E X T O X N E T
Extension Toxicology Network
A Pesticide Information Project of Cooperative Extension Offices of
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University of California at Davis. Major support and funding was provided
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Pesticide
Information
Profile
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Warfarin
Publication Date: 9/95
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TRADE OR OTHER NAMES
The active ingredient warfarin is found in a variety of commercial
rodenticides. Some trade names for products containing warfarin include Cov-R-
Tox, Co-Rax, d-Con, Dethmor, Mar-Fin, Rattunal, Rax, Rodex, Rodex Blox, Rosex,
Solfarin, Tox-Hid, Warf, and Warfarat (3, 4, 11). Warfarin is called coumafene
in France, zoocoumarin in the Netherlands and Russia, and coumarin in Japan
(1, 3, 8).
REGULATORY STATUS
Warfarin is a general use pesticide (GUP). Check with specific state
regulations for local restrictions which may apply. The Signal Word for
technical and high concentrations of warfarin is "Danger". The Signal Word
"Caution" is used for low concentrations and ready-to-use baits (3).
INTRODUCTION
Warfarin was the first anticoagulant rodenticide introduced and was first
registered for use in the United States in 1952 (4, 13). Warfarin is used for
controlling rats and house mice in and around homes, animal and agricultural
premises, and commercial and industrial sites. It is odorless and tasteless
and effective in very low dosages. Action is not rapid; usually about a week
is required before a marked reduction in the rodent population is noticeable.
Rodents do not tend to become bait-shy after once tasting warfarin; they
continue to consume it until its anti-clotting properties have produced death
through internal hemorrhaging. The prothrombin content of the blood is reduced
and internal bleeding is induced. Repeated ingestion is needed to produce
toxic symptoms. This rodenticide can be used year-after-year wherever a
rodent problem exists. Mice are harder to control than rats, and complete
control may take a longer period. Recently, resistant strains of rats and mice
are developing (3, 4, 11, 13).
Warfarin comes in water soluble, ready-to-use bait, concentrate, powder,
liquid concentrate, nylon pouch, coated talc and dust formulations. The
compound also comes in mixed formulations with pindone, calciferol, and
sulphaquinoxaline. It is considered compatible with other rodenticides (1, 2, 3).
Warfarin is only slightly dangerous to humans and domestic animals when
used as directed, but care must be taken with young pigs, which are especially
susceptible (1).
TOXICOLOGICAL EFFECTS
ACUTE TOXICITY
The amount of Warfarin that is lethal to one-half (50%) of experimental
animals fed the material is referred to as its acute oral lethal dose fifty,
or LD50. The acute oral toxicity for warfarin in rats is variously reported
to be 3 mg/kg (3, 4, 6, 7, 11, 12);
1,600 ug/kg (5); 186 mg/kg (Hartley and
Kidd, 1987) (7, 11); 58 mg/kg in female rats (9, 12). The acute oral LD50 for
rats over 4-5 days is 1 mg/kg/day (1, 2). There was no development of
ingestion tolerance indicated regardless of rodent sex or age (3).
The acute oral LD50 for technical sodium warfarin in rats was 323 mg/kg
for males and 58 mg/kg for females (12). A single, large dose of warfarin is
about as toxic as a single, small dose. On a multiple-dose basis, the reported
LD100 for rats is 0.2 mg/kg/day for 5 days (4, 11).
The dermal LD50 for rats was 1,400 mg/kg; 420 mg/kg intraperitoneal LDlo
(Lethal Dose, Low. The lowest dose which causes death in test animals.); and
320 mg/m3 inhalation LC50 (5). The same source indicated the acute oral LD50
for mice was 60 mg/kg; 800 mg/kg subcutaneous LDlo; and 165 mg/kg intravenous
LD50 (5).
Toxicity values for warfarin in other animals are: an oral LD50 for cats
of 2.5-20 mg/kg (6, 12); an acute oral LD50 of 35 mg/kg for a single dose or
3 mg/day for 5 days (1, 2); and 12 mg/kg oral LDlo (5). The acute oral LD50
for dogs exposed to warfarin was 3 mg/kg/day for 5 days (1). Technical sodium
warfarin in dogs had an LD50 of 200-300 mg/kg (12). The acute oral LD50 for
warfarin in cattle was 200 mg/kg/day for 5 days (1). The LD50 for technical
sodium warfarin in guinea pigs was 182 mg/kg (12). The oral LDlo for warfarin
in pigs was reported to be 1,200 ug/kg (5). Death followed 5 daily doses of 1
mg/kg for pigs (2, 11).
Studies done on rabbits indicated the dermal LD50 of warfarin to be
greater than 8 g/kg (6, 12). Technical sodium warfarin in rabbits had an LD50
of 800 mg/kg. Rabbits exhibited mild to slight conjunctival irritation in
response to technical warfarin (12).
Toxicity values for humans exposed to warfarin indicated an oral-woman
TDlo of 15 mg/kg/21 weeks intermittent; 10,200 ug/kg oral-man TDlo; and 6,667
mg/kg oral-human LDlo. Average or large doses of warfarin in humans may cause
hemorrhage (9). Warfarin is not known to be an eye irritant. It has produced
hemorrhages in the retina, however, through its systemic toxicity (11). The
compound is considered highly toxic by inhalation and ingestion and moderately
toxic by dermal absorption. A dose of warfarin at 200 mg/m3 is considered
highly toxic and immediately dangerous to life or health (5).
CHRONIC TOXICITY
A farmer whose hands were intermittently wetted with a 0.5% solution of
warfarin over a period of 24 days developed gross hematuria two days after the
last contact with the solution; the following day, spontaneous hematomas
appeared on the arms and legs. Within four days, there were also epistaxis,
punctate hemorrhages of the palate and mouth, and bleeding from the lower lip.
The bleeding time was over 30 minutes; the clotting time was 11 minutes and 30
seconds; the prothrombin index was 17; and the prothrombin percentage
(thrombotest) was 5. Four days later, after treatment for two days with
phytonadione, the values were in the normal range (11).
Another source indicated that two human fatalities occurred after
ingesting 0.25% warfarin on corn meal over 15 days (12).
Reproductive Effects
No information currently available.
Teratogenic Effects
Warfarin has been established as a human teratogen, because it causes
birth defects in the offspring of women receiving clinical doses of the
compound during any trimester of pregnancy. Therapeutic use by pregnant women
has resulted in fatal hemorrhaging of the fetus and malformations and mental
retardation in infants. However, the amount of warfarin contained in the
rodenticide bait is very low. A single ingestion of warfarin-treated bait by
an adult female would not be likely to cause teratogenic effects (5, 13, 12).
Other studies also indicated fetal abnormalities in humans exposed to
clinical sodium warfarin (12).
Mutagenic Effects
No information currently available.
Carcinogenic Effects
No information currently available.
Organ Toxicity
Warfarin causes organ damage by inhibiting blood coagulation (1).
Absorption by the lungs may result in hemorrhagic effects (5).
Animals killed by warfarin exhibit extreme pallor of the skin, muscles,
and all the viscera. In addition, evidence of hemorrhage may be found in any
part of the body but usually only in one location in a single autopsy. Such
blood as remains in the heart and vessels is grossly thin and forms a poor
clot or no clot (8, 10). Rats injected intraperitoneally with 14C-warfarin
excreted approximately 90% of the activity in 14 days, about half in the urine
and half in the feces (8).
Symptoms of human exposure to warfarin include hematuria, back pain,
hematoma in arms and legs, bleeding lips, mucous membrane hemorrhage,
abdominal pain, vomiting, and fecal blood.
One source stated that serious illness was induced by the ingestion of
1.7 mg of warfarin/kg/day for 6 consecutive days with suicidal intent. This
would correspond to eating almost 1 pound of bait (0.025% warfarin) each day
for 6 days. All signs and symptoms were caused by hemorrhage and, following
multiple transfusions and massive doses of vitamin K, recovery was complete
(10).
Fate in Humans and Animals
When 9 normal men and 5 normal women were given a single oral dose of 1.5
mg/kg warfarin, maximal concentration in plasma was reached in 2 to 12 hours.
Maximal depression of prothrombin activity was between 36 and 72 hours. Their
individual increases in prothrombin time were proportional to their half-times
for disappearance of the warfarin from plasma. In other words, the
pharmacological effect was greatest in those with slower excretion. The half-
times for disappearance from the plasma varied from 15 to 58 hours with an
average of 42 hours. Absorption of warfarin from the gastrointestinal tract
was apparently complete; no warfarin was found in the stool even after massive
doses, and plasma levels and prothrombin activity responses were virtually
identical following oral and intravenous administration at the same rates (8).
Warfarin is readily absorbed by the gastrointestinal tract; absorption in
man requires about 3 hours as indicated by a comparison of the rate of action
of oral and intravenous doses (10).
Another study indicated that 96 hours after intraperitoneal injection of
warfarin, the concentrations of activity in the kidney, liver, and pancreas
were 3, 12, and 15 times, respectively, greater than that in the blood (8).
Metabolites in animals include 4-, 6-, 7- and 8-hydroxycoumarin (1, 8).
ECOLOGICAL EFFECTS
Effects on Birds
The acute avian toxicity of warfarin indicates that it is practically
non-toxic to game birds. In subacute studies, warfarin ranged from moderately
toxic to practically non-toxic to upland game birds and waterfowl (13).
Another source indicated that an acute oral mallard duck study was performed
with a 10% formulation of warfarin. This formulation of warfarin was
considered moderately toxic to mallard ducks (LC50 greater than 120 mg/kg)
when administered as a single dose. However, when exposed to 60 mg/kg for a
period of 14 days, 4 out of 5 ducks died (12).
Chickens are relatively resistant to warfarin (4).
Effects on Aquatic Organisms
The toxicity of warfarin to aquatic organisms is felt to be of low
potential due to the fact that warfarin is insoluble in water. A long field
experience shows no potential hazards to aquatic organisms (13).
A 96-hour rainbow trout study was performed using a 0.54% formulation of
warfarin sodium salt. With a 96-hour LC50 of greater than 10,000 ppm, this
formulation is considered non-toxic to rainbow trout (12).
Effects on Other Animals (Nontarget species)
Warfarin used as a prepared bait (0.13%) is considered non-toxic to bees
when used as prescribed (1, 3).
The use of warfarin as a hand-placed bait limits the potential for any
secondary exposure of nontarget animals. However, because of its high degree
of mammalian toxicity and its use patterns, warfarin could adversely affect
endangered or threatened species (13). One study exists on a 50/50 percent
formulation of warfarin-sulfaquinoxaline technical. The warfarin-
sulfaquinoxaline caused secondary poisoning in mammalian carnivores such as
mink and dogs when ingesting prey killed after they were provided with treated
bait (carrots containing 0.025% by weight of the test material). The first
death occurred after 8 days of continuous exposure to treated nutria (12).
A study by Bucklew et al. investigated the short-term influence of
warfarin on the growth of the gram-positive spore-forming soil microorganism,
Bacillus megaterium. Impregnation of paper disks and subsequent measurement of
the zones of growth inhibition showed that spore germination for this
bacterium was not affected by the presence of warfarin for 15-21 hours at 21
degrees C and at concentrations as high as 1 mg/ml (about 1,000 ppm) (12).
ENVIRONMENTAL FATE
Breakdown of Chemical in Soil and Groundwater
No information currently available.
Breakdown of Chemical in Surface Water
No information currently available.
PHYSICAL PROPERTIES AND GUIDELINES
Exposure Guidelines:
| TLV-TWA: | 0.1 mg/m3 (OSHA) (3, 7, 11) |
| STEL: | 0.3 mg/m3 (11) |
Physical Properties:
| CAS No.: | 81-81-2 |
| Chemical name: | 4-hydroxy-3-(3-oxo-1-phenylbutyl)coumarin; 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one (1, 2) |
| Chemical Class/Use: | Rodenticide, anticoagulant |
| Specific gravity: | greater than 1 (5) |
| Solubility in water: | Practically insoluble (1.7 mg/100 ml at 20 degrees C) (1, 5, 9) |
| Solubility in other solvents: | Soluble to very slightly soluble in acetone, benzene, ethanol, ether, toluene, xylene, methyl ethyl ketone and cyclohexane.
Moderately soluble in methanol, ethanol, and isopropanol.
In acetone 6.5, chloroform 5.6, dioxane 10.0 (all in g/100 ml at 20 degrees C).
Dissolves in aqueous alkalis with the formation of water-soluble salts (1, 2, 7, 8, 9) |
| Melting point: | 161-162 degrees C (1, 7); 159-165 degrees C (3); 318-322 degrees F (5) |
| Boiling point: | decomposes (7, 11) |
| Vapor pressure: | 9 x 10 to the minus 2 mbar at 21.5 degrees C |
| Koc: | 2.96 (calculated) (7) |
| Kow: | 3.20 (calculated) (7) |
BASIC MANUFACTURERS
HACCO, Inc.
P. O. Box 7190
537 Atlas Avenue (53714)
Madison, WI 53707
Phone: 608-221-6200
Fax: 608-221-6208
Review by Basic Manufacturer:
Comments solicited: November, 1994
Comments received:
Prentiss, Inc.
CB 2000
Floral Park, NY 11001
Phone: 516-326-1919
Fax: 516-326-2312
Review by Basic Manufacturer:
Comments solicited: November, 1994
Comments received:
REFERENCES
The Agrochemicals Handbook. 1983. The Royal Society of Chemistry, The
University, Nottingham, England.
Worthing, C. R. (ed.). 1983. The Pesticide Manual: A World Compendium.
Seventh edition. Published by The British Crop Protection Council.
Farm Chemicals Handbook. 1994. Meister Publishing Co. Willoughby, OH.
Thomson, W.T. 1991. Agricultural Chemicals. Book III: Rodenticides.
Thomson Publications, Fresno, CA.
OHS Database. 1994. Occupational Health Services, Inc. 1994 (June)
MSDS for Warfarin. OHS Inc., Secaucus, NJ.
U.S. Environmental Protection Agency. 1989. Office of Pesticides. TOX
Oneliners -- warfarin. July, 1989.
Montgomery, J. H. 1993. Agrochemicals Desk Reference: Environmental
Data. Lewis Publishers. Chelsea, MI.
Hayes, W. J. Jr. 1982. Pesticides Studied in Man. Williams and
Wilkins. Baltimore, MD.
Windholz, M. (ed.) 1983. The Merck Index. Tenth edition. Rahway, NJ.
Merck and Company.
Hayes, W. J., Jr. 1963. Clinical Handbook on Economic Poisons:
Emergency Information for Treating Poisoning. US Department of Health,
Education, and Welfare, Public Health Service, Communicable Disease Center,
Toxicology Section. Atlanta, Georgia.
Pesticide Management and Education. An on-line pesticide information
database in CENET, Cornell Cooperative Extension Network. Cornell University,
Ithaca, NY.
United States Environmental Protection Agency. August, 1981. Warfarin
and Its Sodium Salt: Pesticide Registration Standard. USEPA, Office of
Pesticides and Toxic Substances. Washington, DC. 193 pp.
U.S. Environmental Protection Agency. June, 1991. R.E.D. Facts:
Warfarin. USEPA, Office of Pesticides and Toxic Substances. Washington, DC.
Disclaimer: Please read
the pesticide label prior to use. The information contained at this web
site is not a substitute for a pesticide label. Trade names used herein
are for convenience only; no endorsement of products is intended, nor is
criticism of unnamed products implied. Most of this information is historical
in nature and may no longer be applicable.
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