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    IPCS INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
    Health and Safety Guide No. 49

    CAPTAFOL
    HEALTH AND SAFETY GUIDE






    UNITED NATIONS ENVIRONMENT PROGRAMME

    INTERNATIONAL LABOUR ORGANISATION

    WORLD HEALTH ORGANIZATION




    WORLD HEALTH ORGANIZATION, GENEVA 1990

    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

    Captafol : health and safety guide.

    (Health and safety guide ; no. 49)

    1. Captan - analogs & derivatives  I. Series

    ISBN 92 4 151049 8          (NLM Classification: WA 240)
    ISSN 0259-7268

    (c) World Health Organization 1990

    Publications of the World Health Organization enjoy copyright
    protection in accordance with the provisions of Protocol 2 of the
    Universal Copyright Convention.  For rights of reproduction or
    translation of WHO publications, in part or  in toto, application
    should be made to the Office of Publications, World Health
    Organization, Geneva, Switzerland.  The World Health Organization
    welcomes such applications.

    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. Human exposure to captafol
         2.2. Uptake, metabolism, and excretion
         2.3. Effects on animals
         2.4. Effects on human beings
         2.5. Effects on the environment

    3. CONCLUSIONS AND RECOMMENDATIONS

    4. HUMAN HEALTH HAZARDS, PREVENTION AND PROTECTION, EMERGENCY ACTION
         4.1. Main human health hazards, prevention and protection,
              first aid
              4.1.1. Prevention and protection
              4.1.2. First aid
         4.2. Advice to physicians
         4.3. Explosion and fire hazards
         4.4. Storage and transport
         4.5. Spillage and disposal

    5. HAZARDS FOR THE ENVIRONMENT AND THEIR PREVENTION

    6. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS
         6.1. Exposure limit values
         6.2. Specific restrictions
         6.3. Transport and labelling
    

    INTRODUCTION

    This Health and Safety Guide is not based on an existing Environmental
    Health Criteria document, but on critical national reviews.  The
    hazard evaluation in the Health and Safety Guide was made on the basis
    of carefully selected studies, after scrutiny of the original
    publications.

    In order to assist the peer-review process of the present Health and
    Safety Guide, a background companion document was prepared by the IPCS
    and can be obtained from the Manager on request;  the IPCS does not
    intend that the background document should be published. 

    The first three sections of this Health and Safety Guide present
    essential technical information and the hazard evaluation.  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. 
    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.

    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 Manager
    International Programme on Chemical Safety
    Division of Environmental Health
    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

    Chemical formula:             C10H9Cl4NO2S

    Common name:                  captafol

    Chemical structure:

    CHEMICAL STRUCTURE 1

    Relative molecular mass:      349.1

    Common trade names            Captafol; Captatol; Captofol; Captaspor;
    (including formulations):     Difolatan; Difosan; Merpafol; Folcid;
                                  Ortho-5865; Ortho Difolatan 80W; Ortho
                                  Difolatan 4 Flowable; Sanseal; Sanspor;
                                  Sulfonimide; Sulpheimide

    CAS chemical name:             N-((1,1,2,2-tetrachloroethyl)thio)-4-
                                  cyclo-hexene-1,2-dicarboximide

    Synonyms:                      N-(1,1,2,2-tetrachloroethylthio)-
                                  cyclohex-4-ene-1,2-dicarboximide;
                                   N-(1,1,2,2-tetrachloraethylthio)-
                                  tetra-hydrophthalamid;
                                   N-1,1,2,2-tetrachloroethylmercapto-4-
                                  cyclohexene-1,2-carboximide;
                                   N-((1,1,2,2-tetrachloroethyl)-
                                  sulfenyl)- cis-4-cyclohexene-1,2-
                                  dicarboximide; 
                                   N-(1,1,2,2-tetra-chloroethylthio)-4-
                                  cyclo-hexene-1,2-dicarboximide

    CAS registry number:          2425-06-1

    RTECS registry number:        GW4900000

    In the past, captafol was available in a wide range of mixtures and
    formulations.  However, information on currently available
    formulations is not available.

    Technical captafol, previously manufactured in the USA, contained
    97-99% active ingredient with tetrahydrophthalimide (4-cyclohexene-
    1,2-dicarboximide) as the main impurity (0.5-1.5%) together with
    0.5-1.5% toluene and 0.1-0.2% of unknown chlorinated substances.

    1.2  Physical and Chemical Properties

    Technical captafol is a light tan powder with a characteristic odour. 
    It is stable at room temperature in the dry state, but is readily
    hydrolysed, especially in an alkaline environment.  The melting point
    of the pure compound is 162 C; a range of 156-161 C has been
    recorded for the technical product.  The vapour pressure at room
    temperature is negligible.

    Captafol is practically insoluble in water (1.4 mg/litre) and only
    slightly soluble in aliphatic hydrocarbon solvents:  it has a
    solubility of 25 g/litre at 77 C in isopropanol, and of 428 g/litre
    in toluene at 24 C.

    Sulfhydryl compounds, such as glutathione and cysteine, cause rapid
    chemical decomposition of captafol.

    1.3  Analytical Methods

    Capillary gas-liquid chromatography with electron-capture detection is
    a multi-residue method suitable for the routine determination of five
    fungicides including captan, folpet, captafol, vinclozolin, and
    iprodione.

    1.4  Production and Uses

    Captafol was introduced in 1961; although it was withdrawn in many
    countries in the late 1980s, production and use continue in some
    countries.

    Captafol is a non-systemic broad-spectrum fungicide, leaving
    relatively stable deposits when applied to foliage.  This pesticide
    can be combined with commonly used insecticides and fungicides, except
    for oil sprays and strongly alkaline materials.  Captafol is mainly
    used to control foliage and fruit diseases in various vegetable and
    fruit crops.  It has also been used in the lumber and timber
    industries for the control of wood rot fungi on logs and wood
    products.

    Captafol is formulated as a wettable powder, dust, emulsifiable
    concentrate, flowable suspension, and as water-dispersible granules. 
    It is applied by dusting, spraying, and misting, and by dipping under
    pressure (wood treatment).

    2.  SUMMARY AND EVALUATION

    2.1  Human Exposure to Captafol

    The highest exposures to captafol are occupational and are associated
    with its use in agriculture.  Dermal exposure can be important because
    of local effects on the skin.  Low-level exposure of the general
    population may occur through residues in food.  However, captafol is
    extensively hydrolysed during thermal and other food processing. 
    Because of the nature of the captafol residues, they are readily
    reduced by, for example, peeling, washing, and blanching.

    2.2  Uptake, Metabolism, and Excretion

    Captafol may be absorbed through ingestion as well as through
    inhalation, and to a very limited extent through skin exposure. 
    Following oral administration, captafol appears to be extensively
    hydrolysed to tetrahydrophthalimide (THPI; 4-cyclohexene-1,2-
    dicarboximide) and tetrachloro-ethylmercaptan (TES).  Captafol and its
    metabolites do not accumulate in the tissues of animals and are
    rapidly eliminated; after a single oral dose of labelled captafol,
    most of the radioactivity appeared to be excreted within 3-4 days,
    primarily in the urine.  Tetrahydrophthalimide (THPI) has been
    identified as the major metabolite of captafol in both animals and
    plants, as is the case for the closely related fungicide, captan. 
    THPI is further metabolized into a large number of metabolites.  More
    important for the toxicity of captafol is the further metabolism of
    TES.  To explain the formation of the end metabolite, 2-chloro-
    2-methyl-thioethylene sulfonic acid, the formation of a cyclic
    sulfonium ion is assumed to be a transient intermediate.  This
    intermediate is a potential alkylating agent and is probably
    responsible for the toxic and carcinogenic action of captafol.

    2.3  Effects on Animals

    The acute toxicity of captafol, when ingested, is low.  However, the
    inhalation toxicity is considerably higher, and it is irritating to
    the skin and also to the mucous membranes of the respiratory tract. 
    The substance is highly irritating to the eye and may cause eye
    damage.  There are several reports indicating that captafol induces
    sensitization in guinea-pigs.

    After repeated administration in the diet to experimental animals,
    captafol caused toxic effects involving several organs, notably kidney
    damage, and pathological changes of the gastric mucosa.  Long-term
    administration to rats and mice induced tumours at multiple sites. 
    These results constitute sufficient evidence for the carcinogenicity
    of captafol.  Captafol, which is an alkylating agent, has produced
    genotoxic effects in several  in vitro systems, but, so far, it has
    not been possible to demonstrate any mutagenic effects  in vivo. 
    Thus, though captafol may induce genotoxic events in somatic cells,
    the results obtained seem to indicate that the potential for causing

    heritable effects in mammals is extremely low.  There is no evidence
    that captafol constitutes a teratogenic hazard, but it may induce
    fetotoxicity at doses toxic for the mother.

    2.4  Effects on Human Beings

    Captafol has caused allergic and contact dermatitis in man.  During
    occupational exposure, it has also been reported to cause severe
    irritation of the respiratory tract, eye damage, and other systemic
    effects.  In a limited study of employees involved in the manufacture
    of captafol, no significant excess in mortality could be associated
    with exposure to this pesticide.

    2.5  Effects on the Environment

    Captafol, administered as a single oral dose, or in short-term dietary
    studies, was not toxic for birds (LC50 >5620 mg/kg diet).  However,
    high levels of exposure may cause reproductive impairment.  The
    toxicity of captafol for bees is low.  Captafol is highly toxic for
    fish and moderately to very highly toxic for freshwater invertebrates
    (96-h LC50s ranged between 0.04 and 3 mg/litre).  The 96-h LC50
    reported in three investigations on rainbow trout ranged from 0.027 to
    0.19 mg/litre.

    Captafol is not persistent.  Its half-life in soil is less than 11
    days.  The environmental impact of the pesticide is likely to be
    limited by its high chemical reactivity, high rate of biodegradation,
    and lack of tendency to bioaccumulate.  However, because of its
    demonstrated high toxicity, exposure of aquatic organisms to captafol
    through drift and/or run-off is a cause for concern.  Fish kills have
    been associated with the use of this pesticide.

    3.  CONCLUSIONS AND RECOMMENDATIONS

    In view of the established carcinogenic potential of captafol and the
    availability of alternatives, it is recommended that this pesticide
    should not be used.

    Captafol is highly toxic for fish, and moderately to highly toxic for
    freshwater invertebrates.  Because of this demonstrated high aquatic
    toxicity, it is recommended that adequate precautions be taken to
    prevent contamination of surface and ground water.

    4.  HUMAN HEALTH HAZARDS, PREVENTION AND PROTECTION, EMERGENCY ACTION

    4.1  Main Human Health Hazards, Prevention and Protection, First Aid

    The acute oral toxicity of technical captafol for human beings is low. 
    The compound causes severe irritation of the respiratory tract, and
    allergic dermatitis.  Captafol also has a potential for causing eye
    damage.

    In view of the severe toxicity induced in experimental animals with
    repeated exposure, including a proven carcinogenic action, exposure of
    human beings should be kept to a minimum.

    4.1.1  Prevention and protection

    The following precautions should be observed during the handling and
    use of captafol, in order to reduce the risk of accidental
    contamination:

    (a)  Avoid contact with the skin and eyes. 

    (b)  Do not smoke, drink, or eat in the work-place.  Wash hands and
    any exposed skin before eating, drinking, or smoking, and after work.

    (c)  Avoid raising a dust cloud when handling wettable powder
    formulations.

    (d)  Avoid breathing dust from powder products.

    (e)  When unloading and handling containers, wear protective PVC or
    neoprene gloves.

    (f)  When handling leaking containers, or when dealing with leaks and
    spills, wear overalls, PVC or neoprene gloves, boots, and eye/face
    protection.  If overalls become contaminated, change and wash them
    thoroughly before re-use.

    (g)  Store products in closed original containers, out of reach of
    children, and away from food, drink, and animal feed.

    4.1.2  First Aid

    Acute poisoning by captafol is unlikely, unless large amounts are
    ingested.  In cases of over-exposure, apply routine first-aid
    measures.  If the compound has been spilled on the skin, immediately
    remove the patient from the source of contamination, remove all
    contaminated clothing, and wash affected areas with soap and running
    water.  If the material is in the eyes, flush with clean water for at
    least 15 minutes.  In case of ingestion of significant quantities, if
    the patient is conscious, give several glasses of water.  Do not
    induce vomiting.  In serious cases, medical attention should be
    sought.

    4.2  Advice to Physicians

    The acute oral toxicity of captafol for human beings is low.  There is
    no specific antidote.  Treat symptomatically, paying special attention
    to respiratory and dermal symptoms when necessary.  In cases of
    ingestion of large amounts, gastric lavage may be indicated.

    4.3  Explosion and Fire Hazards

    Captafol is not flammable but, on heating, may produce toxic fumes,
    such as sulfur dioxide, hydrochloric acid, and phosgene.  Concentrated
    products react violently with alkali.

    Extinguish small fires with carbon dioxide, dry powder, or
    alcohol-resistant foam.  Water spray can be used for larger fires and
    for the cooling of unaffected stock, but avoid the accumulation of
    polluted run-off from the site.  Fire service personnel should be
    advised that self-contained breathing apparatus may be required,
    because of the generation of noxious fumes.

    4.4  Storage and Transport

    All products should be stored in secure buildings, out of reach of
    children and animals, and local regulations should be complied with. 
    Containers should be sound and adequately labelled.

    4.5  Spillage and Disposal

    Avoid contact with the solid or dust.  Keep spectators away from any
    leakage.  This pesticide is highly toxic for fish.  Prevent
    contamination of other goods or cargo, and of nearby vegetation and
    waterways.

    Absorb spilled liquid products using earth or sand.  If available,
    sawdust, peat, moss, or straw are also suitable absorbents; sweep up
    and place in a separate container.  Empty any product remaining in
    damaged or leaking containers into a clean empty container, which
    should be suitably labelled.  Sweep up any spilled powder with damp
    sawdust, taking care not to raise a dust cloud (use a vacuum cleaner). 
    Remove trapped material with suction hoses.  Place in a separate
    container for subsequent disposal.  Use mechanical dredges or lifts to
    remove immobilized masses of pollutants and precipitates.

    Before disposal, captafol can be concentrated by gravity separation
    followed by dual media filtration and activated carbon adsorption. 
    Alkaline treatment of captafol leads to the formation of degradation
    products of much lower toxicity.  For treatment of large spills, or
    for the decontamination of equipment, the use of an aqueous solution
    of commercial low-foaming, hard-water detergent in 5% trisodium
    phosphate or 10-25% sodium hydroxide is recommended.  During
    neutralization, hydrogen sulfide may be formed, if insufficient alkali
    is used.

    Do not deposit in landfill.  Captafol is not amenable to biological
    treatment at municipal sewage plants.

    5.  HAZARDS FOR THE ENVIRONMENT AND THEIR PREVENTION

    Captafol is not persistent and small quantities of the compound are
    readily hydrolysed in soil and surface waters.  However, it is highly
    toxic for aquatic organisms.  Contamination of ponds, waterways, and
    ditches with captafol should be avoided.  In case of spills, and for
    the decontamination of equipment and containers, apply the methods
    recommended in section 4.5.

    6.  CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

    The information given in this section has been extracted from the
    International Register of Potentially Toxic Chemicals (IRPTC) legal
    file. A full reference to the original national document from which
    the information was extracted can be obtained from IRPTC.  When no
    effective date appears in the IRPTC legal file, the year of the
    reference from which the data are taken is indicated by (r).

    The reader should be aware that regulatory decisions about chemicals
    taken in a certain country can only be fully understood in the
    framework of the legislation of that country.  Furthermore, the
    regulations and guidelines of all countries are subject to change and
    should always be verified with appropriate regulatory authorities
    before application.

    6.1  Exposure Limit Values

    The threshold limit value (TWA) recommended by the US ACGIH for
    captafol is 0.1 mg/m3 in air.  This value is also enforced in
    Argentina, Australia, Canada, the Netherlands, and the United Kingdom.

    In 1985, the Joint FAO/WHO Meeting on Pesticide Residues (JMPR)
    recommended that the temporary ADI should be withdrawn, saying that, 
    "In view of the established carcinogenic potential of this compound,
    the meeting recommended that captafol should not be used where its
    residues in food can arise."

    Some tolerances for food and animal feed are given in the table
    opposite.

    6.2  Specific Restrictions

    Captafol has never been granted registration in the German Democratic
    Republic or Sweden.  In 1987, the pesticide was voluntarily withdrawn
    from the US market by the main producers.  It was banned in the
    Netherlands as from 21 May 1986 and also in Cyprus, the Federal
    Republic of Germany, Hungary, and Italy.


        TOLERANCES AND MAXIMUM RESIDUE LIMITS FOR FOOD PRODUCTS

                                                                                                                                         

    Country/                Food product                    Exposure limit description          Value              Effective
    organization                                                                                (mg/kg)            date
                                                                                                                                         

    Brazil                  Specified plant products        Acceptable limit                    0.04-15

    Czechoslovakia          Plants products                 Maximum residue limit               2-15               October 1978

    EEC                     Specified plant products        Maximum residue limit               0.058a             1988


    Sweden                  Fruits and vegetables           Maximum acceptable                  0.5-3.0            January 1985
                                                              concentration

    USA                     Raw agricultural products       Tolerance                           0.25-100           May 1986



                                                                                                                                         

    a Limit of detection.
    

    6.3  Transport and Labelling

    Conveyance labelling should be as follows:

    FIGURE 1

     Supply and use labelling

    European Economic Community legislation requires labelling as a
    dangerous substance using the symbol:

    FIGURE 2

    The label must read:

    R20                  Harmful by inhalation

    R36/37/38            Irritating to eyes, respiratory system and skin

    R40                  Possible risk of irreversible effects

    R41                  Risk of serious damage to eyes

    R43                  May cause sensitization by skin contact

    R45                  May cause cancer

    S2                   Keep out of reach of children

    S13                  Keep away from food, drink, and animal feeding
                         stuffs

    S20/21               When using do not eat, drink, or smoke

    S22                  Do not breathe dust

    S24/25               Avoid contact with skin and eyes

    S36/37/39            Wear suitable protective clothing gloves and
                         eye/face protection 

    


    See Also:
       Toxicological Abbreviations
       Captafol (ICSC)
       Captafol (PIM 097)
       Captafol (FAO/PL:1969/M/17/1)
       Captafol (WHO Pesticide Residues Series 3)
       Captafol (WHO Pesticide Residues Series 4)
       Captafol (Pesticide residues in food: 1976 evaluations)
       Captafol (Pesticide residues in food: 1977 evaluations)
       Captafol (IARC Summary & Evaluation, Volume 53, 1991)