Hi !!!
It has been came to the notice recently that N-nitroso bupropion is one of the NDSRI in Bupropion formulations whose limit has not been defined by any regulatory agency.
What will be the AI of N-nitroso bupropion ???


Bupropion: [smiles O=C(C(C)NC(C)(C)C)C1=CC=CC(Cl)=C1]

N-nitroso-Bupropion [smiles CC(N(N=O)C(C)(C)C)C(C1=CC=CC(Cl)=C1)=O]


I would say that the “tert” group heavilly diminish the potency of that nitrosamine, and even can be expected to be non-carcinogenic, as also indicated in a recent research specifically talking about this tert butyl groups (I can`t put screenshots as the research is not open access).

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients | Journal of Medicinal Chemistry (acs.org)

And in older studies like the following:

Clues to the non-carcinogenicity of certain N-Nitroso compounds: Role of alkylated DNA bases - ScienceDirect

Taking into account this two sources, I would look to put this nitrosamine at the TTC perhaps 1500 ng/day. However, I cant say for sure this limit would be accepted and further tox data would be needed.

Nevertheless, the CHMP is already asking the NcWP to develop an acceptable intake:

PROM Minutes 5 September 2022 (europa.eu)


Of course further feedback from the community would be useful.


@David @MichaelBurns could you help us understand this case… thanks!

Some info I would like to add here. In December 2022, it was mentioned in the following press advertisement that a Bupropion formulation is getting a withdrawal from the market that is actually causing some shortages.

Microsoft Word - Zyban supply disruption - update and guidance on alternatives for clients.docx (ncsct.co.uk)

It is not mentioned what nitrosamine was detected but it would not be a surprise if it is an NSDRI. It is interesting taking into account the theoretical aspects around the toxicity of the suspected specific nitrosamine.

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