Developmental toxicity evaluation of diethyl and dimethyl phthalate in rats

Abstract

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.

Development of a zebrafish embryo teratogenicity assay and quantitative prediction model

“…BMS-2 is not a selective developmental toxicant in the rat, but at doses greater than or equal to 10 times the maternal LOAEL, it produced reduced fetal body weights, resorptions, fetal edema, encephalocele, and malformations of the abdomen and tail. Dimethyl phthalate is a short chain phalatic acid ester that has been found to be non-teratogenic in mammalian studies (Plasterer et al, 1985;Field et al, 1993). However, zebrafish embryos treated with dimethyl phthalate developed a low incidence of general dysmorphology at 1 Â 10 À5 or 1 Â 10 À4 M that appeared to be compoundrelated.…”

A Two-Generation Reproductive Toxicity Study of Diethyl Phthalate (Dep) in Rats

“…An increased incidence of fetuses with skeletal defects was observed in rats administered DEP (0.338-1.125 mL/kg) by intraperitoneal injections on days 5, 10 and 15 of gestation (Singh et al, 1972). It is also reported that supernumerary ribs (a skeletal vari-ation) in fetuses was induced following dietary administration to maternal rats on days 6 through 15 of gestation at a dose level of 5% DEP (Field et al, 1993). No maternal or developmental toxicity was found after oral administration of DEP to the dam at 750 mg/kg from gestation day 14 to postnatal day 3 (Gray et al, 2000).…”

Sex differences, endogenous sex‐hormone hormones, sex‐hormone binding globulin, and exogenous disruptors in diabetes and related metabolic outcomes

“…Numerous animal studies have reported adverse effects of BPA at doses below the current RfD of 50 μg/kg per day on a range of phenotypes, including metabolic processes such as pancreatic function and insulin and glucose homeostasis. [89][90][91][92][93] Some report that pre-and postnatal developmental exposure to low doses of BPA and phthalates stimulates weight gain, [94][95][96][97][98][99] and has catabolic effects at high levels. 100,101 These studies and those discussed below suggest that these chemicals may increase the risk of T2D by affecting multiple biological pathways that are of critical importance in T2D development.…”