Carbamates and ICH M7 classification: Making use of expert knowledge

Carbamates are widely used in the chemical industry so understanding their toxicity is important to safety assessment. Carbamates have been associated with certain toxicities resulting in publication of structural alerts, including alerts for mutagenicity. Structural alerts for bacterial mutagenicity can be used in combination with statistical systems to enable ICH M7 classification, which allows assessment of the genotoxic risk posed by pharmaceutical impurities. This study tested a hypothetical bacterial mutagenicity alert for carbamates and examined the impact it would have on ICH M7 classifications using (Q)SAR predictions from the expert rule-based system Derek Nexus and the statistical-based system Sarah Nexus. Public datasets have a low prevalence of mutagenic carbamates, which highlighted that systems containing an alert for carbamates perform poorly for achieving correct ICH M7 classifications. Carbamates are commonly used as protecting groups and proprietary datasets containing such compounds were also found to have a low prevalence of mutagenic compounds. Expert review of the mutagenic compounds established that mutagenicity was often only observed under certain (non-standard) conditions and more generally that the Ames test may be a poor predictor for the risk of carcinogenicity posed by chemicals in this class. Overall a structural alert for the in vitro bacterial mutagenesis of carbamates does not benefit workflows for assigning ICH M7 classification to impurities.