What is CPCA Score for “N-nitroso of 3-Amino-1,2,4-triazole"

What is CPCA Score for “N-nitroso of 3-Amino-1,2,4-triazole".

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The potency categorisation approach (CPCA) does not apply to N-nitrosamines where the N-nitroso group is attached to a nitrogen within a hetero aromatic ring (e.g., nitrosated indole).
ref.to:
Carcinogenic Potency Categorisation Approach for Nnitrosamines

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Can you please provide a bit more context with the question? Thanks

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This nitrosamine impurity is coming from “3 Amino 1,2,4-Triazole” and it does not follow CPCA rules to assign an exact category. My question is how we assign CPCA category.

Thanks, Dinkar. I think this post should help you with the limit definition and justification. The same framework was used to develop CPCA.

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Thank you so much, sir, for your insightful feedback. It is really beneficial to our pharmaceutical society as well as to myself.

Hello, good day!

Could you help me please?

Appendix 2 of EMA/451665/2023, mentions the following:

The carcinogenic potency categorization method applies to N-nitrosamines that have:

  • A carbon atom on both sides of the N-nitroso group and where the carbon is not directly linked by a double bond to a heteroatom (i.e. N-nitrosamides, N-nitrosoureas, N-nitrosoguanidines and other related structures are excluded).

In addition, the potency categorization method does not apply to N-nitrosamines:

  • Where the N-nitroso group is attached to a nitrogen within a heteroaromatic ring (e.g. nitrosated indole).

These limitations are due to the fact that these subclasses of N-nitroso compounds are not expected to follow the α-hydroxylation metabolic activation pathway, which is believed to be responsible for the highly potent mutagenic and carcinogenic activity of nitrosamines.

That said, does this mean that nitrosamines that do not meet these characteristics may not be considered for future confirmatory testing?

For example, the following molecule:

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Hi Lucia

The molecule you are showing is a dinitrosated derivative of something that if I am not wrong is impurity A of HCTZ.
In general when you have more than one nitrosation possible, I would look for the CPCA value for each nitrosamine individually. It is unlikely that in a drug product, where you normally have a deficiency of nitrites when compared to the concentration of amines, you will have a second nitrosation taking place in the same molecule.

Nitrosation of a sulfonamide does not yield a nitrosamine as we know since it is not attached to carbons and, in the case it is mutagenic, it would not follow the same toxicologic pathway.
The other nitrosamine is similar to that of HCTZ itself, which is considered a Non-Mutagenic Impurity by EMA and has a limit of 1500 ng/day by FDA. None of them list a nitroso-hctz impurity A

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