PINK BOOK 3 Sebacic Acid/Dicarboxylic Acids CIR EXPERT PANEL MEETING AUGUST 30-31 ...

292 Pages·2010·7.6 MB·English

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as HPV robust summaries, that cite unpublished sources.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 Additional unpublished data received from Council,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

CIR Panel Book Page 2
CIR Panel Book Page 3
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.

CIR Panel Book Page 4
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

CIR Panel Book Page 5
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.

CIR Panel Book Page 6
Transcripts/
Minutes
PANEL - DEC 2009
CIR Meeting day 2 Page: 40 CIR Meeting day 2 Page: 41
1 isononanoates and all that -- those parts. And, 1 the aim of splitting the acids and salts into one
2 hopefully, we can have our -- you know, at the 2 group -- they are used as pH adjusters -- and then
3 next meeting, have a good discussion on whether 3 the esters into another group, rather than having
4 these are long shots or not, in other words, if 4 them all mixed in as is in the present document.
5 they're lipophilic, probably really concerned and 5 That could either be, as we discussed,
6 so forth, because I'd hate to pull -- 6 whether this should be two separate documents or
7 unnecessarily pull ingredients off the list when 7 one document and just have the document organized
8 there's a good reason to believe that it's not a 8 so these ingredients were split, and we felt that
9 problem. 9 we could proceed with one document. And then we
10 DR. BERGFELD: Well, thank you for that 10 also felt that within this list, that we should
11 clarification of who does what. 11 reopen three of the esters that have already been
12 All right. Well, then we move on. 12 determined to be safe by the CIR panel, and that's
13 We're moving on to the second ingredient under the 13 the diethylhexyl adipate, the dibutyl adipate, and
14 reports advancing and that's sebacates by Dr. 14 the diisopropyl adipate. So, we felt some more
15 Marks. 15 work needed to be done on the document and,
16 DR. MARKS: So, this is the second time 16 therefore, recommend to table it.
17 we've looked at the sebacates. In the September 17 DR. BERGFELD: Is there a second to
18 2009 meeting we decided to table these ingredients 18 table?
19 so that we could expand the number and I have a 19 SPEAKER: Second.
20 feeling we're going to have a discussion again 20 DR. BERGFELD: Second. There's no
21 procedurally how to go. Our team felt that we 21 discussion on the table. Motion, all those in
22 should continue to table these ingredients with 22 favor of tabling, please indicate by raising your
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CIR Meeting day 2 Page: 42 CIR Meeting day 2 Page: 43
1 hand? 1 into two or split into two pieces in one document.
2 DR. BELSITO: Any discussion? 2 We have lots of experience with both approaches.
3 DR. BERGFELD: No discussion on the 3 It's simply a question of approach. It doesn't
4 table. It's four against four? So, the chair has 4 address the question of any real additional data
5 to vote. I'll vote to table. So, this particular 5 needs. So, I'm not sure there's a benefit to
6 ingredient has been tabled and let's go over why 6 tabling from that standpoint.
7 it's being tabled again. 7 DR. BERGFELD: How about the addition of
8 DR. MARKS: Well, the first is that we 8 the other previously approved ingredients?
9 felt the document could be reorganized and that 9 DR. ANDERSON: I think --
10 really by uses, so the acids and the salts are 10 DR. BERGFELD: Does that fit with the
11 used as pH adjusters and then the esters had other 11 first comment?
12 uses. And so the document would be split to 12 DR. ANDERSON: There is -- there are
13 discuss those two groups together, and that we, as 13 data that are available in the other safety
14 part of this document, reopened three esters which 14 assessments that previously the panel has
15 had previously been determined by the CIR as all 15 completed. To the extent that you want those data
16 are safe to be included in this new amended. 16 incorporated, tabling it to do that step is, I
17 DR. BERGFELD: May I ask, Alan, is this 17 think, a valid thing to do because clearly they're
18 really editorial or is this truly -- does it truly 18 not in there now.
19 have a need for being tabled? 19 DR. BERGFELD: Don? Comment?
20 DR. ANDERSON: Yes, I would have said 20 DR. BELSITO: Well, I mean, we obviously
21 that was an editorial change. It's just a matter 21 didn't vote to table, but some comments. First,
22 of reorganizing the document, whether it is split 22 yes, I mean, I think the other three should be
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CIR Panel Book Page 7
CIR Meeting day 2 Page: 44 CIR Meeting day 2 Page: 45
1 included. Jim, I think you said dibutyl, you mean 1 review and grapple with.
2 dioctyl. 2 DR. LIEBLER: If I could just elaborate
3 DR. MARKS: Okay. Thank you, Don. 3 on that.
4 DR. BELSITO: The biggest discussion we 4 DR. BERGFELD: Don?
5 had revolving around this was oxalic acid, which 5 DR. LIEBLER: Yeah, I think the idea of
6 did not -- I mean, all of the safety data on that 6 including the smaller diacids and their esters and
7 specific acid, particularly in terms of causing 7 salts was mainly to expand the chemical space to
8 renal calculi, was not in this document. And we 8 things that are possibly relevant. But in getting
9 actually thought since we didn't see it listed as 9 down to oxalic acid, you run into some unique
10 having any cosmetic uses, that unless there were 10 toxicology that's very well documented, very
11 cosmetic uses for oxalic acid or its esters that 11 prominent, and quite problematic, and we don't
12 it be dropped from this family because of those 12 even know if this is used as a cosmetic
13 issues with renal toxicity. 13 ingredient. So, rather than get tangled up in all
14 DR. BERGFELD: So, your recommendation 14 of that, it's worth considering deleting the
15 under the conditions that we were tabling this is 15 oxalic acid from this report.
16 to reconsider the inclusion of oxalic acid? 16 DR. BERGFELD: John Bailey?
17 DR. BELSITO: Well, to first of all 17 MR. BAILEY: Yeah, I think we didn't
18 confirm whether, in fact, it's used -- currently 18 have time in getting these additional ingredients
19 being used, and, if not, then our recommendation 19 to survey -- do our usual survey of use and use
20 would be to remove it from this family because of 20 levels, so we can't answer definitively whether
21 those issues that were being countered and because 21 that's the situation or not, so I think we need
22 of the huge amount of data that we'd have to 22 some more information. I would point out that in
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CIR Meeting day 2 Page: 46 CIR Meeting day 2 Page: 47
1 Europe, oxalic acid is on annex 3 for hair dyes, 1 better simply to keep all the ingredients, which
2 so presumably, you know, that may be a use. And 2 is a large number of ingredients we have right
3 we haven't done the research necessary to get more 3 now, get rid of oxalic acid and, in fact, if it's
4 information about how it got there and use levels 4 used, we can always look at oxalic acid
5 and so forth. So, I would say, certainly oxalic 5 specifically rather than as a member of this
6 acid is in the textbooks. We all know about it, 6 group? Because I just think we're going to get
7 but there may be some additional information that 7 hugely bogged down even if it's used in trying to
8 would be relevant that we simply, you know, didn't 8 explain why it'd say brief discontinuous use on
9 have time to get. 9 the hair, no absorption, yadda, yadda, yadda. But
10 DR. BERGFELD: So, that's a promise to 10 we're going to have to look at all the data
11 get? 11 anyway.
12 MR. BAILEY: Certainly, yeah. We'll do 12 MR. BAILEY: Yeah, I concur.
13 our usual survey of -- 13 DR. BERGFELD: So, we might entertain a
14 DR. BERGFELD: Okay. Any further 14 motion at this time to delete oxalic acid from the
15 discussion? Don? 15 list.
16 DR. BELSITO: Yeah, I guess, just to 16 DR. BELSITO: I would like to make that
17 follow up on Dan's point, there is such a 17 motion.
18 voluminous amount of literature on oxalic acid 18 DR. BERGFELD: Is there a second?
19 that even if it's used in cosmetics, do we want to 19 Second. Is there a discussion of that
20 get bogged down dealing with why that is going to 20 recommendation?
21 be safe in a cosmetic product and reviewing all of 21 Curt?
22 that literature on oxalic acid? Or would it be 22 DR. KLAASSEN: No problem.
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CIR Panel Book Page 8