Defining Protein Reactivity Through Electrophilic Chemistry to Allow for Chemical Grouping and Read-Across

Steve Enoch and Mark Cronin, Liverpool John Moores University, UK

Grouping of similar chemicals to form categories allows for read-across and, when possible, robust and transparent toxicity prediction. Since many toxicity endpoints such as skin and respiratory sensitisation, mutagenicity and elevated acute toxicity depend on covalent interaction with proteins, there is much interest in the use of electrophilic reactivity to group chemicals. This study reports the analysis of compilations of structural alerts for electrophilic reactivity, and their subsequent re-evaluation, in order to place the information contained within the literature alerts into a mechanistic chemistry framework. This mechanistic chemistry can be used as the basis for chemical category formation; it has been implemented in the OECD QSAR Toolbox. The structural alerts identified within each of the five mechanistic domains have been organised into mechanistic alerts based on the presence of common reactivity sites. This has resulted in the development of 17 mechanistic alerts covering 92 structural alerts. These data are supported by mechanistic chemistry and references to the scientific literature. The funding of the European Chemicals Agency (EChA) Service Contract No. ECHA/2008/20/ECA.203. is gratefully acknowledged.

(presenting author: Mark Cronin)