EMA Q&A Appendix 1 update posted Sept 28,2023

Looks like there is an update posted today: Appendix 1 Nitrosamine AIs (europa.eu)

A few compounds added and CAS’s added for many. There is one (Sertraline) noted as limit based on bacterial mutation test with 1500 ng/day.


Thank you for updating the information, @stefanierentfrow. Three compounds are newly included.
The AI of N-nitroso-sertraline was updated from 100 ng/day to 1500 ng/day by negative mutation tests.
The AI of N-nitroso-varenicline was updated from 37 ng/day to 400 ng/day by CPCA.

3-amino-N-nitrosopiperidine: 400 ng/day
N-nitroso derivative of rotigotine impurity B: N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylnitrous amide: 400 ng/day
N-nitroso derivative of rotigotine impurity C: N-(5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(-2-(thiophen-2-yl)ethyl)lnitrous amide: 1500 ng/day
N-nitroso-sertraline: 1500 ng/day
N-nitroso-varenicline: 400 ng/day


Thanks, this is exciting! While I’m very much in favour of read-across for getting more chemically-accurate limits, I’ve argued for a while now about the unsuitability of the previously-used nitrosotetrahydropyridine as an analogue for nitrosovarenicline, so to see that moved to CPCA (with a corresponding order of magnitude relaxation of the limit) is great.


We are seeing fantastic progress on the adoption of Ames and tgt to expand the safety limits of impurities. Great example what Yosuke just report on Sitagliptin…


EMA has now assigned an AI of NMT 400ng/day for MeNP

It looks like N-nitroso-piperazine (NPZ) has been deleted from Appendix 1. Is someone aware of the reason?


Well, I’m disconcerted :confused:. I assume it is a transcription error (human error). I suppose that if they had intentionally removed it from the list, they would have given an explanation. Because this nitrosamine is carcinogenic…

That is really strange! I’ve just been and counted, and am reasonably comfortable that’s the only removal (there are 85 compounds in the new doc, and my list from which I hadn’t removed that had 86), and they’ve been really clear about all the other changes to track…

Especially since the limit in the guidance was CPCA-set, so people are presumably going to submit the same number to them!

As an aside, while it is carcinogenic, it is a really weak carcinogen (with some reasonably-robust data…)


I sent an inquiry to the EMA about NPZ. I think it will be corrected secretly like the error in the Q&A ver17.


Thank you very much for asking the EMA !

Thank you very much for the comment.
This nitrosamine is one that I follow closely.
Long before the EMA specification came out, colleagues were discussing its potential.
I leave what I argued at the time, through an Australian safety sheet on its precursor, piperazine.
You know much more than I about the subject. But I have doubts… It may be that the residual piperazine itself in medications is a risk that has not been well evaluated. (as we must also take into account for our fellow plant operators exposed to piperazine).
Delighted to hear your comments.

Australian Industrial Chemicals Introduction Scheme
Pag 9/17
Piperazine_Human health tier II assessment.pdf (177,4 KB)

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I received an answer from EMA. They said “Although the categorisation of N-nitroso-piperazine was correct according to the CPCA, it is still being considered whether the AI based on empirical data is more appropriate for this substance.” We should pay attention to the further information.


Thank you very much!

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NPZ returned to the updated list secretly. :grinning: