Diethylbenzene

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards, well-documented and acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Diethylbenzene-induced sensorimotor neuropathy in rats

Author:

Gagnaire, F., Marignac, B., and de Ceaurriz, J

Year:

1990

Bibliographic source:

J. Applied Toxicology 10(2): 105-112.

Materials and methods

Principles of method if other than guideline:

Method: similar to repeated dose oral study with focus on assessing neurotoxicity

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Diethylbenzene

EC Number:

246-874-9

EC Name:

Diethylbenzene

Cas Number:

25340-17-4

Molecular formula:

C10H14

IUPAC Name:

diethylbenzene

Details on test material:

IUCLID4 Test substance: other TS: as prescribed by 1.1-1.4 and individual isomers

Diethylbenzene (DEB) mixture (approx. 7% 1,2-diethylbenzene, 58% 1,3-diethylbenzene, and 35% 1,4-diethylbenzene)

Purity of isomers:95% 1,2-diethylbenzene, 99% 1,3-diethylbenzene, 96% 1,4-diethylbenzene

Supplied by Aldrich Chemie, Steinhein, FRG.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

not specified

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: olive oil

Details on oral exposure:

500 or 750 mg/kg (in olive oil) for DEB  mixture; 100 mg/kg for 1,2-diethylbenzene; and 500 mg/kg for 1,3- and  1,4-diethybenzene
Control group and treatment: Concurrent, given olive oil vehicle

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

8 weeks (1,2-DEB isomers) and 10 weeks (1,3-DEB; 1,4-DEB mixed isomers)

Frequency of treatment:

5 days/week (mixture, 1,3- or 1,4-diethylbenzene isomers); 4 days/week (1,2-diethylbenzene)

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
500 or 750 mg/kg (in olive oil) for DEB  mixture
Basis:
other: nominal

Doses / concentrations 2

Remarks:

Doses / Concentrations:
 100 mg/kg for 1,2-diethylbenzene
Basis:
other: nominal

Doses / concentrations 3

Remarks:

Doses / Concentrations:
 500 mg/kg for 1,3- and  1,4-diethybenzene
Basis:
other: nominal

No. of animals per sex per dose:

There were 12 rats/group.  

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: Postexposure observation period: 8 weeks (isomer study only)

Examinations

Observations and examinations performed and frequency:

Rats were subjected to  neurophysiological measurements every week during the treatment period.   The survivors were kept for observation and neurophysiological  measurements during the post-exposure period.  The motor conduction  velocity (MCV) and sensory conduction velocity (SCV) of the tail nerve  and the amplitude of the sensory action potential (ASAP) were adopted as  parameters for testing peripheral nerve function in rats.

Statistics:

Statistical methods:  Differences in mean body weight, motor and sensory  conduction velocities, and amplitude of the sensory action potential  between experimental and control groups were analyzed using Student's  t-test for independent data.  Mean electrophysiological deficits in the  tail nerve were also analyzed, as a function of the length of treatment,  by least-squares regression.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Haematological findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

effects observed, treatment-related

Details on results:

Diethylbenzene mixture
 Rats given diethylbenzene (DEB) mixture with either 500 or 750 mg/kg  exhibited a blue discoloration of the skin and urine as soon as the 3rd  day of treatment.  These doses exceeded the maximum tolerated dose (MTD).  A significant reduction in weight gain was observed from the first week  of treatment in the group treated with 750 mg/kg.  Two animals died in  the 750 mg/kg dose group during the first week of treatment.  Two rats  died in the 500 mg/kg group during the 4th and 7th weeks of treatment.   No animals died in the control group.  Rats in the DEB-dosed groups  developed severe weakness in hind limbs and disturbances in gait from the  4th week of treatment.  This weakness got worse in the following weeks,  resulting in a complete paralysis of the hind limbs for some rats.  There  was a time-dependent decrease in MCV, SCV, and ASAP.                               

Diethylbenzene isomers                    
1,3- and  1,4-Diethylbenzene-treated rats (500 mg/kg) did not display any signs of  neurotoxicity or any other signs of systemic toxicity.

Rats given 1,2-diethylbenzene 100 mg/kg developed the same symptoms  (decreased body weight, blue discoloration of skin and urine, weakness of  hind limbs, paralysis) as those described for the diethylbenzene mixture.  The MTD was exceeded. One rat died in the first week of treatment and  another died in the 5th week of treatment.  During the recovery period,  the 1,2-diethylbenzene treated rats regained weight, became more mobile  but presented trailing hind limbs, when attempting to walk.  On the 4th  week of recovery, all animals treated with 1,2-diethylbenzene succeeded  in standing up.  

A time-dependent decrease in MCV, SCV, and ASAP was observed in animals  dosed with 1,2-diethylbenzene, but no changes were seen with 1,3- or  1,4-diethylbenzene.

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

other: DEB mixture

2

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

other: 1,2-diethylbenzene

3

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

other: 1,3-diethylbenzene

4

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

other: 1,4-diethylbenzene  

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Repeated oral exposure to diethylbenzene mixture and 1,2-diethylbenzene at doses exceeding the MTD resulted in some lethality and produced adverse effects on the peripheral nervous system whereas 1,3- and 1,4-diethylbenzene did not cause any systemic or neurotoxic effects at doses of 500 mg/kg.