《化妆品成分测试及其安全性评价的SCCS指南注释(第10次修订)》10th--Revision-THE-SCCS-NOTES-OF-GUIDANCE-FOR-THE-TESTING-OF-COSMET.pdf

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 ii 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 iii 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 iv 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 v 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 1 ACKNOWLEDGMENTS SCCS members listed below are acknowledged for their valuable contribution to the finalisation of this guidance document.SCCS members Dr U.Bernauer Dr L.Bodin Prof.Q.Chaudhry (SCCS Chair)Prof.P.J.Coenraads (SCCS Vice-Chair)Prof.M.Dusinska Dr J.Ezendam Dr E.Gaffet Prof.C.L.Galli Dr B.Granum Prof.E.Panteri Prof.V.Rogiers (SCCS Vice-Chair and rapporteur)Dr Ch.Rousselle Dr M.Stepnik Prof.T.Vanhaecke Dr S.Wijnhoven SCCS external experts Dr A.Koutsodimou Dr A.Simonnard Prof.W.Uter Dr N.von Goetz All Declarations of Working Group members are available on the following webpage:http:/ec.europa.eu/health/scientific_committees/experts/declarations/sccs_en.htm Keywords:SCCS,SCCS Notes of Guidance for the Testing of Cosmetic Ingredients and their Safety Evaluation,10th revision,SCCS/1602/18 Opinion to be cited as:SCCS(Scientific Committee on Consumer Safety),SCCS Notes of Guidance for the Testing of Cosmetic Ingredients and their Safety Evaluation 10th revision,24-25 October 2018,SCCS/1602/18 2 ABOUT THE SCIENTIFIC COMMITTEES Two independent non-food Scientific Committees provide the Commission with the scientific advice it needs when preparing policy and proposals relating to consumer safety,public health and the environment.The Committees also draw the Commissions attention to the new or emerging problems which may pose an actual or potential threat.These Committees are:the Scientific Committee on Consumer Safety(SCCS)and the Scientific Committee on Health,Environmental and Emerging Risks(SCHEER)and they are made up of scientists appointed in their personal capacity.In addition,the Commission relies upon the work of the European Food Safety Authority(EFSA),the European Medicines Agency(EMA),the European Centre for Disease prevention and Control(ECDC)and the European Chemicals Agency(ECHA).SCCS The Committee shall provide Opinions on questions concerning all types of health and safety risks(notably chemical,biological,mechanical and other physical risks)of non-food consumer products(for example:cosmetic products and their ingredients,toys,textiles,clothing,personal care and household products such as detergents,etc.)and services(for example:tattooing,artificial sun tanning,etc.).SCIENTIFIC COMMITTEE MEMBERS Bernauer Ulrike,Bodin Laurent,Chaudhry Qasim,Coenraads Pieter-Jan,Dusinska Maria,Ezendam Janine,Gaffet Eric,Galli Corrado Lodovico,Granum Berit,Panteri Eirini,Rogiers Vera,Rousselle Christophe,Stpnik Maciej,Vanhaecke Tamara,Wijnhoven Susan Contact European Commission Health and Food Safety Directorate C:Public Health,Country Knowledge,Crisis Management Unit C2 Country Knowledge and Scientific Committees L-2920 Luxembourg SANTE-C2-SCCSec.europa.eu European Union,2018 ISSN ISBN Doi:ND-The Opinions of the Scientific Committees present the views of the independent scientists who are members of the committees.They do not necessarily reflect the views of the European Commission.The Opinions are published by the European Commission in their original language only.http:/ec.europa.eu/health/scientific_committees/consumer_safety/index_en.htm 3 Applicants are invited to visit the SCCS website:https:/ec.europa.eu/health/scientific_committees/consumer_safety/opinions_en where Applicants will find a checklist for submitting a safety dossier of a cosmetic ingredient.Applicants are invited to visit the following website for further legislative information:https:/ec.europa.eu/growth/sectors/cosmetics/legislation_en 4 MAIN CHANGES IN 10TH REVISION OF THE SCCS NOTES OF GUIDANCE(NOG)Structural changes The general structure of the Notes of Guidance has been changed to give priority to non-animal methods,followed by older in vivo strategies.Information on Regulation 1223/2009/EC and guidance related to finished cosmetic products(Product Information File,PIF)is now included in the Annexes.A(revised)checklist for submitting a safety dossier to the SCCS has been added.An update of the data needed for safety evaluation has been included and information for re-submitting is also given in case of a negative opinion.References and abbreviations lists have been updated.The exposure chapter has been updated with subdivisions for external and internal exposure tiered approach and aggregate exposure are discussed.Changes in content An update on non-animal toxicological studies for cosmetic ingredients has been included.Weight of Evidence(WoE)and use of a toolbox(genotoxicity/mutagenicity)are discussed.An update of criteria for multi-constituent natural ingredients and chemical identity has been included.The Threshold of Toxicological Concern concept TTC-remains the same,i.e.new suggested values in publication have not yet been evaluated.A literature overview of consumer exposure data has been added in Appendix 7.5 1.INTRODUCTION Since July 2013,Regulation(EC)No 1223/2009 applies for cosmetic products.Their safety-in-use is,as was also the case for Directive 76/768/EEC,established by controlling the safety of the ingredients.For those ingredients for which some concern exists with respect to human health(e.g.colourants,preservatives,UV-filters,hair dyes),safety evaluation is done at the Commission level by the Scientific Committee on Consumer Safety(SCCS).These substances are addressed in the Annexes of Regulation(EC)No 1223/2009.For the safety evaluation of cosmetic ingredients,all available scientific data are considered,taking into account the testing and marketing bans in force under Regulation(EC)No 1223/2009.This includes the physical and chemical properties of the compounds under investigation,in silico data such as results obtained from(Q)SAR(Quantitative)Structure Activity Relationship modelling,chemical categories,grouping,read-across,Physiologically-Based PharmacoKinetics(PBPK)/ToxicoKinetics(PBTK)modelling,in vitro and ex vivo experimental results and data obtained from animal studies(in vivo)that have been carried out for the purpose of cosmetics before the testing and marketing bans.The animal testing ban on finished cosmetic products applies since 11 September 2004;the testing ban on ingredients or combination of ingredients applies since 11 March 2009.The marketing ban applies since 11 March 2009 for all human health effects with the exception of repeated-dose toxicity,reproductive toxicity,and toxicokinetics.For these specific health effects,the marketing ban applies since 11 March 2013,irrespective of the availability of alternative non-animal methods.In addition,clinical data,epidemiological studies,information derived from accidents,data from Post-Marketing Surveillance(PMS)or other human data are also taken into consideration.In the present update,the state-of-the-art with respect to the validated methods of the 3Rs(Refinement,Reduction and Replacement)strategy of Russell et al.(1959),is incorporated with emphasis on New Approach Methodologies(NAMs).In view of the testing and marketing bans in the cosmetic regulation,the SCCS gives special attention to those alternative methods that are suitable for the safety testing of cosmetic substances.Although the Notes of Guidance are concerned with the testing and safety evaluation of the cosmetic substances listed in the Annexes of Regulation(EC)No 1223/2009 and those for which safety concerns have been expressed,they could b