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EC number: 247-384-8
CAS number: 25973-55-1
In the Inbifo study (No. A 0176/049, 1970) the oral repeated dose toxicity (90 days, subchronic) in the dog was determined similar to the OECD guideline 409 and a NOAEL was set at 30 mg/kg body weight in the dog. In the TNO study (No. R 2640, 1968) the oral repeated dose toxicity (90 days, subchronic) in the rat was determined similar to the OECD guideline 408 and a LOAEL was at 10 mg/kg body weight in the rat (lowest concentration tested). The NOAEL is assumed to be < 10 mg/kg bw.
Subchronic study (repeated dose 90 days, oral)
In the Inbifo study (No. A 0176/049, 1970) the subchronic oral
toxicity of the test substance was determined in non-rodents (dogs). The
study was conducted similar to the OECD-Guideline 409 (1998). 3 beagle
dogs each dose level and sex were fed with food containing the test
compound in dose levels of 15, 30, 60, 120, and 240 mg/kg body weight.
The control animals (5 animals each sex) were fed plain diets. The dogs
were observed and examined concerning food consumption and clinical
signs, haematology, clinical chemistry, pathology, and histopathology.
One male dog of the 240 mg/kg bw dose group died on day 55 after had had
lost 33% of its initial body weight. No further mortalities occurred.
The food consumption considerably decreased in the higher dose groups
and hence a loss of body weight and a sleepy and weak behaviour was
observed in those animals. Effects were observed in the haematological
examinations, concerning primarily decreased numbers of erythrocytes,
decreased haemoglobin concentrations in the blood, anisocytosis, and
shrivelled formed erythrocytes. Distinct effects of the clinical
chemistry were observed, like a test material related increase of the
serum activity of glutamic oxaloacetic transaminase (GOT) (up to 4 fold
compared to the control group), glutamate pyruvate transaminase (GPT)
(up to 15 fold compared to the control group) and the alkaline
phosphatase (up to 13 fold compared to the control group). Distinct
effects already occurred in the lowest dose group of 15 mg/kg bw. The
male dogs of all dose groups had increased bilirubin concentrations and
one male dog of the highest dose level, which died during the study,
showed extremely high bilirubin figures (> 180 mg/l, approximately 70
times higher than the mean of the control group). The main pathological
finding was an icterus in three of the 120 and 240 mg/kg bw dose groups.2
and 1 male dogs of the 120 and 240 mg/kg bw dose groups showed low liver
weights which were relative to body weight within normal limits, whereas
the relative weights of a number of other organs of these dogs, e.g.
brain lung, kidneys and adrenals, were larger than those of all other
dogs. The forementioned three dogs were also remarkable because of their
low testes and epididymes weights.The histopathological
examination revealed test substance related changes in the liver. These
changes concerned the KUPFFER’ cells (fatty change, hyperplasia) and
hepatocytes (fatty change, protein globules in the cytoplasma,
monocellular necrosis). Furthermore, signs of inflammation and fibrosis
were detected. The effects occurred throughout all dose groups and even
in the 15 mg/kg bw dose group distinct histopathological changes could
be observed. Furthermore, in spleen, uterus, prostate, and testis test
material related changes were detected. In higher dose groups (120 and
240 g/kg bw) compound related thymus atrophy was observed. The kidneys
revealed histopathological changes in the glomeruli of the 30 mg/kg bw
dose group and higher. Few of the treated animals showed changes in the
adrenals, but the relation to the test material was reported to be
questionable. The changes in the adrenals of the dog which died during
the study were assumed to be compound related.
Based on these findings, a LOAEL was set at 60 mg/kg bw in the
dog, and the NOAEL was established at 30 mg/kg/d. Liver and kidney
determined to be the target organs due to test-material induced changes
of organ weights, histopathology and enzyme activities.
In the TNO study (No. R 2640, 1968) the subchronic oral toxicity
of the test substance was determined in rodents (rats). The study was
conducted similar to the OECD-Guideline 408. 10 male and 10 female
albino rats per dose group were fed with food containing the test
compound in dose levels of 100, 200, 400, 800, and 1600 ppm (equal to
10, 19, 40, 81, and 173 mg/kg body weight, calculation based on body
weight and food consumption). The control animals (10 each sex) were fed
plain diets. During exposure, clinical signs, body weight development,
food consumption and food efficiency were observed. At the end of the
study haematology, enzymology, pathology, and histopathology were
examined. No mortalities occurred during the study. At the highest
feeding level, some male animals were of poor general state. No other
clinical signs were described. Significant growth depression of 15-20%
occurred only at the highest feeding level (173 mg/kg bw) in males. In
females this effect was likewise observed at the highest level, although
less pronounced and only during the first four weeks of the experimental
period. Food efficiency figures were distinctly decreased only in males
of the highest dose group. At lower dose levels no consistent
differences in food efficiency occurred between groups, neither in males
nor in females. Few effects were observed in the haematological
examinations, concerning primarily haemoglobin content and packed cell
volume in males (for both parameters up to -11%) at feeding levels of 19
mg/kg bw and above. In females this phenomenon occurred likewise,
although the effect was significant only at higher dose levels (173
mg/kg bw). The activity of the enzyme glucose-6-phosphatase in the case
of the livers, when expressed as G6P-ase activity or specific G6P-ase
activity, increased with increasing levels of the test substance in the
ration up to 19 mg/kg bw in both males and females. At higher feeding
levels no further increase was observed. In contrast to the liver, the
G6P-ase activity in the kidneys did not show a dose-effect relationship
as a result of the ingestion of test substance. Average relative liver
weights were distinctly increased at all feeding levels in both sexes
after 90 days (up to 200%). Relative kidney weights were increased at
the three highest dose levels (40, 81, and 173 mg/kg bw) in both males
and females (up to 20%). Relative spleen weights of male rats were
decreased at the 81, and 173 mg/kg bw level (up to 30%), and relative
testicle weights were increased at the three highest dose levels (40,
81, and 173 mg/kg bw) (up to 30%). Relative thyroid weights of all test
groups were higher than those of the controls in both sexes and
increased with increasing dose levels of test substance. Gross
pathologic examination after 13 weeks revealed distinct enlargement and
greenish-drab discolouration of livers. In males, discolouration was
observed at all dose levels, in females only at 81 and 173 mg/kg bw.
Greenish discolouration of kidneys occurred in males and females at the
two highest feeding levels (81 and 173 mg/kg bw). Microscopic
examination of the livers revealed a dose-dependent hepatic damage in
both males and females. Foci of necrosis were occasionally present in
males, and in smaller number in females, at the 81 and 173 mg/kg bw
feeding levels. Further results were primarily extremely enlarged and
altered parenchymal cells, binucleated hepatocytes, necrotic cells, and
proliferation of bile ducts. Microscopic examination of kidneys revealed
tubular nephrosis at the two highest feeding levels (81 and 173 mg/kg
bw) in males. In females yellowish-brown pigment granules in the
cytoplasm of proximal tubular cells were noticed at 19 mg/kg bw and
above; the amount of the pigment increased with increasing levels of
Based on these findings, a NOAEL was set at 10 mg/kg bw in the
rat, which was the lowest administered dose in this study. Liver and
kidney were determined to be the target organs due to test-material
induced changes of organ weights and histopathology.
Dangerous Substance Directive (67/548/EEC)
The available experimental test data is reliable and suitable for the
purpose of classification under Directive 67/548/EEC.
Based on the data, the test substance has to be classified for oral
repeated dose toxicity: Xn R48/22.
Classification, Labeling, and Packaging Regulation (EC) No.
The available experimental test data are reliable and suitable for the
purpose of classification under Regulation (EC) No.1272/2008.
Based on the data, the test substance has to be classified for specific
target organ toxicity - repeated exposure (STOT RE): Cat. 2.
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