Dimethylformamide pharmacokinetics following inhalation exposures to rats and mice

Whole-body inhalation exposures to N,N-dimethylformamide (DMF) were conducted with rats and mice. The exposure concentrations were 10, 250, and 500 ppm DMF. The exposure routines consisted of single 1-, 3-, or 6-hour exposures and ten 6-hour exposures (ten exposure days in 2 weeks). Area under the plasma concentration curve (AUC) values were determined following exposure for DMF and "N-methylformamide" ["NMF" represented N-methylformamide plus N-(hydroxymethyl)-N-methylformamide (DMF-OH)]. The DMF AUC values increased 8- and 29-fold for rats and mice, respectively, following single six-hour exposures to 250 and 500 ppm DMF. These data are indicative of saturation of DMF metabolism. Peak "NMF" plasma concentrations for rats and mice, following single 6-hour exposures, did not increase as DMF exposure concentrations increased from 250 to 500 ppm. In addition, the "NMF" plasma levels in rats following a single 6-hour 500 ppm DMF exposure did not decay by 24 hours post exposure. These "NMF" plasma data also indicate saturation of DMF metabolism. Multiple exposures to 500 ppm DMF resulted in a 3- and 4-fold reduction in DMF AUC values for rats and mice, respectively, compared to AUC values following a single six-hour 500 ppm DMF exposure. This indicates enhanced metabolism of DMF resulting from multiple 500 ppm DMF exposures and together with saturation of DMF metabolism suggest using exposure levels below 500 ppm in a chronic bioassay. Selected plasma samples were simultaneously assayed for NMF and DMF-OH. The "NMF" values consisted of between 30 to 60 percent DMF-OH depending upon the exposure group (conversely NMF represented 30 to 60 percent of the "NMF" levels). Urinary analysis of all samples revealed DMF-OH represented over 90 percent of the summed DMF, DMF-OH and NMF quantities.