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EC number: 202-826-9 | CAS number: 100-18-5
The objectives of the study were to evaluate the potential toxic effects of the test item, 1,4-diisopropylbenzene, when administered to rats for 28 days and to evaluate the potential of the test item to affect male and female reproductive performance such as gonadal function, mating behavior, conception, parturition, and early postnatal development.
STUDY DESIGN: The test item, 1,4-diisopropylbenzene, was administered orally by gavage once daily to 3 groups of Crl:CD(SD) rats, each group consisting of 10 males and 10 females. Dosage levels were 100, 300, and 1000 mg/kg/day administered at dose volumes of 0.12, 0.35, and 1.18 mL/kg. A concurrent control group of 10 rats/sex received the control item (deionized water) at a dose volume of 1.18 mL/kg on a comparable regimen. Males and females were approximately 10 weeks of age at the beginning of test item administration. Males received 14 daily doses prior to mating. Males were dosed throughout the mating period through 1 day prior to euthanasia for a total of 28-29 doses. Females received 14 daily doses prior to pairing and were dosed through lactation day 13 for a total of 49-59 doses; the female that failed to deliver was dosed through the day prior to euthanasia (post-mating day 25) for a total of 39 doses. All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and food consumption were recorded at appropriate intervals. FOB and motor activity data were recorded for 5 males/group following 23 days of dose administration and for 5 females/group on lactation day 13. All F0 females were allowed to deliver and rear their pups until lactation day 13. F1 clinical observations, body weights, and sexes were recorded at appropriate intervals and anogenital distance was recorded on PND 1. To reduce variability among the litters, 8 pups per litter, 4 per sex when possible, were randomly selected on PND 4; blood samples for possible thyroid hormone analysis were collected from the culled pups (1/sex/litter) but were not analyzed. All F1 male pups were evaluated for areolae/nipple anlagen on PND 12. Remaining F1 pups were euthanized on PND 13; blood samples for thyroid hormone analysis were collected and selected organs were weighed from 1 pup/sex/litter. Clinical pathology evaluations (hematology and serum chemistry) were performed on 5 F0 animals/sex/group just prior to scheduled necropsy. Blood samples for thyroid hormone analysis were collected from F0 males and females prior to euthanasia; only male samples were analyzed. F0 males were euthanized following completion of the mating period and F0 females were euthanized on lactation day 14 for females that delivered or post-mating day 25 for females that failed to deliver. Complete necropsies were conducted on all F0 animals, and selected organs were weighed. Selected tissues were examined microscopically from all F0 animals in the control and 1000 mg/kg/day groups. In addition, the adrenal cortex (males) and liver (males and females) were identified as potential target tissues and were examined from all animals.
RESULTS: All F0 males and females survived to the scheduled necropsies. Red and/or clear material around the mouth was noted in a dose-related manner for males and females in all test item-treated groups approximately 1 hour following dose administration throughout the treatment period. The aforementioned material observations did not persist to the weekly examinations and were
considered nonadverse in the absence of other signs of systemic toxicity (body weight and food consumption decrements). No test item-related clinical observations were noted for F0 males and females at the weekly examinations at any dosage level. Mean body weight gain in the 1000 mg/kg/day group males was similar to the control group during the pre-mating treatment period (study days 0-13) and during study days 13-21. A test item-related, lower mean body weight gain was noted in this group during study days 21-27 and when the entire treatment period (study days 0-27) was evaluated. However, the effect on mean body weight gain during the last week of treatment was not of sufficient magnitude to affect absolute mean body weights, and therefore, was not considered adverse. Mean body weights, body weight gains, and food consumption for F0 males at 100 and 300 mg/kg/day and females at
100, 300, and 1000 mg/kg/day were unaffected by test item administration throughout the study. No test item-related effects were noted during the FOB or motor activity evaluations at any dosage level. There was 1,4 -diisopropylbenzene-related minimal to mild nonadverse hepatocellular hypertrophy in the 300 and 1000 mg/kg/day group males and 1000 mg/kg/day group females that was associated with higher liver weights in males and females at 1000 mg/kg/day and nonadverse elevations in alkaline phosphatase, alanine aminotransferase, bile acids, and cholesterol in females at 1000 mg/kg/day. Nonadverse angiectasis of the liver was noted in the 300 and 1000 mg/kg/day group males and correlated with gross observations of dark red discoloration. Increased incidence and severity of nonadverse adrenal cortical vacuolation was noted in the 1000 mg/kg/day group males. Other nonadverse findings included lower glucose values (1000 mg/kg/day group males and females), higher urea nitrogen values (1000 mg/kg/day group females), and higher phosphorus (300 and 1000 mg/kg/day group males and 1000 mg/kg/day group females). There were no test
item-related changes in hematology and coagulation parameters for F0 males and females. T4 levels in F0 males were unaffected by test item administration. F0 male and female mating and fertility, male copulation and female conception indices, mean number of days between pairing and coitus, gestation length, and the process of parturition were unaffected by test item administration at all dosage levels. There were no test item-related effects on the mean number of implantation sites and unaccounted-for sites at any dosage level.
There were no test item-related effects on the number of F1 pups born, live litter size, percentage of males at birth, F1 clinical observations, postnatal survival and growth, anogenital distance, or areolae/nipple anlagen. There were no test item-related macroscopic findings for F1 pups that were found dead at any dosage level. There were no test item-related changes in T4 levels or
thyroid/parathyroid weights in F1 males or females on PND 13.
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