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    CAPTAN         JMPR 1978

    Explanation

         Captan has been evaluated by Joint Meetings in 1965, 1969,
    1973, 1974 and 1977 (FAO/ WHO, 1965b, 1970b, 1974b, 1975b, 1978b).
    In 1977 the Meeting advised that further information was required
    before it would be possible to determine, with confidence, the MRL
    appropriate for cherries. No further information on this topic was
    received but the Canadian Government advised that supervised trials
    are planned for 1979.

         Various countries had submitted information on their current
    use patterns and provided new data on the results of residue
    trials. The results of further toxicological studies had also
    become available for evaluation.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    Special studies on mutagenicity

         Captan (93%) was investigated for mutagenic activity in
    vitro in the Ames test, using S. typhimurium strains TA 1535, TA
    1536, TA 1537 and TA 1538 with and without rat liver microsomes.
    Positive results were obtained in the TA 1535 strain.

         In an assay using Streptomyces coelicolor, forward
    mutations, measured as induction of resistance to low doses of
    streptomycin, were studied. Captan (purity 93%) showed a weak
    mutagenic activity with a plate technique, whereas the spot test
    was negative (Carere et al., 1978).

         Captan (> 98%) was administered orally to groups of male rats
    (5 animals/group), in a single dose (500, 1000 or 2000 mg/kg), or
    at 5 consecutive doses (200, 400 or 800 mg/kg/ day). 21 hours after
    the last administration colchicine (2 mg/kg i.p.) was injected and
    the animals were sacrificed 3 hrs later. From each animal 50 bone
    marrow cells were observed for chromosomal aberrations. No
    abnormalities were observed at any dose of captan tested.

         In a dominant lethal test groups of 15 male mice were treated
    orally with 0, 200 or 600 mg captan/kg/day for 5 successive days.
    Then each male was mated with one untreated female. Replacement of
    the female was made at intervals of 2-4 days and continued for 6
    weeks. Fertilized females were killed 12 or 13 days after
    copulation for examination of uterine contents. Male fertility,
    mean number of corpora lutea, implants, live embryos, and early and
    late embryonic deaths were within normal limits throughout the
    experiment.

         Cultures of human diploid skin fibroblasts were incubated in
    presence of captan. At doses used mitotic inhibition and
    cytotoxicity were observed, however no chromosomal aberrations were
    induced (Tezuka et al., 1978).

         Captan (50 WP, 50% techn. captan) was administered i.p. to
    mice in a dose of 0 or 250 mg/kg. 6, 12, 30 and 54 hours following
    injection animals were killed and bone marrow cells collected. 5
    hours prior to killing, animals were injected i.p. with colchicine
    (1 mg/kg). The incidence of chromosomal aberrations did not deviate
    significantly from that in controls. However 3 metacentric
    chromosomes were observed in 1001 metaphases from captan treated
    animals (0/1495 in controls). According to the authors it cannot be
    stated with certainty that 250 mg captan/kg i.p. does not break
    chromosomes in vivo because of these unique chromosome
    rearrangements (Fry and Ficsor, 1978).

    Miscellaneous studies

         Groups of rats were maintained on a diet containing 24, 8 or
    4% protein and 0.01 or 0.1% captan for 12 weeks. Captan toxicity
    was increased in the animals kept on protein deficient diets. Due
    to protein deficiency the aminotransferase activities were altered.
    The fructose diphosphate aldolase activity changed significantly as
    a function of both protein deficiency and captan treatment (summary
    only) (Urbanek-Karlowska, 1977).

    COMMENTS

         Positive mutagenicity studies have been noted in several
    microbiological systems. In vivo, and in vitro cytogenetic studies
    in mammalian systems; as well as a mouse dominant lethal study were
    negative.

         The Meeting endorsed the opinion of the 1975 Joint Meeting
    (FAO/WHO 1976a) that more weight should be attributed to the
    results of mutagenic tests in mammalian systems than to those
    obtained from microbial or other non-mammalian systems or isolated
    all systems. The available mutagenicity data did not, in the
    opinion of the Meeting, affect the previously determined Acceptable
    Daily Intake.

    TOXICOLOGICAL EVALUATION

    Level causing no significant toxicological effect

            Mouse:         7500 ppm in diet equivalent to 1070 mg/kg bw
  
            Rat:           2000 ppm in diet equivalent to 100 mg/kg bw

            Dog:           100 mg/kg bw/day

            Monkey:        12.5 mg/kg bw/day

    Estimate of acceptable daily intake for man

              0 - 0.1 mg/kg

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         Captan, which was introduced to the market in about 1947 is
    approved in most countries for use on a wide variety of fruits,
    vegetables, ornamentals, oil and fibre crops and many types of
    seed. Information confirmed that it is still widely used for these
    purposes with pre-harvest intervals as short as 1 day for some
    crops.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         The Meeting received details of many trials carried out in the
    Netherlands between 1956 and 1975 in which captan was applied to
    apples, cherries, pears, currants, raspberries, strawberries,
    endive and wheat. Data were received from Denmark on trials on
    black currants; from Finland on apples and potatoes; from Japan on
    apples, pears, cucumbers, eggplant and tomatoes and from Norway on
    lettuce. The residues found at harvest are given in Table 1.

         These new data indicate that the MRLs previously recommended
    are adequate to cover most of the residues resulting from approved
    uses. Exceptions were with (a) currants, where residues 10 days
    after application (34 mg/kg) exceeded the MRL (20 mg/kg); (b)
    strawberries grown under glass where residues 14 days after
    treatment (27 mg/kg) exceeded the MRL 20 mg/kg); (c) endive, grown
    outdoors where residues 21 days after treatment (23 mg/kg) exceeded
    the MRL (15 mg/kg) and (d) lettuce, where residues 7 days after
    treatment (14.0 mg/kg) exceeded the MRL (10 mg/kg). The pre-harvest
    intervals mentioned are those approved in the countries concerned.
    It may be necessary to review the use patterns in these cases or to
    revise the MRLs.

         Information was provided from the Netherlands from a trial
    done to determine whether there is any significant difference in
    the residues remaining on apples following the practical use of
    captan by farmers in comparison to those found in supervised
    trials. In this experiment apple trees were treated with captan
    w.p. at the rate of 1.8 kg/ha according to the directions
    appropriate for Gleosporium rot control. Two treatments were
    applied 7 days apart and the fruit was harvested 4 and 7 days after
    the last treatment.

         At the same time apples were collected from 50 commercial
    orchards where the growers had used captan under the same regime
    (same rate, same number of treatments, same time interval and same
    pre-harvest interval). Apples were analysed for captan residues.
    The results were as follows:

                                                                                             

                             Days after          Residue             Coefficient
                             last treatment      (mg/kg)             of variance (%)
                                                                                         

    "Supervised trial"       4                   2.01 (0.51-2.45)    25
                             7                   1.99 (0.77-2.60)    32

    50 orchards              4                   2.46 (0.17-10.3)    85
    (practical treatment)    7                   2.08 (0.37-5.0 )    69
                                                                                         
    
         Whilst the residues found following practical field use are of
    the same order of magnitude as those resulting from applications made
    by trained technicians, the range of values is somewhat greater. The
    highest levels are still below the recommended MRL.

    RESIDUES IN COMMERCE OR AT CONSUMPTION

         Data were provided by the Netherlands (1978) from food inspection
    monitoring of domestic and imported fruits and vegetables analysed
    during 1973/77. With very few exceptions the many samples examined
    confirmed with the MRLs recommended by the Meeting.

         The New Zealand Ministry of Agriculture advised that during
    1971-73, 61 samples of apples were anlaysed for captan residues, with
    three positive results ranging from 0.02-0.06 mg/kg.


    APPRAISAL

         Notwithstanding requests made by the 8th, 9th and 10th Sessions
    of CCPR and by the 1976 and 1977 Joint Meetings, no useful data have
    been received to answer the question about an appropriate MRL for
    cherries.

         Information on use patterns was received from various countries
    and data from residue trials from Denmark, Finland, Japan, Netherlands
    and Norway. These include information on apples, cherries, currants,
    raspberries, strawberries, endive, cucumbers, eggplant, lettuce,
    pears, potatoes and tomatoes. Results obtained by monitoring fruit and
    vegetables moving in commerce were provided by the Netherlands and
    data on apples by New Zealand.

         None of the information provides a basis or justification for
    amending the recommendations made previously but it appears desirable
    to recommend an MRL for potatoes.


        TABLE 1. Captan residues found in supervised trials

                                                                                                                          

                                 Application               Residues in mg/kg, at intervals (days) after last application
                                                                                                                          

    Crop and             Number of       Rate w.p. per
    Country              treatments      treatment kg      0            6            12            20           40
                                         a.i./ha
                                                                                                                          

    Netherlands
    apple                9               6 g/tree                                    3.6
    (Jonathan)                                                                       (2.2-5.0)
    "                    10              6 g/tree                                                               3.3
                                                                                                                (1.5-5.0)
    "                    4               2.5               4.4          2.8                        1.0
                                                           (3.7-5.4)    (2.1-3.6)                  (0.4-1.5)

    "                    3               2.5               4.5          6.6                        1.4
                                                           (4.2-4.7)    (6.4-6.8)                  (0.5-2.4)

    apple                9               10 g/tree                                   6.5
    (Goudreinette)                                                                   (4.6-8.4)
                                                                                                                          
                                                           0            6/7          10            14/15        21
                                                                                                                          

    apple                1               4 g/tree          3.1
    (Golden Delicious)                                     (2.4-4.6)
    "                    1               4 g/tree                                    2.4           4.4
                                                                                     (2.0-2.9)     (4.1-4.8)

    "                    13              1.5               1.0          1.3                        0.5
    "                    3               1.5               4.8          5.1                                     1.4
                                                           (4.5-5.2)    (4.6-5.6)                               (0.9-1.7)

    TABLE 1. (Cont'd)
                                                                                                                          

                                 Application               Residues in mg/kg, at intervals (days) after last application
                                                                                                                          
    Crop and             Number of       Rate w.p. per
    Country              treatments      treatment kg      0            6            14            50
                                         a.i./ha
                                                                                                                          

    apple                1               4.0               1.2          0.8          0.9
    (Notaris)

    apple                1               4.0               1.1          1.0          0.5
    (Worchester)

    Japan
    apple                11              2.5                                                       0.01
                         1               3.6                            0.8
                         2               2.5                                                       0.04

    Finland
    apple                1               6 g/tree                       17
                                         6 g/tree                       20
                                         6 g/tree                       1.6
                                                                        (washed before
                                                                        analysis)

                                                                                                                          
                                                           7            9            10            12           50
                                                                                                                          

    Netherlands
    sweet cherry         2               22.5 g/tree                                 7.6
    "                    2               15 g/tree                      9.5
                                                                        (6-13)
    "                    2               15 g/tree         3.0
                                                           (0.8-4.0)
    sweet cherry         2               18.75 g/tree      23.3                      12.4
    (Meikers)                                              (15.6-29.0)               (11.2-14.2)

    TABLE 1. (Cont'd)
                                                                                                                          

                                Application                Residues in mg/kg, at intervals (days) after last application
                                                                                                                          

    Crop and            Number of    Rate w.p. per
    Country             treatments   treatment kg          7            9            10            12           50
                                     a.i./ha
                                                                                                                          

    pear                 9           6 g/tree                                                      6.4
    (Bonne Louise)                                                                                 (4.5-8.2)

    pear                 9           6 g/tree                                                      3.6
    (Conference)

    Japan
    pears                5           0.9-1.6                                                                    0.002
    "                    3           0.9-1.6                                                                    0.002

                                                                                                                          

                                                           6            10           14            21
                                                                                                                          

    Netherlands
    red current          2           2.25-2.51)            21.9         21.6         15.9          7.8
    (Jonkheer van Tets)                                    (15.6-34.2)  (16.2-36.9)  (6.0-19.8)    (5.2-10.2)

                                                                                                                          

                                                 0            7             14           21          28         50
                                                                                                                          

    Netherlands
    red currant          1           3.751)                   9.2           8.3          3.7         2.1
    (Jonkheer van Tets)                                       (5.0-13.2)    (3.8-11.4)   (3.1-4.1)   (1.2-2.6)

    "                    2           3.751)      22.5         17.2          9.6          6.7
                                                 (16.3-38.4)  (13.5-20.0)   (6.3-13.1)   (4.4-9.3)

    TABLE 1. (Cont'd)
                                                                                                                          
                          Application            Residues in mg/kg, at intervals (days) after last application
                                                                                                                          
    Crop and        Number of    Rate w.p. per
    Country         treatments   treatment kg    0            7             14           21          28         50
                                 a.i./ha
                                                                                                                          

    Denmark
    black currant       1          1.75                                     2.28                     0.39       1.36
                        2                                                                            2.0        1.3
                        3                                                                            3.2
                        4                                                   5.2

                                                                                                                          
                                                 1            3             6            11
                                                                                                                          

    Netherlands
    raspberry           2          1.0           5.2          2.1           0.8          0.9
                                                 (3.5-8.0)    (1.0-4.0)     (0.6-1.0)    (0.4-1.5)
    strawberry          7          1.88                       1.7-4.8
    outdoor (Chinax)

                                                                                                                          
                                                 0              2            4            7             14
                                                                                                                          

    strawberry          2         1.88           0.6            0.4          0.4
    outdoor (Yucunda)                            (0.3-0.8)      (0.3-0.6)    (0.2-0.6)

    strawberry          2         2.41)          16.9                                     18.3          20.5
    under glass (Glasa)                          (12.0-24.5)                              (15.8-20.0)   (15.0-27.0)

                                                                                                                          
                                                 10             17           24
                                                                                                                          

    strawberry          1         2.41)          13.0           14.6         12.3
    under glass (Glasa)                          (9.9-16.8)     (10.6-18.5)  (8.0-20.0)

    TABLE 1. (Cont'd)
                                                                                                                          
                             Application         Residues in mg/kg, at intervals (days) after last application
                                                                                                                          
    Crop and         Number of    Rate w.p. per
    Country          treatments   treatment kg   0            7             14           21
                                  a.i./ha
                                                                                                                          

    endive              3         1.2            15.8         9.0           4.9          1.0
    outdoor                                      (11.9-18.7)  (7.3-11.0)    (2.6-9.8)    (0.5-1.3)

    Netherlands
    endive              3         2.25           82.7         22.2          17.3         15.5
    outdoor                                      (40-117)     (19-26.5)     (10.1-25.1)  (6.8-23.0)

    "                   6         1.5            18.9         18.5          7.3
                                                 (14.7-23.1)  (16.4-20.8)   (6.5-8.6)

    "                   4         1.5            51.7         21.9          9.6
                                                 (44.6-58.6)  (17.6-28.2)   (6.8-12.3)
                                                                                                                          
                                                 2           7           14          21          28          50
                                                                                                                          
    Norway
    lettuce             1         2.5                        7.6-14.0    3.9-6.6     2.9-6.6     4.0-5.6
    (greenhouse)                                             (10.8)      (5.3)       (4.8)       (4.8)

    Japan
    cucumbers           1         3                                                                          0.008

                        5         3              0.04

                        3         1.8            0.04

                        2         1.8            0.002

                        1         2              0.53

                                                 0.61

    TABLE 1. (Cont'd)
                                                                                                                          
                             Application         Residues in mg/kg, at intervals (days) after last application
                                                                                                                          
    Crop and         Number of    Rate w.p. per
    Country          treatments   treatment kg   2            7             14           21          28         50
                                  a.i./ha
                                                                                                                          

                                                 2.14

                        3         2              0.05

                        5         2              0.07

                        5         2.4            2.03

                        1         1.25           0.36

                        5         1.1                        0.1

                        1         3.7                        0.016                   0.005

    eggplant            4         1.5                                       ND                       ND

    tomatoes            1         1.6                                                                           < 0.02

                        1         1.25                        0.09

                        3         1.5            0.01

                        7         4              0.13

                        1         4              0.5          0.35

                        5         1.7            0.8

                        1         2.4            4.9

                        3         2.4            1.9

    TABLE 1. (Cont'd)
                                                                                                                          
                             Application         Residues in mg/kg, at intervals (days) after last application
                                                                                                                          
    Crop and         Number of    Rate w.p. per
    Country          treatments   treatment kg   2            7             14           21          28         50
                                  a.i./ha
                                                                                                                          

    Finland
    potatoes            4         1.25                                                               0.01
    (unwashed, washed
    and peeled)
                                                                                                                          
                                                             42
                                                                                                                          

    Netherlands
    winter wheat        2         0.850 + 2.1                0.01
    (Bango)                       (sulphur) +0.5
                                  (maneb)

    winter wheat        2         0.85+2.1(sulphur)+
    (Lely)                        0.5 (maneb)                0.01
                                                                                                                          

    w.p. = wettable powder

    1) low volume application
    

    RECOMMENDATIONS

         The following additional maximum residue limit if recommended:

                        potatoes                 0.1 mg/kg

    FURTHER WORK OR INFORMATION

    Desirable

         Investigation of the significance of hematoma formation in the
    foetus in relation to foetal death or malformation.

    REFERENCES

    Carere A., Ortali, V.A., Cardamons, G., Torracca, A.M., Raschetti, R.
    (1978)                   Microbiological mutagenicity studies of
                             pesticides in vitro. Mut. Research, 57, p.
                             277-286.

    Fry, S.M.,  Ficsor, G. Cytogenetic test of captan in mouse bone
    (1978)                   marrow. Mut. Research, 58, p. 111-114.

    Tezuka H., Teramoto, S., Kaneda, M., Henmi, R., Murakami, N.,
    (1978)                   Shirasu, Y. Cytogenetic and dominant lethal
                             studies on captan. Mut. Research, 57 p.
                             201-207.

    Urbanek-Kaslowska, B. Effect of protein deficiency in rats on
    (1977)                   captan toxicity. Part II. The activity of
                             selected enzymes in rat serum and liver
                             depending on dietary level of protein and
                             captan. Roczn. Panstw. Zakl. Hig., 28 p.
                             121.132, cited in Pest. Abstr. nr. 77-2446.
    


    See Also:
       Toxicological Abbreviations
       Captan (HSG 50, 1990)
       Captan (ICSC)
       Captan (PIM 098)
       Captan (FAO/PL:1969/M/17/1)
       Captan (WHO Pesticide Residues Series 3)
       Captan (WHO Pesticide Residues Series 4)
       Captan (Pesticide residues in food: 1977 evaluations)
       Captan (Pesticide residues in food: 1980 evaluations)
       Captan (Pesticide residues in food: 1982 evaluations)
       Captan (Pesticide residues in food: 1984 evaluations)
       Captan (Pesticide residues in food: 1984 evaluations)
       Captan (Pesticide residues in food: 1990 evaluations Toxicology)
       Captan (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)
       Captan (IARC Summary & Evaluation, Volume 30, 1983)