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Description of key information

Short description of key information on bioaccumulation potential result: 
Xylene isomers are well absorbed orally (approx 90%) and by inhalation (60-65%). Following inhalation exposure, approximately 5% of retained dose is eliminated in exhaled air with the remainder excreted as metabolites in urine. For DNEL derivations, 100% 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.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - dermal (%):
15

Additional information

The metabolism and kinetics of xylene isomers has been reviewed extensively by ATSDR (2007) and a brief summary is presented below since, for the purposes of REACH, a full assessment is not required.

All the xylene isomers are well absorbed via the oral route. They are rapidly distributed through the body and any unmetabolised compound quickly eliminated in exhaled air. In gavage dosing experiments in animals, 90% absorption has been estimated. In humans, inhalation absorption has been estimated at about 60-65% based on human data.

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. 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). In rats the primary metabolic pathway is oxidation of one of the methyl groups and, unlike humans, a relatively larger percentage is metabolized to methylmercapturic acid. Possible formation of xylenols and their reactive intermediates resulting via aromatic oxidation is likely to be minimal, as shown by Sedivec and Flek (1976) who detected only trace amounts in exposed volunteers. Following exposure of human volunteers by inhalation (0.2 or 0.4mg/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.

The major pathway of xylene metabolism in humans involves mixed function oxidases in the liver, with minor metabolism occurring in the lung and kidneys.  Xylenes are transformed primarily to methylbenzoic acid followed by conjugation with glycine to form the main metabolites, the corresponding methylhippuric acid isomers, which are eliminated in the urine and may be used as an index of exposure for occupational monitoring. 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). 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.

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 be used for DNEL derivation and therefore are not discussedfurther in this submission.

Discussion on absorption rate:

The permeability of xylene through skin from hairless rats was determined in-vitro; when applied occluded, the flux was 0.22mg/cm2/h with dermal penetration of 0.224% in 8h (Ahaghotu et al., 2005).

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 0.000254mg/cm2/min (ten Berge, 2009).

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/hr, 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/cm2per hour on the condition that the skin is not damaged by intermittent exposure of the skin of workers. Furthermore, due to intermittent worker exposure of the skin the 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 2µg/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).