Dosimetry considerations for in vivo and in vitro test data and a novel surrogate iTTC approach for read-across based on metabolites

Abstract In the context of REACH and the EU ban on animal testing of cosmetic ingredients, development, adoption and acceptance of non-animal methods is urgent. Read-across is the predominate non-animal method being used for higher tier endpoints (repeat dose and developmental and reproductive toxicity). The limitations of read-across include the lack of suitable analogs and analog data for all chemicals of interest, as well as concerns with missing a potential adverse response that results from small differences in chemical structure. In this manuscript we explore two possible enhancements to read-across approaches in the context of a single case study: read-across assessments based on metabolite data and incorporation of in vitro data to support the read-across hypothesis. We use this case study to explore possible paths forward in implementing these enhancements, but more importantly to raise issues that need to be resolved prior to extensive use and hopefully acceptance of these expanded approaches. For the case of read-across based on metabolites, we explore the potential application of an internal dose TTC (iTTC) approach to address uncertainty associated with potential toxicity from exposure to residual parent chemical. This is a relevant scenario for the many cosmetic ingredients containing ester structures. For the use of in vitro data we explore considerations that must be taken before the application of ToxCast™ data to the read-across to ensure positive responses are reliable and relevant. As more cosmetic ingredients are tested in in vitro systems, guidance on the appropriate interpretation of these data will be essential. The concept of dosimetry is a unifying need that must be addressed in both these approaches. In the present paper, we explore how to use and apply internal dose metrics to address some issues associated with expanded approaches in read-across.