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Toxicological information

Neurotoxicity

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Description of key information

A number of studies addressing neurobehavioural effects of xylenes in rodents and humans have been reported, however these often use a limited range of exposure concentrations with some conflicting results and are therefore considered to be generally unreliable. However when reviewing this information, the EU Scientific Expert Group (SEG; 1992) concluded that indications of mild CNS effects noted in some individuals exposed to 100 ppm (442 mg/m3) provided the best available basis for setting an exposure limit for xylene isomers. As the effects seen were minimal, 50 ppm (221 mg/m3) was considered a NOAEC by the SEG.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Effect on neurotoxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
neurotoxicity: inhalation
Remarks:
other: regulatory review
Type of information:
other: Recommendation from the Scientific Expert Group on Occupational Exposure Limits
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Scientific position underpinning EU occupational exposure limit for xylene isomers
Qualifier:
no guideline required
Principles of method if other than guideline:
Scientific review of underlying humn effects data, in support of Dir 2000/39/EC
GLP compliance:
no
Species:
other: human
Route of administration:
inhalation: vapour
Details on results:
The critical health effects underpinning the IOELV for xylene isomers were mild irritation of the eye and upper respiratory tract and mild CNS effects noted in some individuals exposed to 100 ppm (442 mg/m3). The findings were considered by the SEG to provide the best available basis for setting an exposure limit for xylene isomers. As the effects seen were minimal, 100 ppm (442 mg/3) was taken as a LOAEL. Application of an uncertainty factor of 2 gave an 8-hr TWA for xylene isomers of 50 ppm (221 mg/m3). A STEL of 100 ppm (442 mg/m3) was recommended to limit peak exposures which could result in eye and respiratory tract irritation.
Dose descriptor:
other: 8-hr TWA
Effect level:
50 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: based on mild CNS effects reported in humans; equivalent to 221 mg/m3
Remarks on result:
other:

The critical health effects underpinning the IOELV for xylene isomers were mild irritation of the eye and upper respiratory tract and mild CNS effects noted in some individuals exposed to 100 ppm (442 mg/m3). The findings were considered by the SEG to provide the best available basis for setting an exposure limit for xylene isomers. As the effects seen were minimal, 100 ppm (442 mg/3) was taken as a LOAEL. Application of an uncertainty factor of 2 gave an 8-hr TWA for xylene isomers of 50 ppm (221 mg/m3). A STEL of 100 ppm (442 mg/m3) was recommended to limit peak exposures which could result in eye and respiratory tract irritation.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
221 mg/m³
Study duration:
chronic
Species:
other: human
Quality of whole database:
Opinion from EU Scientific Expert group.

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Mixed xylene (CAS 1330-20-7) comprises individual xylene isomers (m-xylene, o-xylene, p-xylene) and ethylbenzene. Data for these substances 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.

Ethyl benzene induces transient, depression and neuromuscular impairment in experimental animals exposed to high concentrations of inhaled ethyl benzene (RAR, 2008).  In a 90 day oral guideline study (Mellert et al, 2006) specifically designed for the detection of neurotoxic effects of ethyl benzene 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 ethyl benzene 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).

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.

When reviewing this information, the EU Scientific Expert Group (SEG; 1992) concluded that indications of mild CNS effects noted in some individuals exposed to 100 ppm (442 mg/m3) provided the best available basis for setting an exposure limit for xylene isomers. As the effects seen were minimal, 50 ppm (221 mg/m3) was considered a NOAEC.

For ethyl benzene 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 ethyl benzene.


Justification for selection of effect on neurotoxicity via inhalation route endpoint:
The EU Scientific Expert Group (SEG; 1992) concluded that indications of mild CNS effects noted in some individuals exposed to 100 ppm (442 mg/m3) provided the best available basis for setting an exposure limit for xylene isomers. As the effects seen were minimal, 50 ppm (221 mg/m3) was considered a NOAEC by the SEG.

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 CLP as STOT-RE Cat 2 H373 (see Specific Investigations: other studies - ototoxicity).