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

Abstract

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.

A mode-of-action ontology model for safety evaluation of chemicals: Outcome of a series of workshops on repeated dose toxicity

“…Even more than for the other 3 pillars of the MoA ontology model, the focus of the toxicological aspects is dictated by the nature and intended use of the chemical under investigation. For some cosmetic ingredients, liver and kidney have been previously identified as potential toxicity targets, albeit upon oral administration of high doses to rodents (Vinken et al, 2012). This was based on combined listing of toxicity endpoints as described in available animal testing reports, which is a major source of input for this aspect of the MoA ontology model.…”

“…In this respect, a screening of RDT data present in safety evaluation reports issued by the Scientific Committee on Consumer Safety between 2000 and 2009 revealed the liver as a potential target of toxicity for cosmetic ingredients based on animal studies using oral gavage. The inflicted hepatotoxicity hereby is mainly manifested as steatosis and cholestasis (Vinken et al, 2012). A plethora of data are already available for populating the different pillars of the RDT MoA ontology model for these 2 specific types of liver toxicity without necessitating the need for large-scale additional experimentation.…”

SEURAT-1 liver gold reference compounds: a mechanism-based review

“…Reference standards for chemical reactivity Compounds with alkylating and oxidizing activity feature prominently in the MoAs of the hepatotoxic drugs (Evans et al 2004;Gomez-Lechon et al 2010) and are significant in the chemical space of cosmetic ingredients (Vinken et al 2012). In this section, we consider oxidizing agents and thiol-selective alkylating agents that share GSH and essential protein thiols as common targets.…”

“…In this section, we consider oxidizing agents and thiol-selective alkylating agents that share GSH and essential protein thiols as common targets. For example, quinones are prototypical thiol reagents with both redox and alkylating activities that are a common source of toxicity from drugs and drug metabolites (Evans et al 2004) and are used as colorants in hair dyes (Vinken et al 2012). The first four reference standards described in this section are hydrophilic and characterized by 2-electron chemistry.…”

The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing

“…[3] A critical element of this cluster is its focus on repeated dose toxicity and the adoption of a mode-of-action (MOA) framework based on an understanding of key biological events driven by levels of exposure over time. [4][5][6][7][8] The SEURAT-1 cluster is comprised of five complementary research projects (COSMOS, [9,10] DETECTIVE, [11,12] HeMiBio, [13][14] NOTOX, [15][16][17] Abstract: The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses.…”