AI Limit for Nitroso Nebivolol

Hi Everyone,

Recently it has been came to the notice that N-nitroso nebivolol is one of the NDSRI in the Nebivolol Tablets formulation whose limit has not been defined by any of the regulatory authority.

Could any one suggest any AI limit based on the read across approach or literature based or any other way?

Someone can help me to prepare justification report based on PDE, read across, Q (SAR) for set the AI limit for N-nitroso nebivolol.

As per my little bit knowledge gain by above literature (Practical and Science-Based Strategy for Establishing Acceptable) Intakes for Drug Product N‑Nitrosamine Impurities N-nitroso nebivolol lies under group 5 structure which has structural similarity with N-Nitroso is(2-hydroxypropyl)amine, and this group AI of 440 ng/day.

acs.chemrestox.1c00369.pdf (3.6 MB)

Your views are very much appreciated.

Thanks in advance,


Additionally Below is the structure for Nebivolol hydrochloride
and Below is structure for Nitroso Nebivolol
(N,N- bis (2-(6-fluorochroman-2-yl)-2-hydroxyethyl)nitrous amide)

@Naiffer_Host your guidance is highly appreciated.

Based on structural similarity of N-nitroso nebivolol and read across approach, the available toxicity data for N-Nitrosodiethanolamine (NDELA) is used for risk assessment of N-nitroso nebivolol and calculation of AI. The calculated AI is 0.00317 mg/day or 3170 ng/day.

Is applied approach is correct, can anybody guide me on this. @Naiffer_Host can you pls guide.

@Naiffer_Host @Diego_HM @Yosukemino can you please guide me.

Hi, @Yuvraj.
I’m sorry for my delayed response. And I’m not a toxicological chemist.

Nitroso Nebivolol looks more similar to N-Nitrosobis(2-hydroxypropyl)amine or 3-[(2-Hydroxypropyl)nitrosoamino]-1,2-propanediol. I couldn’t find the other surrogates from LCDB.


So you can select the appropriate one from 18ng/day, 26.5ng/day, 53.5ng/day, 440ng/day, 891(or GOLD: 881)ng/day, and others.

And @sumitkumarjain may help you to share his experience to decide the AI value with the literature.

I hope it will help you.

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No limit has yet been published, as you observe; this may well be due to the difficulty of selecting a suitable read-across analogue, and I would be hesitant to do so myself without a lot more information. It may be that without further analysis (ongoing) of the complex nitrosamine data to allow us to understand how to make the extrapolations from small molecules, selection of a suitable analogue for this compound would be an impossible task.

I do not believe that the compound will be potent enough - partially simply due to size; there will be many fewer molecules and thus mutation events per gram than for e.g. NDEA - that control to 18 ng/day is required, but am not currently aware of sufficient evidence to justify this statement with suitable rigour to support a submission.

I would be very hesitant before using NDELA, which is very polar and I believe fairly easily excreted, for the read-across for what I assume is a less polar drug. The other small beta-hydroxy compounds are significantly more potent.

Some questions and principles that might be worth addressing:

  • is it mutagenic? If so, what is the Ames strain profile? It might be advantageous if your analogue follows a comparable profile.
  • by what metabolic system is nebivolol normally processed, and if P450, where (particularly high concern if metabolism of nebivolol is at the amine alpha-carbons)?
  • local similarity to a small molecule is not the only necessary measure to consider for analogue selection; what is the global similarity in terms of of molecular weight? Of logP? Of clearance rate? The weighted local similarity stretching out to a search depth of 7 or 8 atoms?

I look forward to seeing whether the submission was approved, do report back!


Hi, @David.
Thank you for sharing your deep insights. I appreciate your help. The number of available nitrosamines with reliable toxicological information is not large. And selecting the best surrogate for NDSRIs is challenging in many cases. A conservative class-specific threshold(18 ng/day) tends to apply to complex nitrosamines.

I understand not only local similarity but also global similarity are important to select the surrogates in the read-across method. The other features are also worth addressing. But we know there are gaps between current regulation and knowledge. I hope the gaps will solve in the future.

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Thanks for providing valuable information and support