N-nitroso-desmethyl-doxylamine
As per CPCA this is Potency Category 1 and AI limit should be 18 ng/day. Yet, in the EMA Appendix this is 100 ng/day based on read-across with NNK. Does anybody know the basis on why read-across was applied? Can all NDSRI’s without in vivo data which belong to Potency Category 1 can be 100 ng/day?
N-Nitroso-desmethyl-doxylamine belongs to the category of N-Nitroso-N-methyl-N-alkylaryls for which an AI of 100 ng/day has been accepted based on a read-across with NNK.
No, you cannot assign an AI of 100 ng/day for all Potency Category 1 NDSRIs without in vivo data. I am tagging the relevant string on this topic.
Thank you Dr. @Muzaffar for the clarification. Does N-methyl-N-nitrosophenethylamine (NMPEA) belong to the category of N-Nitroso-N-methyl-N-alkylaryls? It is 8 ng/day based on TD50 data. Previously N-Nitroso nortriptyline and N-Nitroso amitriptyline were set 8 ng/day based on read-across with NMPEA which was later revised to 18 ng/day based on CPCA.
Interesting question 
I am reproducing the response from the published article by George Johnson et. al: 10.1016/j.yrtph.2025.105888
The TD50 for N-Methyl-N-nitrosophenethylamine (NMPEA) as reported in the CPDB with a harmonic mean TD50 value 7.88 μg/kg/day (or an Acceptable Intake (AI) level of 8 ng/day) did not follow the recommendations of ICH M7. Mixed tissues (oesophagus, forestomach, tongue, and nasal cavity) were combined into a single group termed “upper gastro-intestinal tract”. Upon examination of the original data, the oesophagus was considered the most sensitive organ of effect. The TD50 value for the oesophagus was recalculated to 40.1 μg/kg/day (or an AI of 40.1 ng/day). Subsequently, Benchmark Dose (BMD) analysis was performed on the same data set yielding a BMD10 of 3.06-17.6 μg/kg/day in rat (or Permitted Daily Exposure range of 306-1760 ng/day). Theses updated values are 5 times (or higher than) the current AI level of 8 ng/day and could result in significantly higher AI limits for marketed drug impurities that use NMPEA as a suitable analog (e.g., N-nitroso- nortriptyline) to derive an AI.
Dr. @Muzaffar I have provided the same justification to many authorities using NMPEA as surrogate. Unfortunately none have agreed.
Dr. @Muzaffar is AI can be increased for nitroso desmethyl amitriptyline? Kindly comment.
It depends for which market you are considering.
N-Nitroso-desmethyl amitriptyline is a CPCA Potency Category 1 nitrosamine and as per EMA, you have to consider an AI of 18 ng/day for this impurity.
As per USFDA, it’s a complete mix-up. This impurity is listed in Table 1: FDA Recommended AI Limits, with an AI of 26.5 ng/day and in Table 3: Recommended Interim AI Limits* with AI limits of 450 ng/day in tablets & 600 mg/day in capsules!
If you wish to propose any other alternate limit, you may explore performing read-across with a suitable surrogate with comprehensive & sufficient justification for the surrogate selection (preferably supported by QM-based ESRA) or performing an in vivo study.
To make it simple, N-Nitroso-desmethyl amitriptyline being an N-Nitroso-N-methyl-N-alkylaryl, can be read-across with NNK.
Recent updates from EMA have added complexity to the interpretation of acceptable intake (AI) limits. EMA has confirmed that N-Nitroso amitriptyline tested positive in an in vivo transgenic rodent (TGR) mutagenicity study and hence CPCA is applicable for setting its AI. Given this positive in vivo result, it is unlikely that EMA will accept a read-across approach using NNK as a surrogate for N-Nitroso amitriptyline, since EMA previously used NMPEA as a surrogate in its May 2024 assessment for N-Nitroso amitriptyline. It is high time to give recognition to benchmark dose lower confidence limits (BMDL) derived from in vivo data.
Yes Dr. @Sushant N-Nitroso-desmethyl amitriptylin is indeed in vivo mutagen and I should have mentioned that before! EMA did realize that NMPEA was not the most ideal surrogate and the compound specific AI of NMPEA itself is questionable.
Thank you for bringing this interesting and valid argument that the HAs should consider BMDL derived limits from in vivo data.
If an NDSRI is an in vivo mutagen, you can still perform a read-across with a suitable surrogate (or) apply the CPCA approach.
I am reproducing the excerpts from EMA Query # 10: Which limits apply for nitrosamines in medicinal products? (Updated)
If N-nitrosamines are identified without sufficient substance specific data to derive a substance specific limit for lifetime exposure as recommended in ICH M7(R2) guideline,
A good example is N-Nitroso Duloxetine, where EMA derived the limit using structure-activity-relationship (SAR)/read-across approach using the TD50 of NNK as point of departure as substance tested positive in in vivo mutagenicity study.
Thank you Dr. @Muzaffar
