In fact it was limited below 10 ppm in the harmonized monograph (Ph.Eur, USP-NF, JP) on Povidone.
Even if all the content will undergo hydrolysis to give 4-(vinylamino)butanoic acid and assuming that part of this will be nitrosated to give 4-(nitroso(vinyl)amino)butanoic acid, I do not think that these traces of nitroso impurity may significantly increase the risk of cancer related to 1-Vinyl-2-Pyrrolidinone.
What about the nitrosation product of 2-Pyrrolidone? It is not a nitrosamine, but a nitrosamide of course I would go under ICH M7. Unfortunately, there is no roubst carc. data for nitrosamides that from where an acceptable intake could be derived.
Based on Ph. Eur. monograph up to 3.0% of the impurity could be expected. In highly acidic formulations (pH 3.0) as indicated in literature, the compound could be formed.
Fully agree, maybe to clarify more my question. It was related to the opinion on the possible presence of the nitroso product of 2-pyrrolidone coming from 2-pyrrolidone impurity in Povidone, etc.
Therefore, I should have separated my question and indicate it was a different topic and/or open another topic. Nonetheless, already posted here
N-Nitroso-2-pyrrolidone (CAS 54634-49-0) is mutagenic, but at the same time it seems to be a very weak carcinogen. This is the only article that I could find (Japanese with abstract in English)
On the other hand, N-Nitroso-2-pyrrolidone may be formed in vivo in the acidic gastric environment. This risk has been evaluated by EFSA as negligible:
the Panel concluded that PVP used as a food additive does not raise a concern with respect to genotoxicity. The Panel considered that this conclusion would also apply to PVPP. The Panel also noted that even under the scenario of 3% content of 2-PY in PVP, the risk related to endogenous nitrosation of 2-PY is very low.
Summarizing, the formation of N-Nitroso-2-pyrrolidone in drug products containing PVP (Povidone) may be possible, but in my opinion the overall risk is negligible.
Thanks for your answer. I would agree on the endogenous topic, that the risk is negligible. But, I would suggest as a conservative measure to have further experimental info on the exogeneous formation (e.g., modified NAP test in the drug product where Povidone is used and the pH is expected to be approx. 3.0 as at higher pH the rate of formation is exponentially lower Occurrence of the nitrosamide precursor pyrrolidin-(2)-one in food and tobacco - PubMed (nih.gov)).
Nonetheless, theoreticaly, w/o anything experimental there are arguments to dismiss the risk. But may be challenged back if a conservative position is taken from the counterpart. Of course there is no guideline for nitrosamides = timelines, but may be part of the genotoxic evaluation as part of ICH M7.
