Warfarin

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: No guideline mentioned, no test substance information

Data source

Reference

Reference Type:

publication

Title:

Toxic Effects of Warfarin in Rats fed Different Diets

Author:

Colvin HW, Wang WL

Year:

1974

Bibliographic source:

Toxicology and Applied Pharmacology, 28:pp 337-348

Materials and methods

Test guideline

Qualifier:

no guideline followed

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Warfarin

EC Number:

201-377-6

EC Name:

Warfarin

Cas Number:

81-81-2

Molecular formula:

C19H16O4

IUPAC Name:

4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one

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:

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

Vehicle:

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

Remarks:

Doses / Concentrations:
0.8 mg/ kg
Basis:
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.

Examinations

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.

Statistics:

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)

Sex:

male

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

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.