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Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
Study duration:
subacute
Species:
rat
Additional information

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, using a Combined 28-Day Repeated Dose Oral (Gavage) Toxicity Study with the

Reproduction/Developmental Toxicity Screening Test (OECD 422 test guidance).

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.

Under the conditions of this screening study, no test item-related effects were observed on reproductive performance at any dosage level. Therefore, a dosage level of 1000 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive toxicity of 1,4-diisopropylbenzene when administered orally by gavage to Crl:CD(SD) rats. There were no adverse test item-related clinical observations or effects on mean body weights, body weight changes, and food consumption noted at any dosage level. Furthermore, there were no adverse effects on organ weights, clinical pathology parameters, thyroid hormones, or macroscopic/microscopic alterations in F0 males and females at any dosage levels. Therefore, the NOAEL for systemic toxicity was considered to be 1000 mg/kg/day. The NOAEL for postnatal toxicity was 1000 mg/kg/day based on the absence of effects on F1 offspring at all dosage levels.


Justification for selection of Effect on developmental toxicity: via oral route:
Under the conditions of this oecd 422 screening study, no test item-related effects were observed on reproductive performance at any dosage level. Therefore, a dosage level of 1000 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for reproductive toxicity of
1,4-diisopropylbenzene when administered orally by gavage to Crl:CD(SD) rats. There were no adverse test item-related clinical observations or effects on mean body weights, body weight changes, and food consumption noted at any dosage level. Furthermore, there were no adverse effects on organ weights, clinical pathology parameters, thyroid hormones, or macroscopic/microscopic alterations in F0 males and females at any dosage levels. Therefore, the NOAEL for systemic toxicity was considered to be 1000 mg/kg/day. The NOAEL for postnatal toxicity was 1000 mg/kg/day based on the absence of effects on F1 offspring at all dosage levels.

Justification for classification or non-classification