Safety Assurance of Cosmetic in Japan: Current Situation and Future Prospects

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1 Journal of Oleo Science Copyright 2014 by Japan Oil Chemists Society doi : /jos.ess13501 REVIEW Safety Assurance of Cosmetic in Japan: Current Situation and Future Prospects Shinji Inomata * Shiseido Research Center (2-2-1, Hayabuchi, Tsuzuki-ku, Yokohama-shi, Kanagawa , Japan) Abstract: The Japanese Pharmaceutical Affairs Law distinguishes cosmetics from quasi-drugs, and specifies that they must have a mild effect on the human body and must be safe to use over the long term. Therefore, the safety of cosmetics needs to be thoroughly evaluated and confirmed, taking into account the type of cosmetic, application method, conditions of use and so on. Post-marketing surveys of customers complaints and case reports of adverse effects are important to monitor and confirm the safety of products. Although manufacturing and marketing of cosmetics are becoming more globalized, the regulations relevant to cosmetics safety still vary from country to country. Thus, compliance with different regulations in various markets is a major issue for producers. In particular, further development of alternatives to animal testing remains an urgent global issue. Key words: cosmetic, quasi-drug, safety assurance, animal testing, alternatives 1 INTRODUCTION The Japanese Pharmaceutical Affairs Law distinguishes cosmetics from quasi-drugs, but specifies that both should have a mild effect on the human body. The amended Pharmaceutical Affairs Law in 2001 repealed the previous approval system, so that manufacturers obtained greater flexibility, while retaining potential liability. Cosmetics must be safe to use over the long term, so safety assurance is critical. For this purpose, appropriate testing for hazard identification and appropriate exposure assessment are important for risk assessment and calculation of safe exposure levels. It is also important to confirm the safety of cosmetics ingredients, as well as the product itself. Furthermore, post-marketing survey of customers complaints and case reports of adverse effects is necessary to monitor and confirm safety. The procedure of safety assurance is outlined in the first half of this report. In the second half of this report, I discuss the implications of globalization for cosmetic safety assurance. In particular, development of alternatives to animal testing is an urgent global issue, because the EU cosmetics directive 7th amendment in March, 2013, banned cosmetics company from selling products that have been tested on animals in response to public concern. This situation is expected to accelerate the development of alternatives to animal testing. Here we review the current situation and the prospects for development of alternatives to animal testing, especially skin sensitization testing, which is important for regulatory acceptance. 2 OUTLINE OF CURRENT COSMETIC SAFETY ASSURANCE REQUIREMENTS 2.1 Cosmetic categorization based on Japanese cosmetic regulation The Japanese Pharmaceutical Affairs Law requires that a cosmetic should have only mild effects on the human body 1. A cosmetic may be rubbed, spread, or applied for cleansing, beautifying, or enhancing the attractiveness of the human body, to change physical appearance, or to maintain skin or hair in a healthy condition. On the other hand, a quasi-drug or medicated cosmetic, such as hair restorer or skin-whitening agent, is categorized as having an intermediate position between a cosmetic and a drug. The activity of both cosmetics and quasi-drugs should be mild, considering that a customer may use them for much of his or her lifetime. Table 1 summarizes the legal distinction between a cosmetic and a quasi-drug. Comprehensive manufacturing and * Correspondence to: Shinji Inomata, Shiseido Research Center (2-2-1, Hayabuchi, Tsuzuki-ku, Yokohama-shi, Kanagawa , Japan) shinji.inomata@to.shiseido.co.jp Accepted October 21, 2013 (received for review August 29, 2013) Journal of Oleo Science ISSN print / ISSN online 1

2 S. Inomata Table 1 Regulations for cosmetic or quasi-drug. Cosmetic Approval for manufacturing and sales Required Required Approval for manufacturing each item Not required Required Approval for ingredients Ingredient labeling *JCIA: Japan Cosmetic Industry Association Not required (Excluding UV filters, preservatives, tar colorants etc.) Required for all ingredients Table 2 Category of Cosmetic Products. Quasi-drug Required (Excluding previously approved ingredients) Required specified ingredients (*JCIA voluntary standards; required for all ingredients) For skin For hair For oral Category Aim Products Cleansing Cleansing cream and foam Skin care Conditioning the skin Lotion, Facial mask, Massage cream Protecting the skin Emulsion, Moisturizing cream Make-up Body care Hair Hair care Scalp Oral care Base makeup Foundation, Face powder Point makeup Lipstick, Cheek and eye shadow, Nail varnish Bath Soap, Liquid soap, Bath additive UV protection Sunscreen Antiperspirant, Deodorant Deodorant Decoloration, hair removal Decolor, Hair remover Repellent Repellent lotion, spray Cleansing Shampoo Conditioner Rinse aid, Hair conditioner Styling Hair mousse, Hair bleach, Color rinse Permanent wave Permanent wave lotion Hair dye, Decolorizer Hair dye, Hair bleach, Color rinse Hair growth, Pilatory Pilatory, Hair tonic Conditioner Scalp conditioner Tooth brushing Toothpaste Mouth freshener Mouthwash Fragrance Fragrance Fragrance, eau de cologne sales approval are required for both items. For a quasidrug, manufacturing, sales, and formulation of ingredients in each item are subject to the requirements of the Japanese Ministry of Health, Labour and Welfare. For a cosmetic, however, manufacturing, sales, and formulating ingredients can be done at a company s own responsibility since the relaxation of cosmetics regulation in However, labeling of all ingredients is still required. Thus, manufacturers have more flexibility, but remain liable for adverse effects. 2.2 Process of cosmetic safety assurance According to the textbook Toxicology, All substances are poisons: There is none which is not a poison. The right dose differentiates a poison and a remedy. 2. This means that in formulating cosmetics, we have to take account of concentrations and interactions of components to ensure that effects on the human body are mild and that the cosmetic is safe to use over the long term. There are various categories of cosmetics and their components Table 2, including skin care and make-up, body care, hair care, oral care, and fragrances. Cosmetics in each category may be applied in different ways, in different 2

3 Safety Assurance of Cosmetic in Japan: Current Situation and Future Prospects Fig. 1 Procedure of Safety Assurance. amounts and in different locations. In order to assess potential exposure to cosmetics constituents, a person responsible for assessing the safety has to take account of product type, application and usage conditions, concentrations of constituents in the product, amount of product used, frequency, total contact area of skin, contact site skin, mucosa, or nails, reasonably foreseeable misuse, subpopulation adult, child, or sensitive skin, and external conditions sun exposure or not, etc.. Hazard identification is also needed for risk assessment Fig. 1. Some international toxicological databases are available for hazard assessment. For example, CIR Cosmetic Ingredient Review 3 reviews and SCCS Scientific Committee on Consumer Safety 4 opinions are considered reliable. To assess hazard and potential exposure, test data may also be needed. Appropriate hazard identification and exposure assessment should enable appropriate risk assessment, and allow calculation of a safe dose. A cosmetic product may contain many ingredients. In safety evaluation of each ingredient, the category and potency of the toxicity should be considered, and then the maximum permissible concentration is calculated. In the manufacturing process, formulation is configured using ingredients at safe concentrations based on data or previous usage, then the product safety must be confirmed according to the product type, application usage and potential interaction of ingredients. Table 3 shows endpoints for safety evaluation of cosmetics and quasi-drugs. For cosmetics, 9 endpoints no. 1 to 9 are needed in gereral. In contrast, 12 endpoints no. 1 to 12 are needed for quasi-drugs 1. Additional endpoints may be needed in particular circumstances. Despite careful safety prediction based on a variety of safety data of ingredients and products, regulations in Japan require the manufacturer to survey customers complaints and case reports of adverse effects post marketing. Such market validation can substantiate the methodology of safety evaluation and its results can thus lead to method improvement Fig FUTURE ISSUE 3.1 Issues accompanying globalization The shipment value of cosmetics in Japan reached 1400 billion yen in the middle of the 1990 s, and has not changed greatly since then. In other words, the cosmetics market is mature in Japan. Consequently, Japanese cosmetic manufacturers need to expand their overseas markets to achieve growth. Such globalization is associated with various risks and issues. In particular, local regulation determines the acceptability of cosmetic ingredients in each country, so that some ingredients can be formulated in one country, but not in others. Since regulations may be amended, it is important to have current legal information to ensure compliance. 3

4 S. Inomata Table 3 Endpoints for Safety Evaluation in Cosmetics and Quasi-drugs. No. Endpoints Check point 1 Acute toxicity test Check systemic effects at single dose (Provide data in case of accidental ingestion) 2 Primary skin irritation test Check skin irritation 3 Cumulative skin irritation test Check skin irritation in case of repeated application 4 Skin sensitization test Check skin allergy 5 Phototoxicity test Check skin irritation in the presence of UV irradiation 6 Photo-sensitization test Check skin allergy in the presence of UV irradiation 7 Eye irritation test Check eye irritation 8 Genotoxicity test Check gene effect 9 Human patch test Check irritation in human skin 10 Repeated dose toxicity test Check systemic effects at repeated dose 11 Reproductive and developmental toxicity test Check effects on parental reproduction and their conceptus 12 Absorption, Distribution, Metabolism, Excretion (ADME) Check absorption, distribution, metabolism and excretion characteristics Fig. 2 Concept of methodology of safety evaluation. Moreover, safety testing requirements and endpoints are different in different countries. Fortunately, International Cooperation on Cosmetics Regulation ICCR 5 is as available as a forum for discussion, communication and international cooperation relating to cosmetic safety. Regulatory authorities and industrial associations from the US, Canada, the EU, and Japan have membership of ICCR. Alternatives to animal testing have been a discussion item since the first conference in Progress in alternatives to animal testing To promote animal welfare, new regulations were implemented last March in the EU. Table 4 summarizes key points of The European Cosmetics Directive 7th Amendment. The 7th amendment came into effect in March 2003, banning animal testing for final products by September 2004 and for cosmetic ingredients by 11th March 2009 within the EU area. After March 2009, cosmetics and ingredients tested in animals were banned. However, there was a grace period for testing of toxicokinetics, reproductive and developmental toxicity, and repeated toxicity until March Now, animal testing of cosmetics is completely banned 6. It is possible that similar bans will be introduced elsewhere. Thus, development of non-animal test methods 4

5 Safety Assurance of Cosmetic in Japan: Current Situation and Future Prospects Date Table 4 The European Cosmetics Directive (7th Amendment). 2003/3/11 Date of coming into force Contents 2004/9/11 Banning animal testing for final products in EU Banning animal testing for both final products and ingredients in EU 2009/3/11 Banning the sale of cosmetics and ingredients evaluated by animal experiments, except in the case of ADME, reproductive and developmental toxicity and repeat dose toxicity 2013/3/11 Banning the sale of cosmetics and ingredients evaluated by animal experiments Table 5 Adoptation of alternative testing in OECD testing guideline. No. Endpoint In vitro test method adopted in OECD 1 Acute toxicity None 2 Primary skin irritation EpiSkin TM EpiDerm TM SIT SkinEthic TM RHE (Reconstructed human epidermis) 3 Cumulative skin irritation None 4 Skin sensitization None 5 Phototoxicity 3T3 NRU PT 6 Photosensitization None 7 Eye irritation BCOP(Bovine cornea) ICE(Isolated Chicken Eye) 8 Mutagenicity Ames Chromosomal aberration In vitro micronucleus 9 Human patch test - 10 Repeated dose toxicity None 11 Reproductive toxicity None 12 ADME None (excluding dermal absorption testing) as an alternative to animal testing is a global issue of urgency. Several organizations for validation of alternatives to animal testing exist in the US ICCVAM: Interagency Coordinating Committee on the Validation of Alternative Methods 7, in the EU EURL ECVAM: European Union Reference Laboratory for alternatives to animal testing 8 and in Japan JaCVAM: Japanese Center for the Validation of Alternative Methods 9. Collaboration among industry, government and academia is essential for the development and implementation of effective alternatives to animal testing. Table 5 shows uptake of alternative test methods in the Organization for Economic Co-operation and Development OECD testing guideline. For primary skin irritation, phototoxicity, eye irritation and mutagenicity, the OECD has adopted alternative methods 10. However, alternatives to animal testing for skin sensitization and systemic toxicity repeated dose toxicity, reproductive toxicity, ADME and so on have not been established. The EU is sponsoring extensive research to develop alternative methods for systemic toxicological endpoints. Furthermore, some alternatives to skin sensitization testing are being developed based on the OECD guideline. h-clat human Cell Line Activation Test, which has been developed by Shiseido Co. Ltd. and Kao Corporation in collaboration, is in the final stage of development and is expected to be listed in the OECD guideline within a few years. An outline of this method is described below. Figure 3a shows a schematic illustration of the mechanism of skin sensitization. Once a chemical sensitizer invades the epidermis, dendritic cells are activated and migrate to regional lymph nodes, where they present the antigen and induce proliferation of antigen-specific T-cells. The LLNA in mice utilizes T-cell proliferation, but h-clat utilizes activation of dendritic cells, which occurs in the induction phase of skin sensitization. For example, if cells are exposed to TNCB trinitrochlorobenzene, which is a strong sensitizer, the cell-surface characteristics change data not shown, and this change can be quantified Fig. 3b by measuring cell-surface antigens. Therefore, sensitization potential can be evaluated by using cultivated cells. Ashikaga reported that there was a good relationship between h-clat and LLNA for 100 chemicals 11. Development of alternatives to animal testing is likely to 5

6 S. Inomata Fig. 3 Schematic mechanism of skin sensitization and detection of sensitizers in cell culture. accelerate further in the future. 4 CONCLUDING REMARKS The key points of this review are itemized below. The Japanese Pharmaceutical Affair Law defines and distinguishes cosmetics and quasi-drugs, which are required to have mild effects on the human body. Cosmetic safety requires safety assessment of both ingredients and products. Post marketing surveillance is a key aspect of safety assessment, utilizing customers complaints and case reports of adverse effects. Accompanying globalization, compliance with different regulations in various markets is a major issue for producers. The animal testing ban in Europe is likely to extend globally in due course, and further development of alternatives to animal testing remains an urgent global issue. 5 ACKNOWLEDGEMENTS Thanks are due to the members of the Safety Research & Development Laboratories of Shiseido Research Center for their help during the preparation of this paper. REFERENCES AND NOTES 1 Kesyohin Iyakuhin Seizouhanbai Guide Book , Yakuji Nippo Ltd TOXICOLOGY Journal of Toxicological Sciences ed., New edition, Asakura Publishing Co., Ltd. Tokyo consumer_safety/ 5 qo1.html 6 animal-testing/ guidelines-for-the-testing-of-chemicals-section- 4-health-effects_ Ashikaga T, Sakaguchi H, Sono S, Kosaka N, Ishikawa M, Nukada Y, Miyazawa M, Ito Y, Nishiyama N, Itagaki H. A comparative evaluation of in vitro skin sensitisation tests: the human cell-line activation test h-clat versus the local lymph node assay LLNA. Altern Lab Anim. 38 4,