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Key value for chemical safety assessment

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Additional information

In this study performed according to OECD Guideline 421, male and female Sprague Dawley rats were dosed with a mixture of m-DIPB and p-DIPB orally via gavage with 0, 6, 30, 150, or 750 mg/kg bw over 50 -52 days (male) and from 14 days before mating to day 3 of lactation (females). terminal kill in males was on days 51 -53 and in females on day 4 of lactation.

In males, exopthalmos was noted in 2 animals at 750 mg/kg bw. Transiently lowered food consumption was also noted at 750 mg/kg bw. No changes caused by the substance were noted in terms of body weight, necropsy findings, organ weights, or sperm examination. On histopathological examination, vacuolization of lens fibers and hyperplasia of epithelium lentis were noted in 2 and 1 animal, respectively, at 750 mg/kg bw.

In females, mydriasis was noted at 750 mg/kg bw. Transiently lowered body weight were evident at 750 mg/kg bw during the pregnancy period and transiently reduced food consumption was noted before mating. No changes caused by the substance were noted with regard to necropsy, organ weights, or histopathological examination.

From this study a NOAEL of 150 mg/kg bw for male and female rats was derived

m-DIPB was further evaluated in an OECD 414 study, where the material was administered orally by gavage to 3 groups of 25 bred female Crl:CD(SD) rats once daily from gestation days 1 through 19. Dosage levels were 100, 300, and 1000 mg/kg/day administered at dosage volumes of 0.12, 0.35, and 1.16 mL/kg, respectively. A concurrent control group composed of 25 bred females received the control item, deionized water, on a comparable regimen at a dosage volume of 1.16 mL/kg. The females were approximately 13 weeks of age at the initiation of dose administration. All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and food consumption were recorded at appropriate intervals. On gestation day 20, a laparohysterectomy was performed on each surviving female. The uteri, placentae, and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations, and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations and developmental variations.

Three females in the 1000 mg/kg/day group were found dead prior to the scheduled necropsy. One female was found dead on gestation day 20 with 13 dead fetuses (with no apparent malformations) in utero; this female was noted with rales on gestation day 2 but had no remarkable clinical findings thereafter. At necropsy, the cause of death was not determined but a relationship to the test item cannot be ruled out. Two pregnant females were found dead on gestation day 12 with necropsy findings (lungs that were not fully collapsed and/or foamy contents in the trachea) that were suggestive of the deaths being related to the dosing procedure, and therefore were not considered test item-related. All other females survived to the scheduled necropsy; no test item-related macroscopic findings were observed at any dosage level. Dose-related increased incidences of clear and/or red material around the mouth were noted at 1 hour following dose administration in the 300 and 1000 mg/kg/day groups when compared to the control group. These findings were noted as early as gestation day 1 and persisted through gestation day 19. There were no test item-related clinical observations noted in the 100 mg/kg/day group. A test item-related mean maternal body weight loss was noted in the 1000 mg/kg/day group following the first day of treatment (gestation day 1-2) resulting in lower mean maternal body weight gain during gestation days 1-3 (1 g compared to 10 g in the control group) and 15-20, resulting in a lower mean body weight gain for the overall treatment period (gestation days 1-20) and slightly lower mean body weights (up to 5.3% lower) during gestation days 18-20 compared to the control group. The lower weight gain in the 1000 mg/kg/day group during gestation days 1-3 correlated with test item-related lower food consumption during this same interval. Although not statistically significant, mean net body weight gain (12.5%) was lower than in the control group. The lower mean net body weight gain in the 1000 mg/kg/day group was not of sufficient magnitude to result in a lower mean net body weight. Lower mean food consumption was noted in the 100 and 300 mg/kg/day groups following the initiation of dose administration (gestation days 1-3). Mean food consumption in these group was similar to the control group for the remainder of the treatment period. In the absence of an effect on maternal mean body weights or body weight gains in the 100 and 300 mg/kg/day group, the initial decrements in mean food consumption were considered nonadverse. There were no test item-related effects on mean net body weights, net body weight gains, or gravid uterine weights, at 100 and 300 mg/kg/day. Although the mean litter proportion of pre-implantation loss was unaffected by test item administration at all dosage levels, the mean number of implantation sites in the 1000 mg/kg/day group was lower than the concurrent control group value. As a result, the mean number of viable fetuses in the 1000 mg/kg/day group was lower than the concurrent control group. The lower mean number of implantation sites was attributed a lower number of corpora lutea in the 1000 mg/kg/day group compared to the control group. Because ovulation occurred prior to initiation of test item administration on gestation day 1, the lower number of implantation sites in the 1000 mg/kg/day group was not considered to be test item-related. Mean fetal body weights (male, female, and combined) in the 1000 mg/kg/day group were slightly lower than the concurrent control group values. However, all high-dosage group values were equal to the respective mean values in the WIL Research historical control data; therefore, the slightly lower mean fetal body weights in the 1000 mg/kg/day group were not considered test item-related. Intrauterine growth and survival was unaffected by test item administration at dosage levels of 100 and 300 mg/kg/day. No test item-related fetal malformations or developmental variations were noted at any dosage level.

Based on maternal toxicity in the 1000 mg/kg/day group, a dosage level of 300 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity. Based on a lack of developmental toxicity at all dosage levels, a dosage level of 1000 mg/kg/day was considered to be the NOAEL for prenatal developmental toxicity when 1,3-diisopropylbenzene (DIPB) was administered orally by gavage to bred Crl:CD(SD) rats.

Justification for classification or non-classification

m-DIPB was evaluated in an OECD 414 study at daily dosages of up to 1000 mg/kg. Data indicate that no evidence of developmental toxicity was observed in this study.