To examine the effects of continuous exposure over two generations and the possibility of non-linearities in the dose responses over a wide dose range, dibutyl phthalate (DBP), was administered in the diet at concentrations of 1 ppm (Control), 4, 10, 30, 100, 1,000, and 10,000 ppm to groups (n=17 male and 17 female) of Sprague-Dawley rats over two generations. The F0 generation began exposure as adults and were bred to produce F1a, F1b, and F1c pups. The F1b adults were raised and bred to produce F2a, F2b, and F2c pups. An Outbreeding Cohabitation was conducted by mating 10,000 ppm F1 males with naive females and 10,000 ppm F1 females with naive males. Parameters evaluated over the course of the study included body weights, feed consumption, clinical observations, vaginal cytology, reproductive performance, neonatal anogenital distance (AGD), pup survival, sexual development, computer-assisted sperm analyses, gross pathology, organ weights, and selected histopathology.
Body weights, feed consumption, clinical observations, incidental gross findings, and mortality were not adversely affected by any dose of DBP during the F0, F1, or F1 Outbreeding Cohabitations. During the F0 and F1 Cohabitations, there were several deaths with no apparent relationship to treatment. No mortality was observed among the F1 animals during the rearing or outbreeding periods.
There were no consistent treatment-related effects noted in litter data from the F0 and F1 Cohabitations. During the F0 Cohabitation, the mean AGD of 10,000 ppm F1a male pups decreased by *15 % on Postnatal Day 1 (PND 1), while the AGD of the 10,000 ppm F1b male pups was not decreased significantly (10%). During the F1 Cohabitation, the mean AGD of 10,000 ppm F2a, F2b, and F2c male pups decreased by *13-15%. In the Outbreeding Cohabitation the mean AGD of male pups born to 10,000 ppm F1 dams decreased by *14%. Sexual development data of 10,000 ppm F1b males revealed a mean delay of *2.0 days (45.58 vs 43.60) in preputial separation and a delay of *2.8 days (26.54 vs 23.77) in testicular decent, as compared to the control animals.
No gross pathology, organ weight changes, or microscopic pathology was noted in the adult F0 or F1 animals at necropsy, except for seminiferous tubular atrophy noted in the 10,000 ppm F1 males. No changes were noted in sperm endpoints in the F0 or F1 males.
The results of this study show that DBP at these doses is not a general toxicant, but it is a male developmental and reproductive toxicant at concentrations greater than or equal to 10,000 ppm, as evidenced by decreased AGD in F1 and F2 pups and delayed preputial separation, delayed testicular descent, and seminiferous tubular atrophy in the high dose F1 animals.
*Statistically significantNTIS # PB2003-100084
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