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Sodium Lauriminodipropionate

CIR EXPERT PANEL MEETING

SEPTEMBER 26-27, 2011

Memorandum

To: CIR Expert Panel Members and Liaisons

From: Christina L. Burnett

Scientific Writer/Analyst

Date: August 15, 2011

Subject: Draft Tentative Amended Report on Lauriminopropionic Acid and its Sodium Salts

Based on newly available unpublished data, the CIR Expert Panel concluded that the data requested in the original safety assessment insufficient data conclusion now were provided and reopened the final report on sodium lauriminodipropionate in June 2011. The following report is a compilation of those new data and summary data from the original safety assessment on sodium lauriminodipropionate. Because of chemical similarities to sodium lauriminodipropionate, the Panel decided to add lauriminodipropionic acid and the disodium salt to this reopened safety assessment. Because no new data were available on sodium lauraminopropionate, the CIR Expert Panel did not reopen this ingredient and reaffirmed the conclusion of insufficient data for sodium lauraminopropionate. Since the June meeting, the Personal Care Products Council has submitted still further new data on the composition of a trade name material and the method of manufacture. This information is included in this book.

A total of 10 uses for sodium lauriminodipropionate were reported to the VCRP. Half of the uses were reported in hair conditioners. Industry reports that the use concentration is 0.05% in hair conditioners. No uses or were reported for the parent acid compound. For the disodium salt, however, the VCRP reports that there are 2 total uses in face and neck formulations. We are still awaiting the results of an industry survey for the use concentrations.

The Panel should carefully review the discussion and conclusion for this report. Presuming that all of the data needs are met, the Panel should issue a Tentative Amended Report.

Distributed for Comment Only -- Do Not Cite or Quote

CIR Panel Book Page 1

History of Sodium Lauraminopropionate and Sodium Lauriminodipropionate December 12-13, 1994 The Panel voted unanimously in favor of issuing an Insufficient Data Announcement on Sodium Lauraminopropionate and Sodium Lauriminodipropionate with the following data requests: (1) Concentration of use (2) Chemical characterization (impurities/purity data) (3) Chemical and physical properties of Sodium Lauraminopropionate (4) Method of manufacture (5) 28-day dermal toxicity (6) Dermal teratogenicity (7) Ocular irritation at concentration of use, if available (8) Dermal irritation and sensitization at concentration of use (9) Two different genotoxicity studies (one using a mammalian system); if positive, dermal carcinogenesis assay by NTP standards will be required Depending upon the results of these studies, additional tests may be required. March 16-17, 1995

The Panel voted unanimously in favor of issuing a Tentative Report on Sodium Lauraminopropionate and Sodium Lauriminodipropionate with the following conclusion: The Expert Panel concludes that the available data are insufficient to support the safety of Sodium Lauraminopropionate and Sodium Lauriminodipropionate for use in cosmetics.

The data that are needed in order for the Panel to complete its safety assessment are listed in the discussion section of the Tentative Report as follows:

(1) Concentration of use (2) Chemical characterization (impurities/purity data) (3) Chemical and physical properties of Sodium Lauraminopropionate (4) Method of manufacture (5) 28-day dermal toxicity (6) Dermal teratogenicity (7) Ocular irritation at concentration of use, if available (8) Dermal irritation and sensitization at concentration of use (9) Two different genotoxicity studies (one using a mammalian system); if positive, a dermal carcinogenesis assay by NTP standards will be required

August 28-29, 1995 The Panel unanimously approved the issuance of a Final Report on Sodium Lauraminopropionate and Sodium Lauriminodipropionate with the following conclusion: The CIR Expert Panel concludes that the available data are insufficient to support the safety of Sodium Lauraminopropionate and Sodium Lauriminodipropionate for use in cosmetics. The data that are needed in order for the Panel to complete its safety assessment of Sodium Lauraminopropionate and Sodium Lauriminodipropionate are listed in the discussion section of the Final Report as follows:

(1) Concentration of use (2) Chemical characterization (impurities/purity data) (3) Chemical and physical properties of Sodium Lauraminopropionate (4) Method of manufacture (5) 28-day dermal toxicity (6) Dermal teratogenicity (7) Ocular irritation at concentration of use, if available (8) Dermal irritation and sensitization at concentration of use (9) Two different genotoxicity studies (one using a mammalian system); if positive, a dermal carcinogenesis assay by NTP standards will be required

June 27-28, 2011 New data provided by the Personal Care Products Council’s CIR Science and Support Committee for sodium lauriminodipropionate:



Use concentration in hair conditioners - 0.05% (rinse off), 10 VCRP uses in 2011 for Sodium Lauriminodipropionate (as hair conditioners, bath soaps and detergents, and skin cleansers); no uses or use concentrations for Sodium Lauraminopropionate

28 and 91 Day Subchronic Percutaneous Toxicity Study of a formulation with 10.5% Sodium Lauriminodipropionate IRDC No. 392-373 – through report page 28; data pages 29 – 386 available online

developmantal and reproductive toxicity assessment prepared by CIR SSC Ocular tox of shampoo with 3.56% Sodium Lauriminodipropionate - Institut ASTER Study No.

R.01.94.U.K.DH025.01- through report page 42; data pages 44-128 available online HRIPT on a formulation with 2.3% Sodium Lauriminodipropionate - TKL Research, Inc. Study No. 911021 HRIPT on a formulation with 3.5% Sodium Lauriminodipropionate - North Cliff Consultants, Inc. Study

#9112-3 Ames Test of a commercially available cosmetic ingredient (30% Sodium Lauriminodipropionate) -

Microbiological Associates, Inc. Study No T9102.501 In Vitro chromosome aberration assay in CHO cells of a commercially available cosmetic ingredient (30%

Sodium Lauriminodipropionate) - Microbiological Associates, Ind., Study No. T9102.338). Based on these data, the CIR Expert Panel reopened the final report on sodium lauriminodipropionate. Because of chemical similarities to sodium lauriminodipropionate, the Panel decided to add lauriminodipropionic acid and the disodium salt to this reopened safety assessment. Because no new data were available on sodium lauraminopropionate, the CIR Expert Panel did not reopen this ingredient and reaffirmed the conclusion of insufficient data for sodium lauraminopropionate.



Search Strategy for Sodium Lauriminodipropionate, Lauriminodipropionic Acid, and Disodium Lauriminodipropionate

July 6, 2011: SCIFINDER search for CAS Nos. 14960-06-6 and 3655-00-3 Limited search to references published since 1995; 95 references returned. Refined search to books, clinical trials, journals, preprints, reports, and reviews; 13 references returned.

July 6, 2011: SCIFINDER search for CAS No.17066-08-9 Limited search to references published since 1995; 39 references returned. Refined search to books, clinical trials, journals, preprints, reports, and reviews; 9 references returned.

July 6, 2011: SCIFINDER search for CAS Nos. 26256-79-1 and 150375-07-8 Limited search to references published since 1995; 50 references returned. Refined search to books, clinical trials, journals, preprints, reports, and reviews; 7 references returned.

TOXLINE PUBMED EU July 6, 2011 Sodium Lauriminodipropionate

9 No restrictions.

14960-06-6 AND 3655-00-3 AND 1995-

2

Lauriminodipropionic Acid

1 No restrictions.

17066-08-9 AND 1995- 1

Disodium Lauriminodipropionate

0 No restrictions.

26256-79-1 AND 150375-07-8 AND 1995-

0

10 References Ordered/Downloaded Total



Tran

scripts

Sodium Lauriminodipropionate transcript excerpts Belsito team – June 27, 2011 DR. BELSITO: So the sodium lauraminodipropionate, in '97, we concluded the data were insufficient for the dipropionate and the propionate. Interestingly, we're going to come up against the propionate later on when we're at another document, so it's good that we're looking at this first. There is a long list of data needs. Industry provided data for one of the ingredients, the dipropionate, but not the propionate which is what's going to come up later. And it looks like there were eight of the nine data needs that we asked for, and the one we didn't get was impurities. But in the past we've always said well, it was tested and then whatever impurities were there, it didn't seem to have a problem. So the question is whether the data for the lauraminodipropionate is adequate. And then I guess the second question there is that is the dipropionate -- and this I don't know because I'm not a chemist -- sufficiently different from the propionate that the data for the dipropionate cannot be used to assume safety of the propionate? So maybe, Dan, you can start answering that question? DR. LIEBLER: Okay, so I think that sodium lauraminopropionate and sodium lauriminodipropionate are sufficiently different that the data available for the imino compound -- the data for the imino compound I think supports reopening for the imino, but not for the amino because I think the amino is different enough chemically, perhaps in terms of metabolism, in terms of potential for nitrosamine, that it should be considered separately. DR. BELSITO: So actually we should reopen it, but split this into sodium lauriminodipropionate and aminopropionate, that they should not be grouped together? DR. LIEBLER: Correct. So reopen for imino. DR. BELSITO: Okay, dipropionate. DR. LIEBLER: Yes. DR. BELSITO: And the data -- when we reopen, can we move this along and say that the data would be sufficient for the iminodipropionate? DR. LIEBLER: I thought so. DR. BELSITO: Paul? Curt? DR. SNYDER: I'm fine with that. DR. KLAASSEN: It appears to be okay. DR. BELSITO: I just wrote for some reasons that I don't remember because I reviewed this a while ago, do we need a 91-day dermal of the impurities? I said no. We had a 91-day dermal that was negative. Sorry. Okay. So I was okay with this. So we're suggesting that we go ahead, reopen the lauraminodipropionate, which will be safe as used. As



long as we're doing that, if there are any other aminodipropionates that can be added, maybe we can do that? DR. EISENMANN: The acid is in the dictionary, and the disodium salt is now in the dictionary. DR. BELSITO: Okay, so if we could add those, but we would get rid of the sodium lauraminopropionate and then perhaps put that into another group of aminopropionates. And our conclusion would be "safe as used" so can we -- that would go out as a tentative final, Alan? DR. ANDERSEN: No, we would come back to you at the next meeting with a draft tentative amended for you to formally approve. So the decision at this meeting is on sufficiency of the data. DR. BELSITO: Right. DR. ANDERSEN: You've said that it's sufficient for the imino compound, and you've suggested that it's likely to be safe as used. You've suggested that there are additional imino compounds that can be added. We will do all of that, package it, and give it to you in September. And you can issue it as a tentative and wrap it up in December. DR. LIEBLER: And there will be 68 additional imino compounds identified. DR. ANDERSEN: Yeah, I -- Carol, could you say again what you think the additional ones might be? DR. EISENMANN: Lauriminodipropionate acid and disodium. DR. ANDERSEN: Oh, disodium, okay. DR. EISENMANN: Right. So they're really completely related and it's not -- DR. BELSITO: No esters, aldehydes, amines? DR. ANDERSEN: Add the acid and the disodium salt to this. Marks team June 27, 2011 DR. MARKS: Good. Okay. Buff Book, sodium lauriminodipropionate. DR. SHANK: Yeah. The vowel is important, imino versus amino. DR. MARKS: Amino, right. So this is --so this is with the "I" iminodipropionate. And then in 1997, the Panel reviewed the amino and sodium imino and found it was insufficient. Now we've received data on the sodium lauriminodipropionate. Do we want to reopen this? DR. SHANK: I think we should because we can change the conclusion to safe; that's where I'm coming from. DR. SLAGA: Based on the --



DR. SHANK: The new data. Yeah. DR. ANDERSEN: For the one ingredient? DR. MARKS: For the one, sorry. For the iminodipropionate. DR. SHANK: Yes. DR. MARKS: So reopen the conclusion for the dye is safe. Method of manufacture, that's not going to be that -- that was a data need, but we haven't received anything, impurity data? DR. HILL: We didn't get anything, right? DR. MARKS: Right. DR. HILL: No. DR. MARKS: So it is still -- we got everything else. DR. ANDERSEN: I think if you're willing to make the presumption that says I don't care what the impurities are, I don't care how they made it. Whatever it is they made, it's been tested in 28 91-day subchronic. It's been run through a couple of HRIPTs, the AMES test of what's actually sold, you know, yadda, yadda, yadda. DR. HILL: Right. DR. ANDERSEN: So empirically it supports that there is an absence of things that do bad stuff. DR. HILL: Correct. DR. MARKS: Okay. DR. ANDERSEN: And we have to make that argument because we didn't get the data. Okay. That could be in a discussion if we want. So safe conclusion for sodium -- DR. SHANK: You can say imino. DR. MARKS: -- lauriminodipropionate, safe. Okay. And the other one? So if we're reopening this, then we say the other is still insufficient? DR. ANDERSEN: At least our interpretation was that these data don't apply to the aminopropionate part of this. DR. MARKS: Is that correct? DR. SHANK: Yes. DR. MARKS: Yeah. That's what I asked. Is there a cross with the other one?



DR. SHANK: And the industry wasn't pushing it either, so the request was just for the one. DR. MARKS: Now, just to confuse things a little bit, there is -- if we reopen this, since it sounds like you guys would like to reopen it, there's a disodium lauriminodipropionate. There's just no reason why we couldn't add that. DR. SHANK: Yeah. That's -- that was my last question, add-ons. DR. ANDERSEN: That's a real no-brainer. DR. SHANK: And then there's lauriminodipropionic acid. DR. HILL: Is that actually a dictionary ingredient? DR. ANDERSEN: Yes. DR. HILL: So it's a solution. It's going to probably be a salt anyway. DR. ANDERSEN: Okay. DR. HILL: So we actually could get a couple of add-ons here. DR. SHANK: Okay. DR. MARKS: So the sodium lauriminodipropionate is safe plus two add-ons, and that was the disodium salt. DR. ANDERSEN: And the acid. DR. MARKS: Disodium. And then the acid was? DR. ANDERSEN: Lauriminodipropionic acid. You can sound erudite and just say "the acid." DR. MARKS: Yes. Okay. And then we'll leave the A compound as insufficient. Okay. Will be the conclusion. Any other comments about that? So I will move that we reopen the safety assessment from 1997 with a conclusion of safe for the primary compound there with two add-ons and insufficient for the A compounds, which is not a dipropionate. DR. ANDERSEN: Thank you to the Science and Support Committee for providing the data. DR. HILL: Let me just be clear, though. We did not also get data pertaining to dermal teratogenicity, is that correct? That was where we identified insufficiencies. DR. MARKS: Development and reproductive toxicity assessment for -- DR. HILL: We didn't get teratogenicity data. MR. BOYER: No. There was a one- or two-page discussion about the potential metabolites and how some of those metabolites --potential



metabolites have been effectively (inaudible) developmental or reproductive toxicants. DR. HILL: Okay. So that's going to show up in (inaudible) if we reopen. DR. ANDERSEN: Yeah. You'll see this at the next meeting as -- before it goes anyplace. We've approved the direction we should go, and now we'll go in that direction. So you'll see it in September. Full Panel June 28, 2011 DR. BERGFELD: Okay. Any other comments? All right, call for the question, those in favor of reopening? Unanimous. Thank you. Moving on to two new data ingredients. Dr. Marks, sodium lauriminodipropionate. DR. MARKS: I'm going to refer to these as the I compound, the idi, and the A compound, since it's a long -- and I'm not sure the transcriber will get the difference between "ime" and "ame." So, at any rate, in '97, these two compounds were reviewed and there was an insufficient data conclusion. We've now received a number of data points for the ime-di, the lauriminodipropionate, which would support its safety. And then there was a disodium salt and an acid which we felt could be added on to this report. There still was not sufficient data to suggest that the A compound could be considered safe. So, the motion is to reopen this, to issue a draft amended tentative report, that the idi compound plus the two add- ons are safe and that we remain insufficient for the A compound. DR. BERGFELD: And that's a motion. Is there a second or comment? DR. BELSITO: Yes, and no. We actually felt that the lauraminoproprionate and the lauramidodiproprionate do not belong in the same report, so we had actually suggested that the reports be opened, that they be split, and that the aminodiproprionate group would be safe as used and the aminoproprionate group would be insufficient for all the reasons listed previously. DR. BERGFELD: Friendly amendment. DR. MARKS: I see. No, it's a little bit different in that there would be two reports generated, not one. DR. BELSITO: Right. DR. MARKS: And that's, I think, fine. The reason to separate it is because chemically they're just so dissimilar that it – they shouldn't be grouped together? DR. BERGFELD: Dan and then Alan. DR. LIEBLER: That's how we felt. Chemically they were quite distinct. They kind of look alike at first glance, but chemically they're hooked



up differently enough that it's going to really influence their properties. DR. BERGFELD: Alan. DR. MARKS: I know -- I have no problem with that change in the motion, so it would be reopened. The im-di (?) compound plus the salt and acid would be safe, and then splitting into a second draft tentative report that the A compound be insufficient. DR. BERGFELD: And you're going to second that motion? DR. BELSITO: I'll second that. Sure. DR. BERGFELD: Alan. DR. ANDERSEN: A little glitch. The information I got this morning that Carol provided from a supplier notes that sodium lauraminodiproprionate can be present in the laurimino product at 5 percent. So, yeah, they're different, but the amino appears to be part of the synthesis pathway for making it and it doesn't all disappear. DR. BELSITO: So maybe we should table this, let the reports include that information in the imino report and reassess what that means in terms of the data needs we had for the amino. DR. ANDERSEN: Well, this is certainly a twist that we hadn't understood previously. DR. BERGFELD: Well, the other possibility is to go insufficient to the amino. DR. BRONAUGH: The question is to open it or not, so I think you want to -- DR. BELSITO: I think we want to open it. I think we still want to split it because there are differences in chemistry and I think we want to get this information and go ahead, but there will be no conclusion. The conclusion at this point would simply be to open and then split the documents. DR. MARKS: Correct. DR. ANDERSEN: I think that leads us to the September meeting at which point a tentative amended document will be prepared and you can look at the impact of all of these data. DR. BELSITO: Right. DR. ANDERSEN: And decide just how you want to move at that point. DR. BELSITO: Right. DR. ANDERSEN: So, reopening isn't really a problem and I would suspect that there's even an outside chance that you would determine to not split these, but I understand that right now your thinking is to split them.



DR. BERGFELD: Do you want to retract your motion? Restate it? DR. MARKS: Yes. I'll retract the motion, and this new data that we just received a minute ago from Alan and propose that we table this. DR. BERGFELD: Reopen. DR. BELSITO: No, not table. Just reopen. DR. MARKS: Reopen. I'm sorry. DR. BERGFELD: Do you agree with that, Don? DR. BELSITO: Reopen, split the documents, and start looking at them. DR. BERGFELD: I don't think we have to vote on that. We can assume everyone agrees? Yes. Thank you.



Rep

ort

Tentative Amended Safety Assessment

Sodium Lauriminodipropionate as Used in Cosmetics

September 26, 2011 All interested persons are provided 60 days from the above date to comment on this Tentative Amended Safety Assessment and to identify additional published data that should be included or provide unpublished data which can be made public and included. Information may be submitted without identifying the source or the trade name of the cosmetic product containing the ingredient. All unpublished data submitted to CIR will be discussed in open meetings, will be available at the CIR office for review by any interested party and may be cited in a peer-reviewed scientific journal. Please submit data, comments, or requests to the CIR Director, Dr. F. Alan Andersen. The 2011 Cosmetic Ingredient Review Expert Panel members are: Chair, Wilma F. Bergfeld, M.D., F.A.C.P.; Donald V. Belsito, M.D.; Curtis D. Klaassen, Ph.D.; Daniel C. Liebler, Ph.D.; Ronald A Hill, 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 Christina Burnett, Scientific Writer/Analyst.

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

[email protected]



i

TABLE OF CONTENTS Table of Contents .......................................................................................................................................................................... i

Introduction ................................................................................................................................................................................. 1

Chemistry ..................................................................................................................................................................................... 1

Definition and Structure .......................................................................................................................................................... 1

Physical and Chemical Properties ........................................................................................................................................... 1

Method of Manufacture ........................................................................................................................................................... 1

Impurities ................................................................................................................................................................................ 1

Use ............................................................................................................................................................................................... 1

Cosmetic .................................................................................................................................................................................. 1

Non-Cosmetic .......................................................................................................................................................................... 2

Toxicokinetics.............................................................................................................................................................................. 2

Absorption, Distribution, Metabolism, and Excretion ............................................................................................................. 2

Toxicological Studies .................................................................................................................................................................. 2

Acute Toxicity ......................................................................................................................................................................... 2

Dermal – Non-Human ......................................................................................................................................................... 2

Oral – Non-Human ............................................................................................................................................................. 2

Repeated Dose Toxicity .......................................................................................................................................................... 2

Percutaneous – Non-Human ............................................................................................................................................... 2

Reproductive and Developmental Toxicity ................................................................................................................................. 3

Genotoxicity ................................................................................................................................................................................ 3

In Vitro .................................................................................................................................................................................... 3

Carcinogenicity ............................................................................................................................................................................ 3

Irritation and sensitization ........................................................................................................................................................... 3

Irritation ................................................................................................................................................................................... 3

Dermal – Non-Human ......................................................................................................................................................... 3

Ocular – Non-Human .......................................................................................................................................................... 4

Ocular – Human .................................................................................................................................................................. 4

Sensitization ............................................................................................................................................................................ 4

Dermal – Non-Human ......................................................................................................................................................... 4

Dermal – Human ................................................................................................................................................................. 4

Summary ...................................................................................................................................................................................... 5

Discussion .................................................................................................................................................................................... 5

Conclusion ................................................................................................................................................................................... 5

Tables and Figures ....................................................................................................................................................................... 6

References ................................................................................................................................................................................... 9



1

INTRODUCTION Sodium lauriminodipropionate is the sodium salt of a substituted propionic acid that is used as a surfactant, a hair conditioning agent and an antistatic agent in cosmetic formulations. A safety assessment for sodium lauriminodipropionate and sodium lauraminopropionate was published by the Cosmetic Ingredient Review (CIR) in 1997.1 At that time, the CIR Expert Panel concluded that the available data were insufficient to support safety for use in cosmetics. Data needs included:

Concentration of use; Chemical characterization (impurities/purity data); Method of manufacture; 28-day dermal toxicity; Dermal teratogenicity; Ocular irritation at concentration of use; and Two different genotoxicity studies (one using a mammalian system), and if positive, a dermal

carcinogenesis assay following National Toxicology Program standards.

Based on newly available unpublished data that described all the above for sodium lauriminodipropionate, the CIR Expert Panel reopened the final report on sodium lauriminodipropionate in June 2011. The following report is a compilation of new data and summary data from the original safety assessment on sodium lauriminodipropionate. Because of chemical similarities to sodium lauriminodipropionate, the available data may be extrapolated to the parent compound, lauriminodipropionic acid, and to the disodium salt, in a process termed read-across.

Because no new data were available on sodium lauraminopropionate, the CIR Expert Panel did not reopen the final report to include this ingredient and reaffirmed the conclusion of insufficient data for sodium lauraminopropionate.

CHEMISTRY Definition and Structure

The definition and structure of these ingredients are presented in Table 1. Physical and Chemical Properties

The available information on the physical and chemical properties of lauriminodipropionic acid and its sodium salts are presented in Table 2.

Lauriminodipropionic acid can exist in both anionic and cationic forms depending on pH.2 Method of Manufacture

The salts of lauriminodipropionic acid are produced in a 2-step synthesis.2-4 First, dodecylamine (laurylamine) undergoes a Michael addition to acrylic acid or methyl acrylate, in methanol, to yield monopropionic acid methyl ester and dipropionic acid methyl ester. These esters can be separated using flash column chromatography.3 The esters are then saponified with sodium hydroxide or sodium trimethylsilanolate to yield either the mono- or disodium salts. 2-4 Either of these salts can be acidified to the free acid under the appropriate pH.

Impurities SODIUM LAURIMINODIPROPIONATE The main impurity in the manufacture of sodium lauriminodipropionate is sodium acrylate.4 Trace amounts of dodecyl-chain compounds associated with the starting material, dodecylamine, may also be present. Total impurities are typically found at levels less than 2% in the product as sold. Dodecylamine, polyacrylic acid, or sodium polyacrylate have not been detected in batch samples of the commercial product. In the production of sodium lauriminodipropionate, minor amount of sodium lauraminopropionate may occur. A commercial product that is approximately 30% solids contains about 25% sodium lauriminodipropionate and about 5% sodium lauraminopropionate.

USE

Cosmetic Lauriminodipropionic acid, sodium lauriminodipropionate, and disodium lauriminodipropionate are used as hair conditioning agents and surfactant-cleansing agents in cosmetic formulations.5 The monosodium and disodium salts are also used as antistatic agents and the monosodium salt is used as a surfactant-foam booster.

Table 3 presents the historical and current product formulation data for sodium lauriminodipropionate. According to information supplied to the Food and Drug Administration (FDA) by industry as part of the Voluntary Cosmetic Registration Program (VCRP), sodium lauriminodipropionate was used in a total of 23 cosmetic formulations at the time of the first safety assessment. An industry survey reported use concentration range of 1-10%. Currently, VCRP data indicate that sodium lauriminodipropionate is used in 10 cosmetic formulations, half of which are in hair conditioners. In a survey of current use concentrations conducted by the Personal Care Products Council, sodium lauriminodipropionate is used at a concentration of 0.05% in hair conditioners.



Currently, the VCRP data indicate that disodium lauriminodipropionate is used in 2 cosmetic formulations, both of which are face and neck preparations. No uses are reported for lauriminodipropionic acid. At this time, the Personal Care Products Council is performing a use concentration survey and CIR is awaiting those results.

Non-Cosmetic Sodium lauriminodipropionate has applications in heavy-duty alkaline cleaners, corrosion inhibitors, leather cleaners, and acid cleaners. From the Final Report on the Safety Assessment of Sodium Lauriminodipropionate.1

The Environmental Protection Agency (EPA) has ruled that the sodium and potassium salts of N-alkyl (C8-C18)-beta-iminodipropionic acid do not need a maximum permissible level when they are used as inert ingredients in pesticide formulations for pre- and post-harvest applications in food crops (40 CFR §180). Sodium lauriminodipropionate is an N-alkyl (C8-C18)-beta-iminodipropionic acid, and thus fits within the EPA ruling.

TOXICOKINETICS Absorption, Distribution, Metabolism, and Excretion

SODIUM LAURIMINODIPROPIONATE While specific information on the absorption, distribution, metabolism, and excretion of sodium lauriminodipropionate were not found, a possible metabolic scheme was described based on features of a structure activity relationship (SAR) assessment (see Scheme 1).6 According to the assessment, sodium lauriminodipropionate is likely to be metabolized by glucuronidation and/or N-dealkylation. Glucuronide products are known to be rapidly excreted and not likely to be biologically active.

N-Dealkylation products are usually dietary chemicals, such as straight chain fatty acids, that undergo intermediary metabolism. (The CIR Expert Panel has concluded that lauric acid and other straight chain fatty acids and related ingredients are safe for use in cosmetic products.7-9) In this scheme, the tertiary amine group of sodium lauriminodipropionate may undergo oxidative N-dealkylation to form 3,3’-azanediyldipropanoic acid, lauric acid, and/or 3-(dodecylamino)propanoic acid. Other N-dealkylation products may be laurylamine and/or malonic acid. This reaction is nearly always catalyzed by cytochrome P450s. The mechanism involves hydrogen abstraction and hydroxylation at a carbon atom alpha to the nitrogen atom.

In this scheme, sodium lauriminodipropionate may also undergo C-hydroxylation reactions on the alkyl chain. The products of this reaction may be 3,3’-(11-hydroxydodecylazanediyl)dipropanoic acid and 3,3’-(12-hydroxydodecylazanediyl)dipropanoic acid. On the longer alkyl chain, hydroxylation at the methylene group and hydroxylation at the terminal methyl group may be favorable. 6

TOXICOLOGICAL STUDIES

Acute Toxicity Dermal – Non-Human SODIUM LAURIMINODIPROPIONATE

In acute dermal studies, no deaths or adverse reactions were observed in rabbits treated with 6.8 g/kg or 10.2 g/kg sodium lauriminodipropionate (10% active). From the Final Report on the Safety Assessment of Sodium Lauriminodipropionate.1

Oral – Non-Human SODIUM LAURIMINODIPROPIONATE

The oral LD50 in albino mice treated with sodium lauriminodipropionate, 16% solids and pH 7.0, was estimated to be 17.8 ml/kg. From the Final Report on the Safety Assessment of Sodium Lauriminodipropionate.1

Repeated Dose Toxicity Percutaneous – Non-Human SODIUM LAURIMINODIPROPIONATE

The percutaneous toxicity potential of sodium lauriminodipropionate was evaluated in a 91 day study in New Zealand White rabbits.10 There were 5 male and 5 female rabbits in the test group that received 2 ml/kg/day of 20% w/w solution in distilled water of 10.5% sodium lauriminodipropionate (35% of a 30% solution) in a foaming face wash. A control group of 5 male and 5 female rabbits received distilled water. The rabbits received the treatment or the control solutions daily, 5 days/week, to clipped, intact dorsal skin. The animals were checked twice daily for mortality and once daily for clinical signs of toxicity. Body weights were measured prior to study commencement, once a week during treatment, at 28 days, and at study termination. Hematology parameters were measured prior to study commencement and at study termination. All animals were killed at the end of the treatment period and underwent macro- and microscopic examination. Absolute and relative weights of the liver and kidney were determined.

Dermal irritation was observed in the test group, which included slight to moderate erythema (starting on day 7), slight to moderate edema (starting on day 7), and slight to marked desquamation (days 7-14). There were no signs of systemic toxicity. All animals survived until study termination. Body weights of the treated animals were comparable to the



control animals. There were no treatment-related changes to hematology parameters or differences in organ weights when compared to controls. No macroscopic or microscopic changes that suggested systemic toxicity were observed at necropsy in any of the animals. This study concluded that while sodium lauriminodipropionate did not cause dermal toxicity, it was a dermal irritant.10 DISODIUM LAURIMINODIPROPIONATE

In a hair dye formulation containing 1.5% disodium lauriminodipropionate, no systemic effects were observed in New Zealand white rabbits after topical application twice weekly for 13 weeks.11

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

SODIUM LAURIMINODIPROPIONATE While there is no information available in the literature on the reproductive and developmental toxicity of sodium lauriminodipropionate, a SAR assessment was conducted that considered the potential metabolites of this ingredient (see Figure 1).6 Sodium lauriminodipropionate is likely to be metabolized by glucuronidation and/or N-dealkylation. The specific glucuronide product for sodium lauriminodipropionate has not been assessed for reproductive or developmental toxicity, however, glucuronides in general have not been classified a developmental or reproductive hazards. Among the products of N-dealkylation, straight-chain fatty acids, such as lauric acid, have been evaluated for reproductive and developmental hazards and no adverse effects have been reported.6,12 The CIR Expert Panel has reviewed several straight-chain fatty acids, including lauric acid, and related ingredients, including plant-derived fatty acid oils, and has found these ingredients to be safe for use in cosmetic ingredients.7-9 While the possible N-dealkylation product laurylamine has not been tested for reproductive toxicity, a similar compound, oleylamine has been assessed and found to not affect development in rats and rabbits, even at maternally toxic oral doses.6 The developmental NOAEL was 80 mg/kg/day for rats and 30 mg/kg/day for rabbits in these studies. Another possible N-dealkylation product, a mixture of tallow alkyl amines, did produce a decrease in offspring weight and a decrease in fertility at severely toxic levels, but this can be attributed to being secondary to the toxicity. Malonic acid may also be a product of N-dealkylation. This chemical, which has been previously assessed by the CIR Expert Panel and determined to be safe for use in cosmetic products, has been evaluated for developmental toxicity in rats.13 At concentration of 9 or 12% malonate in feed (approximate dosage for 9% malonate was 4.5 g/kg/day), low toxicity was observed in dams and fetuses.14 A few malformations were reported for 4.5 g/kg/day, but these incidences were within historical control ranges, and this dose was considered the NOAEL for developmental toxicity. DISODIUM LAURIMINODIPROPIONATE

In a hair dye formulation containing 1.5% disodium lauriminodipropionate, no embryotoxic or teratogenic effects were observed in Charles River CD rats.11

GENOTOXICITY In Vitro

SODIUM LAURIMINODIPROPIONATE The mutagenicity potential of 30% sodium lauriminodipropionate was assessed in an Ames test with Salmonella

typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538.15 The assay was performed with and without S9 metabolic activation. The concentration ranges tested were 0.003-10 μl/plate with S9 and 0.01-1.0 μl without S9. Because of lack of toxicity in test strains TA98, TA1535, and TA1538 without S9, additional assays were run using concentration ranges of 0.33-20 μl/plate. No positive responses were observed in any of the test strains, with or without S9. The vehicle control water and the positive controls 2-nitrofluorene, 2-aminoanthracene, sodium azide, and ICR-191 yielded expected results. It was concluded that sodium lauriminodipropionate was not mutagenic in this Ames test.

A Chinese hamster ovary (CHO) cell assay was performed to assess the potential of 30% sodium lauriminodipropionate to induce chromosome aberrations.16 Following a range finding study, the concentration ranges for the 8 h incubation study were 0.21, 0.28, and 0.38 μl/ml without S9 and 0.48, 0.63, and 0.84 μl/ml with S9. In the 12 h incubation study, the concentration ranges were 0.28, 0.38, and 0.50 μl/ml without S9 and 0.63, 0.84, and 1.13 μl/ml with S9. Relative cloning efficiency at the highest doses in the 8 h study were 34% and 70% without and with S9, respectively, while in the 12 h study, the values were 1% and 38% without and with S9, respectively. The controls, which were water, untreated cells, cyclophosphamide (CP), and triethylenemelamine (TEM), yielded expected results. The test material did not induce significant chromosome aberrations in either incubation period, with or without S9 metabolic activation. It was concluded that sodium lauriminodipropionate was not clastogenic.

CARCINOGENICITY

Published carcinogenicity data were not found.

IRRITATION AND SENSITIZATION Irritation

Dermal – Non-Human SODIUM LAURIMINODIPROPIONATE



Sodium lauriminodipropionate, 10% solids, had a mean primary irritation index (PII) of 3.04/8 and was considered corrosive to the skin of rabbits due to eschar formation. In another study, sodium lauriminodipropionate, 16% solids at pH 7.0, was a moderate irritant to rabbit skin, with a PII of 2.17. From the Final Report on the Safety Assessment of Sodium Lauriminodipropionate.1

Ocular – Non-Human SODIUM LAURIMINODIPROPIONATE

A solution of sodium lauriminodipropionate, 10% solids, was classified as mildly irritating to the eyes of rabbits without rinsing, and practically nonirritating with rinsing. Another solution of sodium lauriminodipropionate, 16% solids at pH 7.0, was a moderate irritant. From the Final Report on the Safety Assessment of Sodium Lauriminodipropionate.1

Ocular – Human SODIUM LAURIMINODIPROPIONATE Two shampoo formulations containing 3.56% active sodium lauriminiodipropionate (11.86% of a 30% solution) were tested for ocular tolerance in a total of 102 human subjects.17 The study was comprised of 2 phases. In Phase I, the test materials were instilled into one eye of each subject at single rising concentrations (5% or 10%). The other eye received sterile water. In Phase II, the test material was instilled into one eye at a concentration determined to be likely tolerable from Phase I (10%) while the other eye received sterile eye. Eyes were evaluated before instillation, and objective and subjective tolerance was measured immediately after instillation, between 30 and 60 seconds after instillation, 15 minutes, and 1 h after instillation. Objective evaluations were measured with slit lamp examination, bulbar and conjuctival irritation, and assessment of lacrimation. Albumin levels in tears before and after application of the test material were evaluated with the turbidimetric method in Phase II only. Subjective evaluations included reports by the subjects of stinging and itching sensation and epiphora. No opthalmological lesions were observed with any of the test materials. The test materials also did not induce a significant increase in albumin levels in tears. Minimal observations of stinging or dryness sensations were made in either phase of the study.

Sensitization Dermal – Non-Human SODIUM LAURIMINODIPROPIONATE

No sensitization was observed in guinea pigs injected intracutaneously with 0.1% sodium lauriminodipropionate. From the Final Report on the Safety Assessment of Sodium Lauriminodipropionate.1

Dermal – Human SODIUM LAURIMINODIPROPIONATE

Sodium lauriminodipropionate was reported to be “practically nontoxic” to the skin and “minimally irritating” upon skin contact. It was also reported to be “minimally irritating” to the eye. Sodium lauriminodipropionate was “practically nontoxic” upon ingestion. From the Final Report on the Safety Assessment of Sodium Lauriminodipropionate.1 A human repeat insult patch test (HRIPT) of the potential of 2.2% sodium lauriminodipropionate (7.34% of 30%

solution) to induce contact sensitization was conducted using 104 subjects.18 The subjects received 0.2 ml applications of a 2.0% foaming face wash solution in distilled water. Induction applications were made to the infrascapular region of the back with a 2 cm2 Webril pad portion of an adhesive dressing. The test sites were occluded. The patches were removed after 24 h and there were 9 consecutive applications. Following 2 week non-treatment period, the challenge application was applied to a previously untreated site for 24 h, and the site was scored 24 and 48 h after patch removal. During the induction phase, there were as few as 3 (days 1and 2) and as many as 39 (day 9) “?”responses (doubtful response, barely perceptible erythema). There were no other responses during the induction phase. In the challenge phase, there were 8 and 7 “?” responses at 24 h and 48 h after patch removal, respectively. There were no other responses during the challenge phase. The study concluded that there was no evidence of sensitization to a foaming face wash formulation containing 2.2% sodium lauriminodipropionate.

In another HRIPT, the potential of 3.5% active sodium lauriminodipropionate (11.67% of a 30% solution) to induce contact sensitization was studied in 116 subjects.19 The subjects received 0.5 ml applications of 2.5% shampoo formulation solution in distilled water. Induction applications were made to the arm with a 7/8 inch diameter Webril disc secured with adhesive dressing. The test sites were occluded. The patches were removed after 24 h and there were 9 consecutive applications. Following 2 week non-treatment period, the challenge application was applied to a previously untreated site for 24 h, and the site was scored 48 and 96 h after application. One subject had mild to moderate erythema during the induction and had a positive response at challenge in the original test site. The subject subsequently underwent rechallenge patching with the test material, with a 2.5% w/v aqueous solution of another shampoo formulations containing 3.5% sodium lauriminodipropionate, and a 0.4% w/v solution of the fragrance used in the original test formulation in mineral oil. Mild erythema was observed to the similar shampoo formulation at the 48 h scoring, which resolved completely at the 96 h scoring. No other responses were observed in this subject. Mild erythematous reactions were reported in several other subjects during the induction phase as well as during challenge. These reactions, and the ones observed in the subject that underwent rechallenge, were determined to be irritant responses consistent with surfactant use. The study concluded that



there was no evidence that the shampoo formulation containing 3.5% sodium lauriminodipropionate caused delayed contact hypersensitivity.

SUMMARY Lauriminodipropionic acid and its sodium salts are used as surfactants, a hair conditioning agents, and an antistatic

agents in cosmetic formulations. Current FDA VCRP data indicate that sodium lauriminodipropionate is used in 10 cosmetic formulations, mainly in hair conditioners. The current concentration of use for sodium lauriminodipropionate is 0.05% in hair conditioners. Disodium lauriminodipropionate has been reported to have uses in 2 face and neck preparations. No uses are reported for lauriminodipropionic acid. A concentration survey on the disodium salt and the acid are currently being performed.

Sodium lauriminodipropionate has applications in heavy-duty alkaline cleaners, corrosion inhibitors, leather cleaners, and acid cleaners. The Environmental Protection Agency (EPA) has ruled that the sodium and potassium salts of N-alkyl (C8-C18)-beta-iminodipropionic acid do not need a maximum permissible level when they are used as inert ingredients in pesticide formulations for pre- and post-harvest applications in food crops.

A possible metabolic scheme based on features of a structure activity relationship (SAR) assessment determinded that sodium lauriminodipropionate is likely to be metabolized by glucuronidation and/or N-dealkylation.

In studies of 10% active solutions of sodium lauriminodipropionate, the oral LD50 for rats was 31.3 g/kg, and the dermal LD50 was greater than 10.2 g/kg; the oral LD50 for mice of a 16% solids solution was estimated as 17.8 ml/kg.

A 91 day study in rabbits that received 20% w/w solution in distilled water of 10.5% sodium lauriminodipropionate (35% of a 30% solution) concluded that while sodium lauriminodipropionate did not cause dermal toxicity, it was a dermal irritant. No systemic effects were observed in rabbits that received topical applications of a hair dye formulation containing 1.5% disodium lauriminodipropionate for 13 weeks.

While there is no information available in the literature on the reproductive and developmental toxicity of sodium lauriminodipropionate, a SAR assessment conducted for potential metabolites of this ingredient concluded that the metabolites were not developmental or reproductive hazards. A developmental study in rats on a hair dye formulation containing 1.5% disodium lauriminodipropionate did not observe embryotoxic or teratogenic effects.

Sodium lauriminodipropionate was not mutagenic in this Ames test, nor was it clastogenic in a CHO cell assay. Sodium lauriminodipropionate at 10% active solution was severely irritating to the skin of rabbits. Sodium

lauriminodipropionate at 16% solids was a moderate irritant to rabbit skin. Sodium lauriminodipropionate was irritating to the eyes of rabbits. Two shampoo formulations containing 3.56%

active sodium lauriminiodipropionate did not cause opthalmological lesions or induce a significant increase in albumin levels in tears in humans. Minimal observations of stinging or dryness sensations were made in either phase of the study.

There was no evidence of sensitization in studies with guinea pigs. A foaming face wash containing 2.2% active sodium lauriminodipropionate and a shampoo formulation containing 3.5% active sodium lauriminodipropionate did not cause delayed contact hypersensitivity in HRIPT studies.

DISCUSSION The Expert Panel noted gaps in the available safety data for lauriminodipropionic acid and its sodium salts. The available data on sodium lauriminodipropionate are sufficient, however, and similarity between structural activity relationships and biologic functions in cosmetic use can be extrapolated to support the safety of the entire group.

The Panel also recognizes that there are data gaps regarding use and concentration of these ingredients. However, the overall information available on the types of products in which these ingredients are used and at what concentrations indicate a pattern of use, which was considered by the Expert Panel in assessing safety.

CONCLUSION

The CIR Expert Panel concluded that lauriminodipropionic acid, sodium lauriminodipropionate, and disodium lauriminodipropionate are safe in the present practices of use and concentration described in this safety assessment.1

1 Were ingredients in this group 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 the group.



6

TABLES AND FIGURES Table 1. Names, CAS registry numbers, definitions, and structures of dipropanoic acid ingredients.

Ingredient CAS No. Definition Formula/structure Lauriminodipropionic acid 17066-08-9

Lauriminodipropionic acid (dodecylazanediyldipropanoic acid) is the tertiary amine substituted with dodecane and two equivalents of 3-propionic acid.

HO N CH3

O

OHO

Sodium lauriminodipropionate 14960-06-6 and 26256-79-1

Sodium lauriminodipropionate is the partial sodium salt of dodecylazanediyldipropanoic acid.

HO N CH3

O

OONa

Disodium lauriminodipropionate 3655-00-3

Disodium lauriminodipropionate is the disodium salt of dodecylazanediyldipropanoic acid.

O N CH3

O

OONa

Na

Table 2. Chemical properties.

Property Value Reference

Lauriminodipropionic Acid

Molecular Weight g/mol 329.47 20

Molecular Volume cm3/mol @ 25oC 760 mmHg 322.1 20

Vapor pressure mmHg@ 25 oC 1.35 x 10-10 20

Boiling Point oC @ 760 mmHg 481.6 20

logP @ 25oC 5.82 20


Physical Form Thin, clear liquid 1

Color Yellow to light amber 1

Odor Mild fruity, faint metallic 1

Density/Specific Gravity @ 25 oC 1.03 1

Boiling Point oC 100 1

Solubility Soluble in water,

partially soluble in ethanol 1



Scheme 1. Purported Metabolic Pathways of Lauriminodipropionic Acid, Sodium Lauriminodipropionate, and Disodium Lauriminodipropionate.6

O N CH3

O

OHO

OH

OH

HO

O

O

HO

HO N CH3

O

OHO Glucuronidation

HO N

O

OHOHO N CH3

O

OHO

OH

OHC-hydroxylation

Oxidative N-Dealkylation

HO

O

NH

OHO

HO CH3

O

HO

O

OH

O

HO NH

CH3

O

H2N CH3

3,3'-(12-hydroxydodecylazanediyl)dipropanoic acid

3,3'-(11-hydroxydodecylazanediyl)dipropanoic acid

Lauriminodipropionic acid(3,3'-(dodecylazanediyl)dipropanoic acid)

(2S,3S,4S,5R,6S)-6-(3-((2-carboxyethyl)(dodecyl)amino)propanoyloxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

3,3'-azanediyldipropanoic acid

malonic acid

lauric acid (dodecanoic acid)

3-(dodecylamino)propanoic acid

laurylamine (dodecan-1-amine)



Table 3. Historic and current uses and concentrations of sodium

lauriminodipropionate.

# of Uses Conc. of Use (%)


1995 2011 1995 2011

Exposure Type

Eye Area NR NR NR NR

Incidental Ingestion NR NR NR NR Incidental Inhalation-Sprays NR NR NR NR Incidental Inhalation-Powders NR NR NR NR

Dermal Contact 13 5 5-10 NR

Deodorant (underarm) NR NR NR NR

Hair - Non-Coloring 8 5 1 0.05

Hair-Coloring 2 NR NR NR

Nail NR NR NR NR

Mucous Membrane 4 1 NR NR

Baby Products NR NR NR NR

Duration of Use

Leave-On 3 NR 5 NR

Rinse Off 20 10 1-10 0.05

Diluted for (Bath)Use NR NR NR NR

Totals 23 10 1-10 0.05 NR = Not Reported; Totals = Rinse-off + Leave-on Product Uses.

Note: Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure type uses may not equal the sum total uses.



REFERENCES

1. Andersen FA (ed.). Final report on the safety assessment of Sodium Lauraminopropionate and Sodium

Lauriminodipropionate. IJT. 1997;16(S1):1-9.

2. Tokiwa F and Ohki K. Potentiometric titration of amphoteric surfactants in micellar solutions. J Phys Chem. 1967;71(6):1824-1829.

3. Bettayeb B, Descoteaux C, Benoit F, Chapados C, and Berube G. Pure N-alkylaminopropionic acid and n-alkylaminodipropionic acid sodium salts: Synthesis, characterization, and physicochemical properties. J Surfact Deterg. 2009;12237-247.

4. Ranborn KC. 2011. Sodium Lauriminodipropionate. Method of Manufacture.

5. Gottschalck TE and Bailey JE eds. International Cosmetic Ingredient Dictionary and Handbook. 13th ed. Washington, D.C.: Personal Care Products Council; 2010.

6. Cosmetic Ingredient Review Science and Support Committee. 2011. Developmental and reproductive toxicity assessment for Sodium Lauriminodipropionate.

7. <[04] Authors, primary>. <[03] Title, primary>. <[11] Periodical>. <[05] Date, primary>;6(3):321-401.

8. <[04] Authors, primary>. <[03] Title, primary>. <[11] Periodical>. <[05] Date, primary>;25(Suppl. 2):1-89.

9. Burnett C, Fiume M, Bergfeld WF, Belsito DV, Hill RA, Klaassen CD, Liebler DC, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final Report on Plant-Derived Fatty Acid Oils as Used in Cosmetics. Cosmetic Ingredient Review. 3-4-2011.

10. International Research and Development Corp. 1990. 28-Day/91-Day Subchronic Percutaneous Toxicity (MV#2607-198). Study number P89-020.

11. Burnett C, Goldenthal EI, Harris SR, Wazeter FX, Strausburg J, Kapp R, and Voelker R. Teratology and percutaneous toxicity studies on hair dyes. J Toxicol Environ Health. 1976;11027-1040.

12. Human & Environmental Risk Assessment on Ingredients of European Household Cleaning Products.Fatty Acid Salts Human Health Risk Assessment - Draft for Public Comment. http://www.heraproject.com/files/5-HH-04-HERA%20Fatty%20acid%20salts%20HH%20web%20wd.pdf. Date Accessed 8-15-2011.

13. Fiume MM, Heldreth BA, Bergfeld WF, Belsito DV, Klaassen CD, Liebler DC, Hill RA, Marks JG, Shank RC, Slaga TJ, Snyder PW, and Andersen FA. Final Report on Dicarboxylic Acids and Their Salts and Esters as Used in Cosmetics. Cosmetic Ingredient Review. 12-14-2010.

14. Mackler B, Grace K, and Tippit DF. Studies of the development of congenital anomalies in rats. III. Effects of inhibitors of mitochondrial energy systems on embryonic development. Teratology. 1975;12291-296.

15. Microbiological Associates, Inc. 1990. Salmonella/mammalian microsome mutagenesis assay (Ames test). Final Report. Test Article (TSIN) MV #2716-040. MBA study no. T9102.501.

16. Microbiological Associates, Inc. 1990. Cytogenicity study - Chinese hamster ovary (CHO) cells in vitro. Final Report. Test Article MV# 2716-040. MBA study no. T9102.338.

17. Institut Aster. 1994. Comparative ocular tolerance study of shampoo products RE-0276.01, RE-0277.01, RE-0278.01, RE-0279.01, RE-0280.01, and RE-0251.02 after single topical instillation in normal healthy volunteers. Institut Aster Study No. R.01.94.U.E.DH 025.01.

18. TKL Research, Inc. 1991. Repeated insult patch test. TKL study no. 911021.

19. North Cliff Consultants. 1991. Human sensitization test. North Cliff Study #9112-3.



20. Advanced Chemistry Development (ACD/Labs). Advanced Chemistry Development software v11.02. 2011.



Personal Care Products CouncilCommitted to Safety,Quality & Innovation

DATE:

Memorandum

F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CW)

John Bailey,Industry Liaison to the CIR Expert Panel

July 6, 2011

SUBJECT: Composition Denphat 160C (Sodium Lauriminodipropionate)

The trade name material Deriphat 160C (30% solution of Sodium Lauriminodipropionate) was testedin the studies provided on April 26, 2011. The supplier has indicated that Deriphat 160C does notcontain any Sodium Lauraminopropionate.

1101 17th Street, N.W., Suite 30O Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org

TO:

FROM:



Personal Care Products CouncilCommitted to Safety,Qua’ity & Innovation

Memorandum

TO: F. Alan Andersen, Ph.D.Director - COSMETIC INGREDIENT REVIEW (CIR)

FROM: John Bailey, Ph.D_. i,_._i2.__ v-fl i”iIndustry Liaison to the CW Expert Panel

DATE: July 6, 2011

SUBJECT: Method of Manufacture, Toxicity Data Sodium Lauriminodipropionate (Mirataine H2C-HA)

Ranbom KC. 2011. Sodium Lauriminodipropionate, method of manufacture.

Rhodia Inc. 2003. Mirataine H2C-HA (Sodium Laurimindipropionate) toxicity data.

11011 7th Street, N.W., Suite 3O0 Washington, D.C. 20036-4702 202.331.1770 202.331.1969 (fax) www.personalcarecouncil.org



JhodiaCrrn y s r world. Res ty our way

Rhodia-No i’ecareCN 7500Cranbury, NJ 08512-7500 USA

June 20, 2011

Ms. Carol EisenmannSenior ToxicologistPersonal Care Products CouncilWashington, DC

via email: [[email protected]]

Subject: Sodium Lauriminodipropionate - CIR Review

Dear Carol:

In response to your request for manufacturing and impurity information on the above namedingredient, Rhodia Inc. respectfully provides the following information for review by the CosmeticIngredients Review Board.

Manufacture of Sodium Lauriminodipropionate:

Sodium lauriminodipropionate is formed by the Michael addition of acrylic acid to laurylamine(dodecylamine). The reaction mixture is then partially neutralized with Sodium Hydroxide to yieldthe sodium salt. The reaction scheme is shown below:

1 CE143(H2)VCH2NH2 + CH2=CHCO2H- Cf-(CH23CH2N1-12CH2CH2CO

dodecyl amine acrylic acid dodecylarninopropionic acid

2. CK(CH2)CH2NH2CK2CH2COj + cH2=cHcG2H- CHCH)cCH2N1t(CH2CH2CO2)2H

dodecylamino-dipropionic acid

3,

CH3(CH2)CH2N1-12CH2CH2CO2

4-

CH3(CH2)CH2N1-1(CH2CH2CO2)2H

NaO-YH2O C(CH)I,CH2NH2CH2CH2COj

pR=&5-75 LCH3(CHCH2NH(CH2CH2cO)2Na

complexinterconnectedstructure

The reaction yields predominantly the sodium lauriminodipropionate salt with minor amounts ofsodium lauraminopropionate. A typical commercial product sold at roughly 30% solids will contain



hodiaChemistry is our world, Responsibility is our woy

about 25% sodium lauriminodipropionate salt and about 5% of the sodium lauraminopropionatecompound. The balance of the “as sold” product is predominantly water.

Impurities:

Based on analysis of multiple batches of commercial product, the primary impurity is sodiumacrylate. Trace amounts of C12 compounds associated with the laurylarnine starting material mayalso be present. The total impurities are typically found at levels less than 2% total in the productas sold. The presence of the dodecylamine (laurylamine) starting material and polyacrylic acid orsodium polyacrylate have not been detected.

We hope that this information will be useful in the assessment of Sodium Lauriminodipropionate. Ifyou have any questions or need additional information, please contact me at 609-860-3452, or bye-mail at [email protected]

Very truly yours,Rhodia Inc

Karen C RanbomManager, Regulatory AffairsRhodia Novecare

. •. ,.

11-0181.doc ,:.



®iodiaRhodia Inc.CN 7500Cranbury, NJ 08512

odJ L

MIRATAINE H2C-HA TOXICITY DATA

ACUTE ORAL LD50An acute oral LD50 study was conducted using 3 groups of 5 male and 5 female healthy albinomice each dosed once by gavage with the test substance at 16% solids and pH 7.0. Feed andwater were provided ad-libitum after dosing and each mouse was observed daily for mortality andother signs of gross toxicity for 5 days. The estimated oral LD50 is 17.8 mI/kg.

Product Safety Labs, May 24, 1982 (Ref: PS-I 557)

DERMAL IRRITATIONThree albino rabbits were evaluated for erythema, eschar and edema formation on abraded andintact skin after the application via patches of 0.5 ml of the test material at 16% solids and pH 7.0.The patches were removed 24 hours after application and the reactions were noted then andagain at 72 hours. The Primary Irritation Index was determined to be 2.17 which classifies thesubstance as a moderate irritant to rabbit skin under the conditions of the test.

Product Safety Labs, May 19, 1982 (Ref: PS-i 558)

OCULAR IRRITATIONA test to determine the potential for eye irritation was conducted using three albino rabbits. Eachanimal was administered 0.1 ml of the test material at 16% solids and pH 7.0, to one eye with theother eye serving as a negative control. Observations were recorded at 24, 48, and 72 hours andagain at 4 and 7 days. The Maximum Mean Total Score was 20.7 (24 hours) and 12.0 (7 days). Itwas concluded to be a moderate irritant to rabbit eyes under the test conditions.

Product Safety Labs, May 19, 1982 (Ref: PS-i 559)

AQUATIC TOXICITYA static aquatic bioassay was run on Daphnia magna. Tests were conducted in 1000 ml glassvessels. The pH, DO and temperature were monitored during the study. The 24-hour EC50 wasdetermined to be 67 ppm, with a 48-hour EC50 of 32 ppm.

RP Industries, April, 1994 (Ref: PS-3537)

Summary date: February 11, 2003



sodium lauri pink

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