Limit for Nitroso Ramipril

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

I would like to share some theoretical considerations on N-nitroso Ramipril.

Considering the the great similarity between Ramipril:
and Imidapril:

(they slightly differ only in the structure of the pyrrolidine ring)

The following nitrosation study on Imidapril and its diketopiperazine may be significant also for Ramipril.

“Imidapril and its DKP after nitrite treatment give a negative result in the Ames test with S. typhimurium TA 98 and TA 100 strains, both with and without metabolic activation system (S9 mix). These results indicate that the in vivo nitrosation of IMD and its degradation impurity probably has no impact on cancer initiation by the mechanism of mutagenesis studied in our research”

However, it should be emphasized that only two strains of Salmonella (TA98 and TA100) were used in this study against the 5 strains recommended by the OECD 471 guideline:

  1. S. typhimurium TA1535, and
  2. S. typhimurium TA1537 or TA97 or TA97a, and
  3. S. typhimurium TA98, and
  4. S. typhimurium TA100, and
  5. E. coli WP2 uvrA, or E. coli WP2 uvrA (pKM101), or S. typhimurium TA102.

However, these two strains (TA98 and TA100) appear to detect 93% of the mutagenic substances detected in the “complete” Ames test, so in my personal opinion the above study is quite reliable:

An Ames test with only two strains is generally considered a “mini-Ames test” and I don’t think that it may be accepted at a regulatory level.
Moreover the study was not performed on the impurity itself, but on the mixture of Imidapril and its diketopiperazine +nitrite, so we do not know if the conversion of Imidapril to N-nitroso Imidapril was complete or not.

Summarizing, in order to confirm that N-nitroso-Ramipril is NOT mutagenic, you must carry out the complete Ames test (according OECD 471) on the impurity N-nitroso Ramipril.

In the meantime, the above consideration may be useful to propose an interim limit of 1500 ng/day (standard TTC of ICH M7 guideline), excluding N-nitroso Ramipril from the Cohort of Concern.

Disclaimer: this is only my personal opinion, not an official position of my company. Nor Ramipril, nor Imidapril are part of our portfolio.
kind regards