2-chloroacetamide

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Only limited details were available from literature, therefore these data are considered relevant, but less adequate and reliable for classification.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1980

Report date:

1979

Materials and methods

Principles of method if other than guideline:

other: not specified

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-chloroacetamide

EC Number:

201-174-2

EC Name:

2-chloroacetamide

Cas Number:

79-07-2

Molecular formula:

C2H4ClNO

IUPAC Name:

2-chloroacetamide

Details on test material:

No data

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 180-200g
- Fasting period before study: In some experiments rats fasted overnight were used
- Diet: Standard laboratory rat diet (Astra-Ewos, R3, with a vitamin E content of 20 mg/kg), ad libitum
- Water: Ad libitum

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

physiological saline

Details on exposure:

Chloroacetamide was administered intraperitoneally as a single dose.

Doses:

75 mg/kg bw

No. of animals per sex per dose:

3 - 5 rats

Control animals:

yes

Details on study design:

The treatment was administered between 8 and 10 AM.

The rats were killed by decapitation and the liver immediately perfused in situ with ice-cold 0.9% NaCI solution
and homogenized in 9 vol of ice-cold 0.15 M KCL. Aliquots of whole homogenate were deproteinized with
1% H3PO4 and 0.6% thiobarbituric acid (TBA) added. The mixture was then heated for 45 min in a boiling water
bath. After cooling TBAreactive material was extracted with n-butanol, and the absorbance at 535 nm of the
organic phase (=TBA value) was determined (Uchiyama and Mihara, 1978).
Hepatic glutathione (GSH) was measured as low molecular weight thiols (Saville, 1958).

Statistics:

from 3-5 rats, mean TBA-values +- SD were plotted vs hours after treatment

Results and discussion

Effect levels

Dose descriptor:

other: Hepatotoxicity

Effect level:

75 mg/kg bw

Mortality:

112.5 mg/kg bw chloroacetamide resulted in a high mortality within 5-6 hrs.

Clinical signs:

A single dosage of 37.5 mg/kg bw had no apparent effect on TBA values or liver morphology.
75 mg/kg bw was nonlethal but induced morphological and biochemical changes.

Gross pathology:

Livers from rats treated with 75 mg/kg usually showed swelling, hydropic degeneration, and single , necrotic hepatocytes.
These alterations appeared to be accentuated in the peripheral and midzonal areas after 6 and 8 hr.
After the high dose (112.5 mglkg bw), three of four of these rats died after 4-5 hr. They exhibited fatty degeneration and extensive necrosis of the centrilobular areas accompanied by leucocytic infiltration. In the periphery of the lobu!e there was pronounced capillary congestion with hemorrhages and disruption of the normal lobular architecture.

Other findings:

3-6 h p.a.: Lesions in the liver parenchyma and enhancement of lipid peroxidation. 24-48 h p.a.: Reversible morphological changes notably hydropic degenerations. GSH content decreased rapidly. 1 h p.a. GSH increased and was slightly higher than normal at 48 and 72 h p.a.. The authors conclude that GSH depletion leads to lipid peroxidation without permanent damage of hepatocytes.

Applicant's summary and conclusion

Conclusions:

The authors’ suggestion that compartmentalization applies to peripheral cells only is supported by the observation
that GSH concentrations are lower in the center than in the periphery of the lobule. (Smith et al. 1979).
The reversible nature of the peripheral lesion indicates that cells in this area have a considerable capacity to
withstand lipid peroxidation.

Executive summary:

Intraperitoneal administration in rats of 75 mg/kg bw Chloroacetamide indicates that hepatic GSH depletion leads to lipid peroxidation, which can be significantly increased without causing permanent damage to hepatocytes.