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.
Di-n-propylphthalate (DPrP) was tested using the Fertility Assessment by Continuous Breeding (FACB) protocol in Swiss CD-1 mice as part of a structure-activity evaluation of a variety of phthalates. Body weights, food and water consumptions, and clinical signs in a dose-range-finding study were used to set doses for the main study of 0.0, 1.25, 2.50, and 5.00% in feed. Based on measured feed consumption (which was not reduced by DPrP exposure) , these concentrations produced calculated consumption estimates of nearly equal to 1.9, 4.06, and 8.63 g/kg/d.
Over the course of Task 2 (the continuous breeding phase of the study), male mice gained an average of 15, 7, 5, and 2% of their pre-start body weight in the control to high dose group, respectively. The seven deaths on study were distributed among the groups, and were not attributed to DPrP exposure. While there were no adverse reproductive effects observed at the low dose, there was a 44% reduction in the number of live pups/litter in the middle dose group, and an 8% reduction in live pup weight adjusted for litter size. The high dose group was sterile; no high dose pairs had any pups.
These significant reproductive effects prompted a crossover mating trial to determine the affected sex, using the control and 5% dose groups. This was performed after the last litter was weaned for F1 fertility evaluation. While equal proportions of the groups showed evidence of mating, none of the treated females bore any young when bred to control males. Litters from treated males were 34% smaller than those from control males; pup body weights were unchanged.
After the crossover mating and delivery, the control and high dose F0 mice were killed and necropsied. Treated females weighed 14% less than controls, while liver weight and kidney weights, adjusted for body weight, were 185% and 86% of control values, respectively. Terminal male body weights were 15% less than controls, while adjusted liver weights were 61% greater. Adjusted weights of kidneys, seminal vesicles, epididymis, and prostate were reduced by 22%, 24%, 20%, and 20%, respectively. Absolute testis weight was reduced by 36%. Sperm count was reduced by 41%, sperm motility by 8%, and sperm abnormalities were elevated by 51%.
Although there was significant liver weight increase and the livers of treated animals appeared darker at necropsy, there were no hepatic changes noted microscopically. Major microscopic findings were limited to testicular atrophy and associated epididymal effects.
An evaluation of the second generation was not conducted.
In summary, di-N-propylphthalate caused reproductive toxicity at doses that reduced parental weight gain. Both sexes were affected, based on fertility performance (fewer litters and fewer pups in Task 3) and necropsy findings of the high dose group (reduced reproductive organ weights and sperm indices).