Appendix 1 - rev 13 just published
260605_appendix-1-acceptable-intakes-established-n-nitrosamines_en.pdf (1.8 MB)
New and updated AIs included in the pdf for ready ref. Also note has been included for previous Acceptable intake.
new-and-update-260301-260601.pdf (288.0 KB)
BR
Thank you for sharing information, Eleni.
As far as I know, this is the first time that BMDL10 has been used to determine the acceptable intake (AI) of nitrosamines. The resulting AI exceeds 1500 ng/day. This NTMZ may therefore be used as a surrogate for nitrosamines containing a piperazine ring.
I found that control according to ICH Q3A/B is justified for N-nitroso-N-descyclopropanecarbaldehyde olaparib.
According to EMA Q&A (Q10), if the active substance itself is mutagenic or clastogenic at therapeutic concentrations, N-nitrosamine impurities should be controlled at limits for non-mutagenic impurities according to ICH M7(R2).
To our knowledge, this is also the first such case.
Monumental changes. It will be interesting to see where this leads the current set of controlled nitrosamines in coming months.
In Rev.12, meglumine is described as a “CPCA derived AI as substance tested positive in in vivo mutagenicity study,” with an AI of 100 ng/day.
In contrast, Rev.13 states “Limit based on negative bacterial reverse mutation test,” without any explicit notification of the change, and the AI is set at 1500 ng/day.
This substantial change may suggest that the in vivo study results have been re-evaluated; however, the details are not clear from the publicly available information.
Does anyone have further insight on this?
Also the AI for N-nitroso-desmethyl-diltiazem was removed. What could this indicate?
This is really crazy. How can we possibly hit a moving targets?
Hi, yes but its BMDL AI Derivation based on in vivo carcinogenicity study which is not TGR Mutation Assay I believe…the breakthrough would be if the BMDL AI Derivation would be possible based on in vivo mutageniity no?
The Limit for N-nitroso-meglumine was updated today - they included the previous limit again. Was the deletion of the Limit for N-nitroso-desmethyl-diltiazem perhaps also a mistake?
this was my first though when i saw that!!!…The new limit is about 10 times higher than the ‘‘usual’’ 1500ng/day!!
Monumental error I believe…
It looks like my inquiry to EMA paid off. 
According to the person who sent me the email, it seems it was just a mistake.
I have seen a couple of posts saying that N-nitrosomeglumine AI has been changed back to 1500 ng/day. Is that right? I have been checking and, to me, Rev. 13 shows N-nitrosomeglumine at 100 ng/day
It appears that there was a confusion. The previous values along with the justification of that value indicated in the last column have been considered as the current change (1500 - NEGATIVE EAT).
The current AI is 100ng/day since 15 February 2024 (update) based on CPCA derived AI as substance tested positive in in vivo mutagenicity study.
Hi!
You will never get access to such data, since it is not publicly available. Since it is listed by EMA, that should be sufficient as the fact that a Regulatory Authority has indeed reviewed the study. The only problem is that sometimes other authorities may not absolutely accept this, at least to directly control according to ICH Q3A (FDA being the most relevant one).
In any case, it should be sufficient to at least start a discussion with the Korean Authority. It cannot be expected that studies such as TGR are duplicated, it would be nonsense
Hello,
Could you please let me know how I can access previous revisions of the Appendix-1? I need to review an older version for a specific matter.
I am afraid this is not available.
however, which version you re looking for?
What are you referring to being a mistake?
Hi Hasan,
i have kept some older versions of Apeendices-1 in my files.
Which one do you want?
please share an e-mail so in case i have this available to send to you
kind regards
Christos
Hello,
Thank you for your request for assistance. I was able to obtain the necessary document from someone else
