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Several repeat-dose ototoxicity studies in rats have been conducted with exposure via inhalation to mixed xylenes or the individual xylene isomers.  These studies have demonstrated that ototoxicity occurs following exposure to p-xylene or mixed xylenes.  The NOAEC for p-xylene (6 hours/day, 5 days/week for 13 weeks) is 450 ppm. The NOAEC for mixed xylenes cannot be specified because it is affected by the relative proportions of the constituents and, in particular the presence of ethylbenzene which is a more potent ototoxicant.  Toluene may also be present in streams, which is also otoxic.

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 specific component substances benzene, toluene and styrene have been considered in this summary.

Several repeat-dose ototoxicity studies in rats have been conducted with exposure via inhalation to mixed xylenes or the individual xylene isomers. These studies have demonstrated that ototoxicity occurs following exposure to p-xylene or mixed xylenes (Gagnaire et al, 2001, 2005; Maguin et al, 2006). Ototoxicity has been demonstrated using electrophysiological, behavioural and morphological techniques and is characterised by shifts in auditory thresholds and loss of outer hair cells in the cochlea. No evidence of recovery from such effects was seen following an 8 week recovery period and effects are considered to be permanent (Gagnaire et al, 2001). Ototoxicity has been shown to occur within 3 weeks using inhalation exposures of 6 hours/day, 5 days/week at 1800 ppm p-xylene (Maguin et al, 2006). The NOAEC for p-xylene (6 hours/day, 5 days/week for 13 weeks) was shown to be 450 ppm. 

Using electrophysiological, behavioural and morphological techniques no evidence of ototoxicity has been seen for m- and o-xylene at the highest concentrations tested 1800 ppm, 6 hours/day, 5 days/week for 13 weeks (Gagnaire, 2005) which is therefore the NOAEC. 

The NOAEC for mixed xylenes is affected by the relative proportions of the constituents and, in particular the presence of ethylbenzene (a common impurity in mixed xylenes) which is a more potent ototoxicant than xylenes (Gagnaire and Langlais, 2005). There is also some evidence that exposure duration may influence the induction of ototoxicity. With exposure durations of 6 hours/day, 6 days/week for 13 weeks evidence of ototoxicity was seen at concentrations ≥ 250 ppm with a mixture containing 20% o-xylene, 20% p-xylene, 40% m-xylene and 20% ethylbenzene, whereas a mixture containing 30% o-xylene, 10% p-xylene, 50% m-xylene and 10% ethylbenzene showed ototoxic effects at ≥ 1000 ppm with a NOAEC of 500 ppm (Gagnaire et al, 2007).  The same study (Gagnaire et al, 2007) evaluated exposure concentrations of 200, 400, 600 and 800 ppm ethylbenzene and moderate to severe ototoxicity was observed. Microscopic examination of the organ of Corti and basilar membrane demonstrated clear reductions in hair cells with a LOAEC of 200 ppm ethylbenzene.

 

A mixture including 10% p-xylene (10% p-, 80% m-, 10% o-xylene) but with long exposure durations (14 hours/day, 7 days/week) for 6 weeks showed ototoxic effects at concentrations ≥ 800 ppm (Pryor et al, 1987). Using single exposures Pryor et al. (1987) also reported hearing loss in rats exposed to 1450 ppm mixed xylenes for 8 hours but not in rats exposed to 1700 ppm for 4 hours.

Considering potential components:

Toluene is ototoxic in rats producing loss of cochlea hair cells which is considered to be an irreversible effect. However, effects have been insufficiently documented to enable determination of a NOAEC. Hearing loss has been reported in humans, especially when toluene exposure is associated with high exposure concentrations and a noisy environment. In addition there have been reports of disturbances of colour vision. For both these effects epidemiology studies (Schaper et al, 2003, 2004) have demonstrated that adverse changes do not occur when exposures are maintained below the current indicative occupational exposure limit of 50 ppm (188 mg/m3).

For styrene (discussed further under repeat dose toxicity), inhalation studies in animals have reported ototoxicity in rats

 

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