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EC number: 217-568-2
CAS number: 1889-67-4
objective of this study was to obtain information on the possible health
hazards likely to arise from repeated exposure to the test item at three
dose levels over a prolonged period of time (90 days) followed by a
28-day recovery period in order to assess reversibility, persistence or
delayed occurrence of potential toxicological effects.
item was administered orally (by gavage) to Hsd.Han: Wistar rats (n=15
animals/sex in the control and high dose groups, n= 10 animals/sex in
the low and middle dose groups) once a day at 0 (vehicle control), 30,
10 and 3 mg/kg bw/day corresponding to concentrations of 0, 15, 5 and
1.5 mg/mL, applied in a dose volume of 2 mL/kg bw for 90 or 91 days. 5
animals/ sex in the control and high dose groups assigned to the
recovery groups were handled identically up to Day 89 and then observed
without administration for another four weeks (recovery observations).
suitability of the chosen vehicle for the test item and sufficient
stability of the test item in the vehicle was analytically verified up
front. The test item was stable in the applied concentrations in
sunflower oil at room temperature for one day and in a refrigerator (5 ±
3°C) for 3 days.
of the test item in the dosing formulations varied from 95 % to 106 % of
nominal concentrations at each analytical occasion, thereby confirming
were observed for mortality twice a day during the course of the study.
Daily general clinical observations and weekly detailed clinical
observations were performed. A functional observation battery was
conducted in the last week of treatment. The body weight and food
consumption were measured and evaluated weekly. Clinical pathology
examinations (including hematology, blood coagulation and clinical
chemistry) and gross pathology were conducted one day after the last
treatment and at the end of the recovery period. The absolute and
relative weights of selected organs were measured. Sperm examinations
were conducted in animals of the control and high dose groups at the end
of the treatment period. Full histopathology was performed on the
preserved organs or tissues of the animals of the control and high dose
groups, including recovery groups. In addition, the thymus was also
processed histologically in single male animals of 3 mg/kg bw/day dose
group based on macroscopic observation at necropsy.
of study were interpreted comparing test item treated groups with
respect to controls, which were administered concurrently with vehicle
died during the course of the study. Toxic signs related to the test
item were not detected at any dose level (30, 10 or 3 mg/kg bw/day) at
the daily and detailed weekly clinical observations and in the course of
the functional observation battery.
weight development of male and female animals was reduced in male and
female animals at 30 mg/kg bw/day by, which was reversible only in male
animals but not in females. Slight reduction of body weight development
in female animals at 10 mg/kg bw/day occurred at < 10%. Hence, it was
not considered to be toxicologically relevant.
daily food consumption was comparable in animals of the control and test
item treated groups (30, 10 and 3 mg/kg bw/day).
no abnormalities in the eyes of animals in the high dose group at
termination of the treatment (male and female at 30 mg/kg bw/day).
A test item
influence on the estrous cycle was not detected (30, 10 and 3 mg/kg
examinations did not reveal test item related toxic changes in the
evaluated parameters (30, 10 and 3 mg/kg bw/day). Slight elongation of
blood coagulation times (PT, APTT) in male and female animals at 30
mg/kg bw/day were judged to be toxicologically not relevant due to the
low degree (mean values remained well within the historical control
changes were not detected at the evaluation of clinical chemistry
parameters in male or female animals at 30, 10 or 3 mg/kg bw/day.
Slightly elevated activity of gamma glutamyl transferase at 30 and 10
mg/kg bw/day (mainly in females) were indicative of a test item
influence on the hepatic function as an adaptation response to the
altered demand. However, there were no related histopathological changes
to substantiate their toxicological relevance.
macroscopic alterations related to treatment with the test item were not
observed at the terminal necropsy or at the end of the recovery period.
A test item
influence on the examined organ weights was not detected.
analysis did not reveal test item influence on the sperm cells (count,
motility and morphology) at 30 mg/kg bw/day.
no histological lesions related to the test item effect.
conditions of the present study, a dose of 30 mg/kg bw/day the test item
reduced the body weight development in male and female Hsd.Han:Wistar
rats after the consecutive 90-day oral (gavage) administration.
Bodyweight changes were reversible in male animals but not in the female
no toxicologically relevant changes of the examined parameters in male
or female animals at 10 mg/kg bw/day or 3 mg/kg bw/day.
these observations, the No Observed Adverse Effect Level (NOAEL) was
determined to be 10 mg/kg bw/day for male and female Hsd.Han:Wistar rats.
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