Assessment of the Developmental Toxicity, Metabolism, and Placental Transfer of Di-n-butyl Phthalate Administered to Pregnant Rats

Abstract

The developmental toxicity and placental transfer of di-n-butyl phthalate (DBP) were evaluated in Sprague-Dawley rats given a single oral dose of DBP on Gestational Day 14. In the developmental toxicity study, dams were dosed with 0, 0.5, 1, 1.5, or 2 g DBP/kg and were necropsied on GD21. Increased incidence of resorptions and reduced fetal body weight were observed at 1.5 and 2 g/kg. Higher incidences of skeletal variations were found at doses > or = at 1 g/kg. No embryotoxic or teratogenic effects were observed at a dose of 0.5 g/kg. In the placental transfer study, dams were dosed with 0.5 or 1.5 g [14C]DBP/kg. Maternal and embryonic tissues were collected at intervals from 0.5 to 48 h. Embryonic tissues accounted for less than 0.12-0.15% of the administered dose. Levels of radiocarbon in placenta and embryo were one-third or less of those in maternal plasma. No accumulation of radioactivity was observed in the maternal or embryonic tissues. From HPLC analyses, it was shown that unchanged DBP and its metabolites mono-n-butyl phthalate (MBP) and MBP glucuronide were rapidly transferred to the embryonic tissues, where their levels were constantly lower than those in maternal plasma. MBP accounted for most of the radioactivity recovered in maternal plasma, placenta, and embryo. Unchanged DBP was found only in small amounts. These findings support the hypothesis that MBP, a potent teratogen, largely contributes to the embryotoxic effects of DBP.

Disposition of Orally Administered 2,2-Bis(4-Hydroxyphenyl)Propane (Bisphenol A) in Pregnant Rats and the Placental Transfer to Fetuses

“…As reported by Iguchi (23), when mice were administered 100 mg/kg BPA, a considerable amount of unconjugated BPA was detected in maternal and fetal plasma and organs. Saillenfait et al (32) reported that the distribution profile of metabolites in tissues of pregnant rats was not affected by increasing the dose of di-n-butyl phthalate from 0.5 to 1.5 g/kg, whereas the time course of tissue concentrations was dose-dependent. The dose-dependent effect was caused by the saturation of esterase converting di-n-butyl phthalate into mono-n-butyl phthalate but not glucuronidase (32).…”

“…Saillenfait et al (32) reported that the distribution profile of metabolites in tissues of pregnant rats was not affected by increasing the dose of di-n-butyl phthalate from 0.5 to 1.5 g/kg, whereas the time course of tissue concentrations was dose-dependent. The dose-dependent effect was caused by the saturation of esterase converting di-n-butyl phthalate into mono-n-butyl phthalate but not glucuronidase (32). In a study of the disposition of thiabendazole, Yoneyhama et al (33) also used a large dose (1 g/kg).…”

“…Placental transfer of 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyls (PCBs), hydroxylated PCBs, 1,1,1-trichloro-2,2-bis(4chlorophenyl)ethane (p,p´-DDT), 1, 1-dichloro-2,2-bis(4-chlorophenyl)ethene (p,p´-DDE), and pentachlorophenol, with high octanol/water partition coefficients (log P ow = 5.0 to 6.0), may be limited or very slow (35 to 40), although these chemicals can be accumulated. Chemicals with lower partition coefficients (logPow=-0.9 to 5.0), such as diethylstilbestrol (DES), 1,2-diethylbenzene, mono-n-butyl phthalate, salicylic acid, 1,2-dichloroethane, N,N-dimethylformamide, and thiabendazole, move relatively easily across the placenta into fetuses, and the transfer rate may depend on the structure of each compound (32,33,(41)(42)(43)(44)(45). Their maximal fetal concentrations are 30-100% of their maximal maternal plasma levels.…”

Dibutyl Phthalate (DBP)-Induced Apoptosis and Neurotoxicity are Mediated via the Aryl Hydrocarbon Receptor (AhR) but not by Estrogen Receptor Alpha (ERα), Estrogen Receptor Beta (ERβ), or Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Mouse Cortical Neurons

“…Furthermore, DBP accumulation was much higher after chronic (3 or 6 months) exposure than after a single inhalation (Kawano 1980), thus indicating effective accumulation of the phthalate in brain tissue. DBP has also been shown to pass through the placental and blood–brain barriers in rats (Williams and Blanchfield 1975; Kawano 1980; Saillenfait et al 1998; Huang et al 2014). However, little is known about mechanisms of action of DBP in the nervous system, especially in the early developmental stages.…”

Reproductive toxicity and pharmacokinetics of di‐n‐butyl phthalate (DBP) following dietary exposure of pregnant rats

“…The pharmacokinetics of DBP and MBP administered by gavage have been investigated in male rodents, and in both pregnant and nonpregnant female rodents (Calafat et al, 2006; Clewell et al, 2009; Fennell et al, 2004; Kremer et al, 2005; Saillenfait et al, 1998). A glucuronide conjugate of the monoester (MBP‐G) is the major metabolite of MBP (Foster et al, 1982) and is not thought to be biologically active.…”