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NOAEL (subacute, rat, m/f) ≥ 1000 mg/kg bw/day (OECD 407)
Repeated dose toxicity oral
A preliminary dose-range finding with the test substance over a period
of 14 days was performed in rats as outlined in OECD 407 to provide a
basis for the selection of dose levels for a subsequent 28-day repeated
dose oral toxicity study (Holalagoudar, 2012). During the study period,
the test substance diluted in sterile water was administered 7 days/week
at dose levels of 250, 500 and 1000 mg/kg bw/day to groups of 3 male and
3 female Crl:WI (Han) rats by oral gavage. A similar constituted group
received the vehicle (sterile water) and served as control. There were
no clinical signs recorded in any of the animals during the treatment
period. No mortalities and no clinical signs of toxicity were observed
in any of the animals during the study. Body weights development and
food intake were not affected in treated animals when compared to
corresponding control group. In males, the individual and mean values of
examined haematological parameters (haematocrit (HCT), haemoglobin (Hb),
red blood cell count (RBC), platelet count (PLT) and white blood cells
(WBC)) of treatment groups were within the biological range and
comparable to the corresponding control group. In females,
treatment-related decrease in mean values of WBC was observed among all
dose groups compared to the controls. At necropsy, no macroscopic
findings and no changes in organ weights attributable to treatment were
observed in any animal. Based on the results of this study, doses levels
of 100, 300 and 1000 mg/kg bw/day were considered to be adequate for the
28-day oral repeated dose toxicity study in rats.
In a GLP-conform 28-day toxicity study according to OECD 407, groups of
each 5 male and 5 female Crl:WI (Han) rats received the test substance
diluted in sterile water at 100, 300 and 1000 mg/kg bw/day via oral
gavage (Holalagoudar, 2012). A control group, consisting of 5 animals
per sex, was administered the vehicle (sterile water) alone. During the
study period, no mortalities were observed in any of the treatment
groups. Clinical signs of toxicity involved discoloured skin (reddish in
colour) in animals treated with 1000 mg/kg bw/day of the test substance.
The slight piloerection noted in 1/5 males of the 100 mg/kg bw/day group
and the slightly increased spontaneous activity in 2/5 females of 300
mg/kg bw/day group were considered incidental. Furthermore, also a few
unspecific findings like alopecia and eschar (1/5 females in the 300
mg/kg bw/day group) and exophthalmos (1/5 males in the 1000 mg/kg
bw/day) were observed after administration of the test substance.
However, these findings were considered to be of spontaneous nature and
not related to treatment. Detailed clinical examination,
ophthalmological examination and investigation of the parameters of the
functional observation battery did not reveal any test substance-related
findings when compared to controls. Body weights, body weight gain and
food consumption were comparable between treated and control animals.
Haematological analysis revealed a statistically significant increase in
mean corpuscular haemoglobin concentration (MCHC) and eosinophil count
in males treated with 1000 mg/kg bw/day compared to controls. MCHC was
also significantly increased in females treated with 300 mg/kg bw/day.
Since these changes were within the historical control range, they were
not considered to be toxicologically relevant. Due to the high
variability among treated animals, changes in blood coagulation
parameters in males of the 100 mg/kg bw/day group were also not
considered to be treatment-related.
At clinical chemistry analysis, a considerable and treatment-related
decrease in mean total bile acids (TBA) was noted in males and females
treated with 1000 mg/kg bw/day. Furthermore, a consistent increase in
total bilirubin (TBIL) concentration was noted in both male and female
animals of all dose groups, showing a clear dose response pattern and
attaining statistical significance at higher dose levels. However, in
the absence of any histopathological changes in liver, this finding was
considered to be non-adverse. In males treated with 1000 mg/kg bw/day, a
statistically significant decrease in mean activity of aspartate
aminotransferase (ASAT), alanine aminotransferase (ALAT), alkaline
phosphatase (AP), and a statistically significant increase in mean
concentrations of total protein (TP) and cholesterol was noted. The mean
ASAT activity was also decreased in males of the 300 mg/kg bw/day group.
However, the decrease in ASAT and ALAT activity was not considered to
have biological relevance, whereas the observed changes in AP, TP and
cholesterol were very likely to be treatment-related. In females, the
statistically significant increase in the mean concentration of AP and
TP at 300 and/or 1000 mg/kg bw/day was not considered to be of
toxicological relevance, since changes were either within the range of
historical controls or not dose-related.
Visual examination of the urine revealed a yellowish to orange and rose
or reddish colouration in animals of all dose groups, which were
considered to be a result of excretion of the red-coloured test
substance in the urine. Individual females of the 1000 mg/kg bw/day
group also showed increases in the concentrations of urinary
urobilinogen and bilirubin as well as elevated levels of leukocytes in
urine. In the absence of corresponding effects noted during microscopic
examination of kidneys or in haematology and clinical biochemistry, the
toxicological relevance of these findings was not clear.
Macroscopic examination of treated animals revealed discoloured organs
at and above 300 mg/kg bw/day. These findings were due to absorbed test
item and, under the conditions of this study, without toxicological
significance. Marginal changes in organ weights of thymus, adrenal
gland, spleen and ovary as well as mild to marked increase in uterus
weights were not associated with any histopathological alterations in
the respective organs, and were thus not considered to be adverse
effects. At histopathological examination, minimal or mild epithelial
hyperplasia of the limiting ridge observed in the non-glandular part of
the stomach in a majority of males and females at 1000 mg/kg bw/day was
considered to be of toxicological relevance. However, this effect was
most likely a result of local irritation of the test item formulation.
Based on the results of the study, the NOAEL for male and female rats
was greater than 1000 mg/kg bw/day.
Based on the available data on repeated dose toxicity via the oral
route, the test substance does not meet the criteria for classification
according to Regulation (EC) No 1272/2008 or Directive 67/548/EEC.
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