Mutagenicity assessment strategy for pharmaceutical intermediates to aid limit setting for occupational exposure

The use of in silico methods to predict mutagenicity is increasingly acknowledged and implemented in the recently released ICH M7 guideline for the limitation of DNA reactive impurities. In this study we investigate the possibility to apply (quantitative) structure-activity-relationships ((Q)SARs) during hazard identification to reduce the number of Ames tests needed for a hazard assessment of IM while maintaining high standards of protection of the employees. Ames test outcomes for 188 substances used in the pharmaceutical production were compared with their in silico predictions using two different (Q)SAR methodologies (knowledge based and statistical) complemented by expert knowledge.