Roberts L G, Nicolich M J, Schreiner C A
American Petroleum Institute Developmental Workgroup, Washington, DC, United States.
Reprod Toxicol. 2007 Jun;23(4):521-31. doi: 10.1016/j.reprotox.2007.01.009. Epub 2007 Feb 12.
The developmental toxicity of toluene was evaluated via whole body inhalation exposure, in pregnant Sprague Dawley rats exposed to toluene (99.9% pure) from gestation day (GD) 6-15 inclusive, 6h/day, at concentrations of 0, 250, 750, 1500 and 3000ppm (0, 938, 2812, 5625 and 11250mg/m(3)). Doses were selected from a preliminary study performed over a range of concentrations from 0 to 5000ppm, in which maternal and fetal toxicity were observed at 2000ppm and above. This study has been cited in various regulatory documents and is presented here to allow greater accessibility to results and conclusions. Toluene induced clinical signs in pregnant dams (ataxia, hyper-responsivity, increased water intake, decreased food consumption) at 3000ppm, ataxia and hyper-responsivity at 1500ppm, and reduced maternal body weight gain at 1500 during the exposure period only and at 3000ppm from initiation of exposure to GD20. At Caesarean section on GD20, no adverse effects on implantation, number and viability of fetuses, or fetal sex distribution were observed. Litter weight and mean fetal weight was reduced at 3000ppm and mean fetal weight was reduced at 1500ppm. Instances of reduced or unossified skeletal elements occurred at the same dose levels. Mean fetal weight was also reduced at 250ppm but not at 750ppm. Extensive statistical analysis of fetal body weight data support the conclusion that there is no toxicologically significant dose-related effect on fetal body weight at or below 750ppm. Low incidences (<or=2.5%) of various malformations occurred in the 250, 1500, and 3000ppm groups; there was no increase in the incidence of specific or total malformations with increased exposure and thus these were not attributed to toluene. In this Toluene study, the maternal toxicity NOAEL was 750ppm with a defined maternal and developmental toxicity LOAEL of 1500ppm.
通过对怀孕的斯普拉格-道利大鼠进行全身吸入暴露,评估甲苯的发育毒性。这些大鼠在妊娠第6天至第15天(含)期间,每天暴露6小时,暴露于纯度为99.9%的甲苯中,浓度分别为0、250、750、1500和3000ppm(0、938、2812、5625和11250mg/m³)。剂量是从一项在0至5000ppm浓度范围内进行的初步研究中选取的,在该研究中,2000ppm及以上浓度观察到母体和胎儿毒性。本研究已被各种监管文件引用,在此呈现以便更易获取结果和结论。甲苯在3000ppm时可使怀孕母鼠出现临床症状(共济失调、反应过度、饮水量增加、食物摄入量减少),在1500ppm时出现共济失调和反应过度,仅在暴露期1500ppm以及从暴露开始至妊娠第20天3000ppm时,母体体重增加减少。在妊娠第20天剖宫产时,未观察到对胎儿着床、数量和活力或胎儿性别分布有不良影响。窝仔体重和平均胎儿体重在3000ppm时降低,平均胎儿体重在1500ppm时降低。骨骼元素减少或未骨化的情况在相同剂量水平出现。平均胎儿体重在250ppm时也降低,但在750ppm时未降低。对胎儿体重数据的广泛统计分析支持以下结论:在750ppm及以下,对胎儿体重没有毒理学上显著的剂量相关影响。在250、1500和3000ppm组中出现各种畸形的发生率较低(≤2.5%);随着暴露增加,特定或总畸形的发生率没有增加,因此这些畸形不归因于甲苯。在本甲苯研究中,母体毒性未观察到有害作用水平(NOAEL)为750ppm,确定的母体和发育毒性最低观察到有害作用水平(LOAEL)为1500ppm。