Risk (Re)assessment of N-Methyl-N-nitrosophenethylamine for use in computing risk levels of N-Nitrosamine drug substance related impurities.

Management of N-Nitrosamine impurity levels in pharmaceutical drug substances and products is guided by ICH M7 where N-nitrosamines are defined as Cohorts of Concern. Regulatory agencies have suggested using read-across of rodent carcinogenicity TD50 values for structurally similar compounds to assess the potency of various data-poor N-nitrosamines. The TD50 for N-Methyl-N-nitrosophenethylamine (NMPEA) as reported in the CPDB with a harmonic mean TD50 value 7.88 μg/kg/day (or an Acceptable Intake (AI) level of 8 ng/day) did not follow the recommendations of ICH M7. Mixed tissues (oesophagus, forestomach, tongue, and nasal cavity) were combined into a single group termed "upper gastro-intestinal tract". Upon examination of the original data, the oesophagus was considered the most sensitive organ of effect. The TD50 value for the oesophagus was recalculated to 40.1 μg/kg/day (or an AI of 40.1 ng/day). Subsequently, Benchmark Dose (BMD) analysis was performed on the same data set yielding a BMD10 of 3.06-17.6 μg/kg/day in rat (or Permitted Daily Exposure range of 306-1760 ng/day). Theses updated values are 5 times (or higher than) the current AI level of 8 ng/day and could result in significantly higher AI limits for marketed drug impurities that use NMPEA as a suitable analog (e.g., N-nitroso- nortriptyline) to derive an AI.