The definition of the applicability domain relevant to skin sensitization for the aromatic nucleophilic substitution mechanism

Abstract

This study outlines how a glutathione reactivity assay (so-called in chemico data) can be used to define the applicability domain for the nucleophilic aromatic substitution (S_NAr) reaction for benzenes. This reaction is one of the six mechanistic domains that have been shown to be important in toxicological endpoints in which the ability to bind covalently to a protein is a key molecular initiating event. This study has analysed the experimental data, allowing a clear and interpretable structure–activity relationship to be developed for the S_NAr domain. The applicability domain has resulted in a series of structural alerts. The definition of the applicability domain for the S_NAr reaction and the resulting structural alerts are likely to be beneficial in the development of computational tools for category formation and read-across. The study concludes with how this information can be used in the development of adverse outcome pathways.

Keywords:

• in chemico
• S_NAr
• structural alerts
• electrophilic reaction chemistry
• adverse outcome pathways

Acknowledgements

The funding of the European Chemicals Agency Service Contract No. ECHA/2008/20/ECA.203 is gratefully acknowledged. The project was sponsored by Defra through the Sustainable Arable Link Programme.