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EC number: 915-730-3
CAS number: -
Analysis of the dosing dilutions
- The substance was homogeneously
distributed in the carrier at each test concentration.
- The substance was stable in the carrier
under the experimental conditions (storage in the animal room for 4
hours or in the refrigerator (2-10°C for 7 days).
- The content of the substance in the
test dilutions was close to intended in all five batches analysed,
except for the low-dose level prepared on 13 March 2016 (the difference
with intended was -16%). This finding was, however, attributed to the
relatively high intercept of the calibration curve obtained during this
- On the basis of the above it is concluded
that the rats received the intended concentrations.
The key study is a sub-chronic (13-week) repeated dose toxicity
study performed according to OECD TG 408 and GLP principles, rated
Klimisch 1. Wistar Han IGS rats (Crl:WI(Han)) were administered daily by
oral gavage at dose levels of 30, 120 and 500 mg/kg bw/day. A control
group treated with vehicle (corn oil) was included. In each dose group
10 male and 10 female animals were included. Analytical verification of
dose and stability of the test in vehicle showed that the rats received
the intended concentrations. All parameters are measured in accordance
with the current guideline.
Clinical signs and body weights: There was no
mortality. Salivation was noted just prior to or after dosing, mainly in
the high dose group. There were no other treatment-related clinical
signs. Neurobehavioral observations and motor activity assessment did
not indicate any neurotoxic potential of the test substance.
Ophthalmoscopic examination did not reveal any treatment related ocular
changes. There were no relevant changes in growth parameters. Food and
water intake were increased in the high-dose group in both sexes.
Haematology: Haematology parameters were
studied in all rats at necropsy. In the high-dose group haemoglobin
concentration was decreased in both sexes, and red blood cell count and
packed cell volume were decreased in males at maximum with 12%.
Thrombocytes were increased in males, and prothrombin time was reduced
in females of this group. Total white blood cell counts were increased
in males of the high-dose group.
Clinical chemistry was conducted in all rats
at necropsy. An increase cholesterol and phospholipids concentrations in
females of the high-dose group was seen.
Urinalysis, conducted in all rats in week 13
of the study, did not reveal relevant changes in renal concentrating
ability or in semi-quantitative (dipstick) urinary measurements.
Microscopic examination of the urinary sediment showed increases in
epithelial cells, amorphous material and casts in males of the high-dose
group. Casts were also noted in two males of the mid-dose group.
Spleen: the relative weight of the spleen
(37%) was increased in males of the high-dose group. Macroscopic
examination at necropsy revealed no treatment-related changes. The
changes in the spleen were characterized by increased extramedullary
erythropoiesis in 8/10 high-dose males, in 3/10 mid-dose females and in
5/10 high-dose females. Extramedullary erythropoiesis in the spleen may
be regarded as a physiological mechanism to meet an increased demand for
the production of red blood cells. However, a reason for the increased
demand could not be established; the bone marrow did not show
abnormalities indicating that the normal production of red blood cells
was impaired. Further, no signs of an increased red blood cell turnover
were found (such as haemorrhages, elevated reticulocytes or increased
accumulation of iron pigment in the spleen). Taking into account that
the extramedullary erythropoiesis noted in a few females in the mid-dose
group was not accompanied by functional disturbances in red blood cell
system, this finding in the mid-dose group is not considered adverse.
Liver: The relative weight of the liver was
increased in males and females of the mid- and high dose groups (12-15%
in the mid-dose group and 50% in the high-dose group). The microscopic
changes in the liver were characterized by centrilobular hepatocellular
hypertrophy (enlarged cells as well as enlarged nuclei) and
hepatocellular vacuolation. The incidence of centrilobular
hepatocellular hypertrophy was 3/10, 6/10 and 9/10 in the low-, mid- and
high-dose males, respectively; and 8/10 and 9/10 in the mid- and
high-dose females, respectively. In addition, 10/10 mid-dose and 10/10
high-dose females showed a minimal increased incidence of
macro-vesicular hepatocellular vacuolation. This minimal vacuolation was
seen in all groups in the males with a lower incidence. The incidence of
hepatocellular hypertrophy in the liver showed a clear dose-effect
relationship in males of all dose groups and in females of the mid- and
high dose group. The elevated blood lipids, increase in relative liver
weight in combination with hepatocellular hypertrophy. These effects may
be considered a reaction to an increased metabolic demand. Liver weight
increase and hepatocellular hypertrophy in the absence of clinical
pathology or histologic alterations indicative of overt hepatocellular
damage may be considered an adaptive non-adverse effect ESTP Expert
Workshops (2012, 2016). This may be concluded for the high dose too but
in view of the high relative liver weight increase (and accompanying
effects) the mid-dose is considered non-adverse for liver effects.
Kidney: The relative weight of the kidneys was
increased in males of the mid- and high-dose groups (13% and 36%,
respectively) and in females of the high-dose group (13%). Microscopy
revealed alpha 2urinary microglobulins (accumulation of hyaline droplets
in tubules of the outer cortex of the kidneys accompanied by an
increased number of basophilic tubules, and/or dilated tubules with
eosinophilic casts consisting of granular debris) and identified by
Other effects: There were no neurotoxicity and
immunological toxic findings in this study. There were also no
neoplastic findings in this study.
In conclusion, a NOAEL of 120 mg/kg bw/day could be derived based
on the effects in the spleen and liver which were accompanied by changes
in haematology or clinical biochemistry in the high dose group only.
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