Hello,
just to inform you that Rev. 14 of “Appendix 1: Acceptable intakes established for N-nitrosamines” has been published on 13-oct-2026. (EMA/CHMP/219920/2026/Rev. 14; 1 October 2026)
Regards
mbrg
13 New nitrosamines
| NA | Source | AI(ng/day) | Note |
|---|---|---|---|
| 6,7-dichloro-4-nitroso-1,3,4,5-tetrahydro-2H-benzo[e][1,4] diazepin-2-one | Anagrelide | 100 | CPCA Cat.2 |
| Ethyl N-(2,3-dichloro-6-nitrobenzyl)-N-nitrosoglycinate | Anagrelide | 100 | CPCA Cat.2 |
| Ethyl N-(6-amino-2,3-dichlorobenzyl)-N-nitrosoglycinate | Anagrelide | 100 | CPCA Cat.2 |
| N,N-dinitroso-desmethyl-sumatriptan | Sumatriptan | 18 | CPCA Cat.1 |
| N-nitroso-demethyl-roxithromycin | Roxithromycin | NMI | Limit derived from N-nitroso-desmethyl-azithromycin |
| N-nitroso-desmethyl-erythromycin | Erythromycin | NMI | Limit derived from N-nitroso-desmethyl-azithromycin |
| N-nitroso-desmethyl-maralixibat | Maralixibat | 1500 | Negative bacterial reverse mutation test |
| N-nitroso-donepezil impurity A | Donepezil | 400 | CPCA Cat.3 |
| N-nitroso-N-methyl-benzylamine | 18 | CPCA Cat.1 | |
| N-nitroso-phenoxybenzamine HCl impurity A | Phenoxybenzamine HCl | 1500 | CPCA Cat.4 |
| N-nitroso-phenoxybenzamine HCl impurity B | Phenoxybenzamine HCl | 400 | CPCA Cat.3 |
| N-nitroso-torasemide | Torasemide | 1500 | CPCA Cat.5 |
| N-nitroso-tranexamic-acid dimer | Tranexamic acid | 1500 | CPCA Cat.4 |
2 Updated Nitrosamines
| NA | Source | AI(ng/day) | Note |
|---|---|---|---|
| N-nitroso-desmethyl-diltiazem | Diltiazem | 100 | Read across from NNK, Positive in in vivo test |
| N-nitroso-landiolol | Landiolol | 1500 | Negative bacterial reverse mutation test |
New Other N-nitroso-structure
| ONC | Source | AI(ng/day) | Note |
|---|---|---|---|
| N-nitroso-xylometazoline | Xylometazoline | 18 | In the absence of a suitable surrogate or specific carcinogenicity data for amidine-containing molecules the limit of 18 ng/day is based on the substance specific TTC as that dataset included “other nitroso” structures. |
N-nitroso-xylometazoline
What do you think about this? Please post your opinion.
9 Likes
I am somewhat undecided about the classification of N-nitroso-xylometazoline as an “other nitroso structure”.
I understand the limitations of applying the CPCA to this moiety, but the resulting AI of 18 ng/day effectively places it in the same potency as standard Class 1 nitrosamines.
In my view, this is a very interesting EMA precedent for future assessments of nitroso-amidines.
3 Likes
Agreed. When we decide on a conservative approach, it should be based on worst real world possible scenario, not the worst imaginable scenario. It seems that the latter was chosen.
2 Likes
The o-NNO (Other N-Nitroso Compounds) Working Group at HESI is developing a science-based framework for evaluating the genotoxic and carcinogenic potential of o-NNOs. In light of this ongoing work, I believe it is premature to establish a conservative acceptable intake limit of 18 ng/day for o-NNOs.
Reference:
Raphael Nudelman, Nudelman ChemTox Consulting, “Other N-Nitroso Compounds,” FY26 GDUFA Public Workshop, June 8–9, 2026.
https://www.fda.gov/media/194006/download
3 Likes
Nonetheless, I struggle to see any other limit w/o evidence to be based on. In such situation, and in general since years ago, the issue is the Cat 1 limit.
1 Like
You are right. Amidines are not included in the LCDB, with the exception of N-nitrosochlordiazepoxide. I do not think the available data support the assumption that N-nitroso amidines have high potency. Further investigation into their reactivity and mechanisms of mutagenicity is needed before establishing acceptable intakes for other N-nitroso compounds with unknown potency.
N-Nitrosochlordiazepoxide
3 Likes
The problem is we find ourselves in the same situation as in 2020. Lack of data defaults in absurdly low Acceptable Intakes, which then end up producing large headaches for companies, including recalls or simply discontinuation of a product. I think it is safe to say now, with the current knowledge on nitrosamines, that the AI of 18 ng/day is too low, specially for NDSRIs. Why would then we go back to establish the same limit for a molecule that is not even expected to go through the same metabolic pathway? Unless there is any suspicion that this may be expected to be a very potent nitrosamine somehow, and then, we would all benefit if that was also transparently explained.
5 Likes
i agree with Javier that is really frustrating to see again, for a NDSRIs, the limit of 18ng/day.
Apart of this, does anyone want to comment also for the appearance of N-nitrosotorasemide in this list?
We have tried before some years to purchase a relative reference and we have received 2 failure reports and a fake reagent which at the end was not the N-nitrosotorasemide.
Does any one have any updated information on its synthetic possibility?
thanks a lot,
Christos
what i could comment on failure report is related to another recently published NDSRI. back then, suppliers had revert with synthesis failure, but no it is apparent that some of them have eventually managed to synthesize the molecule. So, maybe it is the same for your molecule.
1 Like
I nonetheless wonder, if it takes a lot of fine chemistry to get something synthesized, is it really going to be happening significantly in a drug product? I have been telling this to some of the standard suppliers. It would be great not only to be able to get failure reports, but also to understand how they managed to synthesize the nitrosamine (and what failed during the way).
Did they try aqueous acidic conditions and failed once and again only to find that using high temperatures, specific nitrosating reagents and conditions to manage to get it? Then, is the nitrosamine unstable in aqueous media? does it require low temperatures for storage? All of that gives indications that maybe it may not be that relevant for a drug product
6 Likes
It is great that someone FINALLY claims this @JavierFernandez BIG THANK YOU.
I am thinking that during our huuuuge efforts to manage all the analytical requirements, we almost forget what it is relevant for the drug product (also in terms of actual practice and from the biochemistry perspective)
5 Likes
Released an updated version of EMA Appendix I (rev. 14), that includes 11 additional nitrosamines. To my surprise, N,N-dinitroso-desmethyl-sumatriptan has been added. Does this really make sense, considering the lower reactivity of the indole moiety? In other words, if N-nitroso-desmethyl-sumatriptan is not detected, does it make sense to look for the dinitrosated derivative? Also, what if less than 30% of the AI for the mononitrosated derivative is detected?
1 Like