Unnecessary Development of Highly Sensitive Assays for Potentially

Letter to the Editor pubs.acs.org/OPRD

Unnecessary Development of Highly Sensitive Assays for Potentially Mutagenic Impurities (PMIs)

I

Compound-specific mutagenicity/carcinogenicity data are available on three compounds (methyl carbazate, ethyl chloroformate, and formaldehyde), whereas read-across from model compounds is necessary for boc-S-3-amino-3-phenylpropanal and tetrafluorobenzoyl chloride. When literature data demonstrate only that a compound is Ames’-negative, the normal ICH Q3A/B qualification thresholds can be employed for limitsetting purposes. Acid chlorides should be considered as special cases in a number of respects. First, there are many examples of Ames’-negative acid chlorides in the literature, and second any Ames’-positive result should be treated with caution since acid chlorides are known to react with DMSO (the default solvent for the Ames’ assay) to form mutagenic chloromethylmethyl sulfide.3 An example is the description of 2,5-dichlorobenzoyl chloride by Fu et al.4 as “genotoxic” (claimed to be based on a Derek evaluation), whereas literature data indicate a lack of mutagenic activity when tested in five bacterial strains using anhydrous acetone as solvent.5 A further, similar case is provided by 4-chlorobutyryl chloride which is considered by Raman et al.6 as “genotoxic”, leading to the development of an assay method capable of detecting