Mark can you share your preliminary assessment on structures? I would be a tremendous didactic contribution!
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Community Members !!! @trust_user_a @trust_user_c @trust_user_b
By now, you are probably aware of the significant update published last Friday (July 7th) on EMAโs ๐๐ฎ๐๐ฌ๐ญ๐ข๐จ๐ง๐ฌ ๐๐ง๐ ๐๐ง๐ฌ๐ฐ๐๐ซ๐ฌ ๐๐จ๐ซ ๐ฆ๐๐ซ๐ค๐๐ญ๐ข๐ง๐ ๐๐ฎ๐ญ๐ก๐จ๐ซ๐ข๐ฌ๐๐ญ๐ข๐จ๐ง ๐ก๐จ๐ฅ๐๐๐ซ๐ฌ/๐๐ฉ๐ฉ๐ฅ๐ข๐๐๐ง๐ญ๐ฌ ๐จ๐ง ๐ญ๐ก๐ ๐๐๐๐ ๐๐ฉ๐ข๐ง๐ข๐จ๐ง ๐๐จ๐ซ ๐ญ๐ก๐ ๐๐ซ๐ญ๐ข๐๐ฅ๐ ๐(๐) ๐จ๐ ๐๐๐ ๐ฎ๐ฅ๐๐ญ๐ข๐จ๐ง (๐๐) ๐๐จ ๐๐๐/๐๐๐๐ ๐ซ๐๐๐๐ซ๐ซ๐๐ฅ ๐จ๐ง ๐ง๐ข๐ญ๐ซ๐จ๐ฌ๐๐ฆ๐ข๐ง๐ ๐ข๐ฆ๐ฉ๐ฎ๐ซ๐ข๐ญ๐ข๐๐ฌ ๐ข๐ง ๐ก๐ฎ๐ฆ๐๐ง ๐ฆ๐๐๐ข๐๐ข๐ง๐๐ฅ ๐ฉ๐ซ๐จ๐๐ฎ๐๐ญ๐ฌ - ๐๐๐๐๐ ๐ก๐๐ข๐๐ฉ๐จ ๐๐ฅ๐ฅ๐ก๐ฎ ๐๐ค๐ง ๐ฃ๐๐ฉ๐ง๐ค๐จ๐๐ข๐๐ฃ๐๐จ ๐๐ฃ ๐ข๐๐๐๐๐๐ฃ๐๐ก ๐ฅ๐ง๐ค๐๐ช๐๐ฉ๐จ?
But what you did not know is about the insightful conversation we are hosting here in the Nitrosamine Exchange about the update. Even graphics examples have been generated to illustrate the guidanceโs ranking framework!
Kudos to our community members @Yosukemino @Pradpharma @sushantkamath @David and @lucas10mauriz for driving the whole discussion about the guidance over the weekend as soon as the update got published!
This week, the industry is meeting EMAโs Nitrosamine Implementation oversight group (NIOG) to discuss the guidance, and Iโm sure additional details will also emerge from this meeting.
Stay tuned and share any insight!
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Of course @Naiffer_Host.
Back of an envelope scribblings at the moment, but will pull together something a little more explanatory tomorrow and share.
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Thanks for sharing! This post and all of the conversation that has been shared by others is very helpful to inform others of these very important changes.
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It is worth noting that while this is great progress, the CPCA categories are still quite conservative (which is acknowledged by EMA) and read-across might provide a more appropriate basis for an AI. For example, EMA has an AI of 78,000 ng/d for nitroso-mefenamic acid based on read-across from nitroso-diphenylamine. If they used a CPCA-derived AI rather than read-across, the limit would be 1500 ng/day (52-fold lower). Itโs important to continue to have the flexibility to use read-across when it can be justified, so hopefully a CPCA-derived AI is treated as a refined default (analogous to a tiered TTC approach) and not a firmly established AI.
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Dear @David
Thank you for your helpful and informative explanation. Of course, I remember you helped us in this community many times. And I want to illustrate your explanation to understand nitrosamines deeply.
If the most-hindered side is CH2, then whether the right-hand side is CH2 or CH3 makes little difference, both sides can react and highly-reactive diazonium ions can form, hence the score of 1 - reflected in a number of potent carcinogens that match this unhindered pattern.
Isopropyl groups, as I have been saying for a number of years, lead to a dramatic reduction in potency, hence the score of 3 for either (1,3) or (1,2).
Aryl groups are interesting, because there are a few potent examples such as nitrosomethyl aniline (NMA or NMPA) which explains the lower score for (0,3), and ethyl groups are just as reactive as methyl hence the exception in (0,2). All other groups (other than activating groups) are less labile, making the rest of (0,2) have a score of 3. These also have some potential alternative mechanisms not available to the isopropyl ones, hence the lower scores for NMA and nitrosoethylaniline and ring-substituted derivatives.
As a caveat, tert-butyl groups [(0,0) (0,1), (0,2), (0,3) where the 0 is sp3], as well as the fully-hindered (0,1) and (1,1) have an effective CPCA score of >5, enough to make them category 4 if they did need the CPCA but of course donโt need it, and the only (3,3) is NDMA - which of course has a compound-specific limit. This is why not all permutations are in the CPCA.
If I made a mistake, please point it out.
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N-Nitroso Orphenadrine.
Nitroso Orphenadrine AI limit 18ng/day currently published EMA Q&A Rev.16 aapendix1 as per option 1.
Although can we justify the limit based on read-across approach?
Toxicology data information for one chemical N-Methyl-N-nitrosoethanolamine (the surrogate chemical) is used to predict the same for another chemical (the target chemical), which is considered to be โsimilarโ on the basis of structural similarity functional group and chain length. Hence, common functional group or substructure (e.g., Aminoalkyl ethers) present in both chemical moiety of N-Methyl-N-nitrosoethanolamine as well as N-nitroso Orphenadrine impurity
N-Nitroso Orphenadrine
N-Methyl-N-nitrosoethanolamine
Data from surrogate chemical on either side of N-Methyl-N-nitrosoethanolamine can to be used of an TD 50 value as 1.29 (mg/kg/day) (Koepke SR et at., Cancer Res. 1988 Mar 15; 48(6):1533-6) to predict the Acceptable intake limit 1290ng/day for N-nitroso Orphenadrine impurity.
Lhasa Limited Carcinogenicity Database
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That looks about right - I think thereโs a few places where โany except hydrogenโ may apply, where you currently have a carbon (such as the top row of the aryls), but that might just muddy the watersโฆ
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That study certainly supports arguments for a limit higher than 18 ng/day, but looking into the details of it I suspect it is not sufficient by itself which would be why it wasnโt used.
- Single dose plus control
- Short study duration with respect to lifetime
- Only 20 male rats per dose group
In other words, there are several significant issues with the study. The lower CI is 0.522 mg/kg/day, which may be able to be argued for, and it should be noted that at the administered dose less than 50% of rats had tumours.
Watch out for an upcoming paper in RTP (Felter et al) where we dig into how to make use of these less-than-perfect studies in more detail.
Separately, the proposed analogue is a beta-hydroxy which is known to be potency-reducing, whereas in nitroso-orphenadrine the hydroxy has an aryl group on it which will significantly change the nature thereof, so the read-across may need additional justification.
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Certainly, itโs a bubbling of ideas! Thatโs how science works, thatโs how science thrives and evolves. @Naiffer_Host , the gratitude is all mine for the opportunity to be part of the community and contribute to this important discussion.
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Excellent summary! Clear, concise, direct, and very informative.
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Dear all,
how do you interpret the bold text in the last paragraph on page 27?
The Carcinogenic Potency Categorization Approach applies 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 (i.e., N-nitrosamides, N-nitrosoureas, N-nitrosoguanidines and other related structures are excluded). Additionally, the potency categorization approach does not apply to Nnitrosamines where the N-nitroso group is within an aromatic ring (e.g., nitrosated indole). For Nnitrosamines containing two N-nitroso groups, the group with the highest predicted carcinogenic potency (i.e., the group with the lowest numerical potency category) defines the AI for the entire molecule.18 The ฮฑ- and ฮฒ-carbons are defined relative to the N-nitroso group, as illustrated in Figure 1.
Is the CPCA not applicable here and we have to use 18ng/day as AI, or are nitrosamines based on these structures not to be considered at all? This would make life quite easy for all potential imidazole-based nitrosamines.
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This has the potential to be very positive for the industry but only if the FDA and Health Canada follow suit. Is there any information to indicate that the FDA and Health Canada will align their guidance to Rev.16 update of the EMA guidance?
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Fantastic thank you for this!
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As you know, if transgenic mice assays are done, most of these will be non-COC. this is what at one time I was pushing for endogenous nitrosation studies. I was thinking that even in some models, they can show that the secondary amines nitrosate, we can justify not controlling them at the ridiculous levels that were initially proposed. However, we should not be too excited, for high dose drugs, we still need to do work to make sure that the nitrosamines can be controlled above 1.5 mcg/day. I am especially worried about some antibiotics.
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Koepke worked downstairs from me and we both worked on beta hydroxy nitrosamines. This is just a one dose study. That is why it is not acceptable to the agencies. But there are drugs like orphenadrine where more work needs to be done.
I worked a lot with this compound and you are right David, this study was quickly done and had a different purpose.
As EMA was starting to look at nitrosamides, I wrote a white paper in a hurry to indicate that these are not nitrosamines but โNitrosamidesโ. I have a posting here โNitrosamides - horse of a different colorโ. These products are direct acting carcinogens and should not be treated as nitrosamines. So, you can do a general Ames assay to see if they are positive. also, treat them as mutagenic impurity and use SAR. Most of them will have higher limits. Again, they are not nitrosamines. So, dont apply any nitrosamine related limits to these. Also, they dont have to meet any nitrosamine related deadlines.
NitrosamidesโShould They Be Treated the Same as Nitrosamines?
Published on: October 15, 2022
Aloka Srinivasan, Chuck Lambert
Pharmaceutical Technology, Pharmaceutical Technology, Trends in Formulation, October 2022, Volume 2022 eBook, Issue 3
Pages: 42โ50
check my paper NitrosamidesโShould They Be Treated the Same as Nitrosamines?
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As we discussed, โdipinesโ are considered impossible to be synthesized. Example 1 may not be appropriate.
Example 1 โN-Nitroso-felodipine
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