PINK BOOK 3 Sebacic Acid/Dicarboxylic Acids...July 10, 2009: SLR was issued September 2009 Panel...

PINK BOOK 3

Sebacic Acid/Dicarboxylic Acids

CIR EXPERT PANEL MEETING

AUGUST 30-31, 2010

Memorandum

To: CIR Expert Panel Members and Liaisons From: Monice M. Fiume MMF Senior Scientific Analyst/Writer Bart A. Heldreth, Ph.D. BAH Chemist Date: July 30, 2010 Subject: Draft Report on Dicarboxylic Acids (previously called Diisopropyl Sebacate) The draft report on dicarboxylic acids was last reviewed in December 2009, under the title Diisopropyl Sebacate. At that time, the report was tabled for reorganization. Also at that time, it was determined that oxalic acid would not be part of the safety assessment. The entire report has been reorganized and rewritten. It will be obvious that the Chemistry section is now prepared in a way that allows you to view the dicarboxylic acids in order of increasing chain length. Also included are charts demonstrating the relationship between molecular weight and the log octanol – water partitioning coefficient. Additionally, the report, from the General Biology section on, is now divided into two sections, as was suggested by the Panel in December. The first section addresses dicarboxylic acids and their salts, while the second part addresses esters of dicarboxylic acids. These two subsets of ingredients have different functions in cosmetics, and this will allow the Panel to view the data on each subset separately. In addition to the reorganization, the report has change greatly in the extent of data included. A complete new search of the literature has been performed, and a substantial amount of new data has been added. A great deal of the information included in this report has come from summary documents, such as HPV robust summaries, that cite unpublished sources. Whatever details were available have been included, but often the summaries were brief. Additional unpublished data received from Council, including concentration of use data, have been added. Also included are summaries of information from the 1984 Final Assessment of Dioctyl Adipate and Diisopropyl Adipate and from the 2006 Amended Final Report on the Safety Assessment of Dibutyl Adipate as Used in Cosmetics. (Dioctyl adipate is now correctly named diethylhexyl adipate.) These reports have been included for your use. The diesters have been shown to metabolize. Accordingly, data on esterase metabolites have been included as support information. For your ease in use of this data, an Appendix to the report, that

CIR Panel Book Page 1

summarizes these data, immediately follows the reference section. When applicable, these data are also included in the appropriate tables. There are many aspects for discussion in this report, and we have tried to present it to you as cohesively as possible. The following are included as paper copy:

1. Final report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate; 2. Amended Final Report on the Safety Assessment of Dibutyl Adipate as Used in Cosmetics; 3. Updated concentration of use data – dated February 25, 2010; 4. Unpublished data on Diethylhexyl Succinate, Diisobutyl Adipate, Diisocetyl Adipate,

Diisodecyl Adipate, Dioctyldodecyl Adipate, Diethylhexyl Sebacate and Diisopropyl Sebacate; submitted January 27, 2010. (One in French has not yet been translated, so is not included in text.);

5. Unpublished data on Diisostearyl Adipate, Diisocetyl Dodecanedioate, and Dioctyldodecyl Dodecanedioate; submitted January 15, 2010; and

6. Unpublished data - Physical/Chemical Properties on Dibutyl Octyl Sebacate, Dihexyldecyl Sebacate, and Dioctyldodecyl Sebacate; dated February 15, 2010


REPORT HISTORY: DICARBOXYLIC ACID AND THEIR SALTS AND ESTERS July 10, 2009: SLR was issued September 2009 Panel meeting Initial review of the draft report. The recommendation was made to add 5 additional dicarboxylic acids – oxalic, malonic, succinic, glutaric, and adipic – and their salts and esters December 2009 Panel meeting The report was tabled for reorganization into (1) acids and salts and (2) esters. It was also agreed that oxalic acid should be removed. It was also felt that more data should be available. August 2010 Panel meeting The report has been completely reorganized. A new search was done and the text was updated with much new data.


Sebacates Search Update June 2010 Toxline NTP HPV EU/SCCP EPA IARC OTC SIDS

Sebacic Acid 0 0 NR/NS 0 0 Dibutyl Sebacate 0 0 NR/NS 0 0 Dibutyloctyl Sebacate 0 0 NR/NS 0 0 Dicapryl/Capryl Sebacate 0 0 NR/NS 0 0 Diethyl Sebacate 0 x NR/NS 0 0 Diethylhexyl Sebacate G 0 NR/NS 0 0 Dihexyldecyl Sebacate 0 0 NR/NS 0 0 Diisooctyl Sebacate 0 0 NR/NS 0 0 Diisopropyl Sebacate 0 0 NR/NS 0 0 Diisostearyl Sebacate 0 0 NR/NS 0 0 Dioctyldodecyl Sebacate 0 0 NR/NS 0 0 Disodium Sebacate 0 0 NR/NS 0 0 Isostearyl Sebacate 0 0 NR/NS 0 0 Malonic Acid G 0 NR/NS 0 0 Diethyl Malonate 0 0 NR/NS 0 0 Succinic Acid 0 x NR/NS 0 0 Sodium Succinate 0 0 NR/NS 0 0 Disodium Succinate 0 0 NR/NS 0 0 x Dimethyl Succinate G x NR/NS 0 0 Diethyl Succinate 0 0 NR/NS 0 0 Diethylhexyl Succinate 0 0 NR/NS 0 0 Decyl Succinate 0 0 NR/NS 0 0 Dicapryl Succinate 0 0 NR/NS 0 0 Dicetearyl Succinate 0 0 NR/NS 0 0 Diisobutyl Succinate 0 0 NR/NS 0 0 Glutaric Acid G x NR/NS 0 0 Dimethyl Glutarate G x NR/NS 0 0 Diisostearyl Glutarate 0 0 NR/NS 0 0 Diisobutyl Glutarate 0 0 NR/NS 0 0 Adipic Acid G x NR/NS 0 0 x Dimethyl Adipate G x NR/NS 0 0 Diethyl Adipate 0 0 NR/NS 0 0 Diethylhexyl Adipate C,G x NR/NS x 2 0 x Dipropyl Adipate 0 0 NR/NS 0 0 Dibutyl Adipate 0 x NR/NS 0 0 x Di-C12-15 Alkyl Adipate 0 0 NR/NS 0 0 Dicapryl Adipate 0 0 NR/NS 0 0 Dicetyl Adipate 0 0 NR/NS 0 0 Diheptylundecyl Adipate 0 0 NR/NS 0 0 Dihexyl Adipate 0 0 NR/NS 0 0 Dihexyldecyl Adipate 0 0 NR/NS 0 0 Diisobutyl Adipate 0 0 NR/NS 0 0 Diisocetyl Adipate 0 0 NR/NS 0 0 Diisodecyl Adipate 0 x NR/NS x 0 0 Diisononyl Adipate 0 x NR/NS x 0 0 Diisooctyl Adipate 0 x NR/NS x 0 0 Diisopropyl Adipate 0 0 NR/NS 0 0 Diisostearyl Adipate 0 0 NR/NS 0 0 Dioctyldodecyl Adipate 0 0 NR/NS 0 0 Ditridecyl Adipate 0 x NR/NS x 0 0 Azelaic Acid 0 0 NR/NS 0 0 Dipotassium Azelate 0 0 NR/NS 0 0 Disodium Azelate 0 0 NR/NS 0 0 Dodecanedioic Acid 0 x NR/NS 0 0 x Diisocetyl Dodecanedioate 0 0 NR/NS 0 0 Dioctyldodecyl Dodecanedioate 0 0 NR/NS 0 0 Totals 2744


Toxline - searched 6-10-10; included Medline NTP - searched 6-20-10; G - genotoxicity, C - carcinogenicity HPV - searched 6-20&21-10; x - listed in HPV database EU - searched 6-20-10; NR - no restrictions; NS - no SCCP opinion IARC - searched 6-21-10 OTC - searched 6-22-10 (April 7, 2010 update) EPA - searched 7-8-10 found updated Robust Summaries for HPV items

TOXNET Search Strategy: Sebacic 06-11-10 306 hits 111-20-6 OR 184706-97-6 OR 109-43-3 OR 110-40-7 OR 122-62-3 OR 359073-59-9 OR 10340-41-7 OR 7491-02-3 OR 69275-01-0 OR 17265-14-4 OR 478273-24-4 OR (DICAPRYL AND CAPRYL AND SEBACATE) OR (DIISOSTEARYL AND SEBACATE) Malonic-Succinic-Glutaric 06-10-10 2511 hits 141-82-2 OR 105-53-3 OR 110-15-6 OR 2922-54-5 OR 150-90-3 OR 106-65-0 OR 123-25-1 OR 2915-57-3 OR 2530-33-8 OR 14491-66-8 OR 93280-98-9 OR 925-06-4 OR 110-94-1 OR 1119-40-0 OR 71195-64-7 OR (DIISOSTEARYL AND GLUTARATE) Adipic 06-10-10 1167 hits 124-04-9 OR 627-93-0 OR 141-28-6 OR 103-23-1 OR 106-19-4 OR 105-99-7 OR 105-97-5 OR 26720-21-8 OR 155613-91-5 OR 110-33-8 OR 141-04-8 OR 57533-90-1 OR 58262-41-2 OR 59686-69-0 OR 27178-16-1 OR 33703-08-1 OR 108-63-4 OR 6938-94-9 OR 62479-36-1 OR 155613-91-5 OR 85117-94-8 OR 16958-92-2 OR (ALKYL AND ADIPATE) OR (DIHEXYLDECYL AND ADIPATE) Azelaic-Dodecanedioic 06-10-10 208 hits 123-99-9 OR 9619-43-3 OR 52457-54-2 OR 17265-13-3 OR 27825-99-6 OR 132499-85-5 OR 693-23-2 OR 131252-83-0 OR 129423-55-8 Combined files minus existing references – 2744 June 21, 2010 – 47 published papers ordered July 8, 2010 - 20 additional papers ordered July 15, 2010 – 10 additional papers ordered *Metabolite alcohols and monoesters were searched for supplemental information in TOXLINE and RTECS, via STN. CAS Registry files were used to search in each of the databases. 55 published papers were ordered. Numerous other references on metabolite alcohols were available from prior safety assessments.


Transcripts/ Minutes

CIR Meeting day 2 Page: 40

Anderson Court Reporting -- 703-519-7180 -- www.andersonreporting.net

1 isononanoates and all that -- those parts. And,

2 hopefully, we can have our -- you know, at the

3 next meeting, have a good discussion on whether

4 these are long shots or not, in other words, if

5 they're lipophilic, probably really concerned and

6 so forth, because I'd hate to pull --

7 unnecessarily pull ingredients off the list when

8 there's a good reason to believe that it's not a

9 problem.

10 DR. BERGFELD: Well, thank you for that

11 clarification of who does what.

12 All right. Well, then we move on.

13 We're moving on to the second ingredient under the

14 reports advancing and that's sebacates by Dr.

15 Marks.

16 DR. MARKS: So, this is the second time

17 we've looked at the sebacates. In the September

18 2009 meeting we decided to table these ingredients

19 so that we could expand the number and I have a

20 feeling we're going to have a discussion again

21 procedurally how to go. Our team felt that we

22 should continue to table these ingredients with

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PANEL - DEC 2009 CIR Meeting day 2 Page: 41


1 the aim of splitting the acids and salts into one

2 group -- they are used as pH adjusters -- and then

3 the esters into another group, rather than having

4 them all mixed in as is in the present document.

5 That could either be, as we discussed,

6 whether this should be two separate documents or

7 one document and just have the document organized

8 so these ingredients were split, and we felt that

9 we could proceed with one document. And then we

10 also felt that within this list, that we should

11 reopen three of the esters that have already been

12 determined to be safe by the CIR panel, and that's

13 the diethylhexyl adipate, the dibutyl adipate, and

14 the diisopropyl adipate. So, we felt some more

15 work needed to be done on the document and,

16 therefore, recommend to table it.

17 DR. BERGFELD: Is there a second to

18 table?

19 SPEAKER: Second.

20 DR. BERGFELD: Second. There's no

21 discussion on the table. Motion, all those in

22 favor of tabling, please indicate by raising your




1 hand?

2 DR. BELSITO: Any discussion?

3 DR. BERGFELD: No discussion on the

4 table. It's four against four? So, the chair has

5 to vote. I'll vote to table. So, this particular

6 ingredient has been tabled and let's go over why

7 it's being tabled again.

8 DR. MARKS: Well, the first is that we

9 felt the document could be reorganized and that

10 really by uses, so the acids and the salts are

11 used as pH adjusters and then the esters had other

12 uses. And so the document would be split to

13 discuss those two groups together, and that we, as

14 part of this document, reopened three esters which

15 had previously been determined by the CIR as all

16 are safe to be included in this new amended.

17 DR. BERGFELD: May I ask, Alan, is this

18 really editorial or is this truly -- does it truly

19 have a need for being tabled?

20 DR. ANDERSON: Yes, I would have said

21 that was an editorial change. It's just a matter

22 of reorganizing the document, whether it is split




1 into two or split into two pieces in one document.

2 We have lots of experience with both approaches.

3 It's simply a question of approach. It doesn't

4 address the question of any real additional data

5 needs. So, I'm not sure there's a benefit to

6 tabling from that standpoint.

7 DR. BERGFELD: How about the addition of

8 the other previously approved ingredients?

9 DR. ANDERSON: I think --

10 DR. BERGFELD: Does that fit with the

11 first comment?

12 DR. ANDERSON: There is -- there are

13 data that are available in the other safety

14 assessments that previously the panel has

15 completed. To the extent that you want those data

16 incorporated, tabling it to do that step is, I

17 think, a valid thing to do because clearly they're

18 not in there now.

19 DR. BERGFELD: Don? Comment?

20 DR. BELSITO: Well, I mean, we obviously

21 didn't vote to table, but some comments. First,

22 yes, I mean, I think the other three should be



mmfTypewritten TextFULL PANEL - DEC 2009



1 included. Jim, I think you said dibutyl, you mean

2 dioctyl.

3 DR. MARKS: Okay. Thank you, Don.

4 DR. BELSITO: The biggest discussion we

5 had revolving around this was oxalic acid, which

6 did not -- I mean, all of the safety data on that

7 specific acid, particularly in terms of causing

8 renal calculi, was not in this document. And we

9 actually thought since we didn't see it listed as

10 having any cosmetic uses, that unless there were

11 cosmetic uses for oxalic acid or its esters that

12 it be dropped from this family because of those

13 issues with renal toxicity.

14 DR. BERGFELD: So, your recommendation

15 under the conditions that we were tabling this is

16 to reconsider the inclusion of oxalic acid?

17 DR. BELSITO: Well, to first of all

18 confirm whether, in fact, it's used -- currently

19 being used, and, if not, then our recommendation

20 would be to remove it from this family because of

21 those issues that were being countered and because

22 of the huge amount of data that we'd have to




1 review and grapple with.

2 DR. LIEBLER: If I could just elaborate

3 on that.

4 DR. BERGFELD: Don?

5 DR. LIEBLER: Yeah, I think the idea of

6 including the smaller diacids and their esters and

7 salts was mainly to expand the chemical space to

8 things that are possibly relevant. But in getting

9 down to oxalic acid, you run into some unique

10 toxicology that's very well documented, very

11 prominent, and quite problematic, and we don't

12 even know if this is used as a cosmetic

13 ingredient. So, rather than get tangled up in all

14 of that, it's worth considering deleting the

15 oxalic acid from this report.

16 DR. BERGFELD: John Bailey?

17 MR. BAILEY: Yeah, I think we didn't

18 have time in getting these additional ingredients

19 to survey -- do our usual survey of use and use

20 levels, so we can't answer definitively whether

21 that's the situation or not, so I think we need

22 some more information. I would point out that in




1 Europe, oxalic acid is on annex 3 for hair dyes,

2 so presumably, you know, that may be a use. And

3 we haven't done the research necessary to get more

4 information about how it got there and use levels

5 and so forth. So, I would say, certainly oxalic

6 acid is in the textbooks. We all know about it,

7 but there may be some additional information that

8 would be relevant that we simply, you know, didn't

9 have time to get.

10 DR. BERGFELD: So, that's a promise to

11 get?

12 MR. BAILEY: Certainly, yeah. We'll do

13 our usual survey of --

14 DR. BERGFELD: Okay. Any further

15 discussion? Don?

16 DR. BELSITO: Yeah, I guess, just to

17 follow up on Dan's point, there is such a

18 voluminous amount of literature on oxalic acid

19 that even if it's used in cosmetics, do we want to

20 get bogged down dealing with why that is going to

21 be safe in a cosmetic product and reviewing all of

22 that literature on oxalic acid? Or would it be




1 better simply to keep all the ingredients, which

2 is a large number of ingredients we have right

3 now, get rid of oxalic acid and, in fact, if it's

4 used, we can always look at oxalic acid

5 specifically rather than as a member of this

6 group? Because I just think we're going to get

7 hugely bogged down even if it's used in trying to

8 explain why it'd say brief discontinuous use on

9 the hair, no absorption, yadda, yadda, yadda. But

10 we're going to have to look at all the data

11 anyway.

12 MR. BAILEY: Yeah, I concur.

13 DR. BERGFELD: So, we might entertain a

14 motion at this time to delete oxalic acid from the

15 list.

16 DR. BELSITO: I would like to make that

17 motion.

18 DR. BERGFELD: Is there a second?

19 Second. Is there a discussion of that

20 recommendation?

21 Curt?

22 DR. KLAASSEN: No problem.





1 DR. BERGFELD: Paul? Dan? Ron?

2 That's okay.

3 DR. HILL: I have no problem with that.

4 DR. BERGFELD: Okay, we'll call for the

5 vote to delete oxalic acid from the list of

6 ingredients. All those in favor? Unanimous, with

7 the intent of taking it up as a separate

8 ingredient at some time in the future when it's

9 been declared how it's used and how frequent it's

10 used.

11 MR. BAILEY: To that end, we'll include

12 that in our survey just so we'll have that

13 information.

14 DR. BERGFELD: Thank you. Ron?

15 DR. HILL: Yeah, in our discussions

16 yesterday our starting point was really a

17 suggestion that Ron Shank made to separate into

18 two documents, and then we talked about two sort

19 of separate sections of the main document because

20 in the consideration of the diacids, they're

21 pretty much -- their uses are as pH adjusters and

22 then similar like that. There are a lot of esters




1 here. You'd have to pull out that list, Ron, that

2 you had where we would seem to be depending on

3 read-across data for things like genotoxicity,

4 tumor-promoting potential, and even sensitization.

5 Am I mistaken there? We have direct data on the

6 sebacates, some of the adipates, and a number of

7 the others we don't. Isn't that correct?

8 DR. SHANK: That's correct.

9 DR. HILL: So, we're looking at a pretty

10 high number of read-across, which was another

11 reason, I think, basis, for why we had suggested

12 the tabling idea, so that we had the time to

13 really better assess those gaps.

14 DR. BERGFELD: We need to record your

15 response, Ron.

16 DR. SHANK: I agree with Dr. Hill that

17 we have some information on the esters, but the

18 esters are used quite differently from the acids

19 and salts. And that's why I had suggested that we

20 split them, either two reports or within the same

21 report, make it very clear that the acids and

22 their salts are -- can be handled one way and the




1 esters will have to be handled a different way.

2 DR. ANDERSON: Yeah, I really don't

3 think that that's a problem in terms of overall

4 strategy. It provides the opportunity to be a lot

5 clearer to the reader, that we understand the

6 fundamental difference between how these chemicals

7 are used in cosmetics. So I think we'll simply do

8 that.

9 Now, I am concerned about the suggestion

10 that read-across may be problematic. I would ask

11 the panel to reserve that, to focus on the data,

12 where the data gaps are, and what your comfort

13 level is going to be with the ability to use data

14 on one chain length ester of dicarboxylic acid to

15 inform your decision about another chain length,

16 all other things being equal. So, having all data

17 on all ingredients is not the norm. So, I think

18 there needs to be a comfort level with some degree

19 of read-across as you evaluate these data. Only

20 you folks on the panel can reach that level of

21 comfort, but I would ask you not to veto it a

22 priori.




1 DR. HILL: Well, I'm relatively new,

2 but, you know, I mean, I still have the same

3 issues. There's some of the alcohols that we just

4 talked about in the pelargonate section that show

5 up again here. And if there's no reason to

6 believe that there's any significant generation of

7 those alcohols in the skin, if there's no reason

8 to believe that those alcohols would lead to

9 sensitization in the skin, then there's probably

10 -- and there's no reason to believe that either

11 the alcohols or, in fact, these esters that we

12 have no data on could promote tumor development in

13 skin, then we don't have a problem. But I'd like

14 to know, when I make a final vote, that I'm

15 comfortable whether that is valid scientifically,

16 and that's really the only concern I have is that

17 it's scientifically valid to make that conclusion.

18 DR. ANDERSON: Point well taken.

19 DR. BERGFELD: Thank you. So we're

20 going to be tabling the sebacates and we've had

21 the discussion and we're going to reorganize the

22 document, and we're going to get some more





1 information on some of the ingredients. Is that

2 correct?

3 DR. ANDERSON: Mm-hmm.

4 DR. BERGFELD: All right.

5 DR. ANDERSON: And we're deleting oxalic

6 acid --

7 DR. BERGFELD: And we're deleting oxalic

8 acid, thank you.

9 DR. ANDERSON: Deleting oxalic acid.

10 Nobody has specifically said it, but let me say

11 it, we're also going to delete the oxalic acid

12 esters.

13 DR. BERGFELD: Correct. All right.

14 It's time to move on to the next ingredient, the

15 PEGs. Dr. Belsito.

16 DR. BELSITO: Yes. At our September

17 meeting, we reviewed results from industry

18 essentially done on tape- stripped skin as a

19 method of looking at PEG toxicity on damaged skin

20 because previously we had a conclusion that

21 restricted the use of PEGs on damaged skin. We

22 had a chance to look at what would be absorbed.



Cosmetic Ingredient Review Panel December 8, 2009 Page: 143


1 Sebacate? Sebacate?

2 SPEAKER: You asked that last time.

3 DR. BELSITO: Sebacates. Sebaceous.

4 Okay, so we're going to go to the --

5 SPEAKER: Sebacates.

6 DR. BELSITO: Dicarboxylic Acid Salts

7 and Ester Report. That, I know how to pronounce.

8 Okay. And I guess as part of the

9 add-ins now, we've been provided with a final

10 report that we did on dioctyl and diisopropyl

11 adipate. And we're back in December. We tabled

12 this to look at a whole bunch of related

13 dicarboxylic acids that we agreed to incorporate

14 into this report. And we've gone out and got

15 information on azelaic acid as used in topical

16 drugs. And we've got some new unpublished data

17 that we saw briefly at the September meeting but

18 didn't really have time to digest. And so now

19 we've got this tentative safety assessment and all

20 of the information in it is in here, short of a

21 discussion and a conclusion, so.

22 Then we've heard a little bit from Bob




1 this morning on dermal penetration. We don't have

2 a lot of genotox and carcinogenicity here. But we

3 do for the azelaic acid, which is used as a

4 topical, have some information. So if there is a

5 concern about that, I guess we still have Bob here

6 and he can tell us what he would think about the

7 absorption of these.

8 So with that as an intro, the question

9 is do we have enough here for this group of

10 dicarboxylic acids, which now will contain azelaic

11 acid, malonic, succinic, glutaric, adipic, and

12 sebacic acid and their salts and esters that are

13 listed in the Cosmetic Dictionary to go with a

14 safe as used conclusion?

15 SPEAKER: We have, to date, not received

16 use data.

17 MS. ROBINSON: It's forthcoming. Carol

18 (inaudible) by the next --

19 SPEAKER: Mic, please.

20 MS. ROBINSON: The use information is

21 forthcoming. Carol has said that it may be here

22 by the next meeting.




1 DR. BELSITO: But how can we --

2 SPEAKER: By the next meeting? April?

3 DR. ANDERSON: We don't have it.

4 DR. LIEBLER: Can I get a clarification

5 of that? Were these the data that were from the

6 American Chemistry Council?

7 MR. ANSELL: That data has been

8 included. This is the use concentration on all

9 the add-ons, which came to us in too short a time

10 to turnaround between these.

11 DR. LIEBLER: Okay, so we did -- last

12 time we did talk about the American Chemistry

13 Council data that we thought would be useful. And

14 there was a question of whether or not we joined

15 -- or CIR joined in or somehow got access to that.

16 So I see some of the data in this report. And

17 just, I'm curious, how do we get that?

18 MS. ROBINSON: Well, to date, we haven't

19 received any additional data from the last

20 meeting, from the reports. So what you see in the

21 report is essentially the same that we saw at the

22 last meeting.




1 DR. BELSITO: Okay. And one comment I

2 have is are the impurities sufficient? We have

3 impurities only for dimethyl malonate and

4 diethylmalonate and diethylhexyl adipate. We

5 don't have impurities for the other compounds

6 we're reviewing.

7 So I just, you know, sort of throw that

8 out as an aside, to get the sense of chemists

9 looking at the way these are manufactured as to

10 whether they would be concerned about that.

11 DR. LIEBLER: I'd like to see data that

12 describes the impurities, at least the types of

13 compounds that would be present as impurities and

14 their approximate ranges of concentrations.

15 DR. BELSITO: And then in terms of

16 concentrations of use, I mean, we do have some

17 information here if we go to Table 4, particularly

18 for the sebacic acid groups we have. We have some

19 for the succinate. We have some for adipic acid

20 and its groups, and then we have azelaic acid. So

21 we have some concentrations of use. And we have

22 that standard, you know, asterisk boilerplate that



mmfTypewritten TextBELSITO TEAM - DEC 2009



1 if where we're not giving a concentration of use,

2 we assume it's being used in the same

3 concentration as the other groups.

4 So I'm not sure -- I mean, it would be

5 nice to get updated information, and there are

6 lots and lots of blanks here, I agree. But I

7 think the issue that bothered me the most was the

8 lack of impurities in all these groups that we're

9 adding in.

10 And then, of course, we're relying on

11 azelaic acid and the data from the Finacea and the

12 Azelex cream to support a lot of our systemic or

13 lack thereof of systemic toxicity. So again, I

14 just throw out is there any concern here about

15 absorption of the other molecules? Because for --

16 and again, it's back to Dan whether you can. You

17 know, is the systemic toxicity going to be

18 generalizable across all these dicarboxylic acids

19 or are there any that you would be concerned

20 about?

21 DR. LIEBLER: Aside from parameters that

22 would affect absorption and distribution, I'm not




1 aware of any sort of pharmacodynamic reasons why

2 different chain length dicarboxylates would have

3 different toxicological effects.

4 DR. BELSITO: Curt?

5 DR. KLAASSEN: I agree.

6 DR. SNYDER: And the overall toxicity is

7 relatively low. Pretty high OB50s.

8 SPEAKER: Okay.

9 DR. BRONAUGH: I guess there was an

10 absorption study in guinea pig skin of the diethyl

11 -- what is it? -- the diethylhexyl sebacate, which

12 the molecular weight looks to be under 500. You

13 know, sometimes, if you have a large family of

14 ingredients, it might be useful if we could know

15 what the molecular weight is, what the logP is, so

16 you could look through and have a better sense.

17 But, you know, this data is in a

18 hairless guinea pig -- or the guinea pig, anyway,

19 that was given to us, where they said it was

20 readily absorbed. But I would imagine some of

21 these molecules are absorbed. But, you know, it's

22 really kind of hard to say without, you know, how




1 to compare them without knowing a little bit more

2 about their chemistry.

3 DR. KLAASSEN: One would think that

4 these would be extremely water soluble and not be

5 absorbed so well, right?

6 SPEAKER: (inaudible) the mic.

7 DR. KLAASSEN: Yeah.

8 SPEAKER: Sometimes I -- if it --

9 DR. KLAASSEN: You know, in regard to

10 these dicarboxylic acids, I guess it'd be my

11 impression that they'd be so water soluble that

12 they probably wouldn't be absorbed. I think it

13 would be nice to see some partition coefficients,

14 etcetera.

15 DR. BRONAUGH: It would take a little

16 extra time, but maybe it'd be worthwhile if -- I

17 mean, this data could be calculated in a family

18 like this and we'd have a better idea.

19 DR. KLAASSEN: And in your talk this

20 morning didn't you say that there was some EPA or

21 FDA website that had a lot of that data on there.

22 DR. BRONAUGH: It has the software where




1 you can calculate logP and water solubility just

2 knowing the SMILES code of any ingredient. And

3 again, the SMILES codes are available on the NIH

4 site, for many compounds.

5 So it might be useful to have that

6 sometimes.

7 DR. KLAASSEN: Yeah, I agree 100

8 percent.

9 DR. BELSITO: But if the toxicity is the

10 same, at least systemic toxicity is, that was the

11 reason I asked the question. And we have use that

12 looks like it's not going to above 10 percent in

13 cosmetics. And then we have Azelex cream, which

14 has been looked at by FDA, that's 20 percent for

15 treatment of acne. Then I think I'm okay as long

16 as I don't see cosmetic products coming out above

17 10 percent or certainly over the 20 percent in

18 terms of, you know, okay, you know, is there

19 absorption, you know, and what are slight

20 differences in absorption.

21 But I agree in principle with what Bob

22 is saying. As we create these superfamilies, it





1 would be nice if CIR would go to that website and

2 provide us with a list of molecular weights and

3 logPs. You know, particularly when it comes to

4 picking, you know, if there is an issue about

5 absorption, what ingredient do we want as the

6 model ingredient to assure the safety for the

7 entire family. Well, it would be the one that we

8 would predict from these various parameters would

9 be most likely to be absorbed. So I think it

10 would be helpful.

11 MR. ANSELL: To the discussion on

12 systemic safety, we would like to point out that

13 CIR has already conducted and found safe as used

14 three of the adipates, including diethylhexyl,

15 dibutyl, and diisopropyl. And that the

16 diethylhexyl has already gone through a complete

17 NTP screen through carcinogenicity.

18 DR. ANDERSON: I think the, excuse me,

19 Table 2 already includes many of the data you're

20 talking about. Admittedly they are buried in

21 amongst all of the other chemical and physical

22 properties. But the American Chemistry Council




1 report, in fact, did use the EPA program to

2 calculate logPs, and these are included. So for

3 dimethyl sebacate, it's 3.4 for a logP; for

4 diethylhexyl sebacate, it's 3.74 there. Just

5 outside, if you will, of the -1 to 3 range that

6 would suggest penetration, but not far enough

7 outside so that I'd be comfortable for giving them

8 a free ride. I think you'd have to presume there

9 is some absorption of these things. Then the

10 question becomes what's the toxicity, which is

11 rather low. And I wouldn't kiss them off on the

12 basis of dermal penetration.

13 SPEAKER: Yeah.

14 DR. ANDERSON: But I take your point

15 that a table that presents just molecular weight

16 and logP, if those data are available, paints an

17 interesting picture that you'd like to see.

18 DR. BRONAUGH: Yeah, I forgot about that

19 data. I don't have a copy. Linda has our copy of

20 the book. I forgot that that was done for this

21 series of compounds. And I think it was very

22 useful. There were some gaps in there that maybe




1 could have been filled in, but I think that's

2 useful.

3 SPEAKER: That's good to know.

4 DR. LIEBLER: You could represent the

5 calculated logP values in a plot, like the plot

6 for the phenyls that Bob showed during his talk,

7 in which you'd number, instead of just using round

8 dots as the points, you actually use numbers as

9 the points. And the numbers could refer back to

10 the compounds in a table. And what that would

11 allow us to do is see much better which compounds

12 are within the range or close to the range that's

13 typically associated with the potential for

14 absorption.

15 DR. ANDERSON: That raises an

16 interesting idea of what would that plot look like

17 since we have calculated logP values on one axis

18 as a function of molecular weight on another.

19 DR. KLAASSEN: Well, those are two of

20 the more important characteristics of chemicals

21 that are important to us. And, you know, a lot of

22 these that we have, you know, like boiling point,




1 vapor pressure, density even, we have all of these

2 other things. It's kind of like the important

3 data gets lost in the minutiae.

4 SPEAKER: Yep, the --

5 DR. LIEBLER: With the Henry's Law

6 constant, you're saying.

7 DR. ANDERSON: I take your point. Just,

8 we need a good chemist on staff.

9 DR. BELSITO: Now, were the data from --

10 all of the data from this dioctyl and diisopropyl

11 adipate report incorporated into this report?

12 Because it seems like they have not been.

13 And did I understand, Jay, from your

14 comment, that there is another adipate that we've

15 also previously reviewed out there?

16 MR. ANSELL: Yeah, we have three

17 adipates that were CIR reviewed, which have not

18 been included. These were diethylhexyl, dibutyl,

19 and diisopropyl adipate.

20 DR. BELSITO: Okay. So then there's the

21 diethylhexyl has also not been incorporated into

22 this at this point?





1 MS. ROBINSON: If it was from the

2 original report, it has not been incorporated.

3 But an updated search was performed, so anything

4 outside of that is in the report.

5 DR. BELSITO: Okay. So we have one

6 other report, other than this one, that needs to

7 be incorporated into this document, as well?

8 SPEAKER: (inaudible)

9 DR. BELSITO: Okay.

10 MR. ANSELL: We also -- the NTP study,

11 we don't believe has been incorporated on a whole

12 series of materials. I'm also unclear as to

13 whether the -- we did obtain from ACC robust

14 summaries that we were requested to -- and the

15 cover letter suggests they were included, but

16 Valerie's suggesting they're not. So I think

17 there's some data that needs to be included.

18 MS. ROBINSON: The robust summaries from

19 ACC were incorporated, but we haven't received any

20 additional information that we asked for prior.

21 MR. ANSELL: The data which was

22 requested of us in September, though, I think was




1 Dan's question. And we did find robust summaries,

2 and I do believe they have been incorporated.

3 DR. LIEBLER: I couldn't tell what was

4 different. I guess I didn't have the previous

5 book, so. I saw some references to the American

6 Chemistry Council HPV summaries. Is that what

7 you're referring to, Jay?

8 MR. ANSELL: Yeah.

9 MS. ROBINSON: Yes, those are new.

10 DR. LIEBLER: Those are new.

11 MS. ROBINSON: Yes.

12 DR. LIEBLER: Since September.

13 DR. ANDERSON: That's correct. Those

14 were not in the document.

15 DR. LIEBLER: Okay.

16 DR. ANDERSON: And the only issue from

17 the panel's perspective is that now that you

18 understand dicarboxylic acids were in the American

19 Chemistry Council report, there is a couple of

20 points of overlap with this safety assessment, and

21 is that enough?

22 DR. BELSITO: Okay. Where do we get the




1 information as to what was in the American

2 Chemical report? How do we divine that from this

3 document?

4 DR. ANDERSON: Well, if you go to page

5 34, for example, for the question, really, of the

6 genotoxicity data, then there's specific mention,

7 you know: Mammalian cell gene mutation assay.

8 Two ingredients in this assessment were included

9 in the ACC report and were negative in the mouse

10 lymphoma assay.

11 DR. BELSITO: Okay, so you're talking

12 about the mutagenicity studies, in particular.

13 DR. ANDERSON: Yes.


15 DR. ANDERSON: Yeah, that was the --

16 DR. BELSITO: Wasn't clear where you

17 were.

18 DR. ANDERSON: Yeah, I'm sorry. That

19 was the major gap. Without those data, the

20 genotoxicity section was really quite bleak.

21 DR. BELSITO: Okay. So where are we

22 with this? Are we going insufficient for




1 impurities? Are we going insufficient for more

2 concentration of use? Are we going safe as used

3 when we add in the NTP summaries and the

4 information from the dioctyl, diisopropyl,

5 diethylhexyl adipate documents that were

6 previously published?

7 Paul, where are you?

8 DR. SNYDER: Sounding an awful lot like

9 insufficient. I mean, Dan's comment to the

10 impurities issue, he's not comfortable with the

11 absence of additional impurities data.

12 DR. LIEBLER: So I'd be happy with

13 representative data for some of these compounds

14 for impurities. I mean, we have a wide range of

15 things from small dicarboxylates to big,

16 long-chain esters, which are going to result from

17 different processes and are going to have

18 different impurities. We may not have impurity

19 data for every compound in the table, but I'd like

20 to see representative impurity data from compounds

21 that represent the processes that go into these

22 products.





1 And I was struck, in concentrations and

2 frequency of use, that it seemed like they were

3 inversely related. The compounds with recorded

4 significant frequencies of use had almost no

5 concentration data and the compounds with bigger

6 numbers for frequency of use tended to have no

7 concentration data.

8 Talking about Table 4.

9 DR. ANDERSON: Yeah, and that's very

10 likely an artifact of the late addition of many of

11 the compounds.

12 DR. LIEBLER: Do you think the

13 information's available and we just haven't gotten

14 it into a table yet?

15 DR. ANDERSON: I think that's the case.

16 DR. BELSITO: That's what we're told,

17 that Carol --

18 DR. LIEBLER: I see, okay.

19 DR. BELSITO: So then what we're looking

20 at is Dan would like some representative impurity

21 data. Would you like to mention any specific ones

22 you'd like or just leave it open-ended back to the




1 council and industry for some representative

2 impurity data?

3 DR. LIEBLER: I'd like to see impurity

4 data on the dicarboxylates.

5 DR. BELSITO: But which ones? Any

6 specific one that you're concerned about, or?

7 DR. LIEBLER: How about sebacate.


9 DR. LIEBLER: As representative. And

10 then how about succinate as -- or malonate as

11 representative? So you get a longer one and a

12 shorter one.


14 DR. LIEBLER: And then how about the

15 impurity data on short esters of both of those and

16 long esters of both of those? I think that

17 represents the chemical space reasonably well.

18 DR. BELSITO: Okay. So then what we're

19 suggesting is that we are going insufficient for

20 impurities. And we would like to see something on

21 the sebacates or sebacic acid, and either malonic

22 or succinic acid, and then whatever two you




1 choose, some impurity data on short- and a

2 long-chain ester of each of those acids. And we

3 would appreciate getting updated concentration of

4 use, particularly for those ingredients that have

5 considerable use. And assuming that that data

6 looks clear, I am guessing that we would be going

7 safe as used for these dicarboxylic acids.

8 DR. BERGFELD: So are you going out

9 insufficient or are you tabling it?

10 DR. BELSITO: No, insufficient. I mean,

11 it's only -- it's at a pink stage.

12 MR. ANSELL: But there's so much data

13 which was not included in the report, and so many

14 added after, it would be possible for us to have

15 provided the data. We would prefer it be tabled

16 to include CIR's reports, to include the NTP

17 study, to include the actual concentrations of

18 use.

19 DR. BELSITO: But I guess, Jay, I don't

20 see how tabling it versus us telling you what we

21 find is insufficient in the current report really

22 changes things since it's at a pink stage. I




1 mean, it's not like it's going out for a final.

2 And if we were going out for a final, it was going

3 to be, you know, we're saying it's insufficient,

4 and you're going to get the data for us before the

5 next meeting. But, I mean, if anything, I mean,

6 PC has been --

7 DR. BERGFELD: Are you asking for an

8 announcement?

9 DR. BELSITO: -- after us to expedite

10 the process. Well, this expedites the process.

11 It moves it up to the next stage and it tells you

12 where we're at.

13 DR. BERGFELD: Are you going out for

14 insufficient data announcement or --

15 DR. BELSITO: Yeah.

16 DR. BERGFELD: -- insufficient final

17 announcement?

18 DR. BELSITO: No, this is not even a

19 final. This is pink, Wilma.

20 DR. BERGFELD: No, no, I know, but I'm

21 --

22 DR. BELSITO: We haven't even gotten --





1 DR. BERGFELD: I know, but we had jumped

2 over the announcement part in our new progression.

3 But you're going to input in this one

4 announcement, insufficient data announcement.

5 DR. BELSITO: Right.

6 DR. BERGFELD: It's different than a

7 final.

8 DR. BELSITO: It's not a final, it's

9 just a --

10 DR. BERGFELD: No, no, I know that. But

11 we had done away with announcements. We've done a

12 few of them, but we've done away with that process

13 a little bit. Haven't we? Alan? We were trying

14 to expediate the flow.

15 DR. ANDERSON: Yeah. I think in terms

16 of process, at the last meeting the panel agreed

17 to move forward to prepare a draft report which in

18 our judgment, given your comments, would be ready

19 to be issued as a tentative report. There were a

20 couple of oopses in that process in that a couple

21 of background reports prepared by the panel didn't

22 get captured. The other oops is that the panel




1 flagged these very long list of additions too late

2 for the council to in any way be expected to

3 respond with use concentration data. So those are

4 -- there's some serious gaps in those data.

5 But it is at a stage when you would be

6 expected to do one of two things: Issue an

7 insufficient data announcement or issue a

8 tentative report. And you flag that there are

9 clearly data that you want. In our expedited

10 process of keep it moving, this is ready for an

11 insufficient data announcement. That's,

12 processwise, that's where it is.

13 There is the issue of the couple of

14 oopses. And I wouldn't be upset if you used that

15 as a basis for saying, look, we got to fix these

16 gaps. We've got the reports from previous safety

17 assessments that weren't captured. You need to do

18 that. And arguably that would allow enough time

19 for the use data to come in. And I don't see any

20 difficulty in tabling it. I would write in the

21 post-meeting announcement that part of tabling it

22 is the expectation for the impurities data that




1 Dan has outlined.

2 The risk of that is that we get to April

3 and those data don't show up.

4 DR. BELSITO: Exactly.

5 DR. ANDERSON: And that's --

6 DR. BERGFELD: However, the document is

7 cleaned up and all of the --

8 DR. ANDERSON: Yeah, but you just

9 delayed it --

10 DR. BELSITO: But cleaning up the

11 document is not -- I mean, if all of the

12 information we needed was in the oops documents

13 that didn't get in and an update in the

14 concentration of use, then I would be very happy

15 tabling it. But I'm just concerned that if we

16 want the impurities data and, you know, Dan is the

17 man I go to to tell me if we need that, and we

18 just table it, even if Alan says, oh, by the way,

19 you know, I don't think, based upon past

20 performance of industry, we're going to get it.

21 And then we're going to be sitting at the April

22 meeting where we were at the December meeting.




1 So, I mean, it's -- we go insufficient, we list

2 what we need, clean up the document, update

3 concentration of use, give us some impurities,

4 then I think it's very clear what we're looking at

5 for safety. And that's what I would -- I mean,

6 that's my argument. In the spirit of trying to

7 expedite getting these documents done, I think the

8 best way to expedite it is to be very upfront as

9 to where we are.

10 SPEAKER: Well said.

11 DR. KLAASSEN: There's one additional

12 comment I'd like to make. And that is one major

13 group of chemicals in this larger class is oxalic

14 acid and its various compounds. And the toxicity

15 of oxalic acid is well known, if it gets absorbed,

16 in that it's quite -- produces kidney injury.

17 And, in fact, that's the toxicity from ethylene

18 glycol, is that it's metabolized oxalic acid and

19 it causes severe kidney injury. And while I don't

20 think we're probably getting enough absorbed here

21 to be a problem, there's really not much data in

22 this entire document on oxalic acid. And I just





1 want to make sure people are aware of that.

2 DR. BELSITO: There's a lot of

3 literature on it.

4 DR. KLAASSEN: There's a lot of

5 literature, but it's not in here.

6 DR. BELSITO: Yeah, I know.

7 DR. KLAASSEN: And I think somehow we

8 need to at least address oxalic acid in a

9 discussion or something, if there is good reasons

10 why we haven't kind of paid special attention to

11 it. And, in fact, it's -- yes, there's a lot of

12 information out there. In fact, it's -- also, a

13 lot of plants contain oxalic acid and -- so,

14 anyhow, it needs to be somehow addressed.

15 DR. LIEBLER: I didn't see oxalic acid

16 listed in Table 4, or any of its derivatives

17 listed in Table 4. Is it used in cosmetic

18 products? Oxalic acid or oxalate esters?

19 MR. HAVERY: We don't have any reported

20 uses for oxalic acid.

21 DR. LIEBLER: So I think that -- my

22 recollection is that last time we met, in




1 September, this category was expanded at Ron

2 Shank's suggestion based on incorporating the

3 greater range of chemistries. But I think the

4 rationale was going across the chemical space as

5 opposed to the cosmetic ingredient space, and we

6 might have picked up some unnecessary compounds in

7 doing so; oxalic acid and its esters being

8 representative of that.

9 DR. BELSITO: But they're in the

10 dictionary. And we thought we could cover them in

11 this report. One of the things that we get

12 criticized for by groups such as the Environmental

13 Working Group is that there are X-number of

14 thousands of chemicals in the dictionary and we

15 have looked at only a certain small percentage of

16 them. And so that was the whole purpose for

17 grouping these. And so if oxalic acid is in the

18 dictionary and the functions are similar to the

19 other dicarboxylic acids, and we feel that the

20 safety can adequately be reviewed, you know, we do

21 it. And then there's that footnote at the end

22 saying, well, you know, oxalic acid and its esters




1 aren't being used, but if they were to be used,

2 we're assuming that they would have the same

3 function and the same concentration as everything

4 else in this report.

5 SPEAKER: (inaudible) review.

6 DR. LIEBLER: They may just -- and

7 oxalic acid may be somewhat unrepresentative of

8 this class of compounds. I mean, in the case of

9 oxalic acid in the kidney, it forms these very

10 insoluble crystals with calcium, calcium oxalate,

11 very insoluble. So it's kind of the --

12 mechanistically, it's an outlier.

13 DR. KLAASSEN: And it is at the end of

14 the chain that we're talking about. I mean, it is

15 the smallest one.

16 DR. BELSITO: Well, if mechanistically

17 it's an outlier, and if that's the issue, and then

18 if you're concerned about absorption, then we

19 could easily delete it by saying that it is an

20 outlier. You know, that we cannot group this

21 specific dicarboxylic acid with the others. On

22 the other hand, if you're not concerned about the




1 level of absorption from a cosmetic product, I

2 mean, if it's a true no-brainer, then we should

3 add it. If it's not a true no- brainer, then we

4 shouldn't. And I guess that's a point that, I

5 mean, if you want to raise tomorrow, we can

6 certainly do that.

7 DR. LIEBLER: Yeah, I just don't know

8 what the data are on absorption of oxalic acid in

9 a use that would be consistent with a cosmetic

10 product, oxalic acid or oxalic acid derived from

11 oxalate esters.

12 So if it's insignificant, yeah, then I'm

13 not worried. If it's likely to be more

14 significant, then I would worry.

15 DR. BELSITO: Well, 10 percent would the

16 highest concentration, at least from the limited

17 use data we have right now, in a cosmetic product.

18 Bob, what is your sense for absorption

19 of oxalic acid versus a shorter chain acid?

20 DR. BRONAUGH: I don't know. It's

21 really hard to say. Oh, excuse me. It's really

22 hard to say. I guess, and not being a chemist, I





1 don't automatically know solubility properties. I

2 mean, it's certainly an acid; it's going to be

3 water soluble. I don't know to the extent that it

4 would penetrate through the stratum corneum if it

5 has no lipid solubility. But it depends. I don't

6 know the pKa of oxalic acid. I'm not sure what

7 that is.

8 DR. BELSITO: Well, we have in, let's

9 see, the table, the solubility is 1 gram per 7 mls

10 of water. And --

11 SPEAKER: That's very soluble.

12 DR. BELSITO: -- that's it.

13 DR. KLAASSEN: But then you have the --

14 DR. BELSITO: We don't have a --

15 DR. KLAASSEN: That's the dibutyl

16 oxalate.

17 DR. BRONAUGH: Right. Now there you

18 would start expecting some penetration.

19 DR. KLAASSEN: Yeah.

20 DR. BRONAUGH: In lipophilicity.

21 DR. KLAASSEN: I guess the point is this

22 is not a no-brainer. I mean, there's enough doubt




1 here, or at least in my mind.

2 DR. SNYDER: I guess my question goes to

3 why didn't the scientific literature review then

4 identify some of this information regarding the

5 renal toxicity? So did you search under the term,

6 all of those terms?

7 MS. ROBINSON: Mm-hmm. Yes, I did.

8 Yes, I did the search on the terms. And a couple

9 of the studies Halyna and I took out because there

10 wasn't enough information in the published report.

11 I can actually bring those back in.

12 DR. BELSITO: Well, what I'm hearing is

13 that, at least from both Dan and Curt, is that

14 they have enough concern that, again, the add-ons

15 are supposed to be no- brainers, and we've now

16 spent at least 10 minutes discussing whether

17 oxalic acid actually fits into this report, and

18 we're not seeing any evident cosmetic use of it.

19 So the no- brainer, you know, swore it would say

20 that we should eliminate oxalic acid and its

21 esters from this report.

22 DR. KLAASSEN: I agree. And just to put




1 this in perspective, some people, like myself, and

2 maybe us around this table have a job because of

3 the toxicity of oxalic acid. So in the 1930s, to

4 get a drug on the market what you had to do was to

5 show that it was effective. But then in the

6 1930s, when the sulphonamides came out, they

7 dissolved the sulphonamides in ethylene glycol.

8 And then we had a number of people that died,

9 especially children, from kidney injury. And the

10 toxicity really was due to the ethylene glycol

11 being metabolized oxalic acid. And as a result of

12 that, the FDA, Congress changed the laws for FDA

13 to get a drug on the market. You not only had to

14 show that it was effective, but that it was not

15 toxic. So this whole business around oxalic acid

16 is kind of, like, no small story in the history of

17 toxicology, for whatever that's worth.

18 MR. ANSELL: And, you know, I certainly

19 agree with these comments. I just want to throw

20 out that I can't actually find the reference for

21 it, but apparently it's used as a pH adjuster to a

22 concentration of about 5 percent in hair products.




1 So we'll follow up on that and see whether that

2 would have any bearing on that conclusion.

3 DR. BELSITO: So, to recap. We are

4 suggesting that the addition of oxalic acid to

5 this group is not a no-brainer and that we would

6 recommend that oxalic acid and the esters be

7 removed. Once that is done, if it's done, we find

8 this group to be insufficient for impurities, and

9 we would like impurities on a representative short

10 and long chain. The suggested ones were sebacate

11 and malonic or succinic acid. And then

12 subdividing those, we would like short- and long-

13 chain esters of a short- and long-chain acid,

14 impurities for those representative ones. And

15 then concentration of use. And the assumption,

16 also, is that when this document comes back to us,

17 that the NTP summary and that the information on

18 the dioctyl, diisopropyl, and diethylhexyl adipate

19 studies will be included in this report.

20 Is that where we're at?

21 SPEAKER: Mm-hmm.

22 DR. BERGFELD: Well, and use, because





1 they promised you use.

2 DR. BELSITO: I said that.

3 DR. BERGFELD: Did you say that?

4 DR. BELSITO: Yeah.

5 DR. BERGFELD: Okay.

6 DR. SNYDER: Unless we're provided data

7 on oxalic acid regarding dermal absorption

8 toxicity.

9 DR. BELSITO: Yeah, I suppose that could

10 be done. But again, the boilerplate that we've

11 had for the decision to go ahead with additions

12 has been that it be a no-brainer. And that we

13 wouldn't need that additional data; that the data

14 was already there. I don't know.

15 DR. ANDERSON: I think the option would

16 always exist for any interested party to provide

17 data.

18 DR. BELSITO: Yeah, if there was data

19 provided on lack of absorption, then I guess that

20 the no-brainer part of it is if it gets absorbed,

21 how much and what would it do to the kidney. If

22 we see information that, you know, it's used




1 at.001 percent in a hairspray and it's not going

2 to get absorbed, then, you know, we might change

3 our minds. So I guess that we're considering

4 deleting oxalic acid unless we get information on

5 absorption and concentration of use in products

6 that it would be used in. But if it's open-ended

7 and we assume that it's going to be used in all

8 the same type of products as these other

9 dicarboxylic acids in concentrations up to 10

10 percent, we don't have any information, we'll

11 probably just remove it from the report.

12 SPEAKER: Lunchtime.

13 DR. BELSITO: It is 12:10. Be back at

14 1:10.

15 (Recess)

16 DR. BELSITO: Okay, welcome back. So,

17 we're back here at the PEGS. And at the last

18 meeting, as you know, the issue here is to reopen

19 it to get rid of this damaged skin restriction in

20 the conclusion. At the last meeting we had a

21 wonderful presentation on transepidermal water

22 loss and various skin diseases, including atopic



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PINK BOOK 3 Sebacic Acid/Dicarboxylic Acids...July 10, 2009: SLR was issued September 2009 Panel...

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Transcript of PINK BOOK 3 Sebacic Acid/Dicarboxylic Acids...July 10, 2009: SLR was issued September 2009 Panel...