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    FOLPET

    EXPLANATION

         Folpet was evaluated for acceptable daily intake by the Joint
    Meeting in 1969, and reviewed in 1973, 1982, and 1984 (Annex 1,
    FAO/WHO, 1970a, 1974a, 1983a, and 1985b). A toxicological monograph
    was prepared by the Joint Meeting in 1969 (Annex 1, FAO/WHO, 1970b)
    and monograph addenda were prepared in 1973 and 1984 (Annex 1,
    FAO/WHO, 1974b and 1985c). The previously established temporary ADI
    was withdrawn in 1984 because of possible teratogenicity and the
    absence of a 90-day oral study in rats, long-term oral studies in rats
    and mice, a 12-month oral study in dogs, a reproduction study in rats,
    and a teratology study in rabbits. These and other data have now been
    received and are reviewed in this monograph addendum.

    EVALUATION FOR ACCEPTABLE INTAKE

    Toxicological studies

    Special studies on carcinogenicity

    Mice

         Groups of 52 male and 52 female B6C3F1 mice were fed folpet
    (89.0% pure) in the diet at 0, 0.1, 0.5, or 1.0% for 21 weeks and
    thereafter at 0.1, 0.35, or 0.7% for 83 weeks. Dietary analyses at
    weeks 0, 1, 13, and 26 showed that about 88 - 91% of the nominal
    dietary concentrations were fed. Food consumption was depressed among
    mid- and high-dose only during the first weeks of treatment. However,
    body-weight gain was reduced in mid- and high-dose animals throughout
    the study. Clear signs of toxicity, observed principally in high-dose
    groups, were erythema, dry flaking skin, reddish fur discoloration,
    and weeping skin, particularly in the first 21 weeks. There was no
    apparent effect of treatment on leucocyte counts of suvivors at 52,
    78, or 104 weeks. The longevity of mid- and high-dose groups was
    reduced.

         At necropsy, relative weights of the brain, heart, lungs, liver,
    kidneys, and testes were increased in a dose-related manner,
    reflecting the reduced body weight of treated animals. Macro-
    scopically, a dose-related increase in the ulceration of the
    non-glandular gastric mucosa and thickening of the gastric and
    duodenal walls were observed. The jejunal wall was thickened in
    mid-dose females and in the high-dose groups. Dose-related distension
    of the duodenal lumen also occurred. From 79 weeks onward there was a
    dose-related increase in the incidence of nodules or masses on the
    luminal surface of the stomach or duodenum or on the duodenal serosa.

         Microscopically, the mid- and high-dose groups exhibited
    dose-related epidermal hyperkeratosis and acanthosis and oesophageal
    hyperkeratosis. Increased areas of marked acanthosis and hyper-
    keratosis of non-glandular gastric mucosa were also seen in the
    mid-dose groups and the high-dose males. Microscopic gastric
    ulceration occurred without apparent relation to dose. Dose-related
    areas of atypical duodenal glandular hyperplasia and mucosal gland
    proliferation were seen in all treated animals, but especially in the
    males. These atypical hyperplasia were often associated with duodenal
    adenomas or adenocarcinomas. Atypical glandular proliferation was seen
    only occasionally in the jejunum of treated female mice.

         Gastric papillomas and squamous cell carcinomas, which may have
    been secondary to mechanical obstruction of the duodenal lumen, were
    found in all groups of treated male mice, but not in control males. A
    dose-related incidence of gastric papillomas was also found in all
    treated female groups, but similar lesions occurred in 2/51 control
    females. Duodenal tumours, adenomas, and adenocarcinomas were found in
    all treated groups of both sexes, with an even more significant dose
    relationship. A single case of jejunal adenocarcinoma occurred in the
    highest-dose group.

         Primary or metastic tumours of uncertain aetiology were found in
    all treated male groups. However, the incidences of broncio-alveolar
    adenomas and malignant lymphomas were less in all treated male groups,
    suggesting a high incidence of these conditions in control male
    animals (Rubin & Nyska, 1985a; Nyska, 1985).

    Rats

         Groups of 60 male and 60 female F-344 rats were fed folpet (89%
    purity) in the diet at 0, 500, 1,000, or 2,000 ppm for 104 weeks. Test
    diets were prepared weekly and analysed for folpet content regularly.
    Food intake was generally less in all treated groups than in controls,
    but only the mean body weights of treated males were lower than those
    of controls throughout the study. There were no signs of toxicity
    attributable to treatment during the study.

         At necropsy, there was a tendency toward increased incidences of
    gastric ulceration in treated groups, which was significant only in
    female rats. Folpet exposure was also associated with an increased
    incidence of ulceration of the non-glandular stomach of the high-dose
    group. Histologically, folpet treatment produced hyperkeratosis of the
    oesophagus of rats in the high-dose groups and of the non-glandular
    stomach of animals in the mid- and high-dose groups. There was also a
    slight increase in gastric ulceration in the non-glandular stomach of
    both males and females in the high-dose groups. The incidences of
    C-cell adenoma, benign mammary fibroepithelioma, and malignant
    lymphoma showed a positive significant trend with dose; only the
    latter neoplasms were statistically significant, but the incidences of
    all remained within the range of spontaneous incidences of these
    neoplasms in F-344 rats. Accordingly, the results of this study
    indicate that folpet is not carcinogenic to F-344 rats
    (Crown et al., 1985).

    Special studies on mutagenicity

         Folpet was mutagenic in E. coli strain PQ37, but inactive in
    the presence of S-9 microsomal mix. It was without genotoxic activity
    in Chinese hamster V79 cells and in somatic cell mutation and
    micronucleus tests in mice. Results are presented in Table 1. Dietary
    analysis confirmed the stability of folpet in the test diet for the
    somatic cell mutation study (Slagowski & Leary, 1985a).

    Special study on reproduction

    Rats

         In a 2-generation reproduction study, groups of 30 male and 30
    female Crl:COBS/CD (SD)/Charles River rats were fed folpet (89.5%
    pure) in the diet at 0, 200, 800, or 3600 ppm during growth, mating,
    gestation, and lactation for 2 litters per generation. Mating was
    allowed after 62 days of dietary exposure. The test diets were fed to
    the F0 males until the end of the mating periods for the F1b
    litters and to the F0 females until the weaning of the F1b
    litters. Pups were sacrificed 21 - 23 days after parturition, with the
    exception of those F1b pups selected to parent the F2 generation.

         Mating of these F1b pups began after 12 weeks of dietary
    exposure and the above sequence repeated. Gross necropsy was performed
    on all parental rats and on the F1a, F1b, and F2b litters.

         The test diet was changed 3 times per week and each batch was
    analysed for folpet content. Analyses showed that the test diets
    contained 79.9 - 101% of the nominal folpet concentration.

         The body weights of the high-dose males (F0 and F1) and
    females (F1) and of the pups from high-dose litters were depressed
    by treatment. This effect was most marked in the adult males,
    especially in the second generation. Food consumption was
    correspondingly reduced. Treatment had no significant effect on
    mating, fertility indices, pregnancy rates, litter sizes, pup weights,
    growth, or litter survival rates. There were no treatment related
    effects found at necropsy or on histopathological examination. Based
    on the finding of reduced body weight at the high dose, the no-effect
    level determined in this study was 800 ppm (Hardy & Richter, 1985;
    Slagowski & Leary, 1985c).

    Special studies on teratology

    Rats

         In a pilot study, groups of 6 pregnant CD rats were treated daily
    with 10, 65, 420, or 2750 mg folpet/kg b.w. (88.6% pure) by
    intragastric gavage during days 6 to 15 of gestation. The high-dose
    treatment caused maternal toxicity, reduced maternal body-weight gain,
    and reduced fetal weight, but the lower doses were without apparent
    effect (Rubin, 1985a).

        Table 1. Results of mutagenicity studies on folpet
                                                                                                             

    Test                  Test
    system                organism         Purity        Concentration         Results         Reference
                                                                                                             

    E. coli               E. coli          90%           0.03, 0.10,           positive        Abir, 1986
       PQ37               PQ371                          0.3, 1.0
       mutation                                          g/ml (-S-9)
                                                         3.0, 10.0,30.0        negative
                                                         g/ml (+S-9)

    Chinese               V79              90.1%         0.125, 0.25,          negative        Bootman et al.,
       hamster            cells2                         0.5, 1.0, 2.0                         1986
       fibroblast                                        g/ml (-S-9)
                                                         3.125, 6.25           negative
                                                         12.5, 50
                                                         g/ml (+S-9)

    Mouse                 T-strain         88.7%         0, 100, 1500,         negative        Moore & Brusick,
       somatic            male mice                      & 5000 ppm,           (decreased      1985
       cell               C57B1/6                        fed days 8.5          pup body
       mutation           female                         - 12.5 of             weight and
                          mice                           gestation             survival
                                                                               occurred)

    Mouse                 Charles          91.0%         10, 50, 250           negative        Jacoby, 1985
       micro-nucleus      River CD-1                     mg/kg
                          mice3
                                                                                                             

    1   Positive controls using 0.0156 - 1.0 g/ml 4-nitroquinoline-1-oxide or 0.156 - 10.0 g/ml
        2-aminoanthracene gave positive results.
    2   Positive controls using 1000 g/ml ethylmethane sulfonate (-S-9) or 10 g/ml
        7,12-dimethylbenzanthracene (+S-9) gave positive results.
    3   A positive control using chlorambucil gave the expected response.
    
         Subsequently, groups of 22 mated female Charles River CD rats
    were dosed daily by oral gavage with 0, 150, 550, or 2000 mg
    folpet/kg b.w. (91.1% pure) suspended in 0.5% acetic acid containing
    0.5% carboxymethylcellulose from days 6 to 15 of gestation. The
    animals were sacrificed on day 20 and the uterine contents were
    removed for pathological examination. One dam of the high-treatment
    group died, while clear signs of toxicity were observed in the rest of
    this group, namely, soft faeces (21/21), staining of fur (4/21), and
    perianal staining (8/21).

         Food consumption was markedly decreased in the high-dose group
    during treatment; it was decreased in the intermediate group only
    during the first days of treatment. Maternal body weight was
    significantly reduced in the high-dose group throughout the study, and
    to a lesser extent in the mid-dose group. Mean gravid uterine weights
    were significantly depressed in the high- and mid-dose groups, but
    terminal maternal body weight (i.e. net of gravid uterus) was
    significantly depressed only in the high-dose group. Pre- and
    post-implantation losses were increased over controls in the mid-dose
    group only, while fetal weights were reduced in the high- and mid-dose
    groups. Fetal crown-rump length was decreased slightly in mid- and
    high-dose groups. The high-dose group contained a single fetus (1/277)
    with multiple major malformations. On sectioning, another fetus in the
    high-dose group was found to have unilateral microthalmia. Hepatic
    discolouration was significant in the high-dose group. Skeletal
    anomalies occurred in all treated groups. Reduced ossification of
    cranial and pubic bones, sternebrae, metacarpals, and metatarsals was
    significant in mid- and high-dose groups. There was a dose-related
    reduction in the ossification of the interparietal bone of all treated
    groups. In addition, angulated ribs occurred in a dose-related manner
    in all treated groups. As a consequence, this study did not
    demonstrate a no-observed-effect level (Rubin & Nyska, 1985b).

    Rabbits

         In a pilot study, groups of 6 mated HY/CR female New Zealand
    white rabbits were treated with folpet (91.1% purity) at 0, 10, 60, or
    150 mg/kg b.w./day by intragastric intubation from day 6 to day 18 of
    gestation, inclusively. A marked loss of body weight occurred at the
    high dose. Although fetal size was not affected by treatment, fetal
    death was more marked at the high dose.

         Post-implantation losses were increased in the mid-dose group
    (Rubin & Nyska, 1985c).

         Subsequently, groups of 14 mated HY/CR New Zealand white rabbits
    were treated with technical folpet (91.1% purity) suspended in 0.5%
    carboxymethylcellulose in 0.5% acetic acid at 0, 10, 40, or
    160 mg/kg b.w./day by oral gavage from day 7 to day 19, inclusive, of
    gestation. Administered doses were corrected daily for body weight.
    The dams were sacrificed at day 29 and their uterine contents removed
    and necropsied.

         The body-weight gain of high-dose dams was reduced after
    initiation of treatment, while that of the mid-dose group was reduced
    during the initial few days of treatment only. There was a
    corresponding decrease in food consumption of the high-dose animals
    during treatment.

         No animals died during treatment. At necropsy, the gravid uterine
    weight was significantly reduced in the mid- and high-dose groups.
    Fetal death (post-implantation loss) occurred more frequently in the
    high-dose group than in controls. The proportion of small fetuses was
    also greater in this group, and the mean fetal weight was reduced, but
    not significantly.

         There was evidence of delayed skeletal maturation in the
    high-dose group and, to a lesser degree, in the mid-dose group. The
    incidence of bilateral lumbar ribs increased in an apparently
    dose-related manner in the mid- and high-dose groups. Ossification of
    caudal vertebrae, sternebrae, and long-bone epiphyses were reduced at
    the high dose. Other minor skeletal variations were not apparently
    related to treatment. There was no evidence of hydrocephalus in either
    treated or control rabbits (Rubin, 1985b).

         Groups of 20 artificially inseminated female Hazleton Dutchland
    New Zealand white (Dla Hra; (NZW)SPF) rabbits were dosed by oral
    gavage with a suspension of folpet (89.5% pure) in Tween 80 (10.5% by
    weight) and carboxymethylcellulose (0.7% by weight) at a volume of
    5 ml/kg b.w./day. The test material was administered at 60 mg/kg b.w.
    daily by stomach tube, using the pulse-dose regime tabulated in Table
    2, at selected days of gestation.

    Table 2.  Pulse-dose regime for teratology study in rabbits
                                                                        

                        Dosage
    Treatment group     (mg/kg b.w./day)     Days of administration
                                                                        

      I                      0                    7-18
     II                     60                    7-9
    III                     60                   10-12
     IV                     60                   13-15
      V                     60                   16-18
                                                                        

         Analysis of dosage formulations, prepared daily, for folpet
    content ranged from 87.8 to 104% of nominal dosage.

         The dams were sacrificed on gestation day 29, necropsied, and
    uterine contents examined. Animals which aborted or delivered (and the
    single animal which died) during the study were subjected to similar
    procedures.

         The abortion of 2 rabbits which received folpet on days 7 - 9 and
    10 - 12 of gestation may have been related to treatment. Otherwise, no
    clinical signs of toxicity were observed during the study, although
    the incidences of dams with soft or liquid faeces increased in all
    treatment groups, usually after the treatment period. At necropsy, no
    gross lesions were attributable to treatment. Maternal body weights,
    however, were significantly reduced in all treated groups, although
    less so in groups II and III than in the others. Food consumption was
    correspondingly reduced. Treatment had no apparent effect on the rate
    of abortion or on fetal resorption.

         Average litter sizes were unaffected, as were average fetal
    weights, the number of viable fetuses, and the sex ratio. A
    significantly-increased incidence of fetuses with an irregularly
    shaped fontanelle was observed in Group IV. The control incidence was
    4.5%, but this variation did not occur in Groups II and V. It was
    possibly related to treatment, but the significance of this effect was
    not clear. There were no other significant variations in fetal skull
    morphology, and the incidence of hydrocephalus was not increased in
    any group. Gastric or pulmonary anomalies were not increased in any
    groups. The results of this study indicate that folpet is not
    teratogenic in rabbits at 60 mg/kg b.w./day (Feussner et al., 1985;
    Slagowski & Leary, 1985b).

    Short-term studies

    Rats

         In a pilot study, groups of 20 male and 20 female F-344 rats were
    fed folpet (89% purity) in the diet at 0, 0.2, 0.4, or 0.8% for
    13 weeks. During treatment, body weights and food consumption of mid-
    and high-dose males and of high-dose females were significantly
    reduced. After 10 weeks there were no significant differences between
    treated and control groups, but there were dose-related decreases in
    the following serum enzymes: alkaline phosphatase and alanine
    aminotransferase in treated groups, aspartate-aminotransferase in all
    treated males and in high-dose females, and lactate dehydrogenase in
    all treated male groups. Blood urea and chloride levels were
    increased, but total serum proteins were reduced in mid- and high-dose
    male groups. Blood urea was reduced in treated females, while total
    protein was reduced in the high-dose groups and albumin was reduced in
    the mid- and high-dose groups.

         Treatment-related irritation of the proximal gastrointestinal
    tract was evident at necropsy, as was hyperkeratosis of the
    non-glandular gastric mucosa. Slight acanthosis of the stomach
    occurred in 1 female rat in each group.

         The kidneys of mid- and high-dose male rats showed a slight but
    dose-related increase in the number of foci of atrophic basophilic
    renal tubules, which was considered to be unrelated to treatment
    (Sela et al., 1982).

         Groups of 20 male and 20 female Sprague Dawley rats received
    folpet (purity unspecified) in the diet at 0, 0.03, 0.1, 0.3, or 1.0%
    for 13 weeks. Half the rats in each group were then sacrificed, while
    the remainder were administered the basal diet for 2 weeks, until they
    too were sacrificed.

         There were no signs of toxicity and no deaths occurred during the
    study period. The growth of high-dose male and female rats was
    significantly reduced throughout the treatment period. This growth
    retardation was not recovered during the 2-week recovery period after
    treatment. (Dietary analyses showed that achieved doses were 85 - 106%
    of nominal values.) Food consumption and haematological parameters
    were unaffected by treatment. There were no treatment-related
    variations in serum hepatic enzyme levels or renal function
    parameters.

         At necropsy, high-dose groups of both sexes exhibited reduced
    mean body weights. Their relative brain weights were also reduced,
    while their kidney weights were increased. However, there were no
    significant differences in the organ weights of those animals
    permitted to recover for 2 weeks. No gross pathological findings
    attributable to treatment were observed. However, histopathological
    findings of acanthosis, hyperkeratosis, submucosal oedema, and
    pleocellular inflammatory infiltrate, together with occasional focal
    gastric erosions or ulcerations, were found in the non-glandular
    stomachs of high-dose rats after 13 weeks of treatment. These lesions
    were not evident in stomach sections of high-dose rats after the
    2-week recovery period.

         Based on reduced body weight and other effects seen in the
    high-dose group, the 0.3% dose level was the no-observed-effect level
    in this study (Reno et al., 1981; Leary & Tucker, 1982).

    Dogs

         In a pilot study, groups of 4 male and 4 female beagle dogs were
    dosed orally with encapsulated folpet (89.8 - 91.1% purity) at 0, 790,
    1800, or 4000 mg/kg b.w./day for 13 weeks. Treated dogs generally
    consumed less food than controls. Body-weight gain, which was reduced
    in all treated groups, was significantly depressed in the mid- and

    high-dose groups. Vomiting and diarrhoea occurred in all treated dogs,
    but these symptoms were especially marked in the intermediate- and
    high-dose groups. Treatment-related physical changes, including poor
    condition, abdominal distension, excessive salivation, and progressive
    decrease in testicular size, were especially prevalent in mid-and
    high-dose groups. All high-dose males and 1 high-dose female died or
    were killed in extremis. Neurological examination of these dogs and
    those males which survived 12 weeks of treatment was unremarkable, as
    was ophthalmoscopy of survivors. Most dogs killed in extremis had a
    leucocytosis and some had decreased serum phosphate levels; 1 dog had
    normochromic normocytic anaemia. Surviving dogs exhibited decreased
    serum calcium and total plasma protein concentrations but increased
    serum chloride levels. At necropsy, most treated dogs had decreased
    weights of the brain, liver, kidney, spleen, and testicles.

         Pathological examination showed atrophy, depletion, and fibrosis
    of the lymphatic and haematopoetic systems, gonadal degeneration with
    prostatic atrophy and fibrosis, thyroid degeneration, and muscular
    dystrophy (Barel et al., 1985).

         In a subsequent study groups of 6 male and 6 female beagle dogs
    received technical folpet (89.5% purity) orally in gelatine capsules
    at 0, 10, 60, or 140 mg/kg b.w./day. The high-dose treatment rate was
    reduced to 120 mg/kg b.w./day at day 50 due to poor food consumption
    and reduced body-weight gain. After a year of treatment, the animals
    were sacrificed and necropsied.

         All high-dose and 3 mid-dose male dogs exhibited initial loss of
    body weight. The mean body weights of the mid- and high-dose males and
    females were reduced, although not significantly, throughout the rest
    of the study in a dose-related manner. There were dose-related
    decreases in food consumption of mid- and high-dose males for the
    first 3 months and of the mid- and high-dose females for the first
    month. Although food consumption of the males was subsequently
    comparable to controls, there was a tendency for reduced food
    consumption in treated female groups, but not in a dose-related
    manner. Ophthalmoscopy, performed at 6 and 12 months, revealed no
    effects of treatment.

         There was a tendency for reduced male leucocyte counts at 1, 2,
    3, and 6 months, but not at 9 or 12 months; however, these changes
    were not significantly different from control values. Clinical
    chemistry showed a significant decrease in mean serum cholesterol,
    total protein, albumin, and globulin levels in mid- and high-dose male
    groups. In high-dose female dogs, there were significantly reduced
    mean serum protein, albumin, and cholesterol levels. Urinalysis showed
    no significant treatment-related effects.

         No significant treatment-related effects were found at necropsy
    or subsequent histopathological examination. According to observed
    body-weight changes, reduced food consumption, and serum biochemical
    changes, the no-observed-effect level of this study was 10 mg/kg
    b.w./day (Daly & Knezevich, 1986).

    Long-term study

    Rats

         In a combined chronic toxicity and carcinogenicity bioassay,
    groups of 60 male and 60 female Charles River Crl: CD(SD)BR albino
    rats received technical folpet (89.5% purity) in the diet at 0, 200,
    800, or 3200 ppm for 104 weeks. An interim sacrifice of 10 rats
    randomly selected from each group was conducted at 52 weeks. Ophthal-
    moscopy was conducted on all rats prior to initiation and at weeks 52
    and 105. Blood and urine samples were collected from 10 rats/sex/group
    at weeks 27, 78, and 104 for clinical and biochemical analysis and
    urinalysis. Rats dying during the course of the study were necropsied
    and subjected to the usual investigations.

         Growth rates and survival were not significantly affected by
    treatment, although there was a slight tendency for reduced body
    weights in the high-dose females during the first year. Food
    consumption was correspondingly reduced at this dose level. There were
    no treatment-related ophthalmoscopic findings. Conventional haemato-
    logical, biochemical, and urinalysis parameters were unaffected
    by treatment.

         At necropsy, there were no organ-weight changes attributable to
    treatment. Histopathology revealed an increase in lesions of the
    non-glandular stomach, principally hyperkeratosis and/or acanthosis,
    but also erosion and/or ulceration in both high-dose treatment groups.
    These lesions occasionally were accompanied by submucosal oedema and
    submucosal inflammatory cellular infiltrate. As there were no other
    significant histopathological findings, the no-observed-effect level
    in this study was determined to be 800 ppm (Cox et al., 1985).

    Observations in humans

         In a retrospective mortality study, a cohort of 134 workers
    occupationally exposed during manufacture of captan for up to 9 months
    annually, and to folpet for up to 3 months annually, was studied.
    There was an apparent increase in the total number of mortalities from
    all causes (18) for the cohort, compared to the number expected from
    US mortality rates (S.M.R. 164). The excess mortality was principally

    attributable to cardiovascular disease and "external causes" unrelated
    to occupation. Statistically-significant increases were not observed
    for any specific cause of death, including neoplasia, but the number
    of deaths was too few to evaluate cause-specific mortality. Lack of
    adequate industrial-hygiene monitoring data precluded satisfactory
    estimation of the historical exposures (Palshaw, 1980).

    COMMENTS

         The 1984 Joint Meeting withdrew the ADI for folpet because of
    substantial deficiencies in its toxicological data base and because of
    possible teratogenicity in rabbits. Two independent studies now
    indicate that folpet is not teratogenic in rabbits, even at a dose
    that is clearly maternally toxic. Folpet was also without apparent
    effect on the reproduction of rats in a 2-generation reproduction
    study, but it apparently reduced the body weight and survival of
    murine pups.

         Further mutagenicity studies have confirmed that folpet is
    mutagenic in procaryotes in vitro. It is not genotoxic in the
    Chinese hamster fibroblast or mouse micronucleus assays, and it did
    not induce mouse somatic cell mutations in vivo.

         A short-term feeding study in rats produced acanthosis,
    hyperkeratosis, submucosal oedema and cellular infiltration, and
    occasional focal erosions in the non-glandular stomach. These lesions
    resolved 2 weeks after cessation of exposure and are suggestive of an
    irritant effect of folpet treatment. Similar irritative effects were
    found in a chronic feeding bioassay in rats but, significantly, there
    was no indication of a carcinogenic response.

         No remarkable pathology was seen in a 1-year feeding study in
    dogs.

         The carcinogenicity of folpet to mice has been demonstrated
    further. Dietary exposure produced dose-related increases in gastric
    papillomas and squamous cell carcinomas, duodenal adenomas, and
    adenocarcinomas. Accompanying irritant changes, oesophageal
    hyperkeratosis, acanthosis and hyperkeratosis of the non-glandular
    gastric mucosa, microscropic gastric ulceration, duodenal glandular
    hyperpalsia, and mucosal glandular proliferation were also present.

         Although the 1984 Joint Meeting noted that folpet produced a
    dose-related increase in the incidence of duodenal adenomas and
    adenocarcinoams in CD-1 mice at dietary concentrations of 5000 and
    12,000 ppm, but not at 1000 ppm, the present study clearly
    demonstrated carcinogenicity in B6C3F1 mice at 1000 ppm. Duodenal
    adenomas and carcinomas, observed in the previous study with CD-1
    mice, occurred in all treatment groups. In addition, gastric
    papillomas and squamous cell carcinomas occurred. The development of
    squamous cell neoplasia may correspond to the hyperkeratotic changes
    and acanthosis seen in rats. The other neoplastic changes may be
    related to the localized effects of the compound. If tumour induction
    is related to "swamping" of the gut and passage of large amounts of
    irritant compound into the small bowel, the significance of the
    lesions for man is limited.

         An epidemiological study showed no evidence of neoplasia among
    workers occupationally exposed to captan and to a lesser degree to
    folpet during manufacture, but the data are inadequate to evaluate
    long-term exposure to folpet in man.

         Since the concern over the potential teratogenicity of folpet has
    been resolved and the previous toxicological data deficiencies now
    have been met, the meeting agreed to re-establish a temporary ADI.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Rat:    800 ppm in the diet, equal to 40 mg/kg b.w./day.

         Dog:    10 mg/kg b.w./day.

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.01 mg/kg b.w.

    STUDIES WITHOUT WHICH THE DETERMINATION OF A FULL ADI IS
    IMPRACTICABLE, TO BE SUBMITTED TO WHO BY 1988:

         1. Investigations directed towards determining the mechanism of
    gastrointestinal neoplasia. The dynamics of passage of the compound
    through the stomach, rate of release, and time spent in the duodenum
    should be studied at varying doses in mice and rats to investigate the
    possibility that induction of adenocarcinoma is a local exposure
    effect. An evaluation of whether 2 mechanisms are operating, 1 for
    squamous and another for adenocarcinomatous lesions, should be made.

         Noting that a jejunal tumour occurred only at the highest dose,
    local administration of the compound (via a gut loop) would also be of
    interest. This may be impractical.

         2. Comparative studies of the metabolic fate of the
    trichloromethylthio moiety in mice and rats.

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
    EVALUATION OF THE COMPOUND

         Further observations in man.

    REFERENCES

    Abir, H. An assessment of the mutagenic potential of folpet technical
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    Barel, Z., Nyska, A., & Waner, T. Folpan: 90-day preliminary toxicity
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    Bootman, J., Hodson-Walker, G., & Lloyd, J.M. Folpan Tech.:
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    Cox, R.H., Marshall, P.M., Voelker, R.W., Vargas, K.J., Alasker, R.D.,
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              Chemical Company, Richmond, CA, USA.

    Crown, S., Nyska, A., & Waner, T. Folpan. Carcinogenicity study in the
    1985      rat. Unpublished report No. MAK/022/FOL from Life Science
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              by Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.

    Daly, I.W. & Knezevich, A.L. A one-year subchronic oral toxicity study
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              Richmond, CA, USA.

    Feussner, E.L., Hoberman, A.M., Johnson, E.M., & Christian, M.S.
    1985      Teratology study in rabbits with folpet technical using a
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              No. 303-004 from Argus Research Laboratories, Inc.,
              Horsham, PA, USA. Submitted to WHO by Chevron Chemical
              Company, Richmond, CA, USA.

    Hardy, L.M. & Richter, W.R. SOCAL 2140 (S-2323): Two generation (two
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    Jacoby, O. Folpan. Mouse micronucleus test. Unpublished report
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    Leary, J.B. & Tucker, B.V. Phaltan 90-day dietary study in rats.
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    Moore, M.R. & Brusick, D.J. Evaluation of Chevron folpet technical in
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    Nyska, A. Neoplasia in the stomach. Unpublished report No. MAK/015/FOL
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    Palshaw, M.W. An epidemiologic study of mortality within a cohort of
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    Reno, F.E., Burdock, G.A., Serota, D.G., Voelker, R.W., Alasker, R.D.,
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    Rubin, Y. Folpan. Preliminary teratology study in rats. Unpublished
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    Rubin, Y. Folpan. Preliminary teratology study in the rabbit.
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              by Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.

    Rubin, Y. & Nyska, A. Folpan. Oncogenicity study in the mouse.
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              Research Israel Ltd., Ness Ziona, Israel. Submitted to WHO
              by Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.

    Rubin, Y. & Nyska, A. Folpan. Teratology study in the rat. Unpublished
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              Ltd., Ness Ziona, Israel. Submitted to WHO by Makhteshim
              Chemical Works Ltd., Beer-Sheva, Israel.

    Rubin, Y. & Nyska, A. Folpan. Preliminary teratology study in rabbits.
    1985c     Unpublished report No. MAK/050/FOL from Life Science
              Research Israel Ltd., Ness Ziona, Israel. Submitted to WHO
              by Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.

    Sela, J., Nyska, A., Pitel, Z., & Rambach, H. Folpan. Toxicity in
    1982      dietary administration to rats for 13 weeks. Unpublished
              final report No. MAK/021/FOL from Life Science Research
              Israel Ltd., Ness Ziona, Israel. Submitted to WHO by
              Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.

    Slagowski, J.L. & Leary, J.B. Addendum to an evaluation in the mouse
    1985a     somatic cell mutation assay with Chevron folpet technical
              (SX-1388). Unpublished report (Litton Bionetics Project
              No. 21994-491 and Ortho Test No. S-1971 diet analysis) from
              Chevron Chemical Company, Ortho Agricultural Chemicals
              Division, Development Research Department. Submitted to WHO
              by Chevron Chemical Company, Richmond, CA, USA.

    Slagowski, J.L. & Leary, J.B. Addendum to teratology study in rabbits
    1985b     with folpet technical (SX-1388) using a "pulse-dosing"
              regimen. Unpublished report (Argus Research Laboratories
              Project No. 303-004 and Ortho Test No. S-2512 dosage formula
              analysis) from Chevron Chemical Company, Ortho Agricultural
              Chemicals Division, Development Research Department.
              Submitted to WHO by Chevron Chemical Company, Richmond, CA,
              USA.

    Slagowski, J.L. & Leary, J.B. Addendum to reproduction study in rats
    1985c     with folpet technical (SX-1388). Unpublished report (SOCAL
              Project No. 2140 and Ortho Test No. S-2323 diet analysis)
              from Chevron Chemical Company, Ortho Agricultural Chemicals
              Division, Development Research Department. Submitted to WHO
              by Chevron Chemical Company, Richmond, CA, USA.
    


    See Also:
       Toxicological Abbreviations
       Folpet (HSG 72, 1992)
       Folpet (ICSC)
       Folpet (FAO/PL:1969/M/17/1)
       Folpet (WHO Pesticide Residues Series 3)
       Folpet (WHO Pesticide Residues Series 4)
       Folpet (Pesticide residues in food: 1984 evaluations)
       Folpet (Pesticide residues in food: 1990 evaluations Toxicology)
       Folpet (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)