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    CAPTAFOL        JMPR 1976

    Explanation

         This fungicide was evaluated by the Joint Meetings in 1969,
    1973 and 1974 (FAO/WHO 1970b, 1974b and 1975b).

         The 1973 Joint Meeting considered the following information
    desirable.

    1.   Studies to investigate the 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 in commodities moving in commerce.

    4.   Additional 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.

         No new data were obtained on question 1 and only limited data
    on questions 2 and 3. Information was received on both uses and
    residues resulting therefrom on pineapple but not on any other
    crops mentioned in question 4. However some information was
    provided on extensions of the use pattern in some countries on pea
    nuts, potatoes, tomatoes and wheat, and on the resulting residues.

         A further evaluation of captafol for acceptable daily intake
    is planned for 1978, for the reasons given in the Report of the
    present Meeting (FAO/WHO, 1977a).

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         Information on recently introduced uses of captafol is given
    in Table 1.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Residue data became available from supervised trials on
    pineapple and on some crops not included in the 1973 monograph,
    namely peanuts, potatoes, tomatoes and wheat. A summary of the data
    is provided in Tables 2-4.


    
    TABLE 1. Use pattern. Information not included in the monographs of the 1969, 1973
             and 1974 Joint Meetings

                                                                                                                            

                                                     Application                                      Recommended
                                                                                                      pre-harvest
                                Target         No. of                      Mode of                    interval       In use
    Crop          Country       organism       treatments   kg a.i./ha     treatment                  (days)         since
                                                                                                                            

    peanuts       U.S.A.                       5-10         1.5            spraying                   14             1973

    pineapple     South         heart rot      4 times      8              spraying (200              21             1973/
                  Africa                       monthly                     g a.i./100 l)                             1974

    potatoes      South         early &        7-11         max. 1.6       spraying at 7              3              1972
                  Africa        late                                       day intervals
                                blight

                  U.S.A.        early &                                                                              1971
                                late
                                blight

    tomatoes      South         early &        4-5          max. 4.8       spraying at 7              3              1972
                  Africa        late                                       day intervals
                                blight                                     (160 g a.i./
                                                                           100 1).

    wheat         Netherlands   mildew and     1            1              one or two sprayings       42             1975
                                ripening                    mixed with     from development
                                diseases                    other          of the ear until the
                                                            fungicides     until the beginning
                                                                           of flowering Feekes
                                                                           scale 10.1 - 10.5.1.
                                                                                                                            

    

    Peanuts (Chevron 1975)

         Thirteen experiments were carried out in 1973 and 1974: 4 in
    Florida, 3 in Texas, 2 in Georgia, 2 in Alabama, 1 in Oklahoma and 1
    in North Carolina.

         In all the experiments the fungicide was applied at the
    recommended rate i.e. 1.5 kg a.i./ha. Multiple applications were made
    6-10 times, using ground or air equipment.

         The peanuts were dug 9-27 days and combined 16-28 days after the
    last application.

         Residues were determined on whole pods, hulls, shelled nuts, oil,
    meal, peanut butter, roasted beans and vines at various stages of
    dryness.

         The maximum residues observed after application of 1.5 kg a.i./ha
    were:

                                         maximum residue
       commodity                            in mg/kg

    whole mature pods                       0.46

    hulls                                   1.3

    shelled nuts                            <0.01

    oil (hexane extracted or hydrolic
    pressed)                                <0.01

    peanut meal                             <0.01

    peanut butter                           <0.01

         Details are given in Table 2. In the Table the residues of
    captafol in shelled nuts, peanut meal, peanut oil and peanut butter
    are omitted since the maximum residue values found were all at or
    about the limit of determination.

    FATE OF RESIDUES

    In animals

         A feeding study was carried out in which 6 mature lactating
    Holstein cows, all at a medium stage of lactation, received either 5.7
    or 11.4 mg 14C-captafol orally for 30 days. These levels correspond
    to 0.5 and 1 ppm respectively in the total diet. The latter levels are
    considerably higher than those which would occur from the inclusion of
    peanut hulls or potatoes at normal proportions in the total diet.


        TABLE 2. Residues of captafol in peanuts in U.S.A. (Chevron, 1975)
                                                                                                                                               
                                                                Interval after application                                                     
                                                              14-17 days                                                                     
                    Application                  Residue, mg/kg                                             Residue, mg/kg
                                                                                         moisture                                       moisture
    Year            rate          formulation    whole                                   content   whole                                content
              no    kg a.i./ha                   pods           hulls          vines     vines %   pods         hulls       vines       vines %
                                                                                                                                               

    1973      10    1.5           wp             0.04-0.07a     0.57-0.64a     20-23a    75a                                13-14a  14a
    1973      10    3             wp             <0.01-0.27                    76-90     75
    1973      10    1.5           wp                                                               0.06-0.14    1.1 - 1.3   184-230     21.5
    1973      9     1.5           wp                                                               0.25-0.46    1.1 - 1.3   194-211     21.8
    1973      9     3.0           wp                                                               1.1 - 1.4                568-588     20.4
    1973      7     1.5           wp                                                               <0.01-0.02   0.45-0.50   117-176     9.9
    1973      7     3             wp                                                               <0.01-0.02               100-203     13.7
    1973      11    1.5           wp                                                               <0.01        <0.01       24-30       16.6
    1973      8     1.5           wp             0.02-0.11      0.48-0.97      82-97
    1973      8     3.0           wp             0.04-0.08                     32-33
    1974      8     1.5           wp                                                               0.09-0.15    1.3 - 1.4   75-102      14.5
    1974      10    1.5                                                        110-122b  78b       0.36-0.39b               39-52b      38b
    1973      5     1.2                                                                            0.02-0.02    0.03-0.08
    1973      5     2.4                                                                            0.02-0.03    0.13-0.16
    1973      11    1.2                                                                            <0.01-0.01   0.49-0.88   101-109
    1973      11    2.4                                                                            0.01-0.01    1.25-1.27   85.5-107
    1974      7     1.5                                                                            0.18-0.23
    1974      10    1.5                                                                            0.36-0.39
                                                                          42-50 days                                 51-54 days
              4     1.2           wp                                                               <0.01-0.02   0.06-0.11
              4     2.4           wp                                                               <0.01        0.25-0.51
              5     1.0           wp                                                               0.03-0.04    0.17-0.24   36-82.9
              5     2.0           wp                                                               0.01-0.03    0.26-0.45   122-133
    1973      10    1.5           wp                                           7.6-11.0a 12.2a
    1974      10    1.15          wp                                           39-41b    13.5b
                                                                                                                                               
    a Results from a single trial

    b Results from a single trial

    TABLE 3. Residues of captafol in pineapple, potatoes and tomatoes

                                                                                                                    
                                                                     Residues, mg/kg, at interval (days)
                                 Application                                   after application                    
                                  rate         formulation
    Crop           Country   no   kg a.i./ha                    0      1-3       7        13/14      27/28       89
                                                                                                                    

    Pineapple      South     41   200g/100 l   wp
                   Africa
     whole fruit                                                       15.7      22.8     1.6        5.1         2.5

     rind                                                              35.5      55.6     23.8       8.6         6.25

     pulp                                                              <0.3      <0.3     <0.3       <0.3        <0.3

    Potatoes       South     11   1.6 kg/ha    wp                                         <0.05
                   Africa

    Tomatoes       South     4    2.4          wp               4.7    4.1,      2.4      2.5
                   Africa                                              2.9
                                                                                                                    

    1 monthly

    TABLE 4. Residues of captofol in wheat
                                                                                                                                     
                                                                          Residues, mg/kg, at interval (days) after
                                            Application                   application, average (range)
                                                                                                                         
    Wheat                              no   rate         formulation
    fraction   Country        Year          kg a.i./ha                    38        42/43          48        66                Ref.
                                                                                                                                     

    grain      Netherlands    1974     1    0.75         wpa                                                 (<0.05-<0.05)     ICI
                              1974     1    1.00         wpa                                                 (<0.05-<0.05)     1975

    grain                     1975     1    1.0          wpa                        0.03                                       ICI
                                                                                    (0.01-0.09)                                1975
    straw                                                                           3.6
                                                                                    (1.5-4.8)
    grain                     1975     1    1.0          wpa                        0.1                                        ICI
                                                                                    (0.07-0.14)                                1975
    straw                                                                           1.8
                                                                                    (0.7-2.9)
    grain                     1975     1    1.0          wpa                                       <0.01                       ICI
    straw                                                                                          <0.01                       1975

    grain                     1975     1    1.0          wpa                        <0.01                                      ICI
    straw                                                                           1.3                                        1975

    grain                     1975     1    1.0          wpb              <0.01                                                ICT
    straw                                                                 <0.1                                                1975

    grain                     1975     1    1.0          wpb                        0.05                                       CIBA-
    straw                                   1.0          wpb                        0.22                                       Geigy
                                                                                    (0.16-0.31)                                1975

    grain                     1975     1    1.0          wpb              0.05                                                 Ciba-
                                                                                                                               Geigy
    straw                                                                 0.74                                                 1975
                                                                          (0.51-0.87
                                                                                                                                     

    a mixture with ethirimol            b mixture with CGA 30599
    

         For peanut hulls, the maximum used in the diet is 20%, in most
    instances only 10% in a maize/soybean base diet. For peanut meal the
    maximum amount in the diet could be about 25%, with the normally used
    maximum being 10%.

         The maximum residue level found in peanut hulls, after 6-11 spray
    applications at the recommended rate of 1.5 kg a.i./ha was 1.3 mg/kg,
    thus leading to a maximum of 0.26 mg/kg in the diet. The peanut meal,
    with maximum levels of 0.03 mg/kg will not contribute significant
    captafol residues. The feeding levels chosen are 5-10 times higher
    than the amounts in the total diet derived from potatoes, when these
    constitute no more than 20% of the total diet and residues are
    approximating the proposed maximum residue limit of 0.5 mg/kg. 20%
    potatoes is the maximum ratio recommended, normally the proportion is
    lower.

         An excellent recovery of captafol was obtained in this study, the
    range being 84-101%. By far the major route of excretion was the
    urine, with faeces accounting for a lesser but significant quantity.
    In the same feeding study Bio-Test Laboratories (1970) showed that
    captafol was rapidly excreted from cows receiving daily oral doses of
    14C captafol. The major excretion route was the urine, the remainder
    (about 10%) being excreted in the faeces. No captafol was found in
    either the milk or tissues at any time. The total concentration of
    captafol and its main metabolites containing 14C in whole milk at
    any time was also insignificant (< 0.01 mg/kg).

         Radioactivity was monitored in samples of milk, tissue, urine and
    faeces. The average counting efficiency was 70% in the milk samples,
    58% in blood and 54% in tissue. The limit of detection of
    radioactivity in this study was set at 20% above background. From the
    data the following limits of detection of captafol and its 14C-
    metabolites may be calculated.

    milk                0.0004 mg/kg Captafol +  14C-containing
                                                 metabolites calculated
                                                 as captafol

    fat                 0.004 mg/kg  "           "

    blood               0.002 mg/kg  "           "

    other tissues       0.002 mg/kg  "           "

                                                 (Chevron 1970)

    Milk

         At the lower feeding rate of 5.7 mg 14C-captafol the levels of
    14C calculated as captafol equivalents found in the daily pooled milk
    varied between 0.001 and 0.003 mg/kg. Two days after the last dosing
    no residues could be detected in the milk. At the feeding rate of

    11.4 mg captafol the corresponding levels ranged from 0.002 to
    0.006 mg/kg. The levels of 14C in the milk of treated cows followed a
    rapid equilibration and elimination pattern. Within 24 hours of the
    first dose the radioactivity in the milk reached a level which was not
    exceeded during the entire 30 days dosing period. Once the
    administration of captafol was stopped the 14C concentration in the
    milk dropped quickly; two days later no measurable amounts of 14C
    were found. (Chevron, 1970)

    Tissues

         14C captafol residues (mg/kg total metabolites calculated as
    captafol) were measured in tissues obtained from cows, 24 hours and 8
    days after the last dose of 14C captafol. In the former group the
    levels of radioactivity did not exceed 0.01 mg/kg of total metabolites
    except in liver and kidney. Since it was shown that over 90% of the
    administered dose was excreted in the urine it is not surprising that
    the concentration of 14C was somewhat higher in these organs (Table
    5).

    Blood

         Only traces of radioactivity were found in the blood, the highest
    value being 0.005 mg/kg.

    In storage, processing and cooking

         Only limited data were obtained on the effect of household
    washing on captafol residues. In an experiment on leeks (ten Broeke
    and Dornseiffen 1973) it was shown that normal household washing
    removed 62-84% of the residue (Table 6).

    NATIONAL TOLERANCES REPORTED TO THE MEETING

         Since the 1969 and 1973 evaluations of captafol (WHO/FAO 1970b,
    1974b) the national tolerances for several commodities have been
    amended and new tolerances for other commodities established.

    APPRAISAL

         This fungicide was evaluated by the Joint Meetings in 1969, 1973,
    and 1974 (FAO/WHO, 1970b, 1974b, 1975b).

         Only limited information was obtained on the questions listed as
    desirable in the 1973 evaluation. Of the crops on which captafol is
    authorised or recommended in various countries and on which further
    information was desired, additional data became available only on
    residues and use on pineapple. No information was obtained about uses
    on asparagus, beans, cabbage, celery, citrus fruit, coffee, grapes,
    lettuce, strawberries or tea and the maximum residue limits concurrent
    with these uses.


    
    TABLE 5. 14C residues in cow tissues

                                                                                                  
                                  Total metabolites calculated as captafol, mg/kg
                                                                                                  
                        Feeding level 5.7 mg 14C captafol/day        11.4 mg 14C captafol/day

    Time      Tissues   Cow no.   1         2           3            4         5         6
                                                                                                  

              brain                         0.001       0.003        0.006               0.003

              heart                         0.002       0.001        0.005               0.006

    day       muscle                        0.002       0.004        0.006               0.008

    30        fat                           0.001       0.000        0.001               0.001

              liver                         0.005       0.005        0.010               0.019

              kidney                        0.007       0.006        0.014               0.021
                                                                                                  

              brain               0.001                                        0.003

              heart               0.001                                        0.002

    day       muscle              0.002                                        0.004

    38        fat                 0.000                                        0.001

              liver               0.002                                        0.004

              kidney              0.002                                        0.003
                                                                                                  

    

    TABLE 6. Effect of washing on captafol residues in leeks (ten Broeke and Dornseiffen, 1973)

                                                                                                                                 
                               Application                   Residues, mg/kg, at interval(days) after application, mean (range)
                                                                                                                                 
                  Country          rate        formulation           7                     14/14                  20/21
    Crop          & year       no  kg a.i./ha                unwashed   washed     unwashed   washed      unwashed    washed
                                                                                                                                 

    Leek          Netherlands  6   1.2         EC 384 g/l
                  1972
    var.Olifant                                              4.7        1.8        3.2        0.4         1.7         0.3
                                                             (3.0-6.2)  (1.0-2.4)  (1.6-5.1)  (n.d.-0.9)  (1.1-3.4)   (0.3-0.4)

    var.Iglo                                                 2.6        0.5        1.4        0.2         1.5         0.2
                                                             (2.0-3.4)  (0.2-0.9)  (0.6-2.5)  (0.2-0.3)   (0.7-4.0)   (0.1-0.6)
                                                                                                                                 

    

    TABLE 7. National tolerances reported to the Meeting

                                                                           
                                                     Maximum residue limit
    Country        Commodity                                   mg/kg
                                                                           

    Australia      apricots, nectarines, peaches                15
                   cherries (sour)                              5
                   other fruit & vegetables                     2
                   cucumbers, melons                            2
                   cherries (sweet)                             2

    Belgium        fruit & vegetables, except                   3
                   potatoes

    Canada         peaches                                      15
                   cherries (sour)                              10
                   tomatoes                                     5
                   cherries (sweet), cucumbers,                 2
                   melons

    Fed.Rep. of    leaves of celeriac, leek,
    Germany          lettuce                                    7-5
                   fruit of vegetables (incl.
                     tomatoes, cucumbers, gherkins,
                     eggplant)                                  5
                   fruit                                        5
                   other commodities of plant
                   origin                                       0.2

    Japan          cabbage, radish (leaves &
                     roots), sweet potatoes, tea                1
                   apples, japanese pear                        5

    Netherlands    (1 tolerance under consideration; it may be expected
                    that the revised tolerances will come into force in
                    1977)

                   peaches                                      151
                   cherries (sour                               101
                   other fruits                                 51
                   leek                                         8
                   fruits of vegetables, i.e. bell
                     peppers, eggplant, cucumbers,
                     melons, tomatoes                           51
                   other vegetables                             3
                   raw grain                                    0.2
                   other food commodities                       0.05*

    South Africa   pineapple                                    10
                   potatoes, tomatoes                           5

    TABLE 7. (Cont'd.)

                                                                           
                                                     Maximum residue limit
    Country        Commodity                                   mg/kg
                                                                           

    U.S.A.         cherries (sour)                              50
                   apricots, peaches                            30
                   tomatoes                                     15
                   cranberries                                  8
                   melons                                       5
                   cherries (sweet), cucumbers,
                     nectarines, peanut hulls, plums            2
                   citrus fruits, potatoes                      0.5
                   apples                                       0.25
                   corn (incl.sweet corn) kernels &
                     cob, husk removed, macadamia
                     nuts, onions, pineapple                    0.1**
                   peanuts (meals with hulls removed            0.05**
                   taro corn                                    0.02**
                                                                           

    * at or about the limit of determination.

    ** negligible residues.


         The information obtained on residues on pineapple includes a use
    which was not evaluated at former Meetings. For this crop an amendment
    of the earlier established maximum residue limit is recommended. Since
    no additional information was obtained on other use patterns covered
    in earlier monographs, except some data on residues on tomatoes, the
    limits previously recommended are retained.

         Some information was provided on extensions of the use pattern in
    some countries and on residues occurring in crops at harvest as a
    consequence of these applications. These new data allow additional
    maximum residue limits to be recommended for peanuts and wheat.

         Limited information was obtained on the effect of washing,
    cooking and processing. In a supervised trial on leeks it was shown
    that 62-84% of the residue remaining on the crop as marketed was
    removed by normal household washing.

    RECOMMENDATIONS

         The following temporary maximum residue limits are recommended in
    addition to or amending those previously recommended.

                                            Pre-harvest intervals
                                  Limits    on which recommendations
    Commodity                     mg/kg     are based(days)

    Pineapple(whole fruit)        10        21

    Peanut hulls                  2         14

    Peanuts                       0.5       14

    Wheat                         0.2       42

    Peanut kernels                0.05      14

    FURTHER WORK OR INFORMATION

    REQUIRED (by 1978)

    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.

    DESIRABLE

    1.   Further studies to investigate the metabolism of the
         tetrachloroethylthio moiety of captafol.

    2.   Considerably more information from countries where captafol is
         used to clearly indicate use patterns and resulting residues.

    3.   Further data on the effects of washing, peeling and
         blanching on residue levels in various crops.

    4.   Information, including information from studies now
         in progress, on new methods for the analysis of the parent
         compound together with the main metabolites in products of animal
         origin.

    5.   Results of on-going studies to show the level and nature of
         captafol residue in meat, milk, poultry and eggs.

    6.   Results of studies now in progress to show the fate of captafol
         residues in citrus and citrus pulp.

    REFERENCES

    Bio-Test Lab. Milk and meat residue studies in dairy cows.
    1970                Report provided to Chevron no. IBT 78909.

    ten Broeke, R. & Dothseiffen, J.W. Residues of captafol
    1973                on leek. Unpublished report no. 169 Food
                        Inspection Service, Amsterdam (in Netherlands
                        language).

    Chevron             The fate of difoletan in lactating cows.
    1970                Unpublished Report Chevron Chemical Company no.
                        72114.

    Chevron             Difoletan residues in peanuts. Unpublished Report
    1975                provided to Joint Meeting 1976.

    Ciba-Geigy          Residues in winter wheat (grain and straw) after
    1975                treatment with RTilt 60 w.p.

    ICI                 Residues in cereals, trials in Holland 1974.
    1974                Unpublished report provided by the Netherlands to
    1974                Joint Meeting 1976.

    ICI                 Residue summary ethirimol/captafol in cereals.
    1975                Unpublished report no. BPA/YV/132/09.01.76
                        provided by the Netherlands to Joint Meeting 1976

    Olthof, P.D.A., & Lagemaat, L. Residues of difoletan in leek.
    1971                Unpublished Report no. 3886. Central Institute for
                        Nutrition and Food Research, the Netherlands.

    de Vos, R.N., & Pot, W. Residues of difoletan in pears. Unpublished
    1971                Report no. 3340. Central Institute for Nutrition
                        and Food Research, the Netherlands.

    


    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 3)
       Captafol (WHO Pesticide Residues Series 4)
       Captafol (Pesticide residues in food: 1977 evaluations)
       Captafol (IARC Summary & Evaluation, Volume 53, 1991)