# EMA - Appendix - rev 13 **URL:** \ **Category:** Toxicology\ **Tags:** ema, Limits\ **Created:** [June 5, 2026, 9:29am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104 "2026-06-05T09:29:47Z")\ **Posts on this page:** 20\ **Page:** 1
**Author:** ![elenipoliti](https://sea3.discourse-cdn.com/usp/user_avatar/knowledgeexchange.usp.org/elenipoliti/32/2499_2.png) [@elenipoliti](https://knowledgeexchange.usp.org/u/elenipoliti)\ **Post date:** [June 5, 2026, 9:29am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/1 "2026-06-05T09:29:47Z")
Appendix 1 - rev 13 just published [260605\_appendix-1-acceptable-intakes-established-n-nitrosamines\_en.pdf](https://knowledgeexchange.usp.org/uploads/short-url/uhpX02alJXTZmrz4x2zwcoqf5zW.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](https://knowledgeexchange.usp.org/uploads/short-url/1q1sRMveiPLP0wjYNgAqnn0S51j.pdf) (288.0 KB) BR ---
**Author:** ![Yosukemino](https://sea3.discourse-cdn.com/usp/user_avatar/knowledgeexchange.usp.org/yosukemino/32/519_2.png) [@Yosukemino](https://knowledgeexchange.usp.org/u/Yosukemino)\ **Post date:** [June 6, 2026, 5:28am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/2 "2026-06-06T05:28:54Z")
Thank you for sharing information, Eleni. ![image](https://us1.discourse-cdn.com/usp/original/2X/3/3bb0ea88b74882bddfe2fe24341e5d5a7875f4e0.png) 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. ---
**Author:** ![Yosukemino](https://sea3.discourse-cdn.com/usp/user_avatar/knowledgeexchange.usp.org/yosukemino/32/519_2.png) [@Yosukemino](https://knowledgeexchange.usp.org/u/Yosukemino)\ **Post date:** [June 6, 2026, 5:46am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/3 "2026-06-06T05:46:35Z")
I found that control according to ICH Q3A/B is justified for N-nitroso-N-descyclopropanecarbaldehyde olaparib. ![image](https://us1.discourse-cdn.com/usp/original/2X/a/aabadb5fcecacec48d22f37cdc383f7a19f6c7b4.png) 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. ---
**Author:** ![jason.brown](https://sea3.discourse-cdn.com/usp/user_avatar/knowledgeexchange.usp.org/jason.brown/32/2712_2.png) [@jason.brown](https://knowledgeexchange.usp.org/u/jason.brown)\ **Post date:** [June 6, 2026, 10:07am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/4 "2026-06-06T10:07:26Z")
Monumental changes. It will be interesting to see where this leads the current set of controlled nitrosamines in coming months. ---
**Author:** ![Tokumei](https://avatars.discourse-cdn.com/v4/letter/t/f14d63/32.png) [@Tokumei](https://knowledgeexchange.usp.org/u/Tokumei)\ **Post date:** [June 9, 2026, 12:47am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/5 "2026-06-09T00:47:42Z")
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? ---
**Author:** ![hwnra](https://avatars.discourse-cdn.com/v4/letter/h/f04885/32.png) [@hwnra](https://knowledgeexchange.usp.org/u/hwnra)\ **Post date:** [June 9, 2026, 12:28pm UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/6 "2026-06-09T12:28:42Z")
Also the AI for _N-nitroso-desmethyl-diltiazem_ was removed. What could this indicate? ---
**Author:** ![Igor](https://avatars.discourse-cdn.com/v4/letter/i/dec6dc/32.png) [@Igor](https://knowledgeexchange.usp.org/u/Igor)\ **Post date:** [June 9, 2026, 1:22pm UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/7 "2026-06-09T13:22:34Z")
This is really crazy. How can we possibly hit a moving targets? ---
**Author:** ![Igor](https://avatars.discourse-cdn.com/v4/letter/i/dec6dc/32.png) [@Igor](https://knowledgeexchange.usp.org/u/Igor)\ **Post date:** [June 9, 2026, 1:55pm UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/8 "2026-06-09T13:55:21Z")
> [@Yosukemino](#): > > I know, this is the first time that BMDL10 has been used to determine the acceptable intake (AI) of nitrosamines. 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? ---
**Author:** ![hwnra](https://avatars.discourse-cdn.com/v4/letter/h/f04885/32.png) [@hwnra](https://knowledgeexchange.usp.org/u/hwnra)\ **Post date:** [June 10, 2026, 5:58am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/9 "2026-06-10T05:58:04Z")
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? ---
**Author:** ![chrischar](https://avatars.discourse-cdn.com/v4/letter/c/c4cdca/32.png) [@chrischar](https://knowledgeexchange.usp.org/u/chrischar)\ **Post date:** [June 10, 2026, 6:58am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/10 "2026-06-10T06:58:37Z")
> [@Yosukemino](#): > > This NTMZ may therefore be used as a surrogate for nitrosamines containing a piperazine ring. this was my first though when i saw that!!!…The new limit is about 10 times higher than the ‘‘usual’’ 1500ng/day!! ---
**Author:** ![Igor](https://avatars.discourse-cdn.com/v4/letter/i/dec6dc/32.png) [@Igor](https://knowledgeexchange.usp.org/u/Igor)\ **Post date:** [June 10, 2026, 1:30pm UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/11 "2026-06-10T13:30:43Z")
Monumental error I believe… ---
**Author:** ![Yosukemino](https://sea3.discourse-cdn.com/usp/user_avatar/knowledgeexchange.usp.org/yosukemino/32/519_2.png) [@Yosukemino](https://knowledgeexchange.usp.org/u/Yosukemino)\ **Post date:** [June 10, 2026, 2:24pm UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/12 "2026-06-10T14:24:26Z")
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. ---
**Author:** ![JavierFernandez](https://avatars.discourse-cdn.com/v4/letter/j/9de053/32.png) [@JavierFernandez](https://knowledgeexchange.usp.org/u/JavierFernandez)\ **Post date:** [June 12, 2026, 8:55am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/13 "2026-06-12T08:55:13Z")
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 ---
**Author:** ![mflorea](https://avatars.discourse-cdn.com/v4/letter/m/eb9ed0/32.png) [@mflorea](https://knowledgeexchange.usp.org/u/mflorea)\ **Post date:** [June 12, 2026, 4:48pm UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/14 "2026-06-12T16:48:39Z")
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. ---
**Author:** ![JavierFernandez](https://avatars.discourse-cdn.com/v4/letter/j/9de053/32.png) [@JavierFernandez](https://knowledgeexchange.usp.org/u/JavierFernandez)\ **Post date:** [June 15, 2026, 7:47am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/15 "2026-06-15T07:47:47Z")
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 ---
**Author:** ![Hasan\_T](https://avatars.discourse-cdn.com/v4/letter/h/edb3f5/32.png) [@Hasan\_T](https://knowledgeexchange.usp.org/u/Hasan_T)\ **Post date:** [August 31, 2026, 5:27am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/16 "2026-08-31T05:27:34Z")
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. ---
**Author:** ![elenipoliti](https://sea3.discourse-cdn.com/usp/user_avatar/knowledgeexchange.usp.org/elenipoliti/32/2499_2.png) [@elenipoliti](https://knowledgeexchange.usp.org/u/elenipoliti)\ **Post date:** [August 31, 2026, 5:46am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/17 "2026-08-31T05:46:34Z")
I am afraid this is not available. however, which version you re looking for? ---
**Author:** ![Emelia](https://sea3.discourse-cdn.com/usp/user_avatar/knowledgeexchange.usp.org/emelia/32/2521_2.png) [@Emelia](https://knowledgeexchange.usp.org/u/Emelia)\ **Post date:** [September 14, 2026, 5:27pm UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/18 "2026-09-14T17:27:12Z")
What are you referring to being a mistake? ---
**Author:** ![chrischar](https://avatars.discourse-cdn.com/v4/letter/c/c4cdca/32.png) [@chrischar](https://knowledgeexchange.usp.org/u/chrischar)\ **Post date:** [September 17, 2026, 8:15am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/19 "2026-09-17T08:15:12Z")
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 ---
**Author:** ![Hasan\_T](https://avatars.discourse-cdn.com/v4/letter/h/edb3f5/32.png) [@Hasan\_T](https://knowledgeexchange.usp.org/u/Hasan_T)\ **Post date:** [September 17, 2026, 11:51am UTC](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104/20 "2026-09-17T11:51:39Z")
Hello, Thank you for your request for assistance. I was able to obtain the necessary document from someone else [Next page](https://knowledgeexchange.usp.org/t/ema-appendix-rev-13/17104.md?page=2)