Hundley S G, Lieder P H, Valentine R, Malley L A, Kennedy G L
E. I. du Pont de Nemours & Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware 19714.
Drug Chem Toxicol. 1993;16(1):21-52 sW. doi: 10.3109/01480549309038660.
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.
对大鼠和小鼠进行了N，N - 二甲基甲酰胺（DMF）的全身吸入暴露实验。暴露浓度分别为10、250和500 ppm的DMF。暴露程序包括单次1小时、3小时或6小时暴露以及十次6小时暴露（两周内进行十天暴露）。在暴露后测定DMF和“N - 甲基甲酰胺”（“NMF”代表N - 甲基甲酰胺加上N - （羟甲基） - N - 甲基甲酰胺（DMF - OH））的血浆浓度曲线下面积（AUC）值。在大鼠和小鼠单次6小时暴露于250和500 ppm DMF后，DMF的AUC值分别增加了8倍和29倍。这些数据表明DMF代谢出现饱和。大鼠和小鼠单次6小时暴露后，随着DMF暴露浓度从250 ppm增加到500 ppm，“NMF”血浆峰值浓度并未增加。此外，大鼠单次6小时暴露于500 ppm DMF后，“NMF”血浆水平在暴露后24小时内并未下降。这些“NMF”血浆数据也表明DMF代谢出现饱和。与单次6小时暴露于500 ppm DMF后的AUC值相比，多次暴露于500 ppm DMF导致大鼠和小鼠的DMF AUC值分别降低了3倍和4倍。这表明多次暴露于500 ppm DMF会增强DMF的代谢，并且与DMF代谢饱和一起表明在慢性生物测定中应使用低于500 ppm的暴露水平。对选定的血浆样本同时进行NMF和DMF - OH测定。“NMF”值中DMF - OH占30%至60%，具体取决于暴露组（相反，NMF占“NMF”水平的30%至60%）。对所有样本的尿液分析显示，DMF - OH占DMF、DMF - OH和NMF总量之和的90%以上。
