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EC number: 200-753-7
CAS number: 71-43-2
Female Sprague-Dawley rats were exposed to
dose levels of 1, 10, 30 or 300 ppm benzene (6 h/day, 5 d/week) during
10 weeks pre-mating, mating, gestation and lactation periods up to p.n.
day 21. Five groups of 26 females and 13 proven fertile males were used.
To determine if oestrous was affected by treatment, daily vaginal smears
were made and evaluated for each female beginning 2 weeks prior to
initiation of mating. Observations of females for mortality and clinical
signs were made twice daily. Detailed physical examinations were
performed weekly throughout the study. Body weights were recorded once
weekly through completion of the mating period. Mated females were
weighed on days 0, 7, 14, and 21 of gestation and on days 0, 4, 14, and
21 of lactation. Pups were counted, weighed, and sexed on days 0, 4, 14,
and 21 of lactation. Litters were observed twice daily. On day 4 of
lactation, litters of more than 10 pups were randomly culled to 10 with
equal number per gender where possible. Pups that died were weighed and
sexed by internal examination. All dams were given a gross post mortem
examination. Uteri were examined for the presence and number of
implantation sites, and along with ovaries, were fixed and saved. Gross
post mortem examinations, including internal gender determinations, were
performed on all pups sacrificed on day 21 of lactation and on pups
found dead during lactation. The latter were also checked for the
presence or absence of milk in the stomach. Liver, kidney, and in males,
testes weights were recorded for each pup. Thirty-three organs and
tissues along with any abnormal lesions were fixed in 10% neutral
buffered formalin from two pups per sex per litter and saved for future
There were no effects on maternal body
weight and body weight gain nor were there adverse effects on fertility
as measured by percentage pregnant animals, mean gestational length,
number of litters, litter size, and viability of the pups and the
weanlings at any dose tested. The only statistically significant
differences for offspring were lower female pup body weight on day 21
and lower liver weight at the 300 ppm exposure level. These differences
were small and considered not to be adverse. No treatment related
effects were seen in pup survival or at gross post mortem on post natal
An exposure concentration of 300ppm (960 mg/m3)
is a NOAEC for both adult and offspring toxicity and female fertility.
In a one-generation reproduction toxicity
study, there were no significant effects at any dose tested (up to 300
ppm) on maternal body weight and body weight gain and on
fertility/reproductive endpoints as measured by percentage of pregnant
animals, mean gestational length, number of litters, litter size, and
viability of the pups and the weanlings. The only statistically
significant postnatal developmental effects for offspring were lower
female pup body weight on day 21 and lower liver weight at the 300 ppm
exposure level. These differences were small (10 and 14%, respectively)
and considered not to be adverse. An exposure concentration of 300 ppm
(960 mg/m3) is a NOAEC for fertility/reproductive toxicity in
adults and postnatal developmental effects for offspring.
Short description of key
It is recognised that there is a
data gap for a multi-generation study (REACH reference 8.7.3). The
applicant submits that this study does not need to be conducted as
benzene is known to be a mutagenic and carcinogenic substance and
appropriate risk management measures are implemented. Benzene is
produced and used under strictly controlled conditions. In addition, a
single generation study with a high dose of 300ppm (960 mg/m3) showed no
effects on female fertility.
Justification for selection of Effect on fertility via inhalation
There were no significant effects on fertility/reproductive
endpoints or postnatal development in a one generation study involving
exposures up to 300 ppm (960 mg/m3).
Developmental toxicity of inhaled benzene has been investigated in 3 species (rat, mouse and rabbit). No evidence of teratogenicity was seen in any species. Minor fetotoxic effects (reduced foetal weight, length and associated delays in skeletal ossification) were seen at concentration > 50 ppm and generally accompanied by maternal toxicity. The NOAEC for maternal and pre-natal developmental toxicity was 10 ppm (32 mg/m3).
deaths or signs of toxicity were noted in the dams and the pregnancy
rate was within the expected range.
Number of dams mated
Number of dams pregnant
Pregnancy rate (%)
weight at 50 and 500 ppm was significantly lower than control on day 15
and maternal weight gain from days 5 -15 was also reduced at these dose
Mean weight (g)
Mean gain days 5-15 (g)
Mean gain days 15-20 (g)
significantly different from control
treatment-related effects were seen in any of the haematology
parameters, at necropsy or on the number of implantation sites, resorbed
and dead foetuses, incidence of live foetuses or sex distribution of the
significant decreases in the mean crown-rump distance of the high-dosed
foetuses and mean body weights of the mid- and high-dosed live foetuses
were noted when compared with the controls.
Mean body weight (g)
Mean crown-rump length (cm)
significant increases in the incidence of skeletal findings indicative
of incomplete ossification of the skeleton at 50 and 500 ppm. There was
no evidence of treatment-related foetal dysmorphogenesis.
Number of litters examined
Number of foetuses examined
Foetuses with delayed ossification:
In vertebral column
In rib cage
In pelvic girdle
Foetuses with variants:
Foetuses with anomalies
No. of caudals
No. of metacarpals and phalages
No of metatarsals and phalages
based on Kuna and Kapp, 1981 Table 3
examination revealed slight dilation of the ventricles in the brain in
five mid- and four high-dosed animals but there was no clear evidence
for an association with treatment with benzene.
toxicity was investigated in groups of pregnant female rats exposed
7h/day from day 6 to day 15 of gestation to benzene concentrations of 0,
10, 50 or 500 ppm (0, 32, 160, 1600 mg/m3). On gestation day 5 and prior
to termination venous blood samples were taken from each female and
erythrocyte, total leukocyte and differential leukocyte counts
determined. Dams were killed on day 20 and the following observations
made: number of corpora lutea, number of resorptions, number of live and
dead foetuses. Foetuses were examined for external, skeletal and
visceral abnormalities, sex was determined and body weight and
crown-rump length measured.
deaths or signs of toxicity were noted in the dams. Maternal body weight
and body weight gain was decreased at 50 and 500 ppm. No
treatment-related effects were seen in any of the haematology
parameters, necropsy findings or on the number of implantation sites,
resorbed and dead foetuses, incidence of live foetuses or sex
distribution of the foetuses. Statistically significant decreases in the
mean crown-rump length of the 500 ppm group foetuses and mean body
weights of the 50 ppm and 500 ppm live foetuses were noted when compared
with the controls. As a consequence these foetuses showed signs of
incomplete ossification in comparison with the larger and heavier
control foetuses. Visceral examination revealed slight dilation of the
ventricles in the brain in five 50 ppm and four 500 ppm animals.
NOAEC for teratogenicity was 500 ppm (1600 mg/m3); the NOAEC for
maternal and developmental toxicity was 10 ppm (32 mg/m3).
pre-natal developmental toxicity (or teratogenic) potential of benzene
inhaled at doses ranging from 1 to 500 ppm by pregnant Sprague-Dawley
rats on gestation days 6-15 has been investigated in two studies (Coate
et al, 1984; Kuna and Kapp, 1981). No
maternal toxicity was observed at 100ppm (Coate et al, 1984) but
maternal body weight and bodyweight gain were decreased at 50 and 500
ppm (Kuna and Kapp, 1981). Reduced
foetal weight was seen at 100 ppm (Coate et al, 1984) and at 50 and 500
ppm (Kuna and Kapp). Reduced crown rump lengths and associated delay in
ossification of extremities and sternebrae were seen in the same
the NOAEC for teratogenicity in the rat was 500 ppm (1600 mg/m3),
the NOAEC for maternal and developmental toxicity was 10 ppm (32 mg/m3).
effect of inhaled benzene on pre-natal developmental
toxicity/teratogenicity was also assessed in CF-1 mice and New Zealand
white rabbits. There
were no significant effects on maternal clinical condition, body weight
or body weight gain. Benzene exposure did not significantly affect the
incidence of pregnancies or the average number of live foetuses or
resorptions per litter in either species. Mean foetal body weight, but
not crown-rump length, was decreased significantly in benzene exposed
mice but there were no effects in rabbits. No teratogenic malformations
were observed in either species. However, increases in the occurrence of
several minor skeletal variants (including delayed ossification of
sternebrae, skull bones and of unfused occipital bones of the skull)
were reported in offspring of benzene-exposed mice.
NOAEC for maternal toxicity was 500 ppm (1600 mg/m3) in
rabbits and mice. 500 ppm (1600 mg/m3) was the NOAEC for
pre-natal developmental toxicity in rabbits and the LOAEC for pre-natal
developmental toxicity in mice.
Justification for selection of
Effect on developmental toxicity: via inhalation route:
The pre-natal developmental
toxicity of benzene has been investigated in rats, mice and rabbits.
Reductions in maternal and foetal body weights (together with reduced
crown rump lengths and associated delays in ossification of extremities
and sternebrae) were reported in rats, with a NOAEC of 10 ppm (32
mg/m3). The NOAEC for teratogenicity was 500 ppm (1600 mg/m3), the
highest level tested.
on the results of a rat single generation toxicity/fertility study and
developmental toxicity studies in 3 species, classification of benzene
as a reproductive or developmental toxicant is not warranted under (EC)
No 1272/2008 (CLP).
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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