MAGAZINE. Reprint. The Global Publication of the International Federation of Societies of Cosmetic Chemists.

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1 Volume 17 Number 1 January/March 2014 MAGAZINE The Global Publication of the International Federation of Societies of Cosmetic Chemists Reprint Ennen, Joachim; Degwert, Joachim; Duttiné, Monika; Gerlach, Nicole; Jassoy, Claudia; Jünger, Michael; Matthies, Wolfgang; Mehling, Anette; Merk, Hans; Rossow, Uwe; Welzel, Julia; Wigger-Alberti, Walter; Wilhelm, Klaus-Peter Studies on the Skin Compatibility of Cosmetics Involving Human Subjects Study Portfolio and Test Strategy

2 Studies on the Skin Compatibility of Cosmetics Involving Human Subjects Study Portfolio and Test Strategy Ennen, Joachim 1 ; Degwert, Joachim 2 ; Duttiné, Monika 3 ; Gerlach, Nicole 4 ; Jassoy, Claudia 5 ; Jünger, Michael 6 ; Matthies, Wolfgang 7 ; Mehling, Anette 8 ; Merk, Hans 9 ; Rossow, Uwe 10 ; Welzel, Julia 11 ; Wigger-Alberti, Walter 12 ; Wilhelm, Klaus-Peter 13 1 Beiersdorf AG, Hamburg; 2 Skin Investigation and Technology, Hamburg; 3 WIN Cosmetics, Flörsheim-Dahlheim; 4 DermaTronnier, Witten-Herdecke; 5 Henkel AG & Co. KGaA; 6 University of Greifswald, Greifswald; 7 SBM Consulting, Düsseldorf; 8 BASF SE, Düsseldorf; 9 RWTH Aachen University, Aachen; 10 Johnson&Johnson GmbH, Neuss; 11 Klinikum Augsburg, Augsburg; 12 BioSkin GmbH, Hamburg; 13 proderm GmbH, Schenefeld/Hamburg Position Paper of the DGK, German Society for Scientific and Applied Cosmetics (GSSAC) Work Group I Safety and Compatibility, presented at the 19 th DGK Symposium, 4 th to 6 th of May 2011, Würzburg, Germany Educational contribution INTRODUCTION Cosmetic products are substances or mixtures, in particular those applied to external parts of the human body with a view to keep them in good condition or change their appearance, e.g. shampoos, body lotions, face creams, or decorative cosmetics. Manufacturers or distributors of cosmetic products are required to ensure the safety of the products they place on the market in accordance with EU Regulation No 1223/2009 on Cosmetic Products [1]. The EU Regulation defines the general framework for evaluating the safety of cosmetic products. To this accord, the product, instructions for use and advertising claims are to be formulated by the manufacturer or distributor in such a way that the product is safe for normal or foreseeable use. The EU Cosmetics Regulation prohibits or restricts the use of certain substances; it includes positive lists of colorants, UV filters and preservatives that specify those substances that may be used for the stated purpose. A key sentence in this Regulation states: Cosmetic products put on the market must not be harmful to human health when applied under normal or reasonably foreseeable conditions of use. According to Annex 1, 8 a particular focus should lie on local toxicity (e.g. skin and eye irritation, sensitization). Studies using human volunteers and conducted to substantiate the skin compatibility are therefore of particular importance. Consumers regularly use cosmetic products. They are usually well tolerated and skin reactions rarely occur. To ensure that cosmetic products maintain a high level of compatibility, different types of methods are available for testing in human volunteer studies. Each test method must be evaluated for its applicability to assess the relevant parameters pertaining to the respective product category. A distinction must also be made depending on the purpose of a study, in particular between test ABSTRACT Local skin compatibility of cosmetics appears to be the crucial item which has to be substantiated before market release of a finished product. Human volunteer studies for confirmation of skin compatibility are an essential but not the only element of a safety assessment. The present paper first focuses on the basic principles for conducting human volunteer studies by reviewing the existing guidelines and recommendations. Then test strategies to ensure the skin compatibility of cosmetics are developed taking into account the methods intended to elicit certain levels of reactions, e.g. those used for screening of prototypes, and in-use study designs that are used for the substantiation of the skin compatibility of the finished product. This paper provides guidance and presents test strategies for substantiation of the skin compatibility of products of different categories. Market analyses Feedback from consumer studies and post market surveillance can provide information on undesirable reactions to cosmetics. product category, i.e. leave on versus rinse off, and type of study protocol, i.e. provocative designs versus in use study types. Moreover, the intended mode of application of the product also always has to be taken into consideration. For instance, application of an eye care product differs from that of a body care product, although both belong to the leave on skincare category. All this work helps the manufacturer or distributor of cosmetics to gain a comprehensive overview of the skin compatibility of the finished product and offers safety assessors the basis for their market release decision. IFSCC Magazine

3 Consumers can experience a number of skin reactions to cosmetics such as irritation, allergy or skin discomfort due to stinging or burning sensations. According to newer surveys these subjective sensations make up the vast majority at 70% of unwanted skin reactions [2]. In a survey analyzing whether consumers consider cosmetic products to be safe, a total of 4373 questionnaires were distributed to pharmacy customers. Of the respondents, 77% of which were women and 23% were men, 24% reported already having experienced skin reactions to cosmetics. However, no additional medical diagnoses were made in this study. A large-scale analysis was performed in Stockholm in 1997 based on a total of 15,000 questionnaires distributed to adults between the ages of 19 and 80 containing 87 questions on the topic of health, allergies and environmental factors [3]. The survey included questions about individual symptoms like hand eczema, childhood eczema, nickel allergy, skin symptoms on the face and intolerance to cosmetics and/or hygiene products. Approximately 9% of all those surveyed reported sensitivity to cosmetics or hygiene products, but once again this was not confirmed by medical diagnosis. Only a very small fraction of reactions to cosmetics are allergic reactions, and just 2% of the dermatologically diagnosed skin reactions of customers of beauty salons also resulted in positive reactions in allergy patch tests [4]. However, this type of survey does not allow the differentiation of whether the cosmetic product/ingredient itself actually caused the allergy or if the allergy was induced by exposure to another substance. Usually several factors are involved when skin reactions or sensitivities occur in connection with cosmetics. The cause can only be established by diagnostic procedures or confirmation and clarification of the circumstances. Basic principles for conducting human studies To ensure the maximum possible safety of a new cosmetic product, it should be tested extensively before being placed on the market. Although not mandatory, studies substantiating the skin compatibility of cosmetic products in human subjects may be advisable both scientifically and ethically. Human studies are justifiable only if toxicological approval of the cosmetic formulation has been obtained and no toxic or undesirable reactions are to be expected under the test conditions. When planning and performing human studies, various ethical and scientific aspects must be taken into consideration according to SCCP Notes of guidance for Testing of Cosmetic Ingredients and Their Safety Evaluation by the SCCS: SCCS/1501/12 [5]. These include protection of the test subjects, including the Declaration of Helsinki, a comprehensive safety assessment of the formulation and a scientifically sound and relevant study protocol with a statistically relevant number of volunteers. Protection of the test subjects: The Declaration of Helsinki establishes ethical guidelines for conducting research involving humans. A first draft was approved by the World Medical Association in 1964, although it has been revised repeatedly, in some cases fundamentally, up to the present. One principle or excerpt from the Declaration of Helsinki states: The patient s health shall be the primary concern. Medical progress depends on research, which in turn must be supported by experiments in humans, but the well-being of test subjects has priority over the interests of science or society. In light of this, basic conditions were defined in the Declaration of Helsinki (latest version: Seoul, Korea in 2008), such as those for planning and conducting clinical trials and designing the study protocol. Safety assessment: In accordance with EC Regulation 1223/2009 on Cosmetic Products Annex 1 [6], a manufacturer of cosmetic products must prepare a safety assessment or have a safety assessment prepared for his products before placing them on the market. This must comply with Annex I of the EU Cosmetics Regulation and takes several criteria into account including the general toxicological profile of the ingredients, their chemical structure as well as the exposure level. The regulation defines that a qualified safety assessor is required and responsible for the preparing the safety evaluation, including the product information file. To this end, an evaluation of both the raw materials used as well as the composition of the finished product and the anticipated safety of the application is prescribed, whereby a special focus should be given to the expected skin compatibility. In the safety assessment, all relevant product information available must be taken into account. The key elements of a safety assessment are defined not only in Annex I of the EU Cosmetics Regulation but also further described in the guidance documents provided by the SCCP [7] and Cosmetics Europe [8]. The points to be included in the product information file include: Part A Cosmetic Product Safety Information 1. Quantitative and qualitative composition of the product 2. Physical/chemical characteristics and stability of the cosmetic product 3. Microbiological quality 4. Impurities, traces, information about packaging materials 5. Normal and reasonably foreseeable use 6. Exposure to the cosmetic product 7. Exposure to the substances 8. Toxicological profile of the substances 9. Undesirable effects and serious undesirable effects (cosmetovigilance) 10. Information on the cosmetic product Part B Cosmetic Product Safety Assessment 1. Assessment conclusion 2. Labeled warnings and instructions of use 3. Reasoning 4. Assessor s credentials and approval of part B Study protocol: Cosmetics Europe has specified accepted guidelines for performing human studies in cosmetic research: Guideline for the safety assessment of cosmetic products [8, 9, 10] Guideline for the assessment of the skin compatibility of cosmetic products [11] Guideline for assessment of the skin compatibility of potentially irritant cosmetic actives and ingredients [12] 20 IFSCC Magazine

4 One definition of skin compatibility is: Skin compatibility is defined as the absence of skin irritation under normal conditions of use and reasonable foreseeable misuse, taking into account objective reactions as well as subjective responses such as stinging, burning or itching [13]. The Cosmetics Europe Guidelines describe criteria for selection of a specific study design and a representative group of subjects, but it also specifies study protocols that are generally accepted. Important content and elements of a study protocol or documentation are, for example: Studies on the skin compatibility must be performed by trained, qualified and experienced people. General ethical requirements have to be considered. The study objective must be clearly defined. An appropriate (meaningful) sample size is essential. A well-defined data management is a prerequisite. The sponsor and test institute must be clearly identified. A system for management of any skin reactions or adverse effects must be specified. Test strategies to ensure the skin compatibility of cosmetics A general test strategy has to take the following into account: When substantiation of the skin compatibility is being planned, a case-bycase decision on the strategy and based on the relevance for the specific project is necessary. In general, a step-by-step approach with increasing exposure to the sample should is preferred. The study design should have sufficient statistical power to achieve the study objective without subjecting the participants to undue risk. When designing a specific test strategy, on the one hand the novelty of the raw materials and formula must be taken into account and on the other hand the irritation potential of the product category (for example, leave on vs. rinse off). Protocols Fig. The Relationship between the Irritation Potential of a Product Category and the Recommended Provocation Level for the Study Design for the rinse off product category can be modified, e.g. in that the mode of application (semi-occlusive instead of occlusive) is adjusted and/or the products can be tested in a diluted form. As the application site is an important variable and should be taken into account, e.g. in the case of eye creams, ophthalmologic factors should be considered. The inclusion and exclusion criteria should also be adapted to ensure that participant selection is representative of the product s target group. It has proved to be extremely useful for the evaluation of the skin compatibility of prototypes and finished products to concomitantly test benchmarks as reference samples. Benchmarks are usually wellknown and adequately studied market products that are used for the same application and are thought to have a similar performance profile or skin compatibility. These benchmarks are chosen specifically for each product category to serve in studies as the standard for evaluation of the skin compatibility of new products. In general, the new product should have a comparable level of compatibility as the benchmark. If it does not, the product may need to be reformulated. The diagram above (Fig.) presents the relationship between the irritation potential of a product category and the recommended provocation level for the study design. Open epicutaneous tests (single/repeated application) and in-use studies should be chosen for product categories with a high irritation potential (hair colorants, permanents), whereas occlusive epicutaneous patch tests (single/repeated application) and in-use studies should be used for product categories that should have a low irritation potential (e.g. skincare products). The diagram outlines the range of possible study designs and conditions in relation to the irritation potential of the respective product categories. Considering the given frame conditions, the selection of suitable study designs and testing conditions depends apparently on the irritation potential of the respective Educational contribution IFSCC Magazine

5 product category. Furthermore, for a comprehensive evaluation of skin compatibility it is necessary to combine studies with exaggerated test conditions and use tests with less provoking but more realistic conditions, the latter being highly relevant in the case of possible unpleasant subjective sensations. Several options for study designs are compiled in the table following the Cosmetics Europe guideline Product Test Guidelines for the Assessment of Human Skin Compatibility. Table Options for Study Designs The single application open epicutaneous test, single application patch test and inuse study are suitable as standard tests for initial testing. Further tests should be planned if application to special areas (e.g. face), special skin types (e.g. sensitive skin) or formula changes (substitution of raw material) need to be evaluated. In this case a stinging study, a study with a subpopulation of subjects with sensitive skin or a cumulative application test would be the study designs of choice. Additional use of findings for similar formulations and additional studies (e.g. efficacy studies) are helpful for rounding off the compatibility profile of a test formulation. This means that the results of compatibility studies on comparable formulas and data from claim support and market research studies should also be used and evaluated. This approach allows targeted and efficient use of resources to clarify product-specific questions relating to local tolerability. CONClUSION Data from human studies form the basis for the final evaluation of the skin compatibility of a product and is an integral part of the safety assessment. When conducting the safety assessment, the safety assessor evaluates all test results, and results on skin compatibility can be pivotal for the decision to place a product on the market. Carefully selected compatibility studies with products before they are put on the market, combined with the information already available on similar formulas and the ingredients used, enables a good prediction of the overall compatibility of products for consumers. Despite 22 all efforts to develop and market products that are well tolerated, it is impossible to exclude the occasional occurrence of skin reactions in particularly sensitive persons. When undesirable reactions are reported from the market, it should also be taken IFSCC Magazine

6 into consideration that reactions can also result from misuse, use by or on certain individuals, or on skin areas that as stated in the product information are excluded from product use. References [1] Regulation (EC) No. 1223/2009 on Cosmetic Products: UriServ.do?uri=OJ:L:2009:342:0059:0209:en:PDF [2] Di Giovanni. C., Arcoraci, V., Gambardella, L., and Sautebin, L., Cosmetovigilance survey: are cosmetics considered safe by consumers?, Pharmacol. Research, 53 (2006) [3] Meding, B., Liden, C., and Berglind, N., Self-diagnosed dermatitis in adults: Results from a population survey in Stockholm, Contact Dermatitis, 45 (2001) [4] De Groot, A.C.,, Beverdam, E.G.A., Tjong Ayong, C., Coenraads, P.J., and Nater, J.P., The role of contact allergy in the spectrum of adverse effects caused by cosmetics and toiletries, Contact Dermatitis, 19 (1988) [5] SCCP Notes of Guidance for Testing of Cosmetic Ingredients and their Safety Evaluation by the SCCS: SCCS/1501/12, health/scientific_committees/consumer_safety/ docs/sccs_s_006.pdf [6] Guidelines on Annex I to Regulation (EC) No 1223/2009 on the Cosmetic Product Safety Report, Final draft of August 2012, in preparation [7] SCCS Notes of Guidance for the Testing of Cosmetic Ingredient sand their Safety Evaluation: SCCS/1416/11; Draft Annex 1 13_2927_00_e tbt/eec/13_2927_00_e.pdf [8] Cosmetics Europe (COLIPA) Guidelines on the Product Information File P I F Requirement 2011: html?view=item&id=85 [9] Cosmetics Europe Guidelines: Guidelines for the Safety Assessment of a Cosmetic Product, html?view=item&id=27 [10] Cosmetics Europe Guidelines: Product Test Guidelines for the Assessment of Human Skin Compatibility publications-cosmetics-europe-associa-tion/guidelines.html?view=item&id=24 [11] Cosmetics Europe Guidelines: Guidelines for Assessment of Skin Tolerance of Potentially Irritant Cosmetic Ingredients, [12] SCCNFP Guideline for assessment of the skin compatibility of potentially irritant cosmetic actives and ingredients, 2000: sc/sccp/out130_en.pdf [13] Walker, E.P., Basketter, D.A., Bavere, l.m., Diembeck, W., Matthies, W., Mougin, D., Roethlisberger, R., and Coroama, M., Test Guideline for the assessment of skin tolerance of potentially irritant cosmetic ingredients in man, Food and Chemical Toxicology, 35 (1997) [14] Mehling, A., Chkarnat, C., Degwert, J., Ennen, J., Fink, E., Matthies, W., Roethlisberger, R., Rossow, U., Schnitker, J., Tronnier, H., Wigger-Alberti, W., and Wilhelm, K.P., Interlaboratory studies with a pro-posed patch test design to evaluate the irritation potential of surfactants, Contact Dermatitis, 62 (2010) Corresponding Author Joachim Ennen Beiersdorf AG Hamburg Germany joachim.ennen@beiersdorf.com G Educational contribution IFSCC Magazine