Do Carboxylic/Sulfonic Acid Halides Really Present a Mutagenic and Carcinogenic Risk as Impurities in Final Drug Products?

A substantial amount of mutagenicity data on acyl/sulfonyl halides is available in the public domain, and these data are the basis for many in silico models of mutagenicity (e.g., Derek Nexus and Leadscope). A review of these data indicates that the perceived mutagenic potential of this class of compounds is based on a number of nonreproducible positive findings in the bacterial mutagenicity assay and positive bacterial mutagenicity data on a series of compounds where formation of reactive halodimethyl sulfides (HDMSs) in DMSO may have compromised the interpretation of the Ames data (HDMSs are typically mutagenic). The only genuine mutagenic, genotoxic, and carcinogenic compound within the 50+ acyl/sulfonyl halides described herein is dimethylcarbamic chloride, which is appropriately considered to be a potential human carcinogen. Some in silico systems, such as Derek Nexus, contain rules detailing that the activity of this class should be considered a false positive flag for mutagenicity, and ideally, any...