Sponsored jointly by FAO and WHO


    The monographs

    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
    Rome, 24 September - 3 October 1984

    Food and Agriculture Organization of the United Nations
    Rome 1985



         Folpet was evaluated by the Joint Meeting in 1969 and 1973 1/
    and a full ADI of 0-0.1 mg/kg bw was allocated on the basis of the
    no-effect levels taken exclusively from studies done by Industrial
    Bio-Test Laboratories. The Joint Meeting in 1982 was not presented
    with information on the validation of these studies and no additional
    data were made available. The meeting was informed, however, that
    certain replacements or new studies were in progress or were to be
    initiated. Consequently, the meeting agreed that the ADI should be
    replaced by a temporary ADI pending evaluation of the new studies.
    Further work required by 1984 included short-term test in rats, a
    12-month study in dogs, long-term studies in mice and rats, a
    reproduction study in rats and teratology studies in rats and rabbits.
    Some new studies were submitted and are reviewed in this monograph



    Special Studies on Teratogenicity


         A pilot study using mated CRL:COBS CD (S.D.) BR female rats
    (8 per group was performed wherein Folpet was administered via gavage
    at doses of 0, 20, 80, 320, and 640 mg/kg bw on days 6 through 19 of
    gestation. No rats died. Clinical signs consisted of rales, excess
    salivation, chromorhinorrhea, gasping, soft/liquid faeces, decreased
    motor activity, dyspnea and distended gastrointestinal tract. Reduced
    maternal body weight gains were recorded in the 80, 320, and 640 mg/kg
    does groups, as well as reduced food consumption in the 320 and
    640 mg/kg dose groups. Reduced average foetal body weight occurred
    also at 320 and 640 mg/kg. No other compound-related effects or
    external anomalies were observed (Christian & Hoberman, 1983a).

         Groups of mated CRL:COBS CD (S.D.) BR rats (25 per group) were
    administered 0, 10, 60 and 360 mg/kg bw Folpet (89 percent pure)
    orally via gavage on days 6 through 19 of gestation. Rats were
    observed for clinical signs of toxicity, abortion, death, body weight
    change and food consumption. Animals were killed on day 20 and pups
    delivered by caesarean section. The uterus was weighed and examined
    for number of live/dead foetuses and early and late resorptions.
    Clinical signs consisted of excess salivation, chromorhinorrhea,


    1/  See Annex 2 for FAO and WHO documentation.

    decreased motor activity, soft/liquid faeces, dyspnea and
    urine-stained fur. Three rats in the high dose group dies, two from
    intubation error. In the surviving rats no gross lesions were
    attributed to Folpet. Pregnant rats given 10, 60 and 360 mg/kg gained
    less weight during the dosing period than controls. Food consumption
    was significantly reduced in the high dose groups only. The number of
    implantations, live/dead foetuses, foetal viability, resorptions,
    average foetal body weight per litter, foetal sex ration and number or
    corpora lutea were comparable to controls. There were no differences
    in gross external, visceral or skeletal anomalies between treated and
    control groups and no compound-related effects on ossification were
    seen (Christian & Hoberman, 1983b).


         Groups of New Zealand white rabbits (20 per group), artificially
    inseminated, were administered Folpet (89 percent pure) via oral
    intubation at dose levels of 0, 10, 20 and 60 mg/kg bw on days 6
    through 28 of gestation. Rabbits were observed for body weight gain,
    food consumption and clinical signs of toxicity. Does which died were
    autopsied. On day 29, does were killed and pups delivered by caesarean
    section. The death of one doe at 60 mg/kg was considered to be related
    to ingestion of Folpet. No other compound-related deaths occurred. One
    doe in each of the low and high dose groups aborted on day 21 and 22
    of gestation, respectively. One doe in each of the control and high
    dose groups naturally delivered a litter on days 28 and 29,
    respectively. Significant inhibition of maternal body weight gain and
    food consumption was determined in the mid and high dose groups.
    Average number of corpora lutea, implantations, resorptions, foetuses
    per litter, sex ratio and dead/resorbed implantations per litter were
    comparable among all groups. Male and female mean foetal body weights
    decreased in the mid and high dose groups compared to the control
    group. There was a significant increase in the incidence of
    hydrocephalic foetuses. A total of four foetuses from three different
    high dose litters also had skull, gastric and lung abnormalities
    (Feussner et al., 1984).

    Special Study on Carcinogenicity


         Groups of CD-1 (ICR derived) mice (80 males and 80 females per
    group) were administered Folpet (93 percent pure) in the diet at dose
    levels of 1 000, 5 000 and 12 000 ppm for 112-113 weeks. An untreated
    control group consisted of 104 mice of each sex. Animals were observed
    routinely for food consumption, body weight gain, pharmacological and
    toxicological effects. Survival was unaffected by treatment. Body
    weight gain was adversely affected at the mid- and high-dose. Food
    consumption was sporadic and no dose-related effects were evident.
    Haematological data at one year revealed no significant differences
    between groups. However, haematological data at termination
    demonstrated a possible macrocytic anaemia in high dose males and
    females. Gross pathology at termination was unremarkable except for

    duodenal lesions and related gastrointestinal abnormalities. A
    positive dose-related increase in the incidence of duodenal adenomas
    and adenocarcinomas was observed for the 5 000 and 12 000 ppm groups,
    but not in the 1 000 ppm group. The incidence of duodenal tumours in
    females and males, respectively, were 0 and 1 percent (controls), 2
    and 3 percent (low dose), 10 and 12 percent (mid-dose), and 52 and 54
    percent (high dose). High dose males also demonstrated an increased
    incidence of jejunal adenocarcinomas. No other oncogenic or neoplastic
    changes were evident in other tissues (Eisenlord & Wong, 1982).

    Short-Term Studies


         Groups of Sprague-Dawley rats (20 per sex per dose) were
    administered Folpet in the diet at dosage levels of 0, 300, 1 000,
    3 000, and 10 000 ppm for 13 weeks. Technical problems encountered in
    the diet analysis preclude use of this data since the analysis could
    not be verified according to currently acceptable standards (Reno
    et al., 1981).


         The 1981 JMPR noted that the ADI for Folpet, established
    originally in 1973, was based exclusively on studies performed by
    Industrial Bio-Test Laboratories. Information on the validity of these
    studies has not been provided. The 1982 JMPR required submission, by
    1984, of the following studies: 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 teratology studies in rats and rabbits.

         The Meeting evaluated the required teratological studies and some
    additional mutagenicity data. Although teratogenic effects were not
    observed in rats, the Meeting was unable to evaluate the significance
    of teratogenicity observed in rabbits. Technical problems with the
    study precluded the use of data from a new 90-day oral study in rats.

         In view of the absence of the other required data and because of
    concern over the possible teratogenicity in the rabbit, the meeting
    withdrew the temporary ADI.


    Christian, M.S. & Hoberman, A.M. Teratology study in rats with folpet
    1983a     technical. Report from Argus Research Laboratories, Inc.
              submitted by Chevron Chemical Co. to WHO. (Unpublished)

    Christian, M.S. & Hoberman, A.M. Pilot teratology study in rats with
    1983b     folpet technical. Report from Argus Research Laboratories
              Inc. submitted by Chevron Chemical Co. to WHO. (Unpublished)

    Eisenlord, G.H. & Wong, Z.A. Lifetime oncogenic feeding study of
    1982      Phaltan Technical in CD-1(ICR derived). Report from
              Environmental Health and Toxicology, Chevron Environmental
              Health Center, submitted by Chevron Chemical Co. to WHO.

    Feussner, E.L., Hoberman, A.M., Johnson, E.M. & Christian, M.S.
    1984      Teratology study in rabbit with folpet technical. Report
              from Argus Research Laboratories, Inc. submitted by Chevron
              Chemical Co. to WHO. (Unpublished)

    Reno, F.E., Burdock, G.A., Serota, D.G., Voelker, R.W., Alsaker, R.D.,
    1981      Milad, G.M. & Zurek, E.K. Subchronic toxicity study in rats.
              Phaltan: Final Report. Report from Hazelton Laboratories
              America, Inc. submitted by Chevron Chemical Co. to WHO.

    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: 1986 evaluations Part II Toxicology)
       Folpet (Pesticide residues in food: 1990 evaluations Toxicology)
       Folpet (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)