Mutagenic impurities in pharmaceuticals: A critique of the derivation of the cancer TTC (Threshold of Toxicological Concern) and recommendations for structural-class-based limits

The cancer TTC (Threshold of Toxicological Concern) concept is currently employed as an aid to risk assessment of potentially mutagenic impurities (PMIs) in food, cosmetics and other sectors. Within the pharmaceutical industry the use of one default cancer TTC limit of 1.5 μg/day for PMIs is being increasingly questioned. Its derivation, originally in the context of foodstuffs, can be broken down into five key elements: dataset composition; determination of carcinogenicity/mutagenicity status and carcinogenic potency (based on TD50s) of compounds in the dataset; linear extrapolation of carcinogenic potencies; evaluation of the more potent compounds in each structural category, and presence of representative structural alerts amongst the more potent compounds. A detailed evaluation reveals that the derivation process is distorted by the use of the lowest statistically significant TD50s (which can produce a false-carcinogen phenomenon) and by employing linear extrapolation for non-mutagenic carcinogens. By correcting for these two factors, it is concluded that only around 50% of conventional structural-alert categories were adequately addressed and that limits higher than the default value appear to be justified in many cases. Using similar criteria for PMIs in pharmaceuticals, four distinct potency categories of conventional structural alerts can be distinguished, ranging from alerts with questionable validity to those with high potency, which are considered to provide a range of flexible and pragmatic limits for such impurities.