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    PESTICIDE RESIDUES IN FOOD - 1984


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1984




    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

    DIMETHOATE

    Explanation

         Dimethoate was evaluated by the Joint Meetings in 1965, 1966 and
    1967 (FAO/WHO, 1965, 1967 and 1968). The ADI (0.02 mg/kg bw/day was
    derived from a study in humans where the NEL of 0.2 mg/kg bw/day was
    based on plasma cholinesterase depression. Animal studies comprised
    essentially short-term studies (rat, 15 weeks and 6-12 months; dog, 13
    weeks), and a three-generation, two-litter per generation,
    reproduction study in mice. Several studies have been obtained through
    open literature and are summarized in this monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Effects on Enzymes and Other Biochemical Parameters

         Dimethoate significantly inhibited the active transport of
    glucose though the isolated intestine of the mouse (Guthrie, Shah &
    Moreland, 1980).

    TOXICOLOGICAL STUDIES

    Special Studies on Reproduction

    Mice

         Five generations of CD-1 mice were maintained on a diet
    containing 60 ppm of Dimethoate in drinking water. Dimethoate
    treatment significantly altered reproductive performance as indicated
    by reduced mating success and longer gestation period. At birth,
    litter size or weight were not reduced, but pup mortality increased
    significantly with treatment. Growth rate of the pups was generally
    lower than that observed for controls. Dimethoate did not show
    teratologic potential or adverse effects on organ weights or histology
    (Budreau & Singh, 1973).

    Special Studies on Teratogenicity

    Rat

         Groups of pregnant female rats were administered 0, 3, 6, 12 or
    24 mg/kg bw of Dimethoate daily from days 6 to 15 of gestation. The
    dams were killed on day 22 of gestation; the uterine content was
    removed, the carcass weighed, the number of corpora lutea was
    determined, and the animals were necropsied. The foetuses were weighed
    and examined for viability and external malformations. Live foetuses
    were studied for skeletal development and visceral anomalies. Maternal
    weight decreased significantly in the 24 mg/kg group. Clonic spasms
    and muscular tremors were seen in females treated with 24 mg/kg. Mean

    foetal weight was not reduced in treated groups. Dimethoate treatment
    (12 and 24 mg/kg) was associated with an increased number of litters
    with abnormal foetuses and foetuses with wavy ribs. No effect was seen
    at a dose of 6 mg/kg bw of formulated product, equal 2.84 mg/kg of
    Dimethoate (Khera, et al., 1979).

    Cat

         Teratogenic effects were studied in four groups of 17 cats each,
    which were mated and treated with Cygon-4E, a commercial insecticide
    containing 47.3 percent Dimethoate, in single daily doses of 0, 3, 6
    or 12 mg/kg bw on days 14 to 22 of pregnancy. The cats were necropsied
    on day 43 of pregnancy. Foetuses were removed, weighed, and examined
    for external malformations. The total number of anomalous foetuses in
    the 12 mg/kg group was higher, but not statistically different from
    that of controls. The only treatment-related malformation observed at
    this dose was forepaw polydactyly in eight of the 39 foetuses. A dose
    relationship was not established, due to the limited response and the
    common occurrence of this anomaly in the cat population. It is
    suggested that 6 mg/kg of Cygon-4E, or 2.84 mg/kg of Dimethoate be
    considered a no-effect level (Khera 1979).

    Special Studies on Mutagenicity

         See Table 1.

    Special Studies on Carcinogenicity

    Mouse

         Groups of B6C3F1 mice (50 males and 50 females/group) were fed
    diets containing Dimethoate (technical grade, 90-100 percent purity)
    at levels of 250 or 500 ppm for 60 to 80 weeks. Following the exposure
    period, mice were returned to control diets until they were sacrificed
    at 94 weeks. The matched control group consisted of seven male and ten
    female mice. The doses were selected after 1 000 and 500 ppm, used in
    a preliminary study, appeared too toxic. All animals were observed for
    signs of toxicity and body weights recorded. Tissues and organs from
    almost all animals in the study were subjected to histopathological
    examinations.

         In the first year of the study the average weight gain in all
    groups except the low-dose female group was less than that of the
    matched controls. In the second year the average gain in weight in the
    treated groups was generally similar. Tremors and hyperexcitability
    were observed in both sexes.

         During the second year of the study adverse clinical signs were
    observed in all treatment groups. Animals surviving at termination
    were generally in very poor physical condition. The Dimethoate
    treatment had no apparent effect on survival rates. Several non-
    neoplastic proliferative or inflammatory conditions occurred with
    approximately equal frequency in control and Dimethoate-treated mice.



        TABLE 1 -  Special Studies on Mutagenicity

                                                                                                                                             
    Test system              Test object         Concentration                 Purity            Results               Reference
                                                 of dimethoate used
                                                                                                                                             
    5-methyl tryptophan      E. coli             1 - 6.10-3 M                  not indicated     positive              Mohn, 1973
    resistant mutation                           during 60 min.
    assay

    host-mediated            mouse;              3 equal oral doses of         not indicated     positive              Rani, Reddi & Reddy,
    assay                    S. typhimurium      155 mg/kg body weight                                                 1980
                                                 S. typhimurium injected,
                                                 collected, and plated

    sister-chromatid         Chinese hamster     0, 10, 20, 40, and 80         94%               positive in SCE;      Chen, et al.,1981
    exchange; cell           ovary cells         g/ml + 10 picograms/ml                         positive in cell
    cycle delay              V79                 of 5-bromo deoxyuridine                         cycle delay
                                                 (BUdR)

    micronucleus test        mouse; bone         2 equal oral doses of         not indicated     positive              Rani, Reddi & Reddy,
                             marrow              51.7 mg/kg b.w. at                                                    1980
                                                 24-h interval

    human cells              human Chang         50 - 500 g/ml                99.8%             cytotoxic in          Gabliks & Friedman,
    in vitro                 liver and HeLa                                                      both cell lines;      1965
                             cells                                                               ID50 = 170 g/ml
                                                                                                 (liver cells)
                                                                                                 ID50 = 200 g/ml
                                                                                                 (HeLa cells)

    human cells              human HeLa          2.0-300 g/ml                 99.8%             cytotoxic in          Gabliks, 1965a
    in vitro                 cells                                                               minimal toxic
                                                                                                 dose = 20 g/ml

    human cells              human HeLa          2.0 -300 g/ml                99.8%             treated cells         Gabliks, 1965b
    in vitro (up to          cells                                                               more susceptible
    108 days exposure)                                                                           to poliovirus
                                                                                                 infection
                                                                                                                                             
    

    The most commonly occurring neoplasm in male mice was hepatocellular
    carcinoma and malignant lymphoreticular tumours in female mice but
    there was no significant difference in the incidence of tumours among
    the Dimethoate-treated mice and their controls (Nat. Canc. Inst.,
    1976).

    Rat

         Groups of Osborne-Mendel rats (50 males and 50 females/group)
    were fed diets containing Dimethoate (technical grade, 90-100 percent
    purity) at time-weighted average levels of 155 or 310 ppm (male rates)
    and 192 or 384 ppm (female rats) for 80 weeks, and then returned to
    control diets until they were sacrificed at 114 weeks. The matched
    control group consisted of ten male and ten female rats. Pooled
    control groups from other studies were also considered. The initial
    treatment levels (250 or 500 ppm) were selected after a six-week study
    showed weight depression in male and female rats fed 250 or 500 ppm,
    while all rats receiving 1 000 ppm died. As the initial treatment
    levels were toxic, levels for treated rats were lowered for the
    varying treatment periods indicated in Table 2. All animals were
    observed for signs of toxicity and body weights were recorded. Tissues
    and organs of almost all animals in the study were subjected to
    histopathological examinations. Cholinergic signs of toxicity were
    evident in treated animals. Early in the study tremors and
    hyperexcitability were observed in both male and female rats. In
    general there appeared to be a dose-related depression in both low-
    and high-dose groups. Adverse clinical signs in all treatment groups
    were noted with frequent incidence during the second year of the
    study. Animals that survived to termination were generally in poor
    physical condition. At termination there appeared to be a dose-related
    mortality with Dimethoate (58 and 51 percent survival to 115 weeks for
    males and females, respectively). However the significance of this
    observation is not clear, since survival was lowest in the male
    matched and pooled control group. Numerous inflammatory, degenerative
    and proliferative lesions, commonly seen in aged rats, occurred with
    approximately equal frequency in treated and control animals. Several
    non-neoplastic lesions occurred more frequently in treated rats than
    in controls, but were generally not dose-related. The pituitary and
    thyroid were the most common primary sites of neoplasia in both
    treated and control rats but there was no significant increase in the
    incidence of tumours between the treated and control groups (Nat.
    Canc. Inst., 1976).

    Acute Toxicity

         The acute toxicity of Dimethoate to rats via oral and dermal
    routes is summarized in Table 3.

        TABLE 2.  Design of Dimethoate Chronic Feeding Study in Rats and Mice

                                                                                                

                          Initial        Dimethoate        Time on Study         Time-Weighted
                          No. of         in Diet        Treated    Untreated     Average Dose
                          Animals        (ppm)          (weeks)    (weeks)       (ppm)
                          (a)            (b)            (c)                      (d)
                                                                                                

    RATS
    Male

    Matched Control        10               0             0        114

    Low                    50             250            19                         155
                                          125            61
                                            0                      34-35

    High                   50             500            19
                                          250            61                         310
                                            0                      33-34

    Female

    Matched Control        10               0             0        114

    Low                    50             250            43
                                          125            37                         192
                                            0                      33-34

    MICE
    Male

    Matched Control        10 (e)           0             0        94

    Low                    50             250            69                         250
                                            0                      24

    High                   50             500            60                         500
                                            0                      34
    Female

    Matched Control        10               0             0        94

    Low                    50             250            80                         250
                                            0                      13

    High                   50             500            80                         500
                                            0                      14
                                                                                                

    TABLE 2.  (continued)

    (a) All animals were 35 days of age when placed on test.

    (b) Initially 1 000 and 500 ppm of Dimethoate were fed to mice of each sex; these doses were 
        too toxic, however, and the mouse study was terminated and restarted as shown in the table.

    (c) When diets containing Dimethoate were discontinued, treated rats and their matched controls 
        were fed plain feed diets (without corn oil) for 8 weeks, then control diets (2 percent 
        corn oil added) for an additional 25 to 27 weeks. Mice received the control diet until 
        termination.

    (d) Time-weighted average dose = Sigma (dose in ppm x no. of days at that dose)
                                     Sigma (no. of days receiving each dose)

    (e) Examination at necropsy subsequently revealed that 3 of 10 mice designated as male matched 
        controls were females.


    TABLE 3.  Acute Toxicity of Dimethoate in Animals

                                                                                                

    Species        Sex            Route          Purity         LD50                Reference
                                                                                                

    Rat            m/f            oral           97.6-99%       540-600             Dal Re &
                                                                mg/kg               Vola Gera
                                                                                    1980

    Rat            m/f            dermal         97.6-99%       >7 000              Dal Re &
                                                                mg/kg               Vola Gera
                                                                                    1976
                                                                                                
    
    COMMENTS

         The last evaluation of Dimethoate was conducted in 1967, when an
    ADI of 0-0.02 mg/kg bw was derived from a no-effect level in humans of
    0.2 mg/kg/day for plasma cholinesterase. Since that time several
    studies on the toxicology of Dimethoate have been published and have
    now been reviewed to supplement the data on short-term rat and dog.
    toxicology studies and a mouse three-generation study used in previous
    toxicological evaluations.

         A five-generation study of Dimethoate in mice showed decreased
    success in mating, longer reproduction time and increased pup
    mortality, but no teratogenic potential. Teratogenicity studies with
    Dimethoate-formulated products enabled no-effect levels to be
    established for rats and cats (2.8 mg Dimethoate/kg bw).

         Dimethoate was shown not to be oncogenic in mouse and rat
    studies, but was mutagenic in a number of in vivo and in vitro
    short-term tests.

         The meeting was informed that several additional toxicological
    studies are in progress and will be available by 1987. In the absence
    of a complete data base for this compound the ADI was replaced by a
    temporary ADI at a lower level.

    Level Causing no Toxicological Effect

         Rats:     5 ppm in the diet, equivalent to 0.25 mg/kg bw

         Humans:   0.2 mg/kg bw/day

    Estimate of Temporary Acceptable Daily Intake for Humans

         0 - 0.002 mg/kg bw

    FURTHER WORK OR INFORMATION

    Required (by 1987)

         1.   Submission of the on-going toxicological studies sponsored
              by the "Dimethoate Task Force".

         2.   A dog study of at least six months' duration.

    Desirable

         Observations in humans.

    REFERENCES

    Budreau, C.H. & Singh, R.P. Effect of Fenthion and Dimethoate on
    1973      reproduction in the mouse. Toxicol. Appl. Pharmacol. 26:
              29-38.

    Chen, H.H., Hsueh, J.L., Sirianni, S.R. & Huang, C.C. Induction of
    1981      Sister-Chromatid exchanges and Cell Cycle Delay in cultured
              mammalian cells treated with eight organophosphorous
              pesticides. Mutat. Res. 88: 307-316.

    Dal Re, V. & Vola Gera, F. Determination of the acute dermal toxicity
    1976      of technical Rogor. Report from Centro Ricerche
              Antiparassitari, Montedison, Italy, submitted by Farmoplant,
              Italy to WHO. (Unpublished)

    Dal Re, V. & Vola Gera, F. Acute oral toxicity of technical Rogor
    1980      samples recently produced in albino rats. Report from Centro
              Ricerche Antiparassitari, Montedison, Italy, submitted by
              Farmoplant, Italy to WHO. (Unpublished)

    Gabliks, J. Responses of cell cultures to insecticides II. Chronic
    1965a     toxicity and induced resistance. Proc. Soc. Expt. Biol. Med.
              120: 168-171.

    Gabliks, J. Responses of cell cultures to insecticides III. Altered
    1965b     susceptibility to Poliovirus and Diptheria toxin. Proc. Soc.
              Expt. Biol. Med. 120: 172-175.

    Gabliks, J. & Friedman, L. Responses of cell cultures to insecticides
    1965      I. Acute toxicity to human cells. Proc. Soc. Expt. Biol.
              Med. 120: 163-168.

    Guthrie, F.E., Shah, P.V. & Moreland, D.E. Effects of pesticides on
    1980      active transport of glucose through the isolated intestine
              of the mouse. J. Agric. Food Chem. 22: 3.

    Khera, K.S. Evaluation of Dimethoate (Cygon 4E) for teratogenic
    1979      activity in the cat. J. Environ. Pathol. Toxicol. 2:
              1283-1288.

    Khera, K.S., Whalen, C., Trivett, G. & Angers, G. Teratogenicity
    1979      studies on pesticidal formulations of Dimethoate, Diuron and
              Lindane in rats. Bull. Environ. Contam. Toxicol. 22:
              522-529.

    Mohn, G. 5-methyl tryptophan resistance mutations in Escherichia Coli
    1973      K-12. Mutat. Res. 20: 7-15.

    National Cancer Institute. Bioassay of Dimethoate for possible
    1976      carcinogenicity. NCI-CG-TR-4 DHEW Publication No. (NIH)
              77-80.

    Rani, M.V.U., Reddi, O.S. & Reddy, P.P. Mutagenicity studies involving
    1980      Aldrin, Endosulfan, Dimethoate, Phosphamidon, Carbaryl and
              Ceresan. Bull. Environ. Contam. Toxicol. 25: 277-282.


    See Also:
       Toxicological Abbreviations
       Dimethoate (EHC 90, 1989)
       Dimethoate (HSG 20, 1988)
       Dimethoate (ICSC)
       Dimethoate (FAO Meeting Report PL/1965/10/1)
       Dimethoate (FAO/PL:CP/15)
       Dimethoate (FAO/PL:1967/M/11/1)
       Dimethoate (JMPR Evaluations 2003 Part II Toxicological)
       Dimethoate (AGP:1970/M/12/1)
       Dimethoate (Pesticide residues in food: 1983 evaluations)
       Dimethoate (Pesticide residues in food: 1984 evaluations)
       Dimethoate (Pesticide residues in food: 1987 evaluations Part II Toxicology)
       Dimethoate (Pesticide residues in food: 1996 evaluations Part II Toxicological)