For this class of nitrosamines, the read-across when setting limits can be quite challenging. We have seen the case of N-nitroso-varenicline (37 ng/day). This afternoon Dr. Nudelman presented the use of MW adjustment and ratios as a potential path to set AIs for complex Nitrosamines. @conudel would you help us understand bit more about that concept and how has been the regulatory acceptance of this concept? Thx
For our community members, any experience to share on the use of this option?
Worth noting: This concept (MW adjustment) has been supported as scientifically appropriate for TTC because the chemical activity should be considered on a molar (vs MW) basis. It has not (as yet) been taken up by regulators mostly because the initial analyses to support TTC were based on MW and regulators are used to setting limits based on MW. But, the principal is acknowledged as being scientifically supported (and in fact, preferred). This is described in the 2015 WHO/EFSA workshop: [https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/sp.efsa.2016.EN-1006]
In addition, scientifically it makes sense to use a molar conversion because after all we are talking about the number of nitrosamine molecules that a person is exposed to and not their weight. The bioburden causing mutations (without taking into account any other considerations) is a function of the number of nitrosamines that convert to diazonium that eventually react with DNA. A complex nitrosamine with a higher molecular weight has the same number of nitrosamine functional groups as a small nitrosamine and it will give the same overall number of mutations. That is the ultimate measure and not the weight of the nitrosamine. If anything, the higher molecular weight can only interfere with the CYP mediated bioactivation and also sterically hinder the reaction with with DNA. So overall the molecular weight has a large effect on the mutagenic activity.