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•N-Nitrosamine carcinogenic potency ranges from extreme to negligible or negative.•Specific structural features have clear effects on N-nitrosamine carcinogenic potency.•Analysis of ...N-nitrosamine SAR may require investigation of potentials for metabolism, DNA binding and DNA repair.•Presence or absence of structural features can support read-across for novel N-nitrosamines.
The detection of N-nitrosodimethylamine (NDMA) in several marketed drugs led regulatory agencies to require that N-nitrosamine risk assessments be performed on all marketed medical products EMA/351053/2019 rev 1 (2019). Regulation of N-nitrosamine impurity levels in pharmaceutical drug substances and products is described in the ICH M7(R1) guideline where they are referred to as “cohort-of-concern” compounds as several are potent rodent carcinogens Kroes et. al. 2004. EMA, U.S. FDA and other regulatory agencies have set provisional acceptable daily intake limits for N-nitrosamines calculated from rodent carcinogenicity TD50 values for experimentally measured N-nitrosamines or the measured TD50 values of close analogs. The class-specific limit can be adjusted based upon a structure activity relationship analysis (SAR) and comparison with analogs having established carcinogenicity data EMA/369136/2020, (2020). To investigate whether improvements in SARs can more accurately predict N-nitrosamine carcinogenic potency, an ad hoc workgroup of 23 companies and universities was established with the goals of addressing several scientific and regulatory issues including: reporting and review of N-nitrosamine mutagenicity and carcinogenicity reaction mechanisms, collection and review of available, public relevant experimental data, development of structure–activity relationships consistent with mechanisms for prediction of N-nitrosamine carcinogenic potency categories, and improved methods for calculating acceptable intake limits for N-nitrosamines based upon mechanistic analogs. Here we describe this collaboration and review our progress to date towards development of mechanistically based structure–activity relationships. We propose improving risk assessment of N-nitrosamines by first establishing the dominant reaction mechanism prior to retrieving an appropriate set of close analogs for use in read-across exercises.
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