The latest FDA guidance is allowing to define acceptable intakes for NDSRIs based on several approaches namely by CPCA, read-across or established toxicity.
It also allows us to support the toxicity assessment via the use of EAT or in-vivo mutagenicity studies (ex: mutamouse).
However, I am struggling to understand the FDA position in case of a positive EAT or in-vivo mutagenicity study. In this respect, the EU guidance defaults to the CPCA categorization.
Q: Does anyone have any experience on the FDA expectations in case of a positive read-out during safety assessment? Is it expected that the acceptable intake of an NDSRI is defined by the CPCA approach or is a justified read-across sufficient/also acceptable?
When positive results shown in EAT, it doesn’t affect the AI setting of nitrosamines. So CPCA and read across are both available. You don’t have to hesitate testing EAT. We discussed in symposium in Japan that conventional AMES tests might be enough for nitrosamines which positive results are expected.
But we should be careful that FDA doesn’t show their position to the Negative Results of EAT and in vivo mutagenicity tests. They are still likely to be one of WOE.
As per my understanding US FDA has different views when compared to EMA on using experimental toxicological data.
Nevertheless, in one case FDA dealt similar to EMA. N-nitroso propranolol is positive in EAT but the limit set to 1500 ng/day by both FDA and EMA based on CPCA. This is one aspect.
Coming to another aspect on weighing a value on experimental toxicological data, EMA looks clear and allowing a relaxation if experimentally a nitrosamine found to be not of concern. However, FDA still sticks to CPCA despite of data availability (or FDA might not have reviewed that data so, still sticking to CPCA- That could be also reason!)
So, sticking to CPCA- FDA might allow.
However, this looks strange for me generally in vitro or in vivo overrides in-silico. But currently for nitrosamines it is taking different angle!!