Is there a Real Case for Cumulative Control of Structurally Related Genotoxic Impurities?

Abstract

Recent guidance from U.S. and E.U. regulators is that “structurally similar” impurities should be evaluated as a class and not on an individual basis. However, the perceived additive risks do not appear to have been particularly well articulated by regulators. Recent modelling studies have indicated that there is a slight increased cancer risk from multiple (≤3) genotoxic impurities, but this is insignificant compared to the very conservative assumptions incorporated into the TTC. There are serious difficulties associated with defining both “common mechanisms of toxicity” and “concurrent exposure”, and this together with the limited data and associated methodologies required to conduct cumulative risk assessment suggests that these procedures are not well established. Methyl and ethyl chloride could be considered structurally similar; however, the spectrum of tumours induced by each compound is quite distinct. McGovern and Jacobsen-Kram recognized that the TTCs that are being proposed by regulators could ...