Dimethylacetamide pharmacokinetics following inhalation exposures to rats and mice

Abstract

Whole-body inhalation exposures to N, N-dimethylacetamide (DMAC) were conducted with male rats (Crl:CD®BR) and mice (Crl:CD-l®(ICR)BR). Exposure concentrations were 50, 150, 300 and 500 ppm. The exposure routines consisted of single 1-, 3-, or 6-h exposures and ten 6-h exposures (10 exposure days in 2 weeks). Area under the plasma concentration curve (AUC) values were determined for DMAC and its metabolite N-methylacetamide (NMAC), following 6-h exposures (single exposure or last in a series of 10 exposures). The range of exposures was chosen to assess the exposure-dependent nature of DMAC pharmacokinetics in rats and mice. Plasma profiles indicated mice metabolized DMAC rapidly with plasma half-lives from 0.3 to 0.5 h for DMAC. The DMAC AUC values from mice were underestimated due to the required time (< 30 min) between termination of exposure and the initial blood sample. DMAC plasma half-life in rats ranged from 0.6 to 1.5 h. The AUC values for DMAC in rats increased approximately 5-fold and 3-fold as exposure concentrations increased from 150 to 300 ppm and 300 to 500 ppm, respectively. NMAC persisted in plasma for at least 24 h after the 150, 300 and 500 ppm exposures to rats. NMAC was not detected in plasma from mice beyond the 12-h post-exposure timepoint for the 300 and 500 ppm exposures. Regardless of exposure level, repeated DMAC exposures to both rats and mice resulted in plasma profiles of DMAC and NMAC similar to those from a single exposure. The dose-dependent nature of the DMAC AUC data and the absence of effects of repeated 300 and 500 ppm DMAC exposures supported a toxicity-driven upper limit of 350 ppm for a chronic inhalation study.