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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%). 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% 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.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
15
Absorption rate - inhalation (%):
100

Additional information

The metabolism and kinetics of xylene isomers has been reviewed extensively by ATSDR (2007) and a brief summary is presented below.

Absorption

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, 2007).

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 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 0.000254 mg/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/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

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). 

(Retention) Excretion

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.