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!