Drawing a Line: Where Might the Cohort of Concern End?

The definitions of the chemical classes in the Cohort of Concern (CoC) by Kroes and co-workers are based on broad structural alerts, in particular for N-nitroso compounds─for which the alert consists essentially of the N–N═O substructure without further refinement. Recent pharmaceutical recalls have focused on the presence of dialkyl N-nitrosamine impurities, some of which are exceptionally potent carcinogens─2 orders of magnitude more potent than the pharmaceutical Threshold of Toxicological Concern (TTC), 1.5 μg/day. However, the class of "N-nitroso compounds" is potentially significantly broader. This Perspective looks at the N-nitroso compounds that are at the edges of the cohort, where changes in mechanism, metabolic activation potential, stability, or indeed toxicity data lead to questions about whether these compounds should be classed as CoC. The critical mechanism of action, metabolic α-hydroxylation leading to a diazonium ion, is presented, along with the pathways by which N-nitroso compounds that are not dialkyl N-nitrosamines can lead to comparable DNA adducts.