E. Mylchreest et al., Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to di(n-butyl) phthalate during late gestation, TOXICOL SCI, 55(1), 2000, pp. 143-151
Di(n-butyl) phthalate (DSP) is a commercially important plasticizer and ubi
quitous environmental contaminant. Since previous, limited dose-response st
udies with DBP that reported alterations in male reproductive development a
nd function failed to establish a NOAEL (no-observed-adverse-effect level),
an extensive dose-response study was conducted. Pregnant CD rats were give
n DBP by gavage at 0, 0.5, 5, 50, or 100 mg/kg/day (n = 19-20) or 500 mg/kg
/day (n = Il)from gestation day 12 to 21. In male offspring, anogenital dis
tance was decreased at 500 mg DBP/kg/day. Retained areolas or nipples were
present in 31 and 90% of male pups at 100 and 500 mg/kg/day, respectively.
Preputial separation was not delayed by DBP treatment in males with normal
external genitalia, but cleft penis (hypospadias) was observed in 5/58 rats
(4/11 litters) at 500 mg/kg/day. Absent or partially developed epididymis
(23/58 rats in 9/11 litters), vas deferens (16/58 animals in 9/11 litters),
seminal vesicles (4/58 rats in 4/11 litters), and ventral prostate (1/58 a
nimals) occurred at 500 mg/kg/day. In 110-day-old F-1 males, the weights of
the testis, epididymis, dorsolateral and ventral prostates, seminal vesicl
es, and levator anibulbocavernosus muscle were decreased at 500 mg/kg/day.
At 500 mg/kg/day, widespread seminiferous tubule degeneration was seen in 2
5/58 rats (in 9/11 litters), focal interstitial cell hyperplasia in 14/58 r
ats (in 5/11 litters), and interstitial cell adenoma in 1/58 rats (in 1/11
litters). For this 10-day prenatal (embryonic and fetal) exposure to DBP, t
he NOAEL and LOAEL (lowest-observed-adverse-effect level) were 50 and 100 m
g/kg/day, respectively. This is currently the lowest NOAEL described for th
e toxicity of DBP.