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EC number: 203-650-5 | CAS number: 109-13-7
Supporting study (OECD 422)
The purpose of the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental toxicity screening test was to provide initial information concerning the toxic potential of TBPIB and on its possible effects on male and female reproductive performance such as gonadal function, mating behavior, conception, pregnancy, parturition as well as on development of the F1 offspring from conception to day 4 post-partum associated with oral administration to rats at repeated doses. Four groups of Hsd.Brl.Han:Wist rats (n=12/sex/group) were administered orally (by gavage) once a day at 0 (vehicle only), 60, 200 and 600 mg/kg bw/day at concentrations of 30 mg/mL, 100 mg/mL and 300 mg/mL mg/mL, corresponding to 2 mL/kg bw dose volume. The suitability of the chosen vehicle for the test item at the intended concentrations was analytically verified up front. TBPIB was stable at room temperature for 4 hours and in a refrigerator (5 ± 3 °C) for 4 days. Concentration of the test item in the dosing formulations varied in the range of 97 % to 102 % in comparison to the nominal values, thereby confirming proper dosing. All animals of the parent (P) generation received test item or vehicle prior to mating (14 days) and throughout mating. Test item or vehicle was administered to male animals post mating up to the day before the necropsy. For females with living pups, test item was administered through the gestation period and up to lactation days 3 – 8, i.e. up to the day before the necropsy. Observations included mortality, clinical signs, body weight, food consumption, mating, pregnancy and delivery process, as well as development of pups. Five dams and males cohabited with were selected from each group for further toxicity examinations such as functional observations, hematology, clinical chemistry, gross necropsy, organ weighing and histopathology. The dams were allowed to litter, and rear their young up to termination on days 4 postpartum and offspring were euthanized. Pups were weighed and observed for possible abnormalities. All parental animals were subjected to gross pathology one day after the last treatment. Selected organs were weighed. Full histopathology was performed in the selected animals of control and high dose groups. Histopathology examination was performed on reproductive organs and pituitary of the remaining animals in the control and high dose groups. The reproductive organs and pituitary of non-pregnant and not mated female animals and males cohabited with in the low and mid dose groups were also processed and evaluated histologically.
The results were interpreted comparing treatment groups with respect to controls, which were treated concurrently with vehicle (sunflower oil) only.
There was no test item related mortality at any dose level (600, 200 or 60 mg/kg bw/day).
Test item related salivation was observed in male and female animals at 600, 200 or 60 mg/kg bw/day with variable occurrence within a group in a dose related onset and frequency after the daily treatment. Salivation appeared immediately before the daily treatment in some cases at 600 mg/kg bw/day (male and female). No toxic signs related to the test item were found at the detailed weekly and terminal functional observations. The behavior and physical condition of animals were normal during the entire observation period (pre-mating, mating, post-mating, gestation and lactation periods).
The body weight and body weight gain was reduced with respect to controls in male animals at 600 mg/kg bw/day. The less body weight gain resulted in a slightly less body weight with respect to controls from day 7 up to the termination of the study.
A test item influence on the mean daily food consumption was observed in male animals at 600 mg/kg bw/day during the premating and post mating week 1.
Hematology examinations revealed slightly less number of red blood cell count and higher reticulocyte count in male animals administered with 600 mg/kg bw/day.
No test item-related changes were observed in investigated clinical chemistry parameters. Necropsy Specific macroscopic alterations related to the test item were not found during the necropsy.
Slightly higher mean weights of spleen and adrenal gland (absolute and relative to body and brain weights) were indicative of test item influence on function of these organs in male animals at 600 mg/kg bw/day dose.
Histological examination did not detect any toxic or test substance related lesions in the genital and other organs of the experimental animals.
Under the conditions of the present study, TBPIB- caused salivation (male and female), changes in body weight (male), food consumption (male), red blood cell parameters (RBC, RET; male) and in weight of spleen and adrenal glands (male) following an oral administration at 600 mg/kg bw/day to Hsd.Brl.Han:Wistar rats during the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test. At 200 and 60 mg/kg bw/day, salivation was observed in male and female animals. No indication of a toxic effect on the reproduction performance was noted in this study up to the highest concentration tested. No test item related adverse effect on the offspring development was observed. Based on these observations the No Observed (Adverse) Effect Levels (NO(A)EL) were determined as follows:
NO(A)EL for male rats: 200 mg/kg bw/day
NO(A)EL for female rats:600 mg/kg bw/day
Based on the results of the subacute repeated oral toxicity study, tert-butyl peroxyisobutyrate was not classified and labelled according to Regulation (EC) No 1272/2008 (CLP).
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