Field E A, Price C J, Sleet R B, George J D, Marr M C, Myers C B, Schwetz B A, Morrissey R E
Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194.
Teratology. 1993 Jul;48(1):33-44. doi: 10.1002/tera.1420480107.
Diethyl phthalate (DEP) and dimethyl phthalate (DMP), phthalic acid ester (PAE) plasticizers, were evaluated for developmental toxicity because of reports in the literature that some PAE were embryotoxic and teratogenic. A previous study (Singh et al., '72) suggested that an increased incidence of skeletal defects in rats might result from gestational exposure to DEP (0.6-1.9 g/kg) or DMP (0.4-1.3 g/kg), ip, on gestational days (gd) 5, 10, and 15. In the current study DEP (0, 0.25, 2.5, and 5%) or DMP (0, 0.25, 1, and 5%) in feed (approximately 0.2-4.0 g/kg/day) were supplied to timed-mated rats from gd 6 to 15. Treatment with 5% DMP resulted in increased relative maternal liver weight. Also, animals exhibited reduced body weight gain during treatment (5% DEP or DMP) and during gestation (5% DEP). Weight gain corrected for gravid uterine weight was also reduced in animals fed 5% DEP. However, high-dose treatment with either DEP or DMP resulted in changes in food and water consumption paralleling the body weight reductions, suggesting that apparent toxic effects on maternal body weight may reflect PAE/feed unpalatability. Treatment with 2.5% DEP resulted in only transient changes in body weight during early treatment. The only maternal effects at 0.25 or 1% DMP were minor changes in food and/or water consumption, and there were no effects at 0.25% DEP. Thus, the NOAELs for maternal toxicity were 1% DMP and 0.25% DEP. In contrast to the observed maternal toxicity, there was no effect of DEP or DMP treatment on any parameter of embryo/fetal development, except an increased incidence of supernumerary ribs (a variation) in the 5% DEP group. These results do not support the conclusion of other investigators that DEP and DMP are potent developmental toxicants. Rather, they suggest that the short-chain PAE are less developmentally toxic than PAE with more complex substitution groups, e.g., di(2-ethylhexyl) phthalate, mono(2-ethylhexyl) phthalate, and butyl benzyl phthalate.
邻苯二甲酸二乙酯（DEP）和邻苯二甲酸二甲酯（DMP）作为邻苯二甲酸酯（PAE）类增塑剂，因其在文献中报道某些PAE具有胚胎毒性和致畸性，所以对其发育毒性进行了评估。之前的一项研究（Singh等人，1972年）表明，妊娠第5、10和15天腹腔注射DEP（0.6 - 1.9 g/kg）或DMP（0.4 - 1.3 g/kg）可能导致大鼠骨骼缺陷发生率增加。在本研究中，从妊娠第6天至第15天，将饲料中含0、0.25%、2.5%和5%的DEP或0、0.25%、1%和5%的DMP（约0.2 - 4.0 g/kg/天）提供给定时交配的大鼠。5% DMP处理导致母体肝脏相对重量增加。此外，动物在处理期间（5% DEP或DMP）和妊娠期（5% DEP）体重增加减少。喂食5% DEP的动物经妊娠子宫重量校正后的体重增加也减少。然而，DEP或DMP的高剂量处理导致食物和水消耗量的变化与体重减轻平行，这表明对母体体重的明显毒性作用可能反映了PAE/饲料的适口性差。2.5% DEP处理仅在早期处理期间导致体重短暂变化。0.25%或1% DMP对母体的唯一影响是食物和/或水消耗量的轻微变化，0.25% DEP则无影响。因此，母体毒性的无观察到有害作用水平（NOAEL）为1% DMP和0.25% DEP。与观察到的母体毒性相反，DEP或DMP处理对胚胎/胎儿发育的任何参数均无影响，除了5% DEP组中额外肋骨（一种变异）的发生率增加。这些结果不支持其他研究者关于DEP和DMP是强效发育毒物的结论。相反，它们表明短链PAE的发育毒性低于具有更复杂取代基团的PAE，例如邻苯二甲酸二（2 - 乙基己基）酯、邻苯二甲酸单（2 - 乙基己基）酯和邻苯二甲酸丁苄酯。
