GREEN Benzyl Alcohol, Benzoic Acid, and its Salts and Ester CIR EXPERT PANEL MEETING JUNE 27-28, 2011 A d m i n i s t r a t i v e June 3, 2011 Memorandum To: CIR Expert Panel From: Wilbur Johnson, Jr. Manager/Lead Specialist Subject: Draft Report on Benzyl Alcohol, Benzoic Acid, and its Salts and Ester In 1998, the CIR Expert Panel issued a final safety assessment on Benzyl Alcohol, Benzoic Acid and Sodium Benzoate, concluding that these ingredients are safe for use in cosmetics at concentrations up to 5%, but that the data are insufficient to support the safety of these ingredients in cosmetic products in which inhalation is a primary route of exposure. In June of 2010, the Expert Panel reviewed new inhalation toxicity data on benzyl alcohol and benzoic acid provided by the Council. The Panel decided to reopen its review of this report to consider the new data. A Scientific Literature Review (SLR) on this group of ingredients was announced on February 24, 2011. Technical comments and use concentration data were received from the Council during the 60-day comment period. Additionally, an inhalation toxicity study on benzyl alcohol and benzoic acid and a RIFM synopsis of data on benzyl benzoate were received in 2010. These data have been added to the draft report for the Expert Panel’s review at this meeting. A copy of the draft report on these ingredients is included along with the following: CIR report history, Minutes from the June 2010 Panel meeting, Literature search strategy, Data profile, the Council’s technical comments on the SLR (pcpc, in pdf), Transmittal memo for inhalation toxicity study (data 1, in pdf), Inhalation toxicity study (data 2, in pdf), RIFM synopsis on benzyl benzoate (data 3, in pdf), Use concentration data (data 4, in pdf), and 2001 published CIR final report on benzyl alcohol, benzoic acid, and sodium benzoate (finalrep, in pdf). After reviewing the draft report, the Expert Panel needs to determine whether the data included in this report are sufficient for evaluating the safety of benzyl alcohol, benzoic acid, and its salts and ester in cosmetic products. Distributed for Comment Only - Do Not Quote or Cite CIR Panel Book Page 1 Distributed for Comment Only - Do Not Quote or Cite CIR History of: Benzyl Alcohol, Benzoic Acid, and its Salts and Ester In 1998, the CIR Expert Panel issued a final safety assessment of Benzyl Alcohol, Benzoic Acid and Sodium Benzoate, concluding that they are safe for use in cosmetics up to 5%, but that the data are insufficient to support the safety of these ingredients in which the primary route of exposure is inhalation. The report was published in 2001. In June, 2010, the Expert panel reviewed new data provided by the Council on the safety of benzyl alcohol and benzoic acid for inhalation use. The Panel decided to reopen its review of this report to consider the new data. New Data Review, Belsito and Marks Teams/Panel: June 28-29, 2010 The Council provided data in response to the insufficient data determination on the inhalation use of benzyl alcohol, benzoic acid and sodium benzoate. The Personal Care Products Council provided a 4-week inhalation toxicity study (rats) of aerosolized benzyl alcohol and benzoic acid. After reviewing this study, the Expert Panel determined that the final report on the safety assessment of benzyl alcohol, benzoic acid, and sodium benzoate should be reopened to amend the original conclusion. Furthermore, the Panel determined that data available in the original safety assessment, with the addition of the new inhalation toxicity data, were likely sufficient to support the safety of other simple salts of benzoic acid (calcium, magnesium, and potassium benzoate) and the benzyl benzoate ester. Thus, it was agreed that the safety of these ingredients and those reviewed in the original final report would be reviewed in the SLR that will be developed. SLR in February, 2011 The availability of a scientific literature review (SLR) on this group of ingredients was announced on February 24, 2011. Technical comments and use concentration data from the Council were received during the 60-day comment period. Draft Report, Belsito and Marks Teams/Panel: June 27-28, 2011 Technical comments on the SLR and use concentration data, received from the Council during the 60-day comment period have been added to the draft report. The draft report also contains an inhalation toxicity study on benzyl alcohol and benzoic acid and studies from a RIFM synopsis of data on benzyl benzoate that were received in 2010. 1    CIR Panel Book Page 2 Distributed for Comment Only - Do Not Quote or Cite Literature Search on Benzyl Alcohol and Related Ingredients* Ingre- Toxline ChemIDplus Multidatabase DART Household Beilstein Registry Kosmet Napralert RTECS CAplus dients &PubMed (See legend*) Products BZA 1098 1 5 44 1 1 1 5 341 674 1534 (1997 to (1997 2011) to 2011) BA 1610 1 6 293 1 4 1 19 1263 3830 3648 (1997 to (1997 2011) to 2011) SB 226 1 4 21 1 2 1 0 5 13 643 1997 to 2011) CB 6 1 0 0 0 1 1 0 0 1 26 MB 0 1 0 0 0 1 1 0 0 1 12 PB 23 1 1 0 0 1 1 0 1 0 58 BB 331 1 1 11 1 1 1 1 117 31 227 (1997 to 2011) *Data in Table: Total no. publications in search; Multidatabase = HSDB, CCRIS, ITER, IRIS, Gene-Tox, and LacMed; Searches Performed on 7/9 and 12/2010, and 3/2011 (1 chemical name and 1 CAS No.; Toxline added additional chemical names to search term); Any limitations on years searched indicated. Website list also searched. Ingredients (BZA) Benzyl Alcohol OR 100-51-6 (BA) Benzoic Acid OR 65-85-0 (SB) Sodium Benzoate OR 532-32-1 (CB) Calcium Benzoate OR 2090-05-3 (MB) Magnesium Benzoate OR 553-70-8 (PB) Potassium Benzoate OR 582-25-2 (BB) Benzyl Benzoate OR 120-51-4 Benzyl Alcohol OR 100-51-6 OR Benzoic Acid OR 65-85-0 OR Sodium Benzoate OR 532-32-1 OR Calcium Benzoate OR 2090-05-3 OR Magnesium Benzoate OR 553-70-8 OR Potassium Benzoate OR 582-25-2 OR Benzyl Benzoate OR 120-51-4 1    CIR Panel Book Page 3 Distributed for Comment Only - Do Not Quote or Cite         Benzyl Alcohol Group Check List for June, 2011.  Writer – Wilbur Johnson          Repeated dose          Acute toxicity   Irritation  Sensitization  toxicity  Penetration Skin  Enhancement Penetration  ADME  Oral  Parenteral  Dermal  Inhale  Oral  Parenteral  Dermal  Inhale  Irritation Ocular  Animal Dermal Irr.  Human Dermal Irr  Animal Sensitization  Human Sensitization  toxicity Repro/Devel  Genotoxicity  tyCarcinogenici Phototoxicity  Benzyl alcohol  X    X  X    X  X X X X X X X  X  X X X Benzoic acid  X    X  X    X  X X X X X X X  X  X X X Sodium  benzoate      X  X    X  X X X X  X  X X X Calcium benzoate                  Magnesium                  benzoate  Potassium      X  X    X  X X    X X benzoate  Benzyl benzoate  X    X  X  X  X  X X X X X X X  X  X X X   CIR Panel Book Page 4 T r a n s c r i p t s Distributed for Comment Only - Do Not Quote or Cite Day 1 of the June 28-29, 2010 CIR Expert Panel Meeting – Dr. Marks’ Team DR. MARKS: Okay. So let me see. I'm the one tomorrow who will make the motion, and I'll make the motion to DR. MARKS: Okay. Next, Buff book 2, benzyl alcohol, benzoic acid, and sodium benzoate. And that's right reopen to amend the conclusion and, as we've said, add the four salts. And as you said, Alan, we'll get a draft with behind – the new inhalation data and more, if there is available -- DR. ANDERSEN: Ron Hill, you won't understand this. Ron Shank and Tom will understand it. This is one more DR. ANDERSEN: Maybe August, for sure in December. (inaudible). We've been here before. DR. HILL: On the benzyl alcohol? Day 1 of the June 28-29, 2010 CIR Expert Panel Meeting – Dr. Belsito’s Team DR. ANDERSEN: Yes. DR. BELSITO: So, moving right along to benzyl alcohol, benzoic acid, and sodium benzoate. So, we had had DR. HILL: Yeah, okay. I got that sense, honestly, without you even having to say it. (Laughter) issues about these primarily due to some inhalation toxicity data. It sort of took an interesting approach. It started DR. MARKS: So, from the memo from Alan there are two questions. One, do we reopen this safety assessment? off with us worrying about the potential for pericardial reactions in the bronchial tree because of their report of non- To recall, in '98 the CIR expert Panel completed its final assessment of these three ingredients, concluding a "safe immunologic contact pericardia from benzoic acid and sodium benzoate. And then we ended up with data for use in cosmetics" up to 5 percent. But it was insufficient to support the safety from an inhalation route. And then suggesting some other effects on the lung, but there were issues with the control population being equally affected benzyl alcohol was also safe for use in hair dyes up to 10 percent. The additional data need in '98 was inhalation potentially viral infections in the colonies. And so now we have data coming back on yet another study to try and toxicity. And we're at the point now, do we have that? And can we amend it? And then also Alan raised the issue assess whether aerosol exposures to benzyl alcohol, benzoic acid, sodium benzoate are adequate to allow us to just of adding, potentially, four additional salts. So -- Ron, Ron? go with a safe as used rather than safe except for inhalation. And I don't know, Alan. Should I recluse myself on this DR. SHANK: I would recommend reopening to remove the inhalation, the need for inhalation data. What we have since I'm part of RIFM and RIFM did these studies for us? Or? was acceptable. And then DR. ANDERSEN: No, I don't think so. I think data will speak for themselves. DR. SLAGA: I agree with that. DR. BELSITO: Okay. So, we have these data. So, what do you think, guys? DR. HILL: I'm good with that. DR. LIEBLER: My note here is yes. DR. MARKS: So I'll move tomorrow we reopen this safety assessment, that we now have inhalation data, that we DR. SNYDER: Safe as used. can delete that "insufficient" need. And that we add the four salts. And so, basically, if we look on page 46 of the DR. BELSITO: Safe as used? Okay. original document -- that's on Panel book page 135 -- the available data are, "insufficient to support the safety of DR. LIEBLER: Under take to amend the safety assessment -- these ingredients in which the primary route of exposure is inhalation." We can delete that sentence in the DR. BERGFELD: Yes to open -- conclusion. Okay. Any – DR. LIEBLER: -- yes, it's safe to use. Yes -- yes, and also is yes, should four additional salts be added as CIR DR. ANDERSEN: If we get -- assuming the other team agrees, what you will see next time --and I'm not sure I can prepares an amended safety assessment. I said yes. promise that that will be August, but what you will see next time is a draft amended safety assessment that DR. BELSITO: Yeah, so did I. The only issue is, I think we need to bring in not only the data that RIFM has incorporates all the new inhalation toxicity data, adds the four salts -- plus any available literature on those four supplied that allows us to say safe as used, but remember we had -- we actually have two studies. We had one -- or salts. I don't expect that to be massive, but we will look, and if there are any data, we will include those, as well. was it one study and then we had the teleconference with Unilever in London over how to interpret the study? Or DR. MARKS: It's a draft. whether it was two studies, I don't remember. But those studies, whatever they were -- the one where there were DR. ANDERSEN: A draft conclusion that simply deletes that sentence. bronchial alveolar changes and the question mark whether there was a viral infection in the colony -- those studies DR. MARKS: Okay. So this -- is this technically a re-review? should be brought in and I think explained. No? DR. ANDERSEN: No, it isn't because we don't re- review things that were "insufficient," in which the onus is on DR. ANDERSEN: Well, that's a good question. I -- left to my own devices, I was not going to bring those in. the industry or any other interested party to come in and say, "Here are the data you asked for. Now let's move on to Because the panel had -- amend it." So we're reopening it, but it's not a re-review. DR. BELSITO: Discounted them. DR. SLAGA: So have we reviewed the inhalation data? DR. ANDERSEN: Considered those and then reconsidered those and disposed of them as -- DR. MARKS: Okay. Well, we won't – I -- DR. BELSITO: Flawed. MR. BAILEY: That was under the "insufficient data" umbrella. DR. ANDERSEN: -- being methodologically flawed. DR. BELSITO: Okay. 1  2      DR. ANDERSEN: And, you know, just -- you weren't going to resolve this question based on those data. Day 2 of the June 28-29, 2010 CIR Expert Panel Meeting DR. BELSITO: I don't have a problem with that. I just wanted to make note that there was data out there that we DR. BERGFELD: The last item is the benzyl alcohol group. Dr. Marks? had looked at, found it inadequate, and thought the studies were flawed. And whether we should bring that in. DR. MARKS: In 1998 the CIR Expert Panel issued a final safety assessment of benzyl alcohol, benzoic acid and But I'm fine not bringing it in. sodium benzoate. Within that conclusion the available are data to support the safety of these ingredients in cosmetic DR. SNYDER: Yeah, I don't -- I think they should be deleted from the report. products in which a primary route of exposure is inhalation. We now have received new data which would ally that DR. ANDERSEN: Yeah, they're not in -- concern and so our team moves to reopen this safety assessment, delete the insufficient sentence in the conclusion, DR. BELSITO: It's not in the report. and then also at the same time add four salts. DR. ANDERSEN: They're not in, and the of the revised report will be these robust data with basically no effected DR. BERGFELD: That's a motion? levels at the highest exposures. DR. MARKS: Correct. DR. BELSITO: Good, okay. DR. BERGFELD: Is there a second? DR. LIEBLER: So I had one question here. In the memo -- in the cover memo, it refers to the council provided use DR. BELSITO: Second. concentration -- oh, I'm sorry. The previous sentence is: If these data are sufficient, the panel determines to reopen, DR. BERGFELD: Is there any further discussion regarding reopening and adding the salts? then there's an opportunity to also consider available data support of the simple salts, benzoic acid -- of benzoic acid DR. BELSITO: Yes. We discussed there were one or two studies that we felt were flawed but raised concerns such as calcium benzoate, magnesium benzoate, potassium benzoate, and benzyl benzoate, which is not a salt. It's a about potential pulmonary issues with inhalation and we discussed whether they should be included in this report de-ester of itself -- and then as updated use concentration for benzyl alcohol, benzoic acid, and sodium benzoate. and then discussed as being flawed. However, I think our team felt that since we clearly felt these studies were So, what about benzyl benzoate? Is that under consideration as well or not? flawed, there was a viral infection in the colony, that it wouldn't really do any justice to include them, that it would DR. ANDERSEN: Yeah, it's -- it was presented as a possible addition. What I thought I had heard is that there's a just confuse the reader and elected not to do so. comfort level with the salts. Is the panel equally comfortable with benzyl benzoate? DR. SNYDER: An additional comment is we have more robust studies with NOAEL. DR. LIEBLER: Just to follow up on that. I am, and I was just wondering why it wasn't – it seemed unclear to me DR. LIEBLER: One other point of clarification. You mentioned the three salts I guess, calcium, magnesium and and I'm just registering that I am comfortable with that. Particularly if you're going to do benzoic acid and benzyl potassium benzoates. Also listed on the memo was benzyl benzoate and I thought that that would be reasonable to alcohol. include as well. It's not a salt. It would be an ester. I don't know if you discussed that or if you have a differing DR. BELSITO: Well, if you're comfortable, Dan, I'm comfortable. view on it. DR. ANDERSEN: Well -- and we have the data for benzyl benzoate use concentrations that have been provided DR. MARKS: That's fine. and they are, if anything, less than the others across the board, so. DR. BERGFELD: Are there any other comments? Seeing none, I'll call for the vote to reopen. All those in favor? DR. BELSITO: Any other comments? Unanimous. DR. SNYDER: I just had one query. So, we received that there was a new comment assay that was performed in results? But I didn't see the data in the new data section. DR. ANDERSEN: Correct. Its genotoxicity really hasn't ever been an issue with these. The comet assay was basically negative. I figured I would simply add it in once we took the next step. But it addressed an issue that wasn't an issue -- wanted you to focus on the inhalation tox stuff. But thank you for bringing it up because I should have just mentioned that upfront. DR. BELSITO: All right. Anything else? If not, we're done. 3  4    CIR Panel Book Page  5 R e p o r t