THE SCCS NOTES OF GUIDANCE FOR THE TESTING OF …

SCCS/1602/18 Final version

Scientific Committee on Consumer Safety SCCS

THE SCCS NOTES OF GUIDANCE FOR THE TESTING OF COSMETIC INGREDIENTS AND

THEIR SAFETY EVALUATION 10TH REVISION

The SCCS adopted this guidance document at its plenary meeting on 24 ? 25 October 2018

TABLE OF CONTENTS

ACKNOWLEDGMENTS................................................................................................................................................... 1 About the Scientific Committees .................................................................................................................................. 2 SCCS .............................................................................................................................................................................. 2 Scientific Committee members .................................................................................................................................... 2 Main changes in 10th REVISION of the SCCS Notes of Guidance (NoG)....................................................................... 4 1. INTRODUCTION .................................................................................................................................................... 5 2. THE SCIENTIFIC COMMITTEE ON CONSUMER SAFETY, SCCS................................................................................ 6

2-1 HISTORICAL BACKGROUND........................................................................................................................... 6 2-2 MANDATE ..................................................................................................................................................... 6 2-3 RULES OF PROCEDURE.................................................................................................................................. 6 2-4 OPINIONS ...................................................................................................................................................... 6

2-4.1 The "Notes of Guidance" ........................................................................................................................ 6 2-4.2 SCCS Cosmetic ingredient dossiers ......................................................................................................... 7 2-4.3 Specific issues taken up in NoG .............................................................................................................. 7 3. SAFETY EVALUATION OF COSMETIC INGREDIENTS .............................................................................................. 8 3-1 SAFETY EVALUATION OF COSMETIC INGREDIENTS AS APPLIED BY THE SCCS .............................................. 8 3-2 CHEMICAL AND PHYSICAL SPECIFICATIONS OF COSMETIC INGREDIENTS.................................................. 11 3-2.1 Chemical identity .................................................................................................................................. 11 3-2.2 Physical form......................................................................................................................................... 12 3-2.3 Molecular weight .................................................................................................................................. 12 3-2.4 Identification and purity of the chemical and isomer composition...................................................... 12 3-2.5 Characterisation of the impurities or accompanying contaminants .................................................... 13 3-2.6 Relevant physicochemical specifications .............................................................................................. 13 3-2.7 Solubility ............................................................................................................................................... 13 3-2.8 Partition coefficient (Log Pow) ............................................................................................................... 14 3-2.9 Homogeneity and stability .................................................................................................................... 14 3-3 EXPOSURE ASSESSMENT............................................................................................................................. 14 3-3.1 Functions and uses of cosmetic ingredients ......................................................................................... 14 3-3.2 Identification of relevant exposure scenarios ...................................................................................... 14 3-3.3 Identification of the targeted dose for safety evaluation..................................................................... 15 3-3.4 External exposure ................................................................................................................................. 15

3-3.4.1 Exposure models and tiered approach ........................................................................................ 15 3-3.4.1.1 Dermal exposure models......................................................................................................... 16 3-3.4.1.2 Oral exposure models.............................................................................................................. 17 3-3.4.1.3 Inhalation exposure models .................................................................................................... 17

3-3.4.2 Model parameters ....................................................................................................................... 20 3-3.4.2.1 Daily use amounts and retention factors ................................................................................ 20 3-3.4.2.2 Concentrations ........................................................................................................................ 24 3-3.4.2.3 Parameters specific for inhalation exposure ........................................................................... 24

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3-3.4.3 Aggregate exposure ..................................................................................................................... 24 3-3.5 Internal Exposure.................................................................................................................................. 25

3-3.5.1 Toxicokinetics (ADME) ................................................................................................................. 25 3-3.5.1.1 Dermal/percutaneous absorption ........................................................................................... 26 3.3.5.1.2 absorption after ingestion ...................................................................................................... 29 3.3.5.1.3 Inhalation................................................................................................................................. 29

3-3.5.2 Differences in metabolism for different routes ........................................................................... 30 3-3.5.2.1 Systemic metabolism............................................................................................................... 30 3-3.5.2.2 Dermal metabolism ................................................................................................................. 31 3-3.5.2.3 Lung metabolism ..................................................................................................................... 32

3.3.5.3 PBPK modelling ............................................................................................................................ 32 3-3.5.4 Calculation of the systemic exposure dose (SED) ........................................................................ 34 3-3.5.5 Aggregation of the systemic dose ................................................................................................ 36 3-4 RELEVANT TOXICOLOGICAL STUDIES ON COSMETIC INGREDIENTS ........................................................... 36 3-4.1 Introduction .......................................................................................................................................... 36 3-4.2 In silico Assessment of Toxicological Hazard ........................................................................................ 36 3-4.3 Adverse Outcome Pathway (AOP) ........................................................................................................ 39 3-4.4 Acute toxicity ........................................................................................................................................ 39 3-4.4.1 Acute oral toxicity ........................................................................................................................ 39 3-4.4.2 Acute dermal toxicity ................................................................................................................... 40 3-4.4.3 Acute inhalation toxicity .............................................................................................................. 40 3-4.5 Skin corrosion and skin irritation .......................................................................................................... 40 3-4.5.1 Skin corrosion............................................................................................................................... 40 3-4.5.2 skin irritation ................................................................................................................................ 41 3-4.6 Serious eye damage and eye irritation ................................................................................................. 42 3-4.7 Skin sensitisation .................................................................................................................................. 44 3-4.8 Repeated dose toxicity ......................................................................................................................... 47 3-4.9 Reproductive toxicity ............................................................................................................................ 48 3-4.10 Mutagenicity / Genotoxicity............................................................................................................. 49 3-4.11 Carcinogenicity ................................................................................................................................. 54 3-4.12 Photo-induced toxicity ..................................................................................................................... 56 3-4.12.1 Photo-irritation and photo-sensitisation ..................................................................................... 56 3-4.12.2 Photo-mutagenicity / Photo-genotoxicity.................................................................................... 57 3-4.13 human data in hazard assessment ................................................................................................... 58 3-4.14 Human Biomonitoring ...................................................................................................................... 59 3-4.14.1 Definition ..................................................................................................................................... 59 3-4.14.2 Fields of application ..................................................................................................................... 59 3-4.14.3 Other considerations ................................................................................................................... 60 3-5 GENERAL PRINCIPLES FOR THE CALCULATION OF THE MARGIN OF SAFETY AND THRESHOLD OF

TOXICOLOGICAL CONCERN .......................................................................................................................... 60 3-5.1 Calculation of the Margin of Safety of a cosmetic ingredient .............................................................. 60

3-5.1.1 The POD value ............................................................................................................................. 61 3-5.1.2 The PODsys value ........................................................................................................................ 62

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3-5.1.3 MoS Analysis ................................................................................................................................ 63 3-5.2 The threshold of toxicological concern (TTC) ....................................................................................... 65

3-5.2.1 General concept of TTC in risk assessment.................................................................................. 65 3-5.2.2 TTC approach for human health risk assessment of chemical substances and cosmetic substances 65 3-6 SPECIAL CONSIDERATION FOR CERTAIN COSMETIC INGREDIENTS ............................................................ 67 3-6.1 Multi-constituent natural ingredients .................................................................................................. 67 3-6.2 Identification of mineral, animal, botanical and biotechnological ingredients in a cosmetic product. 67 3-6.3 Animal-derived cosmetic substances ................................................................................................... 69 3-6.4 Sun protection substances.................................................................................................................... 69 3-6.5 Endocrine active substances (EAS) ....................................................................................................... 70 3-6.5.1 Definitions .................................................................................................................................... 70 3-6.5.2 Stepwise approach for cosmetics and their ingredients.............................................................. 71 3-6.6 CMR Substances.................................................................................................................................... 74 3-6.7 Nanomaterials ...................................................................................................................................... 74 3-6.7.1 Definition of nanomaterial........................................................................................................... 74 3-6.7.2 Potential safety issues of nanomaterials ..................................................................................... 74 3-6.7.3 Required information for nanomaterials ..................................................................................... 76 3-6.8 Hair dyes and hair dye components ..................................................................................................... 76 3-6.8.1 MoS calculations for hair dye formulations ................................................................................. 77 3-6.8.2 Assessment of oxidative hair dye substances and reaction products.......................................... 77 3-6.9 Cosmetic ingredients for baby and children products.......................................................................... 78 3-6.9.1 Definitions .................................................................................................................................... 78 3-6.9.2 Age-related susceptibilities/sensitivities...................................................................................... 78 3-6.10 Substances with very low dermal absorption .................................................................................. 81 3-7 FURTHER REMARKS FOR APPLICANTS ........................................................................................................ 81 4. REFERENCE LIST .................................................................................................................................................. 83 APPENDIX 1: INFORMATION ON REGULATION (EC) No 1223/2009 AND THE SCCS ................................................. 113 APPENDIX 2: LISTS OF SUBSTANCES ......................................................................................................................... 119 APPENDIX 3: STANDARD FORMAT OF THE OPINIONS .............................................................................................. 122 APPENDIX 4: ANIMAL TESTING: INTERFACE BETWEEN REACH AND COSMETICS REGULATIONS............................. 132 APPENDIX 5: CMR GUIDANCE ON SAFE USE OF CMR SUBSTANCES IN COSMETIC PRODUCTS ................................ 133 APPENDIX 6: REQUIREMENTS FOR THE CERTIFICATE OF ANALYSIS FOR A COSMETIC INGREDIENT........................ 137 APPENDIX 7: DETAILED EXPOSURE DATA FOR COSMETIC PRODUCTS ..................................................................... 138 APPENDIX 8: KEY CHARACTERISTICS OF CARCINOGENS........................................................................................... 140 ABBREVIATIONS AND GLOSSARY OF TERMS ............................................................................................................ 141

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Nam et ipsa scientia potestas est For knowledge itself is power

Francis Bacon (1561 - 1626) Essays

The "Notes of Guidance for the Testing of Cosmetic Ingredients and Their Safety Evaluation by the SCCS" is a document compiled by the members of the Scientific Committee on Consumer Safety (SCCS, replacing the former SCCP, SCCNFP and SCC). The document contains relevant information on the different aspects of testing and safety evaluation of cosmetic substances in Europe. The emphasis of this guidance is on cosmetic ingredients, although some guidance is also indirectly given for the safety assessment of finished products. It is designed to provide guidance to public authorities and to the cosmetic industry in order to improve harmonised compliance with the current cosmetic EU legislation. An important development in recent years was the full implementation of the cosmetic legislation, Regulation (EC) No 1223/2009, meaning that the animal testing and marketing bans fully apply from 2013 onwards: no in vivo testing of finished products after March 2004; no in vivo testing for local toxicity after March 2009 and no in vivo testing for repeated dose toxicity (including sensitisation) toxicokinetics and developmental toxicity from March 2013 onwards for the purpose of cosmetics. For this reason, the SCCS has closely followed the progress made with regard to the development and validation of alternative methods, with emphasis on replacement methodology. The "Notes of Guidance" are regularly revised and updated in order to incorporate the progress of scientific knowledge in general, and the experience gained, in particular in the field of testing and safety evaluation of cosmetic ingredients. The previous revision of the Notes of Guidance took place in 2015 (SCCS/1564/15). Since then, several new addenda, opinions and memoranda of importance to the content of this guidance document have been adopted and they form the basis of this new revision. Focus is on exposure and the application of alternative methods, more specifically on non-animal methods. As was also the case in previous revisions, individual opinions are not provided in detail but are briefly summarised and clearly referred to. The "Notes of Guidance" have been compiled to provide assistance in the complex process of the testing and safety evaluation of cosmetic ingredients in the EU. Input of scientists from the scientific committee SCHEER and Cosmetics Europe is gratefully acknowledged.

The Chairperson

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