1,4-dichlorobenzene

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: OECD guideline not defined.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1988

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1987

Reference 3

Reference Type:

publication

Title:

Unnamed

Year:

1988

Materials and methods

Principles of method if other than guideline:

Method: other: Repeated Dose Toxicity study , focusing on the effects on the kidney during the oral administration by gavage of test substance in F344 rats during 13 weeks).

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,4-dichlorobenzene

EC Number:

203-400-5

EC Name:

1,4-dichlorobenzene

Cas Number:

106-46-7

Molecular formula:

C6H4Cl2

IUPAC Name:

1,4-dichlorobenzene

Test material form:

other: solid

Details on test material:

IUCLID4 Test substance: as prescribed by 1.1 - 1.4
purity of 99,9%.

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Age at study initiation: 6-8 weeks
-Mean Weight at study initiation: males 176g; females: 114g
- Fasting period before study:
- Housing: individuelly
- Diet ad libitum
- Water ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 55
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 1

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Groups of 10 male and 10 female rats redeived once daily by gavage, 7 days per week 13 weeks different doses of testsubstance dissolved in conrn oil ,

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 wk

Frequency of treatment:

once daily, 7 days per week.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 75, 150, 300 or 600 mg/kg bw /d
Basis:

No. of animals per sex per dose:

10 male and 10 female rats per each dose. (0, 75, 150 300 600 mg/kg bw).

Control animals:

yes, concurrent vehicle

Details on study design:

Groups of 10 male and 10 female rats redeived once daily by gavage, 7 days per week 13 weeks different doses of testsubstance dissolved in conrn oil , interim kill of 5 rats/sex/dose was performed after 5 experimental weeks. Post-exposure period: none

Positive control:

no

Examinations

Observations and examinations performed and frequency:

The experimental animals were inspected twice daily.
The body weight of the experimental animals was recorded at the start of the study and weekly thereafter.
Laboratory investigations of blood and urine samples were performed after 2 and 8 days and after 4 and 12 weeks in 5 animals per dose and sex.

Sacrifice and pathology:

interim kill after 5 experimental weeks; terminal killl after the end of treatment
animals were subjected to makroscopical examination, organ weight determination and histopathological evaluation mainly of kidney tissue

Statistics:

arithmetic group mean values, significance test (U test) according to Mann and Whitney

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

Food efficiency:

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Details on results:

A study (GLP) focusing on the effects on the lidney during the oral administration by gavage of the test substance in F344 rats was carried out during 13 weeks. Following doses were tested: 75, 150, 300 or 600 mg/kg bw d. No substance related effects on mortality, clinical signs, food consumption or growth in male or female rats were observed. A dose-dependent increased water consumption in all treated males from 20% (75 mg/kg) to 40% (600 mg/kg) was seen and slightlyelevated water intake (23%) in females at 600 mg/kg were noticed. No evidence of a dose-related pathological condition at any time in treated rats of either sex regarding hematological and clinical-chemical parameters could be seen. An increased urinary lactate dehydrogenase and epithelial cell excretion and exacerbation of hyaline droplet accumulation in the cytoplasm of renal cortical cells in male rats in all treated groups was noticed; further a tubular single cell necrosis, dilated tubules with granular cast formation in male rats after 4 and 13 weeks at 150 to 600 mg/kg was observed. There was no indication of a nephrotoxic action in females. The effects on the kidney in males correspond to the light hydrocarbon nephrotoxicity. The NOAEL was found to be <75 mg/kg bw/day.

Effect levels

Dose descriptor:

NOAEL

Effect level:

< 75 mg/kg bw/day (nominal)

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

One male in both the 300 and the 600 mg/kg dose group died.

Mortality was not increased by treatment, because the pathological-anatomical findings suggest that inadvertent insertion of the stomac tube into the lung may be the cause of death.

Applicant's summary and conclusion

Executive summary:

A study (GLP) focusing on the effects on the lidney during the oral administration by gavage of the test substance in F344 rats was carried out during 13 weeks. Following doses were tested: 75, 150, 300 or 600 mg/kg bw d. No substance related effects on mortality, clinical signs, food consumption or growth in male or female rats were observed. A dose-dependent increased water consumption in all treated males from 20% (75 mg/kg) to 40% (600 mg/kg) was seen and slightlyelevated water intake (23%) in females at 600 mg/kg were noticed. No evidence of a dose-related pathological condition at any time in treated rats of either sex regarding hematological and clinical-chemical parameters could be seen. An increased urinary lactate dehydrogenase and epithelial cell excretion and exacerbation of hyaline droplet accumulation in the cytoplasm of renal cortical cells in male rats in all treated groups was noticed; further a tubular single cell necrosis, dilated tubules with granular cast formation in male rats after 4 and 13 weeks at 150 to 600 mg/kg was observed. There was no indication of a nephrotoxic action in females. The effects on the kidney in males correspond to the light hydrocarbon nephrotoxicity. The NOAEL was found to be <75 mg/kg bw/day.