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EC number: 905-588-0
CAS number: -
In repeated dose studies, the principle effects of xylenes were adaptive changes in the liver, organ weight and body weight changes. Inhalation studies in rodents have demonstrated a potential to cause ototoxicity.
toxicity of mixed xylene was investigated in male and female F344/N rats
following oral (gavage) administration at doses of 0, 250 or 500 mg/kg
bw/day for 103 weeks. Animals were observed for survival, clinical signs
and body weight gain and subject to a full necropsy with tissue
histopathology at sacrifice. There was no evidence of treatment-related
systemic toxicity in either sex under these conditions.
Male dogs were exposed 6h/day for 5 days in
each of 13 weeks to 0, 0.77, 2.0 or 3.5 mg/L (0, 180, 460 or 810 ppm)
mixed xylenes. The NOAEC was >=3515 mg/m3.
The multi-constituent substances covered by
this registration comprise individual xylene isomers (m-xylene,
o-xylene, p-xylene) and ethyl benzene (>10% - <20%). The following
information is available to characterise their repeated dose toxicity.
Repeated dose toxicity: oral
Data are available for laboratory animals
exposed to high doses of mixed xylene, adverse effects have been
observed in the kidney and liver (IARC, 1989).
A near-guideline (equivalent or similar to
OECD 408) subchronic oral gavage study with mixed xylene (comprising 18%
o-xylene, 62% m- and p-xylene, 20% ethyl benzene) 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 xylene. In the study, groups
of 10 male and 10 female rats were given 0, 150, 750, or 1500 mg/kg
bw/day of mixed xylene 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 xylene 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 higher.
Treatment levels between 150 and 750 mg/kg
bw/day are covered in a carcinogenicity study in rats (NTP, 1986). The
test sample comprised 60% m-xylene, 14% p-xylene, 9% o-xylene, and 17%
ethyl benzene. 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
xylene 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.
A supporting subchronic oral gavage study
was conducted by NTP (1986) using groups of 10 male and 10 female rats
treated via gavage 5 days/week for 13 weeks with 0, 62.5, 125, 250, 500
or 1000 mg/kg/day. In the same study, groups of 10 male and 10 female
mice were similarly dosed with 0, 125, 250, 500, 1000 or 2000 mg/kg/day
of mixed xylene in corn oil. The composition of the sample was as
Limited toxicological endpoints were
Treatment-related 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.
No studies are available for the individual
In an OECD Guideline 90-day oral study ethyl
benzene 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.
Repeated dose toxicity: dermal
No studies are available for xylenes
(including mixed xylene and the individual xylene isomers) or ethyl
Repeated dose toxicity: inhalation
The available subchronic inhalation studies
are designed primarily to address neurological endpoints (including
ototoxicity) in male rats and dogs. These endpoints are discussed in
In a recent study (Gagnaire et al., 2007a)
the potential ototoxicity of two samples of mixed xylene was
investigated in groups of male rats exposed to 250, 500, 1000 and 2000
ppm for 6 h/day, 6 d/wk over 13 weeks, with a recovery period of 8
weeks. One sample contained 10% ethyl benzene, the other 20% ethyl
benzene. There was no adverse effect on body weight at any of the dose
In another investigation (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.
In 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 xylene. The highest exposure level was a
NOAEC for both species.
Ethyl benzene has also been the subject of a
recent study to assess potential ototoxicity (Gagnaire et al, 2007b).
Groups of male rats were exposed to 0, 200, 400, 600 and 800 ppm ethyl
benzene 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
No classification of mixed xylenes is
warranted when ethylbenzene content is <10%
Where ethylbenzene is >=10%, mixed xylene
classification under DSD or CLP as Xn, R48/20 with the equivalent
classification as STOT-RE Cat 2 H373 under CLP [see Specific
Investigations: other studies (ototoxicity)].
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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