Effects of Mono‐n‐butyl Phthalate on the Development of Rat Embryos: In vivo and in vitro Observations

Abstract: The present study was conducted to further characterize the embryotoxic effects mono‐n‐butyl phthalate, a major metabolite of the plasticizer di‐n‐butyl phthalate, and evaluate its role in the developmental toxicity of di‐n‐butyl phthalate. The embryotoxic effects of mono‐n‐butyl phthalate were compared to those of the parent compound di‐n‐butyl phthalate after a single oral administration of 1.8, 3.6, 5.4, or 7.2 mmol/kg di‐n‐butyl phthalate or mono‐n‐butyl phthalate to Sprague‐Dawley rats on gestational day 10 (Day 10). Embryos were evaluated for growth and development on Day 12. Both chemicals induced concentration‐dependent developmental toxicity (i.e. decreased growth and malformations) which became apparent at 3.6 mmol/kg. Di‐n‐butyl phthalate and mono‐n‐butyl phthalate were approximately equally potent and produced qualitatively similar dysmorphogenic effects. Macroscopically, the most common malformations involved the prosencephalon, the optic system, and the mandibular and maxillary processes. In addition, the embryotoxic potential of mono‐n‐butyl phthalate was evaluated in vitro using the rat whole embryo culture system. Day 10 embryos were cultured for 48 hr in the presence of 0.5 to 5 mM mono‐n‐butyl phthalate and were then evaluated as the embryos grown in utero . Mono‐n‐butyl phthalate was a potent direct acting embryotoxicant, causing concentration‐related growth retardation and dysmorphogenesis. The spectrum of morphological defects observed in mono‐n‐butyl phthalate‐exposed embryos in vitro was comparable to those seen in vivo in the embryos at the same developmental stage after maternal administration of di‐n‐butyl phthalate or mono‐n‐butyl phthalate. These data provide additional evidence in support of the hypothesis that mono‐n‐butyl phthalate may be the active species for the developmental toxicity of ingested di‐n‐butyl phthalate in rats.