Application of chemical reaction mechanistic domains to an ecotoxicity QSAR model, the KAshinhou Tool for Ecotoxicity (KATE)

Abstract

The validity of chemical reaction mechanistic domains defined by skin sensitisation in the Quantitative Structure–Activity Relationship (QSAR) ecotoxicity system, KAshinhou Tools for Ecotoxicity (KATE), March 2009 version, has been assessed and an external validation of the current KATE system carried out. In the case of the fish end-point, the group of chemicals with substructures reactive to skin sensitisation always exhibited higher root mean square errors (RMSEs) than chemicals without reactive substructures under identical C- or log P-judgements in KATE. However, in the case of the Daphnia end-point this was not so, and the group of chemicals with reactive substructures did not always have higher RMSEs: the Schiff base mechanism did not function as a high error detector. In addition to the RMSE findings, the presence of outliers suggested that the KATE classification rules needs to be reconsidered, particularly for the amine group. Examination of the dependency of the organism on the toxic action of chemicals in fish and Daphnia revealed that some of the reactive substructures could be applied to the improvement of the KATE system. It was concluded that the reaction mechanistic domains of toxic action for skin sensitisation could provide useful complementary information in predicting acute aquatic ecotoxicity, especially at the fish end-point.

Keywords:

• KATE
• chemical reaction mechanistic domain
• ecotoxicity
• applicability domain

Acknowledgements

KATE was researched and developed by the Research Centre for Environmental Risk at the National Institute for Environmental Studies (NIES) between 2004 and 2009 under contract to the Japan MoE.

We are grateful to the US EPA for permission to use KOWWIN in “KATE on PAS”, the standalone version of the KATE system. We also wish to thank Drs S.J. Enoch and M.T.D. Cronin for providing the raw data for the SMARTS strings 25.