It is also a possibility. However, at the end it depends on the health authority to accept. Nevertheless, the idea to use a lower limit (10% of 8 ng/day) is about the analytical method developed and the LOQ, in case the BoH goes for NMPEA not do an addendum to the validation for example.
We have seen crazy surrogates in the past.
I am sorry to say that no, it would not be a valid surrogate. Betahistine has a methyl substituent, and an aromatic ring attached to the beta position. NNK fulfills those two characteristics, but the surrogate you are proposing, while having the methyl group has a carbonyl group attached to the gamma position, and then there is the aromatic ring. It is different enough to not be comparable, even more when you have a suitable analogue.
At the moment I would not expect betahistine getting and AI over 8 ng/day
Hi thank you for your opinion, but I do not agree. Similar argumentation of non-appropriate surrogate selection can be applied while comparing betahistine with N-Nitroso-N-methyl-2-phenylethylamine (phenyl aromatic ring in NMPEA surrogate instead of pyridine which is the part of N-Nitroso betahistine is presenting huge difference from electronic point of view, and compounds characteristics as basicity, polarity…)
Sure, you are right, but it is important to see the approach EMA is taking. Nortryptiline has nothing to do with NMPEA, but it has two carbon atoms before the double bond which has electronic comunication with the phenyl rings. So basically, two carbon atoms and then aromaticity. There are other big differences between nortryptiline and NMPEA that are not taken into account, such as it is going to be the polarity, or even the molecular weight of the molecule. That is the basic feature they are using in this case to establish the 8 ng/day
Sure, unfortunatelly I dont see EMA apprach as good benchmark since many controversial SAR/Read Across they made so far…As a good example of that is the case of 1-Methyl-4-nitrosopiperazine, MeNP (16339-07-4), where the Limit was derived using NDEA as point of departure even there is plenty tox data available on similar nitrosopiperazines. See papers below where they discuss it in detail:
