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EC number: 254-996-9
CAS number: 40601-76-1
Sprague-Dawley rats were used in this study. 20 males and 20 females
were assigned to control, and to each of the test groups (25, 100 and
400 mg/kg). The length of the treatment period was 90 days.
One animal in the mid-dose group (100 mg/kg) died after 12 days of
treatment but was an isolated case and so not related to administration
of test material. Animals were generally healthy during the study, but
exhibited alopecia around the nares and paws, diarrhea, watery eyes
(animals that were bled, only) and encrustment around the nares. These
signs were attributed to ingestion of a powdered food and were not
considered to be related to test material.
Food intake was measured weekly, other than a random week where a
particular test group ate less food than comparable test groups or
control groups, there was no significant difference in food intake
between control and test animals in any sex grouping. Animals were
weighed initially and then weekly thereafter. Weight gains were
essentially comparable in treated and control groups with only a sex
difference noted; males gained more weight than females.
Gamma-glutamyl transpeptidase (GGTP), glutamix-oxaloacetic
transpeptidase, glutamic-pyruvic transaminase and urea were measured at
90 days in 5 males and 5 females from each test group. GGTP values were
variable within the different dose groups but were within the values
usually observed in this strain of rat. Glucose levels of treated
animals were lower than controls but were within the range of normal
values reported for this strain of rat. Since there were not
statistically significant differences between the means of treated
animals, the significant difference between the high-dose females and
their control was considered to be a result of some unusually high
values among the controls and was not considered to be the result of
administering the test material. Glutamic-oxaloacetic transaminase,
Glutamic-pyruvic transaminase and urea were unaffected by the treatment.
At 45 days, no changes in erythrocyte counts were noted. At 90 days,
there was a trend toward increased red blood cells in low and mid-dose
animals; however, counts in high dose animals were similar to controls.
Since the increase was not dose-related, this observation was thought to
be artifactual in nature and not related to administration of test
material. There were no changes in hematocrit, hemoglobin, leukocyte
count, platelet estimate and erythrocyte morphology.
There was no effect of treatment on urinalysis, organ weights, or gross
pathology. One of the males with a high GGTP value had focal
perivascular and periductal mononuclear leukocyte infiltration in the
liver, but the other animal did not demonstrate any liver pathology.
Livers of other males in the high dose group had histopathology similar
to that of controls. Other mild inflammatory lesions characterized by
leukocytic infiltration also occurred in the lungs, liver and kidneys of
a few animals in each group. All changes were considered to be
spontaneous and not related to administration of test material.
Therefore it is concluded that the test material did not affect
adversely the rats after 90 days of administration at the highest dose
tested. The NOAEL is 400 mg/kg bw.
a key study conducted in rats, groups of 20 COBS Sprague-Dawley
rats/sex/dose were treated with the test material in the diet for 90
days at nominal dose levels of 0, 25, 100 or 400 mg/kg bw/d. Elevated
gamma-glutamyl transpeptidase (GGTP) in high dose male rats, decreased
glucose in females and increased red blood cell counts in mid-dose males
at 90 d were not considered to be treatment related since effects were
not dose related and were within normal limits for the measured
endpoints. The NOAEL was reported as 400 mg/kg bw/d.
a 30-d range finding study, groups of 5 Sprague-Dawley rats/sex/dose
were treated with the test material in the feed at 0, 0.5, 1.0 or 2.0%.
At necropsy, discoloration of the livers in 2 high dose males and 2 high
dose females was present but there were no corresponding
histopathological effects that correlated in 3 of 4 of these. One
high-dose male displayed minimal intralobular scattered foci of extra
medullary hematopoiesis with mononuclear infiltrates. It was concluded
that liver effects were not due to test material. There was a
significant trend toward increased food consumption in females, with the
value at week 4 significantly different from control. The NOAEL reported
was 1190 mg/kg bw/d (1% in diet) and the LOAEL was 2380 mg/kg bw/d (2%
older supporting studies, dogs have been treated with the test material
in the diet for up to 90 days with only minimal effects observed. In the
first of two 90-day studies, groups of 4 beagle dogs/sex/dose were
treated with the test material in the diet at 46 mg/kg bw/d (actual
ingested) for 13 weeks. No significant effects related to compound
administration were identified in this study. The NOAEL was reported as
46 mg/kg bw/d. In a separate 90-day study, groups of 4 beagle
dogs/sex/dose were treated with the test material in the diet for 90
days at dose levels of 0, 7.5, 15.0 or 30.0 mg/kg bw/d. In this study,
reduced body weights in female dogs at the highest dose were not
considered treatment related because food consumption was comparable
among groups and there were no abnormal clinical signs. There were no
other significant treatment-related changes. The NOAEL was reported as
30 mg/kg bw/d.
In a range-finding study conducted in conjunction with an
OECD 421 reproductive effects screening study, groups of 6
Sprague-Dawley rats/sex/dose were treated with the test material in the
diet at 0, 1000, 10000 or 20000 ppm (0, 50, 500, 1000 mg/kg/day) for 14
days. No significant toxicological findings were reported.
Justification for selection of repeated dose toxicity via oral
route - systemic effects endpoint:
A well-conducted study in rats by the most appropriate exposure route
In well conducted repeated dose oral
toxicity studies in rats, no significant toxicity was noted up to a dose
level of 400 mg/kg bw/day. No classification is warranted for
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