الوارفارين

موضوع: الوارفارين الجمعة يناير 01, 2010 8:14 am

الوار فارين

WORLD HEALTH ORGANIZATION FOOD AND AGRICULTURE
ORGANIZATION
ORGANISATION MONDIALE DE LA SANTE ORGANISATION POUR L'ALIMENTATION
ET L'AGRICULTURE

VBC/DS/78.35
ORIGINAL: ENGLISH

WARFARIN

CLASSIFICATION:
Primary Use: Rodenticide
Secondary Use: Medical
Chemical Group: Hydroxycoumarin compound
Date Issued:

It must be noted that the issue of a Data Sheet for a
particular pesticide does not imply endorsement of the pesticide by
WHO or FAO for any particular use, or exclude its use for other
purposes not stated. While the information provided is believed to
be accurate according to data available at the time when the sheet
was compiled, neither WHO nor FAO are responsible for any errors or
omissions, or any consequences therefrom.

The issue of this document does Ce document ne constitue pas une
not constitute formal publication. Il ne doit faire
publication. It should not be l'objet d'aucun compte rendu ou
reviewed, abstracted or quoted résumé ni d'aucune citation sans
without the agreement of the l'autorisation de l'Organisation
Food and Agriculture des Nations Unies pour
Organization of the United l'Alimentation et l'Agriculture
Nations or of the World Health ou de l'Organisation Mondiale de
Organization. la Santé.

CLASSIFICATION:

Primary Use: Rodenticide

Secondary Use: Medical

Chemical Group: Hydroxycoumarin compound

Date Issued:

1. GENERAL INFORMATION

1.1 COMMON NAME: Warfarin (ISO)

1.1.1 Identity: 4-hydroxy-3-(3-oxo-l-phenylbutyl)-2H-1-benzopyran-2-
one

1.1.2 Synonyms:
WARF 42
Athrombine-K
Coumadin
Coumafene
Zoocoumarin

Local synonyms:

1.2 SYNOPSIS - An anticoagulant rodenticide that is highly toxic to
mammals on repeated ingestion, but of variable toxicity to
different species when given-as a single acute oral dose. It
does not accumulate in body tissues.

1.3 SELECTED PROPERTIES

1.3.1 Physical characteristics - Colourless, tasteless, and odourless
crystals of m.p. 159-161°C.

1.3.2 Solubility - Of a low solubility in water, benzene, cyclohexane
and hexane. Moderately soluble in alcohol and methanol and
readily soluble in acetone and dioxane.

1.3.3 Stability - The sodium salt of warfarin is relatively stable.

1.3.4 Vapour pressure - No information.

1.4 AGRICULTURE, HORTICULTURE AND FORESTRY

1.4.1 Common formulations - Powdered concentrates containing 0.5%
warfarin for mixture in ratio 1:19 with protein rich bait, e.g.
cornmeal, oatmeal, dogmeal, stockfeed; also 1% dusts.

1.4.2 Susceptible pests - A broad range of rodent species. Resistance
to this compound has developed in geographically widely
scattered rat populations, based on changes in vitamin K
metabolism.

1.4.3 Use pattern - Used in rodent holes and runs as bait or dusts.
Baiting should be continued for 14 days.

1.4.4 Unintended effects - No information.

1.5 PUBLIC HEALTH PROGRAMME: Widely used as a rodenticide: see
above 1.4.2

1.6 HOUSEHOLD USE: May be used as a household rodenticide, usually
at concentrations of 0.005% to 0.25% w/w.

2. TOXICOLOGY AND RISKS

2.1 TOXICOLOGY - MAMMALS

2.1.1 Absorption route - Absorbed from the gastrointestinal tract and
by inhalation; absorbed to a much lesser extent through the intact
skin.

2.1.2 Mode of action - Warfarin, possible as the 4-hydroxycoumarin
moiety, inhibits the formation of prothrombin by replacing
vitamin K in the complex and so reduces the clotting capacity of
blood; it also increases capillary permeability.

2.1.3 Excretion products - Warfarin is metabolised by the liver.
Excretion by the rat after intraperitoneal dosage, is two-thirds
via the urine and one-third via the faeces. The metabolites
found include warfarin itself, 4, 6, 7 and 8 hydroxy coumarins
and 2,3-dihydro-2-methyl-4-phenyl-5-oxo- e-pyrano (3,2-CX1)
benzopyran. 7 and 4 hydroxycol-arins make up approximately 56%
of the metabolites in urine.

2.1.4 Toxicity, single dose

Oral: LD50 rats (M) 323 mg/kg
rats (F) 58 kg/kg
in aqueous suspension

LD50 rats (M) 3.0 mg/kg
dissolved in peanut oil

From a single dose, the maximum effect on the prothrombin level
is seen at 4 days: spontaneous recovery to normal occurs at about
8 days.

Most susceptible species: probably the pig. Deaths have been
recorded in this species at 5.0, 10.0 and 30.0 mg/kg.

2.1.5 Toxicity, repeated doses

Oral: The 5 day, repeated dose, oral LD50 is given as:

Pig 0.4 mg,/kg/day
Rat 1.0 mg,/kg/day
Cat and dog 3.0 mg,/kg,/day
Poultry 10.0 mg,/kg/day

Inhalation: No information available.

Cumulation of compound: Warfarin does not accumulate to any
extent in body tissues; most is excreted within two days after
an intraperitoneal dose; after seven days only trace amounts can
be found in urine.

Cumulation of effect: Repeated ingestion of warfarin causes a
drastic lowering of prothrombin levels and is the basis of its
rodenticidal action.

2.1.6 Dietary studies

Short-term: Four rats of both sex survived for eight months when
fed at a level of 1 mg/kg diet; 6.25 mg/kg diet proved fatal to
all the rats with the mean survival time 10.7 days. Deaths in
pigs have been recorded at eight daily doses at 0.2 mg/kg bw.
Three out of four dogs survived 175 days feeding experiments at
levels of 10 mg/kg diet. Two dogs out of four survived for 220
days when fed at 20 mg/kg diet.

Long-term: No information available.

2.1.7 Supplementary studies of toxicity

Increased susceptibility to warfarin toxicity has been observed
during pregnancy in dogs, with foetal death. It is probable that
warfarin can cross the placenta and is secreted in the milk.
Deaths in foetuses and newborn have been due to haemorrhage;
some resorptions were observed.

2.1.8 Modification of toxicity - Predosing with phenobarbitone,
chlorinated hydrocarbons or other enzyme inducers may decrease
the toxicity by a factor of 10 by increasing the rate of
metabolism of warfarin.

2.2 TOXICOLOGY - MAN

2.2.1 Absorption - Warfarin may be absorbed from the gastrointestinal
tract or by inhalation, and to a much lesser extent, through the
intact skin.

2.2.2 Dangerous doses

Single: Acute poisoning from a single dose contained in a bait
is unlikely.

Repeated: 1-2 mg/kg for periods of 6-15 days has caused serious
illness and death in man. Serious illness was induced by the
ingestion of 1.7 mg/kg,/day for six consecutive days with
suicidal intent. All signs and symptoms were caused by
haemorrhage.

2.2.3 Observations of occupational exposed workers - No information
available.

2.2.4 Observations of exposure of the general population - No exposure
of the general population to warfarin should occur when used
correctly.

2.2.5 Observations of volunteers - Warfarin has been used in human
therapy as anticoagulant. A single intravenous dose of 1 mg/kg
increases the prothrombin time within 14 hours. In the
treatment of thromboembolic disease, a dose of 5-10 mg/day may
be required to keep the prothrombin level at 10-30% of nomal.
Patients have been thus maintained for years. Dematologic side
effects have been observed in patients undergoing warfarin
therapy.

2.2.6 Reported mishaps - A family of 14 persons lived for 15 days on a
diet consisting almost entirely of cornmeal containing warfarin.
The dosage was determined as 1-2 mg/kg/day. As a result of this
exposure and without treatment, two of the 1. persons died.

2.3 TOXICITY TO NON-MAMMALIAN SPECIES

2.3.1 Fish - No information available

2.3.2 Birds - Moderately toxic

2.3.3 Other species - No data available

3. FOR REGULATORY AUTHORITIES - RECOMMENDATIONS OF REGULATIONS OF
COMPOUND

3.1 RECOMMENDED RESTRICTIONS ON AVAILABILITY

(for definition of categories, see introduction)

All formulations Category 4 except pre-prepared baits,
Category 5

3.2 TRANSPORTATION AND STORAGE

All formulations should be stored in clearly labelled, sealed
containers under lock and key, secure from access by
unauthorized persons or children. No food or drink should be
stored in the same compartment.

3.3 HANDLING

All formulations - Adequate washing facilities should be
available at all times during handling and should be close to
the site of handling. Eating, drinking and smoking should be
prohibited during handling and before washing after handling.
Warfarin baits should be removed when their purpose has been
fulfilled.

Pre-prepared baits - No facilities other than those for handling
of any chemical need be required.

3.4 DISPOSAL AND/OR DECONTAMINATION OF CONTAINER

All formulations - Containers must either be crushed and buried
below the topsoil or burned. Care must be taken to avoid
subsequent contamination of water sources. Decontamination of
containers in order to use them for other purposes should not be
pemitted.

3.5 SELECTION, TRAINING AND MEDICAL SUPERVISION OF WORKERS

All formulations - Pre-employment and routine medical
examination of workers desirable. Special account should be
taken of the workers' mental ability to comprehend and follow
instructions.

3.6 ADDITIONAL REGULATIONS RECOMMENDED IF DISTRIBUTED BY AIRCRAFT

All fomulations - Not applicable.

3.7 LABELLING

All formulations - Minimum cautionary statement: Warfarin is a
toxic substance. Do not inhale dust. Keep this material or
baits containing it, out of reach of children and domestic
animals and well away from foodstuffs, animal feed and their
containers.

3.8 RESIDUES IN FOOD

3.8.1 Maximum residue levels - The Joint FAO/WHO Meeting on Pesticide
Residues has not recommended any maximum residue level. If used
correctly as a bait, residues of warfarin will not appear in
human food.

4. PREVENTION OF POISONING IN MAN AND EMERGENCY AID

4.1 PRECAUTIONS IN USE

4.1.1 General - Warfarin is an anticoagulant rodenticide which is
highly toxic on repeated ingestion. It is readily absorbed by
the gastrointestinal tract and by inhalation but not very
readily through the intact skin.

4.1.2 Manufacture and formulation - TLV: (ACGIH) 0.I/mg/m3 (USSR).
Closed system and forced ventilation may be required to reduce
as much as possible the exposqre of workers to the chemical.

4.1.3 Mixers and applicators - Particularly when opening the container
and when mixing baits, Tlean overalls and gloves should be worn.
Contact with the mouth should be avoided. Particular care is
needed when equipment is being washed after use. Before eating,
drinking or smoking, hands and other exposed skin should be
washed. Baits should not be used where there is a risk of
contaminating food, animal feeding stuffs, or drinking or
washing water. Exposed baits should be laid in containers
clearly marked. Poison baits should not be laid unless all
access by children or domestic animals can be prevented. All
exposed baits and their containers should be removed after
treatment and burned. Rodent bodies should be searched for and
destroyed by burning.

4.1.4 Other associated workers (including flagmen in aerial
operations) - not applicable.

4.1.5 Other populations likely to be affected - With correct use as
described under mixers and applicators (4.1.3 above) other
populations will not be exposed to hazardous amounts of
warfarin.

4.2 ENTRY OF PERSONS INTO TREATED AREAS - Care should be taken that
children and animals cannot gain access to exposed baits.

4.3 DECONTAMINATION OF SPILLAGE AND CONTAINERS - Residues in
containers should be emptied into a deep pit, taking care to
avoid contamination of ground waters. Decontamination of
containers to use them for other purposes should not be
permitted. Spillage should be removed as much as possible into
a deep dry pit and the remainder washed away with large
quantities of water.

4.4 EMERGENCY AID

4.4.1 Early symptoms of poisoning - Acute poisoning from a single dose
of warfarin is unlikely. On repeated exposure symptoms may
occur from the sixth or seventh day and include back and
abdominal pain followed by vomiting, nose and gum bleeding,
massive bruising and haematoma fomation.

4.4.2 Treatment before person is seen by a physician, if these
symptoms appear following exposure - Medical help should be
obtained. Vitamin KI is a specific antidote.

5. FOR MEDICAL AND LABORATORY PERSONNEL

5.1 MEDICAL DIAGNOSIS AND TREATMENT IN CASES OF POISONING

5.1.1 General information - Warfarin is an anticoagulant rodenticide
normally used in bait form. It is readily absorbed from the
gastrointestinal tract and by inhalation and to a much lesser
extent through the intact skin. Its main toxic hazard is from
repeated exposure. It inhibits prothrombin formation with a
resultant decrease in the clotting capacity of the blood.

5.1.2 Symptoms and signs - Symptoms are likely to occur after 5-7 days
repeated exposure. Initially there is back and stomach pain,
followed later by nose and gum bleeding, bruising and
haemorrhage formation. All symptoms are associated with
haemorrhage either into body cavities or tissues. Haemorrhagic
shock may occur teminally.

5.1.3 Laboratory - Of greatest significance is the markedly reduced
prothrombin activity of blood plasma, which can be measured by
the method of Quick or its modifications. Though less specific,
the clotting time will also be altered. If haemorrhage has been
extensive, haematological indices will also be affected.

5.1.4 Treatment - Vitamin Kl in a dose of 65 mg should be given three
times on the first day of treatment irrespective of symptoms.
(it will be noted that the suggested dosage of vitamin K is far
in excess of the 1 mg dosage recommended in the Pharmacopoeia.
It is however, a safe dosage and is based on that already used
successfully for some years in the treatment of excessive
hypoprothrombinemia in the course of medication with coumarin
drugs.) Smaller doses of vitamin KI should be continued until
the prothrombin time has reached normal. In a seriously ill
patient, in addition to vitamin K treatment, a transfusion of
carefully matched whole blood should be given and repeated daily
as necessary. Any large haematoma should be the subject of
surgical consultation, but no action should be taken until the
clotting power of the blood has returned to normal.

5.1.5 Prognosis - The prognosis is good; however, bleeding associated
with the central nervous system may give rise to serious
complications.

5.1.6 References of previously reported cases - W. J. Hayes,
Clinical Handbook on Economic Poisons. US Dept. Hlth Educ.
& Welfare, Atlanta, Georgia, 1963.

5.2 SURVEILLANCE TESTS - The progress of the patient should be
followed by the prothrombin test (Quick or its modifications)
which should be made at least twice daily until a return to
normal is clearly established.

5.3 LABORATORY METHODS

5.3.1 Detection and assay of compound - Methods for the detection and
assay of warfarin, both in baits and in post-mortem tissues are
given and discussed, see: H. Wanntorp, Acta Pharm et Tox, Vol
16 Supplementum 2, 1960. Two methods of analysis involving thin
layer chromatography have also been published, see: Ruessel H.
A. (1970) Z Anal. Chem. 250(2) 125 and Welling, P. G. (1970)
J. Pharm. Sci. 59(11) 1621.

5.3.2 Other tests in cases of poisoning - Methods of estimation of
prothrombin and coaaulation time will be found in most
haematology handbooks, e.g.: Disorders of the Blood, Whitby and
Britton, 10th edition, J. A. Churchill Ltd., London 1979.
Laboratory Medicine Haematology, John B. Miable. The C. V.
Mosby Co. 1958. Measurement of coagulation time method can be
used to confirm exposure. Note that bleeding time is not
affected by warfarin poisoning; prothrombin time is the method
of choice in diagnosing warfarin poisoning.

See Also:
Toxicological Abbreviations
Warfarin (HSG 96, 1995)
Warfarin (ICSC)
Warfarin (PIM 563)