cir expert panel meeting december 5 – 6, 2016page 2 – 141 st meeting of the cir expert panel —...

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CIR EXPERT PANEL MEETING DECEMBER 5 – 6, 2016

Commitment & Credibility since 1976

MEMORANDUM

To: CIR Expert Panel Members and Liaisons From: Director, CIR Subject: 141st Meeting of the CIR Expert Panel — Monday and Tuesday, December 5-6, 2016 Date: November 11, 2016

Enclosed are the agenda and accompanying materials for the 141st CIR Expert Panel Meeting to be held on December 5-6, 2016. The meeting will be held at the Melrose Georgetown Hotel, which is located at 2430 Pennsylvania Ave., Washington, DC. Phone: (202) 955-6400; Fax: (202) 775-8489. The hotel is located close to the Foggy Bottom Metro Station. This is the last meeting of 2016 and the last meeting at this hotel. Beginning with the April 10-11, 2017 meeting, all of the 2017 CIR Panel meetings will be held at the Hamilton Crowne Plaza Hotel, which is located at 1001 14th Street, N.W., Washington, DC.

The meeting agenda includes the consideration of 14 ingredient groups advancing in the review process. The Panel is also asked to provide guidance on the review of Lead Acetate, an ingredient recommended by the FDA during the CIR priorities setting process for year 2017. Lastly, the agenda includes an update on endocrine disruption by Dr. Ellen Mihaich. This presentation was requested by the Council after the September Panel meeting. Dr. Mihaich is the Owner and Principal Scientist of Environmental and Regulatory Resources, LLC (ER2), a company focused on environmental toxicology and risk assessment. Since 2000, Dr. Mihaich has been a Business and Industry Advisory Committee (BIAC) representative to the OECD Endocrine Disruptor Testing and Assessment Validation Management Group for Ecotoxicity Testing (VMG-Eco), and has been an author or contributor to numerous BIAC comments on detailed review papers, validation reports, and protocols involving endocrine-focused studies. She is currently the scientific coordinator for the Endocrine Policy Forum, a consortium of scientific and regulatory experts coordinating industry participation in the US Endocrine Disruptor Screening Program.

Schedule and hotel accommodations

We have reserved rooms for the nights of Sunday, December 4 and Monday, December 5, at the Melrose Georgetown Hotel. If you encounter travel problems, please contact me on my cell phone at 410-299-0777.

Team meetings Draft reports - there are 5 draft reports for review.

1. Ethers and Esters of Ascorbic Acid (agenda and flash drive name – ethers of ascorbate). This is

the first time the Panel is seeing this report on 7 Ethers and Esters of Ascorbic Acid that are all alkylated or acylated derivatives of Ascorbic Acid, which is also known as Vitamin C. These ingredients are reported to function mostly as antioxidants; skin-conditioning agents; skin protectants; fragrance ingredients; and skin bleaching agents. Are the data sufficient to proceed with a tentative report, or should an insufficient data announcement be issued?

2. Hydroxyethyl-3,4-Methylenedioxyaniline HCl (agenda and flash drive name – hydroxy-3,4-

methylenedioxyaniline) – This is the first time the Panel is seeing this safety assessment of this hair colorant that is an amine salt and contains a free, secondary aromatic substituted amine (aniline derivative).

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141st Meeting of the CIR Expert Panel — Monday and Tuesday, December 5-6, 2016

According to the European Commission Scientific Committee on Consumer Safety (SCCS), this ingredient is referred to as both a precursor and a coupler, and is limited to a maximum concentration of 1.5% on the head, following mixing. Are the available data sufficient for issuing a tentative report, or should an insufficient data announcement be issued?

3. Monoalkylglycol Dialkyl Acid Esters (agenda and flash drive name – dialkyl acid esters). This is

the first time that the Panel is seeing this report on 31 ingredients that are structurally related to each other as alkyl esters of monoalkyl diols. These ingredients are reported to mostly function in cosmetics as film formers, hair conditioning agents, opacifying agents, plasticizers, skin-conditioning agents (emollient, miscellaneous, and occlusive), slip modifiers, solvents, surface modifiers, and viscosity increasing agents – nonaqueous. 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?

4. Persulfates (agenda and flash drive name – persulfates) – This is the first time that the Panel is

seeing this report on 19 ingredients. At the June meeting, the Panel agreed to reopen the Final Report on Persulfates (published in 2001) to examine the current uses of the 3 ingredients in the report in product categories other than hair coloring products. Updated frequency of use data that verify other uses, such as in leave-on products and dentifrices, were received and have been added. Are the data sufficient to proceed with a tentative report, or should an insufficient data announcement be issued?

5. Plant-Derived Proteins and Peptides (agenda and flash drive name - plant-derived proteins) –

This is the first time that the Panel is seeing this report on 19 ingredients that are reported to function mainly as skin and hair conditioning agents in personal care products. The majority of the ingredients in this report were included in a larger hydrolyzed source proteins safety assessment from 2013, which was divided by the Panel into multiple reports. Are the data sufficient to proceed with a tentative report, or should an insufficient data announcement be issued?

Tentative reports – there is one draft tentative amended report.

1. Butyl Polyoxyalkylene Ethers (agenda and flash drive name - polyoxyalkylene ethers). At the

June meeting, the Panel opened this re-review that is a compilation of the 23 butyl polyoxyalkylene ethers that were reviewed previously in two reports, as well as an additional 23 butyl polyoxyalkylene ethers that were not previously reviewed by the Panel. The Panel reopened the safety assessment and issued an insufficient data announcement requesting sensitization data on PPG-40 Butyl Ether at the maximum concentration for leave-on use (which is now reported to be 71%). Updated concentrations of use data, and data from additional studies have been included in the report. Are the available data sufficient for issuing a tentative report with a safe as used or safe with qualifications conclusion, or should an tentative report with an insufficient data conclusion be issued?

Final reports - there are 8 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. Acid Violet 43 (agenda and flash drive name – acid violet 43). At the June meeting, the Panel issued

a tentative 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 conclusion supersedes the conclusion published in 2001. The report presented to the Panel in June included new data on Acid Violet 43 and Ext. D&C Violet No. 2. As a result, the impurity specifications included in the 2001 conclusion have been removed. Technical comments have been addressed.

2. Alkoxyl Alkyl Silanes (agenda and flash drive name - alkoxyl silanes). At the June meeting, the Panel issued a tentative report with the conclusion that 4 alkoxyl alkyl silanes are safe in the present practices of use and concentration. No new data were submitted. Council comments have been addressed

3. Carbonate Salts (agenda and flash drive name – carbonate salts). At the June meeting, the Panel

issued a tentative report with the conclusion that 6 Carbonate Salts are safe in the present practices of use and concentration in cosmetics when formulated to be non-irritating. Additional


141st Meeting of the CIR Expert Panel — Monday and Tuesday, December 5-6, 2016

toxicity and irritation and sensitization data from Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) dossiers that are accessible at the European Chemicals Agency’s (ECHA) website are included. Technical comments have been addressed.

4. Citrus Flower- and Leaf-Derived Ingredients (agenda and flash drive name – Citrus flower and

leaf) – At the September meeting, the Panel issued a revised tentative report with the conclusion that 33 Citrus flower- and leaf- derived ingredients are safe as used in the present practices of use and concentration when formulated to be non-irritating and non-sensitizing. Some additional data were added, including information on the phototoxicity of methyl-N-methylanthranilate (or dimethyl anthranilate) from the European Commission’s SCCS opinion and the International Fragrance Association (IFRA) standard. Updated concentrations of use data have been added. Technical comments have been addressed.

5. Citrus Plant- and Seed-Derived Ingredients (agenda and flash drive name – Citrus plant and seed).

At the September meeting, the Panel issued a revised tentative report with the conclusion that 13 Citrus plant- and seed-derived ingredients are safe as used in the present practices of use and concentration when formulated to be non-irritating and non-sensitizing. The Panel concluded that the data on the remaining 19 ingredients are insufficient to determine safety. The Panel requested additional data on method of manufacturing, composition and impurities, and irritation and sensitization, and systemic toxicity studies if the composition of these ingredients is different from the peel, flower, leaf-derived ingredients; none of the requested data were received. Updated concentrations of use data have been added. Technical comments have been addressed.

6. Dialkyl Carbonates (agenda and flash drive name - dialkyl carbonates). At the June meeting, the

Panel issued a tentative report for public comment with a conclusion that 6 dialkyl carbonate ingredients are safe as used in cosmetics in the present practices of use and concentration when formulated to be non-irritating. In response to the Panel’s concern about the dermal penetration of diethylhexyl carbonate, data from an in vitro metabolism study on non-cosmetic carbonate esters are included in the report. Technical comments have been addressed.

7. PEG Propylene Glycol Esters (agenda and flash drive name - propylene glycol esters). At the

June meeting, the Panel issued a tentative report for public comment with the conclusion that 7 PEG Propylene Glycol Esters are safe as used in cosmetics in the present practices of use and concentration. This conclusion removed the caveat that ingredients containing PEGs should not be used on damaged skin. No new data were submitted. Technical comments have been addressed.

8. Saccharide Esters (agenda and flash drive name - saccharide esters). At the June meeting, the

Panel issued a tentative report for public comment with the conclusion that 40 saccharide esters are safe as used in cosmetics in the present practices of use and concentration. Additional genotoxicity and irritation data have been added. Industry has asked for additional clarification on the use of structure-activity relationships for Sucrose Acetate Isobutyrate. Other 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 8 reports to be issued as final safety assessments, followed by the remaining reports advancing in the process and a discussion of the lead acetate strategy.

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.


Agenda 141st Cosmetic Ingredient Review Expert Panel Meeting

December 5 - 6, 2016 The Melrose Georgetown Hotel

2430 Pennsylvania Avenue, N.W. Washington, D.C. 20037

Monday, December 5

8:00 am CONTINENTAL BREAKFAST

8:30 am WELCOME TO THE 141st EXPERT PANEL TEAM MEETINGS Drs. Bergfeld/Gill

8:35 am PRESENTATION – Update on Endocrine Disruption Dr. Ellen Mihaich

9:30 am TEAM MEETINGS Drs. Marks/Belsito

Dr. Marks’ Team* Dr. Belsito’s Team

FR (LB) alkoxyl silanes FR (WJ) carbonate salts

FAR (LB) propylene glycol esters FR (WJ) dialkyl carbonates

DR (LB) dialkyl acid esters DR (WJ) ethers of ascorbate

FR (CB) Citrus flower and leaf DAR (WJ) persulfates

FR (CB) Citrus plant and seed FAR (MF) acid violet 43

DR (CB) plant-derived proteins TAR (MF) polyoxyalkylene ethers

Admin (BH) lead acetate strategy FR (LB) alkoxyl silanes

FR (LS) saccharide esters FAR (LB) propylene glycol esters

DR (LS) hydroxy-3,4-methylenedioxyaniline DR (LB) dialkyl acid esters

FR (WJ) carbonate salts FR (CB) Citrus flower and leaf

FR (WJ) dialkyl carbonates FR (CB) Citrus plant and seed

DR (WJ) ethers of ascorbate DR (CB) plant-derived proteins

DAR (WJ) persulfates FR (LS) saccharide esters

FAR (MF) acid violet 43 DR (LS) hydroxy-3,4-methylenedioxyaniline

TAR (MF) polyoxyalkylene ethers Admin (BH) lead acetate strategy

Noon Lunch for Panel, liaisons, and staff

1:00pm Team meetings - continue as needed

5:00 pm ADJOURN DAY 1 SESSION FR: Final Report FAR: Final Amended Report TAR: Tentative Amended Report DR: Draft Report DAR: Draft Amended Report 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.


Tuesday, December 6

8:00 am CONTINENTAL BREAKFAST

8:30 am WELCOME TO THE 141st FULL CIR EXPERT PANEL MEETING Dr. Bergfeld Dr. Bergfeld

8:45 am Admin Dr. Bergfeld MINUTES OF THE SEPTEMBER 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

FAR (MF) Acid violet 43 – Dr. Belsito reports

FR (LB) Alkoxyl silanes – Dr. Marks reports

FAR (LB) Propylene glycol esters – Dr. Belsito reports

FR (WJ) Carbonate salts – Dr. Marks reports

FR (WJ) Dialkyl carbonates – Dr. Belsito reports

FR (CB) Citrus flower and leaf– Dr. Marks reports

FR (CB) Citrus plant and seed – Dr. Belsito reports

FR (LS) Saccharide esters – Dr. Marks reports

Reports Advancing

DR (LS) Hydroxy-3,4-methylenedioxyaniline – Dr. Belsito reports

DR (LB) Dialkyl acid esters – Dr. Marks reports

DR (WJ) Ethers of ascorbate – Dr. Belsito reports

DAR (WJ) Persulfates – Dr. Marks reports

DR (CB) Plant-derived proteins – Dr. Belsito reports

TAR (MF) Polyoxyalkylene ethers – Dr. Marks reports

Admin (BH) Lead acetate strategy – Dr. Belsito reports

ADJOURN - Next meeting Monday and Tuesday, April 10-11, 2017 at The Hamilton Crowne Plaza Hotel, 1001 14th Street, NW, Washington, DC 20005

FR: Final Report FAR: Final Amended Report TAR: Tentative Amended Report DR: Draft Report DAR: Draft Amended Report


ONE HUNDRED FORTIEFH MEETING

OF THE

EXPERT PANEL

September 26-27, 2016

Melrose Georgetown Hotel

Washington, D.C.

Expert Panel Members Liaison Representatives

Wilma F. Bergfeld, M.D., Chair Consumer

Donald V. Belsito, M.D. Michael Best, Esq.

Ronald A. Hill, Ph.D.

Curtis D. Klaassen, Ph.D. Industry

Daniel C. Liebler, Ph.D. Beth A. Lange, Ph.D.

James G. Marks, Jr., M.D.

Ronald C. Shank, Ph.D.

Thomas J. Slaga, Ph.D. Government Paul W. Snyder, D.V.M., Ph.D. Linda Katz, MD., M.P.H.

Adopted (Date)

Wilma F. Bergfeld, M.D.



http://www.cir-safety.org/

Others Present at the Meeting

Robena Am FDA F. Alan Andersen FDA/CIR Retired, Nevada Lillian Becker CIR Don Bjerke P & G Ivan Boyer CIR Christina Burnett CIR Kapal Dewa FDA Carol Eisenmann PCPC Monice Fiume CIR Kevin Fries CIR Lillian Gill CIR Bart Heldreth CIR Carla Jackson CIR Wilbur Johnson, Jr. CIR Dennis Laba Presperse Jon Lalko Estee Lauder Damani Parran Akzo Alex Perez L’Oreal Galen Roth EWG Nakina Sadrieh FDA Laura Scott CIR Noriko Shibuya Shiseido


MINUTES FROM THE 140th CIR EXPERT PANEL MEETING

CHAIRMAN’S OPENING REMARKS

The 140th meeting of the Cosmetic Ingredient Review (CIR) Expert Panel was called to order at 8:30 a.m by Dr. Wilma Bergfeld. She noted that this meeting marks the 40th Anniversary of CIR, and thanked Dr. Lillian Gill and Ms. Carla Jackson for the wonderful Anniversary Celebration that was held last evening. Dr. Bergfeld commented that CIR is a very successful voluntary safety evaluation program for cosmetic ingredients, and has completed safety assessments on more than 4,000 cosmetic ingredients. Having testified recently at a Senate hearing on cosmetics, she remarked that this hearing indicates the level of awareness of the CIR program. Dr. Bergfeld extended a very cordial thank you to the CIR staff for their excellent work and support of the Expert Panel in their mission.

Dr. Bergfeld stated that 15 ingredient reports are scheduled for review at this Panel meeting. Eight reports are advancing to the final report stage and the remaining 7 are advancing to other levels of report development. She noted that determining a margin of safety for the consumer is very important, taking into consideration the application of multiple cosmetic products to the skin on a daily basis (i.e., aggregate exposure). Dr. Bergfeld remarked that the Panel is also faced with evaluating data that result from the use of alternative methods in the absence of data from animal testing, and that a presentation on alternative methodologies given by Dr, Don Bjerke, with Procter and Gamble, on the preceding day was quite helpful in understanding the challenges that the Panel and Industry face. Lastly, Dr. Bergfeld commented on the persistent problem relating to the absence of composition data on botanical ingredients.

APPROVAL OF MINUTES The minutes of the June 6-7, 2016 CIR Expert Panel meeting were unanimously approved. DIRECTOR’S REPORT Dr. Gill seconded Dr. Bergfeld’s comments on the wonderful dinner and celebration for the 40th Anniversary of CIR. Mr. Peter Hutt, who was instrumental in founding and developing the organization, gave a brief history of CIR, complemented the organization for its impressive work to date and challenged the Panel and staff to continue building on the current successes. Family, friends and colleagues including past Director of CIR, Dr. Alan Andersen, attended the celebration held in Georgetown. Dr. Gill mentioned Dr. Bergfeld’s participation in a hearing before the Senate Health, Education, Labor, and Pension Committee on September 22, 2016. She provided the Committee with information on the work of the CIR Expert Panel. At the June 2016 meeting, the Panel requested a presentation on an in chemico skin sensitization test method named the Direct Peptide Reactivity Assay (DPRA). The results of a DPRA were summarized in the safety assessment of Butyrospermum parkii (shea)-Derived Ingredients. The DPRA was noted as a method recently validated by the European Centre for the Validation of Alternative Methods (ECVAM) and the subject of the Organisation of Economic Co-operation and Development (OECD) Test Guideline (TG 442C). In response to the Panel’s request, Dr. Donald Bjerke presented a briefing titled “Skin Sensitization: In Vitro Methods and Risk Assessment.” Dr. Gill, and the Panel, expressed the CIR’s appreciation to Dr. Donald Bjerke’s for his informative presentation. Dr. Bjerke is a toxicologist, Principal Scientist at the Procter & Gamble Company, and member of the CIR Science and Support Committee (CIR SSC). Lastly, Dr. Gill reminded the meeting participants that the next meeting is scheduled for December 5-6. 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 the December 2016 meeting, to provide that data as soon as possible. Final Safety Assessments


Citrus Peel-Derived Ingredients The Panel issued a final report with the conclusion that the following 47 Citrus peel-derived ingredients are safe as used in the present practices of use and concentration when formulated to be non-sensitizing and non-irritating, provided that leave-on products do not contain more than 0.0015% (15 ppm) 5-methoxypsoralen (5-MOP). Citrus Aurantifolia (Lime) Peel* Citrus Aurantifolia (Lime) Peel Extract Citrus Aurantifolia (Lime) Peel Powder Citrus Aurantifolia (Lime) Peel Water* Citrus Aurantium Amara (Bitter Orange) Peel Citrus Aurantium Amara (Bitter Orange) Peel Extract Citrus Aurantium Amara (Bitter Orange) Peel Powder Citrus Aurantium Bergamia (Bergamot) Peel Water Citrus Aurantium Dulcis (Orange) Peel Extract Citrus Aurantium Dulcis (Orange) Peel Powder Citrus Aurantium Dulcis (Orange) Peel Wax Citrus Aurantium Sinensis Peel Extract* Citrus Aurantium Tachibana Peel Extract Citrus Depressa Peel Extract Citrus Depressa Peel Powder* Citrus Grandis (Grapefruit) Peel* Citrus Grandis (Grapefruit) Peel Extract Citrus Grandis (Grapefruit) Peel Powder* Citrus Hassaku/Natsudaidai Peel Powder* Citrus Iyo Peel Extract* Citrus Iyo Peel Water* Citrus Jabara Peel Extract Citrus Jabara Peel Powder*

Citrus Jabara Peel Water* Citrus Junos Peel Extract Citrus Junos Peel Powder Citrus Junos Peel Water* Citrus Limon (Lemon) Peel Citrus Limon (Lemon) Peel Extract Citrus Limon (Lemon) Peel Powder Citrus Limon (Lemon) Peel Water* Citrus Limon (Lemon) Peel Wax Citrus Natsudaidai Peel Extract* Citrus Nobilis (Mandarin Orange) Peel Extract Citrus Nobilis (Mandarin Orange) Peel Powder* Citrus Paradisi (Grapefruit) Peel Extract Citrus Reticulata (Tangerine) Peel Extract Citrus Reticulata (Tangerine) Peel Powder* Citrus Shunkokan Peel Extract* Citrus Sunki Peel Extract* Citrus Tachibana/Reticulata Peel Powder* Citrus Tangelo Peel Powder* Citrus Tangerina (Tangerine) Peel* Citrus Tangerina (Tangerine) Peel Extract Citrus Unshiu Peel Extract Citrus Unshiu Peel Powder Citrus Unshiu Peel Water*

*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 available dermal irritation and sensitization data supported the safety of these Citrus peel-derived ingredients. However, these ingredients have the potential to cause phototoxicity. The Panel determined that the International Fragrance Association (IFRA) standard for the quantity of 5-MOP that may be present in these ingredients is adequate to prevent 5-MOP-induced phototoxicity. The Panel acknowledged that multiple botanical ingredients combined in one formulation, may each contribute to the final concentration of a single constituent of concern. When formulating products containing Citrus peel-derived ingredients, manufacturers should avoid reaching levels of plant constituents that may cause sensitization or other adverse effects. Fatty Acyl Sarcosines and Their Salts The Panel issued a final amended report with the conclusion that the following 10 previously reviewed fatty acyl sarcosines and salts, as well as 4 additional salts that have not been previously reviewed, are safe as used in the present practices of use and concentration when formulated to be non-irritating; these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed: Previously Reviewed Cocoyl Sarcosine Lauroyl Sarcosine Myristoyl Sarcosine

Oleoyl Sarcosine Stearoyl Sarcosine Ammonium Cocoyl Sarcosinate* Ammonium Lauroyl Sarcosinate


Sodium Cocoyl Sarcosinate Sodium Lauroyl Sarcosinate

Sodium Myristoyl Sarcosinate

Additional Salts Potassium Cocoyl Sarcosinate* Potassium Lauroyl Sarcosinate*

Sodium Oleoyl Sarcosinate* Sodium Palmitoyl Sarcosinate

*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’s conclusion supersedes the original conclusion issued for the 10 previously reviewed ingredients. The original conclusion that was published in 2001 specified a concentration limit for use in leave-on products, and stated that the data were insufficient to determine safety in products that are likely to be inhaled. The Panel removed the concentration limit because concentration of use data, which were not included in the 2001 report, are now available, and sensitization data are available from studies conducted at the highest concentration reported to be used. Data are also available to address concerns about incidental inhalation. Helianthus annuus (Sunflower)-Derived Ingredients The Panel issued a final report with the conclusion that the following 9 Helianthus annuus (sunflower)-derived ingredients are safe as used in the present practices of use and concentration as described in this safety assessment: Helianthus Annuus (Sunflower) Seed Extract Helianthus Annuus (Sunflower) Flower Extract Helianthus Annuus (Sunflower) Seed Helianthus Annuus (Sunflower) Seed Butter* Helianthus Annuus (Sunflower) Seedcake Helianthus Annuus (Sunflower) Seed Flour* Helianthus Annuus (Sunflower) Seed Wax Hydrogenated Sunflower Seed Extract* Hydrolyzed Sunflower Seed Wax The Panel concluded that the available data are insufficient for evaluating the safety of the following 3 Helianthus annuus (sunflower)-derived ingredients in cosmetic products: Helianthus Annuus (Sunflower) Extract Helianthus Annuus (Sunflower) Leaf/Stem Extract* Helianthus Annuus (Sunflower) Sprout 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 include:

• Method of manufacture • Composition of these ingredients, especially protein content (including 2S albumin) • Impurities

The Panel discussed the potential for albumins of the 2S protein fraction of sunflower seeds to cause IgE-mediated-immediate (Type I) hypersensitivity reactions. The incidence of persons with sensitivity to Helianthus annuus (Sunflower)-derived ingredients is low, and the Panel noted that reactions attributable to contact with products containing such ingredients not been observed in their clinical experience. The Panel agreed with Dr. Stefano Luccioli, Senior Medical Advisor at the Food and Drug Administration’s (FDA) Office of Food Additive Safety (OFAS), who indicated that a warning label for seed or tree nut allergic individuals would not be warranted, but


labelling cosmetic products as containing Helianthus annuus (sunflower) seed-derived ingredients would likely satisfy any pertinent condition of safety for these ingredients. However, the Panel emphasized that persons with sensitivity to 2S albumins from seeds, nuts or legumes should be cautious when using formulations that contain Helianthus annuus (Sunflower)-derived ingredients. The Expert Panel expressed concern about pesticide residues, heavy metals, and substances from plants of other species (weeds) that may be present in botanical ingredients. To address these concerns, the cosmetics industry should continue to use current good manufacturing practices (cGMPs) to limit impurities. Phosphoric Acid and Its Salts The Panel issued a final report with the conclusion that the following 31 ingredients are safe as used in the present practices of use and concentration as described in this safety assessment, when formulated to be non-irritating: Phosphoric Acid Ammonium Phosphate Dicalcium Phosphate Calcium Dihydrogen Phosphate Calcium Phosphate Calcium Potassium Sodium Phosphate* Calcium Pyrophosphate Diammonium Phosphate Dicalcium Phosphate Dihydrate Dipotassium Phosphate Disodium Phosphate Disodium Pyrophosphate Magnesium Hydrogen Phosphate* Magnesium Phosphate* Metaphosphoric Acid* Pentapotassium Triphosphate

Pentasodium Triphosphate* Phosphate Buffered Saline* Potassium Metaphosphate Potassium Phosphate Potassium Polyphosphate* Sodium Hexametaphosphate Sodium Metaphosphate Sodium Polyphosphate* Sodium Phosphate Sodium Trimetaphosphate* Tetrapotassium Pyrophosphate Tetrasodium Pyrophosphate Tricalcium Phosphate Trimagnesium Phosphate Trisodium Phosphate

*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 the broad range of results for irritation reported for Phosphoric Acid or its salts at concentrations within and outside of the range of those used in cosmetic products. The Panel discussed reports suggesting that Potassium Phosphate can cause renal damage, and may be associated with renal cancer. They stated that the high doses of Potassium Phosphate used in the studies most probably promoted tumors through irritation. Furthermore, there are a large number of negative genotoxicity studies, and human and animal studies that indicate Potassium Phosphate exposures are not strongly associated with renal damage or renal cancers. The greatest reported use frequency is for Phosphoric Acid (489 formulations, mostly rinse-off), followed by Dicalcium Phosphate (327 formulations, mostly leave-on). Dicalcium Phosphate Dihydrate has the highest maximum concentration of use; it is used at concentrations up to 49% in rinse-off products (dentifrices). Polyglyceryl Fatty Acid Esters The Panel issued a final report with the conclusion that the following 274 polyglyceryl fatty acid esters are safe as used in the present practices of use and concentration when formulated to be non-irritating: Adansonia Digitata Seed Oil Polyglyceryl-6 Esters* Almond Oil/Polyglyceryl-10 Esters* Apricot Kernel Oil Polyglyceryl-3 Esters* Apricot Kernel Oil Polyglyceryl-4 Esters* Apricot Kernel Oil Polyglyceryl-5 Esters*

Apricot Kernel Oil Polyglyceryl-6 Esters* Apricot Kernel Oil Polyglyceryl-10 Esters* Argan Oil Polyglyceryl-6 Esters* Astrocaryum Vulgare Oil Polyglyceryl-6 Esters* Avocado Oil Polyglyceryl-6 Esters*


Babassu Oil Polyglyceryl-4 Esters Babassu Oil Polyglyceryl-6 Esters Bertholletia Excelsa Seed Oil Polyglyceryl-6 Esters* Borage Seed Oil Polyglyceryl-4 Esters* Borage Seed Oil Polyglyceryl-6 Esters* Candelilla/Jojoba/Rice Bran Polyglyceryl-3 Esters Caprylic/Capric Glycerides Polyglyceryl-10 Esters Carapa Guaianensis Oil Polyglyceryl-6 Esters* Castor Oil Polyglyceryl-6 Esters* Cocoa Butter Polyglyceryl-6 Esters* Coconut Oil Polyglyceryl-6 Esters Coffee Seed Oil Polyglyceryl-6 Esters* Diisostearoyl Polyglyceryl-3 Dimer Dilinoleate Glyceryl/Polyglyceryl-6 Isostearate/Behenate Esters Hazelnut Seed Oil Polyglyceryl-6 Esters* Linseed Oil Polyglyceryl-4 Esters* Macadamia Seed Oil Polyglyceryl 6 Esters* Macadamia Seed Oil Polyglyceryl 6 Esters Behenate Mauritia Flexuosa Seed Oil Polyglyceryl-6 Esters* Olive Oil Polyglyceryl-3 Esters* Olive Oil Polyglyceryl-4 Esters* Olive Oil Polyglyceryl-6 Esters* Palm Kernel Oil Polyglyceryl-4 Esters* Palm Oil Polyglyceryl-3 Esters* Palm Oil Polyglyceryl-4 Esters Palm Oil Polyglyceryl-5 Esters* Palm Oil Polyglyceryl-6 Esters* Parinari Curatellifolia Oil Polyglyceryl-6 Esters* Pinus Sibirica Seed Oil Polyglyceryl-6 Esters* Polyglyceryl-2 Caprate Polyglyceryl-2 Caprylate* Polyglyceryl-2 Diisostearate Polyglyceryl-2 Dioleate* Polyglyceryl-2 Distearate* Polyglyceryl-2 Isopalmitate Polyglyceryl-2 Isopalmitate/Sebacate* Polyglyceryl-2 Isostearate Polyglyceryl-2 Laurate Polyglyceryl-2 Myristate* Polyglyceryl-2 Oleate Polyglyceryl-2 Palmitate* Polyglyceryl-2 Sesquicaprylate* Polyglyceryl-2 Sesquiisostearate Polyglyceryl-2 Sesquioleate* Polyglyceryl-2 Sesquistearate Polyglyceryl-2 Stearate Polyglyceryl-2 Tetrabehenate/ Macadamiate/Sebacate* Polyglyceryl-2 Tetraisostearate Polyglyceryl-2 Tetraoleate* Polyglyceryl-2 Tetrastearate* Polyglyceryl-2 Triisostearate Polyglyceryl-3 Beeswax Polyglyceryl-3 Behenate* Polyglyceryl-3 Caprate Polyglyceryl-3 Caprylate

Polyglyceryl-3 Cocoate* Polyglyceryl-3 Dicaprate* Polyglyceryl-3 Dicitrate/Stearate Polyglyceryl-3 Dicocoate* Polyglyceryl-3 Di Hydroxystearate* Polyglyceryl-3 Diisostearate Polyglyceryl-3 Dioleate* Polyglyceryl-3 Distearate Polyglyceryl-3 Isostearate Polyglyceryl-3 Laurate Polyglyceryl-3 Myristate* Polyglyceryl-3 Oleate Polyglyceryl-3 Palmitate Polyglyceryl-3 Pentacaprylate/Caprate* Polyglyceryl-3 Pentaolivate* Polyglyceryl-3 Pentaricinoleate Polyglyceryl-3 Rice Branate* Polyglyceryl-3 Ricinoleate Polyglyceryl-3 Soyate/Shea Butterate* Polyglyceryl-3 Stearate Polyglyceryl-3 Stearate SE* Polyglyceryl-3 Triisostearate* Polyglyceryl-3 Triolivate* Polyglyceryl-4 Almondate/Shea Butterate* Polyglyceryl-4 Caprate Polyglyceryl-4 Caprylate* Polyglyceryl-4 Caprylate/Caprate* Polyglyceryl-4 Cocoate Polyglyceryl-4 Dilaurate* Polyglyceryl-4 Distearate* Polyglyceryl-4 Hazelnutseedate* Polyglyceryl-4 Isostearate Polyglyceryl-4 Isostearate/Laurate* Polyglyceryl-4 Laurate Polyglyceryl-4 Laurate/Sebacate* Polyglyceryl-4 Laurate/Succinate Polyglyceryl-4 Oleate Polyglyceryl-4 Pentaoleate* Polyglyceryl-4 Pentapalmitate/Stearate* Polyglyceryl-4 Pentastearate* Polyglyceryl-4 Punicate* Polyglyceryl-4 Stearate* Polyglyceryl-4 Sweet Almondate* Polyglyceryl-4 Tristearate* Polyglyceryl-5 Caprate* Polyglyceryl-5 Dicaprylate* Polyglyceryl-5 Dilaurate* Polyglyceryl-5 Dioleate Polyglyceryl-5 Hexastearate* Polyglyceryl-5 Isostearate Polyglyceryl-5 Laurate Polyglyceryl-5 Myristate* Polyglyceryl-5 Oleate Polyglyceryl-5 Pentamyristate* Polyglyceryl-5 Ricinoleate* Polyglyceryl-5 Stearate


Polyglyceryl-5 Tribehenate* Polyglyceryl-5 Triisostearate Polyglyceryl-5 Trimyristate* Polyglyceryl-5 Trioleate Polyglyceryl-5 Tristearate* Polyglyceryl-6 Adansonia Digitata Seedate* Polyglyceryl-6 Apricot Kernelate* Polyglyceryl-6 Argan Kernelate* Polyglyceryl-6 Behenate* Polyglyceryl-6 Caprate* Polyglyceryl-6 Caprylate* Polyglyceryl-6 Caprylate/Caprate Polyglyceryl-6 Citrullus Lanatus Seedate* Polyglyceryl-6 Dicaprate* Polyglyceryl-6 Diisostearate* Polyglyceryl-6 Dioleate Polyglyceryl-6 Dipalmitate* Polyglyceryl-6 Distearate Polyglyceryl-6 Heptacaprylate* Polyglyceryl-6 Hexaoleate* Polyglyceryl-6 Hexastearate* Polyglyceryl-6 Isostearate Polyglyceryl-6 Laurate* Polyglyceryl-6 Myristate* Polyglyceryl-6 Octacaprylate* Polyglyceryl-6 Octastearate Polyglyceryl-6 Oleate Polyglyceryl-6 Palmitate* Polyglyceryl-6 Palmitate/Succinate* Polyglyceryl-6 Pentacaprylate* Polyglyceryl-6 Pentaoleate* Polyglyceryl-6 Pentaricinoleate* Polyglyceryl-6 Pentastearate Polyglyceryl-6 Ricinoleate Polyglyceryl-6 Schinziophyton Rautanenii Kernelate* Polyglyceryl-6 Sclerocarya Birrea Seedate* Polyglyceryl-6 Sesquicaprylate* Polyglyceryl-6 Sesquiisostearate* Polyglyceryl-6 Sesquistearate* Polyglyceryl-6 Stearate* Polyglyceryl-6 Tetrabehenate* Polyglyceryl-6 Tetracaprylate* Polyglyceryl-6 Tetraoleate* Polyglyceryl-6 Tricaprylate Polyglyceryl-6 Trichilia Emetica Seedate* Polyglyceryl-6 Tristearate* Polyglyceryl-6 Undecylenate* Polyglyceryl-6 Ximenia Americana Seedate* Polyglyceryl-8 C12-20 Acid Ester* Polyglyceryl-8 Decabehenate/Caprate Polyglyceryl-8 Decaerucate/Decaisostearate/ Decaricinoleate Polyglyceryl-8 Oleate* Polyglyceryl-8 Stearate* Polyglyceryl-10 Apricot Kernelate*

Polyglyceryl-10 Behenate/Eicosadioate Polyglyceryl-10 Caprate* Polyglyceryl-10 Caprylate* Polyglyceryl-10 Caprylate/Caprate Polyglyceryl-10 Cocoate* Polyglyceryl-10 Decaethylhexanoate* Polyglyceryl-10 Decahydroxystearate* Polyglyceryl-10 Decaisostearate Polyglyceryl-10 Decalinoleate* Polyglyceryl-10 Decamacadamiate* Polyglyceryl-10 Decaoleate Polyglyceryl-10 Decastearate* Polyglyceryl-10 Dicocoate* Polyglyceryl-10 Didecanoate* Polyglyceryl-10 Diisostearate Polyglyceryl-10 Dilaurate* Polyglyceryl-10 Dimyristate* Polyglyceryl-10 Dioleate Polyglyceryl-10 Dipalmitate Polyglyceryl-10 Distearate Polyglyceryl-10 Dodecabehenate* Polyglyceryl-10 Dodecacaprate* Polyglyceryl-10 Dodecacaprylate* Polyglyceryl-10 Dodeca-Caprylate/ Caprate* Polyglyceryl-10 Eicosanedioate/Tetradecanedioate* Polyglyceryl-10 Hepta(Behenate/Stearate)* Polyglyceryl-10 Heptahydroxystearate Polyglyceryl-10 Heptaoleate* Polyglyceryl-10 Heptastearate* Polyglyceryl-10 Hexaerucate* Polyglyceryl-10 Hexaisostearate* Polyglyceryl-10 Hexaoleate* Polyglyceryl-10 Hydroxystearate/Stearate/Eicosadioate Polyglyceryl-10 Isostearate Polyglyceryl-10 Laurate Polyglyceryl-10 Linoleate* Polyglyceryl-10 Mono/Dioleate* Polyglyceryl-10 Myristate Polyglyceryl-10 Nonaerucate* Polyglyceryl-10 Nonaisostearate Polyglyceryl-10 Oleate Polyglyceryl-10 Palmate* Polyglyceryl-10 Palmitate* Polyglyceryl-10 Pentacaprylate* Polyglyceryl-10 Pentahydroxystearate Polyglyceryl-10 Pentaisostearate Polyglyceryl-10 Pentalaurate* Polyglyceryl-10 Pentalinoleate* Polyglyceryl-10 Pentaoleate Polyglyceryl-10 Pentaricinoleate* Polyglyceryl-10 Pentastearate Polyglyceryl-10 Sesquistearate* Polyglyceryl-10 Stearate Polyglyceryl-10 Tetradecanedioate* Polyglyceryl-10 Tetralaurate*


Polyglyceryl-10 Tetraoleate* Polyglyceryl-10 Tricocoate* Polyglyceryl-10 Tridecanoate* Polyglyceryl-10 Trierucate* Polyglyceryl-10 Triisostearate* Polyglyceryl-10 Trilaurate* Polyglyceryl-10 Trioleate* Polyglyceryl-10 Tristearate Polyglyceryl-10 Undecylenate* Polyglyceryl-15 Diisostearate* Polyglyceryl-20 Docosabehenate/Isostearate* Polyglyceryl-20 Docosabehenate/Laurate* Polyglyceryl-20 Docosabehenate/Oleate* Polyglyceryl-20 Heptacaprylate* Polyglyceryl-20 Heptadecabehenate/Laurate* Polyglyceryl-20 Hexacaprylate* Polyglyceryl-20 Octadecabehenate/Laurate* Polyglyceryl-20 Octaisononanoate* Pumpkin Seed Oil Polyglyceryl-4 Esters* Pumpkin Seed Oil Polyglyceryl-4 Esters Succinate* Rice Bran Oil Polyglyceryl-3 Esters* Rosa Rubiginosa Seed Oil Polyglyceryl-6 Esters* Safflower Seed Oil Polyglyceryl-6 Esters*

Schinziophyton Rautanenii Kernel Oil Polyglyceryl-6 Esters* Sclerocarya Birrea Seed Oil Polyglyceryl-6 Esters* Sclerocarya Birrea Seed Oil Polyglyceryl-10 Esters* Sesame Oil Polyglyceryl-6 Esters* Shea Butter Polyglyceryl-3 Esters* Shea Butter Polyglyceryl-4 Esters* Shea Butter Polyglyceryl-6 Esters* Soybean Oil Polyglyceryl-6 Esters* Sunflower Seed Oil Polyglyceryl 3 Esters* Sunflower Seed Oil Polyglyceryl-4 Esters* Sunflower Seed Oil Polyglyceryl-5 Esters* Sunflower Seed Oil Polyglyceryl 6 Esters* Sunflower Seed Oil Polyglyceryl 10 Esters* Sweet Almond Oil Polyglyceryl-4 Esters* Sweet Almond Oil Polyglyceryl-6 Esters* Theobroma Grandiflorum Seed Butter Polyglyceryl-6 Esters* Trichilia Emetica Seed Oil Polyglyceryl-6 Esters* Triisostearoyl Polyglyceryl-3 Dimer Dilinoleate Watermelon Seed Oil Polyglyceryl-6 Esters * Watermelon Seed Oil Polyglyceryl-10 Esters* Ximenia Americana Seed Oil Polyglyceryl-6 Esters*

*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 ingredients are esterification products of polyglycerin chains and fatty acids that vary in numbers of glycerin and fatty-acid equivalents and lengths of the fatty acids. The Panel discussed the penetration enhancement properties of some of these ingredients, and noted that these ingredients are extensively metabolized to yield common nutrients and physiological intermediates. Also, the extensive negative irritation and sensitization data and the concentration of use data indicate that these ingredients are safe as used under the conditions described in the safety assessment. Trimellitic Anhydride Copolymers The Panel issued a final report with the conclusion that Adipic Acid/Neopentyl Glycol/Trimellitic Anhydride Copolymer and Phthalic Anhydride/Trimellitic Anhydride/ Glycols Copolymer are safe as used in the present practices of use and concentration in nail product formulations, but the data are insufficient to enable adequate evaluation of the safety of these ingredients in other types of cosmetic product formulations. Irritation and sensitization data are needed to determine safety of the use of Adipic Acid/Neopentyl Glycol/Trimellitic Anhydride Copolymer and Phthalic Anhydride/Trimellitic Anhydride/Glycols Copolymer in cosmetics other than nail products. The Panel stated that the available data are insufficient to determine that the following 4 trimellitic copolymers, which are not reported to be in use, are safe for use in cosmetic formulation: Adipic Acid/CHDM/MA/Neopentyl Glycol/Trimellitic Anhydride Copolymer Isostearoyl Trimellitic Anhydride/Trimethylolpropane Copolymer Propylene Glycol/Sebacic Acid/Trimellitic Anhydride Trimethylpentanediol/Isophthalic Acid/Trimellitic Anhydride Copolymer) The additional data needed to evaluate the safety of these ingredients for use in nail products are:

• Method of manufacture; and


• Composition data. In addition, the following data are needed to evaluate the safety of these ingredients for uses other than in nail products:

• Molecular weight; • Impurities, specifically, the amount of residual monomer in each copolymer • Metabolism, specifically, whether these ingredients are metabolized in the skin; • Dermal absorption; if absorbed, then genotoxicity and reproductive toxicity data are needed; and • Dermal irritation and sensitization at maximum leave-on concentration of use.

In April, the Panel issued a tentative conclusion that the data were insufficient to determine safety for any type of cosmetic use for all 6 trimellitic anhydride copolymers. Since that meeting, method of manufacture and composition data were received for Adipic Acid/Neopentyl Glycol/Trimellitic Anhydride Copolymer, and an Australian National Industrial Chemicals Notification and Assessment Scheme (NICNAS) determined Phthalic Anhydride/Trimellitic Anhydride/Glycols Copolymer is a polymer of low concern (PLC) and is not considered to pose an unreasonable risk to public health of workers and the public when used as a component of cosmetic nail products. The Panel’s final conclusion supersedes the tentative conclusion issued in April. Tentative Safety Assessments Acryloyldimethyltaurate Polymers The Panel issued a tentative report for public comment with the conclusion that the following 21 acryloyldimethyltaurate polymers are safe as used in the present practices of use and concentration: Acrylamide/Sodium Acryloyldimethyltaurate Copolymer Acrylamide/Sodium Acryloyldimethyltaurate/Acrylic Acid Copolymer* Ammonium Acryloyldimethyltaurate/Beheneth-25 Methacrylate Crosspolymer Ammonium Acryloyldimethyltaurate/Carboxyethyl Acrylate Crosspolymer Ammonium Acryloyldimethyltaurate/Laureth-7 Methacrylate Copolymer Ammonium Acryloyldimethyltaurate/Steareth-25 Methacrylate Crosspolymer* Ammonium Acryloyldimethyltaurate/Steareth-8 Methacrylate Copolymer Ammonium Acryloyldimethyltaurate/Vinyl Formamide Copolymer* Ammonium Acryloyldimethyltaurate/VP Copolymer Ammonium Polyacryloyldimethyl Taurate Dimethylacrylamide/Sodium Acryloyldimethyltaurate Crosspolymer HEA/Sodium Acryloyldimethyltaurate/Steareth-20 Methacrylate Copolymer Hydroxyethyl Acrylate/Sodium Acryloyldimethyl Taurate Copolymer Sodium Acrylate/Acryloyldimethyltaurate/Dimethylacrylamide Crosspolymer Sodium Acrylate/Sodium Acryloyldimethyl Taurate Copolymer Sodium Acrylate/Sodium Acryloyldimethyl Taurate/Acrylamide Copolymer Sodium Acryloyl Dimethyl Taurate/PEG-8 Diacrylate Crosspolymer* Sodium Acryloyldimethyl Taurate/Acrylamide/VP Copolymer Sodium Acryloyldimethyltaurate/Methacrylamidolauric Acid Copolymer Sodium Acryloyldimethyltaurate/VP Crosspolymer Sodium Polyacryloyldimethyl Taurate * 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 the group. The Panel noted that these are large molecules and that dermal penetration would be unlikely to occur. The Panel advised that formulators should use current good manufacturing practices (cGMPs) to ensure that residual monomers (i.e., vinyl formamide and methacrylamidolauric acid) are minimized in these ingredients and the final products. The Panel noted that the presence of acrylamide is limited to 5 ppm in cosmetic formulations containing Polyacrylamide and that this limit was also appropriate for the acryloyldimethyltaurate polymers.


Butyrospermum parkii (Shea)-Derived Ingredients The Panel issued a tentative report for public comment with the conclusion that the following 9 ingredients are safe as used in the present practices of use and concentration as described in this safety assessment: Butyrospermum Parkii (Shea) Butter Buyrospemum Parkii (Shea) Oil Butyrospermum Parkii (Shea) Butter Extract Butyrospermum Parkii (Shea) Butter Unsaponifiables Hydrogenated Shea Butter

Hydrogenated Shea Oil* Shea Butter Glyceride Shea Butter Glycerides Shea Oleine

The Panel concluded that the data on the 4 ingredients listed below are insufficient to determine safety. Butyrospermum Parkii (Shea) Nut Extract Butyrospermum Parkii (Shea) Nut Shell Powder Butyrospermum Parkii (Shea) Seedcake Extract Hydrolyzed Shea Seedcake 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 evaluate the safety of these 4 ingredients are:

• Method of manufacturing • Composition and impurities data • Sensitization data

The Panel noted that, because botanical ingredients are complex mixtures, there is the concern that multiple botanical ingredients in one formulation may each contribute to the final concentration of a single constituent. Therefore, when formulating products, manufacturers should avoid reaching levels in the final formulation of botanical constituents that may cause sensitization or other adverse effects. The ingredient Butyrospermum Parkii (Shea) Butter is reported to be used at concentrations up to 100%. While there are no safety test data for this ingredient at this maximum concentration, the Panel was not concerned about dermal irritation or sensitization because of clinical experience and the absence of adverse event reports. Citrus Flower- and Leaf-Derived Ingredients The Panel issued a revised tentative report for public comment with the conclusion that the following 33 ingredients are safe as used 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*

*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. Multiple botanical ingredients in one formulation may each contribute to the final concentration of a single constituent. When formulating products containing Citrus flower- and leaf-derived ingredients, manufacturers should avoid reaching levels of plant constituents that may cause sensitization or other adverse effects. Constituents of concern found in some of these ingredients include limonene and linalool, the hydroperoxides of which are skin sensitizers. The International Fragrance Association (IFRA) limit for these peroxides is 20 mmol/L. Citrus Plant- and Seed-Derived Ingredients The Panel issued a revised tentative report for public comment with the conclusion that the following 13 ingredients are safe as used 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 Peel/Seed Extract* Citrus Grandis (Grapefruit) Seed Extract Citrus Junos Seed Extract Citrus Junos Seed Oil Citrus Paradisi (Grapefruit) Seed Extract Citrus Sunki Seed Extract* Citrus Sunki Seed Oil*

The Panel concluded that the data on 19 ingredients listed below are 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 Grandis (Grapefruit) Extract Citrus Iyo Oil* Citrus Jabara Pericarp Extract*

Citrus Junos Extract 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) Citrus Nobilis (Mandarin Orange) Oil Citrus Nobilis (Mandarin Orange) Water* Citrus Reticulata (Tangerine) Extract Citrus Unshiu Extract* Citrus Unshiu Pericarp 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 that are comparable to others in this group. The data needed to evaluate the safety of these 19 ingredients are:

• Method of manufacturing • Chemical composition and impurities • Irritation and sensitization data


• If the composition data for these Citrus plant- and seed-derived ingredients are substantially different from that of the Citrus peel-, flower-, and leaf-derived ingredients, then systemic toxicity studies such as a 28-day dermal toxicity, reproductive and developmental toxicity, and genotoxicity studies are needed, as well as UV absorption spectra

Multiple botanical ingredients, in one formulation, may each contribute to the final concentration of a single constituent. When formulating products containing Citrus plant- and seed-derived ingredients, manufacturers should avoid reaching levels of plant constituents that may cause sensitization or other adverse effects. Etidronic Acid and Its Salts The Panel issued a tentative report for public comment with the conclusion that the following 4 ingredients are safe as used in the present practices of use and concentration as described in this safety assessment. Etidronic Acid Disodium Etidronate Tetrapotassium Etidronate Tetrasodium Etidronate The Panel acknowledged the moderately widespread clinical use of these ingredients to treat bone diseases and determined that there were no systemic concerns about their use in cosmetics based on the data presented. Although there were no phototoxicity or photosensitization data, the Panel agreed that these ingredients are not expected to absorb UV light. Inhalation data on sodium etidronate and genotoxicity data on sodium etidronate and trisodium etidronate were used to address concerns about the lack of inhalation toxicity data and the minimal genotoxicity data available for the ingredients in this safety assessment. Etidronic Acid was reported to have the greatest number of uses (341) in cosmetic formulations. Etidronic Acid also had the highest reported maximum concentration of use (0.9% in other hair coloring preparations) in rinse-off products and the highest maximum concentration of use (0.12% in other fragrance preparations) reported in leave-on products. Hydrofluorocarbon 152a The Panel issued a tentative report for public comment with the conclusion that Hydrofluorocarbon 152a is safe as used in the present practices of use and concentration. This ingredient is a gas that functions as a propellant and is used at concentrations up to 80% in hair sprays and 35% in underarm deodorants. Hydrofluorocarbon 152a is largely inert, is rapidly volatilized and dispersed in ambient air upon application, and, when inhaled, is rapidly cleared from the body in exhaled air. The Panel found the overall safety profile of this ingredient to be favorable and concluded that it was safe for use in cosmetics. Rosa canina-Derived Ingredients The Panel issued a tentative report for public comment with the conclusion that the following 12 Rosa canina-derived ingredients are safe as used in the present practices of use and concentration in cosmetics as described in this safety assessment when formulated to be non-irritating and non-sensitizing: Rosa Canina Fruit Extract Rosa Canina Bud Extract* Rosa Canina Flower Rosa Canina Flower Extract Rosa Canina Flower Powder* Rosa Canina Flower Oil*

Rosa Canina Fruit Rosa Canina Fruit Juice* Rosa Canina Leaf Extract Rosa Canina Seed* Rosa Canina Seed Extract Rosa Canina Seed Powder


*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 inhibition of skin pigmentation by Rosa Canina Fruit Extract was reported in in vitro and in vivo studies. The Panel discussed the potential of quercetin and proanthocyanidins to cause skin depigmentation. However, the Panel noted that the use concentrations of this ingredient and, thus, the levels of these components in cosmetics, are below the threshold of concern for this effect. The Panel observed that linalool and eugenol, which are components of Rosa canina-derived ingredients, are constituents of concern because of the potential for their hydroperoxides to induce sensitization. The IFRA has established a limit for the peroxides of these 2 components, which should not be exceeded. The Panel noted that because final product formulations may contain multiple botanical ingredients, each possibly containing similar constituents of concern, formulators are advised to be aware of these constituents and to avoid reaching levels that may be hazardous to consumers. The Panel expressed concern about pesticide residues, heavy metals, and substances from plants of other species (weeds) that may be present in botanical ingredients. To address these concerns, the cosmetics industry should continue to use current good manufacturing practices (cGMPs) to limit impurities. Insufficient Data Announcements Alkane Diols The Panel issued an insufficient data announcement for the following 10 ingredients: Propanediol 1,4-Butanediol 1,5-Pentanediol Hexanediol Octanediol 1,10-Decanediol Methylpropanediol 2,3-Butanediol Butyl Ethyl Propanediol Isopentyldiol The additional data needed included:

• Method of manufacturing data for all ingredients • Impurities data for all ingredients, particularly indicating whether or not 2,5-Hexanediol is an impurity of Hexanediol i.e., 1,6-Hexanediol) • Additional Penetration Enhancement data for all ingredients • Neurotoxicity data for Isopentyldiol • Concentration of use data for 1,4-Butanediol

Humulus lupulus (hops)-derived ingredients The Panel issued an Insufficient Data Announcement for the following 6 Humulus lupulus (hops)-derived ingredients: Humulus Lupulus (Hops) Extract Humulus Lupulus (Hops) Cone Extract Humulus Lupulus (Hops) Cone Oil Humulus Lupulus (Hops) Flower Extract


Humulus Lupulus (Hops) Stem Extract* Humulus Lupulus (Hops) Strobile The data needs are: • Composition and sensitization for Humulus Lupulus (Hops) Extract at maximum concentration of use (0.6%) • Composition for Humulus Lupulus (Hops) Stem Extract. The Panel noted the presence of β-myrcene at 25.4% in Humulus Lupulus (Hops) Cone Oil. This constituent is a potential irritant, and there is a National Toxicology Program study showing increased incidences of kidney tumors in male rats and liver tumors in male mice after oral administration of 1.0 g/kg/day β-myrcene for 2 years. The Panel noted that the increased incidence of kidney tumors in this study is likely attributable to a mechanism that is not relevant to humans, and the increased incidence of liver tumors is attributable to the high background incidence and susceptibility to the development of liver tumors that is characteristic of the mouse strain used in the study, and is also not predictive of carcinogenicity in humans. Further, the dosage rates of β-myrcene administered orally to the rats and mice in the study were much greater than any reasonable worst-case exposure to β-myrcene that could occur from hops-derived ingredients in cosmetics. However, concerns about β-myrcene, and possibly other constituents, cannot be addressed fully by the Panel, because the available information is not sufficient to characterize adequately the compositions of hops-derived cosmetic ingredients. The Panel emphasized the importance, generally, of adequately characterizing the compositions of cosmetic ingredients derived from plants, as manufactured and supplied to formulators of cosmetic products.


Presentation on in vitro Skin Sensitization Test Methods Dr. Donald Bjerke summarized the evolution of skin-sensitization testing methods, beginning with the development of in vivo methods, including the guinea pig tests circa 1970 and the Local Lymph Node Assay (LLNA) in the 1990s, followed by more recent efforts to develop alternatives to whole animal tests. The latter include in silico, in vitro, and in chemico approaches, such as computational modeling of molecular interactions, tests of dendritic- cell gene activation, and peptide reactivity assays, respectively. He also stated that there are several computational tools available to predict the dermal penetration and metabolism of haptens and hapten precursors, the small electrophilic molecules that cause skin sensitization after penetrating the stratum corneum of the skin. In fact, the mechanism of skin sensitization is well characterized and represented by a well-defined Adverse Outcome Pathway (AOP) that describes sensitization as a series of key chemical and biological events. Dr. Bjerke noted three non-animal test methods that have been developed to differentiate sensitizers from non-sensitizers based on the ability of chemicals to react with skin proteins. These methods include the DPRA and the Peroxidase Peptide Reactivity Assay (PPRA), which are both in chemico assays, and a cell-based assay that signals the covalent binding of the hapten to cellular proteins through the expression of luciferase-gene constructs. He also mentioned other in vitro assays that reflect subsequent key events along the AOP. Of these assays, 3 have been scientifically validated and have achieved regulatory acceptance, including the DPRA, and 5 are under assessment for validation by the ECVAM.

Dr. Bjerke used the slide shown to illustrate, conceptually, that the results of in chemico protein reactivity assays (like the DPRA), in silico predictions, and in vitro assays that represent, in aggregate, multiple key events of the AOP, can be integrated to estimate the potencies of chemicals identified as sensitizers. He emphasized that the ultimate goal of these efforts is to develop integrated testing strategies (ITSs) that directly predict the risk of skin sensitization in human beings, rather than the likelihood of positive results in LLNAs. Dr. Bjerke also discussed some of the limitations of the DPRA, in particular. For example, the DPRA depends on the ability of a hapten to react with the cysteine and lysine residues of proteins. Thus, the DPRA cannot be used to identify haptens that react preferentially with other amino acids. Further, the DPRA cannot be used to identify pro-


haptens, and the extent to which the DPRA can be used to identify pre-haptens is not clear. Research is ongoing to advance the development of the DPRA to address these limitations. The slides for this presentation are available at http://www.cir-safety.org/sites/default/files/CIREP_092616_DL_Bjerke.pdf


http://www.cir-safety.org/sites/default/files/CIREP_092616_DL_Bjerke.pdf

Commitment & Credibility since 1976

Memorandum

To: CIR Expert Panel Members and Liaisons CC: Dr. Linda Katz, US FDA From: Bart Heldreth, PhD, Chemist Date: November 11, 2016 Subject: Review Strategy for Lead Acetate

The CIR Expert Panel has reviewed a number of oxidative hair dye ingredients, but has not yet assessed the safety of a progressive hair dye (progressive hair dye products are applied over a period of time to achieve a gradual coloring effect). During the CIR priorities setting process for year 2017, the liaison from the US FDA requested that the CIR Expert Panel assess the safety of the progressive hair dye ingredient, Lead Acetate (Pb(OAc)2). The Expert Panel agreed to review this dye. This ingredient is recited in the Code of Federal Regulations, Title 21, as permissible in cosmetic products with a lead content, calculated as Pb, of no more than 0.6% (weight to volume), intended only for application to the hair on the scalp (Attachment 1). This translates to roughly 0.9% Lead Acetate permissible in a final formulation (atomic weight of Pb = 207 g/mol; formula weight of 2 acetate ions = 118 g/mol), with no permissible concentration for other cosmetic uses (the only use category reported to the VCRP for this ingredient is “Other Hair Coloring Preparation”).

According to the FDA, “the safety data submitted in support of this [color additive] included results from trials on humans using the products. In the trials, those using the product under controlled conditions of use were monitored for the amount of lead in their bloodstream. No significant increase in blood levels of lead was seen in the trial subjects and the lead was not shown to be absorbed into the body through such use” (Attachment 2). Despite these findings, there is current global interest in the dermal absorption/penetration of this ingredient. Indeed, a few studies have demonstrated that monitoring blood levels of lead may not be an adequate method of determining dermal absorption (Attachments 3 & 4).

While there are some published studies available on the dermal absorption of Lead Acetate, and

cationic lead in general, are there specific data (absorption-related or other) requests that the CIR Expert Panel would like to make to the FDA and other stakeholders, or guidance that the Panel would like to provide to the CIR staff, before the first draft of this report is prepared?

Also, should a detailed, quantitative risk assessment be included in this report? If so, should one

or more quantitative risk assessment(s) be requested from stakeholders (e.g., industry), and to what endpoint(s)?




[Code of Federal Regulations] [Title 21, Volume 1] [Revised as of April 1, 2016] [CITE: 21CFR73.2396]

TITLE 21--FOOD AND DRUGS

CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES

SUBCHAPTER A--GENERAL

PART 73 -- LISTING OF COLOR ADDITIVES EXEMPT FROM CERTIFICATION

Subpart C--Cosmetics

Sec. 73.2396 Lead acetate.

(a) Identity. The color additive lead acetate is the trihydrate of lead (2 + ) salt of acetic acid. The color additive has the chemical formula Pb (OOCCH3)2.3H2O).

(b) Specifications. Lead acetate shall conform to the following specifications and shall be free from impurities other than those named to the extent that such impurities may be avoided by good manufacturing practice:

Water-insoluble matter, not more than 0.02 percent.

pH (30 percent solution weight to volume at 25 deg. C), not less than 4.7 and not more than 5.8.

Arsenic (as As), not more than 3 parts per million.

Lead acetate, not less than 99 percent.

Mercury (as Hg), not more than 1 part per million.

(c) Uses and restrictions. The color additive lead acetate may be safely used in cosmetics intended for coloring hair on the scalp only, subject to the following restrictions:

(1) The amount of the lead acetate in the cosmetic shall be such that the lead content, calculated as Pb, shall not be in excess of 0.6 percent (weight to volume).

(2) The cosmetic is not to be used for coloring mustaches, eyelashes, eyebrows, or hair on parts of the body other than the scalp.

(d) Labeling requirements. (1) The label of the color additive lead acetate shall conform to the requirements of 70.25 of this chapter, and bear the following




https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=73

statement or equivalent:

Wash thoroughly if the product comes into contact with the skin.

(2) The label of the cosmetic containing the color additive lead acetate, in addition to other information required by the act, shall bear the following cautionary statement, conspicuously displayed thereon:

CAUTION: Contains lead acetate. For external use only. Keep this product out of children's reach. Do not use on cut or abraded scalp. If skin irritation develops, discontinue use. Do not use to color mustaches, eyelashes, eyebrows, or hair on parts of the body other than the scalp. Do not get in eyes. Follow instructions carefully and wash hands thoroughly after each use.

(e) Exemption for certification. Certification of this color additive for the prescribed use is not necessary for the protection of the public health and therefore batches thereof are exempt from the certification requirements of section 721(c) of the act.




The following copyrighted material has been removed:

Moore MR, Meredith PA, Watson WS, Sumner DJ, Taylor MK, Goldberg A. The percutaneous absorption of lead-203 in humans from cosmetic preparations containing lead acetate, as assessed by whole-body counting and other techniques. Food Cosmet Toxicol. 1980 Aug;18(4):399-405.


Journal Abstracts on Dermal Absorption of Lead


Journal of Nutritional & Environmental Medicine (1998) 8, 19±23


Peripheral Neuropathy After Hair Dye Exposure: A Case Report Wissam Deeb, MD,* David Cachia, MD,† Colin Quinn, MD,* and Johnny Salameh, MD*


Vet Hum Toxicol 33 (3) June 1991


See also “Skin Absorption of Lead”, Letter to the Editor, “The Lancet”, July 16, 1988


cir expert panel meeting december 5 – 6, 2016page 2 – 141 st meeting of the cir expert panel —...

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