Based on the appendix 2, The Carcinogenic Potency Categorisation Approach does not apply to N-nitrosamines bearing a carbon atom on both sides of the N-nitroso group, and where the carbon is not directly double bonded to a heteroatom.
However, some nitrosamines with this structure have been listed on the appendix 1, such as the following:
So how should we consider this kind of structures (such as the N-nitroso acyclovir impurity K)?
Should they be considered as N-nitrosamines or just as mutagenic impurities (but not within the cohort of concern)?
You added a not too much.
Correct is:
The Carcinogenic Potency Categorisation Approach does apply to N-nitrosamines bearing a carbon atom on both sides of the N-nitroso group where the carbon is not directly double bonded to a heteroatom.
In addition to this “carbon not directly double bonded to a heteroatom” is typically interpreted restrictively, in the sense of nitroso-amide/urea/carbamate/amidine/guanidine functionality sensu stricto and not those patterns being part of a heteroaromatic structure (heteroaromatic classification beats heteroatom-carbon double bond so to say). So you have to judge the aromaticity of the system and the delocalisation of the double bonds and evaluate if the focus should be guanine or guanidine (cf. check of 4n+2 pi-electron rule).
See example of N-nitroso-abacavir in the limit lists.
Same: N-nitroso-maribavir, N-nitroso-rilpivirine impurities, N-nitroso-etravirine.
For discussion on N-nitroso-maribavir and treating guanidine fragments in NDSRIs:
It can be useful to verify CPCA applicability with NDSRIs in the limit list or an automated CPCA tool that has been validated if you have doubts on the aromaticity judgement of model compounds or consistency in the application of the rule heteroaromaticity prior to C=X.
