ADMIN. Memo Agenda Minutes Aerosols Precedents and Frameworks Hair Dye Findings

Transcription

1 ADMIN Memo Agenda Minutes Aerosols Precedents and Frameworks Hair Dye Findings CIR EXPERT PANEL MEETING APRIL 10 11, 2017

2 MEMORANDUM Commitment & Credibility since 1976 To: CIR Expert Panel Members and Liaisons From: Director, CIR Subject: 142 nd Meeting of the CIR Expert Panel Monday and Tuesday, April 10-11, 2017 Date: March 17, 2017 Welcome to the first CIR Expert Panel meeting of 2017! Enclosed are the agenda and accompanying materials for the 142 nd CIR Expert Panel Meeting to be held on April 10-11, We have a new location for our 2017 Panel meetings. This year, all meetings will be held at The Hamilton Crowne Plaza Hotel, which is located at th Street, N.W., Washington, DC. Phone: (202) ; Fax: (202) The hotel is located close to the McPherson Metro Station. The meeting agenda includes the consideration of 12 ingredient groups advancing in the review process and 3 re-reviews. In response to the Panel s request at the December meeting, the agenda also includes a review of the revised Hair Dye boilerplate and the Aerosols Precedents Document and Framework. A draft boilerplate on endocrine disruption will be included in the Wave 2 documents. Lastly, the draft 2018 CIR Priority List of ingredients will be forwarded in wave 2 for the Panel s review and discussion. This list will be published for public comment and finalized at the June 2017 meeting. Schedule and hotel accommodations We have reserved rooms for the nights of Sunday, April 9 and Monday, April 10, at the Hamilton Crowne Plaza Hotel. If you encounter travel problems, please contact me on my cell phone at Team meetings Re-Review reports there are 3 safety assessments to re-review and decide either not to reopen or to reopen to revise the conclusion or add ingredients. 1. Lard and Lard-derived ingredients (agenda and flash drive name lard). Lard and Lard-derived ingredients were reviewed previously (published in 2001) with the conclusion that the 6 ingredients are safe as used in cosmetic products, provided that established limitations on heavy metal and pesticide concentrations are not exceeded. Some additional impurities data are included in the report L Street, NW, Suite 1200, Washington, DC (Main) (Fax) ( ) cirinfo@cir-safety.org (Website)

3 2. Mentha piperita (Peppermint)-Derived Ingredients (agenda and flash drive name peppermint). Mentha piperita (Peppermint)-derived ingredients were previously reviewed (published in 2001) with the conclusion that 4 ingredients are safe as used in cosmetic formulations and that the concentration of pulegone in these ingredients should not exceed 1%. Although the previous assessment was based primarily on data on Mentha Piperita (Peppermint) Oil, newly available data have been provided, including a National Toxicology Program (NTP) carcinogenicity study on pulegone (published in 2012). Six ingredients are proposed for addition to this family. If the Panel agrees that the data in the existing reports and the new data presented in this re-review document support the safety of these proposed ingredients, the Panel should re-open this assessment and add these ingredients. 3. Triglycerides (agenda and flash drive name triglycerides). This report includes the combination of 25 previously reviewed ingredients and 29 ingredients for which safety has not yet been assessed. At the September 2014 meeting, the Panel agreed that the CIR strategy to include Trilaurin, 22 additional glyceryl triesters, and two add-on ingredients to the re-review of Trihydroxstearin was appropriate. The Panel also discussed the 27 other ingredients that have been added to this report. Although the frequency and concentrations of use for most of the ingredients have increased since they were originally reviewed, uses for Caprylic/Capric Triglyceride have increased most significantly, from 763 uses reported in 2003 to 6000 reported in If the Panel agrees that the data in the existing reports and the new data presented in this re-review document support the safety of these proposed ingredients, the Panel should re-open this assessment and add these ingredients. Draft reports - there are 4 draft reports for review. 1. Milk Proteins and Protein Derivatives (agenda and flash drive name milk-derived proteins). This is the first time that the Panel is seeing this report on 15 Milk Proteins and Protein derivatives. Originating from bovine-sourced milk, these ingredients are reported to function mainly as skin and hair conditioning agents. Earlier data provided to support the safety assessment of these ingredients as part of a larger group of hydrolyzed source proteins(revised in 2013 into smaller reports) and data submitted more recently are included in the report. Are the data sufficient to proceed with a tentative report, or should an insufficient data announcement be issued? 2. Panthenol, Pantothenic Acid, and Derivatives (agenda and flash drive name panthenol) This is the first time the that Panel is seeing this report on 7 ingredients, 5 of which are derivatives (the ethyl ether, acetyl ester) or simple salt forms of Pantothenic Acid (vitamin B 5 ) or its alcohol analogue, Panthenol. This is not a re-review of Panthenol and Pantothenic Acid (prioritization was based on high frequency of use of other ingredients in this report), but new data for these structurally similar, previously reviewed ingredients have been included in this safety assessment. Are the available data sufficient for issuing a tentative report, or should an insufficient data announcement be issued? 3. Polyaminopropyl Biguanide (agenda and flash drive name polyaminopropyl biguanide). This is the first time that the Panel is seeing a report on this polymer that is used as a preservative in cosmetics. At the March 2016 meeting, the CIR Expert Panel agreed to advance the review of Polyaminopropyl Biguanide as a priority ingredient because the recent revision of the opinion by the European Commission s Scientific Committee on Consumer Safety (SCCS). There has also been a significant change in our understanding of the nomenclature and meaning for this ingredient. It is our current understanding that all known instances of the ingredient, Polyaminopropyl Biguanide, soley comprise the chemical polyhexamethylene biguanide hydrochloride (PHMB HCl). Are the available data sufficient for issuing a tentative report with a safe as used or safe with qualifications conclusion, or should an insufficient data announcement be issued? Page nd Meeting of the CIR Expert Panel Monday and Tuesday, April 10-11, 2017

4 4. Polyurethanes (agenda and flash drive name polyurethanes). This is the first time that the Panel is seeing this report on 66 ingredients that are reported to function as artificial nail builders, binders, film formers, hair fixatives, plasticizers, and surface modifiers. The Panel has previously reviewed several of these ingredients, several polyurethane-type ingredients with non- Polyurethane-x ingredient names (e.g., HDI Copolymers), and several of their precursors and moieties. Are the data sufficient to proceed with a tentative report, or should an insufficient data announcement be issued? Tentative reports there are 2 draft tentative reports. 1. Alkane Diols (agenda and flash drive name Alkane diols). At the September 2016 meeting, the Panel issued an Insufficient Data Announcement for 10 alkane diol ingredients. Data requested on method of manufacture, impurities, and skin penetration enhancement were received and are included in the report. Updated concentration of use data for 1,4-Butanediol and neurotoxicity data for Isopentydiol were not received. If the data are still insufficient, then a tentative report with a conclusion of insufficient data should be issued. If the data are sufficient, the Panel should issue a tentative report with an appropriate discussion and conclusion. Are the data sufficient to proceed with a tentative report, or should an insufficient data announcement be issued? 2. Humulus lupulus (Hops)-Derived Ingredients (agenda and flash drive name Humulus lupulus (hops)). At the September 2016 meeting, the Panel issued an Insufficient Data Announcement for 6 Humulus lupulus (hops)-derived ingredients. Data were requested on the composition of Humulus Lupulus (Hops) Stem Extract and the composition and sensitization potential of Humulus Lupulus (Hops) Extract at the greatest reported maximum concentration of use (0.6%). Genotoxicity and irritation and sensitization data received have been added to the report. Concentration of use data have been updated. Additionally, the names and monographs for these ingredients have changed significantly, which may affect the presentation of data for the ingredients as well as the total number of ingredients (from 6 to 2) included in this report. Are the new data and the monograph changes sufficient to proceed with a tentative report, or should an insufficient data announcement be issued? Final reports - there are 6 draft final reports for consideration. After reviewing these drafts, especially the rationales provided in the Discussion sections, the Panel should issue them as final reports, as appropriate. 1. Acryloyldimethyltaurate Polymers (agenda and flash drive name Dimethyltaurate polymers). At the September 2016 meeting, the Panel issued a tentative report for public comment with the conclusion that 21 Acryloyldimethyltaurate Polymers are safe in the present practices of use and concentration in cosmetics. The Panel also advised that formulators should use current good manufacturing practices (cgmps) to ensure that residual monomers are minimized in these ingredients and the final products in which they are used. The frequency of use data have been updated. Technical comments have been addressed. 2. Butyl Polyoxyalkylene Ethers (agenda and flash drive name - Polyoxyalkylene ethers). At the December 2016 meeting, the Panel issued a tentative amended report for public comment with the conclusion that 46 butyl polyoxyalkylene ethers are safe in the present practices of use and concentration in cosmetics when formulated to be non-irritating. As requested, the read-across data have been reformatted. Updated frequency of use data have been added. Technical comments have been addressed. 3. Butyrospermum parkii (Shea)-Derived Ingredients (agenda and flash drive name Butyrospermum parkii (shea)). At the September 2016 meeting, the Panel issued a tentative report for public comment with the conclusion that 9 ingredients are safe in the present practices of use and concentration in cosmetics. The Panel also concluded that data for 4 of the ingredients are insufficient and requested data on method of manufacture, composition, impurities, and sensitization. Additional data were received for 2 of the ingredients with insufficient data. Updated frequency of use data have been added. Technical comments have been addressed. Page nd Meeting of the CIR Expert Panel Monday and Tuesday, April 10-11, 2017

5 4. Etidronic Acid and its Salts (agenda and flash drive name Etidronic acid). At the September 2016 meeting, the Panel issued a tentative report for public comment with the conclusion that 4 ingredients are safe as in the present practices of use and concentration in cosmetics. Updated frequency of use data have been added. No other data were submitted. Technical comments have been addressed. 5. Hydrofluorocarbon 152a (agenda and flash drive name Hydrofluorocarbon 152a). At the September 2016 meeting, the Panel issued a tentative report for public comment with the conclusion that this ingredient is safe in the present practices of use and concentration in cosmetics. Additional information about the European Union s environmental regulations on fluorocarbons in personal hygiene and household products has been added. Updated frequency of use data have been received and addressed. Technical comments have been addressed. 6. Rosa canina-derived Ingredients (agenda and flash drive name Rosa canina). At the March 2016 meeting, the Panel issued a tentative report for public comment with the conclusion that 12 Rosa canina-derived ingredients are safe in the present practices of use and concentration in cosmetics when formulated to be non-irritating and non-sensitizing. Changes in the ingredient uses in various product categories reflect the updated frequency of use data that were received. Technical comments have been addressed. Full Panel Meeting Remember, the breakfast buffet will open at 8:00 am and the meeting starts at 8:30 am on day 1 and on day 2. The Panel will consider the 6 reports to be issued as final safety assessments, followed by the remaining reports advancing in the process, the revised boilerplates and the 2018 Priorities. The majority of the agenda involves reviewing the draft and final reports. It is likely that the full Panel session will conclude before lunch on day 2, so plan your travel accordingly. Have a safe journey! Page nd Meeting of the CIR Expert Panel Monday and Tuesday, April 10-11, 2017

6 Agenda 142 nd Cosmetic Ingredient Review Expert Panel Meeting April 10-11, 2017 The Hamilton Crowne Plaza Hotel th Street, N.W. Washington, D.C Monday, April 10 8:00 am CONTINENTAL BREAKFAST 8:30 am WELCOME TO THE 142 nd EXPERT PANEL TEAM MEETINGS Drs. Bergfeld/Gill 8:40 am TEAM MEETINGS Drs. Marks/Belsito Dr. Marks Team Dr. Belsito s Team* FR (CB) Butyrospermum parkii (shea) FR (WJ) Rosa canina FR (CB) Hydrofluorocarbon 152a DR (WJ) Polyaminopropyl biguanide DR (CB) Milk-derived proteins RR (WJ) Peppermint FR (LB) Dimethyltaurate polymers TR (LS) Alkane diols FR (LB) Etidronic acid DR (LS) Panthenol TR (LB) Humulus lupulus (hops) Admin (BH) Priorities DR (LB) Polyurethanes FR (CB) Butyrospermum parkii (shea) RR (LB) Lard FR (CB) Hydrofluorocarbon 152a FAR (MF) Polyoxyalkylene ethers DR (CB) Milk-derived proteins RR (MF) Triglycerides FR (LB) Dimethyltaurate polymers Admin (IB) Boilerplates FR (LB) Etidronic acid TR (LS) Alkane diols TR (LB) Humulus lupulus (hops) DR (LS) Panthenol DR (LB) Polyurethanes FR (WJ) Rosa canina RR (LB) Lard DR (WJ) Polyaminopropyl biguanide FAR (MF) Polyoxyalkylene ethers RR (WJ) Peppermint RR (MF) Triglycerides Admin (BH) Priorities Admin (IB) Boilerplates Noon 1:00pm Lunch for Panel, liaisons, and staff Team meetings - continue as needed 5:00 pm ADJOURN DAY 1 SESSION FR: Final Report FAR: Final Amended Report TR: Tentative Report DR: Draft Report RR: Re-review NOTE: The order of presentation and discussion of each topic will be maintained. However, the scheduled times may be accelerated or delayed depending upon the time required for the Expert Panel to complete its review of each subject. *Team moves to breakout room.

7 Tuesday, April 11 8:00 am CONTINENTAL BREAKFAST 8:30 am WELCOME TO THE 142 nd FULL CIR EXPERT PANEL MEETING Dr. Bergfeld 8:45 am Admin MINUTES OF THE DECEMBER 2016 EXPERT PANEL MEETING Dr. Bergfeld 9:00 am DIRECTOR S REPORT Dr. Gill 9:10 am FINAL REPORTS, REPORTS ADVANCING TO THE NEXT LEVEL Final Reports FR (LB) FR (LB) FAR (MF) FR (WJ) FR (CB) FR (CB) Dimethyltaurate polymers Dr. Belsito reports Etidronic acid Dr. Marks reports Polyoxyalkylene ethers Dr. Belsito reports Rosa canina Dr. Marks reports Butyrospermum parkii (shea) Dr. Belsito reports Hydrofluorocarbon 152a Dr. Marks reports Reports Advancing DR (CB) TR (LS) DR (LS) TR (LB) DR (LB) RR (LB) DR (WJ) RR (WJ) RR (MF) Admin (IB) Admin (BH) Milk-derived proteins Dr. Belsito reports Alkane diols Dr. Marks reports Panthenol Dr. Belsito reports Humulus lupulus (hops) Dr. Marks reports Polyurethanes Dr. Belsito reports Lard Dr. Marks reports Polyaminopropyl biguanide Dr. Belsito reports Peppermint Dr. Marks reports Triglycerides Dr. Belsito reports Boilerplates Dr. Marks reports Priorities Dr. Belsito reports ADJOURN - Next meeting Monday and Tuesday, June 12-13, 2017 at The Hamilton Crowne Plaza Hotel, 1001 K Street, NW, Washington, DC FR: Final Report FAR: Final Amended Report TR: Tentative Report DR: Draft Report RR: Re-review Report

8 Commitment & Credibility since 1976 ONE HUNDRED FORTY-FIRST MEETING OF THE EXPERT PANEL December 5-6, 2016 Melrose Georgetown Hotel Washington, D.C. Expert Panel Members Wilma F. Bergfeld, M.D., Chair Donald V. Belsito, M.D. Liaison Representatives Consumer Michael Best, Esq. Ronald A. Hill, Ph.D. Curtis D. Klaassen, Ph.D. Daniel C. Liebler, Ph.D. Industry Beth A. Lange, Ph.D. James G. Marks, Jr., M.D. Ronald C. Shank, Ph.D. Thomas J. Slaga, Ph.D. Paul W. Snyder, D.V.M., Ph.D. Government Linda Katz, MD., M.P.H. Adopted (Date) Wilma F. Bergfeld, M.D L Street, N.W., Suite 1200, Washington, DC (Main) (Fax) ( ) cirinfo@cir-safety.org (Website)

9 Others Present at the Meeting Robena Aziz FDA Lillian Becker CIR Don Bjerke P & G Ivan Boyer CIR Roshil Budhram L-Brands Kristen Buono Presperse Christina Burnett CIR Pushpa Rao Combe, Inc. Kapal Dewa FDA Carol Eisenmann PCPC Monice Fiume CIR Kevin Fries CIR Lillian Gill CIR Breanne Gilpatrick Dave Gossai L Oreal Bart Heldreth CIR Carla Jackson CIR Wilbur Johnson, Jr. CIR Lois Kotkoske Croda Dennis Laba Presperse Ellen Mihaich ER 2 Emily Manoso PCPC Lauren Nardella Damani Parran Akzo Alex Perez L Oreal Galen Roth EWG Nakissa Sadrieh FDA Anthony Santini Combe, Inc Laura Scott CIR David Steinberg Steinberg and Associates

10 CHAIRMAN S OPENING REMARKS MINUTES FROM THE 141 st CIR EXPERT PANEL MEETING The 141 st meeting of the Cosmetic Ingredient Review (CIR) Expert Panel was called to order at 8:30 a.m by Dr. Wilma Bergfeld. She stated that 14 ingredient reports, reviewed in Teams on the preceding day, are also being reviewed at today s meeting. The 14 reports include 8 final reports, 2 amended final reports, 3 re-opened final reports, and 1 new draft report. Also, prior to Team discussions on the preceding day, the Panel heard a presentation on endocrine disruption by Dr. Ellen Mihaich, which provided some degree of guidance relative to this very public issue as the Panel proceeds with reviews of ingredients with this type of activity. Dr. Bergfeld noted that the composition of botanical ingredients continues to be an issue of concern and is actually expanding, taking into consideration multiple botanicals in one ingredient in a given formulation and the use of multiple formulations on a daily basis. She also noted the possibility of some type of threshold problem resulting from this expanding issue. Dr. Bergfeld stated that the Panel needs to continue their review of CIR boilerplate statements, including new boilerplates and those that have not been updated. She remarked that at least one new boilerplate was developed in Teams on the preceding day, which relates to some type of citation in CIR reports that captures how the review was actually done. The need to re-review CIR s compilation of hair dye epidemiology studies was also mentioned. APPROVAL OF MINUTES The minutes of the September 26-27, 2016 CIR Expert Panel meeting were unanimously approved. The following correction was stated by Dr. Belsito: Regarding established limits on components of Rosa canina-derived ingredients, he noted that the limitation on linalool relates to the presence of hydroperoxides, whereas the limitation on eugenol relates to eugenol and not the hydroperoxide composition of eugenol. DIRECTOR S REPORT At the September 2016 meeting, the Council suggested an update on the scientific and regulatory issues surrounding the topic of substances with potential endocrine disrupting activities. Dr. Ellen Mihaich presented a briefing titled Of Lists and Legends: An Endocrine Disruptor Update. Dr. Gill, and the Panel, expressed appreciation to Dr. Mihaich for her thoughtful and comprehensive update on endrocrine disruption. Dr. Mihaich is the owner and principal scientist of Environmental and Regulatory Resources, LLC (ER2) and an adjunct faculty member at Duke University. Dr. Gill highlighted some of the many accomplishments of the Expert Panel and CIR Staff in As of October 1, the Panel assessed the safety of over 460 ingredients, with the following conclusions: 34 safe, 408 safe with qualifications, 5 with split decisions of safe with qualifications and insufficient data, and 14 with insufficient data. When the 2016 CIR Compendium is published in early 2017, it will reflect the review of over 4500 ingredients. In 2014, 8 ingredients had insufficient data to make a safety determination. In accordance with the CIR Procedures, 7 Camellia sinensis-derived ingredients, and the ingredient Avena Sativa (oat) Meristem Cell Extract will be categorized as No Reported Use at the end of December 2016; no new data were received and none of these ingredients are listed as being in use in the VCRP data. In 2017, 3 ingredients (Hydrolyzed Carrageenan, MEA Hydrolyzed Silk, and Silk Cocoon Extract) were found to have insufficient data to determine safety; these ingredients are scheduled to be categorized as Use Not Supported by Data or No Reported Use at the end of 2017 if additional data are not submitted by the end of next year. Dr. Gill also restated the announcement made on the first day of the Panel meeting that the Panel discussion of the Lead Acetate strategy would be tabled at this meeting to allow for CIR review of additional information that arrived just before the Panel meeting.

11 Lastly, Dr. Gill reminded the meeting participants that the next meeting is scheduled for April 10-11, She encouraged all who have data to submit for safety assessments that were reviewed at this meeting and those that are scheduled to be discussed at April 2017 meeting, to provide that data as soon as possible. All 2017 Panel meetings will be held at the Hamilton Crowne Plaza Hotel, in Washington, D.C. Final Safety Assessments Acid Violet 43 The Panel issued a final amended report with the conclusion that Acid Violet 43 is safe in the present practices of use and concentration for use in hair dye formulations. This supersedes the conclusion published in the original assessment on this ingredient published in In the original report, safety test data on the certified color Ext. D&C Violet No. 2 (which has the same chemical structure as Acid Violet 43) were used to evaluate the safety of Acid Violet 43 because there were no data available for Acid Violet 43. Therefore, the conclusion for Acid Violet 43 included impurity specifications for the certified color. In 2013, the European Commission Scientific Committee on Consumer Safety issued an opinion on Acid Violet 43 that included test data on both Acid Violet 43 and Ext. D&C Violet No. 2. The Panel determined that the new information was sufficient to assess the safety of Acid Violet 43 and removed the impurity specifications for the certified color from the conclusion. Alkoxyl Alkyl Silanes The CIR Panel issued a final report with the conclusion that the following 4 alkoxyl alkyl silanes are safe as used in the present practices of use and concentration: Bis-Stearoxydimethylsilane Stearoxytrimethylsilane Triethoxycaprylylsilane Trimethoxycaprylylsilane The ingredients in this report are structurally-related silanes bearing both alkyl and alkoxyl groups. The functions of these ingredients include: binder, skin-conditioning agent miscellaneous, skin-conditioning agent emollient, and surface modifier. The Panel noted positive results in dermal, oral, inhalation, and developmental and reproductive toxicity studies at test concentrations much greater than those reported to be used in cosmetics. However, studies conducted at concentrations similar to those used in cosmetics indicated that these ingredients do not damage the skin or cause other toxicities. Triethoxycaprylylsilane is reported to be used in 417 formulations at maximum concentrations up to 2.6% in suntan products. Carbonate Salts The Panel issued a final report with the conclusion that the following 6 ingredients are safe in the present practices of use and concentration when formulated to be non-irritating: Magnesium Carbonate Ammonium Bicarbonate Ammonium Carbonate Calcium Carbonate Potassium Bicarbonate* Potassium Carbonate *Not reported to be in current use. Were this ingredient to be used in the future, the expectation is that it would be used in product categories and at concentrations comparable to others in this group.

12 These carbonate salts are reported to function as absorbents, bulking agents, opacifying agents, ph adjusters, buffering agents, abrasives, and oral care agents. Magnesium Carbonate has the highest reported frequency of use, 317 cosmetic formulations, and Calcium Carbonate has the highest maximum concentration of use, 35% in leave-on products. The Panel initially expressed concern about the potential for skin and ocular irritation from exposures to carbonate salts because study data indicated that Potassium Bicarbonate was mildly irritating to the abraded skin (but not intact skin) of rabbits, and potash hydrate (surrogate chemical for Potassium Carbonate) and sodium carbonate monohydrate (surrogate chemical for Potassium Carbonate) were skin and ocular irritants in rabbits, respectively. These concerns were addressed by additional studies demonstrating that Calcium Carbonate was negative for skin irritation in vivo, and Ammonium Bicarbonate, Ammonium Carbonate, Calcium Carbonate, and Magnesium Carbonate were negative for skin irritation in vitro. Study results also indicated that Magnesium Carbonate and Ammonium Bicarbonate were positive and negative, respectively, for ocular irritation in vitro and Ammonium Carbonate, Calcium Carbonate, Magnesium Carbonate, and Potassium Bicarbonate were negative for ocular irritation in vivo. The Panel noted that the carbonate salts alone would not likely be irritating at concentrations used in cosmetic products. However, these ingredients may contribute to the irritation potential of other ingredients in cosmetic formulations. Thus, the Panel determined that cosmetic products containing carbonate salts should be formulated to be non-irritating. The Panel noted studies that reported renal toxicity and neoplastic lesions of the urinary bladder in animals fed Potassium Bicarbonate. However, the Panel concluded that the effects reported in these studies are attributable to irritation of the bladder lining after repeated daily exposure to high dietary concentrations of Potassium Bicarbonate over an extended period. The Panel agreed that the dietary exposures tested in these studies do not reflect the much lower exposures that can reasonably be expected from the use of carbonate salts in cosmetic products. Pertinent toxicity data on ammonium carbamate was added to the report because the ingredient named Ammonium Carbonate is a mixture of ammonium bicarbonate and ammonium carbamate. Industry reported that the Cosmetic Ingredient Dictionary and Handbook (Dictionary) monograph on Ammonium Carbonate has been revised to include a CAS number [( (mixture)] that represents the mixture. Citrus Flower- and Leaf-Derived Ingredients The Panel issued a final report with the conclusion that the following 33 ingredients are safe in the present practices of use and concentration when formulated to be non-irritating and non-sensitizing: Citrus Aurantifolia (Lime) Flower Extract Citrus Aurantifolia (Lime) Leaf Oil* Citrus Aurantium Amara (Bitter Orange) Flower Extract Citrus Aurantium Amara (Bitter Orange) Flower Oil Citrus Aurantium Amara (Bitter Orange) Flower Water Citrus Aurantium Amara (Bitter Orange) Flower Wax Citrus Aurantium Bergamia (Bergamot) Leaf Cell Extract* Citrus Aurantium Bergamia (Bergamot) Leaf Extract Citrus Aurantium Bergamia (Bergamot) Leaf Oil Citrus Aurantium Dulcis (Orange) Flower Extract Citrus Aurantium Dulcis (Orange) Flower Oil Citrus Aurantium Dulcis (Orange) Flower Wax Citrus Aurantium Dulcis (Orange) Flower Citrus Aurantium Dulcis (Orange) Leaf Extract Citrus Clementina Leaf Cell Extract* Citrus Depressa Flower Water* Citrus Grandis (Grapefruit) Leaf Extract* Citrus Hystrix Leaf Extract* Citrus Hystrix Leaf Oil Citrus Junos Flower Oil* Citrus Limon (Lemon) Flower Water* Citrus Limon (Lemon) Leaf Extract* Citrus Limon (Lemon) Leaf Cell Extract* Citrus Natsudaidai Flower Water* Citrus Natsudaidai Flower Oil* Citrus Reticulata (Tangerine) Leaf Oil Citrus Reticulata (Tangerine) Leaf Water* Citrus Sinensis (Orange) Flower Water Citrus Tamurana Flower Extract* Citrus Unshiu Flower Extract* Citrus Unshiu Flower Powder* Citrus Unshiu Flower Water* Citrus Unshiu Leaf Extract*

13 *Not reported to be in current use. Were ingredients in this group not in current use to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group. The Panel noted that certain cultivars of Citrus reticulata leaf oil may contain approximately 50% methyl-nmethylanthranilate (or dimethyl anthranilate), which is phototoxic. The International Fragrance Association (IFRA) and the European Union s Scientific Committee on Consumer Safety (SCCS) have issued a limit on this constituent of 0.1% in leave-on products. The maximum reported concentration of use for Citrus Reticulata (Tangerine) Leaf Oil in a leave-on product has been reported as 0.1%. Because the potential concentration of methyl-nmethylanthranilate in this ingredient would be below the limit established by IFRA and the SCCS, the Panel determined that there are no safety concerns regarding the use of Citrus Reticulata (Tangerine) Leaf Oil in cosmetics. Citrus Plant- and Seed-Derived Ingredients The Panel issued a final report with the conclusion that the following 18 ingredients are safe in the present practices of use and concentration when formulated to be non-irritating and non-sensitizing. Citrus Aurantium Amara (Bitter Orange) Leaf/Twig Extract* Citrus Aurantium Amara (Bitter Orange) Leaf/Twig Oil Citrus Aurantium Dulcis (Orange) Seed Extract Citrus Australasica Seed Oil* Citrus Depressa Seed Oil* Citrus Glauca Seed Oil* Citrus Grandis (Grapefruit) Extract Citrus Grandis Peel/Seed Extract* Citrus Grandis (Grapefruit) Seed Extract Citrus Junos Extract Citrus Junos Seed Extract Citrus Junos Seed Oil Citrus Nobilis (Mandarin Orange) Citrus Nobilis (Mandarin Orange) Oil Citrus Paradisi (Grapefruit) Seed Extract Citrus Reticulata (Tangerine) Extract Citrus Sunki Seed Extract* Citrus Sunki Seed Oil* The Panel concluded the data on the following 12 ingredients were insufficient to determine safety: Citrus Aurantifolia (Lime) Oil Citrus Aurantium (Bitter Orange) Oil Citrus Aurantium Dulcis (Orange) Flower/Leaf/Stem Powder* Citrus Aurantium Dulcis (Orange) Oil Citrus Aurantium Sinensis Powder Citrus Grandis (Grapefruit)* Citrus Iyo Oil* Citrus Limon (Lemon) Flower/Leaf/Stem Extract Citrus Limon (Lemon) Flower/Leaf/Stem Oil* Citrus Limon (Lemon) Leaf/Peel/Stem Oil* Citrus Nobilis (Mandarin Orange) Water* Citrus Unshiu Extract* *Not reported to be in current use. Were ingredients in this group not in current use to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group. The additional data needed to determine the safe use of these 12 ingredients are: Method of manufacturing Chemical composition and impurities Irritation and sensitization If the composition data for these Citrus plant- and seed-derived ingredients are substantially different from those of the Citrus peel-, flower-, and leaf-derived ingredients, then studies of systemic endpoints such as a 28-day dermal toxicity, reproductive and developmental toxicity, and genotoxicity are needed, as well as UV absorption spectra The Panel determined that the conclusion of safe with the listed qualifications could be extended to Citrus Grandis (Grapefruit) Extract, Citrus Junos Extract, Citrus Nobilis (Mandarin Orange), Citrus Nobilis (Mandarin Orange) Oil, and Citrus Reticualta (Tangerine) Extract because these ingredients are largely used in rinse-off formulations at very low concentrations. The ingredients Citrus Jabara Pericarp Extract and Citrus Unshiu Pericarp Extract have been

14 removed from this report and administratively added to the Citrus Peel-Derived Ingredients report because it was determined that these ingredients are alternate names for Citrus Jabara Peel Extract and Citrus Unshiu Peel Extract (ingredients which are already recited in that report). Dialkyl Carbonates The Panel issued a final report with a conclusion that the following 6 ingredients are safe in the present practices of use and concentration when formulated to be non-irritating: Dicaprylyl Carbonate Bis-Propylheptyl Carbonate* C14-15 Dialkyl Carbonate Diethylhexyl Carbonate Dimethyl Carbonate* Dipropyl Carbonate* *Not reported to be in current use. Were ingredients in this group not in current use to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group. These alkyl diesters of carbonic acid mainly function as skin conditioning agents in cosmetic products; dimethyl carbonate functions as a fragrance ingredient, propellant, or solvent. Dicaprylyl Carbonate has the highest frequency of use (384 formulations) and the highest maximum concentration of use, 34.5% in leave-on products. The Panel agreed that data on propylheptyl caprylate can be used to evaluate the following toxicity endpoints for Propylheptyl Carbonate: acute dermal toxicity, acute oral toxicity, subchronic oral toxicity, genotoxicity, skin irritation, skin sensitization, and ocular irritation. Additionally, the Panel reaffirmed their concerns about one immunotoxicity study on dimethyl carbonate; they determined that the results of the study are contradictory. Toxicology data on 2-ethylhexanol (a hydrolysis product of Diethylhexyl Carbonate) were included in the report to assess the safety of Diethylhexyl Carbonate. An animal study reported positive embryotoxicity and teratogenicity in test animals exposed to test materials containing 2-ethylhexanol at the highest dosages but not at the lower dosage tested. The Panel agreed that the exposures tested that produced positive results are much greater than can reasonably be expected from the use of Dialkyl Carbonate in cosmetic products. The Panel also noted that Dicaprylyl Carbonate was negative in a chromosomal aberration test, which indicated the absence of excess DNA methylation. The Panel expressed concern about the irritation potential of dialkyl carbonates. Although some studies of this ingredient reported slight to well-defined irritation in animals, a study using a 31% test solution of Dicaprylyl Carbonate had very low cutaneous irritation potential. PEG Propylene Glycol Derivatives The Panel issued a final amended report for public comment with the conclusion that the following 7 ingredients are safe as used in the present practices of use and concentrations: PEG-25 Propylene Glycol Stearate PEG-75 Propylene Glycol Stearate* PEG-120 Propylene Glycol Stearate* PEG-10 Propylene Glycol* PEG-8 Propylene Glycol Cocoate PEG-55 Propylene Glycol Oleate PEG-6 Propylene Glycol Caprylate/Caprate*

15 *Not reported to be in current use. Were ingredients in this group not in current use to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group. The Panel opened this safety assessment for re-review because of the substantial increase in the number of reported uses of PEG-55 Propylene Glycol Oleate since the original safety assessment was published in There were no reported uses for this ingredient in the 2001 safety assessment. However, according to Food and Drug Administration (FDA) Voluntary Cosmetic Reporting Program (VCRP) data submitted in 2016, PEG-55 Propylene Glycol Oleate is reported to now be used in 149 formulations. The frequency of use of the other ingredients has decreased or remained at zero. The highest maximum concentration of use has decreased from 10% to 2%. The Panel reiterated that the restriction in the original report, which states that ingredients containing PEGs should not be used on damaged skin, is no longer warranted because the data on PEGs reviewed in 2010 supported the conclusion that there was no safety concern associated with using cosmetic products containing PEGs on damaged skin. In the original safety assessment, the Panel relied on data from CIR reports on related ingredients and moieties and component parts of these ingredients to support the evaluation of the limited data on these ingredients. In the current assessment, they reaffirmed that this approach is appropriate for determining the safety of these ingredients. Saccharide Esters The Panel issued a final report with the conclusion that the following 40 saccharide ester ingredients are safe in the present practices of use and concentration: Glucose Pentaacetate* Maltitol Laurate Raffinose Isostearate* Raffinose Myristate* Raffinose Oleate* Sucrose Acetate Isobutyrate Sucrose Acetate/Stearate Sucrose Benzoate Sucrose Cocoate Sucrose Dilaurate Sucrose Dipalmitate Sucrose Distearate Sucrose Hexaerucate* Sucrose Hexaoleate/Hexapalmitate/Hexastearate Sucrose Hexapalmitate* Sucrose Laurate Sucrose Myristate Sucrose Octaacetate* Sucrose Oleate* Sucrose Palmitate Sucrose Palmitate/Stearate or Sucrose Stearate- Palmitate Ester Sucrose Pentaerucate* Sucrose Pentahydroxystearate* Sucrose Polybehenate Sucrose Polycottonseedate Sucrose Polylaurate Sucrose Polylinoleate* Sucrose Polyoleate Sucrose Polysoyate Sucrose Polystearate Sucrose Stearate Sucrose Tetrahydroxystearate* Sucrose Tetraisostearate Sucrose Tetrastearate Triacetate Sucrose Tribehenate* Sucrose Trilaurate Sucrose Tristearate Trehalose Isostearate Esters Trehalose Undecylenoate Xylityl Sesquicaprylate* *Not reported to be in current use. Were ingredients in this group not in current use to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group. The Panel discussed the data gaps for some of these ingredients. The similarities in chemical structures and in the reported functions and concentrations of use in cosmetics of the saccharide ester ingredients enabled the Panel to extrapolate or interpolate (read-across) the available safety data on some of the ingredients to address the ingredients with data gaps. For example, the data available for Sucrose Polybehenate were used to assess the potential for dermal irritation and sensitization of the single-chain length saccharide esters; multiple-endpoint data for Sucrose Acetate Isobutyrate and dermal irritation and sensitization data for Sucrose Polycottonseedate were used to assess the safety for the mixed-chain length saccharide esters.

16 The Panel noted that Sucrose Acetate Isobutyrate has a lower molecular weight, and therefore, greater potential for oral and dermal absorption, and thus would have a greater potential to exert biological effects than most of the ingredients for which it was used as a read-across analog. The Panel also noted the use of several of the saccharide esters as direct and indirect food additives, especially the GRAS (generally recognized as safe) status of Sucrose Acetate Isobutyrate for use as a direct food additive and determined that these uses allayed their concerns about the possibility of systemic effects from the potential oral or dermal absorption of these ingredients. Tentative Safety Assessments Butyl Polyoxyalkylene Ethers The Panel issued a tentative amended report for public comment with the conclusion that the following 46 butyl polyoxyalkylene ethers are safe as used when formulated to be non-irritating: PPG-2-Buteth-1* PPG-2-Buteth-2* PPG-2-Buteth-3* PPG-3-Buteth-5* PPG-4-Buteth-4* PPG-5-Buteth-5 PPG-5-Buteth-7* PPG-7-Buteth-4 PPG-7-Buteth-10 PPG-9-Buteth-12 PPG-10-Buteth-9* PPG-12-Buteth-12* PPG-12-Buteth-16 PPG-15-Buteth-20 PPG-17-Buteth-17 PPG-19-Buteth-19* PPG-20-Buteth-30* PPG-24-Buteth-27* PPG-26-Buteth-26 PPG-28-Buteth-35 PPG-30-Buteth-30* PPG-33-Buteth-45 PPG-36-Buteth-36* PPG-38-Buteth-37 PPG-2 Butyl Ether PPG-3 Butyl Ether* PPG-4 Butyl Ether* PPG-5 Butyl Ether* PPG-9 Butyl Ether* PPG-12 Butyl Ether* PPG-14 Butyl Ether PPG-15 Butyl Ether* PPG-16 Butyl Ether* PPG-17 Butyl Ether* PPG-18 Butyl Ether* PPG-20 Butyl Ether* PPG-22 Butyl Ether* PPG-24 Butyl Ether* PPG-26 Butyl Ether* PPG-30 Butyl Ether* PPG-33 Butyl Ether PPG-40 Butyl Ether PPG-52 Butyl Ether PPG-53 Butyl Ether* Propylene Glycol Butyl Ether* Buteth-3 *Not reported to be in current use. Were ingredients in this group not in current use to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group. Twenty-three of these ingredients were reviewed previously; 4 were reviewed in 2000 and found to be safe as used and 19 were reviewed in 2001 and found to be safe when formulated to avoid irritation. The conclusion reached at this meeting supersedes the conclusion reached in 2000 for PPG-12-Buteth-16, PPG-9-Buteth-12, PPG-26-Buteth- 26, and PPG-28-Buteth-35. In a European Chemicals Agency (ECHA) dossier on [(Butoxymethylethoxy)methylethoxy]propan-1-ol, the CAS No. for this ingredient is the same as the CAS No. given in the Dictionary for PPG-3 Butyl Ether, even though these ingredients have different chemical structures. The Panel stated that chemical and physical properties and metabolism of these two compounds should be essentially identical and, therefore, the information included in the ECHA dossier is useful for read-across. The Panel also found it appropriate to include data on 1-(2-butoxy-1- methylethoxy)-propan-2-ol because this compound is a potential metabolite of some of the ingredients and therefore

17 strengthens the toxicology profile. However, the Panel did not consider the data on PPG-3 methyl ether and on methoxyisopropanol to be needed for read-across in this assessment. Because of the potential for dermal irritation, the Panel specified that products containing these ingredients must be formulated to be non-irritating. Also, some of the ingredients in this group are ethoxylated; therefore, the Panel specified that industry should use good manufacturing practices to minimize the presence of ethylene glycol and dioxanes in finished products. The Panel noted that, although the smaller compounds are more rapidly absorbed, the weight of the evidence clearly indicates low systemic toxicity across the group. Ethers and Esters of Ascorbic Acid The Expert Panel issued a tentative report for public comment with a conclusion that the following 7 ingredients are safe in the present practices of use and concentration: Tetrahexyldecyl Ascorbate Ascorbyl Isostearate* Ascorbyl Linoleate Ascorbyl Tetraisopalmitate Ascorbyl Palmitate Ascorbyl Dipalmitate Ascorbyl Stearate *Not reported to be in current use. Were the ingredient in this group not in current use to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group. These ingredients are reported to function in cosmetics products as antioxidants, skin-conditioning agents, and skin protectants. Ascorbyl Palmitate is also reported to function as a fragrance ingredient, and Ascorbyl Linoleate as a skin bleaching agent. Skin bleaching is a drug function, not a cosmetic function. Therefore, the Panel did not evaluate safety for skin bleaching. A study reported that Ascorbyl Palmitate strongly promoted UVB-induced lipid peroxidation in human keratinocyte cultures, and the author suggested that Ascorbyl Palmitate may intensify skin damage by this mechanism following exposures to UV radiation. However, the Panel characterized the results of this study as an artifact of an irrelevant model, and disagreed with the author s interpretation of the results. Furthermore, the results of this study were not consistent with the results of a clinical study in which topical application of Ascorbyl Palmitate prior to UVB exposures resulted in decreased or no erythema (3% Ascorbyl Palmitate cream) or enhanced resolution of UVBinduced erythema (5% Ascorbyl Palmitate cream). The Panel noted the absence of data on developmental and reproductive toxicity, but agreed that pertinent data on ascorbic acid, mono- and di-acyl-saccharides, and mono- and di-acyl-glycols from prior CIR safety assessments would address any safety concerns. The Panel also noted the positive results in an animal sensitization test for Ascorbyl Tetraisopalmitate. However, negative results in a human skin sensitization study for Ascorbyl Tetraisopalmitate and a human maximization study for Ascorbyl Dipalmitate alleviated their concerns. Because the Dictionary included use as a skin bleaching agent as a possible function of Ascorbyl Linoleate, the Panel noted that Ascorbyl Linoleate must not have this effect at use concentrations in cosmetic products. Hydroxyethyl-3,4-Methylenedioxyaniline HCl The Panel issued a tentative report for public comment with the conclusion that Hydroxyethyl-3,4- Methylenedioxyaniline HCl is safe as a hair dye ingredient in the present practices of use and concentration.

18 VCRP data submitted in 2016 indicate 67 uses of this hair colorant ingredient. The Industry survey (2016) reported maximum use concentrations ranging from 0.52% to 0.75% in hair dyes and colors. Hydroxyethyl-3,4- Methylenedioxyaniline HCl contains a free, secondary aromatic substituted amine group (aniline derivative), which warrants concerns about the potential for N-nitrosation. The Panel recommended that manufacturers formulate products to reduce the formation of nitrosamines, and eliminate the presence of impurities (i.e., 3,4-methylenedioxyaniline) that are N-nitrosated or contain nitrosating agents. Consequently, hair dye formulations containing Hydroxyethyl-3,4-Methylenedioxyaniline HCl, and formulations intended for admixture with this ingredient, should not contain nitrosating agents. The Panel concurs with the limit stated in the 2009 Scientific Committee on Consumer Safety Opinion Report on Hydroxyethyl-3,4-Methylenedioxyaniline HCl, issued by the European Commission, that nitrosamine content for this hair dye ingredient should be < 50 ppb. Many hair dyes, including Hydroxyethyl-3,4-Methylenedioxyaniline HCl, are potential skin sensitizers. This ingredient is considered to be a coal tar hair dye for which regulations require caution statements and instructions for consumer patch testing (for skin irritation/sensitization) to exempt the dye from adulteration and color additive provisions of the United States Federal Food, Drug, and Cosmetics Act. Insufficient Data Announcements Monoalkylglycol Dialkyl Acid Esters The Panel issued an insufficient data announcement for this safety assessment. The 28 monoalkylglycol dialkyl acid esters included in this report are: Trimethyl Pentanyl Diisobutyrate Butylene Glycol Dicaprylate/Dicaprate Butylene Glycol Diisononanoate* Diethylpentanediol Dineopentanoate Dioctadecanyl Didecyltetradecanoate* Dioctadecanyl Ditetradecyloctadecanoate* Glycol Dibehenate* Glycol Diethylhexanoate Glycol Dilaurate Glycol Dioleate* Glycol Dipalmate/Palm Kernelate/Olivate/ Macadamiate* Glycol Dipalmate/Rapeseedate/Soyate* Glycol Dipivalate* Glycol Distearate Glycol Ditallowate* Hexanediol Distearate* Neopentyl Glycol Dicaprate Neopentyl Glycol Dicaprylate/Dicaprate Neopentyl Glycol Dicaprylate/ Dipelargonate/Dicaprate* Neopentyl Glycol Diethylhexanoate Neopentyl Glycol Diheptanoate Neopentyl Glycol Diisononanoate Neopentyl Glycol Diisostearate Neopentyl Glycol Dilaurate* Propanediol Dicaprylate Propanediol Dicaprylate/Caprate Propanediol Diisostearate* Propanediol Dipelargonate* Not reported to be in current use. Were ingredients in this group not in current use to be used in the future, the expectation is that they would be used in product categories and at concentrations comparable to others in this group. The additional data needed to determine the safe use of these ingredients are: Dermal penetration for Diethylpentanediol Dineopentanoate, Dioctadecanyl Didecyltetradecanoate, and Dioctadecanyl Ditetradecyloctadecanoate If there is dermal absorption for any of the three ingredients specified in the previous bullet, then: 28-day dermal toxicity, genotoxicity, and irritation and sensitization at maximum concentration of use or greater ( 57%) Because these ingredients can potentially form ester hydrolysis products, toxicity data on the hydrolysis products of these three ingredients including: Diethylpentanediol Dineopentanoate Ethylpentanediol Neopentanoic Acid

19 Dioctadecanyl Didecyltetradecanoate Octadecanol Decyltetradecanoic Acid Dioctadecanyl Ditetradecyloctadecanoate Octadecanol (repeat from above) Tetradecyloctadecanoic Acid The Panel removed 1,4-Butanediol Bisdecanoate and 1,2-Hexanediyl Dicaprate from the report because their only reported function (in the Dictionary) is as a skin bleaching agent. Skin bleaching agent is not a cosmetic function. The Panel also removed Butylethylpropanediol Dimer Dilinoleate because it could not be determined whether the chemical structure of this ingredient is similar to those of the other ingredients in the group. Persulfates The Panel issued an insufficient data announcement for the following 3 ingredients: Ammonium Persulfate Potassium Persulfate Sodium Persulfate The Expert Panel agreed that the original report (published in 2001) on the 3 Persulfates should remain reopened to evaluate the safety of these ingredients in leave-on products and dentifrices. The additional data needed to evaluate the safety of these ingredients in leave-on products and dentifrices are: No-Observed-Effect-Level (NOEL) for sensitization and urticaria Concentrations of use in leave-on products and dentifrices. The original report (published in 2001) concluded that the 3 persulfates are safe as used as oxidizing agents in hair colorants and lighteners designed for brief discontinuous use followed by thorough rinsing from the hair and skin. The Panel agreed that this conclusion remains valid for the stated uses. The 2016 survey data indicates uses in additional leave-on product categories (e.g., eye makeup preparations, tonics, dressings, and other hair grooming aids) and in dentifrices (rinse-off). The FDA confirmed that the uses of Sodium Persulfate in dentifrices, which are toothpastes that are applied to real teeth. and the uses of persulfates in dental cleansers, which are classified as medical devices. An FDA public health notification was issued regarding the risk of allergic reactions in users of denture cleansers containing Sodium Persulfate, and the risks of misusing these products. They noted the literature and research suggesting that the ingredient in denture cleansers responsible for these reactions is persulfate, which is a known allergen. Thus, the Panel reopened the original report on Ammonium Persulfate, Potassium Persulfate, and Sodium to evaluate the safety of these ingredients for the newly reported uses. Additionally, the Panel restated their previous recommendation that the language in the original conclusion relating to brief and discontinuous use followed by thorough rinsing from the hair and skin be applied to users of these products such as hairdressers. Plant-Derived Proteins and Peptides The Panel reviewed the following 19 ingredients and found the data were insufficient to determine safety of one ingredient: Hydrolyzed Amaranth Protein Hydrolyzed Avocado Protein Hydrolyzed Barley Protein Hydrolyzed Brazil Nut Protein Hydrolyzed Cottonseed Protein Hydrolyzed Extensin Hydrolyzed Hazelnut Protein Hydrolyzed Hemp Seed Protein Hydrolyzed Jojoba Protein Hydrolyzed Lupine Protein Hydrolyzed Maple Sycamore Protein Hydrolyzed Pea Protein Hydrolyzed Potato Protein Hydrolyzed Sesame Protein

20 Hydrolyzed Sweet Almond Protein Hydrolyzed Vegetable Protein Hydrolyzed Zein Lupinus Albus Protein Pisum Sativum (Pea) Protein The additional data needed to evaluate the safety of Hydrolyzed Maple Sycamore Protein are: Method of manufacturing Chemical composition and impurities Clarification on food safety status, specifically whether this ingredient is generally recognized as safe (GRAS) If this ingredient is not GRAS, then studies of systemic endpoints such as a 28-day dermal toxicity, reproductive and developmental toxicity, and genotoxicity are needed, as well as UV absorption spectra The Panel determined that the data were sufficient to support safety of the remaining 18 plant-derived protein and peptide ingredients in the present practices of use and concentration. The Panel acknowledged that Type I immediate hypersensitivity reactions could possibly occur following exposure to a protein-derived ingredient. Traditional HRIPTs and related test data do not detect Type I reactions. Thus, the Panel recommends that people with known allergies to tree nut, seed, and avocado proteins avoid using personal care products that contain these ingredients. Presentation on Endocrine Disruption Issues and Methods Dr. Mihaich presented the World Health Organization (WHO) International Program on Chemical Safety (IPCS) definition of an endocrine disruptor. By this widely accepted definition, endocrine disruptors cause adverse health effects in living organisms specifically by altering the function of the endocrine system. Endocrine disruption is distinct from endocrine activity, which is simply the ability of a chemical to interact with the endocrine system without necessarily posing a health risk. Dr. Mihaich emphasized that less rigorous definitions of endocrine disruptors has had regulatory consequences, where substances have been banned based on the assessment of hazard (i.e., capability to cause harm) rather than risk (i.e., probability of causing harm under specified exposure conditions). As noted in her presentation, the legislative mandates of the 1996 Food Quality Protection Act (FQPA) and amendments to the Safe Drinking Water Act (SDWA) led to the establishment of the U.S. EPA Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC). The EDSTAC developed the conceptual framework that provides the structure for screening (Tier 1) and testing (Tier 2) for endocrine disruptors under the U.S. EPA Endocrine Disruptor Screening Program (EDSP). Dr. Mihaich outlined the critical elements of a weight-of-evidence (WoE) assessment. She noted the importance of evaluating the consistent pattern of responses across studies for or against explicitly defined hypotheses. She also explained how the concept of the Adverse Outcome Pathway (AOP) can be used to enhance the development and presentation of a WoE analysis, and how acute-to-chronic ratios (ACRs) can be used to help determine whether the

21 endocrine-mediated effects of a chemical at chronic low doses or concentrations can be attributed to primary interactions of the chemical with the endocrine system. Dr. Mihaich noted the proliferation of lists of substances that have been suggested to be endocrine disruptors or potential endocrine disruptors and the potential downsides of using such lists without considering factors such as the different purposes for which they were developed, specificity for potentially endocrine-active chemicals, differences in methodologies and criteria, appropriate requirements for data quality, or the weight of the evidence. She discussed two WHO reports on the state of the science on endocrine disrupting chemicals. The slides for this presentation are available at

22 Memorandum To: CIR Expert Panel Members and Liaisons From: Ivan J. Boyer, Senior Toxicologist Date: March 17, 2017 Subject: Draft Revised Aerosols Precedents and Framework Document Commitment & Credibility since 1976 Enclosed is the revised draft of the CIR Precedents Aerosols document. The version currently posted on the CIR Website was revised in 2012, and additional revisions were made in 2016 to incorporate new information and analysis submitted by the CIR Science and Support Committee (CIR SCC) to address incidental inhalation exposures to ingredients in loose powder cosmetic products. The present draft incorporates the comments of the Panel during the March 2016 Panel meeting, and the Framework of this version has been used by the CIR writers/analysts in their reports since then. The Panel recommended this approach to gain some experience with the revised Framework before finalizing the draft. The revisions are visible in the enclosed MS Word file (aeroso032017rep.doc) in Show Markup mode. The Panel should review the revisions and determine whether any additional revisions are warranted L Street NW, Suite 1200, Washington, DC (Main) (Fax) ( ) cirinfo@cir-safety.org (Website)

23 COSMETIC INGREDIENT REVIEW CIR Precedents Aerosols 9/20124/2017 This document is a compilation of issues discussed by the CIR Expert Panel along with precedent language used in CIR Reports to articulate the Panel s views. Standard formats used in Panel Reports are also addressed. This is intended to provide background on issues and serve as a reference explaining the reasoning behind previous Panel decisions. 1

24 Sprays/Powders Update 1/2012 BACKGROUND Inhalation toxicity is an important consideration for sprays and loose powders containing cosmetic ingredients. The inhalation toxicity of ingredients in such products depends, in part, on where the ingredients may contact tissues in the respiratory tract and whether they can cause local adverse effects in the respiratory tract tissues or systemic effects after absorption from the respiratory tract. 1 The deposition and absorption of gases and vapors in the respiratory tract depend mainly on their water solubility and reactivity with the fluids or other components of the surfaces of the airways. 2-4 For example, absorption of an insoluble, non-reactive gas is negligible. A moderately soluble or reactive gas will be deposited throughout the respiratory tract. A highly soluble or reactive gas will be rapidly deposited or absorbed almost entirely in the nose and upper airways. Aerosols are broadly defined as multiphase systems of particulate solids or liquids dispersed in air or other gases, including mists, fumes and dusts. 1 The deposition, absorption, clearance and, ultimately, the effects of ingredients in aerosols (liquid droplets or solid particles) in the respiratory tract depend on the solubility, reactivity, and toxicity of the ingredients. However, the size of the inhaled aerosol droplets/particles also plays an important role. 1,3,5 The physical parameter most strongly associated with the deposition pattern of an aerosol in the respiratory tract is the aerodynamic equivalent diameter, d ae. 6,7 The d ae of a droplet/particle is defined as the diameter of a hypothetical, smooth sphere of unit density (1 g/cm 3 ) that has the same gravitational settling velocity as the droplet/particle in calm air, regardless of its actual geometric size, shape and density. 5,8 The droplets/particles of an aerosol can be divided into three mass fractions, based on the depth to which they will penetrate the respiratory tract. These fractions include the inhalable fraction (median d ae =100 µm), which can enter the nasopharyngeal region through the nose or mouth, the bronchial fraction (median d ae =10 µm), which can pass through the larynx to enter the trachea, bronchi and bronchioles, and the respirable fraction (median d ae =4 µm), which can enter the alveolar region of the lungs. 1-3,9 In the nasopharyngeal and bronchial regions of the respiratory tract, mucus-secreting and ciliated cells form a protective mucociliary blanket that carries deposited droplets/particles to the throat. Thus, droplets/particles deposited in these regions can be sneezed or spit out or swallowed. 10 In the pulmonary region, the clearance of inert, poorly soluble particles is mediated primarily by alveolar macrophages, and is slow and limited by comparison. However, the potential for toxic effects is not limited to respirable droplets/particles deposited in the lungs. Inhaled droplets/particles deposited in the nasopharyngeal and bronchial regions of the respiratory tract may cause toxic effects in these regions depending on their chemical and physical properties. There is broad scientific consensus that the probability of penetration of droplets/particles with d ae >10 µm into the pulmonary region is essentially zero. 1,5,11-15 Thus, only droplets/particles with d ae <10 µm are considered to be respirable. This is a conservative assumption because a d ae of 5 µm is often reported in the scientific literature as the threshold below which droplets/particles can reach the alveoli. 1 In addition, there is consensus that droplets/particles with d ae >15 µm are deposited almost exclusively in the nasopharyngeal and bronchial regions of the respiratory tract, and that healthy people will clear particles with d ae >7 µm from these regions within 24 hours through mucociliary action. 1 Particle size distributions are product specific. Numerous factors determine the initial size distribution of droplets or particles released from a spray product, including the product formulation (e.g., volatile or nonvolatile solvent), propellant, can size, and differential pressure through the nozzle for propellant sprays, and formulation and nozzle characteristics for pump sprays. 1,16 After release to the air, 2

25 the particle size distribution can change rapidly through aggregation, agglomeration, sedimentation, evaporation of volatile components, or hygroscopic absorption of water. 1,8,9,12,17,18 For example, all of the water and other volatile solvents and propellants in droplets with d ae <40 μm will evaporate within 1 second of release from a spray can, so that the remaining particles will contain non- or low-volatile constituents (e.g., polymers with little or no biological activity in hair sprays). 1,17,19,20 Accordingly, a wide spectrum of particle size distributions can be released from cosmetic sprays. Both pump sprays and propellant sprays (also called aerosol sprays ) produce aerosols, but the aerosols from propellant sprays have larger fractions of respirable droplets/particles than aerosols from pump sprays. 1 For example, the median d ae of the airborne droplets/particles of pump hair sprays range from 60 µm to 80 µm. 1,16,17 Typically, <1% of the airborne droplets/particles released from pump sprays are in the range considered to be respirable (i.e., d ae <10 µm). 16 In comparison, the median d ae of the airborne droplets/particles of propellant hair sprays range from 25 µm to 50 µm. 1,16,17 Usually, 1% to 2.5% but no more than 5% of the droplets/particles emitted from propellant hair sprays are within the respirable range. 16 Further, different types of propellant-spray products may yield substantially different particle size distributions. For example, conservative estimates indicate that propellant hair-spray aerosols have a median d ae of 35 µm with a coefficient of variation of ,17 Thus, the insoluble aerosol particles inhaled during hair-spray use will be deposited primarily in the nasopharyngeal and bronchial regions, where they can be trapped and cleared from the respiratory tract through mucociliary action. In contrast, analogous estimates indicate that the tested deodorant-spray aerosols have a median d ae of 10 µm with a coefficient of variation of 0.3, suggesting that half of these particles are within the range considered to be respirable. 12,17 These differences in droplet/particle size distributions between pump and propellant spray products, and between the few hair spray and deodorant spray products tested, are important considerations for evaluating the safety of cosmetics ingredients that may be respired during use. This is because they suggest that the margin of safety may be lower for propellant sprays compared to pump sprays, and for propellant deodorant sprays compared to propellant hair sprays. The inhalation of respirable droplets/particles from cosmetic products, including pump and propellant hair sprays and deodorant sprays, is likely to be very small, even negligible, compared with dermal contact and other exposure routes associated with the use of these products. Further, products like underarm deodorant and foot sprays are not usually sprayed in the direction of the face, so less of these products will likely be sprayed directly into the users breathing zone compared with hair sprays, for example. However, the limited evidence currently available does not provide adequate support for these assumptions. The droplets/particles released from a propellant hair spray are distributed within a 1 to 2 m 3 space in the breathing zone during the first 2 minutes after spraying, which expands to form an homogenous 10-m 3 cloud (about the size of a bathroom) over the subsequent 18 minutes. 1,16 Simulation studies revealed that all of the droplets/particles released from both pump sprays and propellant sprays settle quickly after spraying, including the respirable and inhalable fractions, which substantially reduces the overall potential for inhalation exposure. 5,8,16-18 Specifically, about 35% of the airborne droplets/particles drop away from the breathing zone in the first minute, 60% in the second minute, 90% in six minutes, and 95% in eight minutes after spraying. 16 The droplets/particles are likely to be undetectable in the breathing zone within 10 minutes after spraying. Pulmonary overload is a condition in which the accumulation of any inert, poorly soluble particulate material in the lungs overwhelms the capacity of the alveolar macrophages to clear the material from the lungs. Chronic pulmonary overload can cause persistent inflammatory responses, fibrosis and tumors, 21 although the mechanism(s) of overload-induced tumor formation is not completely understood The European Union s current threshold for protecting workers from pulmonary overload during occupational exposure to respirable dust particles is 1.5 mg/m 3 8-hour time-weighted average. In comparison, inhalation exposures to aerosols from cosmetic sprays will be much lower than this threshold, primarily because of the much shorter exposure duration associated with cosmetic spray use (i.e., only a few minutes). 1,16 3

26 Industry can ensure that inhalation exposures to cosmetic sprays and powders are minimized. 16 For example, particle size distributions can be characterized and exposures estimated each time a significant change is made in the formulation or spray mechanisms of spray products to ensure that potential inhalation exposures are very low. Similarly, industry can minimize airborne particles from cosmetic powder products by controlling the milling of the ingredients and adding binding materials, such as oils, waxes or hygroscopic ingredients, in the formulations. 25 The binding materials foster the agglomeration of the ingredients and substantially increase their cohesivity. These measures increase the size of the particles in the product. However, characterizing the particle size distributions released from finished powder products under use conditions is difficult. This is because the methods used to measure the particle sizes of powder products involve dispersing the powder in a solvent or applying a pressure differential to break up the agglomerated particles. 25 Thus, these measurements do not correlate well with the size distributions of the particles released from the product under use conditions. Some photographic methods are being developed to characterize the actual sizes and shapes of the particles released from powder products during use. However, it is not clear whether these methods are amenable to characterizing the aerodynamic equivalent diameters of such particles. The CIR Expert Panel noted that, in practice, 95% to 99 % of the droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters greater than 10 µm. Thus, most aerosol droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and bronchial regions of the respiratory tract and would not be respirable to any appreciable amount. However, some of the droplets/particles are respirable, including up to 5% of the particle size distribution during the use of some products. Such information should be included in each safety assessment for which the ingredient(s) may be used in a pump or propellant spray. Information will continue to be sought from suppliers and formulators to specifically identify such spray uses. The Panel recognized that aerosols from propellant sprays are distinct from aerosols from pump sprays. For each ingredient or ingredient group assessed, the Panel would like to know whether the current practices of use include propellant sprays, pump sprays, or both, when appropriate and the information is available. Identifying the use of ingredients in deodorant spray products may be especially important, because they potentially release the largest amount of respirable droplets/particulates among the products evaluated. However, better information about particle size distributions and their variability (within and across product types) that can be reasonably expected, generally, from a broad range of products (e.g., hair, sunscreen, indoor suntanning, foot and deodorant sprays, and loose powders) would substantially increase confidence in safety assessments of ingredients in products that may be aerosolized. The Panel recognizes that the distribution of aerodynamic equivalent diameters of cosmetic aerosol droplets/particles is an important parameter determining where the inhaled particles/droplets will be deposited in the respiratory tract. However, the Panel also emphasizes that the chemical properties of the particles/droplets will be critical factors determining whether they will cause inhalation toxicity where they are deposited. The Panel will continue to review all of the relevant inhalation toxicity, use, and other data to determine the safety of cosmetic ingredients. The Panel will evaluate the importance of the inhalation route for assessing the safety of an ingredient or group of ingredients, and evaluate data that may be available to estimate potential respiratory doses from aerosolized products. Factors to consider include whether or how much of the spray products enter the breathing zone, the likely droplet/particle size distributions in the breathing zone, and the exposure durations that can be expected during product use. The Panel agreed that, generally, inhalation exposure to ingredients in aerosolized cosmetic products is unlikely to be significant compared to the dermal or other exposure routes associated with the use of cosmetic products. 4

27 For example, conservative estimates indicate that inhalation exposures for once-a-day application of a propellant deodorant spray, pump hair spray, or propellant hair spray containing 10% of an ingredient would be no more than 3, 7, and 20 µg/kg/day. 26 These estimates were based on the following conservative assumptions: All of the spray enters the breathing zone (i.e., 100% is available for inhalation) Exposure duration: 20 minutes The droplets/particles: o o Form a 1-m 3 cloud in the first 2 minutes after spraying Dissipate to fill 10-m 3 space around the user in the next 18 minutes 25% of the inhaled droplets/particles are exhaled Breathing rate: 0.01 m 3 /minute Body weight: 60 kg Amount of product used: 1.43, 15.6 and 9.89 g/day deodorant, pump-hair, and propellant-hair spray, respectively 27 Respirable fraction: 5%, 1%, 5% for deodorant, pump-hair, and propellant-hair spray, respectively Similarly, conservative estimates indicate that inhalation exposures for once-a-day application of a loose face powder or body dusting product range from 0.1 to 1.05 µg/kg/day for infants or adults, based on the following assumptions: Concentration of respirable particles: 0.19 to 2.03 mg/m 3 in the breathing zone Breathing rate: 0.01 m 3 /minute Body weight: 10 kg (infant) or 60 kg (adult) Exposure duration: 0.3 to 5 minutes However, even such small inhalation exposures may be significant for an ingredient that has the potential to act as a potent systemic or local respiratory tract toxicant or to accumulate in the body. The Panel noted that inhalation toxicity studies on test animals are often conducted using high concentrations of droplets/particles with size distributions well within the respirable range and long exposure durations to ensure that the potential for pulmonary or systemic toxicity will be detected. In contrast, the concentrations of respirable droplets/particles and the inhalation exposure durations from the use of cosmetic products will be much less than those of the animal studies. Thus, the adverse effects reported in such studies may have little or no relevance for evaluating the inhalation safety of cosmetic ingredients. For example, the Panel noted studies that reported pulmonary granulomas in animals exposed to high concentrations of inhaled silylates sheared to form particles with aerodynamic equivalent diameters ranging from 1 to 4 µm, which is well within the range considered to be respirable. However, this ingredient, as supplied to formulators, has an average aerodynamic equivalent diameter of about 20 µm, and the ingredient aggregates and agglomerates to form clusters and chains with d ae >125 µm and none <90 µm. Thus, the formation of granulomas in the animals was not considered to be relevant for evaluating the inhalation safety of this ingredient as used in cosmetic products. If inhalation toxicity data are absent or provide an insufficient basis to support the safety of an ingredient used in products that may be aerosolized, the Panel will evaluate the sufficiency of other data that may be available on a case-by-case basis. Such data would include, for example, the potential for 5

28 the ingredient to cause systemic toxicity, ocular or dermal irritation or sensitization, or other effects after repeated exposures. Other factors to consider include whether the ingredient belongs to a class of toxicants recognized to have the potential to cause lung injury after exposure via inhalation or other routes, possesses structural alerts based on known structure-activity relationships, or has a noteworthy potential to yield reactive intermediates or other metabolites of concern in the lungs. 6

29 Precedent language for specific report sections: Cosmetic Use Section [INGREDIENT(S)] was/were reported to be used in [LIST TYPE(S) OF SPRAY PRODUCT(S), e.g., cosmetic sprays, including hair, deodorant, foot, and other propellant and pump spray products], and could possibly be inhaled. [NOTE THE HIGHEST MAXIMUM USE CONCENTRATION OF THE INGREDIENT IN A SPRAY PRODUCT IF THIS INFORMATION IS AVAILABLE, e.g., These ingredients are reportedly used at concentrations up to 4% in spray products] In practice, 95% to 99% of the droplets/particles released from cosmetic sprays have aerodynamic equivalent diameters >10 µm [IF PRODUCT(S) MAY INCLUDE BOTH PROPELLANT AND PUMP SPRAYS, ADD:, with propellant sprays yielding a greater fraction of droplets/particles below 10 µm compared with pump sprays]. (Rothe et al 2011, Bremmer et al 2006, Rothe 2011, Johnsen 2004). 1,12,16,31 Therefore, most droplets/particles incidentally inhaled from cosmetic sprays would be deposited in the nasopharyngeal and bronchial regions and would not be respirable (ie, they would not enter the lungs) to any appreciable amount. Rothe et al 2011, Bremmer et al 2006). 1,12 [IF PRODUCT(S) INCLUDE DEODORANT SPRAY(S), ADD: There is some evidence indicating that deodorant spray products can release substantially larger fractions of particulates having aerodynamic equivalent diameters in the range considered to be respirable (Bremmer et al 2006). 12 However, the information is not sufficient to determine whether significantly greater lung exposures result from the use of deodorant sprays, compared to other cosmetic sprays. [IF PRODUCTS INCUDE POWDER(S), ADD: INGREDIENT(S)] was/were reported to be used in [LIST TYPE(S) OF POWDER PRODUCT(S), e.g., baby powders, dusting powders, talc powders, face powders, foot powders], and could possibly be inhaled. [NOTE THE HIGHEST MAXIMUM USE CONCENTRATION OF THE INGREDIENT IN A POWDER PRODUCT IF THIS INFORMATION IS AVAILABLE, e.g., These ingredients are reportedly used in loose powder products at concentrations up to 4%]. Conservative estimates of inhalation exposures to respirable particles during the use of loose-powder cosmetic products are 400-fold to 1000-fold less than protective regulatory and guidance limits for inert airborne respirable particles in the workplace. Aylott et al 1979, Russell et al 1979, CIR SSC 2015) ] Discussion Section For Tentative Reports The Panel discussed the issue of incidental inhalation exposure from [LIST PERTINENT PRODUCT TYPES FOR THE INGREDIENT(S); EXAMPLE: body and hand sprays, hair color sprays, fragrance preparations and foot powders.] [IF APPROPRIATE, ADD: There were no inhalation toxicity data available.] The Panel considered pertinent data indicating that incidental inhalation exposures to [this ingredient OR these ingredients OR some of these ingredients] in such cosmetic products would not cause adverse health effects, including [BRIEFLY LIST WHATEVER DATA THE PANEL DEEMED TO SUPPORT THE CONCLUSION; THIS WILL VARY FROM INGREDIENT (GROUP) TO INGREDIENT (GROUP); EXAMPLE: data characterizing the potential for [INGREDIENT(S)] to cause systemic toxicity, ocular or dermal irritation or sensitization, and other effects]. The Panel noted that 95% 99% of droplets/particles produced in cosmetic aerosols would not be respirable to any appreciable amount. The potential for inhalation toxicity is not limited to respirable droplets/particles deposited in the lungs; in principle, Inhaled droplets/particles deposited in the nasopharyngeal and thoracic regions of the respiratory tract may cause toxic effects depending on their chemical and other properties. However, coupled with the small actual exposure in the breathing zone and the concentrations at which the ingredients are used, the available information indicates that incidental inhalation would not be a significant route of exposure that might lead to local 7

30 respiratory or systemic effects. A detailed discussion and summary of the Panel s approach to evaluating incidental inhalation exposures to ingredients in cosmetic products is available at For Final Reports and Re-Review Summaries The Panel discussed the issue of incidental inhalation exposure from [LIST PERTINENT PRODUCT TYPES FOR THE INGREDIENT(S); Example: body and hand sprays, hair color sprays, fragrance preparations and foot powders.] [NOTE INHALATION TOXICITY DATA, IF APPLICAPLE: Examples: (1) The limited data available from inhalation studies, including acute and chronic exposure data, suggest little potential for respiratory effects at relevant doses OR (2) The data available from multiple inhalation studies, including acute and chronic exposure data, indicate little potential for respiratory effects at relevant doses.] [ADDRESS PARTICLE SIZES TESTED, IF APPLICABLE; EXAMPLE: Although particles appear to have reached the lungs in these animal studies, the sizes of the particles used were either clearly within the respirable range (i.e., 10 µm) or were not reported.] [ALTERNATIVELY, ADD THE FOLLOWING, IF APPROPRIATE: There were no inhalation toxicity data available.] [ADDRESS PARTICLE SIZES IN COSMETICS, IF POSSIBLE; EXAMPLES: (1) The Expert Panel believes that the sizes of a substantial majority of the particles of these ingredients, as manufactured, are larger than the respirable range and/or aggregate and agglomerate to form much larger particles in formulation. Thus, the adverse effects reported using high doses of respirable particles in the inhalation studies do not indicate risks posed by use in cosmetics OR (2) The particle sizes of these ingredients was reported to range from 50 nm 1000 μm with the largest portion being in the μm range. The Panel believes that the sizes of a substantial majority of the particles of these ingredients, as manufactured, are larger than the respirable range and/or aggregate and agglomerate to form much larger particles in formulation OR (3) Several of these ingredients are used to increase viscosity, indicating that they tend to swell and aggregate in water and other solvents and would, thus, be too large to be inhaled or respired.] [NOTE MAXIMUM USE CONCENTRATIONS IN SPRAYS AND/OR LOOSE POWDERS; EXAMPLES: (1) These ingredients are reportedly used at concentrations up to 4% in cosmetic products that may be sprayed and up to 97% in other loose powder products that may become airborne OR (2) These ingredients are reportedly used at concentrations up to 0.01% in cosmetic products that may be aerosolized.] The Panel noted that 95% 99% of droplets/particles from cosmetic products would not be respirable to any appreciable amount. [ADDRESS POTENTIAL EXPOSURES TO UPPER AND MID RESPIRATORY TRACT, AS APPROPRIATE; EXAMPLES: (1) Furthermore, droplets/particles deposited in the nasopharyngeal or bronchial regions of the respiratory tract present no toxicological concerns based on the chemical and biological properties of this ingredient OR (2) Furthermore, these ingredients are not likely to cause any direct toxic effects in the upper respiratory tract, based on the properties of the [INGREDIENT(S)] and on data that shows that these ingredients are not 8

31 irritants OR (3) The potential for inhalation toxicity is not limited to respirable droplets/particles deposited in the lungs; In principle, inhaled droplets/particles deposited in the nasopharyngeal and thoracic regions of the respiratory tract may cause toxic effects depending on their chemical and other properties.] Coupled with the small actual exposure in the breathing zone and the concentrations at which the ingredients are used, the available information indicates that incidental inhalation would not be a significant route of exposure that might lead to local respiratory or systemic effects. The Panel considered other data available to characterize the potential for [INGREDIENT(S)] to cause [LIST PERTINENT TOXICITIES EVALUATED; EXAMPLES: (1) irritation and sensitization OR (2) systemic toxicity, irritation, sensitization, reproductive and developmental toxicity, and genotoxicity.] [SUM UP PERTINENT TOXICOLOGY RESULTS; EXAMPLES: (1) They noted the lack of systemic toxicity at high doses in several acute and subchronic oral exposure studies and one chronic oral exposure study, little or no irritation or sensitization in multiple tests of dermal and ocular exposure, the absence of genotoxicity in multiple Ames tests and a Chinese hamster ovary test, and lack of carcinogenicity in a lifetime oral exposure study OR (2) They noted the lack of irritation or sensitization in tests of dermal exposure, no systemic toxicity at 5000 mg/kg, and the absence of genotoxicity in an Ames test of a related chemical.] [SUM UP PERTINANT PHYSICOCHEMICAL PROPERTIES, IF APPLICABLE; EXAMPLES: (1) [INGREDIENT(S) is/are chemically inert and thus not systemically toxic OR (2) In addition, these ingredients are large macromolecules, insoluble in water, and chemically inert under physiological conditions or conditions of use, which supports the view that they are unlikely to be absorbed or cause local effects in the respiratory tract.] A detailed discussion and summary of the Panel s approach to evaluating incidental inhalation exposures to ingredients in cosmetic products is available at 9

32 References 1. 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 ;205(2): PM: Bailey MR, Ansoborlo E, Etherington G, Gregoratto D, Guilmette R, Marsh J, Paquet F, and Smith J. Proposed updating of the ICRP human respiratory tract model. 12th International Congress of the International Radiation Protection Association Bakand S, Winder C, Khalil C, and Hayes A. Toxicity assessment of industrial chemicals and airborne contaminants: transition from in vivo to in vitro test methods: a review. Inhal.Toxicol ;17(13): PM: Roy M. Dosimetry of the respiratory tract pp World Health Organization (WHO). Hazard Prevention and Control in the Work Environment: Airborne Dust. Geneva, Switzerland, Report No. WHO/SDE/OEH/ pp de Winter-Sorkina R and Cassee FR. From concentration to dose Factors influencing airborne particulate mater deposition in humans and rats Report No. RIVM /2002. pp Phalen RF, Mendez LB, and Oldham MJ. New developments in aerosol dosimetry. Inhal.Toxicol. 2010;22 Suppl 2:6-14. PM: Phalen RF and Oldham MJ. Aerosol dosimetry considerations. Clin Occup Environ Med. 2006;5(4): PM: European Commission Joint Research Center. Guidance Document on the Determination of Particle Size Distribution, Fibre Length and Diameter Distribution of Chemical Substances. Luxembourg, Office for Official Publications of the European Communities %20EN.pdf. Report No. EUR EN. pp Witschi HP and Last JA. Toxic Responses of the Respiratory System. Chapter: 15. Klaassen CD. In: Casarett & Doull's Toxicology: The Basic Science of Poisons. 6 ed. New York: McGraw- Hill; 2001: International Commission on Radiological Protection (ICRP). Human Respiratory Tract Model for Radiological Protection. Didcot, Oxfordshire, England, ICRP

33 Report No. =Ann ICRP 24 (1-3), ICRP Publication 66. pp Bremmer HJ, Prud'homme de Lodder LCH, and van Engelen JGM. Cosmetics Fact Sheet: To assess the risks for the consumer; Updated version for ConsExpo Date Accessed Report No. RIVM /2006. pp Hatch TF. Distribution and deposition of inhaled particles in respiratory tract. Bacteriol.Rev. 1961;25: PM: Heyder J, Gebhart J, Rudolf G, Schiller CF, and Stahlhofen W. Deposition of particles in the human respiratory tract in the size range um. J.Aerosol.Sci. 1986;17(5): Oberdorster G, Oberdorster E, and Oberdorster J. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ.Health Perspect. 2005;113(7): PM: Rothe H. Special aspects of cosmetic spray safety evaluation Unpublished information presented to the 26 September CIR Expert Panel. Washington D.C. 17. Delmaar JE and Bremmer HJ. The ConsExpo Spray Model Report No. RIVM / Eickmann U, Eickmann J, and Tischer M. Exposure to Sprays: Comparison of the available exposure models. Gefahrstoffe - Reinhaulting der Luft. 2007;67(7/8): Greim H, Borm P, Schins R, Donaldson K, Driscoll K, Hartwig A, Kuempel E, Oberdorster G, and Speit G. Toxicity of fibers and particles. Report of the workshop held in Munich, Germany, October Inhal.Toxicol. 2001;13(9): PM: Muhle H and Mangelsdorf I. Inhalation toxicity of mineral particles: critical appraisal of endpoints and study design. Toxicol Lett ; : PM: Morrow PE. Mechanisms and significance of "particle overload". Mohr U, Dungworth DL Mauderly JL Oberdörster G. In: Toxic and Carcinogenic Effects of Solid Particles in the Respiratory Tract. Washington, DC: International Life Sciences Institute (ILSI) Press; 1994: Mossman BT. Mechanisms of action of poorly soluble particulates in overload-related lung pathology. Inhal.Toxicol. 2000;12(1-2): PM: Nikula KJ. Rat lung tumors induced by exposure to selected poorly soluble nonfibrous particles. Inhal.Toxicol. 2000;12(1-2): PM: Oberdorster, G. Lung particle overload: implications for occupational exposures to particles. Regul Toxicol Pharmacol. 1995;21(1): PM:

34 25. Rothe H. Special aspects of powders in decorative cosmetics Unpublished information presented at the 26 September 2011 CIR Expert Panel Meeting. Washington, DC. 26. CIR Science and Support Committee of the Personal care Products Council. Sample Exposure Calculations pp Loretz L, Api AM, Barraj L, Burdick J, Davis de A, Dressler W, Gilberti E, Jarrett G, Mann S, Laurie Pan YH, Re T, Renskers K, Scrafford C, and Vater S. Exposure data for personal care products: hairspray, spray perfume, liquid foundation, shampoo, body wash, and solid antiperspirant. Food Chem Toxicol. 2006;44(12): PM: CIR Science and Support Committee of the Personal Care Products Council (CIR SSC) Cosmetic Powder Exposure. Unpublished data submitted by the Personal Care Products Council. 29. Aylott RI, Byrne GA, Middleton, J, and Roberts ME. Normal use levels of respirable cosmetic talc: preliminary study. Int J Cosmet Sci. 1979;1(3): PM: Russell RS, Merz RD, Sherman WT, and Sivertson JN. The determination of respirable particles in talcum powder. Food Cosmet Toxicol. 1979;17(2): PM: Johnsen MA. The Influence of Particle Size. Spray Technology and Marketing. 2004;14(11): Unpublished references are available from CIR upon request. 12

35 Memorandum To: CIR Expert Panel Members and Liaisons From: Ivan J. Boyer, Senior Toxicologist Date: March 17, 2017 Subject: Draft Update of the CIR Expert Panel Hair Dye Epidemiology Findings Document Commitment & Credibility since 1976 Enclosed is an updated draft of the CIR Expert Panel Hair Dye Epidemiology findings document. The version currently posted on the CIR Website was last revised in The present draft is identified as hdyepi042017rep in the admin pdf. Several studies have appeared in the published scientific literature since 2014 these studies were summarized and added to the 2014 version of the Hair Dye Epidemiology document, and the summaries appear in Final Showing Markup mode in the enclosed draft. The studies include two meta-analyses and two case-control studies addressing lymphoma and leukemia, one case control study addressing breast cancer, and one case-control study addressing polymorphisms in DNA repair-enzyme genes. In addition, an older meta-analysis addressing breast cancer, among other cancers, was included the practice of including meta-analyses in the CIR Expert Panel Hair Dye Epidemiology document began with the 2014 edition of the document. The Panel should review the revisions and determine whether any additional revisions are warranted, including revisions of the Conclusion L Street NW, Suite 1200, Washington, DC (Main) (Fax) ( ) cirinfo@cir-safety.org (Website)