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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:
other information
Study period:
no data
Reliability:
3 (not reliable)

Data source

Reference
Reference Type:
publication
Title:
Effects on growth and metabolism of rat liver by halothane and its metabolite trifluoroacetate
Author:
Stier, A.; Kunz, H.W.; Walli, A.K. and Schimassek, H.
Year:
1972
Bibliographic source:
Biochemical Pharmacology, 21:2181-2192

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
TFA was administered with the drinking water for 5-6 days. Analysis of fluorine content and biochemical procedures were done to evaluate the effects of TFA on liver growth and metabolism.
GLP compliance:
no
Type of method:
in vivo
Endpoint addressed:
basic toxicokinetics

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Trifluoroacetate (TFA)
- Analytical purity: no data
- Composition of test material, percentage of components: no data

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 200-260 g
- Fasting period before study: no data
- Housing: no data
- Diet: standard commercial rat diet ("Altromin", Lage-Lippe, Germany) ad libitum
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS: no data

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
TFA was neutralized with NaOH
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
5-6 days
Frequency of treatment:
Administered with drinking water
Post exposure period:
No
Doses / concentrations
Remarks:
Doses / Concentrations:
130 µmoles TFA/100 g bw/day
Basis:
nominal in water
No. of animals per sex per dose:
No data
Control animals:
yes
Details on study design:
Every day, two to three rats were removed from the experimental series and killed under ether anaethesia. The series were repeated and the data quoted in the tables represent mean values established on four to six animals per day.

Examinations

Examinations:
In liver: determination of substrates, ATP, ADP, AMP, enzymes, protein, glycogen and neutral fat. Total fluorine content was also determined.
Positive control:
No

Results and discussion

Details on results:
The relative liver weight had increased by 43 % after 5 days of TFA treatment. Total protein content did not change but a 20 % decrease in glycogen content was noted. No change in neutral fat was observed. The most strinking changes in enzymes activities were a 42 % decrease in pyruvate kinase and a 125 % rise in glycerol-1-phosphate oxidase activity. TFA did not augment the acticity of NADPH oxydase.
Between day 1 and day 4-5 of treatment, there was a fall in the level of triose phosphates, with greater decreases in lactate and pyruvate. These changes in substrates levels were apparent after only 1 day of TFA administration, indicating its rapid action on liver. In some of the treated animals a rise in the intracellular content of malate and alpha-ketoglutarate in liver was noted after the fifth day of treatment. The content of glucose and total adenine nucleotides and the ATP-ADp ratio did not change.

Any other information on results incl. tables

The amount of organically bound fluorine in plasma and liver reached a steady level on the second day with a ration 1:1 ratio of liver to plasma concentration, which declined on days 4 and 5. Inorganic fluoride amounted to less than 1 % of total fluorine. The average daily amount of TFA taken up from the drinking water by a rat weighing 200 g is about 260 µmoles. Thus the fluorine content of the liver or of the plasma represents about 10 % of the administered amount of TFA.

Applicant's summary and conclusion

Conclusions:
The liver enlargement observed conforms to a co-ordinated growth of hepatic cells including the protein content and some enzyme activities.
Executive summary:

In this study, TFA was administered to males Wistar rats for 4 -5 days in drinking water at dose level of 130 µmoles/100 g bw/day. Relative liver weight; content of protein, glycogen and neutral fat in livers; activities of some important enzymes in rat livers and content of some important substrates in liver were measured during the study (2 to 3 animals evaluated per day).

TFA causes as much as 40 % enlargement of liver within 4 -5 days. This liver enlargement conforms to a co-ordinated growth of hepatic cells including the protein content and some enzyme activities. There is a marked decrease in the activity of pyruvate kinase and an increase of glycerol 1 -phosphate oxidase. TFA causes a decrease in phosphorylated trioses common to glycolysis and gluconeogenesis, but an increase in certain tricarboxylic acid cycle intermediates.