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
    Rome, 23 November - 2 December 1982

    Food and Agriculture Organization of the United Nations
    Rome 1983




         Parathion methyl was evaluated by the Joint Meeting in 1968,
    1975, 1929 and 1980 (FAO/WHO 1969, 1976, 1980 and 1981)1 and a
    temporary ADI of 0 - 0,001 mg/kg bw/day was allocated. Reproduction
    study in species appropriate to such a test and results of adequate
    long-term study reported to be in progress then were required by the
    1980 Meeting. These studies, as well as other additional toxicological
    data, have been received and are reviewed in this monograph addendum.



    Absorption, Distribution and Elimination

         In male rats, treated with a single oral dose of 14C-parathion
    methyl (benzene ring-labelled) at 0.1, 1.0 or 5 mg/kg bw and in female
    rats given a single oral dose of 1 mg/kg bw, over 99% of the
    administered dose was excreted in the urine and the faeces within
    48 hours. Elimination in the faeces accounted for only 5 - 7% after
    1 or 5 mg/kg bw, but amounted to about 20% after 0.1 mg/kg bw. Male
    rats treated with an intravenous dose of 1 mg/kg bw excreted about 99%
    of the administered radioactivity in the urine within 48 hours, and
    approximately 1% of the dose in the faeces. Total radioactive residues
    recovered in the 12 tissues analysed (excluding the gastrointestinal
    tract) from rats given a single oral dose of 5 mg/kg bw were about 11%
    of the administered dose 1 hour after treatment, declining to 0.3% at
    24 hours, about 0.1% at 48 hours and to only 0.04% 6 days later. The
    kidney had the highest relative activity up to 8 hours post-treatment.
    The 14C activity in the plasma was initially about 5 times higher
    than that in the erythrocytes. However, from day 2 to day 6 after
    dosing, the 14C-activity in the erythrocytes was greater than that in
    the plasma and remained constant. Following an intraduodenal dose of


    1  See Annex 2 for WHO and FAO documentation.

    1 mg/kg bw, male rats with fistulated bile duct excreted only 3% of
    the radioactive dose in the bile with the remainder being eliminated
    primarily (95%) in the urine within 24 hours (Weber  et al 1979).

         The elimination of parathion methyl was rapid in the dog. A
    terminal half-life of 7.2 hours was estimated in dogs given an
    intravenous dose of 10 mg/kg bw (Braeckman  et al 1980).


    Special Studies on Reproduction


         Groups of 10 male and 20 female rats (SPF-Wistar W74 strain, 5-6
    weeks old) were fed a diet containing technical parathion methyl
    (95% pure) at 0, 2, 10 or 50 ppm for 77 days and then mated to
    initiate a standard 3-generation (2 litters/generation) reproduction
    study. Pups of the second litters (F1b and F2b) provided the parents
    of the next generation. Through the parental generations, there was no
    mortality related to compound. Treatment at the top dietary level
    (50 ppm) induced convulsions in F1 parents, growth retardation in
    both F0 and F1 adults (both sexes) and significant adverse effects
    on litter size and pup weight at birth and through lactation
    practically through all progeny generations. All F2b pups at 50 ppm
    died 5 days after birth, resulting in the absence of data on F3a and
    F3b litters for this dosage group. Fertility rate was slightly
    decreased at 10 ppm in F2 generation (both mating trials, i,e. F3a
    and F3b litters). A reduction in litter size occurred at 10 ppm in
    F3a litters at birth, in F1b litters after 5 days and in F2a and F2b
    litters at 5 weeks. At 2 ppm, a non-dose-related decrease in litter
    size at birth and a slightly depressed survival of pups to 5 days were
    observed in F2b litters. These findings, occurring in a single
    progeny generation, were not believed to be attributable to parathion-
    methyl in the diet. Gross examination of F2b and F3b pups at birth
    and during rearing revealed no malformations. Histopathological
    evaluation of reproductive tract plus liver and kidney from 5 males
    and 5 females per group of F2 parents and of a set of about 15
    tissues including the reproductive tract from 10 male and 10 female
    F3b weanlings per group showed no microscopic changes associated with
    treatment. The no-effect level in the study was 2 ppm (Lösen and Eiben
    1982; Glaister 1981).

    Special Studies on Mutagenicity

         Parathion methyl (94.3 - 94.5% pure) was tested for its mutagenic
    potential in  in vitro microbial assays with and without the presence
    of a metabolic activation preparation (S-9 fraction from liver of rats
    induced with Aroclor 1254). The indicator organisms used were

     Salmonella typhimurium strains TA 1535, TA 100, TA 1537 and TA 98.
    Positive mutagenic response was obtained with and without metabolic
    activation in strain TA 1535 at concentrations at and above
    1 000 µg/plate and in strain TA 100 at and above 500 µg/plate. There
    were no indications of mutagenic activity in assays with tester
    strains TA 1537 and TA 98 at concentrations of 20 to 2 500 µg/plate
    with or without metabolic activation (Herbold 1982a).

         Parathion methyl (96.8% pure) was shown to induce a significant
    increase (dose-related) of sister chromatid exchanges and cell cycle
    delay in Chinese hamster cell line V79 and in two human lymphoid cell
    lines (Chen  et al 1981).

         In a micronucleus test, groups of 5 male and 5 female mice were
    intubated with parathion methyl (95.6%) at 0, 5 or 10 mg/kg bw/day for
    2 consecutive days with an interval of 24 hours between doses. The
    animals were sacrificed 6 hours after the second dose and femoral bone
    marrow smears were prepared. Results of examination of the smears did
    not indicate any significant increase in incidence of micronucleated
    polychromatic erythrocytes in the treated groups (Herbold 1982b).

    Special Studies on Eye and Skin Irritation

         Results of irritation studies with New Zealand White rabbits
    indicated parathion methyl (96.1%/95.6%) to be slightly irritating to
    the skin. The compound was not an irritant to eyes (Thyssen and Lorke

    Long-Term Studies


         Groups of 5 to 6 weeks old male and female rats (SPF, Wistar
    TNO/W74 strain; 100 male and 100 female controls, 50 males and 50
    females/treated group) were fed parathion methyl (94.8% pure) in their
    diet at 0, 2, 10 or 50 ppm for 2 years. Additional groups of 10 males
    and 10 females per group were included for interim sacrifice of 5
    males and 5 females/group after 6 and 12 months. Mortality was
    increased in females at 50 ppm during the first year but about 79-90%
    males and 58 - 78% females of control and treated groups still
    survived at the end of the study. Animals (both sexes) in the top
    dosage group exhibited cholinergic symptoms (tremors) at times during
    the study and growth retardation throughout the experiment.
    Haematology, clinical chemistry and urinalysis carried out at five
    intervals during the study indicated deviations from control values
    essentially only at 50 ppm in a number of parameters. These included
    an increase in reticulocyte counts and a decrease in hematocrit and
    haemoglobin values in both sexes after 6 and/or 24 months, depressed
    plasma protein levels in females at all intervals, elevated serum urea
    in females at most intervals and in males after 24 months, increased

    plasma alkaline phosphatase activity in females after 3 and 6 months
    and a rise in urinary protein level in females after 1 and 6 months.
    (Plasma protein level was also depressed in females at 10 ppm but only
    after 1 month.) Cholinesterase in plasma and erythrocyte, assayed nine
    times over the course of the study, was consistently inhibited
    (>20%), in a dose-dependent pattern, at 50 ppm at all intervals and
    at 10 ppm frequently during the study. The extent of depression was
    greater with plasma cholinesterase than with erythrocyte
    cholinesterase. Terminal brain cholinesterase was inhibited (>20%) in
    males at both 10 and 50 ppm and in females at 50 ppm.

         Gross pathological findings in animals dying or sacrificed in
    moribund condition during the study and in those sacrificed at interim
    or terminally were comparable to those in the controls. A reduction of
    absolute weight, but not organ/body weight ratio, of several organs
    was demonstrated in animals at 50 ppm. Histopathological evaluation of
    a wide range of tissues from animals of control and top dosage groups
    only revealed a significant increase in frequency of males at 50 ppm
    (33% vs 4% in controls) displaying very slight to moderate degree of
    "excessive Oil Red 0(ORO)-positive substance in hepatocytoplasm". A
    no-effect level on this particular liver lesion could not be defined
    due to the absence of data on microscopic findings in the liver
    of treated animals below 50 ppm. No other non-neoplastic
    histopathological changes attributable to treatment were evident.
    Notably, histopathological data were available for only half of the
    animals in the control group.

         When histopathological and tumour data from only 50 male and 50
    female controls were used as the basis of comparison, there did not
    seem to be any significant difference between the control and top
    dosage groups in the incidence of animals with tumours (benign and/or
    malignant), malignant tumours, benign tumours or multiple primary
    tumours. However, there appeared to be an increase in incidence at
    50 ppm of thyroid adenoma in males (11/45 vs 4/43 controls) and of
    uterine adenocarcinoma (8/42 vs 3/44 controls)2. The increase was not
    statistically significant if incidence for the respective tumours in
    43 and 44 concurrent controls were used for comparison. Whether the
    control incidence for the tumours in question would be significantly
    altered, if histopathological findings in all 100 male and 100 female
    concurrent controls were taken into consideration, is not known. The
    incidence of uterine adenocarcinoma at 50 ppm was indicated in the


    2  According to "Table: Tumour hosts with descriptions of all
    tumours" included in the report, 4 female controls had adenocarcinoma
    of the uterus. An examination of "histopathological single finding" in
    Tables 344-347 revealed the uterus of one (animal No.149) of the 4
    supposedly affected control animals was not examined microscopically.

    report to "remain within the variability of untreated animals of this
    strain observable in other virtually parallel studies". Background
    incidences of this particular malignancy and thyroid adenoma were not
    given (Bomhard  et al 1981).

    Observations in Humans

         In 15 healthy male workers (with blood cholinesterase level
    <75% of presumably the mean normal levels) in a pesticide plant who
    were repeatedly or chronically exposed to parathion methyl for
    durations ranging from 1 week to 7 years, but with intermittent
    periods of non-exposure, there was no increased frequency of
    chromosome aberrations in lymphocyte cultures, as compared to 13
    matched controls (having a blood cholinesterase level of 100%) not
    occupationally exposed to any chemical (Stocco  et al 1982),


         The reproduction and long-term studies required by the 1980 Joint
    Meeting and other additional studies have been made available. A
    no-effect level of 2 ppm on re-production capability was demonstrated
    in the 3-generation rat reproduction study. Parathion methyl was
    mutagenic in the  in vitro microbial assays to 2 of the 4
     Salmonella typhimurium tester strains and in sister-chromatid
    exchanges and cell cycle delay studies with Chinese hamster cell line
    V79 and with 2 human lymphoid cell lines. On the other hand, a
    micronucleus test in mice was negative. Also, workers exposed to
    parathion methyl occupationally for long periods exhibited no
    increased frequency of chromosome aberrations in lymphocyte cultures.
    In the case of the 2-year feeding study in rats, the available data
    did not permit a complete evaluation of the carcinogenic activity of
    the compound or the determination of a definite no-effect level in the
    species. The Meeting, therefore, decided to extend the temporary ADI
    and requested that additional data pertaining to the study be


    Level Causing no Toxicological Effect

         Man : 0.3 mg/kg bw/day

    Estimate of Temporary Acceptable Daily Intake for Man

         0 - 0.001 mg/kg bw


    Required (by 1984)

         Additional data on the 2-year feeding study in rats including:

         a.   Historical data on incidences of thyroid adenoma and
              adenocarcinoma of the uterus in the particular strain of
              rats (SPF Wistar TNO/W74) used in the study.

         b.   Histopathological data, not presently available, on the
              remaining 50 males and 50 females in the control group or
              satisfactory and acceptable explanation for the absence of
              such data.

         c.   Results of microscopic examination of the liver from treated
              males below 50 ppm.


    Bomhard, E., Löser, E. and Schilde, B. E605-Methyl (parathion-methyl)
    1981      chronic toxicological study on rats (feeding experiment of
              two years). Report from Bayer AG submitted to the World
              Health Organization by Bayer AG. (Unpublished)

    Braeckman, R.A., Godefront, M.G., Blondeel, G.M., Belpaire, F.M. and
    1980      Williams, J.L. Kinetic analysis of the fate of methyl
              parathion in the dog. Arch. Toxicol. 43: 263-271.

    Chen, H.H., Haveh, J.L., Sirianni, S.R. and Huang, C.C. Induction of
    1981      sister-chromatid exchanges and cell cycle delay in cultured
              mammalian cells treated with eight organophosphorus
              pesticides. Mutat. Res. 88: 307-316.

    Glaister, J.R. E605-methyl rat breeding study (histopathology). Report
    1981      from Hazleton Laboratories Europe, Ltd., England, submitted
              to the World Health Organization by Bayer AG. (Unpublished)

    Herbold, B. E 120 parathion-methyl ( Salmonella/microsome test to
    1982a     evaluate forepoint mutation. Report from Bayer AG submitted
              to the World Health Organization by Bayer AG. (Unpublished)

    Herbold, B. E 120 parathion-methyl micronucleus test on the mouse to
    1982b     evaluate for mutagenic effect. Report from Bayer AG
              submitted to the World Health Organization by Bayer AG.

    Löser, E. and Eiben, R. E 605-methyl multigeneration studies on rats.
    1982      Report from Bayer AG submitted to the World Health
              Organization by Bayer AG. (Unpublished)

    Stocco, R. de Cassia, Becak, W., Gaeta, R. and Rabello-Gay, M.N.
    1982      Cytogenetic study of workers exposed to methyl-parathion.
              Mut. Res. 103:71-76.

    Thyssen, J. and Lorke, D. Parathion-methyl (E120) tests for irritant
    1982      effects on the skin and eye. Batch No. 23010618. Report from
              Bayer AG submitted to the World Health Organization by Bayer
              AG. (Unpublished)

    Weber, H., Patzschke, K. and Wegner, L.A. (14C)methyl-parathion
    1979      (benzene ring-labelled compound) biokinetic studies on rats.
              Report from Bayer AG submitted to the World Health
              Organization by Bayer AG. (Unpublished)

    See Also:
       Toxicological Abbreviations
       Parathion methyl (Pesticide residues in food: 1984 evaluations)