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EC number: 203-149-1
CAS number: 103-83-3
Result of the dose range finding “pre-experiment” as indicated in the
Dosing was chosen with regard to the results of a pre-experiment. 150
mg/kg b.w. of the test substance was the highest non-lethal dose.
With this dose the animals expressed the following toxic reactions but
no mortality: reduction of spontaneous activity, no food and water
uptake for 1 hour after administration.
With higher doses of the test substance animals died in the dose range
finding “pre-experiment”. The following results were reported:
200 mg/kg b.w. dosing: 1 out of 6 treated animals died.
250 mg/kg b.w. dosing: 1 out of 6 treated animals died.
300 mg/kg b.w. dosing: 3 out of 6 treated animals died.
Therefore the following doses in the main study were used:
Number of animals analyses
Males : females = 5 : 5
CPA = Cyclophosphamide
The requirements specified in the OECD guideline no. 474 are as follows:
“If a preliminary range-finding study is performed because
there are no suitable data already available to aid in dose selection,
it should be performed in the same laboratory, using the same species,
strain, sex, and treatment regimen to be used in the main study. The
study should aim to identify the maximum tolerated dose (MTD), defined
as the highest dose that will be tolerated without evidence of
study-limiting toxicity, relative to the duration of the study period
(for example, by inducing body weight depression or hematopoietic system
cytotoxicity, but not death or evidence of pain, suffering or distress
necessitating humane euthanasia)” are fulfilled.
Based on the data of the dose range finding “pre-experiment” the
selected dose of 150 mg/kg is considered appropriate according to the
OECD TG 474.
In addition, reduction in the proportion of immature erythrocytes among
total erythrocytes in the bone marrow might be considered to conclude if
a compound reached the target tissue. Within the main study the
relationship PE/NE (polychromatic erythrocytes (PE) / normochromatic
(NE) was examined.
It is considered that a decrease of the ratio of polychromatic
erythrocytes to normochromatic erythrocytes (PE/NE) in the
micronucleus test is an indicator to conclude if a compound reached the
0 - 5
0 - 3
0 - 2
4 - 24
0 - 4
0 - 2
The effects of a decrease of the ratio of PE/NE (polychromatic
erythrocytes / normochromatic erythrocytes in the highest dose applied
(150 mg/kg b.w.) is not evident compared to the solvent at 24 and 72
hours after administration of the test substance, however a clear effect
exists at 48 hours.
The mean value of the solvent is 592 (at 24, 48 and 72 h NE is (455 +
885 + 435) : 3) whereas the mean value of the test substance at 150
mg/kg bw is 528 (at 24, 48 and 72 h NE is (441 + 702 + 442) : 3).
This means, the ratio of polychromatic erythrocytes to normochromatic
erythrocytes = (PE/NE) decreased from 592 to 528.
In a range finding “pre-experiment” the maximum non-lethal tolerated
dose (MTD) was 150 mg/kg b.w. At higher doses (200 mg/kg b.w. and above)
mortality was observed. Consequently the selected high dose of 150 mg/kg
b.w. in the main experiment is considered appropriate according to the
OECD TG 474 and the negative result in this guideline study is
The test substance was assessed for mutagenic activity in the
micronucleus test in vivo with bone marrow cells of the mouse.
Male and female mice were given single oral doses by gavage 0, 15, 50,
150 mg/kg bw. (24 h); 150 mg/kg bw (48h); 150 mg/kg bw (72 h).diluted in
DMSO. Toxicity was examined in a pre-experiment. 150 mg/kg bw was the
highest non-lethal dose but animals showed reduction of spontaneous
activity and no food and water uptake was observed for up to 1 hour post
application in that test..
Preparation of mice bone marrow cells was done 24, 48 and 72 h after the
administration of the test substance.
With no dose at no preparation time any enhanced micronucleus rates were
found. The sensitivity of the test system was shown by administration of
cyclophosphamide (positive control) which induced a significantly higher
micronucleus rate as compared to the negative controls.
The test substance did not show any mutagenic activity as determined by
the micronucleus test with bone marrow cells.
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