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systemic toxic potential of test item was assessed by oral
administration to Crl:CD (SD) rats over a period of four weeks followed
by a two week recovery period. Doses up to 1000 mg/kg bw/day were
tolerated with treatment-related changes observed mainly in clinical
pathology, kidney and liver weights and microscopic changes within the
liver (centrilobular hypertrophy), kidneys (hyaline droplets) and
thyroid (follicular cell hypertrophy).
examination identified the liver as a target organ. There was evidence
of adaptive changes in the liver at 1000 mg/kg bw/day (males and
females) and to a lesser extent at 300 mg/kg bw/day (females). These
changes included increased cholesterol levels, increased liver weights
and centrilobular hypertrophy. Orally administered substances are
metabolized by the liver, therefore increased activity levels in the
liver are considered to be a normal adaptive response. There was
evidence of full recovery in the females and partial recovery in the
males and as these changes reflect an adaptive change they are not
considered to be adverse.
follicular cell hypertrophy in the thyroid observed in males at 300 or
1000 mg/kg bw/day might be linked to enzymatic induction in the liver,
of which is a well-recognized rodent specific phenomenon. Hepatic
microsomal enzyme induction in the liver can lead to an increased
breakdown of thyroid hormones and consequent stimulation of the normal
feedback control of the thyroid (Richardson and Klaasen, 2010). This
finding is therefore considered secondary to the effect in the liver
and, given that it is not relevant to humans, it is considered not to be
an adverse finding.
this study, follicular cell hypertrophy and centrilobular hypertrophy
were observed in thyroid and liver respectively of the males treated
with 1000 mg/kg bw/day, but only follicular cell hypertrophy of the
thyroids was observed in males treated with 300 mg/kg bw/day. In males
treated with 300 mg/kg bw/day, the thyroid effects are likely secondary
to a low grade hepatocellular hypertrophy which was undetectable by
light microscopy due to its minimal severity and the small number of
animals in each group. Similarly, centrilobular hypertrophy of the liver
was observed in females treated with 300 and 1000 mg/kg bw/day, but no
changes were recorded in the thyroids. Although the correlation between
thyroid and liver changes was not clear-cut at 300 mg/kg bw/day, the
presence of both changes together in males treated with 1000 mg/kg
bw/day is indicative of a causal relationship between the liver and
the kidney, males treated with 300 mg/kg bw/day or 1000 mg/kg bw/day
showed accumulation of hyaline droplets in the proximal tubules. The
accumulation of hyaline droplets is indicative of alpha2μ-globulin
nephropathy, which is peculiar to mature male rats (De Rijk, 2003). This
finding correlated with a slight increase of the kidney weights in this
group of animals. Hyaline droplet production is not relevant to humans
and, therefore, this finding is not a sign of adverse toxicity.
disturbances in urinary pH, specific gravity (females only) and
electrolytes were noted at the Week 4 investigation and in Week 3 a
small increase in water consumption was observed amongst animals
receiving 1000 mg/kg bw/day when compared with controls. At the end of
the recovery period the urinary parameters in the previously treated
animals were generally similar to control except for specific gravity
which remained very high in two females previously given the test
material. The aetiology of these findings is unknown and in the absence
of any pathological findings in the kidney of both sexes these changes
in urinary parameters are not considered to be adverse.
and chin rubbing, which were observed shortly after dosing during Week
1, are frequently observed signs in studies where the test material is
administered by gavage and are considered to be typically related to the
taste of the test-substance.
findings at 1000 mg/kg bw/day consisted of high bodyweight gain during
the first week of treatment for females, reduced plasma urea (females),
increased albumin and consequent total protein (males), plasma
electrolyte disturbances (reduced chloride and increased calcium) in
males, high urinary sodium and chloride (males). These findings were not
consistent between the sexes, did not correspond with changes in any
other parameter and generally showed reversibility, therefore, they were
considered not to represent adverse toxicity.
the findings on this study were considered to be adaptive, non-adverse
and with evidence of reversibility the dose of 1000 mg/kg bw/day was
considered to be the no-observed-adverse-effect-level (NOAEL) in this
a repeated dose toxicity study performed in accordance with OECD test
guideline No. 407 and in compliance with GLP, test item was administered
by gavage to 5 male and 5 female Crl:CD(SD)
doses of 100,
300 or 1000 mg/kg bw/day. A similarly constituted control group received
the vehicle, corn oil, at the same volume-dose. A further five male and
five female rats were assigned to each of the control and high dose
groups. These animals were treated for 28 days, followed by a 14 day
period without treatment to assess the potential for any
treatment-related change to recover. During the study, clinical
condition, detailed physical and arena observations, sensory reactivity,
grip strength, motor activity, body weight, food consumption, water
consumption (visually assessed), haematology (peripheral blood), blood
chemistry, urinalysis, organ weight, macropathology and histopathology
investigations were undertaken.
were no deaths on study and no clinical signs were observed at the
routine weekly examinations that were considered related to treatment.
reactivity, grip strength and motor activity assessments did not reveal
any response to treatment with test item.
weight gain for females that received 1000 mg/kg bw/day was high (x1.3
Control; achieving statistical significance) during Week 1 but
thereafter was comparable to the control group. Body weight gain of male
rats was not affected during treatment but in the first week of the
recovery period the body weight gain for males previously treated with
1000 mg/kg bw/day was high (x1.8 Control; achieving statistical
significance) when compared with the controls. In females previously
treated with 1000 mg/kg bw/day overall body weight gain in the recovery
period was slightly low (x0.64 Control; statistical significance was not
achieved) when compared with the controls.
consumption was not affected by treatment.
examination did not reveal any changes that were clearly attributable to
administration with test item.
28 days of treatment, biochemical analysis of the plasma revealed low
urea concentration in females that received 1000 mg/kg bw/day (resolved
at the end of the recovery period); higher than control albumin and
consequently higher total protein concentrations in males that received
1000 mg/kg bw/day (resulting in a lower mean albumin:globulin ratio in
these animals: the A:G ratio remained low at the end of the recovery
period); decreased chloride and increased calcium concentrations in
males that received 1000 mg/kg bw/day with the effect on calcium still
present after two weeks of recovery; decreased plasma chloride
concentrations and increased plasma phosphorus concentrations in females
that received 1000 mg/kg bw/day (these differences were still apparent
in at the end of the two week recovery period). At the end of the
recovery period a low mean albumin:globulin ratio was noted for females
previously treated with
test item (no effect noted in high dose females at the end of the
treatment period) and, similarly, cholesterol concentrations were high
in males and females that received 1000 mg/kg bw/day, an effect also not
observed at the end of the treatment period (this was previously
observed only one female that received 1000 mg/kg bw/day).
investigations after 28 days of treatment revealed the following changes
that were considered to be related to treatment: low pH in all treated
female groups and in males that received 1000 mg/kg bw/day, marginally
high specific gravity in all female treated groups and high total sodium
and total chloride levels in males that received 1000 mg/kg bw/day.
Higher than control urinary glucose was recorded for all treated male
groups; however, the control mean was skewed by low values in two
animals. Microscopic evaluation revealed the presence of unidentified
crystals/clumps of material in the sediment of two males given 300 mg/kg
bw/day and in two animals given 1000 mg/kg bw/day; however, this was not
observed at the end of the recovery period. After 2 weeks of recovery,
urinary pH (males and females) and total sodium and total chloride
concentrations (in males) were comparable with control, demonstrating
full recovery. Specific gravity remained slightly high in previously
treated females and glucose levels remained slightly high in previously
treated males when compared with the controls.
weight adjusted liver weight was higher than control in males and
females given 1000 mg/kg bw/day. There was evidence of recovery in the
females. Higher than control body weight adjusted kidney weights were
evident in males given 300 mg/kg bw/day and in males and females given
1000 mg/kg bw/day; recovery was evident in both sexes.
were no macroscopic abnormalities detected at scheduled termination
after four weeks of treatment or after two weeks of recovery that were
attributable to treatment with test item.
examination following 28 days of treatment revealed minimal, non-adverse
changes in the liver of both sexes, and kidneys and thyroids of the
males. Centrilobular hypertrophy was observed in the livers of one
female treated with 300 mg/kg bw/day and in five males and three females
treated with 1000 mg/kg bw/day. Hyaline droplets were recorded in the
kidneys of three males treated with 300 mg/kg bw/day and three males
treated with 1000 mg/kg bw/day. Follicular cell hypertrophy of the
thyroids was recorded in all male groups including controls, with a high
incidence at 300 and 1000 mg/kg bw/day. At 100 mg/kg bw/day the change
was considered likely to be background and unrelated to treatment, as
the incidence was only slightly above control levels and some level of
variation is normal in thyroids of young males. At the end of the two
week recovery period centrilobular hypertrophy was still present in the
liver of one male previously treated with 1000 mg/kg bw/day indicating
partial recovery in this sex and complete recovery in the females. The
thyroid and kidney changes had completely resolved.
findings were not consistent between the sexes, did not correspond with
changes in any other parameter and generally showed reversibility,
therefore, they were considered not to represent adverse toxicity. As
the findings on this study were considered to be adaptive, non-adverse
and with evidence of reversibility the NOAEL was considered to be 1000
the test conditions, the NOAEL was considered to be 1000 mg/kg bw/day.
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