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EC number: 287-502-5
CAS number: 85536-20-5
In repeated dose studies, the principle effects of xylenes were adaptive changes in the liver, changes in kidney and liver weights, body weight changes and minimal nephropathy in females.
xylene (CAS 1330-20-7) comprises individual xylene isomers (m-xylene,
o-xylene, p-xylene) and ethylbenzene. Data
for these substances and the specific component substances benzene,
toluene and styrene have been included as supporting information.
dose toxicity: oral
studies are available for the individual xylene isomers.
are available for laboratory animals exposed to high doses of mixed
xylenes, adverse effects have been observed in the kidney and liver
near-guideline (equivalent or similar to OECD 408) subchronic oral
gavage study with mixed xylenes (20% ethylbenzene) was conducted by
Condie et al. (1988). It includes the range of toxicological endpoints
routinely investigated in regulatory subchronic studies and is a key
study for identifying the effects of mixed xylenes. In the study, groups
of 10 male and 10 female rats were given 0, 150, 750, or 1500 mg/kg
bw/day of mixed xylenes in corn oil for 90 consecutive days. A decrease
in body weight was observed in males only at 1500 mg/kg bw/day. Although
increased relative liver weights were seen at all dose levels in males
and in females at 750 and 1500 mg/kg bw/day there were no adverse
histopathology findings in the liver. An
increased relative kidney weight was observed in high dose males and
females and in intermediate dose males. In males there was a
dose-related increase in the incidence of slight to mild hyaline droplet
formation in tubules at all dose levels. This finding is indicative of
alpha-2u-globulin which is considered to be male rat-specific and is not
relevant for humans. In
females the incidence of minimal nephropathy in females was
statistically significantly increased in the 750 and 1500 mg/kg bw/day
groups. This finding described as scattered tubular dilation and
atrophy, with occasional regeneration and is the chronic progressive
nephropathy typically seen in ageing rats.
No NOAEL was
established in this study for males based on liver weight increases.
However increases in liver weight with no adverse histopathological
findings are considered to be an adaptive response to administration of
mixed xylenes rather than an adverse toxicological effect. A dose of 750
mg/kg bw/day is the NOAEL based on effects on male body weight. In
females a NOAEL of 150 mg/kg bw/day is based on liver weight increases
and the kidney effects observed at dose levels of 750 mg/kg bw/day and
levels between 150 and 750 mg/kg bw/day are covered in a carcinogenicity
study in rats (NTP, 1986). Although
this study did not include all of the end points included in chronic
studies to current guidelines, the key parameters affected in the sub
chronic study, i.e. body weights and detailed pathology and
histopathology are included. Rats
were dosed with mixed xylenes at concentrations of 0, 250 or 500 mg/kg
bw/day 5 days per week for 103 weeks. The
main finding was a decrease in body weights in males receiving 500 mg/kg
bw/day in the second year of the study.There
was no other evidence of systemic toxicity including no
treatment-related pathology findings. A dose of 250 mg/kg/day was a
NOAEL for both sexes and this is considered to be the key study for
determining the NOAEL for repeated dose exposure to mixed xylenes via
the oral route.
findings in rats were limited to a reduction in overall body weight gain
(15% for males and 8% for females) with a NOAEL of 500 mg/kg/day. High
dose mice exhibited transient CNS effects 5-10 minutes after dosing that
lasted 15-60 minutes. Other treatment-related findings were limited to a
reduction in overall body weight gain (7% for males and 17% for females)
with a NOAEL of 1000 mg/kg/day. Neither blood clinical chemistry nor
organ weight data were collected for either species. No
treatment-related macroscopic or microscopic lesions were observed in
the tissues examined including the liver and kidney.
an OECD Guideline 90-day oral study ethylbenzene was gavage dosed at 0,
75, 250 and 750 mg/kg in corn oil (Mellert et al. 2007). The NOAEL for
this study was 75 mg/kg/day based on changes in haematology indicative
of a mild regenerative anaemia and changes in clinical chemistry
parameters. There was also an increase in liver weights with
centrilobular hepatocellular hypertrophy indicative of hepatic
microsomal enzyme induction.
dose toxicity: dermal
studies are available for mixed xylene, the individual xylene isomers or
dose toxicity: inhalation
subchronic inhalation studies are designed primarily to address
neurological endpoints in male rats and dogs. These endpoints are
discussed in section 18.104.22.168.
a recent study by Gagnaire et al (2001) the potential ototoxicity of
individual xylene isomers was evaluated using electrophysiological
methods in male rats exposed by inhalation to three different
concentrations 6 hours/day, 5 days/week for 13 weeks was evaluated. The
highest exposure concentration of 1800 ppm had no significant effect on
body weight or body weight gain.
assessed following a comparable protocol (Gagnaire et al, 2007a). Groups
of male rats were exposed to 250, 500, 1000 and 2000 ppm mixed xylenes,
one mixture with 10% and one with 20% ethylbenzene for 6 h/day, 6 d/wk
over 13 weeks with a recovery period of 8 weeks. There was no adverse
effect on body weight at any of the dose levels.
an older study by Carpenter (1975), male rats and male dogs were exposed
6h/day for 5 days in each of 13 weeks to 0, 180, 460 or 810 ppm mixed
xylenes. The highest exposure level was a NOAEC for both species.
Ethylbenzene (Not currently classified): No
repeated dose toxicity studies in humans have been identified. The EU
transitional RAR (EU, 2008b) concluded "Repeat-dose or prolonged
exposure to ethylbenzene specifically affected the nervous system, but
did not induce overt toxicity of any other organ system. " The auditory
system is the most sensitive to the toxic effects of ethylbenzene after
inhalation exposure (Gagnaire et al, 2007) while the liver is the most
sensitive following oral exposure (Mellert et al, 2006). The LOAEL for
ototoxicity was 200 ppm (868 mg/m3) and the NOAEL for hepatotoxicity was
75 mg/kg/day in a 13 week oral gavage study in rats.
specific components which have been identified as potentially present in
some streams are styrene, benzene and toluene. These are all identified
as producing serious target organ toxicity following repeated oral,
dermal or inhalation exposures in animals and man.
Styrene (Not currently classified):
Inhalation studies in animals have reported damage to the nasal
olfactory epithelium in rats and mice, liver damage in mice, eye
irritation in rats and guinea pigs, ototoxicity in rats and impaired
nerve conduction velocity. The EU transitional RAR (EU, 2008b) has
identified a NOAEC of 50 ppm in humans based on colour vision
discrimination effects in occupationally exposed workers.
(Classification: EU -Toxic T, R48/23/24/25; GHS/CLP - STOT-RE Category
1, H372): After repeated dose exposure via oral or inhalation routes,
benzene causes adverse effects on the haematopoietic system of animals
and man. The oral LOAEL was 25 mg/kg bw/day for male and female mice
(NTP, 1986) and the inhalation LOAEC for haematotoxicity in mice is 10
ppm (32 mg/m3) (Ward et al, 1985). For human a NOAEC of 3.5
ppm (11.2 mg/m3) is obtained based on the 95% LCL for the
threshold level of neutrophils, the most sensitive endpoint reported by
Schnatter et al. (2010).
(Classification: EU - Harmful Xn, R48/20; GHS/CLP - STOT-RE Category 2,
H373): Toluene exposure can produce central nervous system pathology in
animals after high oral doses. Repeated inhalation exposure can produce
ototoxicity in the rat and high concentrations are associated with local
toxicity (nasal erosion). In humans neuropsychological effects and
disturbances of auditory function and colour vision have been reported,
particularly when exposures are not well controlled and/or associated
with noisy environments. The NOAEC for subchronic oral toxicity in rats
is 625 mg/kg/day based on neuropathology (Huff, 1990). The NOAEC for
inhalation toxicity in the rat is 300 ppm (1131 mg/m3) based
on effects on body weight, mortality and adverse local effects (nasal
erosion) (Gibson and Hardisty, 1983). The NOAEC for neuropsychological
effects, auditory dysfunction and disturbances of colour vision in
humans is 26 ppm (98 mg/m3) (Seeber et al, 2004); Schaper et
al, 2003, 2004).
ACC, (2005). US
High Production Chemical Program. Category summary for Fuel Oils
Category. American Chemical Council. http: //www. epa.
Cragg ST, Clarke
EA, Daly IW, Miller RR, Terrill JB and Quellette RE(1989). Subchronic
inhalation toxicity of ethylbenzene in mice, rats, and rabbits. Fundam
Appl Toxicol 13, 399-408.
Toxicity studies of ethylbenzene in F344/N rats and B6C3F1 mice
(inhalation studies). Research Triangle Park, NC: National Toxicology
Program. NTP Tox 10. http: //inmagic. syrres.
com/esc-images/NTIS/NTP/TOX010. pdf. August 02, 2007.
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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