Di-N-octylphthalate (DOP) was tested using the RACB 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%, 2.5%, and 5% in feed. Feed consumption was unchanged by DOP addition. Based on measured consumption, these concentrations of DOP produced calculated consumption estimates of nearly equal to 1.8, 3.6, and 7.5 g DOP/kg body weight/d.
Three controls and two middle dose mice died during the continuous breeding phase. Both treated and contol mice gained an average of 12-14% of their original body weight. There was no effect of DOP exposure on the number of litters/pair, the mean number of live pups per litter (control value: 11.5 ± 0.4 pups), proportion born alive, live pup weight adjusted for litter size (control: 1.60 ± 0.01 gr) or days to deliver each litter.
In the absence of any demonstrable reproductive toxicity, a Task 3 crossover mating was not performed, and the fertility of the second generation was evaluated for the controls and high dose groups.
In the F1 mice, growth and viability were unaffected by DOP consumption. Reproduction was also unaffected: the same proportion of treated and control mice mated, and bore live litters. The size and viability of these litters was also unaffected by DOP (11.5 pups/litter, controls), as was adjusted pup weight (1.50 ± 0.03 gr).
The F1 adults were killed and necropsied after the F2 litters were delivered and evaluated. In F1 females, body weight was unaffected by 5% DOP exposure, but when adjusted for body weight, both liver weight and kidney weight was increased by 22% and 10%, respectively. Treated male terminal body weight was also unchanged by DOP, while adjusted liver weight was increased by 28%, and seminal vesicle weight was decreased by 12%. Epididymal sperm concentration and motility were unchanged by DOP exposure at 5%; the proportion of morphologically abnormal forms was reduced in the treated mice, from a control value of 5% abnormal to 3.5% abnormal in the DOP-exposed males. Estrous cycle length and stage distribution (the proportion of time spent in each estrous stage) was unchanged by DOP exposure.
The single finding of a slight reduction in F1 seminal vesicle weight is interesting in light of current concerns about second-generational reproductive toxicity, but needs confirmation. Overall, these data show that, at doses that induced significant hepatomegaly, di-n-octyl-phthalate was without any adverse reproductive effect in Swiss mice.
NTIS# PB85218147