EU legislations affecting safety data availability of cosmetic ingredients

With the introduction of the 6th and 7th Amendments (OJ L151, 32-37, 23 June 1993; OJ L066, 26-35, 11 March 2003) to the Cosmetic Products Directive (OJ L262, 169-200, 27 September 1976), imposing a testing and marketing ban on cosmetic products tested on animals, the retrieval of toxicological data on individual ingredients became of greater need. Since the majority of cosmetic ingredients are used for many other purposes than their cosmetic function, they fall under the scope of more than one EU Directive. An overview is given of EU legislation that could potentially affect the availability and interpretation of cosmetic safety data. It will become clear that, although cosmetics are regulated by a specific so-called "vertical" legislation, "horizontal" influences from other products' legislations play a role since they determine the type and amount of data that theoretically could be found on the specific substances they regulate. This knowledge is necessary while performing extended searches in databases and becomes indispensable when initiating negotiations with manufacturers or suppliers for obtaining the safety data required.     

Screening of repeated dose toxicity data present in SCC(NF)P/SCCS safety evaluations of cosmetic ingredients

Alternative methods, replacing animal testing, are urgently needed in view of the European regulatory changes in the field of cosmetic products and their ingredients. In this context, a joint research initiative called SEURAT was recently raised by the European Commission and COLIPA, representing the European cosmetics industry, with the overall goal of developing an animal-free repeated dose toxicity testing strategy for human safety assessment purposes. Although cosmetic ingredients are usually harmless for the consumer, one of the initial tasks of this research consortium included the identification of organs that could potentially be affected by cosmetic ingredients upon systemic exposure. The strategy that was followed hereof is described in the present paper and relies on the systematic evaluation, by using a self-generated electronic databank, of published reports issued by the scientific committee of DG SANCO responsible for the safety of cosmetic ingredients. By screening of the repeated dose toxicity studies present in these reports, it was found that the liver is potentially the most frequently targeted organ by cosmetic ingredients when orally administered to experimental animals, followed by the kidney and the spleen. Combined listing of altered morphological, histopathological, and biochemical parameters subsequently indicated the possible occurrence of hepatotoxicity, including steatosis and cholestasis, triggered by a limited number of cosmetic compounds. These findings are not only of relevance for the in vitro modeling efforts and choice of compounds to be tested in the SEURAT project cluster, but also demonstrate the importance of using previously generated toxicological data through an electronic databank for addressing specific questions regarding the safety evaluation of cosmetic ingredients.     

Safety evaluation of cosmetics in the EU. Reality and challenges for the toxicologist

Council Directive 76/768/EEC, its seven amendments and 30 adaptations to technical progress form the basis of the cosmetic EU legislation today. There are actually four key principles for safety in the cosmetic legislation. (i) The full responsibility for the safety of cosmetics for human health is placed on the manufacturer, first importer in the EU or marketer. (ii) The safety evaluation of finished products is based on safety of individual ingredients, more specifically on their chemical structure, toxicological profile and their level of exposure. (iii) A compilation of information on each cosmetic product (dossier) must be kept readily available for inspection by the competent authorities of the Member State concerned. This information source, usually called a technical information file (TIF) or product information file/requirements (PIF(R)), contains, as the most important part, the safety assessment of the product undersigned by a competent safety assessor. (iv) The use of validated replacement alternative methods instead of animal testing forms the 4th key principle for safety of cosmetic products on the EU market. The 7th amendment imposes strict deadlines for the abolition of animal in vivo studies on cosmetic ingredients. These legal requirements induce a number of important challenges for the cosmetic industry and more specifically for the toxicologist involved as safety assessor.     

Special aspects of cosmetic spray safety evaluations: principles on inhalation risk assessment

The consumer exposure to the vast majority of cosmetic products is limited to dermal contact. Even spray applications tend to be topically exposed to skin or hair. Besides this skin contact, spray products require additional considerations in regard to potential inhalation for building a robust and reliable safety assessment.Over the years, cosmetic industry developed prediction models for the best estimate of inhalation exposure combining data from computer simulation programs available in the market, individual real measured data and last but not least the experience from the market. Such attempt is driven by the toxicological profile of individual used ingredients. The focus of this review is on the determination of inhalation exposure, and the derivation of safe exposure levels for cosmetic spray products. Many of the methods employed to ensure product safety of cosmetic sprays in accordance with the general requirements of the EC Cosmetics Directive are based on industry experience which are not necessarily consistent across companies.This paper presents an approach to compile common principles for risk assessment and thus contribute to standardisation of safety assessment methodologies utilized for spray product evaluation without interfering with the flexibility of the individual safety assessor. It is based on the experience within the author's companies and may be useful as a support document as well for SME (Small and Medium Enterprises) companies safety assessors. In this respect it can be seen as one fundamental step in a tiered approach of cosmetic spray safety evaluation.     

A tiered approach to the use of alternatives to animal testing for the safety assessment of cosmetics: Eye irritation

The need for alternative approaches to replace the in vivo rabbit Draize eye test for evaluation of eye irritation of cosmetic ingredients has been recognised by the cosmetics industry for many years. Extensive research has lead to the development of several assays, some of which have undergone formal validation. Even though, to date, no single in vitro assay has been validated as a full replacement for the rabbit Draize eye test, organotypic assays are accepted for specific and limited regulatory purposes. Although not formally validated, several other in vitro models have been used for over a decade by the cosmetics industry as valuable tools in a weight of evidence approach for the safety assessment of ingredients and finished products. In light of the deadlines established in the EU Cosmetics Directive for cessation of animal testing for cosmetic ingredients, a COLIPA scientific meeting was held in Brussels on 30th January, 2008 to review the use of alternative approaches and to set up a decision-tree approach for their integration into tiered testing strategies for hazard and safety assessment of cosmetic ingredients and their use in products. Furthermore, recommendations are given on how remaining data gaps and research needs can be addressed.     

European consumer exposure to cosmetic products, a framework for conducting population exposure assessments Part 2

Access to reliable exposure data is essential for the evaluation of the toxicological safety of ingredients in cosmetic products. This study complements the data set obtained previously (Part 1) and published in 2007 by the European cosmetic industry acting within COLIPA. It provides, in distribution form, exposure data on daily quantities of five cosmetic product types: hair styling, hand cream, liquid foundation, mouthwash and shower gel. In total 80,000 households and 14,413 individual consumers in five European countries provided information using their own products. The raw data were analysed using Monte Carlo simulation and a European Statistical Population Model of exposure was constructed. A significant finding was an inverse correlation between the frequency of product use and the quantity used per application recorded for mouthwash and shower gel. The combined results of Part 1 (7 product types) and Part 2 (5 products) reported here, bring up to date and largely confirm the current exposure parameters concerning some 95% of the estimated daily exposure to cosmetics use in the EU. The design of this study, with its relation to demographic and individual diversity, could serve as a model for studies of populations’ exposure to other consumer products.     

A tiered approach to the use of alternatives to animal testing for the safety assessment of cosmetics: Skin irritation

Evaluation of the skin irritancy and corrosivity potential of an ingredient is a necessity in the safety assessment of cosmetic ingredients. To date, there are two formally validated alternatives to the rabbit Draize test for skin corrosivity in place, namely the rat skin transcutaneous electrical resistance (TER) assay and the Human Skin Model Test using EpiSkin™, EpiDerm™ and SkinEthic™ reconstructed human epidermal equivalents. For skin irritation, EpiSkin™, EpiDerm™ and SkinEthic™ are validated as stand-alone test replacements for the rabbit Draize test. Data from these tests are rarely considered in isolation and are evaluated in combination with other factors to establish the overall irritating or corrosive potential of an ingredient. In light of the deadlines established in the Cosmetics Directive for cessation of animal testing for cosmetic ingredients, a COLIPA scientific meeting was held in Brussels on 30th January, 2008 to review the use of alternative approaches and to set up a decision tree approach for their integration into tiered testing strategies for hazard and safety assessment of cosmetic ingredients and their use in products. In conclusion, the safety assessments for skin irritation/corrosion of new chemicals for use in cosmetics can be confidently accomplished using exclusively alternative methods.     

Narrow-and-sharp or broad-and-blunt--regulations of hazardous chemicals in consumer products in the European Union

Chemicals are incorporated into a vast number of consumer products, and it has been recognized that considerable exposures of humans and the environment to chemicals are due to diffuse emissions from everyday products. Different approaches to the management of risks concerning chemicals in products are discussed on the international arena, but no general strategy has yet been adopted. The aim of this study is to investigate how health and environmental risks associated with chemicals in consumer products are currently managed in European Union legislations, mainly by the Toys Directive, the RoHS Directive, and REACH. Significant differences were found between the risk reduction strategies in these legislations, including substance prioritization, type of restrictions and requirements, and information dissemination to consumers. REACH regulates chemicals in products to a limited extent, and via quite complicated processes. Product-specific rules are therefore useful supplements to REACH for regulating chemicals in products. The combined effects of the RoHS and WEEE directives seem to be effective in promoting substitution of substances identified as problematic in electrical and electronic equipment, and it is recommended that the possibility to develop similar systems should be considered also for other product categories.     

Alternative (non-animal) methods for cosmetics testing: current status and future prospects-2010

The 7th amendment to the EU Cosmetics Directive prohibits to put animal-tested cosmetics on the market in Europe after 2013. In that context, the European Commission invited stakeholder bodies (industry, non-governmental organisations, EU Member States, and the Commission's Scientific Committee on Consumer Safety) to identify scientific experts in five toxicological areas, i.e. toxicokinetics, repeated dose toxicity, carcinogenicity, skin sensitisation, and reproductive toxicity for which the Directive foresees that the 2013 deadline could be further extended in case alternative and validated methods would not be available in time. The selected experts were asked to analyse the status and prospects of alternative methods and to provide a scientifically sound estimate of the time necessary to achieve full replacement of animal testing. In summary, the experts confirmed that it will take at least another 7-9?years for the replacement of the current in vivo animal tests used for the safety assessment of cosmetic ingredients for skin sensitisation. However, the experts were also of the opinion that alternative methods may be able to give hazard information, i.e. to differentiate between sensitisers and non-sensitisers, ahead of 2017. This would, however, not provide the complete picture of what is a safe exposure because the relative potency of a sensitiser would not be known. For toxicokinetics, the timeframe was 5-7?years to develop the models still lacking to predict lung absorption and renal/biliary excretion, and even longer to integrate the methods to fully replace the animal toxicokinetic models. For the systemic toxicological endpoints of repeated dose toxicity, carcinogenicity and reproductive toxicity, the time horizon for full replacement could not be estimated.     

European consumer exposure to cosmetic products, a framework for conducting population exposure assessments.

Access to reliable exposure data is essential to evaluate the toxicological safety of ingredients in cosmetic products. This study was carried out by European cosmetic manufacturers acting within the trade association Colipa, with the aim to construct a probabilistic European population model of exposure. The study updates, in distribution form, the current exposure data on daily quantities of six cosmetic products. Data were collected using a combination of market information databases and a controlled product use study. In total 44,100 households and 18,057 individual consumers in five European countries provided data using their own products. All product use occasions were recorded, including those outside of home. The raw data were analysed using Monte Carlo simulation and a European Statistical Population Model of exposure was constructed. A significant finding was an inverse correlation between frequency of product use and quantity used per application for body lotion, facial moisturiser, toothpaste and shampoo. Thus it is not appropriate to calculate daily exposure to these products by multiplying the maximum frequency value by the maximum quantity per event value. The results largely confirm the exposure parameters currently used by the cosmetic industry. Design of this study could serve as a model for future assessments of population exposure to chemicals in products other than cosmetics.     

The use and interpretation of in vitro data in regulatory toxicology: cosmetics,toiletries and household products

There is currently a drive to eliminate animal testing for cosmetics, toiletries and household products; indeed, the European Union Cosmetics Directive aims to prohibit the use of experimental animals for the testing of finished cosmetic products after 2002. At present, national prohibitions are in place in the UK, Germany, Austria and the Netherlands, for the testing of finished cosmetic products and cosmetic ingredients. In the USA animal testing for certain types of finished products is mandatory. Against this background, the currently available regulatory in vitro tests comprise methods for eye irritation, skin corrosivity, genotoxicity, dermal penetration and photoirritation. The draft updates to the Organisation for Economic Co-operation and Development guidelines for eye and skin irritation advocate the use of in vitro or ex vivo methods prior to the commencement of animal studies. At present, testing for these endpoints cannot be completed in vitro, but potentially corrosive substances and products can be classified without the need for animal studies. Regulatory genotoxicity testing can be completed using only in vitro methods, provided that a clear negative outcome is obtained for each test. Data from dermal penetration studies may be used to refine risk assessments. Current developments in areas such as skin sensitisation and skin irritation promise that in the reasonably near future such information may be generated without the use of animals.     

Novel database for exposure to fragrance ingredients in cosmetics and personal care products

Exposure of fragrance ingredients in cosmetics and personal care products to the population can be determined by way of a detailed and robust survey. The frequency and combinations of products used at specific times during the day will allow the estimation of aggregate exposure for an individual consumer, and to the sample population. In the present study, habits and practices of personal care and cosmetic products have been obtained from market research data for 36,446 subjects across European countries and the United States in order to determine the exposure to fragrance ingredients. Each subject logged their product uses, time of day and body application sites in an online diary for seven consecutive days. The survey data did not contain information on the amount of product used per occasion or body measurements, such as weight and skin surface area. Nevertheless, this was found from the literature where the likely amount of product used per occasion or body measurement could be probabilistically chosen from distributions of data based on subject demographics. The daily aggregate applied consumer product exposure was estimated based on each subject’s frequency of product use, and Monte Carlo simulations of their likely product amount per use and body measurements. Statistical analyses of the habits and practices and consumer product exposure are presented, which show the robustness of the data and the ability to estimate aggregate consumer product exposure. Consequently, the data and modelling methods presented show potential as a means of performing ingredient safety assessments for personal care and cosmetics products.     

Guidelines for safety evaluation of cosmetics ingredients in the EC countries.

The Scientific Committee on Cosmetology (SCC) of the Commission of the European Communities was established in 1978 to assist the Commission in the application of the 76/768 Directive, which regulates the production and marketing of cosmetics products. The Committee has been asked to update the general guidelines, defined in 1982, for testing cosmetics ingredients with the aim of ensuring consumers' safety. In the present paper the full document approved by the SCC in October 1990 is reported. This new document is based on the experience of the Committee over the last 10 years, during which more than 400 cosmetics ingredients have been evaluated. The document also highlights the need to proceed to define standard methods to be used to assess dermal absorption and phototoxicity--areas in which international guidelines have not yet been approved. The document also includes some comments made by the author in order to explain better the position of the Committee in relation to certain items.     

European regulations on nutraceuticals, dietary supplements and functional foods: a framework based on safety

This article describes the legislation that is relevant in the marketing of functional foods in the European Union (EU), how this legislation was developed as well as some practical consequences for manufacturers, marketers and consumers. It also addresses some concrete examples of how the EU's safety requirements for food products have impacted a range of product categories. In the late nineties, research into functional ingredients was showing promising prospects for the use of such ingredients in foodstuffs. Due mainly to safety concerns, these new scientific developments were accompanied by an urgent call for legislation. The European Commission 2000 White Paper on Food Safety announced some 80 proposals for new and improved legislation in this field. Among others, it foresaw the establishment of a General Food Law Regulation, laying down the principles of food law and the creation of an independent Food Authority endowed with the task of giving scientific advice on issues based upon scientific risk assessment with clearly separated responsibilities for risk assessment, risk management and risk communication. Since then, more than 90% of the White Paper proposals have been implemented. However, there is not, as such, a regulatory framework for 'functional foods' or 'nutraceuticals' in EU Food Law. The rules to be applied are numerous and depend on the nature of the foodstuff. The rules of the general food law Regulation are applicable to all foods. In addition, legislation on dietetic foods, on food supplements or on novel foods may also be applicable to functional foods depending on the nature of the product and on their use. Finally, the two proposals on nutrition and health claims and on the addition of vitamins and minerals and other substances to foods, which are currently in the legislative process, will also be an important factor in the future marketing of 'nutraceuticals' in Europe. The cornerstone of EU legislation on food products, including functional foods and nutraceuticals is 'safety'. Decisions on the safety-basis of legislation are based on risk analysis, in which scientific risk assessment is performed by the European Food Safety Authority and risk management is performed by the European Commission, the Member States, and in case of legislation, together with the European Parliament. In the risk management phase, both the precautionary principle and other legitimate factors may be considered in choosing the best way of dealing with an issue. Due to the numerous pieces of legislation applying and to the different procedures to be followed, the process of having 'functional foods' ready for the market is certainly a costly and time-consuming task. However, it may also be clearly worth it in terms of market success and improved consumer health.     

Regulation of medicinal plants for public health - European community monographs on herbal substances

The European legislation on medicinal products also addresses the medicinal use of products originating from plants. The objective of the legislation is to ensure the future existence of such products and to consider particular characteristics when assessing quality, efficacy, and safety. Two categories are defined: i) herbal medicinal products can be granted a marketing authorisation; and ii) traditional herbal medicinal products can be granted a registration based on their longstanding use if they are complying with a set of provisions ensuring their safe use. The Committee on Herbal Medicinal Products (HMPC) was established at the European Medicines Agency (EMA) to provide monographs and list entries on herbal substances and preparations thereof. Meanwhile, approx. 100 monographs have been published, which define a current scientific and regulatory standard for efficacy and safety of herbal substances and herbal preparations used in medicinal products. This harmonised European standard will facilitate the availability and adequate use of traditional herbal medicinal products and herbal medicinal products within the European Union. Consequent labelling shall also enable patients and health care professionals to differentiate medicinal products from other product categories like cosmetics, food supplements, and medical devices.     

Final report on the safety assessment of human placental protein,hydrolyzed human placental protein,human placental enzymes,human placental lipids,human umbilical extract,placental protein,hydrolyzed placental protein,placental enzymes,placental lipids,and umbilical extract

Various proteins, lipids, or other extracts from human or other animal placentas are described as cosmetic ingredients. Human Placental Protein comprises protein derived from human placentas. Placental Protein is derived from animal placentas. Similarly, Human Placental Lipids and Placental Lipids are the lipid fractions from the same source materials. Hydrolyzed Human Placental Protein and Hydrolyzed Placental Protein are produced from the respective protein extracts by acid, enzyme, or other hydrolysis methods. Human Placental Enzymes and Placental Enzymes are enzymes obtained by aqueous extraction of human or other animal placental material. Human Umbilical Extract and Umbilical Extract are unspecified extracts of material from human or other animal umbilical cords. Different materials called Human Placental Extracts and Placental Extracts, assumed to contain estrogenic hormones or other biologically active substances, are not recognized as cosmetic ingredients, even though the use of these ingredients in cosmetics have been reported to the Food and Drug Administration (FDA). Human-derived ingredients are prohibited from use under the provisions of the European Union cosmetics directive based on concerns about transmission of human spongiform encephalopathies and viral diseases, for example, human immunodeficiency virus (HIV). Umbilical Extract has precedent for unrestricted use in Japan, except for certain products. Most of these ingredients are described as hair-conditioning agents and miscellaneous skin-conditioning agents, although the umbilical extracts function as biological additives in cosmetics. Of the human-derived ingredients, only Human Placental Protein is currently reported to be used. Animal-derived placental proteins, hydrolyzed proteins, lipids, and enzymes were all currently reported to be used. No current uses of the umbilical extracts were reported. Most of the available data relates to placental derivatives that appear to have estrogenic or other biological activity. The one clinical study that appears to utilize proteinaceous material only reported no irritant reaction. Clearly, the available data are insufficient to support safety of these ingredients in cosmetics. The additional data needed include (1) skin sensitization at concentration of use; (2) gross pathology and histopathology in skin and other major organ systems associated with repeated exposures, and dermal reproductive and developmental toxicity data; (3) photosensitization; (4) one genotoxicity assay in a mammalian system; if positive, then a 2-year dermal carcinogenicity study using National Toxicology Program (NTP) methods may be needed; (5) ocular toxicity, if available. Any studies should be done on all ingredients unless chemical analysis data show similarity among ingredients. Because there is confusion and concern about the use of substances with estrogenic or other biological activity in cosmetic formulations, it was concluded that none of these ingredients used in cosmetics should deliver any metabolic/endocrine activity. In addition, any current use of these ingredients should be free of detectable pathogenic viruses or infectious agents.     

Refinement of the Dermal Sensitisation Threshold (DST) approach using a larger dataset and incorporating mechanistic chemistry domains

An essential step in ensuring the toxicological safety of ingredients in consumer products is the evaluation of their skin sensitising potential. Where skin exposure is low, it is possible to conduct a risk assessment using the Dermal Sensitisation Threshold (DST), a process similar to that of the Threshold of Toxicological Concern. This paper describes work building on that previously published, whose aim was to produce a more robust tool for assessing the safety of consumer products. This consisted of expanding the Local Lymph Node Assay dataset used to define the original DST and classifying chemicals in the dataset according to their mechanistic chemistry domains. A DST of 900μg/cm(2) was derived for chemicals classified as non-reactive and non-proreactive. This value was benchmarked against human potency data for 58 fragrance allergens and was lower than the measured No Expected Sensitisation Levels for those classified as non-reactive. Use of this DST will help to eliminate the need for animal testing of non-reactive and non-proreactive chemicals where skin exposure is sufficiently low. For chemicals where a Quantitative Risk Assessment based on the DST does not give an adequate margin of safety, and those classified as reactive, a case-by-case risk assessment will be required.     

Toxicological profile of diethyl phthalate: a vehicle for fragrance and cosmetic ingredients.

Diethyl phthalate (DEP; CAS No. 84-66-2) has many industrial uses, as a solvent and vehicle for fragrance and cosmetic ingredients and subsequent skin contact. This review focuses on its safety in use as a solvent and vehicle for fragrance and cosmetic ingredients. Available data are reviewed for acute toxicity, eye irritation, dermal irritation, dermal sensitization, phototoxicity, photoallergenicity, percutaneous absorption, kinetics, metabolism, subchronic toxicity, teratogenicity, reproductive toxicity, estrogenic potential, genetic toxicity, chronic toxicity, carcinogenicity, in vitro toxicity, ecotoxicity, environmental fate and potential human exposure. No toxicological endpoints of concern have been identified. Comparison of estimated exposure (0.73 mg/kg/day) from dermal applications of fragrances and cosmetic products with other accepted industrial (5 mg/m(3) in air) and consumer exposures (350 mg/l in water; 0.75 mg/kg/day oral exposure) indicates no significant toxic liability for the use of DEP in fragrances and cosmetic products.     

皮肤毒理学检验中的替代方法和整合测试评估方法

近些年,随着实验动物“3R”原则的兴起,动物替代实验的研究越来越重要。为了使国产化妆品的开发和国际标准接轨,中国加快了替代实验方法在化妆品“安全性”检验中的应用。针对化妆品对皮肤可能造成的刺激性、致敏性和光毒性等不良反应,本文分别对化妆品皮肤毒理学检验中的替代实验方法及毒理学终点相应的整合测试评估方法（IATA）进行概述。同时,本文也为三维重组皮肤模型和模式生物斑马鱼在化妆品皮肤毒性检验中的应用提供重要依据。