Registration Dossier

Toxicological information

Carcinogenicity

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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.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Studies conducted in rats and mice demonstrate no evidence of carcinogenicity.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

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%). The following information is available to characterise their carcinogenic mutagenic potential.

Non-human information

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

The carcinogenicity of mixed xylene (17% ethyl benzene) 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 xylenes 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 ethyl benzene following inhalation exposure has been evaluated in chronic studies with F344 rats and B6C3F1 mice (NTP, 1999). Increases in tumor 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) ethyl benzene. The RAR (2008) concluded that genotoxicity was not the responsible mode in the initiation of the reported tumors and that other non-genotoxic mechanisms may be involved. Furthermore, the rapporteur concluded that there is sufficient evidence to conclude that the kidney tumors 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.

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.


Justification for selection of carcinogenicity via oral route endpoint:
Results of chronic oral studies with mixed xylenes have been negative, with no increase in tumour incidence in treated rats given up to 500 mg/kg bw/d for 103 weeks or in mice following chronic oral treatments of up to 1000 mg mixed xylenes/kg bw/d (NTP, 1986).

Justification for classification or non-classification

No classification of mixed xylenes streams for carcinogenicity is warranted under DPD or GHS/CLP.