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Captafol

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Hazardous characteristics
4. USES
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstance of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY
   7.1 Mode of Action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI)
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced Elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    CAPTAFOL

    International Programme on Chemical Safety
    Poisons Information Monograph 097
    Chemical

    1.  NAME

        1.1  Substance

             Captafol

        1.2  Group

             Chloroalkyl thio fungicide

        1.3  Synonyms

             Difolatan;
             N-(1,1,2,2-tetrachloroethylthio)cyclohex-4-ene-1,2-
             dicarboximide (UPAC);

        1.4  Identification numbers

             1.4.1  CAS number

                    2425-06-1

             1.4.2  Other numbers

                    formula:  C10H9Cl4NO2S
                    RTECS   NIOSH/GW4900000

        1.5  Main brand names, main trade names

             Alfloc 7020
             Alfloc 7046
             Captaspor
             Captofol
             CS 5623
             Difosan
             Haipen 50
             Kenofol
             Folcid
             Nalco 7046
             Ortho-5865 (First introduced by Chevron as Code no.)
             Ortho Difolatan 80W
             Ortho Difolatan 4 Flowable
             Proxel EF
             Sanspor
             Sanseal
             Sulfonimide
             Sulfeimide

    
             A number of formulations are commercially available which
             include captafol together with other pesticides.

        1.6  Main manufacturers, main importers

             CHEVRON
             SANDOZ
             ICI Plant protection division
             Atlas Interlates Ltd
             Keno Gard VT AB

    2.  SUMMARY

        2.1  Main risks and target organs

             The acute oral toxicity is low.  Skin, eyes and
             respiratory tract are targets for local irritation and
             sensitization. Animal studies have demonstrated a
             carcinogenic potential.

        2.2  Summary of clinical effects

             Following ingestion of large quantities of captafol,
             vomiting and  diarrhoea may occur. Both allergic and contact
             dermatitis have been reported. Respiratory sensitization and
             conjunctivitis are also known to occur. Systemic disorders
             including hypertension, and hepatic and renal disturbances,
             usually paralleling the degree of dermatitis, have been
             reported following captafol exposure.

        2.3  Diagnosis

             Wheezing due to bronchospasm, contact dermatitis and
             vomiting and diarrhoea are the features of exposure to
             captafol by inhalation, skin contact and ingestion
             respectively. Chronic exposure can cause hypertension,
             depression of liver function, dermatitis, conjunctivitis and
             anaemia.
    
             Although a sensitive assay is available for captafol, the
             usefulness with respect to the clinical management of
             exposures to captafol seems remote in view of its low
             toxicity.

        2.4  First-aid measures and management principles

             In the event of exposure to captafol, contaminated
             clothing and contact lenses should be removed to prevent
             further absorption.In the case of skin contact, the affected
             area should be washed carefully with soap and water.  Wash
             eyes for 10-15 minutes with clean running water.  First aid
             personnel should wear rubber or plastic gloves and avoid
             contamination.
    
             Ingestion of small amounts of captafol do not constitute a
             significant risk, and may be managed by dilution with
             water.
    
             The management of large quantities of ingested captafol
             should be primarily directed towards decontamination and
             supportive care, as there is no specific antidote.  The use
             of Ipecac Syrup and activated charcoal are indicated in the
             event of ingestion.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Captafol, a synthetic chloroalkyl thio fungicide, was
             introduced by the Chevron Chemical Company in 1961 as Code
             Number "Ortho-5865" under the trade name "Difolatan".
    
             Captafol is formed by reacting the imide, produced by the
             action of ammonia on tetrahydrophthalic anhydride, with
             1,1,2,2-tetrachloroethyl sulfenyl chloride (Merck,
             1983).

        3.2  Chemical structure

             The empirical formula for captafol is C10H9C14NO2S with
             a molecular weight of 349.09.

        3.3  Physical properties

             3.3.1  Colour

             3.3.2  State/form

             3.3.3  Description

                    Melting point 160 to 161C (slowly decomposes).
                    Vapour pressure negligible at room temperature. 
                    Solubility practically insoluble in water (1.4 mg/L)
                    slightly soluble most organic solvents.

    
                    Captafol is a white crystalline solid.  The technical
                    trade is a light tan powder with a characteristic
                    odour.  It is stable except under strongly alkaline
                    conditions.  Commercially, captafol is available as
                    dusts, wettable powders and flowable
                    formulations.

        3.4  Hazardous characteristics

             Although captafol will not burn it is likely that under
             fire conditions toxic decomposition products such as sulphur
             oxides, phosgene, chlorine, nitrogen oxides will be produced,
             and these may be harmful by inhalation and dermal
             contamination.
    
             Although the pure substance is practically insoluble in
             water, the formulated product may pose an environmental risk
             if released  into an aquatic environment.  The LC50(96-h) is
             for:
    
                    rainbow trout           0.5 mg/L
                    goldfish                3.0 mg/L
                    bluegill                0.15 mg/L (Worthing, 1987)
    
             Captafol applied at 50 and 100 ppm persisted in four soil
             types up to 60 days (Venkatramesh, 1988).  Persistent on
             plant surfaces for 7-10 days.
    
             Structurally captafol is chemically similar to captan, for
             which alkaline treatment leads to the formation of nontoxic
             degradation products and is considered to be an
             environmentally acceptable disposal method (Dillon,
             1981). Since captafol is also degraded by strong alkali, small
             spillages and residues could be treated with alkali before
             burial in an approved landfill area.  Personnel involved in
             captafol disposal should be provided with protective
             equipment which should minimize dermal, ocular and
             respiratory exposure. Empty containers should be thoroughly
             drained before disposal.

    4.  USES

        4.1  Uses

             4.1.1  Uses

             4.1.2  Description

                    Captafol is a protective non-systemic fungicide
                    widely used to control foliage and fruit diseases of
                    tomatoes, coffee berry disease, potato blight, tapping
                    panel disease of rubber and many other diseases.  It
                    is also used in the lumber and timber industries to
                    reduce losses from wood rot fungi in logs and wood
                    products  (Worthing, 1987).

        4.2  High risk circumstance of poisoning

             Accidental among adult farm or timber workers and
             secondary exposure to their children.

        4.3  Occupationally exposed populations

             Workers involved in formulating and dispensing
             pesticides.
    
             Agricultural spray workers.
    
             Crop harvesters during disease vector control periods.
    
             Timber workers.

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Although no literature accounts were available at the
             time of preparation of this monograph, the ingestion of
             captafol either accidentally or intentionally is
             possible.

        5.2  Inhalation

             Inhalation of captafol as spray mists or powders have
             been reported in an occupational context. A TLV has been
             established by ACGIH (see Section 7.2.4).

        5.3  Dermal

             Dermal absorption is appreciable but has not been
             experimentally determined in humans. Studies in rabbits have
             shown a high dermal LD50 (see Section 7.2.2).

        5.4  Eye

             No data available.

        5.5  Parenteral

             No data available.

        5.6  Other

             No date available

    6.  KINETICS

        6.1  Absorption by route of exposure

             No data available.

        6.2  Distribution by route of exposure

             No data available.

        6.3  Biological half-life by route of exposure

             No data available.

        6.4  Metabolism

             Animal feeding studies have shown that most of the
             captafol is excreted unchanged, the major metabolite being
             tetrahydrophthalimide (see Section 6.5).

        6.5  Elimination by route of exposure

             When rats, dogs, and monkeys were fed 14C-captafol,
             almost 80% was excreted with 36 hours, mainly in the urine
             and none via expired carbon dioxide. Most of the small amount
             in the faeces was unmetabolized and probably unabsorbed. No
             unchanged captafol was detected in the blood tissues or
             urine.
    
             The major single metabolite, tetrahydrophthalimide, was
             detected in blood, faeces, and urine, but most of the
             activity in the blood and urine was in the form of more
             soluble metabolites. No captafol epoxide was detectable
             (Hayes, 1982).

    7.  TOXICOLOGY

        7.1  Mode of Action

             No data available.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             No data available.

                    7.2.1.2  Children

                             No data available.

             7.2.2  Relevant animal data

                    Rat oral LD50 varies from 2500 to 6200 mg/kg,
                    depending on  whether it is presented as an oil
                    solution or aqueous suspension.
    
                    Rabbit dermal LD50 is > 15400 mg/kg (80% wettable
                    powder).

             7.2.3  Relevant in vitro data

                    No data available.

             7.2.4  Workplace standards

                    TLV 0.1 mg/m3 (ACGIH, 1986).

             7.2.5  Acceptable daily intake (ADI)

                    A 14-day withholding period has been
                    recommended for fruit and vegetables that have been
                    treated with captafol (New Zealand Pesticide Board,
                    1983).

        7.3  Carcinogenicity

             In a dietary study of captafol fed to rats (250 to 5000
             ppm) the incidence of tumours was not increased at any dosage
             (Hayes, 1982).
    
             Rats initially given a single dose (200 mg/kg) of
             diethylinitrosamine i.p. were fed two weeks later with a diet
             containing 3000 ppm of captafol for six weeks, and then
             killed. Carcinogenic potential was scored by comparing the
             number and area per cm2 of induced glutathione S-transferase
             placental form positive foci in the liver with those of a
             corresponding control group given diethylinitrosamine alone.
             Captafol showed a significant increase in the value of
             foci.

    
             The authors of this study commented that this positive result
             for captafol, which they had shown previously to induce liver
             tumours in mice but not in rats (Ito et al., 1984), was
             further evidence for the carcinogenic potential of captafol
             (Ito et al., 1988).

        7.4  Teratogenicity

             Several teratology studies have been conducted with
             captafol in many mammalian species, including non-human
             primates. In most studies, where captafol was administered
             throughout organogenesis, low to no teratogenic potential was
             demonstrated.  However, results of studies with rabbits were
             contradictory.  There have been two studies with no malformed
             foetuses and one in which 9 of 75 foetuses were malformed.
             Further investigation (371 foetuses) did not produce a single
             increase in the number of abnormalities.
    
             In a study with golden hamsters, effects of single
             administration of captafol was compared with effects of
             repeated administration throughout organogenesis. At the
             highest single doses maternal mortality increased and some
             abnormal foetuses were reduced. At the lowest single doses
             and all multiple doses there were no indications of
             teratogenic activity (Clayton & Clayton, 1981).

        7.5  Mutagenicity

             Many authors have evaluated the mutagenicity of captafol
             and other related pesticides using the Salmonella/mammalian
             microsome with strains containing both A-T and G-C base
             pairs. The S9 mix decreased the mutagenic activity of
             captafol. Mutagenic activity varied, depending upon the
             strain tested  (Barrueco & de la Pena, 1988).
    
             In studies to test for the ability to induce chromosomal
             mutations captafol was not mutagenic, except in a single
             dominant lethal test which has been repeated by others
             several times with negative findings. In other tests (i.e.,
             sister chromatid exchange and testicular DNA synthesis)
             captafol was negative (Clayton & Clayton, 1981).

        7.6  Interactions

             Captafol has strong sensitization reactions in
             combination with daconil, kelthane, and bordeaux mixture
             (Matsushita & Aoyama, 1980).

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                    8.3.1.2  Urine

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
              interpretation

        8.5  Overall Interpretation of all toxicological analyses and
              toxicological investigations

             Sample collection
    
             Blood should be drawn in a heparinized tube and the red blood
             cells and plasma separated by centrifuging and then frozen if
             they must be kept for analysis.
    
             Samples from gastric lavage washing should be frozen and
             stored if subsequent analysis is desired. If the formulation
             of captafol is available, it should also be stored for
             possible subsequent analysis.
    
             Biomedical analysis
    
             Liver and renal function tests are indicated in the case of
             large ingestion of captafol.
    

             Toxicological analysis
    
             Although a sensitive assay is available for captafol the
             usefulness with respect to the clinical management of
             exposures to captafol seems remote in view of its low
             toxicity.
    
             An HPLC analysis has been developed for determining technical
             captafol and captafol in formulations. Captafol in ethyl
             acetate can also be determined using GLC with detection
             limits of 0.01 ppm (electron capture detector) and 0.03 ppm
             (flame photometric detector). Recoveries were 78-95%
             (Carlstrom, 1978).
    
             Other investigations
    
             No data available.

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    The acute oral toxicity is low (LD50 2500
                    mg/kg), probably due to rapid hydrolysis in the gut
                    (Gosselin et al., 1984).  Since dogs that received
                    captafol 300 or 100 mg/kg/day suffered frequent
                    vomiting and diarrhoea  (Hayes, 1982), it is not
                    unlikely that similar symptoms would occur in humans
                    following the ingestion of large quantities of
                    captafol.

             9.1.2  Inhalation

                    Respiratory sensitization has been reported
                    (see Section 9.4.2).

             9.1.3  Skin exposure

                    Both allergic and contact dermatitis have been
                    reported  (Hayes, 1982). Arimatsu (1970) reported that
                    farmers using captafol experienced numerous incidences
                    of skin irritation in a survey conducted between
                    1966-1969 in Kumamoto Prefecture (Japan). These
                    surveys revealed 442 cases (31.4%) of captafol-related
                    skin irritations in 1966, 572 cases (40.5%) in 1967,
                    442 cases (31.1%) in 1968, and 332 cases (24.6%) in
                    1969. Farmers affected with acute contact dermatitis

                    were engaged in spraying and other related operations.
                    Eruptions appeared as erythematous dermatitis of the
                    eyelids with local oedema,and eruptions were often of
                    the phototoxic type. Some affected individuals
                    suffered from photoallergic dermatitis. Most eruptions
                    disappeared about one week after exposure.
    
                    Similarly, Matsushita et al. (1979) have reported
                    rashes caused by captafol from other localities in
                    Japan. Twenty-three percent of 133 New Zealand timber
                    workers who were exposed to captafol, gave histories
                    suggestive of occupationally-induced dermatitis.
                    Although allergic dermatitis can occur, irritant
                    dermatitis is far more common (Stoke, 1979).

             9.1.4  Eye contact

                    Conjunctivitis and periorbital oedema has been
                    reported following occupational exposure to captafol
                    (Hayes, 1982).

             9.1.5  Parenteral exposure

                    No data available.

             9.1.6  Other

                    No data available.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    In a dietary study of captafol fed to rats (250
                    to 5000 ppm) liver and kidney abnormalities were
                    observed at 1500 ppm and above (Hayes, 1982).

             9.2.2  Inhalation

                    Respiratory sensitization has been reported
                    (see Section 9.4.2).

             9.2.3  Skin exposure

                    Both allergic and contact dermatitis have been
                    reported (Hayes, 1982). Patch tests to captafol were
                    positive in two laboratory chemists who had previously
                    worked with the chemical. In one case the chemist had
                    not handled captafol for several years but had
                    exhibited skin irritation towards the end of that
                    period. In the second case there was no previous
                    evidence of sensitivity but when contact had resumed
                    after an interval of several months the chemist
                    developed a rash on the neck and cheeks (Brown, 1984)
                    (see Section 11.1).

             9.2.4  Eye contact

                    Conjunctivitis and periorbital oedema has been
                    reported following occupational exposure to captafol
                    (Hayes, 1982).

             9.2.5  Parenteral exposure

                    No data available.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             No human fatalities have been reported. The toxicity is
             low.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Hypertension has been reported to occur,
                    especially in individuals who exhibited marked oedema
                    following dermal exposure to captafol (Hayes, 1982).
                    9.4.2 Respiratory

             9.4.2  Respiratory

                    Wheezing can occur after exposure (Royce et al,
                    1993). The sudden appearance of wheezing of a welder
                    was attributed to contact with bags of captafol in the
                    course of maintenance work for a company that
                    distributed captafol. Subsequent exposures lead to
                    re-occurrences.  Patch tests were positive 
                    (Groundwater, 1977).

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             No data available.

                    9.4.3.2  Peripheral nervous system

                             No data available.

                    9.4.3.3  Autonomic nervous system

                             No data available.

                    9.4.3.4  Skeletal and smooth muscle

                             No data available.

             9.4.4  Gastrointestinal

                    Since dogs that received captafol 300 or 100
                    mg/kg/day suffered frequent vomiting and diarrhoea
                    (Hayes, 1982), it is not unlikely that similar
                    symptoms would occur in humans following the ingestion
                    of large quantities of captafol.

             9.4.5  Hepatic

                    Depression of liver function usually
                    paralleling the degree of dermatitis has been reported
                    following captafol exposure (Hayes, 1982).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Protein and urobilinogen in the
                             urine have been reported, usually paralleling
                             the degree of dermatitis following captafol
                             exposure (Hayes, 1982).

                    9.4.6.2  Others

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    No data available.

             9.4.8  Dermatological

                    Both allergic and contact dermatitis have been
                    reported (Hayes, 1982) (see Sections 9.1.3 and
                    9.2.3).

             9.4.9  Eye, ears, nose, throat: local effects

                    Conjunctivitis and stomatitis have been
                    reported (Verhagen, 1974).

             9.4.10 Haematological

                    Anaemia has been reported following captafol
                    exposure (Hayes, 1982).

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No data available.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No data available.

                    9.4.12.3 Others

                             No data available.

             9.4.13 Allergic reactions

                    Both allergic and contact dermatitis have been
                    reported (Hayes, 1982) (see Sections 9.1.3 and
                    9.2.3).

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    Pregnancy - No data available.
    
                    Breast feeding - No data available.
    

                    Enzyme deficiencies - Depression of cholinesterase
                    activity has been reported (Hayes, 1982).

        9.5  Other

             No data available.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             The management of captafol poisoning should be
             primarily directed towards decontamination and supportive
             care, as there is no specific antidote. Ipecac Syrup or
             gastric lavage and subsequent activated charcoal and a
             cathartic are indicated in the event of ingestion.

        10.2 Life supportive procedures and symptomatic/specific treatment

             Following large ingestion of captafol, there are no
             specific procedures recommended other than the basic
             techniques for maintaining airways, breathing and
             circulation.

        10.3 Decontamination

             Wash contaminated skin with soap and water.
    
             Flush contaminated eyes (remove contact lenses if worn) with
             copious amounts of fresh water for 10-15 minutes).
    
             Ingestion of small amounts (less than 10 mg/kg bodyweight)
             occurring less than one hour before treatment are probably
             best managed by simpe dilution with water.
    
             Ingestion of large amounts (more than 10 mg/kg bodyweight)
             occurring less than one hour before treatment, are probably
             best treated by:
    
             *      Syrup of Ipecac, followed by 1-2 glasses of water
                    Adults and children over 12 years: 30 ml Children
                    under 12 years: 15 ml.
    
             *      Activated charcoal in water Adults and children over
                    12 years: 50 g in 250 ml water Children under 12
                    years: 30 g in 100 ml water.
    
             *      Ingestion occurring more than one hour before
                    treatment are probably best treated only by activated
                    charcoal (30-50 g).
    

             Because manifestations of toxicity may occasionally occur in
             peculiarly predisposed individuals, maintain contact with
             victim for at least 72 hours so that unsuspected adverse
             effects can be treated promptly (Morgan, 1982).

        10.4 Enhanced Elimination

             No specific elimination procedures have been
             established.

        10.5 Antidote treatment

             10.5.1 Adults

                    There is no specific antidote for captafol.

             10.5.2 Children

                    There is no specific antidote for captafol.

        10.6 Management discussion

             There is an absence of clinical data in the human
             overdose situation. Research into the allergic response
             mechanism is required.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Case 1. Adult male, research chemist, occupational
             exposure contact sensitivity.
    
             A 37-year-old male research chemist who, after several years
             away from contact with captafol, once again became interested
             in research on certain aspects. He had, in his first period
             of work with the substance, noticed towards the end that
             occasional contact resulted in skin irritation and a mild
             rash on the hands with irritation of the periorbital and
             nasal skin. Before embarking on a further series of
             experiments, it was decided that his apparent sensitivity
             should be investigated. He was asthmatic but had not
             experienced any exacerbation with captafol. Prick testing
             confirmed his atopic status. Patch testing to captafol was
             positive. Further occupational exposure to captafol was
             avoided (Brown, 1984).
    

             Case 2. A 34-year-old chemical manufacturing worker had new
             onset of work-related asthma after several years of exposure
             to captafol. On specific bronchial challenge testing, he
             demonstrated a marked and persistent fall in FEV1. Cessation
             of exposure resulted in improved symptoms and pulmonary
             function. The delay in symptoms after several years of
             work-place exposure and the dual reaction demonstrated on
             specific bronchial challenge testing suggest sensitization to
             some component of technical grade captafol, but an IgE
             response was not detected (Royce et al, 1993).

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             It is essential that persons intending to use captafol
             are provided with adequate health precautions and other
             safety instructions prior to usage. This information should
             be provided by the manufacturer in the form of either an
             information leaflet or on a label attached to the captafol
             container.
    
             Protective clothing is important. Captafol may cause dermal
             irritation and sensitization. The risk of this is greatest in
             hot weather when the user is sweating. Protective measures
             may include wearing a long-sleeved shirt, long trousers or
             overalls, and a hat of some sort. Respiratory protection
             should be considered. The label should give these details. 
             Clothing worn during spraying should be washed daily after
             use. Contaminated clothing should be washed separately from
             the general wash to avoid cross-contamination. When working
             with liquids, there is often a danger of a splash in the
             eyes. This may damage the eyes.  Simple goggles or a face
             shield will protect against this. Eye protection is most
             important if wearing contact lenses because captafol may get
             in behind the lenses. They must be removed before the eyes
             are washed, and in the time this takes, serious damage can
             occur.
    
             Greater precautions are necessary when mixing the
             concentrated material than when spraying. Measurements should
             be accurate and spillages should be cleaned up promptly. Mix
             the chemical carefully using a stick or paddle. Ensure there
             is minimal skin exposure by the use of gloves. if any
             concentrate is spilled on the skin, wash it off as soon as
             possible.
    
             The hazards of spraying increase dramatically on windy days
             as there is an increased risk of inhaling spray drift or
             contaminating the skin. Also, the risk of drift on to other
             properties or crops is increased.
    

             Always wash hands before eating, drinking or smoking. After
             spraying, shower and change clothing.
    
             By preference, captafol should be stored in a locked shed,
             safely out of reach of children and animals. Captafol should
             also be kept away from work areas and separate from other
             stored materials such as animal foods. Always leave captafol
             in its original containers, or if it must be transferred to
             another container ensure that this is one not normally used
             for food or drink. This secondary container should be
             well-labelled and of a variety that is not likely to
             leak.
    
             Empty containers must be disposed of carefully so as to
             ensure that rivers, streams, and other water sources are not
             polluted, and that unsuspecting people or animals are not
             exposed to residues of concentrate. Crushing or burning,
             followed by burial, is generally the best method. Workers
             involved in harvesting crops must adhere carefully to
             re-entry standards which have been set in order to prevent
             toxicity from captafol.
    
             First Aid Sheet
    
             Poisoning from captafol may occur after it is absorbed
             following:
    
             -  ingestion
    
             -  contact with the skin
    
             -  contact with the eyes
    
             -  inhalation.
    
             Signs and symptoms
    
             -  Ingestion may cause vomiting and diarrhoea.
    
             -  Skin contact and inhalation may result in local
                irritation and also sensitization.
    
             -  Eye contact may produce conjunctivitis.
    
             Decontamination
    
             -  It is important that captafol is removed as quickly as
                possible.  Contaminated clothing and contact lenses
                should be removed. Avoid contact of captafol with skin
                and eyes; first-aid personnel should wear rubber or
                plastic gloves and avoid contamination.

    
             Treatment - general
    
             -  Never give fluids or induce vomiting if the patient is
                unconscious or fitting.
    
             -  The patient must be watched constantly.
    
             -  It is important to keep the airways open and to
                prevent inhaling the vomit if nausea and vomiting is a
                problem.
    
             -  Give artificial respiration if the patient is not
                breathing.
    
             Treatment - ingestion
    
             -  Give 1-2 cups of cold water. Vomiting may be induced
                if advised by medical personnel. Obtain medical
                attention.
    
             Treatment - skin
    
             -  Remove all contaminated clothing immediately.
    
             -  Wash affected area carefully with soap and rinse with
                copious amounts of water. Obtain medical
                attention.
    
             Treatment - eyes
    
             -  Make sure any contact lenses are removed.
    
             -  Flush with water for 10-15 minutes. Obtain medical
                attention.
    
             Treatment - inhalation
    
             -  Remove the patient from the area of exposure.
    
             -  Be careful to avoid any contact with captafol.
    
             -  Protect skin and eyes. Give oxygen if available.
                Obtain medical attention.

        12.2 Other

             No data available.

    13. REFERENCES

        ACGIH (1986) Threshold limit values and biological exposure
        indices with intended changes for 1986-1987. American Conference
        of Governmental Industrial Hygienists, Cincinnatti, Ohio.
    
        Arimatsu Y Jr (1970) Study on the skin hazards caused by fungicide
        "Difolatan". Kumamot Igakkai Zasshi, 44(8): 692-721.
    
        Barrueco C & de la Pena E (1988) Mutagenic evaluation of the
        pesticides captan, folpet, captafol, cichlofluanid and related
        compounds with the mutants TA102 and TA104 of Salmonella
        typhimurium. Mutagenesis, 3(6): 467-480.
    
        Brown R (1984) Contact sensitivity to difolatan (captafol) Contact
        D  Dermatitis, 10: 181-182.
    
        Carlstrom AA (1978) Captafol. Anal. Methods Pestic. Plant Growth
        Regul., 10: 173.
    
        Clayton GD & Clayton FE, eds. (1981) Patty's industrial hygiene
        and toxicology. Volume 2A. Toxicology. Wiley-Interscience, New
        York, 2878.
    
        Dillon AP, ed. (1981) Pesticide disposal and detoxification.
        Processes and techniques. Noyes Data Corporation, New Jersey,
        588.
    
        Gosselin RE, Smith RP & Hodge HC (1984) Clinical toxicology of
        commercial products. Williams & Wilkins, Baltimore.
    
        Groundwater J (1977) Difolan dermatitis in a welder; 
        non-agriculture exposure. Contact Dermatitis, 3: 104.
    
        Hayes WJ Jr (1982) Pesticides studied in man. Williams & Wilkins,
        Baltimore, 672.
    
        Ito N, Ogiso T, Fukushima S, Shibata M & Hagiwara A (1984)
        Carcinogenicity of captafol in B6C3F1 in mice. Gann., 75:
        853-865.
    
        Ito N, Tsuda H, Tatematsu M, Inoue T, Tagawa Y, Aoki T, Uwagawa
        S,Kagawa M, Ogiso T, Masui T, Imaida K, Fukushima S & Asamoto M
        (1988) Enhancing effect of various hepatocarcinogens on induction
        of preneoplastic glutathione S-transferase placental form positive
        foci in rats - an approach for a new medium-term bioassay system.
        Carcinogenesis, 9(3): 387-394.
    
        Matsushita T & Aoyama K (1980) Participation of cross-reaction in
        skin sensitization by pesticides. Nippon Eiseigaku Zasshi (Jpn J
        Hyg) 35(1): 171.
    

        Matsushita T, Nomura S, Wakatsuki A, Matsushima S & Sugaya H
        (1979) Actual state of occurrence of skin impairment due to
        agricultural chemicals in Japan. J. Jap. Soc. Rural Med., 28:
        454-455.
    
        Morgan DP (1982) Recognition and management of pesticide
        poisonings. 3rd Edition. United States Environmental Protection
        Agency, Washington DC, 120.
    
        New Zealand Pesticide Board (1983) Pesticide Withholding
        Periods.
    
        Royce R, Wald P, Sheppard D, Balmes J (1993) Occupational asthma
        in a pesticides manufacturing worker. Chest, 103: 295-296.
    
        Stoke, JCJ (1979) Captafol dermatitis in the timber industry.
        Contact Dermatitis, 5(5): 284-292.
    
        Venkatramesh M & Agnihothrudu V (1988) Persistence of captafol in
        soils with and without amendments and its effects on soil
        microflora. Bull. Environ. Contam. Toxicol. 41: 548-555. 
    
        Verhagen ARHB (1974) Contact dermatitis in Kenya. Trans. St. Johns
        Hosp. Dermatol. Soc., 60: 86-90.
    
        Worthing CR ed. (1987) The pesticide manual. British Crop
        Protection Council, Worcestershire, 1077.

    14.  AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES),
         COMPLETE ADDRESS(ES)

        Authors:             Dr Wayne A. Temple
                             National Poisons and Hazardous
                             Chemical Information Centre
                             Dr Nerida A. Smith
                             Department of Pharmacy
                             University of Otago Medical School
                             P.O. Box 913
                             Dunedin
                             New Zealand
    
        Date:                16 October 1989
    
        Peer Review:         London, United Kingdom, March 1990.
                             Strasbourg, France, April 1990
    
        Update:              Dr R. Fernando
    
        Date:                June 1993
    





    See Also:
       Toxicological Abbreviations
       Captafol (HSG 49, 1990)
       Captafol (ICSC)
       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)