DEA Amides blue - Cosmetic Ingredient Review · 2020-02-29 · TOXNET Search Statements – DEA Family of Ingredients – Jan 7, 2011 SS1 DEA OR DIETHANOLAMINE OR 111-42-2 (only search

BLUE

DEA Amides

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 DEA Amides as Used in Cosmetics Included is the draft Final Amended Safety Assessment on DEA Amides as Used in Cosmetics. Because DEA Amides were not considered appropriate to review with DEA and its salts, this group of diethanolamides was addressed separately, nominally as a re-review of Cocamide DEA with the addition of 32 other diethanolamides. The draft report was reviewed in June, and the list of ingredients included in the re-review was narrowed to include only those for which a read-across approach using the avail-able data (e.g., data on Cocamide DEA, as well as relying on past CIR reports on components of the diethanolamides) would be appropriate. At the June meeting, the Expert Panel issued a Tentative Amended Safety Assessment that concluded the DEA amides are safe when formulated to be non-irritating. The Panel included the caveat that 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 TEA and DEA 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 DEA amides 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.

Distributed for Comment Only -- Do Not Quote or Cite

CIR Panel Book Page 1

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1‐25

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A 12

0‐40

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x

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Myristam

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Lauram

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Palm

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A 75

45‐24‐6

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Stearamide DE

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Behe

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Lactam

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Isostearam

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A 52

794‐79

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Oleam

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863‐02

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4046

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x

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Apricotam

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A 18

5123

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Avocadam

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A 12

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A

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716‐42

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Sesamide DE

A 12

4046

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x

III

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X

Soyamide DE

A 68

425‐47

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A 68

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TOXNET Search Statements – DEA Family of Ingredients – Jan 7, 2011 SS1 DEA OR DIETHANOLAMINE OR 111-42-2 (only search last 12 mos) 50 hits in toxline; 31 in DART (all years) SS2 ((COCAMIDE OR ISOSTEARAMIDE OR MYRISTAMIDE OR STEARAMIDE) AND (DEA OR DIETHANOLAMINE)) OR 61791-31-9 OR 52794-79-3 OR 7545-23-5 OR 93-82-3 (only since 1990) 26 hits in toxline SS3 59219-56-6 OR 65104-36-1 OR 59231-42-4 OR 53404-39-0 OR 61693-41-2 OR 51541-51-6 OR 26545-53-9 OR 58855-36-0 OR 143-00-0 OR 64131-36-8 OR 65104-61-2 OR 58855-63-3 OR 102-79-4 OR 124046-18-0 OR 185123-36-8 OR 124046-21-5 OR 124046-24-8 OR 70496-39-8 OR 136-26-5 OR 68440-32-4 OR 120-40-1 OR 124046-27-1 OR 93-83-4 OR 5299-69-4 OR 124046-30-6 OR 73807-15-5 OR 7545-24-6 OR 40716-42-5 OR 124046-35-1 OR 68425-47-8 OR 68155-20-4 OR 68140-08-9 OR 25377-64-4 OR 60239-68-1 OR 124046-39-5 OR 68938-05-6 OR 56863-02-6 169 hits in toxline; 2 hits in DART SS4 ((DIETHANOLAMINE OR DEA) AND (BISULFITE OR ISOSTEARATE OR LAURAMINOPROPIONATE OR LINOLEATE OR MYRISTATE OR LAURATE OR STEARATE OR ((ALKYL OR PARETH OR CETYL OR LAURETH OR LAURYL OR MYRETH OR MYRISTYL) AND SULFATE) OR ((CETEARETH OR CETYL OR OLETH OR HYDROXYPALMITYL) AND PHOSPHATE) OR DODECYLBENZENESULFONATE OR (METHYL AND MYRISTATE AND SULFONATE) OR (HYDROLYZED AND LECITHIN) OR BUTYL OR LAURYL OR METHYL)) 3 hits in toxline SS5 ((DIETHANOLAMINE OR DEA) AND (ALMONDAMIDE OR APRICOTAMIDE OR AVOCADAMIDE OR BABASSUAMIDE OR BEHENAMIDE OR CAPRAMIDE OR COCAMPHODIPROPIONATE OR DIETHANOLAMINOOLEAMIDE OR (HYDROGENATED AND TALLOWAMIDE) OR LACTAMIDE OR LANOLINAMIDE OR LAURAMIDE OR (LAURAMIDE AND MYRISTAMIDE) OR LECITHINAMIDE OR MINKAMIDE OR OLEAMIDE OR OLIVAMIDE OR (PALM AND KERNELAMIDE) OR PALMAMIDE OR PALMITAMIDE OR (PEG AND (TALLOWAMIDE OR COCAMIDE)) OR RICEBRANAMIDE OR RICINOLEAMIDE OR SESAMIDE OR (SHEA AND BUTTER AND CASTORAMIDE) OR SOYAMIDE OR (STEARAMIDE AND DISTEARATE) OR (STEARYAMIDOETHYL AND (HCL OR HYDROCHOLORIDE)) OR TALLAMIDE OR TALLOWAMIDE OR UNDECYLENAMIDE OR (WHEAT AND GERMAMIDE) OR (COCYL AND SARCOSINAMIDE) OR CORNAMIDE OR (CORNAMIDE AND COCAMIDE) OR LINOLEAMIDE)) 15 hits in toxline SS6 (Jan 12, 2011) 8035-40-3 OR 529486-73-5 OR 577979-07-8 OR 173447-16-0 OR 1079914-70-7 OR 173104-11-5 OR 1541-67-9 OR 105-59-9 OR 37345-28-1 OR 85408-88-4 OR 15517-64-3 OR 92680-75-6 OR 83452-99-7 OR 83590-20-9 OR 39341-48-5 OR 267663-44-5 OR 8036-36-0 OR 95914-64-9 OR 137763-96-3 OR 73380-02-6 OR 39390-56-2 OR 118814-41-7 OR 65256-28-2 OR 68308-73-6 OR 68603-49-6 155 hits in toxline; 2 hits in DART



CIR History: Re-Review of Cocamide DEA and Related DEA Amides 1986 The CIR Expert Panel concluded that cocamide, lauramide, linoleamide, and oleamide DEA are safe as used, and that they should not be used in products containing nitrosating agents 1996 Cocamide DEA was re-reviewed; the Panel concluded that cocamide DEA is safe as used in rinse-off products and safe at concentrations ≤10% in leave-on products; cocamide DEA should not be used in cosmetic products in which N-nitroso compounds are formed March 3-4, 2011: Re-Review Draft Report The DEA amides family was created after it was determined that it was not appropriate for these ingredients to be reviewed in the safety assessment of DEA and Its Salts. June 27-28, 2011: Draft Amended Report

- The following 8 ingredients were deleted from the report: Cocoyl Sarcosinamide; Diethanolaminooleamide DEA; Lactamide DEA; PEG-2 Tallowamide DEA; PEG-3 Cocamide DEA; Stearamide DEA-Distearate; Stearmidoethyl Diethanolamine HCl

- A tentative amended safety assessment was issued with a conclusion of 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 26-27, 2011: Draft Final Amended Report



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Tran

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June 2011 Meeting – Belsito Team

DR. BELSITO: Okay. So, now the DEA amides, which is a Green Book.

DR. EISENMANN: (inaudible) DEA --

DR. BELSITO: Amides or DEA itself?

DR. EISENMANN: DEA itself. Although it's -- I just wanted to make it clear that you understand although it's not permitted for direct

addition in Europe, if you add TEA or fatty acid dialkanolamides or monoalkanolamides, then you can have a small amount of secondary

amides in your product. Okay? So, for -- if you add fatty acid dialkanolamides, you can have up to 0.5 percent DEA in your product. I

thought that should be added, because just saying it's not permitted in Europe is not really the whole story. Because you can have it as a

contaminant, and they do have limits when you have those three different components.

DR. BELSITO: So will you craft some language for Monice to put in the report or work with her?

MS. FIUME: I actually have a question on that. Because the DEA ingredients themselves are prohibited for use in Europe, which is

reflected in the DEA report, the DEA amide report and the TEA report reflect the amount of secondary amide that's allowed. So, is there

really reason? If there is, then --

DR. EISENMANN: Because if you're only reading the DEA report, you don't pick up that it is -- you just think -- you get the impression

that, oh, no DEA is allowed in Europe, which is not necessarily the case. A small amount can be present. But you don't necessarily have to

give the details, but just say that they should be checking these Annex 3, too, for these other categories.

MS. FIUME: But DEA as an ingredient is not allowed. DEA as a contaminant is allowed in those other ingredients. Right?

DR. EISENMANN: Correct.

MS. FIUME: So they should only -- so that should only appear in those main reports?

DR. BELSITO: Well, except our DEA report includes some other ingredients in which DEA could be a contaminant. It's not simply DEA.

MS. FIUME: But I believe those ingredients are also not allowed in Europe.

DR. BELSITO: Okay. Then in which case, I would agree with you, Monice. It shouldn't be mentioned until we get to the DEA amides,

where you could say something about that.

MS. FIUME: Okay. And that is in that report already.

DR. BELSITO: Yes.

MS. FIUME: Okay.

DR. EISENMANN: Okay. I just --

DR. BELSITO: Yeah, I mean, if those ingredients are not allowed, then I think the appropriate place for that allowance for contaminates is

in the DEA amides report where we say, by the way, you know -- whereas if you read the report on DEA and relate, yadda, yadda, you'll see

it's banned in Europe. These are allowed in Europe with residual amounts of DEA contaminant.

DR. EISENMANN: I just think it's helpful to have that in the DEA report, too, because I think it's misleading to say it's not permitted in

Europe because -- low levels are. And I suspect the concentration of use that I've gotten reported are -- not as a result of people adding DEA,

it's adding TEA and they're keeping track of the residual DEA because they have to for your --

DR. BELSITO: I don't have a problem with adding a sentence after saying DEA is now allowed and say, however, DEA may be present in

cosmetic preparations marketed in Europe as a contaminant of cosmetic ingredients derived from this source.

DR. EISENMANN: Right. That's -- one sentence is fine.

DR. BERGFELD: Do you want to put the range that they gave (inaudible)?

DR. BELSITO: Microphone.

DR. BERGFELD: Do you want to put the range that they accept in Europe?

DR. BELSITO: Gee, I don't know. Is there a range, Monice?

DR. BERGFELD: I think Carol stated there was a range.



DR. EISENMANN: It's for fatty acid dialkanolamides is 0.5 percent in finished products.

DR. BELSITO: So, fine. Okay, DEA amides. Gosh, Monice, someone really didn't like you this time, did they?

MS. FIUME: Can I go back and clarify something, though, Carol? Just so I make sure I have the information correct. Does it state DEA or

it states secondary amines?

DR. EISENMANN: Secondary amines.

MS. FIUME: Okay.

DR. EISENMANN: It states secondary amines.

MS. FIUME: Okay. Because I know Dr. Hill was concerned that there other secondary amines besides DEA. So you would like it stated as

secondary amines?

DR. EISENMANN: You can state it as it says.

MS. FIUME: Okay.

DR. BELSITO: Okay. So, here we go. This was a re-review of cocamide DEA that started this all off. And then we last time around split up

the enthanolamines in doing DEAs, and now we're doing a whole family of DEA amides. So, this is what we're getting. And there are a total

of 41, is that correct? And some of them, we've already reviewed, such as cocamide, lauramide, linolamide, oleamide in '86, isostearamide,

myristamide, and stearamide in '95. I would say let's throw them all in and get it done with so we don't need to review them later on. And

basically having said that, safe as used. Just include the ones we've reviewed before again, and let's lump -- let's make reasonable families and

not add -- not add things back simply because they haven't reached the 15 year timeline yet.

DR. BERGFELD: Can we ask Dan about the 41 additions?

DR. LIEBLER: I have no problems with the proposed ingredients. One of the issues I have with this is the question of whether there is

hydrolysis of these in the skin, how much there is. They're basically two issues. Obviously, there's how much DEA is in the skin. It could

come from contamination, residual DEA as the products are made, and it could also come from enzymatic hydrolysis in the skin. Now, it

seems to me that we don't know too much about that. But here are the couple of things that we do know. Well, actually, I'll first of all point

out that under chemistry definition and structure, that first paragraph on page 2, Panel Book 35. The last reference there or the last sentence,

"Amide hydrolysis tends to occur more commonly with high lipophilic amides." And then the reference is basically a med chem textbook.

And I don't think that's an adequate reference for this particular class of compounds, particularly for a kind of important issue like this. I

don't know if there are any data available on hydrolysis of these. Elsewhere in the report, there's evidence for metabolism studies in vitro that

the metabolism mainly happens at the other end of the chain, that there's hydroxylation and further oxidation at the other end of the chain.

That may be where the action is, and that even though hydrolysis enzymatically is a theoretically possible reaction, it's not -- it doesn't

compete with oxidative metabolism. So, I'm anticipating possible concerns perhaps raised by the other team involving metabolism of these

compounds. I would say that we don't know much about that.

DR. BELSITO: But we've looked at DEA and, I mean, most of the chemicals that are conjugated to this we've looked at, also. Well?

DR. LIEBLER: So if we're going to reaffirm the original conclusion, it will also conclude --

DR. BELSITO: So even if we're --

DR. LIEBLER: -- it will also include the less than 10 percent in leave-ons?

MS. FIUME: I can address that, because we have discussed that.

DR. LIEBLER: Okay.

MS. FIUME: If you look at some of the other conclusions, it might say up to 40 percent or less than 10 percent in leave-ons. The less than

10 percent in leave- ons, I believe originated because at that time concentration of use was not provided. So, a maximum was probably

placed on it. For the 3 that state with a maximum of 40 percent use, the myristamide DEA, stearamide DEA, and isostearamide DEA? They

were actually used up to 15 percent, but that was probably at the time -- if there was a maximum concentration tested, that was often thrown

into the conclusion because they were only used up to 15 percent at the time of the report.

DR. BELSITO: What Monice is saying is that at one point, Dan, we suddenly stopped getting concentration of use, which put us in a

situation where we couldn't possibly say safe as used, so we began using the lowest toxicity endpoint, which often times was sensitization

and irritation data. So we would go with a limit based upon the highest number we had provided. And we're limiting things that necessarily

didn't have to be limited, but because we had no other way of doing it.

DR. LIEBLER: So, I don't want to -- maybe not make myself clear here. I'm not raising a red flag about hydrolysis of these to DEA because

actually I think the available evidence suggests that's not happening very much with these compounds. And my main concern was that the



one thing that you had flagged, Monice, as a reference there? I don't think is a good reference. And it implies that there's data that these

things are hydrolyzed in the skin. And you know, unless that textbook entry is about DEA amides, then we delete it.

DR. BELSITO: Okay.

MS. FIUME: Delete it?

DR. LIEBLER: Yeah, that's what I suggest.

DR. BELSITO: So you're comfortable with the safe as used, though?

DR. LIEBLER: Yeah.

DR. BELSITO: Okay. So, then in the discussion, we need to comment on presence of impurities, especially the DEA. We need to formulate

to avoid nitrosamines. We need the inhalation boilerplate. And I think the safe as used criteria or conclusion comes with a when formulated

to be non-irritating.

MS. FIUME: Dr. Belsito, does the -- to avoid formation of nitrosamines or whatever we're stating it as right now, does that also go in the

conclusion?

DR. BELSITO: No.

MS. FIUME: No.

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.

June 2011 Meeting – Marks Team

DR. MARKS: Okay, the last ingredients were the DEA amides. And from this morning, we know that at the March meeting, the panel

decided to reopen the assessment of DEA and selected ingredients, and now we have the DEA amides to be -- one of those amides is

cocamide DEA, and that was reviewed in 1996. And this was concluded to be safe as used in rinse-off in safer concentrations of less than 10

percent in leave-on cosmetics. So, do we reopen cocamide DEA, do we do the add-ons, which are on page 40, and we get back into this

NTPA study and carcinogenicity. So, how do we want to proceed with this? Do we want to reopen the cocamide DEA and include that in

this? DEA amides.

DR. SLAGA: Going through it, I put no. But I don't know, I'd prefer to (inaudible) what he thinks about the addition.

DR. HILL: I almost hear (inaudible).

DR. SLAGA: Huh?

DR. HILL: I might have to move given the noise level coming from the next room, but.

DR. MARKS: And if we look at page 34, we have the 40 amides that are potential add-ons here or not to be included. So, Rons, what do you

think about the cocamide DEA?

DR. SHANK: It should be part of the list.

DR. MARKS: Right.

DR. SHANK: And it's here, so.

DR. HILL: Yes, and we've got quite a few of these where there are reported uses.

DR. MARKS: Six of those on page 34 for the 40 amides are already, again, they view them safe. The isostearamide, the oleamide, the

linoleamide, the stearamide. They're asterisked, as you can see there.

DR. HILL: So, for me, I thought I'd reopen and add that there were a few ingredients that they just jumped out at me as being very different

or at least oddball. Was there anything added to the list from our previous review when we had it all rolled into DEA? I'm guessing there

were a few more things added. But I'm not sure.

MS. FIUME: These all came from that report.

DR. HILL: Okay, so, the December one that --



MS. FIUME: March.

DR. HILL: March, which I should have, but I'm not positive. It doesn't matter. There are these glycol ether ones that are quite a bit different

and the ones that have amidoethyl linkage in between. Those are really vastly different. And diethanol, amino, oleamide, DEA is a lot

different because it has a DEA moiety on the other end, and then stearamide DEA distearate, and this last one, the sarcosinamide, those are

kind of a lot different, too. So, I'll just put those out there, and if we do reopen and add, I wanted other people's opinions on whether we keep

-- and how about lactamide, which is a short alpha hydroxy, which seem to me very different? And then beyond that, I guess that, for me, the

toxicology reviews seem to be very kind of founded by the fact that almost everything was tested with means in their sometimes significant

levels. And so, when you pair down the toxicology studies where we have very pure amides being tested, there aren't very many of those

studies.

DR. SLAGA: One of the concerns I had, that a number of them, they were either safe in rinse-off or not safe in leave-ons in different

concentrations. It's hard to relate all of those different levels and how they come up with a standard conclusion now. In terms of containing

nitrous-laden agents, that can be dealt with, but how do we do it with all of these different levels? I mean, the conclusion would get

horrendous to me. I don't know, maybe I'm not looking at in too simplistic of a way, but, once again, when we add on the (inaudible) it's

supposed to be something simple, and that it leads me to do a read across and add things.

DR. HILL: Well, I went into the 900-and-some pages of supplemental posts that were on the website and looking for the reports on the

ingredients that had been previously reviewed. And I at least printed for myself abstracts and discussion pages and a few selected pages. And

I think, again, when you look at what's there on toxicology, there's kind of limited data on the ones that have been reviewed and are solid, but

yet, again, I come back to we've got a lot of these things in use. If we just hunt, we're just kicking the can down the road, I guess. It's really

bothersome to me that the NTP studies were done with contaminated ingredient, given that there were carcinogenicity issues with DEA itself.

And, so, there are new enough studies where it seemed like they could have come up with pure material and remove that confounding

variable because you really can't tell in most all of these studies where there is toxicology, is it coming from DEA or is it coming from the

amides? There's really no way to separate it.

DR. BOYER: And based on those four or five compounds that they did test, there seemed to be a correlation between the DEA impurity --

DR. HILL: Yes, absolutely.

DR. BOYER: -- and the level of impurity and the findings.

SPEAKER: So, I suspect we have a huge table of ingredients for which there's really no problem toxicologically, but it's really hard based on

the data to say we've got enough information to know that for sure. And my gut feeling is we got a bunch of clean compounds in cosmetic

users not (inaudible).

DR. SHANK: Well, if DEA very slowly penetrates skin, why is a contaminant of a DEA amide, does it cause cancer? Is the amide DEA

change the barrier quality of the skin so that the DEA passes through?

DR. BOYER: In fairly high levels of test high concentrations, and I believe they were associated with some skin irritation and so forth, so,

there could be some increased penetration as a result of --

DR. SLAGA: Based on --

DR. BOYER: -- long-term nature of the exposure.

DR. SHANK: Okay, because we're re-reviewing DEA in another document by itself at much slower concentrations than 18 percent. There

is no reproductive toxicity to the (inaudible) data, toxicity data that these compound.

DR. HILL: No, there's not.

DR. SHANK: And they do penetrate the skin.

DR. MARKS: You mean the add-ons? The cocamide DEA, presumably, since it was concluded to be safe in '96.

DR. HILL: (inaudible) be pro tox on that either.

DR. MARKS: And, of course, the concentration level was based on sensitization studies.

DR. SHANK: Okay. The tox data, the reproductive and developmental tox data aren't on the DEA amides, they're on DEA and the other

components, but not on the DEA amides. So, I would think that data would be necessary.

DR. MARKS: So, you would want the reproductive and the development tox data --

DR. SHANK: Based on the sum representative compounds.

DR. MARKS: Are we going to reopen cocamide DEA? We said yes. If we're going to include the -- so, we go back.



DR. SLAGA: Yes, if we include them, we'd say yes. Yes. But if we don't --

DR. SHANK: Well, what are you going to do, reopen that and that add all of this to that? Or are you just going to add cocamide DEA to

this?

DR. MARKS: Well, I think if we add cocamide DEA to this report, essentially, we reopened it.

DR. SHANK: Yes.

DR. MARKS: I don't know that --

DR. ANDERSEN: It's time to re-review cocamide DEA.

DR. SHANK: Okay.

DR. ANDERSEN: So, that happy coincidence allows us to consider whether we want to expand the report to include other DEA amides.

DR. SHANK: I see.

MS. FIUME: And I believe the NTP report on cocamide DEA came out after the last re-review.

DR. SHANK: It did. It did.

MS. FIUME: So, that, keep in mind.

DR. HILL: Yes, but, like I say it's really not helpful because the way they did the studies with contaminated compound as opposed to pure

compound, which in 1993, 1994, 1995, 1996, shouldn't have been necessary. It really compounds all the negative. With all due respect to

NTP people.

DR. ANDERSEN: At the risk of you guys having had the conversation about DEA in the morning, it's not clear to me just why that's an

issue. You have a protracted conversation.

DR. SHANK: Why, what's an issue?

DR. ANDERSEN: Whatever was used in those studies was carcinogenic. Are you arguing that if a purer form had been used, it would not

have been carcinogenic?

DR. HILL: That's what I'm arguing.

DR. ANDERSEN: Okay, now I understand.

DR. HILL: But you'd like to know the answer.

DR. ANDERSEN: Correct.

DR. LORETZ: Well, I mean, the oleamide DEA, for example, which was the purest, that was clean.

DR. ANDERSEN: Yes.

DR. HILL: Yes.

DR. LORETZ: There was no evidence. I mean, there's a story that --

DR. ANDERSEN: There is a pattern.

DR. LORETZ: -- folds, yes.

MS. FIUME: Do they exist without the DEA in manufacturing, because all of the information from the old reports list the amount of free

DEA that's available.

DR. LORETZ: Yes.

MS. FIUME: And I don't think it's ever zero.

DR. LORETZ: No.

MS. FIUME: Yes.



DR. HILL: But if it's 1 percent or even 4 or 5 percent, I think we don't have a problem, and I don't know about leave-on for sure, but when

it's higher than that, which in some cases it is, and knowing that we sort of have the correlation. Well, we don't "sort of," there is what

appears to be pre-correlation between results and DEA contaminate.

DR. BOYER: Up to about 20 percent.

DR. HILL: Yes.

DR. BOYER: Eighteen percent (inaudible).

MR. HILL: But this is huge because I know cocamide DEA and several of these others are used in many products. Many.

DR. MARKS: And we have, as I mentioned, we have ones that have been declared safe, but they're already in this list.

DR. LORETZ: I think most of them with any significant uses are being reviewed.

DR. HILL: There are qualifications on the cocamide DEA and its conclusions.

DR. MARKS: Right.

DR. HILL: And their qualifications on the isostearamide and the myristamides, stearamide.

DR. MARKS: Correct.

DR. HILL: Yes, there are qualifications on them.

DR. MARKS: And that's what I think Tom was addressing in his first comment is how can we come up with a conclusion that takes in

consideration these various limits without having a really long conclusion?

DR. ANDERSEN: But I think a possible way around that is to consider that these were done some time ago and we were not making any use

of the present practices of use and concentration at the time. So, for example, stearamide DEA has this kicker at the end of the conclusion

with a maximum use concentration of 40 percent. And none of the others, except for its companion, isostearamide had that phrase,

myrristamide. So, three of them have it and none of the others do. Why is that? Well, the answer is simple. They were only tested up to 40

percent. And what you guys said was screw it, if that's all they're going to give us, that's what we're going to say. It doesn't say that 45

percent is problematic. It said you only gave us certain data, so there. So, I think that the discrepancies in conclusion, if you focus on the

issue that is common, which is we've got a problem about nitrosamines. So, let's deal with that. For the rest of it try and roughly translate to

present practices and use.

DR. HILL: And, see, I don't even think nitrosamines is the problem with these amides if they're not contaminated with (inaudible).

DR. ANDERSEN: If they're not contaminated, yeah. But you put a limit on contamination, which is what you're discussing and deal with it

that way.

MS. FIUME So, the ones that have a limit of 40 percent in the report, they were only used up to 15 percent. So, the safe as used conclusion,

which (inaudible) seemed to be, it would have --

DR. SLAGA: Would.

DR. ANDERSEN: It could have been a safe as used conclusion.

MS. FIUME: Yeah.

DR. MARKS: It just wasn't.

DR. SLAGA: Well, that should --

DR. MARKS: So, and that takes care of cocamide DEA, also? Do we need to point out that less than or equal to 10 percent on leave-ons, or

can that be handled in a discussion?

MS. FIUME: I think that may have been a different situation because that was at the time where concentration of use was not being

provided. So, that's probably why it has a number.

DR. MARKS: So, let me see what it is now.

MS. FIUME: Right now --

DR. MARKS: What's the cocamide DEA?



MS. FIUME: As used, it's 7 percent.

DR. MARKS: Leave-on is 6.

MS. FIUME: Leave-on is 6, sorry.

DR. MARKS: So, that's taken care of there. Well, thank you.

DR. SLAGA: So, we don't even have to put a limit then?

DR. MARKS: No, we can, just as you suggested, Alan, we can just put present use in concentration. So, that resolves that, so.

DR. HILL: So, where is the table that has the concentration -- I think the full table was in the online, wasn't it?

DR. MARKS: No, it's --

MS. FIUME: The concentration of use (inaudible) reports?

DR. HILL: No, for everything that's a potential add-on.

DR. MARKS: It's here.

DR. HILL: We have that --

DR. MARKS: Yes, page 61.

DR. ANDERSEN: There's just a handful that are current.

DR. HILL: Right.

MS. FIUME: And then the next page is the ingredients that were not previously reviewed that are currently in use. CIR Panel Book page 62.

It's very little use on anything else. It is 29 of the ingredients are not reported to be in use.

DR. HILL: Twenty-nine of them?

MS. FIUME: Yes.

DR. MARKS: So, do you like the way that cocamide DEA was in the previous conclusion? Should not be used in ingredient cosmetics in

which N nitroso compounds are formed? As a general in this whole group. So, it still doesn't get back to the -- so, it sounds like we've

handled the various percentages that varied. If we used that as the way to deal with the carcinogenic potential, then as the reproductive and

development tox, is that the only data need we need?

DR. SHANK: For me. We should that limit that free DEA content concentration.

DR. MARKS: Do we do that --

DR. SHANK: To not exceed what we just reviewed in the DEA document which was, I think,.3 percent.

DR. MARKS: Alan, you'll hear what we said. We said our conclusion, we didn't put a limit, we said that DEA is safe. Now, of course,

that's relevant to what it was being used in the cosmetics at the time. And it's related safe salts are safe in rinse-off in sufficient leave-on, and

that was one leave-on we were concerned about, and to be formulated as non-irritative. So, we did actually --

DR. SHANK: But it's safe for the present concentration use, right?

DR. MARKS: Yes.

DR. SHANK: The DEA?

DR. MARKS: Yes.

DR. SHANK: And what's that concentration, is that.3?

DR. MARKS: Let's see. Is this it here?

MS. FIUME: Yes.

DR. MARKS: Yes, DEA. So, the concentration totals was 0.3.



DR. SHANK: Yes. So --

MS. FIUME: And that's rinse-off. Does it matter what the leave-on -- the leave-on was 0.06.

DR. SHANK: Okay, so, those concentrations should not be exceeded in DEA amide use. Right?

DR. MARKS: Right, so --

DR. SHANK: Because DEA was approved here.

DR. MARKS: Yes.

DR. SHANK: Now DEA is a contaminant here. So, that contaminant should be limited by what we just reviewed here.

DR. MARKS: And should we actually put it as this or should we just refer the document, they should not exceed DEA

concentrations as --

DR. SHANK: Reviewed by the panel because that may change later.

DR. MARKS: Yes. Yes. And that way, you wouldn't have to keep going back --

DR. SHANK: Right.

DR. MARKS: If we had new data that said it can be used as a higher concentration, it could be re-reviewed.

DR. SHANK: Correct.

DR. LORETZ: But you're saying that that it's.3 percent in the product?

DR. MARKS: No, well, the high in leave-on is 0.06 and the high in a rinse-off is 0.3. That's on page 26 of the DEA document. So, now,

going back, so, how did we get the cocamide DEA and these other, lauramide and linoleamide, et cetera, were safe, yet it doesn't sound like

we had a reproductive and developmental toxicity on those? That seems --

DR. SHANK: The panel didn't always ask for that.

DR. MARKS: Oh. Now, this one would have been last. Okay, the cocamide DEA was last reviewed in 1996. And let's see, we have an

1986, we have a 1995, so these are back in the mid-'90s and the mid '80s here. If we want to hold them, we would have to come out with an

insufficient amount.

DR. SHANK: Right.

DR. SLAGA: Right, we usually do things on the absorption (inaudible) for reproductive.

DR. SHANK: Okay, but (inaudible).

DR. LORETZ: I'm just going to grab a journal to see if there's anything of discussion referring --

DR. MARKS: Okay, good. As we're looking for the absorption.

DR. HILL: I've got the discussion section cocamide DEA.

DR. SHANK: Okay, and when was that reviewed?

DR. HILL: That was in 1996.

DR. SHANK: Okay. What's it say about redevelopment?

DR. SLAGA: At that time, I thought we were (inaudible). I didn't think (inaudible) based on the form that we're handed, absorption data.

DR. LORETZ: There's some information on rodents.

DR. MARKS: Tables. No.

DR. HILL: And there's no mention in the summary of discussion whatsoever of repro or developmental toxicity. It's not even mentioned.

DR. MARKS: Log P for oleamide DEA is 6.68. This is on page 60. For linolemide, it is 6.2. cocamido, it's 4.8. So, you wouldn't expect to

be much absorption on either of those. Log P.



DR. SLAGA: Four point eight, yes. It's usually around 3.

DR. MARKS: Yes.

DR. SLAGA: To the maximum rate of penetration.

DR. MARKS: Right.

DR. ANDERSEN: I think all of the previous safety assessments on DEA or MEA containing compounds probably revert back to a couple of

studies. Two percent of rats treated topically with hair dyes containing 2 percent DEA or TEA composite hair dye contained 22 percent

MEA. No dose-related significant differences in male or female fertility and no teratogenic effects. Switch columns. And 22 percent MEA

by gavage in rabbits. Pregnant rabbits during gestation, no teratogenic effects were observed. So, we've got a couple of the rat studies and a

rabbit study relating to the ethanolamine part of the molecule. And that would be consistent, and my guess is --

DR. SHANK: On diethanol.

DR. ANDERSEN: I'm guessing what did the discussions that (inaudible) at all.

DR. SHANK: And those were on diethanolamine or monoethanol?

DR. ANDERSEN: Diethanolamine and monoethanol amine, both.

DR. SHANK: Both.

DR. ANDERSEN: Both had no effect.

DR. MARKS: And that's from the DEA, MEA, and TEA statement?

DR. ANDERSEN: It's actually from the stearamide. It was picked up and has been repeated in the body of all these safety assessments.

DR. SHANK: Okay.

DR. ANDERSEN: But I think Ron is right. The discussion is bodied on what it picks up. So, you could very well look to the discussion and

not found any mention of repro-tox. I'm looking at it for this one, and I don't see any big discussion and I don't see any discussion of

reproductive developmental toxicity in the discussion. But the data were provided as I described.

SPEAKER: I can't picture you (inaudible) no impact.

DR. ANDERSEN: The data are there.

DR. MARKS: So, Ron, does that reassure you then with these or that with DEA and MEA based on those studies on the rat and rabbit that

we can proceed forward? Were they used --

DR. SHANK: Because the doses were high enough where you get some innovation, yes.

DR. MARKS: Yes, I mean, what was it that was fairly large like --

DR. SHANK: One gram per kilogram bodyweight.

DR. ANDERSEN: As I'm looking at this discussion, it clearly follows the pattern for all of these. The issue that you talked about was

sensitization for monoethanolamine and nitrosamine formation. That was your focus.

DR. MARKS: So, what do you think, Ron?

DR. HILL: See, for me, just looking at the structures, the issue that I think about is here we've got long chain molecules with what amounts

to a polar head group on one end. And, so, what I'd like to see is biology relating to membrane, potential for membrane incorporation in the

skin. Really nothing else much worries me about these. So, that would be like either tumor-promoting ability or something along those lines

in the skin. And we don't have any data like that whatsoever. This lag in sensitization, will he tell us something about that or not?

DR. SHANK: Well, we have dermal carcinogenicity data on cocamide DEA.

DR. HILL: We do?

DR. SHANK: Yeah. That's the NTP study.



DR. HILL: But there's a difference between carcinogenicity and promoting activity. I mean, you already have cancerous cells there and

you're promoting the rate of growth or promoting the transformation of pre-cancerous cells into cancerous cells. Promotion is more

stimulating proliferation to this, but something has to be mutated before you can get to cancer.

DR. SLAGA: Yes. But I'm just saying somebody has a small melanoma, and what's the effect of the compound?

DR. ANDERSEN: But wouldn't the irritant respond --

DR. HILL: That's what I'm guessing.

DR. MARKS: Yes.

DR. ANDERSEN: -- to a better indicator --

SPEAKER: Irritant.

DR. ANDERSEN: Under those circumstances?

DR. SLAGA: Yes.

DR. ANDERSEN: Indicate -- indicative of (inaudible).

DR. SLAGA: And that's why a lot of occasions where we would say non-irritating.

DR. ANDERSEN: Yes.

DR. HILL: Yes.

DR. MARKS: Yes, I have that as a question here. So, Ron Shank, in terms of I think at least it sounds like we're down to making a

recommendation for the DEA amides. And it would appear we could go with safe unless the reproductive and developmental toxicity of a

representative compound are necessary or that the data that we have on DEA and MEA in rat or rabbit, are they sufficient to say safe for --

so, I think, let me see. I am the one who proposes this tomorrow, so I'm going to propose that we reopen cocamide DEA and that we are

going to add these other 40 --

DR. HILL: Well, I wanted to talk about several of the amines that --

DR. MARKS: Okay. I know you initially highlighted a couple, Ron Hill, but you didn't say I want to take them off the table, so, we'll go to

that and it seems like we've taken care of the issue with sensitivity because the use concentrations are below what we are concerned about we

deal with it and use the N nitroso compounds that they reformulated to avoid that.

DR. SHANK: I withdraw that request for --

DR. MARKS: Okay, so --

DR. SHANK: -- reproductive toxicity.

DR. MARKS: Okay, fine. Well, it's important to explore it, obviously, and make sure, and that should be, I recall, I think at least in either

the summary or the discussion why we can rely on those previous DEA-MEA results, so.

DR. SLAGA: Yeah, the discussions are going to have to be pretty detailed extensively.

DR. MARKS: Yes, so, we want to reopen, correct? Cocamide. So, we'll move, and add-ons. And those 40 going back to those, and you say

amides or amides or it doesn't matter, it depends on --

DR. HILL: Potato, potato.

DR. MARKS: Yes. So --

DR. HILL: You can even say amides. You can say amide, amide, amide.

DR. MARKS: Yes. So, of those 40 --

DR. SLAGA: Which one?

DR. MARKS: Presumably, we aren't going to eliminate the ones that have already been reviewed.

DR. ANDERSEN: Right.



DR. MARKS: (inaudible) sound safe.

DR. ANDERSEN: You scare me (inaudible).

DR. MARKS: Yeah. Anything, Tom, that you would eliminate.

DR. SLAGA: I would refer to Ron on that.

DR. MARKS: Ron and Ron.

DR. SLAGA: Twenty-nine are not being used, as you stated --

DR. MARKS: Yes, I have that, but that doesn't mean that we don't --

DR. SLAGA: I know, it doesn't --

DR. MARKS: We don't eliminate it because it's not used. We have that caveat if it were used; it would be used in similar products and

similar concentration.

DR. HILL: Yes, the ones that I pulled out for at least consideration of elimination aren't because they're structurally dissimilar, and my guess

would be reading across for me becomes much more problematic.

DR. SLAGA: Which are those?

DR. HILL: All right, so, let me go from the end of the table working backwards. The last three on panel book page 56, which is page 23 of

the report.

DR. MARKS: Hold on a second. Fifty-six.

DR. HILL: Of course, part of the structure is missing out of the one, but we know what that is.

DR. MARKS: Hold it a second. That was on 34 looking at it, but you're on 56.

DR. HILL: It's easier to see because the structures are there. Panel Book 56, report page 23.

DR. MARKS: Right. Does this correspond? This isn't in the same. Okay, so, we go to this table, the ones you want to eliminate. So, on

page 56, you would eliminate those three?

DR. HILL: I would.

DR. SLAGA: The last three?

DR. HILL: I would.

DR. SHANK: I had a question marked from those.

DR. MARKS: Okay. And we can work this out tomorrow, but, okay, one page 55.

DR. HILL: The last four. The last two are diethanolamines, so now we have a propinable amine moiety. I would expect that to cause big

differences in both physical chemical characteristics for those who would have to worry about potential nitrosamine formation, and

biologically, there's no reason to believe that those would be the same as the others. If they're structurally quite dissimilar, if you really look

at them carefully. And the other two on those pages are PEGs, and that doesn't necessarily mean to me that they're going to be a problem, but

one thing is that the reference that's given is for PEG 4, 6, et cetera, et cetera, but these are PEG 2 and PEG 3 compounds, so it would be

extrapolating downwards, and I know we have some precedent for that, but not with these kinds of molecules.

DR. SLAGA: Well, we reviewed --

DR. SHANK: Yes, we did.

DR. SLAGA: We did PEGs again, and --

DR. HILL: Yes, but they were the PEGs, not these amides. There was no nitrogen in them. So, these are quite different than the PEGs

themselves, and they referenced similar molecules starting with PEG 4 and up. No PEG 2 and 3. That's reference 44, I think, or is that just

straight PEGs? I thought there was an amino version that we're referring to that this was an appropriate reference, but let's see, 44. No, these

are just polyethylene glycols. There are no PEG 2 and 3.

DR. MARKS: So, do you still want to eliminate the glycol --



DR. HILL: And I'm not even sure that's relevant anyway because, honestly, I think there's no way that amide is going to get cleaved to

PEGs, and there's a nitrogen in there, they're just different.

MS. FIUME: If they weren't, Doctor, would the triethylene glycol that was in the report correspond to the PEG 3?

DR. HILL: Because of the amide moiety in the middle of these, they're just quite different than PEGs.

DR. MARKS: Okay, so --

DR. HILL: I look at those and say there's no reason to believe the biology of these should be similar to PEGs.

DR. MARKS: So, you would eliminate those 4 on page 55?

DR. HILL: I would.

DR. MARKS: So, that's the glycol ethers and amidoethyl compounds?

DR. HILL: I don't know if any of those are in current use. I didn't check.

DR. ANDERSEN: And then the rest of it --

DR. HILL: The only other one --

DR. ANDERSEN: -- has the differences in the R group.

DR. HILL: Yes. Right. Well, except -- right, and then the R group that's very different that jumps out at me is the lactamide DEA.

DR. MARKS: And what --

DR. HILL: And that's on page 19.

DR. MARKS: Panel Book.

DR. HILL: Panel Book 52.

DR. MARKS: Fifty-two. Lactamide DEA, that one.

DR. HILL: Structurally, that just jumps out at me as why is this in with all these others that are long chained?

DR. MARKS: That's the alpha hydroxy. Okay.

DR. HILL: And not that I have any reason to believe, but we have limited toxicology on that molecule that we know, toxicology on that

molecule.

DR. ANDERSEN: Let's see. On the (inaudible) molecule, yes, on lactic acid --

DR. HILL: No, lactamide DEA, which is, I mean, I don't think that that lactamide DEA should relate to lactic acid toxicology at all because I

don't believe that molecule would be cleaved to lactic acid and DEA. I highly doubt that. So, metabolism would be quite different, biology

should be quite different, lactic acid, looking at that is irrelevant as far as I'm concerned.

DR. MARKS: So, that means, and, actually, again, the principles we were doing with reopening was they should be no-brainer add-ons. So,

if you have any question at all, it seems to me we should eliminate these eight ingredients. Does that sound --

DR. HILL: Because, for me, the rest --

DR. MARKS: Because I've heard you've got a couple questions, too. So, that means that we would have the cocamide DEA and 32 add-ons.

Is that correct?

DR. ANDERSEN: There are 41 total.

DR. MARKS: Oh, yes.

DR. ANDERSEN: And you subtract the nine --

DR. MARKS: Eight.

MS. FIUME: Eight.



DR. ANDERSEN: Subtract the 8, so there should now be 33, which is cocamide plus 32.

DR. MARKS: Thirty-two.

DR. ANDERSEN: Yes.

DR. MARKS: Yes.

MS. FIUME: I just wanted to point out that, not that it probably makes a difference, but lecithin (inaudible) DEA is insufficient for products

where it's likely to be inhaled. It's not in use, so, I'm guessing it doesn't matter, but just so that you're aware that that does have insufficiency

in the conclusion.

DR. HILL: Yes, it just didn't trouble me because what we're really talking about is the fatty acids that came from the hydrolysis of lecithin,

which are then converted to DEA amides, which I would wager that amongst the others in the table, every single one of those will be there.

Lecithin has a fairly limited spectrum of fatty acids that are present in large amount.

DR. SLAGA: But you said it was insufficient?

MS. FIUME: In the products that could be inhaled.

DR. SLAGA: Oh.

MS. FIUME: Otherwise, it was safe as used in rinse-offs, safe at less than or equal to 50 percent in leave-ons.

DR. HILL: But that's lecithin itself, right?

MS. FIUME: Lecithin itself.

DR. HILL: Yes, and, so, I don't think that's relevant. To me, I wrote irrelevant.

DR. MARKS: So, reopen cocamide DEA, add on these amides, and then the conclusion's going to be safe, and do we want to include that,

that it should not be used ingredients in cosmetic products in which N nitroso compounds are formed? That's what was in the cocamide DEA

in 1996. Did we want to include that?

DR. SHANK: I would.

DR. MARKS: Pardon?

DR. SHANK: I would.

DR. MARKS: Would, yes. Okay.

DR. LORETZ: Is that the wording you want or do you want the should not be used in products containing N nitroso agents?

DR. HILL: I think --

DR. LORETZ: Isn't that the old warning because you said cosmetic products shouldn't contain N nitroso agents. So, right, so, the cocamide

DEA re-review was newest warning?

DR. ANDERSEN: Linda, could you read that again, the --

DR. LORETZ: Yes, the two --

DR. ANDERSEN: -- one that you suggested?

DR. LORETZ: Well, the two wordings are should not be used in products containing nitroso agents.

DR. SHANK: That's really not the best way you can say it.

DR. MARKS: This is should not be used as an ingredient in cosmetic products in which N nitroso compounds are formed. Okay.

MS. FIUME: So, the wording in the DEA itself document is different. Is that okay? That is that these ingredients should be formulated to

avoid the formation of nitrosamines.

DR. SHANK: It's different wording. The same. But to say whether nitrosating agents in the formulation, that's really not correct.

MS. FIUME: But should the wording between the DEA amide report and the DEA report be --



DR. SHANK: Well, this is a boilerplate, so whatever the boilerplate comes out to be.

MS. FIUME: Okay.

DR. SLAGA: And that's the new one, right?

DR. ANDERSEN: Well, I like what we what we're saying for this report better than what Monice just read for the --

DR. SHANK: DEA.

DR. ANDERSEN: -- earlier discussion.

DR. SHANK: Okay. So, the one the

DR. Marks read.

DR. MARKS: Yes, so, it'll be safe obviously in the present use and concentration, and that these ingredients should not be used as an

ingredient cosmetic products in which N nitroso compounds are formed.

DR. ANDERSEN: And one other question for Ron Hill, the European review flagged a limit on, let's see, let me get it right the first time.

Maximum secondary amine content of 5 percent. Do you care about that?

DR. HILL: I assume that's referring to DEA when it says that.

DR. ANDERSEN: Probably.

DR. HILL: However, actually, with the complete list of ingredients, there are a couple where there could be secondary amines as part of this.

So, two of the ones that I propose that we remove, there could be secondary amines in the structure other than DEA. But if we removed

those, then that's not relevant, and we're just talking about the contaminants. So, maybe language still needs to be there, but it would refer to

the contaminant.

DR. ANDERSEN: Well, the European document included all 41. So, maybe that's exactly what they flagged, as well.

DR. HILL: Right, because actually not just those two, but the sarcosinamide, also there's a potential for -- no, not that one, I lied. The third

to the last one, diethanolamine oleamide DEA, because an amino moiety in there, so there could be a secondary amine. This one has it.

DR. ANDERSEN: Yes.

DR. HILL: It's not an amide. So, there could be a secondary amine if there was a contaminant from production.

DR. ANDERSEN: But you were talking about a DEA limit. So, to some extent, that covers it. And then the other thing I found fascinating

that I had not seen before, hadn't heard in our discussions, it says, "Keep in nitrite- free containers." I would just like --

DR. SHANK: Well, that's a commonly misunderstood thing that nitrite is a nitrosating agent, and it's just not. It can lead to the formation of

nitrosating agents, but nitrite will not nitrosate anything.

MS. FIUME: Before we move up, can I ask for the discussion, the specific items that you would like in there?

DR. MARKS: You anticipated my --

MS. FIUME: Am I going a step ahead of you?

DR. MARKS: No, no, you're right on, that's good. So, reopen cocamide DEA, we're going to propose that a -- let's see, this would be a

tentative report at this point. Tentative report with a conclusion.

DR. ANDERSEN: Tentative amended because --

DR. MARKS: Tentative, right. Thank you. Amended report with a conclusion that these 33 compounds are safe, and I'll go over those, as

long as they are formulated, should not be used as ingredients in cosmetic products in which -- and we talked about that -- compounds are

formed, and then I think now we're into the discussion points, yes. So, one of the discussion points is going to be the reproductive and

developmental toxicity.

DR. HILL: Logic for why we don't need it.

DR. MARKS: Yes.

MS. FIUME: And that's because of the information that's already included in the DEA and --



DR. MARKS: MEA.

MS. FIUME: MEA report.

DR. MARKS: Right, and the --

DR. SHANK: And all of the other half of or other side of the molecule.

MS. FIUME: Yes.

DR. MARKS: Okay, other important discussion points?

DR. SHANK: DEA content.

DR. SLAGA: Yeah. And the reason why eliminating the limits of cocamide DEA because of the concentration of use.

DR. MARKS: DEA content, specifically, what did you want to --

DR. SHANK: To refer to the DEA document that --

DR. MARKS: Oh, yes.

DR. SHANK: That it shouldn't exceed what the DEA document says. However you want to word that.

DR. MARKS: DEA limits, yes.

DR. SHANK: The nitrosation point of the -- in nitrosation (inaudible).

DR. HILL: And I don't know if it's possible, and it might just lead to more problems than it's worth, but if there were a way to capture what

Ivan's mentioning, that the correlation for the biologic response and (inaudible) tends to be related to DEA contamination. If you'll know

what I'm talking about. I don't know if there will be a clean way to capture it.

DR. MARKS: Okay, anything else?

MS. FIUME: There are a few inhalation uses. So, would you like that in the discussion, as well, the boilerplate (inaudible) discussion or just

DEA section?

DR. SHANK: Use for inhalation as possible. It's not used for inhalation, so.

MS. FIUME: Cocamide DEA has one use --

DR. SHANK: Where inhalation's possible, right?

MS. FIUME: -- (inaudible), yes.

DR. SHANK: Then we need the usual caveat there.

DR. MARKS: And what was that?

MS. FIUME: The inhalation --

DR. SHANK: Caveat.

MS. FIUME: -- boilerplate (inaudible).

DR. MARKS: Okay. So, the N nitro boilerplate and the inhalation boilerplate. And then what you're referring to, Tom, about the use and

concentration of sensitivity, that's not only for cocamide DEA, but when we go down here, it's also for the --

DR. SLAGA: The ones that have been reviewed.

DR. MARKS: Reviewed before. I think that's important --

DR. SLAGA: Yes.

DR. MARKS: -- in the discussion to say we were aware of these limitations that the present use that's below those. So, it alerts the reader

that maybe they need to go back to those original documents that they want to see why those concentrations were established. Okay.



DR. SHANK: How about cocamide being on the carcinogenicity of the NTP study, cocamide DEA? We handled that in the DEA document.

Should that be repeated again here because we talked about the carcinogenicity.

DR. SLAGA: Right.

DR. SHANK: I don't think you should just leave it out.

DR. MARKS: So, that --

DR. SHANK: So, whatever we are going to say with the DEA document, we should repeat here. On the carcinogenicity. That NTP study.

DR. MARKS: NTP carcinogenicity study.

MS. FIUME: And that would build in with what you were talking about, correct, about development?

DR. HILL: Yes, absolutely.

DR. MARKS: Okay. Anything else?

DR. SLAGA: (inaudible) the discussion anyway.

DR. MARKS: Okay. These are loaded up front. Ron, before you take off and run away. So, next, we're into -- you think it's going to get

any easier now?

DR. ANDERSEN: TEA.

DR. MARKS: TEA. And we laid the groundwork to make it easier. And just --

SPEAKER: Yeah.

DR. SHANK: It's a good term.

Full Panel

DR. MARKS: DEA keeps coming up a lot and TEA and MEA in this meeting, and in March of this year the panel decided to reopen the

safety assessment in DEA and we split these out, the recommendation. And actually in looking that cocamide DEA was reviewed in 1996,

we took this opportunity to consider reopening that safety assessment also. So, if we go to page 52 in the book we'll go over the ingredients.

There are a number of add-ons and on page 52 we felt the alpha hydroxy should be eliminated. That was not a no-brainer add-on, the

lactimide DEA. And if we go on page 55 and 56, the glycol ethers and amidoethyls and the others, we would delete those last seven

compounds in this Table 1. So, we would make a motion that a tentative amended report with cocamide DEA be reopened, that there be 32

add-ons and that there would be formulated -- they're safe as long as they're formulated to be non-irritating and also that, again, the caveat

about the N-nitrosa compounds be included.

DR. BERGFELD: Would that be included in the conclusion or in the discussion?

DR. MARKS: If you look there in the second paragraph, the memo, it was actually in the conclusion for cocamide DEA, so I would

suggest that it should be not used as an ingredient in a cosmetic product in which N-nitroso compounds are formed. If it's strong

enough to be in the conclusion we leave it there, if the panel feels that it could be in the discussion, then that's fine, too, although

previously this morning we included it in the conclusion.

DR. BELSITO: We're fine with that in the conclusion. I'll second that. There needs to be an inhalation boilerplate. Otherwise we agree.

DR. BERGFELD: And you agreed with the deletion of those certain ingredients?

DR. BELSITO: Dan.

DR. LIEBLER: I was just browsing through and I didn't get to the table when you were actually reading those. Could you just read those

one more time for me? Thanks.

DR. MARKS: Sure, if you go on the actual Panel Book, page 52, so that's Table 1.

DR. LIEBLER: Right.

DR. MARKS: There was one compound on that table, that was the lactamide DEA, that's under the alpha hydroxy group, it's only one

compound.

DR. LIEBLER: Okay.



DR. MARKS: Then we keep going over the next two pages, nothing there, and then the next compounds were all at the end. So, on page 55

it was the glycol ethers. Also on 55 it was the amidoethyl compounds, and then under 56 it was the others. So, all four -- I mean, seven of

those compounds would be eliminated as add-ons.

DR. LIEBLER: Okay.

DR. BELSITO: Yeah, I mean, again, I think the whole principle of add-ons, they should be no-brainers. If we're going to sit here and argue

about it then it's not a no-brainer, so fine.

DR. LIEBLER: I'm fine with it. Yes.

DR. BERGFELD: Good. Any other comments?

DR. MARKS: Are we into the discussion points?

DR. BERGFELD: Yes, discussion.

DR. MARKS: So, I think, Don, you had made one. We -- since there were previous ingredients that were reviewed in various

concentrations, we felt that that could be handled in the discussion, again referring back to the use in concentration in terms of the

sensitization issue. We thought in the discussion that we should talk about the DEA content and DEA limit, reference that. There weren't

significant reproductive and development toxicity data in this report, but we felt that representative compounds like DEA, MEA in a rabbit

and rat were okay and should reference that. Don, you had mentioned the inhalation and then again we felt the NTP carcinogenicity study

should be mentioned in the discussion.

DR. BERGFELD: Any other additions to the discussion? Or any major comments about the rest of the document? Seeing none I'm going to

call for the question. All those in favor indicate by raising your hand.



Rep

ort

Final Amended Report

DEA Amides 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, and Bart Heldreth, Ph.D., Chemist.

© Cosmetic Ingredient Review 1101 17th Street, NW, Suite 412 " Washington, DC 20036-4702 " ph 202.331.0651 " fax 202.331.0088 "

[email protected]



ii

Table of Contents

Abstract ............................................................................................................................................................................................................ 1 Introduction ...................................................................................................................................................................................................... 1 Chemistry ......................................................................................................................................................................................................... 2

Definition and Structure .............................................................................................................................................................................. 2 Method of Manufacture ............................................................................................................................................................................... 2 Impurities .................................................................................................................................................................................................... 2

Use .................................................................................................................................................................................................................... 3 Cosmetic ..................................................................................................................................................................................................... 3 Non-Cosmetic ............................................................................................................................................................................................. 4

Toxicokinetics .................................................................................................................................................................................................. 4 Absorption, Distribution, Metabolism and Excretion .................................................................................................................................. 4

In Vitro ................................................................................................................................................................................................... 4 Dermal .................................................................................................................................................................................................... 5

Non-Human ...................................................................................................................................................................................... 5 Oral ........................................................................................................................................................................................................ 5

Non-Human ...................................................................................................................................................................................... 5 Intravenous ............................................................................................................................................................................................. 5

Non-Human ...................................................................................................................................................................................... 5 Toxicological Studies ....................................................................................................................................................................................... 6

Single Dose (Acute) Toxicity ...................................................................................................................................................................... 6 Dermal .................................................................................................................................................................................................... 6 Oral ........................................................................................................................................................................................................ 6

Repeated Dose Toxicity .............................................................................................................................................................................. 7 Dermal .................................................................................................................................................................................................... 7 Oral ........................................................................................................................................................................................................ 9

Reproductive and Developmental Toxicity ...................................................................................................................................................... 9 Genotoxicity ................................................................................................................................................................................................... 10 Carcinogenicity ............................................................................................................................................................................................... 11

Dermal .................................................................................................................................................................................................. 11 Irritation and Sensitization .............................................................................................................................................................................. 13

Dermal Irritation........................................................................................................................................................................................ 13 Non-Human .................................................................................................................................................................................... 13 Human ............................................................................................................................................................................................ 14

Sensitization .............................................................................................................................................................................................. 14 Human .................................................................................................................................................................................................. 14

Provocative Testing ........................................................................................................................................................................ 15 Co-Reactivity .................................................................................................................................................................................. 15 Case Studies .................................................................................................................................................................................... 15

Phototoxicity/Photosensitization ............................................................................................................................................................... 15 Human .................................................................................................................................................................................................. 15

Ocular Irritation ......................................................................................................................................................................................... 15 In Vitro ........................................................................................................................................................................................... 15 Non-Human .................................................................................................................................................................................... 16

Summary ........................................................................................................................................................................................................ 16 Discussion....................................................................................................................................................................................................... 18 Conclusion ...................................................................................................................................................................................................... 19 Tables ............................................................................................................................................................................................................. 20

Table 1. Conclusions of previously reviewed ingredients and components ............................................................................................. 20 Table 2. Definitions and Structures .......................................................................................................................................................... 21 Table 3. Physical and chemical properties ............................................................................................................................................... 24 Table 4a. Frequency and concentration of use according to duration and type of exposure ..................................................................... 26 Table 4b. Ingredients not reported to be in use ........................................................................................................................................ 27 Table 5. Status for use in Europe according to the EC CosIng Database ................................................................................................. 28 Table 6. Conclusions of NTP dermal carcinogenicity studies .................................................................................................................. 28

References ...................................................................................................................................................................................................... 29



1

ABSTRACT

The CIR Expert Panel re-reviewed the safety of cocamide DEA, and also assessed the safety of 32 diethanolamides as used in cosmetics. Cocamide DEA is reported to function in cosmetics as a surfactant-foam booster or a vis-cosity increasing agent; most of the amides included in the safety assessment have these same functions, although a few may function differently. The Panel reviewed available animal and clinical data, as well as information from previous CIR reports; while these ingredients are not salts and do not readily dissociate in water, amidases present in human skin could potentially convert these amides to DEA and the corresponding fatty acids. The Panel concluded that the diethanolamides named in this safety assessment 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

While the CIR Expert Panel re-opened the safety assessment of diethanolamine (DEA) to include DEA salts and

esters, a determination was made to address the safety of DEA amides separately as a re-review of the previously reviewed

Cocamide DEA. Cocamide DEA was last reviewed in 1996, with the conclusion that this particular diethanolamide is safe

as used in rinse-off products and safe at concentrations ≤10% in leave-on cosmetic products, and that cocamide DEA should

not be used as an ingredient in cosmetic products in which N-nitroso compounds are formed.1 (Cocamide DEA originally

had been reviewed in 1986.2)

The Panel has determined that the following 32 diethanolamides should be included because the data for Cocamide

DEA and other available information supports the safety of the entire group:

Almondamide DEA Apricotamide DEA Avocadamide DEA Babassuamide DEA Behenamide DEA Capramide DEA Cornamide DEA Cornamide/Cocamide DEA Hydrogenated Tallowamide DEA Isostearamide DEA* Lanolinamide DEA Lauramide DEA* Lauramide/Myristamide DEA Lecithinamide DEA Linoleamide DEA* Minkamide DEA

Myristamide DEA* Oleamide DEA Olivamide DEA* Palm Kernelamide DEA Palmamide DEA Palmitamide DEA Ricebranamide DEA Ricinoleamide DEA Sesamide DEA Shea Butteramide/Castoramide DEA Soyamide DEA Stearamide DEA* Tallamide DEA Tallowamide DEA Undecylenamide DEA Wheat Germamide DEA

The ingredients marked with an asterisk (*) also have been reviewed previously by the CIR Expert Panel.

Lauramide DEA, linoleamide DEA, and oleamide DEA were reviewed in 1986, at which time the Panel concluded that these

ingredients are safe as used, and that they should not be used in products containing nitrosating agents.2 In 1995, the Expert

Panel concluded that isostearamide DEA, myristamide DEA, and stearamide DEA are safe for use in rinse-off products.3 In

leave-on products, these ingredients are safe for use at concentrations that will limit the release of free ethanolamines to 5%,

with a maximum use concentration of 40%.

The ingredients included in this review consist of DEA and one or more components. The safety of many of these

components has been reviewed by the CIR. The conclusions of the previously reviewed ingredients, and of the components

that have been reviewed, are provided in Table 1.



2

CHEMISTRY

Definition and Structure

The diethanolamides consist of covalent, tertiary amides, whereby two of the nitrogen substituents are ethanol (or at

least an ethanol residue) and the third is a carbonyl attached substituent. For example, behenamide DEA is a tertiary amide

wherein two of the nitrogen substituents are ethanol and the third is a 22 carbon, carbonyl attached chain (Figure 1). These

ingredients are not salts and do not readily dissociate in water. However, amidases, such as fatty acid amide hydrolase which

is known to be present in human skin, could potentially convert these amides to DEA and the corresponding fatty acids.4-6

N

O

OH

OH

CH3(CH2)20

Figure 1. Behenamide DEA

The structures and definitions of cocamide DEA and all the DEA amides are provided in Table 2, and available

chemical and physical properties are provided in Table 3.

Method of Manufacture

Specific methods of manufacture of most of the ingredients included in this assessment were not found.

Cocamide DEA

Cocamide DEA is produced by a condensation reaction at a 1:1 or 1:2 molar ratio of a mixture of methyl cocoate, coconut oil, whole coconut acids, or stripped coconut fatty acids to DEA. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2 Cocamide DEA has been produced by the reaction of refined coconut oil with diethanolamine in the presence of sodium methoxide (catalyst), yielding cocamide DEA, 10% glycerine, and 5% coconut fatty acid amide. From the Amended Final Report on the Safety Assessment of Cocamide DEA.1

Lauramide DEA

Lauramide DEA is produced by a condensation reaction at a 1:1 or 1:2 molar ratio of a mixture of lauric and myristic acid to DEA. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Lauramide DEA is produced by the condensation of lauric acid methyl ester with DEA at elevated temperature and

in the presence of a catalyst.7

Oleamide DEA

Oleamide DEA is produced by a condensation reaction at a 1:1 or 1:2 molar ratio of a mixture of oleic acid to DEA. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Linoleamide DEA

Linoleamide DEA is produced by a condensation reaction at a 1:1 or 1:2 molar ratio of a mixture of linoleic acid or its methyl ester to DEA. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Impurities

In the manufacture of the 1:2 mixture of fatty acid to DEA, ethylene glycol and free DEA residues are present. The 1:1 mixture contains much less free amine. Alkanolamides manufactured by base-catalyzed condensation of DEA and the methyl ester of long chain fatty acids are susceptible to nitrosamine formation. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Cocamide DEA

Various grades of cocamide DEA are available. Cocamide DEA contains 4.0-8.5% free DEA. From the Amended Final Report on the Safety Assessment of Cocamide DEA.1



3

In the National Toxicology Program (NTP) studies, cocamide DEA contained approximately 18.2% free DEA by

weight, alkanolamides of unsaturated acids, and amine salts of the acids. N-Nitrosodiethanolamine (NDELA) was detected at

a concentration of 219 ppb.8

Commercial samples of cocamide DEA were analyzed for DEA.9 The amount of DEA in the 9 samples ranged from

3.2-14.0%. NDELA was not found in any of the samples.

Lauramide DEA

Various grades of lauramide DEA are available for cosmetic use. The free amine value is 10-35. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

In the NTP studies, the purity of lauramide DEA was approximately 90% for lauric acid DEA condensate, with

approximately 5% amine (probably DEA) and approximately 5% other organic impurities.7 NDELA was detected at a

concentration of 3600 ppb. The report also stated that, based on data provided by the manufacturer, lauramide DEA

contained 0.83% free DEA by weight, and approximately 9% other organic impurities.

Commercial samples of lauramide DEA were analyzed for DEA.9 The amount of DEA in the 9 samples ranged

from 1.2-12.4%. NDELA was not found in any of the samples.

Stearamide DEA

Stearamide DEA is characterized by 9-12% free fatty acids (as oleic acid) and 2-6% free amines (as DEA). From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA3

Oleamide DEA

Oleamide DEA contains 6.0-7.5% free fatty acids (as oleic acid). From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

In the NTP studies of oleamide DEA, the oleic acid DEA condensate content was 47.5%.10 Impurities were

identified as other fatty acid alkanolamides (approximately 30%), other fatty acids, and unidentified impurities. Free DEA

was estimated at 0.19%; NDELA was detected at a concentration of 68 ppb.

Linoleamide DEA

Commercial sample of linoleamide DEA were analyzed for DEA, and 4.3-5.0% was detected.9 NDELA was not

found in any of the samples.

USE

Cosmetic

Cocamide DEA is reported to function in cosmetics as a surfactant-foam booster or a viscosity increasing agent.11

Most of the other diethanolamides are reported to have these same functions, although a few are reported to function as a hair

conditioning agent, skin conditioning agent, surfactant-cleansing or surfactant-emulsifying agent, or as an opacifying agent.

Voluntary Cosmetic Registration Program (VCRP) data obtained in 2011 indicate that cocamide DEA is used in 710

cosmetic formulations, the majority (596) of which are rinse-off formulations.12 According to data submitted in response to a

survey conducted by the Personal Care Products Council (Council), cocamide DEA is used at concentrations of 0.5-7%.13,14

The highest concentration of cocamide DEA reported to be used in leave-on products is 2%. Lauramide DEA is reported to

be used in 281 cosmetic formulations at 0.2-9%; the use of lauramide DEA at 9% is the highest concentration of use in a

leave-on product reported for any of the diethanolamides. Linoleamide DEA has the highest concentration of use reported,

12%, and that is in rinse-off formulations. The remaining diethanolamides have less than 35 reported uses, and the majority

of the ingredients are not reported to be in use. Concentration and frequency of use data for in-use diethanolamides are



4

provided in Table 4a. Ingredients not reported to be in use, according to VCRP data and the Council survey, are listed in

Table 4b.

Cocamide and lauramide DEA are reported to be used in baby products, and some of the dialkanolamides are used

in products that come in contact with the mucous membranes. Additionally, some of the dialkanolamides are reported to be

present in hair sprays or fragrance formulations, and effects on the lungs that may be induced by aerosolized products con-

taining these ingredients are of concern. The particle size of aerosol hair sprays and 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.

Fatty acid dialkanolamides are listed in Annex III of the European Cosmetics Directive, which is a list of substances

cosmetic products must not contain except subject to the restrictions laid down.15 The restrictions for these ingredients are:

maximum secondary amine content of 0.5% in the finished product; do not use with nitrosating systems; maximum second-

ary amine content of 5% for raw materials; maximum nitrosamine content of 50 µg/kg; and keep in nitrite free containers.

The ingredients listed in Annex III with these restrictions, as well as additional EC information,16 are provided in Table 5.

Non-Cosmetic

Many of the ingredients included in this safety assessment have use as indirect food additives.17

Cocamide DEA

Cocamide DEA is used as a corrosion inhibitor in metalworking fluids and in polishing agents. From the Amended Final Report on the Safety Assessment of Cocamide DEA1

TOXICOKINETICS

Absorption, Distribution, Metabolism and Excretion

[14C]Lauramide DEA partitioned well into rat and human liver slices, and the absorbed radioactivity was mostly unchanged lauramide DEA. In the media, 18-42% of the radioactivity was present in the form of metabolites. Using micro-somes to compare hydroxylation, lauramide DEA 12-hydroxylase activity in human liver microsomes was similar to that in rat liver microsomes, but three times the rate observed in rat kidney microsomes.

Mice and rats were exposed dermally to 5-800 mg/kg and 25 or 400 mg/kg [14C]lauramide DEA, respectively. In rats, absorption was similar for each dose when calculated as a percentage of dose, and absorption was greater in mice (50-70% of the applied dose) than in rats (20-24%). In rats, the parent compound and the half-acid amide metabolites were de-tected in the plasma. Repeated application of 25 mg/kg/day lauramide DEA did not appear to affect absorption or excretion. In rats dosed orally with 1000 mg/kg [14C]lauramide DEA, after 72 h, 4% of the dose was recovered in the tissues and 79% in the urine; at 6 h, no DEA, DEA metabolites, or unchanged lauramide DEA were found in the urine; only very polar metab-olites were found. With intravenous (i.v.) dosing, a 50 mg/kg dose of lauramide DEA was quickly metabolized and eliminated by mice; approximately 95% of the dose was excreted in the urine in 24 h. More than 80% of a 25 mg/kg dose was excreted in the urine by rats in 24 h. In Vitro

Lauramide DEA

Human liver slices, and liver slices from diethylhexyl phthalate-(DEHP) induced and untreated male F344 rats, were

incubated with [14C]lauramide DEA.18 Lauramide DEA “partitioned well” into the human liver slices and the liver slices

from DEHP-induced and treated rats. Approximately 70% of the radioactivity absorbed into the slices in 4 h. The absorbed

radioactivity was present mostly as lauramide DEA. In the media from the human, rat, and DEHP-induced rat liver slice

incubations, 32, 18, and 43% of the radioactivity, respectively, was present in the form of metabolites. The analytes present

in the incubation media included half-acid amides, parent lauramide DEA, and three other metabolites that are products of ω-

and ω-1 to 4 hydroxylation.



5

The in vitro metabolism of [14C]lauramide DEA, randomly labeled on the DEA moiety, was examined in liver and

kidney microsomes from rats and humans to determine the extent of hydroxylation, and to determine the products formed.19

Incubation of lauramide DEA with liver microsomes from control and DEHP-treated rats produced two major high perform-

ance liquid chromatography peaks that were identified as 11-hydroxy- and 12-hydroxy-lauramide DEA. Treatment with

DEHP increased the 12-hydroxylation rate 5-fold, while the 11-hydroxylase activity was unchanged. Upon comparison of

lauramide DEA hydroxylation rates using human liver microsomes from the rates measured using rat liver and kidney

microsomes, the lauramide DEA 12-hydroxylase activity in human liver microsomes was similar to the activity in liver

microsomes from control rats. The 12-hydroxylase activity in liver microsomes was 3 times greater than that observed in rat

kidney microsomes.

Dermal

Non-Human

Lauramide DEA

Groups of four male B6C3F1 mice and four F344 rats were dosed dermally with [14C]lauramide DEA that was

randomly labeled on the DEA moiety.18 The vehicle was ethanol. A non-occlusive application was made to a 0.5 sq. in. area

of skin of mice and to a 1 sq. in. area of skin of rats. At the end of the study, the excised skin was rinsed with ethanol.

Absorption was calculated from the total disposition of radioactivity in the tissues, urine, feces, and dose site. In mice dosed

with 5-800 mg/kg [14C]lauramide DEA, 50-70% of the applied radioactivity was absorbed at 72 h, and absorption was similar

for all the doses. Approximately 32-55% of the radioactivity was excreted in the urine. In rats dosed with 25 or 400 mg/kg

lauramide DEA, 21-26% of the radioactivity penetrated the skin in 72 h, and 3-5% was recovered at the site of application.

Approximately 20-24% of the radioactivity was recovered in the urine. The tissue/blood ratio was greatest in the liver and

kidney. Lauramide DEA and the half-acid amide metabolites were detected in the plasma, with maximum levels found 24 h

after dosing.

The researchers also applied 25 mg/kg/day lauramide DEA, 5 applications/wk for 3 wks, to a group of 5 rats to

examine the effects of repeated administration on absorption and excretion. The rate of absorption of lauramide DEA did not

vary much at the different collection time points, and the amounts excreted were similar at each collection period.

Oral

Non-Human

Lauramide DEA

Three male F344 rats were dosed orally with [14C]lauramide DEA that was randomly labeled on the DEA moiety,

16-18 µCi/dose, and that was formulated with an appropriate amount of unlabeled lauramide DEA and water to give delivery

of the target dose in a volume of 5 ml/kg bw.18 After oral dosing with 1000 mg/kg [14C]lauramide DEA, approximately 10,

60,and 79% of the dose was recovered in the urine after 6, 24, and 72 h, respectively. Approximately 4% of the dose was

recovered in the tissues after 72 h, with almost 3% found in adipose tissue and 1.3% in the liver. At 6 h, no DEA, DEA

metabolites, or unchanged lauramide DEA were present in the urine; only very polar metabolites were found. The re-

searchers postulated that the metabolites were carboxylic acids, and that the acid function was formed from the lauryl chain.

Intravenous

Non-Human

Lauramide DEA

Three male B6C3F1 mice and four F344 rats were dosed i.v. with [14C]lauramide DEA that was randomly labeled on

the DEA moiety, 3-5 µCi and 16-17 µCi, respectively, and that was formulated to deliver a target dose in a volume of 4



6

ml/kg in mice and 1 ml/kg in rats.18 The dose for mice was 50 mg/kg and the dose for rats was 25 mg/kg. In B6C3F1 mice,

lauramide DEA was quickly metabolized and eliminated. At 24 h after dosing, approximately 95% of the dose was excreted,

with 90% found in the urine; the highest concentrations and total amounts of the lauramide DEA were in adipose tissue. In

F344 rats, 50% of the dose was excreted in the urine within the first 6 h, and more than 80% was excreted in the urine by 24

h. The rats were killed at 72 h after dosing, and only 3% of the dose was recovered in the tissues; 1% of the dose was in the

adipose tissue and 0.67% was found in the liver.

TOXICOLOGICAL STUDIES

Acute dermal testing with 50% lauramide DEA and undiluted and 10% aq linoleamide DEA, and acute oral testing with several fatty acid diethanolamides, did not result in significant toxicity.

In repeated dose dermal studies with cocamide, lauramide, and oleamide DEA in mice and/or rats, irritation was observed at the site of application. Increases in liver and kidney weights were observed in most studies, while decreases in body weight were observed sporadically. The incidence of renal tubule regeneration was greater in female rats dosed with 100-400 mg/kg cocamide DEA when compared to controls. A formulation containing 3% linoleamide DEA was not a cumulative systemic toxicant in a 13-wk dermal study; dermal irritation was observed.

With repeat oral dosing of lauramide DEA, the no-observed effect level (NOEL) was 0.1% in feed in a study with SPF rats and 250 mg/kg/day in a study using Wistar rats. The NOEL for Beagle dogs fed lauramide DEA for 12 wks was 5000 ppm.

Data on the reproductive and developmental toxicity of the diethanolamides were not found. Available reproductive and developmental toxicity data on DEA and some of the fatty acids and other components from previous CIR reports were reviewed, and no significant effects were noted.

Single Dose (Acute) Toxicity

Dermal

Lauramide DEA

In an acute dermal toxicity study using guinea pigs, 50% lauramide DEA in corn oil was non-toxic. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Linoleamide DEA

Linoleamide DEA, tested as 10% aq. and undiluted, was nontoxic in acute studies with guinea pigs. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Oral

Cocamide DEA

In an acute oral toxicity test in male and female Sprague-Dawley rats, undiluted cocamide DEA had an LD50 of 12.2 g/kg. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

The acute oral toxicity of cocamide DEA was determined using groups of 3 male and 3 female Wistar rats. Three or

more animals per group died with doses of ≥6.3 g/kg.20

Lauramide DEA

In rats, the oral LD50 of 25% lauramide DEA in corn oil was >5 g/kg, of 10% aq. was 2.7 g/kg, of a shampoo formulation containing 8% lauramide DEA was 9.63 g/kg, and of a bubble bath containing 6% lauramide DEA was >15 g/kg. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Stearamide DEA

The oral LD50 of a mixture containing 35-40% stearamide DEA was >20 g/kg in CFW mice. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA3

Oleamide DEA

In rats, the oral LD50 of undiluted oleamide DEA was 12.4 ml/kg. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2



7

Linoleamide DEA

In rats, the oral LD50 of undiluted and 10% aq. linoleamide DEA was >5 g/kg, and the LD50 of a product containing 1.5% linoleamide DEA was 3.16 g/kg. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Repeated Dose Toxicity

Dermal

Cocamide DEA

A shaving cream containing 1.92% cocamide DEA was applied to the intact or abraded skin on the back of 8 New Zealand White (NZW) rabbits. Applications of 500 mg/kg of the test product were made 5x/wk for 4 wks. Dermal irritation was observed at both intact and abraded application sites. No systemic effects attributed to dosing were observed. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

The repeated-dose dermal toxicity of cocamide DEA (containing 18.2% free DEA by wt) was evaluated using mice

and rats. Groups of 10 male and 10 female B6C3F1 mice were dosed with 50, 100, 200, 400, or 800 mg/kg bw cocamide

DEA in ethanol (20-320 mg/ml), 5 exposures/wk, for 14 wks.8 Vehicle only was applied to the negative control group. All

animals survived until study termination. Dermal irritation was observed at the application site of males and females of the

800 mg/kg dose group. Epidermal and sebaceous gland hyperplasia, parakeratosis, chronic active inflammation, and

ulceration were observed; severity generally increased with increased dose. Final mean body weights and mean body weight

gains were similar for test and control animals. The absolute and relative liver and kidney weights to body weights of males

and females of the 800 mg/kg group, relative liver weights to body weights of females of the 400 mg/kg group, and absolute

and relative lung weights to body weights of females of the 800 mg/kg group were significantly greater than for those of the

controls. The epididymal spermatozoal concentration was significantly greater in males of the 800 mg/kg dose group.

Groups of 20 male and 20 female F344/N rats were dosed dermally with 25, 50, 100, 200, or 400 mg/kg/bw

cocamide DEA in ethanol (30-485 mg/ml), 5 exposures/wk, for 14 wks; 10 rats per group were used for clinical chemistry

and hematology evaluation.8 Vehicle only was applied to the negative control group. All animals survived until study

termination. Dermal irritation was observed at the application site of 2 males and one female of the 100 mg/kg group and in

nearly all males and females of the 200 and 400 mg/kg dose groups. Lesions included epidermal and sebaceous gland

hyperplasia, parakeratosis, chronic active inflammation, and ulceration; incidence and severity generally increased with in-

creasing dose. Final mean body weights and mean body weight gains of males and females of the 200 and 400 mg groups

were significantly less than those of the controls. Kidney weights of females of the 50 mg/kg group were significantly

greater than those of the controls. Decreases in epididymal weights in 200 and 400 mg/kg males were attributed to decreased

body weights. Changes in some hematology and clinical chemistry parameters were noted and the researchers stated there

was an indication of altered lipid metabolism, as evidenced by decreased cholesterol and triglyceride concentrations. The

incidences of renal tubule regeneration were greater in females of the 100 dose group, and the incidences and severities were

greater in females of the 200 and 400 mg/kg dose groups, as compared to controls.

Lauramide DEA

The dermal toxicity of lauramide DEA was evaluated in two 13-wk studies using Sprague-Dawley rats. A 0.45% aq. solu-tion of a cream cleanser containing 4.0% lauramide DEA, tested in 15 females, and a medicated liquid cleanser containing 5.0% lauramide DEA, tested in 10 males and 10 females, did not have any systemic toxic effects. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

The repeated-dose dermal toxicity of lauramide DEA (90% purity; 0.83% free DEA by wt) was evaluated in mice

and rats. Groups of 10 male and 10 female B6C3F1 mice were dosed with 50, 100, 200, 400, or 800 mg/kg bw lauramide

DEA in ethanol, 5 exposures/wk, for 14 wks.7 Vehicle only was applied to the negative control group. All animals survived

until study termination. Dermal irritation was observed at the application site in males and females dosed with 400 or 800



8

mg/kg lauramide DEA. Final mean body weights and mean body weight gains were similar for test and control animals. The

absolute kidney weights of males of the 100, 400 and 800 mg/kg bw groups, the relative kidney to body weights of all dosed

males, and the liver weights of females of the 200, 400, and 800 mg/kg bw groups, were statistically significantly greater than

those of the control mice. The absolute thymus weights of males of the 400 and 800 mg/kg groups were significantly less

than those of the controls. There were no statistically significant differences in reproductive tissue evaluation or estrous cycle

between the treated and control groups. At the application site, incidences of non-neoplastic lesions of the skin, including

hyperplasia of the epidermis and sebaceous gland, chronic inflammation, parakeratosis, and ulceration, were increased in

males and females dosed with ≥200 mg/kg lauramide DEA.

Groups of 20 male and 20 female F344/N rats were dosed dermally with 25, 50, 100, 200, or 400 mg/kg bw

lauramide DEA in ethanol, 5 exposures/wk for 14 wks; 10 rats per group were used for clinical pathology.7 Vehicle only was

applied to the negative control group. All animals survived until study termination. Dermal irritation was observed at the

application site of males dosed with ≥100 mg/kg and in females dosed with 200 or 400 mg/kg lauramide DEA. Final mean

body weights and mean body weight gains of males of the 200 and 400 mg/kg bw group were statistically significantly less

than those of the control group. Kidney weights of females dosed with 200 or 400 mg/kg bw were statistically significantly

greater, and absolute liver weights of males dosed 400 mg/kg lauramide DEA were statistically significantly less, than those

of the control groups. There were no statistically significant differences in reproductive tissue evaluation or estrous cycle

between the treated and control groups. At the application site, incidences of non-neoplastic lesions of the skin, including

hyperplasia of the epidermis and sebaceous gland, chronic inflammation, parakeratosis, and ulceration, were statistically

significantly increased with increasing dose.

Oleamide DEA

The repeated-dose dermal toxicity of oleamide DEA (47.5% oleic acid DEA condensate content; 0.19% free DEA)

was evaluated using mice and rats. Groups of 10 male and 10 female B6C3F1 mice were dosed with 50, 100, 200, 400, or

800 mg/kg bw oleamide DEA in ethanol (20-320 mg/ml), 5 exposures/wk, for 13 wks.10 Vehicle only was applied to the

negative control group. All animals, except one high dose male, survived until study termination. Final mean body weights

and body weight gains of males of the 800 mg/kg group and females of the 400 mg/kg group were statistically significantly

less than those of controls. Dermal irritation was observed at the application site of all treated males and for most females

dosed with ≥100 mg/kg oleamide DEA. Lesions included epidermal hyperplasia, parakeratosis, suppurative epidermal and

chronic active dermal inflammation, sebaceous gland hypertrophy, and ulceration; severity generally increased with increased

dose. Heart weights of females of the 200 mg/kg and males and females of the 400 and 800 mg/kg groups, kidney weights of

males of the 50, 100, and 400 mg/kg groups, and liver weights of all dose groups were statistically significantly greater than

those of controls. The incidences of hematopoietic cell proliferation of the spleen of males of the 800 mg/kg group and

females of the 400 and 800 mg/kg groups were statistically significantly greater than the controls. Sperm motility and

vaginal cytology parameters of dosed mice were similar to those of the controls.

Groups of 20 male and 20 female F344/N rats were dosed dermally with 25, 50, 100, 200, or 400 mg/kg bw olea-

mide DEA in ethanol (30-485 mg/ml), 5 exposures/wk for 13 wks; 10 rats per group were used for clinical chemistry and

hematology evaluation.10 Vehicle only was applied to the negative control group. All animals survived until study termina-

tion. Dermal irritation was observed at the application site of most males dosed with ≥100 mg/kg and all females dosed with

≥50 mg/kg oleamide DEA. Lesions included epidermal hyperplasia, parakeratosis, suppurative epidermal and chronic active

dermal inflammation, and sebaceous gland hypertrophy; severity generally increased with increased dose. The final mean

body weights and mean body weight gains of males of the 200 and 400 mg/kg groups and mean body weight gains of females



9

of the 400 mg/kg group were statistically significantly less than controls; some associated lower organ weights were ob-

served. Kidney weights were statistically significantly greater for females of the 200 and 400 mg/kg groups as compared to

controls. Some increases in segmented neutrophil counts and alkaline phosphatase concentrations were reported. There were

no biologically significant differences in sperm motility or vaginal cytology parameters between treated and control rats.

Linoleamide DEA

The dermal toxicity of a shampoo formulation containing 3.0% linoleamide DEA was evaluated in a 13-wk study. The test article was applied as a 2.5% solution, a 25% solution, or a 25% solution that was rinsed after 15 min, to groups of 10 male and 10 female Sprague-Dawley rats. Dermal irritation was observed, but the formulation containing 3% linoleamide DEA was not a cumulative systemic toxicant. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Oral

Lauramide DEA

The oral toxicity of lauramide DEA was evaluated in two 13-wk dietary studies. In the first study, 0-2% lauramide DEA was evaluated using groups of 15 male and 15 female SPF rats. A reduction in growth was associated with reduced feed intake at doses of ≥0.5% lauramide DEA. There were no treatment-related gross or microscopic lesions. The no-effect dose was 0.1% lauramide DEA. In the second study, groups of 20 male and 20 female Wistar rats were fed 0-250 mg/kg/day. No adverse effects were reported, and the no-effect dose for rats was 250 mg/kg/day. Groups of 4 male and 5 female Beagle dogs were fed 0-5000 ppm lauramide DEA for 12 wks. No adverse effects were reported, and the no-effect dose for dogs was 5000 ppm lauramide DEA. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

Data on the reproductive and developmental toxicity of the diethanolamides were not found. Since DEA may be

present as an impurity in the DEA amides, and since amidases in the skin might convert some of the DEA amide to DEA and

the corresponding fatty acid, summary data from the reports on DEA and the other “components” of these dialkanolamides is

being provided.

DEA: Hair dyes containing up to 2% DEA were applied topically to the shaved skin of groups of 20 gravid rats on days, 1, 4, 7, 10, 13, 16, and 19 of gestation, and the rats were killed on day 20 of gestation. No developmental or reproductive effects were observed.21 In a study in which gravid mice were dosed dermally with 20-320 mg/kg DEA from day 6 of gestation through PND 21, no effects on skeletal formation were observed, but dose-dependent effects on some growth and developmental parameters were observed. In a study in which parental mice were treated dermally with 20-320 mg/kg DEA for 4 wks prior to mating, sperm motility was decreased in a dose-dependent manner. In rats and rabbits, dermal dosing with up to 1500 mg/kg/day and 350 mg/kg/day DEA, respectively, during gestation, did not have any fetotoxic or teratogenic effects. The NOEL for embryonal/fetal toxicity was 380 mg/kg/day for rats and 350 mg/kg/day for rabbits.22 In an oral developmental study in which rats were dosed with up to 1200 mg/kg/day DEA on days 6-15 of gestation, maternal mortality was observed at doses of ≥50 mg/kg; the NOEL for embryonal/fetal toxicity was 200 mg/kg/day. In a study in which gravid rats were dosed orally with up to 300 mg/kg/day DEA, the dams of the 300 mg/kg group were killed due to excessive toxicity; the LD50 was calculated to be 218 mg/kg. The LOAEL for both maternal toxicity and teratogenicity was 125 mg/kg/day.22 In a developmental study in which rats were exposed by inhalation to DEA on days 6-15 of gestation, the NOAEC for both maternal and developmental toxicity was 0.05 mg/l, and the NOAEC for teratogenicity was >0.2 g/ml.22 Lecithin: In oral studies, ≤1600 mg/kg lecithin was not a reproductive toxicant in mice or rats and ≤47 mg/kg was not a reproductive toxicant in rabbits. In an i.v. reproductive study, the lowest toxic daily i.v. dose for rats was >1000 mg/kg. Lecithin, ≤3.0 mM, had no significant effect on human sperm motility.23 Palm Oil: Crude palm oil was not a reproductive toxicant in a study in which male and female Wistar/NIN inbred weanling rats were fed a diet containing this ingredient (10%) prior to mating. Mean litter sizes were comparable between test and control groups. No significant changes were found in liver or kidney weight in adult animals. Neither untreated palm oil (15%) nor 15% heated palm oil in the diet induced anomalies with respect to fertility and in utero growth when fed to male and female Sprague-Dawley SPF rats prior to mating. In a study investigating the effects of palm oil on sexual maturation and endocrine function, vaginal opening was observed significantly earlier (compared to 5% corn oil control) in weanling rats fed 20% palm oil in the diet. No significant differences were observed in endocrine function.24



10

Palm Kernel Oil: In the second generation resulting from the mating of adult Mongolian gerbils fed a diet containing 8.75% w/w palm kernel oil, no statistically significant differences were found with respect to the following: frequency of litters, mean litter size, total of newborns, and suckling death. Animals receiving a basal diet served as the control.24 Ricinus Communis (Castor) Seed Oil: Groups of mice and rats fed diets containing 0.62%, 1.25%, 2.5%, 5.0%, and 10% castor oil continuously for 13 wks had a slight decrease in epididymal weight (6% to 7%) in mid and high-dose groups of male rats; however, this finding was not dose-related. No effects on any other male reproductive endpoint (testes weight and epididymal sperm motility, density, or testicular spermatid head count) or female reproductive endpoint (estrous cycle length, or time spent in each phase of the cycle) were noted. Castor oil served as the vehicle control in a study evaluating the effect of long-term treatment with ICI 182,780 (an anti-estrogen) on the rat testis. In the control group, four male Sprague-Dawley rats were injected subcutaneously with castor oil (0.2 ml) once per week and then killed 100 days after the first injection. Spermatogenesis appeared normal in each of the four control rats.25 Sesamum Indicum (Sesame) Seed Oil: Although not teratogenic, oral dosing with sesame oil (4 ml doses) increased the incidence of resorptions in rats when compared to controls. In a 42-week two-generation reproduction study involving rats, sesame oil (vehicle control, dose volume not stated) did not induce any adverse effects on reproductive performance, fertili-ty, or reproductive organ weights of male or female rats through 2 consecutive generations. Oral dosing with sesame oil (vehicle control, single intragastric dose [not stated]) on day 9 of gestation also had no adverse effect on the fetal survival rate or crown-rump length in mice. Dosing with sesame oil subcutaneously (s.c.) did not adversely affect the development of mice receiving doses (0.05 ml injections) beginning at 3 to 5 days of age or induce teratogenic effects in their offspring. In a study involving rats, dosing with sesame oil s.c. (0.05 ml injections) did not have an adverse effect on the following when compared to untreated controls: uterine and ovarian weight (female rats) and weight of the testes, prostate, and semi-nal vesicles (male rats). Dosing with sesame oil intraperitoneally (0.4 ml) was associated with a marked increase in the incidence of deciduomas in mice.26 Tall Oil Acid: No treatment-related effects were observed in rats used in rats fed diets containing 5% and 10% tall oil acid in a two-generation study.27

GENOTOXICITY

Cocamide DEA, lauramide DEA, and oleamide DEA were, generally, non-genotoxic in a number of assays. Excep-tions were an increase in the frequency of micronucleated erythrocytes in mice by cocamide DEA and the induction of SCEs in CHO cells by lauramide DEA. Cocamide DEA

Cocamide DEA was not mutagenic in an Ames assay (0.1-200 µg/plate), did not induce mutations in L5178Y mouse

lymphoma cells (1.25-50 nl/ml), nor SCEs (0.5-30 µg/ml) or chromosomal aberrations (16-50 µg/ml) in CHO cells; all tests

were performed with and without metabolic activation.8 However, at the end of a 14-wk repeated dose study (described

earlier), significant increases in the frequencies of micronucleated normochromatic erythrocytes were found in peripheral

blood of male and female mice.

Lauramide DEA

Lauramide DEA was not mutagenic or genotoxic in multiple Ames assays, a DNA damage assay using Bacillus subtilis, an in vitro transformation assay using Syrian golden hamster embryo cells, or an in vivo transformation assay using hamster embryo cells. Lauramide DEA was mutagenic in the spot test with two strains of S. typhimurium, but quantitative results were not provided. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Lauramide DEA (0.3-1000 µg/plate) was not mutagenic in the Ames test with or without metabolic activation, and it

was negative in a L5178Y mouse lymphoma assay (2.5-60 µg/ml), did not increase the number of chromosomal aberrations

in CHO cells (1.5-100 µg/ml), with or without metabolic activation, and was not clastogenic in a mouse micronucleus test

(50-800 mg/kg).7 Lauramide DEA (2.49-49.7 µg/ml) induced SCEs in CHO cells, in the presence and the absence of

metabolic activation.

Oleamide DEA

Oleamide DEA was not mutagenic in an Ames test (0.1-200 µg/plate) and did not induce mutations in L5178Y

mouse lymphoma cells (1.25-20 nl/ml), with or without metabolic activation.10



11

CARCINOGENICITY

The carcinogenic potential of dermally applied cocamide, lauramide, and oleamide DEA was evaluated in B6C3F1 mice and F344/N rats by the NTP. (The doses tested are included in parentheses). Cocamide DEA produced clear evidence of carcinogenic activity in male and female mice (100-200 mg/kg) based on increased incidences of hepatic and renal tubule neoplasms, equivocal evidence in female rats (50-100 mg/kg) based on a marginal increase in the incidences of renal tubule neoplasms, and no evidence in male rats (50-100 mg/kg). Lauramide DEA produced some evidence of carcinogenic activity in female mice (100-200 mg/kg, based on increased incidences of hepatocellular neoplasms, and no evidence in male mice (100-200 mg/kg) or male and female rats (50-100 mg/kg). Oleamide DEA produced no evidence of carcinogenic activity in male or female mice (15-30 mg/kg) or male or female rats (50-100 mg/kg). Dermal

Table 6 summarizes the conclusions of the NTP dermal studies on lauramide DEA, oleamide DEA, and cocamide

DEA. (The results from the DEA carcinogenicity study are also provided in this table).

Cocamide DEA

The carcinogenic potential of dermally applied cocamide DEA (containing 18.2% free DEA by wt) was assayed by

the NTP, using B6C3F1 mice and F344/N rats.8 Groups of 50 male and 50 female mice were dosed dermally with 0, 100, or

200 mg/kg cocamide DEA in ethanol, 5 days/wk, for 104-105 wks. There were no statistically significant differences in

survival between the test animals and the controls. Mean body weights of 100 and 200 mg/kg females were less than controls

from wks 93 and 77, respectively. Dermal irritation was observed at the application site of 200 mg/kg males. The incidences

of epidermal and sebaceous gland hyperplasia and hyperkeratosis were statistically significantly greater in all dose groups

compared to the controls, and in the in 200 mg/kg dose group, the incidences of ulceration in males and inflammation and

parakeratosis in females were increased. The incidences of hepatic neoplasms were statistically significantly greater in dosed

male and female mice compared to controls. The incidences of eosinophilic foci in dosed groups of males were increased

compared to controls, and the incidence of nephropathy was statistically significantly less than that of the controls. The

incidences of renal tubule adenoma and of renal tubule adenoma or carcinoma (combined) in 200 mg/kg males were

statistically significantly greater than controls and exceeded the historical control ranges for these neoplasms. In the thyroid

gland, the incidences of follicular cell hyperplasia in all dosed groups of males and females were statistically significantly

greater than the controls. The researchers concluded there was clear evidence of carcinogenic activity in male B6C3F1 mice,

based on increased incidences of hepatic and renal tubule neoplasms, and in female B6C3F1 mice, based on increased

incidences of hepatic neoplasms. The researchers hypothesized these increases were associated with the concentration of free

DEA present as a contaminant in the DEA condensate.

In the rats, groups of 50 males and 50 females were dosed dermally with 0, 50, or 100 mg/kg bw cocamide DEA in

ethanol (0, 85, or 170 mg/ml, respectively), 5 days/wk for 104 wks. Survival and mean body weights were similar in test and

control animals. Dermal irritation was observed at the application site of 100 mg/kg females. The incidences of epidermal

and sebaceous gland hyperplasia, parakeratosis, and hyperkeratosis were statistically significantly greater in all dose groups

compared to the controls; the severity of the lesions generally increased with increasing dose and ranged from minimal to

mild. Incidences of renal tubule hyperplasia in dosed females and of renal tubule adenoma or carcinoma (combined) in

females of the 50 mg/kg group were statistically significantly greater than in the controls. Incidences of nephropathy were

similar between test and control rats; severity in females increased with increasing dose. In the forestomach, the incidences

of chronic, active inflammation, epithelial hyperplasia, and epithelial ulcer were statistically significantly increased in 100

mg/kg females. The incidence of pancreatic acinar atrophy was statistically significantly greater in the 100 mg/kg males than

in the controls. The researchers concluded there was no evidence of carcinogenic activity in male F344/N rats dosed



12

dermally with 50 or 100 mg/kg cocamide DEA. There was equivocal evidence of carcinogenic activity in female F344/N

rats, based on a marginal increase in the incidences of renal tubule neoplasms.

Lauramide DEA

The NTP evaluated the carcinogenic potential of lauramide DEA (90% purity; 0.83% free DEA by wt) using

B6C3F1 mice and F344/N rats.7 Groups of 50 male and 50 female mice were dosed dermally with 0, 100, or 200 mg/kg/day

lauramide DEA in ethanol (0, 50, or 100 mg/ml, respectively), 5 days/wk, for 105-106 wks. There were no clinical findings

attributable to lauramide DEA. In female mice, the incidence of hepatocellular adenoma and carcinoma (combined) were

statistically significantly increased in all dose groups, of hepatocellular adenoma was statistically significantly increased in

females of the 100 mg/kg group, and of eosinophilic foci was statistically significantly increased in the 200 mg/kg group.

The incidences of these lesions in male mice were not statistically significantly different from controls. Incidences of non-

neoplastic lesions of the skin at the site of application were statistically significantly increased in treated males and females;

the lesions were mostly epidermal and sebaceous gland hyperplasia. The incidence of focal hyperplasia of thyroid gland

follicular cells was statistically significantly greater in males of the 200 mg/kg group compared to controls; there were not

corresponding increases in the incidences of follicular cell neoplasms. There was no evidence of carcinogenic activity in

male mice. There was some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of

hepatocellular neoplasms; the researchers hypothesized these increases were associated with free DEA, which was present as

a contaminant.

Groups of 50 male and 50 female rats were dosed dermally with 0, 50, or 100 mg/kg bw lauramide DEA in ethanol

(0, 85, or 170 mg/ml, respectively), 5 days/wk, for 104-105 wks. Survival and mean body weights of test animals were simi-

lar to controls. The only treatment-related clinical finding was minimal to moderate irritation at the application site; epider-

mal and sebaceous gland hyperplasia, hyperkeratosis, and chronic inflammation were statistically significantly increased

compared to controls. The incidence of neoplasms was similar for treated and control rats. The incidence of forestomach

ulcer in the 100 mg/kg group males, of inflammation of the nasal mucosa in all test males, and of chronic inflammation of the

liver in 100 mg/kg females was statistically significantly lower than in the controls. There was no evidence of carcinogenic

activity of lauramide DEA in male or female F344/rats.

Oleamide DEA

The NTP also examined the carcinogenic potential of dermally applied oleamide DEA (47.5% oleic acid DEA

condensate content; 0.19% free DEA) using B6C3F1 mice and F344/N rats.10 Groups of 55 male and 55 female mice were

dosed dermally with 0, 15, or 30 mg/kg oleamide DEA in ethanol (0, 7.5, or 15 mg/ml, respectively), 5 days/wk, for 105 wks;

5 males and 5 females per group were used for a 3-mos interim evaluation. Survival was similar for treated and control mice.

Mean body weights of females of the 30 mg/kg group were less than controls as of wk 76 of the study. Increased incidence

of dermal irritation was observed at the application site of males of the 30 mg/kg dose group. The incidences of epidermal

and sebaceous gland hyperplasia were statistically significantly increased in all male and female dose groups, as compared to

controls, at both the 3-mos and 2-yr evaluation. Additional dermal lesions were observed, but a dose-related increase in

neoplasms was not observed. The incidence of malignant lymphoma in female mice increased with increasing dose, and the

increase was statistically significant in the high dose group. However, the researchers noted that the incidence in the high-

dose group was similar to the incidences observed in other studies that used ethanol as the vehicle. There was no evidence of

carcinogenic activity in male or female mice dosed dermally with ≤30 mg/kg oleamide DEA.

The researchers also dosed groups of 50 male and 50 female rats dermally with 0, 50, or 100 mg/kg oleamide DEA

in ethanol (0, 85, or 170 mg/ml, respectively), 5 days/wk, for 104 wks. Survival was similar for treated and control rats.



13

Mean body weights of males of the 100 mg/kg group were slightly less than controls throughout the study, while in the

females of this dose group, a decrease in body weights was observed from wk 24 on. Mild to moderate irritation was ob-

served at the application site of dosed rats. Skin lesions observed at the application site, including statistically significant

increases in epidermal and sebaceous hyperplasia, were considered indicative of local irritation, with no neoplastic or

preneoplastic changes. The researchers did not consider increased incidences of lesions in the forestomach, testis, and

thyroid gland test article-related. There was no evidence of carcinogenic activity in male or female rats dosed dermally with

≤100 mg/kg oleamide DEA.

IRRITATION AND SENSITIZATION

The dermal irritation of fatty acid diethanolamides, in non-human and human testing, varied greatly with formulation and test conditions. Lauramide DEA and linoleamide DEA were not sensitizers in humans. Cocamide DEA, 0.01-10%, produced positive results in provocative sensitization studies. Lauramide DEA was not phototoxic in humans. The ocular irritation of fatty acid diethanolamides varied greatly with formulation and test conditions

Dermal Irritation

Non-Human

Cocamide DEA

Cocamide DEA, 30% in propylene glycol, was a moderate skin irritant in an irritation study using an occlusive covering. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Lauramide DEA

The dermal irritation potential of lauramide DEA was evaluated in numerous tests using rabbits and guinea pigs. In immer-sion tests using guinea pigs, lauramide DEA, as 0.1-0.5% aq solutions of lauramide DEA was minimally to mildly irritat-ing, a shampoo formulation containing 8% lauramide DEA, tested as a 0.5% solution, was a slight irritant, and a bubble bath containing 6% lauramide DEA, tested as a 0.5% aq. solution, was practically non-irritating. In rabbits, lauramide DEA, tested as a 1.25-10% aq solution, was practically non- to slightly irritating, while a 20% aq. solution was a severe irritant. In a 14-day cumulative irritation test using rabbits, a 1% aq. solution of lauramide DEA was not an irritant, a 5% solution was a moderate irritant, and a 25% solution was a severe irritant. Liquid soap formulations containing 10% lauramide DEA ranged from mildly to severely irritating in rabbit skin. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Stearamide DEA

A mixture containing 35-40% stearamide DEA had a primary irritation score of 0 in a dermal study using rabbits. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA3

Oleamide DEA

Oleamide DEA in propylene glycol was mildly irritating to rabbit skin when tested at 5% and moderately irritating, when tested at 70%. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Linoleamide DEA

Linoleamide DEA, tested as a 0.1-0.5% aq. solution, was non- to slightly irritating in immersion tests with guinea pigs, and a formulation containing 1.5% linoleamide DEA, tested as a 0.5% aq. solution, was a slight irritant in an immersion test. In primary irritation tests using rabbits, 5-10% aq. linoleamide DEA was non to mildly irritating, while an aq. solution of 20% linoleamide DEA was a severe dermal irritant in rabbits. A formulation containing 1.5% linoleamide DEA, tested as a 2.5% aq. solution, was a minimal dermal irritant in rabbits. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Ricinoleamide DEA

Undiluted PEG-20 glyceryl ricinoleate + ricinoleamide DEA was evaluated for dermal irritation in a Draize test

using NZW rabbits.28 A semi-occlusive patch with 0.5 g of the test material was applied to a 6 cm2 shaved site on the dorsal

area of the trunk for 4 h. No signs of irritation were observed, and the surfactant was non-irritating to rabbit skin.



14

Human

Cocamide DEA

The irritation potential of a solution containing 10% cocamide DEA and 20% sodium lauryl sulfate was evaluated in 15 subjects in conjunction with 5 other cosmetic-grade surfactant solutions. Adverse reactions were not observed. The re-searchers concluded that skin irritation was not simply related to the total concentration of the surfactants in contact with the skin, but rather the combination of surfactants present. From the Amended Final Report on the Safety Assessment of Cocamide DEA1

An aq. solution of 12.5 mmol/l cocamide DEA was applied to the forearm of 15 volunteers.29 Twice a day, 5

days/wk, 0.3 ml of the test material was applied for 45 min/exposure, using a plastic chamber, for a total of 28 applications.

The mean transepidermal water loss (TEWL) with cocamide DEA was 7.0 g/m2 l; as a point of comparison, the TEWL with

12.5 mmol/l sodium lauryl sulfate was 15.2 g/m2 l.

The irritation potential of 0.5% aq. cocamide DEA was evaluated in a single insult occlusive patch test using 105

subjects, 14.3% of which were atopic patients.30 A volume of 40 µl was applied using Haye’s test chambers for 48 h, and the

test site was evaluated erythema and edema 15 min and 24 h after patch removal. An untreated occlusive patch was used as a

negative control. Cocamide DEA had a total average index of skin irritation (AII) of 0.065, and was non-irritating (AII <

0.5) based on an amended Draize scale.

Lauramide DEA

Numerous studies were conducted in humans to evaluate the dermal irritation potential of formulations containing laura-mide DEA. In primary irritation tests (single patch) using 17-19 subjects of a shampoo containing 8% and a bubble bath containing 6% lauramide DEA, both tested as a 1.25% aq solution, and an unspecified product containing 5% lauramide DEA, tested as a 1% aq. solution, minimal to mild irritation was observed. In three cumulative irritation soap chamber tests using 12-15 subjects, liquid soap formulations containing 10% lauramide DEA, tested as 8% aq solutions, were essentially non- to mildly irritating. In a 21-day cumulative irritation study, a medicated liquid soap containing 5% lauramide DEA, tested as a 25% solution, was a moderate skin irritant. In use studies, a liquid soap containing 10% lauramide DEA, evaluated in 114 subjects for 4 wks, was minimally irritating under normal use and an acne liquid cleanser containing 5% lauramide DEA, evaluated in 50 subjects with twice daily use for 6 wks, was a mild irritant. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Linoleamide DEA

In a primary irritation (single patch) study, a product containing 1.5% linoleamide DEA, tested as a 1.25% aq. solution in 20 subjects, was a mild skin irritant. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Sensitization

Human

Cocamide DEA

Numerous provocative studies were performed, mostly using patients with occupational exposure to cocamide DEA, to evaluate the sensitization potential of cocamide DEA. Concentrations of 0.01-10% were tested. Positive results were seen in all eight studies. However, during discussion by the Panel, it was noted that there is a need to recognize that, while occupational exposure to cocamide DEA can result in sensitization, cosmetic use does not present the same concerns. From the Amended Final Report on the Safety Assessment of Cocamide DEA1 An in-use study was performed with a shampoo containing 2% cocamide DEA using 104 female subjects. The subjects were patch tested with 2% aq. shampoo before and 10 days after 87 days of using the shampoo. The shampoo containing 2% cocamide DEA was an irritant, but not a sensitizer. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Lauramide DEA

Six repeat insult patch tests (RIPTs) using 41-159 subjects were performed on formulations containing 4-10% lauramide DEA, as 0.25-1.25% solutions. Lauramide DEA was not a sensitizer in any of the studies. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2



15

Linoleamide DEA

In an RIPT conducted with 100% linoleamide DEA on 100 subjects, no irritation or sensitization reactions were observed. A dandruff shampoo containing 1.5% linoleamide DEA, tested as a 1% aq. solution in a RIPT using 101 subjects, was an irritant, but not a sensitizer. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Provocative Testing

Cocamide DEA

Metalworkers that were dermatitis patients were patch tested with 2% DEA in pet.31 The patches were applied for

1-2 days. On day 3, one of 215 patients (0.5%) had a positive reaction.

Co-Reactivity

Cocamide DEA

Thirty-five patients that had positive patch tests to cocamidopropyl betaine, amidoamine, or both, were tested for co-

reactivity with cocamide DEA.32 Two of the patients (5.7%) had positive reactions to cocamide DEA.

Case Studies

Cocamide DEA

One patient with dermatitis on the hands and face, and two with dermatitis on the hands and forearms, were patch

tested using the North American Contact Dermatitis Group standard tray and some additional chemicals.33 The three patients

had either personal or industrial exposure to cocamide DEA-containing products. All three had positive patch test results

(2+) to cocamide DEA, and two had reactions to several other chemicals. In all patients, the dermatitis cleared with avoid-

ance of DEA-containing products.

Undecylenamide DEA

One patient with dermatitis of the hands and axillae had positive test reaction to a liquid soap.34 Subsequent testing

with 0.1 and 1% aq. undecylenamide DEA, an ingredient in the soap, gave positive reactions. In 10 control subjects, testing

with 0.1% undecylenamide DEA was negative.

Phototoxicity/Photosensitization

Human

Lauramide DEA

A liquid soap containing 10% lauramide DEA, tested as a 10% aq. solution in 25 subjects, was not phototoxic. In a photo-sensitivity study of a liquid soap containing 10% lauramide DEA, tested as a 1% aq. solution in 25 subjects, slight irritation was seen in 9 subjects at induction and 4 at challenge, but the test substance was not a photosensitizer. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Ocular Irritation

In Vitro

Cocamide DEA

The ocular irritation potential of cocamide DEA was evaluated in the EpiOcular tissue model, and the irritation

classification was compared to the results of a Draize test.35 In the assay, a 10% solution was classified as a non- to minimal

ocular irritant. This result was similar to a non-irritant score obtained in the Draize test.

Myristamide DEA

The irritation potential of various concentrations of myristamide DEA was evaluated in a neutral red assay. The IC50 values in Chinese hamster fibroblast V79 cells, rabbit corneal cells, and human epidermal keratinocytes were 15.2, 23.9, and 6.2 µg/ml, respectively. The DS20 (concentration predicted to produce a Draize score of 20/110) was 14.4% w/w myristamide DEA. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA3



16

Non-Human

Cocamide DEA

A substance composed of >64% cocamide DEA and <29% DEA was a severe irritant in rabbit eyes. From the Amended Final Report on the Safety Assessment of Cocamide DEA1 Cocamide DEA, 30% in propylene glycol, was at least a mild eye irritant in rabbits. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Lauramide DEA

Five ocular irritation studies were performed in rabbits with lauramide DEA at concentrations of 1-25% One percent aq. lauramide DEA was mildly irritating, 5% was slightly to moderately irritating, 10-20% was moderately irritating, and 25% was moderately to severely irritating. One bubble bath formulation containing 6% lauramide DEA was practically non-irritating, while another was moderately irritating, and three shampoo formulations containing 8% lauramide DEA were non- to moderately irritating. In a mucous membrane irritation test, a soap containing 10% lauramide DEA was significant-ly more irritating than water to vaginal mucosa of rabbits. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Stearamide DEA

A mixture containing 35-40% stearamide DEA was not-irritating to rabbit eyes. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA3

Isostearamide DEA

A formulation containing 8.0% isostearamide DEA was a moderate irritant in rabbit eyes. From the Final Report on Isostearamide DEA & MEA, Myristamide DEA & MEA, and Stearamide DEA & MEA3

Oleamide DEA

Undiluted oleamide DEA was practically non-irritating to rabbit eyes. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Linoleamide DEA

Linoleamide DEA, 10% aq, was practically non-irritating to rabbit eyes, while the undiluted test article was minimally to moderately irritating. A product containing 1.5% linoleamide DEA, applied as a 25% aq solution, and a formulation con-taining 15% linoleamide DEA, were moderate eye irritants in rabbits, while a formulation containing 15% linoleamide DEA, applied as a 25% aq. solution, was mildly irritating. From the Final Report on the Safety Assessment of Cocamide, Lauramide, Linoleamide, and Oleamide DEA2

Ricinoleamide DEA

Undiluted PEG-20 glyceryl ricinoleate + ricinoleamide DEA was evaluated for ocular irritation using NZW

rabbits.28 (The amount of ricinoleamide DEA present was not stated.) No signs of irritation were observed, and the

surfactant was a non-irritant.

SUMMARY

This report assesses the safety of cocamide DEA and 32 additional DEA amides as used in cosmetics. Some of

these ingredients have been previously reviewed by the CIR, and are included here to create a report on the complete family

of ingredients.

Amidases, such as fatty acid amide hydrolase which is known to be present in human skin, could potentially convert

the diethanolamides to DEA and the corresponding fatty acids. The yield of DEA from metabolism of DEA amides in

human skin is unknown.

The diethanolamides generally have some amount of free DEA, and that amount can vary greatly by ingredient. For

example, in the NTP studies, it was estimated that oleamide DEA contained 0.19% free DEA, while cocamide DEA con-

tained 18.2% free DEA by weight.



17

Cocamide DEA is reported to function in cosmetic formulations as a surfactant-foam booster or a viscosity

increasing agent. Most of the other diethanolamides are reported to have these same functions, although a few are reported to

function as a hair conditioning agent, skin conditioning agent, surfactant-cleansing or emulsifying agent, or an opacifying

agent.

VCRP data obtained in 2011 indicate that cocamide DEA is used in 710 cosmetic formulations, the majority of

which are rinse-off formulations. With the exception of lauramide DEA, which is reported to be used in 281 cosmetic

formulations, the remaining DEA amides have less than 35 uses, and most are not reported to be used. The reported concen-

tration of use of the DEA amides ranges from 0.2-12%; the greatest leave-on concentration reported was 9%. Fatty acid

dialkanolamides are allowed for use in products in Europe with restrictions; the restrictions address secondary amine content.

[14C]Lauramide DEA partitioned well into rat and human liver slices, and the absorbed radioactivity was mostly un-

changed lauramide DEA. In the media, 18-42% of the radioactivity was present in the form of metabolites. Using micro-

somes to compare hydroxylation, lauramide DEA 12-hydroxylase activity in human liver microsomes was similar to that in

rat liver microsomes, but three times the rate observed in rat kidney microsomes.

Mice and rats were exposed dermally to 5-800 mg/kg and 25 or 400 mg/kg [14C]lauramide DEA, respectively. In

rats, absorption was similar for each dose when calculated as a percentage of dose, and absorption was greater in mice (50-

70% of the applied dose) than in rats (20-24%). In rats, the parent compound and the half-acid amide metabolites were

detected in the plasma. Repeated application of 25 mg/kg/day lauramide DEA did not appear to affect absorption or excre-

tion. In rats dosed orally with 1000 mg/kg [14C]lauramide DEA, 4% of the dose was recovered in the tissues and 79% in the

urine after 72 h; at 6 h, no DEA, DEA metabolites, or unchanged lauramide DEA were found in the urine; only very polar

metabolites were found. With i.v. dosing, a 50 mg/kg dose of lauramide DEA was quickly metabolized and eliminated by

mice; approximately 95% of the dose was excreted in the urine in 24 h. More than 80% of a 25 mg/kg dose was excreted in

the urine by rats in 24 h.

Acute dermal testing with 50% lauramide DEA and undiluted and 10% aq linoleamide DEA and acute oral testing

with several fatty acid diethanolamides did not result in significant toxicity.

In repeated dose dermal studies with cocamide, lauramide, and oleamide DEA in mice and/or rats, irritation was

observed at the site of application. Increases in liver and kidney weights were observed in most studies, while decreases in

body weight were observed sporadically. The incidence of renal tubule regeneration was greater in female rats dosed with

100-400 mg/kg cocamide DEA when compared to controls. A formulation containing 3% linoleamide DEA was not a

cumulative systemic toxicant in a 13-wk dermal study; dermal irritation was observed.

With repeat oral dosing of lauramide DEA, the NOEL was 0.1% in feed in a study with SPF rats and 250 mg/kg/day

in a feeding study using Wistar rats. The NOEL for Beagle dogs fed lauramide DEA for 12 wks was 5000 ppm.

Data on the reproductive and developmental toxicity of the diethanolamides were not found. Available reproductive

and developmental toxicity data on DEA and some of the fatty acids from previous CIR reports were summarized, and no

significant toxic effects were noted. (For DEA, the NOEL for embryonal/fetal toxicity with dermal application was 380

mg/kg/day for rats and 350 mg/kg/day for rabbits. On one oral study, he NOEL for embryonal/fetal toxicity was 200

mg/kg/day in rat, and in another, the LOAEL for both maternal toxicity and teratogenicity was 125 mg/kg/day in rats. In an

inhalation study, in rats, the NOAEC for both maternal and developmental toxicity was 0.05 mg/l, and the NOAEC for

teratogenicity was >0.2 g/ml.)



18

Cocamide DEA, lauramide DEA, and oleamide DEA were, generally, non-genotoxic in a number of assays. Excep-

tions were an increase in the frequency of micronucleated erythrocytes in mice by cocamide DEA and the induction of SCEs

in CHO cells by lauramide DEA.

The carcinogenic potential of dermally applied cocamide, lauramide, and oleamide DEA was evaluated in B6C3F1

mice and F344/N rats by the NTP. (The doses tested are included in parentheses). Cocamide DEA produced clear evidence

of carcinogenic activity in male and female mice (100-200 mg/kg) based on increased incidences of hepatic and renal tubule

neoplasms, equivocal evidence in female rats (50-100 mg/kg) based on a marginal increase in the incidences of renal tubule

neoplasms, and no evidence in male rats (50-100 mg/kg). Lauramide DEA produced some evidence of carcinogenic activity

in female mice (100-200 mg/kg), based on increased incidences of hepatocellular neoplasms, and no evidence in male mice

(100-200 mg/kg) or male and female rats (50-100 mg/kg). Oleamide DEA produced no evidence of carcinogenic activity in

male or female mice (15-30 mg/kg) or male or female rats (50-100 mg/kg).

The dermal irritation of fatty acid diethanolamides, in non-human and human testing, varied greatly with formula-

tion and test conditions. Lauramide DEA and linoleamide DEA were not sensitizers in humans. Cocamide DEA, 0.01-10%,

produced positive results in provocative sensitization studies. Lauramide DEA was not phototoxic in humans. The ocular

irritation of fatty acid also varied greatly with formulation and test conditions.

DISCUSSION

Cocamide DEA has previously been reviewed by the CIR, and the Expert Panel considered whether a re-review

should be re-opened. The Panel agreed to re-open the re-review of cocamide DEA to add 32 similar diethanolamides. Some

of the ingredients included in this re-review, specifically isostearamide DEA, lauramide DEA, linoleamide DEA, myrista-

mide DEA, oleamide DEA, and stearamide DEA, have been reviewed by the CIR in the past. The Panel stated that it was

appropriate to include these previously reviewed ingredients in order to create a complete family. The conclusions regarding

the safety of each of these ingredients were essentially the same, but the wording varied between reports; the conclusions on

each of these ingredients will now be consistent.

While the Panel noted gaps in the available safety data for many of the DEA amides included in this group, the

Panel was able to extrapolate the existing data, including the data from previous CIR assessments as well as data that has

come available since those assessments have been published, to support the safety of all the DEA amides included in this

safety assessment. Those data could be read-across to support the safety of these ingredients due to similar structure activity

relationships and function.

A specific concern of the Panel was the lack of reproductive and developmental toxicity data for any of the DEA

amides. Since DEA may be present as an impurity in the DEA amides, and since amidases in the skin might convert some of

the DEA amide to DEA and the corresponding fatty acid, the Panel determined that data from the CIR safety assessment on

DEA as well as from assessments on the other “components” could be used to resolve this issue. The lack of reproductive

toxicity for DEA or any of the components alleviated this concern.

The Panel was also concerned with levels of free DEA that could be present as an impurity in DEA amides. It was

the opinion of the Panel that the “clear evidence of carcinogenic activity” of cocamide DEA reported for male and female

mice and the “equivocal evidence of carcinogenic activity” of cocamide DEA reported in female rats, as well as “some evi-

dence of carcinogenic activity” of lauramide DEA in female mice, was due to the presence of free DEA. This opinion was

supported by the fact that in carcinogenicity studies on cocamide DEA, lauramide DEA, and oleamide DEA, the level of

carcinogenic activity in the DEA amides corresponded to the amount of free DEA found in the test substance.



19

The Panel was also concerned that free DEA present as an impurity in the diethanolamides could be converted

(nitrosated) into N-nitrosamines that may be carcinogenic. Because of the potential for this process to occur, DEA amides

should not be used in cosmetic products in which N-nitroso compounds are formed.

For the reasons described above, the Panel stated that the amount of free DEA available in DEA amides must be

limited to no more than that considered safe by the Panel, as described in the current CIR report on DEA. (The CIR report on

DEA includes a discussion regarding carcinogenic potential of DEA in animals compared to the relevance in humans.)

The Expert Panel was concerned that the potential exists for dermal irritation with the use of products formulated

using DEA amides. The Expert Panel specified that products must be formulated to be non-irritating.

DEA amides are used in cosmetic products that may be inhaled during use. In practice, however, the particle sizes

produced by cosmetic aerosols are not respirable.

CONCLUSION

The CIR Expert Panel concluded that the cocamide-DEA and the 32 diethanolamides, listed below, are safe when

formulated to be non-irritating. Were ingredients in this group not in current use (as indicated by *) to be used in the future,

the expectation is that they would be used at concentrations that would be formulated to be non-irritating. The Expert Panel

cautions that ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed. The ingre-

dients reviewed in this safety assessment are:

Almondamide DEA* Apricotamide DEA* Avocadamide DEA* Babassuamide DEA* Behenamide DEA* Capramide DEA Cornamide DEA* Cornamide/Cocamide DEA* Hydrogenated Tallowamide DEA* Isostearamide DEA Lanolinamide DEA* Lauramide DEA Lauramide/Myristamide DEA Lecithinamide DEA* Linoleamide DEA Minkamide DEA*

Myristamide DEA Oleamide DEA Olivamide DEA* Palm Kernelamide DEA Palmamide DEA* Palmitamide DEA* Ricebranamide DEA* Ricinoleamide DEA* Sesamide DEA* Shea Butteramide/Castoramide DEA* Soyamide DEA Stearamide DEA Tallamide DEA* Tallowamide DEA* Undecylenamide DEA* Wheat Germamide DEA*



20

TABLES

Table 1. Conclusions of previously reviewed ingredients and components

Ingredient Conclusion Reference

PREVIOUSLY REVIEWED INGREDIENTS

Cocamide DEA safe as used in rinse-off products; safe at concentrations ≤10% in leave-on products; should not be used as an ingredient in cosmetic products in which N-nitroso compounds are formed

1

Isostearamide DEA safe for use in rinse-off products; in leave-on products, safe for use at a concentration that will limit the release of free ethanolamines to 5%, with a maximum use concentration of 40%

3

Lauramide DEA safe as used; should not be used in products containing nitrosating agents 2 Linoleamide DEA safe as used; should not be used in products containing nitrosating agents 2 Myristamide DEA safe for use in rinse-off products; in leave-on products, safe for use at a concentration that will limit the

release of free ethanolamines to 5%, with a maximum use concentration of 40%

3

Oleamide DEA safe as used; should not be used in products containing nitrosating agents 2 Stearamide DEA safe for use in rinse-off products; in leave-on products, safe for use at a concentration that will limit the

release of free ethanolamines to 5%, with a maximum use concentration of 40%

3

COMPONENTS

DEA (likely an impurity) current Tentative conclusion: DEA and its salts, except for DEA lauraminopropionate, are safe in the present practices of use and concentration when formulated to be non-irritating; these ingredients should not be used in cosmetic products in which N-nitroso compounds are formed; the available data are insufficient to conclude that DEA-Lauraminopropionate is safe under the intended conditions of use

22

Butyrospermum Parkii (Shea) Butter safe as used 36 Coconut Acid safe as used 36 Corn Acid safe as used 36 Elaeis Guineensis (Palm) Kernel Oil Elaeis Guineensis (Palm) Oil

safe as used 36

Isostearic Acid safe as used 37 Lanolin Acid safe as used in topical applications 38 Lauric Acid safe as used 39 Lecithin safe as used in rinse-off products; safe for use in leave-on products at concentrations of ≤15%; and the

data were insufficient to determine the safety for use in products where lecithin is likely to be inhaled; should not be used in cosmetic products in which N-nitroso compounds may be formed

23

Mink Oil safe as used 40 Myristic Acid safe as used 41 Olea Europaea (Olive) Fruit Oil safe as used 36 Oleic Acid safe as used 39 Orbignya Oleifera (Babassu) Oil safe as used 36 Palmitic Acid safe as used 39 Persea Gratissima (Avocado) Oil safe as used 36 Prunus Amygdalus Dulcis (Sweet Almond) Oil

safe as used 36

Prunus Armeniaca (Apricot) Kernel Oil safe as used 36 Rice Bran Acid safe as used 36 Ricinoleic Acid safe as used 25 Ricinus Communis (Castor) Seed Oil safe as used 25 Sesamum Indicum (Sesame) Oil safe as used 36 Soy Acid safe as used 36 Stearic Acid safe as used 39 Tall Oil Acid safe as used 27 Tallow safe as used 42 Wheat Germ Acid safe as used 36 Zea Mays (Corn) Oil safe as used 36



Table 3. Physical and chemical properties (continued)

21

Table 2. Definitions and Structures

Ingredient CAS No. Definition Function(s) Formula/structure

-Alkyl amides Capramide DEA 136-26-5

a mixture of ethanolamides of capric acid

Surf. - Foam Boosters; Visc. Incr. Ag. - Aq.

N

O

OH

OH

CH3(CH2)8

Undecylenamide DEA 60239-68-1 25377-64-4

a mixture of ethanolamides of undecylenic acid

Hair Cond. Ag.; Surf. - Foam Boosters; Visc. Incr. Ag. - Aq.

N

O

OH

OH

CH(CH2)8CH2

Lauramide DEA 120-40-1

a mixture of ethanolamides of lauric acid

Surf. - Foam Boosters

N

O

OH

OH

CH3(CH2)10

Myristamide DEA 7545-23-5

a mixture of ethanolamides of myristic acid


N

O

OH

OH

CH3(CH2)12

Lauramide/ Myristamide DEA

a mixture of ethanolamides of a blend of lauric and myristic acids


N

O

OH

OH

R

wherein RC(O) represents a 12 or 14 carbon fatty acid residue

Palmitamide DEA 7545-24-6

a mixture of ethanolamides of palmitic acid.


N

O

OH

OH

CH3(CH2)14

Stearamide DEA 93-82-3

a mixture of ethanolamides of stearic acid.


N

O

OH

OH

CH3(CH2)16

Behenamide DEA 70496-39-8

a mixture of ethanolamides of behenic acid


N

O

OH

OH

CH3(CH2)20

-Branched Isostearamide DEA 52794-79-3

a mixture of ethanolamides of isostearic acid


N

O

OH

OH

CH(CH2)14

H3C

H3C

one example of an “iso”

-Partially unsaturated Oleamide DEA 5299-69-4 93-83-4

a mixture of ethanolamides of oleic acid


N

O

OH

OH

CH(CH2)7CH3(CH2)7CH

Linoleamide DEA 56863-02-6

a mixture of ethanolamides of linoleic acid

Hair Cond. Ag.; Surf. - Foam Boosters; Visc. Incr. Ag. - Aq.; Hair Cond. Ag.; Surf. - Foam Boosters; Visc. Incr. Ag. - Aq.

N

O

OH

OH

CH(CH2)7CHCH2CHCH3(CH2)4CH




22


Ingredient CAS No. Definition Function(s) Formula/structure

-Natural source mixtures Almondamide DEA 124046-18-0

a mixture of ethanolamides of the fatty acids derived from almond oil


N

O

OH

OH

R

wherein RC(O) represents the fatty acid residues derived from

almond oil Apricotamide DEA 185123-36-8

a mixture of ethanolamides of the fatty acids derived from Prunus Armeniaca (Apricot) Kernel Oil


N

O

OH

OH

R


Prunus Armeniaca (Apricot) Kernel Oil Avocadamide DEA 124046-21-5

a mixture of ethanolamides of the fatty acids derived from Persea Gratissima (Avocado) Oil


N

O

OH

OH

R


Persea Gratissima (Avocado) Oil

Babassuamide DEA 124046-24-8

a mixture of ethanolamides of the fatty acids derived from Orbignya Oleifera (Babassu) Oil


N

O

OH

OH

R


Orbignya Oleifera (Babassu) Oil Cocamide DEA 61791-31-9

a mixture of ethanolamides of coconut acid


N

O

OH

OH

R


coconut acid Cornamide DEA a mixture of ethanolamides of

corn acid Surf. - Foam Boosters; Visc. Incr. Ag. - Aq.

N

O

OH

OH

R


corn acid Cornamide/ Cocamide DEA

the diethanolamide of a mixture of coconut acid and the fatty acids obtained from Zea Mays (Corn) Oil


N

O

OH

OH

R


coconut acid and Zea Mays (Corn) Oil Hydrogenated Tallowamide DEA 68440-32-4

a mixture of ethanolamides of the fatty acids derived from hydrogenated tallow


N

O

OH

OH

R


hydrogenated tallow Lanolinamide DEA [85408-88-4]

a mixture of ethanolamides of Lanolin Acid


N

O

OH

OH

R


lanolin acid




23


Ingredient CAS No. Definition Function(s) Formula/structure Lecithinamide DEA the mixture of reaction products

of DEA and the fatty acids of lecithin.


N

O

OH

OH

R


lecithin Minkamide DEA 124046-27-1

a mixture of ethanolamides of the fatty acids derived from mink oil.


N

O

OH

OH

R


mink oil Olivamide DEA 124046-30-6

a mixture of ethanolamides of the fatty acids derived from olive oil


N

O

OH

OH

R


olive oil Palm Kernelamide DEA 73807-15-5

a mixture of ethanolamides of the fatty acids derived from Elaeis Guineensis (Palm) Kernel Oil


N

O

OH

OH

R


Elaeis Guineensis (Palm) Kernel Oil Palmamide DEA a mixture of ethanolamides of

the fatty acids derived from Elaeis Guineensis (Palm) Oil


N

O

OH

OH

R


Elaeis Guineensis (Palm) Oil Ricebranamide DEA a mixture of ethanolamides of

rice bran acid Surf. - Foam Boosters; Visc. Incr. Ag. - Aq.

N

O

OH

OH

R


rice bran acid Ricinoleamide DEA 40716-42-5

a mixture of ethanolamides of ricinoleic acid


N

O

OH

OH

R

wherein RC(O) represents the ricinoleic acid residue

Sesamide DEA 124046-35-1

a mixture of diethanolamides of the fatty acids derived from Sesamum Indicum (Sesame) Oil


N

O

OH

OH

R


Sesamum Indicum (Sesame) Oil Shea Butteramide/Castoramide DEA

a mixture of diethanolamides of the fatty acids derived from Butyrospermum Parkii (Shea Butter) and Ricinus Communis (Castor) Seed Oil

Visc. Incr. Ag. - Aq.

N

O

OH

OH

R

wherein RC(O) represents the fatty acid residues derived from Butyrospermum Parkii (Shea Butter) and Ricinus Communis

(Castor) Seed Oil




24


Ingredient CAS No. Definition Function(s) Formula/structure Soyamide DEA 68425-47-8

a mixture of ethanolamides of soy acid


N

O

OH

OH

R


soy acid Tallamide DEA 68155-20-4

a mixture of ethanolamides of the fatty acids derived from tall oil acid


N

O

OH

OH

R


tall oil acid Tallowamide DEA 68140-08-9

a mixture of ethanolamides of tallow acid


N

O

OH

OH

R


tallow acid Wheat Germamide DEA 124046-39-5

a mixture of diethanolamides of wheat germ acid


N

O

OH

OH

R


wheat germ acid

Table 3. Physical and chemical properties

Property Value Reference

Cocamide DEA Physical Form clear viscous liquid 1,8 Color amber or yellow 1,8 Odor faint coconut 1 Molecular Weight 280-290 8 Melting Point 23-35°C 1 Water Solubility soluble in water 1 pH (10% aq. solution) 9.5-10.5 1 Acid Value 3.0 max 1

Capramide DEA Molecular Weight 259.39 43 Density (predicted) 1.001 ± 0.06 g/cm3 43 Boiling Point (predicted) 417.9 ±30.0°C 43 log P (predicted) 3.014 ±0.270 43

Undecylenamide DEA Molecular Weight 271.40 43 Density (predicted) 1.002 ± 0.06 g/cm3 43 Boiling Point (predicted) 440.4 ±40.0°C 43

Lauramide DEA Physical Form viscous liquid or waxy solid 7 Color light yellow (liquid) or white to light yellow (solid) 2 Odor faint, characteristic 2 Molecular Weight 287.44 43 Density 0.984 ± 0.06 g/cm3 (at 20°C) 43 Refractive Index 1.4708 (n30/L) 2 Melting Point 37-47°C 2 Boiling Point 443.2 ± 0.270°C 43 Water Solubility dispersible 2 pH (10% aq. dispersion) 9.8-10.8 2 Acid Value 0.1-14 2




25

Property Value Reference

Alkaline Value 6-200 2 log P (predicted) 4.033 ± 0.270 (at 25°C) 43 pKa pKb

14.13 (at 25°C) -0.85 (at 25°C)

43

Myristamide DEA Physical Form waxy solid 3 Color white to off-white 3 Melting Point 40-54°C 3 Water Solubility dispersible 3 Other Solubility soluble in alcohol, chlorinated hydrocarbons, and aromatic hydrocarbons; dispersible

in mineral spirits, kerosene, white mineral oils, and natural fats and oils

3

pH (10% aq. dispersion) 9.5-10.5 3 log P (predicted) 5.025±0.270 43 Acid Value 1 (max) 3 Alkaline Value 26-50 3

Palmitamide DEA Molecular Weight 343.54 43 Density (predicted) 0.959 ± 0.06 g/cm3 (20°C) 43 Boiling Point (predicted) 492.5 ±30.0°C 43 log P (predicted) 6.071 ±0.270 43

Stearamide DEA Physical Form wax-like solid 3 Color white to pale yellow 3 Molecular Weight 371.60 43 Density (predicted) 0.959 ± 0.06 g/cm3 (20°C) 43 pH (1% aq. dispersion) 9-10 3 log P (predicted) 7.090 ±0.270 43

Behenamide DEA Molecular Weight 427.70 43 Density (predicted) 0.935 ± 0.06 g/cm3 (20°C) 43 Boiling Point (predicted) 562.1 ±30.0°C 43 log P (predicted) 9.128 ±0.270 43

Oleamide DEA Physical Form liquid 2 Color amber 2 Molecular Weight 387.68 10 Specific Gravity 0.99 (25/25°C) 2 Phase Transition congeals at -8°C 2 Boiling Point (predicted) 525.6 ±45.0°C 43 Water Solubility dispersible 2 Other Solubility soluble in alcohols, glycols, ketones, esters, benzenes, chlorinated solvents, and

aliphatic hydrocarbons

2

pH 9-10 2 log P (predicted) 6.681 ±0.275 43

Linoleamide DEA Physical Form syrup-like liquid or wax-like mass 2 Color light yellow (liquid) or white to yellow (mass) 2 Odor characteristic 2 Specific Gravity 0.972-0.982 (25°/25°C) 2 Water Solubility slightly soluble 2 Boiling Point (predicted) 525.6 ±50.0°C 43 Other Solubility soluble in ethanol, propylene glycol, and glycerin; insoluble in mineral oil 2 Acid Value Alkaline Value

2.0 (max) 25-50 (calculated as DEA)

2

log P (predicted) 6.277 ±0.275 43 Ricinoleamide DEA

Molecular Weight 385.58 43 Density (predicted) 1.007± 0.06 g/cm3 (20°C) 43 Boiling Point (predicted) 560.5 ±50.0°C 43 log P (predicted) 4.867 ±0.289 43



26

Table 4a. Frequency and concentration of use according to duration and type of exposure Capramide DEA Cocamide DEA Isostearamide DEA

# of Uses12 Conc of Use (%)13 # of Uses12 Conc of Use (%)13 # of Uses12 Conc of Use (%)13

Totals* 1 NR 710 0.5-7 2 NR Duration of Use

Leave-On NR NR 37 0.5-2 2 NR Rinse Off 1 NR 596 1-7 NR NR Diluted for (Bath) Use NR NR 77 0.4-6 NR NR

Exposure Type

Eye Area NR NR 2 NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Sprays NR NR 1 NR NR NR Incidental Inhalation-Powders NR NR NR NR NR NR Dermal Contact NR NR 342 0.5-6 2 NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 1 NR 221 1-7 NR NR Hair-Coloring NR NR 147 NR NR NR Nail NR NR NR NR NR NR Mucous Membrane NR NR 274 0.4-6 NR NR Baby Products NR NR 10 2 NR NR Lauramide DEA Lauramide/Myristamide DEA Linoleamide DEA

# of Uses12 Conc of Use (%)13 # of Uses12 Conc of Use (%)13 # of Uses12 Conc of Use (%)13

Totals* 281 0.2-9 1 NR 32 1-12

Duration of Use

Leave-On 21 0.2-9 NR NR 3 NR

Rinse-Off 232 0.2-8 1 NR 19 1-12

Diluted for (Bath) Use 28 2-8 NR NR 10 3

Exposure Type Eye Area NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation- Sprays 13a 0.2-9 NR NR 1 NR Incidental Inhalation-Powders NR NR NR NR NR NR Dermal Contact 165 0.2-9 1 NR 20 1-7 Deodorant (underarm) 1 2 NR NR NR NR Hair - Non-Coloring 115 0.3-8 NR NR 4 3-7 Hair-Coloring 2 0.2 NR NR 7 7-12

Nail NR NR NR NR NR NR Mucous Membrane 139 2-8 NR NR 17 3-7 Baby Products 1 NR NR NR NR NR

Myristamide DEA Oleamide DEA Palm Kernelamide DEA

# of Uses12 Conc of Use (%)13 # of Uses12 Conc of Use (%)13 # of Uses12 Conc of Use (%)13 Totals* NR 0.8 5 5 4 2

Duration of Use

Leave-On NR NR 3 NR NR NR

Rinse Off NR 0.8 2 5 4 2

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-Sprays NR NR NR NR NR NR

Incidental Inhalation-Powders NR NR NR NR NR NR

Dermal Contact NR 0.8 4 NR NR NR

Deodorant (underarm) NR NR NR NR NR NR

Hair - Non-Coloring NR NR 1 NR 4 2

Hair-Coloring NR NR NR 5 NR NR

Nail NR NR NR NR NR NR

Mucous Membrane NR 0.8 NR NR NR NR

Baby Products NR NR NR NR NR NR



27

Table 4a. Frequency and concentration of use according to duration and type of exposure Soyamide DEA Stearamide DEA

# of Uses12 Conc of Use (%)13 # of Uses12 Conc of Use (%)13

Totals* 1 NR 10 0.5

Duration of Use

Leave-On NR NR 9 NR

Rinse-Off 1 NR 1 0.5

Diluted for (Bath) Use NR NR NR NR

Exposure Type Eye Area NR NR NR NR Incidental Ingestion NR NR NR NR Incidental Inhalation-Sprays NR NR NR NR Incidental Inhalation-Powders NR NR NR NR Dermal Contact NR NR 9 NR Deodorant (underarm) NR NR NR NR Hair - Non-Coloring 1 NR 1 0.5 Hair-Coloring NR NR NR NR Nail NR NR NR NR Mucous Membrane NR NR NR NR Baby Products 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. NR – none reported

Table 4b. Ingredients not reported to be in use Almondamide DEA Apricotamide DEA Avocadamide DEA Babassuamide DEA Behenamide DEA Cornamide DEA Cornamide/Cocamide DEA Hydrogenated Tallowamide DEA Lactamide DEA Lanolinamide DEA Lecithinamide DEA Minkamide DEA Olivamide DEA Palmamide DEA Palmitamide DEA Ricebranamide DEA Ricinoleamide DEA Sesamide DEA Shea Butteramide/Castoramide DEA Tallamide DEA Tallowamide DEA Undecylenamide DEA Wheat Germamide DEA



28

Table 5. Status for use in Europe according to the EC CosIng Database Fatty Acid Dialkanolamides – listed in Annex III - restrictions15 (maximum secondary amine content of 0.5% in the finished product; do not use with nitrosating systems; maximum secondary amine content of 5% for raw materials; maximum nitrosamine content of 50 µg/kg; keep in nitrite free containers) Almondamide DEA Apricotamide DEA Avocadamide DEA Babassuamide DEA Behenamide DEA Capramide DEA Cocamide DEA Cornamide DEA Cornamide/Cocamide DEA Hydrogenated Tallowamide DEA Isostearamide DEA Lanolinamide DEA Lauramide DEA Lauramide/Myristamide DEA Lecithinamide DEA Linoleamide DEA

Minkamide DEA Myristamide DEA Oleamide DEA Olivamide DEA Palm Kernelamide DEA Palmamide DEA Palmitamide DEA Ricebranamide DEA Ricinoleamide DEA Sesamide DEA Soyamide DEA Stearamide DEA Tallamide DEA Tallowamide DEA Undecylenamide DEA Wheat Germamide DEA

Listed in EC Inventory – no annex specified16 Shea Butteramide/Castoramide DEA Table 6. Conclusions of NTP dermal carcinogenicity studies

Cocamide DEA8 Lauramide DEA7 amount of free DEA 18.2% 0.83% B6C3F1 mice 0, 100, or 200 mg/kg 0, 100, or 200 mg/kg Males clear evidence of carcinogenic activity no evidence of carcinogenic activity Basis increased incidences of hepatic and renal tubule

neoplasms

Females clear evidence of carcinogenic activity some evidence of carcinogenic activity Basis increased incidences of hepatic neoplasms increased incidences of hepatocellular neoplasms F344/N rats 0, 50, or 100 mg/kg 0, 50, or 100 mg/kg Males no evidence of carcinogenic activity no evidence of carcinogenic activity Basis Females equivocal evidence of carcinogenic activity no evidence of carcinogenic activity Basis marginal increase in the incidences of renal tubule

neoplasms

Oleamide DEA10 DEA44 amount of free DEA 0.19% >99% pure B6C3F1 mice 0, 15, or 30 mg/kg 0 , 40, 80, and 160 mg/kg Males no evidence of carcinogenic activity clear evidence of carcinogenic activity Basis increased incidences of liver neoplasms and renal

tubule neoplasms Females no evidence of carcinogenic activity clear evidence of carcinogenic activity Basis increased incidence of liver neoplasms F344/N rats 0, 50, or 100 mg/kg 0, 16, 32, and 64 mg./kg Males no evidence of carcinogenic activity no evidence of carcinogenic activity Basis Females no evidence of carcinogenic activity no evidence of carcinogenic activity Basis



29

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31

41. Becker LC, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report on the amended safety assessment of myristic acid and its salts and esters as used in cosmetics. Int J Toxicol. 2010;29:(Suppl 3):162S-186S.

42. Elder RL (ed). Final report on the safety assessment of tallow, tallow glyceride, tallow glycerides, hydrogenated tallow glyceride, and hydrogenated tallow glycerides. J Am Coll Toxicol. 1990;9:(2):153-164.

43. Advanced Chemistry Development (ACD/Labs). Advanced Chemistry Development software v11.02. 2011. ((C) 1994-2011 ACD/Labs).

44. National Toxicology Program. Toxicology and carcinogenesis studies of diethanolamine (CAS No. 111-42-2) in F344/N rats and B6C3F1 mice. (Dermal studies.) NTP TR 478. 1999. Report No. NTIS PB99-167553.



Data

Personal Care Products CouncilCommitted to Safety,Quality & Innovation

Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)

FROM: 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 thefollowing language in the conclusions of the DEA, DEA Amides and TEA reports: “These ingredientsshould not be used in cosmetic products in which Nnitroso compounds are formed.” This language isalso found in various places in the Tentative reports on “Diethanolamine and its salts as used incosmetics”,”DEA amides as used in cosmetics”, and “Triethanolamine (TEA) and TEA-containingingredients as used in cosmetics”.

Although this language has been used in some CIR reports in the past, it is not appropriate as it impliesthat some cosmetic products are formulated to form N-nitroso compounds. The goal of the cosmeticsindustry 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 Panelmeeting, suggested the following appropriate boilerplate language which should be used in the newDEA, DEA Amides and TEA reports: “The Expert Panel cautions that products containing theseingredients should be formulated to avoid the formation of nitrosamines.”

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Persona’ Care Products Counci’Committed to Safety,Quality & Innovation

Memorandum


FROM: Halyna Breslawec, Ph.D.Industry Liaison to the CIR Expert Panel

DATE: August 3,2011

SUBJECT: Comments on the Tentative Amended Safety Assessment on DEA Amides as Used inCosmetics

Abstract - Please do not use the language “...cosmetic products in which N-nitroso compounds areformed” as it implies that some products are specifically formulated to form nitrosamines.Please use the language in the draft boilerplate document: “The Expert Panel cautions thatproducts containing these ingredients should be formulated to avoid the formation ofnitrosamines.” In the abstract, it would also be helpful to note that DEA is an impurity of theDEA condensate ingredients.

p.3, p.21-22, Table 4a, Cosmetic Use Information - What is the source for the maximum useconcentration for Cocamide DEA of 6% in leave-on products? The Council concentration ofuse information reports a 6% concentration for bath oils, tablets and salts and skin cleansingproducts; neither are considered leave-on products. The maximum leave-on productconcentration for Cocamide DEA appears to be 2% in body and hand products. In Table 4a,what is the source of 0.46% Cocamide DEA for products diluted before use? Perhaps thisshould be 0.4-6. If this range is presented at the top of the table, it should also be presentedunder bath products (it is currently presented as 6%). The Council Concentration of use surveyreported 5% Oleamide DEA in hair dyes and colors. Therefore, the 5% concentration should bein the Hair-Coloring row not the Hair - (non-coloring) row.

p.4- - In the summary of the Toxicological Studies section, please indicate that the 0.1% concentrationin the oral study in SPF rats was in food.

p.6 - Studies in which animals were exposed only during gestation (last two paragraphs under DEAReproductive and Developmental Toxicity) should be called developmental studies rather thanreproductive studies.

p.7 - Please remove the In Vitro subheading from the Genotoxicity section, as an in vivo study isdescribed under the Cocamide DEA subheading. Please add reference numbers to the 14-weekrepeated dose study of Cocamide DEA and the SCE study (in CHO cells) of Lauramide DEA.

p.8, paragraph before Irritation and Sensitization heading - Please correct: “at the application site ofdoses rats”

p.11 - How much Ricinoleamide DEA was in the mixture tested for ocular irritation in rabbits?

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p.12 - In the Summary, it would be helpful to include the maximum dose of DEA that was not areproductive or developmental toxicant.

p.12 - It is not clear what is meant by “biological function”.p.12 - Please do not use the language “...cosmetic products in which N-nitroso compounds are formed”

as it implies that some products are specifically formulated to form nitrosamines. Please usethe language in the draft boilerplate document: “The Expert Panel cautions that productscontaining these ingredients should be formulated to avoid the formation of nitrosamines.”

p.12 - It would be helpful to actually state the concentration(s) of DEA that the C]R Expert Panelconsiders safe.

2



Persona Care Products CouncilCommitted to Safety,Quality & Innovation

Memorandum


FROM: John Bailey, Ph.D.—T——\Industry Liaison to the CIR Expert Panel

DATE: June 24, 2011

SUBJECT: Comments on the Draft Report on DEA Amides Prepared for the June 27-28, 2011 CIRExpert Panel Meeting

p.1 - It is not clear what is meant by “While the ingredients in each subgroup listed above are presentedalphabetically...”, as the ingredients are not presented in subgroups.p.4 - Please indicate that fatty acid dialkanolamides are listed in Annex II of the “European Cosmetics

Directive” rather than the “EC Coslng database”. The Coslng database is a tool to make iteasier to find information regarding cosmetic ingredients in Europe, but the official listing is inthe Cosmetics Directive (soon to be changed to the Cosmetic Regulation). More informationabout cosmetic regulations in Europe can be found athttp ://ec.europa.eu/consumers/sectors/cosmetics/documents/index en.htm

p.8 - In the description of the 14 week mouse study in reference 8 it states that the mice were “dosedwith 50-800 mg/kg bw lauramide DEA in ethanol”. Then it states: “The absolute kidneyweights of males of the 10, 400 and 800 mg/kg bw groups...” Was there a 10 mg/kg dosegroup, or should 10 be 50 mg/kg?

p.10 - What was the dose of Lactic Acid used in the oral study in mice?p.13 - Under Cocamide DEA in the Non-Human Skin Irritation section, it states that irritation potential

was evaluated in “15 subjects”. If the subjects are human, this description needs to be moved tothe human subsection. If the subjects are “non-human”, please provide the species.

p.16 - What was the concentration of Ricinoleamide DEA used in the ocular irritation study in rabbits?p.17 - Please revise the following sentence. “Fatty acid dialkanolamides are allowed [in use] for use in

products in Europe with restrictions.” It should be stated that the restrictions concern levels ofimpurities.

p.17 - The following sentence is not complete. “Mice and rats exposed dermally to 5-800 mg/kg and25 or 400 mg/kg [14C]lauramide DEA, respectively.”

p.18 - Please provide the dose (or concentration) of Cocamide DEA that increased the frequency ofmicronucleated erythrocytes in mice and the dose (or concentration) of Lauramide DEA thatinduced SCEs in CHO cells.

p.19-23, Table 1 - Please provide the reference(s) for Table 1.

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COCAMIDE DEA 6 01A - Baby ShampoosCOCAMIDE DEA 4 01C - Other Baby ProductsCOCAMIDE DEA 6 02A - Bath Oils, Tablets, and Salts 274COCAMIDE DEA 47 02B - Bubble BathsCOCAMIDE DEA 24 02D - Other Bath Preparations 77COCAMIDE DEA 2 03E - Eye Makeup Remover 342COCAMIDE DEA 1 04E - Other Fragrance PreparationCOCAMIDE DEA 1 05A - Hair Conditioner 221COCAMIDE DEA 1 05E - Rinses (non-coloring)COCAMIDE DEA 202 05F - Shampoos (non-coloring)COCAMIDE DEA 7 05G - Tonics, Dressings, and Other Hair Grooming AidsCOCAMIDE DEA 1 05H - Wave SetsCOCAMIDE DEA 3 05I - Other Hair PreparationsCOCAMIDE DEA 144 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests)COCAMIDE DEA 2 06D - Hair Shampoos (coloring)COCAMIDE DEA 1 06G - Hair BleachesCOCAMIDE DEA 2 07I - Other Makeup PreparationsCOCAMIDE DEA 138 10A - Bath Soaps and DetergentsCOCAMIDE DEA 59 10E - Other Personal Cleanliness ProductsCOCAMIDE DEA 2 11E - Shaving CreamCOCAMIDE DEA 2 11F - Shaving SoapCOCAMIDE DEA 33 12A - CleansingCOCAMIDE DEA 7 12C - Face and Neck (exc shave)COCAMIDE DEA 9 12D - Body and Hand (exc shave)COCAMIDE DEA 2 12H - Paste Masks (mud packs)COCAMIDE DEA 4 12J - Other Skin Care Preps 710

LAURAMIDE DEA 1 01C - Other Baby ProductsLAURAMIDE DEA 1 02A - Bath Oils, Tablets, and Salts 139LAURAMIDE DEA 17 02B - Bubble BathsLAURAMIDE DEA 10 02D - Other Bath PreparationsLAURAMIDE DEA 4 05A - Hair Conditioner 115LAURAMIDE DEA 12 05B - Hair Spray (aerosol fixatives)LAURAMIDE DEA 93 05F - Shampoos (non-coloring)LAURAMIDE DEA 4 05G - Tonics, Dressings, and Other Hair Grooming AidsLAURAMIDE DEA 2 05I - Other Hair PreparationsLAURAMIDE DEA 1 06B - Hair TintsLAURAMIDE DEA 1 06D - Hair Shampoos (coloring)LAURAMIDE DEA 59 10A - Bath Soaps and DetergentsLAURAMIDE DEA 1 10B - Deodorants (underarm)LAURAMIDE DEA 52 10E - Other Personal Cleanliness ProductsLAURAMIDE DEA 21 12A - CleansingLAURAMIDE DEA 1 12H - Paste Masks (mud packs)LAURAMIDE DEA 1 12J - Other Skin Care Preps

STEARAMIDE DEA 1 05A - Hair ConditionerSTEARAMIDE DEA 9 12D - Body and Hand (exc shave)

ISOSTEARAMIDE 2 07C - Foundations

OLEAMIDE DEA 1 05F - Shampoos (non-coloring)OLEAMIDE DEA 1 12A - CleansingOLEAMIDE DEA 1 12D - Body and Hand (exc shave)OLEAMIDE DEA 2 12F - Moisturizing

LINOLEAMIDE DEA 1 02A - Bath Oils, Tablets, and Salts 17LINOLEAMIDE DEA 3 02B - Bubble BathsLINOLEAMIDE DEA 1 02C - Bath CapsulesLINOLEAMIDE DEA 5 02D - Other Bath PreparationsLINOLEAMIDE DEA 1 04E - Other Fragrance Preparation



LINOLEAMIDE DEA 4 05F - Shampoos (non-coloring)LINOLEAMIDE DEA 7 06A - Hair Dyes and Colors (all types requiring caution statements and patch tests)LINOLEAMIDE DEA 5 10A - Bath Soaps and DetergentsLINOLEAMIDE DEA 1 10C - DouchesLINOLEAMIDE DEA 1 10E - Other Personal Cleanliness ProductsLINOLEAMIDE DEA 1 12A - CleansingLINOLEAMIDE DEA 1 12D - Body and Hand (exc shave) 20LINOLEAMIDE DEA 1 12J - Other Skin Care Preps

CAPRAMIDE DEA 1 05F - Shampoos (non-coloring)

LAURAMIDE/MYRI 1 12A - Cleansing

PALM KERNELAM 4 05F - Shampoos (non-coloring)

SOYAMIDE DEA 1 05C - Hair Straighteners



Documents

DEA Amides blue - Cosmetic Ingredient Review · 2020-02-29 · TOXNET Search Statements – DEA Family of Ingredients – Jan 7, 2011 SS1 DEA OR DIETHANOLAMINE OR 111-42-2 (only search