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EC number: 238-270-9
CAS number: 14324-55-1
ANALYTICAL VERIFICATION OF DOSES OR
- Linearity: The correlation
coefficient was 1.000 during the 6 runs which were performed during this
study and therefore the preset criterion (the correlation coefficient of
the calibration curves should be ≥ 0.996) was met.
- Homogeneity: The RSD between the
mean concentrations at three different locations was < 5% for all dose
levels and/or p was ≥ 0.01. Therefore the test substance was considered
to be homogeneously distributed in the gavage liquids.
- Content: The concentration of the
test substance was close to intended (85-115%) for all gavage liquids at
all dose levels, except for the mid-dose level of the gavage liquids
prepared (-23%). This single deviation is considered acceptable. It is
concluded that the animals received the intended levels of test
substance at all dose levels.
The repeated dose
toxicity of the test substance was determined in a GLP-compliant 90-day
study in accordance with OECD Guideline 408 (Triskelion B.V., 2017). The
test substance was administered daily oral gavage as a suspension in
corn oil to groups of 10 male and 10 female Wistar rats at dose levels
of 0 (vehicle control), 10 (low-dose group), 50 (mid-dose group) and 250
mg/kg bw/day (high-dose group). Because of mortality observed in the
high-dose group, the initial high-dose level in was reduced to 125 mg/kg
bw/d from study day 35 and onwards.
Four males and
four females in the high-dose group were found dead or killed in
moribund condition. These deaths were treatment-related and also
occurred after the high-dose level had been reduced from 250 to 125
mg/kg bw/day. Clinical signs noted mainly in the high-dose group and to
a lesser extent also in the mid-dose group, included salivation, chewing
movements, sliding with the ventral parts of the head and neck over the
cage bottom soon after dosing, piloerection, soiled fur, soft/ mucoid/
yellowish faeces, dyspnoea, sniffing, grunting, weakness and hunched
posture. Results of the neurobehavioral observations and motor activity
assessment did not indicate any neurotoxic potential of the test
substance. Ophthalmoscopy examination of all surviving animals in week
13did not reveal any treatment-related changes. Mean body weights were
decreased in the mid- and high-dose groups in both sexes.In the initial
stage of the study, food intake tended to be lower in the mid- and
high-dose groups, but there were no differences in overall food intake.
Water intake was increased in the high-dose group in both sexes
throughout the study. In the course of the study, water intake also
tended to be elevated in the mid-dose group and in males of the low-dose
group. Haematology was conducted in 10 rats/sex/group at necropsy.
Packed cell volume was decreased in the mid- and high-dose groups in
both sexes. In females of these groups, red blood cell count was
decreased, and MCH and MCHC were increased. In males of the high-dose
group red blood cell count and haemoglobin concentration were decreased
and reticulocytes were slightly increased. There were no relevant
changes in clotting variables. The absolute neutrophil count was
increased in males of the high-dose group. Clinical chemistry, conducted
in 10 rats/sex/group at necropsy, showed changes in total protein and
albumin concentrations (mid- and high-dose), albumin/globulin ratio
(high-dose), ALAT and ASAT activities (mid- and high-dose), creatinine
concentration (high-dose) and inorganic phosphate concentration (high
dose). Urinalysis conducted in 10 rats/sex/group in week 13 of the
study, did not reveal any relevant changes in renal concentrating
ability or in microscopy of the urinary sediment. Semiquantitative
(dipstick) urinary measurements showed an increase in the incidence of
urinary ketones in females of the mid- and high-dose group. Changes in
organ to body weight ratios were noted in kidneys (high-dose), liver
(mid- and high-dose), spleen (high-dose), adrenals (mid- and high-dose),
thyroid (mid- and high-dose) and thymus (high-dose). Macroscopic
examination at scheduled necropsy at the end of the study showed red
discoloured mesenteric lymph nodes in surviving high-dose males.
Histopathological findings in high-dose animals that died intercurrently
were myocardial degeneration in the heart, single cell necrosis in the
pancreas, increased accumulation of brown pigment in the spleen and
decreased cortical cellularity in the thymus. Decreased cellularity was
also occasionally seen in the mesenteric and axillary lymph nodes.
Microscopic examination of surviving rats showed single cell necrosis in
the pancreas of high-dose males and females and increased accumulation
of brown pigment in the spleen of high-dose males and females and
extramedullary erythropoiesis in high-dose males.
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