Defining boundaries: which N-nitroso compounds might not belong in the cohort of concern?

Originally coined by Kroes et al, the term ‘cohort of concern’ is typically used to refer to chemical classes considered to be high-potency carcinogens. ICH M7 dictates that genotoxic impurities belonging to the cohort of concern (aflatoxin-like, alkyl azoxy and N-nitroso) require a compound-specific assessment, as there is appreciable carcinogenic risk below the general 1.5 ug/day TTC limit. The structural definitions of these classes remain vaguely defined by name only; N-nitroso compounds are broadly represented by N-N=O. This seems appropriate considering recent pharmaceutical recalls due to dialkyl N-nitrosamine impurities, some of which are at least two orders of magnitude more potent than the TTC. However, around half the N-nitroso compounds analysed have lower carcinogenic potency than the TTC. High potency is attributed to those N-nitroso compounds mechanistically capable of undergoing facile alpha-hydroxylation to form a diazonium ion in close proximity to DNA. Through industry-wide collaborations, an understanding of structural features which mitigate activity has been curated and used to suggest subclasses of N-nitroso compounds which are not predicted to exhibit high carcinogenic potential. Refinement of the structural definition of the cohort should allow N-nitroso compounds with low carcinogenic risk to reside outside the cohort of concern and be assessed in the same manner as other chemical impurities under ICH M7 without increasing the risk to human health.