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.
To evaluate the mutagenicity/genotoxicity of cosmetic ingredients at the regulatory level, usually a battery of three in vitro tests is applied. This battery, designed to be very sensitive, produces a high number of positive results, imposing the need for in vivo follow-up testing to clear the substance under study. In Europe, the use of experimental animals has become impossible for cosmetic ingredients due to the implementation of animal testing and marketing bans. Consequently, the possibility to 'de-risk' substances with positive in vitro results disappear and potentially safe cosmetic substances will be lost for the EU market unless currently used in vitro assays can be adapted or new non-animal mutagenicity/genotoxicity studies become available. Described strategies to improve the specificity of existing in vitro assays include optimisation of the used cell type and cytotoxicity assay and lowering of the applied top concentration. A reduction of the number of tests in the battery from three to two also has been suggested. In this study, the performance of the 'standard' in vitro mutagenicity/genotoxicity testing battery is analysed for a number of cosmetic ingredients. We composed a database with toxicological information on 249 cosmetic ingredients, mainly present on the Annexes of the European cosmetic legislation. Results revealed that the in vitro mutagenicity/genotoxicity tests showed a low specificity for the cosmetic ingredients concerned, comparable to the specificity published for chemicals. Non-confirmed or 'misleading' positive results amounted up to 93% for the in vitro test batteries. The cell type and top concentrations did not have a major impact on the specificity. With respect to cytotoxicity determinations, different end points were used, potentially leading to different testing concentrations, suggesting the need for a consensus in this matter. Overall, the results of this retrospective analysis point to an urgent need of better regulatory strategies to assess the potential mutagenicity/genotoxicity of cosmetic ingredients.
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Currently, there is clear political incentive in the EU to minimize the number of animals involved in the chemical risk assessment process, particularly holding true for the cosmetics sector. Stringent requirements of full replacement of animals in safety testing are laid down in the EU Cosmetics Directive 76/768/EEC by the implementation of the 7th Amendment (2003/15/EC), setting a rigid time frame for the availability of valid 3R-alternative methods for the safety testing of cosmetic products and their ingredients (EU 2003). An important step forward to achieve this goal has recently been made through a joint initiative by DG Research and Colipa (The European Cosmetics Association). A cluster of calls was launched under the FP7 health programme specifically addressing the replacement of repeated dose systemic toxicity testing in human safety assessment. As such, 6 large-scale collaborative research projects started from January 2011 onwards, covering key themes related to human stem cell technology (SCREEN-TOX), organ-simulating devices (HeMiBio), human-relevant biomarker detection (DETECTIVE), computational modelling (COSMOS), systems biology (NOTOX) and integrated data analysis (TOXBANK). An umbrella coordination and support action project (COACH) is responsible for monitoring progress and potential gaps occurring throughout the 5-year running period. A major task, however, will be to streamline and combine the outcomes of the different projects in order to establish a realistic in vitro strategy to assess repeated dose toxicity.As in all projects the liver is involved as target organ, one might expect that hepatotoxicity could be used as a test case. This would be of particular interest since it is the major type of toxicity observed during in vivo repeated dose toxicity testing for cosmetic ingredients (Pauwels et al. 2009) and pharmaceutical compounds (Russmann et al. 2009). Figure 1 demonstrates how such an in vitro testing strategy could look, taking into consideration, the current approach of quantitative risk assessment for cosmetic ingredients using data derived from animal studies. Thus, a margin of safety (MoS) of at least 100 is applied for intraspecies and interspecies variation using the following equation:MoS ¼ NOAEL ðno observable adverse effect levelÞ systematic exposure dosage ! 100In the proposed strategy, a computed NOAEL value, preferably derived from human data (hNOAEL c ), could be used for the compound of interest. This estimated in vivo dosage could be obtained via processing of the compound concentration (hNOAEC) that does not cause any adverse effect using an in vitro model. For that purpose, physiologically based pharmacokinetic (PBPK) computational modelling can be applied taking into account an appropriate uncertainty factor for the in vitro/in vivo extrapolation. The hNOAEC value of the compound of interest could, for example,
This volume of Current Problems in Dermatology presents the reader with a portrait of the scientifi c background of the complex process of safety assessment of cosmetics as well as information on European cosmetic legislation. A practical approach to the search for toxicity data on cosmetic ingredients and a compilation of the legally required technical dossier of a fi nished cosmetic product as well as an in-depth analysis of the safety assessment of cosmetic ingredients performed at the EU level by the Scientifi c Committee on Consumer Products (SCCP) are available. The current status of 3R alternatives to animal testing and the extent to which they are implemented by the cosmetic industry and considered by the SCCP in the risk assessment process is discussed. As such, guidance is provided in relation to the manifold challenges cosmetic safety assessors are faced with in the current EU regulatory setting. In this valuable handbook, qualifi ed cosmetic safety assessors, suppliers of raw materials, dermatologists and pharmacists, toxicologists as well as EU offi cials and administrators dealing with cosmetics will fi nd relevant information on the European cosmetic legislation, the compilation of cosmetic technical dossiers, toxicological database searches, and the availability and use of alternative methods in the fi eld of cosmetics.
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