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    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
    publication do not imply the expression of any opinion whatsoever on
    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:

                               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 20C 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
    215-219C. 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 (45C)                         0.16 mPa
    Solubility in water at                         less than 0.01 g/litre
    20C, 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:

    FIGURE 1

    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