How to define AI for compounds having multiple Nitrosamine substituents in structure.
Regarding 1,4-Dinitrosopiperazine (CAS 140-79-4), you could set an AI based on the worst TD50 (rat, 0.038 mg/kg/day). See the examples in the ICH M7 guideline.
Where available, you could find TD50 values in the Lhasa Carcinogenicity Database (free registration).
If you are applying the CPCA criteria to a new NDSRI with multiple Nitrosamine substituents in structure, in my opinion you should calculate the CPCA score for each of them and then apply the AI of the worst case.
However I think that this is a very theoretical case.
kind regards
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Hi @paliog,
You are right. Regarding CPCA, Appendix 2 describes that N-nitrosamines containing two N-nitroso groups, the group with the highest predicted carcinogenic potency (i.e., the group with the lowest numerical potency category) defines the AI for the entire molecule.
On the other hand, I am susceptible to whether the second nitrosation will happen or not with trace amounts of nitrite and a huge amount of API or Impurities. I guess the second one is negligible in that case.
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Thank you very much for the clarification
Thank you for the response and clarification.