12 NAs are newly included, and the limit of two NAs is updated. In addition, 17 other nitroso compounds are included. Details will be described in the following posts.
New nitrosamines;
| Name | Source | CPCA Category | AI(ng/day) |
|---|---|---|---|
| N-nitroso-anabasine | Nicotine | 4 | 1500 |
| N-nitroso-anatabine | Nicotine | 4 | 1500 |
| N-nitroso-desmethyl-chlorphenamine | Chlorphenamine | 1 | 18 |
| N-Nitroso-desmethyl-eletriptan | Eletriptan | 4 | 1500 |
| N-nitroso-desmethyl-galantamine | Galantamine | 1 | 18 |
| N-nitroso-desmethyl-rizatriptan | Rizatriptan | 1 | 18 |
| N-nitroso-desmethyl-zolmitriptan | zolmitriptan | 1 | 18 |
| N-nitroso-ivacaftor | Ivacaftor | 5 | 1500 |
| N-nitroso-nilotinib | Nilotinib | 5 | 1500 |
| N-nitroso-nornicotine | Nicotine | 100 | |
| N-nitroso-nor-oxycodone | Nalmefene | 4 | 1500 |
Updated nitrosamines;
| Name | Source | CPCA Category | AI(ng/day) |
|---|---|---|---|
| N-nitroso-bupropion | Bupropion | NMI | |
| N-nitroso-ketamine | Ketamine | 5 | 1500 |
For N-nitroso-ketamine, the AI is the same as before. However, a note is added. “LTL cannot be applied and the AI will be capped at 1500ng as the substance tested positive in in vivo and in in vitro mutagenicity studies.”
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Other N-nitroso compounds;
| Name | Source | AI(ng/day) |
|---|---|---|
| N-nitroso-biotin | D-biotin | 1500 |
| N-nitroso-cimetidine | Cimetidine | 553 |
| N-nitroso-clonidine | Clonidine | 553 |
| N-nitroso-clonidine-2 | Clonidine | 553 |
| N-nitroso-eletriptan | Eletriptan | 1500 |
| N-nitroso-melatonin | Melatonin | 1500 |
| N-methyl-N’-nitro-N-nitrosoguanidine | 553 | |
| 1-Nitroso-moxonidine Impurity 3 | Moxonidine | 553 |
| 1-Nitroso-moxonidine | Moxonidine | 553 |
| N-nitroso-naratriptan | Naratriptan | 1500 |
| N-nitroso-rizatriptan | Rizatriptan | 1500 |
| N-nitroso-sumatriptan | Sumatriptan | 1500 |
| N-nitroso-tadalafil | Tadalafil | 1500 |
| N-nitroso-tizanidine | Tizanidine | 553 |
| N-nitroso-tizanidine Impurity 3 | Tizanidine | 553 |
| N-nitroso-tryptophol | Tryptophol | 1500 |
| N-nitroso-zolmitriptan | Zolmitriptan | 1500 |
According to the note, the AI of N-methyl-N’-nitro-N-nitrosoguanidine was calculated to 553 ng/day from TD50 and used as a surrogate for some N-nitroso compounds whose alfa-carbon is double-bonded to nitrogen.
The AI of N-nitroso compounds with negative bacterial reverse mutation test and N-nitroso-indoles is 1500 ng/day.
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dear Yosuke thank you for the updates
what is a bit confusing to me is that CPCA (which its base is Limit derived using structure-activity-relationship, physicochemical features and weight of evidence for N-nitroso-indoles based on C- nitro and C-nitroso-aromatic compounds) should not be applied for N-nitrosamines where the N-nitroso group is attached to a nitrogen within a hetero aromatic ring (e.g., nitrosated indole).
so i would welcome any comments and insights from your end and from other colleagues as well.
BR
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According to ICH M7, nitroso-derivatives are included in the so called Cohort of concern, however, health authorities have limited the guidance documents so far to nitrosamines. Including nitroso-ureas, nitroso-guanidines, aromatic nitrosamines, nitroso (3 substituted) indoles in this list appears to be a logical step toward harmonization with ICH M7.
As these compounds have a different mutagenic mechanism then dialkylnitrosamines, their AI levels do not align with the CPCA approach, adding another level of complexity.
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Dear Mircea,
i think you got the point very well, your explanation seems very reasonable.
And yes, complexity will be levels up…
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Dear @elenipoliti,
Thank you for asking. I agree with Mircea. You might confuse other N-nitroso compounds (ex. N-nitroso-indoles) with nitrosamines. The EMA separated other N-nitroso compounds from nitrosamines in the document. They are not considered nitrosamines because they have different characteristics from nitrosamines. The following thread helps you understand the key points.
Yosuke
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The TGA have added a new list to their website with similar structures on Friday - I haven’t had a chance to crosscheck to see if they are the same, but TGA normally follow EMA.
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You are correct, Mark. New 17 “other nitroso-structures” in TGA are identical to those in EMA Appendix 1.
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