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EC number: 701-362-9
CAS number: -
Table 1 - Clinical signs:
Pre-mating (females) or whole study (males)
. Round back
. Loud breathing
Number of animals affected
Table 2 -
Days 1 - 8
Days 8 -15
when excludingthe abnormal data(no statistics performed)
Days 0 - 7p.c.
Days 7 - 14p.c.
Days 14 - 20p.c.
Days 1- 5p.p.
applicable; statistically significant:*: p<0.05; **:
Table 3 - Hematology:
White blood cell count (G/L)
Lymphocytes +Large unstained cells (G/L)
Red blood cell count (T/L)
Packed cell volume (PCV) (L/L)
significant from controls: *: p<0.05, **: p<0.01.
Table 4 -
Inorganic phosphorus (mmol/L)
Alanine aminotransferase (ALAT) (IU/L)
significant from controls: *: p<0.05; **: p<0.01.
Table 5 - Organ weights:
Number of animals
significant from controls: *: p<0.05, **: p<0.01
significance concerned the organ weights values and not the percentages.
Table 6 -
Vacuolation, Kuffer cells
The objective of this study was to
evaluate the potential toxic effects of the test item following daily
oral administration (gavage) to male and female rats from before mating,
through mating and, for females, through gestation until day 5 post-partum
(p.p.), based on the OECD guideline No. 421, 27 July 1995.
This study provides information on
male and female reproductive performance, such as gonadal function,
mating behavior, conception, development of the conceptus and
The study was conducted in compliance
with the principles of Good Laboratory Practice Regulations.
Three groups of
ten male and ten female Sprague-Dawley rats received the test item
daily by oral (gavage) from before pairing, through pairing and, for the
females, through gestation until day 5 p.p. The
test item was administered as a suspension in the vehicle,corn
oil, at dose-levels of 50, 250 or
Another group of
ten males and ten females received the vehicle alone under the same
experimental conditions and acted as a control group. A constant
dosage-volume of 5 mL/kg/day was used.
of the dose formulation was checked in study weeks 1, 3 and 6.
The animals were
checked at least twice daily during the dosing period for mortality and
morbidity and once daily for clinical signs. Body weight and food
consumption were recorded at leastonce
a week. The animals were paired for
mating after 2 weeks of treatment and the dams were allowed to litter
and rear their progeny until day 5 p.p. The litter sizes and
numbers of pups per sex were recorded after birth. The pups were
observed daily for clinical signs, abnormal behaviour and external
abnormalities, and weighed on days 1 and 5 p.p.
Hematology and blood biochemistry were
carried outfor all males and all females sacrificed on day 6 p.p.
The males were sacrificed after 5
weeks of treatment and the dams on day 6 p.p. Final body weights
and selected organs weights (epididymides, liver, ovaries, testes,
thyroid with parathyroids) were recorded and a macroscopic post-mortem
examinationof the principal thoracic and abdominal organswas
performed, with particular attention paid to the reproductive organs.
A microscopic examination was performed on selected organs from the
control and high-dose groups (epididymides, liver, testes, thyroid with
parathyroids), on the liver from low- and intermediate-dose groups and
on all macroscopic lesions.
The pups were
sacrificed on day 5 p.p. and submitted for a macroscopic post-mortem
examination of the principal thoracic and abdominal organs.
The test item concentrations in the
administered dose formulations analyzed in weeks 1, 3 and 6 were within
the acceptance criteria (± 15% of the nominal concentrations) and no
test item was found in control samples.
There were no unscheduled deaths.
Ptyalism was observed in males at all dose-levels (half of the animals
at 50 mg/kg/day, all animals at 250 and 1000 mg/kg/day) and in all
females at 1000 mg/kg/day. Round back was noted from the end of week 2
in females (7/10) at 250 mg/kg/day and in both sexes at 1000 mg/kg/day
(7/10 males, 9/10 females). Piloerection was also observed at 250
mg/kg/day in females (2/10) and at 1000 mg/kg/day in all males and 4/10
females. At 1000 mg/kg/day, round back and piloerection lasted 3 to 6
days and were considered to be adverse. During gestation, one female
still had round back on the first day of gestation, and four females
piloerection at the beginning of gestation only.
There were no toxicologically
significant effects on mean body weight gain and mean body weight. When
compared with controls, mean food consumption at 1000 mg/kg/day was
lower in males; this change was considered not to be adverse because of
no relevant impact on mean body weight and on animal survival.
At hematology, there was a slight
lower mean white blood cell count than in controls at 250 and 1000
mg/kg/day in males and at 1000 mg/kg/day in females, mainly related to
lower mean numbers of lymphocytes. This was considered to be non adverse
and of minor toxicological importance.
At blood biochemistry and when
compared with controls, there was a dose-related higher mean cholesterol
level from 250 mg/kg/day. This effect was considered to be adverse at
1000 mg/kg/day in view of the amplitude of differences from control and
historical control data. In females, there was also a dose-related lower
mean concentration of inorganic phosphorus from 50 mg/kg/day and a
slightly higher mean urea blood concentration at 1000 mg/kg/day. These
changes in mean inorganic phosphorus and urea levels were considered not
to be adverse and of minor toxicological importance.
There were no test item-related
macroscopic changes or effects on mean thyroid/parathyroid,
epididymides, testis and ovary weights at necropsy. The microscopic
examination and mean organ weights showed test item-related changes in
liver only. Administration of the test item in rats at
1000 mg/kg/dayinduced mild centrilobular hypertrophy and vacuolation of
Kupffer cells in the liver which correlated with the higher mean liver
weight at necropsy. Centrilobular hypertrophy alone was also observed in
males at 250 mg/kg/day. In the absence of any associated degenerative
liver changes, these observations were considered not to be adverse.
There were no test item-related
effects on pairing, mating and fertility data. There were no
toxicologically relevant effects on delivery data.
In pups, there were no test
item-related deaths or clinical signs andno test item-related effects on
mean pup body weights, mean pup body weight gains,on the percentage of
male pups at birth and no test item-related findings noted at necropsy.
The test item was administered daily
by oral gavage to male and female Sprague-Dawley rats, for 2 weeks
before pairing, during pairing, gestation and until day 5p.p., at
dose-levels of 50, 250 or 1000 mg/kg/day.
At 1000 mg/kg/day,round back and
piloerection noted in both sexes in weeks 2/3, as well as the higher
mean cholesterol level at the end of the treatment period were
considered to be adverse.
There were no adverse findings at 50
and 250 mg/kg/day.
Therefore, based on the experimental
conditions of this study:
No Observed Adverse Effect Level (NOAEL) for parental toxicity was
considered to be 250 mg/kg/day,
NOAEL for reproductive performance (mating and fertility) was considered
to be 1000 mg/kg/day,
NOAEL for toxic effects on progeny was considered to be 1000 mg/kg/day.
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