In terms of specific limits, the general TTC (1.5 ug/day) will definitely not be applicable since it is a nitrosamine, and I would hope that we can go higher than the 18 ng/day class-specific TTC. I’m unaware of any specific limits that have been accepted for this compound by regulators; however, would suggest that @sumitkumarjain investigates the local environment around the nitrosamine group. It is essentially a heavily 4-substituted nitrosopiperidine ring, so comparison other nitrosopiperidines with CH2 groups on both sides of the nitrosamine may be suitable.
There is only one compound that matches that description listed in the Lhasa carcinogenicity database (all other nitrosopiperidines listed have branching at an alpha carbon), which is nitrosopiperidine itself (Lhasa Carcinogenicity Database) with a rodent Lhasa TD50 of 1.12 mg/kg/day (rat) and rodent Gold TD50 of 1.3 mg/kg/day (mouse).
I would be very interested to hear from industry members of the exchange whether the AIs derived from this (1.12 ug/day or 1.3 ug/day) have been accepted for this compound.
In that sense, the final limit for the finished product would be around 224 ppm which is quite closer to TTC limit of 300 ppm (1.5 microgram/day).
However, another justification presented by API supplier is reproduced below for your reference.
As per Genotoxicity and carcinogenicity studies of antihistamines (Article enclosed and highlighted yellow), Desloratadine tested negative in all genotoxicity assays. But were carcinogic in mice and rats respectively. So, product itself carcinogen product. When product is carcinogenic, the same importance will be applicable for N-Nitroso Desloratadine Impurity. Monographs on the evaluation of Carcinogenic risks to humans, the daily exposure to which is often lower than 1 mg (Means 1000 ppm).
Can we explore above justification to support TTC limit assigned to N-nitroso desloratadine as it seems loratadine/desloratadine are carcinogenic?
N-Nitroso-desloratidine tested negative in the Ames test with and without bioactivation with rat S9, however, with hamster S9 it tested positive in strain TA100, so it is considered a positive mutagen. By SAR-read-across looking in the LCDB for nitroso-piperidine surrogates, the compound N-nitroso-piperidine has robust enough data to be used as a surrogate to set the acceptable intake (AI) for nitroso-desloratidine. By linear extrapolation from the lowest Lhasa TD50 of 0.974 mg/kg/day for nitroso-piperidine, an AI of 974 ng/day can be set and used also for N-nitroso-desloratidine.
The closest structure is “N-nitroso-4-piperidinone” and is considered to be structurally similar to the COI. Hence based on literature and QSAR study we can follow the TD50 of “N-nitroso-4-piperidinone” to calculate the predicted AI limit for “Nitroso Desloratadine” as 499 ng/person/day according to ICH M7 (R1).