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Toxicological information

Specific investigations: other studies

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Administrative data

Endpoint:
hepatotoxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: acceptable, well-documented publication report which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
The differential hepatotoxicity and cytochrome P450 responses of Fischer-344 rats to the three isomers of dichlorobenzene
Author:
Allis, J.W. et al.
Year:
1992
Bibliographic source:
J. Biochem. Toxicology 7, 257-264 (1992)

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
The acute hepatotoxicity and response of hepatic cytochrome P450 to treatment of 1,2-dichlorobenzene was investigated. Therefore, F-344 rats (one animal per dose level) were gavaged with up to 25 different dosages of 1,2-dichlorobenzene. The onset of toxicity was estimated and the role of cytochrome P450 in the metabolism and toxicity was elucidated in rats 24h after treatment.

GLP compliance:
not specified
Type of method:
in vivo

Test material

Constituent 1
Chemical structure
Reference substance name:
1,2-dichlorobenzene
EC Number:
202-425-9
EC Name:
1,2-dichlorobenzene
Cas Number:
95-50-1
Molecular formula:
C6H4Cl2
IUPAC Name:
1,2-dichlorobenzene
Details on test material:
- Analytical purity: 99%

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles RIver Laboratories, Raleigh, NC
- Age at study initiation: 60-days-old
- Weight at study initiation: results not reported
- Housing: individually
- Diet: Purina Rodent Lab Chow (Number 5001, Ralston Purina, Checkerboard Square, MO)
- Water (e.g. ad libitum): yes
- Acclimation period: 5-8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +- 2
- Humidity (%): 55 +- 5
- Photoperiod (hrs dark / hrs light): 12h

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Amount of vehicle (if gavage): 10mL/kg bw
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
24h
Frequency of treatment:
once
Post exposure period:
none
Doses / concentrations
Remarks:
Doses / Concentrations:
up to 25 different dosages, up to 1.27mL/kg bw (about 1784mg/kg bw)
Basis:
other: nomimal dose
No. of animals per sex per dose:
one
Control animals:
yes, concurrent vehicle

Examinations

Examinations:
24h after dosing, rats were anesthetized, weighed and exsanguinated. Blood was centrifuged and serum concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase were determined by commercial assays. After weighing of livers, slices were removed for histopathological examination. Microsomes were prepared after homogenization and centrifugation of about 2g liver. In addition, meta- and para-dichlorobenzene were investigated concurrently.
Positive control:
Not reported

Results and discussion

Details on results:
The acute hepatotoxicity and response of hepatic cytochrome P450 to treatment with o-dichlorobenzene were investigated in male rats that were gavaged with single doses, then evaluated 24 hours later. Centrilobular hepatic necrosis at the minimal level first appeared at 172mg/kg bw, increased to mild at 246 mg/kg bw and remained at that level for all higher dosages. The activities of aspartate aminotransferase and alanine aminotransferase were increased at 172mg/kg bw, and higher o-dichlorobenzene dosages generally reflected a dose-dependent increase in both enzyme activities. Centrilobular vacuolar degeneration first appeared at 98mg/kg bw, with severity increasing to mild soon thereafter. Hepatic cytochrome P450 levels were decreased from control levels by about 20 % at dosages as low as 75mg/kg bw and at the highest dosages (up to 1784 mg/kg bw) the decrease reached more than 50 %.

Any other information on results incl. tables

Investigated parameters exhibited similar patterns demonstrating that ortho-dichlorobenzene was the most toxic in terms of both earliest onset and degree of response at higher dosages.

Applicant's summary and conclusion

Executive summary:

The acute hepatotoxicity and response of hepatic cytochrome P450 to treatment with the three isomers of dichlorobenzene was investigated. In a study design employing one animal per dose level, F-344 rats were gavaged with up to 25 different dosages (up to 1784mg ortho-dichlorobenzene /kg bw). Preparation and analysis started 24h later after anesthetizing and exsanguination of rats. Hepatic necrosis and vacuolar degeneration were examinated by open light-microscopic histopathological examination of liver slices. Serum alanine aminotransferase and serum aspatate aminotransferase were assayed commercially.

Centrilobular hepatic necrosis at the minimal level first appeared at 172mg/kg bw, increased to mild at 246mg/kg bw and remained at that level for all higher dosages. The activities of aspartate aminotransferase and alanine aminotransferase were increased at 172mg/kg bw, and higher o-dichlorobenzene dosages generally reflected a dose-dependent increase in both enzyme activities. Centrilobular vacuolar degeneration first appeared at 98mg/kg bw, with severity increasing to mild soon thereafter. Hepatic cytochrome P450 levels were decreased from control levels by about 20% at dosages as low as 75mg/kg bw and at the highest dosages (up to 1784mg/kg bw) the decrease reached more than 50%. Ortho-dichlorobenzene produced a dose-dependent decrease in P450 beginning at dosages lower than the onset of necrosis and appeared to be a suicide substante for P450.

Results exhibited similar patterns demonstrating that ortho-dichlorobenzene was the most toxic in terms of both earliest onset and degree of response at higher dosages.

(Allis, J.W. et al., 1992)