Updated EMA-Acceptable intakes (AIs) established for N-nitrosamines

[ranjithrnd]

Updated EMA-Acceptable intakes (AIs) established for N-nitrosamines.pdf (1.2 MB)

[Yosukemino]

Thank you for sharing the updated AI list, @ranjithrnd. The link to the original Appendix 1 is here. The URL means “pdf”, but the file is made in Excel.

New or updated compounds/ Category or Study/ AI(ng/day)
5-chloro-4-methyl-2-[(2S)-2-methyl-1-nitrosopyrrolidin-2-yl]-1H-benzimidazole/ Cat.5/ 1500
N-nitroso-ambroxol/ EAT? Nega/ 1500
N-nitroso-calcium folinate/ in vivo Nega/ NMI
N-nitroso-celiprolol/ Cat.5/ 1500
N-nitroso-desethyllidocaine/ Cat.2/ 100
N-nitroso-desmethyl-azelastine/ Cat.2/ 100
N-nitroso-desvenlafaxine/ Cat.1/ 18
N-nitroso-dorzolamide/ Cat.2/ 100
N-nitroso-esmolol/ Cat.4/ 1500
N-nitroso-ethylenediamine-triacetic acid/ Cat.4/ 1500
N-nitroso-iminodiacetic acid/ Cat.4/ 1500
N-nitroso-indapamide/ Cat.5/ 1500
N-nitroso-leniolisib/ Cat.5/ 1500
N-nitroso-N-methylaniline(NMPA)/ Cat.2/ 100
N-nitroso-tetracaine/ Cat.3/ 400
N-Nitroso-ticagrelor/ Cat.5/ 1500

NMPA is updated from 34.3ng/day to Cat.2(100ng/day).

[mflorea]

Interestingly, Nitroso-Indapamide = Indapamide Impurity A is included in the Ph. Eur. Indapamide monograph with a limit of 5 ppm. It appears as a contradiction to deal with.
There was a previous discussion on the topic on the site

EMA Q&A Rev. 16 EMA/409815/2020 - MAJOR UPDATE

Only one of those is a nitrosated aromatic system - the two indolines both have the nitrosamine in non-aromatic rings (though fused to aromatic, yes) and the nitrogen has true single bonds. [image] 1-nitrosoindoline would be category 4 by CPCA: (0,2) for hydrogen count, and in a generic 5-membered ring, for a total of 5 points. 3-methyl-1-nitrosoindoline would be category 4 as well, with the same features but also the beta-methyl for an activating feature and a total of 4 points I’m unsure …

N-Nitrosoiminodiacetic acid and N-nitroso-ethylenediamine-triacetic acid are included with an AI of 1.5µg/day, originating from Isosorbide mononitrate. N-Nitrosoiminodiacetic acid has negative data in LCDB, however they are not considered reliable.

[David]

My answer for the indapamide case would be the same as in that thread - the monograph limits appear to be limits based on achievable quality standards and the existing batches on the market (independent of the toxicity of the impurities, there is real value in having drug substances as pure and well-characterised as possible) rather than the safety-threshold-determined limit that would be permissible under the CPCA or any other guidance.

[MarkS]

So NMPA has moved from a limit of 34.3 ng/day to 100 ng/day based upon it falling into Category 2 if you put it through the CPCA calculation.

Does this mean that we could see the limit changing for NMPA from the FDA as well, where it is still currently 26.5 ng/day?

I hadn’t considered putting the original small molecules back through the calculation.

[E_da_Silva]

Hi everyone
(and thanks to all that have contribute until now, particularly Yosukemino ¡! )

Apart of the format change (PDF to Excel Table)…some new columns added or am I driving crazy? e.g. I do not remember seeing “Structures” in previous list in PDF

[Diego_HM]

Indeed, now structures, that is more visually appealing

[Yosukemino]

Smiles are very useful for searching nitrosamines in QSAR and DB. Similarity search is also available for read-across. That’s great progress!!

[Yosukemino]

As far as I know, the FDA never changed the AI from the original except for the interim limit. The AI of varenicline is still different between FDA and EMA(37 vs 400). And NMPA is separated from NDSRIs.

As @conudel explained in the webinar today, there are lots of gaps in policy between the FDA and the EMA. We should pay attention to the FDA’s next approach.

[Naiffer_Host]

It was fantastic presentation by @conudel today. I hope Lhasa made available the recording soon, the cases and the regulatory gaps was very insightful.

Eye opening to me: “Aproximately 25% of NDSRIs are positive in vitro mutagens and have a good chance of being positive in vivo. Currently, no method is available to use positive in vivo mutagenicity data to rank the potency of NDSRIs”

[Diego_HM]

One of the reasons, something not as harsh to perfom as a carcinogenic study is needed. The nitrosamine topic is still long to be solved.

The CPCA even with its limitations helped quite a bit. But this is one of the reasons the joint cooperation between industry and regulators is needed. To focus a bit more on positive Ames compounds rather than putting efforts on compounds that are out of the CoC. Where nonetheless, more evidence is coming of certain drug classes for example.

[mflorea]

Here is the link to Lhasa webinar “How to establish acceptable intake limits for NDSRIs” 22nd Nov 2023
How to establish acceptable intake limits for NDSRIs (vimeo.com)