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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 substances and the specific component substances benzene, toluene and styrene have been included as supporting information. In vitro and in vivo data are available for mixed xylenes and the robust summaries are included in this submission with discussion following.

In vitro data

Mixed xylene has been examined for activity on both gene mutation and cytogenetic endpoints.  It was not mutagenic in bacterial mutagenicity assays using Salmonella typhimurium (Litton Bionetics, 1978). In assays examining for chromosomal effects in mammalian cells, mixed xylene (composition unspecified) did not induce either sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells (Anderson, 1990) or gene mutation in mouse lymphoma L5178Y cells (Litton Bionetics, 1978).  Litton Bionetics (1979) also reported negative results for gene mutation from the evaluation of mitotic recombination in Saccharomyces cerevisiae. A recent assay examining for DNA damage, the comet assay (Chen, 2008), reported increases in fragmentation when isolated human peripheral blood lymphocytes were exposed to levels of m-, o- or p-xylene. Their investigations suggested that reactive oxygen species may play a role in the damage observed. The relevance of the small changes possibly due to active oxygen species observed in isolated lymphocytes is considered limited. In particular, no evidence to support a consequence of any radical-induced damage was seen in a cytogenetic assay (Anderson, 1990). In view of the available studies including the key endpoints of gene mutation and chromosomal damage, additional in vitro assays of the genotoxicity potential of mixed xylene are considered unnecessary, as also concluded by the recent ATSDR (2007) review.

In vivo data

Non-human information

Mixed xylenes do not induce chromosome aberrations in the bone marrow of treated rats (0.044, 0.147 and 0.441 cc/kg by intraperitoneal injection), Litton Bionetics (1978). A negative result was obtained for mixed xylenes in dominant lethal assays conducted in rats and mice (Hine Laboratories Inc., for API, 1973). In view of the lack of significant genotoxicity observed in the in vitro studies, and the available negative results examining for chromosomal damage in vivo, mixed xylene is considered not to have genotoxic potential.

Human information

Limited data is available demonstrating a lack of genotoxicity of mixed xylenes following inhalation in humans (ATSDR, 2007). The genotoxicity of ethylbenzene is reviewed in the recent RAR (2008) and it was concluded from various in vitro and in vivo mutagenicity tests that there is no relevant indication that ethylbenzene is genotoxic. The same conclusion has been drawn for xylene isomers in the recent comprehensive review of ATSDR (2007).  Neither ethylbenzene or any of the xylene isomers are classified for mutagenicity under the DSD (Dir. 67/548/EEC).

The specific potential component benzene which has been identified as present in some streams at up to 1% has been shown to be mutagenic in vivo: Benzene (Classification: EU –Toxic T Mutagen Cat 2 R46; GHS/CLP - Category 1B, H340): Benzene has been extensively examined for mutagenicity both in vitro and in vivo in a range of recognised core assay types. It has shown mixed results for mutagenicity in vitro although in mammalian cells there is overall evidence for potential mutagenic activity (EU RAR, 2008). Benzene has been shown to be mutagenic in vivo in both somatic cells and germ cells (Ciranni et al, 1991).

Short description of key information:

Available data from both in vitro and in vivo studies indicate that the individual xylene isomers, ethylbenzene and mixed xylene have no significant genotoxicity. Since a number of negative studies have been reported covering both mutation and cytogenetic endpoints, additional in vivo or in vitro assays of the genotoxicity potential of xylenes are considered unnecessary.  However the specific component benzene is known to be genotoxic and streams with >= 0.1% benzene require classification for mutagenicity.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

No classification is warranted under DSD or CLP since all xylene isomers, ethylbenzene and mixed xylene show no evidence of genotoxicity in vitro or in vivo.

For those streams with >=0.1% benzene classification is warranted as Mutagenic “May cause heritable genetic effects” Cat 2, R46 under Dir 67/548/EEC and “May cause genetic defects” Cat 1B, H340 under Reg (EC) 1272/2008.

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