IPCS INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
Health and Safety Guide No. 95
DIFENACOUM
HEALTH AND SAFETY GUIDE
UNITED NATIONS ENVIRONMENT PROGRAMME
INTERNATIONAL LABOUR ORGANISATION
WORLD HEALTH ORGANIZATION
WORLD HEALTH ORGANIZATION, GENEVA 1995
This is a companion volume to Environmental Health Criteria 175:
Anticoagulant Rodenticides
Published by the World Health Organization for the International
Programme on Chemical Safety (a collaborative programme of the United
Nations Environment Programme, the International Labour Organisation,
and the World Health Organization)
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization
WHO Library Cataloguing in Publication Data
Health and safety guide for Difenacoum
(Health and safety guide ; no. 95)
1.Rodenticides 2.Anticoagulants
3.4-Hydroxycoumarins - toxicity 4.Environmental exposure I.Series
ISBN 92 4 151095 1 (NLM Classification: WA 240)
ISSN 0259-7268
The World Health Organization welcomes requests for permission to
reproduce or translate its publications, in part or in full.
Applications and enquiries should be addressed to the Office of
Publications, World Health Organization, Geneva, Switzerland, which
will be glad to provide the latest information on any changes made to
the text, plans for new editions, and reprints and translations
already available.
(c) World Health Organization 1995
Publications of the World Health Organization enjoy copyright
protection in accordance with the provisions of Protocol 2 of the
Universal Copyright Convention. All rights reserved.
The designations employed and the presentation of the material in this
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the part of the Secretariat of the World Health Organization
concerning the legal status of any country, territory, city or area or
of its authorities, or concerning the delimitation of its frontiers or
boundaries.
The mention of specific companies or of certain manufacturers'
products does not imply that they are endorsed or recommended by the
World Health Organization in preference to others of a similar nature
that are not mentioned. Errors and omissions excepted, the names of
proprietary products are distinguished by initial capital letters.
CONTENTS
INTRODUCTION
1. PRODUCT IDENTITY AND USES
1.1. Identity
1.2. Physical and chemical properties
1.3. Analytical methods
1.4. Production and uses
2. SUMMARY AND EVALUATION
2.1. Identity, physical and chemical properties, and analytical
methods
2.2. Sources of human and environmental exposure
2.3. Environmental transport, distribution, and transformation
2.4. Environmental levels and human exposure
2.5. Kinetics and metabolism in laboratory animals and
humans
2.6. Effects on laboratory mammals and in vitro test systems
2.7. Effects on humans
2.8. Effects on other organisms in the laboratory and field
2.9. Evaluation of human health risks and effects on the
environment
2.9.1. Evaluation of human health risks
2.9.2. Evaluation of effects on the environment
3. CONCLUSIONS AND RECOMMENDATIONS
3.1. Conclusions
3.2. Recommendations for the protection of human health and the
environment
4. HUMAN HEALTH HAZARDS, PREVENTION AND PROTECTION, EMERGENCY ACTION
4.1. Main human health hazards, prevention and protection,
first aid
4.1.1. Advice to physicians
4.1.2. Health surveillance advice
4.2. Explosion and fire hazards
4.3. Storage
4.4. Transport
4.5. Spillage
4.6. Disposal
5. HAZARDS FOR THE ENVIRONMENT AND THEIR PREVENTION
6. SUMMARY OF CHEMICAL SAFETY INFORMATION
7. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS
7.1. Previous evaluations by international bodies
7.2. Exposure limit values
7.3. Specific restrictions
7.4. Labelling, packaging, and transport
7.5. Waste disposal
BIBLIOGRAPHY
INTRODUCTION
The Environmental Health Criteria (EHC) monographs produced by the
International Programme on Chemical Safety include an assessment of
the effects on the environment and on human health of exposure to a
chemical or combination of chemicals, or physical or biological
agents. They also provide guidelines for setting exposure limits.
The purpose of a Health and Safety Guide is to facilitate the
application of these guidelines in national chemical safety
programmes. The first three sections of a Health and Safety Guide
highlight the relevant technical information in the corresponding EHC.
Section 4 includes advice on preventive and protective measures and
emergency action; health workers should be thoroughly familiar with
the medical information to ensure that they can act efficiently in an
emergency. Within the Guide is a Summary of Chemical Safety
Information which should be readily available, and should be clearly
explained, to all who could come into contact with the chemical. The
section on regulatory information has been extracted from the legal
file of the International Register of Potentially Toxic Chemicals
(IRPTC) and from other United Nations sources.
The target readership includes occupational health services, those in
ministries, governmental agencies, industry, and trade unions who are
involved in the safe use of chemicals and the avoidance of
environmental health hazards, and those wanting more information on
this topic. An attempt has been made to use only terms that will be
familiar to the intended user. However, sections 1 and 2 inevitably
contain some technical terms. A bibliography has been included for
readers who require further background information.
Revision of the information in this Guide will take place in due
course, and the eventual aim is to use standardized terminology.
Comments on any difficulties encountered in using the Guide would be
very helpful and should be addressed to:
The Director
International Programme on Chemical Safety
World Health Organization
1211 Geneva 27
Switzerland
THE INFORMATION IN THIS GUIDE SHOULD BE CONSIDERED AS A STARTING POINT
TO A COMPREHENSIVE HEALTH AND SAFETY PROGRAMME
1. PRODUCT IDENTITY AND USES
1.1 Identity
Common name: difenacoum
Chemical formula: C31H24O3
Chemical structure:
Common trade names: Compo, Diphenacoum, Matrak, Neosorexa,
Rastop, Ratak, Ratrick, Silo
CAS chemical name: 3-[3-(1,1'-biphenyl)-4-yl-1,2,3,4,-
tetrahydro-1-naphthalenyl]-4-hydroxy-2 H-
1-benzopyran-2-one
IUPAC chemical name: 3-(3-biphenyl-4-yl-1,2,3,4-tetrahydro-
1-naphthyl)-4-hydroxycoumarin
CAS registry number: 56073-07-5
RTECS registry number: GN4934500
1.2 Physical and Chemical Properties
Difenacoum is an off-white powder. Its solubility in water is very low
(less than 10 mg/litre at 20°C and pH 7). It is slightly soluble in
benzene, and soluble in acetone and chloroform. It is a weak acid, but
its sodium and potassium salts are sparingly soluble in water.
Further physical and chemical properties of difenacoum are given in
the "Summary of Chemical Safety Information" (section 6).
1.3 Analytical Methods
Analytical methods for the determination of difenacoum include
UV-spectrometry and high-performance liquid chromatography with a
detection limit of 0.01 mg/litre for HPLC.
1.4 Production and Uses
The rodenticidal properties of difenacoum were described in 1975. It
is an anticoagulant that is effective against rats and mice, including
warfarin-resistant strains. It is used in agriculture and urban rodent
control as ready-to-use baits of low concentration (usually 0.005%
difenacoum).
2. SUMMARY AND EVALUATION
2.1 Identity, Physical and Chemical Properties, and Analytical
Methods
Difenacoum is an off-white powder. It has a melting point of
215-219°C. The solubility of difenacoum in water is very low. It is
slightly soluble in benzene, and soluble in acetone and chloroform.
The determination of difenacoum is based on high performance liquid
chromatography.
2.2 Sources of Human and Environmental Exposure
Difenacoum does not occur naturally. It is used as a rodenticide
against pest rodents and acts by preventing the production of blood
clotting factors.
2.3 Environmental Transport, Distribution, and Transformation
Difenacoum does not enter the atmosphere, because of its low
volatility. It is practically insoluble in water. Difenacoum is bound
to soil particles and is not taken up by plants. The rate of
degradation is relatively slow and depends on soil type. Residues in
crops have never been detected in field studies.
2.4 Environmental Levels and Human Exposure
Difenacoum is not intended for direct application to growing crops or
for use as a food additive.
No information is available on concentrations in air, water, and soil.
Residues of difenacoum were detected in dead barn owls in the United
Kingdom at levels of 0.005-0.106 mg/kg.
2.5 Kinetics and Metabolism in Laboratory Animals and Humans
Difenacoum is absorbed through the gastrointestinal tract, skin, and
respiratory system. The major route of elimination in different
species, after oral administration, is via the faeces. The liver is
the main organ of accumulation and storage. Difenacoum has been found
in the liver as both the parent compound and metabolites. The
metabolism and elimination of the trans-isomer was more rapid than
those of the cis-isomer. The elimination from the liver and kidney
is biphasic with an initial rapid phase of three days and a slower
phase with a half-life of 118-120 days. In the pancreas, the
concentration declined more slowly (a half-life of 182 days). No data
are available for the kinetics and metabolism of difenacoum in humans.
2.6 Effects on Laboratory Mammals and in vitro Test Systems
The acute oral toxicity of difenacoum is high, i.e., LD50s of 1.8
and 2 mg/kg body weight for rats and rabbits, respectively, and
between 50 and 100 mg/kg body weight for various non-rodent mammals.
The acute dermal LD50 is greater than 50 mg/kg body weight in rats
and rabbits. Signs of poisoning are those associated with an increased
tendency to bleed.
Difenacoum is not a skin or eye irritant.
In repeated oral feeding studies on mammals, the only effect was that
associated with anticoagulant action. No long-term studies have been
carried out. No experimental evidence is available to conclude the
absence of mutagenicity and teratogenicity.
2.7 Effects on Humans
Symptoms of acute intoxication by difenacoum include an increased
tendency to bleed in less severe cases of poisoning and massive
haemorrhaging in more severe cases. The signs of poisoning develop
with a delay of one to several days after ingestion.
Incidents of poisoning, both intentional and unintentional, have been
reported.
2.8 Effects on Other Organisms in the Laboratory and Field
No data are available on the effects of difenacoum on microorganisms
in water and soil as well as on aquatic plants, invertebrates, and
fish.
Bird species appear to be less susceptible to difenacoum than rodents.
Secondary poisoning through the consumption of rats and mice killed
with difenacoum may occur in dogs and cats in urban situations, but
more likely in farm situations.
2.9 Evaluation of Human Health Risks and Effects on the Environment
2.9.1 Evaluation of human health risks
Difenacoum is used in urban rodent control and against rodent pests in
agriculture. It is used as low-concentration baits. Increased levels
in air are unlikely. Being slightly soluble in water, its use cannot
be a significant source of water pollution. Difenacoum is not intended
for direct application to growing crops and no residues in plant
foodstuff are expected. Occupational exposure may occur during
manufacture, formulation, and bait application, but data indicating
the levels are not available. Difenacoum may be absorbed through the
gastrointestinal tract. The major route of elimination is via the
faeces. The urine is a minor route of excretion. The liver is the
major organ for the accumulation of difenacoum, which is mainly found
in the liver as the parent compound together with metabolites. Its
elimination from the liver is slow.
As a technical material, difenacoum is highly to extremely toxic for
various mammalian species. Signs of poisoning in all species,
including humans, are associated with an increased tendency to bleed.
Some incidents of poisoning, both intentional and unintentional have
been reported.
The level of prothrombin time is a satisfactory guide to the severity
of acute intoxication, and also to the effectiveness and duration of
the therapy.
The specific antidote for both animals and man is vitamin K1.
2.9.2 Evaluation of effects on the environment
Difenacoum is applied to discrete sites in the form of
low-concentration baits. It is stable under normal conditions.
Difenacoum is slightly soluble in water and in bait formulation it is
unlikely to be a source of water pollution. The toxic concentrations
for fish far exceed any level of difenacoum that could be expected to
occur in accidental contamination of water during normal usage.
Non-target organisms are potentially at risk through direct
consumption of baits (primary hazard) and through eating poisoned
rodents (secondary hazard).
Bird species appear to be less susceptible to difenacoum than rodents.
Small pellets and whole grain baits are highly attractive to birds.
The primary hazard is usually expressed by the amount of finished bait
that must be consumed to approach the lethal dose. To reach the toxic
or lethal dose, the non-target species must consume comparatively
large amounts of bait with a concentration of 0.005% active
ingredient.
Some secondary toxicity laboratory studies on wildlife have shown that
captive predators could be intoxicated by no-choice feeding of
difenacoum-poisoned or dosed prey. The significance of these results
in terms of hazard under field conditions is difficult to assess,
because the predators would not be expected to eat only poisoned
animals. However, predators may take poisoned, but not dead, small
mammals preferentially. In areas close to baiting, poisoned rodents
may represent a high proportion of the diet for individual birds.
However, only few individuals will be affected, unless there is very
widespread and constant use of the baits.
3. CONCLUSIONS
3.1 Conclusions
Exposure of the general population to difenacoum through air,
drinking-water, or food is unlikely and does not constitute a
significant health hazard. Incidents of poisoning may occur in cases
of massive intentional, or unintentional, ingestion or prolonged
exposure during manufacture and formulation.
Difenacoum is relatively persistent in the environment, but its
specific use in the form of low-concentration bait formulations cannot
be a significant source of air, water, soil, and food contamination.
Direct and secondary poisoning of birds, domestic and farm animals,
and wildlife may occur.
3.2 Recommendations for the Protection of Human Health and the
Environment
Potentially exposed workers should receive appropriate biomonitoring
and health evaluation.
To prevent primary poisonings, baits should be placed where they
cannot be readily available to non-target species, e.g., in bait
stations.
Killed rodents should be burned or buried, to prevent secondary
poisoning in predators.
4. HUMAN HEALTH HAZARDS, PREVENTION AND PROTECTION, EMERGENCY ACTION
4.1 Human Health Hazards, Prevention and Protection, First Aid
The oral toxicity of difenacoum for rodents is extremely high (rat
oral LD50, 1.8 mg/kg; mouse oral LD50, 1.8 mg/kg). No definite
toxic dose has been established for humans because of the limited
number of clinical reports available.
The main features of difenacoum poisoning in less severe cases are
excessive bruising, nose and gum bleeding, and blood in the urine and
faeces. Bleeding from several organs within the body, leading to shock
and possibly death, occurs in the more severe cases. The onset of the
signs of poisoning may not be evident until a few days after
ingestion.
Difenacoum is not a skin or eye irritant.
Difenacoum is slowly metabolized by mammals and following repeated
exposure it may accumulate in the liver reaching toxic levels.
In the handling of technical material or powder concentrates, full
air-fed protection and the wearing of an impervious suit, suitable for
wash-down, are necessary. In operations with liquid concentrates, PVC
or nitrile-rubber gloves, armlets, and an apron must be worn, together
with a face shield and rubber boots.
All persons who are bleeding must obtain medical attention.
4.1.1 Advice to physicians
If poisoning has occurred recently (within a few hours), gastric
lavage and repeated administration of charcoal is recommended.
A venous blood sample should be taken to measure the haemoglobin
level, prothrombin time, blood grouping, and cross-matching.
If a patient is bleeding severely, 25 mg of vitamin K1
(phytomenadione) should be given by slow intravenous injection. The
patient should be transfused with whole blood or plasma. Fresh, frozen
plasma may be given. Prothrombin time should be checked at 3-h
intervals and injections of vitamin K1 repeated, if no improvement
occurs.
In less severe cases of poisoning, vitamin K1 may be given in lower
doses, together with fresh, frozen plasma to rapidly restore the blood
clotting factors. Prothrombin time should be checked after 8-10 h and
vitamin K1 administration repeated, if necessary. Oral treatment may
be sufficient in minor cases.
Once the prothrombin time has stabilized, vitamin K1 (10 mg) should
be administered orally, four times daily.
The patient should be kept in hospital until the prothrombin time has
remained normal for three days.
The patient should be discharged from hospital with the following
treatment: vitamin K1 orally (10 mg) twice daily, for up to 60 days,
with close monitoring of the prothrombin time. It may be possible to
reduce the length of treatment.
4.1.2 Health surveillance advice
Workers handling concentrates must have periodic determination of the
potential disturbances of the clotting mechanisms, using the most
appropriate method, such as measurement of the circulating
descarboxy-prothrombin, prothrombin concentration, or prothrombin
time.
4.2 Explosion and Fire Hazards
Heating of containers will cause a pressure rise, with the risk of
bursting and subsequent ignition. Fire-exposed containers should be
kept cool by spraying with water.
High-temperature decomposition or burning in air will lead to the
formation of toxic gases, which may include carbon monoxide as well as
fumes of unchanged rodenticide; breathing apparatus must be worn in
fire-fighting.
The use of carbon dioxide or dry powder is recommended for
extinguishing small fires, and foam or water fog for larger fires. A
water jet should not be used.
Run-off water from the fire should be prevented from entering
surface-water drains or water sources.
4.3 Storage
Technical difenacoum and formulations should be stored in sealed
containers in locked, well-ventilated, dry areas away from frost,
direct sunlight, and sources of heat and ignition. Keep products out
of reach of children and unauthorized personnel. Do not store near
food or animal feed.
4.4 Transport
Comply with any local regulations regarding the movement of hazardous
goods. Before despatch, ensure that the containers are sound and that
labels are securely fixed and undamaged.
4.5 Spillage
During decontamination, the operator must wear protective clothing,
PVC gloves, a face shield, and rubber boots.
Dry spillages should be collected at once, by suction, and disposed of
as toxic waste, according to local legislation.
Liquid spillages should be absorbed on vermiculite or other inert
absorbent and treated similarly.
Contaminated areas should be washed down with cold water containing
surfactant; the washings must be prevented from entering surface-water
drains.
4.6 Disposal
Disposal should be carried out according to national regulations.
5. HAZARDS FOR THE ENVIRONMENT AND THEIR PREVENTION
Difenacoum is stable but rapidly binds to soil, with very slow
desorption and without leaching. It is only slightly soluble in water,
and in the form of bait formulations is unlikely to be a source of
water contamination.
Do not place baits where domestic or farm animals and birds can reach
them. Burn or bury any uneaten bait. Do not dump it in water. Look for
dead rats and mice and burn or bury them.
6. SUMMARY OF CHEMICAL SAFETY INFORMATION
This summary should be easily available to all health workers
concerned with, and users of, difenacoum. It should be displayed at,
or near, entrances to areas where there is potential exposure to
difenacoum, and on processing equipment and containers. The summary
should be translated into the appropriate language(s). All persons
potentially exposed to the chemical should also have the instructions
in the summary clearly explained.
Space is available for insertion of the National Occupational Exposure
Limit, the address and telephone number of the National Poison Control
Centre, and local trade names.
DIFENACOUM
Chemical formula: C31H24O3
CAS chemical name: 3-[3-(1,1'-biphenyl)-4-yl-1,2,3,4-tetrahydro-1-naphthalenyl]-4-hydroxy-2H-1-benzopyran-2-one
IUPAC chemical name: 3-(3-biphenyl-4-yl-1,2,3,4-tetrahydro-1-naphthyl)-4-hydroxycoumarin
CAS registry number: 56073-07-5
RTECS number: GN4934500
PHYSICAL PROPERTIES OTHER CHARACTERISTICS
Physical state powder Difenacoum is an anticoagulant rodenticide; it is formulated as
Colour off-white low-concentration baits (usually 0.005% of active ingredient)
Relative molecular mass 444.5
Melting point (°C) 215-219
Vapour pressure (45°C) 0.16 mPa
Solubility in water at less than 0.01 g/litre
20°C, pH 7
Solubility in acetone 59 g/litre
chloroform 50 g/litre
benzene 600 mg/litre
HAZARDS/SYMPTOMS PREVENTION AND PROTECTION FIRST AID
GENERAL: Readily absorbed following Avoid exposure Obtain medical attention;
ingestion or inhalation, or through the antidote - vitamin K201
skin; if absorbed, signs may range from an
increased tendency to bleed to massive
haemorrhaging
HAZARDS/SYMPTOMS PREVENTION AND PROTECTION FIRST AID
SKIN: Non-irritant; skin absorption may Wear gloves when handling concentrate Wash with soap and water;
occur from liquid concentrates seek medical advice
EYES: Non-irritant Use face shield when handling concentrates Flush eyes with water for at least
15 min
INHALATION: Significant vapour Avoid inhaling concentrate aerosols Obtain medical attention
exposure unlikely or bait dust
INGESTION: Nausea/vomiting; acute Wash hands before eating, drinking, Rinse out the mouth with water;
anticoagulant poisoning may occur in or smoking transfer to hospital immediately
several hours or days
SPILLAGE STORAGE FIRE/EXPLOSION
Wear protective clothing during Store in sealed containers in a dry, Combustible solid; burning in
decontamination; dry spillage should be ventilated and locked storeroom, away air will lead to the formation of
collected by suction and disposed of as from children, unauthorized persons, and toxic gases; to extinguish small
toxic waste; liquid spillage should be domestic animals, food, and animal feed fires use carbon dioxide, halons,
absorbed on vermiculite or other inert or dry powder; for larger fires
absorbent and treated similarly; do not use foam or water fog; keep
contaminate surface-water drains containers cool by spraying with
water
WASTE DISPOSAL NATIONAL INFORMATION
Proper incineration is the method of
choice
7. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS
7.1 Previous Evaluations by International Bodies
Technical difenacoum has been classified by WHO in Class Ia -
Extremely Hazardous, based on the acute, oral LD50 of 1.8 mg/kg for
rats.
7.2 Exposure Limit Values
No information is available.
7.3 Specific Restrictions
Difenacoum has been officially approved for use as a rodenticide in
many countries. In some countries, specific uses are defined, as well
as limitations and precautions.
7.4 Labelling, Packaging, and Transport
Technical difenacoum is considered to be a very toxic chemical and the
European Economic Community legislation requires specific labelling
with the symbol T+ and the following pictogram:
The United Nations, in its Recommendations on the Transport of
Dangerous Goods, classified brodmadiolone in category 6.1 as a
poisonous substance (No. 3027).
7.5 Waste Disposal
No specific information is available.
BIBLIOGRAPHY
Hayes WJ Jr & Laws ER Jr (1991) Handbook of pesticide toxicology,
Vol. 3, New York, Academic Press.
IPCS (1995) Environmental Health Criteria No. 175, Anticoagulant
rodenticides, Geneva, World Health Organization.
WHO (1994) The WHO recommended classification of pesticides by hazard
and guidelines to classification 1994-1995, Geneva, World Health
Organization (unpublished document, WHO/PCS/94.2).
Widdershoven J, van Munster P, De Abreu R, Bosman H, van Lith Th, van
der Putten-van Meyel M, Motohara K, & Matsuda I (1987) Four methods
compared for measuring des-carboxy-prothrombin (PIVKA-II), Clin Chem,
33/11: 2074-2078.
Worthing CR & Hance RJ, ed. (1991) The pesticide manual, 9th ed.,
Farnham, United Kingdom, The British Crop Protection Council.
See Also:
Toxicological Abbreviations