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EC number: 261-332-1 | CAS number: 58567-11-6
The purpose of this study was to generate preliminary information concerning the effects of the substance on possible health hazards likely to arise from repeated exposure over a relatively limited period of time. In addition it provides information on possible effects on male and female reproductive performance such as gonadal function, mating behaviour, conception, development of the conceptus and parturition. The substance was administered to male rats for 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 3 post-partum, one day before necropsy.
The following dose levels were applied:
Group 1: 0 mg/kg body weight/day (control group)
Group 2: 50 mg/kg body weight/day
Group 3: 300 mg/kg body weight/day
Group 4: 1000 mg/kg body weight/day
A standard dose volume of 4 mL/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (corn oil).
Mortality and General Tolerability
All animals survived scheduled study period. Bedding in mouth and salivation were noted in males and females at the dose level of 1000 mg/kg bw/day. Bedding in mouth alone was noted in females at the dose level of 300 mg/kg bw/day. These observations were considered to be sign of discomfort caused by the treatment with the test item. No further clinical signs or observations were noted in males or females at any dose level.
Functional Observational Battery
With exception for salivation noted in one male and one female at the dose level of 1000 mg/kg bw/day, no further test item-related findings were noted during the tests of functional observational battery or measurement of locomotor activity.
At the dose level of 1000 mg/kg bw/day in females, transient reduction in food consumption was noted at the beginning of the treatment. No test item-related effects on food consumption were noted in males at any dose level or females at dose levels of 50 and 300 mg/kg bw/day.
No effects on absolute body weights or body weight gain were noted in males or females at any dose level.
Clinical Laboratory Investigations
In males statistically significantly higher creatinine concentration was noted in all dose groups. This finding was accompanied by statistically significantly reduced concentration of phosphorus in high- and mid-dose groups. These findings were considered to most probably be secondary to lesions in the kidneys which were considered sex- and species-specific for male rats and therefore not relevant for humans. Further findings were statistically significantly lower concentrations of total bilirubin and statistically significantly lower concentration of bile acids in males at the dose level of 1000 mg/kg bw/day. These findings were considered to possibly be secondary to the adaptive changes in the liver metabolism caused by the treatment with the test item and not to be adverse. No further test item-related changes in hematology or biochemistry parameters were noted in males or females at any dose level.
At the dose level of 1000 mg/kg bw/day, statistically significantly increased liver weights were noted in males. This finding was considered to be due to adaptive changes in the liver metabolism caused by the treatment with the test item and not adverse.
Macroscopical Findings and Histopathological Examinations
During macroscopical examination enlarged liver was found in one female at the dose level of 1000 mg/kg bw/day. This finding was considered to be related to the treatment with the test item.
During microscopic examinations, test item-related findings were noted in the liver of males and females at the dose level of 1000 mg/kg bw/day. These changes consisted of centrilobular hypertrophy of the hepatocytes and were considered to be an adaptive change due to the increased metabolism of the liver. In addition, hypertrophy of the follicular epithelium of the thyroid gland was noted in males at the dose level of 1000 mg/kg bw/day. This finding was considered to be very likely secondary to the increased metabolism in the liver.
Based on the lesions in the kidneys found in males at the dose levels of 1000 and 300 mg/kg bw/day which were considered to be adverse, general NOAEL (No Observed Adverse Effect Level) for males was established at 50 mg/kg bw/day. However, lesions in the kidneys were considered to be specific for male rats and therefore not toxicologically relevant for humans. NOAEL for females was considered to be 1000 mg/kg bw/day, the highest dose level used in the study.
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