N-Nitroso Sertraline

Limits of Nitrosamines
1

It was turbulent period for N-Nitroso Sertraline this year, with several changes to its Acceptable Intake (AI) levels. The last change put the AI back to 100ng/day, a CPCA-derived AI, as substance was tested positive in in vivo mutagenicity study.
The question is:

  • Are those in vivo mutagenicity study data publicly available? Who was the sponsor?

  • Why did regulators not use them as the basis for AI calculation and instead revert to the CPCA-derived AI?

  • Can we expect another limit change in the near future?

2

Hi,

I could not comment about the sponsor, but at least publicily no paper has been released in comparison with other NDSRIs.

For the 2nd question that is because in-vivo +tive mutagenicity studies (TGR) are still not accepted to be used to set up limits. There is a proposal up to EMA level but still on discussion. What is now at least case-by-case accepted is to use In-vivo +tive data to perhaps move into the CPCA category. Here, the easiest option was just to fall back to Category 2.

For the 3rd question, yes, if the proposal in my 2nd parragraph is accepted in some point in the future, the limits may be changed again. Less or more? I cant say without having access to the TGR data.

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3

There might be other reasons for change,
e.g. acceptance of the Bercu 2024 CPCA refinement (N-nitroso-sertraline MW > 200 Da → 150 ng/day) N-Nitrosamine drug substance related impurities (NDSRIs) – A proposal for the addition of subcategories to carcinogenic potency categorization approach categories 1 and 2 for NDSRIs with a molecular weight > 200 Da - ScienceDirect
e.g. temporary/LTL approaches like currently in Table 3 of FDA (N-nitroso-sertraline 600 ng/day untill August 2025) CDER Nitrosamine Impurity Acceptable Intake Limits | FDA

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4

Can you give an example of in vivo + data leveraged to go one CPCA category higher? Was this temporary or final?

5

Igor - this might be an interesting compound to consider with QM, which is accepted in WOE to set higher AIs than the CPCA (assuming the QM can provide robust evidence for a higher limit). If interested msg me at jakub@gwu.edu and we can discuss further.

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6

Hi what exactly do you mean by QM? Thanks.

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7

Thank you all for the feedback!

8

Quantum mechanics approaches. Used either for high-level read-across (as in 10.1021/acs.chemrestox.4c00087 or 10.1021/acs.chemrestox.4c00133) or as a predictive model of carc potency (10.1021/acs.chemrestox.2c00380).

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