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EC number: 700-597-4
CAS number: 1215841-86-3
Nominal concentration (mg/mL)
Measured concentrations with the 95% confidence intervals (mg/mL)
Measured concentration in percentage of the nominal
13 May 2014
9.96 ± 0.34
30.1 ± 1.16
105 ± 5.25
16 June 2014
10.4 ± 0.10
31.4 ± 0.67
106 ± 3.49
05 August 2014
10.2 ± 0.23
30.8 ± 0.51
99.2 ± 3.32
Females, Day 90
Dose (mg/kg bw/day)
Red Blood Cell (erythrocyte) count (RBC), M/mL
Haemoglobin concentration (HGB), g/dL
Haematocrit value (Hct),
Dose Group (mg/kg bw/day)
Albumin concentration, g/L
Total Protein concentration, g/L
Albumin to Globulin ratio
The purpose of this study was to obtain information on the toxicity of
the test item when administered daily for 90 days by oral gavage to
Wistar rats of both sexes at dose levels of 100, 300 and 1000 mg/kg
bw/day. The doses were selected by the Sponsor in consultation with the
Study Director, based on previous data available, with the aim of
inducing toxic effects but no death or suffering at the highest dose and
a NOAEL at the lowest dose.
Male and female Wistar
rats were treated according to the following experimental design:
The control group was treated concurrently with the vehicle only
Main animals were euthanized after 90 days of daily treatment, the
first day of treatment was Day 0. Rats assigned to Recovery groups (10
male and 10 female in Control and High dose groups), were kept for a
28-day observation period following the completion of the 90-day
treatment period, and then euthanized.
Analysis of test item formulations for concentration and
homogeneity was performed three times during the treatment period
(during the first, sixth and last week of treatment) using validated
Parameters monitored during the study included
mortality/morbidity, clinical signs, body weights and body weight gain,
food consumption. Blood for haematology and clinical chemistry
measurements was collected on Day 90 for the main animals and on Day 118
for the recovery animals. Urinalysis was also performed at the end of
the treatment or recovery period. Animals were subjected to neurological
assessments during the week 13. Examinations included functional
observation battery (FOB), landing foot splay and grip strength
measurements, and automated locomotor activity measurements (SMART).
Ophthalmology was performed pre-treatment and at the end of the
treatment period. Necropsy and macroscopic examination was performed on
all animals at the end of treatment period on Day 90 and the end of the
recovery period on Day 118, selected organs were weighed and preserved.
Tissues from control and high dose groups were processed to slides and
All formulations were found to be in the range of 99 to 106% of
nominal concentration and were homogeneous. No test item was detected in
the control samples. Based on these results, test item formulations were
considered suitable for the study purposes.
There was no test item
related mortality observed during the study.
There were no clinical
signs or unscheduled mortality during the study.
There were no signs of toxicity observed on body weights, body
weight gains or food consumption.
There were no toxicologically significant changes in the animal
behaviour, general physical condition, in the reactions to different
type of stimuli, grip strength or motor activity in the control or
treated groups, at the evaluation performed on last week of the
There were no test item
related changes in the animal oestrus cycle evaluated prior to necropsy
and the animals showed the normal distribution of the oestrus phases.
No test item related
changes were noted at ophthalmoscopy examination.
Evaluation of the haematological parameters revealed the following
effects at 1000 mg/kg bw/day on Day 90: statistically lower than control
Red Blood Cell (erythrocyte) count (RBC), Haemoglobin concentration
(HGB) and Haematocrit value (Hct) in females. In the Recovery females,
the RBC and HGB concentrations were still lower than the control
(p<0.05), although both parameters measured in the recovery animals,
were within the historical control range.
There were no toxicologically significant effects in coagulation
parameters at any dose levels.
Evaluation of the clinical chemistry analysis
revealed the following effects at 1000 mg/kg on Day 90:Albumin
concentration was slightly higher in both sexes (7% increase in males
and 19% in females). The differences attained statistical significance
and exceeding the historical control ranges in females. Consequently,
Total protein concentration and the Albumin to Globulin ratio were also
higher attaining statistical significance in both high dose male and
female groups. These changes were fully reversed by the end of the
No effects were noted at urinalysis which could be related to the
There were no macroscopic findings considered related to test item
administration under the conditions of this study.
Evaluation of liver weight values revealed test item related
differences at 1000 mg/kg bw/day (High dose) in females. The absolute
liver weight was higher by approximately 14%. Following the recovery
period, the values were still slightly higher in females (approximately
7% for body weight relative values and 12-13% for absolute and brain
relative values, respectively). But only the brain relative liver weight
value was statistically higher in the females after recovery. On day 90
in males only the body weight relative liver value is statistically
enhanced in high dose group compared to control. There is no
statistically significant difference regarding the absolute liver weight
and the brain relative liver value in high dose males compared to
day 90. After recovery, the liver values were comparable with the
control in males. These changes are consistent correlations with the
clinical chemistry parameters (increased albumin and total protein
Compared to control, slightly higher absolute kidneys weights,
body relative and brain relative kidney weight values were recorded for
females in the High dose groups on Day 90. Following the recovery
period, the kidney values were still slightly higher in females. In
males, the values were comparable with the controls except for a higher
body relative kidney weight value on Day 90. Following the recovery
period, the kidney values were comparable with the respective controls
No clear test item related microscopic changes were seen at
A daily oral (gavage) administration of the test item to Wistar rats for
90 consecutive days at 100, 300 and 1000 mg/kg bw/day was associated
with minor effects at the highest dose level only. High dose group
findings included slight anaemia with lower RBC and HGB concentrations
(females only), increased Albumin and consequently increased Total
Protein concentrations, and increased A/G ratio in both sexes with
association to statistically significant increased liver weight values
(including the brain and body weight relative values) in females and
statistically significant increased body weight relative values in
males. Statistically significant increased kidney weight values
(including the brain and body weight relative values) in females and
statistically significant increased body weight relative values in males
were observed after 90 days exposure without relevant histopathological
changes. Although signs of reversibility were observed in recovery
animals, the changes in female liver (brain weight relative value only),
kidneys and haematology parameters persisted to some extent. No effects
of toxicological relevance were observed at the low or mid dose levels.
In conclusion, the NOAEL of the test item administered by oral gavage to
Wistar rats for 90 consecutive days is considered to be
300 mg/kg bw/day based on a precautionary worst case approach.
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