邻苯二甲酸二（2-乙基己基）酯对Fischer 344大鼠和CD-1小鼠发育毒性的评价

Developmental toxicity evaluation of dietary di(2-ethylhexyl)phthalate in Fischer 344 rats and CD-1 mice.

作者信息

Tyl R W, Price C J, Marr M C, Kimmel C A

机构信息

Research Triangle Institute, Research Triangle Park, North Carolina 27709.

出版信息

Fundam Appl Toxicol. 1988 Apr;10(3):395-412. doi: 10.1016/0272-0590(88)90286-2.

DOI:10.1016/0272-0590(88)90286-2

PMID:3371580

Abstract

Di(2-ethylhexyl)phthalate (DEHP), a widely used plasticizing agent, was evaluated for developmental toxicity in timed-pregnant Fischer 344 rats (22-25 dams/dose) and CD-1 mice (24-30 dams/dose). DEHP was administered in the diet on gestational Days (gd) 0 through 20 at 0.0, 0.5, 1.0, 1.5, or 2.0% (rats) and on gd 0 through 17 at 0.00, 0.025, 0.05, 0.10, or 0.15% (mice). At termination (gd 20, rats; gd 17 mice), all fetuses were examined for external, visceral, and skeletal malformations and variations. In rats, maternal toxicity and reduced fetal body weight per litter were observed at 1.0, 1.5, and 2.0%. Increased resorptions and decreased number of live fetuses/litter were observed at 2.0%. Maternal food consumption was reduced and water consumption was increased in all DEHP groups. The number and percentage of fetuses malformed per litter were unaffected by treatment. In mice, maternal toxicity, increased resorptions and late fetal deaths, decreased number of live fetuses, and reduced fetal body weight per litter were observed at 0.10 and 0.15%. Maternal food and water consumption exhibited a dose-related upward trend with food consumption significantly increased at 0.15%. The number and percentage of fetuses malformed per litter (open eye, exophthalmia, exencephaly, short, constricted, or no tail, major vessel malformations, fused or branched ribs, and fused or misaligned thoracic vertebral centra) were elevated at 0.05, 0.10, and 0.15% DEHP. In conclusion, DEHP was not teratogenic at any dose tested in Fischer 344 rats when administered in the feed throughout gestation but did produce maternal and other embryofetal toxicity at 1.0, 1.5, and 2.0%. In contrast, DEHP administration throughout gestation in CD-1 mice resulted in an increased incidence of malformations at doses which produced maternal and other embryofetal toxicity (0.10 and 0.15%) and at a dose (0.05%) which did not produce significant maternal toxicity. No treatment-related embryofetal toxicity including teratogenicity was observed in mice at 0.025% or in rats at 0.5% DEHP.

摘要

邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种广泛使用的增塑剂，在定时受孕的Fischer 344大鼠（每个剂量组22 - 25只母鼠）和CD - 1小鼠（每个剂量组24 - 30只母鼠）中评估其发育毒性。在妊娠第0天至第20天，以0.0%、0.5%、1.0%、1.5%或2.0%（大鼠）的剂量通过饮食给予DEHP；在妊娠第0天至第17天，以0.00%、0.025%、0.05%、0.10%或0.15%（小鼠）的剂量通过饮食给予DEHP。在实验结束时（大鼠为妊娠第20天；小鼠为妊娠第17天），检查所有胎儿的外部、内脏和骨骼畸形及变异情况。在大鼠中，1.0%、1.5%和2.0%剂量组观察到母体毒性以及每窝胎儿体重减轻。2.0%剂量组观察到吸收增加和每窝活胎数量减少。所有DEHP组母体食物摄入量减少，饮水量增加。每窝畸形胎儿的数量和百分比不受处理影响。在小鼠中，0.10%和0.15%剂量组观察到母体毒性、吸收增加和晚期胎儿死亡、活胎数量减少以及每窝胎儿体重减轻。母体食物和水的摄入量呈现剂量相关的上升趋势，在0.15%剂量时食物摄入量显著增加。0.05%、0.10%和0.15% DEHP剂量组每窝畸形胎儿（睁眼、眼球突出、无脑儿、短尾、狭窄或无尾、大血管畸形、肋骨融合或分支、胸椎椎体融合或排列不齐）的数量和百分比升高。总之，在整个妊娠期通过饲料给予DEHP时，在Fischer 344大鼠中测试的任何剂量下DEHP均无致畸性，但在1.0%、1.5%和2.0%剂量时确实产生了母体和其他胚胎 - 胎儿毒性。相比之下，在整个妊娠期给CD - 1小鼠给予DEHP，在产生母体和其他胚胎 - 胎儿毒性的剂量（0.10%和0.15%）以及未产生显著母体毒性的剂量（0.05%）下，畸形发生率均增加。在0.025%剂量的小鼠或0.5%剂量的大鼠中未观察到与处理相关的胚胎 - 胎儿毒性，包括致畸性。