Diethylbenzene

Neurotoxicity

Description of key information

A series of subchronic studies, both oral (up to 10 weeks) and inhalation (18 weeks) administration, specifically investigated the neurotoxic potential of DEB mixed isomers and of the individual DEB isomers

Key value for chemical safety assessment

Effect on neurotoxicity: via inhalation route

Endpoint conclusion

Dose descriptor:

NOAEC

610 mg/m³

Study duration:

subchronic

Species:

rat

Additional information

A series of subchronic studies, both oral (up to 10 weeks) and inhalation (18 weeks) administration, specifically investigated the neurotoxic potential of DEB mixed isomers and of the individual DEB isomers. Adverse clinical observations, and peripheral and central nervous system effects were noted for the 1,2-DEB isomer in repeated oral exposure to the lowest tested dose of 100 mg/kg bw/day, a dose that caused some mortality. These effects were observed as severe weakness or paralysis of hind limbs at high doses. The decrease in peak amplitude of the BAEP (brainstem auditory evoked potentials) components was seen and it did not recover during the follow up. Similar data collected from rats treated with the individual isomers 1,3-DEB or 1,4-DEB were negative, with NOAEL values for those individual isomers of 500 mg/kg bw/day indicating that the observed neurotoxicity is due to the 1,2-DEB isomer. A NOAEL for the 1,2 DEB isomer was not demonstrated. However, in a 13-week inhalation study in rats, repeated inhalation exposure to DEB mixed isomers (190, 610 and 1400 mg/m3) reported clinical signs of neurotoxicity (head tilt and loss of balance) only in one high-dose male. A NOAEL for neurotoxicity signs of 610 mg/mg3 (calculated oral equivalent ~ 152 mg/kg bw/day) can be derived for DEB-mixed isomers based on this study.

Justification for classification or non-classification

In the CLP guidance documents, the cut off values for STOT-RE Category 2 for inhalation of vapour are 0.2 to 1.0 mg/L for a 6 hour period. In the 13 week study, neurotoxic effects were only observed at the highest dose level (1.4 mg/L) and the No effect level therefore lies somewhere between 0.6 mg/L and 1.4 mg/L. This dose of 0.6 mg/L is approximately exuivalent to an oral exposure to 150 mg/kg bw/day and this is greater than upper guidance value for oral studies of 100 mg/kg bw for classification as STOT-RE. Therefore, even though one component of the DEB mixed isomers (1,2 -DEB) is clearly producing neurotoxicity, exposure to the mixed isomers of DEB at levels <100 mg/kg bw/day would not be expected to produce neurotoxicity in rats, therefore classification for STOT-RE Category 2 is not considered appropriate.