Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bürkle-de-la-Camp-Platz 1, 44789, Bochum, Germany.
National Research and Safety Institute, 1 rue du Morvan, CS 60027, 54519, Vandoeuvre Cedex, France.
Arch Toxicol. 2019 Apr;93(4):921-929. doi: 10.1007/s00204-019-02404-x. Epub 2019 Feb 7.
The toxicokinetics of N-ethyl-2-pyrrolidone (NEP), an embryotoxic organic solvent, has been studied in Sprague-Dawley rats after oral exposure. NEP and its metabolites 5-hydroxy-N-ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI) were measured in plasma of pregnant and non-pregnant rats, and fetuses after NEP administration by gavage for 14 consecutive days at 50 mg/kg/day, and in plasma of non-pregnant rats after a single NEP administration. Additionally, amniotic fluid and 24-h urine samples of the pregnant rats were analyzed for NEP metabolites. Furthermore, 24-h urine samples from a repeated dose 28-day oral toxicity study in female (non-pregnant) and male rats administered developmentally non-toxic (0, 5, and 50 mg/kg/day) or toxic (250 mg/kg/day) doses of NEP were analyzed. Median peak plasma concentrations in non-pregnant rats after a single dose and repeated doses were 551 and 611 (NEP), 182 and 158 (5-HNEP), and 63.8 and 108 µmol/L (2-HESI), respectively; whereas in pregnant rats and fetuses 653 and 619 (NEP), 80.5 and 91.7 (5-HNEP) and 77.3 and 45.7 µmol/L (2-HESI) were detected. Times to reach maximum plasma concentrations for NEP, 5-HNEP, and 2-HESI were 1, 4, and 8 h, respectively, and were comparable to N-methyl-2-pyrrolidone (NMP) and its corresponding metabolites. In pregnant rats, plasma elimination of NEP and metabolite formation/elimination was much slower compared to non-pregnant rats and efficient placental transfer of NEP was observed. Our data, overall, suggest differences in the toxicokinetics of chemicals between pregnant and non-pregnant rats which need to be addressed in risk assessment, specifically when assessing developmental toxicants such as NEP.
已研究经口给予 N-乙基-2-吡咯烷酮（NEP），一种胚胎毒性有机溶剂后，Sprague-Dawley 大鼠的毒代动力学。通过灌胃给予怀孕和未怀孕大鼠 14 天，每天 50mg/kg，连续给予 NEP 后，测量了 NEP 及其代谢物 5-羟-N-乙基-2-吡咯烷酮（5-HNEP）和 2-羟-N-乙基琥珀酰亚胺（2-HESI）在血浆中的浓度，并在单次给予 NEP 后，测量了未怀孕大鼠的血浆浓度。此外，还分析了怀孕大鼠的羊水和 24 小时尿液样本中的 NEP 代谢物。此外，还分析了在雌性（未怀孕）和雄性大鼠中进行的重复剂量 28 天口服毒性研究中，24 小时尿液样本，给予发育非毒性（0、5 和 50mg/kg/天）或毒性（250mg/kg/天）剂量的 NEP。单次和重复剂量后，非怀孕大鼠的 NEP、5-HNEP 和 2-HESI 的中值峰值血浆浓度分别为 551 和 611（NEP）、182 和 158（5-HNEP）和 63.8 和 108µmol/L（2-HESI）；而在怀孕大鼠和胎儿中，检测到 653 和 619（NEP）、80.5 和 91.7（5-HNEP）和 77.3 和 45.7µmol/L（2-HESI）。NEP、5-HNEP 和 2-HESI 达到最大血浆浓度的时间分别为 1、4 和 8 小时，与 N-甲基-2-吡咯烷酮（NMP）及其相应代谢物相当。在怀孕大鼠中，与未怀孕大鼠相比，NEP 和代谢物形成/消除的血浆消除速度要慢得多，并且观察到 NEP 的有效胎盘转移。总的来说，我们的数据表明，怀孕和未怀孕大鼠之间的化学毒代动力学存在差异，在风险评估中需要加以解决，特别是在评估 NEP 等发育毒物时。
