BLUE. Sodium Lauriminodipropionate

Transcription

1 BLUE Sodium Lauriminodipropionate CIR EXPERT PANEL MEETING DECEMBER 12-13, 2011

2 Memorandum To: From: CIR Expert Panel Members and Liaisons Christina L. Burnett Scientific Writer/Analyst Date: November 21, 2011 Subject: Draft Final Amended Report on Lauriminodipropionic Acid and its Sodium Salts At the September meeting, the CIR Expert Panel concluded the available data were insufficient to make a determination of safety for lauriminodipropionic acid and its sodium salts. The current use concentration data were not available for lauriminodipropionic acid and the disodium salt. This finding was related more to an artifact of timing of receipt of data than on an actual absence of data. Since the meeting, we have received the results of the Council s concentration of use survey. There are no reported use concentrations for lauriminodipropionic acid and its disodium salt. Now that we know that, we can use the language Were the ingredients not in current use (as indicated by *) to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to sodium lauriminodipropionate. 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 Final Amended Report.

3 Distributed for Comment Only -- Do Not Cite or Quote )CI(JVn l_&ll( c) ch i SAFETY ASSESSMENT FLOW CHART Public Comment CIR Expert Panel Re-Reviews Report Color d.i cz-4,cje lsyears;or F-H )rp) Draft Priority List 4 New Data; or >1 Draft Priority List * DRAFT PRIORITY LIST [ 60 day public comment period : ANNOUNCE 4 ment Priority Listi INGREDIENT I SLR Decision not to reop_ the report* PRIORITY LIST YES Is new data cause to reopen? NO DOES NEW DATA SUPPORT ADDING NEW INGREDIENTS? A Y ES * * Re-review to Panel c,jt, I it c uc4 s Buff Cover nod UIG4. y-_o Buff Covert 4ii n. 4e4 pen4 60 day public comment period Draft Report DRAFT REPORT Draft Amended Report Green Cover 1 time; Table 2s SD ISD Notice 4 ISO I,, Pink Cover 2nd time. 60 day public comment period Draft TR ISD DRAFT TENTATIVE REPORT Draft Amended Tentative Report Pink Cover Table -io ot Tentative Report 4 Issue TR Tentative Amended Report 60 day Public comment period DraftFR DRAFT FINAL REPOR Draft Amended Final Report Blue Cover ul Table Difft Conci. PUBLISH 4 Final Report FR *The CIR Staff notifies of the public of the decision not to re-open the report and prepares a draft statement for review by the Panel. After Panel review, the statement is issued to the Public. **Jf Draft Amended Report (DAR) is available, the Panel may choose to review; if not, CIR staff prepares DAR for Panel Review. Expert Panel Decision I i Document for Panel Review Option for Re-review CIR Panel Book Page 1

4 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 CIR Panel Book Page 2

5 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 % (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 through report page 28; data pages 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 U.K.DH through report page 42; data pages available online HRIPT on a formulation with 2.3% Sodium Lauriminodipropionate - TKL Research, Inc. Study No HRIPT on a formulation with 3.5% Sodium Lauriminodipropionate - North Cliff Consultants, Inc. Study # Ames Test of a commercially available cosmetic ingredient (30% Sodium Lauriminodipropionate) - Microbiological Associates, Inc. Study No T In Vitro chromosome aberration assay in CHO cells of a commercially available cosmetic ingredient (30% Sodium Lauriminodipropionate) - Microbiological Associates, Ind., Study No. T ). 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. September 26-27, 2011 A tentative safety assessment with a conclusion that the available data were insufficient to support the safety of these ingredients was issued. The CIR Expert Panel noted that current use concentration data were not available for lauriminodipropionic acid and disodium lauriminodipropionate and requested that current concentration of use data be provided. This finding was related more to timing of anticipated survey results than to an actual lack of data. The Panel was informed that the survey results would be ready before the December 2011 meeting. CIR Panel Book Page 3

6 Lauriminodipropionic Acid Family Data Profile* December 2011 Writer, Christina Burnett 1 Distributed for Comment Only -- Do Not Cite or Quote Reported Use log P value Toxicokinetics Data Animal Tox Acute, Dermal Animal Tox Acute, Oral Animal Tox, Acute, Inhalation Animal Tox Rptd Dose, Dermal Animal Tox, Rptd Dose, Oral Animal Tox Rptd Dose, Inhalation Repro/Dev Tox Genotoxicity Carcinogenicity - Dermal Dermal Irr/Sens Mucosal Irritation Lauriminodipropionic Acid X X Sodium Lauriminodipropionate X X X X X X X X X Disodium Lauriminodipropionate X X X * X indicates that data were available in a category for the ingredient CIR Panel Book Page 4

7 Search Strategy for Sodium Lauriminodipropionate, Lauriminodipropionic Acid, and Disodium Lauriminodipropionate July 6, 2011: SCIFINDER search for CAS Nos and 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 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 and 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 AND AND Lauriminodipropionic Acid 1 No restrictions AND Disodium Lauriminodipropionate AND AND No restrictions. 10 References Ordered/Downloaded Total Search updated October 26, CIR Panel Book Page 5

8 Minutes

9 Dr. Marks Team Minutes September 26, 2011 DR. MARKS: We'll move on to sodium lauriminodipropionate. And so at the last meeting we reopened this safety assessment. It was originally reviewed in the late 1990s. Now we have available data that addresses the safety of the asset and the sodium I-compound. MS. BURNETT: We have two published studies that we did not incorporate into the report because Alan and I felt that they really didn't contribute anything, but I brought them. We're free to look at just in case. One discusses the disodium lauriminodipropionate and tocopheryl phosphate complex together in a shaving cream. We felt you couldn't really discern what the action was, whether it was from the tocopheryl or from the laurimino compound but we brought it along just in case. And the other one discusses how surfactants inhibit staph RAS production in Toxic Shock Syndrome. So I'll pass them down. You can take a look. If you feel that they should be incorporated, we can incorporate them. DR. SHANK: In the first paper, was there a health effect due to the -- MS. BURNETT: It's mediating shaving irritation. DR. SHANK: Okay. DR. HILL: Because one of the major issues that arose was the fact that the lauriminodipropionate -- I wanted to crosscheck that -- could be present as an impurity in at least the raw material up to five percent. We were awaiting concentration of use data for this particular product, excuse me, ingredient. Do we have that information yet? DR. EISENMANN: No, not yet. It's not done. It takes about four months usually to get the use survey and it's not complete yet. DR. HILL: Understood. DR. EISENMANN: So far I don't have any uses report of the disodium or the acid. It's still the same. DR. HILL: Right. And that's what I would expect. And it's sort of an academic issue anyway because you're going to have a product that's probably buffered at some point in the production to a particular ph where what's in there is in there. I just wondered because even right up front in the memo and in the transcript when Alan was CIR Panel Book Page 6

10 discussing this, he says, he writes a little -- he said "a little glitch." Now we're talking about five percent and we don't have the concentration of use data and we have insufficient on that lower iminodipropionate to draw conclusions. So if we knew what the total concentrations of use are and we knew what the relevance of that five percent might potentially be and could make some conservative estimates, then we'd have a better chance of knowing what the conclusions need to be here. I know we don't review based on the safety of the impurity per se, but at least our discussion could say the impurity level needs to be kept below thus and such percent if we had something to go on. DR. MARKS: So we issued the draft tentative amended report with the I-, the iminodipropionate and the acid and the salts as being safe. Do we want to move on to issue a tentative amended report with that conclusion? DR. HILL: If we do that we're going to need some work on the discussion from where I sit. DR. MARKS: So I think in the discussion, picking up on that, Ron, is in the previous report it included the amino, the A-compound. Now we're splitting this out so we're not including that in this report. So I think we have to have that in the discussion. And the reason that we split it out was chemically it was different. Is that correct? So it really shouldn't have been included in the original report as a group. So that should be in the discussion. Any other discussant points? DR. BERGFELD: I'm wondering about the current concentrations of use, if you need those before you move forward on this. DR. EISENMANN: That's what I would think. DR. HILL: That's what I was trying to state is we're lacking key information. Is this why we -- DR. MARKS: So would you suggest then we table this until we get the concentration of use? It sounds like we have to. DR. EISENMANN: I wouldn't have brought it to you to begin with but, yes, that's -- DR. MARKS: Okay. So, team members, table until we get the concentration of use? Okay, since I will be the presenter tomorrow. DR. BERGFELD: Could I ask a question? Is there any further discussion items other than those CIR Panel Book Page 7

11 mentioned? I mean, everything is borrowed in this document. Do we need to discuss the lack of carcinogenicity data? Do the genotox cover that and the 28 day? DR. SLAGA: That's a good question. We have genotoxicity data. DR. BERGFELD: Right. That will cover it? DR. SLAGA: Both bacterial, as well as the mammalian. DR. BERGFELD: So if we could put that in the discussion though. DR. SLAGA: Mm-hmm. DR. HILL: I will, you know, say it is a little bothersome that we're really making an assessment based on analogous compounds and likely routes of metabolism without actually knowing anything about that. So I am bothered by that. But yet on the other hand, the things that are likely, including ones that aren't further mentioned like continued change shortening by beta glu -- excuse me, beta oxidation cycles and so forth, don't lead to anything that cause an issue in my mind. It's bothersome that we're going by analogy to similar compounds without any sort of data on the add-me. I wasn't sufficiently bothered by it to say we have to just shut this down or that we need a lot of new data. DR. BERGFELD: So would you make a comment in the discussion regarding the lack of that information "but because of" whatever you said? DR. HILL: Yeah. Tabling it would allow time to say what should that "but because of" need to be. MS. VERGNES: Excuse me. Just to be clear, that invoking the ADME and likely metabolism was done in the context of the developmental tox because that was an endpoint for which there weren't data. DR. HILL: Correct. MS. VERGNES: Just to be clear on that. DR. HILL: Yes. DR. MARKS: And then -- DR. HILL: Well, we had no carcinogenicity data and no developmental tox data. That's the thing. MS. BURNETT: Back to the concentration of use, in the past we have issued reports where I wouldn't say that we haven't received a survey yet and I anticipate we probably will receive that by December, but CIR Panel Book Page 8

12 we do have some data on the disodium. Up to 1.5 percent, they didn't see any systemic effects in a hair dye solution, nor did they see it in repro. There's only two reported uses for the disodium VCRP and there are no reported uses for the acid. I'm pretty sure we're not going to find anymore data unless something is submitted as unpublished. DR. HILL: It was the low concentrations that we had that gave me the comfort level that even though we're missing some pieces of data and the lack of any structural alerts in this molecule or any structural alerts in any of the metabolites that could reasonably be expected to be formed, gave me enough comfort to say I think we're okay here. But if we suddenly discovered that there was a leave-on use at 10 percent, then that will be potentially a different deal. DR. EISENMANN: I don't think that's going to happen. DR. HILL: I don't either. DR. EISENMANN: But like I said, I just don't have the information yet for sure. So, I mean, you could go forward and say if it changes you're going to have to come back with it, but when it gets to going to a final, I would prefer to see the reports delayed until I get a chance to actually get the information. When you're going, I mean, earlier on, no, there's no reason to delay them for more concentration of use information, but when it's going to be final it would be nice to have a pause in order to let them have a chance to get the information. DR. HILL: Right. And quite frankly, I mean, there might not even be a safety issue if it's leave-on at 10 percent. It's just that we don't have the data to support that. That's the main thing. And also given that -- DR. EISENMANN: It's going final. DR. HILL: -- that potential impurity, we have to reflect on that. DR. EISENMANN: Or going tentative. DR. BERGFELD: So what are you going to do with it? DR. MARKS: Well, first thing, I had another editorial comment on page one under the introduction, the last paragraph also refers to the amino, the A-compound that was in the original report. I would just, again, clarify that and make sure it corresponds with the discussion. It's the reason we actually did reopen the report. We're just not including the amino compound in here because it was chemically different. My understanding is tomorrow we're going to move that we table this tentative amended report for CIR Panel Book Page 9

13 needing the concentration of use table updated at this point. We assume we're going to move on with safe as used for the iminodipropionate acid and its sodium salts, but we need to see that use table. Is that fine, team? DR. HILL: And also whenever we get it back, this is the book that has the imino. If we're not going to rule any of that data into the report for the imino, if we discover that there's a five percent concentration of use in leave-on and knowing that there's a potential five percent impurity, then we either need to capture it or I need this book back. It has what information we do have on imino or the references to that. Do you get what I'm saying? MS. BURNETT: You want your book back? DR. HILL: Well, I mean, or -- because this is the June book. MS. BURNETT: You can keep that. DR. HILL: I could hang onto that? MS. BURNETT: Yeah. DR. HILL: Okay. MS. BURNETT: I don't need that. DR. MARKS: Okay. Any other discussant points? I'm going to move that we table this until we get the use concentrations for these ingredients. DR. BERGFELD: I'm just going to come back as a devil's advocate here. In your discussion then at the present time you're going to discuss the concentrations and it would be 1.5 percent or lower unless so stated by the new use concentrations. You're going to discuss lack of carcinogenicity that the genotox covers. You're going to report no reported use of the acids. And then you have to put a caveat in your conclusion on that if you should be blah blah blah. We've done those caveats if used to be in concentrations of use as reported in this document. DR. MARKS: And we're going to discuss the imino compound and why that was not included in this report. CIR Panel Book Page 10

14 Dr. Belsito s Team Minutes September 26, 2011 DR. BELSITO: Okay, so we're not reopening it. Sodium lauriminodiproprionate and related ingredients. This is the pink. Last meeting we agreed to reopen it based on new data submitted to industry. We also agreed that the available data were sufficient to address the safety of the aminodiproprionic acid and disodium lauriminoproprionate. And so we've got this pink book here. We also had agreed that we're getting rid of the a-mino, but that's no longer an issue here, it's been done, right, so. DR. ANDERSEN: Not a part of this. DR. BELSITO: So, basically, what we're really being asked to do, since we came to the conclusion, is to look at a discussion that supports our conclusion. We said there were data gaps, the available data were sufficient, data gaps with the ingredients, but if they were used -- so, we had two boilerplates on data gaps. Is there -- as Alan said before, is there anything here that we need to point out that we were concerned about or why we weren't concerned? We have some information on metabolism. We have some repeat dose toxicity percutaneous. We have reproductive. We have geno but no carcinogenicity. Irritation and sensitization -- DR. LIEBLER: So, I agree with the conclusion. I didn't come up with anything that I felt would need to be included to expand the conclusion or the discussion. DR. SNYDER: No reason to think that impurities for proprionate would be different than diproprionate under method of manufacture? DR. BELSITO: Thank you, Monice. DR. SNYDER: Because that was one of our data needs previously, right? DR. BELSITO: Yes, impurities. DR. LIEBLER: Well, so, it says the commercial price is approximately 30 percent solids, contains about 25 percent sodium laurimino dipropionic and 5 percent sodium lauramino. So, it's 5 percent of 30 percent, right? DR. ANDERSEN: But that supplier should find that (inaudible) cosmetics industry -- DR. LIEBLER: Right. DR. ANDERSEN: -- because we've said lauramino, it's insufficient data. CIR Panel Book Page 11

15 DR. LIEBLER: Yeah, right. DR. ANDERSEN: It's a true statement. And use concentrations are a tad lower. So, even if there were trace impurities, I'm not sure there's -- DR. SNYDER: Okay, I just think we need a discussion to capture that because we did ask -- DR. ANDERSEN: Yes. DR. SNYDER: We did declare it as insufficient -- DR. LIEBLER: Let's simply say that the panel noted that sodium lauramino dipropionate is a possible contaminate, although this institution found -- some insufficient, the panel has already found. I'm getting punchy. DR. BELSITO: Well, I mean, I guess the only issue there is you say they're low because we don't have any reported uses for the 5 leave-ons that pop up as dermal contact in the VCRP, but the reported uses we have in 1995, potentially for those 5 products, were 5 to 10 percent. So, I guess I have a little bit of a problem there because someone's reporting it to be used. When Carol or whoever went out to get concentrations of use, she got no data reported, but the last time we did it, 16 years ago, we're getting 5 to 10 percent in that category. And I know our categories have changed. Julie? MS. SKARE: Carol told the other team that the concentration of use survey is still out in the field, it's not back yet, so, that question still needs to be clarified, but we expect that there's going to be low concentration of use for the dipropionate monosodium, and we don't know yet about the other two, the acid and the disodium, but we're anticipating that that's going to be low, as well, and not nearly what's previously reported. But that's not yet available. DR. BELSITO: Okay, so, this is (inaudible), so insufficient for concentration of use in leave-on products. DR. LIEBLER: Yes. DR. SNYDER: Well, and then the impurity issue because we were going to justify the absence of impurities based on the low concentration of use, right? DR. BELSITO: Okay, so, insufficient for -- CIR Panel Book Page 12

16 DR. SNYDER: Concentration of use. DR. BELSITO: Concentration of use in dermal leave-ons and insufficient for impurities in the dipropionate. We can always say that, and if we find the leave-on concentration is very low and we don't have impurities data, we can always say that we're not that worried about it because of the low concentration. Is that where we're going? DR. SNYDER: Correct. DR. LIEBLER: And the impurities were really interested in -- there's a study in lauramino, right? DR. SNYDER: Yes, right. DR. BELSITO: Lauramino. DR. SNYDER: Right. DR. BELSITO: Right, typically, given the comment on Panel Book page 14, that it could be up to 5 percent. DR. SNYDER: Yes, right, exactly. DR. ANDERSEN: Yes, I didn't read that sentence as suggesting impurity. I read that sentence as suggesting that's a product formulation. DR. LIEBLER: Oh, okay. DR. BELSITO: Yes, because it says approximately percent solids, and it's 25 of this and 5 percent of that. DR. ANDERSEN: And that's -- DR. LIEBLER: Well, it's under impurities. DR. ANDERSEN: Yes. DR. LIEBLER: So, I'm thinking impurities, might have read that, so. DR. ANDERSEN: Likewise. DR. LIEBLER: Anyway, we need just need a clarification on that. Obviously, that's something that could be addressed. DR. BELSITO: Yes. DR. ANDERSEN: Certainly clarified. I'm just wondering whether tabling it because, in a way, CIR Panel Book Page 13

17 it's disingenuous to say, gee, we want data that we know that the council is in the process of developing. DR. ANSELL: Yes, I mean -- DR. ANDERSEN: Waiting for it, it's just wait for it. DR. ANSELL: Okay. DR. BELSITO: Yes, but if we table it, doesn't that slow down the process, whereas if we go insufficient because we get to the next time, we have a final. DR. ANSELL: But there was -- DR. ANDERSEN: You have to come back, I think, at some point. SPEAKER: Yes. DR. BELSITO: Why? DR. ANDERSEN: Because you've not issued it yet as to table it. DR. BELSITO: But if we issue it as an insufficient -- DR. ANDERSEN: Oh, I see what you're saying. DR. BELSITO: Yeah. DR. ANDERSEN: Had it been sufficient -- DR. BELSITO: Right. DR. ANDERSEN: Get the data, you can go -- DR. BELSITO: Go file. DR. ANDERSEN: Ah. DR. BELSITO: Don't get the data, we don't file. Whereas if we table it, then we don't get the data, we're insufficient, and we're then going out to -- DR. ANDERSEN: Yes. DR. ANSELL: Yes, but there was never any expectation that you could have the data for this meeting. So, the question is: Why is it here at all? DR. BELSITO: I don't know. DR. ANSELL: That's the -- DR. BELSITO: Well, I mean, if we're going to get the data, Jay, in three months, then what are CIR Panel Book Page 14

18 you worried about if we go insufficient? DR. ANSELL: Why not start everything at green then? It's just procedural. There's a certain amount of time it takes us to turn these around. This came up in June. We went out immediately for July. It shows up in September, and there never could have been any expectation that that data would have been here. I guess I throw this back to staff as to -- DR. ANDERSEN: Somehow, it doesn't seem fair that there's a penalty linked to the speed. It's what's concerning me at this point. And it seems like declaring it insufficient is saying something negative, when Jay's right, there's no way that that there's no way that those data -- no way, but -- DR. ANSELL: Right. DR. ANDERSEN: In what we know of the responsiveness that Carol surveys, chances are, we weren't going to have those data. It's not a big setup. DR. LIEBLER: Well, I would table it. DR. BELSITO: I mean, I think that's fine. All I'm saying is then why did it get on the docket when we're already overwhelmed with material, number one. Number two, we've been told that the PCPC is pushing us to do more and more -- DR. ANDERSEN: That's the other point. DR. BELSITO: And I would like to go on the record as saying this was -- DR. ANDERSEN: Too much. DR. BELSITO: -- too much. DR. SNYDER: Yes, I second that. DR. ANDERSEN: Well, I thought it might have been, but -- DR. BELSITO: So, we're going to table this, and there's no discussion on the table, so, the reason, we don't even have to say why we're tabling it, really. SPEAKER: Yes. DR. BELSITO: Table it to give more time to get the data we need. CIR Panel Book Page 15

19 Full Panel Meeting September 27, 2011 DR. BERGFELD: We're going to move on to the last item that falls under reports advancing to the next level with Dr. Marks presenting on sodium lauriminodipropionate. DR. MARKS: This is the eye compounds, salts and acids, and as you'll recall, in 1997 we had an insufficient conclusion. Then at the June meeting we reopened this safety assessment and particularly looked at the amino, the dipropionate and added the acids and salts. We felt that it's safe. We split out the amino, the A compound, because it's a different chemical, and we were prepared to move that we issue a tentative amended safety report with a safe conclusion, but then we don't have the concentration of uses table so the question is do we issue a tentative amended without that? Could there be a concentration or use that might affect our conclusion? So we ended up with tabling to get that last piece of data. I guess it's how confident do we feel that we could move forward without it. DR. BERGFELD: Before a motion to table, can I gave a Belsito response? DR. BELSITO: We went through the same iterations and whether to go with insufficient for concentration of use in dermal leave-ons since it's a pink and we fully expect that Carol would be able to get it for us and then we would be able to go with a final in December and boost our numbers or table it in which case we wouldn't be able to get a final because we'd have to go out again. We also wanted some information on the impurities on the dipropionate. Is that correct or not? DR. BERGFELD: Dan? Paul? Curt? Yes? No? DR. SNYDER: That was the 1997 report and part of the insufficient data announcement was based on impurities. DR. BELSITO: For the amino. Someone asked for impurities on laurimino. DR. LIEBLER: Laurimino, the impurity being the lauramino. DR. BELSITO: Actually because it said that one of the manufacturers had lauramino in their trade-name product. Do you remember this discussion? DR. SNYDER: We have a memo from John Bailey that says that it does not contain sodium lauriminodipropionate. DR. BELSITO: That's right. On page 14 of the Panel Book under impurities under sodium CIR Panel Book Page 16

20 laurimino, it says the commercial product that is approximately 30-percent solids contains about 25 percent sodium laurimino and 5 percent amino, we're being told that would not be considered in this report so that should be deleted from the report. We were toying with either tabling for concentration of use data. I felt why not go insufficient and move it head, we'll get it and we'll be done with it, but I could go either way. DR. MARKS: Procedurally, Alan, can you go from an insufficient with a final without putting a tentative out? DR. BERGFELD: A tentative final. DR. ANDERSEN: If this is issued as a tentative safety assessment with an insufficient data finding and the only insufficiency is the concentrations of use, when you get those concentrations of use and arguably you'll have them in December, you can issue it as a final. Yes, it is more expeditious if we're looking to knock it out this year to issue it as insufficient data without prejudice because it's not like the council really had time to get those data in. They just didn't. DR. ANSELL: Yes, we have to express our concern. There was never any expectation that these data could be available for this report. The idea that the report got advanced absent the data which we knew would not be available seems to me to be somewhat inconsistent with procedures and fair process. Otherwise we might as well just go tentative final on everything and that will accelerate things enormously. DR. BERGFELD: A little sarcastic there. DR. MARKS: Jay, you would feel that it would be better to table it? DR. ANSELL: We would suggest that reports in this state do not come onto the agenda at all, that the panel should not have seen this at this time and it puts us in a very awkward position to have advanced reports without any expectation that the data could have been complete. DR. BERGFELD: What is your suggestion? I'm not quite sure where your suggestion is going. DR. ANSELL: We suggest tabling it. DR. BERGFELD: Thank you. DR. BELSITO: I appreciate where you're coming from and I fully agree particularly at a meeting like this where we were inundated with information. However, in a way you should be thrilled that the only thing we're asking for is something that you should simply be able to provide us and that is concentration of use data. I CIR Panel Book Page 17

21 would assume that since the next meeting is 2-1/2 months away that you could get it in that timeframe. about 4 months. DR. EISENMANN: These ingredients went out in the July survey, yes, but normally it takes DR. BELSITO: I understand. My only question is I don't want to embarrass you because I fully agree and understand Jay's point. However, if you think that you can reasonably get the one little piece of information we're asking for by the December meeting -- in the future we understand that it should have never come to the table, but it did, and the only data we need are concentration of use. It went out in July and it usually takes 4 months and that's November. We don't meet until December. Why don't we go insufficient, hopefully we'll have it in December and we'll be done with the whole thing? DR. BERGFELD: Alan? DR. ANDERSEN: On the matter of principle I can assure you that we've gotten the message. The practical matter here might be to take advantage of the error. DR. SNYDER: This is just a one-of circumstance, that it in no way sets a precedent that we'll proceed this way. DR. BERGFELD: Jay? DR. ANSELL: We of course serve at your pleasure. DR. BERGFELD: Thank you. DR. MARKS: I withdraw my motion to table it and, Don, I concur with your motion to move on as insufficient and in the minutes make it clear that this is not precedent setting as Dr. Snyder has suggested. DR. BERGFELD: But done for efficiency. Do you want to second that? DR. BELSITO: Second. DR. BERGFELD: Is there any further discussion? Seeing none, I call for the vote. Those in favor please raise your hands. Thank you. Unanimous. CIR Panel Book Page 18

22 Report

23 Draft Final Amended Safety Assessment Lauriminodipropionic Acid, Sodium Lauriminodipropionate, and Disodium Lauriminodipropionate as Used in Cosmetics December 13, 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 Christina Burnett, Scientific Analyst/Writer. Cosmetic Ingredient Review th Street, NW, Suite 412 " Washington, DC " ph " fax " cirinfo@cir-safety.org CIR Panel Book Page 19

24 TABLE OF CONTENTS Table of Contents... i Introduction... 2 Chemistry... 2 Definition and Structure... 2 Physical and Chemical Properties... 2 Method of Manufacture... 2 Impurities... 2 Use... 2 Cosmetic... 2 Non-Cosmetic... 3 Toxicokinetics... 3 Absorption, Distribution, Metabolism, and Excretion... 3 Toxicological Studies... 3 Acute Toxicity... 3 Dermal Non-Human... 3 Oral Non-Human... 3 Repeated Dose Toxicity... 4 Percutaneous Non-Human... 4 Reproductive and Developmental Toxicity... 4 Genotoxicity... 5 In Vitro... 5 Carcinogenicity... 5 Irritation and sensitization... 5 Irritation... 5 Dermal Non-Human... 5 Ocular Non-Human... 5 Ocular Human... 5 Sensitization... 6 Dermal Non-Human... 6 Dermal Human... 6 Summary... 6 Discussion... 7 Conclusion... 7 Tables and Figures... 7 References i CIR Panel Book Page 20

25 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 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 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 readacross. 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. 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 2 CIR Panel Book Page 21

26 formulations at the time of the first safety assessment. 1 An industry survey reported use concentration range of 1-10%. 1 Currently, VCRP data indicate that sodium lauriminodipropionate is used in 10 cosmetic formulations, half of which are in hair conditioners. 6 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. 7 Currently, the VCRP data indicate that disodium lauriminodipropionate is used in 2 cosmetic formulations, both of which are face and neck preparations. 6 No uses are reported for lauriminodipropionic acid. 6 No use concentrations were reported for the acid or the disodium salt in a survey of current use concentration conducted by the Personal Care Products Council. 7 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). 8 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. However, while this reaction is conceivable, it is rare for carboxylic acids to be glucuronidated. 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 ) 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. 8 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 LD 50 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 3 CIR Panel Book Page 22

27 Repeated Dose Toxicity Dermal Non-Human SODIUM LAURIMINODIPROPIONATE The percutaneous toxicity potential of sodium lauriminodipropionate was evaluated in a 91 day study in New Zealand White rabbits. 12 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. 12 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. 13 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). 8 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 as 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. 8,14 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 products 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. 8 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. 15 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. 16 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 that were exposed to the formulation on days 1, 4, 7, 10, 13, 16, and 19 of gestation CIR Panel Book Page 23

28 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 TA The assay was performed with and without S9 metabolic activation. The concentration ranges tested were μl/plate with S9 and 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 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. 18 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 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. 19 The study consisted 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 water. 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. 5 CIR Panel Book Page 24

29 Sensitization 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 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. 20 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 cm 2 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 nontreatment 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. 21 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 reported to function 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. No use concentrations were reported for the disodium salt or the acid. 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 determined that sodium lauriminodipropionate is likely to be metabolized by glucuronidation and/or N-dealkylation. 6 CIR Panel Book Page 25

30 In studies of 10% active solutions of sodium lauriminodipropionate, the oral LD 50 for rats was 31.3 g/kg, and the dermal LD 50 was greater than 10.2 g/kg; the oral LD 50 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 or systemic 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 to sodium lauriminodipropionate 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 A safety assessment for sodium lauriminodipropionate and sodium lauraminopropionate was published by CIR in 1997 with the conclusion that the available data were insufficient to support their safety in cosmetics. The Expert Panel reopened the final report on sodium lauriminodipropionate based on new data and determined that the report should also address the safety of lauriminopropionic acid and disodium lauriminodipropionate. The Panel did not reopen the final report to include the aminopropionate moiety and reaffirmed the conclusion of insufficient data for sodium lauraminopropionate. The CIR Expert Panel considered that the available acute and repeated dose animal studies and the reproductive and developmental studies were supportive of the safety of sodium lauriminodipropionate. The Expert Panel noted the absence of carcinogenicity, but also noted that sodium lauriminodipropionate was not mutagenic or clastogenic in in vitro genotoxicity studies and determined that sodium lauriminodipropionate was not likely to be a carcinogen. The Expert Panel noted gaps in the available safety data for lauriminodipropionic acid and its disodium salt. The available data on the monosodium salt are sufficient, however, and similarity between structural activity relationships and cosmetic function in cosmetic concentrations of use can be extrapolated to support the safety of the entire group. CONCLUSION The CIR Expert Panel concluded that lauriminodipropionic acid, sodium lauriminodipropionate, and disodium lauriminodipropionate are safe as cosmetic ingredients in the present practices of use and concentration. Were the acid and the disodium salt to be used in the future, the expectation is that they would be used at concentrations similar to the monosodium salt. 7 CIR Panel Book Page 26

31 TABLES AND FIGURES Table 1. Names, CAS registry numbers, definitions, and structures of dipropanoic acid ingredients. Ingredient CAS No. Definition Formula/structure Lauriminodipropionic acid Lauriminodipropionic acid (dodecylazanediyldipropanoic acid) is the tertiary amine substituted with dodecane and two equivalents of 3-propionic acid. O HO N CH 3 HO O Sodium lauriminodipropionate and Sodium lauriminodipropionate is the partial sodium salt of dodecylazanediyldipropanoic acid. O HO N CH 3 Disodium lauriminodipropionate Na O O O Disodium lauriminodipropionate is the disodium salt of dodecylazanediyldipropanoic acid. Na O N CH 3 Na O O Table 2. Chemical properties. Lauriminodipropionic Acid Property Value Reference Molecular Weight g/mol Molecular Volume cm 3 25 o C 760 mmhg Vapor pressure mmhg@ 25 o C 1.35 x 10 Boiling Point o 760 mmhg o C Sodium Lauriminodipropionate Physical Form Color Odor Thin, clear liquid Yellow to light amber Mild fruity, faint metallic Density/Specific 25 o C 1.03 Boiling Point o C 100 Soluble in water, Solubility partially soluble in ethanol CIR Panel Book Page 27

32 Scheme 1. Purported Metabolic Pathways of Lauriminodipropionic Acid, Sodium Lauriminodipropionate, and Disodium Lauriminodipropionate. 8 O Lauriminodipropionicacid (3,3'-(dodecylazanediyl)dipropanoic acid) HO N CH 3 C-hydroxylation HO O 3,3'-(12-hydroxydodecylazanediyl)dipropanoicacid N O OH OH HO O Glucuronidation HO HO N CH 3 O 3,3'-(11-hydroxydodecylazanediyl)dipropanoicacid Oxidative N-Dealkylation O O HO O O HO O O N CH 3 HO NH HO OH 3,3'-azanediyldipropanoic acid O O OH HO O (2S,3S,4S,5R,6S)-6-(3-((2-carboxyethyl)(dodecyl)amino)propanoyloxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid HOmalonic acid OH HO O O HO lauricacid(dodecanoicacid) CH 3 O HO N CH 3 H 3-(dodecylamino)propanoic acid H 2 N CH laurylamine (dodecan-1-amine) 3 9 CIR Panel Book Page 28

33 Table 3. Historic and current uses and concentrations of sodium lauriminodipropionate. 1,6,7 # of Uses Conc. of Use (%) Sodium Lauriminodipropionate Exposure Type Eye Area NR NR NR NR Incidental Ingestion NR NR NR NR Incidental Inhalation- Sprays NR NR NR NR Incidental Inhalation- Powders NR NR NR NR Dermal Contact NR Deodorant (underarm) NR NR NR NR Hair - Non-Coloring 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 Diluted for (Bath)Use NR NR NR NR Totals 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. 10 CIR Panel Book Page 29

34 REFERENCES 1. Andersen FA (ed.). Final report on the safety assessment of Sodium Lauraminopropionate and Sodium Lauriminodipropionate. IJT. 1997;16(S1): Tokiwa F and Ohki K. Potentiometric titration of amphoteric surfactants in micellar solutions. J Phys Chem. 1967;71(6): 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;12: Ranbom KC Sodium Lauriminodipropionate. Method of Manufacture. Unpublished data submitted by the Personal Care Products Council on July 6, Gottschalck TE and Bailey JE eds. International Cosmetic Ingredient Dictionary and Handbook. 13th ed. Washington, D.C.: Personal Care Products Council; Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients. FDA Database Washington, DC: FDA. 7. Personal Care Products Council Concentration of Use by FDA Product Category: Lauriminodipropionic Acid, Sodium Lauriminodipropionate and Disodium Lauriminodipropionate. Unpublished data submitted by the Personal Care Products Council. 2 pages. 8. Cosmetic Ingredient Review Science and Support Committee Developmental and reproductive toxicity assessment for Sodium Lauriminodipropionate. Unpublished data submitted by the Personal Care Products Council on April 26, Andersen FA (ed.). Annual Review of Cosmetic Ingredient Safety Asssessments /2005. IJT. 2006;25(Suppl. 2): 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 Elder RL. Final Report on the Safety Assessment of Oleic Acid, Lauric Acid, Palmitic Acid, Myristic Acid, and Stearic Acid. JACT. 1987;6(3): International Research and Development Corporation Day/91-Day Subchronic Percutaneous Toxicity (MV # ). Study number P 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): Human & Environmental Risk Assessment on Ingredients of European Household Cleaning Products. Fatty Acid Salts Human Health Risk Assessment - Draft for Public Comment. HERA%20Fatty%20acid%20salts%20HH%20web%20wd.pdf. Date Accessed 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 CIR Panel Book Page 30

35 16. 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;12: Microbiological Associates, Inc Salmonella/mammalian microsome mutagenesis assay (Ames test). Final Report. Test Article (TSIN) MV # MBA study no. T Unpublished data submitted by the Personal Care Products Council on April 26, Microbiological Associates, Inc Cytogenicity study - Chinese hamster ovary (CHO) cells in vitro. Final Report. Test Article MV# MBA study no. T Unpublished data submitted by the Personal Care Products Council on April 26, Institut Aster Comparative ocular tolerance study of shampoo products RE , RE , RE , RE , RE , and RE after single topical instillation in normal healthy volunteers. Institut Aster Study No. R U.E.DH Unpublished data submitted by the Personal Care Products Council on April 26, TKL Research, Inc Repeated insult patch test. TKL study no Unpublished data submitted by the Personal Care Products Council on April 26, North Cliff Consultants Human sensitization test. North Cliff Study # Unpublished data submitted by the Personal Care Products Council on April 26, Advanced Chemistry Development (ACD/Labs). Advanced Chemistry Development software v ((C) ACD/Labs). 12 CIR Panel Book Page 31

36 Data

37 Personal Care Products Council Committed to Safety, Quality & Innovation Memorandum TO: FROM: DATE: SUBJECT: F. Alan Andersen, Ph.D. Director - COSMETIC INGREDIENT REVIEW (Cll) Halyna Breslawec, Ph.D. Industry Liaison to the CW Expert Panel October 25, 2011 Concentration of Use by FDA Product Category: Lauriminodipropionic Acid, Sodium Laurimindipropionate and Disodium Launminodipropionate th Street, N.W., Suite 30O Washington, D.C (fax) CIR Panel Book Page 32

38 Concentration of Use by FDA Product Category* Lauriminodipropionic Acid Sodium Laurimindipropionate Disodium Lauriminodipropionate Ingredient Product Category Maximum Concentrations of Use Sodium Lauriminodipropionate Hair conditioners 0.05% *Ingredients included in the title of the table, but not found in the table were included in the concentration of use survey, but no uses were reported. Information collected in 2011 Table prepared October 25, 2011 CIR Panel Book Page 33

39 Is In As Ranborn COSMETIC Distributed for Comment Only -- Do Not Cite or Quote Personal Care Memorandum iproducts Council Committed to Safety, Quality & Innovation TO: FROM: F. Alan Andersen, Ph.D. Director - INGREDIENT REVIEW (CIR) Halyna Breslawec, Ph.D. Industry Liaison to the CIR Expert Panel DATE: September 23, 2011 SUBJECT: Comments on the Draft Report on Lauriminodipropionic Acid and its Sodium Salts Prepared for the September 26-27, 2011 CIR Expert Panel Meeting As page numbers are not all pages of this report, Panel book page numbers are provided below. p.15 - there a difference between dermal and percutanous exposure? The heading under Acute Exposure uses Dermal, while the heading under Repeated Dose Exposure uses Percutaneous. p.16 - the second paragraph in the Reproductive and Developmental Toxicity section, please revise: found these ingredients to be safe for use in cosmetic ingredients. The second ingredients should be changed to products (or cosmetic should be changed to cosmetics ). p.16 - In the description of the hair dye (contained 1.5% Disodium Lauriminodipropionate) study, please include the time during gestation the rats were exposed. p.19, Table 1 - this is a review of cosmetic ingredients, the definitions in the International Cosmetic Ingredient Dictionary and Handbook should also be given in Table 1. For ingredients defined by their structure, it would be appropriate to add a footnote to indicate which ingredients are defined only by their structure in the Dictionary. p.22, reference 4 - should be Ranbom th Street, N.W., Suite 300 Washington, D.C (fax) CIR Panel Book Page 34

40 As Please It As As Ranborn COSMETIC Distributed for Comment Only -- Do Not Cite or Quote Personal Care Memorandum Products Council Committed to Safety, Quality & Innovation TO: FROM: DATE: SUBJECT: F. Alan Andersen, Ph.D. Director - INGREDIENT REVIEW (CIR) Halyna Breslawec, Ph.D. Industry Liaison to the CW Expert Panel November 1, 2011 Comments on the Tentative Report on Lauriminodipropionic Acid and its Sodium Salts As Used in Cosmetics As the report now includes Lauriminodipropionic Acid and well as its mono and disodium salts, please consider changing the title to include all three ingredients. p.4, 7 - the 91 day dermal study looked at systemic toxicity endpoints in addition to dennal effects, please state that the study showed that the test material did not cause systemic toxicity. p.6 - there is no other route of exposure under the Sensitization heading, is it really necessary to include Dermal in the subheadings? The summary from the Clinical section from the old report is not appropriate under the Sensitization heading as it includes more than one endpoint, e.g., dermal and eye irritation and systemic toxicity. p.6, Summary - there are few uses of these ingredients, it would be better to state that the reported functions are... rather than these ingredients are used as... p.7 - include the material with which guinea pigs were treated in the sensitization studies. p.7 - is not clear what is meant by biologic function. It suggests that these ingredients have a normal function in the body p.22, reference 4 - should be Ranbom th Street, N.W., Suite 3OO Washington, D.C (fox) CIR Panel Book Page 35