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EC number: 292-697-5
CAS number: 90989-41-6
After repeated dose exposure via oral or inhalation routes, benzene causes adverse effects on the haematopoietic system of animals and in humans.
Benzene toxicity following sub-chronic
and chronic oral (gavage) exposure was investigated in studies
using F344/N rats and B6C3F1 mice conducted as part of the
National Toxicology Program (NTP, 1986). Animals were dosed 5 days
per week for 17 or up to 103 weeks. The most significant findings
in rats were a dose-related leukopenia and lymphocytopenia
observed in males at ≥ 200 mg/kg and in females at ≥ 25 mg/kg in
the 17 week study and in all groups dosed for one and two years.
No NOAEL could be determined in the
2-year study. The LOAEL was 50 mg/kg/day for male rats and
25 mg/kg/day for female rats, i.e. the lowest doses administered.
In mice, tremors were observed
intermittently at 400 and 600 mg/kg throughout the 17 week study.
White blood cell and lymphocyte counts were decreased in males at
50 mg/kg bw or more and in females white blood cells were
decreased at 600 mg/kg and lymphocytes were decreased at 400 mg/kg
or more. In the chronic toxicity study weight gain reductions
occurred in male and female mice at 100 mg/kg. Haematotoxic
effects were limited to lymphocytopenia and associated
leukocytopenia in all dose groups (males from 3 to 18 months,
female mice from 12 to 18 months). Benzene increased the frequency
of micronucleated normochromatic peripheral erythrocytes in male
and female mice of all dose groups, males were more sensitive than
females. Haematopoietic hyperplasia in the bone marrow and splenic
haematopoiesis was observed in all dosed mice groups. The LOAEL
was 25 mg/kg bw/day for male and female mice. A NOAEL was,
therefore, not achieved.
In the rat, the key study is
considered to be that of Ward et al, 1985. Animals were exposed to
concentrations of 0, 1, 10, 30 or 300 ppm (0, 3.2, 9.6, 960 mg/m3)
benzene vapour, 6 h/day, 5 days/week, for 13 weeks. Decreased
blood lymphocyte counts, relative increase in neutrophil
percentages and slightly decreased femoral marrow cellularity were
the only significant treatment-related parameters noted in animals
exposed to 300 ppm. The NOAEC for toxicity at 28 and 90 days was
30 ppm (96 mg/m3) for both male and female rats.
In mice haematotoxic effects following
repeated inhalation exposure to benzene include: decreases in
haematocrit, total haemoglobin, erythrocyte count, leukocyte count,
platelet count, myeloid/erythroid ratios, and percentage of
lymphocytes at 300 ppm (960 mg/m3) (Ward et al, 1985);
depressed bone marrow and splenic Multipotential Haematopoietic
Stem cells (CFU-S) and Granulocyte/Macrophage Progenitor cells
(GM-CFU-C) at benzene concentrations ≥103 ppm (Green et al, 1981a,
b); bone marrow erythroid progenitor cell numbers were depressed 1
day after exposure to concentrations ≥ 10 ppm (32 mg/m3)
(Dempster and Snyder, 1990); significant depression in femoral
lipopolysaccharide (LPS) -induced B-colony-forming ability and
splenic phytohaemagglutinin (PHA) -induced blastogenesis at 31 ppm
(Rozen et al, 1984); a reduction in bone marrow cellularity and
the number of pluripotent stem cells in the bone marrow at ≥ 100
ppm for 10 exposures (Cronkite et al, 1985).
On the basis of these studies the
LOAEC for haematotoxicity in mice is 10 ppm (32 mg/m3).
A NOAEC could not be defined.
No published data are available
For updated Human data (see section
7.10 Endpoint Summary). This section will be revised in the next
the next dossier update.
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Justification for selection of
repeated dose toxicity via oral route - systemic effects endpoint:
Sub-chronic and chronic studies indicate that benzene causes adverse
effects on the haematopoietic system of rats and mice following repeated
Justification for selection of repeated dose toxicity inhalation -
systemic effects endpoint:
In the rat, decreased blood lymphocyte counts and slightly decreased
femoral marrow cellularity were the only significant treatment-related
parameters noted in animals exposed to 300 ppm with a sub-acute and
sub-chronic NOAEC of 30 ppm (96 mg/m3). In mice, reductions in a range
of haematological parameters were recorded with a LOAEC of 10 ppm (32
mg/m3). Human data show haematological changes in neutraphil counts with
a NOAEC of 3.5 ppm (11.2 mg/m3).
Repeated dose toxicity: via oral route - systemic effects (target
organ) cardiovascular / hematological: bone marrow
Repeated dose toxicity: inhalation - systemic effects (target organ)
cardiovascular / hematological: hematopoiesis
After repeated dose exposure via oral or
inhalation routes, benzene causes adverse effects on the haematopoietic
system of animals and in humans. Consequently, benzene is classified as
T, Cat 1 (H372) according to Regulation
(EC) No 1272/2008 of the European Parliament.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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