The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings were not evaluated in accordance with the levels of evidence for reproductive or developmental criteria established by NTP in March 2009. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.
Diethylhexyl phthalate (DEHP), a widely used plasticizer, was administered to timed-mated Fischer 344 rats (F0 generation) on gestational days (gd) 0-20. Treatment groups received either O%, 0.25%, 0 50%, or 1.00% DEHP in the diet, with resultant average doses of 0, 164, 313 or 573 mg DEHP/kg/day, respectively. Maternal food consumption (g/kg/day) and weight gain during treatment were reduced in a dose-related manner; food consumption was significantly lower than controls in the mid- and high-dose groups, but maternal weight gain was significantly reduced only at the high dose. Postpartum maternal body weight was reduced at the high dose on postnatal day (pnd) 1, but no further maternal effects were observed through scheduled sacrifice of F0 dams on pnd 28.
The number of implantation sites per dam did not differ across groups, nor were treatment-related effects observed for the % fertile matings, % live litters (pnd 1), or % viable litters (pnd 1-4). Postimplantation mortality was increased in the mid- and high-dose groups (7.80%, 8.57%, 21.40% and 19.52% per litter for the control through high- dose groups, respectively), but this effect was statistically significant only at the mid dose. On pnd 1, average litter size and average pup body weight per litter were decreased in a dose-related manner (9.47, 9.3, 8.18, and 8.0 live pups per litter, and 4.91, 4.86, 4.75 and 4.52 g, respectively, in the control through high-dose groups); the effect upon pup body weight was statistically significant only for the high-dose group.
During the postnatal period (pnd 4 through sacrifice), F1 litters from DEHP-treated dams were comparable to controls for postnatal growth and viability, age of acquisition for developmental landmarks (i.e., incisor eruption, wire grasping, eye opening, testes descent or vaginal opening), and levels of spontaneous locomotor activity on pnd 21, 35, 38 and 55. Exposure of F0 dams to DEHP failed to result in any adverse effect upon reproductive performance in the F1 generation, or upon growth and viability of F2A litters through pnd 4. Appropriate statistical analysis of F1 reproductive organ weights could not be performed since potential confounding factors, especially age of F1 animals at sacrifice and relative timing of prior reproductive events, were not systematically controlled in this study. However, microscopic evaluation of reproductive organs from F1 males and females revealed no treatment-related histopathologic effects.
In summary, F0 females were exposed to DEHP (0%, 0.25%, 0.50%, or 1.00%) in the diet on gd O through 20. No adverse effects were observed in the 0 25% DEHP group (average intake = 164 ng DEHP/kg/day). Moderate maternal toxicity (decreased food intake; decreased maternal weight gain), as well as reduced pre- and perinatal growth and viability of the F1 generation were observed in the 0.50% and/or 1.00% DEHP groups (average intake = 313 and 573 ug DEHP/kg/day, respectively). Despite the presence of significant maternal and developmental toxicity at 0.5% and 1.00% during treatment and during the perinatal period, no residual or delayed effects were observed upon the growth, viability, development or reproductive performance of the F1 generation between pnd 4-128.