Developing Structure-Activity Relationships for N -Nitrosamine Activity.

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 TD 50 values for experimentally measured N- nitrosamines or the measured TD 50 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.