AI value for Nitroso Folic acid

[hgajjar]

Hello experts, What could be the limit for Nitroso Folic acid based on read across?. We have been asked by Health Canada to provide results and to propose a limit for same. Is there any literature or study available to de-risk Nitroso Folic acid?

[Naiffer_Host]

Please feel free to review and engage with previous post on this

CMHP meeting from January: N-nitroso-Mefanamic Acid & N-Nitroso-Folic Acid

The European committee for Medicinal Products for Huma Use (CHMP) held its January meeting on 24/27 Jan 2022. Report attached: IDRAC_341767_18-Mar-2022_CHMP 24_27-Jan-2022 Meeting.pdf (3.3 MB) CMDh question to Safety Working Party (SWP) to determine the acceptable intake for nitrosamine N-nitroso-Mefanamic Acid based on lifetime daily exposure including information on the points of departure and methodology used. [image] Update on Q&A for marketing authorization holders/applicants on the …

[hgajjar]

In my knowledge, one of the API supplier has done the AMES test and found negative. The test was run using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and E. Coli WP2uvrA (pKM101) strain. Does anyone provide guidance on how to proceed further with Health Authority based on AMSE study?. What kind of supportive information or any additional study will be needed to support de-risking?

[Pradpharma]

Thanks for sharing this @hgajjar -Harish.
I can suggest following based on my experience/knowledge.

1. Start dialogue with the Agency- Agency would be interested to review in detail the conduction of Ames assay and design. If flaws observed- it may straight away reject. If success, follow the next step
2. In parallel, try to build WoE with SAR and few additional justifications (experimental and theoretical).
3. Maximum in the current context, the agency may recommend to go for follow-up in vivo testing.

Nevertheless, taking actions of 1&2 will help to save the product by not following default TTC limits!

Request others also to share inputs- If anything more we can do.

[Yosukemino]

Now AI of nitroso-folic acid is included in EMA appendix 1. As @hgajjar explained, 1500 ng/day is applicable based on negative bacterial reverse mutation test.