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EC number: 221-312-5
CAS number: 3064-73-1
Dose formulation analysis
All test item formulations were shown to be homogeneous. The
measured concentrations of WILLING TiBTD evaluated for each test
item-dose group varied between 94% and 104%. No test item was detected
in the control samples. These results were within the acceptable ranges
(85% - 115%) and were considered suitable for the study purposes. Based
on the study sample analysis, and the validation date, the
concentration, homogeneity and stability of the dose formulations were
considered to be fully satisfactory. The results of the dose formulation
including concentration and homogeneity analysis are presented below.
Nominal concentration (mg/mL)
Percentage of the nominal concentration(%)
10 March 2020
19.67 ± 0.257
60.85 ± 0.852
207.37 ± 2.49
07 April 2020
19.23 ± 0.362
57.97 ± 0.660
200.73 ± 1.86
05 May 2020
19.27 ± 0.307
58.15 ± 0.834
195.36 ± 2.08
02 June 2020
18.74 ± 0.307
57.68 ± 1.87
194.21 ± 1.91
All formulations proved to be homogeneous. Acceptance criteria for
homogeneity is that the relative standard deviation (RSD%) of the
replicates must be less than 10%.
In a repeated dose toxicity study (OECD 408/GLP), WILLING TiBTD (97%)
was administered to Crl:WI Wistar rats (10/sex/dose) by gavage in 1%
(w/v) aqueous methylcellulose at dose levels of 0, 100 (low dose), 300
(mid dose) and 1000 (high dose) mg/kg bw/day daily for 90 days.
All test item formulations were shown to be homogeneous and stable at
room temperature. The measured concentrations of WILLING TiBTD evaluated
for each test item-dose group varied between 94% and 104%.
A statistically significant lower body weight (-11.2%) and body weight
gain (-23.7%) was seen in High dose males with the difference between
controls and High dose appearing later in the study. The overall High
dose weight gain was significantly affected in males. A similar trend
was seen in High dose females (-24.3% lower overall weight gain) but
generally without statistical significance. The High dose group growth
rates were below the historical control minimums in both sexes; the
lower growth rates were attributed to a treatment effect. The Mid and
Low dose groups were not affected. There were no significant test
item-related differences in the mean daily food consumption in treated
groups when compared to the controls.
The functional observation battery (FOB) showed no changes in animal
behaviour, general physical condition, grip strength, motor activity, or
in the reactions to different type of stimuli in the control or test
groups. No treatment-related changes were noted on ophthalmoscopy
No clearly adverse treatment-related findings were seen in the clinical
pathology parameters (haematology, clinical chemistry, urinalysis). High
dose males had a statistically significant RBC count close to the
historical control minimum; however, the percentage difference was
relatively low (<6%). No change was seen in females in RBC count,
however, mean values were slightly out of the historical control range
(also in the Control group). Other statistically significant differences
in haematology and clinical chemistry were considered to be incidental,
were not related to dose and/or the recorded values were within the
historical control ranges. These differences were considered not to
reflect an adverse effect of the test item.
No adverse treatment-related macroscopic or microscopic findings were
detected at necropsy. The statistical differences in organ weights did
not reflect an adverse effect of the test item. Most statistical
differences were a result of the lower High dose body weight or were not
part of a dose response. The only changes that are considered to be
potentially related to the test item are increased relative kidney
weights in High dose males and females and relative liver weight in High
dose females. However, there were no histopathological changes in these
organs, indicating that these differences were common adaptive changes,
not considered to be adverse.
No treatment-related changes were observed in the sperm number,
morphology and motility in any of the treated males, or in thyroid
hormone levels (T3, T4, TSH) in males or females. None of the required
endpoints recommended for detection of endocrine activity per the
guideline (organ weights, histopathology, serum/plasma
biochemistry/hormone analysis) gave indications of concern.
In conclusion, under the conditions of this study, the no observed
adverse effect level (NOAEL) for systemic toxicity in male and female
Wistar rats for WILLING TiBTD is considered to be 300 mg/kg bw/day
(based on a reduction in body weight at the High dose level).
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