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EC number: 248-698-8
CAS number: 27859-58-1
The mean concentrations of the test material in the formulations
prepared for Week 1 were between -6.8 % and -12.2 % of nominal
concentrations for all groups. These were within the applied limits of
-15 % / +10 % of the nominal concentrations, demonstrating accurate
The nominal concentrations for Group 2 (3.2 mg/mL), Group 3 (8 mg/mL)
and Group 4 (20 mg/mL) in Week 4 were -18.4 %, -23.6 % and -25.5 % of
the nominal concentrations, respectively. The exact cause of these low
concentrations could not be established but since no analytical errors
were evident, it is suspected that there may have been a formulation
error at this occasion.
It is considered that exposure of the test substance to animals assigned
to the treated groups would have been close to nominal in terms of
expected dose levels (on a mg/kg/day basis) for three out of the four
weeks of treatment. Overall, it is considered that all treated groups of
animals would have been adequately exposed to test material formulations
in this study and that receiving lower than intended dose levels during
the final week of treatment did not have any significant impact on the
overall interpretation of the findings in this study and/or the
establishment of the No-Observed-Adverse-Effect-Level (NOAEL).
Table 2: Results of formulation analysis
Week of Formulation
The potential for the test material to cause repeated dose toxicity was
investigated in a GLP study conducted in accordance to the standardised
guidelines OECD 407, EU method B7, OPPTS 870.3050 and Japanese
guidelines Yakushokuhatsu No. 0331. 7, Seikyoku No. 5 and Kanpokihatsu
The systemic toxic potential of the test material was investigated in a
4-week oral gavage study in the Han Wistar (RccHan™;WIST) rat. Recovery
from any effects was evaluated during a 2-week recovery period.
Main study animals received the vehicle (corn oil) or the test material
(16, 40 or 100 mg/kg/day) by oral gavage for four weeks. Recovery
animals were similarly treated for four weeks followed by a two-week off
During the study, clinical condition, detailed physical and arena
observations, sensory reactivity, grip strength, motor activity, body
weight, food consumption, hematology (peripheral blood), blood
chemistry, urinalysis, organ weight, macropathology and histopathology
investigations were undertaken.
The achieved concentration results of formulations that were prepared
for administration during the final week (Week 4) of treatment were
lower than expected. Whilst it was not possible to confirm the exact
cause of these low results, an error at the time of formulation
preparation (possibly due to inadequate mixing procedures) was the most
likely cause given that there was no evidence of analytical failure.
Overall, it is considered that all treated groups of animals would have
been adequately exposed to the test material formulations in this study
and that receiving slightly lower than intended dose levels during the
final week of treatment did not have any significant impact on the
overall interpretation of study findings.
There were no deaths observed throughout the study.
The general appearance and behavior, sensory activity, grip strength and
motor activity of the animals were not affected by treatment.
There was no effect of treatment on body weight gain or food consumption
and a visual assessment of water intake did not reveal any suspicion of
any treatment-related effect.
The haematological investigation at the end of the treatment period
revealed a few findings of uncertain relationship to treatment at 100
mg/kg/day (slightly low haematocrit and red cell distribution width in
males, slightly low haemoglobin concentration in females, slightly high
monocyte count in males and slightly low neutrophil and total white
blood cell counts in females) but none was associated with any test
item-related histopathological change. Some differences were still
apparent at the end of the 2-week recovery period (haematocrit remained
slightly low in males and monocyte counts remained slightly high and
neutrophil counts remained slightly low in males and females,
respectively) but none of these differences attained statistical
Slightly low platelet count occurred in females at 100 mg/kg/day and a
slight decrease in prothrombin time occurred in all treated groups of
females (without dose-relationship) at the end of the treatment period
but neither finding was evident at the end of the 2-week recovery period.
The biochemical examination of the blood and urinalysis performed at the
end of the treatment period did not reveal any test item-related
Marginally low spleen weights were evident at the end of the treatment
period in males at 40 or 100 mg/kg/day but there was no associated
histopathological correlate and the finding showed complete recovery.
None of the above differences from control was considered adverse. There
were no treatment related macroscopic or microscopic findings.
It is concluded that oral administration of the test material to Han
Wistar (RccHan™;WIST) for 4 weeks at dosages up to 100 mg/kg/day was
well tolerated. There were no target organs identified at
Under the conditions of the study, the No Observed Adverse Effect Level
(NOAEL) was considered to be 100 mg/kg/day.
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