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    CAPTAN       JMPR 1977

    Explanation

    The Joint Meeting evaluated this fungicide in 1969 (a full revision of
    the 1965 evaluation) and 1973 (FAO/WHO, 1970, 1974). An acceptable
    daily intake of 0-0.1 mg/kg was established but further information on
    the significance of hematomas in the foetus in relation to foetal
    death and malformation was desired. Further data have been made
    available and are summarized in this monograph addendum.

    At the 8th (1976) Session of the Codex Committee on Pesticide
    Residues, reservations were expressed by the delegations of the
    Netherlands and the Federal Republic of Germany on the recommended
    maximum residue limit of 40 mg/kg for apples and cherries. Residue
    trials in those countries showed that residues mould not exceed 5
    mg/kg on apples (Netherlands) or 15 mg/kg on cherries (FRG). The CCPR
    decided to return the proposals for apples, cherries and pears to Step
    6 and requested governments to send data.

    The requested data were not available for the 1976 Joint Meeting, and
    the 9th Session of the CCPR issued an urgent request to governments to
    send data. Data were made available to the 1977 Joint Meeting from the
    U.S.A. and the Netherlands, and are reviewed below.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, distribution, biotransformation and excretion

    Captan was fed to a dairy cow during 4 days at a level of 5 mg/kg in
    feed, amounting to a total dose of 0.454 g. Gas-chromatographic
    analyses were carried out on milk and urine samples, collected 1 day
    prior to feeding the fungicide, daily throughout the feeding period
    and for 6 days thereafter. Residues of intact captan were not detected
    in any of the milk or urine samples.

    The detection limits were estimated to be 0.01 mg/kg for milk and 0.1
    mg/kg for urine (St. John and Lisk, 1976).

    TOXICOLOGICAL STUDIES

    Special studies on mutagenicity

    Captan showed both frame-shift and base pair substitution mutagenesis
    in S. typhimurium strains (TA 1535 series, without excision repair).
    Exposure to rat liver homogenate decreased the mutagenic activity of
    captan (Marshall et al., 1976).

    Captan was investigated for mutagenic activity by the host mediated
    assay with S. typhimurium in rats after 14 days oral treatment (by
    gavage) with 125 or 250 mg captan/kg b.w. No increases in the number

    of reverant bacteria were obtained as compared with controls.

    Two groups of 12 male mice received a single i.p. injection of 3 or 6
    mg captan/kg b.w. in corn oil. For 6 consecutive weeks one male was
    mated with 3 untreated females, which were replaced weekly. Females
    were killed 1 week after removal from the breeding cage. No
    differences were found in the numbers of implantation sites,
    resorption sites or embryos between control and treated groups
    (Kennedy et al., 1975 a).

    The mutagenicity of captan was tested by reversion of histidine
    auxotrophs of S. typhimurium in the peritoneal cavity of rats and
    mice. Negative results were obtained with maximal tolerable s.c. or
    oral doses of captan. The fluid mediated assay using blood and urine
    also gave negative results. In vitro, human and rat blood inactivated
    the mutagenic action of captan at a level of 500 g/ml but not at 1000
    g/ml blood (Fiscor et al., 1977).

    Captan caused His+ reversions (S. typhimurium), Try+ (E. coli
    WP 2) and mitotic recombinations (Saccharomyces cerevisiae)
    irrespective of metabolic activation. The unscheduled DNA synthesis
    assay was positive in the presence of mouse liver homogenate.

    In a dominant lethal test, groups of 20 adult male mice were fed 0,
    1250, 2500 and 5000 ppm captan for 7 weeks. Each male was mated with
    two virgin females for 7 days. These females were then replaced by two
    others and this sequence was continued for 8 weeks. Females were
    sacrificed at mid-term of pregnancy and each female was scored for
    early and late foetal deaths and living foetuses. Captan was not
    mutagenic in the mouse by the dominant lethal test.

    In a heritable translocation test male mice were fed 0, 2500 or 5000
    ppm captan in their diet for 8 weeks. After this treatment males of
    each group were mated with 2 untreated females. The F1 males were
    raised to maturity and 200 animals from each experimental group were
    mated with 3 virgin females. These females were sacrificed 14 days
    after mating and the number of total, live and dead implants was
    determined. Males, classified as sterile, partially sterile or
    non-breeder were re-bred and the same evaluation was made for the
    second and third breeding. The data on the F0 and F1 generation's
    fertility, breeding and litter size distribution as well as the data
    on the F1 generations dead implants and re-breeding show that captan
    tends to induce dose-related effects on the reproductive performance
    of male mice (Simmon at al., 1977).

    Special studies on teratogenicity

    Groups of 6 female beagles were fed captan (89.6%; 0, 30 and 60 mg/kg
    b.w.) throughout the gestation period. The graded levels of captan
    were adjusted weekly on the basis of food consumption and body weight.
    Litters were delivered normally and X-rays were taken of all pups at
    birth. After whelping, three mothers from each test group were placed

    on stock diet and the remaining ones received the test material
    through the lactation period. Pups were killed at 8 weeks of age and
    liver, kidneys, heart, brain, spleen, gonads and adrenal, thyroid and
    pituitary glands were weighed and histological examination was
    conducted on three pups of each sex per group. Following weaning the
    mothers were killed and complete gross and histopathological
    examination was performed on the same organs. No toxic signs or
    effects on skeletal or organ structure were observed. The number and
    development of pups were not different in treated and control groups.
    Gross and histopathological examination and evaluation of organ weight
    data revealed no alteration (Kennedy at al., 1975b).

    Special studies on reproduction

    See "Special studies on mutagenicity".

    COMMENTS

    The Meeting was aware of the existence of recent studies on the
    mutagenicity and carcinogenicity of this compound. Since the
    additional information was not available in detail, consideration of
    this pesticide was deferred to a future meeting.

    RESIDUES IN FOOD AND THEIR EVALUATION

    Apples, pears

    Permitted uses in the U.S.A. are as follows:

    (a) multiple treatments with 0.12% spray, with no pre-harvest interval
    (PHI)

    (b) up to 8 lbs a.i./acre (9 kg/ha), dust treatment with no PHI

    (c) 0.12% post-harvest fruit spray or dip

    Most of the data made available from the U.S. dates from the mid-1950s
    and much of it is not germane to the registered use patterns. Analyses
    were by the colorimetric method of Kittleson (1952). Data from residue
    trails approximating the maximum registered use conditions were
    extracted from the body of data and are tabulated below (Table 1). The
    sources of the original data were the two basic U.S. manufacturers,
    California Spray Chemical Co. (now Chevron), and Stauffer Chemical Co.
    It appears likely that the same data were evaluated by the 1969 Joint
    Meeting (FAO/WHO, 1970).

        TABLE 1. Residues in apples and pears from field treatments.

                                                                                 
    Crop           Application rate    no. of       Days from      residues,
                                       treatments   last spray     mg/kg
                                                                                 
    Apples         0.12%               1            1               9.7
    "              "                   "            "               7.4
    "              "                   "            "               8.0
    "              "                   "            "              12.3
    "              "                   "            "              11.0
    "              "                   "            "              13.6
    "              "                   "            "              10.0
    "              "                   "            "              10.6
    "              "                   "            "              11.0
    "              "                   "            "              11.4
    "              "                   "            "              12.0
    "              "                   "            "              10.1
    Pears          0.12%               "            "               6.6
    "              "                   "            "               5.1
    "              "                   "            "               4.3
    "              "                   "            "               5.6
    "              "                   "            "               5.0
    "              "                   "            "               7.5
    "              "                   "            "               5.9
    "              "                   "            "               6.0
    "              "                   "            "               4.8
    "              "                   "            "               5.7
    "              "                   "            "               6.0
    Apples         0.12%               10           1               6.0
    "              "                   "            "               4.0
    "              "                   "            "               6.0
    "              "                   "            "               5.1
    "              "                   "            "               5.8
    "              "                   "            "               6.0
    "              "                   "            "               5.7
    "              "                   "            "               5.9
    "              "                   "            "               5.9
                                                                                 


    

    Table 2 shows residues on fruit sprayed in the laboratory in an
    experiment which simulates post-harvest treatments to control storage
    diseases.

    TABLE 2. Residues in fruit sprayed post-harvest with 0.12% solution of
    a 50% WP formulation of captan

    Crop    captan, mg/kg          Average, corrected for blank

    pear
    exp. 1    6.6, 5.1, 4.3, 5.6,
              5.6                      5.3
    exp. 2    7.5, 5.9, 6.0, 4.8,
              5.7, 6.0                 5.9

    apples
    exp. 1    9.7, 7.4, 8.0, 12.3,
              11.0, 13.6               9.9
    exp. 2    10.0, 10.6, 11.0,
              11.4, 12.0, 10.1         10.3

    The primary U.S. Manufacturer submitted to the 1977 Meeting some more
    recent (1976) data which consisted of four analyses of whole fruit.
    The residues were from field sprays and were in the range 3.2-5.4
    mg/kg.

    The data indicate that maximum residues approximating 10-15 mg/kg
    could be expected on fruit treated up to harvest with the 0.12% spray
    as registered in the U.S. Maximum residues from the permitted
    post-harvest sprays or dip could contribute additional residues
    approximating 10 mg/kg. This apparently is the rationale for the
    current 25 mg/kg U.S. tolerances for apples and pears.

    The rationale for the 1969 Joint Meeting recommendation of 40 mg/kg
    for apples and 30 mg/kg for pears is not clear. It would appear that
    the recommendation was based on the highest residue reported, without
    allowing for excessive dosages applied in the residue trials.

    The proposal of the Netherlands delegation to the 8th Session of the
    CCPR for a 5 mg/kg maximum residue limit would obviously be inadequate
    for the uses permitted in the U.S.A. In the absence of data from other
    countries it cannot be determined whether the recommended 40 mg/kg
    would be required. It would therefore be appropriate for the 1977
    Meeting to recommend that the present limits of 40 and 30 mg/kg on
    apples and pears (respectively) be reduced to 25 mg/kg for each.

    Cherries

    The permitted U.S. uses are:

    multiple treatments with 0.12 to 0.24% WP sprays, or 2 to 3 lbs. a.i.
    per acre (2.2 - 3.3 kg/ha) as a dust, with no pre-harvest interval; or
    0.12% post-harvest dip or spray

    The limited data on cherries made available to the 1977 Meeting are
    shown in Table 3.

        TABLE 3. Residues of captan in cherries resulting from supervised trials

                                                                                       
    Application rate        No. of treatments      Pre-harvest      Residue, mg/kg
                                                   interval,
                                                   days
                                                                                       
    0.12%                   3                      20                6.9
    "                       1                      9                11.7
    "                       1                      0                28.0
    0.24%                   1                      9                25.0
    "                       1                      0                53.0
    0.12%                   1                      30                0.59
    "                       1                      23                0.12
    "                       1                      16                0.63
    "                       1                      9                 7.5
    "                       1                      1                 5.1
    0.16                    1                      30                0.60
    "                       1                      23                0.56
    "                       1                      16                0.12
                                                                                       

    
    Only three of the analyses on cherries were on samples taken within
    one day after treatment. No data on residues from post-harvest dips
    were submitted. These data are not adequate to support the maximum
    residue limit of 40 mg/kg recommended by the 1969 Joint Meeting, nor
    the proposal to the 8th Session of the CCPR by the Federal Republic of
    Germany that a limit of 15 mg/kg would be adequate.

    APPRAISAL

    Questions originally raised at the 8th Session (1975) of the Codex
    Committee on Pesticide Residues and reaffirmed by the 9th Session were
    referred to the 1977 Joint Meeting, with a request for the evaluation
    of data to determine whether the recommendations for MRLs of 40 mg/kg
    on apples and cherries and 30 mg/kg on pears could be reduced.

    Reports of supervised residue trials in the USA and the Netherlands
    were made available to the 1977 Meeting. A summary of the occurrence
    of captan residues in apples, pears, and cherries in channels of
    commerce in the USA and the Netherlands was also available.

    The relatively low residues on which the reservations raised at the
    1975 CCPR Session were based, were apparently due to the differences
    in good agricultural practices in different countries. Some countries,
    in particular the USA, require post-harvest treatments. On the basis
    of available data, it was concluded that an MRL of 25 mg/kg would be
    adequate to cover residues resulting from both field treatments and
    post-harvest sprays or dips to apples and pears. The available data on

    cherries were not adequate to support the proposed reductions to 15
    mg/kg.

    RECOMMENDATIONS

    The previously recommended maximum residue limits for captan on apples
    and pears are replaced by the single limit shown below.

    The present recommended MRL of 40 mg/kg for cherries is maintained
    until additional information on national use patterns and supervised
    trails is submitted.

              Commodity         Limit, mg/kg

              Apples, pears       25

    FURTHER WORK OR INFORMATION

    Desirable

    1. Investigation of the significance of haematoma formation in the
    foetus in relation to foetal death and malformation.

    2. Details of recent studies on mutagenicity and carcinogenicity
    mentioned in the Report of the 1977 Meeting (FAO/WHO, 1978), Section
    4.7, "Toxicology".

    3. Information on current national use patterns and corresponding
    supervised residue trials.

    REFERENCES

    FAO/WHO (1970) 1969 evaluations of some pesticide residues in food.
    FAO/PL:1969/M/17/1; WHO/Food Add./70.38.

    FAO/WHO (1974) 1973 evaluations of some pesticide residues in food.
    AGP:1973/M/9/1; WHO Pesticide Residues Series, No. 3.

    Fiscor G., Bordas, S., Wade, S.M., Muthiani, E., Wertz, G.F., Zimmer,
    D.M. (1977) Mannalian host and fluid-mediated assays of captan and
    streptozotocin in Salmonella typhimurium. Mut. Res. 48, 1-16.

    Kennedy, G.L., Arnold, D.W., Keplinger, M.L. (1975a) Mutagenicity
    studies with captan, captafol, folpet and thalidomide. Fd.
    Cosmet. Toxicol. 13, 55-61.

    Kennedy, G.L., Fancher, O.E., Calandra, J.C. Nonteratogenicity of
    captan in beagles. Teratology 11, 223-226.

    Kittleson, A.R. (1952) Anal. Chem., 4:1173.

    Marshall, T.C., Dorough, H.W., Swim, H.E. (1976) Screening of
    pesticides for mutagenic potential using Salmonella typhimurium
    mutants. J. Agric. Food Chem. 24, 560-563.

    Simmon, V.F., Mitchell, A.D., Jorgenson, T.A. (1977) Evaluation of
    selected pesticides as chemical mutagens. In vitro and in vivo
    studies. Environmental Health Effects Research Series
    EPA-600/1-77-028.

    St. John, L.E., Lisk, D.J. (1976) A feeding study with captan
    fungicide in the dairy cow. Bull. Environ. Cont. Toxicol. 16,
    474-476.
    


    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: 1978 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)