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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:
experimental study
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 human 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

Non-human information

A number of studies addressing neurobehavioural effects of xylenes have been reported.  However, these often only use a single exposure concentration or limited dose response and show some conflicting results and are considered to be generally unreliable. The effects reported include: impaired rotarod performance after acute (6 hour) exposures to the individual xylene isomers at a concentration of 3000 ppm (Korsak, 1990) or after repeated exposures to 100 ppm m-xylene for 3 months (Korsak et al, 1992, 1994). Other effects reported at 100 ppm and lower exposure concentrations (increased sensitivity to pain) were considered unreliable as a later study (Gralewicz and Wiaderna, 2001) reported conflicting effects (decreased pain sensitivity) at 100 ppm m-xylene. This later study also reported increased motor activity at 100 ppm which casts some doubt on the significance and reliability of the rotorad effects. Nevertheless, 50 ppm (217 mg/m3) was a clear NOAEC for effects on rotarod (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 800 ppm was an acute NOAEC for exposure by inhalation.

No animal studies were located regarding neurological effects following chronic inhalation exposure to mixed xylene or its isomers.

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 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.


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 is warranted under CLP. Classification of p-xylene as STOT-RE Cat 2 is not warranted as the NOAEC exceeds 1000 mg/m3.