Registration Dossier

Diss Factsheets

Toxicological information


Currently viewing:

Administrative data

Description of key information

The key chronic study was conducted by NTP (1986).  The study comprises the oral gavage administration of mixed xylenes to rats (0, 250, or 500 mg/kg/day) and mice (0, 500 or 1000 mg/kg/day) for 5 days/week for 103 weeks.  There was no evidence of carcinogenicity.

No studies are available regarding cancer in animals exposed via inhalation to mixed xylene or the individual xylene isomers.

Streams containing ≥ 0.1% benzene will require classification as carcinogens.

Key value for chemical safety assessment

Justification for classification or non-classification

No classification of mixed xylenes streams for carcinogenicity is warranted under DPD or GHS/CLP unless benzene is present at ≥0.1% in which case classification as: Carcinogenic Cat 2, R45 “May cause cancer” according to DPD and Cat 1B, H350 “May cause cancer” under CLP.

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.The carcinogenicity of mixed xylenes and the xylene isomers was reviewed and reported in the ATSDR (2007). The carcinogenicity of ethylbenzene was reviewed in the recent RAR (2008).

Neither the individual xylene isomers nor ethylbenzene are classified for carcinogenicity under the DSD (Dir. 67/548/EEC).

Non-human information

No animal studies are available on the carcinogenic effects of the individual xylene isomers following dermal or inhalation exposure. 

The carcinogenicity of mixed xylene (17% ethylbenzene) following oral exposure has been evaluated in chronic studies with rats and mice; however, no animal studies are available on the carcinogenic effects of the individual xylene isomers following oral exposure. Results of the chronic oral studies with mixed xylene have been negative (NTP, 1986), with no increase in tumour incidence compared with the control animals. Treatment involved administration of 0, 250, or 500 mg/kg/day doses of mixed xylene in corn oil by gavage 5 days/week for 103 weeks to groups of F344/N rats, 50 animals per group. B6C3F1 mice were treated in a similar manner but given 0, 500 or 1000 mg/kg/day of mixed xylenes in corn oil by gavage. A large number of gavage-related deaths were a confounding factor. This study did not comprehensively examine systemic effects but it did include a complete histopathological examination of all tissues as well as determination of body weight gain. Based on histopathology of all organ systems, a NOAEL of 500 mg/kg/day was observed for rats and a NOAEL of 1000 mg/kg/day was observed for mice. In conclusion there was no evidence of carcinogenicity of mixed xylenes following oral administration.

Equivocal results reported by Maltoni et al (1983, 1985) following exposure of rats to xylene are viewed to be unreliable (IPCS, 1997) as analysis was conducted by combining all tumours; this is an unacceptable basis for analysis particularly in aged animals. In addition, no data were provided to allow an analysis on an individual tumour-type basis.

The carcinogenicity of ethylbenzene following inhalation exposure has been evaluated in chronic studies with F344 rats and B6C3F1 mice (NTP, 1999). Increases in tumour rates in male (kidney and testis) and in female rats (kidney), in male mice (lung) and in female mice (liver) were reported following exposure to 750 ppm (3255 mg/m3) ethylbenzene. The RAR (2008) concluded that genotoxicity was not the responsible mode in the initiation of the reported tumours and that other non-genotoxic mechanisms may be involved. Furthermore, the rapporteur concluded that there is sufficient evidence to conclude that the kidney tumours in the male and female rats are associated with the rat strain-specific high incidence of chronic progressive nephropathy (CPN) which is not found in humans. The testis, liver and lung tumours were types that occur at high or very high spontaneous rates in the F344 rat and B6C3F1 mice strains used. The rapporteur concluded that ethylbenzene may enhance tumour development in genetically disposed animals or reduce the latency periods in tumour development. There are currently no detailed mechanisms explaining the increase in tumour rates some species and strain specificity is postulated (RAR, 2008). Consequently the toxicological significance and relevance to human health of these findings is uncertain and it is considered that ethylbenzene does not pose a carcinogenic risk for humans (no classification proposed under DSD).

Considering the potential component: Benzene (Classification: EU -Toxic T, Carcinogen Cat 1 R45; GHS/CLP - Category 1A, H350): Long term experimental carcinogenicity bioassays have shown that benzene is a carcinogen producing a variety of tumours in animals (including lymphomas and leukaemia).

Human information

There is no data indicating any convincing evidence of an increased risk of cancer as a consequence of exposure to xylenes. IARC (1999) has placed xylene in Group 3: "The agent is not classifiable as to its carcinogenicity to humans". The animal data indicates that xylenes would not be carcinogenic or genotoxic in humans.

Considering the potential component: Benzene (Classification: EU -Toxic T, Carcinogen Cat 1 R45; GHS/CLP - Category 1A, H350): Human epidemiological studies indicate a causal relationship between benzene exposure and acute non-lymphatic leukaemia (Crump, 1994; Glass et al, 2003, 2004, 2006; Rinsky et al, 2002; Schnatter, 2004).

Categories Display