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EC number: 944-817-9
CAS number: 244626-73-1
Result tables are included in "Attached
A 28-day repeat dose gavage study was
performed in the rat (Fraunhofer, 2013). The maximum dose level was
limited to 300 mg/kg bw/day based on the observation of ketones in urine
from an old study performed on the supporting substance (1989). However,
the highest dose level did not induce toxic effects on the registered
substance and therefore should have been higher.
In addition, this 28-day study is not
in accordance with Japan requirements for CSCL notification since it was
not inspected by quality assurance unit.
Therefore, to submit the notification
in Japan, a new 90-day study was conducted (HLS, 2015).
a repeated dose toxicity study performed in accordance with OECD test
guideline No. 408 and in compliance with GLP, test material solution in
corn oil was administered by gavage to 10 male and 10 female CD rats at
doses of 100, 300 and 1000 mg/kg bw/day. A
similarly constituted control group received the vehicle, corn oil. A
further five male and five female rats were assigned to each of the
control and high dose group. These animals were treated for 13 weeks,
followed by a four week period without treatment to assess the potential
for any treatment-related change to recover. During
the study, assessment of clinical condition, detailed physical and arena
observations, sensory reactivity, grip strength, motor activity, body
weight, food consumption, water consumption (visual observations),
ophthalmoscopy, haematology, coagulation, blood chemistry,
organ weights, macropathology and histopathology were undertaken.
signs and mortality
were no premature deaths, no test article-related signs observed during
the detailed physical examination and arena observations and no signs
observed in relation to dose administration.
weight and weight gain
given 1000 mg/kg bw/day showed low body weight gain during Week 0-1 and
Weeks 6 13 of dosing, such that overall mean weight gain during the
13-week dosing period was 86% of Control; the mean weight gain of males
receiving 100 or 300 mg/kg bw/day was unaffected. Following the
cessation of dosing, the mean body weight gain of males previously given
1000 mg/kg bw/day was slightly higher than Control over the 4-week
recovery period. The body weight performance of all groups of treated
females was slightly variable throughout the study, such that overall
mean weight gain from Week 0 to 13 of treatment was slightly higher than
Control, although an obvious dose response was absent (114, 110 and 104
% of Control at 100, 300 and 1000 mg/kg bw/day, respectively). During
the 4 week recovery period, the body weight performance of females
previously given 1000 mg/kg bw/day was similar to Control.
food consumption in Week 1 of treatment for all groups of males and
females was similar to that recorded during the pre-treatment period. From
Week 2 to Week 13, there was a non-adverse trend towards marginally
higher food intake among all groups of treated females and for males
receiving 300 or 1000 mg/kg bw/day when compared to Controls, which
continued for the first 2 or 3 weeks of the recovery period for those
animals which had previously been given 1000 mg/kg bw/day, with partial
recovery evident by Recovery Week 3 (females) or 4 (males).
assessments for all groups of animals during Week 12 were unaffected by
of haematological parameters during Week 13 of treatment revealed lower
than Control erythrocyte and haemoglobin concentrations and haematocrit
in all groups of treated females, associated with a slightly lower than
Control mean cell haemoglobin concentrations and a concomitant higher
than Control red cell distribution width in females given 1000 mg/kg
bw/day. All groups of treated males showed longer than Control
prothrombin times and activated partial thromboplastin times, with some
evidence of a dose-related trend. Conversely,
females receiving 300 or 1000 mg/kg bw/day showed shorter than Control
prothrombin times. All of these differences were no longer evident 4
weeks after the cessation of dosing, demonstrating full recovery.
Week 13, biochemical analysis of plasma revealed a trend towards
slightly low aspartate amino-transferase concentrations in all groups of
treated males and females. Slightly
low alkaline phosphatase concentrations were apparent in all groups of
treated females, and slightly high plasma urea and d’3 hydroxybutyrate
concentrations in all groups of treated males and females. Creatinine
concentrations were also slightly high in all groups of treated males
and in females given 100 or 1000 mg/kg bw/day. For
males given 300 or 1000 mg/kg bw/day glucose concentrations were
slightly low and gamma glutamyl transpeptide levels were slightly high,
with slightly higher bilirubin concentrations also apparent in males
given 1000 mg/kg bw/day. In the 1000 mg/kg bw/day group, low
triglyceride, slightly high cholesterol and an increase in total protein
was apparent in both sexes; among females, the increase was associated
with an increase in albumin levels, but in males the increase was
attributable to globulin levels resulting in a slight decrease in
albumin/globulin ratio. Males
given 300 mg/kg bw/day and males and females given 1000 mg/kg bw/day
showed slightly low chloride concentrations; calcium concentrations were
also marginally high in females given 1000 mg/kg bw/day. All of these
differences showed partial or full recovery after 4 weeks off-dose.
of urine collected during Week 13 of treatment revealed darker and/or
orange urine in all groups of treated males and females, and was
associated with slightly lower than Control urinary pH for males given
300 mg/kg bw/day and for males and females given 1000 mg/kg bw/day.
Slightly higher than Control specific gravity was evident among males
and females receiving 1000 mg/kg bw/day, and females given 300 or 1000
mg/kg bw/day showed lower than Control sodium and chloride
concentrations. All of these differences were no longer evident 4 weeks
after the cessation of dosing. Microscopic examination of the urine
sediment did not reveal any abnormalities at any dose level investigated.
reactivity observations, grip strength and motor activity assessments
for all groups of animals during Week 12 were unaffected by treatment.
The analysis of organ weights following 13
weeks of treatment indicated dose-dependent and statistically
significantly higher than Control body weight-adjusted liver weight in
females given 300 mg/kg/day and in males and females given 1000
mg/kg/day. Body weight-adjusted kidney weights were higher than Control
in males given 1000 mg/kg/day and low body weight-adjusted epididymal
weights were apparent for males given 300 or 1000 mg/kg/day. In
addition, body weight-adjusted ovary weights were slightly high in
females given 1000 mg/kg/day. Following 4 weeks of recovery, body
weight-adjusted liver weights in males and females previously given 1000
mg/kg/day remained slightly higher than Control, although the magnitude
of the difference was lower than that recorded at the end of the
treatment period suggestive of partial recovery. In males previously
given 1000 mg/kg/day, body weight-adjusted kidney weights remained
higher than Control, whereas epididymal weights were similar to Control
indicating full recovery. In contrast to the end of the dosing period,
the ovary weights of females in the 1000 mg/kg/day group were
statistically significantly lower than Control at the end of the
were no macroscopic abnormalities detected at scheduled termination
after 13 weeks of treatment or after 4 weeks of recovery that were
attributable to treatment with test item.
evaluation of the retained tissues of the 1000 mg/kg bw/day animals
killed after 13 weeks of treatment did not reveal any test
article-related micropathological changes.
biochemistry and analysis of urine revealed several slight changes in
composition which were indicative of adaptations of metabolism/excretion
in the liver and kidneys, and were accompanied by increases in liver and
kidney weight. In
the absence of any evidence of degenerative or functional change in the
liver and kidneys during histopathological evaluation, the slight
disturbances of biochemical and urine parameters were considered not to
on results of the study, the NOAEL was concluded to be 1000 mg/kg bw/day.
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