FC02.1 A diene identified as a prohapten metabolised to epoxides in the skin

To predict the sensitising capacity of a chemical, the only existing reliable method is testing in animals and alternative methods are requested. One approach is to use databases that predict the toxicity of novel compounds by comparing the chemical structure with data stored in the database. A chemical (hapten) must contain a chemically reactive site to be able to bind to skin macromolecules and a good predictor for sensitising capacity is the electrophilic character of the molecule. Objectives:  The aim of this study was to investigate the sensitising capacity of 5-isopropenyl-2-methyl-1-methylene-2-cyclohexene, a conjugated diene with no electrophilic positions or any other structural alert for skin sensitisation. Methods:  5-Isopropenyl-2-methyl-1-methylene-2-cyclohexene and two possible epoxide metabolites of the model compound were synthesised. Sensitisation and elicitation experiments were performed using the predictive guinea pig method FCAT. The diene system was analysed in the computer based knowledge system DEREK (Deductive Estimation of Risk from Existing Knowledge). Results:  The model diene was found to be a potent contact allergen able to sensitise the control animals after only one dermal exposure. Both epoxides gave elicitation in the animals sensitised to the diene indicating that they are formed from the diene in the skin during induction. The diene system was considered as a non-sensitiser in DEREK. Conclusions:  This study demonstrates that conjugated dienes can be metabolised to strong contact allergens in the skin and that it is important to consider possible metabolic pathways when constructing predictive databases, otherwise potent prohaptens might be considered as harmless chemicals.