The effects of 4-nonylphenol in rats: a multigeneration reproduction study

Abstract

The alkylphenol breakdown products of alkylphenol ethoxylates have been shown in in vitro studies to be weakly estrogenic, but few in vivo data address this issue in mammals. Because estrogens have been found to be most potent during developmental/perinatal exposures, this study maximized developmental exposure to nonylphenol (NP) by treating 3.5 generations of Sprague-Dawley rats to NP in diet at 200, 650, and 2000 ppm to determine the range and severity of any toxicity. Dose rate was higher for younger rats; calculated dose ranges were 9-35, 30-100, and 100-350 mg/kg/d for the low (200NP), middle (650NP), and high (2000NP) dose groups, respectively. There were adult (F0, F1, F2) and postnatal day (pnd) 21 (F1, F2, F3) necropsies; the oldest F3 rats were killed on pnd 55-58. Body weight gain was reduced by 8-10% in the 650NP and 2000NP groups. Vaginal opening was accelerated by approximately 2 days (650NP) and approximately 6 days (2000NP) in F1, F2, and F3 generations. Uterine weights at pnd 21 were increased in 650NP (14%) and 2000NP (50%) F1 females, but not in other generations. Testis descent, anogenital distance, and preputial separation were not consistently changed. No consistent changes were seen in pup number, weight or viability, litter indices, or other functional reproductive measures. Relative ovary weight in F2 adults was decreased at 650NP and 2000NP by 12%; relative ovary was unchanged in other generations. Follicle counts were unchanged in F2 adults. Sperm indices, including CASA measures, were unchanged in F0 and F1 males. In F2 rats, epididymal sperm density was reduced by 8% and 13% at 650NP and 2000NP, respectively. Testicular spermatid count was reduced by 13% in 2000NP F2 males; testis and epididymis weights were unchanged. Erosion of gastric and duodenal mucosa was monitored grossly and microscopically, and never found. Kidney weights were increased in 650NP and 2000NP males, and renal medullary tubular dilatation and cyst formation were noted in all generations of males, and often at the lowest dose tested. These data show that NP had limited effects on the reproductive system in the presence of measurable nephrotoxicity. The F2 sperm effects are either statistical/biological "noise," or imply heretofore unknown pharmacokinetics or toxicodynamics. These sperm data should be interpreted cautiously until the findings are repeated.

The OECD program to validate the rat uterotrophic bioassay. Phase 2: dose-response studies.

“…NP was negative at 15 mg/kg/day in all laboratories and positive at 75 mg/kg/day (Table 17). This compares favorably with LOEL observations of about 35 mg/kg/day in two multigeneration studies (Chapin et al 1999;Nagao et al 2001). BPA was negative at 200 mg/kg/day in all laboratories and was positive over a range of 375-1000 mg/kg/day.…”

Lack of Modification by Environmental Estrogenic Compounds of Thyroid Carcinogenesis in Ovariectomized Rats Pretreated with N‐bis(2‐hydroxypropyl)nitrosamine (DHPN)

“…at a level of 50 mg/kg, 51) although 2000 ppm of NP did not induce significant uterine changes in a subchronic study using rats 52) and in a multigeneration reproductive study. 53) In the present study, the dose of 250 ppm NP administered in the diet corresponds to approximately 11-44 mg/kg/day in rats. It did not induce uterine or thyroid lesions.…”

The OECD program to validate the rat uterotrophic bioassay: an overview.

“…Phase 2 was conducted with compounds with weak agonists that likely represented target compounds of regulatory interest. To assess the predictivity of the uterotrophic bioassay, the weak agonists were selected because of the availability of reproductive and developmental studies with a battery of estrogen-sensitive end points (Chapin et al 1999;Tyl et al 2002). The chemicals were also selected with a range of potencies and different metabolic and pharmacokinetic properties in mind.…”