Modeling mode of action of industrial chemicals: Application using chemicals on Canada's Domestic Substances List (DSL)

Traditionally quantitative structure activity relationships (QSARs) are derived on the assumption that similar chemicals should behave in a toxicologically similar manner. The development of mechanistic models for acute toxicity requires the chemical classification to be based on similar mode of toxic action. Currently, the classification approaches used to predict the mode of toxic action are predominantly based on chemical fragments and, to a lesser extent, on their electronic properties: The discrete nature of the fragment-based approach, however, yields a classification that does not consider the electronic features of the entire chemical that has "continuous character". The present study is based on the assumption that chemicals with the same mode of toxic action should possess commonality in their steric and electronic structure. The Common REactivity PAtterns (COREPA) approach has been applied to define the global physical properties and quantum-chemical descriptors best clustering chemicals according to their behavioural mode of action (MOA). The derived COREPA models for each mode were translated into decision trees and applied to screen the organic chemicals on Canada's Domestic Substances List (DSL) for their mode of toxic action.