Chemical reagents as potential impurities of pharmaceutical products: investigations on their genotoxic activity.

The genotoxic activity of chemical reagents and intermediates as potential impurities of final pharmaceutical products have been investigated by the AFI Mutagenesis Study Group. A number of compounds employed in the synthesis of beta-lactam (12), quinolone (6), antiviral (3), and other drugs (11) were analyzed. The information reported in this article was mainly obtained experimentally in our laboratories. In addition, attempts were made to obtain reference data; however, these were available for only a few compounds. The genetic end-point taken into account was principally gene mutation in bacteria. All chemical reagents used in the synthesis of quinolones and antivirals were negative in the Ames test. As far as reagents employed in beta-lactam synthesis were concerned, genotoxic activity was shown by the alkylating agents bromomethanol acetate and chloromethanol acetate, by carbon disulfide, and by the different dimethylanilines. The other chemicals generically considered as involved in "other syntheses" did not induce gene mutation, except for 2,5-dibromopentyl acetate, which was positive in the Ames test. For this compound, as for the halogenated methanol acetates, genotoxic activity was expected in view of its alerting chemical structure.