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Description of key information

Information available for xylene isomers and ethyl benzene suggests rapid absorption, metabolism and elimination of these multi-constituent substances.
Dermal absorption of xylenes is around 15% while uptake of ethyl benzene is around 4%.

Key value for chemical safety assessment

Additional information

The multi-constituent substances covered by this registration comprise individual xylene isomers (m-xylene, o-xylene, p-xylene) and ethyl benzene (>10% - <20%). Information available for these components is discussed below. Toxicokinetic behaviour of some pure substances has been extensively studied and reported. In many circumstances the body burden of the substance and/or metabolites is dependent upon several factors such as the rate and extent of uptake, distribution, metabolism and excretion. In complex mixtures, however, the toxicokinetics of even well-studied pure substances may vary depending upon interaction with other chemical species available within the mixture. For example, the substances present may compete for the uptake, metabolism, and/or elimination of the complex mixture. This situation, already complicated, is further exacerbated when the composition of the mixture is uncertain and variable. Discussion on bioaccumulation potential: 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 x 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). 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 urinary metabolite was methyl hippuric acid; trace amounts of xylenols were also detected (Sedivec and Flek, 1976). After exposure of volunteers to 200mg 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 methyl hippuric 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 excretion and concluded that this could be used as a marker of exposure. The metabolism of ethyl benzene has been reviewed in the recent RAR (2008). Absorption via inhalation and the oral route was considered and it was concluded that for risk characterisation purposes inhalation absorption of 65 % was applicable for humans and 45 % for animals. For inhalation via the oral route, 100% oral absorption should be assumed for animals and humans. Although ethyl benzene is rapidly distributed through the body, there is no evidence of ethyl benzene accumulation in fat or fat-rich tissues (RAR, 2008). There are some species differences in metabolism. Side-chain oxidation leads to major metabolites in humans being e. g. mandelic acid, phenylglyoxylic acid with hippuric acid and benzoic acid being the major metabolites in rats. Ring oxidation is a minor metabolic pathway. With rapid metabolism, ethyl benzene and its metabolites are eliminated rapidly, mainly as urinary metabolites with minor loss via exhalation and excretion in faeces. Following exposure, excretion is virtually complete within 24 hrs. 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. The dermal penetration of xylene was 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). 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). However 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/cm2 per hour on the condition that the skin is not damaged. The dermal absorption of ethyl benzene is comprehensively reviewed in the recent RAR (2008). Liquid ethyl benzene is rapidly absorbed through the skin, whereas absorption is negligible after exposure of humans to ethyl benzene vapour. For human volunteers, who had immersed one hand for up to 2 hrs in aqueous solutions of ethyl benzene (Dutkiewicz and Tyras, 1967 cited in RAR, 2008) dermal absorption was up to 45%. However an uptake value of 4% by skin (Susten et al, 2005) is considered to be more representative for incidental contact.