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EC number: 435-680-1
CAS number: -
An investigation according to the OECD Guidelines 421 “Reproduction /
Developmental Toxicity Screening Test” was performed with Wistar rats
and oral administration. Doses used: 0 - 100 - 300 - 1000 mg/kg bw/d.
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 54 days). Females were additionally exposed through the gestation
period and up to lactation days 13 - 17, i.e. up to the day before
necropsy (altogether for 54, 55, 62 or 67 days).
Observations included mortality, clinical signs, body weight, food
consumption, mating, pregnancy and delivery process, as well as
development of offspring. Estrous cycle was monitored by examining
vaginal smears before the treatment for 16 days and for two weeks from
the beginning of the treatment period (two weeks pre-mating period) and
during the mating period until evidence of mating. Blood samples were
collected for possible determination of serum levels of thyroid hormones
(T4) from at least two pups per litter (where it was feasible) on
post-natal day 4, from all dams and at least two pups per litter at
termination on post-partum/ post-natal day 13 and from all parent male
animals and from one non-pregnant female at termination (Day 54).
The dams were allowed to litter, and rear their offspring up to day 13
post-partum. Litters were weighed and offspring were observed for
possible abnormalities and were euthanized on post-natal day 13. All
parental animals were subjected to gross pathology one day after the
last treatment. The body weight, brain weight and weight of the testes
and epididymides of adult male animals were determined. Thyroid gland
was preserved from all adult males and females and one male and one
female pup per litter (at day 13) for the intended subsequent
Mortality: There was no test item related mortality at any dose level in
males of females.
Clinical observation: Clinical signs of systemic toxicity related to the
test item were not detected at any dose level, neither at the daily nor
the detailed weekly clinical observations. At the same intervals, the
behavior and physical condition of the animals was not impaired at each
dose level during the entire treatment period.
Body weight and body weight gain: The body weight development of male
and female animals was not disturbed and it was comparable in the
control and test item treated groups.
Food consumption: The mean daily food consumption was not adversely
affected by the test item in male or female animals. The mean daily food
consumption was slightly transitionally reduced with respect to the
control in male and female animals at 100, 300 and 1000 mg/kg bw/day in
the first week of the treatment period.
Estrous cycle: There was no test item effect on the estrous cycle of
Reproductive performance: There were no test item related differences
between the control and test item treated groups in the gonadal
function, mating behavior, conception, pregnancy, parturition of male or
There were no test item related differences between the control and test
item treated groups in delivery data of dams.
Clinical biochemistry: The serum T4 levels were not influenced in
parental male animals or in PN 13 offspring in test item administered
groups comparing to their control.
Necropsy: Macroscopic findings (dilatation of the caecum) related to the
test item treatment were found in male and female animals in the low
dose (1/12 male, 4/12 female), mid dose (3/12 male, 11/12 female) and
high dose (12/12 male and 12/12 female). The incidence of the
observation increased in a dose-dependent manner.
Organ weight: There were no test item related changes in the weights
(absolute and relative to body or brain weights) of brain, testes and
epididymides, prostate, seminal vesicles with coagulating gland as a
whole of male animals at any dose level.
Histopathology: Histopathological examinations of the selected organs
(ovaries, testes, epididymides, prostate and seminal vesicles with
coagulating gland) did not reveal any test item related adverse changes
at any dose level. However, dilatation of caecum related to the test
item treatment in a proportion of animals belonging to the treated
groups without pathological lesion was observed in the test item treated
Offspring: The offspring’s development was not influenced at any dose
level. No effect on mortality, clinical signs, body weight or necropsy
findings were detected in the offspring terminated as scheduled. The
anogenital distance (male and female) or nipple retention (male) were
The test substance at 100, 300 or 1000 mg/kg bw/day did not adversely
influence the reproductive performance and did not cause adverse
systemic toxicity in parental male and female rats. However macroscopic
findings (dilatation of the caecum) related to the test item treatment
were found in male and female animals in each test item treated groups
which incidence increased dose-dependently. In the lack of any
histopathological alterations in the caecum this macroscopic observation
is considered to be a non-adverse effect of the test item treatment and
might be a physiological phenomenon.
The development of the F1 offspring was not impaired at any dose level
from birth to post-natal day 13 after repeated oral administration of
Based on these observations the No Observed Adverse Effect Levels
(NOAEL) were determined as follows:
NOAEL for systemic toxicity of male/female rats: 1000 mg/kg bw/day
NOAEL for reproductive performance of male/female rats: 1000 mg/kg bw/day
NOAEL for F1 Offspring: 1000 mg/kg bw/day
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