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Administrative data

Description of key information

In repeated dose studies, the principle effects of xylenes were adaptive changes in the liver, organ weight and body weight changes. Inhalation studies in rodents have demonstrated a potential to cause ototoxicity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Results are available from chronic and sub-chronic studies that have investigated the repeated dose toxicity of mixed xylene in rodents.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
3 515 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Several studies are available that report the systemic toxicity and ototoxicty of xylene isomers (including mixed xylenes) in the rat following inhalation exposure.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

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 repeated dose toxicity.

Repeated dose toxicity: oral

Data are available for laboratory animals exposed to high doses of mixed xylene, adverse effects have been observed in the kidney and liver (IARC, 1989).

A near-guideline (equivalent or similar to OECD 408) subchronic oral gavage study with mixed xylene (comprising 18% o-xylene, 62% m- and p-xylene, 20% ethyl benzene) was conducted by Condie et al. (1988). It includes the range of toxicological endpoints routinely investigated in regulatory subchronic studies and is a key study for identifying the effects of mixed xylene. In the study, groups of 10 male and 10 female rats were given 0, 150, 750, or 1500 mg/kg bw/day of mixed xylene in corn oil for 90 consecutive days. A decrease in body weight was observed in males only at 1500 mg/kg bw/day. Although increased relative liver weights were seen at all dose levels in males and in females at 750 and 1500 mg/kg bw/day there were no adverse histopathology findings in the liver. An increased relative kidney weight was observed in high dose males and females and in intermediate dose males. In males there was a dose-related increase in the incidence of slight to mild hyaline droplet formation in tubules at all dose levels. This finding is indicative of alpha-2u-globulin which is considered to be male rat-specific and is not relevant for humans. In females the incidence of minimal nephropathy in females was statistically significantly increased in the 750 and 1500 mg/kg bw/day groups. This finding described as scattered tubular dilation and atrophy, with occasional regeneration and is the chronic progressive nephropathy typically seen in ageing rats.

No NOAEL was established in this study for males based on liver weight increases. However increases in liver weight with no adverse histopathological findings are considered to be an adaptive response to administration of mixed xylene rather than an adverse toxicological effect. A dose of 750 mg/kg bw/day is the NOAEL based on effects on male body weight. In females a NOAEL of 150 mg/kg bw/day is based on liver weight increases and the kidney effects observed at dose levels of 750 mg/kg bw/day and higher.

Treatment levels between 150 and 750 mg/kg bw/day are covered in a carcinogenicity study in rats (NTP, 1986). The test sample comprised 60% m-xylene, 14% p-xylene, 9% o-xylene, and 17% ethyl benzene. Although this study did not include all of the end points included in chronic studies to current guidelines, the key parameters affected in the sub chronic study, i.e. body weights and detailed pathology and histopathology are included. Rats were dosed with mixed xylene at concentrations of 0, 250 or 500 mg/kg bw/day 5 days per week for 103 weeks. The main finding was a decrease in body weights in males receiving 500 mg/kg bw/day in the second year of the study. There was no other evidence of systemic toxicity including no treatment-related pathology findings. A dose of 250 mg/kg/day was a NOAEL for both sexes and this is considered to be the key study for determining the NOAEL for repeated dose exposure to mixed xylenes via the oral route.

A supporting subchronic oral gavage study was conducted by NTP (1986) using groups of 10 male and 10 female rats treated via gavage 5 days/week for 13 weeks with 0, 62.5, 125, 250, 500 or 1000 mg/kg/day. In the same study, groups of 10 male and 10 female mice were similarly dosed with 0, 125, 250, 500, 1000 or 2000 mg/kg/day of mixed xylene in corn oil. The composition of the sample was as described above.

Limited toxicological endpoints were evaluated.

Treatment-related findings in rats were limited to a reduction in overall body weight gain (15% for males and 8% for females) with a NOAEL of 500 mg/kg/day. High dose mice exhibited transient CNS effects 5-10 minutes after dosing that lasted 15-60 minutes. Other treatment-related findings were limited to a reduction in overall body weight gain (7% for males and 17% for females) with a NOAEL of 1000 mg/kg/day. Neither blood clinical chemistry nor organ weight data were collected for either species. No treatment-related macroscopic or microscopic lesions were observed in the tissues examined including the liver and kidney.

No studies are available for the individual xylene isomers.

In an OECD Guideline 90-day oral study ethyl benzene was gavage dosed at 0, 75, 250 and 750 mg/kg in corn oil (Mellert et al. 2007). The NOAEL for this study was 75 mg/kg/day based on changes in haematology indicative of a mild regenerative anaemia and changes in clinical chemistry parameters. There was also an increase in liver weights with centrilobular hepatocellular hypertrophy indicative of hepatic microsomal enzyme induction.

Repeated dose toxicity: dermal

No studies are available for xylenes (including mixed xylene and the individual xylene isomers) or ethyl benzene.

Repeated dose toxicity: inhalation

The available subchronic inhalation studies are designed primarily to address neurological endpoints (including ototoxicity) in male rats and dogs. These endpoints are discussed in section 5.10.1.1.

In a recent study (Gagnaire et al., 2007a) the potential ototoxicity of two samples of mixed xylene was investigated in groups of male rats exposed to 250, 500, 1000 and 2000 ppm for 6 h/day, 6 d/wk over 13 weeks, with a recovery period of 8 weeks. One sample contained 10% ethyl benzene, the other 20% ethyl benzene. There was no adverse effect on body weight at any of the dose levels.

In another investigation (Gagnaire et al., 2001), the potential ototoxicity of individual xylene isomers was evaluated using electrophysiological methods in male rats exposed by inhalation to three different concentrations 6 hours/day, 5 days/week for 13 weeks was evaluated. The highest exposure concentration of 1800 ppm had no significant effect on body weight or body weight gain.

In an older study by Carpenter (1975), male rats and male dogs were exposed 6h/day for 5 days in each of 13 weeks to 0, 180, 460 or 810 ppm mixed xylene. The highest exposure level was a NOAEC for both species.

Ethyl benzene has also been the subject of a recent study to assess potential ototoxicity (Gagnaire et al, 2007b). Groups of male rats were exposed to 0, 200, 400, 600 and 800 ppm ethyl benzene for 6 h/day, 6 d/wk over 13 weeks with a recovery period of 8 weeks. There was no adverse effect on body weight at any of the dose levels.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Results from oral repeated dose studies conducted on mixed xylene in the rat indicate a sub-chronic LOAEL of 750 mg/kg bw/d (Condie et al., 1988) and a chronic NOAEL of 250 mg/kg bw/d (NTP, 1986). A sub-chronic NOAEL of 75 mg/kg bw/d has been reported for ethyl benzene (Mellert et al., 2007).

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
A NOAEC of 3515 mg/m3 was reported by Carpenter et al. (1975) for generalised systemic effects in male rats and male dogs. Other studies have shown that some xylene isomers adversely affect hearing in the rat, with a sub-chronic NOAEC of 1950 mg/m3 reported for p-xylene; the NOAEC for ototoxicity of m-xylene and o-xylene was greater than 7810 mg/m3 (Gagnaire et al., 2001). The ototoxicity of mixed xylene appears to be dependent upon composition (Gagnaire et al., 2007), with a sub-chronic LOAEC of 1080 mg/m3 reported for one sample while another had a NOAEC of 2170 mg/m3. A LOAEC of 868 mg/m3 was reported for the ototoxicity of ethyl benzene in the rat (Gagnaire et al, 2007), equivalent to an extrapolated NOAEC of 500 mg/m3.

Repeated dose toxicity: via oral route - systemic effects (target organ) other: all gross lesions and masses

Repeated dose toxicity: inhalation - systemic effects (target organ) other: all gross lesions and masses

Justification for classification or non-classification

No classification of mixed xylenes is warranted when ethylbenzene content is <10%

Where ethylbenzene is >=10%, mixed xylene streams warrant classification under DSD or CLP as Xn, R48/20 with the equivalent classification as STOT-RE Cat 2 H373 under CLP [see Specific Investigations: other studies (ototoxicity)].