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    IPCS INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
    Health and Safety Guide No. 81



    BENOMYL
    HEALTH AND SAFETY GUIDE




    UNITED NATIONS ENVIRONMENT PROGRAMME

    INTERNATIONAL LABOUR ORGANISATION

    WORLD HEALTH ORGANIZATION



    WORLD HEALTH ORGANIZATION, GENEVA 1993


    This is a companion volume to Environmental Health Criteria
    148: Benomyl

    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

    Benomyl: health and safety guide.

    (Health and safety guide ; no. 81)

    1.Benomyl - standards 2.Benomyl - toxicity 3.Fungicides, Industrial-
    standards 4.Fungicides, Industrial - toxicity
    I.Series

    ISBN 92 4 151081 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 1993

    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. Exposure
         2.2. Uptake, metabolism, and excretion
         2.3. Effects on organisms in the environment
         2.4. Effects on experimental animals and in vitro
              test systems
         2.5. Effects on humans

    3. CONCLUSIONS AND RECOMMENDATIONS

    4. HUMAN HEALTH HAZARDS, PREVENTION AND PROTECTION,
         EMERGENCY ACTION
         4.1. 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
              4.2.1. Explosion hazards
              4.2.2. 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. 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

    1.  PRODUCT IDENTITY AND USES

    1.1  Identity

    Common name:                  Benomyl

    Chemical formula:             C14H18N4O3

    Chemical structure:

    CHEMICAL STRUCTURE 1

    Common trade names
    (including formulations):     Benlate, Tersan, Fungicide 1991,
                                  Fundazol

    CAS chemical name:            Carbamic acid, [1-(butylamino)
                                  carbonyl]-1H-benzimidazol-2-yl]-,
                                  methyl ester

    Synonyms:                     Methyl 1-(butylcarbamoyl)-2-
                                  benzimidazolecarbamate

    CAS registry number:          17804-35-2

    RTECS registry number:        DD647500

    Primary metabolite in
    mammals and degradation
    product in the environment:   Carbendazim

    1.2  Physical and chemical properties

    Benomyl, a tan coloured crystalline solid, is a systemic fungicide
    of the benzimidazole family. It decomposes just after melting at 140
    C and has a vapour pressure of <5.0  10-6 Pa at 25 C. Benomyl
    is essentially insoluble in water (3.6 ppm) at pH 5 and 24 C. It is
    stable under normal storage conditions, but will decompose to
    carbendazim in water.

    1.3  Analytical methods

    Analyses of environmental samples and determination of residues are
    performed by extraction with an organic solvent, purification of the
    extract by a liquid-liquid partitioning procedure, and conversion of
    the residue to carbendazim. Residue levels can be determined using
    HPLC or immunoassay.

    1.4  Production and uses

    In 1991, the estimated value of the worldwide sales of benomyl was
    US$290 million. This was about 50% of the global market for
    benzimidazole products. Carbendazim (20%) and thiophanate-methyl
    (20%) mainly account for the rest of the benzimidazole market.

    Benomyl is a systemic and broad spectrum fungicide that is currently
    registered for use in more than 50 countries on more than 70 crops
    for the control of diseases in fruit trees, nut crops, vegetables,
    cereals, tropical crops and ornamentals, turf, and many field crops.
    It is marketed as a wettable powder and as a dry flowable
    formulation (dispersible granules).

    2.  SUMMARY AND EVALUATION

    2.1  Exposure

    Dietary intake is the primary source of benomyl exposure for the
    general human population. Estimates, based on dietary analysis and
    crop tolerance values, indicate an expected intake substantially
    below the recommended Acceptable Daily Intake (ADI) based on
    no-observed-effect levels in animal tests.

    Occupational exposures during manufacture or crop application are
    below established Threshold Limit Values. Primary routes of exposure
    are inhalation and dermal contact, both of which are easily reduced
    and controlled by the use of dust masks and protective clothing.

    2.2  Uptake, metabolism, and excretion

    Benomyl is well absorbed after oral, but not dermal, exposure.
    Absorbed benomyl is rapidly metabolized and eliminated in the urine
    and faeces.

    2.3  Effects on organisms in the environment

    Because they remain stable for several weeks on plant material, both
    benomyl and carbendazim may become accessible to organisms feeding
    on leaf litter. Soil and sediments may contain residues of
    carbendazim for up to 3 years. However, the strong adsorption of
    carbendazim on soil and sediment particles reduces the exposure of
    terrestrial and aquatic organisms.

    Benomyl, at recommended application rates, has little effect on soil
    microbial activity. Some adverse effects have been reported in
    groups of fungi. Benomyl is algicidal and was toxic for aquatic
    organisms and fish in laboratory studies.

    Benomyl was toxic for earthworms in laboratory studies at realistic
    exposure concentrations and when used at recommended levels in the
    field. Its toxicity for birds is low and its degradation product
    carbendazim is "relatively non-toxic" for honey bees.

    2.4  Effects on experimental animals and  in vitro test systems

    The toxicity of benomyl via ingestion is very low, with an LD50 in
    rats of >10 000 mg/kg. It is moderately toxic via inhalation (4-h
    LC50 >4 mg/litre) and via dermal contact (LD50 >2000 mg/kg).
    Application to the shaved skin of guinea-pigs produced sensitization
    and mild skin irritation. Application to the eyes of rabbits
    produced mild eye irritation.

    The no-observed-effect level (NOEL) was 2500 mg/kg (2500 ppm), the
    highest dose tested in a long-term dietary study on rats. In mice,
    both benomyl and its metabolite carbendazim induced hepatocellular
    tumours in certain strains of mice known to have a high background
    rate for these tumours. No carcinogenic effect was observed in rats.

    Reduced testicular weight, lowered sperm counts, and reduced
    fertility have been observed in studies on laboratory animals. The
    NOEL for reproductive effects was 15 mg/kg, in a study on male rats.
    Benomyl is embryotoxic in rats and mice and has been shown to
    adversely effect postnatal development at dose levels greater than
    15.6 mg/kg in the rat, when administered by gavage.

    Benomyl is not a heritable gene mutagen. However, it produced
    numerous chromosome aberrations or aneuploidy. This was caused by
    the mechanism through which benomyl exerts its fungicidal activity.

    Benomyl was found to bind to fungal tubulin but had a low affinity
    for mammalian tubulin.

    2.5  Effects on humans

    The mammalian toxicity of benomyl is low . No inadvertent poisoning
    of agricultural or factory workers has been documented. The primary
    toxic effect of benomyl is dermal sensitization and contact
    dermatitis. These effects can be reduced by wearing long-sleeved
    shirts, long trousers, and gloves.

    3. CONCLUSIONS AND RECOMMENDATIONS

    Estimates of human exposures based on dietary analysis and crop
    tolerance values indicate the expected intake to be below the
    recommended Acceptable Daily Intake (ADI) based on
    no-observed-effect levels in animal tests. As both the toxicity of
    benomyl and the dietary exposure levels are low, it is unlikely that
    it poses a significant health risk for the general population.

    Occupational exposures during manufacture or crop application are
    below the established Threshold Limit Values. The primary toxic
    effects of benomyl under these conditions of exposure are dermal
    sensitization and contact dermatitis, but these effects can be
    significantly reduced by limited exposure. Benomyl is rapidly
    converted to carbendazim in various environmental compartments.

    Carbendazim is strongly adsorbed on soil organic matter and persists
    in the soil for up to 3 years. It persists on leaf surfaces and,
    therefore, in leaf litter. Earthworms have been shown to be
    adversely affected (population and reproductive effects) at
    recommended application rates. There is no information on other soil
    or litter arthropods that would be similarly exposed.

    The high toxicity for aquatic organisms in laboratory tests is
    unlikely to be seen in the field because of the low bioavailability
    of sediment-bound residues of carbendazim. However, no information
    is available on the sediment-living species that receive the highest
    exposure.

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

    4.1  Human health hazards, prevention and protection, first aid

    The human health hazards associated with certain types of exposure
    to benomyl, together with preventive and protective measures and
    first-aid recommendations, are listed in the Summary of Chemical
    Safety Information (section 6).

    4.1.1  Advice to physicians

    The acute toxicity of benomyl for humans is believed to be very low.
    There is no specific antidote. In case of skin contact, immediately
    wash the skin with soap and water. In case of eye contact,
    immediately flush eyes with plenty of water for at least 15 min.

    4.1.2  Health surveillance advice

    The primary toxic effects of benomyl are dermal sensitization and
    contact dermatitis.  Contaminated skin should be monitored for signs
    of skin irritation.

    4.2  Explosion and fire hazards

    4.2.1  Explosion hazards

    Like most organic powders or crystals, under severe dusting
    conditions, this material may form explosive mixtures in air.
    Hazardous gases/vapours produced during a fire include
     n-butylisocyanate.

    4.2.2  Fire hazards

    Evacuate personnel to a safe area, keeping them away from, and
    upwind of, fire. Wear self-contained breathing apparatus. Use water
    or dry chemical to extinguish fire and water spray to cool
    tank/container.

    4.3  Storage

    Store in a well ventilated area. Keep container tightly closed. Do
    not store or consume food, drink, or tobacco in areas where they may
    become contaminated with this material.

    Never allow benomyl to become wet during storage. This may lead to
    certain chemical changes that could increase its toxicity
    (lacrimation because of the formation of butyl isocyanate) and
    reduce the effectiveness of benomyl as a fungicide.

    4.4  Transport

    All products should be transported in secure vehicles following
    local regulations. Containers should be sound, adequately labelled,
    and kept dry.

    4.5  Spillage

    Sections 4.1 and 4.2 of this Guide should be reviewed before
    proceeding with clean up. Use appropriate personnel protective
    equipment during clean up.

    Prevent liquid from entering sewers, waterways, or low areas.
    Shovel, or sweep, up.

    4.6  Disposal

    Treatment, storage, transportation, and disposal must be in
    accordance with applicable local regulations. Remove non-usable
    solid materials and/or contaminated soil for disposal in an approved
    and permitted landfill. Do not flush into surface water or sanitary
    sewer systems.

    Do not reuse container; dispose of according to approved local
    procedures.

    5.  HAZARDS FOR THE ENVIRONMENT AND THEIR PREVENTION

    The strong adsorption of benomyl and its degradation product
    carbendazim on particulates in the soil and aquatic sediment reduces
    its bioavailability. However, earthworm populations have been
    reduced by benomyl applied at recommended rates. There is no
    information on its toxicity for other soil invertebrates or aquatic
    invertebrates living in sediments. Residues on particulates may
    persist for years.

    Excessive application of benomyl to the same area should be avoided
    to prevent the build up of residues. Disposal should avoid
    contamination of both soil and surface water sediments.

    6.  SUMMARY OF CHEMICAL SAFETY INFORMATION

    This summary should be easily available to all health workers
    concerned with, and users of, benomyl. It should be displayed at, or
    near, entrances to areas where there is potential exposure to
    benomyl, 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.


        BENOMYL

    Carbamic acid, [1-(butylamino) carbonyl]-1 H-benzimidazol-2-yl]-methyl ester

    C14H18N4O3

                                                                                                                              

    PHYSICAL PROPERTIES                                         OTHER CHARACTERISTICS
                                                                                                                              


    Relative molecular mass                   290.3             Tan coloured, crystalline solid; high humidity or moisture 
    Melting point (C)                        140               levels and/or high temperatures can lead to the 
    Boiling point (C)                        decomposes        generation of  n-butyl isocyanate, a strong lacrimator
    Water solubility (mg/litre, pH 5, 25C)   3.6
    Specific density                          0.38
    Relative vapour pressure (Pa, 25 C)      <5.0  10-6
    Explosion limit (LEL, g/litre in air)     0.05

                                                                                                                              
    HAZARD/SYMPTOMS                       PREVENTION AND PROTECTION              FIRST AID
                                                                                                                              


    SKIN: Irritation, possible            Wear long-sleeved shirt and long       Remove contaminated clothing, wash with 
    sensitization                         trousers, chemical resistant gloves,   soap and water and obtain medical treatment;
                                          shoes or boots                         treat as an allergic dermatitis

    EYES: Irritation                      Wear safety goggles or face shield     Flush with plenty of water for at least 15 min
                                                                                 and obtain medical treatment

    INHALATION: Irritation                Avoid breathing dust or spray mist     Remove from exposure; obtain medical
                                                                                 attention

    INGESTION:                            Do not eat, drink, chew, or smoke      Obtain medical attention
                                          during use; keep out of reach of
                                          children
                                                                                                                              

                                                                                                                              
    HAZARD/SYMPTOMS                       PREVENTION AND PROTECTION              FIRST AID
                                                                                                                              

    ENVIRONMENT: Presents                 Contamination of water and soil should
    a risk for aquatic and soil           be avoided by proper methods of
    organisms                             application, storage, transport, and
                                          waste disposal

                                                                                                                              
    SPILLAGE:                                 STORAGE                                  FIRE AND EXPLOSION
                                                                                                                              

    Wear appropriate protective               Store in well ventilated area; keep      Benomyl is a flammable solid; keep away
    equipment during clean up; prevent        container tightly closed; store in       from sources of ignition; under severe dust
    liquid from entering sewers,              original container only, away from       conditions, benomyl may form explosive 
    waterways, or low areas; shovel, or       other pesticides, fertilizer, food,      mixtures in air; hazardous gas/vapour
    sweep, up                                 or animal feed; do not allow to          produced in a fire contains  n-butylisocyanate;
                                              become wet during storage                in case of fire, evacuate personnel to a safe
                                                                                       area, wear self-contained breathing apparatus,
                                                                                       use water or dry chemical to extinguish
                                                                                       fire, and cool tank/container with water spray

                                                                                                                              
    WASTE DISPOSAL
                                                                                                                              

    Treatment, storage, transportation,       National occupational exposure
    and disposal must be in accordance        limit:
    with applicable local regulations
    dispose of non-usable solid
    matter, contaminated soil
    and/or empty containers in an             National Poison Control Centre:
    approved and permitted landfill
    or by incineration; do not flush into
    surface water or sanitary sewer 
    systems
                                                                                                                              

    

    7.  CURRENT REGULATIONS, GUIDELINES AND STANDARDS

    7.1  Previous evaluations by international bodies

    Benomyl was evaluated by the Joint FAO/WHO Meeting on Pesticide
    Residues in 1973, 1975, 1978, 1983, and 1988. The 1978 meeting
    agreed that the Maximum Residue Levels for benomyl, carbendazim, and
    thiophanate-methyl should be combined and expressed as carbendazim.
    The 1983 meeting evaluated benomyl toxicity and set the following
    benomyl no-observed-effect levels (NOELs) and ADI:

         Rat                 2500 mg/kg (2500 ppm) in the diet,
                             equivalent to 125 mg/kg body weight

         Dog                 100 mg/kg (100 ppm) (carbendazim) in the
                             diet, equivalent to 2.5 mg/kg body weight

         Rat (teratology)    30 mg/kg body weight per day.

    The estimated ADI for benomyl was established at 0-0.02 mg/kg body
    weight.

    7.2  Exposure limit values

    Exposure limit values are presented in the table on pp. 20-21.

    7.3  Specific restrictions

    There are no specified restrictions on the use of benomyl.

    7.4  Labelling, packaging, and transport

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

    FIGURE 1

    Exposure limit values

                                                                                                                              
    Medium         Specification       Country/           Exposure limit description                Value
                                       organization
                                                                                                                              


    Food           apples & pears      Argentina          Maximum limit (MXL)                       5 mg/kg

    Food           plant (specified)   Brazil             Acceptable limit (AL)                     0.05-35 mg/kg

    Food           plant (specified)   Germany            Maximum residue limit (MRL)               0.2-7.0 mg/kg

    Food           plant (specified)   India              Maximum tolerable concentration (MTC)     0.1-5.0 mg/kg

    Food           food products       Kenya              Maximum residue limit (MRL)               0.2-15.0 mg/kg
                   (specified)

    Food           food products       Russian            Maximum residue limit (MRL)               0.1-0.5 mg/kg
                   (specified)           Federation

    Food           plant (specified)   United             Maximum residue limit (MRL)               0.1-10.0 mg/kg
                                         Kingdom

    Food                               FAO                Acceptable daily intake (ADI)             0.02 mg/kg body weight

    Food           plant (specified)   FAO                Maximum residue limit (MRL)               0.1-50 mg/kga

    Air            occupational        Argentina          Maximum permissible concentration (MPC)   10 mg/m3

    Air            occupational        Mexico             Maximum limit (8-h) (MXL)                 10 mg/m3
                                                          Maximum limit (15-min) (MXL)              10 mg/m3

    Air            occupational        Russian            Preliminary safety level (PSL)            0.01 mg/m3
                                         Federation
                                                                                                                              

                                                                                                                              
    Medium         Specification       Country/           Exposure limit description                Value
                                       organization
                                                                                                                              


    Air            ambient             Russian            Maximum allowable concentration (MAC)     0.35 mg/m3 (1 time/day)
                   environment           Federation                                                 0.05 mg/m3 (daily
    average)

    Air            occupational        USA                Time-weighted average (TWA)               10mg/m3

    Water          surface water       Russian            Maximum allowable concentration (MAC)     0.5 mg/litre
                                         Federation

    Air            occupational        United             Time-weighted average (8-h) (TWA)         10 mg/m3
                                         Kingdom          Short-term exposure limit (10-min) (STEL) 15 mg/m3
                                                                                                                              

    a Expressed as carbendazim.
    

    The following label statements are required:

         F         Flammable
         R11       Highly flammable
         R40       Possible risk of irreversible effects
         S7        Keep container tightly closed
         S36/37    Wear suitable protective clothing and gloves.

    US EPA requires labelling with a "Caution" signal word.

    Benomyl has been classified as a Marine Pollutant and a Flammable
    Solid by the International Maritime Organization.

    7.5  Waste disposal

    European Economic Community regulations require that benomyl and/or
    its container must be disposed of as hazardous waste. US EPA
    regulations require the wastes be disposed of on site or at an
    approved waste disposal facility. Containers must be disposed of in
    a sanitary landfill or by incineration.

    BIBLIOGRAPHY

    FAO/WHO (1985a) Benomyl. In:  Pesticide residues in food - 1983:
     evaluations 1983. Rome, Food and Agriculture Organization of the
    United Nations, pp. 7-46.

    FAO/WHO (1985b) Carbendazim. In:  Pesticide residues in food - 1983:
     evaluations 1983. Rome, Food and Agriculture Organization of the
    United Nations, pp. 89-121.

    FAO/WHO (1988a) Benomyl. In:  Pesticide residues in food - 1988:
     evaluations 1988. Rome, Food and Agriculture Organization of the
    United Nations, pp. 5-15.

    FAO/WHO (1988b) Carbendazim. In:  Pesticide residues in food - 1988:
     evaluations 1988. Rome, Food and Agriculture Organization of the
    United Nations, pp. 41-54.

    ILO (1991)  Occupational exposure limits for airborne toxic
     substances. Geneva, International Labour Organisation
    (Occupational Safety and Health Series, No. 37).

    UNEP IRPTC (1992)  IRPTC legal file 1992. Geneva, International
    Register of Potentially Toxic Chemicals, United Nations Environment
    Programme.

    WHO (1993)  Environmental Health Criteria 148: Benomyl. Geneva,
    World Health Organization.

    WHO (1993)  Environmental Health Criteria 149: Carbendazim. Geneva,
    World Health Organization.


    See Also:
       Toxicological Abbreviations
       Benomyl (EHC 148, 1993)
       Benomyl (ICSC)
       Benomyl (WHO Pesticide Residues Series 3)
       Benomyl (WHO Pesticide Residues Series 5)
       Benomyl (Pesticide residues in food: 1983 evaluations)
       Benomyl (JMPR Evaluation 1995 Part II Toxicological and environmental)