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EC number: 248-580-6
CAS number: 27619-97-2
Analytical verification of dosing
The test substance was considered to be
homogeneously distributed in the diets and was considered to be stable
in the vehicle (tap water) when stored at 2-10°C for 10 days. The
concentration of the test substance was close to intended (85-115%) for
all diets at all dose levels, except for the lowest level measured on 9
March where a slightly higher deviation of 16.4% was found.
The study was
performed according to OECD TG 422 and GLP principles. The test
substance was administered once daily by oral gavage, as a suspension in
tap water. Controls were treated with vehicle (tap water) only. The
study comprised 4 groups of 12 male and 12 female Wistar Han IGS rats
(Crl:WI(Han)) each, viz. one control group that received the vehicle and
three groups that received the test substance. The dose levels have been
selected in consultation with the sponsor and are based on the results
of a 2-weeks dose-range finding study with the test item in rats. The
test substance was administered at dose levels of 5, 15 or 45 mg/kg body
weight/day during a premating period of 10 weeks and during mating (1
week), gestation and lactation until 14 days after delivery. Male
animals were sacrificed after 90 days of exposure. A dosing volume of 5
mL/kg body weight was applied in all groups.
parameters included clinical observations, body weight, food
and delivery parameters and individual pup parameters up to lactation
day 13. Atnecropsy animals were
macroscopically examined and several organs were examinedmicroscopically.The
oral administration of test substance was well tolerated. There were no
mortalities orchanges in clinical
signs, neurobehavioural observations, growth, food intake, red blood cellvariables,
clotting potential and results on macroscopy.A
treatment-relationship could not be ruled out for the lower mean total
protein levels and mean albumin levels in the low dose and high dose
males. However, in absence of a dose-response relationship and in view
of the limited effect, this was not considered adverse. In addition the
higher mean urea levels in high dose males were considered related to
revealed treatment related histopathological changes in the kidneys,characterized
by mild to moderate (multi)focal tubular dilatationin
1/12 high-dose females. Because of this finding, the kidneys of the low-
and mid-dose animals were also processed and examined microscopically.
In these groups tubular dilatation was not observed. There was no effect
of the test substance on male and female fertility or reproductive
performance. There were no effects on the litter data in the number of
pups, pup survival, growth, sex ratio and developmental parameters.
Based on the
histopathological changes in the kidney the NOAEL for maternal toxicity
was considered to be 15 mg/kg body weight per day.Based
on the absence of effects on fertility and developmental parameters, the
NOAEL forfertility and developmental
toxicity was stablished at ≥ 45 mg/kg body weight per day.
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