pink bis-diglyceryl polyacyladipates bis-diglyceryl polyacyladipates ... repeated insult patch test...

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Bis-Diglyceryl Polyacyladipates

CIR EXPERT PANEL MEETING

JUNE 11-12, 2012

Memorandum

To: CIR Expert Panel Members and Liaisons From: Monice M. Fiume MMF Senior Scientific Analyst/Writer Date: June 11, 2012 Subject: (Draft) Tentative Report on the Safety Assessment on Bis-Diglyceryl

Polyacyladipate-2 and Bis-Diglyceryl Polyacyladipate-1 as Used in Cosmetics Enclosed is the draft tentative report on the safety assessment on bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 as used in cosmetics. The safety assessment was first reviewed in March, and at that meeting the Panel noted that chemistry data were lacking. An Insufficient Data Announcement was issued requesting the following: 1. representative structures; 2. method of manufacture; and 3. impurities data. Data were submitted directly to the CIR in response to these data needs, and the method of man-ufacture and impurities data have been incorporated in the report. A representative structure was also submitted, but the structure did not appear to represent all of the mixtures of chemicals that could be present in these ingredients. Therefore, Dr. Heldreth created Figure 1 of the report, which represents the mixture of all the possible chemicals in bis-diglyceryl polyacyladipate ingredients. The following unpublished data were received from the Council after mail data but prior to the March meeting:

1. Council. 2012. Updated concentration of use. 2. TKL Research. 2009. Repeated insult patch test study of a lipstick containing 36% Bis-

Diglyceryl Polyacyladipate-2. These data have also been incorporated and are included in this submittal, along with the data received in response to the IDA. The new data are indicated by vertical lines. It is expected that the Panel will issue a Tentative Report at the meeting.

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Draft Amended FinalReport

Final Report

*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. AfterPanel review, the statement is Issued to the Public.* *if Draft Amended Report (DAR) Is available, the Panel may choose to review; if not, CIR staff prepares DAR for Panel Review.Expert Panel Decision

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Document for Panel ReviewOption for Re-review

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Tentative AmendedReport

Distributed for Comment Only -- Do Not Cite or Quote

CIR Panel Book Page 1

BIS-DIGLYCERYL POLYACYLADIPATE REPORT HISTORY

August 3, 2011: Notice to Proceed without the Preparation of an SLR Issued March 5-6, 2012: Draft Report The following unpublished data were submitted by the Council:

1. Personal Care Products Council. Concentration of use by FDA product category: Bis-Diglyceryl Polyacyladipate-1 and Bis-Diglyceryl Polyacyladipate-2.

2. Anonymous. 2011. Safety data of Softisan 649 (Bis-Diglyceryl Polyacyladipate-2) - Cumulative skin irritation and human patch test.

The following unpublished data were submitted directly by industry:

1. Sasol Germany GmbH. 1990. Robust study summary of acute dermal toxicity test of Softisan 649 (Bis-Diglyceryl Polyacyladipate-2) in rats.

2. Sasol Germany GmbH. 1989. Robust study summary of acute dermal toxicity of Softisan 645 (Bis-Diglyceryl Polyacyladipate-1) in the rat.

3. Sasol Germany GmbH. 1990. Robust study summary of acute oral toxicity of Softisan 649 (Bis-Diglyceryl Polyacyladipate-2).

4. Sasol Germany GmbH. 1989. Robust study summary of acute oral toxicity of Softisan 645 (Bis-Diglyceryl Polyacyladipate-1) in the rat.

5. Sasol Germany GmbH. 1990. Robust study summary of 4-week oral toxicity study with Softisan 649 (Bis-Diglyceryl Polyacyladipate-2) in rats.

6. Sasol Germany GmbH. 1996. Robust study summary of Softisan 649 (Bis-Diglyceryl Polyacyladipate-2) one to two generation reproduction toxicity study in the rat (limit test).

7. Sasol Germany GmbH. 1990. Robust study summary of genetic toxicity in vitro test (Ames test) in Softisan 649 (Bis-Diglyceryl Polyacyladipate-2).

8. Sasol Germany GmbH. 1996. Robust study summary of in vitro chromosomal aberration assay with Softisan 649 (Bis-Diglyceryl Polyacyladipate-2).

9. Sasol Germany GmbH. 1990. Robust study summary of in vivo micronucleus test of Softisan 649 (Bis-Diglyceryl Polyacyladipate-2) in mice.

10. Sasol Germany GmbH. 1990. Robust study summary of acute dermal irritation/corrosion test of Softisan 649 (Bis-Diglyceryl Polyacyladipate-2) in rabbits.

11. Sasol Germany GmbH. 2003. Robust study summary of human dermal irritation test of Softisan 649 (Bis-Diglyceryl Polyacyladipate-2).

12. Sasol Germany GmbH. 1990. Robust study summary of a guinea pig maximization test of skin sensitisation of Softisan 649 (Bis-Diglyceryl Polyacyladipate-2).

13. Sasol Germany GmbH. 1987. Robust study summary of a Magnusson-Kligman guinea pig maximization study of skin sensitisation of Softisan 645 (Bis-Diglyceryl Polyacyladipate-1) .

14. Sasol Germany GmbH. 1988. Robust study summary of comedogenicity assay of Softisan 649 (Bis-Diglyceryl Polyacyladipate-2) in rabbits.

15. Sasol Germany GmbH. 1988. Robust study summary of a comedogenicity assay of Softisan 645 (Bis-Diglyceryl Polyacyladipate-1).

16. Sasol Germany GmbH. 1990. Robust study summary of an acute eye irritation/corrosion test of Softisan 649 (Bis-Diglyceryl Polyacyladipate-2) in rabbits.

March 9, 2012: Insufficient Data Announcement The Panel noted that chemistry data were lacking, and issued an Insufficient Data Announcement requesting the following:

1. representative structures; 2. method of manufacture; and 3. impurities data.



June 11-12, 2012: (Draft) Tentative Report The following unpublished data were received and incorporated:

1. Sasol North America Inc. 4-25-2012. Method of Manufacture and Impurities for Softisan 645 and Softisan 649.

2. Council. 2012. Updated concentration of use. 3. TKL Research. 2009. Repeated insult patch test study of a lipstick containing 36% Bis-Diglyceryl

Polyacyladipate-2. A representative structure was also submitted, but the structure did not appear to represent all of the mixtures of chemicals that could be present in these ingredients. Therefore, Dr. Heldreth created Figure 1 of the report, which represents the mixture of all the possible chemicals in bis-diglyceryl polyacyladipate ingredients.



1

Bis‐DiglycerylPolyacyladipates DataProfile*– June 2012 –Writer,MoniceFiume

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Bis-Diglyceryl Polyacyladipate Search SciFinder Keep Me Posted results updated weekly SciFinder – July 14, 2011

- Searched 82249-33-0; 135229-94-6; bis-diglyceryl polyacyladipate; softisan 649; softisan 645 - 42 hits; ordered 4 papers

- Searched safety of lanolin substitutes – 3 hits/0 useful PubMed – July 22, 2011 found 2 additional papers FDA – July 26, 2011 – both in use EU – July 26, 2011 – both listed NTP; ChemPortal -0 hits SciFinder Keep Me Posted Results FOIA request – asked Kevin to submit (7-28-11)



Tran

script

FULL PANEL - MARCH 6, 2012 – BIS-DIGLYCERYL POLYACYLADIPATE

DR. BERGFELD: Well taken. Jim, you're up next with the bis-diglyceryl ingredient.

DR. MARKS: There is a 1- and 2-bis-diglyceryl polyacyladipate and this is the first time we've seen this draft safety assessment. Our team moves that we issue a draft tentative report with the conclusion as safe. However, we did request that method of manufacture be added, impurities be added and that a typical chemical structure be added in the future. We did not think that was enough to not move forward with a safe conclusion.

DR. BERGFELD: Donald?

DR. BELSITO: We asked for everything that you asked and went insufficient at this point.

DR. BERGFELD: So you didn't go insufficient report but insufficient data. Is that correct?

DR. BELSITO: We're not going with a tentative final. We're going with an insufficient for what the Marks team just outlined.

DR. MARKS: I think that's an easy one to resolve in terms of we'll ask for that and we'll have an insufficient data notice. So I'll withdraw my motion.

DR. BELSITO: I don't mind trying to expedite it, but I think if we go with a tentative final then industry has to be aware that if we don't get the requested information then we're going to have to retract it and make it insufficient. I've never voted on a report as tentative final safe as used and had a list of -- I really want to know what the impurities are. We have no clue.

DR. BERGFELD: I don't think it's an issue now.

DR. BELSITO: I'm saying there was this brouhaha about lead in lipstick. This is used in lipsticks and I think going ahead and saying it's safe as used when we don't know the impurities or the manufacturing is rather risky.

DR. BERGFELD: Are you making a motion?

DR. BELSITO: I'm making a motion to go insufficient.

DR. BERGFELD: Thank you. Second?

DR. MARKS: Second.

DR. BERGFELD: Is there any further discussion? Halyna?

DR. BRESLAWEC: No problem.

DR. BERGFELD: Ron Hill?

DR. HILL: I have a question with the benefit of this group of esteemed toxicologists. I noticed the guinea pig maximization test was done on the one compound with pure bright white guinea pigs and in the other case Dunkin-Hartley. Is there any significance to the fact that they were using two different guinea pig species?

DR. BELSITO: No.

DR. HILL: It got my curiosity up and I thought I'd take the panel's time for 20 seconds.

DR. BERGFELD: I'll call for the question. All those in favor of an insufficient data announcement? Thank you. It's unanimous.

BELSITO TEAM – MARCH 5, 2012

DR. BELSITO: Okay. Bis-diglyceryl polyacyladipate- and -1, and I guess we have an expert here who can help us if we have any questions here. So, this is the first time we're looking at this. Lots of studies have been incorporated into the draft. The chemistry is pretty scanty, including manufacturing and impurities. And it's, I guess, used up to38 percent in a lipstick and it's the highest concentration of uses in a lipstick. And the question I have to my colleague is: Do we need more oral or is the 28-day oral and the 1 generation repro tox enough to satisfy those needs and to satisfy the needs of the fact that we don't know anything about the impurities in these, at least not from this report?

MS. FIUME: It's 36 percent in lipstick.

DR. BELSITO: Thirty-six, yes.

MS. FIUME: New -- corrected information came in.

DR. BELSITO: Okay, so, not 38, 36?

MS. FIUME: Thirty-six.

DR. SNYDER: I mean, the oral is a pretty robust study. I think we get an NOEL on that at 1.8 grams per kilogram.

DR. BELSITO: Okay. But it was only 28-day. Is that sufficient?

DR. SNYDER: Well, the repro study was negative too and then up to 1000, up to a gram.



DR. BELSITO: And then I guess my biggest issue is here we're dealing with what clearly are just a bunch of fatty acid esters, but we don't know how they're manufactured, we don't know impurities. They're used to 36 percent in a lipstick and do we need to be concerned?

DR. SNYDER: And all the new data was on that Softisan 649. We didn't get any composition data on that (inaudible) contained.

DR. LIEBLER: So, I'm inclined to think that impurities are probably not going to be a big deal, but it would be easier to say that if we knew something about method of manufacture because then we'd know what's used to make these and how they're prepared and purified. I also thought that some generic representation of the chemical structure would be good to have here. You basically have this hexanedioic acid and you've got these two glycerols on the end and then you have the various fatty acyl substitutions. So, those could all be our prime, our double prime, et cetera, but having some structure just to orient the reader would be very helpful and it wouldn't be hard to do.

DR. BELSITO: Well, I mean, this is the first time we're looking at this document or we can go insufficient for manufacturing and impurities and ask for both of them.

DR. LIEBLER: Yes.

DR. BELSITO: And if we have one and not the other, then we can make a decision.

DR. LIEBLER: Right.

DR. BELSITO: It's not like this is a final report.

MS. FIUME: Okay, so, it would be structure, impurities, and method of manufacturer. Is there anything else that you want in the IDA?

DR. BELSITO: I mean, again, I'd just point out that its highest use is a lipstick and we have a 28-day oral and a 1 generation repro tox and those aren't my areas of expertise. Are my other panel members comfortable with that?

DR. KLAASSEN: It turns out I didn't get this document, so, I can't support it or I didn't realize it until now.

MS. FIUME: Do you want me to go grab you the --

DR. KLAASSEN: Oh, it's too late. Too late now.

DR. LIEBLER: Yes, I was prepared to defer to Paul and Curt on the tox studies.

DR. SNYDER: But we had even more, right? All of this Softisan 649 data, is that yet to be incorporated into the report or is it all incorporated?

MS. FIUME: It's all incorporated.

DR. BELSITO: It's all incorporated.

DR. SNYDER: Okay, so, we have --

DR. BELSITO: There's no (inaudible).

DR. SNYDER: I mean, both those were pretty robust. Repro tox was an OECD guidelines and one generation repro tox, it was completely negative. So, I guess very low concern at this point unless we -- well, we don't have an absorption label.

DR. KLAASSEN: What's the molecular weight unless we put log?

DR. LIEBLER: We don't have anything (inaudible).

DR. SNYDER: Because, usually, we have a core and about 200 moleculars, I guess, and then 4 fatty acyl chains of various composition on each. So, they're in the 700+.

MS. FIUME: Yes. With a log P of 3.95. Is that useful?

DR. LIEBLER: Pretty big, pretty greasy.

DR. BELSITO: And it's essentially insoluble in water.

DR. LIEBLER: Right. Yes, I would guess absorption use is pretty minimal. So, there's no data on that?

MS. FIUME: No data.

DR. LIEBLER: I mean, again, the pulling back, the tox data is (inaudible) very low. I mean, they can't even get an LD50 on it. It's in excess of 2 grams, in excess of 5 grams or dermal/oral, and then we do have that 28-day oral and that repro study was negative. I mean, at this point, I think I could live with it.

SPEAKER: Yes.

DR. LIEBLER: Once we see some of the other data regarding impurities and the chemical structure and I guess if that other group wants to add a dermal absorption, wouldn't be opposed to it. At this point, I don't think we need (inaudible).

DR. BELSITO: I mean, I guess the question becomes why would you want dermal absorption if you have a negative repro?

DR. KLAASSEN: Yes.



DR. LIEBLER: Right.

DR. BELSITO: And you have negative genotoxicity, what are we looking for? And you have the presumption that these are totally insoluble in water, so, there's no way they're going to partition into the skin.

DR. LIEBLER: Yes. Agreed.

DR. BELSITO: So, I mean, I think the major question is: How are they made and what is in them other than what we know about them? So, let's go insufficient impurities, method of manufacture, we'd like some chemical structures. We'll see what we get and we'll deal with it when it comes back to us.

Comments?

DR. STACKHOUSE: Not on that part.

DR. BELSITO: Okay.

DR. STACKHOUSE: Shouldn't be a problem.

DR. KLAASSEN: Great. And, also, the reproductive and developmental study, they were giving a gram per kilogram daily and (inaudible) if there are any effects on reproduction or fertility or development and no signs of general toxicity. So, it looks pretty clean.

MARKS TEAM – MARCH 5, 2012

Okay, let's resume. I think we're done with cucumbers now, and we'll move on to the bis-diglyceryl polyacyladipate-2. How do you say that? Ron? Oh, Monice, how do you say it?

DR. SHANK: Adipate.

DR. MARKS: Adipate, yes, adipate. Okay. This is another first time the panel has seen these two ingredients, the 2 and the 1, and I'll throw it open for whatever are our needs, if any.

DR. SHANK: I have no data needs, but Bart's not here. I wonder if we can't have -- I know there are many different structures for this class. Could we get just one typical structure to get an idea of what it looks like? I tried and I have one, but I'm not too sure I want to show it to the chemists.

DR. HILL: I wasn't very clear from what was given, what exactly we were talking about either. So don't feel bad.

DR. SHANK: Okay.

DR. MARKS: So do you think that will generate -- so Ron Shank, will that generate any data needs?

DR. SHANK: No.

DR. MARKS: No, so you just want a chemical structure in this or whatever. That's an editorial.

DR. SHANK: Pick one that's typical of the group.

MS. FIUME: I will pass that along to Bart.

DR. SHANK: Thank you.

DR. HILL: Well, actually what I wrote in the book here was "using our groups, it should be still possible to provide a general structural picture."

DR. SHANK: I have guessed that the molecular weight is about in the range of 1,200, so that'll help knowing that it's a very large molecule.

DR. MARKS: So when I reviewed it, the needs I had were that the 2 undiluted was not an irritant, 25 percent it was not a sensitizer with a GMPT, with the guinea-pig maximization test, and that we have a use concentration of 38 percent.

MS. FIUME: It was not included in Wave 2. The information just came in. The corrected use concentration is actually 36 percent, not much different. And there is an RIPT at 36 percent that was not distributed because it just came in. And there was no evidence of sensitization.

DR. MARKS: Great, okay. So that's been addressed. Thank you, Monice. And then the 1, that was a non-sensitizer at 100 percent, so that's perfectly fine. So this is okay on the skin sensitization. So tomorrow then I would -- I want to ask Tom, and then Rachel, you had a comment. So Tom, everything fine from your perspective? Don't need any --

DR. SLAGA: Well, it has plenty of genotoxicity, both bacterial and mammalian cells. As Ron said, it's not irritating. And since I don't -- the only question is the structure -- there's nothing on impurities -- it's really nothing even on manufacturing -- we don't know.

DR. MARKS: Right, that's what I have.

DR. SLAGA: We don't know really what it is.



DR. MARKS: So do we want to put it in? Do we still want to move forward with safe? We don't need to have impurities or method of manufacture? Do we want to put it insufficient to get those data?

DR. HILL: Well --

DR. MARKS: It won't change probably our conclusion, I assume.

DR. HILL: Right, and I note that if you look at the appearance in the table, in one case we have a --

DR. MARKS: What page are you on?

DR. HILL: Oh, I'm sorry. Panel Book page 13, report page 7. The appearance of the bis-diglyceryl polyacyladipate-

Is a yellow, pasty, tacky, stringy substance. So we shouldn't get yellow given the nature of the compounds unless there's some colored impurities in there I think. Yes, because we're just looking at caprylic, capric, hydroxystearic, and isostearic, there are no double bonds from the fatty acids. So yellow in -2 and yellowish in -1, those have got to be impurities and enough to give color.

DR. MARKS: So do you think -- do you want an insufficient data announcement or move forward with safe and just note that we would like -- Ron, Tom?

DR. HILL: These are used in high concentrations in leave-ons, right?

DR. MARKS: Oh, yes.

DR. HILL: It may very well be that these are the descriptions of the raw materials and that's not the way they end up in the finished products, but we don't have any information on that, do we?

DR. SLAGA: It would be nice to know what the structure is and how it's manufactured.

DR. MARKS: First I'm going to ask David, is this directly related to what we're talking about here? So identify yourself.

DR. STEINBERG: David Steinberg. It's basically a lanolin substitute. So it's used wherever lanolin is used, which is why you have the high concentrations in lip glosses and things like that.

DR. HILL: Right, and that's why I was wondering about if we got yellow color, it's possibly suggestive of -- actually if you have a very small amount of the highly colored something, then that will give a yellow color or it could be 20 percent of something yellowish. I don't know what that might be.

DR. STEINBERG: I think we could find out --

DR. HILL: To make it look like lanolin?

DR. MARKS: Jay and David, how difficult do you think to get the method of manufacture and impurities? I mean, are we going to need to put in an insufficient data announcement to get that?

DR. ANSELL: Well, I think the request is reasonable. I would have an issue, though, with a suggestion for insufficiency in a first-time report, and I can explain that briefly. From a process standpoint, we all support the concept that these reviews that the staff is going to select from the available data those data which they think are most relevant, and we all support that. I think it's entirely appropriate. But in coming through with the staff, if the panel disagrees or concludes that there's some data that they find important, I don't think the conclusion can be that the data isn't available, it's just that it wasn't potentially included. And, therefore, at least in these first-level reviews, if the panel comes back and asks for additional data, I think it should be remanded to the panel -- the panel should remand it back to staff to determine whether that data was something that was there and staff did not perceive that that would be important or not.

So the request is entirely appropriate. We'd be happy to do that. I just would object to -- I don't think it would be appropriate to advance this to the next level with insufficient.

DR. MARKS: Right. We wouldn't move it to a draft tentative report with a conclusion of insufficient. We would just put in an insufficient data notice, request that.

Rachel, in a minute. I know you want -- so how do you want to proceed? Do you want to put an insufficient data notice, I think, rather than safe? Our intent is it's going to be safe, but we really would like to have this data, I presume. How do you feel, Ron, Ron, and Tom?

DR. HILL: One of the reasons I looked over and hoped he would wander up to the microphone and comment is I had thought it's probably a GRAS dye substance that's added to make it look like lanolin. That would have been my guess. I think given that that's the probability here, go forward, but get that information in before we finalize the report.

DR. MARKS: Ron Shank and Tom, safe or insufficient data notice?

DR. SHANK: I would say safe. I have no data needs.

DR. MARKS: Tom?

DR. SLAGA: Well, I had safe down.



DR. MARKS: Okay, so at least at this point we're going to move forward with a safe, but so noted that we really would like the method of manufacture and impurities. Rachel?

MS. WEINTRAUB: Upon my reading, not only are impurities a method of manufacture, it sort of pulls in terms of data provided. But there's two others which seem even more significant -- toxicokinetics and carcinogenicity. Also there was no data provided.

DR. SLAGA: When we have sufficient mutagenicity, we don't need that.

MS. WEINTRAUB: Okay.

DR. SLAGA: And we have both bacterial and mammalian, both in vitro and in vivo.

DR. HILL: And I will say in my case, furthermore, there's no alerting characteristics about the structure that would make me worry about that.

MS. WEINTRAUB: Okay.

DR. HILL: Even not knowing the exact specific structure, anything could possibly -- still that'd be the case.

DR. MARKS: Okay, so tomorrow I'll move that we issue a draft tentative report with a conclusion as safe, but we would like to enhance the report with three items. One is the method of manufacture, the impurities, and the typical chemical structure of these compounds. Anything else? Okay.

DR. HILL: Because it's particularly noteworthy there that if you look at the two ingredients and the way they're described, they're the exact same thing, but obviously they're not.

DR. MARKS: Yes. And obviously we'll get that new skin sensitization data in the draft tentative report.

DR. BERGFELD: Excuse me, do you think in your discussion which you haven't mentioned yet that you should include the lack of this data and the reasons that you are not demanding it?

DR. MARKS: The lack of --

DR. BERGFELD: The toxicokinetic data and the carcinogenicity, and there was another one that you mentioned, Rachel.

MS. WEINTRAUB: I'm sorry?

DR. BERGFELD: That's all right.

MS. WEINTRAUB: Yeah, it was toxicokinetics, carcinogenicity, and then impurities, and there was one other -- method of manufacture.

DR. MARKS: So Tom, do you think that needs to be addressed in a discussion, or if you were reading this as a cosmetic formulator that would be --

DR. SLAGA: We usually when we have sufficient mutagenicity, we don't ask -- especially if the compound is non-irritating -- then we make the decision --

DR. MARKS: And we haven't specifically put that in the discussion in the past? We have enough that we don't need.

DR. SLAGA: Oh, I think we have, Jim.

DR. MARKS: We have, so we would put that in the discussion?

DR. SLAGA: Yeah.

DR. MARKS: Okay, fine. And the toxicokinetics, the reason --

DR. SLAGA: A very large molecule.

DR. MARKS: Very large molecule.

DR. SLAGA: And highly lipid soluble.

DR. MARKS: Okay.

DR. HILL: Well, I don't like that escape valve because it actually gives -- and this was another question I had. I thought it was surprising that in the chemical properties data, they actually give us a specific log P, which is 4. So there's nothing there precluding dermal penetration, and I'm not sure that the molecular weight is large enough to write that off either. But it's just the constituent compounds are nothing of concern for me. Even if it penetrates, there should be no deleterious consequences of that.

DR. MARKS: So I think then, Rachel, and we could put that in the discussion. And even though there may be absorption, even though they're large molecules, even if it's absorbed, we're not concerned.

DR. HILL: At least that's how I feel about it.

DR. MARKS: Right.



DR. HILL: That may not be how they feel about it. But molecular weights we don't have because they're not exact structures; that's the thing. We could have a molecular weight range, and we could make that part of our information request, but I don't know.

DR. MARKS: Ron, that didn't come up. Ron Shank, are you fine with that in the discussion, the way I kind of formed these?

DR. SHANK: Yeah.

DR. HILL: We could see what the other team thinks on that, too, I think.



Rep

ort

(Draft) Tentative Report

On the Safety Assessment of Bis-Diglyceryl Polyacyladipate-2 and Bis-Diglyceryl Polyacyladipate-1 as Used in Cosmetics

June 11, 2012

The 2012 Cosmetic Ingredient Review Expert Panel members are: Chairman, 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 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 safety assessment was prepared by Monice M. Fiume, Senior Scientific Analyst/Writer.

© Cosmetic Ingredient Review

1101 17th Street, NW, Suite 412 ♢ Washington, DC 20036-4702 ♢ ph 202.331.0651 ♢ fax 202.331.0088 ♢ [email protected]



ii

TABLE OF CONTENTS

Draft Abstract .................................................................................................................................................................................................................................... 1 Introduction ....................................................................................................................................................................................................................................... 1 Chemistry .......................................................................................................................................................................................................................................... 1

Definitions ................................................................................................................................................................................................................................... 1 Physical and Chemical Properties ............................................................................................................................................................................................... 1 Method of Manufacture ............................................................................................................................................................................................................... 1 Impurities ..................................................................................................................................................................................................................................... 1

Use ..................................................................................................................................................................................................................................................... 2 Cosmetic ...................................................................................................................................................................................................................................... 2

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

Toxicological studies ......................................................................................................................................................................................................................... 2 Single Dose (Acute) Toxicity ...................................................................................................................................................................................................... 2

Dermal .................................................................................................................................................................................................................................... 2 Oral ......................................................................................................................................................................................................................................... 3

Repeated Dose Toxicity ............................................................................................................................................................................................................... 3 Oral ......................................................................................................................................................................................................................................... 3

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

In Vitro ......................................................................................................................................................................................................................................... 3 In Vivo ......................................................................................................................................................................................................................................... 4

Carcinogenicity ................................................................................................................................................................................................................................. 4 Irritation and Sensitization ................................................................................................................................................................................................................ 4

Skin Irritation ............................................................................................................................................................................................................................... 4 Non-Human ............................................................................................................................................................................................................................ 4 Human .................................................................................................................................................................................................................................... 4

Skin Sensitization ........................................................................................................................................................................................................................ 5 Non-Human ............................................................................................................................................................................................................................ 5 Human .................................................................................................................................................................................................................................... 5

Comedogenicity ........................................................................................................................................................................................................................... 5 Ocular Irritation ........................................................................................................................................................................................................................... 6

Summary ............................................................................................................................................................................................................................................ 6 Draft Discussion ................................................................................................................................................................................................................................ 7 Draft Conclusion ............................................................................................................................................................................................................................... 7 Figures and Tables ............................................................................................................................................................................................................................ 8

Figure 1. Chemical Structures. ................................................................................................................................................................................................... 8 Table 1. Chemical and physical properties .............................................................................................................................................................................. 10 Table 2. Frequency and concentration of use according to duration and type of exposure .................................................................................................... 10

References ....................................................................................................................................................................................................................................... 11



1

DRAFT ABSTRACT

The CIR Expert Panel assessed the safety of bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 as used in cosmetics, finding that these ingredients are [to be completed following the meeting]. Both ingredients are lanolin substitutes and are reported to function in cosmetics as skin conditioning agents – emollients. The Panel reviewed available animal and clinical data in making its determination of safety.

INTRODUCTION

This assessment reviews the safety of bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 as used

in over 400 cosmetic formulations. These ingredients are reported to function as skin conditioning agents - emollients.

Initially in the review process, a Notice to Proceed without the Preparation of a Scientific Literature Review was issued due

to the lack of published information relevant to the safety of these ingredients as used in cosmetic formulations. This assess-

ment includes unpublished data that were submitted in response to that Notice to Proceed.

CHEMISTRY

Definitions

Bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 are mixed fatty acid esters. Bis-diglyceryl

polyacyladipate-2 (CAS No. 82249-33-0) is the adipic acid diester of a mixed diglyceryl ester of caprylic, capric, stearic, iso-

stearic and hydroxystearic acids, while bis-diglyceryl polyacyladipate-1 (CAS No. 135229-94-6;) is the adipic acid diester of

a mixed diglyceryl ester of caprylic, capric, hydroxystearic and isostearic acids.1

Due to the three different isomers (alpha,alpha-, beta,beta-, and alpha,beta-) present in diglycerin, the two different

connectivities (alpha- and beta-) in which diglycerin can be attached to adipic acid, and the variety of fatty acid esters (eg,

caprylate, caprate, stearate, isostearate, and hydroxystearate) to be formed with the reactive hydroxyls of bis-diglyceryl

adipate, there are a multitude of structural configurations possible within each bis-diglyceryl polyacyladipate ingredient.

Figure 1 depicts the structures of the mixture of chemicals present in the bis-diglyceryl polyacyladipate ingredients.

Physical and Chemical Properties

The available physical and chemical properties data are provided in Table 1.

Method of Manufacture

Both bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 are manufactured in one-pot reactions

with heat, catalysts, and reduced pressure.2 The raw materials used in the production of both of these esters are diglycerin,

adipic acid, isostearic acid, 12-hydroxystearic acid, n-octanoic acid, n-decanoic acid, and catalyst. Stearic acid is also a raw

material for the production of bis-diglyceryl polyacyladipate-2.

Impurities

Acid number and hydroxyl number indicate that bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladi-

pate-1 are essentially free of starting raw materials.2 These diesters are yellow in color. However, the color is not an indica-

tion of impurities; these diesters are mainly based on natural raw materials that are not colorless. Additionally, there is no

chemical bleaching applied to the final products.

The following parameters are checked regularly in bis-diglyceryl polyacyladipate-2, with typical findings given as:

aflatoxin B1, B2, G1, and G2, <0.10 ppb each; heavy metals, i.e. As, Cd, Cr, Ni, Pb, Hg, Cu, Sn, <1 ppm each; pesticides –

organochlorine, organocholorophosphorous, and pyrethroids, <0.01 ppm each class; various PCBs, <0.01 ppm each class;

microbiology – pathogens: absent, total viable count: <10 FU/g, and yeast/molds: <10 CFU/g.



2

USE

Cosmetic

Bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 are suitable as lanolin substitutes,3,4 and are

reported to function as skin conditioning agents – emollients.1 The Food and Drug Administration (FDA) collects informa-

tion from manufacturers on the use of individual ingredients in cosmetics as a function of cosmetic product category in its

Voluntary Cosmetic Registration Program (VCRP). VCRP data obtained from the FDA in 2011 indicate that bis-diglyceryl

polyacyladipate-2 is used in 440 cosmetic formulations and that bis-diglyceryl polyacyladipate-1 is used in 5 cosmetic

formulations.5 Data received in response to a survey of the maximum reported use concentration by category conducted by

the Personal Care Products Council (Council) report that bis-diglyceryl polyacyladipate-2 is used in leave-on products at

concentrations of up to 36% (reported for lipsticks) and in rinse-off products at concentrations up to 21% (reported for eye

makeup remover).6 Bis-diglyceryl polyacyladipate-1 is used in leave-on products at concentrations of up to 10% (reported

for tonics, dressings, and other hair grooming aids) and in rinse-off products at a concentration of 4% (reported for eye

makeup remover). Frequency and concentration of use data categorized by exposure and duration of use are provided in

Table 2.

Products containing bis-diglyceryl polyacyladipate-2 may be used near the eye area and in products in which inci-

dental ingestion may occur. Additionally, bis-diglyceryl polyacyladipate-2 is used in face powders at up to 0.8% and in

“other” fragrance preparations at 2%; it is possible that this fragrance preparation is sprayed. In practice, 95% to 99% of the

droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters >10 µm.7-10 Therefore, most drop-

lets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and bronchial regions and

would not be respirable (i.e., they would not enter the lungs) to any appreciable amount.7,9

Both bis-diglyceryl polyacyladipate-2 and polyacyladipate-1 are listed in the European Union inventory of cosmetic

ingredients.11

TOXICOKINETICS

Absorption, Distribution, Metabolism, and Excretion

Published toxicokinetics data were not found and unpublished data were not provided.

TOXICOLOGICAL STUDIES

Single Dose (Acute) Toxicity

Dermal

Bis-Diglyceryl Polyacyladipate-2

Groups of 5 male and 5 female Wistar rats were dosed with a single 24-h application of 2000 mg/kg bw undiluted

bis-diglyceryl polyacyladipate-2.12 The exposure site was a shaved 5 cm x 10 cm area on the back. None of the animals

died, and no signs of dermal irritation were observed. Body wt gains were normal in males but reduced in females. The der-

mal LD50 of bis-diglyceryl polyacyladipate-2 is >2000 mg/kg bw.


Groups of 5 male and 5 female Sprague-Dawley rats were exposed to a single 24-h semi-occlusive application of

2000 mg/kg bw undiluted bis-diglyceryl polyacyladipate-1.13 The exposure site was a shaved 5 cm x 4 cm area on the back.

None of the animals died, and no signs of toxicity or dermal irritation were observed. The dermal LD50 of bis-diglyceryl

polyacyladipate-1 is >2000 mg/kg bw.



3

Oral


Groups of 5 male and 5 female Wistar rats were dosed once by gavage with 2000 mg/kg bw bis-diglyceryl polyacyl-

adipate-2 in corn oil.14 None of the animals died, and the oral LD50 of bis-diglyceryl polyacyladipate-2 is >2000 mg/kg bw.


Groups of 5 male and 5 female Sprague-Dawley rats were dosed once by gavage with 5000 mg/kg bw bis-diglyceryl

polyacyladipate-1 in arachis oil, with a dose volume of 10 ml/kg.15 None of the animals died, and no signs of systemic toxi-

city were reported. The oral LD50 of bis-diglyceryl polyacyladipate-1 is >5000 mg/kg bw.

Repeated Dose Toxicity

Oral


Groups of 5 male and 5 female Wistar rats were dosed by gavage with 0, 180, 1800, and 4500 mg/kg bw (corre-

sponding to 0, 0.2, 2.0, and 5.0 ml/kg bw, respectively) bis-diglyceryl polyacyladipate-2 in corn oil once daily for 28 days.16

The test volume was 10 ml/kg bw. The animals were killed at the termination of dosing, and gross and microscopic examina-

tions were performed. The only observations made were in the high dose group males; the slight but significant reduction in

total bilirubin content and increase is prostate weight were not considered biologically relevant. The no-observable adverse

effect level (NOAEL) was 1800 mg/kg bw (2 ml/kg bw) bis-diglyceryl polyacyladipate-2.

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY


The reproductive toxicity potential of bis-diglyceryl polyacyladipate-2 was determined in a one-generation study us-

ing groups of 24 male and 24 female Sprague-Dawley rats.17 The male animals were dosed daily by gavage with 0 or 1000

mg/kg bw bis-diglyceryl polyacyladipate-2 in corn oil from 10 wks prior to mating until the day before being killed (day 99),

and the female rats were dosed by gavage with the same doses from 2 wks prior to mating until weaning and were killed day

21 following delivery. The dose volume was 10 ml/kg bw. The litters were culled on day 4, and the remaining 8 pups/litter

were killed on day 21. Bis-diglyceryl polyacyladipate-2 had no effects on reproduction, fertility, or development, and no

signs of general toxicity were observed.

GENOTOXICITY

In Vitro


The mutagenic potential of bis-diglyceryl polyacyladipate-2 was evaluated in an Ames test performed using Sal-

monella typhimurium strains TA1535, TA1537, TA1538, TA98, and TA100, with and without metabolic activation.18 The

researcher stated that the test material was insoluble in all solvents specified for the Ames test, and for this reason, a spot test

was performed and the product was tested directly and undiluted. Bis-diglyceryl polyacyladipate-2 was not mutagenic with

or without metabolic activation. Appropriate negative and positive control results were valid.

A chromosomal aberration assay was performed using Chinese hamster lung fibroblasts (V79 cells) with and with-

out metabolic activation with 40-400 µg/ml bis-diglyceryl polyacyladipate-2.19 Ethanol was the solvent. Bis-diglyceryl

polyacyladipate-2 did not induce a significant increase in the incidence of chromosomal aberrations, and was not clastogenic.

Appropriate negative and positive control results were valid.



4

In Vivo


A micronucleus test was performed in mice to evaluate the genotoxic potential of bis-diglyceryl polyacyladipate-

2.20 Three groups of 5 male and 5 female NMRI mice were given a single oral dose of 15,000 mg/kg bw in corn oil, and each

group was killed 24, 48, or 72 h after dosing. The dose volume was 30 ml/kg bw. Bis-diglyceryl polyacyladipate-2 was not

genotoxic. A difference in the number of polychromatic erythrocytes compared to normochromatic erythrocytes in males (an

increase in the 48 h group and decrease in the 72 h group) was not considered a genotoxic effect. Vehicle and appropriate

positive control results were valid.

CARCINOGENICITY

Published carcinogenicity studies were not found and unpublished data were not provided.

IRRITATION AND SENSITIZATION

Skin Irritation

Non-Human


The dermal irritation potential of bis-diglyceryl polyacyladipate-2 was evaluated in an acute dermal irritation/corro-

sion test in 3 rabbits.21 A dose of 2000 mg/kg was applied neat to a shaved 8 cm x 15 cm area on the back of each animal

under a semi-occlusive covering for 4 h. The test site was examined for signs of irritation at various intervals for 0.5-72 h

after patch removal. No erythema or edema was observed, and bis-diglyceryl polyacyladipate-2 was non-irritating to rabbit

skin after a single 4-h semi-occlusive application.

The cumulative irritation potential of 5 and 40% bis-diglyceryl polyacyladipate-2 in petrolatum (pet.) was evaluated

in guinea pigs, 3 per group.22 The test material was applied to a shaved area of the flank of each animal once daily for 3 con-

secutive days, and the test sites were scored 24 h after each application. The test volume was not stated. The cumulative irri-

tation index was 1.2/4 with 5% and 1.3/4 with 40% bis-diglyceryl polyacyladipate-2, indicating that the test material was a

weak irritant in guinea pig skin.

Human


The dermal irritation potential of 5% bis-diglyceryl polyacyladipate-2 in pet. was evaluated in 44 subjects.22 The

test material was applied to the intact skin of the forearm for 24 h under an occlusive patch. The test volume was not stated.

No reactions were observed after 24 h, and 5% bis-diglyceryl polyacyladipate-2 was not irritating to human skin after a single

24-h application.

Fifteen male and 35 female subjects were used to evaluate the dermal irritation potential of undiluted bis-diglyceryl

polyacyladipate-2.23 Twelve subjects were classified as atopic and seven as dermal sensitive. An occlusive patch (defined as

a commercial plaster) containing 2 mg/cm2 of the test article was applied to the back of each subject for 48 h; the size of the

application area was not specified. The test site was scored for irritation upon patch removal and 24 h after patch removal.

Well-defined erythema was observed in one subject upon patch removal, but not 24 h later; the researcher determined this

reaction to be toxic-irritative. It was concluded that undiluted bis-diglyceryl polyacyladipate-2 had no irritating potential in

human skin.



5

Skin Sensitization

Non-Human


A guinea pig maximization test (GPMT) was used to determine the skin sensitization potential of bis-diglyceryl

polyacyladipate-2.24 Groups of 10 male and 10 female Pirbright white guinea pigs were used. A test concentration of 5%

was used during intradermal induction. The topical induction concentration was 25% in pet. (w/v), and the test article was

applied for 48 h under an occlusive patch to a shaved 4 cm x 6 cm area on the shoulder of each animal; the test area was pre-

treated with 10% sodium lauryl sulfate (SLS) 24 h prior to patching. The challenge was performed 14 days after induction,

and a 24-h occlusive patch with 25% bis-diglyceryl polyacyladipate-2 in pet. was applied to a shaved 5 cm x 5 cm area on the

flank of each animal. Vehicle controls (20 animals) were used, and 2,4-dinitrorchlorobenzene was used as a positive control.

Bis-diglyceryl polyacyladipate-2 did not induce any allergic response and was classified as non-sensitizing.


A GPMT was performed in Dunkin-Hartley guinea pigs to determine the sensitization potential of bis-diglyceryl

polyacyladipate-1.25 The test concentration for intradermal induction was 25% (w/v), and the topical induction was 0.2-0.3

ml undiluted test article applied with a 2 cm x 4 cm filter paper without SLS pretreatment. The challenge application was

0.1-0.2 ml undiluted test article applied with a 2 cm x 2 cm filter paper. Ten vehicle control animals were used, and the posi-

tive control was formaldehyde. Bis-diglyceryl polyacyladipate-1 did not produce any sensitization reactions.

Human


A human repeated insult patch test (HRIPT) of a lipstick containing 36% bis-diglyceryl polyacyladipate was initiat-

ed with 114 subjects and completed in 102 subjects.26 None of the subjects discontinued testing because of test-article related

effects. Approximately 0.1 ml of neat test material was applied to a 2 cm x 2 cm occlusive patch, and the patches were ap-

plied three times per wk for 3 wks during the induction phase of the study. The 48-h challenge patches were applied to a

treated and naive site after a 10-15 day non-treatment period. One subject had a reaction score of 2 (moderate erythema) at

induction readings 4-7; there were no other reactions recorded for this subject during induction or at challenge. The lipstick

containing 36% bis-diglyceryl polyacyladipate was not an irritant or a sensitizer.

Comedogenicity


The comedogenic potential of bis-diglyceryl polyacyladipate-2 was evaluated in rabbits.27 A volume of 0.5 ml of

the test article was applied neat once daily, 5 days/wk for 4 wks, to the right ears of 4 male New Zealand White (NZW) rab-

bits. The contralateral ears served as untreated controls. With the initial application, increasing visible hyperkeratosis ex-

tending to possible comedones (score 1/3) was observed in all four test ears. However, the scores were 0/3 for all remaining

test days, and the overall comedogenic score was 0/3 for all four rabbits. It was concluded that bis-diglyceryl polyacyladi-

pate-2 was non-comedogenic. Redness of the treated ears was observed throughout the study.


Three female NZW rabbits were used to evaluate the comedogenic potential of bis-diglyceryl polyacyladipate-1.28

An unspecified volume of the test article was applied neat once daily, 5 days/wk for 3 wks, to the left ears of the rabbits. The

right ears served as untreated controls. Gross examination reported slight transient hyperkeratosis on the control and/or

treated ears of two rabbits. No hyperkeratosis or comedones were found upon microscopic examination. Bis-diglyceryl

polyacyladipate-1 was non-comedogenic.



6

Ocular Irritation


The ocular irritation potential of bis-diglyceryl polyacyladipate-2 was evaluated in an acute eye irritation/corrosion

test using NZW rabbits.29 Undiluted test substance, 0.1 ml, was instilled into the conjunctival sac of one eye of each of three

rabbits, and the contralateral eye served as a negative control. Eyes were examined for up to 72 h post-instillation. Some

mild irritation of the conjunctivae was observed (a single report of a score of 2/4); all effects were reversible after 5 days.

Bis-diglyceryl polyacyladipate-2 was classified as non-irritating to rabbit eyes.

SUMMARY

Bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipdate-1 are reported to function in cosmetics as skin

conditioning agents – emollients. Bis-diglyceryl polyacyladipate-2 is used in 440 cosmetic formulations; it is used in leave-

on products at concentrations of up to 36% (reported for lipsticks) and in rinse-off products at concentrations up to 21%

(reported for eye makeup remover). Bis-diglyceryl polyacyladipate-1 is used in 5 cosmetic formulations, and it is used in

leave-on products at concentrations of up to 10% (reported for tonics, dressings, and other hair grooming aids) and in rinse-

off products at a concentration of 4% (reported for eye make-up remover).

Single dermal doses of undiluted bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipdate-1 were not

irritating to rabbit skin. None of the animals died during the studies, and the dermal LD50 was >2000 mg/kg bis-diglyceryl

polyacyladipate-2 and for bis-diglyceryl polyacyladipdate-1.

Oral single-dose, repeated-dose, and reproductive studies were performed using rats. No mortality was observed fol-

lowing a single dose of 2000 mg/kg bis-diglyceryl polyacyladipate-2 and of 5000 mg/kg bis-diglyceryl polyacyladipate-1. In

a 28-day oral toxicity study, the NOAEL was 1800 mg/kg bw (2 ml/kg bw) bis-diglyceryl polyacyladipate-2. In a one-gener-

ation reproduction study, oral administration of 1000 mg/kg bis-diglyceryl polyacyladipate-2 had no effects on reproduction,

fertility, or development, and no signs of general toxicity were observed during the study.

Undiluted bis-diglyceryl polyacyladipate-2 was not mutagenic in a spot test using S. typhimurium with or without

metabolic activation, and 40-400 µg/ml bis-diglyceryl polyacyladipate-2 was not clastogenic in a chromosomal aberration

assay using Chinese hamster lung fibroblasts. Bis-diglyceryl polyacyladipate-2 was not genotoxic in a micronucleus test in

which NMRI mice were given a single oral dose of 15,000 mg/kg bw in mice in corn oil, and each groups was killed 24, 48,

or 72 h after dosing.

A single 24-h semi-occlusive application of 2000 mg/kg bis-diglyceryl polyacyladipate-2, applied neat, was not irri-

tating in rabbit skin, but 5-40% bis-diglyceryl polyacyladipate-2 in pet. was a weak irritant in guinea pig skin in a 3-day

cumulative irritation study. Bis-diglyceryl polyacyladipate-2 patched occlusively at 5% for 24 h or undiluted for 48 h was

not irritating to human skin. Neither bis-diglyceryl polyacyladipate-2 nor bis-diglyceryl polyacyladipate-1 were sensitizers in

GPMTs. For bis-diglycerylpolyacyladipate-2, the intradermal induction concentration was 5% with SLS pre-treatment, the

topical induction concentration was 25%, and the challenge concentration was 25% with SLS pre-treatment. With bis-digly-

ceryl polyacyladipate-1, 25% without SLS was used for intradermal induction and undiluted test article was used for topical

induction and for the challenge. A lipstick containing 36% bis-diglyceryl polyacyladipate was not an irritant or a sensitizer in

a HRIPT. Neither diester was comedogenic in rabbit ears.

Undiluted bis-diglyceryl polyacyladipate-2 was not an ocular irritant in rabbit eyes.



7

DRAFT DISCUSSION

Both a Notice to Proceed without the Preparation of a Scientific Literature Review and an Insufficient Data

Announcement were issued during the preparation of this safety assessment. Data were received in response to both of these

requests that facilitated the preparation of the assessment. The CIR Expert Panel recognizes that data gaps remain regarding

toxicokinetics and carcinogenicity data. However, bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 are

very large highly lipid-soluble compounds that are not expected to pass through the stratum corneum of the skin, so signifi-

cant dermal absorption is not expected. Even if these ingredients were to penetrate the skin, the constituent compounds do

not present a toxicological concern. Additionally, bis-diglyceryl polyacyladipate-2 was not genotoxic in an Ames test, a

chromosomal aberration assay, or a mouse micronucleus test. Therefore, the Expert Panel determined the existing data were

adequate to assess the safety of these two ingredients.

Because bis-diglyceryl polyacyladipate-2 is reported to be used in “other” fragrance preparations, and that these

preparations may be aerosolized, the Panel discussed the issue of incidental inhalation exposure. In the absence of inhalation

data, the Panel noted that bis-diglyceryl polyacyladipate-2 did not produce systemic toxicity at high doses in single dose oral

and dermal studies or in 28-day oral repeated dose study, was not a reproductive and developmental toxicant, was not geno-

toxic in an Ames test or in a chromosomal aberration assay with Chinese hamster lung fibroblasts, and caused no irritation or

sensitization in humans at concentrations up to 36%. Further, this ingredient is reportedly used at concentrations of ≤2% in

cosmetic products that may be aerosolized. The Panel noted that 95% – 99% of droplets/particles produced in cosmetic aero-

sols would not be respirable to any appreciable amount. However, the potential for inhalation toxicity is not limited to respi-

rable droplets/particles deposited in the lungs. Inhaled droplets/particles deposited in the nasopharyngeal and bronchial

regions of the respiratory tract may cause toxic effects depending on their chemical and other properties. Nevertheless, cou-

pled with the small actual exposure in the breathing zone and the concentrations at which the ingredients are used, the avail-

able information indicates that incidental inhalation would not be a significant route of exposure that might lead to local res-

piratory or systemic effects.

DRAFT CONCLUSION

The CIR Expert Panel concluded that bis-diglyceryl polyacyladipate-2 and bis-diglyceryl polyacyladipate-1 are safe

in cosmetic formulations in the present practices of use and concentration.



8

FIGURES AND TABLES

Figure 1. Chemical Structures. The following structures represent the mixture of chemicals in bis-diglyceryl polyacyladipate ingredients. - Wherein O-R represents the ester of caprylic, capric, stearic, isostearic or hydroxystearic acid, in the case of Bis-Diglyceryl Polyacyladipate-2 - Wherein O-R represents the ester of caprylic, capric, isostearic or hydroxystearic acid, in the case of Bis-Diglyceryl Polyacyladipate-1

O

O

O

O

O

OR

RO

O

OR

OR

RO

RO

O

O

O

O

O

OR

RO

O

OR

OR

RO

RO

O

O

O

O

RO O

ORRO

ORO

ORRO

O

O

O

O

RO O

OROOR

OR

RO

RO

O

O

O

O

O OR

ORO

OR

ORRO

RO

O

O

O

O

O OR

ORO

RO

RO

OR

OR

O

O

O

O

O

OR

RO

O

RO

RO

OR

OR

O

O

O

O

RO

O

RO

RO

RO O

RO OR

O

O

O

O

RO

O

RO

RO

RO O

OR

OR

O

O

O

O

RO

O

RO

RO

O OR

OR

OR

O

O

O

O

RO

O

RO

RO

O OR

RO

RO

O

O

O

O

RO

ORO

RO

RO O

RO OR



9

Figure 1 (continued). Chemical Structures. The following structures represent the mixture of chemicals in bis-diglyceryl polyacyladipate ingredients

O

O

O

O

RO

ORO

RO

RO O

OR

OR

O

O

O

O

RO

ORO

RO

O OR

OR

OR

O

O

O

O

RO

ORO

RO

O OR

RO

RO

O

O

O

O

RO O

ORO

ORRO

OR

OR

O

O

O

O

O OR

ORO

ORROOR

OR

O

O

O

O

O OR

ORO

ORRO

RO

RO

O

O

O

O

O OR

ORO

RO

RO

OR

OR

O

O

O

O

O OR

ORO

RO

RO

RO

RO

O

O

O

O

O OR

ORO

RO

RORO

RO



10

Table 1. Chemical and physical properties

Property Description Reference Bis-Diglyceryl Polyacyladipate-2

appearance yellow, pasty, tacky, stringy substance 3 melting point ca. 35°C 30 density 0.979 g/cm3 (47°C) 30 water solubility <0.001g/l (20°C) 30 solubility (other) soluble in diethylether, hexane, benzene, and hot ethanol; miscible with fats, oils, and paraffin hydrocarbons 3 specific gravity ~0.96 g/ml (40°C) 31 log P 3.95 30 saponification value 270-290 mg KOH/g 3 acid value max. 2 mg KOH/g 3 iodine value max. 3 g I2/100 g 3

Bis-Diglyceryl Polyacyladipate-1 appearance yellowish, high-viscosity fluid 4 water solubility practically insoluble 4 solubility (other) soluble in diethylether, and petroleum benzene miscible with fats, oils, and paraffin 4 saponification value 260-285 mg KOH/g 4 acid value max. 3 mg KOH/g 4 iodine value max. 5 g I2/100 g 4

Table 2. Frequency and concentration of use according to duration and type of exposure

Bis-Diglyceryl Polyacyladipate-2 Bis-Diglyceryl Polyacyladipate-1

# of Use5 Max. Conc. of Use (%)6 # of Uses5 Max. Conc. of Use (%)6

Totals* 440 0.1-36 5 0.2-10

Duration of Use

Leave-On 418 0.1-36 5 0.2-10

Rinse Off 22 0.2-21 NR 4

Diluted for (Bath) Use NR NR NR NR

Exposure Type

Eye Area 51 1-21 NR 2-7

Incidental Ingestion 227 5-36 2 NR

Incidental Inhalation - Spray 8a 0.5a; 2 (in a fragrance) NR NR

Incidental Inhalation - Powder 21 0.1-0.8 1 0.2-2

Dermal Contact 401 0.1-21 4 0.2-7

Deodorant (underarm) NR NR NR NR

Hair - Non-Coloring 19 1-15 1 10

Hair-Coloring 14 3 NR NR

Nail 1 NR NR NR

Mucous Membrane 228 5-36 2 NR

Baby Products NR NR NR NR * Because each ingredient may be used in cosmetics with multiple exposure types, the sum of all exposure types my not equal the sum of total uses. a Includes fragrance and suntan products, in that it is not known whether or not the reported products are sprays. NR – none reported



11

REFERENCES

1. Gottschalck T.E. and Bailey, J. E. International Cosmetic Ingredient Dictionary and Handbook. Washington, DC: Personal Care

Products Council, 2010.

2. Sasol North America Inc. 4-25-2012. [Method of Manufacture and Impurities for Softisan 645 and Softisan 649]. Unpublished data submitted by Sasol North America Inc.

3. Sasol Germany GmbH. Product information for Softisan® 649. http://www.warnergraham.com/images/Softisan649ProdInfo.pdf. 2005.

4. Sasol Germany GmbH. Product information for Softisan® 645. http://www.warnergraham.com/images/Softisan645ProdInfo.pdf. 2003.

5. Food and Drug Administration (FDA). Frequency of use of cosmetic ingredients. FDA Database. 2011. Washington, DC: FDA.Updated Feb 25.

6. Personal Care Products Council. 3-5-2012. Updated Concentration of Use Information for Bis-Diglyceryl Polyacyladipates. Unpublished data submitted by Personal Care Products Council. 3 pages.

7. Bremmer HJ, Prud'homme de Lodder LCH, and Engelen JGM. Cosmetics Fact Sheet: To assess the risks for the consumer; Updated version for ConsExpo 4. 2006. Report No. RIVM 320104001/2006. pp. 1-77.

8. Johnsen MA. The influence of particle size. Spray Technology and Marketing. 2004;November:24-27.

9. Rothe H, Fautz R, Gerber E, Neumann L, Rettinger K, Schuh W, and Gronewold C. Special aspects of cosmetic spray safety evaluations: Principles on inhalation risk assessment. Toxicol Lett. 2011;205:(2):97-104.

10. Rothe H. Special Aspects of Cosmetic Spray Evalulation. 9-26-2011. Unpublished data presented at the 26 September CIR Expert Panel meeting. Washington, D.C.

11. European Commission. European Commission Health and Consumers Cosmetics - Cosing - Database. http://ec.europa.eu/consumers/cosmetics/cosing/. 2010. Date Accessed 2-2-2012.

12. Sasol Germany GmbH. 1990. Robust study summary of acute dermal toxicity test of Softisan 649 in rats. Unpublished data submitted by Industry.

13. Sasol Germany GmbH. 1989. Robust study summary of acute dermal toxicity of Softisan 645 in the rat. Unpublished data submitted by Industry.

14. Sasol Germany GmbH. 1990. Robust study summary of acute oral toxicity of Softisan 649. Unpublished data submitted by Industry.

15. Sasol Germany GmbH. 1989. Robust study summary of acute oral toxicity of Softisan 645 in the rat. Unpublished data submitted by Industry.

16. Sasol Germany GmbH. 1990. Robust study summary of 4-Week oral toxicity study with "SOFTISAN 649" in rats. Unpublished data submitted by Industry.

17. Sasol Germany GmbH. 1996. Robust study summary of Softisan 649 one to two generation reproduction toxicity study in the rat (limit test). Unpublished data submitted by Industry.

18. Sasol Germany GmbH. 1990. Robust study summary of genetic toxicity in vitro test in "SOFTISAN 649".

19. Sasol Germany GmbH. 1996. Robust study summary of in vitro chromosomal aberration assay with Softisan 649. Unpublished data submitted by Industry.

20. Sasol Germany GmbH. 1990. Robust study summary of in vivo micronucleus test of "SOFTISAN 649" in mice. Unpublished data submitted by Industry.



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21. Sasol Germany GmbH. 1990. Robust study summary of acute dermal irritation/corrosion test of SOFTISAN 649 in rabbits. Unpublished data submitted by Industry.

22. Anonymous. 2011. Safety data of Softisan 649 (Bis-Diglyceryl Polyacyladipate-2) - Cumulative skin irritation and human patch test. Unpublished data submitted by Personal Care Products Council. 7 pages.

23. Sasol Germany GmbH. 2003. Robust study summary of human dermal irritation test of SOFTISAN 649. Unpublished data submitted by Industry.

24. Sasol Germany GmbH. 1990. Robust study summary of a guinea pig maximization test of skin sensitisation of Softisan 649. Unpublished data submitted by Industry.

25. Sasol Germany GmbH. 1987. Robust study summary of a Magnusson-Kligman guinea pig maximization study of skin sensitisation of Softisan 645. Unpublished data submitted by Industry.

26. TKL Research Inc. 2009. Repeated insult patch test study of a lipstick containing 36% Bis-Diglyceryl Polyacyladipate-2. TKL Study No. DS105409-9. Unpublished data submitted by Personal Care Products Council. 36 pages.

27. Sasol Germany GmbH. 1988. Robust study summary of comedogenicity assay of SOFTISAN 649 in rabbits. Unpublished data submitted by Industry.

28. Sasol Germany GmbH. 1988. Robust study summary of a comedogenicity assay of Softisan 645. Unpublished data submitted by Industry.

29. Sasol Germany GmbH. 1990. Robust study summary of an acute eye irritation/corrosion test of SOFTISAN 649 in Rabbits. Unpublished data submitted by Industry.

30. Sasol Germany GmbH. EC-Safety Data Sheet for Softisan 649. http://www.warnergraham.com/images/Softisan649MSDS.pdf. 2006.

31. Vaananen, A. and Hannuksela, M. Softisan--a new vehicle for patch testing. Contact Dermatitis. 1986;14:(4):215-216.



SOFTISAN 645 (Bis‐Diglyceryl Polyacyladipate‐1) and

SOFTISAN 649 (Bis‐Diglyceryl Polyacyladipate‐2)

Additional In

form

ation req

uired by CIR Panel

1) M

anufacturing Process for SO

FTISAN 645 and 649

The components needed

for manufacturing of the above m

entioned

SOFTISAN types are charged to a well

cleaned

reactor. After closing the feed

ing valves, p

ressure is red

uced and the reactor is purged

with Nitrogen.

The temperature is raised

slowly to ca. 220°C while the pressure is red

uced in

several steps to less than

100

mbar. W

ater form

ed during reaction is conden

sed. The reaction stops when

the expected amount of water has

been topped

‐up. W

hen

the reaction is completed, the reactor content is transferred to a deo

dorizing unit where

the reaction m

ixture is stripped with steam

. After drying, the final product is discharged to a storage tank.

Raw

materials used for SO

FTSA

N 645: Diglycerin, A

dipic acid, iso‐Stearic acid, 12‐Hydroxystearic acid, n

‐Octanoic

acid, n

‐Decanoic acid and catalyst

Raw

materials used for SO

FTISAN 649: Diglycerin, A

dipic acid, Stearic acid, iso‐Stearic acid, 12‐Hydroxystearic

acid, n

‐Octanoic acid, n

‐Decanoic acid and catalyst

Dis

tribu

ted

for C

omm

ent O

nly

-- D

o N

ot C

ite o

r Quo

te

CIR

Pan

el B

ook

Pag

e 26

H2C‐CH‐CH2‐O‐CH2‐CH‐CH2

H2C‐CH‐CH2‐O‐CH2‐CH‐CH2

RxO

ORx

RxO

O(‐(CO)‐(CH2) 4‐(CO)‐O O

Rx

RxO

O)n orRx

2) Main Structure

WhereasforSO

FTISAN

649

Rx= Acyl group of 12‐Hydroxystearic acid or Stearic acid or Isostearic acid or Octanoic acid or Decanoic acid

orH

forSO

FTISAN

645

Rx= Acyl group of 12‐Hydroxystearic acid or Isostearic acid or Octanoic acid or Decanoic acid or H;

n= 1‐4



Additional In

form

ation req

uired by CIR Panel

Dis

tribu

ted

for C

omm

ent O

nly

-- D

o N

ot C

ite o

r Quo

te

CIR

Pan

el B

ook

Pag

e 27

3) Im

purities and color

Both SOFTISAN types are m

ainly based

on natural raw

materials which are not colorless. Furthermore, there is no

chem

ical bleaching applied to the final product.

Acid number as well as Hydroxyl number give a good indication that the SO

FTISAN types are essen

tially free of

starting materials.

In particular, SOFTISAN 649 is part of an

on‐going monitoring program

, in which the following param

eters are

regularly checked (values given

are typical findings):

Aflatoxins

B1, B

2, G

1 and G2: < 0.10 ppb each

Heavy m

etals As, Cd, C

r, Ni, PB, H

g, Cu, Sn: < 1 ppm each

MicrobiologyPathogens: absent (including sublethal injured)

Total viable count: < 10 CFU

/gYeast/Molds: < 10 CFU

/gPesticides

Organochlorine, Organochlorophosphorus, Pyrethroids: < 0.01 ppm each class

PCBs

28, 52, 101, 118, 138, 153, 180: < 0.01 ppm each class



Additional In

form

ation req

uired by CIR Panel

Dis

tribu

ted

for C

omm

ent O

nly

-- D

o N

ot C

ite o

r Quo

te

CIR

Pan

el B

ook

Pag

e 28

BIS-DIGLYCERYL POLYACYLADIPATE 1 03A - Eyebrow Pencil 03A 51BIS-DIGLYCERYL POLYACYLADIPATE 8 03B - Eyeliner 03BBIS-DIGLYCERYL POLYACYLADIPATE 14 03C - Eye Shadow 03CBIS-DIGLYCERYL POLYACYLADIPATE 1 03D - Eye Lotion 03DBIS-DIGLYCERYL POLYACYLADIPATE 22 03F - Mascara 03FBIS-DIGLYCERYL POLYACYLADIPATE 5 03G - Other Eye Makeup Preparations 03GBIS-DIGLYCERYL POLYACYLADIPATE 2 04B - Perfumes 04B 8BIS-DIGLYCERYL POLYACYLADIPATE 2 04E - Other Fragrance Preparation 04EBIS-DIGLYCERYL POLYACYLADIPATE 2 05A - Hair Conditioner 05A 19BIS-DIGLYCERYL POLYACYLADIPATE 13 05G - Tonics, Dressings, and Other Hair Groomin 05GBIS-DIGLYCERYL POLYACYLADIPATE 4 05I - Other Hair Preparations 05IBIS-DIGLYCERYL POLYACYLADIPATE 14 06A - Hair Dyes and Colors (all types requiring ca 06ABIS-DIGLYCERYL POLYACYLADIPATE 9 07A - Blushers (all types) 07A 401BIS-DIGLYCERYL POLYACYLADIPATE 21 07B - Face Powders 07BBIS-DIGLYCERYL POLYACYLADIPATE 5 07C - Foundations 07CBIS-DIGLYCERYL POLYACYLADIPATE 227 07E - Lipstick 07EBIS-DIGLYCERYL POLYACYLADIPATE 2 07F - Makeup Bases 07FBIS-DIGLYCERYL POLYACYLADIPATE 4 07G - Rouges 07GBIS-DIGLYCERYL POLYACYLADIPATE 33 07I - Other Makeup Preparations 07IBIS-DIGLYCERYL POLYACYLADIPATE 1 08B - Cuticle Softeners 08BBIS-DIGLYCERYL POLYACYLADIPATE 1 10A - Bath Soaps and Detergents 10A 228BIS-DIGLYCERYL POLYACYLADIPATE 1 11E - Shaving Cream 11EBIS-DIGLYCERYL POLYACYLADIPATE 3 12A - Cleansing 12ABIS-DIGLYCERYL POLYACYLADIPATE 5 12C - Face and Neck (exc shave) 12CBIS-DIGLYCERYL POLYACYLADIPATE 12 12D - Body and Hand (exc shave) 12DBIS-DIGLYCERYL POLYACYLADIPATE 17 12F - Moisturizing 12FBIS-DIGLYCERYL POLYACYLADIPATE 1 12G - Night 12GBIS-DIGLYCERYL POLYACYLADIPATE 1 12H - Paste Masks (mud packs) 12H 418BIS-DIGLYCERYL POLYACYLADIPATE 5 12J - Other Skin Care Preps 12J 22BIS-DIGLYCERYL POLYACYLADIPATE 2 13B - Indoor Tanning Preparations 13BBIS-DIGLYCERYL POLYACYLADIPATE 2 13C - Other Suntan Preparations 13C 440

BIS-DIGLYCERYL POLYACYLADIPATE 1 05G - Tonics, Dressings, and Other Hair Groomin 05GBIS-DIGLYCERYL POLYACYLADIPATE 1 07B - Face Powders 07BBIS-DIGLYCERYL POLYACYLADIPATE 2 07E - Lipstick 07EBIS-DIGLYCERYL POLYACYLADIPATE 1 07I - Other Makeup Preparations 07I 5



pink bis-diglyceryl polyacyladipates bis-diglyceryl polyacyladipates ... repeated insult patch test...

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