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Neurotoxicity

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Description of key information

There are no specific data on neurotoxicity in humans by monoexposure to ethylbenzene or xylenes, but for aromatic solvents such as these there is evidence for such effects in humans and animals.  The critical effect, ototoxicity, is discussed under Specific investigations: other studies

Key value for chemical safety assessment

Effect on neurotoxicity: via inhalation route

Endpoint conclusion
Dose descriptor:
NOAEC
217 mg/m³

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 component substances benzene, toluene and styrene have been considered in this summary. Exposure levels of the xylene isomers associated with neurological effects in animals are well defined. 

Acute exposures to concentrations inducing behavioural changes included a 6 hour inhalation exposure to the individual xylene isomers at a concentration of 3000 ppm (Korsak, 1990). Rotarod performance was tested in male rats before and immediately after exposure. The results indicated that the toxic effects of exposure to o- and m-xylene were more pronounced than those of p-xylene at the single exposure level evaluated (Korsak et al, 1994). Sensory deficits resulting from exposure to p-xylene were observed in a key study of the acute neurotoxic effects (Dyer, 1988). A significant depression in amplitude of flash-evoked potential peak N3 was observed following an oral dose of 250 mg/kg or more of p-xylene and following inhalation exposure to 1600 ppm for 4 hours. These effects were indicative of altered processing of visual information but were described as possibly being secondary to changes in arousal or excitability. 125 mg/kg was an acute NOAEL for the oral route and 800ppm was an acute NOAEC for exposure by inhalation.

A variety of neurological effects have been seen in rats following repeated exposures to 100 ppm m-xylene these include impaired passive avoidance learning (when tested 5 weeks after exposure) and impaired acquisition, but not retention, of the two-way active avoidance response tested 9 weeks after exposure) (Gralewicz and Wiaderma, 2001), reduced rotarod performance (Korsak et al, 1992, 1994) and changes in sensitivity to pain (Korsak et al, 1994, Gralewicz and Wiaderma, 2001). In the Korsak 1994 study statistically significant increased sensitivity to pain was observed at 50 and 100 ppm m-xylene (8.6 and 8.7 seconds, respectively, vs. 12.2 seconds for controls; measurements were made 24 hours post exposure) whereas Gralewicz and Wiaderna (2001) reported a statistically significant decrease in pain sensitivity (35 seconds vs. 10 seconds in control) at 100 ppm m-xylene, the lowest dose tested. The variation in the response to m-xylene in these two studies decreases the confidence in using the pain sensitivity endpoint as the critical effect. In summary, the weight of evidence indicates that slight effects on rotarod are noted at the LOAEL of 100 ppm that do not change in severity with increasing duration of exposure. The NOAEL for this endpoint is 50 ppm m-xylene based on the same study (Korsak et al 1994) in which two neurological endpoints were evaluated. The available human data are considered insufficient for derivation of a NOAEL and no chronic inhalation studies in animals are available. The rat subchronic study by Korsak et al. (1994) is selected as the principal study.

Ethylbenzene induces transient, depression and neuromuscular impairment in experimental animals exposed to high concentrations of inhaled ethylbenzene (RAR, 2008).  In a 90 day oral guideline study (Mellert et al, 2006) specifically designed for the detection of neurotoxic effects of ethylbenzene at dose levels up to 500 mg/kg bw/d, did not lead to findings indicative of neurotoxicity in rats.  This is supported by results from an OPPTS 870.6200 (Neurotoxicity Screening Battery) compliant study where no treatment-related changes in FOB and motor activity, or occurrence of microscopic findings in nervous system, were found in male and female rats given ethylbenzene at doses up to 500 mg/kg bw/d by oral gavage for 90 days (Li et al., 2010).No indications for such morphological alterations of the central nervous system have been reported in other animal experiments including the 2-year bioassay with exposures up to 750 ppm (NTP, 1999).

A potential component is toluene. Toluene exposure can produce central nervous system pathology in animals after high oral doses.    

Human information  

According to the ATSDR (2007), the neurological effects of xylene in humans following inhalation exposure have been evaluated in a number of experimental studies, case reports, and occupational studies.  Results of experimental studies with humans indicate that acute inhalation exposure to mixed xylene or m-xylene causes impaired short term memory, impaired reaction time, performance decrements in numerical ability, and alterations in equilibrium and body balance. Available case reports and occupational studies together provide suggestive evidence that acute and chronic inhalation exposure to xylene or solvent mixtures containing xylene may be associated with neurological effects; however, most studies are difficult to evaluate because the exposure conditions either have not been well characterized or the subjects may have been exposed to other chemicals in addition to xylene.

For ethylbenzene there are no specific data on neurotoxicity resulting from (monoexposure) in humans (RAR, 2008). Similar to other aromatic solvents, such as xylene, depressive and narcotic effects in humans and especially in animal are anticipated for ethylbenzene. This relates to depressive and narcotic effects (ototoxicity is discussed below).

A potential component is toluene. In humans neuropsychological effects have been reported, particularly when exposures are not well controlled. There was no association noted between either current or long-term (LWAE) toluene exposure and any of the cognitive outcomes measured, with 26ppm the mean current exposure and 45ppm the mean estimated lifetime exposure.

Justification for classification or non-classification

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

Where ethylbenzene is >=10%, mixed xylenes warrants 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).

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