blue dea - cosmetic ingredient review · 2020. 2. 29. · dea-lauraminopropionate would more...

BLUE

DEA

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 Diethanolamine (DEA) and Its Salts as Used

in Cosmetics A Revised Tentative Amended Safety Assessment on DEA and Its Salts as Used in Cosmetics was issued by the Expert Panel at the June meeting. The conclusion that was originally issued in March stated that all of the ingredients included in the safety assessment were safe as used when formulated to be non-irritating. It was realized after that Tentative Amended Safety Assessment was issued that there were insufficient data to support the safety of sodium lauraminopropionate for cosmetic use, and therefore, there were no read-across data available to support the safety of DEA-lauraminopropionate. As a result, the Panel issued a revised conclusion that stated DEA and all of the salts except DEA-Lauraminopropionate are safe for use in cosmetics when formulated to be non-irritating, and that the available data are insufficient to make a determination that DEA-Lauraminopropionate is safe for use in cosmetics. In comments submitted by the Council, it is opined that DEA-Lauraminopropionate should be removed from the report, with the following reasoning given: “The insufficient data conclusion is based on a lack of data on the Lauraminopropionate portion of this compound, while the focus of this report is the safety of DEA. DEA-Lauraminopropionate would more appropriately by included in a report on Lauraminopropionic Acid (which is in the Dictionary) and its salts (including the sodium and DEA salts). In addition, the safety of ingredients added to the re-reviews should be supported by the data in the original report. This is not true for DEA-Lauraminopropionate.” During the June meeting, both teams discussed this issue of DEA-Lauraminopropionate, and excerpts from the transcripts follow:

(Dr. Belsito:) Maybe in retrospect, it shouldn't be in there, but we've done it. And to dissect this out again and then have to reissue different reports, I think it's much easier just to say, oops, we made a mistake, we didn't have safety for the lauraminopropionate. We're saying it's insufficient for the nine reasons we had before, issue it again as a tentative final and move on. (Ms. Weintraub:) I actually agree. And I don't think it's necessarily a mistake. I mean, really it shows after the analysis by CIR it provides actually more information for industry based upon the evaluation. So I think it's actually more useful to industry and to the public. And it's, you know, based upon, you know, all the work of the panel, so I think that makes a lot of sense. (Dr. Loretz:) Should they be added to the report if they're not no-brainers? (Dr. Marks:) We've actually split this out from the original report anyway, so even though we reopened that report with the DEA, MEA, and TEA, we're really I think looking at this where it says amended. It's really like a whole new report.

(Dr. Shank:) We went over that before. It's not a simple add-on kind of thing, but we’re totally redoing the DEA, MEA, TEA documents.

Also at the June meeting, the Panel changed the wording in another part of the conclusion. The conclu-sion of the Tentative Amended Safety Assessment issued in March stated, “The Expert Panel cautions that products containing these ingredients should be formulated to avoid the formation of nitrosamines.” In June, the wording for this caveat was changed to “The Expert Panel cautions that these ingredients should not be used in cosmetic products in which N-nitroso compounds are formed.” This change also prompted a comment from the Council. (See the ‘Nitrosamine Formation Boilerplate Language’ memo). While not disagreeing in principle, 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 Amides reports. Since avoiding formation of nitrosamines is the goal, the Panel should again address what language it wants to use to achieve that goal. It is expected that the Panel will discuss and resolve these concerns, and issue a Final Amended Safety Assessment at this meeting.

Distributed for Comment Only -- Do Not Cite or Quote

CIR Panel Book Page 1

History: Diethanolamine

Original Report: In 1983, the Expert Panel determined that TEA, DEA, and MEA were safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin. In products intended for prolonged contact with the skin, the concentration of ethanolamines should not exceed 5%. Ethanolamine (MEA) should be used only in rinse-off products. Triethanolamine (TEA) and diethanolamine (DEA) should not be used in products containing N-nitrosating agents. June 1999: discussed NTP carcinogenicity results for DEA; presentations were made by Dr. Lehman-McKeeman and Dr. Stott June 2008: presentation was made by Dr. Stott; Acetamide MEA was discussed, with reference to the MEA, DEA, TEA report June 2009: discussed DEA carcinogenicity; the DEA report was not be reopened December 2010: formal rereview package was presented to the Panel on TEA, DEA, and MEA

- The report was split into 3 separate documents – DEA, TEA, and MEA - additional ingredients are to be added to each report as appropriate

March 3-4, 2011: Re-Review draft report the RR of DEA was presented to the Panel, including the new ingredient subgroups

- the Panel determined that the report should only contain DEA and Its Salts (minus the phosphate esters),

- the Panel issues a Tentative Amended Report, concluding that these ingredients are safe as used when formulated to be non-irritating, and the Panel cautioned that products containing these ingredients should be formulated to avoid the formation of nitrosamines

June 27-28, 2011- Draft Final Amended Safety Assessment

- The Panel was informed that a previous CIR report on sodium lauraminopropionate had a conclusion of insufficient data; therefore, there were no existing data to support the safety of DEA-lauraminiopropionate

- the Expert Panel is issued a Revised Tentative Amended Safety Assessment with the con-clusion 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

- the Panel also concluded that the available data are insufficient to make a determination that DEA-Lauraminopropionate is safe under the intended conditions of use. The types of data needed include:



- chemical characterization (impurities/purity data) - chemical and physical properties - method of manufacture - 28-day dermal toxicity - dermal reproductive and developmental toxicity - ocular irritation at concentration of use, if available - dermal irritation and sensitization at concentration of use - two different genotoxicity studies (one using a mammalian system); if positive, a dermal

carcinogenesis assay by National Toxicology Program standards will be required - - Depending on the results of these studies, additional data may be required.

September 26-27, 2011: Draft Final Amended Safety Assessment



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1‐7&

12‐11

11‐

23

1/11

1‐25

‐11

1‐ 25 1‐ 25

1‐25

‐11

1‐25

‐11

DE

A 111‐42

‐2

392

35

x

x

II

x

x x

DEA Bisulfa

te

59219‐56

‐6

x

II

DEA‐Myristate

53404‐39

‐0

x

II

DEA Stearate

no

DE

A‐Isostearate

II

DEA‐Lino

leate

59231‐42

‐4

x

II

DEA‐

Lauram

inop

ropion

ate

65104‐36

‐1

x

II

DEA‐Lauryl Sulfate

143‐00

‐0

x

II

DEA‐C1

2‐13

Alkyl

Sulfate

II

DEA‐Myristyl Sulfate

65104‐61

‐2

x

II

DEA‐C1

2‐15

Alkyl

Sulfate

II

DEA‐Ce

tyl Sulfate

51541‐51

‐6

x

II



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DEA‐Laureth Sulfate

58855‐36

‐0

x

II

DEA‐C1

2‐13

Pareth‐3

Sulfate

II

DEA‐Myreth Sulfate

II

DEA‐

Dode

cylben

zene

Sulfo

nate

26545‐53

‐9

x

II

DEA‐Methyl

Myristate Sulfo

nate

64131‐36

‐8

II

DEA‐Ce

tyl Pho

sphate

61693‐41

‐2

x

II

DEA‐Ce

teareth‐2

Phosph

ate

II

DEA‐Oleth‐3

Phosph

ate

58855‐63

‐3

II

DEA‐Oleth‐5

Phosph

ate

58855‐63

‐3

x

II

DEA‐Oleth‐10

Phosph

ate

58855‐63

‐3

II

DEA‐Oleth‐20

Phosph

ate

58855‐63

‐3

II



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DEA‐Hy

drolyzed

Lecithin

II

DEA‐Di(2‐

Hydroxypalmity

l) ‐

Phosph

ate[

no

Methyl

Diethano

lamine

[105

‐59‐9 ]

x

no

x

Butyl D

iethanolam

ine

102‐79

‐4

x

X

N‐Lauryl

Diethano

lamine

[1541‐67

‐9 ]

x

III

Capram

ide DE

A 136‐26

‐5

x

III

Und

ecylen

amide DE

A 60239‐68

‐1; 25377

‐64

‐4

x

III

Lauram

ide DE

A 120‐40

‐1

x

III

x

x

Myristam

ide DE

A 7545

‐23‐5

x

III

Lauram

ide/

Myristam

ide DE

A

III

Palm

itamide DE

A 7545

‐24‐6

x

III

Stearamide DE

A 93

‐82‐3

x

III



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Behe

namide DE

A 70496‐39

‐8

x

III

Lactam

ide DE

A

III

Isostearam

ide DE

A 52794‐79

‐3

x

X

Oleam

ide DE

A 5299

‐69‐4; 93‐83

‐4

x

III

x

x

Lino

leam

ide DE

A 56863‐02

‐6

x

III

Almon

damide DE

A 124046

‐18‐0

x

III

Apricotam

ide DE

A 185123

‐36‐8

x

III

Avocadam

ide DE

A 124046

‐21‐5

x

III

Babassuamide DE

A 124046

‐24‐8

x

III

Cocamide DE

A 61791‐31

‐9

x

III

x

x

x

Cornam

ide DE

A

III

Co

rnam

ide/

Cocamide DE

A

III

Hydrogen

ated

Tallowam

ide DE

A

68440‐32

‐4

x

III

Lano

linam

ide DE

A [85408

‐88‐4]

x

III

Lecithinam

ide DE

A

III



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Minkamide DE

A 124046

‐27‐1

x

III

Olivam

ide DE

A 124046

‐30‐6

x

III

Palm

Kerne

lamide

DEA

73807‐15

‐5

x

III

Palm

amide DE

A

III

Ricebranam

ide DE

A

III

Ricino

leam

ide DE

A 40716‐42

‐5

x

III

Sesamide DE

A 124046

‐35‐1

x

III

Shea

Bu

tteram

ide/Castora

mide DE

A

X

Soyamide DE

A 68425‐47

‐8

x

III

x

Tallamide DE

A 68155‐20

‐4

x

III

x

Tallowam

ide DE

A 68140‐08

‐9

x

III

Whe

at Germam

ide

DEA

124046

‐39‐5

x

III

PEG‐2 Tallowam

ide

DEA

X

PEG‐3 Cocam

ide DE

A

X



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Stearamidoe

thyl

Diethano

lamine

X

Stearamidoe

thyl

Diethano

lamine HC

l

X

DEA‐

Cocoam

phod

ipropion

ate

no

Diethano

laminoo

lea

mide DE

A

X

Stearamide DE

A‐Distearate

X

Cocoyl Sarcosin

amide

DEA

68938‐05

‐6

x

X



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 March 4, 2011 search for Dr. Hill searched the terms: DEA AND (phospholipids OR ceramides OR sphingomyelins OR (cell AND (signaling OR pathways)) OR apoptosis) nothing new found Created SciFinder search – Apr 4, 2011

- Keep Me Posted results are checked weekly



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Repro/Dev Tox

Genotoxicity

Carcinogenicity

Dermal Irr/Sens

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Tran

scripts

June Panel Meeting – Dr. Belsito’s Team

DR. BELSITO: Okay? Moving on up, DEA and related DEA-containing ingredients. This is a Blue Book. And so, at the last panel

meeting we were presented with a huge number of ingredients and we had whittled them down to the ones in this report. And I guess

before we go any further with the whittling, since I'm not a chemist and in the initial report under Organo-Substituted Inorganic Acid

Salts, there was DEA 2 phosphate, cetyl phosphate, dis-2 hydroxypalmitoyl phosphate hydrolyzed lecithin, and oleth- phosphates 3

through 20 that weren't included in this report, although they were under the subheading Organo- Substituted Inorganic Salts. I can't

remember why we didn't include them.

DR. LIEBLER: I think the alkyl phosphates had not been reviewed, right? Excuse me. I think the alkyl phosphates had not been

previously reviewed, and our concern was that that part of that moiety of these molecules more than -- perhaps more than DEA could drive

their properties.

DR. BELSITO: So, it was the phosphate issue.

DR. LIEBLER: Right.

DR. BELSITO: And I'm assuming the hydrolyzed lecithin is because we hadn't looked at hydrolyzed lecithin? Is that it?

DR. LIEBLER: I don't remember for that particular one. The other alkyl phosphates, that was the case.

DR. BELSITO: Because we have DEA hydrolyzed lecithin that was included under the organo-substituted inorganic acid salts that is

not in this report.

MS. FIUME: I want to say it was, because it wasn't reviewed. There's also a chance that it could be because lecithin was insufficient

for aerosol products. So I don't know, that could also have been what caused a problem. I'll grab my old book tonight, I didn't bring it with

me today, and see if it says explicitly. But I'm thinking between one of those two that was the reason.

DR. LIEBLER: Hydrolyzed lecithin would give you choline, right? I think so. That's what you're left with, the phosphate part.

Because this would be a DEA salt. So, anyway, I'm -- it would be helpful if you found it.

DR. BELSITO: Anyway, it was on the original list under the organo-substituted inorganic acid salts, and I just didn't know why we

left that alone. Okay. So, next thing that we partially addressed is that there is DEA lauraminopropionate, which we previously reviewed and

found to be insufficient for nine reasons. And we did the iminodipropionate, and decided that is a totally different animal, and separated them

out. So the question is, whereas before we thought we could go safe as used for the entire group, do we now have to say that the data are

insufficient for the DEA lauraminopropionate, which incidentally has no reported cosmetic uses? And if we do that, then I guess we have to

send this out for another public comment.

DR. LIEBLER: So, I suggested that we delete that ingredient.

DR. BELSITO: And if we delete it, do we have to go out for another public comment?

DR. BRESLAWEC: If we delete it, we do not have to go out for public comment. However, I think you need a good reason to delete

it, other than it's insufficient data. I based the reason more on chemical characterization -- similarity. If it's insufficient data, we'll have to go

out with another report. But at least the procedures are being followed. Monice?

MS. FIUME: Yeah. I think it's exactly what Halyna said. If it's taken out, it doesn't need to be re- announced. But if it does –

DR. BELSITO: Really? If it's taken out I think it would need to be re-announced anyway. What if you actually were using it and you

assumed that we're just going to go safe as used and you have data that might support the safety and said, to heck with it, I'm not going to

send it in, they've already approved it? Why should I share my confidential data?

DR. BRESLAWEC: No, we've taken out stuff based on realization, honestly, at the last minute that it was a different chemical, it had

different chemical characteristics, and didn't belong in the group.

DR. BELSITO: Right. But we can't argue that for this.

DR. BRESLAWEC: I don't know that you can. But it has been -- I mean, the public was aware that that particular ingredient had been

insufficient data. So that's not news.

DR. BELSITO: No, the public wasn't aware of that.

DR. BRESLAWEC: No, I think it was.

DR. BELSITO: At the last meeting, we were going safe as used for that entire group.



MS. FIUME: It actually -- we raised it in the discussion to give people an indication that this might change because after the meeting

is when we realized that there were insufficient data. So if you -- I'm trying to find exactly where it is. On Page 21, the very first paragraph.

DR. BELSITO: But that's a new addition in this discussion.

MS. FIUME: For you.

DR. BELSITO: Right.

MS. FIUME: But not what went out in the tentative report. It's highlighted so that you see it.

DR. BELSITO: Okay. I mean, I'm not the legal expert here. But, I mean, then I would say if we don't have to go out for other public

comment by deleting this, I would delete it and just flag it. And if we ever get around to doing lauraminopropionate, we could throw it in

that report?

DR. BRESLAWEC: What would be the reason for your taking out that particular ingredient?

DR. BELSITO: Because, A, it's not used and, B, we don't have sufficient data to look at the lauraminopropionate.

DR. BRESLAWEC: That's an insufficient part of this molecule is going to be -- I think it would be a driver of its biology and

chemistry, more than the DEA. So, I thought the compounds in this report are the ones for which the DEA should be sort of the driver of its

properties.

DR. BRESLAWEC: Right,

DR. LIEBLER: Right?

DR. BRESLAWEC: And my point is, you can go either way.

DR. LIEBLER: Yeah. So, that's the additional logic that this -- there is enough potential dissimilarity between this compound and the

other ones in the report that it doesn't belong.

DR. BELSITO: You don't think --

DR. LIEBLER: In addition to the fact that it -- that there's not much data and there are no uses.

DR. BELSITO: But Dan, you don't think that dodecylbenzenesulfonate is also driving the safety of that report?

DR. LIEBLER: The DEA dodecylbenzenesulfonate? Hasn't that one already been approved --

DR. BELSITO: Yes.

DR. LIEBLER: -- or has been evaluated safe as used?

DR. BELSITO: Yeah.

DR. LIEBLER: That's the reason I didn't touch that one.

DR. BELSITO: I mean, we can't wag two different tails.

DR. EISENMANN: My concern is that it seems to be your kind of -- this is a re-review. And in the past, you've always said that the

data in the current report should support the safety of the added ingredients. And if it doesn't, then you're not supposed to put the ingredients

in. It's just part -- it's really more of a process. If you're going to change the process, then you should change the process and not, you know,

try to slip in these ingredients that if the data in the report don't support -- in the original report -- because I processed them just slightly

differently than original reports. I don't work so hard to try to contact suppliers because I'm making the assumption that the data in the

original report supports the new ingredients.

DR. LIEBLER: So these are supposed to be no- brainers, right?

DR. EISENMANN: Correct.

DR. LIEBLER: So, at least with the lauraminopropionate, it's certainly not a no-brainer in my view.

DR. BELSITO: Well, I mean, it's the only one. And we've already reviewed the report. And I think at this point it's probably

easier for the writers and easier for us to say that the data are insufficient for the lauraminopropionate, to quote the nine data needs

that we had for lauraminopropionate and to issue it again. Rather than to sit down and take out, you know, what was a no- brainer

and what was not a no-brainer from the report, we've got these -- you know, whether it was a no-brainer to put the dodecylbenzene-



sulfonate in or not, we have safety data for it. We're comfortable with it in this report. Maybe in retrospect, it shouldn't be in there,

but we've done it. And to dissect this out again and then have to reissue different reports, I think it's much easier just to say, oops,

we made a mistake, we didn't have safety for the lauraminopropionate. We're saying it's insufficient for the nine reasons we had

before, issue it again as a tentative final and move on.

MS. WEINTRAUB: I actually agree. And I don't think it's necessarily a mistake. I mean, really it shows after the analysis by CIR it

provides actually more information for industry based upon the evaluation. So I think it's actually more useful to industry and to the public.

And it's, you know, based upon, you know, all the work of the panel, so I think that makes a lot of sense.

DR. BELSITO: Okay.

DR. LIEBLER: No objection.

June Panel Meeting - Dr. Mark’s Team

DR. MARKS: Maybe. The next is the final amended report on diethanolamine and diethanolamine salts as used in cosmetics. This was

originally issued in 1983 where we had three ethanolamines, the tri, di, and mono, and then we decided to split these up. From our meeting

in March we issued a tentative amended safety assessment for DEA and DEA salts. We have 16 that are safe and then we were concerned

about DEA propionate, that there was insufficient data and that all these, the ones that are safe, would be formulated to be nonirritating. So

do we want to move forward with a final with 16 safe and then the one insufficient one?

DR. SHANK: That's fine with me, but I would make extensive changes to the discussion and the conclusion wording.

DR. SLAGA: Related to the choline deficiency?

DR. SHANK: Yes. We explained the carcinogenicity as due to choline deficiency and I have some problems with that.

DR. MARKS: Related to kidney?

DR. SHANK: Chronic choline deficiency in animals can lead to liver neoplasm or liver cancer. That's well established. But I can

find no reports where chronic choline deficiency leads to kidney cancer. The NTP study on cocamide DEA demonstrated both liver and

kidney cancers in male and female mice, and kidney cancer in male rats. The choline deficiency might explain the liver cancer, but it doesn't

explain the kidney cancer. We talked about this last time and it was suggested that the kidney cancer in the male rat is due to a special

feature of the male rat, that it has pheromone protein called alpha 2u-globulin and lipid soluble compounds bind to this protein which is

absorbed by the renal tubular epithelial cells, but the cells cannot metabolize it with this lipophilic ligand in the protein. This leads to

repeated necrotic and regeneration in the proximal tubular and this happens only in the male rat.

DR. SLAGA: And not in humans.

DR. SHANK: Not in humans and not in mice, only the male rat. But the NTP study produced renal cancer in male mice and female

mice that do not have this protein. My other point is that cocamide DEA is a water- soluble compound or DEA is a water-soluble compound

and DEA would be an unlikely substrate to bind to alpha 2u-globulin to make it not metabolize by the renal tubular cell, so even that

mechanism would not work so I'm not comfortable in relying on dismissing the carcinogenicity data on that basis. On the other hand, DEA

itself penetrates the skin only very, very slowly and only small amounts would come into contact with the skin, go through the skin or

dissociate from the cells to lead to genotoxic toxicity. So if DEA is a toxic carcinogen it's probably by epigenetic means and therefore would

be subject to threshold. I think we can handle this as safe, but I would not like to dismiss all the carcinogenicity data on the basis of chronic

choline deficiency.

DR. HILL: Well, directly to that point, there was a key type of information that I didn’t find addressed anywhere in the report and it

should have occurred to me last time but really my focus was heavily on those amides and so forth, which is when we have a really

hydrophilic molecule which is DEA in its conjugate acid form, in other words, protonated and positive. However, now if we put a very

lipophilic counter-ion along with it, a molecule that otherwise would very poorly penetrate lipid membranes can penetrate as an ion pair

potentially. I didn't find any information on this. I didn't personally scour the literature to look for it to determine to what extend did the

lipophilic counterions allow more DEA to penetrate the skin than if we were just administering DEA itself. And it's confounded by the fact

that some of these studies were done for example with DEA freebase in water so that's going to give a very different profile than if it could

have been dealt with as lipid counterion salts. So I think you're right, but yet we're lacking the whole body of information that would tell us

that, no, in skin under the typical act of application that ion pair process is unlikely to occur and we're not going to get more DEA into the

system than we would if we were just testing DEA. But I don't know because there's nothing in there at all that addresses that and I didn't

have time to drill down that far when all was said and done.

DR. SLAGA: Ron Shank, if it's epigenetically related to the kidney cancer in the female, the statement in the conclusion that we're

formulating to be nonirritating on the skin, but that has no relationship to the kidney, are you saying because you think it's the irritating

effect in the kidney that's causing the cancer as an epigenetic? I'm trying to get it clear for discussion tomorrow.

DR. SHANK: No. I don't know what the mechanism is for DEA carcinogenicity in liver or kidney. I'm just saying that if DEA is

applied to the skin, little is going to be absorbed systemically and reach the kidney or the liver, so lack of systemic circulation is preventing

any carcinogenicity. The problem with the salts is that if they have significant absorption --



DR. SLAGA: Then they could get through and then --

DR. SHANK: Then they could and DEA would have to be released once it's in circulation.

DR. HILL: Which would happen because ion pairs like that don't get maintained indefinitely, but they do allow penetration through

lipid barriers. That's a very well-known phenomenon, but I didn't look at these specifics. Do we have those lipid salts since the last -- they

weren't there in the previous version. Correct? That was the thing that got raised in my mind. And also there's a line of research

incorporating DEA into membrane phospholipids which presents as another possible mechanism that it seems like nobody has further

researched. That was the one I asked last time, was there any follow-up? You did a search for me and we didn’t find any further

information on phenomena related to DEA incorporation into sphingolipids specifically.

MS. FIUME: Regarding your question with salts, everything that is here is after we pared down the list.

DR. HILL: So the salts were all there previously?

MS. FIUME: Yes.

DR. HILL: I just wasn't focused on that thought until we separated out DEA.

DR. SHANK: There are no reported use concentrations for any of the salts. Is that correct? That's Table 3, I think. No, Table 4-B.

MS. FIUME: Correct. Yes, there were none reported.

DR. SHANK: So the conclusion might be DEA at the concentration that it's used is safe and that the salts are insufficient in lacking

absorption data.

DR. LORETZ: Should they be added to the report if they're not no-brainers?

DR. MARKS: We've actually split this out from the original report anyway, so even though we reopened that report with the

DEA, MEA, and TEA, we're really I think looking at this where it says amended. It's really like a whole new report.

DR. SHANK: We went over that before. It's not a simple add-on kind of thing, but we’re totally redoing the DEA, MEA,

TEA documents.

DR. MARKS: Right. That didn't come up before because this supposedly to the point of final initiated. This would be an amended

tentative report if we decide to change the conclusion, and that's fine if that's what we feel we should do, that we can only say safe for DEA.

And salts, how did you say that, Ron?

DR. SHANK: Insufficient for salts lacking skin absorption data; dermal absorption.

DR. SLAGA: And that is because the salt could get in and dissociate and possibly be related to the female kidney cancer?

DR. BRESLAWEC: Which actually presents you with another option of saying that based on the chemical characteristics, we don't

expect them to act the same way, it there should not be included. We do have two options.

DR. HILL: Yes, because of these lipophilic salts, there are only four of them listed with some uses and we don't have details, so

there's one for DEA stearate in a leave-on product but we don't get a concentration of use, and one for DEA-linoleate, one since-off product,

still no concentration of use, DEA-lauryl sulfate and DEA-laureth sulfate. The laureth is diluted for use. That's probably in something like a

bubble bath. So in the rinse- off products I don't have much concern because it's probably shampoos and that sort of thing and it's coming

back off with very limited opportunity for any absorption to occur, but the leave-ons --

DR. SHANK: For the salts we cannot say safe under present practices of use and concentrations because they're not used --

according to Table 4-B there are no reported concentrations and one use except for DEA-lauryl sulfate with three uses.

DR. HILL: Could we say insufficient information for leave-on use? I know we have other reports that go that way for those

particular ingredients. Right?

DR. SHANK: Yes.

DR. HILL: I would be comfortable with that.

DR. SLAGA: That would be a way to do it.

DR. MARKS: We want to change the conclusion that DEA is safe, the related salts are safe in rinse-off and insufficient for leave-on.

Do I hear that correctly?



DR. SHANK: Yes.

DR. MARKS: Then the insufficient is because of the concern of the disassociation of the salt?

DR. SHANK: Dermal absorption.

DR. HILL: Ion pairs.

DR. MARKS: So the insufficient data need is dermal absorption?

DR. HILL: Yes.

DR. BRESLAWEC: Although again the pattern of use appears to show that there's almost no leave-on use.

DR. HILL: There's just that one, actually. There's that one. Stearate, isn't it?

DR. BRESLAWEC: Yes.

DR. HILL: So it would affect that one product that we know about.

MS. FIUME: And then it would change the conclusion for DEA-dodecylbenzenesulfonate because that was safe as used when

formulated to be non-irritating.

DR. HILL: That was in the other report for benzenesulfonate.

MS. FIUME: That was a re-review that was done in 2009.

DR. MARKS: Bring me up to speed. Where are you now on this one?

MS. FIUME: On page 1 in the middle of the page, "In 2009." It's the full paragraph above the listing which wasn't used.

DR. SHANK: Where the use is only rinse-off?

MS. FIUME: It's not used at all right now, so I'm not sure at that time in the original report or the re- review what it was used as.

DR. HILL: Can we investigate? I think it’s posted on the website.

DR. BRESLAWEC: I guess the other thing we could do is ask FDA to look into that one reported of DEA stearate as a leave-on if

that’s accurate because if it wasn't then just say safe under the conditions of use which is just rinse-offs.

DR. SHANK: Rinse-offs.

DR. SLAGA: Rinse-off.

DR. BRESLAWEC: If you could check though it would be great.

DR. MARKS: The DEA, even though there aren’t many uses on leave-on, there are.

DR. HILL: But DEA itself doesn’t present that same issue.

DR. MARKS: Where I have a problem is if we say safe. Unless we do the salts and at the bottom essentially you say in the read-

across that you'll formulate other personal-care products in the same concentration and same use and if they assume that it's safe for DEA,

will we be giving the wrong message? Or do we just say safe in rinse- offs for the salts?

DR. HILL: Because some people are specifying rinse-off for the salts because that's very clear. Anybody who reads it can't make a

mistake on that. And if there is documentation for safety of that leave-on or any other ones that we don't know about, then industry can

come forward with that.

DR. BRESLAWEC: That would be a safe-with- qualifications conclusion.

DR. HILL: Yes.

DR. MARKS: Right.

DR. HILL: It is.

DR. MARKS: Let me go back to the DEA. That's not in review.



MS. FIUME: It is.

DR. MARKS: Yes, it is. So that would be affected obviously by the conclusion. We need dermal absorption. That's the insufficient

for leave-ons and the concern is that if it's absorbed it may disassociate and be a carcinogen. Is that correct? That's the logic. That's the

initial issue you brought up, Ron.

DR. SHANK: Could you repeat what you just said?

DR. MARKS: We need that data, the dermal absorption, for the salts on leave-ons because if it is absorbed then we're concerned

about the potential carcinogenicity of DEA in that salt, and the reason we aren't concerned about DEA is because it's not absorbed.

DR. SHANK: Correct.

DR. SLAGA: Salts would not be absorbed.

DR. HILL: Can we word it to say dermal penetration as opposed to absorption, because that's a very different basis.

DR. MARKS: We probably would need a comment on that absorption question.

DR. BRESLAWEC: Dr. Marks?

DR. MARKS: Yes?

DR. BRESLAWEC: Could I ask you again to repeat?

DR. MARKS: I'm going to do that shortly because it's also going to be a change in that there was a question of do we go to final

which we can't on this if we're going to change the conclusion, so we're going to recommend an amended tentative. Is that correct in terms

of we would recommend an amended tentative report?

MS. FIUME: Amended tentative amended report.

DR. SHANK: Right. It's amended amended. You'd have to look at your flow sheet.

DR. MARKS: It doesn't have anything for redoing the tentative report.

DR. SHANK: We have final report. A different conclusion goes back to issue a tentative report.

DR. MARKS: This should also generate a lot of discussion tomorrow.

DR. BRESLAWEC: Dr. Marks, you might want to keep your options open depending on what FDA finds out if that one use is not

accurate.

DR. MARKS: Then we could just say safe.

DR. HILL: The discussion would mention specifically that we're talking rinse-off.

DR. BRESLAWEC: Right, because those are the conditions of use.

DR. HILL: Yes.

DR. SHANK: That's good.

DR. MARKS: Do you think we're going to have an answer tomorrow on the DEA stearate, that one use?

DR. BRESLAWEC: She's checking on it right now.

DR. HILL: Since it's lunchtime, if we had an answer after lunch we could come back.

DR. BRESLAWEC: That's right. We could. In addition to everything we talked about in the conclusion --

DR. MARKS: Let's not go back to that yet. We can go back to it in a minute. I want to finish this. Who is going to discuss the issues

with the carcinogenicity tomorrow?

DR. SLAGA: Ron.

DR. MARKS: Ron Shank. That's in the discussion.



DR. SHANK: This is our second report tomorrow morning?

DR. MARKS: I don't know. The last thing I wanted to bring up on this is so far we're at safe with DEA, the related salts safe in

rinse-off, insufficient for the leave-ons although if the DEA stearate is not on a leave-on in that one use then we can eliminate that.

DR. BRESLAWEC: I think we have an answer.

DR. MARKS: We have an answer?

MS. DEWAN: Yes. I just checked. It is stated to be used in the VCRP, one leave-on product body and hand.

DR. MARKS: We'll have to leave it insufficient for leave-on. And then the other issue that came up is the insufficient for the DEA-

lauraminopropionate and that's actually one of the ingredient that's later on and we got a lot of data needs.

DR. HILL: But not on that one.

DR. MARKS: No, it's not that one. It's on the di one.

MS. FIUME: If you consider it related.

DR. MARKS: So rather than going back, in looking at this we've got a lot of data needs on the dipropionate. Will that read across to

the propionate?

DR. HILL: No.

DR. MARKS: That's in Buff Book, doesn't have a number on it. In fact, it's spelled differently. I don't know whether it's an I or an

A.

DR. HILL: There are two different compounds.

MS. FIUME: There's aminopropionate and dipropionate.

DR. MARKS: Yes, so even within this report it starts out with lauramino and then it gets into the imino.

DR. SHANK: Iminodi.

DR. MARKS: So we can't use that. We'll have safe for DEA, for the related salts, safe in rinse-offs, insufficient for leave-on and

insufficient for the DEA-Lauraminopropionate and we have all those data needs. Does that summarize where we're at with this? And

insufficient for the leave-on salts are we need dermal absorption and, Ron, you're going to talk about the carcinogenicity in the discussion.

Did I capture it now do you think in terms of what we're going to do tomorrow? I'm going to move that we reissue an amended tentative

report. Obviously we can't do a final. Does that sound good?

DR. HILL: In my copy I use a red pen, I would use the words blend, but I have a lot of notations so you know those are coming. Do

you want to go back to it again?

DR. MARKS: Ron, I'm going to go back just for a minute to clarify on the DEA report where we said DEA is safe and we did the

related salts. Do the N nitroso compounds caveat on that, also?

DR. SHANK: Yes.

DR. MARKS: That was before. We do. Okay. So, nitroso. I'm just going to put in here N nitroso compounds boilerplate for the

conclusion. Is that okay?

DR. SHANK: Yes.

DR. MARKS: So, really, all these, whether it's DEA, DEA amides, or a TEA, I'm going to get to amino, they all have to have the N

nitroso compounds --

Full Panel

All right, moving on to the second ingredient, which is DEA. Dr. Marks

. DR. MARKS: This was a little bit more discussion by our team and dealing with these ingredients. As you'll recall, in March of

this year we included the salts of DEA and as add-on ingredients to re-review the DEA and a tentative amended report was issued.



We've -- we still had some difficulties and decided that we would like to reissue this amended tentative report because we felt there was

some changes from the one that was sent out and our conclusions were that DEA was safe, that its related salts were safe in rinse-offs, but

insufficient data for leave-ons and the insufficient data need for the salts on leave-ons was the dermal absorption. There's only one

compound actually in use that's a salt and is a leave-on, but we did not have any absorption data and we were concerned, particularly Ron

Hill, about the potential absorption and then the resulting carcinogenicity. And in addition DEA-lauraminopropionate would be -- continue

to be insufficient data. They would be formulated to be non-irritating and they would be not used as an ingredient in cosmetic products in

which N- nitroso compounds are formed. So, we felt there were significant changes in the conclusion and should reissue an amended

tentative report with those conclusions.

DR. BERGFELD: Any comment from the Belsito team?

DR. BELSITO: Well, we would agree with their safe as use in rinse-offs. We did not raise any issue of carcinogenicity and felt that

they were, with the exception, of course, sodium lauraminopropionate, which we agree was insufficient, would also be safe as used in rinse-

offs. Nitrosating agents, has that typically been put into a conclusion or is that part of a discussion? I mean, I was -- that was in our

discussion, nitrosating agents and formulated not to be irritating was part of the conclusion. Contaminants, particularly NDELA, were in the

discussion but really didn't raise any issue of carcinogenicity other than the issue of making sure that the NDELA impurity and no

nitrosamine formation. I'll ask Dan to comment because I'm not sure why you would think that salts would make -- give an enhanced

carcinogenicity risk.

DR. MARKS: Actually, I'll -- I'm going to address the one N-nitroso compounds, Don, that you raised, is that in a conclusion in '96,

in a cocamide DEA -- and we're going to be talking about later -- that is in the conclusion that it should not be used in ingredients in

cosmetic products in which N-nitrosa compounds are formed And we actually like the wording of that conclusion, so we -- that's why we

repeated it. Now, Ron Hill, do you want -- or Ron Shank, do you want to mention the concern we had about this one salt, which is in

a leave-on?

DR. HILL: Yeah. In terms -- and then I'll defer to Dr. Shank for the carcinogenicity -- in terms of the absorption there's the potential

when we have a hydrophobic counterion for passage through lipid membranes as an ion pair, as a tight ion pair, which wouldn't be a

problem for DEA itself at physiological pH, but could potentially be, and we don't have any information whatsoever as to whether ion pairs

can be absorbed to a greater extent than DEA itself when we add in those hydrophobic salts. And I guess the salts were there before the last

time we considered this, but the focus was really on separating out the amides to separate ingredients, and it probably didn't get fully

entertained. So, if that's the case, then there are concerns related to the carcinogenicity of DEA that aren't fully resolved with the

choline deficiency hypothesis. And I'll pass that over to my colleague to --

DR. BELSITO: But the salt is DEA stearate. What are you concerned about with stearate?

DR. HILL: Because it's a large hydrophobic counterion there's the potential for -- even though it is a salt, for the ion pair to be able

to cross biological membranes to a much greater extent than the hydrophilic DEA ion itself, that there's a possibility for partitioning into

lipids of ion pairs. And there's no data in the report, nothing's been captured to address whether that can occur or not. So, there's a

possibility for skin penetration that wouldn't occur with DEA itself when we have such a hydrophobic counterion and we have no data to

address whether that, in fact, could occur or not.

DR. BELSITO: Bob, could you comment on that?

DR. BRONAUGH: I've heard of things like this happening before with other compounds, so I think it's a possibility.

DR. BERGFELD: Ron, were you going to comment?

DR. SHANK: It's just that the DEA itself, the secondary amine, would penetrate skin very, very slowly. If the salt penetrates much faster

then there may be a carcinogenicity problem.

DR. BERGFELD: Curt?

DR. KLAASSEN: Well, the reason I raised my hand a minute ago, I wanted to see what Bob thought about the concept of the

counterion really -- of the likelihood of that really happening across the skin. I mean, we know that in a test tube that can happen, in

column chromatography, but, you know, do we have many examples of this really happening in skin? Is this -- I agree it's hypothetically

possible, but, you know, is it biologically likely?

DR. BRONAUGH: You know, I don't have any specific examples to cite. I remember reading about something like this some time

ago, so I wouldn't rule it out, but I don't know how likely it is to happen.

DR. HILL: And to follow up on concern, I'm -- I think the chances of enough DEA getting to be systemically available to where

we'd have, for example, a renal carcinogenicity risk would be small, but I think the line of research where the incorporation of

diethanolamine into membrane phospholipids and the consequences of that have really never been followed up on. In other words, there

was searching done to try to determine whether further research had been done in that area and it seems that that line of research has died,

but for no good reason because I think that incorporation of DEA into the sphingomyelin, for example, is known. And so whether that

modifies skin biology in such a way that's significant if some DEA could get into the upper layers of the skin -- the viable layers of the

skin, I think is not known and we need to, in terms of due diligence, establish whether or not that could happen or not. And I think at least



the fairly strong hypothetical potential that an ion pair like that could potentially penetrate at least into the viable layers of skin is there and

there's probably information or data out there to support that one way or the other or refute that, but we haven't captured anything in that

regard.

DR. BERGFELD: Dan?

DR. LIEBLER: So, I think the -- it's possible that DEA stearate delivers more DEA into the skin than DEA itself. That's possible,

and that's, I think, what Ron -- sorry, that's what Bob is essentially saying. It seems possible, we don't have data. Right? So -- I see

heads nodding. So, I think that the issue on carcinogenesis comes from DEA administered systemically or orally and its liver

carcinogenesis, right?

DR. HILL: Well, we don't know that for sure because, again, that line of research seems to have been abandoned where the

phospholipid incorporation was -- I mean, that was there in the original transcripts. It's mentioned several times in the reports, but nothing's

ever been followed up in terms of the research in that area.

DR. LIEBLER: Right.

DR. HILL: And with DEA itself I lack that concern because the chances of a significant quantity even penetrating the skin let alone

systemically, unless you're ingesting it, to me is nil. But with these hydrophobic salts, I doubt that enough would get it to kidney or liver

based on dermal administration to cause a problem, but I think effects within the skin can't be just lightly dismissed.

DR. LIEBLER: Well, I doubt it, too, and I come to a different conclusion. So, I actually think that even though it's theoretically

possible that DEA stearate could deliver more DEA to the skin, I don't see any compelling reason to suspect that's a risk for carcinogenesis,

particularly in the absence of any data on DEA carcinogenesis in the skin from these kinds of compounds.

DR. HILL: We don't have any data one way or another to my knowledge because those salts haven't been investigated in terms of

those kinds of effects, best I can tell.

DR. BERGFELD: Don.

DR. BELSITO: But the mechanism is non- genotoxic --

DR. HILL: Yes.

DR. BELSITO: -- and is thought to be due to choline deficiency because when you feed choline you can abrogate that effect. And

we're told that that whole mechanism is not operative in humans, so even if you pushed more DEA through the skin, what would your

concern be in terms of carcinogenicity? Non-genotoxic mechanism that isn’t applicable to humans.

DR. BERGFELD: Ron.

DR. SHANK: I have some problems with relying wholly on a choline deficiency as an explanation for the mechanism for action of

DEA carcinogenesis. In animal models where choline deficiency has been demonstrated to result in liver cancer, renal cancer is never seen,

at least it's not reported. But in the cocamide DEA bioassay both renal and liver cancers were seen. Now, the renal cancer, last time

we talked about this, was dismissed because it was seen in the rat as an alpha-2 globulin situation, which is not important to humans. But in

that cocamide DEA carcinogenicity bioassay male mice also got renal cancer and they don't have that protein, alpha-2 globulin. The

other problem with the renal cancer is that if it is alpha-2 globulin, the compounds that produce male rat kidney cancer via that mechanism

are all very highly lipid soluble and they associate with the lipophilic center in that protein, prevent its biodegradation in the proximal

convoluted tubule epithelia producing repeated cytotoxicity and then renal cancer in the male rat. DEA is highly water-soluble so that

would not be a likely compound to form a ligand interaction with alpha-2 globulin and the male mouse doesn't have that anyway. So,

there are some problems with relying wholly on the choline deficiency hypothesis and I think we're better off relying on the fact that DEA is

absorbed very slowly and the concentration of DEA in the cocamide DEA bioassay was 18 percent. That's much higher than any

concentration that would be found in a cosmetic. It is an epigenetic mechanism which highly suggests a threshold event.

DR. BERGFELD: Paul.

DR. SNYDER: I largely concur with what Ron has said. I've, again, a different interpretation. So, I think that the -- not all of the

renal neoplasms in mice and rats were attributable to the unique protein that's exclusively present in the rat. They're more commonly

associated with a nephropathy, so when there's progressive renal disease you get increased cell turnover and you get more proliferative

lesions and then they can go on and progress to adenomas, et cetera. And I think that's what was happening in these animals was that there

was a nephropathy that was occurring and then there just happened to be a higher incidence of the proliferative lesions because in order to

get significance they had to combine the proliferative lesions and the adenomas all together, so I'm more comfortable with the data set

regarding the carcinogenesis. I don't think it's a real issue particularly from a dermal exposure. We have lots of dermal absorption

data for many of the DEA compounds. We actually have quite a lot of absorption data that we usually don't have, and so I'm, again, less

concerned about that salt that is raising a concern. There was a small study done in which they dosed three humans with a lotion containing

DEA and it was only 1 -- or.5 percent to 1 percent of the amount that was absorbed in the mice. And so there's a significant difference in

the absorption of the skin between the humans and the rodents, and of course the rat -- I mean, the mouse absorbs more than the rat. And so

I think with all of that factor, weight of evidence approach, I don't have any concern about the carcinogenicity.



DR. SLAGA: I agree with what Ron Shank said that, I mean, there's that possibility and the fact that it's epigenetic means that there

would be a threshold, and you -- if you make the assumption that the salt is going to be so slowly or even if it's theoretical, there's really no

example showing that that would be absorbed. The odds are very slender that it would be absorbed, so in a way, although that

carcinogenicity may be there, it's very low.

DR. BERGFELD: Ron.

DR. HILL: Yeah, I think the thing is that the absorption studies were not done with one of these lipophilic counterions, so -- and

there's a leave-on product, the specific product that caused concern was DEA stearate, there's a leave-on product and we don't have a

concentration of use and if that was particularly high, I think, in terms of generating cancerous cells, this is not a likely carcinogen. But in

terms of knowing that we could modify membrane phospholipids, then the possibility of causing transformations or accelerating growth is

there, and I think it would be at least good to know that that in fact is not a problem. It may very well be that the finding is that there isn't

significant penetration into viable layers of skin, there isn't exposure of sebaceous glands and so forth, but it would be awfully good to

know that or else you just don't allow the use in leave-on product.

DR. BRONAUGH: Could I just add something here?

DR. BERGFELD: Go ahead, Bob.

DR. BRONAUGH: DEA seems to possibly bind to chemicals in the skin. You know, we’ve found that in our skin absorption studies

of DEA that we got quite a bit of absorption of the DEA into the skin, but it never left. You know, it seems to bind or some effect like that,

so just because there's some penetration of DEA into the skin doesn't mean you're going to have systemic absorption.

DR. BERGFELD: Dan.

DR. LIEBLER: So, one of the points that Ron has raised is something, I think, we've all noticed in reading about the DEA in that

there are a few reports from the literature cited of apparent incorporation of DEA in -- or its metabolites into lipids, into phospholipid

classes. From my reading of what has been presented to us, that hasn't been very thoroughly characterized, which I guess is one of Ron's

points. I think where we differ is Ron, I think, has the concern that this could contribute to a carcinogenic effect -- this is catching,

Ron, I'm having trouble saying carcinogenicity --

DR. HILL: I'm sorry. Never had that problem before.

DR. LIEBLER: And I just don't see, based on my understanding of mechanisms of chemical and physical carcinogenesis, I don't see

a connection for having aberrant phospholipids translate in any way I understand to carcinogenesis. So, I think that leap, for me, is too

much of a leap. That's why I'm not really particularly concerned about that issue.

DR. HILL: Well, the mechanism would be modification of sphingolipids which modifies lipid raft structure which modifies the

activity of, for example, growth factor receptors and those mechanisms are actually quite well known now.

DR. LIEBLER: Yeah, but that's not the same as carcinogenesis.

DR. HILL: No, it's not --

DR. LIEBLER: (inaudible) perturbing cell biology a little bit and there's a lot more that would have to happen. I think that's really

very speculative.

DR. HILL: Okay.

DR. BERGFELD: I'd like to remind everyone that these are add-on ingredients, they're supposed to be simple. This sounds like

more than simple.

DR. HILL: Well, and again, I mean, the issue was not with the ingredients, it was with the leave-on use of the ingredient and no

science pertaining to that that gives us comfort -- or me comfort.

DR. BERGFELD: All right. I'd like to ask for a motion.

DR. BELSITO: (inaudible)

DR. BERGFELD: Jim, did you actually make a motion?

DR. MARKS: Yes, I made a motion. I think the difference if I interpret what the Belsito team felt is that DEA and its related salts,

all of them could be safe with the exception of the DEA-lauraminopropionate, which was insufficient data. Is that correct?

DR. BELSITO: That's correct.



DR. MARKS: I think I'd ask my team again, Ron, Ron, and Tom, based on the discussion concerning this theoretical carcinogenicity

of the salts and because of dermal absorption, whether or not that's to your -- you feel that's adequate and we should change our motion or

we should leave it as is? That it's insufficient for leave- ons in the salts?

DR. BERGFELD: Tom.

DR. SLAGA: I mean, I'd still go back that I don't think the salt would be absorbed even though hypothetically it may. I have never

seen any situation like that, so I don't know any examples of -- I would say it will not be absorbed very well and, therefore, it's not going to

be at a concentration to even potentially have effect on the kidney.

DR. BERGFELD: Ron.

DR. SHANK: I agree with Dr. Slaga. I'm not concerned about the one use for leave-on.

DR. BERGFELD: Ron Hill.

DR. HILL: I think we're good.

DR. MARKS: Okay, I'll withdraw my motion. I'll rephrase or make a new motion that DEA and its related salts are safe with the

exception of the DEA- lauraminopropionate, which there's insufficient data and that they should be formulated to be nonirritating and they

should not be used as an ingredient in cosmetic products in which N-nitrosocompounds are formed.

DR. BERGFELD: Could I --

DR. BELSITO: Second.

DR. BERGFELD: Second. Could I have a clarification? Are you putting all that in the conclusion or --

DR. MARKS: Yes.

DR. BERGFELD: Any other discussion before we move the question? Then all those in favor of approval please indicate by raising

your hand. Unanimous. I did look at you, Ron Hill.

DR. HILL: I figured you might.

DR. BERGFELD: Okay. Moving on to the third ingredient under the final --

MS. FIUME: I don't have a list for the discussion of what is insufficient for that one ingredient.

DR. BELSITO: It's the same list what was for the ingredient itself.

MS. FIUME: Okay. I just wanted to make sure. Thank you.



Rep

ort

Final Amended Report

Diethanolamine (DEA) and Its Salts 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 ................................................................................................................................................................................................................... 1

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

Use ............................................................................................................................................................................................................................. 2 Cosmetic ............................................................................................................................................................................................................... 2 Non-Cosmetic ....................................................................................................................................................................................................... 3

Toxicokinetics ............................................................................................................................................................................................................ 3 Absorption, Distribution, Metabolism and Excretion ........................................................................................................................................... 3

In Vitro ............................................................................................................................................................................................................. 4 Dermal ............................................................................................................................................................................................................. 6

Non-Human ................................................................................................................................................................................................ 6 Human ........................................................................................................................................................................................................ 6

Oral .................................................................................................................................................................................................................. 7 Non-Human ................................................................................................................................................................................................ 7

Intravenous....................................................................................................................................................................................................... 8 Non-Human ................................................................................................................................................................................................ 8

N-Nitrosodiethanolamine (NDELA) Formation .................................................................................................................................................... 8 Toxicological Studies ................................................................................................................................................................................................. 9

Acute (Single) Dose Toxicity................................................................................................................................................................................ 9 Oral .................................................................................................................................................................................................................. 9 Other ................................................................................................................................................................................................................ 9

Repeated Dose Toxicity ........................................................................................................................................................................................ 9 Dermal ............................................................................................................................................................................................................. 9 Oral ................................................................................................................................................................................................................ 10 Inhalation ....................................................................................................................................................................................................... 12

Reproductive and Developmental Toxicity .............................................................................................................................................................. 13 Dermal ........................................................................................................................................................................................................... 13 Oral ................................................................................................................................................................................................................ 14 Inhalation ....................................................................................................................................................................................................... 14

Effect on Hippocampal Neurogenesis and Apoptosis ......................................................................................................................................... 14 Genotoxicity ............................................................................................................................................................................................................. 15

In Vitro ............................................................................................................................................................................................................... 15 Carcinogenicity ........................................................................................................................................................................................................ 16

Dermal ........................................................................................................................................................................................................... 16 Possible Mode of Action for Carcinogenic Effects ............................................................................................................................................. 16

Irritation and Sensitization ....................................................................................................................................................................................... 17 Irritation .............................................................................................................................................................................................................. 17

Skin ................................................................................................................................................................................................................ 17 Non-Human .............................................................................................................................................................................................. 17 Human ...................................................................................................................................................................................................... 18

Mucosal .......................................................................................................................................................................................................... 18 Non-Human .............................................................................................................................................................................................. 18

Sensitization ........................................................................................................................................................................................................ 18 Non-Human ................................................................................................................................................................................................... 18 Human............................................................................................................................................................................................................ 18

Provocative Testing .................................................................................................................................................................................. 18 Miscellaneous Studies .............................................................................................................................................................................................. 19

Inhibition of Choline Uptake .............................................................................................................................................................................. 19 Occupational Exposure ............................................................................................................................................................................................. 19 Summary .................................................................................................................................................................................................................. 19 Discussion ................................................................................................................................................................................................................ 21 Conclusion ................................................................................................................................................................................................................ 22 Tables ....................................................................................................................................................................................................................... 24

Table 1. Definitions, structures, and function(s) ................................................................................................................................................ 24 Table 2. Conclusions of previously reviewed components/related ingredients .................................................................................................. 26 Table 3. Physical and chemical properties ......................................................................................................................................................... 26 Table 4a. Frequency and concentration of use according to duration and type of exposure .............................................................................. 27 Table 4b. Ingredients not reported to be in use .................................................................................................................................................. 27

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



1

ABSTRACT

The CIR Expert Panel assessed the safety of diethanolamine (DEA) and its salts as used in cosmetics. DEA func-tions as a pH adjuster; the 17 salts included in this re-review reportedly function as surfactants, emulsifying agents, viscosity increasing agents, hair or skin conditioning agents, foam boosters, or antistatic agents. The Panel reviewed available animal and clinical data, as well as information from previous CIR reports. Since data were not available for each individual ingredient, and since the salts dissociate freely in water, the Panel extrapo-lated from previous reports to support safety. The Panel concluded that DEA and its salts, with the exception of DEA lauraminopropionate, are safe for use when formulated to be non-irritating. These ingredients should not be used in cosmetic products in which N-nitroso compounds are formed. The Panel stated that the available data are insufficient to conclude that DEA-Lauraminopropionate is safe for use in cosmetics.

INTRODUCTION

In 1983, the Cosmetic Ingredient Review (CIR) Expert Panel issued a report on the safety of Triethanolamine,

Diethanolamine, and Monoethanolamine. In 2010, the Panel decided to reopen that safety assessment as three separate

reports and to include additional related ingredients in each of the new reviews. This assessment addresses diethanolamine

(DEA) and its salts. The acid salt ingredients (as recited below) would be expected to dissociate into DEA and the corre-

sponding acid, most of which have been reviewed separately. In most cases, this means that the composition of these salts is

stoichiometrically half DEA (i.e. as its conjugate acid).

In the 1983 review, the Expert Panel concluded that DEA, an ingredient that functions in cosmetics as a pH adjuster,

is safe for use in cosmetic formulations designed for discontinuous, brief use followed by thorough rinsing from the surface

of the skin.1 Because of the potential for irritation, the concentration of DEA should not exceed 5% in products intended for

prolonged contact with the skin. DEA should not be used with products containing N-nitrosating agents.

In 2009, the Expert Panel reviewed the safety of DEA-dodecylbenzenesulfonate, an ingredient included in this re-

review.2 It was concluded that DEA-dodecylbenzenesulfonate is safe as used when formulated to be non-irritating.

The safety of most of the components of, or ingredients related to, these salts has been reviewed by the CIR. The

majority of those components or related ingredients had a conclusion of safety. However, one related ingredient, sodium

lauraminopropionate, was found to have insufficient data to make a determination of safety.3

The following 17 salts are included in the re-review of DEA.

Inorganic Acid Salt Diethanolamine Bisulfate Organic Acid Salts DEA-Cocoamphodipropionate DEA-Isostearate DEA-Lauraminopropionate

DEA-Linoleate DEA-Myristate DEA Stearate

Sulfate and Sulfonate Salts DEA-C12-13 Alkyl Sulfate DEA-C12-13 Pareth-3 Sulfate DEA-C12-15 Alkyl Sulfate DEA-Cetyl Sulfate DEA-Dodecylbenzenesulfonate

DEA-Laureth Sulfate DEA-Lauryl Sulfate DEA-Methyl Myristate Sulfonate DEA-Myreth Sulfate DEA-Myristyl Sulfate

The definition, structure, and function(s) of each ingredient are provided in Table 1. The conclusions for the

components/related ingredients that have been reviewed are provided in Table 2.

CHEMISTRY

DEA, shown in Figure 1, is an amino alcohol. DEA is produced commercially by aminating ethylene oxide with ammonia. The replacement of two hydrogens of ammonia with ethanol groups produces DEA. DEA contains small



2

amounts of triethanolamine (TEA) and ethanolamine (MEA).

HONH

OH

Figure 1. DEA

DEA is reactive and bifunctional, combining the properties of alcohols and amines. At temperatures of 140°-160°C, DEA will react with fatty acids to form ethanolamides. The reaction of ethanolamines and sulfuric acid produces sulfates and, under anhydrous conditions, DEA may react with carbon dioxide to form carbamates. DEA can act as an antioxidant in the autoxidation of fats of both animal and vegetable origin. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1

Definition and Structure

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

and R2 are each ethanol), into N-nitrosamines that may be carcinogenic. Of the approximately 209 nitrosamines tested, 85%

have been shown to produce cancer in laboratory animals.4 Nitrosation can occur under physiologic conditions.5 Depending

on the nitrosating agent and the substrate, nitrosation can occur under acidic, neutral, or alkaline conditions. Atmospheric

NO2 may also participate in the nitrosation of amines in aqueous solution.6 Accordingly, DEA and its salts should be formu-

lated to avoid the formation of nitrosamines.

Acid Salts

The acid salts (inorganic acid salt, organic acid salts, sulfates, and sulfonate salts), named above, are ion pairs which

freely dissociate in water (e.g., Figure 2). Therefore, these salts are closely related to the corresponding free acids and DEA.

In other words, DEA stearate is closely related to stearic acid and DEA. Accordingly, the potential formation of nitrosamines

should be a consideration for the ingredients in this group.

Figure 2. DEA Stearate

Chemical and physical properties are provided in Table 3.

Method of Manufacture

DEA is produced by reacting 2 moles of ethylene oxide with 1 mole of ammonia.7 Typically, ethylene oxide is

reacted with ammonia in a batch process to produce a crude mixture of approximately one-third each MEA, DEA, and TEA,

which are then separated, achieving varying degrees of single component purity.

Impurities

Dow Chemical Company reports that DEA is commercially available with a minimum purity of 99.0%, containing

0. 5% max. MEA and 0.5% max TEA.8

USE

Cosmetic

DEA functions in cosmetics as a pH adjuster.9 While a few of the other ingredients might also function as a pH

adjuster, the majority are reported to function as a surfactant, emulsifying agent, viscosity increasing agent, hair or skin con-

ditioning agent, foam booster, or antistatic agent. Voluntary Cosmetic Registration Program (VCRP) data obtained from the

Food and Drug Administration (FDA) in 2011 indicate that DEA is used in 22 formulations, 10 leave-on and 12 are rinse-off



3

formulations.10 According to data submitted in response to a survey conducted by the Personal Care Products Council

(Council), DEA is used at concentrations of 0.0008-0.3%.11 The highest concentration used in leave-on products is 0.06% in

moisturizing products. Only four salts were reported to be used according to VCRP data, no more than 3 reported uses, and

no concentration of use data were reported to the Council for any of the salts.12 Frequency and concentration of use data for

in-use ingredients are provided in Table 4a; ingredients not reported to be in use, according to VCRP data and the Council

survey, are listed in Table 4b.12,13

DEA is reported to be present in hair sprays, and effects on the lungs that may be induced by aerosolized products

containing this ingredient 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.

Dialkanolamines (e.g. DEA) and their salts (i.e., the ingredients included in this re-review) are on the European

Union’s list of substances which must not form part of the composition of cosmetic products.14 (Secondary amines are

allowed as contaminants in raw materials at concentrations up to 0.5% in trialkylamine, trialkanolamines, and their salts and

in monoalkylamines, monoalkanolamines, and their salts, and at up to 5% in fatty acid dialkylamides and dialkanolamides;

secondary amines are allowed at up to 0.5% in finished products containing dialkylamides and dialkanolamides.) The

opinion paper issued by the Committee for Cosmetic Products and Non-Food Products (SCCNFP) stated that amines occur

only in their salt form in all cosmetic products.15 The reasoning is that all amines are alkaline compounds which are always

neutralized by an acid component to produce their salts, and there is concern about the potential for nitrosamine formation; in

principle, secondary amines are potential precursors of nitrosamines.

In Canada, DEA is completely prohibited as per the Cosmetic Hotlist; Health Canada prohibits the use of dialkanol-

amines (e.g., DEA).16 This prohibition is based on the EU prohibition in the Cosmetics Regulation, Annex II. The use of

DEA in product formulations in Canada is being investigated due to reported use at concentrations of up to 3%. (Health

Canada, personal communication).

Non-Cosmetic

DEA is used in the manufacture of emulsifiers and dispersing agents for textile specialties, agricultural chemicals, waxes, mineral and vegetable oils, paraffin, polishes, cutting oils, petroleum demulsifiers, and cement additives. It is an intermedi-ate for resins, plasticizers, and rubber chemicals. DEA is used as a lubricant in the textile industry, a humectant and soften-ing agent for hides, as an alkalizing agent and surfactant in pharmaceuticals, as an absorbent for acid gases, and in organic syntheses. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1

DEA is approved for use as an indirect food additive (21CFR175.105, 21CFR176.170, 21CFR176.180,

21CFR176.210.17

TOXICOKINETICS

Absorption, Distribution, Metabolism and Excretion

In vitro absorption studies of DEA were performed using mouse, rat, and human skin. With in vitro studies using mouse and rat skin, 1.3 and 0.04%, respectively, of the applied dose of undiluted [14C]DEA was absorbed. In studies using human skin samples, the absorption of undiluted DEA, as well as concentrations of <1% DEA in combination with fatty acid dialkanolamides, was less than 1% of the applied dose. Penetration of DEA in aqueous solution was greater than when DEA was undiluted. In studies using human liver slices, DEA was absorbed; the aqueous-extractable radioactivity was primarily unchanged DEA, while analysis of the organic extracts suggested that DEA was incorporated into ceramides, and slowly methylated.

In dermal studies of DEA absorption using mice and rats, absorption through mouse skin was greater than through rat skin, and absorption increased with duration of exposure. In the tissues, the liver generally had the greatest disposition of radioactivity. Urine was the principal route of elimination.



4

In oral dosing studies in rats, DEA accumulated in the tissues, with the greatest disposition being in the liver; radioactivity was primarily as unchanged DEA. Urinary excretion was also primarily as unchanged DEA. In a repeated-dose study, steady-state for bioaccumulation occurred after 4 wks; however, DEA continued to bioaccumulate in blood throughout dosing.

Mice exposed orally to sodium nitrite were dosed orally and dermally with 4 mg/kg DEA. A small amount of NDELA was formed following a single oral dose of DEA. No N-nitrosodiethanolamine (NDELA) was detected following dermal dosing with DEA.

In Vitro

The in vitro absorption of [14C]DEA in an oil-in-water emulsion was determined using fuzzy rat skin.18 Approxi-

mately 2 mg/cm2 was applied to the skin in each diffusion cell; the solution was applied for 24 h. A total of 1.4% of the

applied dose was absorbed over 24 h, with 4% remaining in the skin. (There was 1.9% of the applied dose remaining in the

stratum corneum and 1.9% in the viable dermis/epidermis.) The researchers indicated that little of the DEA that was found in

the skin at 24 h was absorbed into the receptor fluid. Similar results were reported at 72 h.

Three full-thickness skin preparations from CD rats, CD-1 mice, New Zealand White (NZW) rabbits, and 6 from

female mammoplasty patients, were used to compare the dermal penetration of DEA through the skin of different species.19

[14C]DEA (96.5% purity; sp. act. 15.0 mCi/mmol) was applied to the skin sample undiluted, or as an aq. solution, at a dose of

20 mg/cm2. Dose volumes of 35 µl undiluted [14C]DEA or 95 µl of the aq. solution (37% w/w) were applied to the exposed

surface of the skin (1.77 cm2) for 6 h. Skin sample integrity was confirmed with the use of a reference chemical, [14C]etha-

nol. With undiluted DEA, the cumulative dose absorbed (i.e., recovered in the effluent) was 0.04% in rat skin, 1.30% in

mouse skin, 0.02% in rabbit skin, and 0.08% in human skin. With aq. DEA, an increase in the cumulative dose absorbed was

seen in all species: 0.56% in rat skin, 6.68% in mouse skin, 2.81% in rabbit skin, and 0.23% in human skin. The penetration

of undiluted and aq. DEA was greater through mouse skin than any other skin sample. With undiluted DEA, penetration was

similar for rat, rabbit, and human skin samples. The researchers hypothesized that the fact the penetration of DEA was great-

er for an aqueous solution than for undiluted DEA may be attributable to elevated skin hydration caused by the application of

the aqueous solution to the skin.

The percutaneous absorption of DEA in cosmetic formulations spiked with [14C]DEA (95-99% purity) was exam-

ined using viable human skin.20 Two shampoo formulations, both with a [14C]DEA dose of 0.49 µCi were applied as a 1:6

aq. dilution for 5 min; one shampoo contained cocamide DEA with a concentration of 0.092% free DEA in the formulation,

and the other contained lauramide DEA with a concentration of 0.28% free DEA in the formulation. The amount of the

shampoo applied was 1.2 mg (diluted 1:6), and the dose was 1.9 mg/cm2. (The DEA dose was 4.2 µg/cm2 for the first

formulation, and 7.7 µg/cm2 for the second shampoo formulation.) Two hair dye formulations, spiked with 0.49 or 0.43 µCi

DEA, were applied for 30 min. One hair dye contained lauramide DEA and the other contained cocamide and oleamide

DEA. The estimated concentration of free DEA in the hair dye products was 0.61%. An application of 11.2 mg was applied

to the skin samples, with a dose of 17.5 mg/cm2. (The DEA dose was 109.3 µg/cm2 for the first formulation, and 108.9

µg/cm2 for the second hair dye formulation.) Additionally, 3 mg/cm2 of two body lotions (amount applied not stated) with

0.13 or 0.12 µCi DEA was applied for 24 h. (The DEA dose was 1.0 µg/cm2 for the first formulation, and 1.2 µg/cm2 for the

second lotion formulation.) These products contained 0.0155% TEA, with 0.020% free DEA.

In all of these studies, very little DEA was found in the receptor fluid, with only 0.1% of the applied dose recovered

in the receptor fluid for the shampoo and hair dye formulations. While the amount absorbed was similar for these two

product types, the distribution and localization were different, with most of the DEA (62-68%) penetrating from the sham-

poos being localized in the stratum corneum, and that from the hair dyes (52-64%) being found in deeper epidermal and



5

dermal layers. With the lotion, 0.6-1.2% of the dose was recovered in the receptor fluid. Penetration from the lotions

differed from each other. With the first lotion, 15.4% of the applied dose penetrated, with 0.6% found in the receptor fluid

and 14.8% in the skin; approximately 65% of the penetrated DEA from this formulation that was found in the skin was

localized in the epidermis and dermis. With the second lotion formulation, 7.8% of the applied dose penetrated, with 1.2%

found in the receptor fluid and 6.6% in the skin; approximately 56% of the penetrated DEA from this formulation that was

found in the skin was localized in the skin was in the epidermis and dermis.

The researchers examined whether DEA was binding to skin. DEA did not appear to be covalently bound to skin

proteins, and extending the times before analysis to 48 and 72 h did not result in any statistically significant difference when

compared to the values obtained after 24 h. Repeat application studies with viable skin did not produce a significant change

of dose absorbed into receptor fluid. However, with non-viable skin, absorption into the receptor fluid from the lotion in-

creased each day, from 0.6% on the first day to 2.6% on the third day; testing showed that the skin barrier did not remain in-

tact for the entire 72 h. Using a shampoo and a lotion formulation, non-viable skin gave penetration values similar to viable

skin. The researchers concluded that most of the DEA that penetrated was not available for systemic absorption.

Another study examining the percutaneous penetration of seven cosmetic formulations spiked with radiolabeled and

unlabeled DEA was performed, mimicking simulated use conditions using fresh human skin samples.21 Two shampoos both

contained 0.98% DEA and 4.02% cocamide DEA, and two additional shampoo formulations both contained 0.25% DEA and

4.75% lauramide DEA; a100 µl/cm2 (equivalent to 100 mg/cm2) as a 1:10 aq dilution of each formulation were applied for 10

min. A bubble bath containing 0.25% DEA and 4.75% lauramide DEA, applied as a 1:300 dilution at a dose of 100 µl/cm2

(equivalent to 100 mg/cm2) for 30 min, a moisturizer containing 0.008% DEA and 2% TEA, applied at a dose of 5 mg/cm2

for 48 h, and a semi-permanent hair dye containing 0.075% DEA and 1.42% lauramide DEA and an oxidative hair dye con-

taining 0.25% DEA and 4.74% lauramide DEA, both applied at a dose of 100 mg/cm2 for 30 min, were also used. Very little

DEA penetrated through the skin (i.e., was recovered in the receptor fluid); 0.011-0.034% of the applied dose of the shampoo

formulations penetrated, 0.024-0.063% of the applied dose from the hair dye formulations, and 0.508% from the bubble bath

formulation penetrated through the skin. The moisturizer formulation was also applied to frozen skin samples. A total of

0.605% of the applied dose penetrated fresh skin, while 0.456% penetrated frozen skin.

The researchers also examined the penetration of a simple aq. 1% solution of DEA through fresh and frozen human

skin samples. The cumulative 24 h percutaneous absorption was approximately 5-fold greater in frozen skin compared to

fresh skin, i.e., 8.87 µg/cm2 compared to 1.73 µg/cm2. The 24-h cumulative penetration values represented 0.433 and

0.086% of the dose for frozen and fresh skin, respectively. The amounts of DEA remaining on and in the skin were 1.68 and

1.14% of the applied dose recovered from the frozen and fresh skin samples, respectively. The researchers further investigat-

ed the distribution of [14C]DEA between aqueous and lipid fractions of viable skin strata. The radioactivity on the skin

samples from 2 donors (n=12) was determined after a 24 h exposure. At 24 h, the cumulative permeation value was 0.405%

of the applied dose for one donor (abdominal skin) and 0.067% for the other (breast skin). Tape-strip profiles for both

donors appeared to indicate that the DEA had become evenly distributed throughout the stratum corneum. The majority of

DEA was recovered in aqueous extract, as opposed to organic extract, of the epidermal and dermal tissue, which suggested to

the researchers that the material was in the free state and not associated with the lipid fraction.

Human liver slices were incubated with 1 mM [14C]DEA (>97% purity).22 After 4 and 12 h, 11 and 29% of the

DEA, respectively, absorbed into the liver slices. The radioactivity was comprised mostly of DEA (85-97%); four other

metabolites were present at low concentrations. The liver slices were fractionated into aqueous, organic, and pellet fractions.

The aqueous-extractable radioactivity was comprised primarily of DEA, with up to four other components. DEA-derived



6

radioactivity in the organic extracts was predominately (>90%) comprised of phospholipids containing non-methylated head-

groups. DEA was readily absorbed and incorporated into ceramides, forming mostly ceramide-phosphodiethanolamine, and

it was slowly methylated therein.

Dermal

Non-Human

A single occluded dose of ~20 mg/cm2 (1500 mg/kg) [14C]DEA was applied to a 19.5 cm2 area on the back of rats

for 6 h, and the treated site of half of the animals was rinsed after the occlusive wrapping was removed.23 In the animals that

were not rinsed, 80% of the dose was found in the wrappings, and 3.6% found in the skin. In animals that were rinsed,

rinsates from the wrappings contained 58% of the dose, and rinsates from the skin contained 26% of the dose. Unrinsed

animals absorbed 1.4% of the dose, while those animals that were rinsed absorbed 0.64%. The majority of the radioactivity

was found in the carcass, liver, and kidneys.

The researchers also conducted a repeated-dose percutaneous-absorption study in which as a pre-exposure, 1500

mg/kg/day non-radiolabeled DEA was applied occlusively under a 2 in x 2 in gauze square to the backs of rats 6 h/day for 3

or 6 days. [14C]DEA, 1500 mg/kg/day, was then applied for 3-6 consecutive days under occlusion; each dose was left in con-

tact with the skin for 48 h. Totals of 21 and 41% of the dose were absorbed by the animals dosed for 3 and 6 days, respec-

tively. The majority of the recovered radioactivity was in the wrapping. The carcass, liver, and kidneys contained most of

the radioactivity in the animals. Totals of 4.3 and 13% of the radioactivity were recovered in the urine of animals dosed with

non-radiolabeled DEA for 3 and 6 days, respectively. Pre-exposure to DEA resulted in a 1.5- to 3.0-fold increase in the

absorption rate.

Groups of 4-5 male B6C3F1 mice were used in dermal studies of the absorption, distribution, metabolism, and

excretion (ADME) of DEA.24 The dose, which contained 6-20 µCi radiolabel, unlabeled DEA, and 95% ethanol, for a total

volume of 15 µl per dose, was applied to a 1 cm2 area of skin under a non-occlusive covering. At 48 h after dermal applica-

tion of 8 and 23 mg/kg [14C]DEA, 26.8 and 33.8% of the dose was absorbed in the mice. A statistically significant increase

in the amount absorbed after dosing with 81 mg/kg, 58.1%, was observed. The amount of radioactivity found at the site of

application was only 4.0, 3.1,and 2.2% of the dose following application of 8, 23, and 81 mg/kg [14C]DEA, respectively, and

the amount excreted in the urine 48 h after application was 7.5%, 10.4, and 16.4%, respectively. The tissue/blood ratio was

greatest in the liver and kidneys.

Groups of 4-5 male Fischer 344 rats were used to evaluate the ADME of DEA (99% purity) following dermal ad-

ministration.24 The dose, which contained 6-20 µCi radiolabel, unlabeled DEA, and 95% ethanol, for a total volume of 25 µl

per dose, was applied to a 2 cm2 area of skin under a non-occlusive covering. Absorption increased significantly with

increasing dose. After 48 h, only 2.9% of the radioactivity was absorbed following dermal application of 2.1 mg/kg, while

10.5 and 16.2% of the radioactivity was absorbed with doses of 7.6 and 27.5 mg/kg, respectively. Of the amount absorbed,

1.2, 4.3, and 4.5% of the radioactivity was recovered in the skin at the dose site following application of 2.1, 7.6, and 27.5

mg/kg [14C]DEA, respectively. The greatest tissue/blood ratios were found in the liver and lung.

DEA, 80 mg/kg bw in acetone, was applied to a 2 cm2 area on the backs 7 female C57BL/6 mice for 11 days.25

DEA and its methylated metabolites accumulated in the liver and plasma of mice. Also, a statistically significantly decrease

in hepatic concentrations of choline and its metabolites was reported.

Human

Three female subjects applied a lotion containing 1.8 mg DEA/g lotion to their entire body 2x/day for 1 mo.25 The

subjects applied 14.5-22.9 ml lotion/day; DEA exposure following application of 20 ml/day by a 60 kg person would be 0.6



7

mg/kg/day DEA. Blood samples were collected 1 day prior to the start of dosing, at 1 wk, and at 1 mo. Two of the subjects

completed 1 mo of application, while the third completed 3 wks. Application of the DEA-containing lotion for 1 mo resulted

in increased concentrations of DEA in plasma, when compared to control samples. (As a reference point, however, it was

calculated that the concentration of DEA and metabolites in the plasma of humans after a few weeks of application of the

lotion were only 0.5-1% of the concentrations achieved in mice, where 80 mg/kg/day was applied for 11 days.)

Oral

Non-Human

Four male Fischer 344 rats were dosed orally by gavage with 7 mg/kg aq. [14C]DEA to examine the ADME of DEA

(>97% purity).22 The amount of radioactivity excreted in the urine at 24 and 48 h was 9 and 22%, respectively, and the

amount in the feces was 1.6 and 2.4%, respectively. At 48 h after dosing, 27% of the radioactivity accumulated in the liver,

5% in the kidneys, and 0.32, 0.27, 0.19, and 0.18% in the spleen, brain, heart, and blood, respectively. As measured in the

liver and the brain, 87-89% of the radioactivity distributed into the aq. phase, and 70-80% of that total radioactivity was as

unchanged DEA. In the liver, the remaining radioactivity in the aqueous phase was distributed between three methylated

metabolite fractions, while in the brain, only one minor, non-methylated metabolite was present in the aqueous extract.

With repeat oral dosing with [14C]DEA, radioactivity continued to accumulate in tissues, reaching steady states at 4-

8 wks. The levels of DEA equivalents in the blood, brain, and liver were much higher following 8 weeks of repeated oral

doses of 7 mg/kg/day, when compared to the single dose post-48-h values. Again, DEA was the major radioactive compo-

nent. Using HPLC, almost all of the organic-extractable hepatic radioactivity eluted with the phosphatidylcholine fraction,

with greater than 95% of the material in the form of phospholipids containing an N,N-dimethyl-DEA headgroup. In the

brain, the entire organic-extractable radioactivity eluted in the phosphatidylethanolamine fraction, and it was almost entirely

comprised of DEA-containing headgroups.

According to the researchers, the results of this study demonstrated that DEA is O-phosphorylated and N-methyl-

ated, and that these metabolites are incorporated as the polar headgroups in aberrant phospholipids. The researchers felt this

was evidence that DEA and MEA, a naturally-occurring alkanolamine, share common biochemical pathways of transforma-

tion. Retention and bioaccumulation of DEA-derived radioactivity was attributed partly to aberrant phospholipids being

incorporated into tissues, most probably in cell membranes.

Groups of 3-5 male Fischer 344 rats were used to evaluate the ADME of a single oral administration of [14C]DEA

(99% purity).24 The dose administered contained 2-200 µCi radiolabeled, unlabeled DEA, and the amount of water needed to

achieve a target dose of 5 ml/kg bw. Gastrointestinal absorption was nearly complete after doses up to 200 mg/kg DEA. At

48 h after dosing with 7 mg/kg, 22% of the radioactivity was excreted in the urine and 2.4% in the feces, primarily as un-

changed DEA. Radioactivity was not detected in carbon dioxide. Excretion was mostly unchanged DEA. A total of 57% of

the radioactivity was found in the body 48 h after dosing with 7 mg/kg [14C]DEA. Disposition of radioactivity was greatest

in the liver (27.3%), muscle (16.3%), skin (5.1%), and kidneys (5%); only 0.2% of the radioactivity was found in the blood

after 48 h. Dose did not affect distribution in the tissues.

The researchers then evaluated the ADME of DEA upon repeat oral exposure. Four rats were dosed orally with 7

mg/kg/day [14C]DEA for 5 days. Approximately 40% of the total radioactivity was excreted during dosing. At 48 h after the

last dose, a total of 42% of the radioactivity was found in the tissues, with the greatest distribution in the liver (18.2%),

muscle (12.4%), kidneys (5.56%), and skin (4.18%). To further investigate DEA bioaccumulation, rats were dosed with 7

mg/kg/day DEA, 5 days/wk, for 2, 4, or 8 wks. During the last week of each dosing period, 69, 79, and 92% of the dose was

excreted, respectively. After 8 wks of dosing, most of the radioactivity was recovered as unchanged DEA; however there



8

were also significant amounts of poorly retained metabolites, N-methyl DEA, and another metabolite that was tentatively

identified as a quaternized lactone. The radioactivity recovered in the liver after 2, 4, and 8 wks of dosing was 12.3, 7.9, and

4.12%, respectively. It was estimated that steady-state for bioaccumulation occurred after 4 wks of repeat dosing, except for

the blood, which continued to bioaccumulate DEA throughout dosing. Clearance of bioaccumulated DEA appears to be a

first-order process, with a whole body elimination half-life of ~6 days.

Intravenous

Non-Human

Groups of Sprague-Dawley rats (number per group not specified) received an intravenous (i.v.) dose of 10 or 100

mg/kg DEA in physiological saline.23 Animals were killed 96 h after dosing. Peak concentrations appeared in the blood 5

min after dosing. Elimination from the blood was biphasic. Totals of 25 and 36% of the dose were excreted in the urine with

10 and 100 mg/kg DEA, respectively.

Groups of 3-5 male Fischer 344 rats were used to evaluate the ADME of [14C]DEA (99% purity) in phosphate-

buffered saline after i.v. administration.24 After 48 h, 28% of the dose was excreted in the urine, 0.6% in the feces, and only

0.2% in carbon dioxide. Using HPLC, it was determined that most of the radioactivity in the urine was present as unchanged

DEA. A total of 54% of the dose was found in the body 48 h after dosing with 7 mg/kg [14C]DEA, and as with oral dosing,

the greatest disposition was found in the liver (27%), muscle (15%), skin (4.5%), and kidneys (4%). Only 0.2% of the

radioactivity was found in the blood after 48 h.

Groups of 5 female Sprague-Dawley rats were dosed i.v., via the cannulated jugular vein, with 10 or 100 mg/kg

[14C]DEA (97.4% purity).26 The dose volume was 2 ml/kg, and each rat received ~4.2 µCi 14C. Blood samples were taken at

various intervals up to 84 h after dosing. The peak concentrations of radioactivity in both the plasma and the red blood cells

were observed 5 min after dosing. Clearance of radioactivity from the plasma was calculated to be approximately 50 and 93

ml/h/kg for the low and high dose, respectively. In blood, these values were 84 and 242 ml/h/kg, respectively.

Urine and feces were collected for 96 h after dosing. During this time, the major route of excretion was urinary; 25

and 36% of the dose was recovered in the urine. Urinary excretion was rapid at the high dose level, with 23% of the dose

recovered in the first 12 h. Only 8.5% of the dose was recovered with the low dose during this time frame. The majority of

the radioactivity was recovered in the carcass; 35 and 28% for the low and high dose, respectively. At 96 h after dosing with

10 and 100 mg/kg DEA, approximately 21 and 17% of the dose was recovered in the liver, 7 and 5% in the kidneys, and 5

and 5% in the skin, respectively. The researchers stated that because the majority of the applied dose (administered radio-

activity) was recovered in the tissues, particularly in the liver and kidneys, this indicated a propensity for bioaccumulation.

There was some evidence that the bioaccumulation was dose-dependent.

N-Nitrosodiethanolamine (NDELA) Formation

The formation of NDELA upon dosing with DEA (99.7% purity), with and without supplemental oral sodium

nitrite, was determined in male B6C3F1 mice.27 Groups of 5-6 mice were dosed orally with aq. DEA or dermally with DEA

in acetone. DEA, 160 mg/kg/day, was applied for 7 days/wk for 2 wks. One group of mice dosed dermally was allowed

access to the application site, while the other was not. Studies were performed both with and without ~40 mg/kg/day supple-

mental sodium nitrite in drinking water. NDELA was not found in the urine or blood of mice dosed with DEA without nitrite

or in the blood or gastric contents of those given supplemental nitrite with DEA.

NDELA formation from DEA (>99% purity) and nitrite was also examined in another study.28 Female B6C3F1

mice were dosed dermally or orally with 4 mg/kg DEA, in conjunction with oral exposure to sodium nitrite. Following 7

days of dermal dosing, no NDELA was detected in the blood, ingesta, or urine of test, vehicle control, or sodium nitrite



9

control mice. (The limits of detection for the blood, ingesta, and urine were 0.001, 0.006, and 0.47 µg/ml, respectively.)

With a single oral dose, NDELA was formed in all of the animals; the amounts of NDELA detected in the blood and ingesta

of mice 2 h post-dosing were very small; 0.008 ± 0.003 µg/g and 0.424 ± 0.374 µg/g, respectively.

TOXICOLOGICAL STUDIES

In acute oral studies on DEA using groups of 2-3 guinea pigs, all survived dosing with 1 g/kg and none survived dosing with 3 g/kg DEA gum arabic solution. In rats, oral LD50 values have been reported as 0.71-0.80 ml/kg for undiluted DEA, 1.82 g/kg for aq. DEA, and 1.41-2.83 g/kg for 20% aq. DEA. In repeat dermal testing with DEA in mice and/or rats, irritation was observed at the application site following unoccluded dosing with ≥125 mg/kg to rats and 630 mg/kg mice. In-creases in liver and kidney weights were observed in most studies, while decreases in body weight were observed sporadical-ly. The LOAEL for DEA in a 2-wk study in mice was 160 mg/kg bw. In repeat oral testing with DEA, increases in liver and kidney weights and decreases in body weights were seen in mice and rats. Deaths, believed to be test-article related, occurred in most of the studies, and included a mouse given 100 mg/kg DEA by gavage. In inhalation studies with DEA in rats, liver and kidney weights were again increased. In 13-wk studies with ≤400 mg/m3DEA, microscopic effects were observed in the larynx. The 90-day NOAEC was 1.5 mg/m3 DEA.

Acute (Single) Dose Toxicity

Oral

The acute oral toxicity of DEA was determined using guinea pigs and rats. Using groups of 2-3 guinea pigs, all guinea pigs survived dosing with 1 g/kg, but none survived dosing with 3 g/kg DEA gum arabic solution. Using groups of 5 rats, the oral LD50 of undiluted DEA was 0.71-0.80 ml/kg, and for a group of 6 rats, the LD50 of DEA in water was 1.82 g/kg. Using 90-120 rats, 20% aq. DEA had an acute LD50 of 1.41-2.83 g/kg, based on results of testing performed over a 10 yr time period. With groups of 10 rats, a hair preparation containing 1.6% DEA had an LD50 of 14.1 g/kg when diluted and 12.9 ml/kg when undiluted. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1

Other

The intraperitoneal (i.p.) LD50 of DEA was 2.3 g/kg for mice. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1

Repeated Dose Toxicity

Dermal

In a 13-wk study, 1 mg/kg of a hair dye formulation containing 2.0% DEA was applied to the backs of 12 rabbits for 1 h, twice weekly. The test site skin was abraded for half of the animals. No systemic toxicity was observed, and there was no histomorphologic evidence of toxicity. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1 DEA was applied dermally to groups of 5 male and 5 female B6C3F1 mice, 5x/wk for 2 wks, at doses of 160, 320,

630, 1250, and 2500 mg DEA/kg bw in 95% ethanol.29 Vehicle only was applied to the controls. All of the male and 3 of the

female high-dose test animals died during the study. Ulceration, irritation, and crusting were observed at the application site

of male mice of the 1250 and 2500 mg/kg groups and females of the 2500 mg/kg group. Microscopically, moderate to

marked epidermal ulceration and inflammation were observed in these animals. Ulcerative necrosis extended into the

underlying dermis. Minimally severe acanthosis, without inflammation, was seen in the 160, 320, and 630 mg/kg dose

groups. Absolute and relative liver weights increased in a dose-dependent manner in males and females.

Groups of 5 male and 5 female F344/N rats were also dosed with DEA 5x/wk for 2 wks, with 125, 250, 500, 1000,

and 2000 mg DEA/kg bw in 95% ethanol.29 Vehicle only was applied to the negative controls. All of the females and 3 of

the males of the 2000 mg/kg group, and 1 female of the 1000 mg/kg group, died during the study. Irritation and crusting was

observed at the application site of male and female rats of the 500, 1000, and 2000 mg/kg groups. Microscopically,

ulceration with acanthosis and inflammation was observed in these animals. Ulcerative necrosis extended into the underlying

dermis. Minimal acanthosis was seen in female rats of the 250 mg/kg group, and hyperkeratosis was seen in all test groups.



10

Absolute and relative kidney weights increased in a dose-dependent manner in males and females. Renal tubular epithelial

necrosis (mild severity) was observed in the animals that died during the study. Some statistically significant changes in

urinalysis parameters were observed. Mild to moderate seminiferous tubule degeneration in the testis was observed in 4/5

high dose males.

To determine whether repeated dermal administration of DEA induced cell proliferation and/or apoptosis in the

livers of mice, 8 male and 8 female B6C3F1/Crl mice were dosed dermally with 0 and 160 mg/kg bw DEA (99.6% purity) in

96% ethanol for 1 wk followed by a 3-wk recovery period, and groups of 10 male mice were exposed dermally, 5 days/wk, to

0 or 160 mg/kg for 1, 4, or 13 wks.30 A dose response relationship was examined using groups of 8 male mice; applications

of 10-1250 mg/kg DEA were made to male mice for 1 or 13 wks, and controls were exposed to vehicle only. (Application of

630 and 1250 mg/kg DEA was discontinued, and the animals killed, after 1 wk due to severe skin lesions; the high dose was

then 160 mg/kg.) No DEA-related deaths were observed. Body weights were not affected by dosing. Statistically significant

increases in liver weights were seen in mice dosed with ≥10 mg/kg bw/day DEA for 1 or more weeks. After 1 wk of dosing,

increased cell proliferation in the liver was observed in males and females; this effect was reversible. Eosinophilia was found

in animals dosed with ≥40 mg/kg DEA for 1 or more weeks, and hepatocellular giant cells were seen in animals dosed with

160 mg/kg for 13 wks. Repeated application of ≥10 mg/kg DEA to male B6C3F1 mice caused increased liver cell prolifera-

tion. DEA had no effect on the number of apoptotic cells in the liver. Some erythema and/or focal crust formation was

observed and attributed to the procedure and/or the vehicle, but not to DEA.

Unoccluded dermal applications 80, 160, 320, 630, and 1250 mg/kg bw/day DEA (purity >99%) in acetone were

applied to the backs of 10 male and 10 female B6C3F1 mice, 5 days/wk for 13 wks.31 Vehicle only was applied to the

negative control group. (The square area of the dose site was not provided.) Two male mice and 4 female mice dosed with

1250 mg/kg DEA were killed in moribund condition. Final mean body weights of male mice dosed with 1250 mg/kg were

statistically significantly decreased compared to controls. Clinical signs of toxicity, observed in males and females dosed

with 630 and 1250 mg/kg DEA, were irritation, crust formation, and thickening at the application site. Ulceration and in-

flammation were observed in the 630 and 1250 mg/kg dose groups. Dose-dependent increases in absolute and relative liver

weights, associated with hepatocellular changes, were observed, and hepatocellular necrosis was seen in males dosed with

320-1250 mg/kg DEA. Absolute kidney weights were statistically significantly increased in males and females of all test

groups. Relative kidney weights were increased in males of all test groups and females dosed with 630 or 1250 mg/kg DEA;

nephropathy was not found. Heart weights were increased in high dose males and females, and cardiac myocyte degenera-

tion was reported.

Unoccluded dermal applications of 32, 63, 125, 250, and 500 mg/kg bw/day DEA (purity >99%) in 95% ethanol

were applied to the backs of 10 male and 10 female F344/N rats, 5 days/wk for 13 wks.32 Vehicle only was applied to the

negative control group. (The square area of the dose site was not provided.) One male and 2 females given 500 mg/kg died

or were killed in moribund condition during the study. Clinical signs of toxicity, observed in males and females given 125-

500 mg/kg DEA, were irritation and crusting at the application site. Final mean body weights were statistically significantly

decreased in males dosed with 250 and 500 mg/kg and females dosed with 125-500 mg/kg DEA. Increases in absolute and

relative kidney weights were observed with increased incidence of renal lesions. Increases in absolute and relative liver

weights were not accompanied by an increase in hepatic lesions. Demyelination in the medulla oblongata was seen in all

high dose animals and 7 females given 250 mg/kg DEA; this lesion was minimal in severity.

Oral

Oral studies were conducted in which neonatal rats were dosed with 1-3 mM/kg/day DEA, as a neutralized salt, on days 5-15 after birth, male rats were dosed with 4 mg/ml neutralized DEA in drinking water for 7 wks, and rats were fed 0-



11

0.68 g/kg/day DEA in feed for 90 days. Repeated oral ingestion of DEA produced evidence of hepatic and renal damage. Deaths occurred in the 7 wk and 90 day studies. Administration of neutralized DEA in the drinking water at doses of 490 mg/kg/day for 3 days or of 160 mg/kg/day for 1 wk produced alterations of hepatic mitochondrial function. Oral administration of DEA may affect, directly or indirectly, the serum enzyme levels, isozyme patterns, and concentrations of some amino acids and urea in the male rat liver and kidney. Repeated DEA administration in the drinking water increased male rat hepatic mitochondrial ATPase and altered mitochondrial structure and function. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, Monoethanolamine1 Female CD-1 mice, 3 per group, were dosed orally, by gavage, with 10, 100, or 1000 mg/kg bw DEA in distilled

water for 7 days.33 One animal of the 100 mg/kg group died, and the death was considered test article-related. (Two deaths

in the 1000 mg/kg group were attributed to gavage error.)

Groups of 48 female B6C3F1 mice were dosed with 0, 100, 300, or 600 mg/kg bw DEA34 and groups of 48 F344

female rats were dosed with 0, 50, 100, or 200 mg/kg bw DEA,35 orally, by gavage, in distilled water for 14 days. No effect

on body weight gain was observed for mice in any group. Rats exposed to 10 and 200 mg/kg DEA had significant decreases

in body weight and/or body weight gains. Liver weights were increased in a dose-dependent manner in both rats and mice,

and kidney weights were increased in a dose-dependent manner in rats. No effects were seen in thymus, spleen, or kidney

weights of mice. In mice, DEA exposure resulted in an increase in the number of B-cells and a decrease in the number of

CD4+CD8- (18%) T-cell subsets. A dose-dependent decrease in the antibody-forming response to sheep erythrocytes was

observed with 600 mg/kg DEA, and a dose-dependent decrease in the cytotoxic T-lymphocyte response was observed, which

was statistically significant at the lowest dose. The natural killer cell response was not affected. In rats, exposure to DEA

did not alter the number of B-cells, T-cells, or T-cell subsets. The proliferative response to allogenic cells, as measured by

the mixed leukocyte response, was increased in a dose-dependent manner; the increase in the high dose was statistically

significant. Natural killer cell response and cytotoxicity of resident macrophages were decreased in DEA-treated animals.

In a 13-wk study, 10 male and 10 female B6C3F1 mice were dosed orally, by gavage, 5 times/wk, with 50, 100, 200,

400, or 800 mg/kg DEA in deionized water.36 The negative controls were dosed with vehicle only. Two males of the high

dose group died during the study. Body weights and body weight gains of high dose males were decreased. No clinical signs

of toxicity were noted. Treatment-related renal lesions were found, but details were not provided.

Groups of 10 male and 10 female B6C3F1 mice received 630, 1250, 2500, 5000, or 10,000 ppm DEA (>99% purity)

in the drinking water for 13 wks.31 The pH of the solution was adjusted to 7.4. The negative controls were given untreated

water. All males and females of the 5000 and 10,000 ppm groups and 3 females of the 2500 ppm group died during the

study. Body weight gains were decreased in males of the 2500 ppm group and females of the 1250 and 2500 ppm groups.

No significant gross effects were noted at necropsy. Statistically significant, dose-dependent, increases in absolute and

relative liver weights were observed, with hepatocellular cytological alterations and necrosis in animals given ≥2500 ppm

DEA. Absolute and relative kidney weights also increased dose-dependently, with statistically significant increases in mice

given 1250 or 2500 ppm DEA, and nephropathy was observed in all male test groups and female test groups given 2500 or

5000 ppm DEA. Heart weights were increased in female mice given 2500 ppm DEA, and relative heart weights were

increased in males of the 2500 ppm group and females of the 1250 and 2500 ppm groups.

Groups of 10 male F344/N rats received 320, 630, 1250, 2500, or 5000 ppm DEA and 10 female F344/N rats

received 160, 20, 630, 1250, or 2500 ppm DEA in the drinking water for 13 wks.32 Negative controls were given untreated

water. Two males of the high dose group died during the study. The following dose-related effects were observed: decreases

in body weight gains in males and females; hematological effects; increases in kidney weights accompanied by renal lesions;

and increases in relative liver weights in males and females. Demyelination of the medulla of the brain and of the spinal cord

was observed in all males of the 2500 and 5000 ppm groups and all females of the 1250 and 2500 ppm groups.



12

Groups of 10 male albino rats received feed containing 0.01, 0.1, or 1% (10, 100, or 1000 mg/kg bw/day) DEA

(99% purity) for 32 days.37 Nine of the 10 high dose animals died during the study. All test animals had decreased

hemoglobin and hematocrits, with an increased white blood cell count. The relative liver weights of animals fed 0.01 and

0.1% DEA, and the absolute liver weights of animals of the 0.1% group, were increased. In a repeat 30-day study using the

same procedure and dose levels, 7 of the 10 high dose animals died, and the remaining 3 high-dose animals killed, prior to

study termination; body weights and feed consumption were significantly decreased in this group. Again, hemoglobin and

hematocrit were decreased in the 0.1% group, and the hemoglobin value was reduced in the 0.1% group.

Inhalation

Short-term inhalation of 200 ppm DEA vapor or 1400 ppm DEA aerosols (duration of dosing not provided) produced respiratory difficulties and some deaths in male rats. Inhalation of 25 ppm for 216 continuous hours resulted in increased liver and kidney weights, while exposure of male rats to 6 ppm DEA following a “workday” schedule for 13 wks caused decreased growth rate, increased lung and kidney weights, and some deaths. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1 In a 2-wk dose-range finding inhalation study, 10 male and 10 female Wistar rats were exposed, nose only, to target

concentrations of 0, 100, 200, and 400 mg/m3 DEA (>99% pure) for 6 h/day, 5 days/wk.38 Mass median aerodynamic

diameter (MMAD) was 0.6-1.9 µm. Test article-related effects were not seen with 100 or 200 mg/m3 DEA. With 400 mg/m3

DEA, decreased body weights and body weight gains were seen in males and increased relative and absolute liver weights

were seen in females. Microscopically, no effects were seen in the respiratory tract; the larynx was not examined.

Based on the results of the dose-range finding study, target concentrations of 0, 15, 150, and 400 mg/m3 DEA were

used in a 90-day study, in which groups of 13 male and 13 female rats were exposed via inhalation to 65 exposures, 6-h/day 5

days/wk. The MMAD was 0.6-0.7 µm. A functional observational battery was conducted using 10 rats/gender/group. Body

weight gains were reduced in males of the high dose group. Some statistically significant effects on clinical chemistry values

were seen in the mid and high dose group. Males and females of the high dose group had statistically significant increases in

blood in the urine, and males of the mid and high dose groups excreted significantly elevated amounts of renal tubular

epithelial cells. Relative liver weights were statistically significantly increased in males and females of the high dose group

and females of the mid-dose group, and relative kidney weights were statistically significantly increased in males and females

of the mid and high dose groups. Focal squamous metaplasia of the ventral laryngeal epithelium was observed in test

animals of all groups, and a concentration-dependent increase in laryngeal squamous hyperplasia, and in the incidence and

severity of local inflammation of the larynx and trachea, were observed. There were no indications of neurotoxicological

effects.

In a third study, test groups of 10 male and 10 female Wistar rats were exposed to target concentrations of 0, 1.5, 3,

and 8 mg/m3 DEA using the same dosing schedule as above, and recovery groups of 10 females were exposed to 3 or 8

mg/m3, with a post-exposure period of 3 mos. No dose-related clinical signs were observed. Liver weights of test, but not

recovery, females dosed with 8 mg/m3 were statistically significantly increased. Laryngeal effects were similar to those

described above. No microscopic changes were observed in the upper respiratory tract of recovery animals. The 90-day no

observed effect concentration (NOAEC) was determined to be 1.5 mg/m3 DEA.

In inhalation studies, Sprague-Dawley rats, Hartley guinea pigs and Beagle dogs (number per species and sex not

specified) were each exposed to 0.5 ppm DEA for 6 h/day, 5days/wk, for a total of 45 exposures.37 All animals survived

until study termination. There were no clinical signs of toxicity, and no evidence of irritation. No gross or microscopic

lesions were observed at necropsy.



13

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

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 param-eters were observed. In a study in which parental mice were treated dermally with DEA for 4 wks prior to dosing, sperm motility was decreased at all doses (20-320 mg//kg) in a dose-dependent manner. In rats and rabbits dosed dermally with up to 1500 mg/kg and 350 mg/kg 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.

In an oral developmental toxicity 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.

In a developmental toxicity 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.

Dermal

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. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1 A reproductive and developmental toxicity study was performed in which 0, 20, 80, or 320 mg/kg DEA (98.5%

purity) in ethanol was applied to a 2 cm2 area on the back of 15 male C57BL/6 mice, 15 per group, for 4 wks.39 (It was not

stated whether the test area was covered.) These males were then mated with untreated females. In the parental male mice,

sperm motility was significantly decreased at all dose levels and in a dose-dependent manner. In male pups, a significant

decrease in epididymis weight was seen in the 80 mg/kg group at postnatal day (PND) 21, and reductions in weights of

reproductive organs of high-dose males pups was seen at PND 70. There were no significant differences in skeletal

formation or in growth and development parameters.

Doses of 0, 20, 80, or 320 mg/kg DEA (98.5% purity) in ethanol were applied to a 2 cm2 area on the backs of groups

of 10 gravid female C57BL/6 mice on day 6 of gestation through PND 21. The body weights of male and female pups of the

high dose group were statistically significantly decreased compared to controls. No specific differences in organ weights

were observed in pups of the test groups as compared to controls. There were no significant differences in skeletal formation.

Dose-dependent effects on growth and developmental parameters were noted. Sperm motility was decreased in male pups,

but this result was not statistically significant.

CD rats and NZW rabbits were used to evaluate the potential of DEA (≥99.4% purity) to produce developmental

toxicity with dermal exposure.40 Groups of 25 gravid CD rats were dosed dermally with 150, 500, or 1500 mg/kg/day DEA

in deionized water, 6 h/day, on days 6-15 of gestation, under an occlusive covering. Dosing volume was 4 ml/kg/day.

Control animals were dosed with vehicle only. Teratogenic effects were not seen at any dose. Dermal application of 500

mg/kg DEA resulted in alterations of maternal hematological parameters, but did not affect embryonal/fetal development.

Other signs of maternal toxicity were seen at this dose and with 1500 mg/kg/day. The NOEL for embryonal/fetal toxicity

was estimated to be 380 mg/kg/day, which incorporates an adjustment for the 10-24% deficit in expected dose that occurred

on days 12-15 of gestation.

Groups of 15 mated rabbits were dosed dermally with 35, 100, or 350 mg/kg/day DEA in deionized water, 6 h/day,

on days 6-18 of gestation, under an occlusive covering. Dosing volume was 2 ml/kg/day, and controls were dosed with

vehicle only. Dermal administration of 350 mg/kg/day DEA produced severe skin irritation in rabbits, and signs of maternal

toxicity were observed at this dose. No developmental toxicity was observed, and there was no evidence of teratogenicity at



14

any dose. The NOEL for maternal toxicity of DEA in rabbits was 35 mg/kg/day, and the embryonal/fetal NOEL was 350

mg/kg/day DEA.

Oral

In a Chernoff-Kavlock screening test, groups of 4 gravid CD-1 mice were dosed orally, by gavage, with 200, 380,

720, 1370, or 2605 mg/kg bw DEA in distilled water on days 6-15 of gestation; a control group was dosed with vehicle

only.33 Two, 3, and 4/4 animals of the 720, 1370, and 2605 mg/kg dose groups died during the study. Rough hair coats were

observed at all dose levels. Group of 50 female gravid CD-1 female mice were dosed orally, by gavage, with 0 or 450 mg/kg

bw DEA in distilled water on days 6-15 of gestation. No animals died during the study. The reproductive index and average

number of live litters on day 0 were not affected by dosing, but the average number of live litters on day 3 was decreased.

Mean body weights and body weight gains of pups were also decreased on PND 3.

Gravid Sprague-Dawley rats were dosed orally, by gavage, with 50, 200, 500, 800, or 1200 mg/kg/day DEA on days

6-15 of gestation.41 Maternal mortality was observed at doses of 50-1200 mg/kg/day. At doses of 50 and 200 mg/kg/day, no

differences in gross developmental endpoints were found between test and control animals. The NOEL for embryonal/fetal

toxicity was 200 mg/kg/day DEA. However, maternal weight gains were significantly decreased at that dose. (Additional

details were not provided.)

Groups of 12 gravid female Sprague-Dawley rats were dosed orally, by gavage, with 50, 125, 200, 250, or 300

mg/kg bw/day DEA (>98% purity) distilled water on days 6-19 of gestation, while controls were dosed with vehicle only.42

Dosing volume was 5 ml/kg. Surviving dams and pups were killed on PND 21. All females dosed with 300 mg/kg DEA

were killed prior to study termination due to excessive toxicity. Toxicity was also observed for one dam dosed with 200

mg/kg, and only 5 dams of the 250 mg/kg group delivered live litters and survived until study termination. The calculated

LD50 was 218 mg/kg bw/day. No significant maternal or developmental toxicity was seen with 50 mg/kg bw/day DEA.

Signs of maternal and developmental toxicity were seen at doses of ≥125 mg/kg bw/day and included decreased maternal

weight gains, increased kidney weights in dams, increased post-implantation and postnatal mortality, and reduced live pup

weights. The no observable adverse effect level for maternal toxicity and teratogenicity was 50 mg/kg/day, and the LOAEL

for these parameters were 125 mg/kg/day.

Inhalation

In a range-finding study, groups of 10 gravid Wistar rats were exposed, nose-only, to target concentrations of 0.1,

0.2, or 0.4 mg /l DEA, 6 h/day, on days 6-15 of gestation.43 (DEA purity was >98.7%.) All animals survived until study

termination. Relative liver weights were increased in animals of the 0.2 mg/l group, and absolute and relative liver weights

were increased in animals of the 0.4 mg/l group. No treatment-related effects were observed with 0.1 mg/l DEA.

Groups of 25 gravid Wistar rats were exposed, nose-only, to target concentrations of 0.01, 0.05, or 0.2 mg DEA

aerosol/l air, 6 h/day, on days 6-15 of gestation.44,45 (DEA purity >98.7%.) Maternal toxicity, as indicated by vaginal

hemorrhage, was seen at the highest dose level. No treatment-related malformations were observed at 0.2 mg/m3. The

NOAEC for both maternal and developmental toxicity was 0.05 mg/l, and the NOAEC for teratogenicity was >0.2 mg/l,

which was the highest dose tested in this study.

Effect on Hippocampal Neurogenesis and Apoptosis

The effect of DEA on neurogenesis was investigated using C57BL/6 mice.46 DEA, 0, 20, 80, 160, 320, 640 mg/kg

bw in ethanol, was applied to a 2 cm2 area on the backs of gravid female mice, 6 per group, on days 7-17 of gestation. A

dose-related decrease in litter size was observed at doses >80 mg/kg, and the decrease was statistically significant at doses of

160-640 mg/kg bw/day. The livers of the maternal mice were analyzed on day 17 of gestation, and hepatic concentrations of



15

choline and its metabolites were statistically significantly decreased. In the fetal brain, treatment with 80 mg/kg bw/day DEA

diminished the proportion of cells that were in the mitotic phase to 50% of controls. The number of apoptotic cells of the

hippocampal area was >70% higher in fetuses of DEA-treated mice compared to controls. The researchers stated that the

effect observed in the mouse fetal brain after administration of DEA was likely to be secondary to diminished choline levels.

The researchers also hypothesized that a potential mechanism for the effect of choline deficiency, and maybe DEA, on

progenitor cell proliferation and apoptosis involves abnormal methylation of promoter regions of genes.

The doses used in the above study were based on expected concentrations of 1-25% DEA in cosmetic formulations.

However, based on comments from the Cosmetic, Toiletry, and Fragrance Association (now known as the Personal Care

Products Council) indicating the over-estimation of the amount of DEA contained in consumer products,47 the researchers

tested lower doses to establish a dose-response relationship. Groups of 7 mice were dosed dermally with 20-80 mg/kg bw

DEA (purity >99.5%) as described previously, with the exception that acetone was used as the vehicle.46 The negative control

group was dosed with vehicle only. While the results reported in the earlier study with 80 mg/kg bw DEA were confirmed,

no differences were seen between treated and control groups with <80 mg/kg bw.

In a study to identify the potential mechanism for the alterations described above, mouse neural precursor cells were

treated in vitro with DEA.48 Cells exposed to 3 mM DEA had less cell proliferation at 48 h and had increased apoptosis at 72

h. DEA treatment decreased choline uptake into the cells, resulting in diminished choline and phosphocholine. A three-fold

increase in choline concentration prevented the effects of DEA exposure on cell proliferation and apoptosis; intracellular

phosphocholine levels remained low. The researcher hypothesized that DEA interferes with choline transport and choline

phosphorylation in neural precursor cells. Additionally, it was suggested that DEA acts by altering intracellular choline

availability.

GENOTOXICITY

DEA was non-genotoxic in a number of assays. Positive results were reported in an in vitro assay with DEA of DNA strand break in isolated rat, hamster, and pig hepatocytes. Increases in DNA synthesis, in vitro, were reported in mouse and rat hepatocytes treated with DEA, but not in human hepatocytes. Choline decreased the DEA-induced increase in DNA synthesis in mouse and rat hepatocytes.

In Vitro

DEA, with and without metabolic activation using liver preparations from rats induced with a polychlorinated biphenyl mixture, was not mutagenic to Salmonella typhimurium TA100 or TA1535. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1

With or without metabolic activation, DEA (0-3333µg/plate) was not mutagenic in Ames test using S. typhimurium

TA98, TA100, TA1535, or TA1537, was negative in a mouse lymphoma assay (≤400 nl/ml), and did not induce sister

chromatid exchanges (SCEs) or chromosomal aberrations in a Chinese hamster ovary (CHO) cell cytogenetic assay (≤1500

µg/m)l.49 DEA was not clastogenic in a mouse micronucleus test (80-1250 mg/kg, dermal application). Positive results were

reported in an in vitro assay for induction of DNA single-strand breaks in isolated hepatocytes for rats, hamsters (both at ≥25

µmol/tube), and pigs (≥12.5 µmol/tube).

In studies examining species selectivity of effects caused by DEA, increases in DNA synthesis were observed in

mouse and rat, but not human, hepatocytes following treatment with ≥10 µg/ml DEA.50 Additionally, when the hepatocytes

were incubated in medium containing reduced choline, DNA synthesis was increased in mouse and rat hepatocytes, but not

human hepatocytes. Conversely, choline supplementation decreased DEA-induced DNA synthesis in mouse and rat

hepatocytes.



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CARCINOGENICITY

The carcinogenic potential of dermally applied DEA was evaluated by the NTP in B6C3F1 mice and F344/N rats. DEA produced clear evidence of carcinogenic activity in male and female mice (40-160 mg/kg) based on increased inci-dences of liver neoplasms in males and females and increased incidences of renal tubule neoplasms in males; there was no evidence of carcinogenicity in male (16-64 mg/kg) and female rats (8-32 mg/kg). The IARC Working Group concluded that, in the absence of adequate epidemiological information, there was sufficient evidence of carcinogenicity in experimental animals for a classification of DEA as possibly carcinogenic to humans. Because DEA is not mutagenic or clastogenic, a non-genotoxic mode of tumorigenic action is indicated. A plausible mode of action for DEA carcinogenicity in rodents involves cellular choline deficiency. Dermal

The NTP evaluated the carcinogenic potential of DEA (>99% purity) in ethanol using B6C3F1 mice and F344/N

rats.49 Groups of 50 male and 50 female mice were dosed dermally with 0, 40, 80, or 160 mg/kg/day, 5 days/wk, for 103

wks. Survival of dosed females, but not males, was significantly decreased in a dose-dependent manner. Mean body weights

of test animals were decreased at various intervals throughout the study. In male mice, the incidences of hepatocellular

adenoma and of hepatocellular adenoma and carcinoma (combined) in all dose groups, and the incidence of hepatocellular

carcinoma and hepatoblastoma in the 80 and 160 mg/kg group, were statistically significantly increased compared to

controls. In female mice, the incidence of hepatocellular neoplasms was significantly increased. Male mice also had a dose-

related increase in the incidences of renal tubule hyperplasia and renal tubule adenoma or carcinoma (combined), and an

increase in the incidence of renal tubule adenoma. In male and female mice, incidences of thyroid gland follicular cell

hyperplasia were increased. Hyperkeratosis, acanthosis, and exudate were treatment-related changes observed at the applica-

tion site. It was concluded that there was clear evidence of carcinogenic activity of DEA in male and female B6C3F1 mice

based on increased incidences of liver neoplasms in males and females and increased incidences of renal tubule neoplasms in

males.

In the rats, groups of 50 males were dosed dermally with 0, 16, 32, or 64 mg/kg bw DEA, and groups of 50 females

with 0, 8, 16, or 32 mg/kg bw, 5 days/wk, for 103 wks. The only treatment-related clinical finding was irritation at the

application site. Minimal to mild non-neoplastic lesions were found at the site of application of dosed males and females.

The incidence and severity of nephropathy in dosed females, but not males, was significantly greater in the treated groups

compared to controls. There was no evidence of carcinogenic activity of DEA in male or female F344/rats.

The carcinogenic potential of DEA was evaluated using a Tg·AC (zetaglobin v-Ha-ras) transgenic mouse model.51,52

Groups of 10-15 female homozygous mice were dosed dermally with 0, 5, 10, or 20 mg DEA/mouse in 95% ethanol, 5x/wk,

for 20 wks. DEA was inactive in Tg·AC mice.

Previously, the International Agency for Research on Cancer (IARC) Working Group concluded that DEA was not

classifiable as to its carcinogenicity to humans (Group 3), based on inadequate evidence in humans and limited evidence in

experimental animals for the carcinogenicity of DEA.53 Recently, however, taking in to consideration that no or very few

epidemiological studies assessing agent-specific exposure are available, the IARC Working Group concluded that, in the

absence of adequate epidemiological information, there was sufficient evidence of carcinogenicity in experimental animals

for a classification of DEA as possibly carcinogenic to humans (Group 2B).54 (This change was based on a change in the

criteria for classification, not new animal data.)

Possible Mode of Action for Carcinogenic Effects

Choline deficiency has been shown to increase spontaneous hepatocarcinogenesis in rats.55,56 Male F344 rats fed

diets deficient in labile methyl donors, specifically choline and methionine, absent any known carcinogen, had increased

incidence of liver cancer. Addition of choline to the diet prevented this effect. Hepatic effects were also seen in mice.57



17

Male B6C3F1 mice fed a choline-deficient diet resulted in all animals developing either liver nodules or tumors.

In the NTP studies, DEA also increased renal tubule neoplasms in male mice.49 In a study in which male Sprague

Dawley rats were fed a choline deficient diet for 6 days, followed by a normal diet for up to 119 days, acute renal lesions

consisting of tubular epithelial cell necrosis were observed immediately after being fed a choline-deficient diet.58 Chronic

renal lesions consisting of interstitial nephritis characterized by fibrosis and scarring were observed 28-119 days after being

fed the choline-deficient diet. (Hepatic lesions were also observed.) The proximal convoluted tubule was most severely

affected.

Disposition data indicate that DEA is less readily absorbed across rat skin than mouse skin,19 resulting in lower

blood and tissue levels of DEA in rats than in mice, suggesting that, in rats, the levels of DEA that occur are not high enough

to markedly alter choline homeostasis. If true, species differences observed in tumor susceptibility could be a function of the

internal dose of DEA. Alternatively, species differences in tumor susceptibility may explain the increased incidence of

hepatocarcinogenesis in B6C3F1 mice compared to rats exposed to DEA. It is important to note that both rats and mice are

reported to be much more susceptible to choline deficiency than humans.59

A species-selective inhibition of gap junctional intercellular communication by DEA in mouse and rat, but not

human, hepatocytes with medium containing reduced choline concentrations provided additional support that the mechanism

for DEA-induced carcinogenicity in rodents involves cellular choline deficiency.60 Also, Bachman et al. have hypothesized

the DEA-induced choline deficiency leads to altered DNA methylation patterns, which facilitates tumorigenesis.61

Two other hypotheses as to the mode of action of DEA carcinogenicity as possible alternatives to the intracellular

choline deficiency hypothesis have been proposed.62 One involves the nitrosation of DEA to NDELA and the other the for-

mation of DEA-containing phospholipids. The researcher did not find these likely for the following reasons. Regarding the

first alternate hypothesis, nitrosation to NDELA; NDELA was not detected in mouse plasma or urine after cotreatment of

mice with DEA and nitrite. In regards to the second, altered phospholipids; while DEA has been shown to be incorporated

into phospholipids, without qualitative or quantitative differences between rats and mice, carcinogenic effects are seen only

in mice, making it unlikely that incorporation of DEA into the phospholipids is a major determinant of carcinogenic response.

Leung et al reviewed the information available and also felt that choline deficiency is the mechanism responsible for liver

tumor promotion in mice.63

The localization of β-catenin protein in hepatocellular neoplasms and hepatoblastomas in B6C3F1 mice exposed

dermally to 0-160 mg/kg bw DEA for 2 yrs were characterized, and genetic alterations in the Catnb and H-ras genes were

evaluated.64 A lack of H-ras mutations in hepatocellular neoplasms and hepatoblastomas led the researchers to suggest that

the signal transduction pathway is not involved in the development of liver tumors following DEA administration.

IRRITATION AND SENSITIZATION

Undiluted DEA was moderately irritating to rabbit skin. In humans, a hair formulation containing 1.6% DEA was a cumulative irritant. However, no irritation was reported during the induction phase of sensitization studies with formula-tions containing 1.6-2.7% DEA. DEA was not a sensitizer in guinea pig maximization studies with intradermal and epicutaneous induction applications of 1 and 17.6%, respectively, or in humans tested with a formulation containing 2.7% DEA that was applied undiluted. In an ocular irritation study using rabbits, a 30% aq. solution of DEA was essentially non-irritating, and a 50% aq. solution was a severe irritant.

Irritation

Skin

Non-Human

The primary skin irritation potential of DEA was determined using rabbits. Undiluted DEA, applied to an unspecified number of rabbits using 10 open applications of 0.1 ml to the ears and 10 semi-occluded applications to the abdomen, was



18

moderately irritating. No irritation was observed with 10% aq. DEA following the same protocol. Using groups of 6 rabbits, application of 30 and 50% DEA using semi-occlusive patches to intact and abraded skin produced essentially no irritation.

From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1

Human

In a study in which an undiluted hair formulation containing 1.6% DEA was applied to the back of 12 female subjects for 23 h/day for 21 days, the formulation was considered an experimental cumulative irritant. No irritation was reported during the induction phase of sensitization studies for a formulation containing 2% DEA, tested as a 10% solution in distilled water (165 subjects), for a formulation containing 2.7% DEA, tested undiluted (100 subjects), or for a formulation contain-ing 1.6% DEA, tested undiluted (25 subjects). From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine.1

Mucosal

Non-Human

The ocular irritation potential of 30-100% DEA was evaluated using rabbits. As a 30% aq. solution, DEA was essentially non-irritating, while a 50% aq. solution was a severe irritant. Instillation of 0.02 ml undiluted DEA produced severe injury to rabbit eyes. A hair preparation containing 1.6% DEA had a maximum avg. irritation score of 0.7/110 for rinsed and unrinsed eyes. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1

Sensitization

Non-Human

DEA had an EC3 value of 40% in a mouse local lymph node assay (OECD guideline 429), resulting in a categoriza-

tion of weak potency of for skin sensitization.65

In a maximization study using 15 Dunkin-Hartley guinea pigs, intradermal and epicutaneous induction used 1% and

17.6% aq. DEA, respectively, after 10% sodium lauryl sulfate pre-treatment.66 At challenge with 0.7, 3.5, or 7% DEA, 1/15

animals reacted to the lowest and highest challenge concentrations after 2, but not 3 days. In a second maximization test us-

ing 20 Himalayan spotted guinea pigs, the intradermal induction, epicutaneous induction, and epicutaneous challenge con-

centrations were 5%, 75%, and 25% DEA in physiological saline, respectively.66,67 Freund’s complete adjuvant (FCA) was

used at intradermal induction. Two animals had mild erythema at day 1, and one animal had mild erythema at day 2. DEA

was not a sensitizer.

Human

Formulations containing 1.6 and 2.7% DEA, tested undiluted in 12 and 100 subjects, respectively, and a formulation containing 2% DEA, tested as a 10% solution in distilled water in 165 subjects, were not sensitizing in clinical studies. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1

Provocative Testing

Over a 15-yr period, provocative patch testing using DEA was performed on 8791 patients.66 There were 157

(1.8%) positive reactions to DEA, and most of the reactions (129; 1.4%) were weak positives. There were 17 (0.2%) irritant

reactions reported. Co-sensitization was reported; 77% of the patients that reacted to DEA also tested positive to MEA.

Occupational sensitization was reported; of 7112 male patients, 1.0% that did not work in the metal industry had positive

reactions to DEA, as opposed to 3.1 and 7.5% of those working in the metal industry and those exposed to water-based

metalworking fluids, respectively.

Metalworkers that were dermatitis patients were patch tested with 2% DEA in pet.68 The patches were applied for 1-

2 days. On day 3, one of 174 patients (0.6%) had a positive reaction.

Patch testing was performed with 2.5% DEA in pet. in 200 patients with suspected metalworking fluid contact

dermatitis.69 (All patients were metalworkers.) Patches were applied for 1 or 2 days. On day 3, 12 patients had positive

reactions, 6 (?), 5 (+),and 1 (++). The % positive reactions was 3.0%.



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MISCELLANEOUS STUDIES

In male albino rats, following repeated oral administration of 320 mg/kg/day in drinking water of radiolabeled DEA, a decrease was seen in the amount of choline incorporated in the liver and the kidneys after 1, 2, and 3 wks as compared to 0 wks. MEA and choline phospholipid derivatives were synthesized faster and in greater amounts, and were catabolized faster than DEA phospholipid derivatives. This was not seen with a single 250 mg/kg injection of DEA. From the Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine1

Inhibition of Choline Uptake

The ability of DEA to alter cellular choline levels was examined in a number of studies. In the study described pre-

viously in which B6C3F1 mice were dosed orally and dermally with 160 mg/kg/day DEA in conjunction with oral sodium

nitrite, a pronounced decrease in choline and its metabolites was observed in the livers.27 The smallest decreases were seen

in the mice that were dosed dermally and not allowed access to the test site, and the greatest increase was seen in the mice

dosed orally.

In Syrian hamster embryo (SHE) cells, DEA inhibited choline uptake at concentrations ≥50 µg/ml, reaching a

maximum 80% inhibition at 250-500 µg/ml.70 DEA also decreased phosphatidylcholine concentrations in the phospholipds,

was incorporated into SHE lipids, and transformed SHE cells in a concentration-dependent manner. Excess choline blocked

these biochemical effects and inhibited cell transformation, and the researchers hypothesized there is a relationship between

the effect of DEA on intracellular choline availability and utilization and its ability to transform cells. In a study performed

to test the hypothesis that DEA treatment could produce biochemical changes consistent with choline deficiency in mice, it

was found that DEA treatment caused a number of biochemical changes consistent with choline deficiency in mice.71

Hepatic concentrations of S-adenosymethionine (SAM) decreased. Biochemical changes were seen without fatty livers, an

observation often associated with choline deficiency.

The dose-response, reversibility and strain-dependence of DEA effects on hepatic choline deficiency were studied.71

B6C3F1 mice were dosed dermally with DEA in ethanol for 4 wks. Control animals were either not dosed or dosed with

ethanol only. The pattern of changes observed in choline metabolites after DEA treatment was very similar to that observed

in choline-deficient mice, and the NOEL for DEA-induced changes in choline homeostasis was 10 mg/kg/day. Fatty livers

were not observed. (Lehman-McKeeman hypothesized that the lack of fatty livers is the result of an age-dependent

mechanism.62) The reactions were dose-dependent, and reversible. Strain dependency was evaluated by dosing male

C57BL/6 mice with 0 or 160 mg DEA/kg body wt for a similar 4-wk period. Hepatic choline deficiency was found to be

strain-dependent. Dermal application of 95% ethanol decreased hepatic betaine levels, suggesting that used of ethanol as a

vehicle for dermal application of DEA could exacerbate the biochemical effects of DEA.

OCCUPATIONAL EXPOSURE

The National Institute for Occupational Safety and Health recommended exposure limits time-weight average for

DEA is 3 ppm (15 mg/m3).72 The Occupational Safety and Health Administration does not have a permissible exposure limit

for DEA.

SUMMARY

This report assesses the safety of DEA and 17 DEA salts as used in cosmetics. The salts are expected to dissociate

into DEA and the corresponding acid. DEA typically contains some amount of MEA or TEA; according to one supplier,

DEA has a minimum purity of 99.0%, with 0.5% max MEA and 0.5% max TEA. NDELA may also be present in DEA or

DEA-containing ingredients.

DEA functions in cosmetic formulations as a pH adjuster. While a few of the other ingredients function as a pH

adjuster, the majority reportedly function as surfactants, emulsifying agents, viscosity increasing agents, hair or skin



20

conditioning agents, foam boosters, or antistatic agents. In 2011, DEA was reported to be used in 22 formulations at concen-

trations of 0.0008-0.3%. The highest leave-on concentration reported was 0.06%. In Europe, dialkanolamines and their salts

(i.e., DEA and the acid salts) are on the list of substances which must not form part of the composition of cosmetic products.

(Secondary amines are allowed as contaminants in raw materials at concentrations up to 0.5% in trialkylamine, trialkanol-

amines, and their salts and in monoalkylamines, monoalkanolamines, and their salts, and at up to 5% in fatty acid dialkyla-

mides and dialkanolamides; secondary amines are allowed at up to 0.5% in finished products containing dialkylamides and

dialkanolamides.) In Canada, the use of dialkanolamines is prohibited, based on the European ruling.

In vitro absorption studies were performed using mouse, rat, and human skin. In in vitro studies using mouse and rat

skin, 1.3 and 0.04%, respectively, of the applied dose of undiluted [14C]DEA was absorbed. In studies using human skin

samples, the absorption of undiluted DEA, as well as concentrations of <1% DEA in combination with fatty acid dialkanol-

amides, was less than 1% of the applied dose. Penetration of DEA in aqueous solutions was greater than when DEA was

undiluted. In studies using human liver slices, DEA was absorbed; the aqueous-extractable radioactivity was primarily

unchanged DEA, while analysis of the organic extracts suggested that DEA was incorporated into ceramides, and slowly

methylated.

In dermal studies with DEA, absorption through mouse skin was greater than through rat skin, and absorption in-

creased with duration of exposure. In the tissues, the liver generally had the greatest disposition of radioactivity. Urine was

the principal route of elimination. In oral studies, DEA accumulated in the tissues, with the greatest disposition being in the

liver; radioactivity was primarily as unchanged DEA. Urinary excretion was also primarily as unchanged DEA. In a repeat-

ed-dose study, stead-state for bioaccumulation occurred after 4 wks; however, DEA continued to bioaccumulate in blood

throughout dosing.

Mice exposed orally to sodium nitrite were dosed orally and dermally with 4 mg/kg DEA. A small amount of

NDELA was formed following a single oral dose of DEA. No NDELA was detected following dermal dosing with DEA.

In acute oral studies on DEA using groups of 2-3 guinea pigs, all survived dosing with 1 g/kg and none survived

dosing with 3 g/kg DEA gum arabic solution. In rats, LD50 values have been reported as 0.71-0.80 ml/kg for undiluted DEA,

1.82 g/kg for aq. DEA, and 1.41-2.83 g/kg for 20% aq. DEA. In repeat dermal testing with DEA in mice and/or rats, irrita-

tion was observed at the site of application site following unoccluded dosing with ≥125 mg/kg to rats and 630 mg/kg mice.

Increases in liver and kidney weights were observed in most studies, while decreases in body weight were observed sporad-

ically. The LOAEL for DEA in a 2-wk study in mice was 160 mg/kg bw. In repeat oral testing with DEA, increases in liver

and kidney weights and decreases in body weights were seen in mice and rats. Deaths, believed to be test-article related,

occurred in most of the studies, and included a mouse given 100 mg/kg DEA by gavage. In inhalation studies with DEA in

rats, liver and kidney weights were increased. In 13-wk studies with ≤400 mg/m3DEA, irritation effects were observed in the

larynx. The 90-day NOAEC was 1.5 mg/m3 DEA.

In a developmental toxicity 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 DEA for 4 wks prior

to dosing, sperm motility was decreased at all doses (20-320 mg//kg) in a dose-dependent manner. In rats and rabbits, dermal

dosing with up to 1500 mg/kg, and 350 mg/kg 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.

In an oral developmental toxicity 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



21

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.

In a developmental toxicity 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.

DEA was non-genotoxic in a number of assays. Positive results were reported in an in vitro assay with DEA of

DNA strand break in isolated rat, hamster, and pig hepatocytes.

The carcinogenic potential of dermally applied DEA was evaluated by the NTP in B6C3F1 mice and F344/N rats.

DEA produced clear evidence of carcinogenic activity in male and female mice (40-160 mg/kg) based on increased inci-

dences of liver neoplasms in males and females and increased incidences of renal tubule neoplasms in males; there was no

evidence of carcinogenicity in male (16-64 mg/kg) and female rats (8-32 mg/kg). The IARC Working Group concluded that,

in the absence of adequate epidemiological information, there was sufficient evidence of carcinogenicity in experimental

animals for a classification of DEA as possibly carcinogenic to humans. Because DEA is not mutagenic or clastogenic, a

non-genotoxic mode of tumorigenic action is indicated. A plausible mode of action for DEA carcinogenicity in rodents

involves cellular choline deficiency.

Undiluted DEA was moderately irritating to rabbit skin. In humans, a hair formulation containing 1.6% DEA was a

cumulative irritant. However, no irritation was reported during the induction phase of sensitization studies with formulations

containing 1.6-2.7% DEA. DEA was not a sensitizer in guinea pig maximization studies with intradermal and epicutaneous

induction applications of 1 and 17.6%, respectively, or in humans tested with a formulation containing 2.7% DEA that was

tested at 100%. In an ocular irritation study using rabbits, a 30% aq. solution of DEA was essentially non-irritating, and a

50% aq. solution was a severe irritant.

DISCUSSION

The Panel noted that few safety data were available for each of the 17 DEA salts included in this group, and

therefore utilized the data available for DEA, in conjunction with previous safety assessments of the components of the DEA

salts, to assess the safety of these ingredients. The available data could be read-across to support the safety of most of these

salts due to similar structure activity relationships.

The safety of DEA-lauraminopropionate, however, could not be supported. A previous CIR report found that data

were insufficient to make a determination of safety on Sodium Lauraminopropionate. Therefore, the data to support the

safety of DEA-lauraminopropionate were insufficient as well. The types of data needed to determine safety include:

- chemical characterization (impurities/purity data) - chemical and physical properties - method of manufacture - 28-day dermal toxicity - dermal reproductive and developmental toxicity - ocular irritation at concentration of use, if available - dermal irritation and sensitization at concentration of use - two different genotoxicity studies (one using a mammalian system); if positive, a dermal carcinogenesis assay by

NTP standards will be required

Depending on the results of these studies, additional data may be required.

Dermal carcinogenicity studies performed on DEA by the NTP reported “clear evidence of carcinogenic activity” in

male and female B6C3F1 mice, based on increased incidences of liver neoplasms in males and females and increased

incidences of renal tubule neoplasms in male mice. However, there was “no evidence of carcinogenic activity” following



22

dermal application of DEA to male and female F344/N rats. DEA-induced choline deficiency has been postulated to explain

the hepatocarcinomas found in the mice, based on reports that DEA exposure leads to choline deficiency in rodents, and,

choline deficiency causes liver tumors in rodents. Humans are much less susceptible to the effects of choline deficiency than

rodents. While this does not explain the differences between rats and mice treated with DEA, an additional factor, dermal

penetration, may. The dermal penetration of DEA was higher through mouse skin than through rat or human skin. Thus, the

amount of DEA absorbed across rat skin may have been insufficient to substantially perturb choline homeostasis in the rats,

which could be another important reason why liver tumors were observed in the mice but not in the rats in the NTP study.

Given that non-genotoxic mechanisms of action have been postulated for DEA-induced carcinogenicity in animal studies, the

dermal penetration of DEA is sufficiently well-characterized, and the concentration of use of DEA is quite low (≤0.06% in

leave-on products), the hepatocarcinogenicity in mice reported in the NTP study are considered to have little relevance to the

safety of use of DEA in personal care products.

Further, renal lesions have been reported in rats fed choline-deficient diets. While the NTP study reported renal

neoplasms in male mice (adenoma or adenoma and carcinoma combined) and not in female mice or male or female rats, the

cytotoxic effects (and the regenerative mechanisms stimulated as a result) of DEA-induced choline deficiency, in conjunction

with the greater penetration through mouse skin, may explain the development of renal tumors seen in male mice, an

endpoint, again, which has little relevance to the safety of DEA in humans. If renal neoplasms in male mice are not caused

by DEA-induced choline deficiency, the Panel still believes that the use of DEA in cosmetics does not pose a carcinogenic

risk to humans. Not only is DEA most likely carcinogenic in rodent studies by an epigenetic mechanism, but DEA does not

appear to penetrate human skin to any significant extent at concentrations relevant to human exposures from the use of

personal care products.

The conversion (nitrosation) of secondary amines, such as DEA, into N-nitrosamines that may be carcinogenic also

is a concern. It is because of this concern that dialkanolamines and their salts are prohibited for use by the EC and Canada.

The CIR Expert Panel has chosen not to prohibit the use of these ingredients, but instead state that products containing DEA

and its salts should be formulated to avoid the formation of nitrosamines.

The Expert Panel was concerned that the potential exists for dermal irritation with the use of products formulated

using DEA or its salts. The Expert Panel specified that products must be formulated to be non-irritating.

DEA is used in cosmetic products that may be inhaled during use. In practice, however, the particle sizes produced

by cosmetic aerosols are not respirable. Additionally, the safety of use of DEA in products that may be inhaled is supported

by the inhalation studies in animals included in this report. While limits exist for occupational exposure to DEA, exposure

via a cosmetic product is not expected to be of the same level as occupational exposure of the individual chemical.

CONCLUSION

The CIR Expert Panel concluded that the DEA and the related salts listed below are safe for use in cosmetics when

formulated to be non-irritating, but that the available data are insufficient to make a determination that DEA-Lauramino-

propionate (which is not reported to be used) is safe for use in cosmetics. 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 non-

irritating in formulation. The Expert Panel cautions that ingredients should not be used in cosmetic products in which N-

nitroso compounds are formed. The ingredients found safe as used are:



23

DEA Diethanolamine Bisulfate* DEA-C12-13 Alkyl Sulfate* DEA-C12-15 Alkyl Sulfate* DEA-C12-13 Pareth-3 Sulfate* DEA-Cetyl Sulfate* DEA-Cocoamphodipropionate* DEA-Dodecylbenzenesulfonate* DEA-Isostearate*

DEA-Laureth Sulfate DEA-Lauryl Sulfate DEA-Linoleate DEA-Methyl Myristate Sulfonate* DEA-Myreth Sulfate* DEA-Myristate* DEA-Myristyl Sulfate* DEA Stearate



TABLES

Table 1. Definitions, structures, and function(s) Ingredient CAS No. Definition Function(s) Formula/structure

Diethanolamine and inorganic salt Diethanolamine 111-42-2

a secondary amine with two ethanol functional groups

pH adjuster HO

NHOH

Diethanolamine Bisulfate 59219-56-6

the diethanolamine salt of sulfuric acid

Buffering agent; pH adjuster

HONH2

OH

HSO4

Diethanolamine organic acid salts DEA-Cocoamphodipropionate

an amphoteric organic compound

Hair Cond. Ag.; Surf. - Cleansing Ag.; Surf. - Foam Boost-ers; Surf. – Hydrotropes

NH

O

NR

O OH

ONH

OHHO

O

OH

wherein RC(O) represents the fatty acid residues derived from coconut oil

DEA-Myristate 53404-39-0

the diethanolamine salt of myristic acid

Surf. - Cleansing Ag.

DEA Stearate the diethanolamine salt of stearic acid

In VCRP/not in Council Database

DEA-Isostearate the diethanolamine salt of isostearic acid


One example of an “iso”

DEA-Linoleate 59231-42-4

diethanolamine salt of linoleic acid


DEA-Lauraminopropionate 65104-36-1

the diethanolamine salt of lauraminopro-pionic acid

Hair Cond. Ag. Surf. - Foam Boosters

Diethanolamine organo-substituted inorganic acid salts -Alkyl sulfate esters DEA-Lauryl Sulfate 143-00-0

the diethanolamine salt of lauryl sulfate


HONH2

OH

O S O

O

O

CH3(CH2)11

DEA-C12-13 Alkyl Sulfate

the diethanolamine salt of the sulfate of C12-13 alcohols


HONH2

OH

O S O

O

O

R

wherein R is a 12 to 13 carbon alkyl chain

DEA-Myristyl Sulfate 65104-61-2

the diethanolamine salt of myristyl sulfate


HONH2

OH

O S O

O

O

CH3(CH2)13



Table 1. Definitions, structures,and function(s) (continued)

25

Ingredient CAS No. Definition Function(s) Formula/structure DEA-C12-15 Alkyl Sulfate

the diethanolamine salt of the sulfate of C12-15 alcohols



DEA-Cetyl Sulfate 51541-51-6

the diethanolamine salt of cetyl sulfate


HONH2

OH

O S O

O

O

CH3(CH2)15

-PEG sulfate esters

DEA-Laureth Sulfate 58855-36-0

the diethanolamine salt of an ethoxylated lauryl sulfate


HONH2

OH

O S O

O

OO

CH3(CH2)11

n wherein n 1-4

DEA-C12-13 Pareth-3 Sulfate

the diethanolamine salt of the sulfate ester of C12-13 Pareth-3



DEA-Myreth Sulfate the diethanolamine salt of ethoxylated myristyl sulfate


HONH2

OH

O S O

O

OO

CH3(CH2)13

n wherein n 1-4

-Sulfonate esters

DEA-Dodecylbenzenesulfonate 26545-53-9

the diethanolamine salt of dodecylben-zene sulfonic acid


DEA-Methyl Myristate Sulfonate 64131-36-8

the diethanolamine salt of an α-sulfonat-ed fatty acid ester


HONH2

OH

S O

O

O

CH3(CH2)11

O

CH3O



Table 2. Conclusions of previously reviewed components/related ingredients

Ingredient Conclusion Reference

Ammonium Laureth Sulfate Sodium Laureth Sulfate

safe as used when formulated to be non-irritating 73

Ammonium Lauryl Sulfate Sodium Lauryl Sulfate

safe in formulations designed for discontinuous, brief use followed by thorough rinsing from the surface of the skin; in products intended for prolonged contact with skin, concentrations should not exceed 1%

74

Ammonium Myreth Sulfate Sodium Myreth Sulfate

safe as used when formulated to be non-irritating 73

Ammonium Myristyl Sulfate Sodium Myristyl Sulfate

safe as used 75

C12-13 Pareth-3 safe as used when formulated to be non-irritating 76 Cocoamphodipropionate safe as used 77 Isostearic Acid safe as used 78 Myristic Acid safe as used 79 Sodium Cetyl Sulfate safe as used 75 Sodium Lauraminopropionate insufficient data (extensive list of data needs) 80 Stearic Acid safe as used 81

Table 3. Physical and chemical properties Property Value Reference

DEA Physical Form clear viscous liquid 1 white crystalline solid at room temperature

viscous liquid above 28°C

38

Color colorless 8 Odor ammonia-like 8 Molecular Weight 105.14 1 Specific Gravity 1.0966 @ 20°C 82 Melting Point 28.0°C 82 Boiling Point 268.8°C 82 Water Solubility soluble 82 Other Solubility soluble in alcohol, ethanol, and benzene 82 log Kow -2.18 @ 25°C 82 Disassociation Constant ( pKa) 8.88 @ 25°C 82

Diethanolamine Bisulfate Molecular Weight 203.22 83 Density 1.21 g/cm3 84



27

Table 4a. Frequency and concentration of use according to duration and type of exposure

DEA DEA Laureth Sulfate DEA Lauryl Sulfate # of Uses10 Conc. of Use11 # of Uses10 Conc. of Use12 # of Uses10 Conc. of Use12 Totals* 22 0.008-0.3 1 NR 3 NR Duration of Use Leave-On 10 0.008-0.06 NR NR NR NR Rinse Off 12 0.009-0.3 NR NR 3 NR Diluted for (Bath) Use NR NR 1 NR NR NR

Exposure Type Eye Area NR NR NR NR NR NR Incidental Ingestion NR NR NR NR NR NR Incidental Inhalation-Sprays 3 NR NR NR NR NR Incidental Inhalation-Powder NR NR NR NR NR NR Dermal Contact 14 0.009-0.06 1 NR 3 NR Deodorant (underarm) NR NR NR NR NR NR Hair - Non-Coloring 8 0.008-0.3 NR NR NR NR Hair-Coloring NR NR NR NR NR NR Nail NR NR NR NR NR NR Mucous Membrane 5 0.009 1 NR 2 NR Baby Products NR NR NR NR NR NR DEA Linoleate DEA Stearate # of Uses10 Conc. of Use12 # of Uses10 Conc. of Use12 Totals* 1 NR 1 NR Duration of Use Leave-On NR NR 1 NR Rinse Off 1 NR NR NR Diluted for (Bath) Use NR NR NR NR Exposure Type Eye Area NR NR NR NR Incidental Ingestion NR NR NR NR Incidental Inhalation-Spray NR NR NR NR Incidental Inhalation-Powder NR NR NR NR Dermal Contact NR NR 1 NR Deodorant (underarm) NR NR NR NR Hair - Non-Coloring 1 NR NR NR 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. NR – none reported Table 4b. Ingredients not reported to be in use DEA-C12-13 Alkyl Sulfate DEA-C12-15 Alkyl Sulfate DEA C12-13 Pareth-3 Sulfate DEA-Cetyl Sulfate DEA-Cocoamphodipropionate DEA-Dodecylbenzenesulfonate DEA-Isostearate DEA-Lauraminopropionate DEA-Methyl Myristate Sulfonate DEA-Myreth Sulfate DEA-Myristate DEA-Myristyl Sulfate Diethanolamine Bisulfate



28

REFERENCES

1. Elder RL (ed). Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine. J Am Coll Toxicol. 1983;2:(7).

2. Becker LC. Amended safety assessment of dodecylbenzenesulfonate, decylbenzenesulfonate, and tridecylbenezenesulfonate salts as used in cosmetics. 2009.

3. Andersen FA (ed). Final report on the safety assessment of sodium lauraminopropionate and sodium lauriminodipropionate. Int J Toxicol. 1997;16:(Suppl 1):1-9.

4. Shank RC and Magee PN. Toxicity and carcinogenicity of N-nitroso compounds. Chapter: 1. Shank RC.In: Mycotoxins and N-Nitroso Compounds:Environmental Risks. Boca Raton, FL: CRC Press, Inc; 1981:185-217.

5. Rostkowski K, Zwierzl K, Ró¿añski J, Moniuszko-Jakoniuk J, and Roszczenko A. Formation and Metabolism of N-Nitrosamines. Polish Journal of Environmental Studies. 1998;7:(6):321-325.

6. Challis BC, Shuker DE, Fine DH, Goff EU, and Hoffman GA. Amine nitration and nitrosation by gaseous nitrogen dioxide. IARC Sci Publ. 1982;41:11-20.

7. Dow Chemical Company. The alkanolamines handbook. 1988. Midland, MI: The Dow Chemical Company.Secondary reference in Knaak et al. 1997.

8. Dow Chemical Company. Sales Specification: Diethanolamine. 2010.

9. Gottschalck T.E. and Bailey, J. E. eds. International Cosmetic Ingredient Dictionary and Handbook. Washington, DC: Personal Care Products Council, 2010.

10. Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients. FDA Database. 2011. Washington, DC: FDA.Updated Feb 25.

11. Personal Care Products Council. 7-5-2011. Concentration of Use by FDA Product Category: Ethanolamine, Diethanolamine and Triethanolamine.

12. Personal Care Products Council. Concentration of use of diethanolamine salts - submitted by industry in response to a Council survey. 3-15-2011.

13. Personal Care Products Council. Concentration of use data - submitted by industry in response to a Council survey. 10-13-2010. Unpublished data submitted by the Council.

14. European Commission. Cosing Database. Annex II. List of substances which must not form part of the composition of cosmetic products. Secondary alkyl- and alkanolamines and their salts, including diethanolamine. http://ec.europa.eu/consumers/cosmetics/cosing/index.cfm?fuseaction=search.details&id=28757. 2001. Date Accessed 10-4-2010

15. Committee for Cosmetic Products and Non-Food Products (SCCNFP). Opinion concerning Dialkyl- and Dialknaolamines and their salts in cosmetic products adoped by the SCCNFP during the 17th plenary meeting of 12 June 2001. http://ec.europa.eu/health/scientific_committees/consumer_safety/opinions/sccnfp_opinions_97_04/sccp_out144_en.htm. 2001. Date Accessed 1-31-2011.

16. Health Canada. Cosmetic Ingredient Hotlist. http://www.hc-sc.gc.ca/cps-spc/person/cosmet/info-ind-prof/_hot-list-critique/hotlist-liste_1-eng.php. 2010. Date Accessed 10-29-2010.

17. Food and Drug Administration. CFR - Code of Federal Regulations Title 21. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm. 4-1-2010. Date Accessed 3-8-2011.

18. Yourick JJ, Marks A, Lockhead RY, and Bronaugh RL. Diethanolamine (DEA) in vitro dermal absorption in Fuzzy rat skin.

19. Sun JD, Beskitt JL, Tallant MJ, and Frantz SW. In vitro skin penetration of monoethanolamine and diethanolamine using excised skin from rats, mice, rabbits, and humans. J Toxicol -- Cut & Ocular Toxicol. 1996;15:(2):131-146.

20. Kraeling MEK, Yourick JJ, and Bronaugh RL. In vitro human skin penetration of diethanolamine. Food Chem Toxicol. 2004;42:1553-1561.



29

21. Brain KR, Walter KA, Green DM, Brain S, Loretz LJ, Sharma RK, and Dressler WE. Percutaneous penetration of diethanolamine through human skin in vitro: Application from cosmetic vehicles. Food Chem Toxicol. 2005;43:681-690.

22. Mathews JM, Garner CE, and Matthews HB. Metabolism, bioaccumulation, and incorporation of diethanolamine into phospholipids. Chem Res Toxicol. 1995;8:(5):625-633.

23. Waechter JM, Bormett GA, and Stewart HS. Diethanolamine: pharmacokinetics in Sprague-Dawley rats following dermal or intravenous administration. 1995. Secondary reference in Knaak et al. 1997.

24. Mathews JM, Garner CE, Black SL, and Matthews HB. Diethanolamine absorption, metabolism and disposition in rat and mouse following oral, intravenous and dermal administration. Xenobiotica. 1997;27:(7):733-746.

25. Craciunescu CN, Niculescu MD, Guo Z, Johnson AR, Fischer L, and Zeisel SH. Dose response effects of dermally applied diethanolamine on neurogenesis in fetal mouse hippocampus and potential exposure of humans. Toxicol Sci. 2009;107:(1):220-226.

26. Mendrala AL, Waechter JM, Bormett GA, Bartels MJ, and Stott WT. The pharmacokinetics of diethanolamine in Sprague-Dawley rats following intravenous administration. Food Chem Toxicol. 2001;39:931-939.

27. Stott WT, Bartels MJ, Brzak KA, Mar M-H, Markham DA, Thorton CM, and Zeisel SH. Potential mechanisms of tumorigenic action of diethanolamine in mice. Toxicol Lett. 2000;114:67-75.

28. Saghir SA, Brzak A, Markham DA, Bartels MJ, and Stott WT. Investigation of the formation of N-nitrosodiethanolamine in B6C3F1 mice following topical administration of triethanolamine. REg Toxicol Pharmacol. 2005;43:10-18.

29. National Toxicology Program. Toxicity studies of diethanolamine (CAS No. 111-42-2) administered topically and in drinking water to F344/N rats and B6C3F1 mice. Tech. Rep. Series No. 20. 1992.

30. Mellert W, Kaufmann W, Rossbacher R, and van Ravenzwaay B. Investigations on cell proliferation in B6C3F1 mouse liver by diethanolamine. Food Chem Toxicol. 2004;42:127-134.

31. Melnick RL, Mahler J, Bucher JR, Hejtmancik M, Singer A, and Persing RL. Toxicity of diethanolamine. 2. Drinking water and topical application exposures in B6C3F1 mice. J Appl Toxicol. 1994;14:(1):11-19.

32. Melnick RL, Mahler J, Bucher JR, Thompson M, Hejtmancik M, Ryan MJ, and Mezza LE. Toxicity of diethanolamine. 1. Drinking waer and topical application exposures in F344 rats. J Appl Toxicol. 1994;14:(1):1-9.

33. Environmental Health Research and Testing. Screening of priority chemicals for reproductive hazards. Monoethanolamine, diethanolamine, and triethanolamine, ETOX-85-1002. PB98-139067. 4-14-1987.

34. Munson AE, White KL, and McCay JA. Immunotoxicity of diethanolamine in female B6C3F1 mice. Report to the NTP. 1992.

35. Munson AE, White KL, and McCay JA. Immunotoxicity of diethanolamine in female Fischer 344 rats. Report to the NTP. 1992.

36. Gulf South Research Institiute. Subchronic test of diethanolamine (C55174) in B6C3F1 mice and Fischer 344 rats. 5-9-1980. Secondary reference in OECD 2008.

37. Eastman Kodak Company. Health and safety studies for diethanolamine, with cover letter. TSCATS, OTC 0516742, Doc ID 86-890000205. 1989. Secondary reference in OECD 2008.

38. Gamer AO, Rossbacher R, Kaufmann W, and van Ravenzwaay B. The inhalation toxicity of di- and triethanolamine upon repeated exposure. Food Chem Toxicol. 2008;46:2173-2183.

39. Lee ID, Lee GS, Moon HJ, Seok JH, Yang JY, Chae SY, Lee YW, Kim SM, Kim SH, and Jeong SY. A study of the reproductive and developmental toxicity of diethanolamine. (Unofficial translation.). The Annual Report of KFDA. 2007. 11: pp.1802-1824. 8EHQ-0409-17501A; Submission by Dow Chemical Co.

40. Marty MS, Neeper-Bradely TL, Neptun DA, and Carney EW. Developmental toxicity of diethanolamine applied cutaneously to CD rats and New Zealand White rabbits. REg Toxicol Pharmacol. 1999;30:169-181.

41. Gulati DK, Grimes LK, Heindel J, and Schwetz BA. Range finding studies: Developmental toxicity of diethanolamine when administered via gavage in CD Sprague-Dawley rats, NTP 89-RF/DT-002. 1990. Secondary reference in Marty et al. 1999.



30

42. Center for Life Science and Technology. Final study report. Developmental toxicity screen for diethanolamine (CAS No. 111-42-2) administered by gavage to Sprague-Dawley (CD) rats on gestational days 6 through 19: Evaluation of dams and pups through postnatal day 21. 12-22-1999.

43. BASF AG. Range-finding study on the prenatal inhalation toxicity of diethanolamin in pregnant rats. BASF Project No 11R0233/90011. 8-20-1991.

44. Gamer AO, Hellwig J, and Hildebrand B. Study of the prenatal toxicity of diethanolamin n rats after inhalation, Project No. 31R0233/90010; BASF. 1993. Secondary reference in Marty et al. 1999.

45. BASF AG. Study of the prenatal inhalation toxicity of diethanolamine in rats after inhalation. BASF Project No. 31R0233/90010. 7-8-1993. Secondary reference in OECD 2008.

46. Craciunescu CN, Wu R, and Zeisel SH. Diethanolamine alters neurogenesis and induces apoptosis in fetal mouse hippocampus. FASEB J. 2006;20:1635-1640.

47. Bailey J. DEA in consumer products is safe. FASEB J. 2007;21:(1):295.

48. Niculescu MD, Wu R, Guo Z, da Costa KA, and Zeisel SH. Diethanolamine alters proliferation and choline metabolism in mouse neural precursor cells. Toxicol Sci. 2007;96:(2):321-326.

49. 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.

50. Kamendulis LM and Klaunig JE. Species differences in the induction of hepatocellular DNA synthesis by diethanolamine. Toxicol Sci. 2005;87:(2):328-336.

51. Tennant RW, French JE, and Spalding JW. Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environ Health Perspect. 1995;103:942-950.

52. Spalding JW, French J, Stasiewicz S, Furedi-Machacek M, Conner F, Tice RR, and Tennant RW. Responses of transgenic mouse lines p53+/- and Tg·AC to agents tested in conventional carcinogenicity bioassays. Toxicol Sci. 2000;53:213-223.

53. International Agency for Research on Cancer (IARC). Diethanolamine. IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans . 2000;77:349-379.

54. Grosse Y, Baan R, Secretan-Lauby B, Ghissassi F, Bouvard V, Benbrahim-Tallaa L, Guha N, Islami F, Galichet L, and Straif K. Carcinogenicity of chemicals in industrial and consumer products, food contaminants and flavourings, and water chlorination byproducts. Lancet. 2011;12:328-329.

55. Ghoshal AK and Farber E. The induction of liver cancer by dietary deficieny of choline and methionine without added carcinogens. Carcinogenesis. 1984;5:(10):1367-1370.

56. Rogers AE. Methyl donors in the diet and responses to chemical carcinogens. Am J Clin Nutr. 1995;61:(Suppl):659S-665S.

57. Newberne PM, de Camargo JLV, and Clark AJ. Choline deficiency, partial hepatectomy, and liver tumors in rats and mice. Toxicol Pathol. 1982;10:(2):95-106.

58. Keith MO and Tryphonas L. Choline lesions and the reversibility of renal lesions in rats. J Nutr. 1978;108:434-446.

59. Zeisel SH and Blusztajn JK. Choline and human nutrition. Annu Rev Nutr. 1994;14:269-296.

60. Kamendulis LM, Smith DJ, and Klaunig JE. Species differences in the inhibition of gap junctional intercellular communication (GJIC) by diethanolamine. Toxicologist. 2004.

61. Bachman AN, Kamednulis LM, and Goodman JI. Diethanolamine and phenobarbital produce an altered pattern of methylation in GC-rich regions of DNA in B6C3F1 mouse hepatocytes similar to that resulting from choline deficiency. Toxicol Sci. 2006;90:(2):317-325.

62. Lehman-McKeeman LD. Incorporating mechanistic data into risk assessment. Toxicology. 2002;181-182:271-274.

63. Leung H-W, Kamendulis LM, and Stott WT. Review of carcinogenic activity of diethanolamine and evidence of choline deficiency as a plausible mode of action. REg Toxicol Pharmacol. 2005;43:260-271.



31

64. Hayashi S-M, Ton VT, Hong H-HL, Irwin RD, Haseman JK, Devereux TR, and Sills RC. Genetic alterations in the Catnb gene but not the H-ras gene in hepatocellular neoplasms and hepatoblastomas of B6C3Fa mice following exposure to diethanolamine for 2 years. Chemico-Biological Interactions. 2003. 146: pp.251-261. Secondary reference in OECD 2008.

65. Kimber I, Basketter DA, Butler M, Gamer A, Garrigue JL, Gerberick GR, Newsome C, Steiling W, and Vohr HW. Classification of contact allergens to potency. Proposals, Food Chemical Toxciol. 2003. 41: pp.1799-1809. Secondary reference in OECD 2008.

66. Lessmann H, Uter W, Schnuch A, and Geier J. Skin sensitizing properties of ethanolamines mono-, di-, and triethanolamine. Data analysis of a multicentre surveillance network (IVDK) and review of literature. Contact Derm. 2009;60:243-255.

67. RCC. Contact hypersensitivity to Diethanolamine resin in albino Guinea pigs, Maximization test, RCC Project 264903. Unpublished report. 1990.

68. Geier, J, Lessmann H, Frosch, PJ., Koch, Patrick, Aschoff, R, Richter, G, Becker, D, Eckert, C, Uter, Wg, Schnuch, A, and Fuchs, T. Patch testing with components of water-based metalworking fluids. Contact Dermatitis. 2003;49:(2):85-90.

69. Geier, J, Lessmann, H, Dickel, H, Frosch, PJ., Koch, P, Becker, D, Jappe, U, Aberer, W, Schnuch, A, and Uter, W. Patch test results with the metalworking fluid series of the German Contact Dermatitis Research Group (DKG). Contact Dermatitis. 2004;51:(3):118-130.

70. Lehman-McKeeman LD and Gamsky EA. Choline supplementation inhibits diethanolamine-induced morphological transfomation in Syrian hamster embryo cells: Evidence for a carcinogenic mechanism. Toxicol Sci. 2000;55:303-310.

71. Lehman-McKeeman LD, Gamsky EA, Hicks SM, Vassalo JD, Mar M-H, and Zeisel SH. Diethanolamine induces hepatic choline deficiency in mice. Toxicol Sci. 2002;67:38-45.

72. NIOSH Pocket Guide to Chemical Hazards. http://www.cdc.gov/niosh/npg/npgd0208.html. 11-18-2010. Date Accessed 1-16-2011.

73. Robinson VC, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report of the amended safety assessment of sodium laureth sulfate and related salts of sulfated ethoxylated alcohols. Int J Toxicol. 2010;29:(Suppl 3):151S-161S.

74. -Elder RL (ed). Final report on the safety assessment of sodium lauryl sulfate and ammonium lauryl sulfate. J Am Coll Toxicol. 1983;2:(7):127-181.

75. Fiume M, Bergfeld WF, Belsito DV, Klaassen CD, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final report on the safety assessment of sodium cetearyl sulfate and related alkyl sulfates as used in cosmetics. Int J Toxicol. 2010;29:(Suppl 2):115S-132S.

76. Fiume MM and Heldreth BA. CIR Expert Panel final amended report on alkyl PEG ethers as used in cosmetics. 2011.

77. Elder RL (ed). Final report on the safety assessment of cocamphoacetate, cocoamphopropionate, cocoamphodiacetate, and cocoamphodipropionate. J Am Coll Toxicol. 1990;9:(2):121-142.

78. Elder RL (ed). Final report on the safety assessment of isostearic acid. J Am Coll Toxicol. 1986;2:(7):61-74.

79. 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.

80. Andersen FA (ed). Final report on the safety assessment of sodium lauraminopropionate and sodium lauriminodipropionate. Int J Toxicol. 2011;16:(Suppl 1):1-9.

81. Elder RL (ed). Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, and stearic acid. J Am Coll Toxicol. 1987;6:(3):321-401.

82. Knaak JB, Leung H-W, Stott WT, Busch J, and Bilsky J. Toxicology of mono-, di-, and triethanolamine. Review of Environmental Contamination and Toxicology. 1997;149:1-86.

83. Environmental Protection Agency. Substance Registry Services - Ethanol, 2,2'-iminobis-, sulfate (1:1) (salt). http://iaspub.epa.gov/sor_internet/registry/substreg/searchandretrieve/advancedsearch/externalSearch.do?p_type=SRSI



32

TN&p_value=314260. 1-30-2011. Date Accessed 1-30-2011.

84. Zhao C. Journal of Physical Chemistry B. 2008. 112:(23): pp.6923-3936.



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.”

11011 7th Street, N.W, Suite 300 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org




Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)

FROM: John Bailey, Ph.DEL —_.

Industry Liaison to the CIR Expert Panel

DATE: July21, 2011

SIJBJECT: Comments on the Revised Tentative Amended Safety Assessment on Diethanolamine(DEA) and its Salts as Used in Cosmetic

DEA-Lauraminopropionate - DEA-Lauraminopropionate should be removed from the report. Theinsufficient data conclusion is based on a lack of data on the Lauraminopropionate portion ofthis compound, while the focus of this report is the safety of DEA. DEA-Lauraminopropionatewouki more appropriately be included in a report on Lauraminopropionic Acid (which is in theDictionary) and its salts (including the sodium and DEA salts). In addition, the safety ofingredients added to re-reviews should be supported by data in the original report. This is nottrue for DEA-Lauraminopropionate.

Although the disclaimer on the Cifi website is helpful, there should be a disclaimer (“Distributed forComment Only — Do Not Cite or Quote”) on every page of the report.

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.”

Introduction - If DEA-Lauraminopropionate is left in the report, the CW report including SodiumLauraminopropionate should be mentioned in the Introduction.

p.2, Cosmetic Use section, p.15, Summary - It should also be noted that in Europe, fatty aciddialkylamides and dialkanolamides can contain up to 5% secondary amine in the raw materialand 0.5% in the finished product as indicated in the table below.

11011 7th Street, N.W., Suite 3OO Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org



Annex III Listing Secondary amine limits in Secondary amine limits infinished product ingredient

trialkylamines, no limit stated 0.5%trialkanolamines and their salts

fatty acid dialkylamides and 0.5% 5%dialkanolamides

monoalkylamines, no limit stated 0.5%monoalkanolamines and theirsalts

p.5 - In the Dermal, Human section, it is not clear what is meant by “blank samples”. What were thelevels of DEA and metabolites in the pre-exposure blood samples?

p.10, Summary Reproductive and Developmental Toxicity section, p.15, Summary - Studies in whichanimals are exposed only during gestation should be called developmental studies notreproductive studies (last 2 paragraphs of the section summary (p.10), 8 and 9” paragraphs ofthe Summary). . V

p.10 - It is not clear what is meant by “male reproductive weights”. V

p.11 - What dose or concentration of DEA was used in the mouse micronucleus test? 4

p.13, Summary Irritation and Sensitization section - In sensitization studies, induction concentrationsare more important than challenge concentrations. Please change “stud” to “study”. •V

p.14 - In the last paragraph of the Inhibition of Choline Uptake, it states that the reactions were “strain-dependent” but only one strain of mice is discussed. V

V

p.15 - As few of these ingredients have reported uses in cosmetic products, it would be better to statethat the ingredients “reportedly function...” . V

p.16 - It is not clear what is meant by “structure activity relationships and biological function.” What isthe biological function of DEA?

p.17 - In the Conclusion, please indicate that DEA-Lauraminopropionate has no reported uses. Pleaserevise: “..at concentrations that would be formulated to be non-irritating.” as products, notconcentrations are formulated.

p.18-19 - Please provide reference(s) for Table 1.p.20, Table 2 - Please revise the title of the table as some of the reports included in the table concern

related ingredients rather than components.p.21, Table 4a compared to the Concentration of Use Table in the Formaldehyde report- The Use tables

should be consistent among various CIR reports. The table in the Formaldehyde report includesthe 0.04% concentration reported for shampoo use in the hair - non-coloring row and thedermal contact row, while in the table in the DEA report, the 0.3% concentration reported for ashampoo is presented in the hair - non-coloring row, but not in the dermal contact row. Do hairproducts - non-coloring also belong under dermal contact? There should be a key to the usesummary tables that is publically available.

7




Memorandum

F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (Cifi)

John Bailey, Ph.D. I c)—. 1-

Industry Liaison to the CIR Expert Panel

DATE: June24,2011

SUBJECT: Comments on the Draft Report on Diethanolamine (DEA) and its Salts as Used inCosmetics Prepared for the June 27-28, 2011 CIR Expert Panel Meeting

p.3, 19. 21 - The description of the EU regulations for DEA are not complete without mentioning thatsecondary amines, such as DEA can be in cosmetic products as contaminants if trialkylamines,trialkanolamines and their salts, fatty acid dialkylamides and dialkanolamides ormonoalkylamines, monoalkanolamines and their salts are added to cosmetic products. Thisshould also be mentioned in the Summary and Discussicvn sections. Perhaps the following tablewould be useful.

Annex III Listing Secondary amine limits in Secondary amine limits infinished product ingredient

trialkylamines, no limit stated 0.5%trialkanolamines and their salts

fatty acid dialkylamides and 0.5% 5%dialkanolamides

monoalkylamines, no limit stated 0.5%monoalkanolamines and theirsalts

p.6 - What was the dose of[14C]DEA applied to rats in reference 21?p.6 - If available, what was the approximate mg/kg/day dose of DEA for the 3 female subjects in

reference 23 (the human exposure is compared to a mouse dose of 80 mg/kg/day given to mice,so it would be nice if the human exposure could also be expressed as mg/kg/day).

p.9 - Please revise the following in the Toxicological Studies summary. “...at the site of applicationsite with unoccluded application..”

p.12-13 - In the summary of the Reproductive and Developmental Toxicity section, please provide thedermal doses associated with decreased sperm motility in mice.

p.14 - Please provide the low dose used in the study described in reference 44 (effect on neurogenesis).

11011 7th Street, N.W., Suite 30O Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personatcarecouncil.org

TO:

FROM: e’, —2--1



p.16 - At the end of the Carcinogenicity section summary, please state that humans are much lesssusceptible to choline deficiency than rodents.

p.16 - Please note that IARC did not change the classification of DEA based on new animal data. Theclassification was changed based on a change in the criteria for classification. The WHO(2006) Preamble to the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans(amended 2006) (http://monographs .iarc .fr!ENG/Preamble/CurrentPreamble.pdf) now alsostates that “An increased incidence of tumours in both sexes of a single species in awell-conducted study, ideally conducted under Good Laboratory Practices, can also providesufficient evidence” (see p.20 of the preamble, lines 39-4 1).

p.17 - Please add the reference to the new paragraph in the section on Possible Mode of Action forCarcinogenic Effects. This paragraph should be moved to the end of the choline deficiencydiscussion.

p.17 - In the summary of the Irritation and Sensitization section, please add the species in which theocular irritation studies were completed.

p.18, 21 - Please identify the type of fonnulation, e.g., shampoo, containing 1.6% DEA that wasirritating when tested undiluted.

p.21 - Please change “Humans are not susceptible to this deficiency.” to “Humans are much lesssensitive to this deficiency.”

p.22 - The safety of low levels of DEA in products that may result in inhalation exposure should alsobe based on the inhalation exposure data included in the report. For example, a 3 month studyin rats identified a NOAEC of 1.5 mg/rn3.

p.23-24, Table 1 - Please add the reference(s) to this table.p.26, Table 4a - This table is missing the headings for the number of uses and concentration of use

columns.

2



DIETHANOLAMINE 2 04E - Other Fragrance PreparationDIETHANOLAMINE 1 05B - Hair Spray (aerosol fixatives)DIETHANOLAMINE 5 05F - Shampoos (non-coloring)DIETHANOLAMINE 1 05G - Tonics, Dressings, and Other Hair Grooming AidsDIETHANOLAMINE 1 05I - Other Hair PreparationsDIETHANOLAMINE 5 10A - Bath Soaps and DetergentsDIETHANOLAMINE 2 11E - Shaving CreamDIETHANOLAMINE 3 12D - Body and Hand (exc shave)DIETHANOLAMINE 2 12J - Other Skin Care Preps

DEA-LAURETH SULFAT 1 02D - Other Bath Preparations

DEA-LAURYL SULFATE 1 10A - Bath Soaps and DetergentsDEA-LAURYL SULFATE 1 10E - Other Personal Cleanliness ProductsDEA-LAURYL SULFATE 1 12A - Cleansing

DEA-LINOLEATE 1 05F - Shampoos (non-coloring)

DEA-STEARATE 1 12D - Body and Hand (exc shave)



blue dea - cosmetic ingredient review · 2020. 2. 29. · dea-lauraminopropionate would more...

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