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EC number: 905-562-9
CAS number: -
Short description of key information on
bioaccumulation potential result:
Xylene isomers are well absorbed orally (approx 90%) and by inhalation
(60%). Following inhalation exposure, approximately 5% of retained dose
is eliminated in exhaled air with the remainder excreted as metabolites
For DNEL derivations, 100% oral and
inhalation absorption and 15% dermal absorption are assumed.
Short description of key information on absorption rate:
It is assumed, that 1% of xylene is absorbed from the daily dermal dose
caused by intermittent dermal occupational exposure.
The metabolism and kinetics of xylene
isomers has been reviewed extensively by ATSDR (2007) and a brief
summary is presented below.
All the xylene isomers are well absorbed via
the oral and inhalation routes. The distribution is rapid and the
unmetabolised compound elimination occurs quickly through exhalation.
Approximately 90% of xylene is absorbed following oral exposure, whereas
inhalation absorption is estimated to be approximately 60% (ATSDR,
In rats, the individual xylene isomers are
all rapidly absorbed with peak concentrations in blood occurring between
0.5 and 2 hours after oral administration. Peak concentrations in brain
coincided with those in blood but were approximately 2.5-3 fold
greater. The elimination half-life from both blood and brain was
approximately 2.5-4 hours (Gagnaire et al., 2007).
The permeability of xylene through skin from
hairless rats was determined in-vitro; when applied occluded, the flux
was 0.22 mg/cm2/h with dermal penetration of 0.224% in 8 h (Ahaghotu et
The dermal absorption of the individual
xylene isomers was predicted using a model which considers dermal
absorption as a two stage process, permeation of the stratum corneum
followed by transfer from the stratum corneum to the epidermis. The QSAR
for each process was derived by fitting each model equation to
experimentally derived values using an iterative non-linear least
squares approach. Dermal flux and percent absorption were predicted
using physicochemical values using values determined at approximately
25°C. Model predictions for o-, m- and p-xylene isomers were
approximately 13.9, 11.8 and 10.9% respectively (ten Berge, 2009); a
worst-case uptake of 15% has been assumed for the purpose of calculating
a dermal DNEL. The corresponding values for the maximum fluxes were
0.000264, 0.000259 and 0.000254 mg/cm2/min (ten Berge, 2009).
In an in vivo percutaneous absorption study
using hairless mice and a direct method for volatile chemicals, total
absorption of ethylbenzene was 3.61% of the achieved dose. A breath
decay curve indicated absorption was complete 15 minutes after
application. Evaporation rates were used to derive an estimated contact
time of 5 min and the percutaneous absorption rate was calculated to be
For the estimation of skin absorption, more
relevant is a comparison of the aqueous permeability of o-xylene between
rats and volunteers in vivo (Thrall and Woodstock 2003). The estimated
human and rat aqueous permeability coefficients were found to be 0.005
and 0.058 cm/h, respectively. The water solubility of xylene is about
200 mg/litre (0.2 mg/cm3). This means that the maximum absorption
through human skin is estimated to be 0.005 * 0.2 = 0.001 mg/cm2 per
hour on the condition that the skin is not damaged by intermittent
exposure of the skin of workers. Furthermore, due to intermittent worker
dermal exposure, a major part of xylene will evaporate.
In human volunteers exposed dermally to
m-xylene, skin penetration occurred rapidly with detectable
concentrations in blood within minutes of exposure beginning; the dermal
flux was approximately 2 µg/cm2/min. Unchanged xylene was detected in
exhaled air but accounted for only 10-15% of that excreted as methyl
hippuric acid in urine (Riihimaki, 1979; Engstrom et al., 1977).
Metabolism of xylene isomers (using o-xylene
as a typical example) has been summarized by EPA (2003). Briefly,
metabolism primarily involves oxidation of the alkyl group (one of the
methyl groups in this case) to form a methylbenzoic acid metabolite via
a methylbenzyl alcohol intermediate (Ogata et al, 1970; Riihimaki,
1979). Methylbenzoic acid is subsequently excreted in the urine as a
glycine or glucuronic acid conjugate.
The major pathway of xylene metabolism in
humans involves mixed function oxidases in the liver, with minor
metabolism occurring in the lung and kidneys.
Systemic exposure to xylene was lower
following repeated oral doses than after a single oral dose indicating
induction of metabolising enzymes (Gagnaire et al., 2007).
Following exposure of human volunteers by
inhalation (0.2 or 0.4 mg/L for 4 hours) to xylene isomers either
individual or as a mixture, approximately 64% of the inhaled dose was
retained; this value was independent of dose or duration of exposure.
Following exposure, approximately 5% of the retained dose was eliminated
in exhaled air with the remainder excreted as metabolites in urine.
After exposure of volunteers to 200 mg xylene /m3 for 4h, elimination of
unchanged xylene in urine was biphasic with half-lives of approximately
1 and 11 hours; only 0.0015% of the absorbed dose was excreted unchanged
in urine (Janasik et al., 2008).
Excretion predominantly occurs in the form
of the methylhippuric acid metabolite (i.e. the glycine pathway), with
glucuronidation being a minor pathway; a small amount (3-5%) is excreted
as unmetabolized xylene in expired air. Although ring oxidation to
xylenols (dimethylphenol) may also occur, this metabolic pathway is
relatively minor. This pattern of metabolism is the same for all three
xylene isomers, as demonstrated by Sedivec and Fleck (1976) who assessed
the metabolism of individual xylene isomers and isomer mixtures in
healthy volunteers exposed via inhalation. There was no difference in
the metabolic and excretion patterns of each xylene isomer (either
individually or as a mixture) and from a mass balance calculation more
than 95% of the absorbed xylenes were excreted in the urine in the form
of hippuric acid derivatives via the glycine conjugation pathway (ortho
97.1%; meta 99.2%; para 95.1%), with only trace amounts of xylenol
observed (ortho 0.86%; meta 1.98%; para 0.05%) (Sedivec and Flek, 1976).
Kawai et al. (1991) and Inoue et al. (1993) determined methylhippuric
acids (MHA) in end-shift urine samples from workers occupationally
exposed to xylene, both groups found a significant linear correlation
between the time weighted average intensity of exposure and MHA. MHA
isomers, which are eliminated in the urine may be used as an index of
exposure for occupational monitoring.
A number of pharmacokinetic models (PBPK
models) are available for xylenes and these are reviewed in some detail
by, for example, ATSDR (2007). In the context of this submission PBPK
models have not been used for DNEL derivation, however, models developed
by Marchand 2015 can appropriately predict urinary biomarkers for low
level exposures to m-xylene although further efforts are currently
ongoing to validate the use of these models for mixtures.
In order to compare the metabolism of the
different isomers, xylene, and xylene reaction masses, LOA are running a
pilot in vitro study. The new information will be included in the
dossier, once evaluated for usefulness.
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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