Unofficial/official surrogates for read-across

[Yosukemino]

Except for the guidance, there are some official/unofficial surrogates for the read-across method in this Nitrosamine Exchange. I will pick them up for your practice. Please keep in mind that not all of them are correct.

N-nitroso desloratadine?

Hello Experts, I would like to know whether any Agency has adopted an official limit for N-nitroso desloratadine which is categorized as class 3 compound as per QSAR (Expert and statistical based rule). Can we apply TTC limit as it is classified under class 3 compund? Your views are very much appreciated. Thanks

Limit for Nitroso Atenolol

Anyone having idea about AI limit of Nitroso Atenolol? What could be the AI limit as per read across approach?

Nitroso Flecainide

Anyone having idea about AI limit of Nitroso Flecainide? What could be the AI limit as per QSAR and read across approch?

[Yosukemino]

AI limit for N-nitroso betahistine?

Hello Experts, Recently it has been came to the notice that N-nitroso betahistine is one of the NDSRI in the betahistine formulation whose limit has not been defined by any of the regulatory authority. Could any one suggest any AI limit based on the read across approach or literature based or any other leads? Your views are very much appreciated. Thanks, Sumit

AI Limit for Nitroso Nebivolol

Hi Everyone, Recently it has been came to the notice that N-nitroso nebivolol is one of the NDSRI in the Nebivolol Tablets formulation whose limit has not been defined by any of the regulatory authority. Could any one suggest any AI limit based on the read across approach or literature based or any other way? Someone can help me to prepare justification report based on PDE, read across, Q (SAR) for set the AI limit for N-nitroso nebivolol. As per my little bit knowledge gain by above literat…

Limit for Nitroso Ciprofloxacin

Anyone having idea about AI limit of Nitroso Ciprofloxacin? What could be the AI limit as per read across approach?

[Yosukemino]

Pfizer Japan to Curb Shipments and Recall Amoxapine over Carcinogen Risks

Pfizer is restricting the shipments of and eventually plans to recall its antidepressant Amoxan (amoxapine) in Japan after detecting cancer-causing impurities. When I get further information, I will post it. [image] Amoxapine

N-Nitrosobupropion

Hi !!! It has been came to the notice recently that N-nitroso bupropion is one of the NDSRI in Bupropion formulations whose limit has not been defined by any regulatory agency. What will be the AI of N-nitroso bupropion ???

Phathom Pharmaceuticals reported that it has detected trace levels of a nitrosamine impurity in their vonoprazan-based products (may be NDSRI, nitroso-Vonoprazan ? ) that is not described within the FDA Nitrosamine guidance document

Phathom Pharmaceuticals reported that it detected trace levels of a nitrosamine impurity (may be NDSRI, nitroso-Vonoprazan ?? ) that is not described within the FDA guidance document entitled “Control of Nitrosamine Impurities in Human Drugs – Guidance for Industry.” The Company is working with the FDA and plans to obtain approval of and implement an additional test method, specification, including a proposed acceptable intake limit, and additional controls to address this impurity prior to rele…

[1nsekt]

I think is a good approach. I belive You’ve used this publication to establish AI’s? https://pubs.acs.org/doi/10.1021/acs.chemrestox.1c00369

[Yosukemino]

Thank you for asking, @1nsekt. We’ve used it for beta-blocker and amoxapine. And Ministry of Health, Labour and. Welfare, Japan accepted the AI calculated by the strategy you referred to at amoxapine. The risk assessment report of amoxapine translated into English by DeepL translate is as follows;

001004627 en-US.pdf (600.5 KB)

[1nsekt]

Looking for a direct structural similarity seems to always be the best approach.
However, methods presented by LHASA, i.e. the categorization of nitrosamines according to the groups nearby to nitrosoamine and assigning the appropriate effect on TD50 would be more universal https://pubs.acs.org/doi/pdf/10.1021/acs.chemrestox.2c00199 (and his previous paper Developing structure-activity relationships for N-nitrosamine activity - ScienceDirect).
However, the original approach, i.e. converting the molar mass, seems to be inapplicable, as some cases differ greatly - especially the benzyl, ethyl and methyl derivatives of nitrosamines, which are far more potent carcinogens.