EMA Q&A Appendix 1 is updated Sept 4, 2024

Limits of Nitrosamines
10

Hi @chrischar,

I want to remind you that the Japanese government did not accept Lilly’s approach which assigned an AI of 4400ng/day or 1500ng/day (not COC) for N-nitroso atomoxetine from BMDL in in vivo test and other evidence. The points are as follows;

  • N-nitroso atomoxetine is classified as class 2 under ICH M7 because it is positive in in vitro and in vivo mutation tests. The maximum AI for class 2 is 1500 ng/day.
  • ICH M7 Q&A #7.2 explained that in vivo gene mutation assays alone are currently not validated to directly assess cancer risk because the endpoint is mutation and not carcinogenicity (i.e., they are used for hazard identification)
  • The FDA, EMA, and TGA have announced that the AI of N-nitroso atomoxetine is 100 ng/day, but there is currently no information available on any recalls or other measures being taken.

As far as I know, no regulatory authority has accepted this innovative approach. It will probably take some time before the AI calculation from in vivo test is accepted.

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