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EC number: 941-167-8
CAS number: 1584709-99-8
The dosage of 1000 mg/kg/day was well
tolerated with minimal clinical signs comprising transient reddening of
the ears, and for one animal, reddening of the limbs and muzzle on Day
12 and abnormal (swaying) gait on Day 2 for one male. Although abnormal
gait was observed for just one animal (No. 27), it cannot be discounted
that this was related to treatment. Salivation and chin rubbing, which
were observed shortly after dosing during Week 1 are frequently observed
signs in studies where the test material is administered by gavage and
are considered to be typically related to the taste of the
test-substance and not considered of toxicological importance.
Histopathological examination identified the
liver as a target organ. Microvesicular vacuolation was seen in the
cytoplasm of periportal liver cells at a minimal severity in males
treated at 1000 mg/kg/day and a minimal to slight severity in females
treated at 1000 mg/kg/day. Minimal vacuolation, seen in two males given
300 mg/kg/day, was considered unlikely to be treatment-related at this
incidence and severity, particularly as there were no corresponding
clinical chemistry changes. Oil red O fat staining confirmed that the
microvesicular vacuolation was associated with increased fat in
hepatocytes and correlated with statistical significant higher relative
liver weight values. It is also related to the high plasma triglyceride
levels in both sexes and the raised urinary ketone levels seen in
animals of the same group. The lengthened prothrombin times seen for
females receiving 1000 mg/kg/day at the end of the treatment period were
also attributed to the effect of the liver since the liver is the site
of the biosynthesis of several clotting factors. All these changes in
the liver were considered to have recovered at the end of the two week
recovery period. In the absence of any evidence of hepatocellular damage
or necrosis, microvesicular vacuolation is likely to indicate increased
storage of fat, and appears when there is accelerated mobilization of
lipid from adipose tissue (Haschek et al, 2013). This alteration in
lipid metabolism may be secondary to the lower blood glucose levels seen
at 1000 mg/kg/day.
Findings indicative of an effect on the
kidney comprised increased kidney weights at 1000 mg/kg/day in both
sexes and at 300 mg/kg/day in males, increased plasma creatinine in
females receiving 1000 mg/kg/day, though this was not associated with
any increase in urea levels, some minor effects (increases) in some
urinary electrolytes (Na and Cl) and glucose, a slight increase in
plasma phosphorus and low plasma chloride concentration and low pH. The
slightly high glucose, sodium and chloride outputs were considered
directly related to slightly increased urinary volume in these animals,
with the majority of individual values within the background range and
therefore of no biological importance. There were no associated renal
pathology changes, no change in water consumption and all the changes
resolved following cessation of treatment. Therefore, these changes were
considered to be adaptive, possibly in response to the excretion of the
The significance of the low plasma calcium
concentration seen in all treated groups of both sexes, but without
dose-relationship is of unclear relationship to treatment. It may be
associated with the low urinary pH, or with the adaptive change on the
kidney. The majority of individual values were within the HLS background
range and, therefore, considered not of toxicological importance.
The changes in red blood cell parameters
seen predominantly in females receiving 1000 mg/kg/day (low haematocrit,
haemoglobin concentrations, red blood cell and reticulocyte counts and
slightly high mean cell haemoglobin and mean cell haemoglobin
concentration) suggest a potential effect on the haemopoietic system.
There were, however, no associated pathological findings, for example,
in the bone marrow or spleen. The relatively small changes in these
parameters may represent low level toxicity in these animals but were
considered not to be adverse at the magnitude of change observed.
The low bodyweight gain observed during the
first week of treatment for females receiving 1000 mg/kg/day, in the
absence of any associated reduction in food consumption, was considered
to indicate non-specific toxicity. The effect was not apparent from Week
2 onwards, indicating an amelioration of effect.
During Week 4 of treatment, lower than
control motor activity (rearing and cage floor activity) was recorded
for all treated female groups with the total scores showing a
dose-relationship. However, only two of the 6-minute intervals attained
statistical significance, and the majority of the group mean 6-minute
interval scores and the group mean total scores were within the
historical control data range, neither was there any effect in males.
The differences from controls were, therefore, not clearly attributable
to treatment and not of a magnitude to be adverse.
The change in heart weight in males given
1000 mg/kg/day was not associated with any histopathological change and
was, therefore considered of no toxicological importance.
Administration of 1000 mg/kg/day was
associated with transient clinical signs and minor disturbance of
bodyweight, clinical pathology parameters and organ weight change and
microvesicular vacuolation in the liver. Vacuolation of the liver, with
associated increases in liver weight, plasma triglyceride levels and
increases in urinary ketones, indicate accelerated mobilisation of
lipids from adipose tissue. The vacuolation is, therefore, likely to
represent increased storage of fat, secondary to altered lipid
metabolism. In the absence of any hepatocellular damage, necrosis or
increases in liver enzymes, the changes observed in the liver were
considered not to be adverse.
As all the changes were shown to be
reversible during a subsequent two week period without treatment and
none of the findings were considered adverse, the dosage of 1000
mg/kg/day was considered to be the no-observed-adverse-effect level
(NOAEL) in this study.
In a repeated dose toxicity study performed
in accordance with OECD test guideline No. 407 and in compliance with
GLP, test item ST 11 C 13 was administered by gavage to 5 male and 5
female Crl:CD(SD) rats at doses of 30, 300 or 1000 mg/kg bw/day for 28
consecutive days. A similarly constituted control group received the
vehicle, corn oil at the volume dose of 5 mL/kg bw/day. A further five
male and five female rats were assigned to each of the control and high
dose groups. These animals were treated for 28 days, followed by a 14
day period without treatment to assess the potential for any
treatment-related change to recover. During the study clinical
condition, detailed physical and arena observations, sensory reactivity,
grip strength, motor activity, body weight, food consumption, water
consumption (visual observation), haematology (peripheral blood), blood
chemistry, urinalysis, organ weight, macropathology and histopathology
investigations were undertaken.
Two animals died during the study; both
deaths were unrelated to treatment. A control female was found dead on
Day 26 and a female receiving 30 mg/kg bw/day died during routine blood
sampling on Day 29.
The general appearance and behaviour of the
animals during the detailed physical examination and the arena
observations were not affected by treatment. Signs attributed to
treatment with ST11 C13 comprised reddening of the ears during the first
two weeks of treatment for animals receiving 1000 mg/kg bw/day and
reddening of the limbs and muzzle on Day 12 for one male receiving 1000
mg/kg bw/day. In addition, abnormal (swaying) gait was observed on Day 2
of treatment at 1 to 2 hours after dosing for one male at 1000 mg/kg
bw/day, persisting to the end of the working day but not seen on
subsequent days. Salivation was observed shortly after dosing during
Week 1 for animals receiving 1000 mg/kg bw/day and one male receiving
300 mg/kg bw/day, with associated chin rubbing in a small number of
Motor activity assessment in Week 4 revealed
that high beam scores for all treated female groups and the majority of
the group mean low beam scores for females receiving 300 or 1000 mg/kg
bw/day were low compared with Controls, with the total scores showing a
dose-relationship. The majority of the scores were, however, within the
historical control data range and, therefore, the differences from
controls were not clearly attributable to treatment and not of a
magnitude to be adverse.
Body weight gain for females receiving 1000
mg/kg bw/day was slightly low during Week 1 only, with an overall gain
(Days 1 to 28) similar to controls. Males were unaffected. Food
consumption and visual water consumption were not affected by treatment.
The haematological examination after 28 days
of treatment revealed low haematocrit, haemoglobin concentration and
erythrocyte count and high mean cell haemoglobin and mean cell
haemoglobin concentration for females receiving 1000 mg/kg bw/day. There
was also a decrease in reticulocyte count in these animals, though this
did not attain statistical significance. The only similar effect in
males was slightly high mean cell haemoglobin concentration at 1000
mg/kg bw/day. Large unstained cell counts were higher than those of the
controls for males receiving 1000 mg/kg bw/day and prothrombin time was
increased for females receiving 1000 mg/kg bw/day.
The biochemical examination of the blood
plasma obtained after 28 days of treatment revealed low glucose and
chloride concentrations and high triglyceride and phosphorus
concentrations for animals receiving 1000 mg/kg bw/day. In addition,
creatinine concentration was high and bile acid concentration was low
for females receiving 1000 mg/kg bw/day. Calcium concentration was low
for all treated groups, with no dose-relationship.
Urinalysis investigations after 28 days of
treatment revealed low pH for animals receiving 300 or 1000 mg/kg
bw/day. A higher incidence of ketones was also present in the urine of
males receiving 1000 mg/kg bw/day.
Analysis of organ weights for animals killed
after 28 days of treatment revealed, when compared with the controls,
high absolute and bodyweight-relative liver and kidney weights for males
and females at 1000 mg/kg bw/day and for males at 300 mg/kg bw/day and
high absolute and bodyweight-relative heart weights for males which
received 1000 mg/kg bw/day.
The macroscopic examinations performed on
completion of the treatment and recovery periods revealed no test
substance related lesions.
Minimal to slight reversible microvesicular
vacuolation was seen in the periportal liver cells in males and females
treated at 1000 mg/kg bw/day.
All the above changes were no longer
apparent on completion of the two week recovery period, with the
exception of plasma calcium concentration which was still slightly low
for previously treated males but was within normal background ranges
and, therefore, not of toxicological significance.
the test conditions, the NOAEL was concluded to be 1000 mg/kg bw/day in
test material is therefore not classified for damage to organs through
prolonged oral repeated exposure according to the criteria of the
Regulation (EC) No. 1272/2008 (CLP) and to the GHS.
study is considered as acceptable and satisfies the requirement for
sub-acute oral toxicity endpoint.
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