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EC number: 297-025-4
CAS number: 93281-13-1
A Combined Repeated Dose Toxicity Study
with the Reproduction/Developmental Toxicity Screening Test was
conducted to obtain information on the toxic potential of test item,
following the testing method and testing procedures outlined into the
OECD guideline 422.
The substance was administered to rats
orally (by gavage) once daily at 0 (vehicle only), 40, 120 and 350 mg/kg
bw/day doses. The concentration of the test item in the dosing
formulations was checked two times during the study and the
concentrations varied within the range of 97 and 103 % in comparison to
the nominal values.
All animals of the parent (P) generation
were dosed prior to mating (14 days) and throughout mating. In addition,
males received the test item or vehicle after mating up to the day
before the necropsy (altogether for 42 days). Females were additionally
exposed through the gestation period and up to lactation days 14-16,
i.e. up to the day before necropsy (altogether for 51-65 days).
There was no test item related mortality
at any dose level. One male animal at 350 mg/kg bw/day and one female
animal at 120 mg/kg bw/day were found dead on Day 22 and on lactation
day 10 (on Day 49), respectively. Based on clinical observation and
necropsy findings, the cause of the death was independent from the test
Clinical signs of systemic toxicity
related to the test item were not detected at any dose level, neither at
the daily nor at the detailed weekly clinical observations or at the
functional observations. The body weight development was not adversely
affected by the test item in male or in female animals, as well as the
mean daily food consumption.
A test item influence on the estrous cycle
was not found at any dose level and there were no toxicologically
significant differences between the control and test item treated male
or female animals in the examined parameters of reproductive performance
or in the delivery parameters of dams.
Hematological and clinical chemistry
evaluations did not reveal adverse test item related changes in the
examined parameters. There were no test item related changes in the
serum thyroid hormone (T4 and TSH) levels at any dose (parental male or
Macroscopic findings related to the effect
of the test item were not found in male and female animals. Black or
grey colored organs (spleen, submandibular or mesenteric lymph nodes)
and presence of the test item or its metabolite(s) in the stomach and/or
intestines were detected in male animals belonging to the groups dosed
at 120 and 350 mg/kg bw/day at the terminal necropsy. In females, black
or grey staining was observed mainly in mesenteric lymph nodes in
several animals dosed at 120 mg/kg bw/day and in all animals dosed at
350 mg/kg bw/day; the kidneys staining was observed in 2/12 animals
dosed at 350 mg/kg bw/day.
There were no test item related changes in
the weights (absolute and relative to body or brain weights) of brain,
testes and epididymides of male animals at any dose level.
Non-statistically significant changes in spleen weights were observed in
male animals at 40, 120 and 350 mg/kg bw/day and in female animals at
350 mg/kg bw/day; they were considered to be of little or no biological
relevance. The examined organ weights of animals selected for toxicity
examinations were comparable in the control and 40, 120 and 350 mg/kg
bw/day groups at the end of the treatment period.
Histopathological examinations revealed
test item related minimal centrilobular vacuolation in the hepatocytes –
sign of hepatic lipidosis – in male animals at 350 mg/kg bw/day. Hepatic
lipidosis is considered as a slight reversible liver injury in
connection with a disturbance of energy metabolism of affected
hepatocytes. There were no histological patterns of hematopoietic
(erythroid or myeloid) hyperplasia in the splenic tissues or in the
livers of animals in accordance with organ weight changes.
Under the conditions of the study, no
signs of systemic toxicity in male or female animals was recorded; at
350 mg/kg bw/day, test item related minimal centrilobular vacuolation in
the hepatocytes was observed in some male animals (3/5). Centrilobular
vacuolation in the hepatocytes is considered as sign of hepatic
lipidosis, which is a slight reversible liver injury.
NOAEL (rat, male and female): 350 mg/kg
bw/day, systemic toxicity
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