being previously reviewed. because I circled everything that the Council said was previously reviewed. MS. FIUME: Not TEA C14-17 alkyl sec-sulfonate. But there were alkyl sec-sulfonates, I believe, that were in that report. So would that count as previous data? CIR Panel Book Page 10

14 DR. BELSITO: I think what we're trying to do now is go back to the original definition that the add-ons should be relatively no-brainers. And not necessarily dependent upon the fact that we have previously reviewed something and we might be able to sneak it into the report. MS. FIUME: Okay. Because I was going to say -- DR. BELSITO: Is that right, Dan? That was your thinking? DR. LIEBLER: Yeah, that's right. DR. BELSITO: Okay. DR. BRESLAWEC: DR. Belsito, the triethanolamine diester TEA diricinoleate? DR. BELSITO: Where are you? I'm sorry. DR. BRESLAWEC: It's the third category, after organic acid salts and right before hydroxy acid salts on page 1, left-hand side? DR. BELSITO: I'm sorry. I'm -- triethanolamine, I'm just not following what you're saying there. DR. BRESLAWEC: Are we including that or not? DR. BELSITO: Which one? DR. SNYDER: The diester. DR. BELSITO: Okay. I'm -- diester -- DR. BRESLAWEC: Okay, you have a different list. DR. BELSITO: I'm -- DR. LIEBLER: Yeah, that's really pretty different. That's actually interesting, because that's an ester with a hydroxyl group from the triethanolamine on two of the three hydroxyls hanging off the -- or the TEA. So that's actually a different -- really a different beast. DR. BELSITO: Which I'm not -- DR. BRESLAWEC: You know what, you're looking at a different list and I think we had recommended taking it out and just didn't in this particular one. Because if you look on page 2 of the administrative section -- DR. BELSITO: Oh, this is in the report? DR. BRESLAWEC: Yeah, this is actually in the report. It's there, but not there. DR. LIEBLER: It's also listed under the hydroxy acid salts on the Council memo. It's the TEA diricinoleate. DR. BELSITO: Okay. Yeah, the TEA diricinoleate. So why were there two different lists? I didn't even look at the list in the report. I looked at the list -- DR. SNYDER: You're looking under the Council -- DR. BELSITO: Yeah. Okay. DR. EISENMANN: On the attached list, the memo is what was on the CIR website originally of what the ingredients were and they did rearrangement. DR. BELSITO: Okay. So, I mean, I'm assuming that -- well, I'll have to go back and compare. But that other than the triethanolamine diester, pretty much the list I was using is the same list that was here? CIR Panel Book Page 11

15 DR. BRESLAWEC: I think it's the same list. It may have been categorized slightly differently. DR. LIEBLER: Slightly differently. DR. BELSITO: Okay. DR. BRESLAWEC: That's the only difference. DR. BELSITO: Okay. Okie-doke. So, we're also getting rid of the triethanolamine diester. Is that correct? DR. SNYDER: Yes. DR. BELSITO: Yes, okay. And then, we'll be going out safe as used with all -- when formulated not to be irritating with similar caveats that we had for the DEA nitrosamines. There were some inhalation uses here, correct? And so the inhalation boilerplate. DR. LIEBLER: Don, we're just checking out a couple other structures to make sure we haven't missed anything that ought to be thrown out. DR. BELSITO: Okay. DR. BERGFELD: Are you developing a discussion, then, to put the inhalation boilerplate in it? DR. BELSITO: Yes. I'm -- discussion. MS. FIUME: DR. Liebler, while you are looking, the myristaminopropionate I think it is, we do not have any previous reports on that, just so that you're aware. DR. LIEBLER: Okay. MS. FIUME: And I want to say that was thrown out at the original DEA report, but I don't have that original list in front of me. DR. BELSITO: So the discussion is the inhalation boilerplate, impurities, nitrosamine formation. And I'm getting so confused between the DEA amides -- this -- these -- there was also some sensitization issues here, no? This is TEA, okay. Yeah, no. MS. FIUME: I don't think it was a sensitizer. DR. BELSITO: Yeah, no, definitely not a sensitizer. I guess irritation -- yeah. TEA can be a dermal irritant in both animals and humans, but it's not been shown to be a sensitizer. So I think that would be the issue and with such a large group where we don't have irritation data on a lot of them, I think the conclusion should say, "when formulated not to be irritating." But otherwise, "safe as used when formulated not to be irritating." And then the discussion as we just reviewed those points in the discussion. MS. FIUME: DR. Belsito, for the impurity portion of the discussion, should it refer to something as no more DEA allowed than what's allowed in our current report? DR. BELSITO: Yes. MS. FIUME: Okay. DR. BELSITO: I mean, I think that's the issue with all of these, is the NDELA. DR. LIEBLER: Whenever you're ready, I have one more to delete from the organo-substituted inorganic acid salts group. DR. BELSITO: Too late. (Laughter) DR. LIEBLER: And it's never too late to delete a big steroid. This would be the laneth-5 sulfate. CIR Panel Book Page 12

16 DR. BELSITO: And why that and not the laureth sulfate? DR. LIEBLER: So the laureth -- they sound very similar, don't they? DR. BELSITO: Yeah, they do. DR. LIEBLER: Yeah, they do. But picture is worth -- structure is worth a thousand words. Anyway, the laneth is basically - - is a sort of steroid-like structure with a sulfonate -- sulfate. It's -- I would delete it for the fact that it's really not analogous to these straight- chain alkyl or slightly branched alkyl derivatives that we've been mostly including. I don't know if the laneth -- if the laneth molecule has been reviewed and evaluated by CIR, but it's very different and the -- again, I would say that the chemistry of that molecule is mainly driven by the laneth sulfate rather than the TEA. DR. BELSITO: Okay. I mean, I think even if it's been reviewed, I think we ve acknowledged our mistake with the DEA report adding in the dodecylbenzenesulfonate, which we can do because they've been reviewed and they're okay. DR. LIEBLER: Right, yeah. DR. BELSITO: But when we're creating these families, they should be based off of no-brainers, based on whatever the parent compound is. And if there's something added to that parent compound that adds another -- DR. LIEBLER: Right. DR. BELSITO: -- dimension, then we shouldn't be adding it in. DR. LIEBLER: So the laureth sulfate is okay, in my book. I don't think we've decided to delete that. DR. BELSITO: Nope, not unless you want us to, Dan. DR. LIEBLER: No. DR. BELSITO: Dan, you're the man. DR. LIEBLER: Okay. MS. FIUME: Could I ask a question about one more? We deleted the TEA salicylate, but not the TEA lactate. Correct? DR. BELSITO: Correct. MS. FIUME: When giving a conclusion, because TEA lactate is an alpha hydroxy acid which had some sun sensitivity built into the conclusion, does that need to be taken into consideration and giving it a different conclusion or will that not play a role? DR. BELSITO: Well, I think the issue with the lactic is really irritation. As we discussed before, and we're coming in as a total category with this, with when formulated not to be irritating. Whereas I think with salicylate you have issues of absorption and salicylism and issues that go beyond what you'd be concerned about with just lactic acid. I don't know, what was your -- DR. KLAASSEN: I agree, it should come out, the salicylate. I mean, you have also, you know -- with the salicylates you at least theoretically have the GI effects. It's also known that salicylates can have effects to the skin, per se. So, I think we should just leave that out. DR. BELSITO: Okay. Any other order of business? MS. FIUME: I do have just one more question since MEA is on its way? DR. BELSITO: Yes. MS. FIUME: And Dr. Liebler, maybe this might be addressed to you. Do you still want to see MEA in the same way as -- bring everything and then pare it down? DR. BELSITO: Yeah. CIR Panel Book Page 13

17 DR. LIEBLER: Right. MS. FIUME: Okay. DR. LIEBLER: We'd like the opportunity to pick and choose. DR. BELSITO: Okie-doke. Dr. Mark s Team DR. MARKS: A little bit still (inaudible) there. So, again, just to refresh everybody's memory, in the memo on these, in 1983, TEA along with DEA and MEA where it's concluded to be safe as long as they were for discontinuous brief use. Concentration should not exceed 5 percent, and they do not contain any nitrosating agents. And, so, we have potentially 93, and 8 of them have been reviewed. So, let me see, page 20, I don't know if you want to do this, Ron, don't know whether you want to go to page 20 and 21 of the panel book or you want to go to the back, where it has every structure and we go down those pages, as we did before and eliminated by structure. DR. HILL: Well, we have a memo from the CIR Science and Support Committee, discussing why they think we ought to limit, and they have a list. I'm not sure it's all inclusive of the things that they would think ought to be removed. And, pretty much, I totally agree with what they suggested. Which isn't going to make the author of this draft report happy, but -- SPEAKER: Monice? MS. FIUME: Well, you know, it was actually very much written down that you wanted to see everything and -- DR. HILL: I know. SPEAKER: That's why (inaudible). DR. HILL: I think there's a strong merit of having a list of -- DR. MARKS: Yes. DR. HILL: -- the components that have TEA as a counterion. Stronger to that, but I agree with the memo. DR. MARKS: So, do you want to go on to page 20 and 21 and eliminate? So, the inorganic salts are okay. That should be pretty easy, right? DR. HILL: Yes. DR. MARKS: The organic acid salts, of which one has already been reviewed and approved. Are they all okay? DR. HILL: I'm looking to see what they did. This sort of, to me, on some of those presented a chicken and the egg scenario. We'll just review it from a TEA perspective or review it from a fatty acid perspective and they can come to any conclusions, but most of these are cases where I don't think there are any problems with either component. DR. MARKS: Yes. DR. HILL: Or even if we talk about the ion pair issue that we raised earlier for DEA, I don't think that's probably presenting a problem for most of these. So, I didn't come to a clear conclusion, and I didn't strike out; I just wrote in big letters that I agreed with what the Science and Support Committee recommended, and that still left a few that I thought could come out. DR. MARKS: So, organic acids, Ron, Tom, they're all okay? DR. SLAGA: Should be okay. DR. SHANK: Let me see, I have all these codes. And I have to -- what they mean. Yes, those are okay. DR. MARKS: So, let's go to the diester, that's a single compound? DR. SHANK: Yeah. DR. MARKS: That's okay? CIR Panel Book Page 14

18 DR. SHANK: Yes. DR. MARKS: Hopefully, the hydroxy acid salts are okay since they've already been reviewed. DR. SHANK: Yes. DR. MARKS: The amine and amid acid salts, one of those, the TEA-EDTA was reviewed. The rest of these, okay? DR. SHANK: Well, I have eight of them where the counterion has not been reviewed. That's what you call it, the -- DR. HILL: Yes, counterion. DR. MARKS: So, if that isn't reviewed, we can't do a read-across with that. DR. SHANK: That's what I would say. DR. MARKS: So, which ones would you eliminate? DR. SHANK: Well, that would be di-tea-palmitoyl. SPEAKER: Palmitoyl aspartate. DR. SHANK: Thank you. That one. DR. MARKS: Yes. DR. SHANK: TEA-cocoyl glycinate. DR. MARKS: Hold it a second. So, TEA. Go on. SPEAKER: Palmitoyl aspartate. DR. MARKS: Why am I missing on here? SPEAKER: It's under the amino amides salts; it's the fourth one down. DR. MARKS: Oh, yes, okay, right below. Okay, cocoyl glycinate. Okay, eliminate that. DR. SHANK: You go ahead, that's -- SPEAKER: No, you got to march. DR. SHANK: Okay, then the next one, TEA-cocoyl glycinate. Cocoyl glycinate hasn't been reviewed. DR. MARKS: Right. DR. SHANK: TEA-cocoyl -- SPEAKER: Alaninate. DR. MARKS: Alaninate, okay. DR. SHANK: I need new teeth or something. TEA-hydrogenated tallowoyl glutamate. DR. MARKS: Okay. DR. SHANK: TEA-lauroyl glutamate. DR. MARKS: Okay. DR. SHANK: TEA-lauroyl/myristoyl aspartate. DR. MARKS: Okay. SPEAKER: And he's going right down the Science and Support Committee list, by the way, right now. I have to check. DR. MARKS: Okay. CIR Panel Book Page 15

19 DR. SHANK: It is? DR. MARKS: Good. SPEAKER: Yes. DR. SHANK: Okay. TEA-cocoyl glutamate. DR. MARKS: Yes. DR. SHANK: And the next one, glutaminate. DR. MARKS: Yes. DR. SHANK: That's for that group. DR. MARKS: So, let me see, I have one, two, three, four, five, six, seven, eight. DR. SHANK: That's it. DR. MARKS: Okay. And then let's go on to the ester acid -- DR. SHANK: Oh, okay. DR. MARKS: Ester acid salts, okay. DR. SHANK: Yes. DR. MARKS: And then the inorganic acid salts sulfates and sulfonates. And three of those have been reviewed. DR. SHANK: Correct. DR. MARKS: And they're all okay? DR. SHANK: Yes. DR. MARKS: Okay, the phosphates? DR. SHANK: All of those can go. DR. MARKS: Can we eliminate it? SPEAKER: Yes. DR. SHANK: Yes. DR. MARKS: The whole group? DR. SHANK: Yes. DR. MARKS: Okay. That's one, two, three, four, five, six. Okay. And then the polysaccharide and protein salts. DR. SHANK: Okay, the alginate, the second one. DR. MARKS: Okay. DR. SHANK: The fourth one, sodium/tea-lauroyl collagen amino acids. DR. MARKS: Yes. DR. SHANK: Two more down, sodium/tea-lauroyl hydrolyzed keratin. DR. MARKS: Okay. DR. SHANK: Sodium/TEA-lauroyl keratin amino acids. DR. MARKS: Yes. CIR Panel Book Page 16

20 DR. SHANK: Sodium/TEA -- I'm not knowing -- SPEAKER: Undecylenoyl. DR. SHANK: Thank you. SPEAKER: Undecylenoyl. DR. MARKS: Alginate. DR. SHANK: That one. DR. MARKS: The alginate again, okay. DR. SHANK: Okay. Sodium/TEA-undecylenoyl collagen amino acids. DR. MARKS: And the one above that's okay, Ron? DR. SHANK: Yes, carrageenan, we have that one. DR. MARKS: Okay. DR. SHANK: Okay, good grief. Sodium/TEA- undecylenoyl hydrolyzed soy protein, and the one below that, hydrolyzed wheat protein. DR. MARKS: Okay. DR. SHANK: TEA-cocoyl hydrolyzed soy protein. DR. MARKS: Yes. DR. SHANK: TEA-lauroyl collagen amino acids. TEA-lauroyl keratin amino acids. And I have two more here that aren't on the list with question marks, so I found these someplace. TEA-diricinoleate, which we have, but this is also IPDI copolymer. So, that appeared someplace in here, but it's not on the list. DR. MARKS: So, where -- DR. SHANK: Somewhere in this report, I found that. Because I simply wouldn't have picked that up on my own. And then the last one that's not on the list, triethanolamine polyoxyethylene alkylphenyl ether phosphate, which would probably be eliminated anyway. DR. MARKS: So, the polymer salts are fine? DR. SHANK: No, I have three of those to take off. DR. MARKS: Oh. Okay. DR. SHANK: TEA-acrylates/acrylonitrogen copolymer. DR. MARKS: Yes. DR. SHANK: TEA-acrylates/ethylhexyl acrylate copolymer. TEA-diethanolaminoethyl polyisobutenylsuccinate. DR. MARKS: Okay. Ron Hill, did you have anything to add? Did that include all that the scientific panel? DR. HILL: I think it did. Let me crosscheck, but -- DR. MARKS: So, really, the only group which is totally eliminated was the phosphates. DR. SHANK: Correct. DR. MARKS: And the others, there are a number of ones that are, I guess -- let's see how we reconcile that with the teams tomorrow. I'm not sure I want to go through the tongue twisting you just did, Ron Shank. DR. HILL: No, I -- DR. MARKS: Well, I know, Ron, I had it here. Probably Monice and I are the ones that have them all crossed off here that you just read. So, you're -- CIR Panel Book Page 17

21 DR. HILL: I'm not sure my list with comprehensive because I was trying to crosscheck. So, anyway. DR. MARKS: So, these would be the ones we will eliminate. DR. SHANK: I'll practice tonight. MS. FIUME: Can I ask, so, there's no concern about the lauroyl aminopropionate insufficient data? DR. HILL: Yes, we need -- MS. FIUME: It would just be dealt with as insufficient based on the old report or should it be removed from the re-review? DR. SHANK: Oh, that's right. It should be removed then. DR. MARKS: So, which ones? DR. SHANK: Lauryl -- MS. FIUME: Lauryl -- DR. MARKS: Lauryl propionate, okay, TEA or aminopropionate. DR. SHANK: Oh, I know why, because there's the dipropionate that I wanted to ask the chemists will they accept the iminodipropionate data for the aminopropionate. And the answer's no. DR. MARKS: Okay. So, this is going to be the -- no, let's go back. Is this a reopen, Alan? I guess it is. DR. ANDERSEN: I think the fact that we already reopened it. DR. MARKS: Yes. So, this would be a tentative. DR. ANDERSEN: I imagine. DR. MARKS: Yes. DR. ANDERSEN: At the risk of snatching defeat in the jaws of victory, the end of the CIR SSC memo says they recommend taking out TEA laurate because it's already been reviewed, the way I read, and there's a TEA salicylate, yadda, yadda, a bunch of things. That struck me as odd because those are reports that provide supporting information. DR. SHANK: Right. DR. MARKS: Right. MS. LORETZ: Yes, no. Yeah, I think that's an error. DR. ANDERSEN: So, those we'll leave in, I think. DR. MARKS: So, tentative amended report for the conclusion these are safe. We can put non-irritating in the conclusion. DR. SHANK: Yes. DR. MARKS: Safe, non-irritating, and I guess I could do the math of how many we have now. So, do we have -- whatever, it's a lot. DR. SHANK: (inaudible) count. DR. MARKS: Yeah, there's going to be something probably close to around 85, I would guess, to 80. discussion? Okay, anything in terms of the DR. SHANK: In the discussion. DR. ANDERSEN: In the reprise, a lot of the same issues. DR. MARKS: Yeah, I was going to say. DR. SHANK: Mm-hmm. DR. ANDERSEN: (inaudible) in the last two bullets. CIR Panel Book Page 18

22 DR. HILL: And one of the writers or toxicologists explained to me animals were killed due to severe hydration before study termination. MS. FIUME: It's supposed to be dehydration. DR. HILL: Okay, I assumed. I just wanted to -- MS. FIUME: Sorry. DR. HILL: Okay, because there (inaudible). I just want to be sure -- MS. FIUME: They got flooded with water (inaudible) because that happens. DR. HILL: I learn new things massively at every one of these meetings. MS. FIUME: I'm sorry, it's supposed to be dehydration. DR. HILL: So, I try to keep an open mind. DR. MARKS: Twenty-four. By my counts, 93 minus 24. We'll see if that works out. Oh, that's significant, 69. I'll put approximately. Sixty-nine. You can confirm what the numbers are specifically. How do you want to proceed now -- DR. SLAGA: Does that include the two that Ron found that were not included? DR. MARKS: Well, no, I didn't. Do you want to put those -- are they going to be included or not included? DR. SHANK: I just had a question mark about the required to be on this. DR. MARKS: One you said don't include. DR. SHANK: Well, it's one of these phosphates. DR. MARKS: Yes. DR. SHANK: So, it's probably going to be -- DR. MARKS: So, do we -- DR. SHANK: -- tossed out anyway, but -- DR. MARKS: Do you want me to write it here so that we have a -- DR. SHANK: Let me see why I -- DR. MARKS: Is that TEA? What is the name of that one? DR. SHANK: The phosphate? DR. MARKS: Yes. DR. SHANK: Okay, it's very long, triethanolamine. DR. MARKS: TEA, okay. DR. SHANK: Polyoxyethylene. DR. MARKS: Polyoxyethylene. DR. SHANK: Polyoxyethylene. Alkylphenyl ether. DR. MARKS: Alkylphenny ether, okay. DR. SHANK: Phosphate. DR. MARKS: Ether phosphate. DR. SHANK: The other one was DEA-diricinoleate. DR. MARKS: And which compound was that? That sounds like that comes over with Polysaccharide and Protein Salts. CIR Panel Book Page 19

23 DR. SHANK: Well, we have it under triethanolamine diester. We have here the -- DR. MARKS: Ester. DR. SHANK: The diricinoleate. DR. MARKS: Oh, yes, okay. DR. SHANK: But this one is the same with the slash after diricinoleate. DR. MARKS: Okay. DR. SHANK: IPDI copolymer. DR. MARKS: Di-copolymer, okay. DR. SHANK: Now, where did I get that? MS. FIUME: That is on the list from industry. DR. SHANK: From industry. To take it off or put it in? MS. FIUME: To take it off. DR. SHANK: Take if off? MS. FIUME: Yes. DR. SHANK: Huh? Okay. MS. FIUME: Well, it may have gotten somehow put off in our double column format. And I apologize. DR. MARKS: Yes. Now, with that, this raises, for me, an interesting question. Ten years from now, we could obviously go to the minutes and see which ones were eliminated. Is that the only place it's going to be captured is the minutes? And it may be that's the correct when thinking about going back. MS. FIUME: That's what's been precedent. DR. MARKS: Yes, okay. Okay, so, tentative, it'll actually be the Belsito Team that will make the motion, but we will hopefully support a tentative amended report, which finds these ingredients safe, as long as being formulated non-irritating, and it's approximately 69 ingredients found on page 20 and 21 of the Panel Book. Does that sound good? And the discussion is going to be a la DEA, TEA, and just reiterate -- DR. SHANK: Those concerns. DR. MARKS: -- discussion. DEA and -- okay. MS. FIUME: I do have a question though for the nitrose and nitroso formation. DR. SHANK: Yes, I do, too. MS. FIUME: Is it the same concerns or is it because of DEA impurity and the TEA? DR. SHANK: Well, one is TEA can be nitrosating agent. MS. FIUME: Okay. DR. SHANK: Okay. The nitrosation write-up here is inaccurate. So, I've made some changes. MS. FIUME: Okay. DR. SHANK: It says that TEA can react with nitrite or oxygens, nitrogen. Actually, it's nitrogen hydride that nitrosates TEA. And the amides, it's nitosation of ion. There's also on the next page, page 3, it says (inaudible) alkylamines do not tend to form nitrosating agents. That's not true. I have added four references. MS. FIUME: Okay. CIR Panel Book Page 20

24 DR. SHANK: There's a difference between in vivo nitrosation and in vitro. You're right, in vivo, it's not a concern, but the nitrosation reaction is very, very weak, but in vitro, that's not the case, and we are concerned with the in vitro in formulations. DR. SHANK: Okay. That's it. DR. MARKS: Now, so, we don't need to repeat in the conclusion that these TEA compounds should not be used as an ingredient in cosmetic products in which N nitroso compounds are formed? DR. SHANK: Yes. DR. MARKS: Should that be -- DR. SHANK: That should be there. DR. MARKS: Okay. DR. HILL: I had a general question while we're visiting the subject. We're not working on the boilerplate for this meeting, correct? DR. SHANK: Right. DR. HILL: When we say "formulated," are we also taking into account and do we need to take into account storage conditions or containers or that sort of thing? When we say "formulated," to be where nitrosamines can't be formed, does that include containers and storage and all of that? Or we could just -- DR. SHANK: Not specifically. DR. HILL: -- defer that discussion until -- yes. DR. SHANK: We'll have to handle that with the -- DR. HILL: Okay, okay. DR. SHANK: Are their containers that -- DR. HILL: Yes, I think there are -- DR. SHANK: -- favor nitrosation? DR. HILL: I think there are. DR. SHANK: Oh. DR. HILL: And that's discussed somewhere in one of these briefly. DR. SHANK: Okay. DR. MARKS: Ron, I'm going to go back just for a minute to clarify on the DEA report where we said DEA is safe and we did the related salts. Do the N nitroso compounds caveat on that, also? DR. SHANK: Yes. DR. MARKS: That was before. We do. Okay. So, nitroso. I'm just going to put in here N nitroso compounds boilerplate for the conclusion. Is that okay? DR. SHANK: Yes. DR. MARKS: So, really, all these, whether it's DEA, DEA amides, or a TEA, I'm going to get to amino, they all have to have the N nitroso compounds -- DR. SHANK: Pretty much for all secondary amines. DR. MARKS: Right. Okay. DR. HILL: Did we lose Monice to the other room? MS. BURNETT: Yes. DR. HILL: Okay. CIR Panel Book Page 21

25 Full Panel Thank you. Unanimous. Then moving on to the last in this group and that is Dr. Belsito with TEA. DR. BELSITO: Yes, okay, so this is a result of everything you've heard report, splitting the report, ethanolamine reports, and coming back with TEA and then the question is, what could we tag onto TEA? So, let me address that first. So, obviously TEA, we felt we could add the inorganic acid salts, the two listed there. We felt that we could add all of the organic acid salts as listed in the table with the exception of TEA rosinate. The hydroxy acid salts we felt we could add with the exception of TEA salicylate because we thought salicylate would have its own issues on the skin. We did not think -- DR. MARKS: Don, so the TEA salicylate was previously reviewed, is that correct? DR. BELSITO: It was previously reviewed, but -- and found to be safe, but we didn't really want to group it into this group. DR. MARKS: Okay. You didn't want to -- DR. BELSITO: It's already -- DR. LIEBLER: So, it's not that it would have any issues, it's just that it doesn't really fall into this group where the driving characteristics -- the characteristics should be driven by the TEA part. DR. BELSITO: Under the amine and the amide salts we felt that the amides should not be included in the group. The amines could be, the major issue is that there are only two of them -- TEA-myristaminopropionate and lauraminoproprionate and we know that lauraminoproprionate is going to be an issue, so we felt that those should be left out, so essentially all the amines and the amides would be left out. The ester acid salts would be left out, the organo-substituted inorganic acid salts could be added with the exception of all of the phosphates for the same reason that we did with the DEA report, not include the phosphates, and also not include the sulfosuccinate and the sulfonates, so the di-tea-oleamido PEG-2 sulfosuccinate and the TEA C14-17 alkyl sec sulfonate would not be part of the group. And then all of the others would also not be part of this group. We did notice that we had included the dodecylbenzene sulfonates in the DEA report. In retrospect those had both already been reviewed and approved and, again, Dan did not feel that the driving force there was TEA, but more the benzenesulfonate group. So we decided not to include it in this report, admitting our mistake in the DEA for making it part of that family, but they were already reviewed and found to be safe anyway. And with those additions, and the ones that we're not going to include, we felt, again, as with all the ethanolamine reports, safe as used, not irritating, nitrosation boilerplate, inhalation boilerplate, so pretty much the same discussion we're creating for all the ethanolamine reports. DR. BERGFELD: Are you putting the nitrosating -- DR. BELSITO: Yes, in the conclusion -- DR. BERGFELD: -- in the conclusion? DR. BELSITO: If that's how we've done it before. DR. BERGFELD: Okay. DR. MARKS: We largely concur on the ingredients. I would just say -- ask you, Monice, to go through my book and make sure it matches. I think you actually may have eliminated a few more than we did, but that's okay. Obviously we want to err on -- if we don't want to spend a lot of discussion in terms of what to include and what not to include. DR. BERGFELD: So, you're seconding the motion? DR. MARKS: Second the motion. DR. BERGFELD: All right. DR. MARKS: For this -- CIR Panel Book Page 22

26 DR. BERGFELD: Any other discussion? DR. MARKS: -- amended report. DR. BERGFELD: Excuse me. All right, any other comments? I'll call for the question -- DR. ANDERSEN: Before we vote I just want to confirm with my colleague, you got the list? MS. FIUME: I believe I do. DR. BELSITO: I can give it one more time if you want for clarification. DR. MARKS: Well, you can look on your book, Don. I mean, you have it clearly. (Laughter) DR. BELSITO: My book is really marked up. Okay, so both of the inorganic salts, all of the organic salts except TEArosinate, the hydroxy acid salts, we're getting rid of just TEA-salicylate. DR. BRONAUGH: Dr. Belsito, what about the TEA- diricinoleate? DR. BELSITO: That's the one that wasn't in my book. Yes, we're getting rid of that one as well. DR. LIEBLER: We're getting rid of that. That's a different structure. DR. BELSITO: Right. The diricinoleate. The hydroxy acid salts we're getting rid of TEA-salicylate. We're getting rid of the entire amine and amide acid salt group, the entire ester acid salt group, the organo- substituted inorganics, we're getting rid of all of the phosphates and we're getting rid of the sulfosuccinate and the sulfonate, and then all of the other groups we're deleting as well. MS. FIUME: I think the only one I was confused on from yesterday -- so, the TEA-dodecyl and tridecyl benzenesulfonates are not included. DR. BELSITO: They're not included. They were included in the DEA report as part of that, but they were both previously found to be safe. We felt since we're now constructing this family, that they really didn't belong in this family. CIR Panel Book Page 23

27 Report

28 Final Amended Report Triethanolamine (TEA) and TEA-Containing Ingredients as Used in Cosmetics September 26, 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 " CIR Panel Book Page 24

29 Table of Contents Abstract... 1 Introduction... 1 Chemistry... 1 Definition and Structure... 2 Method of Manufacture... 3 Stability... 3 Impurities... 3 N-Nitrosodiethanolamine Formation... 3 Use... 4 Cosmetic... 4 Non-Cosmetic... 5 Toxicokinetics... 5 In Vitro... 5 Dermal... 6 Non-Human... 6 Oral... 6 Non-Human... 6 Other... 6 Non-Human... 6 Toxicological Studies... 7 Acute (Single) Dose Toxicity... 7 Dermal... 7 Oral... 7 Other... 7 Repeated Dose Toxicity... 8 Dermal... 8 Oral... 8 Inhalation... 9 Reproductive and Developmental Studies... 9 Dermal... 9 Oral... 9 Genotoxicity In Vitro In Vivo Carcinogenicity Dermal Oral Possible Mode of Action for Carcinogenic Effects of TEA Carcinogenic Potential in Humans Irritation and Sensitization Dermal Irritation In Vitro Non-Human Human Sensitization Non-Human Human Provocative Testing Phototoxicity/Photoallergenicity Non-Human Human Ocular Irritation In Vitro Non-Human Clinical Assessment Case Reports Summary Discussion Conclusion 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 ii CIR Panel Book Page 25

30 ABSTRACT The CIR Expert Panel assessed the safety of triethanolamine (TEA) and 31 related TEA-containing ingredients as used in cosmetics. TEA is reported to function as a surfactant or ph adjuster; the related TEA-containing ingredients included in this safety assessment are reported to function as surfactants and hair or skin conditioning agents. The exception is TEA-sorbate, which is reported to function as a preservative. The Panel reviewed available animal and clinical data. While data were not available for all ingredients, the Panel relied on the information available for TEA in conjunction with previous safety assessments of components of TEA-containing ingredients. Those data could be read-across to support the safety of all included ingredients. The Panel concluded that TEA and the related TEA-containing ingredients named in this report are safe as used when formulated to be nonirritating. These ingredients should not be used in cosmetic products in which N-nitroso compounds are formed. INTRODUCTION In 1983, the Cosmetic Ingredient Review (CIR) Expert Panel issued a report on the safety of Triethanolamine, Diethanolamine, and Monoethanolamine. In 2010, the Panel decided to reopen that safety assessment as three separate reports and to include related ingredients in each of the new reviews. This assessment addresses triethanolamine (TEA) and 31 related TEA-containing ingredients. TEA, an ingredient reported to function as a surfactant or ph adjuster in cosmetic products, previously had 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 in 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 31 ingredients are also included in this safety assessment of TEA. These ingredients are reported to function in cosmetics as surfactants, skin conditioning agents, or hair conditioning agents. TEA-sorbate is reported to function only as a preservative. Inorganic salts TEA-Hydrochloride TEA-Sulfate Organic acid salts TEA-Laurate TEA-Laurate/Myristate TEA-Myristate TEA-Palmitate TEA-Stearate* TEA-Isostearate TEA-Undecylenate TEA-Sorbate TEA-Oleate TEA-Canolate TEA-Cocoate TEA-Hydrogenated Cocoate TEA-Tallate TEA-Glyceryl Dimaleate 1 Hydroxy Acid Salts TEA-Lactate* Organo-Substituted Sulfates Magnesium/TEA-Coco-Sulfate Sodium/TEA C12-13 Pareth-3 Sulfate TEA-Lauryl Sulfate* TEA-Laureth Sulfate TEA-Oleyl Sulfate 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-Coco-Sulfate TEA-C11-15 Pareth Sulfate TEA-C12-13 Pareth-3 Sulfate TEA-PEG-3 Cocamide Sulfate The ingredients marked with an asterisk have been previously reviewed by the CIR, and the conclusions of safety on these ingredients are provided in Table 1. The safety of many of the components of these ingredients has been reviewed by CIR, and these conclusions are also 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 CIR Panel Book Page 26

31 (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. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine 1 Of concern in cosmetics is the conversion (N-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 N-nitrosating agents to directly form nitrosamines. 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). 2 The resultant secondary amine (i.e. DEA) can then be N-nitrosated (i.e. to N-nitrosodiethanolamine [NDELA]). Accordingly, TEA can react, in a formulation or in vivo, with nitrites or oxides of nitrogen to form a nitrosamine. Nitrous anhydride is the oxide of nitrogen that most commonly initiates nitrosation in vivo. 3-6 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 Organo-Substituted Sulfates The sulfates consist of organic acid salts which have the additional functional group of sulfate. For example, TEA lauryl sulfate is a twelve carbon alkyl chain (i.e. lauryl) bonded to a sulfate anion, balanced with a triethanolammonium cation (Figure 3). Figure 3. TEA-Lauryl Sulfate Definition and Structure The definitions and structures of TEA and TEA-containing ingredients are provided in Table 2. Chemical and physical properties are described in Table 3. 2 CIR Panel Book Page 27

32 TEA Method of Manufacture 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. 7 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. 8 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 aqueous (aq.) TEA. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 9 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. 10 TEA-Stearate Stability TEA stearate was produced as described previously. On cooling, a lamellar gel phase formed. 11 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. 12 (Additional details were not provided). 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. 9 Sodium sulfate and residual alcohols may be present as impurities in commercial alkyl sulfate products. 10 industrial alkyl sulfates contain 1-4% sodium sulfate and % residual alcohol. N-Nitrosodiethanolamine Formation Nitrosamines are compounds containing the R 1 R 2 N-NO functional group. 2 Typically, N-Nitrosation is the process of converting organic compounds (e.g., alkyl amines) into N-nitroso derivatives (e.g., nitrosamines) by reaction with nitrosating agents. These agents include nitrous acid (HNO 2 ), oxides of nitrogen (e.g., nitrous anhydride or nitrite), and other compounds capable of generating a nitrosonium ion, NO +2. vivo. 13 The formation of a specific nitrosamine, NDELA, from reaction of TEA with nitrite was examined in vitro and in The TEA used in these studies had an impurity content of 0.4% DEA. In an 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 CIR Panel Book Page 28

33 inoculum) media. (The percent nitrosation was determined using values that were corrected for DEA impurity-related NDELA formation). In vivo, female B6C3F 1 mice were dosed dermally or orally with 1000 mg/kg TEA, in conjunction with oral exposure to sodium nitrite. 13 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 is reported to function in cosmetics as a surfactant or ph adjuster, and it can be used in fragrances. 14 Most of the other TEA ingredients are reported to function in cosmetics as surfactants, skin conditioning agents, or hair conditioning agents. TEA-sorbate is reported to function only as a preservative. Voluntary Cosmetic Registration Program (VCRP) data obtained from the FDA in 2011 indicate that TEA is used in 3756 formulations; 3023 of those products are leave-on formulations, and 3100 formulations involve dermal exposure. 15 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 %. 16 In leave-on products, the reported use concentrations range from %. With the exception of TEA-lauryl sulfate (302 uses) and TEA-stearate (130 uses), all other in-use TEA-containing ingredients had less than 20 reported uses. 15 TEA-lauryl sulfate had the highest concentrations of use, with 40% being reported for rinse-off and 8% for leave-on formulations. 17 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 the 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. 18 Using an EC algorithm method, the dermal exposure of consumers to TEA in an eye make-up powder is mg/kg bw/day and to TEA in 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. Some of the ingredients reviewed in this assessment may be applied to baby skin, used near the eye area or mucous membranes, or could possibly be ingested. TEA, TEA-lauryl sulfate, and TEA-stearate are 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, the list of substances which cosmetic products must not contain except subject to the restrictions and conditions laid down. 19 The ingredients reviewed in this safety assessment, as trialkylamines, trialkanolamines, and their salts, are allowed at concentrations of up to 2.5% in nonrinse-off products; other product types do not have a concentration limit for TEA. 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. Sorbic acid and its salts and undec-10-enoic acid and its salts, including their ethanolamine salts, are listed by the EC for use as preservatives, with maximum concentrations of use of 0.6 and 0.2%, respectively, based on the free acid CIR Panel Book Page 29

34 According to data obtained from Health Canada, some leave-on type products reportedly use TEA as high 10 and 30%, with some reporting concentration ranges of % (Health Canada, personal communication). TEA Non-Cosmetic 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 TEA, TEA-myristate, TEA-palmitate, TEA-oleate, TEA-cocoate, and TEA-tallate have uses as an indirect food additive. 21 TEA is used as a rust inhibitor in water-based metalworking fluids. 22 TOXICOKINETICS Dermal absorption studies of TEA were performed in vitro using human skin samples and in vivo using mice and rats. In vitro, the absorption of TEA through human skin was low under conditions simulating perceived cosmetic use, i.e., 1-5% at ph 7.0; approximately % of the dose was recovered in the skin after 24 or 72 h, only ~0.5% was recovered in the receptor fluid. 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. In rats 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. In Vitro TEA and TEA-Stearate The penetration of oil-in-water (o/w) emulsions containing TEA was determined in vitro using human skin samples. 23 Emulsions were prepared using 1% TEA and 5% stearic acid and using 5% TEA and 10.5% stearic acid; the ph values of these emulsions were 8.0 and 8.2, respectively. Because the ph values of commercial lotions containing TEA were reported to be ~7.0, emulsions were also prepared with the ph adjusted to 7.0. The test samples were applied to the skin for 24 h at a concentration of 3 mg/cm 2, and the area of exposed skin was 0.64 cm 2. Penetration and absorption was measured at 24 h using the emulsions with a ph of ~8, and at 24 and 72 h using the emulsions with a ph of 7.0. The 24-h skin sample was tape-stripped, while the 72 h sample was not. Using the emulsions with a ph of ~8, there was no statistically significant difference in penetration between a 1 or 5% TEA emulsion; the total TEA recovered in the skin was 20.9 and 15.4% of the applied dose for the 1 and 5% TEA emulsions, respectively, and the amount recovered in the receptor fluid was 1.1 and 1.2% of the applied dose, respectively. Using the emulsion with a ph of 7 and concentration of 1% TEA, there was no statistically significant difference in penetration observed when comparing the 24 and 72 h values; 9.4 and 8.9% of the applied dose was found in the skin and 0.43 and 0.68% of the applied dose was found in the receptor fluid at 24 and 72 h, respectively. There was a statistically significant difference in the total recovery of TEA using the 5% emulsion, ph 7, at 24 h compared to that recovered at 72 h. At this concentration, the amounts found at 24 and 72 h were 5.5 and 6.3% of the total dose, respectively, in the skin and 0.28 and 0.60% of the applied dose, respectively, in the receptor fluid. The researcher stated that all of the TEA in a TEA/stearic acid emulsion presumably existed as the TEA stearate salt, since an excess of stearic acid was used. Radiolabeled TEA stearate was prepared by mixing stearic acid with a radiotracer dose of 0.64 µci [ 14 C]TEA (5 µg TEA) in an o/w emulsion; the ratio of TEA to stearic acid was 1:4. Using this emulsion, at ph 8.2, 50.1% of the applied dose of TEA-stearate was found in the skin and 0.51% in the receptor fluid after 24 h. 5 CIR Panel Book Page 30

35 With ph 7.0, 29.1% of the applied dose was found in the skin and 0.46% in the receptor fluid after 24 h. The researchers stated that the data suggest that the penetration rate of the TEA molecule determines the penetration of its salts. Dermal 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. 24 (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 mg/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 application and 6-11% for the occluded application. The National Toxicology Program (NTP) examined the ADME of TEA following dermal administration to B6C3F 1 mice and F344 rats. 25 With mice, groups of 4 females were given a single dose of 79 or 1120 mg/kg [ 14 C]TEA in acetone; 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. 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. 26 (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. 24 (Non-radiolabeled TEA was 99.6% pure; radiochemical purity was 98.6%). 6 CIR Panel Book Page 31

36 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 after 24 h was 3.1%. The NTP examined the ADME of TEA following i.v. administration to B6C3F 1 mice and F344 rats. 25 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. 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 2000 mg/kg bw neat was applied for 13 wks; irritation was observed at the dosing site. Kidney weights were increased in males and females 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 were all killed due to severe dehydration before study terminations. Treatment-related changes were not observed for animals given 2 or 4% TEA in their water. Acute (Single) Dose Toxicity Dermal TEA 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 Oral TEA 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-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. 9 The oral LD 50 of TEA-lauryl sulfate in male and female Wistar rats was >2 g/kg. 27 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 7 CIR Panel Book Page 32

37 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. 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 and F344 rats, 5 days/wk. 28 Dose levels of TEA were 0.21, 0.43, 0.84, 1.69, and 3.37 g/kg for the mice and 0.14, 0.28, 0.56, 1.13, and 2.25 g/kg for rats. 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. 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 250, 500, 1000, or 2000 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 125, 250, 200, or 1000 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. 9 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 in both species. Some deaths occurred in groups of rats fed 0.3 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 8 CIR Panel Book Page 33

38 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 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 dose-range finding inhalation study, 5 male and 5 female Wistar rats were exposed, nose only, for 5 consecutive days to 100, 200, or 400 mg/m 3 TEA (target concentrations; 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). In 14-day inhalation studies, B6C3F 1 mice and F344 rats were exposed to 125, 250, 500, 1000, or 2000 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 developmental effects were seen in dermal studies in which rats and mice were dosed with 0.5 and 2 g/kg TEA, respectively, in acetone from before mating through lactation or in an oral teratogenicity screening test in mice with 1125 mg/kg/day TEA on days 6-15 of gestation. 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 effects were observed. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. 1 TEA, 0.5 g/kg in acetone (purity not stated), was applied dermally to clipped skin on the back of male and female F344 rats. 36 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 developmental 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 developmental effects were observed. 9 CIR Panel Book Page 34

39 TEA 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 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 TEA (88.2% purity) did not cause gene conversion in Saccharomyces cerevisiae. 40 TEA was negative in a rec assay at doses of µg/disk. No induction of sister chromatid exchanges occurred in Chinese hamster ovary 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 µg/ml in cultured Chinese hamster cells. 39,42 TEA, µg/ml, was negative in a cell transformation assay using hamster embryo cells. 39 In Vivo TEA 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 Results were negative in both male and female mice. CARCINOGENICITY In 2-yr dermal carcinogenicity studies with up to 1000 and 2000 mg/kg/day TEA in male and female mice, respectively, and up to 125 and 250 mg/kg/day TEA in male and female rats, respectively, 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. Based on preliminary data, it has been hypothesized that TEA may cause liver tumors in mice via a choline-depletion mode of action. Dermal TEA 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 200, 630, or 2000 mg/kg/day to male B6C3F 1 mice and at doses of 100, 300, or 1000 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 10 CIR Panel Book Page 35

40 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 32, 63, or 125 mg/kg/day in acetone to males and at doses of 63, 125, or 250 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. 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. 11 CIR Panel Book Page 36

41 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 10, 100, 300, or 1000 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 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. TEA Carcinogenic Potential in Humans 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 IARC is that TEA is not classifiable as to its carcinogenicity to humans (Group 3). In Vitro TEA IRRITATION AND SENSITIZATION The overall evaluation of the 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. Dermal 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. 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 12 CIR Panel Book Page 37

42 mice. 53 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. 1 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%. Concentrations of up to 10% produced slight to mild irritation, while concentrations of 25 and 39% produced moderate irritation. Mild irritation was reported with 40% TEA lauryl sulfate, while testing with 46% TEA-lauryl sulfate produced non-irritant results in some laboratories and irritant results in others. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 9 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. 54 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. 9 The dermal irritation potential of a 10% solution of TEA-lauryl sulfate (vehicle not identified) at neutral ph was determined using 10 subjects. 55 Duhring chambers were applied to the forearm of each subject for 5 days. A 10% solution of TEA-lauryl sulfate caused intense erythema in nearly all subjects by day 4. Testing was terminated. (Additional details were not provided). Sensitization Non-Human TEA 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 CIR Panel Book Page 38

43 BALB/c mice. 53 The sensitization potential of TEA was evaluated in a local lymph node assay (LLNA) performed with groups of 5 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 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. 22 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. 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. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 9 Provocative Testing petrolatum. 57 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 patients. Many of the patients allergic to TEA were also allergic to other ingredients. 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. 58 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 neg- CIR Panel Book Page 39

44 ative 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). Over a 15-yr period, provocative patch testing using TEA was performed on 85,098 dermatological patients. 22 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. Metalworkers that were dermatitis patients were patch tested with 2.5% TEA in pet 59 The patches were applied for 1-2 days. On day 3, one of 216 patients (0.5%) had a positive reaction. Patch testing was performed with 2.5% TEA in pet. in 184 patients with suspected metalworking fluid contact dermatitis. 60 (All patients were metalworkers.) Patches were applied for 1 or 2 days. On day 3, 4 patients had any type of positive reactions, 2 (?) and 2 (+). The % positive reactions was 1.1%. Phototoxicity/Photoallergenicity Non-Human TEA 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 Human TEA 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 TEA-Lauryl Sulfate In Vitro TEA Aq. shampoo formulations containing % TEA-lauryl sulfate were not photosensitizers in clinical studies. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 9 Ocular Irritation The ocular irritation potential of TEA was evaluated in several in vitro studies. The ocular irritation potential of TEA was evaluated in the rabbit corneal epithelium model at concentrations of 0.05, 0.5,and 1%; TEA was classified as non/mildly irritating at these concentrations. 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. 61 EYTEX/Draize equivalent of 42.1, corresponding to a prediction of severe ocular irritant. 62 Non-Human TEA In the EYTEX assay, undiluted TEA had an 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. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine CIR Panel Book Page 40

45 TEA-Lauryl Sulfate TEA 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%. The severity of irritation observed with each concentration varied among the studies, as illustrated by 5% TEA lauryl sulfate causing no ocular irritation in one study, but significant irritation in another. From the Final Report on the Safety Assessment of TEA-Lauryl Sulfate. 9 CLINICAL ASSESSMENT Case Reports Eczema of the face of 2 female patients was exacerbated by a cream that contained TEA. 63 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. Two cases of occupational asthma in metal workers exposed to cutting fluid containing TEA were reported. 64 Exposure to TEA at temperatures higher than that of ambient air was a common feature. TEA-PEG-3 Cocamide Sulfate of the shampoo. 65 Two patients with a reaction to a shampoo were patch tested with the ICDRG standard series and a 1% aq. solution Both patients had positive patch results to the shampoo only. Subsequent patch test with 1% aq. TEA- PEG-3 cocamide sulfate (as well as 1% cocamidopropyl betaine) 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 sulfate. SUMMARY This report is a safety assessment of TEA and TEA-containing ingredients as used in cosmetics. TEA is reported to function as a surfactant or ph adjuster, and the other TEA-containing ingredients as surfactants, skin conditioning agents, or hair conditioning agents. TEA-sorbate is reported to function only as a preservative. TEA is reported to be used in 3756 cosmetic ingredients at concentrations of up to 6% in leave-on formulations, 19% in rinse-off formulations, and 0.7% in products that are diluted for use. All the other ingredients named in this safety assessment that are in use, with the exception of TEA-lauryl sulfate (302 uses) and TEA-stearate (130 uses), are reported to have less than 20 uses. TEA may contain DEA as an impurity. The ingredients reviewed in this report, as trialkylamines, trialkanolamines, and their salts, are allowed for use by the EU at concentrations of up to 2.5% in leave-on products; other product types do not have a concentration limit for TEA. There are additional restrictions regarding conditions for use in leave-on and rinse-off products, including a maximum allowable secondary amine content of 0.5% in raw material and a maximum allowable nitrosamine content of 50 µg/kg. Dermal absorption studies of TEA were performed in vitro using human skin samples and in vivo using mice and rats. In vitro, the absorption of TEA through human skin was low under conditions simulating perceived cosmetic use, i.e., 1-5% at ph 7.0; approximately % of the dose was recovered in the skin after 24 or 72 h, however, only ~0.5% was recovered in the receptor fluid. 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. In rats, 19-28% of the dose was absorbed over a 72-h period, 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. 16 CIR Panel Book Page 41

46 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 2000 mg/kg bw neat was applied to rats for 13 wks, and irritation was observed at the dosing site. Kidney weights were increased in males and females 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 were all killed due to severe dehydration before study termination. 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 developmental effects were seen in dermal studies in which rats and mice were dosed with 0.5 and 2 g/kg TEA, respectively, in acetone from before mating through lactation or in an oral teratogenicity screening test in mice with 1125 mg/kg/day TEA on days 6-15 of gestation. 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 2-yr dermal carcinogenicity studies with doses of up to 1000 and 2000 mg/kg/day TEA for male and female mice, respectively, and up to 125 and 250 mg/kg/day TEA for male and female rats, respectively, 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. Based on preliminary data, it has been hypothesized 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. DISCUSSION While the Panel noted gaps in the available safety data for the 31 TEA-containing ingredients included in this group, the Panel relied on the information available for TEA in conjunction with previous safety assessments of the components of TEA-containing ingredients. Those data could be read-across to support the safety of these ingredients. For example, myristic acid has been found safe as used, and the Panel was able to extrapolate these data to support the safety of TEAmyristate (i.e., the TEA salt of myristic acid). Additionally, some of the ingredients reviewed in this assessment, such as TEA-lauryl sulfate, have previously been reviewed by the CIR and found to be safe for use in cosmetics. The Panel was concerned with levels of free DEA that could be present as an impurity in TEA or TEA-containing ingredients. The Panel stated that the amount of free DEA must be limited to no more than that considered safe by the Panel, as described in the most current CIR report on DEA. Dermal carcinogenicity studies performed by the NTP on TEA reported 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, and equivocal evidence of carcinogenic activity in male rats based on a marginal increase in the incidence of renal tubule cell adenoma. It has been hypothesized that TEA may cause liver tumors in mice via a choline-depletion mode of action. Humans are much less sensitive to this deficiency, and these hepatic findings are considered to have little relevance to humans regarding the safety of use of TEA in personal care products. 17 CIR Panel Book Page 42

47 The Expert Panel was concerned that the potential exists for dermal irritation with the use of products formulated using TEA or TEA-related ingredients. The Expert Panel specified that products containing these ingredients must be formulated to be non-irritating. Tertiary alkyl amines such as TEA do not react with N-nitrosating agents to directly form nitrosamines. However, tertiary amines can act as precursors in nitrosamine formation by undergoing nitrosative cleavage. The resultant secondary amine (i.e. DEA) can then be N-nitrosated to products that may be carcinogenic. Because of the potential for this process to occur, TEA and TEA-containing ingredients should not be used in cosmetic products in which N-nitroso compounds are formed. TEA, TEA-lauryl sulfate, and TEA-stearate are used in cosmetic products that may be inhaled during use. In practice, however, the particle sizes produced by cosmetic aerosols are not respirable. This is consistent with actual inhalation toxicity study results that raised no concerns about the use of TEA and TEA-containing ingredients in products that might be inhaled. CONCLUSION The CIR Expert Panel concluded that the 32 TEA and related TEA-containing ingredients listed below are safe in the present practices of use and concentration described in this safety assessment when formulated to be non-irritating. Were the ingredients not in current use (as indicated by *) to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group. These ingredients should not be used in cosmetic products in which N-nitroso compounds are formed. The ingredients reviewed in this safety assessment are: Triethanolamine Magnesium/TEA-Coco-Sulfate* Sodium/TEA C12-13 Pareth-3 Sulfate* 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-C11-15 Pareth Sulfate* TEA-C12-13 Pareth-3 Sulfate* TEA-Canolate* TEA-Cocoate TEA-Coco-Sulfate* TEA-Glyceryl Dimaleate* TEA-Hydrochloride TEA-Hydrogenated Cocoate* TEA-Isostearate TEA-Lactate TEA-Laurate TEA-Laurate/Myristate* TEA-Laureth Sulfate TEA-Lauryl Sulfate TEA-Myristate TEA-Oleate* TEA-Oleyl Sulfate* TEA-Palmitate TEA-PEG-3 Cocamide Sulfate* TEA-Sorbate* TEA-Stearate TEA-Sulfate TEA-Tallate* TEA-Undecylenate* 18 CIR Panel Book Page 43

48 TABLES Table 1. Conclusions of previously reviewed ingredients and components Ingredient Conclusion Reference TEA TEA-Lactate TEA-Lauryl Sulfate TEA Stearate Alkyl PEG Ethers 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 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 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 Ammonium Lauryl Sulfate Sodium Lauryl Sulfate Coconut Ingredients Isostearic Acid Lauric Acid Myristic Acid Oleic Acid Palmitic Acid Stearic Acid Plant-Derived Fatty Acid Oils Sodium Cetearyl Sulfate and Related Alkyl Sulfates Sodium Laureth Sulfate and Sulfated Ethoxylated Alcohols Sorbic Acid Tall Oil Acid 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 safe as used safe as used safe as used safe as used when formulated to be non-irritating safe as used safe as used , CIR Panel Book Page 44

49 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. TEA-Isostearate TEA-Isostearate is the triethanolamine salt of a branched, eighteen carbon fatty acid, isostearic acid. one example of an iso 20 CIR Panel Book Page 45

50 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-Undecylenate TEA-Undecylenate is the triethanolamine salt of a terminally unsaturated, eleven carbon fatty acid, undecylenic acid. 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 TEA-Tallate TEA-Tallate is the triethanolamine salt of tall oil acid. wherein RC(O)O - = the fatty acid anions derived from hydrogenated coconut TEA-Glyceryl Dimaleate [ ] per CAS TEA-Glyceryl Dimaleate is the triethanolamine salt of the diester of glycerin and maleic acid. wherein RC(O)O - = the fatty acid anions derived from Tall Oil Acid Not enough information for a structure 21 CIR Panel Book Page 46

51 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure Hydroxy Acid Salt TEA-Lactate TEA-Lactate is the triethanolamine salt of the three carbon, α-hydroxy acid, lactic acid Organo-Substituted Sulfates Magnesium/TEA- Magnesium/TEA-Coco-Sulfate is the Coco-Sulfate mixed magnesium and triethanolamine salt of coco-sulfate. O R O S O O HO NH OH OH 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. O O O S O O S O R O Mg 2 R O where R represents the alkyl groups derived from coconut oil TEA-Lauryl Sulfate TEA-Lauryl Sulfate is the triethanolamine salt of lauryl sulfuric acid. 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 = CIR Panel Book Page 47

52 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure TEA-C10-15 Alkyl Sulfate TEA-C10-15 Alkyl Sulfate is the mixture of 10 to 15 carbon alkyl sulfate triethanolamine salts. 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. 23 CIR Panel Book Page 48

53 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure 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. 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 24 CIR Panel Book Page 49

54 Table 2. Definitions and structures Ingredient CAS No. Definition Formula/structure 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. TEA-PEG-3 Cocamide Sulfate TEA-PEG-3 Cocamide Sulfate is the triethanolamine salt of the sulfate ester of triethoxylated cocamide. where RCO- represents the fatty acids derived from coconut oil Table 3. Physical and Chemical Properties Property Value Reference Triethanolamine Physical Form clear viscous liquid 1 Color colorless to pale yellow 25 Odor ammonia-like 1 Molecular Weight Melting Point 21.6 C 25 Boiling Point mm Hg 25 Water Solubility miscible in water 25 Other Solubility insoluble in benzene, ether, and petroleum distillates 1 miscible with methanol or acetone; sparingly soluble in hydrocarbon solvents; readily 80 forms salts with organic and inorganic acids log K ow 20 C 18 pka 25 C 33 Viscosity C 80 TEA-Hydrochloride Melting Point 177 C 81 TEA-Lactate Melting Point C 82 Density g/cm 3 82 TEA Lauryl Sulfate Density approx. 1 g/cm 3 (20 C) CIR Panel Book Page 50

55 Table 4a. Frequency and concentration of use according to duration and type of exposure # of Uses 15,83 Conc of Use (%) 16 # of Uses 15,83 Conc of Use (%) 16 # of Uses 15,83 Conc of Use (%) 16 Triethanolamine TEA-Cocoate TEA-Hydrochloride Totals* NR NR 0.5 Duration of Use Leave-On NR NR NR Rinse-Off NR NR 0.5 Diluted for (Bath) Use NR NR NR NR Exposure Type Eye Area NR NR NR NR Probable Ingestion NR NR NR NR Probable Inhalation-Spray 131 a,b NR NR NR NR Probable Inhalation-Powder NR NR NR NR Dermal Contact NR NR NR Deodorant (underarm) NR NR NR NR Hair - Non-Coloring NR NR NR 0.5 Hair-Coloring NR NR NR NR Nail NR NR NR NR Mucous Membrane NR NR NR Baby Products NR NR NR NR TEA-Isostearate TEA Lactate TEA Laurate Totals* 1 NR NR 8 Duration of Use Leave-On 1 NR NR NR Rinse Off NR NR NR NR NR 8 Diluted for (Bath) Use NR NR NR NR NR NR Exposure Type Eye Area NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Spray NR NR NR NR NR NR Incidental Inhalation-Powder NR NR NR NR NR NR Dermal Contact 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 Baby Products NR NR NR NR NR NR TEA-Laureth Sulfate TEA-Lauryl Sulfate TEA-Myristate Totals* NR Duration of Use Leave-On NR NR NR NR Rinse-Off NR Diluted for (Bath) Use NR NR NR Exposure Type Eye Area NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Spray NR NR 1 b 4-8 NR NR Incidental Inhalation-Powder NR NR NR NR NR NR Dermal Contact NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR Hair-Coloring NR 6 NR 2 NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR Baby Products NR NR 2 NR NR NR 26 CIR Panel Book Page 51

56 Table 4a. Frequency and concentration of use according to duration and type of exposure # of Uses 15,83 Conc of Use (%) 16 # of Uses 15,83 Conc of Use (%) 16 # of Uses 15,83 Conc of Use (%) 16 TEA-Palmitate TEA-Stearate TEA-Sulfate Totals Duration of Use Leave-On 3 NR 108 NR NR NR Rinse Off Diluted for Use NR NR NR NR NR NR Exposure Type Eye Area 1 NR 9 NR NR NR Incidental Ingestion NR NR 1 NR NR NR Incidental Inhalation-Spray NR NR 2 b NR NR NR Incidental Inhalation-Powder NR NR 2 NR NR NR Dermal Contact NR NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring NR NR 16 NR Hair-Coloring NR NR 1 NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR 4 NR NR NR Baby Products NR NR NR NR NR NR * Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types my not equal the sum of total uses. a Includes deodorants, in that it is not known whether or not the product is a spray. b Includes suntan products, in that it is not known whether or not the reported product is a spray. NR no reported uses Table 4b. Ingredients not reported to be used Magnesium/TEA-Coco-Sulfate Sodium/TEA C12-13 Pareth-3 Sulfate 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-C11-15 Pareth Sulfate TEA-C12-13 Pareth-3 Sulfate TEA-Canolate TEA-Coco-Sulfate TEA-Glyceryl Dimaleate TEA-Hydrogenated Cocoate TEA-Laurate/Myristate TEA-Oleate TEA-Oleyl Sulfate TEA-PEG-3 Cocamide Sulfate TEA-Sorbate TEA-Tallate TEA-Undecylenate 27 CIR Panel Book Page 52

57 REFERENCES 1. Elder RE (ed). Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. J Am Coll Toxicol. 1983;2:(7): Ikeda K and Migliorese KG. Analysis of Nitrosamines in Cosmetics. J Soc Cosmet Chem. 1990;41:(Sept/Oct): Mirvish SS. Kinetics of Dimethylamine Nitrosation in Relation to Nitrosamine Carcinogenesis. Journal of the National Cancer Institute. 1970;44:(633): Mirvish SS. Formation of N-Nitroso Compounds - Chemistry, Kinetics, and in vivo Occurence. Toxicol Appl Pharmacol. 1975;31: Turney TA and Wright GA. Nitrous Acid and Nitrosation. Chemical Reviews. 1959;59: Ridd JH. Nitrosation, Diazotization, and Deamination. Quarterly Review of the Chemical Society. 1961;15: 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). 17. 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). 18. 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 CIR Panel Book Page 53

58 22. 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: Kraeling MEK and Bronaugh RL. In vitro absoprtion of triethanolamine through human skin. Cutaneous and Ocular Toxicology. 2003;22:(3): 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 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), 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 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: CIR Panel Book Page 54

59 41. 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): 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): 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: 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: Geier, J, Lessmann H, Frosch, PJ., Koch, Patrick, Aschoff, R, Richter, G, Becker, D, Eckert, C, Uter, Wg, Schnuch, A, and Fuchs, T. Patch testing with components of water-based metalworking fluids. Contact Dermatitis. 2003;49:(2): Geier, J, Lessmann, H, Dickel, H, Frosch, PJ., Koch, P, Becker, D, Jappe, U, Aberer, W, Schnuch, A, and Uter, W. Patch test results with the metalworking fluid series of the German Contact Dermatitis Research Group (DKG). Contact Dermatitis. 2004;51:(3): CIR Panel Book Page 55

60 61. 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): Jones SK and Kennedy TC. Contact dermatitis from triethanolamine in E45 cream. Contact Derm. 1988;19:(3): 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): 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 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. 74. 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 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. 76. 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. 77. 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): CIR Panel Book Page 56

61 79. 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. 80. 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: 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). 32 CIR Panel Book Page 57

62 Data

63 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: July 20, 2011 SUBJECT: Nitrosamine Formation Boilerplate Language The Post Meeting Announcement for the June 26-27, 2011 CIR Expert Panel meeting uses the following language in the conclusions of the DEA, DEA Amides and TEA reports: These ingredients should not be used in cosmetic products in which Nnitroso compounds are formed. This language is also found in various places in the Tentative reports on Diethanolamine and its salts as used in cosmetics, DEA amides as used in cosmetics, and Triethanolamine (TEA) and TEA-containing ingredients as used in cosmetics. Although this language has been used in some CIR reports in the past, it is not appropriate as it implies that some cosmetic products are formulated to form N-nitroso compounds. The goal of the cosmetics industry is to formulate to avoid the formation of N-nitroso compounds in alt products. The revised draft boilerplate language dated 10/20 10, reviewed at the March 2011 CIR Expert Panel meeting, suggested the following appropriate boilerplate language which should be used in the new DEA, DEA Amides and TEA reports: The Expert Panel cautions that products containing these ingredients should be formulated to avoid the formation of nitrosamines th Street, N.W, Suite 300 Washington, D.C (fax) CIR Panel Book Page 58

64 As The Please Please COSMETIC The Personal Care Memorandum Products Council Committed to Safety, Quality & innovation TO: F. Alan Andersen, Ph.D. Director - INGREDIENT REVIEW (CR) FROM: John Bailey, Ph.D.? Industry Liaison to the CIR Expert Panel I DATE: July 18,2011 SUBJECT: Comments on the Tentative Amended Safety Assessment of Triethanolamine (TEA) and TEA-Containing Ingredients as Used in Cosmetics p.1, Abstract, 16, Discussion - following does not make sense: because of the similarity between structural activity relationships and biologic functions in cosmetic concentrations of use, the existing data can be extrapolated to support the safety of the entire group. The meaning of biologic functions is not clear. The CR Expert Panel used data on TEA and components of the other ingredients to support the safety of the ingredients in this report. If a structural activity relationship analysis was completed, what other structures were used as a comparison? A similar statement: due to similar structure activity relationships and biological function is also presented in the Discussion section. What are the biological functions of these ingredients? A biological function suggests TEA acts as a vitamin or has a specific function in the body. p.1, Abstract - language These ingredients should not be used in cosmetic products in which N nitroso compounds are formed. is not appropriate. This sentence implies that companies purposely formulate some products to form N-nitroso compounds, and it is only those products in which TEA ingredients should not be used. Please refer to the 10/20 10 draft CIR Nitrosamine boilerplate document. This document suggests the following appropriate language: The Expert Panel cautions that products containing these ingredients should be formulated to avoid the formation of nitrosamines. p.1, Introduction - change TEA should not be used with products containing N-nitrosating agents. to TEA should not be used in products containing N-nitrosating agents. As TEA Sorbate is not reported to be used, please state that TEA-Sorbate is reported to function only as a preservative. p.4-, Use section - change 20 reported used to 20 reported uses p.4- - there are inhalation data that define a NOAEC (calculated 90-day NOAEC of 4.7 mg/m, is the inhalation boilerplate language really necessary for this report? 3) th Street, N.W., Suite 30O Washington, D.C (fax) CIR Panel Book Page 59

65 Rather For What In In In What Please What If Non-Human Please Please Please As TEA What p.5 - p.5 - p.5 - p.6, Other - p.9 - p.9 - p.14 - p.14 - p.15 - p.17 - than stating that TEA-Undecylenylate and TEA-Sorbate are listed as preservatives in Europe, it would be helpful to state that Sorbic and its salts and Undec-lO-enoic acid and salts including their ethanolamine salts, are listed as preservatives. what type of product(s) did Health Canada report a concentration of 100% TEA? were the dose units used in the study described in reference 23? In the second line (under the Non-Human, TEA headings) it says mg/kg, in the fourth line it says ml/kg. - - is meant by TEA equivalents? If NTP was measuring radioactivity, it should say radioactivity. If NTP was actually measuring specific metabolites, it should say TEA metabolites. If the term TEA equivalents is used in the report, it needs to be defined. the summary of the Reproductive and Developmental Toxicity Studies section, please include the dose used in the oral teratogenicity screening study in mice. the summary of the TEA developmental study from the original report, and in the summary of the Chernoff-Kavlock teratogenicity screening test, it would be better to state that no developmental effects were observed, as these animals were only exposed during gestation in these studies, so the a complete assessment of potential reproductive effects was not completed in these two studies. the Summary of the Human TEA sensitization studies from the original report, were patients studied? Were the studies described in the second paragraph R1PTs? was the concentration of TEA tested in the EYTEX assay (reference 59)? state why the data on TEA-PEG-3 Cocamide DEA are relevant to TEA-PEG-3 Cocamide Sulfate. is the amount of DEA considered safe by the CR Expert Panel as it is not clearly stated in the new CR report on DEA. As there is more than one CR report on DEA, it would be helpful to state which CR report on DEA the reader should consult for the limit on DEA. p.17, Discussion - do not use the following language: TEA and TEA-containing ingredients should not be used in cosmetic products in which N-nitroso compounds are formed. The industry does not formulate products to form N-nitroso compounds. The following language from the draft boilerplate document is more appropriate. The Expert Panel cautions that products containing these ingredients should be formulated to avoid the formation of nitrosamines. p.17 - there are data supporting the safety of TEA following inhalation exposure, why is the boilerplate language regarding particle size necessary? p.18, Conclusion - do not use the following language: These ingredients should not be used in cosmetic products in which N-nitroso compounds are formed. The industry does not formulate products to form N-nitroso compounds. The following language from the draft boilerplate document is more appropriate. The Expert Panel cautions that products containing these ingredients should be formulated to avoid the formation of nitrosamines. 0-25, p.2 Table 2 - provide reference(s) for this table. p.26-27, Table 4a - Possible Ingestion is being used for some products, Possible should also be added to the Inhalation category as frequently it is not known if a product reported to the VCRP or the Council survey is really a spray. For example, the 8% Inhalation product for TEA-Lauryl Sulfate is in the FDA product category, Foot powder and spray. This product 2 CIR Panel Book Page 60

66 may not be a spray. Even if it is a spray, the breathing zone concentration for a product sprayed on the feet is likely to be much lower than for a product sprayed on the head. 3 CIR Panel Book Page 61

67 Based The Personal Care Memorandum Products Council Committed to Safety, Quality & Innovation TO: FROM: DATE: F. Alan Andersen, Ph.D. Director - COSMETIC INGREDIENT REVIEW (CIR) John Bailey, Ph.D.]- -.i Industry Liaison to the CIR Expert Panel June24, SUBJECT: Comments on the Draft Report on Triethanolamine Prepared for the June 27-28, 2011 CIR Expert Panel Meeting p paragraph on p.3 describing potential nitrosamine formation from TEA is clearer than the paragraph on p.2 from the old report. It would be helpful if the paragraph on p.2 was deleted. A reference still needs to be added to the nitrosamine formation paragraph on p.3. p.6 - In the following sentence, are the exposure values given for the products, or do they represent the TEA contained in the products? 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. If it is to the product, what is the TEA exposure? p.6, 20 - In the description of the EU regulations, please also note that Annex ifi has no concentration limits stated for other products (presumably rinse-off products). p.6 - Is the 100% TEA in a leave-on product from Health Canada really correct? if so, additional details about the type of product should be obtained. p.7-9, 20 - Unless the investigators were looking at the effect of TEA on the dermal penetration of salicylic acid, the information concerning the dermal penetration of salicylic acid from TEA Salicylate is not relevant to this report. p.8 - on what observation in the skin irritation studies in guinea pigs led to the conclusion that p.8 - If TEA-Lauryl Sulfate is absorbed? the following sentence from the Salicylic Acid report is left in this report, information such as the compound studied, the dose and the vehicle should be added. In dermal absorption studies in arthritic males, only small amounts of salicylate were found in the synovial fluid, blood and urine. p.9 - In the study described in reference 22, at what time point was 3.1% of the radioactivity recovered in the tissue? p.9, 20 - In the summary under Toxicological Studies, and in the Summary section it says that rats were killed due to severe hydration. The description of this study (p.11, reference 31, 32) says the rats were euthanized early due to severe dehydration. Severe dehydration makes more sense. Were decreases in water consumption also reported? th Street, N.W., Suite 3O0 Washington, D.C (fax) CIR Panel Book Page 62

68 A In Please In In Please The Please As The In Hydrolyzed p.10 - subheading needs to be added before the study on TEA-Cocoyl Hydrolyzed Collagen from the original report. It is currently under a TEA subheading. p.10, 20 - following should not be included in the dermal section. In inhalation studies with TEA in rats and mice, no observations were reported that were indicative of a toxic pulmonary effect. What concentrations of TEA were studied? p.11 - the summary of TEA oral studies from the original report, was evidence of hepatic and renal damage observed in both rats and guinea pigs? If the doses were g/kg/day for rats, how could deaths have occurred at a dose of 0.17 glkglday? p.12, 20 - the summary of the Reproductive and Developmental Studies section, please include the highest dermal dose and the highest oral dose that were not associated with any adverse effects. p.13 - provide some indication of the doses used in the summary of the Carcinogenicity section and the summary of TEA (dermal) information from the original report. p.16 - the information from the original report, please provide the concentration of TEA-Lauryl Sulfate that was non-irritating to rabbit skin. p.17 - the information from the original report, please provide the concentration of TEA-Lauryl Sulfate that was non-irritating to rabbit eyes. p.18 - provide the concentration of TEA-Cocoyl Hydrolyzed Collagen that was not a sensitizer in guinea pig studies. p.18 - following sentence should be moved to the Phototoxicity/Photoallergenicity section. Aq. shampoo formulations containing % TEA-lauryl sulfate were not photosensitizers. p.20 - The neat TEA dose applied to rats was 2000 mg/kg bw, not mg/kg bw as stated in the Summary. p.20 - include some indication of dose in the summary of the 2 year carcinogenicity study of TEA in mice and rats. p.20 - there are least some data to support the hypothesis that TEA may act via a choline-depletion of action, the word speculated is not appropriate. The following better reflects the available information. Based on preliminary data, it has been hypothesized that TEA may cause liver tumors in mice via a choline-depletion mode of action. p.21, Table 1 - Collagen has also been reviewed by CIR (safe as used conclusion) and should be added to Table 1. p Please add reference(s) to this table. 2 CIR Panel Book Page 63