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Description of key information

Short description of key information on bioaccumulation potential result:

Mixed xylene (comprising individual xylene isomers and ethylbenzene) as well as the other specific components present in these streams (e.g. benzene, styrene and toluene) are rapidly absorbed, metabolised and eliminated.

Short description of key information on absorption rate:

Dermal absorption of xylenes is low. (1%) For ethylbenzene a 4% skin uptake value will be used for risk characterisation purposes. Uptake of pure toluene and pure benzene is 1.5% and 3.6%, respectively.

Key value for chemical safety assessment

Additional information

Mixed xylene (CAS 1330-20-7) comprises individual xylene isomers (m-xylene, o-xylene, p-xylene) and ethylbenzene. Data for these component substances have been included as supporting information. Additional components present in this category are styrene, benzene and toluene.

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 result:

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 ethylbenzene 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 ethylbenzene is rapidly distributed through the body, there is no evidence of ethylbenzene 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, ethylbenzene 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.

In the ATSDR review of the toxicokinetics of benzene (ATSDR, 2007b) it is concluded that benzene is readily absorbed following inhalation or oral exposure. Absorbed benzene is rapidly distributed throughout the body and tends to accumulate in fatty tissues. The liver serves an important function in benzene metabolism, which results in the production of several reactive metabolites. Although it is widely accepted that benzene toxicity is dependent upon metabolism, no single benzene metabolite has been found to be the major source of benzene hematopoietic and leukaemogenic effects. At low exposure levels, benzene is rapidly metabolized and excreted predominantly as conjugated urinary metabolites. At higher exposure levels, metabolic pathways appear to become saturated and a large portion of an absorbed dose of benzene is excreted as parent compound in exhaled air. Uptake in humans is estimated to be approximately 50% after inhalation and assumed to be 100% after ingestion.

 

The major uptake of toluene vapour is through the respiratory system (RAR, 2003). Toluene is almost completely absorbed from the gastrointestinal tract. Toluene is distributed to various tissues, the amount depending on the tissue/blood partition coefficient, the duration and level of exposure, and the rate of elimination. Biotransformation of toluene occurs mainly by oxidation. The endoplasmic reticulum of liver parenchymal cells is the principal site of oxidation which involves the P450 system. Analysis of blood and urine samples from workers and volunteers exposed to toluene via inhalation indicated that the majority of toluene is oxidised via benzyl alcohol and benzaldehyde to benzoic acid (Woiwode and Drysch, 1981). Uptake of pure toluene vapour via inhalation is approximately 50% while absorption from the gastrointestinal tract is almost complete (100%)

References

ATSDR (2007a). Draft toxicological profile for styrene. U. S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.

ATSDR (2007b)Toxicological profile for benzene U. S. Department of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry.

EU RAR (2003) Toluene risk assessment report European Union Risk Assessment Report, Volume 30

Woiwode W, Drysch K.1981 Experimental exposure to toluene: further consideration of cresol formation in man Br. J. Ind. Med. 38, 194-197

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 waspredicted 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; 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. Furthermore, due to intermittent exposure of the skin the major part of xylene will evaporate. According to REACH Guidance appendix 14-1 about 1 mg of xylene will evaporate per minute from the skin. So evaporation from the skin will be much faster than absorption. In order to err on the safe side it is assumed, that 1% of xylene is absorbed from the daily dermal dose caused by intermittent dermal occupational exposure.

The dermal absorption of ethylbenzene is comprehensively reviewed in the recent RAR (2008). Liquid ethylbenzene is rapidly absorbed through the skin, whereas absorption is negligible after exposure of humans to ethylbenzene vapour. For human volunteers, who had immersed one hand for up to 2 hrs in aqueous solutions of ethylbenzene (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.

It has been demonstrated that liquid toluene can be absorbed through the skin. Although benzene is also readily absorbed from the skin, a significant amount of a dermal application evaporates from the skin surface. The dermal absorption value of toluene has been 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 (ten Berge, 2009). 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. The model predicted a maximum flux of 0.0000581 mg/cm2/min giving a dermal absorption value, for pure toluene vapour, of approximately 3.6%. The equivalent values for pure benzene were a maximum flux of 0.00082 mg/cm2/min giving a dermal absorption value of approximately 1.5%.

The draft RAR for styrene (EU, 2008) concludes that consistent with its chemical properties, most of the styrene volatilised following dermal application and that its dermal penetration was minimal.