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    DIMETHOATE

    EXPLANATION

         Dimethoate was evaluated for acceptable intake by the JMPR in
    1963 and was also reviewed in 1965, 1966, 1967 and 1984 (Annex 1,
    FAO/WHO, 1964, 1965a, 1967a, 1968a, 1985a). In the absence of a
    complete data base the 1984 JMPR meeting replaced the ADI of
    0-0.2 mg/kg bw. (established at the 1967 meeting, based on a no
    observed effect level in humans of 0.2 mg/kg/day for plasma
    cholinesterase) by a temporary ADI at a lower level
    (0-0.002 mg/kg bw.). The following investigations were 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 month's duration.

         The on-going studies have become available and have been
    summarized in this monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Toxicological Studies

    Special studies on carcinogenicity

         See under long-term studies

    Special studies on teratogenicity

    Rats

         Groups of 25 pregnant female rats (CrL: COBS CD (SD) BR strain)
    received 0, 3, 6 and 18 mg dimethoate (purity 97.3%)/kg bw. by gavage
    from day 6-15 of gestation. The fetuses were delivered by caesarian
    section on day 20 of pregnancy. The dams were observed daily for
    clinical signs, mortality and body weight. The number of corpora
    lutea, implantations and live and dead fetuses were recorded. The
    fetuses were counted and weighed and examined for visceral and
    skeletal abnormalities.

    Salivation and hair loss was observed in females at all dose levels.
    Females of the highest dose group also had brown facial staining,
    small rounded feces (also at 6 mg/kg bw.), hypersensitivity, body
    tremors and unsteady gait. Body weight gain and food consumption were
    significantly reduced. No malformations were found. There was no
    obvious indication of an adverse effect of dimethoate treatment on
    mean incidences of both visceral and skeletal anomalies, although at
    all dosages an unspecific increase was observed relative to control
    values (which were, however, lower than concurrent control values in
    recent preceding studies) (Edwards et al., 1984)

    Rabbits

         Groups of 16 pregnant female rabbits received 0, 10, 20 and 40 mg
    dimethoate (purity 97.3%)/kg bw. in 1% methylcellulose by gavage on
    day 7-19 of gestation. The fetuses were delivered by caesarian section
    on day 29 of pregnancy. The dams were observed daily for clinical
    signs, mortality and body weight. The number of corpora lutea,
    implantations and live and dead fetuses were recorded. The fetuses
    were weighed and sexed and examined for visceral and skeletal
    abnormalities.

         Muscle tremors, an unsteady gait, and a increased incidence of
    animals showing cold ears after dosing and abnormal feces were
    observed at 40 mg/kg. During dosing body weight gain and food
    consumption were significantly reduced at 40 mg/kg. A slightly lower
    body weight gain was observed at 20 mg/kg, while at 10 mg/kg mean
    weight gain was higher. Fetal weight was significantly decreased at
    40 mg/kg, with a tendency at 20 mg/kg bw. Teratogenic effects were not
    observed (Edwards et al., 1984).

    Special studies on mutagenicity

         Dimethoate was not mutagenic in the studies considered in this
    monograph addendum (see table 1).

    Special studies on skin sensitization

         Technical dimethoate (97.3% purity) was not a skin sensitizer in
    guinea pigs when rested by the patch technique (Buehler test)
    (Madison, 1984).

    Long-term studies

    Mice

         Groups of 50 male and 50 female B6 C3 F1 mice were fed diets
    containing 0, 25, 100 and 200 ppm dimethoate (purity > 96.71%) for
    778 weeks. Satellite groups of 10 male and 10 female mice were fed
    diets containing dimethoate at the same dietary levels and sacrificed
    after 51 weeks of treatment. Observations included clinical signs,
    mortality, body weight, food consumption, hematology and
    cholinesterase activities (only after 51 weeks) in plasma and
    erythrocytes. Organs were weighed and comprehensive histopathology was
    performed (from the satellite animals only those dying intercurrently
    or sacrificed in a moribund state).

         Retarded growth was observed in males at all dose levels during
    the first months of the study and in females at 200 ppm in the
    beginning. Towards the end of the study the body weights of the
    females at all dose levels were significantly increased. At all dose
    levels cholinesterase activity in plasma as well as in erythrocytes
    was significantly decreased in both sexes (at 25 ppm only 10 to 30%
    respectively in both sexes). The inhibition was greater for
    cholinesterase in erythrocytes in all cases. Absolute as well as
    relative ovary weight were significantly decreased in females of all
    dose groups at termination of the study. Other changes in organ


        Table 1.  Special studies on the mutagenicity of dimethoate
                                                                                                                 

    Type of test         Test object      Concentration         Purity     Results       References
                                          of dimethoate
                                                                                                                 

    In vitro

    CHO/HGPRT            Chinese          1000 g up to         97.3%      Negative      Johnson et al.,
    mutation assay       hamster          3500 g/ml                                   1984
    (with and without    ovary
    metabolic
    activation)

    In vivo

    Dominant lethal      NMRI mice        5, 10 and 20 mg/kg    96.89%     Negative      Becker, 1985
    test                                  (administered                    (1)
                                          orally, 5 days)

    Micronucleus         CD-1 mice        55 mg/kg              97.3%      Negative      Sorg, 1985
    test                                  (administered i.p.               (1)
                                          twice 24 hr apart)
                                          dissolved in
                                          0.9% saline

    Metaphase            Rat bone         i.p. 15, 75           97.3%      Negative      San Sebastian,
    analysis assay       marrow cells     & 150 mg/kg                      (1)           1985
                                                                                                                 

    (1) Positive control yielded positive results
    
    weights were not consistent or dose related and are probably induced
    by the higher body weight at all dose levels (especially in females).
    At histopathology hepatocellular vacuolization was observed in males
    and females at 200 and 100 ppm. Extramedullary hematopoiesis in the
    spleen was observed in males at 200 ppm and slightly in males at 100
    and 25 ppm and in females at all dose levels.

         No enhanced tumour incidence was observed (Hellwig, 1986a).

    Rats

         Groups of 50 male and 50 female Wistar rats were fed diets
    containing 0, 5, 25 and 100 ppm dimethoate (purity > 96.71%) for
    24 months. Satellite groups of 15 male and 15 female rats received
    diets containing dimethoate at the same dietary levels and were used,
    together with a satellite group of 20 rats/sex receiving a diet
    containing 1 ppm dimethoate, for hematological, clinico-chemical and
    urinalysis examinations. All satellite groups received the diet for
    24 months also. Observations included clinical signs, mortality, food
    consumption, body weight, ophthalmoscopy, hematology, clinical
    chemistry, cholinesterase activities in plasma, erythrocytes and brain
    and urinalysis. Surviving animals were sacrificed after 24 months.
    Organs were weighed and comprehensive histopathological examinations
    were made.

         Towards the end of the study mortality was increased in females
    at 100 ppm. Body weight gain was decreased in males and females at the
    highest dose group during the first 12 months. Hemoglobin and
    hematocrit values were significantly decreased in males and females at
    100 ppm (tendency in males at 25 ppm) and mean corpuscular hemoglobin
    concentration was increased. The number of erythrocytes was
    significantly decreased in males at 100 ppm (tendency at 25 ppm) and
    the number of leucocytes was significantly increased in females at 100
    and 25 ppm and in males at 100 ppm only. Plasma cholinesterase
    activity was significantly decreased (about 50%) in male and female
    rats at 100 and cholinesterase activity in erythrocytes and the brain
    were significantly decreased at 5 (males only), 25 and 100 ppm in both
    sexes (erythrocytes: max. 35%, 55% and 90%, respectively; brain: max.
    23%, 40% and 60% respectively). In females, potassium values in blood
    were significantly decreased at 100 and 25 ppm and alanine
    amino-transferase activity was significantly increased at 100 ppm. In
    males of the same dose group, total protein was significantly
    increased and relative ovary weight in females was significantly
    decreased.

         No enhanced tumor incidence was observed. The NOAEL in this study
    is 1 ppm, equivalent to 0.05 mg/kg bw (Hellwig, 1986b).

    COMMENTS

    Toxicology

         The 1984 JMPR replaced the ADI of 0.02 mg/kg bw by a temporary
    ADI of 0.002 mg/kg bw because the data on which the former ADI was
    based were considered inadequate. The meeting was aware that new
    toxicological studies were under way. These studies were reviewed by
    the present meeting.

         Maternal toxicity and fetotoxicity were observed in
    teratogenicity studies in rats and rabbits, but no teratogenic
    effects.

         In 1984 the Joint Meeting concluded that dimethoate was mutagenic
    in a limited number of  in vitro and  in vivo studies reported in
    the literature. Since then, additional negative mutagenicity data have
    become available. It was concluded that dimethoate is mutagenic in
    bacterial tests, but not in mammalian cells or in  in vivo tests.

         In long-term toxicity/carcinogenicity studies with mice and rats
    no indication of carcinogenicity was found. In the mouse study the
    lowest dose of 25 ppm produced decreased body weight and decreased
    cholinesterase activities in erythrocytes as well as slight
    extramedullary hematopoiesis in the spleen.

         Two years' administration of dimethoate to rats also revealed a
    decrease in body weight, decreased cholinesterase activities
    (in erythrocytes and brain) and slight anemia. No effects were
    observed at 1 ppm (equivalent to 0.05 mg/kg bw/day).

         The required dog study was not available.

         The 1984 evaluation of human data was based on the understanding
    that plasma CHE activity was measured. Re-examination of the data
    showed that they were in fact based on erythrocyte CHE and that a
    NOAEL was present. The present meeting therefore decided that an ADI
    could be established on the basis of these data.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Rat:     1 ppm in the diet, equivalent to 0.05 mg/kg bw/day
         Man:     0.2 mg/kg bw/day

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0-0.01 mg/kg bw.

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
    EVALUATION OF THE COMPOUND

         1.   Observations in man.
         2.   A one-year dog study.
         3.   An up-to-date reproduction study in rats.

    REFERENCES

    Becker, H., 1985. Dominant lethal study with dimethoate technical in
    the mouse. Unpublished report no.: 039003 d.d. September 12, 1985 from
    RCC, Research & consulting Company AG, CH 4452 Itingen/Switzerland.
    Submitted to WHO by Dimethoate Task Force, Milano, Italy.

    Edwards, J.A., Leeming, N.M. & Clark, R., 1984. Effect of dimethoate
    on pregnancy of the rat. Unpublished report no.: DTF 3/84245 d.d.
    April 13, 1984 from Huntington Research Centre. Submitted to WHO by
    Dimethoate Task Force, Milano, Italy.

    Edwards, J.A., et al., 1984. Effect of dimethoate on pregnancy of
    the New Zealand white rabbit. Unpublished report no.: DTF 4/84247 d.d.
    April 19, 1984 from Huntington Research Centre. Submitted to WHO by
    Dimethoate Task Force, Milano, Italy.

    Johnson, E., Caterson, C.R. & Allen, J.S., 1985. Mutagenicity testing
    of dimethoate in the in vitro CHO/HGPRT mutation assay. Unpublished
    report No. 0423 d.d. January 30, 1985 from American Cyanamid Co.,
    Princeton, New Jersey. Submitted to WHO by Dimethoate Task Force,
    Milano, Italy.

    Hellwig, J., 1986a. Report on the study of the toxicity of dimethoate
    in mice after 78-week administration in the diet. Unpublished report
    no.: 75CO326/8242 from BASF, Department of Toxicology, Ludwigshafen/
    Rhein, FRG, Submitted to WHO by Dimethoate Task Force, Milano, Italy.

    Hellwig, J., 1986b. Report on the study of the toxicity of dimethoate
    in rats after 24-month administration in the diet. Unpublished report
    no.: 70CO326/8241 d.d. October 9, 1986 from BASF, Department of
    Toxicology, Ludwigshafen/Rhein, FRG, Submitted to WHO by Dimethoate
    Task Force, Milano, Italy.

    San Sebastian, J.R., 1985. In vivo bone marrow cytogenetics rat
    metaphase analysis. PH 315-AC-00-84, Dimethoate CL 12880. Unpublished
    report d.d. August 29, 1985 from Pharakon Research International,
    Inc., Waverly, PA 18471. Submitted to WHO by Dimethoate Task Force,
    Milano, Italy.

    Sorg, R.M., 1985. Micronucleus Test (MNT). PM 309A-AC-004-84,
    Dimethoate CL 12880. Unpublished report d.d. March 1, 1985 from
    Pharakon Research International, Inc., Waverly, PA 18471. Submitted to
    WHO by Dimethoate Task Force, Milano, Italy.

    


    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: 1984 evaluations)
       Dimethoate (Pesticide residues in food: 1996 evaluations Part II Toxicological)