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EC number: 221-312-5
CAS number: 3064-73-1
Dose formulation analysis
The analysis showed that the mean concentration of all
formulations was found to be in the range of 95-102% of their nominal
concentrations and were found to be homogenous. No test item was
detected in the vehicle control formulations. Based on these analytical
results, test item formulations were considered suitable for the study
Nominal concentration (mg/mL)
Percentage of the nominal concentration(%)
24 June 2020
18.92 ± 0.378
57.51 ± 0.484
194.66 ± 1.87
15 July 2020
19.70 ± 0.300
60.34 ± 0.499
203.15 ± 3.40
*Note: Due to
technical issue one of the taken duplicate samples of the 20 mg/mL
concentration sample was lost,
therefore, the measurement was repeated
on 25 June 2020 from the back up sample in case of this concentration
(the samples were stored at room
temperature until the re-measurement).
In a prenatal developmental toxicity in rats (OECD 414/GLP), WILLING
TiBTD (97%) was administered to pregnant Crl:WI (Han) rats (25/dose) by
oral 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
14 days (GD 6-19).
All test item formulations were within the range of 95-102% of nominal
concentration and were found to be homogenous. No test item was detected
in the vehicle control samples. Test item formulations were considered
suitable stable for the study purposes.
No mortality or clinical observations were recorded in any of the dose
groups. Test item-related adverse effects on body weight parameters and
food consumption were observed in the High dose group (1000 mg/kg
bw/day), when compared to controls. No test item-related effects were
noted in the Mid dose (300 mg/kg bw/day) or Low dose (100 mg/kg bw/day)
No test item-related macroscopic or microscopic findings were present at
necropsy in the evaluated adult animals. There were no statistically
significant changes in the thyroid hormone concentrations of T3, T4 and
TSH between the groups. There were no statistical differences in the
thyroid organ weights between the Control and the Dose groups. There
were no statistically significant differences in the intrauterine
parameters in the test item treated animals when compared to the
controls. No abnormalities were observed in the placentas of any dams in
the Control, Low, Mid, or High dose groups.
Reduced foetal body weights were recorded in the High dose group (1000
mg/kg bw/day); the differences were considered to be possibly treatment
related, but in the presence of significant maternal toxicity, not a
direct effect of the test item (i.e. secondary non-specific consequence
of maternal toxicity effects). No effect was noted in Mid and Low dose
groups (300 and 100 mg/kg bw/day, respectively). There were no test
item-related effects on external, visceral or skeletal development of
the foetuses in the study. Foetal malformations observed in the study
were all considered to be incidental. They showed no dose dependency and
thus were not regarded as test item-related effects.
No endocrine disrupter effect was identified in the study (based on the
lack of effects on thyroid hormones and thyroid histopathology for dams,
and anogenital distance for foetuses).
In conclusion, WILLING TiBTD, when administered daily by oral gavage to
pregnant Hannover Wistar rats from Gestation Day (GD) 6 to 19 at 100,
300 and 1000 mg/kg bw/day induced significant body weight and food
consumption effects at 1000 mg/kg bw/day dose level. No embryotoxic
effect was recorded, but foetotoxicity (slightly reduced foetal body
weight in the presence of significant maternal toxicity) was observed at
1000 mg/kg bw/day. There were no test item-related effects on external,
visceral or skeletal development of the foetuses in the study.
The following NOAELs were derived:
NOAEL for maternal toxicity:300 mg/kg bw/day (based on the effects on
body weight and food consumption at 1000 mg/kg bw/day).
NOAEL for embryotoxicity: 1000 mg/kg bw/day (based on the lack of any
test-item related intrauterine effect in any treatment group.)
NOAEL for foetotoxicity: 300 mg/kg bw/day (based on the effect on foetal
weight at 1000 mg/kg bw/day in the presence of maternal toxicity.)
NOAEL for teratogenicity: 1000 mg/kg bw/day (based on the lack of
treatment-related malformations in any dose group.)
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