🇺🇸 FDA - Recommended Acceptable Intake Limits for NDSRIs Guidance for Industry

Dear @RCREDDYP, as mentioned by @David in the article Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients, similar to tert-butyl groups, aromatic side chains lack the α-hydrogen required for metabolic activation.

However, the available toxicity data for compounds of this nature does not exhibit the same consistent negative trend as that observed with tert-butyl groups. A matter of particular concern upon initial analysis is the discovery that N-nitrosodiphenylamine (NDPhA) demonstrates carcinogenicity in rodents and genotoxicity in the Salmonella Ames assay, even though it lacks an α-carbon oxidation site.

These findings imply that an alternate mechanism, such as trans-nitrosation of DNA base(s) as observed with NDPhA, is likely responsible for DNA reactivity in this case.

3-substituted-N-nitrosoindoles are mutagenic in the Salmonella Ames test in the absence of CYP activation

1 Like