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EC number: 203-396-5
CAS number: 106-42-3
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.
metabolism and kinetics of xylene isomers has been reviewed extensively
by ATSDR (2007) and a brief summary is presented below.
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, 2007).
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).
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 al., 2005).
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
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.
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).
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
major pathway of xylene metabolism in humans involves mixed function
oxidases in the liver, with minor metabolism occurring in the lung and
exposure to xylene was lower following repeated oral doses than after a
single oral dose indicating induction of metabolising enzymes (Gagnaire
et al., 2007).
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).
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
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.
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
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