CAPTAFOL     JMPR 1973


         This fungicide was evaluated by the 1969 FAO/WHO Meeting on
    Pesticide Residues (FAO/WHO, 1970b) and a temporary acceptable daily
    intake for man of 0-0.05 mg/kg estimated. Further information on the
    absorption and distribution following oral administration was
    considered desirable and studies to elucidate the effects seen in
    teratogenicity experiments and the histologically apparent
    abnormalities in liver and kidneys of rats administered captafol were
    considered to be needed. The new date received on the residues deal
    primarily with the fate of captafol in animal tissues and milk and
    include results of supervised trials in additional crops. The expanded
    agricultural uses of captafol justify extension of tolerances to
    additional crops. The further information made available is summarized
    in this monograph addendum.


    Biochemical aspects

         One male and one female monkey, one male and one female dog and
    three male and three female rats were administered a single dose of
    captafol labelled with 14C in the C=0 groups. The dose given was
    about 7 mg/kg to monkeys and dogs and 16 mg/kg to rats, and it
    followed at least two weeks pre-treatment with unlabelled captafol.
    Expired CO2 was collected from rats and blood samples were taken
    periodically from dogs and monkeys. Urine and faeces were collected
    from all species until animals were killed 96 hours after dosage. The
    level of activity was measured in samples of urine, faeces, blood and
    tissues and extracts were examined to determine the metabolites
    present. About 80% of administered activity was excreted within 26
    hours, the majority in urine. Only a trace was excreted in expired
    CO2. Analysis of blood showed that absorption from the
    gastrointestinal tract was rapid; the maximum concentration in blood
    occurred after 10-15 hours. Only traces (0.05% of dose administered)
    of activity were found in liver, heart, kidneys, muscles and fat
    samples taken at autopsy. The rate of excretion was almost identical
    in the three species, as were the chromatographic patterns of extracts
    of faeces, urine and blood. Captafol was detected only in faeces.
    Tetrahydrophthalimide was detected in faeces, blood and urine and
    tetrahydrophthalamic acid in blood and urine. Captafol epoxide was not
    demonstrable in urine, blood or faeces (Crossley, 1968).

         A lactating goat was fed on diet containing 20 ppm captafol for
    seven days following which it received three consecutive daily doses
    of captafol labelled with 14C in the C=0 radicals. Examination of
    urine, faeces, blood, tissues and milk showed that this species
    metabolized captafol in a manner similar to rats, dogs and monkeys but
    at a faster rate. The major part of the 0.5 mg/kg dose was eliminated

    in 24 hours and there was no evidence of cumulation. At a dosage level
    of 0.5 mg/kg bw, milk contained approximately 0.05 ppm
    tetrahydrophthalamic acid but no captafol was detectable (limit of
    method 0.0005 ppm) (Crossley, 1970).

         Lactating cows were administered 14C labelled captafol orally
    at-dosage levels equivalent to a dietary level of 0.5 and 1 ppm for 30
    days. No captafol was detected in milk or tissues and the maximum
    concentration of metabolites in milk and tissues was <0.01 ppm
    (Anon., 1970).


    Special studies on teratogenesis

    Hamster. Groups of 10 pregnant female hamsters were fed diets which
    provided 0, 125, 250, 500 and 1000 mg captafol/kg bw/day on days 4-9
    of pregnancy. Animals were killed on day 15 and the uterine horns
    examined. Body weight gains were reduced between days 4-9 but
    recovered by day 15. In the 125, 500 and 1000 mg/kg groups, two, two
    and six females died during the test. The number of resorption sites
    was increased in the 125 and 500 mg/kg but not in other groups. The
    number of implantation sites was low in the 500 and 1000 mg/kg groups
    and the fetuses were lighter than normal. No specific abnormalities
    which could be attributed to captafol were detected at any of the
    dosage levels, (Arnold et al., 1968).

         Groups of 10 pregnant female hamsters received a single oral dose
    of 0, 125, 250 and 500 mg captafol/kg, or 1000 mg/kg thalidomide. Half
    of each group was dosed on day seven and half on day eight of
    pregnancy. All were killed and examined on day 15. The positive
    control and 250 and 500 mg/kg groups grew at a slower rate than
    controls. The number of live fetuses in each litter was reduced in the
    thalidomide and 250 and 500 mg/kg groups, and thalidomide and 500
    mg/kg captafol caused an increase in the number of resorption sites.
    No specific abnormalities attributable to captafol were found on
    examination of fetuses. The positive control group did not show any
    increase in fetal abnormalities (Arnold et al., 1968).

         Groups of 3-20 pregnant hamsters were administered a single dose
    of between 100 and 1000 mg captafol/kg bw on days seven or eight of
    gestation or were dosed daily with a total of between 500 and 1500 mg
    captafol/kg bw between days six and 10. They were killed and examined
    on the fifteenth day of gestation. The highest dosage levels increased
    maternal mortality and produced some abnormal fetuses but the lowest
    (single) dosage levels and the multiple doses produced no indication
    of teratogenic effect (Robens, 1970).

    Short-term studies

    Rat. Groups of 25 male and 25 female rats were administered captafol
    by gavage at a level of 250 mg/kg between days 1-7, 396 mg/kg between
    days 8-14, 667 mg/kg between days 15-21 and 1000 mg/kg between days

    22-28. A group of 10 males and 10 females acted as controls. Captafol
    was administered in the form of D1 foltan-4-Flowable, the composition
    of which was not stated. Groups of five test animals were killed on
    days seven, 14 and 21 and the remainder after 28 days. The food intake
    and body weight gain of males were depressed at all dosage levels but
    food intake only at the 1000 mg/kg level in females. The total
    leucocyte count was depressed in both sexes at the 1000 mg/kg level;
    the proportion of lymphocytes was decreased and neutrophils increased.
    The 1000 mg/k.g level also elevated SGPT, depressed the activity of
    serum alkaline phosphatase and increased the blood urea concentration;
    these were unaffected by lower dosage levels. At autopsy of the 1000
    mg/kg group distention of the stomach and intestines and erosion of
    the gastric mucosa were noted.  The spleen weight was markedly lower
    in the 1000 mg/kg group than in untreated rats. Microscopic
    examination of a wide range of organs and tissues failed to detect any
    abnormalities attributable to captafol (Plank et al., 1972).


         Biochemical studies demonstrate that captafol is rapidly absorbed
    and rapidly excreted, mainly as metabolites, in urine. No accumulation
    occurs in tissues. The metabolic pathway of the tetrahydrophthalimide
    moiety is likely to be the same as that in captan but the fate of the
    tetrachloroethylthiomoiety has not been examined.

         A teratogenicity studies in hamsters was negative as were
    previously reviewed teratogenicity studies in monkeys and rabbits.

         The results of a test in rats that received increasing daily
    doses of up to 1000 mg/kg/day over a 28 day period did not help to
    elucidate the occurrence of the abnormalities seen in the kidneys and
    liver in an earlier two-year rat study. It did, however, demonstrate
    that at the highest dosage level a lymphocyte to neutrophil shift
    occurred, an effect previously noted in the long-term experiment.

         Although the results of studies requested have not yet been made
    available there is sufficient evidence to allow the establishment of a
    temporary acceptable daily intake.


    Level causing no significant toxicological effect

         Dog - 10 mg/kg bw per day

    Estimate of temporary acceptable daily intake for man

         0-0.05 mg/kg


    Use patterns

         Submissions from five countries; Canada, Japan, Netherlands,
    Australia and New Zealand list accepted agricultural uses for
    captafol. Also the basic manufacturer submitted product labelling for
    the United States of America and France which reflect current usage in
    those countries. The information on hand indicates that the fungicide
    is used on some 22 new commodities, in addition to the eight
    commodities evaluated in 1969.

         The information available on agricultural uses in the responding
    countries is sometimes fragmentary and shows a disparity in spray
    concentrations, spray volume, frequency and timing of treatment, and
    pre-harvest intervals, Table 1 contains a summary of the overall crop
    uses, showing the range in each use parameter whenever possible.

    TABLE 1

    Crop                Application         Number of         Pre-harvest
                        rate. (a.i.)        applications      interval - days
    Apples, pears       0.12-0.62%          1-4               7-15
                        1.4 - 22 kg/ha      1                 pre-bloom

    Beans)              0.096-0.14%         Na(1)             none

    Cabbage             0.8-1.5 kg/ha       4                 10

    Celery              0.1-0.24%           Na                0-14

    Citrus              0.1-0.5%            1-4               7-15

    Coffee              0.6%                2-4               none

    Cranberries         5.5 kg/ha           3                 50

    Grapes              0.8-2.0 kg/6        5                 1

    Leeks               0.12%               No                21

    Lettuce             0.1-0.32%           Na                0-14

    Macadamia           0.2%                1-2               none

    Nuts                12 kg/h.

    Crop                Application         Number of         Pre-harvest
                        rate. (a.i.)        applications      interval - days

    Onions              0.1-0.15%
                        0.6-1.38 kg/ha      6                 0-7

    Pineapple           (a) 0.48-1.6%       1
                        (b) 8.8 kg/ha       8                 indefinite

    Potatoes            0.1-0.3%            7-10 day          none
                        0.8-17.6 kg/ha      intervals

    Pumpkins            0.8-1.0 kg/ha       7                 1

    Strawberries        0.7-1.0 kg/ha       5                 1

    Tea                 Na                  Na                Na

    Na - Not available

    Note: (1)  Larger dosages generally for single early season use
          (2)  Larger dosages generally for treatment when fruit not
          (3)  Treatment (a) is dip of transplani slips, (b) is foliar
               spray. USA directions provide for treatment at planting and
               once monthly for eight months. Because of long growing
               period before harvest there would be an interval of at
               least 12 months.

    Residues resulting from supervised trials

         The new residue data made available in most cases indicate that
    the chemical entity measured was captafol, per se. Unless otherwise
    noted the residue values cited are presumed to be captafol.

    Apples and pears

         Data were available from France, Japan, Netherlands, New Zealand
    and the United States of America. The data is weakened in many cases
    by long periods of fruit storage before analyses. Data are freely
    extrapolated between apples and pears.

         Estimated residue following approved use seven days before
    harvest - 5 ppm.


         No data. Because of the unique cultural practices and physical
    characteristics of asparagus spears and because there are no data from
    other crops which might be extrapolated to asparagus, no opinion
    concerning residue levels is offered.


         No data. Estimated residue - not possible.


         No new data on carrots was made available. In the 1969 evaluation
    it was stated that carrots and radishes in field experiments did not
    take up captafol residues as determined by an analytical method
    sensitive to 0.05 ppm. (FAO/WHO, 1970). It would be consistent to
    establish a uniform low level tolerance of 0.5 ppm for the root crops
    which are under consideration at the 1973 JMPR.


         Limited data from supervised trials indicate very low residues on
    cabbage sampled 10 to 20 days after treatment. The low residues might
    be attributed to the practice of stripping wrapper leaves prior to
    harvest. Because the values reported from this single trial (0.01 to
    0.14 ppm) are inconsistent with deposits from foliar applications on
    other crops it would be desirable to have further field trials with
    details of sample preparation before further consideration is given to
    tolerances on cabbage.


         No data.


         Uses on citrus are sharply divided into those which are applied
    following when no mature fruit are present (primarily to avoid
    reduction of quality of fresh fruit by spotting), and coverage sprays
    with specified pre-harvest intervals ranging from 7-15 days. There are
    ample data to show that residues from the first type of treatment will
    not exceed 0.5ppm. Adequate data are not available to show residues
    which are likely to result from the latter type of treatment.


         No data.


         Data from the United States of America, which is the only country
    indicating use on this crop, show that residues would not exceed 5 ppm
    under the conditions of use.


         Some data on captafol residues when applied with captan are
    available. However, the sampling schedule is not pertinent to the
    pre-harvest interval accepted in some countries (see Table I).
    Additional data on grapes, corresponding to the spray schedules now
    permitted, should be obtained before further consideration is given.


         There are no data on eggplant. In view of the similarity of
    physical characteristics with tomato fruit and similarity of use
    pattern, it can be concluded that the residue data on tomatoes would
    apply. Data on tomatoes show that residues would not exceed 5 ppm.


         No data are available for lettuce or similar leafy vegetables.

    Macadamia nuts

         Residue data from Hawaii, which is the only place where use is
    indicated, show no detectable residues in nut meats above limits of
    detection. A United States tolerance of 0.1 ppm has been established
    to cover incidental contamination of macadamia nut meats.

    Onions and leeks

         Limited data from one country on bulb onions show only trace
    residues (0.01-0.03 ppm) when application is made four and seven days
    before harvest. Consistent with the opinion on other root crops under
    consideration it can be concluded that residues on bulb onions will
    not exceed 0.5 ppm. This opinion does not include green onions, spring
    onions, or shallots in which aerial plant parts are consumed. Data
    from Netherlands show residues on leeks at 8 ppm under good
    agricultural practice (21 day PHI).


         Data on fruit treated according to United States registered
    labels show that residues would not exceed 0.1 ppm. This is a
    restricted use in which no treatments are made after the eighth month
    from planting. From planting to harvest of the first crop is about two
    years. Reports from other pineapple growing areas indicate that sprays
    may be applied up to harvest. Data from such treatments show high

    residues (22 ppm whole fruit and 55 ppm in peel). Before further
    consideration is given, additional information should be required on
    world wide patterns of use.


         Data show that residues on potatoes treated up to harvest will
    not exceed 0.5 ppm.


         There are no data on pumpkins but previous data on melons and
    cucurbits should support extension of present temporary tolerances on
    these commodities to pumpkins.


         Limited data from one country indicate initial deposits of about
    3.5 ppm declining to 1-2 ppm in seven days.  Before further action is
    taken there should be additional information on agricultural uses and
    more residue data.


         A limited number of analyses of green tea and brewed tea are

         Residues in brewed tea are below limits of analytical
    sensitivity. Residues on green tea approach 1.5 ppm. No information
    has been provided at all on use patterns in tea growing countries.
    Additional information on use patterns and residue data are required.

    Fate of residues

         The fate of captafol residues in animals, plants and soil was
    reviewed in detail at the 1969 Joint Meeting (FAO/WHO, 1970). Certain
    degradation mechanisms, including sulfhydryl reactions and hydrolysis
    were recognized as producing tetrahydrophthalimide (THPI),
    tetrahydrophthalamic acid, tetrahydrophthalic acid and dichloroacetic
    acid residues in certain substrates. However, it was noted that
    information was lacking on the absorption, distribution and identity
    of metabolites in animal tissues following oral administration.

         There is now information on the nature and fate of residues in
    animals in two unpublished reports from the basic manufacturer which
    describe radioisotope metabolism studies in a lactating goat
    (Grossley, 1970) and in lactating cows (Chevron, 1970). These studies
    are summarized as follows:

    Goat study

         A single goat received three consecutive daily doses of C14
    labelled captafol (carbonyl position) at a level of 15 ppm in total
    ration. The animal was equilibrated with unlabelled captafol for seven
    days, and conditioned for a further five days prior to sacrifice. A
    balance study was conducted on urine, faeces, blood, milk, organs and
    muscle tissue. Activity in the various substrates was subjected to
    solvent partitioning and metabolites were identified by paper and thin
    layer chromatography. About 80% of the total administered dose was
    accounted for. Eighty-five per cent of the excreted activity was in
    the urine, 14% in the faeces and 0.3% in milk. A total of 0.83% of the
    administered dose was found in the tissues. The predominant metabolite
    in urine was tetrahydrophthalic acid along with other polar
    metabolites including tetrahydrophthalamic acid.

         0.3% of the applied dose was found in milk. None was parent
    compound (limit of detection 0.0005 ppm) but residues of
    tetrahydrophthalamic acid and tetrahydrophthalic acid were detected.
    The average residue level for total metabolites in milk was 0.05 ppm
    (expressed as tetrahydrophthalamic acid) but individual values
    indicate that metabolite residues on the order of 0.1 ppm in milk
    could be expected at this feeding level.

         Residues in tissue accounted for only 0.83% of applied dose, of
    which most (0.74%) was in muscle. This is equivalent to 0.012 ppm.
    However, it should be noted that sacrifice was five days after C14
    administration ceased. In view of the rapid elimination from the body
    it would be reasonable to expect that the liver and kidney would have
    held higher residues if slaughter had occurred earlier. The identity
    of the radioactivity in muscle was not established but only 1% was
    extractable with organic solvents, indicating it was not captafol or
    tetrahydrophthalimide, but probably second or third order metabolites.

    Cow study

         Two groups of three cows each were fed C14-labelled captafol
    (carboryl position) at levels equivalent to 0.3 and 1.0 ppm in total
    ration for 30 days. Accountability of the total administered C14 dose
    was achieved by monitoring the same excreta and tissues as described
    in the goat study. Radio-activity in the substrates examined was
    characterized by solvent partitioning and identified by TLC. The cow
    study differs in two important respects from the goat study. The
    animals were not equilibrated with unlabelled captafol before giving
    the C14 compound, and they were slaughtered within 24 hours after
    medication ceased. The C14 accountability was 84-101%, the major route
    of excretion being in the urine. No parent captafol was detected in
    milk or tissues at any time. Activity in the form of metabolites did
    occur in milk but at no time exceeded 0.005 ppm as total metabolites.
    A similar picture obtains with respect to tissue, where no parent
    captafol was detected and total metabolite residues were <0.01 ppm.

    Residues in meat and milk were dose responsive (in both cow and goat
    work) and should permit interpolation or extrapolation to gauge
    residues from other intake levels.


         The goat and cow studies demonstrate that ruminants degrade and
    excrete captafol in much the same manner as was previously shown for
    the rat, dog and monkey (FAO/WHO, 1970b). Metabolism is somewhat more
    rapid in ruminants and the relative proportions of the water-soluble
    metabolite tetrahydrophthalic acid is greater in ruminants than in
    monogastric animals.

         There are no approved uses of captafol on primary forage crops.
    Certain crop by-products, culls or offal could introduce small amounts
    of residues into animal rations. No data were made available on
    possible residues in offal such as citrus pulp. Potatoes containing
    residues at the tolerance level (0.5 ppm) would contribute only 0.17
    ppm to the total animal diet assuming a maximum of 30% potatoes in the
    ration. Relating this intake level to the cow feeding study, it is
    estimated that residues of metabolites in milk would be <0.005 ppm
    and in tissues <0.01 ppm. It would therefore not appear necessary to
    recommend practical residue limits for meat and milk.

    Methods of residue analysis

         The 1969 evaluation (FAO/WHO, 1970) discussed methods of analysis
    available for captafol residues. There are published methods which
    distinguish between captafol and the related fungicides captan and
    folpet. References are given for methods which determine parent
    captafol and two tetrahydrophthalic acid metabolites (Chevron, 1970a).

         The 1969 monograph also noted that it would be desirable to have
    a collaborative study to validate a method suitable for regulatory
    purposes to determine captafol in the presence of captan and folpet.
    No new information has become available on suitable methods.


         Worldwide agricultural use of captafol has expanded to include 21
    commodities other than the eight commodities for which temporary
    tolerances were recommended in 1969. Seven countries have responded
    with information on current use patterns and/or residue data. The data
    would in many cases support the extension of the present recommended
    tolerances on eight commodities to other crops.

         The animal metabolism studies requested in 1969 are now available
    and do not show the presence of any metabolites in milk or edible
    tissues other than those which were previously known. No residues of
    parent or the tetrahydrophthalimide or its epoxide occur in meat or
    milk at the levels fed. Trace residues of the tetrahydrophthalamic
    acid and tetrahydrophthalic acid do occur. Since captafol is not used

    on primary forage crops it would not appear to be necessary to
    recommend practical residue limits in meat or milk.

         The information requested on effects of washing and processing on
    residue levels, data on residues occurring in raw commodities in
    commerce and the collaborative study on a regulatory method, have not
    become available, but in the light of all the information now
    available may not be regarded as essential.


         The following temporary tolerances are recommended in addition to
    those recommended in 1969 and are based on the pre-harvest intervals

                                  Temporary           Pre-harvest
    Food commodity                tolerances          interval
                                  (in ppm)            (in weeks)

    Cranberries                   8                   50

    Leeks                         8                   21

    Apples and pears              5                   7

    Eggplants                     5                   1

    Pumpkins                      2                   1

    Carrots, onions (bulb),       0.5                 0

    Macadamia nuts (shelled)      0.1                 0


    Required (by 1976)

    1.   Further studies to assist evaluation of histopathological
         changes in the kidneys and liver of rats.

    2.   Studies to investigate the lymphocyte-neutrophil shift
         noted in previous experiments.


    1.   Studies to investigate to metabolism of the
         tetrachloroethylthio-moiety of captafol.

    2.   Data on effects of washing, peeling, and blanching on
         residue levels in various crops.

    3.   Data on residue levels occurring in commodities moving
         in commerce.

    4.   Additional residue data and information on agricultural
         practices in user countries with respect to asparagus, beans,
         cabbage, celery, citrus fruit, coffee, grapes, lettuce,
         pineapple, strawberries, and tea.


    Anon., The fate of difolatan in lactating cows, Unpublished
    1970                report submitted by Chevron Chemical Co.

    Arnold, D., Kodras, R. and Fancher, O. E. Teratogenic study
    1968                on difolatan technical in Golden Syrian hamsters.
                        Unpublished report of Ind. Bio-Test Labs submitted
                        by Chevron Chemical Co.

    Chevron. The fate of difolatan in lactating cows unpublished
    1970                report, Chevron Chemical Co. 30 October.

    Chevron. Method RM6B Chevron method for the tetrahydrophthalamic
    1970a               acid and tetrahydrophthalic acid metabolite.

    Crossley, J. Difolatan: fate in animals. Unpublished report
    1968                submitted by Chevron Chemical Co.

    Crossley, J. The fate of difolatan in a lactating vominant
    1970                (goat). Unpublished report submitted by Chevron
                        Chemical Co.

    FAO/WHO             1969 Evaluation of some pesticide residues in food
    1970                FAO/PL: 1969/m/17/1

    Plank, J. B., Wright, P. L. and Keplinger, M. L. Twenty-eight
    1972                day target organ study with difolatan 4 flowable
                        in albino rats. S.O. No. S139591, S-331
                        Unpublished report of Ind. Bio-Test Labs submitted
                        by Chevron Chemical Co.

    Robens, J. F. Teratogenic activity of several phthalimide
    1970                derivatives in the golden hamsters. Toxicol. Appl.
                        Pharmacol., 16: 24


    See Also:
       Toxicological Abbreviations
       Captafol (HSG 49, 1990)
       Captafol (ICSC)
       Captafol (PIM 097)
       Captafol (FAO/PL:1969/M/17/1)
       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)