The use of so-called “in chemico” methodology - abiotic assays that measure chemical reactivity - is gaining ground as relevant and reliable means of toxicity prediction. In this report we explain the basis of the in chemico approach to toxicity prediction and we review the studies that have developed the concept and its practical application since the 1930s, with special attention being paid to studies aimed at the development of Quantitative Structure-Activity Relationship (QSAR) models and read-across approaches. The studies covered in this review are limited to non-enzymatic experiments and to nucleophiles up to 50 amino acids. The main applications identified are related to the assessment of skin sensitisation, aquatic toxicity and hepatotoxicity. Various experimental measures of nucleophile depletion or adduct formation have been proposed as chemical reactivity descriptors, but no single protocol has emerged as the most generally useful. It is concluded that in chemico approaches provide a promising means of toxicity prediction within their applicability domains and should be further developed and investigated as alternative methods to animal testing, especially when used in the context of integrated testing strategies based on the use of multiple non-animal methods.JRC.DG.I.6-Systems toxicolog
