TEA blue - Cosmetic Ingredient Review · 2020. 2. 29. · December 2010: a formal rereview package...

BLUE

TEA

CIR EXPERT PANEL MEETING

SEPTEMBER 26-27, 2011

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 consid-ered 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.

Distributed for Comment Purposes Only -- Do Not Cite or Quote

CIR Panel Book Page 1

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 “add-ons” 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



TRIETHANOLAMINE: SEARCH STRATEGY

April 21, 2011: SCIFINDER search - 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 17. 2010 DEA not to be used 111-42-2 & choline 13 15 111-42-2 & carcinogen* 83 21

choline & deficiency & human & cancer

38

TEA restrictions 102-71-6 & carcinogen* 55 11 102-71-6 & choline 5 2 MEA restrictions Jan 25, 2010 102-71-6 OR 111-42-2 (1980-current)

1003 (downloaded 58)

UPDATED SEARCH May 31, 2010 (102-71-6 OR 111-42-2 OR 141-43-5) AND (REPRODUCTI* OR TERATOGEN*) – 142 (Toxline); 41 (DART) (102-71-6 OR 111-42-2 OR 141-43-5) AND (DEVELOPMENT* OR FETOTOX*) – 378 (Toxline); 47

(DART) (102-71-6 OR 111-42-2 OR 141-43-5) AND TOX* (102-71-6 OR 111-42-2 OR 141-43-5) AND (GENOTOX* OR MUTAGEN* OR CLASTOGEN*) – 286

Toxline); 7 (DART); 9 (CCRIS) (102-71-6 OR 111-42-2 OR 141-43-5) AND (SENSITIZA* OR SENSITIZE* OR SENSITIS* OR

IRRIT*) – 306 (Toxline); 6 (DART)



(102-71-6 OR 111-42-2 OR 141-43-5) AND (METBOLI* OR ABSORB* OR ABSORP* OR DISTRIBUT* OR EXCRET*) – 403 (Toxline); 18 (DART)

141-43-5 AND CARCINOGEN* – 193 141-43-4 AND CHOLINE - 0 Total Download (most duplicates removed): 1218 UPDATED SEARCH – Sept 21, 2010 – last 12 mos 102-71-8 OR 111-42-2 OR 141-43-5 128 hits/1 useful



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Tran

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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 non-

irritating. 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.



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 14-17. 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 --



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?



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 C14-17 --

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?



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?



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.



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.



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?



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.



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.



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 --



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. Okay, anything in terms of the

discussion?

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.



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.



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.



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.



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 --



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 TEA-

rosinate, 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.



Rep

ort

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.

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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 ................................................................................................................................................................................................... 10 In Vitro ...................................................................................................................................................................................................... 10 In Vivo ...................................................................................................................................................................................................... 10

Carcinogenicity ............................................................................................................................................................................................... 10 Dermal ................................................................................................................................................................................................... 10 Oral ........................................................................................................................................................................................................ 11

Possible Mode of Action for Carcinogenic Effects of TEA ...................................................................................................................... 12 Carcinogenic Potential in Humans ............................................................................................................................................................ 12

Irritation and Sensitization .............................................................................................................................................................................. 12 Dermal Irritation ........................................................................................................................................................................................ 12

In Vitro .............................................................................................................................................................................................. 12 Non-Human ....................................................................................................................................................................................... 12 Human ............................................................................................................................................................................................... 13

Sensitization .............................................................................................................................................................................................. 13 Non-Human ....................................................................................................................................................................................... 13 Human ............................................................................................................................................................................................... 14

Provocative Testing ............................................................................................................................................................................... 14 Phototoxicity/Photoallergenicity ............................................................................................................................................................... 15

Non-Human ....................................................................................................................................................................................... 15 Human ............................................................................................................................................................................................... 15

Ocular Irritation ......................................................................................................................................................................................... 15 In Vitro .............................................................................................................................................................................................. 15 Non-Human ....................................................................................................................................................................................... 15

Clinical Assessment ........................................................................................................................................................................................ 16 Case Reports.............................................................................................................................................................................................. 16

Summary ........................................................................................................................................................................................................ 16 Discussion....................................................................................................................................................................................................... 17 Conclusion ...................................................................................................................................................................................................... 18 Tables ............................................................................................................................................................................................................. 19

Table 1. Conclusions of previously reviewed ingredients and components ............................................................................................. 19 Table 2. Definitions and structures ........................................................................................................................................................... 20 Table 3. Physical and Chemical Properties .............................................................................................................................................. 25 Table 4a. Frequency and concentration of use according to duration and type of exposure ..................................................................... 26 Table 4b. Ingredients not reported to be used ............................................................................................................................................ 27

References ...................................................................................................................................................................................................... 28



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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 ingredi-ents 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 non-irritating. 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

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



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(DEA) and ethanolamine (MEA).

HON

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 Monoethanolamine1

Of concern in cosmetics is the conversion (N-nitrosation) of secondary amines (R1-NH-R2), such as DEA (wherein

R1 and R2 are each ethanol), into N-nitrosamines that may be carcinogenic. Tertiary alkyl amines (NR1R2R3), such as TEA

(wherein R1, R2, and R3 are each ethanol), however, do not tend to react with N-nitrosating agents to directly form nitrosa-

mines. 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.



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TEA

TEA is produced by reacting 3 moles of ethylene oxide with 1 mole of ammonia; additional ethylene oxide will con-

tinue to react to produce higher ethylene oxide adducts of TEA.7 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

Stability

TEA-Stearate

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 Typically,

industrial alkyl sulfates contain 1-4% sodium sulfate and 0.5-18% residual alcohol.

N-Nitrosodiethanolamine Formation

Nitrosamines are compounds containing the R1R2N-NO functional group.2 N-Nitrosation is the process of convert-

ing organic compounds (e.g., alkyl amines) into N-nitroso derivatives (e.g., nitrosamines) by reaction with nitrosating agents.

These agents include nitrous acid (HNO2), oxides of nitrogen (e.g., nitrous anhydride or nitrite), and other compounds

capable of generating a nitrosonium ion, NO+2.

The formation of a specific nitrosamine, NDELA, from reaction of TEA with nitrite was examined in vitro and in

vivo.13 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 hydro-

chloric 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



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inoculum) media. (The percent nitrosation was determined using values that were corrected for DEA impurity-related

NDELA formation).

In vivo, female B6C3F1 mice were dosed dermally or orally with 1000 mg/kg TEA, in conjunction with oral expo-

sure 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 0.001 ± 0.0005 µg/g and 0.044 ± 0.059 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

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