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Repeated dose toxicity: oral

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Administrative data

short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: No guideline mentioned, no test substance information

Data source

Reference Type:
Toxic Effects of Warfarin in Rats fed Different Diets
Colvin HW, Wang WL
Bibliographic source:
Toxicology and Applied Pharmacology, 28:pp 337-348

Materials and methods

Test guideline
no guideline followed
GLP compliance:
not specified

Test material

Details on test material:
No data

Test animals

Details on test animals and environmental conditions:
Male Sprague-Dawley rats were used weighing 250-300 g. They were individually caged in a room at 22 degrees C. Two groups were given different
diets. One was Purina Chow ( 23.4% protein, 3.78% fat, 50.58% nitrogen-free extract, 4.86% fiber). The other group was given oat groats ( 12.0%
protein, 6.0% fat, 65.5% nitrogen free extract, 2.0% fiber).

Administration / exposure

Route of administration:
other: Oral feeding needle
other: 0.1 N NAOH
Details on oral exposure:
A 7 day dietary adjustment period preceeded the Warfarin administration. The Warfarin was administered at a dose of 0.8 mg/kg with a rat
oral feeding needle five hours after fasting
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Five days
Frequency of treatment:
Once every 24 hours
Doses / concentrations
Doses / Concentrations:
0.8 mg/ kg
other: Rat oral feeding needle
No. of animals per sex per dose:
30 male rats per dose group
Control animals:
yes, concurrent no treatment
Details on study design:
The lethal dose of warfarin was reported to be 1 mg/kg. When this dose was administered for 5 days, it was found to be excessive. It was found that
most rats would survive the 5 day period if force fed 0.8 mg/kg/day.


Sacrifice and pathology:
Five rats from each group were sacrificed at 0, 5, 29, 53, 77 and 101 hours after the initial warfarin administration. Once anesthetized, the thorax was
opened and blood samples drawn from the still beating heart and heparinized and used for the determination of total plasma protein, hematocrit and plasma protein fractionation. For the second sample, the blood was diluted with 0.1 m sodium citrate in 0.9% NaCl solution. The citrated blood
was centrifuged immediately and the plasma was used for the determination of warfarin, prothrombin time and fibrinogen.
Other examinations:
The livers were excised, weighed and frozen and used to determine warfarin concentrations.
All statistical techniques that were used , were considered in Steel and Torrie (1960).

Results and discussion

Results of examinations

Details on results:
The Plasma warfarin concentration increased more rapidly in the oat-fed rats. However, in the liver warfarin:plasma warfarin ratio following the first dose of warfarin indicated that the chow fed rats were removing the warfarin from the plasma more rapidly. There was less liver damage in the chow-fed rats because they had lower plasma fibrinogen concentrations then the oat-fed group. The linear decline in total plasma protein in each group was a function of linear declines in plasma albumin and globulin.

Effect levels

Dose descriptor:
dose level:
Effect level:
0.8 mg/kg bw/day (nominal)

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

It was concluded that the repeat doses of warfarin was influenced by protein in the diet. Rats fed higher protein diets were more tolerate to warfarin.