Tyl R W, Ballantyne B, Fisher L C, Fait D L, Dodd D E, Klonne D R, Pritts I M, Losco P E
Bushy Run Research Center, Export, Pennsylvania, USA.
Fundam Appl Toxicol. 1995 Aug;27(1):49-62. doi: 10.1006/faat.1995.1107.
Ethylene glycol (EG; CAS No. 107-21-1) is teratogenic to mice by whole-body (WB) exposure to aerosol (1000-2500 mg/m3). The WB results were confounded by possible exposure from ingestion after grooming and/or from percutaneous absorption. Therefore, CD-1 mice were exposed to EG aerosol (MMAD 2.6 +/- 1.7 microns) on Gestational Days (GD) 6 through 15, 6 hr/day, by nose-only (NO) (0, 500, 1000, or 2500 mg/m3) or WB exposures (0 or 2100 mg/m3, as positive control), 30/group. Five additional "satellite" females each at 2500 mg/m3 NO and 2100 mg/m3 WB were exposed on GD 6 for measurement of EG on fur. Control environments were water aerosol (4200 mg/m3 for NO; 2700 mg/m3 for WB). Females were weighed and evaluated for clinical signs and water consumption throughout gestation. On GD 18, maternal uterus, liver, and kidneys (2) were weighed, with kidneys examined microscopically. Corpora lutea and implantation sites were recorded. Live fetuses were weighed, sexed, and examined for structural alterations. For NO dams, kidney weights were increased at 1000 and 2500 mg/m3; no renal lesions and no other treatment-related maternal toxicity were observed. There were no effects on pre- or postimplantation loss; fetal body weights/litter were reduced at 2500 mg/m3. At 2500 mg/m3, incidences of fused ribs and skeletal variations were increased. The 2500 mg/m3 NO satellite animals had approximately 330 mg/kg extractable EG. The WB group exhibited maternal and developmental toxicity including increased fetal skeletal malformations and variations, confirming previous results, with 1390 mg/kg extractable EG on fur. Therefore, exposure of CD-1 mice to a respirable EG aerosol during organogenesis by NO inhalation resulted in minimal maternal toxicity at 1000 and 2500 mg/m3 and developmental toxicity at 2500 mg/m3. The NOAEL was 500 mg/m3 NO for maternal and 1000 mg/m3 NO for developmental toxicity. This study supports the interpretation of the initial EG WB results as due to systemic exposure from noninhalation routes since limiting noninhalation routes prevented almost all of the effects (including teratogenicity) observed in mice after WB exposure.
乙二醇（EG；化学物质登记号：107 - 21 - 1）通过全身（WB）暴露于气溶胶（1000 - 2500毫克/立方米）对小鼠具有致畸性。全身暴露的结果因梳理毛发后经口摄入和/或经皮吸收可能导致的暴露而受到混淆。因此，将CD - 1小鼠在妊娠第6天至第15天，每天6小时，通过仅经鼻（NO）（0、500、1000或2500毫克/立方米）或全身暴露（0或2100毫克/立方米，作为阳性对照）暴露于EG气溶胶（质量中值空气动力学直径2.6±1.7微米），每组30只。另外每组5只“卫星”雌性小鼠分别在2500毫克/立方米经鼻暴露组和2100毫克/立方米全身暴露组，在妊娠第6天暴露以测量毛发上的EG。对照环境为水汽溶胶（经鼻暴露组4200毫克/立方米；全身暴露组2700毫克/立方米）。在整个妊娠期对雌性小鼠称重，并评估其临床症状和饮水量。在妊娠第18天，称量母体的子宫、肝脏和双肾重量，对肾脏进行显微镜检查。记录黄体数和着床部位。对存活胎儿称重、确定性别，并检查结构改变。对于经鼻暴露组的母鼠，在1000和2500毫克/立方米时肾脏重量增加；未观察到肾脏病变以及其他与处理相关的母体毒性。对着床前或着床后丢失没有影响；在2500毫克/立方米时每窝胎儿体重降低。在2500毫克/立方米时，肋骨融合和骨骼变异的发生率增加。2500毫克/立方米经鼻暴露组的“卫星”动物毛发上可提取的EG约为330毫克/千克。全身暴露组表现出母体和发育毒性，包括胎儿骨骼畸形和变异增加，证实了先前的结果，其毛发上可提取的EG为1390毫克/千克。因此，在器官形成期通过经鼻吸入使CD - 1小鼠暴露于可吸入的EG气溶胶，在1000和2500毫克/立方米时导致最小的母体毒性，在2500毫克/立方米时导致发育毒性。母体毒性的未观察到有害作用水平（NOAEL）为经鼻暴露500毫克/立方米，发育毒性的NOAEL为经鼻暴露1000毫克/立方米。本研究支持将最初的乙二醇全身暴露结果解释为由于非吸入途径的全身暴露，因为限制非吸入途径几乎消除了全身暴露后在小鼠中观察到的所有效应（包括致畸性）。
