CPCA Category 5 (AI 1500 ng/day) for NDIPA by Health Canada

Hello, Can someone please provide rationale for CPCA Category 5 (AI 1500 ng/day) for NDIPA by Health Canada. Your kind response is highly appreciated please.

Tagging @David on this one…

I would say that this is where this compound ought to be, and this is a welcome reassessment - metabolic activation is significantly hindered, and the Druckrey carc data would estimate that it would be less than half as potent again as the limit (Lhasa TD50 - the data wasn’t in CPDB, but we added it to LCDB and can calculate a TD50). Obviously this data is insufficiently robust in its own right, otherwise it would have been used, but with the support of the work that has been published over the last few years - Cross and Ponting, Thomas et al, Ponting et al, Dobo et al, Kruhlak et al and more - it is time for what had at the time been a real shock to be addressed and NDIPA moved in line with the CPCA. I would hope that additional health authorities might follow suit soon.

For some historical context, others who were involved in the crisis back in 2020 might remember the surprise that the reading-across of this to NDEA was, but before all of the SAR work that could support the potency difference to NDEA, this was the best that could be done! It was clear there should be a significant potency difference, but the magnitude thereof couldn’t be evaluated with enough confidence to be sure that 1500 would be a protective limit; the need for the research to support this sort of assessment was one of the initial drivers of the SAR work that we then performed.

Incidentally, of all the compounds that fall into category 5, I would expect this to be comfortably the most potent, being the smallest and least-hindered molecule. Most that we have are actually negative; the other notable positive is NDPhA, which is much less potent again.