Sponsored jointly by FAO and WHO


    Data and recommendations of the joint meeting
    of the FAO Panel of Experts on Pesticide Residues
    in Food and the Environment and the
    WHO Expert Group on Pesticide Residues
    Geneva, 5 - 14 December 1983

    Food and Agriculture Organization of the United Nations
    Rome 1985




           Dichlofluanid was evaluated by the Joint Meetings in 1969, 1974,
    1977, 1979, 1981 and 1982 (see FAO/WHO 1970, 1975, 1978, 1980, 1982
    and 1983).1 A temporary acceptable daily intake (ADI) of 0 - 0.3
    mg/kg body weight was established at the 1974 JMPR and extended at the
    same level in 1977. The temporary ADI was based on the no-effect level
    observed in a 2-year study in dogs at 25 mg/kg body weight. Further
    work and information were required to elucidate the effects of the
    possible accumulation in the thyroid of this organic fluorine
    compound. The meetings in 1979 and 1982 did not consider dichlofluanid
    and the temporary ADI was extended for a further year, pending
    submission of the requested information.

           Some information was available from Belgium, Finland, Norway, and
    The Netherlands on use patterns, results of supervised trials,
    residues in commerce and national maximum residue levels.

           The additional data submitted to WHO and FAO have been reviewed
    and are summarized in the following monograph addendum.



    Special Studies on Mutagenicity

           Dichlofluanid was tested for potential mutagenicity by the sister
    chromatid exchange method in the bone marrow of male and female
    Chinese hamsters. Cyclophosphamide was used as the positive control.
    Groups of five male and five female Chinese hamsters were administered
    doses of 1 000 and 2 000 mg/kg b.w. orally by intubation. The positive
    control group received 20 mg/kg/b.w. of cyclophosphamide and the
    negative control the suspension agent only (0.5 percent cremophor
    emulsion). Animals were killed after 24h. Two hours before the
    administration of the test substance, a tablet of 50 mg 
    5-bromo-deioxyuridine was implanted subcutaneously into each animal
    and 2 h before sacrifice they received 4 mg/kg b.w. colchicin by
    intra-peritoneal injection to arrest mitoses at the metaphase stage.
    For each animal, 50 metaphases were examined and the incidence of
    sister chromatid exchanges per metaphase was established. Wilcoxon's
    non-parametric rank sum test was used for the statistical evaluation
    of the results.


    1    See Annex 2 for FAO and WHO documentation.

           There were no indications of a mutagenic effect for doses up to
    2 000 mg/kg/b.w., no biologically relevant increase in the SCE rate
    was noted compared to the distinct mutagenic effects seen in the
    positive control group (Herbold 1980).

    Special Studies on Embryotoxicity


           Groups of 15 inseminated Himalayan female rabbits were dosed
    orally by gavage with 0, 10, 30, 100 mg/kg b.w, dichlofluanid from day
    6 through day 18 of gestation. All dams survived and generally no
    changes were observed.

           The results demonstrated that pregnant rabbits tolerated oral
    administration of 10 and 30 mg/kg dichlofluanid without evidence of
    maternal toxicity. Administration of 100 mg/kg induced moderate
    maternal toxicity as evidenced by weight loss, reduced food
    consumption and premature delivery of two litters.

           Administration of dichlofluanid at doses of 10 and 30 mg/kg did
    not alter significantly the incidence of resorbed implantations among
    the faetal population, indicating that the test compound was not
    embryo-lethal. Neither of these doses, when administered during the
    period of organogenesis, produced a faetotoxic response in rabbits; no
    deleterious effects on faetal body weight, placental weight or weight
    of gravid uteri were observed. In the 100 mg/kg dose group, the
    weights of the gravid uteri, the number of implantation sites and live
    foetuses were significantly lower in comparison with the control

           The higher incidence of the number of litters with anomalies in
    the 30 or 100 mg/kg group was of no biological significance and was
    not considered related to dichlofluanid, as these anomalies
    occasionally occur spontaneously in this strain of rabbits.

           In conclusion 30 mg/kg can be considered as the no-effect level
    (NOEL) for maternal, embryotoxic and/or faetotoxic effects. No
    teratogenic effects were noted (Parish 1982).

    Special Study on Skin and Eye Irritation

           Skin treatment in White New Zealand rabbits by dichlofluanid
    produced slight irritation, not completely reversible after 72 h. When
    placed in the conjunctival sac of the rabbit's eye, a moderate mucosal
    irritation was observed (Pauluhn 1982).

    Special Study on the Effect on the Thyroid


           The dose-time effect relationship on the thyroid of dichlofluanid
    was evaluated in groups of 80 male rats fed for nine weeks at dietary
    concentrations of 0, 150, 500, 1 500 and 4 500 ppm. The animals showed
    no alterations in appearance, behaviour or mortality that could be
    related to the treatment during the entire period. Food consumption
    was about 5 percent lower than the controls at 4 500 ppm. Body weight
    did not differ significantly from the controls up to doses of 500 ppm.
    In the 1 500 ppm group, body weights were significantly lower compared
    to the control up to the third study week. Body weight gain was
    slightly retarded in the 4 500 ppm group over the entire period.
    Slight or significant differences from the controls were found in the
    serum levels of calcium and inorganic phosphate in all dose groups,
    but the values obtained were within the biological range for rats of
    this age, confirming the lack of any effect on the parathyroids by
    dichlofluanid. Iodine accumulation in the thyroid, both in respect of
    percentage and concentration, was not affected up to 1 500 ppm. In the
    4 500 ppm dose group, a significantly increased value was noted in the
    first examination. At doses up to 1 500 ppm, the clinical-chemical
    (T4) and radioimmunological (T3, T4) determination of the thyroid
    hormone did not indicate any treatment-induced effects on the thyroid.
    The significantly lower concentrations of both hormones in the 4 500
    ppm group at two successive points (7 and 21 days) might be considered
    a result of treatment and would point to a slight effect on the
    synthesis and/or secretion phase of the thyroid. A permanent
    decompensation of the thyroid control system was, however, not
    detected. Gross pathology and histopathology produced no evidence of
    treatment-induced damage of the thyroid in any of the dose groups.
    Organ weights and subsequent histopathological examination did not
    reveal any alterations in the adrenals during the treatment. The lower
    liver weight at 4 500 ppm for 21 study days is considered a
    consequence of the significantly lower animal weights. The higher
    liver weights noted at the end of the study might be interpreted as
    substance-induced. Histopathological examination did not reveal any
    treatment-related alterations in the organs and tissues examined
    (thyroid, liver, adrenal and skeletal musculature).

           The NOEL was considered to be 500 ppm in the diet, corresponding
    to 39.3 mg/kg b.w./day (Krötlinger & Luckhaus 1981).

    Acute Toxicity

           The symptoms and lethality of a 1:1 combination of the equitoxic
    compounds dichlofluanid and captan were determined in an acute oral
    toxicity test in rats. No significant additive effect was observed
    (Mihail 1980). No synergistic effects were found when a single
    combined dose of equitoxic doses of dichlofluanid and triadimefon was
    administered orally to male rats (Mihail 1982).

    Long-Term Toxicity


           Groups of 50 male and 50 female mice were fed dichlofluanid for
    24 months in their diet at levels of 0, 200, 1 000 and 5 000 ppm. Ten
    additional animals/sex/dose were used for laboratory tests; of these
    animals, five/sex/dose were sacrificed and dissected after blood
    samples had been taken, after six and twelve study months.  During the
    entire test period, no alterations in appearance, behaviour or the
    mortality rate were noted when compared to the control group. Growth
    was not affected in the groups up to 1 000 ppm but was significantly
    retarded for both sexes at 5 000 ppm over the entire period. Specific
    changes in haematological parameters were noted at the dosages
    administered but the deviations were considered to be without
    toxicological significance. Clinical chemistry, gross pathology and
    histopathology did not reveal any indication of liver damage in any of
    the dose groups. However, the raised alkaline phosphatase activity in
    the 5 000 ppm group after 24 h of the study might be considered
    treatment-related. This finding was an isolated one and not confirmed
    in later tests. It may have been related to the observed bone
    proliferation. Clinical chemistry provided no indications of a
    treatment-induced effect on the kidney. Higher values for blood sugar
    and cholesterol found at 5 000 ppm at the end of the study were,
    however, within the physiological range. An increased thymus weight
    was noted in males at the 5 000 and 1 000 ppm level. However, no
    pathological alteration was observed and these differences were
    therefore not treatment-related.

           The bone proliferation detected in the femurs and/or ribs by
    gross pathology and histopathology and the hardened crania on female
    animals of the 5 000 ppm group can be considered as skeletal
    alterations induced by the active ingredient. The findings of gross
    pathology and histopathology noted in other organs provided no
    indications of substance-induced organ damage. Doses up to 5 000 ppm
    gave no indication of any significant dose-related increase in
    location, types and total number of tumours. Therefore, in these
    conditions, dichlofluanid was non-carcinogenic in the experimental
    conditions employed.

           The NOEL of dichlofluanid was 1 000 ppm, corresponding to 252
    mg/kg b.w./day for male mice, or 273 mg/kg b.w./day for female mice
    (Krötlinger and Löser 1982).


           The 1979 Meeting, which extended the temporary ADI for
    dichlofluanid, required studies to elucidate the accumulation seen in
    the thyroid. A study on rats, over a period of nine weeks,
    investigated the dose/time relationship of the thyroid effect at dose
    levels up to 4 500 ppm. Increased iodine uptake was observed early in
    the study at 4 500 ppm, while decreases in T3 and T4 levels were noted

    on days 7 and 21 of the study. The NOEL for the thyroid effects was
    greater than 1 500 ppm. However, decreased body weight gain indicates
    an overall NOEL of 500 ppm for the study.

           Additional data evaluated included a sister-chromatid exchange
    study which was negative at doses of 2 000 mg/kg, and a teratogenicity
    study in the rabbit, which demonstrated embryotoxicity, but not
    teratogenicity, at a dose level of 100 mg/kg b.w. A mouse long-term
    carcinogenicity study did not indicate any evidence of oncogenicity at
    dose levels up to 1 000 ppm in the diet.

           Since all the requirements of the 1979 Meeting have been
    satisfied the present Meeting was able to estimate an ADI.


    Level Causing no Toxicological Effect

    Rat: 500 ppm in the diet, equivalent to 30 mg/kg/b.w.

    Dog: 1 000 ppm in the diet, equivalent to 25 mg/kg/b.w.

    Estimate of Acceptable Daily Intake for Man

    0-0.3 mg/kg/b.w.



    Observations in humans.


    Herbold, B. Dichlofluanid - sister chromatid exchange on the Chinese
    1980          hamster in vivo to evaluate for mutagenic effect. Report
                  9391 submitted to WHO by Bayer A.G., F.R.G (Unpublished)

    Krötlinger F. & Loser, E. Dichlofluanid - chronic toxicological study
    1982          on mice (including pathologic report by Newman, A.J. and
                  Wood, C.M.). Report No. 10810 submitted to WHO by Bayer
                  A.G., F.R.G. (Unpublished)

    Krötlinger, F. & Luckhaus, G. Dichlofluanid - subchronic toxicological
    1981          study to ascertain the dose time-effect relationship in the
                  effect on the thyroid. Report No. 10312 submitted to WHO by
                  Bayer A.G., F.R.G. (Unpublished)

    Mihail, F. Dichlofluanid and captan - study for acute combination
    1980          toxicity. Report No. 9388 submitted to WHO by Bayer A.G.,
                  F.R.G. (Unpublished)

    Mihail, F. Dichlofluanid - study for acute combination toxicity.
    1982          Report No. 11206 submitted to WHO by Bayer A.G., F.R.G.

    Parish, H.M. Embryotoxicity study in rabbits with oral application of
    1982          dichlofluanid. Report R2415 from the Institute of
                  Toxicology, Regensburg, submitted to WHO by Bayer A.G.,
                  F.R.G. (Unpublished)

    Pauluhn, J. Dichlofluanid - study for primary skin and mucosa irritant
    1982          effect. Report submitted to WHO by Bayer A.G., F.R.G.




           Dichlofluanid is registered for use in Finland (Finland 1983) on
    apples (0.15-0.2 percent solution) and strawberries and currants (both
    0.25 percent solution) and ornamentals. The waiting period is 14 days.

           Dichlofluanid is approved in Norway (Norway 1983) for use on
    stone fruits, berries, lettuce, onions, tomatoes, cucumbers and
    ornamentals. Application rates are 50-125 g a.i./100 1 water. The
    preharvest intervals are seven days for stone fruits and berries
    (except strawberries), 14 days for onions and lettuce and four days
    for cucumbers and tomatoes.

           The Netherlands (1983) provided some new information on uses on
    grapes (125 g/100 1, 6 weeks preharvest interval, PHI), eggplant (125
    g/100 1, 3 days PAI; 75 mg/m2 of 7.5 percent dust as preventive, 3
    days PHI) and zucchini (75 mg/m2 of 7.5 percent dust as preventive).
    Information on a food survey taken in The Netherlands in 1981 and 1982
    showed that most residues in 1981 were less than 2 mg/kg with only six
    samples (currants (2), raspberry (3) and strawberry (1) out of 200
    having residues above the maximum residue limit (MRL) of 5 mg/kg, with
    a maximum of 6.7 mg/kg in currants). In 1982, five samples of currants
    (4) and raspberry (1) had residues above the MRL, with a maximum of
    32.7 mg/kg in currants. The method of analysis used was not stated.


           Additional data was received from Norway on residues in
    greenhouse tomatoes from five treatments at 10 to 14 day intervals,
    using 0.75 g a.i./100 l. Residues determined at 2, 4, 6 and 8 days
    after spraying ranged from 0.1 to 0.2 mg/kg after the first,
    treatment, 0.4 to 0.5 mg/kg after the third treatment and 0.6 to 0.7
    mg/kg after the fifth treatment. The method of analysis used was not


           The hydrolytic stability of dichlofluanid was determined at pHs
    4, 7 and 9 and at temperatures of 20°, 30° and 40°C. Decomposition was
    rapid at pH 7, with only 25-30 percent remaining after 40 h. At pH 4,
    47 percent remained after eight days at 30°, while 17 percent was left
    after seven days at 40°. The hydrolysis constant at 20° and pH 7 was
    7.5 x 10-6/sec (Wilmes 1982a).

           About 1 mg of dichlofluanid was applied to a thin-layer plate and
    exposed to artificial light for four weeks, at which time 30-42
    percent of the original concentration remained. In aqueous solution
    (2.6 mg/l) exposed to a mercury vapour lamp, dichlofluanid had a half-
    life of about 10 h. In addition to the hydrolysis product
    dimethylsulfanilid, an unidentified polar photoproduct was formed
    (Wilmes 1982b).


           Information was available from Belgium on the results of a survey
    conducted over the years 1979-1982 for residues occurring in food in
    commerce. Dichlofluanid never exceeded the Belgian tolerance of 5
    mg/kg and was non-detectable in the range of 73-100 percent of the
    samples. When present, it was found in a maximum of 27 percent of
    samples at values not exceeding 0.8 mg/kg (Geloux 1983).

           Surveys of domestic and imported food in commerce in Finland were
    reported to the meeting (year unspecified). For domestic food, the
    distribution and frequency is shown in Table 1 while Table 2 gives the
    results for imported food. Again the analytical methodology employed
    was not stated.

           No residues were found in or on other fruits and vegetables. Only
    15 samples of food (all strawberries) out of a total of 1 081 had
    residues exceeding 1 mg/kg.


           New information was received from Finland on permitted uses
    (apples, strawberries, and currants, with a waiting period of 14
    days). Surveys of domestic and imported food in commerce showed that
    residues of dichlofluanid were rarely found, usually at less than 0.1
    mg/kg, and only exceeded 1 mg/kg in 15 samples out of 1 081.

           Information on the results of surveys of food in commerce in
    Belgium covering the years 1979-1982 showed that dichlofluanid never
    exceeded the local MRL of 5 mg/kg, with the maximum level found being
    0.8 mg/kg. It was non-detectable in 73 to 100 percent of the samples.

        Table 1.  Dichlofluanid Residues in Domestic Commodities, Finland


    Commodity           No.                  Residue (mg/kg)
                                   <0.1         0.11-1.0       1.1-2.0      >2.1
    Strawberries        486        221          164            6            8
    Currants            114        1            1
    Gooseberries        15
    Apples              129                     2

    Table 2.  Dichlofluanid Residues in Imported Commodities, Finland

    Commodity           No.                 Residue (mg/kg)
                                   <0.05        0.05           0.51         1.1->2.0         Max.
                                                0.20           1.0          2.0
    (chinese)           130        1            2                                            0.13
    Plums               142        1            1                                            0.10
    Strawberries        54                      1              1                             0.68
    Brussels sprouts    11                      1                                            0.17
           Information on approved uses in Norway was available, where it is
    permitted on stone fruits, berries, lettuce, onions, tomatoes and
    cucumbers. The results of supervised trials on greenhouse tomatoes in
    Norway, treated at recommended rates, gave a maximum residue of 0.7
    mg/kg two days after a fifth biweekly treatment.

           The Netherlands provided new information on uses on grapes,
    eggplant and zucchini, along with data from their 1981 and 1982 food
    surveys. Residues in excess of the MRL of 5 mg/kg occurred in about 3-
    4 percent of the samples, mainly in currants and raspberries.

           In all of the preceding submissions, it was not clear whether the
    analytical method employed measured parent compound only or parent
    plus metabolites. Only the procedure measuring dichlofluanid alone can
    be properly used in evaluations.

           Data from Germany was available on the results of hydrolytic and
    photo stability tests. Decomposition in water at pH 7 and 20° was
    rapid, with only 25-30 percent remaining after 48 h. Photodegradation
    on a TLC plate resulted in 30-42 percent remaining after four weeks
    exposure to artificial light. In aqueous solution, it had a photolytic
    half-life of about 10 h.


           All previous temporary MRLs are replaced by MRLs at the same


    Finland. Information on uses of dichlofluanid in Finland.

    Norway. Information on uses of dichlofluanid in Norway. Data on
    1983          residues in greenhouse tomatoes from supervised trials.

    Netherlands. Information on uses and food surveys in The Netherlands.

    Wilmes, R., Behaviour of crop protection products in water. Bayer A.G.
    1982a         report PF-A/CE-PIQ-ENA. (Unpublished)

    Wilmes, R., Orientating studies on stability to light. Bayer A.G.
    1982b         report PF-A/CE-PIQ-ENA. (Unpublished)

    Geloux, M. Note technique du Central de Recherches Agronomiques de
    1983          l'Etat, Gembloux, Belgique, No. 9/25, 9/26, 9/31 and 9/32,
                  Sept. 1979 - June 1982.

    See Also:
       Toxicological Abbreviations
       Dichlofluanid (FAO/PL:1969/M/17/1)
       Dichlofluanid (WHO Pesticide Residues Series 4)
       Dichlofluanid (Pesticide residues in food: 1977 evaluations)
       Dichlofluanid (Pesticide residues in food: 1979 evaluations)
       Dichlofluanid (Pesticide residues in food: 1981 evaluations)
       Dichlofluanid (Pesticide residues in food: 1982 evaluations)