CAPTAFOL      JMPR 1977

   Explanation

    This fungicide has been evaluated at the Joint FAO/WHO Meetings on
    Pesticide Residues in 1969, 1973, 1974 and 1976 (FAO/WHO, 1970G,
    1974G, 1975G, 1977G). A temporary acceptable daily intake for man of
    0.05 mg/kg was estimated in 1973. The 1973 Meeting required further
    studies (by 1976) to assist evaluation of histopathological changes in
    the kidneys and liver of rats, observed in a long-term study, and to
    investigate the lymphocyte-neutrophil shift noted in previous
    experiments. In 1976, comments from the manufacturers were brought to
    the attention of the Meeting, which was also aware of the existence of
    recent studies of the mutagenicity of this compound. It was therefore
    decided to re-evaluate the compound in 1977. The Codex Committee on
    Pesticide Residues, at its 9th (1977) Session, requested the Joint
    Meeting to re-examine the data on which its recommendations made in
    1973 for maximum residue limits on cranberries, apples and pears were
    based. The re-examination is discussed in the following monograph
    addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    Special studies on mutagenicity

    Captafol was investigated for mutagenic activity by the dominant
    lethal study in mice and by the host-mediated assay in rats using a
    histidine auxotroph of Salmonella typhimurium. Male mice were
    treated with a single intraperitoneal injection of 1.5 or 3.0 mg/kg.
    Each test and control group consisted of 12 mice housed with 3
    untreated virgin females. During 6 weeks these females were replaced
    by others. The number of implantation sites, resorption sites and
    embryos was the same for treated as for control matings.

    For the host-mediated assay 2 separate trials were conducted, using 3
    males in each test group. The animals received daily oral intubations
    at levels of 125 or 250 mg/kg for 14 days. An indicator micro-organism
    recovered from the peritoneal cavity after a 3-hour residence showed
    no increase in numbers of revertants (Kennedy et al, 1975).

    Several pesticides including captafol were studied for mutagenic
    activities in a microbial system. The effect on the mutagenic activity
    of captafol of adding S-9 Mix or L-cysteine to the system was
    investigated. The mutagenicity of captafol observed in Escherichia
    coli WP2 hcr and TA 1535 disappeared after addition of S-9 Mix or
    L-cysteine (Moriya et al., 1975).

   Long-term studies

    Rat

    In a two year study with captafol added to the diet at 0 (70 males and
    70 females), 250, 500, 1500 and 5000 ppm (35 females and 35 males at

    each test level), there was growth depression at the 1500 and 5000 ppm
    levels. Mortality was increased in the 5000 ppm group, with no males
    left alive after 23 months. A lymphocyte to neutrophil shift was
    observed in the surviving males of this group after 21 months. There
    was an increase in the liver to body-weight ratio at the 500, 1500 and
    5000 ppm levels at 12 months. An increase in this ratio was also seen
    in males at 250 ppm. At the end of the experiment there was no longer
    a significant difference at the two lower test levels. Significant
    increases were also observed in organ weight and organ to body-weight
    rations for kidney and adrenal of rats fed at 1500 and 5000 ppm.
    Histopathology revealed liver changes characterized by degeneration of
    hepatic cells, vacuolization, incipient fat alteration, and
    infiltration by mononuclear cells. Kidney changes were characterized
    by alterations in proximal and distal tubular cells, many giant forms
    with large irregular nuclei being present. These changes in liver and
    kidney were only seen in rats fed the two highest dose levels. No
    other histopathological changes were associated with the
    administration of captafol (Kohn at al., 1964).

    COMMENTS

    Captafol appears to be not mutagenic in a dominant lethal test in mice
    and host-mediated assay in rats.

    In a two-year study with rats a non-dose related increase in the
    relative liver weight was evident in males after 12 months, but not at
    24. The absolute liver weight of the males at 12 months was also
    significantly increased at 250 ppm but this effect was not produced in
    the 500 and 1500 ppm groups. The histopathological changes observed in
    the liver and kidneys at 1500 and 5000 ppm were considered to be
    features of long-term toxicity, sometimes seen in old rats.

    It seems justified therefore to consider 250 ppm as a no-effect level
    in rats. The temporary ADI for humans has been changed to an ADI for
    humans at a higher value.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

        Rat: 250 mg/kg in the diet, equivalent to 12.5 mg/kg bw

        Dog: 10 (mg/kg bw)/day

    ESTIMATE OF ACCEPTABLE DAILY INTAKE

        0-0.1 mg/kg bw

   RESIDUES IN FOOD AND THEIR EVALUATION

    Cranberries

    The following comment of the 9th (1977) Session of the Codex Committee
    on Pesticide Residues was referred to the Joint Meeting: "From the
    data summarized in the 1973 Evaluations a MRL of 5 mg/kg appeared
    sufficient. It was decided to refer this item back to the Joint
    Meeting for a review of the available data and to see whether the
    proposed MRL (8 mg/kg) could be lowered to 5 mg/kg."

    The reason is not evident for the discrepancy between the conclusion
    that residues on cranberries would not exceed 5 mg/kg (FAO/WHO 1974,
    p. 125) and the recommendation for a MRL of 8 mg/kg (ibid. p. 130). It
    is possible that 5 mg/kg was a typographical error. The limited data
    available on which the 1973 recommendation was based, are shown in
    Table 1 They show that in some cases the residues from good
    agricultural practice would exceed 5 mg/kg. In consideration of the
    normal variations in residue data, an MRL of 8 mg/kg would be
    appropriate.

        TABLE 1. Residues of captafol on cranberries (USA)
                                                                                           
                             Application 
    Test Number    Rate, kg a.i./ha    Number         Crop part    Interval      Residue,
    & Location                                                     from last     mg/kg
                                                                   spray to
                                                                   harvest,
                                                                   days
                                                                                           
    T-944          5.12                2              mature       80            0.00
    Mass.                                             fruit                      0.00

                   6.0                                                           0.00
                                                                                 0.00

    T-963                              3              mature       33            1.1
    N.J.           3.4                                fruit                      2.6

    T-964                              3              mature       34            4.7
    Wisc.          5.4                                fruit                      5.8

    T-965                              2              mature       38            2.5
    Mass.          4.0                                fruit                      2.0

    T-1808                             3              mature       56            0.81
    Mass.          5.6                                fruit                      0.76

    T-1809                             3              mature       54            6.33
    Wisc.          5.6                                fruit                      4.63

   Apples, pears

    The Codex Committee on Pesticide Residues at its 9th Session made the
    Comment (para. 65, Alinorm 78/24): "In the 1973 Evaluations no residue
    data for these products had been published. The Committee therefore
    felt unable to comment and referred the matter back to the Joint
    Meeting".

    Table 2 contains data available to the 1977 JMPR. It has not been
    ascertained whether these data are identical to those evaluated by the
    1973 Meeting. Apple data are translated to pears.

    It is necessary to relate these data to the information submitted to
    the 1973 Meeting on national use patterns from Canada, U.S.A., Japan,
    the Netherlands, Australia, and New Zealand. The U.S.A. registration
    of captafol is only for dormant sprays. Other countries permit
    multiple foliar sprays at concentrations ranging from 0.12 to 0.62%,
    and with pre-harvest intervals ranging from 7 to 15 days. On the basis
    of these very limited data, it in estimated that the half-life is 10 -
    20 days, and that maximum residue deposits shortly after treatment
    could approximate 17 mg/kg (Table 2, test no. 831). The highest spray
    concentration in these trials was 0.25% as compared with sprays up to
    0.62% registered in come countries. It would thus appear that the 1973
    JMPR recommendation for a 5 mg/kg MRL with a 7 day PHI is not very
    realistic. The available data do not permit any reliable estimates on
    residue levels to be expected from current agricultural practices.

    APPRAISAL

    The Codex Committee on Pesticide Residues has referred questions on
    previously recommended MRLs for captafol on cranberries, apples and
    pears to the Joint Meeting.

    No new data on cranberries have become available. A re-examination of
    the limited data reviewed by the 1973 Meeting shows that residues
    would in some cases exceed 5 mg/kg, and that the previously
    recommended MRL of 8 mg/kg would be appropriate.

    Data on apples made available to the 1977 Meeting were evaluated: it
    has not been ascertained whether they are the same as those evaluated
    by the 1973 Meeting. Information on national use patterns is rather
    limited. Some countries have registered only dormant sprays or early
    season use, while others permit multiple treatments with pre-harvest
    intervals of 7-15 days after foliar sprays at concentrations ranging
    from 0.12 to 0.62%. The available data indicate that the presently
    recommended 5 mg/kg MRL based on a 7-day pre-harvest interval may not
    be appropriate, but adequate information is lacking.

        TABLE 2. Residues -apples, seasonal applications
                                                                                                                                    
                                                                     0      1       2         3         5       7        10     20
    Test No. &   kg a.i./      Dilution      No. of       Crop       Days   Day     Days      Days      Days    Days     Days   Days
    Location     ha            Lbs./         Apple.       Part
                               100 gals.     100 gals.
                                                                                                                                    
    589          3.5           1             9            Fruit      1.9                                1.5              1.3    1.3
    N.J.                                                             2.5                                1.8              1.4    0.9

    590          2.6           1             12           Fruit      8                        7                          6      4
    N.C.

    707          7.0           2             13           Fruit              1.8                                0.9
    N.J.                                                                     1.6                                0.8

    712          1.5-3.1       0.5-1.0       15           Fruit              0.8
    Mich.                                                                    0.5

    713          5.7           1             5            Fruit                     10.5
    N.C.                                                                             8.6

    831          4.4           1.25          12           Fruit             13.7
    N.J.                                                                    12.8

    TABLE 2. (Continued)
                                                                                                                                    
                                                                     0      1       2         3         5       7        10     20
    Test No. &   kg a.i./      Dilution      No. of       Crop       Days   Day     Days      Days      Days    Days     Days   Days
    Location     ha            Lbs./         Apple.       Part
                               100 gals.     100 gals.
                                                                                                                                    
                                             13           Fruit             14.5
                                                                             8.7

                                             13           Fruit             17.5
                                                                            13.2

    1185         2.6           0.75          9            Fruit      2.7
    England                                                          2.3

    1187         1.5           0.8           14           Fruit              2.9
    France                                                                   3.0

    1188         2.6           4             5            Fruit      2.3
    New Zealand                                                      3.8

    1189         2.0           2.25          7            Fruit      1.2
    New Zealand                                                      1.8

    1357         4.4           1             6            Fruit                                                 4.7
    N.C.         (plus one dormant spray at 26 kg/ha)                                                           6.6
                 (6 1b/100 gals)

    NOTES

    All samples mature fruit.

    Formulation used was Difolatan (wettable).

    RECOMMENDATIONS

    1. The 1973 recommendation for maximum residue limit of 8 mg/kg for
    captafol on cranberries, based on a 50 day pre-harvest interval, is
    maintained.

    2. The previously recommended maxim= residue limit of 5 mg/kg for
    captafol on apples and pears is retained until additional information
    becomes available.

    FURTHER WORK OR INFORMATION

    DESIRABLE

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

    2. Additional information on national use patterns and data from
    supervised residue trials, particularly on apples and pears, from
    countries where the product is used.

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

    4. Information, some of it 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 studies now in progress on the level and nature of
    captafol residues in meat, milk, poultry and eggs.

    6. Results of studies now in progress on the fate of captafol residues
    in citrus fruits and citrus pulp.

    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.

    FAO/WHO (1975) 1974 evaluations of some pesticide residues in food.
    AGP:1973/M/11; WHO Pesticide Residues Series, No. 4.

    FAO/WHO (1977) 1976 evaluations of some pesticide residues in food.
    AGP:1976/M/14.

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

    Kohn, F.E., Key, J.H. and Calandra, J.C. (1964) Two-year chronic oral
    toxicity of RE 5865-Albino rats. Unpublished report of Industrial
    Bio-Test Laboratories submitted by Chevron Chemical Go.

    Moriya, M., Kato, K., Shirasu, Y. and Kada, T. (1975) Mutagenicity
    screening of pesticides in microbial systems. III. Fate of
    mutagenicity.  Mutation Research, 38, 333-354. (Summary only)
    
    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: 1976 evaluations)
       Captafol (IARC Summary & Evaluation, Volume 53, 1991)