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    OMETHOATE

    EXPLANATION

         Omethoate was evaluated by the Joint Meeting in 1971, and
    reviewed in 1975, 1978, 1979, and 1981 (Annex 1, FAO/WHO, 1972a,
    1976a, 1979a, 1980a, and 1982a). A toxicological monograph was
    prepared by the Joint Meeting in 1971 (Annex 1, FAO/WHO, 1972b) and
    monograph addenda were prepared in 1975, 1978, 1979, and 1981 (Annex
    1, FAO/WHO, 1976b, 1979b, 1980b, and 1982b). In 1981, the Joint
    Meeting requested carcinogenicity studies in a rodent species at
    higher dose levels than were used in the study that was reviewed,
    while further mutagenicity studies were deemed to be desirable. A
    chronic toxicity study on mice, a teratogenicity study in rabbits, and
    additional mutagenicity studies have become available in the meantime,
    and are summarized in this monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Special studies on the inhibition of cholinesterase activity in mice

         Groups of BOR:NMRI mice (50 males and 50 females/group) were
    given diets containing omethoate (97.1% purity) at concentrations of
    0, 1, 3, or 10 ppm for 4 weeks. Animals were observed twice daily and
    weighed once a week. Plasma, erythrocyte, and brain cholinesterase
    activity were measured on days 1, 3, 7, 14, and 29 of the treatment on
    10 males and 10 females per dose group.

         Appearance, behaviour, and mean body weights were not
    significantly different between the control and the treated groups. No
    mortality occurred. Plasma cholinesterase activity in both sexes was
    significantly lower than in controls in the 10-ppm group after the
    first determination. Erythrocyte cholinesterase activity was depressed
    in females from day 3 onward at 10 ppm, and on day 14 at 3 ppm; in
    males it was depressed only on day 29 at 10 ppm. Brain cholinesterase
    activity of both sexes was significantly lower than in controls at all
    test times at 10 ppm and at nearly all test times at 3 ppm. In
    addition, males in the 1-ppm group also had significantly lower brain
    enzyme activity on days 1 and 3; however, an opposite trend was
    observed on day 7.

         The 1-ppm dose level was the no-effect level on cholinesterase
    activity in this study (Kroetlinger, 1982).

    Toxicological studies

    Special studies on teratogenicity

    Rabbit

         Groups of 14 pregnant New Zealand White rabbits were dosed daily
    by oral gavage with omethoate (96.8% purity), dissolved in distilled
    water, at dose levels of 0, 0.1, 0.3, or 1.0 mg/kg b.w. from day 6 to
    day 18, inclusive, of gestation. On day 29 of gestation the females
    were sacrificed and the uterine contents examined. The reproductive
    tract, complete with ovaries, was dissected out and the following
    recorded; weight of gravid uterus, number of corpora lutea in each
    ovary, number of implantation sites, number of resorption sites
    (classified as early and late), number and distribution of live and
    dead foetuses in each uterine horn, weight and sex of individual
    foetuses, individual placental weights, and external, internal and
    skeletal abnormalities of individual foetuses. Whole-blood
    cholinesterase activity was determined prior to dosing on day 6 of
    gestation and 2 hours after dosing on day 18 of gestation.

         The general condition of control and treated females was
    comparable throughout the study. Maternal mean body weights and
    corrected day-29 body weights were unaffected by the treatment.
    Mortality, the incidence of abortions and total-litter losses, and the
    number of pregnant females with viable young on day 29 were not
    altered by treatment. Whole-blood cholinesterase activity was
    significantly depressed only among the 1.0 mg/kg b.w. females,
    compared both to the pre-dosing level and to the control post-dosing
    level.

         There were no treatment-related differences between the control
    and the treated groups with respect to the corpora lutea count,
    implantations, male and female viable young, early and late
    resorptions, pre- and post-implantation losses, or foetal and
    placental weights.

         Examination of foetuses at necroscopy on day 29 of gestation or
    following skeletal investigation revealed a number of non-dose-related
    findings of the type and incidence previously recorded in this strain
    of rabbit and in the laboratory that performed the study.

         The 1.0 mg/kg b.w. dose level was the no-effect level for
    embryotoxic/teratogenic effects (Tesh et al., 1982).

    Special study on carcinogenicity

    Mouse

         Groups of SPF mice of the BOR:CWF1 strain (50 males and 50
    females per dose level) were fed diets containing omethoate (94%
    purity) at levels of 0, 1, 3, or 10 ppm for 24 months. The animals
    were inspected daily for clinical symptoms. Food consumption was
    determined weekly. The body weights were determined weekly during the
    first 14 weeks and at 3-week intervals thereafter. Necropsy was
    performed on the mice that died or were sacrificed when moribund, and
    on all the animals sacrificed at the end of the experiment. Heart,
    lungs, liver, spleen, kidneys, and testes were weighed. A range of
    organs and all changes detected during gross examination were
    subjected to histopathological examination.

         Appearance, behaviour, and activity were not significantly
    different between the control and treated groups. Total and mean daily
    food consumption were essentially the same among all the animals.

         The body weights of the male mice of all the treated groups were,
    for the most part, higher than those of the controls during the entire
    experiment, whereas there were no differences from controls in the
    body weights of the females.

         Mortality and the frequency-distribution of mortality by death-
    date-intervals were comparable among all the groups. Mortality at 18
    months was between 12% and 27% for the males and between 14% and 31%
    for the females. Absolute and relative organ weights showed no dose-
    related and/or significant differences between control and treated
    groups. Gross anatomical and histopathological examinations revealed a
    range of non-neoplastic changes commonly observed in old mice.
    Comparison of these changes by type, site, and frequency distribution
    by sex and dose level gave no indications of any treatment-related
    toxic effects.

         Neoplastic changes were found primarily in the lungs, liver,
    adrenal cortex, and haemopoietic system. Neither the data concerning
    the type, site, or frequency-distribution of tumours by sex and dose
    level, nor the data regarding the number of tumour-bearing mice, mice
    with benign tumours, mice with malignant tumours, or mice with both
    benign and malignant tumours provided any indication of treatment
    effects.

         The somatic no-effect level in this study was 10 ppm, equal to
    2.1 mg/kg b.w./day and 3.1 mg/kg b.w./day, for male and female mice,
    respectively (Kroetlinger & Loeser, 1982).

    Special studies on mutagenicity

         Several mutagenicity assays have been carried out on omethoate
    (Table 1); omethoate was found to be mutagenic only in gene-conversion
    and mitotic-recombination tests in S. cerevisiae D7. All other tests
    were negative.

    Special studies on delayed neuropathy

         Hens (2-4/dose group) were dosed orally with omethoate dissolved
    in corn oil at levels of 20 to 300 mg/kg b.w. (ca. 4-8 times the
    unprotected LD50) under eserine and atropine protection. Omethoate
    used was a sample that caused a fatal human poisoning accident.

         AChE and neurotoxic esterase (NTE) acitivites of brain
    homogenates were assayed 24 hours after dosing. Pair-dosed birds which
    survived were observed for signs of ataxia for 3-4 weeks after dosing.

         Hens dosed at 4 times the LD50 did not show any inhibition of
    NTE at 24 hours, nor signs of ataxia for 3-4 weeks after dosing. Hens
    dosed at 8 times the LD50 did not survive, despite treatment with
    high doses of atropine; however, the NTE activity in the brain of
    those animals who died within 36 hours was measured immediately after
    death and was found to be normal. In all the birds acute cholinergic
    symptoms were correlated with high inhibition of AChE in the brain. An
    inhibition of 70% of brain AChE in a bird dosed with 20 mg/kg b.w. of
    omethoate was not enough to produce detectable signs of acute
    poisoning.

         The in vitro inhibition activity of pure omethoate and of the
    incriminated sample of omethoate were measured for NTE and AChE
    activities using both hen and human brain enzymes. For both hen and
    human tissue the I50 for AChE was in the range of 0.08-0.15 mM, so
    that it would be virtually totally inhibited at 5 mM, the
    concentration which caused no detectable inhibiton of NTE.

         NTE and AChE activities were measured on samples of brain tissue
    (cortex) taken during the post-mortem examination performed 24 hours
    after death on a 30-year-old male farmer who was acutely poisoned by a
    commercial formulation of omethoate. The NTE acitivity was within the
    normal range, while AChE was strongly inhibited.

         The conclusion was that omethoate is extremely unlikely to cause
    delayed neuropathy in man (Lotti et al., 1981).

        Table 1.  Results of mutagenicity assays of omethoate
                                                                                                           

    Test                          Test           Range of doses or        Result              Reference
    organism                      substance      concentration tested
                                                                                                           

    S. cerevisiae                 Omethoate      0.03-66.67 l/ml*        No significant      Hoorn, 1982
     S138, &                      (96.9%                                  differences in
     S211 alfa                    purity)                                 revertant
                                                                          frequencies
                                                                          compared to
                                                                          control

    S. cerevisiae                 Omethoate      0.03-66.67 l/ml*        Dose-related        Hoorn, 1983
      D7                          (96.0%                                  increases of
                                  purity)                                 frequencies of
                                                                          tryptophan
                                                                          convertants and
                                                                          mitotic
                                                                          recombinants

    Mouse lymphoma                Omethoate      500-2000 g/ml           No significant      Bootman &
     L5178Y                       (96.9%         without S-9 mix,         increase in         Rees, 1982
     (TK +/-)                     purity)        500-5000 g/ml           mutation
     cells -                                     with S-9 mix             frequency at the
     in vitro                                                             TK gene locus*

    Micronucleus                  Omethoate      26 mg/kg b.w.,          No significant      Herbold,
     test on                      (97.1          212 mg/kg b.w.          differences         1981
     mouse                        purity)                                 between control &
                                                                          treated groups
                                                                          with respect to
                                                                          incidence of
                                                                          micronucleated
                                                                          polychromatic
                                                                          erythrocytes
                                                                                                           

    Table 1.  (Con't)
                                                                                                           

    Test                          Test           Range of doses or        Result              Reference
    organism                      substance      concentration tested
                                                                                                           

    E. coli (K12)                 Omethoate      625-10,000 l/           No indication of    Herbold,
     p 3478 with                  (96.0%         plate*                   potential for       1983
     DNA repair                   purity)                                 DNA damage
     deficiency &
     E. coli W3110
     with intact repair
     system
                                                                                                           

    *    With and without S-9 mix
    
    Acute toxicity

         After exposure to omethoate (96.9% purity) for 4 hours, a primary
    irritant effect on the sheared uninjured skin of albino rabbits was
    not observed. The test compound caused a slight conjunctival reaction
    that was completely reversible within 7 days (Pauluhn, 1982).

    Short-term studies

    Dog

         Groups of Beagle dogs (6 males and 6 females/group) received
    omethoate (97.1% purity; dissolved in acidulated water) daily for 12
    months by stomach tube at dose levels of 0, 0.025, 0.125, or
    0.625 mg/kg b.w. All the animals were observed several times daily for
    appearance and behaviour. Food and water consumption were recorded
    daily. Body weights were noted weekly. Reflex tests, ophthalmoscopic
    examinations, body temperatures, pulse-rate measurements, haematology,
    clinical chemistry, and urinalyses were carried out before the start
    of the study and during weeks 6, 13, 26, 40, and 52 of treatment.
    Cholinesterase activity in the plasma and erythrocytes was determined
    1 week before the start and during weeks 1, 3, 6, 9, 13, 26, 40, and
    52 of treatment. On autopsy, after 52 weeks of treatment,
    cholinesterase activies in the brains of all the animals were
    determined.

         All the animals were normal in appearance and behaviour. WP signs
    attributable to treatment were not observed. All the animals survived
    the treatment. There were no significant differences between the
    control and the treated groups with respect to reflex tests,
    ophthalmoscopic examinations, body temperatures, pulse rates, food and
    water consumption, mean body weights, haematology, clinical chemistry
    (except for cholinesterase activity) or urinalysis.

         A clear depression of plasma cholinesterase activity was observed
    only in the 0.625 mg/kg b.w. dose group, ranging between 25% and 32%
    in the males, and 16% and 29% in the females, in comparison to the
    controls. The depression remained essentially constant over the entire
    period of study.

         A marked depression of erythrocyte cholestinerase activity was
    measured in the males (17% to 40%) and females (22% to 40%) at the
    0.625 mg/kg b.w. dose level, which varied only slightly during the
    study. At the 0.125 mg/kg b.w. dose level, only the males in the first
    third of the study showed slight (less than 28%) depression of
    erythrocyte cholinesterase activity.

         Brain cholinesterase activity was depressed in the males of the
    0.125 mg/kg b.w. group (20%) and of the 0.625 mg/kg b.w. group (39%),
    and in the females of the 0.625 mg/kg b.w. group (30%).

         On autopsy, absolute and relative organ weights were not
    significantly different between the control and treated groups. The
    gross pathological and histopathological examinations did not reveal
    dose-related findings.

         The dose level of 0.625 mg/kg b.w. was the no-effect level for
    somatic effects, while 0.025 mg/kg b.w. was the no-effect level for
    erythrocyte cholinesterase activity (Hoffmann & Schilde, 1984).

    COMMENTS

         The results of an adequate chronic toxicity/oncogenicity study in
    mice, in which neither oncogenic effects nor other somatic damage were
    observed, were provided to the meeting.

         A no-effect level of 1.0 mg/kg b.w. was determined for
    embryotoxic/teratogenic effects in the rabbit.

         Delayed neuropathy was not observed in hens. No potential for
    delayed neuropathy was observed in man.

         Omethoate was found mutagenic only in gene-conversion and
    mitotic-recombination tests in S. cerevisiae D7, whereas other tests
    were negative.

         The Meeting estimated an ADI for omethoate.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Rat: 1 ppm in the diet, equivalent to 0.05 mg/kg b.w.
         Dog: 0.025 mg/kg b.w./day.

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.0003 mg/kg b.w.

    FURTHER WORK OR INFORMATION DESIRED

         Observations in man.

    REFERENCES

    Bootman, J. & Rees, R. S 6876: Investigation of mutagenic activity in
    (1982)    the TK +/- mouse lymphoma cell mutation system. Unpublished
              report No. 82/BAG 027/488 from Life Science Research,
              England. Submitted to WHO by Bayer F.R.G.

    Herbold, B. S 6876 (Omethoate, Folimat(R) active ingredient):
    (1981)    Micronucleus test on mouse to evaluate S 6876 for mutagenic
              potential. Unpublished report No. 10,021 from Institute of
              Toxicology, Bayer AG. Submitted to WHO by Bayer F.R.G.

    Herbold, B. S 6876 (Omethoate, Folimat(R) active ingredient): Pol test
    (1983)    on E. coli to evaluate for DNA damage. Unpublished report
              No. 12,126 from Institute of Toxicology, Bayer AG. Submitted
              to WHO by Bayer F.R.G.

    Hoffman, K. & Schilde, B. S 6876 (Omethoate): Chronic toxicity to dogs
    (1984)    on oral administration (twelve-month stomach tube study).
              Unpublished report No. 12,561 from Institute of Toxicology,
              Bayer AG. Submitted to WHO by Bayer F.R.G.

    Hoorn, A.J.W. Mutagenic evaluation of S 6876 (omethoate) in the
    (1982)    reverse mutation induction assay with Saccharomyces
              cerevisiae strains S138/S211-alfa. Unpublished final
              report No. E-9030 from Litton Bionetics, The Netherlands.
              Submitted to WHO by Bayer F.R.G.

    Hoorn, A.J.W. Evaluation of S 6876 (c.n. omethoate; a.i. of Folimat(R))
    (1983)    in the induced mitotic crossing over and gene conversion
              assay in Saccharomyces cerevisiae strain D7. Unpublished
              final report No. E-9127 from Litton Bionetics, The
              Netherlands. Submitted to WHO by Bayer F.R.G.

    Kroetlinger, F. S 6876 (Omethoate, the active ingredient of Folimat(R))
    (1982)    Study of the inhibition of cholinesterase activity in mice.
              (4-week feeding experiment). Unpublished report No. 11,235
              from Institute of Toxicology, Bayer AG. Submitted to WHO by
              Bayer F.R.G.

    Kroetlinger, F. & Loeser, E. S 6876 (Omethoate, the active ingredient
    (1982)    of Folimat(R)): Chronic toxicity study on mice. (2-year
              feeding experiment). Unpublished report No. 11,161 from
              Institute of Toxicology, Bayer AG. Submitted to WHO by Bayer
              F.R.G.

    Lotti, M., Ferrara, S.D., Caroldi, S., & Sinigaglia, F. Enzyme studies
    (1981)    with human and hen autopsy tissue suggest omethoate does not
              cause delayed neuropathy in man. Arch. Toxicol., 48,
              265-270.

    Pauluhn, J. S 6876 (Omethoate, the active ingredient of Folimat(R)):
    (1982)    Study of the irritant/corrosive effect. Unpublished report
              No. 11,977 from Institute of Toxicology, Bayer AG. Submitted
              to WHO by Bayer F.R.G.

    Tesh, J.M., Ross, F.W., Wightman, T.J., & Wilby, O.K. S 6876: Effect
    (1982)    of oral administration upon pregnancy in the rabbit. 2. Main
              study. Unpublished report No. 82/BAG 023/111 from Life
              Science Research, England. Submitted to WHO by Bayer F.R.G.
    


    See Also:
       Toxicological Abbreviations
       Omethoate (WHO Pesticide Residues Series 1)
       Omethoate (WHO Pesticide Residues Series 5)
       Omethoate (Pesticide residues in food: 1978 evaluations)
       Omethoate (Pesticide residues in food: 1979 evaluations)
       Omethoate (Pesticide residues in food: 1980 evaluations)
       Omethoate (Pesticide residues in food: 1981 evaluations)
       Omethoate (Pesticide residues in food: 1984 evaluations)