Hi all 
I have attended a few courses/workshops last year and earlier this year, where it was discussed that HESI Group explores whether a negative EAT could result in an AI established as per ICH Q3B.
Is it something which is still under discussion? Are there any updates on the same? Are there any papers or official docs that I could navigate through?
Thank you in advance!
Hi Eleni,
I am not sure whether is under discussion or not, but at this time, a negative EAT would only grant you an AI of 1.5 µg/day. In order to be able to classify a nitrosamine as non mutagenic and control it according to ICH Q3B you need a negative result in an in vivo assay (transgenic rodent).
While it would be great that an EAT would be enough, I personally would not expect that to happen any time soon.
Indeed, I am aware of the currently effective regulations but also curious (for my reference) whether any publication discuss anything on EAT results in relation to future AI establishment, mostly because I have heard the same during the conferences!
Thank you for your kind feedback
Dear @romnaiffer
do you trust that is there any member who could provide supporting doc on the same?
it would be really appreciated! thank you
Considering the recent FDA update. At least in the US I see a long way forward prior to acceptance of a -tive EAT at ICH Q3A/B levels.
Also, we have the case of N-Nitroso Sertraline that was -tive in an Ames test (not sure if a EAT) and +tive In-vivo. That is the 1st case this happens for NDSRIs.
Hi Diego, is this case published? It’s the first time I hear about this.
HI @fernandaw,
This info was part of the recent update of EMA Appendix 1 from the 1st Sep. 2024. Previously N-Nitroso Sertraline was moved from 100 ng/day to 1500 ng/day based on a negative Ames test (not sure if an EAT, as EMA at that time gave a transition period where “normal” Ames would be still acceptable).
Thank you @Diego_HM!!
Diego_HM
Thank you for your input and clarifications.
FDA scientists have obtained a positive in the EAT for N-nitroso-sertraline (reported May 2024, CAS number was not provided, cf. stereochemistry), so it is not per se the example for a first time that a consistent (E)AT negative yields an in vivo positive in my opinion.
@ccdw
thank you for your feedback.
As I can understand the investigations of HESI are still ongoing on the same, ie negative EAT → ICH Q3B.
At this time, please let me clarify that I am trying to figure out whether a negative conducted EAT, along with literature data support non carcinogenicity can conclude AI as per ICH.
The limitation here is that noncarcinogenicity is based on studies completed back in 1980. However recent article (2022) still accepts the validity of the said study…
Thank you
