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    FOLPET

    Explanation

    First draft prepared by Dr O. Meyer,
    National Food Agency, Denmark

         Folpet was evaluated for acceptable daily intake by the Joint
    Meeting in 1969, and reviewed in 1973, 1982, 1984, and 1986 (Annex 1,
    FAO/WHO 1970a, 1974a, 1983a, 1985b, and 1986d).  A toxicological
    monograph was prepared by the Joint Meeting in 1969 (Annex 1, FAO/WHO,
    1970b) and monograph addenda were prepared in 1973, 1984, and 1986
    (Annex 1, FAO/WHO, 1974b, 1985c, and 1987a).  The data that have been
    reviewed include data on biochemical aspects, acute studies in mice,
    rats, and rabbits; short-term studies in rats and dogs, long-term
    toxicity studies in rats, carcinogenicity studies in rats and mice,
    reproduction studies in rats; teratogenicity studies in rats,
    hamsters, monkeys, rabbits, and chicks and several in vivo and
    in vitro genotoxicity studies.  In addition, data from observations
    in humans have been considered.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    Biological data

    Biochemical aspects

    Absorption, distribution and excretion

         Mice (108) and rats (36) were dosed 0, 50, and 5,000 ppm folpet
    in their diet for 21 consecutive days.  Following a p.o. pulse dose of
    14C-folpet (14C in the trichloromethylthiol moiety) the animals were
    killed either 2, 4 or 6 hours post-dose and the gastrointestinal tract
    removed.

         Quantitation of the amount of radioactivity present as a
    percentage of the administered dose at various times showed that the
    mouse removed a greater proportion of radioactivity from the
    gastrointestinal tract (GI) than did the rat, and the removal of
    radioactivity also occurred at a faster rate in the mouse.

         Unchanged folpet was present in a lower proportion in mice when
    compared to rats at each time interval in both doses.  The proportion
    of the radioactive dose actually in the tissues of the
    gastrointestinal tract was between 1% and 3% in both species. 
    Gastrointestinal transit time (from stomach to caecum) was less than
    2 hours and 4-6 hours for mouse and rat, respectively.

         At each time interval the major portion of parent compound at the
    low dose level was recovered from the stomach in both species.
    However, the lower amounts found for the mouse indicate a faster rate
    of stomach emptying in this species.  Following the high dose the
    largest proportion of unchanged folpet was located in the caecum of
    the mouse and in the stomach in the rat.

         The proportion of residual radioactivity (considered to be
    "covalently" bound to tissues) presented as the ratio of bound
    radioactivity between the high and low dose (expressed in terms of µg
    equivalents) varied between 14:1 and 30:1 in the stomach, up to 115:1
    and 180:1 in ileum of rat and mouse, respectively.

         Folpet is rapidly degraded in the GI-tract.  This occurs to a
    greater extent at lower than at the higher dose levels and in the
    mouse more than in the rat.  The greater amounts of radioactivity
    "covalently" bound after the high dose level indicates lack of
    sufficient GSH for thiophosgene removal (Chasseaud and Waller, 1990).

         An excretion-radioactive-balance study over 5 days with mice (36)
    and rats (12) dosed as in the above study showed that following a
    "pulse dose" of 14C-folpet, 14C was excreted in expired air, urine
    and faeces.  Urinary excretion of radioactivity during the first 24

    hours was lower in the rats treated with 50 ppm (41.8%) than those
    treated with 5,000 ppm (51.5%).  Greater urinary excretion was
    observed at the low dose level in the mouse (50 ppm 59.1% and 5,000
    ppm, 44.3%).

         Examination of the faecal excretion of radioactivity indicated
    that gastrointestinal transit-times in the rat were slower (48 hours)
    than that observed in the mouse (24 hours), and at 5,000 ppm mice
    excreted 5 fold greater amount of radioactivity than did rats.

         Biliary excretion of 14C-folpet was about 2% in rats and less
    than 0.1% in mice (Chasseaud and Waller, 1990).

    Biotransformation

         Mice (108) and rats (36) were dosed 0, 50, and 5,000 ppm folpet
    in their diet for 21 consecutive days.  Following a p.o. pulse dose of
    14C-folpet (14C in the trichloromethylthiol moiety) the animals were
    killed either 2, 4 or 6 hours post-dose and the gastrointestinal tract
    removed.

         At 2 hours after dosing, the disulfonic acid was the major
    metabolite in the rat duodenum with both the thiazolidine and the
    glutathione conjugate of thiophosgene being present.  At 4 hours the
    disulfonic acid predominated and the thiazolidine metabolite was not
    seen.  In the mouse, the same metabolites were seen, but the
    thiazolidine metabolite becomes more prominent in the later timed
    samples indicating that the mouse relied more than did the rat on GSH
    conjugation for the detoxification of the "active metabolite" of
    folpet (Chasseaud and Waller, 1990).

         An excretion-radioactive-balance study over 5 days with mice (36)
    and rats (12) dosed as in the above study, showed quantitative
    differences in the urinary excretion of metabolites.  The sulphonic
    acid metabolite predominated in rat while the thiazolidine metabolite
    predominated in the mouse after the high folpet dose.  This indicated
    a possibly greater utilization of, and requirement for, GSH in the
    mouse (Chasseaud and Waller, 1990).

    Effects on enzymes and other biochemical parameters

         Mice (72) and rats (24) were dosed 0, 50, and 5,000 ppm folpet in
    their diet for 21 consecutive days.  Mean concentration of glutathione
    (GSH) in liver was similar to the controls in rats dosed with 50 and
    5,000 ppm folpet whereas a small decline was observed in mice dosed
    5,000 ppm.

         In both rats and mice, GSH concentrations were significantly
    increased after 50 ppm and 5,000 ppm in both duodenum and jejunum.  A
    similar effect observed in ileum was more pronounced in mice. These

    results suggest an initial depletion of GSH followed by increasing
    de novo synthesis of GSH resulting in a "rebound" elevation in
    tissue GSH concentrations in the GI-tract.

         Tissue weights of stomach, duodenum and jejunum were increased in
    both species.  Mean cytosolic protein concentrations (total mg/tissue)
    were also increased in duodenum and jejunum in both species with the
    increase being greater in rats.  Total cytosolic protein in the mouse
    liver declined to 86% of control value.

         Glutathione-S-transferase levels (with 1-chloro-2,4-
    dinitrobenzene used as substrate) increased significantly in tissue
    from duodenum, jejunum and ileum in both species, in liver in rats and
    in stomach in mice after treatment with 5,000 ppm.  This led to a
    greater capacity to enzymatically conjugate thiophosgene with GSH.

         A marked reduction in the concentrations of lipid peroxides (the
    concentration of malondialdehyde was used as indicator of the overall
    lipid peroxidation state of the mucosal cells) was noted in the
    duodenum of both species receiving 5,000 ppm folpet in their diets. 
    The reduction in the concentration of lipid peroxides was only
    statistically significant in the stomach of mice fed 5,000 ppm folpet. 
    No alteration was found in the level of intracellular conjugated
    dienes in either species when compared to those of the animals in the
    control groups.

         The non-selenium dependent glutathione peroxidase activity (i.e.
    that due to the peroxidase activity of the glutathione S-transferase)
    was increased in duodenum, jejunum and ileum in both species after
    receiving 5,000 ppm folpet in their diet, and in the stomach of rats
    in either dose level (Chasseaud and Waller, 1990).

         In mice (240) and rats (48) dosed as in the above study mean
    microsomal protein (total mg/tissue) was significantly increased in
    rat ileum, jejunum and duodenum.  Although increases were observed in
    the mouse ileum, duodenum and jejunum, they were not statistically
    significant.  Hepatic total microsomal protein declined significantly
    in rat but remained unchanged in the mouse.  Cytochrome P450 was
    reduced in the liver in both species but the reduction was
    statistically significant only in mice receiving 5,000 ppm folpet in
    their diet.

         Both aniline hydroxylase and 7-ethyloxycoumarin o-deethylase were
    reduced in hepatic microsomes in both species following exposure to
    either dose level, the reduction of aniline hydroxylase being
    statistically significant in both species dosed at 5,000 ppm
    (Chasseaud and Waller, 1990).

         In an experiment with mice (90) and rats (54) treated as in the
    above study, a statistically significant decrease in pH was observed
    in duodenum and jejunum of mice dosed with 5,000 ppm folpet.

         Incorporation of 3H-thymidine into the mucosal DNA in mice and
    rats was reduced in most tissues of both species.  In neither species
    was there any evidence of a dose related increase in DNA synthesis
    (Chasseaud and Waller, 1990).

         Mice (150 CD1 males, 30-35 g) and rats (75 Sprague Dawley males,
    230-300 g) received one single dose of 0, 7, 7, 72, and 668 mg
    folpet/kg bw by oral gavage.  At various times thereafter animals were
    killed and GSH concentrations measured in their livers and in
    different regions of their gastrointestinal tracts.

         Depletion of hepatic and gastrointestinal concentrations of GSH
    was observed in both rats and mice, the latter species showing the
    most pronounced effect.  The depletion was evident after half an hour
    in duodenum, jejunum and ileum, with a clear dose-dependent response
    in mice.  By 2 hours after dosing, the effects on GSH depletion in
    duodenum of rat and mouse were similar, and after 6 hours the GSH
    levels were elevated compared to the controls.  The degree of GSH
    rebound in duodenum and jejunum was higher in the mouse than that
    observed in the rat (Chasseaud and Waller, 1990).

         Studies in both young (33 days old) and adult (82 days old)
    Fischer 344 rats with dermal application of [14C] folpet has shown
    that folpet penetrates rat skin, and that dose-absorption was similar
    (Hall et al., 1988).

         Male Sprague-Dawley rats, 200-250 g were dosed with folpet either
    by i.p. injection up to 100 mg/kg (suspended in 0.5 ml corn oil) or
    orally in doses up to 1,000 mg/kg bw (in corn oil).  Fifty mg folpet
    dosed i.p. for up to 24 hours caused a significant decrease in
    benzphetamine N-demethylase and cytochrome P-450, while SGOT activity
    significantly increased.  Oral doses of folpet up to ten times that of
    the i.p. doses did not cause any similar adverse effect (Ashley,
    et al., 1982).

         In vitro incubation of folpet with rat liver microsomes with
    and without NADPH showed that folpet may not require metabolism to
    exert inhibitory effect on the microsomal enzymes.  The inhibition of
    hepatic microsomal cytochrome P-450 by folpet in vitro could be
    prevented by prior addition of reduced glutathione in the incubation
    media (Ashley, et al., 1982).

         Folpet (5µM) inhibited the activity of the Ca2+-transport-ATP-
    ase in human erythrocytes in vitro (Janik, 1986).

    Toxicological studies

    Acute toxicity studies

         The LD50 in Sherman rats dosed with folpet perorally was >
    5,000 mg/kg bw for adult males and females and for female weanlings
    (Gaines and Linder, 1986).

    Short-term studies

    Dogs

         Groups of five male and five female beagle dogs were dosed with
    folpet (technical grade) by oral capsule administration at dosages of
    0, (empty capsules), 325, 650, and 1,300 mg/kg bw/day for 52 weeks.

         No mortalities occurred during the treatment period.  Decreased
    body weight was detected in the high and intermediate dose group in
    both sexes during the dosing period.  A concomitant decrease in food
    intake was found in both males and females in the high dose group. 
    The clinical signs observed in all treated groups were vomiting,
    diarrhoea and salivation, the latter effect only observed in the first
    8 weeks in the low dose group.  The effect was most pronounced in the
    high and intermediate groups.  Dogs of the high and intermediate dose
    groups were poorer in condition as compared to their controls.

         Haematological parameters were affected in all treated females
    after the first third of the study.  These effects included a decrease
    in packed cell volume, haemoglobin and erythrocyte counts.  Clinical
    chemistry changes (e.g. reduced total protein, cholesterol, glucose
    and urea) were observed during the treatment period relating to poor
    physical condition of the dogs.  Chloride level was increased in the
    males, mainly in the high dosage group, and calcium levels were
    decreased in the high dosage group, the latter effect also observed in
    the high and intermediate dosed females but only up to 25 weeks of
    treatment.

         Urine volume was lowered in the high dosed females after 13 weeks
    of treatment.  Urine acidity of the male and female groups was
    increased, this effect persisted in males in high and intermediate
    groups throughout the study.  Tubular testicular degeneration
    associated with no spermatozoa in the epididymides was found in two
    male dog in the high dosage group, one of these having moderate
    atrophy of the prostatic glands.  Absolute testes weights were
    decreased in the high dosage male group.  Changes in relative organ
    weights were recorded in adrenals (all males and intermediate dosed
    females), brain and kidney (high dosed males and intermediate dosed

    females), liver (high dosed females and intermediate dosed males)  and
    thyroid (high dose female and intermediate male group).  The no
    observed adverse effect level is 325 mg folpet/kg bw per day (Waner
    and Nyska, 1988).

    Long-term/carcinogenicity studies

         Groups of 20 male and 20 female rats (F344) were fed a diet
    containing folpet (Technical grade, purity, 91.1%) at concentrations
    of 0, 250, 1,500, and 5,000 ppm for two years.  Average concentrations
    measured on a weekly basis were calculated at 0, 190.4, 1287.7, and
    4532.3 ppm, respectively.

         No effect of the test compound on longevity was found.  In the
    high dosage group, mean body weight and food intake were depressed in
    both males and females (up to 10% in males and 6% in females).  Water
    consumption was depressed for high dose animals with females effected
    to a greater extent than males.

         Reductions in alkaline phosphatase and alanine aminotransferase
    were apparent in treated groups throughout the study.  Sporadic
    decreases in aspartate aminotransferase, creatinine phosphokinase and
    gamma-glutamyl transferase were found.  Blood cholesterol was
    significantly lowered in highest dosed animals, in both sexes,
    throughout the dosing period.  Total plasma protein was reduced in the
    male high dosage group during the first year of treatment.  Phosphate
    was elevated in the male high dosage group at most examinations.  Urea
    was raised in the highest dosage female group up to 18 months.  Most
    male treated groups excreted a more concentrated urine of smaller
    volume at the 3 and 6 month assay.

         Treatment was associated only with non-neoplastic lesions 
    consisting of diffuse hyperkeratosis of the oesophageal and gastric
    squamous epithelium.  The no-observed-effect level was 190 ppm
    (equivalent to 9.5 mg/kg bw/day (Crown, et al., 1989).

    Reproduction studies

         Four groups of CD rats, 25 males and 25 females (F0) were fed a
    diet containing folpet (technical grade, purity 91%) in concentrations
    0, 250, 1,500, and 5,000 ppm, respectively.  

         Body weight gain and food consumption for the top dosage group
    was reduced in parental animals in F0 and F1 -generations.  A minor
    decrease in body weight was observed in F1 and F2 offspring.  

         The principal histopathological effect was hyperkeratosis of the
    nonglandular gastric mucosa in high and intermediate dosage group in
    both F0 and F1 -generations, oesophageal hyperkeratosis in the high
    and intermediate dosage groups of the F1 generation and increased

    incidence of basophilic renal tubules in the high dosage males of the
    F0 generation.  Folpet is concluded not to be a specific reproductive
    toxin in the current test system (Rubin and Nyska, 1986).

    Special studies on embryo/fetotoxicity

         In an in vitro test, the inhibition of attachment by tumour
    cells to polyethylene disks coated with concanavalin was found with
    folpet.  The dose of 4.8 mg/l inhibited attachment by 50% (Braun and
    Howicz, 1983).

    Special studies on genotoxicity

         The effects on chromosomal structure of exposure to folpet
    (technical grade, purity 90.1%) were studied in cultured human
    lymphocytes.  The concentrations of folpet tested in the cytogenetic
    assay was 1, 2 and 3 µg/ml for 24 hours with and without S-9 mix and
    solvent (DMSO) and cyclophosphamide and chlorambucil were used as
    negative and positive controls, respectively.  In addition, a second
    cytogenetic test using 3 and 5 µg/ml folpet for 2 hours with and
    without S-9 mix was performed.

         There was some evidence of weak clastogenic potential of folpet
    following 24 hours of exposure at 3 µg/ml.  However, in view of the
    questionable biological significance of gap-type aberrations, the lack
    of response in activated cultures following 24 hours of exposure, and
    lack of response in all cultures following 2 hours of exposure, no
    clear, biologically significant evidence of clastogenic potential was
    found (Bootman, et al., 1987).

         Folpet (technical grade, purity, 90.1%) was examined for
    mutagenic potential by measuring its ability to induce mutation in
    Chinese hamster cells (V 79) at the hypoxanthine-guanine-
    phosphoribosyl transferase (HGPRT) locus.  The concentrations of
    folpet were 0.125, 0.25, 0.5, 1, and 2 µg/ml in presence of S-9 mix
    for three hours.  DMSO served as negative control, and ethylmethane-
    sulfonate and 7,12 dimethylbenzanthracene as positive controls. 
    Folpet induced no significant increases in mutation frequency at the
    HGPRT gene locus with or without S-9 mix (Bootman, et al., 1986).

         The genetic activity profile of 65 pesticides was tested and
    folpet was active in inducing point/gene mutations and primary DNA
    damage in both pro- and eukaryotes.  In addition folpet was shown to
    cause chromosomal effects in Chinese hamster ovary cells and mouse
    bone marrow and cardiac blood.  Folpet was not found to induce
    unscheduled DNA synthesis in human lung fibroblasts W1-38 or dominant
    lethality in mouse (Garrett, et al., 1986).

         In a computer-assisted analysis of structure-genotoxicity
    relationship, a correlation was found between some structural

    fragments, one of these being C1-C-S-N-C=0 present in folpet and
    Salmonella typhimurium histidine reversion assay, the thymidine kinase
    gene mutation assay using mouse lymphoma L51784 cells, prokaryotic DNA
    repair assays using respectively, pairs of Escherichia coli polA+ and
    polA+ and Bacillus subtilis rec+ and rec+ strains and mitotic
    recombination in strain D3 of the yeast Saccharomyces cerevisiae
    (Klopman, et al., 1985).

         In a review of the sex-linked recessive lethal test for
    mutagenesis in Drosophila melanogaster, folpet is listed as mutagenic
    (Lee, et al., 1983).

    COMMENTS

         The results of a recently-submitted short-term study in beagle
    dogs confirmed earlier findings in this species.  However, a higher
    NOAEL was observed in the present study.  The present study involved
    52 weeks of dosing, while in the earlier study the dogs were
    administered folpet for only 13 weeks.  Tolerance to the effects of
    folpet could partly explain the differences in toxicity observed.

         The results of a recently submitted long-term study in rats
    support earlier findings observed in previous long-term studies in
    this species.  The NOAEL in the present study was 190 ppm folpet,
    equivalent to 10 mg/kg bw/day.  Effects were observed at the next
    highest dose of 1290 ppm.

         Folpet did not cause reproductive effects in a two-generation 2-
    litter/generation rat study.  The NOAEL in this study was 250 ppm
    equal to 13.7 mg/kg bw/day.

         A range of genotoxicity studies suggest that folpet is
    potentially genotoxic.  The presence of the S-9 fraction from liver
    reduced the in vitro effects of folpet.  Folpet was negative in the
    dominant lethal test in mice.

         The importance of glutathione (GSH) in the metabolic degradation
    of folpet was demonstrated.  It is apparently a more important pathway
    in the mouse than the rat.  This difference in metabolism coupled with
    the relatively higher exposure in the mouse than in the rat may
    explain the different susceptibility to tumour induction by folpet in
    the two species.  Data suggest that the upper small intestine is the
    site of tumour formation provided that sufficient levels of the active
    metabolite(s) of folpet are available to exceed the biological defence
    provided by GSH and its associated GSH-S-transferase.

         In 1986 the JMPR allocated a temporary ADI of 0-0.01 mg/kg bw
    based upon a NOAEL in a short-term toxicity study in dogs of 10 mg/kg
    bw/day and using a safety factor of 1000.

         The recently-submitted data does not influence the present
    estimate of the acceptable daily intake for humans.  Since a NOAEL in
    the mouse has not been established and since the mechanism of tumour
    induction in this species has not been defined, the ADI remains
    temporary.  However, the sponsors are to be commended for their
    efforts to elucidate the toxicological mechanisms associated with
    folpet.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat: 800 ppm equivalent to 40 mg/kg bw/day
         Dog: 10 mg/kg bw/day

    Estimate of temporary acceptable daily intake for humans

         0-0.01 mg/kg bw

    Studies without which the determination of a full ADI is impracticable

         To be submitted to WHO by 1992:

         -    Results of further investigation of the relevance of the
              metabolic data in animals for humans.

         -    Further studies to elucidate the mechanism for the induction
              of gastrointestinal tract tumours in mice.

         -    Studies designed to establish a NOAEL in mice.

    REFERENCES

    Ashley, W.M., Smith, R.E., and Dalvi, R.R., (1982).  Hepatotoxicity of
    orally and intraperitoneally administered folpet in male rats. 
    Journal of Toxicology and Environmental Health, 8: 867-876.

    Braun, A.G. and Horowicz, P.B., (1983).  Lectin-mediated attachment
    assay for teratogens:  Results with 32 pesticides. Journal of
    Toxicology and Environmental Health, 11: 275-286.

    Bootman, J., Hodson-Walker, G., and Dance, C.A., (1987).  In vitro
    assessment of the clastogenic activity of Folpan tech in cultured
    human lymphocytes.  Unpublished report no. 87/MAK053/031 from Life
    Science Research Limited, Suffolk, England.  Submitted to WHO by
    Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.

    Bootman, J., Hodson-Walker, G., and Lloyd, J.M., (1986).  Folpan
    tech.: Investigation of mutagenic activity at the HGPRT locus in a
    chinese hamster V79 cell mutation system.  Unpublished report No.
    86/MAK 054/188 from Life Science Research Limited Suffolk, England. 
    Submitted to WHO by Makhteshim Chemical Works Ltd., Beer-Sheva,
    Israel.

    Chasseaud, L.F. and Waller, A.R., (1990).  Summary of investigations
    conducted at Huntingdon Research Centre into the effects of dietary
    administered folpet (N-trichloromethylthio) phthalimide on some
    biochemical and physiological parameters in the rat and mouse. 
    Unpublished report from Huntingdon Research Centre Ltd., Huntingdon,
    England.  Submitted to WHO by Makhteshim Chemical Works Ltd., Beer-
    Sheva, Israel.

    Chidiac, P. and Goldberg, M.T., (1987). Lack of induction of nuclear
    aberrations by Captan in mouse duodenum. Environmental Mutagenesis, 9:
    297-306.

    Crown, S., Nyska, A., Warner, T. and Kenan, G., (1989).  Folpan
    toxicity by dietary administration to the rat for two years. 
    Unpublished report No. MAK/053/FOL from Life Science Research Israel
    Ltd., Ness Zionar, Israel.  Submitted to WHO by Makhteshim Chemical
    Works Ltd., Beer-Sheva, Israel.

    Garrett, N.E., Stack, H.R., and Waters, M.D., (1986).  Evaluation of
    the genetic activity profiles of 65 pesticides.  Mutation Research 
    168: 301-325.

    Gaines, T.B. and Linder, R.E., (1986).  Acute toxicity of pesticides
    in adult and weanling rats.  Fundamental and Applied Toxicology, 7:
    299-308.

    Hall, L.L., Fisher, H.L., Sumler, M.R., Monroe, R.J., Chernoff, N.,
    and Shah, P.V. (1988).  Dose response of absorption in young and adult
    rats. In: S.Z. Mansdorf, R. Sager, and A.P. Nielsen.  Performance of
    protective clothing:  Second symposium, ASTM STP 989, pp. 177-194. 
    American Society for Testing and Materials, Philadelphia.

    Janik, F., (1986).  Effects of biocides on the Ca2+-transport-ATPase
    activity of human erythrocytes.  Naunyn-Schmiedeberg's Archives of
    Pharmacology, 334 (suppl): R20.

    Klopman,G., Contreras, R., Rosenkranz, H.S., and Waters, M.D., (1985). 
    Structure-genotoxic activity relationships of pesticides:  Comparison
    of the results from several short-term assays.  Mutation Research 147:
    343-356.

    Lee, W.R., Abrahamson, S., Valencia, R., von Halle, E.S., Wurgler,
    F.E., and Zimmering, S., (1983).  The sex-linked recessive lethal test
    for mutagenesis in Drosophila melanogester.  Mutation Research 123:
    183-279.

    Rubin, Y. and Nyska, A., (1986).  Two-generation reproduction study,
    Folpan.  Unpublished report No. MAK/052/FOL from Life Science Research
    Israel Ltd., Ness Ziona, Israel.  Submitted to WHO by Makhteshim
    Chemical Works Ltd., Beer-Sheva, Israel.

    Waner, T. and Nyska, A., (1988).  Chronic oral study in beagle dogs
    for 52 weeks, Folpan.  Unpublished report No. MAK/062/FOL from Life
    Science Research Israel Ltd., Ness Ziona, Israel.  Submitted to WHO by
    Makhteshim Chemical Works Ltd., Beer-Sheva, Israel.


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