Officially used surrogates for read-across method

[Yosukemino]

I want to visualize surrogate compounds used for read-across by EMA.

1. NDEA
   NDEA applies to five compounds. NDEA is well-known and has sufficiently robust toxicological data.
   

   

2. NDMA
   NDMA applies only to NMBA, despite its robust toxicological data.
   

3. NTHP
   There are compounds for NDSRI from here. NTHP is used for two, NNV and N-nitroso sitagliptin. The double bond of NTHP is the key feature.
   

   

4. N-Nitrosopiperidine
   N-Nitrosopiperidine applies to NMPH. The AI of 1300 ng/day is almost the same as TTC in ICH M7. I think MeNP looks more similar to this compound than NDEA…
   

5. NMPEA
   NMPEA has an AI of 8 ng/day, less than a class specific threshold of 18 ng/day.
   

Nitrosamines with class specific threshold(18 ng/day):

Now the number of listed compounds is increasing through the update of EMA Q&A. Let’s collect examples of read-across in this thread!!

[Filip]

I hope its OK to post this question here,

does anyone have any experience with the acceptance (or non-acceptance) of regulatory authorities of limits determined by read-across approaches described in the article by Krista L. Dobo et al., (2021) " Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N -Nitrosamine Impurities" ? Has anyone used this article to justify higher limits and was accepted?

Thanks,
Kind Regards, Filip

[Jernej]

In this document (10th revision of Q&A document) EMA established AI 18 ng/ day for N-Nitrosorasagiline and N-Nitrosodabigatran. They stated that Limit was based on a class specific threshold of theoretical concern (TTC) of 18 ng/day.
Perhaps someone knows why they would highlight only these two compounds?
Since they specified their AI, the use of a read-across approach for these two compounds is not possible?
Does anyone have any feedback from the regulatory authorities?

[sumitkumarjain]

Hi Filip,

We have used this approach and are waiting for the Health Authority feedback.

[Nilesh]

@Yosukemino
Excellent one

[Yosukemino]

6. NNK
   NNK is a new example included in EMA Q&A rev12.

[Hinishant]

Hi my question is that the TTC of 18 ng/Day for Nitrosamines not listed in Guidance documents given by the Health Canada is Acceptable to all Regulatory Authorities Including USFDA

[hgajjar]

Can we apply NNK or 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol limit as a read across for N-Nitroso N-Desmethyl Citalopram

NNK AI: 100 ng/day (Ref. HC/EMA)

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol AI: 103 ng/day (Ref. LCDB)

[Yosukemino]

Hi, @hgajjar.
I’m sorry for the delayed response. And I’m not a toxicological chemist. When I took the same approach as the article by Krista L. Dobo et al. (2021) " Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N -Nitrosamine Impurities " to the N-Nitroso N-Desmethyl Citalopram, I searched the following structure on LCDB.

Then eight nitrosamines were on the list.

And the lowest GOLD TD50 was from NNK(0.0688mg/kg/day). I’m not sure why the TD50 of NNK was calculated as 100ng/day, but I think NNK is good for the surrogate.

[Yosukemino]

4-2. N-Nitrosopiperidine

6-2. NNK

7. NDPh
   
   

[Pradpharma]

Thanks for sharing Read-across

[Crystal]

Nice sharing Thank you.

[Naiffer_Host]

Any additional update here?

[Yosukemino]

I want this thread to stay in the range of the guidance. I will add new cases after the update of the guidance. And other surrogates will be summarized in the new threads, official/unofficial surrogates.

[ysreddy2u]

For US it should be 26.5 ng/day