Diethylbenzene

Endpoint summary

Description of key information

A number of oral and inhalation repeated dose studies in rats.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

190 mg/m³

Study duration:

subchronic

Species:

rat

Additional information

In a 13-week inhalation study in rats, repeated inhalation exposure to DEB mixed isomers (190, 610 and 1400 mg/m3; calculated equivalence of 34, 110, and 252 ppm) resulted in decreased mean body weights in the high-dose animals throughout most of the study and abnormal serum chemistry results in some high- and mid-dose animals that were considered treatment-related, as well as moderate decreases in total white cells and lymphocytes in mid and high dose males. Relative liver weights were slightly increased in male animals from all three treated groups, with no treatment-related changes observed microscopically. There were no obvious target organs from repeated inhalation exposure to DEB mixed isomers; the NOAEL value from this GLP study was 190 mg/m3 (34 ppm). Repeated oral exposure (~7 weeks, daily) to the 1,4-DEB isomer (30, 150 and 750 mg/kg) demonstrated enlarged liver and kidney (male mid and high dose), and corresponding liver histopathology and changes in clinical chemistry, likely due to effects on kidney and liver. The repeat dose NOAEL in rats for orally administered 1,4-DEB isomer was 30 mg/kg bw/day in males and 150 mg/kg bw/day in females (increased liver weight).

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.

Considering the available data, the Key critical study for DNEL derivation will be taken as the 13 week inhalation study in rats. This study identified a clear no effect level for an isomer mix representative of that being registered. The No effect level of 190 mg/m3 in this study is also protective of the neurotoxicological effects observed with some of the specific isomers (1,2 -DEB) since neurotoxicity was only observed at the higher dose levels in this study.

Justification for classification or non-classification

No classification for repeated dose toxicity is required.

Although Neurotoxicity was evident in the study conducted with some single isomers and in one animal at the highest does of the 13 week inhalation study, it is considered that the criteria for classification for specific target organ toxicity (repeated dose) Neurotoxicity, are not met due to the high dose at which neurotoxicity was observed when animals were exposed to the mix of isomers subject to registration. (refer to Neurotoxicity section)