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    DIMETHOATE

    First draft prepared by
    M. Watson
    Pesticides Safety Directorate,
    Ministry of Agriculture, Fisheries and Food,
    Mallard House, Kings Pool, York, United Kingdom

    Explanation
    Evaluation for acceptable daily intake
       Biochemical aspects
          Absorption, distribution, and excretion
          Biotransformation
          Effects on enzymes and other biochemical parameters
       Toxicological studies
          Acute toxicity
          Short-term toxicity
          Long-term toxicity and carcinogenicity
          Reproductive toxicity
          Developmental toxicity
          Genotoxicity
          Special studies
             Dermal and ocular irritation and dermal sensitization
             Neurotoxicity
             Immunotoxicity
             Effects on the heart
             Studies on metabolites
                Absorption, distribution, and excretion of omethoate
                Biotransformation of omethoate
                Effects of omethoate on enzymes and other biochemical
                  parameters
                Acute toxicity of omethoate
                Short-term toxicity of omethoate
                Long-term toxicity and carcinogenicity of omethoate
                Reproductive toxicity of omethoate
                Developmental toxicity of omethoate
                Genotoxicity of omethoate
                Neurotoxicity of omethoate
       Observations in humans
    Comments
    Toxicological evaluation
    References

    Explanation

         Dimethoate was evaluated for toxicological effects by the Joint
    Meeting in 1963, 1965, 1967, 1984, and 1987 (Annex 1, references 2, 3,
    8, 42, and 50). In 1987, an ADI of 0-0.01 mg/kg bw was established on
    the basis of a NOAEL of 0.2 mg/kg bw per day for inhibition of
    erythrocyte acetylcholinesterase in volunteers. The compound was
    reviewed at the present Meeting within the CCPR periodic review
    programme.

         Omethoate is the oxygen analogue of dimethoate. It was used
    previously as a pesticide in its own right. Information was available
    to the Meeting to indicate that omethoate will no longer be used in
    this fashion; however, since use of dimethoate on agricultural crops
    can lead to residues of omethoate in treated produce, it is important
    to consider the toxicity of omethoate when evaluating potential use of
    dimethoate. Information on the absorption, distribution, excretion,
    metabolism, and toxicity of omethoate was therefore also considered by
    the Meeting and summarized in this monograph. These data were taken
    from published sources, such as previous JMPR evaluations (Annex 1,
    references 17, 25, 31, 33, 37, and 46) and national regulatory
    documents, as the original reports were not available.

         Formothion is an aldehyde derivative of dimethoate, which was
    also previously used as a pesticide in its own right. Information was
    available to the Meeting to indicate that formothion will no longer
    be used in this fashion. Since use of dimethoate does not lead to
    residues of formothion in treated produce, the toxicity of formothion
    was not considered at the Meeting.

         Data on both dimethoate and omethoate are summarized, including
    data not previously reviewed and relevant data from previous
    monographs and monograph addenda on dimethoate (Annex 1, references
    4, 9, 43, and 52). All of the summaries on omethoate are based on
    previous monographs and monograph addenda on this pesticide (Annex 1,
    references 17, 25, 31, 33, 37, and 46).

    Evaluation for acceptable daily intake

    1.  Biochemical aspects

    (a)  Absorption, distribution, and excretion

         The 1963 JMPR (Annex 1, reference 2) concluded that the various
    studies carried out with dimethoate labelled with 32P showed that it
    is rapidly absorbed from the gastrointestinal tract. The radiolabel
    is concentrated in the liver, bile, kidneys, and urine, with no
    accumulation in fat depots. Elimination is rapid in rats and in
    humans, 76-90% of the radiolabel being found in the urine after 24 h.
    In guinea-pigs, 25-40% of the radiolabel is recovered in the faeces
    (Fenwick  et al., 1957; O'Brien, 1959, 1961; Sanderson & Edson,
    1964).

         The absorption, distribution, metabolism, and excretion of
    dimethoate have been investigated with three differently labelled
    forms of dimethoate, shown in Figure 1, where the asterisk represents
    the position of the radiolabel. In each experiment, male and female
    albino rats (strain and number unspecified) received dimethoate at
    30 mg/kg bw by intraperitoneal injection. With 32P-labelled material,
    'hydrolytic products' recovered from the urine during the first 24 h
    after dosing accounted for 55-63% of the administered activity, while
    unchanged dimethoate constituted 4-7%. After administration of (3) in
    Figure 1, 14C-carbon dioxide (15-18% of the administered activity)
    was detected in the expired air over 24 h after dosing, and 39-45% of
    the administered activity was detected in the urine. Thus, about 60%
    of the administered radiolabel was eliminated in the urine and expired
    air during the 24 h after treatment (Hassan  et al., 1969).

         The blood levels of dimethoate were measured in cats and rats 15,
    30, 60, 90, 120, and 180 min after single oral doses of 50, 75, or
    200 mg/kg bw in the cats and 300 mg/kg bw in the rats. Dimethoate was
    detected in the blood of both species after 30 min and reached a
    maximum after 60-90 min. Nearly 80% of the dimethoate in the blood was
    found in the erythrocytes of both species, and only 15-20% was found
    in the serum. With repeated daily oral doses of dimethoate at doses of
    10 or 20 mg/kg bw, the maximal blood level occurred on day 5-10 of the
    study (Panshina & Klisenko, 1962).

    Figure 1. Labelled forms of dimethoate tested

         1.       CH3O S       O
                      \"       "
                      *P-S-CH2-C-NHCH3
                      /
                  CH3O

         2.      *CH3O S       O
                      \"       "
                       P-S-CH2-C-NHCH3
                      /
                 *CH3O                        * position of the radiolabel

         3.       CH3O S       O
                      \"       " *
                       P-S-CH2-C-NHCH3
                      /
                  CH3O

         About 45% of a dose of 32P-dimethoate administered orally at
    50 mg/kg bw to rats was excreted in the urine and only 5.8% in the
    faeces 72 h after treatment. The equivalent values in rats after
    dermal application were 31 and 6.5%, respectively. More than 95%
    of the materials in the urine and faeces after oral or dermal
    administration to rats were hydrolytic products, as determined by
    chloroform:water partition coefficients (Brady & Arthur, 1963).

         About 87-90% of an oral dose of 10 mg/kg bw dimethoate was
    eliminated in the urine of cattle within 24 h. The same percentage of
    an intramuscular dose of 10 mg/kg bw was excreted within 9 h. Only
    3.7-5% of the oral dose was eliminated in the faeces within 72 h and
    about 1.1% of the intramuscular dose within 24 h (Kaplanis  et al.,
    1959).

         In humans, 76-100% of an administered oral dose of radiolabel
    was reported to be excreted in the urine 24 h after dosing with
    32P-dimethoate (Sanderson & Edson, 1964).

         A 40% commercial formulation of dimethoate was administered to 16
    pregnant rats at a dose of 0 or 21.5 mg/kg bw on day 18 of gestation.
    Blood, brain and liver samples were taken from groups of four dams and
    fetuses 1, 6, 12, and 24 h after treatment and were examined for
    cholinesterase activity. The activity was clearly depressed in
    maternal and fetal blood, brain, and liver from 1 h after dosing with
    dimethoate, by up to 50% relative to controls. The effect was still
    evident 24 h after dosing, although somewhat reduced from the peak
    effect seen 6 or 12 h after administration. The inhibition in the

    fetus was generally comparable to that seen in the maternal tissues
    but was sometimes slightly greater. These results clearly indicate
    that dimethoate or active metabolites cross the placenta and have
    significant effects in the fetus (El-Elaimy, 1986).

    (b)  Biotransformation

         The 1963 JMPR (Annex 1, reference 2) reported that four dimethoate
    metabolites with anticholinesterase activity (molar IC50s within 30
    min at 37°C in rat brain: 4.7 × 10-6, 1.1 × 10-5, about 0.2 × 10-5,
    and about 0.1 × 10-5) have been identified in rats and humans. One
    appeared to be a product resulting from thiono-oxidation, leading to
    the formation of the oxygen homologue of dimethoate, followed by
    hydrolysis with production of a thiocarboxyl derivative, which
    constitutes the chief metabolite of dimethoate in mammals. Although
    this thiocarboxyl derivative has not been found in treated plants,
    the oxygen analogue has been found in crops (Santi & de Pietri Sonelli,
    1959).

         The metabolic pathway was similar in rats given 32P-dimethoate
    orally at a dose of 100 mg/kg bw and in lactating cows given
    10-40 mg/kg bw (Dauterman  et al., 1959). Similar results were
    obtained for sheep (Chamberlain  et al., 1961).

         In the paper by Hassan  et al. (1969), reviewed above, urinary
    metabolites were identified by paper chromatography. Experiments were
    also conducted  in vitro in which radiolabelled materials (1) and (2)
    (Figure 1) were incubated with a rat liver homogenate for 5 h. The
    oxygen analogue (omethoate) was proposed as one metabolite, and
    cleavage of the C-N bond to produce the carboxy derivative was said to
    be a major pathway, along with hydrolysis of the S-C bond to produce
    O,O-dimethylphosphorodithioic acid (Figure 2). The oxygen analogue
    omethoate may produce equivalent metabolites, although the results did
    not clearly confirm this hypothesis. Dimethyl- and monomethyl-
    phosphoric acid and thiophosphoric acid may also be produced. Most of
    the non-phosphorus part of the molecule was reported to become
    conjugated with glucuronic acid.

    Figure 2.  Structures of dimethoate carboxylic acid and
                O,O-dimethylphosphorodithioic acid

             CH3O S       O                    CH3O S
                 \"       "                        \"
                  P-S-CH2-C-OH                      P-SH
                 /                                 /
             CH3O                               CH3O

        dimethoate carboxylic acid      O,O-dimethylphosphorodithioic acid

         Dimethylphosphorodithioate, dimethylphosphorothioate, and
    dimethylphosphate were detected in the urine at concentrations of
    12-14, 11-15, and 12-13%, respectively, after intraperitoneal and
    oral administration of dimethoate to rats at doses of 0.25, 2.5, or
    25 mg/kg bw (Riemer  et al., 1985).

         Dimethoate undergoes rapid degradation in rat liver, but little
    occurs in other tissues (lung, muscle, pancreas, brain, spleen,
    blood). The ability of the livers of various species to degrade
    dimethoate decreased in the order: rabbit > sheep > dog > rat >
    cattle > hen > guinea-pig > mouse > pig. For hens, cattle, mice,
    sheep, and rats, there was a reasonably linear relationship between
    the LD50 values and the degradation ability of the liver (Uchida
     et al., 1964).

         The proposed metabolic pathway for dimethoate in rats is shown in
    Figure 3.

    (c)  Effects on enzymes and other biochemical parameters

         Dimethoate inhibits cholinesterase activity. The concentration of
    pure dimethoate required to inhibit cholinesterase activity in rat
    brain  in vitro by 50% is 8.5 × 10-3 mol/litre. Dimethoate decomposes
    to material(s) that are more toxic than the original substance (Casida
    & Sanderson, 1962).

         Dimethoate significantly inhibited the active transport of glucose
    though the isolated intestine of the mouse (Guthrie  et al., 1980).

         In studies of human liver enzymes  in vitro, it was shown that
    dimethoate can inhibit non-specific esterases to a greater degree than
    acetylesterase (Ecobichon & Kalow, 1963).

    2.  Toxicological studies

    (a)  Acute toxicity

         The results of studies of the acute toxicity of dimethoate are
    summarized in Table 1. Clinical signs of toxicity seen 0.5-2 h after
    dosing dosing with dimethoate were generally those characteristic
    of organophosphate intoxication. The signs included muscular
    fibrillation, salivation, lacrimation, urinary incontinence,
    diarrhoea, respiratory distress, prostration, gasping, coma, and
    death. Macroscopic pathological examination revealed no consistent
    target organ.

    FIGURE 3

        Table 1.  Acute toxicity of dimethoate in experimental animals

                                                                                                           

    Species            Sex             Route         Purity       LD50               Reference
                                                      (%)      (mg/kg bw)
                                                                                                           

    Mouse         Female          Oral                 NR        60           Sanderson & Edson (1964)
    Mouse         Male, female    Oral                 NR        160          Ullman et al. (1985)
    Rat           Male, female    Oral                 NR        314          Ministry of Agriculture,
                                                                              Fisheries and Food (1993a)
    Rat           Male, female    Oral               97.6-99     540-600      Dal Re & Vola Gera (1980)
    Rat           Male, female    Dermal             97.6-99     >7000        Dal Re & Vola Gera (1976)
    Rat           Male            Intravenous          NR        450          Sanderson & Edson (1964)
    Rat           Male, female    Intraperitoneal      NR        175-350      Sanderson & Edson (1964)
    Hamster       Male            Oral                 NR        200          Sanderson & Edson (1964)
    Guinea-pig    Male, female    Oral                 NR        350-600      Sanderson & Edson (1964)
    Rabbit        Male, female    Oral                 NR        300-500      Sanderson & Edson (1964)
    Hen           Male, female    Oral                 NR        30-50        Sanderson & Edson (1964)
                                                                                                           

    NR   not reported
        (b)  Short-term toxicity

    Rats

         Three studies in rats were briefly summarized in the report of
    the 1963 JMPR (Annex 1, reference 2). In a 15-week study, groups of 10
    male rats were fed diets containing 1, 5, 25, or 125 ppm dimethoate,
    equivalent to 0.1, 0.5, 2.5 and 12 mg/kg bw per day. At the high
    dietary level, slight muscular fibrillation and depressed weight gain
    were observed. At 5, 25, and 125 ppm, depressed cholinesterase
    activity was observed. In another study, groups of 20 rats were fed
    diets providing 2, 8, or 32 ppm for 90 days or 50, 100, or 200 ppm
    for 35 days. No haematological abnormalities were reported nor any
    significant pathological change. The highest dose that did not inhibit
    cholinesterase activity was reported to be 32 ppm. In a one-year study
    with groups of 20 male rats, the highest dose that did not inhibit
    cholinesterase activity was reported to be 10 ppm (Edson & Noakes,
    1960; West  et al., 1961; Sanderson & Edson, 1964).

         The report of a 13-week study in Wistar rats was available only
    in an incomplete translation and was neither dated nor signed. Groups
    of 24 male and 24 female rats received doses of 0.02, 0.2, 2, or
    20 mg/kg bw per day for 18 weeks; a group of 32 males and 32 females
    acted as controls. Animals were housed eight per cage, and the
    doses were administered orally on five clays a week as aqueous
    solutions, which were prepared weekly and refrigerated until use. The
    formulations were not analysed for content or for stability in the
    vehicle. Body weights were recorded weekly, and food consumption was
    recorded, but at unspecified intervals. Blood samples were obtained
    from eight males and eight females in each treated group and from 16
    controls of each sex on four occasions; a normal range of parameters,
    including cholinesterase activity, was measured. Urine samples were
    obtained in weeks 12 and 18. Brain cholinesterase activity and a renal
    function test (phenol red test) were carried out after 18 weeks.
    Histological investigations were performed on six animals of each
    sex per group, and the list of tissues chosen for weighing was
    satisfactory; however, the list of those chosen for histopathological
    examination was short and did not include epididymides.

         Slightly reduced body-weight gain was seen in animals treated at
    20 mg/kg bw throughout the test, and food consumption was slightly
    lower in males of this group than in the controls during the latter
    half of the study. There were no treatment-related deaths. During
    weeks 6-11, animals in all groups, including the controls, had
    diarrhoea, but this was more pronounced in animals treated at 2 or
    20 mg/kg bw. Minimally lower haematocrit and erythrocyte count were
    noted in animals at the high dose after seven weeks only. There were
    no other toxicologically significant changes in haematological
    parameters. Plasma cholinesterase activity was 45-75% lower in
    animals at 20 mg/kg bw than in the controls. Erythrocyte and brain

    acetylcholinesterase activity was 70-90% of that in controls for
    animals treated at 2 mg/kg bw and 54-77% in animals at 20 mg/kg bw.
    Renal function was unimpaired by treatment, but no data were
    presented. There were no treatment-related effects on the urine and
    there was no faecal occult blood. Necropsy indicated no effects of
    treatment. Organ weight analysis indicated a number of intergroup
    differences, none of which was clearly of toxicological significance;
    however, the absolute and relative weights of the livers of treated
    animals tended to be lower than those of the controls, and this is
    likely to represent a treatment-related change, as similar effects
    have been seen in other studies. There were no microscopic findings
    related to treatment, but no data were presented. It was concluded
    that the toxicity expressed was minimal and that 0.2 mg/kg bw was the
    NOAEL for inhibition of brain and erythrocyte acetylcholinesterase
    activity (Ministry of Agriculture, Fisheries and Food, 1993a).

         Dimethoate was administered orally to rats on five days a week
    for six weeks at a dose of 10 mg/kg bw per day. The investigations
    were confined to an electroencephalogram and cholinesterase
    determinations. Treatment was associated with increased frequency and
    decreased amplitude on the electroencephalogram, and, as expected,
    inhibition of cholinesterase activity in the tissues examined
    (Nagymajtenyi, 1988). The relevance of these data to the safety
    evaluation of dimethoate is equivocal, and they are not considered
    further in this review.

         Ten male albino rats received dimethoate by intraperitoneal
    injection at 150 mg/kg bw in 0.5 ml saline on alternate days for 30
    days; a similar group was treated for 15 days. Ten controls received
    saline only, but the duration of their treatment was not specified. On
    completion of the treatment, the rats were decapitated and blood
    samples were collected for haematological and biochemical examination.
    The results were presented as means and standard errors for five
    animals per observation. Haemoglobin concentration, haematocrit, and
    erythrocyte and leukocyte counts in treated animals were clearly lower
    than in controls, the greatest effect being seen after 30 days. The
    concentrations of serum urea were greater than in the controls at both
    sacrifices; a higher cholesterol concentration was seen only after 30
    days. The serum activities of aspartate and alanine aminotransferases
    and amylase were higher than in the controls on both occasions. There
    was also a small increase in alkaline phosphatase activity; however,
    as the timing of the collection of control blood samples was not
    given, the significance of this minor change cannot be assessed. The
    activity of acid phosphatase was lower than in controls at both blood
    sample collections. Cholinesterase determinations in serum indicated
    inhibition of 30-50% relative to controls. The above effects were all
    more marked after 30 than after 15 days. These results indicate that
    dimethoate may affect liver and kidney function, although the changes
    were not of pathological significance. Organs were not weighed and no

    microscopic examinations were undertaken in order to correlate the
    changes seen. Although the changes in amylase activity might indicate
    pancreatic effects, confirmatory isoenzyme studies were not carried
    out. The route and frequency of administration in this study and the
    exiguous nature of the examinations performed render this work of
    equivocal use in the safety evaluation of dimethoate (Reena  et al.,
    1989).

    Rabbits

         In a five-month study by oral administration in male rabbits, the
    doses used were said to be one-tenth and one-hundredth of the LD50
    value given once a week, but the actual doses were not specified.
    There were no indications of clinical signs, and most of the data were
    presented graphically on the basis of monthly sacrifice of four
    animals out of a total of 20 animals per group. An initial increase in
    cholinesterase activity was noted at the one-month sacrifice, but a
    subsequent 40% reduction was reported. Although changes in organ
    weights were reported, the body weights of the animals were not, and
    the changes were reported only as percentages of absolute weight of
    controls. The significance of the various findings cannot be assessed,
    and the report is not considered further (Shaker, 1988).

         The dermal toxicity of technical-grade dimethoate was investigated
    in groups of six male and six female New Zealand white rabbits which
    received doses of 100, 300, or 1000 mg/kg bw per day for 21 days; two
    control groups, one untreated and one receiving the vehicle (paraffin
    oil), were similarly constituted. The doses were selected on the basis
    of the results of a five-day range-finding study in two groups of one
    male and one female given doses of 1000 or 2000 mg/kg bw per day. In
    the range-finding study, slight erythema was seen in one animal at 
    1000 mg/kg bw per day and in both at 2000 mg/kg bw per day on days 3,
    4, and 5; fissuring of the skin was seen in one animal treated at
    2000 mg/kg bw per day. Application was made to the abraded skin of
    three animals per group or to non-abraded skin on the back of each
    animal on five days per week at a volume of 2 ml/kg bw. The test site
    was occluded for 6 h with a gauze bandage held in place by tape and
    wrapped in occlusive plaster. Observations and food consumption were
    recorded daily, and body weight was measured weekly. Blood samples were
    taken before treatment and at termination after about 16 h of fasting.
    All animals were subjected to a complete necropsy, and a range of
    tissues was retained. Microscopic examination was restricted to the
    controls and animals at the highest dose. 
 
         There were no significant differences between treated and control
    animals or between those with intact or abraded skin. Pustules were
    seen at the treatment sites of the majority of animals, including
    vehicle controls, during the study. Body-weight gain and food
    consumption were unaffected by treatment, and there were no changes in
    the blood, including cholinesterase activity, that could be ascribed

    to treatment. There were no significant treatment-related intergroup
    differences in organ weights or in macroscopic or microscopic
    pathology. The absence of an effect on cholinesterase activity
    indicates that the test material was not absorbed, even across broken
    (abraded) skin, at doses up to 1000 mg/kg bw per day. It was concluded
    that dimethoate does not irritate rabbit skin (Madison  et al., 1986).

    Dogs

         A study in dogs was briefly summarized in the report of the 1963
    JMPR (Annex 1, reference 2), in which groups of two males and two
    females were fed diets providing 2, 10, or 50 ppm, equivalent to 0.05,
    0.25 and 1.25 mg/kg bw per day dimethoate for 90 days. No significant
    effects were noted, and erythrocyte cholinesterase activity was only
    slightly depressed in animals at 50 ppm (West  et al., 1961).

         Groups of six male and six female beagle dogs received diets
    containing dimethoate at concentrations of 0, 5, 20, or 125 ppm
    for one year. The doses were chosen on the basis of the results
    of a preliminary study of 28 days' duration at concentrations
    < 1250 ppm, at which dose-related changes were observed at
    > 50 ppm, necessitating early sacrifice at 1250 ppm, while changes
    at 50 and 250 ppm were confined to dose-dependent reductions in
    cholinesterase activity. In the main study, clinical signs of reaction
    to treatment and food consumption were recorded daily; body weight was
    recorded weekly. The eyes of each animal were examined before
    treatment and during weeks 26 and 52. Blood samples were taken on two
    occasions before treatment and during weeks 13, 26, and 52. Urine
    samples were collected at similar intervals. The samples were examined
    for a normal range of haematological and biochemical characteristics,
    including plasma and erythrocyte cholinesterase activity; brain
    acetylcholinesterase activity was measured at termination. All animals
    were necropsied after bone-marrow samples had been taken. A range of
    organs was weighed and the tissues preserved for histopathological
    processing and examination.

         There were no deaths or clinical signs of reaction to treatment
    and no effect on body weight, food consumption, or the eyes. The
    achieved intakes of test material were calculated to be 0.19, 0.73,
    and 4.25 mg/kg bw per day for animals at 0, 5, 20, or 125 ppm. Plasma
    cholinesterase activity was reduced by > 20% relative to controls in
    animals of each sex at 125 ppm in weeks 13 and 26 and in males only in
    week 52. These reductions did not exceed 22%, except in females at
    week 13 which had an activity 36% lower than controls. Erythrocyte
    acetylcholinesterase activity was reduced in weeks 13 and 26 by 20-27%
    in animals at 20 ppm and by 63-76% in those at 125 ppm. In week
    52, males at 5 or 20 ppm had marginally, nonsignificantly lower
    erythrocyte acetylcholinesterase activities than the controls; females
    in these groups were unaffected. A clear reduction (about 65%) in
    erythrocyte acetylcholinesterase activity was also seen in animals at

    125 ppm. Statistically significant reductions in brain acetylcholin-
    esterase activity were seen at all doses after 52 weeks, which were
    slight at 5 ppm (about 90% of the control level) and 20 ppm (about 83%
    of control) but clear at 125 ppm (45% of control). There were no other
    biochemical differences in the blood attributable to treatment. The
    urine was unaffected, and there were no findings at necropsy that were
    attributable to treatment. The liver weights of animals at 125 ppm
    were lower than those of the controls. There was a marginally greater
    incidence of pigment, presumed to be haemosiderin, in the livers of
    treated animals in all groups, but there was no clear relationship to
    dose. In the absence of other effects of treatment, notably on blood,
    this effect was considered to be of no toxicological significance. The
    only significant evidence of toxicity attributable to dimethoate was
    the reduction in cholinesterase activity; the effect on erythrocyte
    and brain acetylcholinesterase activity was clearly significant at 20
    and 125 ppm, whereas the effects at 5 ppm were confined to minimal
    reductions in brain acetylcholinesterase (10% lower than controls) and
    a minimal reduction in male plasma cholinesterase activity after 51
    weeks. The NOAEL was 5 ppm, equal to 0.19 mg/kg bw per day (Burford
     et al., 1991).

    (c)  Long-term toxicity and carcinogenicity

    Mice

         Technical-grade dimethoate was administered to groups of 50 male
    and 50 female individually housed B6C3F1 mice for 18 months. Dietary
    concentrations of 0, 25, 100, and 200 ppm (equal to 3.2, 12.3 and
    25.3 mg/kg bw per day) were selected on the basis of the results of
    previous studies, including a study from the US National Cancer
    Institute (1977) in this strain. Blood samples were taken for
    investigations of haematology and cholinesterase activity after 51
    weeks of treatment from an additional 10 males and 10 females
    allocated to each group, which were then killed and necropsied.
    Haematological investigations only were conducted after 78 weeks on 10
    animals of each sex per group. The test diets were mixed weekly, and
    formulated diet and the test material were analysed at approximately
    three-month intervals; the results of these analyses were satisfactory.
    All animals were necropsied; appropriate organs only from animals at
    the terminal kill were weighed. A wide range of tissues from all
    animals, including satellite animals that died before 51 weeks, were
    examined microscopically.

         There were no clinical findings that were considered by the
    authors to be related to treatment. Survival was > 90% in all groups,
    and there was no effect of treatment on mortality. There were no
    differences in group mean food consumption that could be related to
    treatment. The body-weight gain of treated males was lower than that
    of controls during the first few weeks of the study; females receiving
    200 ppm were transiently affected during the first two weeks.

    Subsequently, the body weights of treated females in all groups were
    greater than those of the controls; a similar but less marked
    difference was evident in treated males from about 14 months. Female
    animals at 25 ppm gained notably less weight than those at the two
    higher doses but still gained more than the controls. The overall
    weight gains of females were 16.1 ± 5.9 (SD) for the controls,
    20.4 ± 6.4 for those at 25 ppm, 27.9 ± 7.3 for those at 100 ppm, and
    26.0 ± 5.6 for those at 200 ppm. Haematological analyses after 78
    weeks indicated higher nonspecific leukocyte counts in males at 100 or
    200 ppm and in females at 200 ppm; no similar difference was seen in
    samples taken from satellite animals after 51 weeks of treatment. The
    cholinesterase activity in plasma and erythrocytes from treated
    animals was lower than That in the controls in a dose-related manner
    at all dietary concentrations. No other examination of cholinesterase
    activity and no analyses of brain were undertaken. Organ weight
    analysis indicated greater absolute liver weights in animals at 100 or
    200 ppm; however, the relative liver weights of females were lower
    than those of controls as a result of the increased body weights of
    these animals. The absolute weight of the ovaries of treated females
    was lower than that of the controls after 78 weeks of treatment, but
    no similar difference was seen in animals killed after 52 weeks of
    treatment. Microscopic examination indicated a greater incidence of
    extramedullary haematopoiesis in the spleens of males and females at
    100 or 200 ppm, which was dose-related. A greater incidence of
    hepatocytic vacuolation was seen in males and female at 100 or 200 ppm
    and to a lesser extent in females at 25 ppm; the effect was attributed
    to fat and the nutritional status of the affected groups. There were
    no differences in the incidences of any neoplastic finding that could
    be related unequivocally to treatment. There was no NOAEL, as effects
    were seen at all doses (Hellwig, 1986a)

         Fifty male B6C3F1 mice received a dietary concentration of
    250 ppm dimethoate for 69 weeks or 500 ppm for 60 weeks, and 50
    females received the two doses for 80 weeks. All animals were then
    observed without treatment until about 94 weeks. A control group of 10
    males and 10 females was supplemented by similar groups of animals
    from concurrent studies on other pesticides; this gave a pooled
    control group of 50-60 animals, although the studies were not
    precisely concurrent. The body-weight gain of treated mice, except
    females at the low dose, was lower than that of controls during the
    first 52 weeks of treatment. Occasional generalized tremor was noted
    in treated animals at each dose. During the second half of the study,
    alopecia, abdominal distension, and tumours were seen in treated
    animals but predominantly in those receiving the lower dose. The
    condition of animals at termination was said to be poor. Oncogenic
    potential was not assessed (US National Cancer Institute, 1976, 1977).

    Rats

         Groups of 65 male and 65 female individually housed Wistar rats
    received dimethoate in the diet at concentrations providing 0, 5, 25,
    or 100 ppm for two years. Fifteen animals of each sex in each group
    were allocated for clinical pathology; an additional group of 20 males
    and 20 females received a dietary concentration of 1 ppm and were used
    to establish or confirm a no-effect level. The dietary concentrations
    were selected on the basis of the results of a preliminary study and a
    study by the US National Cancer Institute (1977) on Osborne-Mendel
    rats. Feed was prepared weekly; both the test material and the
    formulated diets were analysed regularly and found to be satisfactory.
    Food consumption was recorded weekly; body weight was recorded
    weekly for 13 weeks and at fortnightly intervals thereafter. Daily
    observations and weekly palpations were recorded; the eyes of all
    animals of the main groups (50 of each sex) were examined before
    treatment and at six-month intervals during the treatment period for
    changes to the refracting media. The ocular fundus of 10 males and 10
    females in the control and high-dose groups were examined after 620
    days of treatment. Blood samples were obtained before treatment and on
    six occasions during the study, and a normal range of chemical and
    haematological parameters, including cholinesterase activity, was
    measured. Brain acetylcholinesterase activity was measured at the end
    of the study. Urine samples were collected twice during the study;
    although basic, qualitative 'stick' tests were conducted, volume and
    specific gravity were not measured. All animals were necropsied, and a
    range of organs was weighed and the tissues retained. Tissues from all
    animals in the main study and from satellite animals that died were
    examined microscopically.

         Females at 100 ppm had a slightly higher mortality rate than
    controls from week 65. There were no clinical signs that were
    considered by the authors to be related to treatment. Animals at doses
    > 25 ppm showed a trend to increased food consumption, especially
    during the second year of treatment. The body-weight gain of animals
    receiving 100 ppm was slightly lower than that of the controls
    during the first half of the study. Examination of the eyes  in vivo
    revealed no treatment-related effect. Reductions in plasma
    cholinesterase activity (generally, 50% of control) were seen in the
    group at 100 ppm at all examinations; in females at 25 ppm, the
    activities in plasma were minimally lower than in the controls after
    four weeks. Reductions in erythrocyte acetylcholinesterase activity
    were clear in animals at 25 or 100 ppm (60-75 and 20-40% of control
    values, respectively); smaller decreases were seen in females at 5 ppm
    during the first 12 months and in males of this group after 24 months.
    Clear dose-related reductions in brain acetylcholinesterase activity
    were seen at termination in animals at 25 or 100 ppm and slightly
    lower values in males at 5 ppm. In animals at this low dose, the
    reductions in erythrocyte and brain acetylcholinesterase activity were
    not consistent between times or sexes; the variations from control

    values are thus of questionable biological significance but probably
    represent an intermittent effect of treatment. There were no
    statistically significant differences in cholinesterase activity in
    the animals at 1 ppm.

         The authors reported minimal anaemia throughout the study in
    males at 100 ppm; however, this effect was also present before
    treatment and was absent in females. Minor variations were also noted
    in leukocyte count, potassium and total protein concentrations, and
    aspartate aminotransferase activity. Although these effects were
    reported to extend in part to the animals at 25 ppm, they were minor;
    they may be related to treatment but are considered not to be of clear
    toxicological significance. There were no treatment-related changes in
    the urine. Animals at 100 ppm had slightly larger spleens and slightly
    smaller ovaries than the controls, but no gross pathological findings
    could be related to treatment. There were no non-neoplastic findings
    that were considered to be related to treatment, and there was no
    statistically significant difference in the distribution of individual
    tumour types. Treated males had a greater number of malignant tumours
    than the controls, but there was no relationship to dose. In a number
    of tissues, however, a greater incidence of tumours was seen in
    treated animals than in controls. These included exocrine and
    islet-cell adenomas in the pancreas of males, haemangiosarcoma in
    the spleen of males, and mammary gland fibroadenoma and carcinoma
    in females. When the combined incidences of haemangioma and
    haemangiosarcoma at any site in treated animals were compared with
    those in controls, the difference was statistically significant for
    all groups of treated males, but there was no relationship to dose and
    females were clearly unaffected. The apparent difference may be due to
    a lower than expected incidence in the controls. A large proportion of
    these tumours were located in the mesenteric lymph node. The incidence
    of these vascular tumours was said to be similar to that of historical
    controls from a number of sources. The authors concluded that there
    was no evidence that dimethoate has oncogenic potential. The NOAEL for
    inhibition of brain and erythrocyte acetylcholinesterase activity was
    1 ppm, equivalent to 0.05 mg/kg bw per day (Hellwig, 1986b).

         The vascular and proliferative lesions from the above study were
    evaluated by a second group of pathologists (Squire, 1988), who were
    unaware of the previous interpretation of each slide. This review
    supported the conclusion of the original pathologist and indicated
    that the Wistar rat is susceptible to these tumours. It also suggested
    that the chemicals that induce vascular neoplasms are genotoxic;
    however, it asserted that dimethoate is not genotoxic and that by
    implication these tumours were not related to treatment.

         Groups of 50 male and 50 female Wistar rats received technical-
    grade dimethoate in the diet at concentrations of 0, 2, 20, or 200 ppm
    for two years, equivalent to 0.1, 1 and 10 mg/kg bw per day. The report
    was available only as an English translation of a nearly illegible 

    German summary with tables of individual data. As no other details of
    procedures or results and no group means were presented, the study
    could not be reviewed satisfactorily (Ministry of Agriculture,
    Fisheries and Food, 1993a).

         Groups of 30 male and 30 female Wistar rats received diets
    designed to provide technical-grade dimethoate at concentrations of 0,
    0.1, 1, 10, or 75 ppm for two years, equivalent to 0.005, 0.05, 0.5
    and 3.8 mg/kg bw per day. The feed was prepared four times a week.
    Body weight and food intake were recorded weekly for the first four
    weeks and every four weeks thereafter. Haematological examinations
    were performed four times between weeks 32 and 100. Cholinesterase
    activity was determined after 1, 3, 12, 50, 75, and 100 weeks on six
    rats of each sex. Brain acetylcholinesterase activity was determined
    after 52 and 104 weeks. Other, limited biochemical assays were
    performed during the study on blood and urine, mostly after two years.
    Six animals of each sex were killed after one year and the surviving
    animals after two years; all were examined macroscopically and their
    organs weighed. Histological examination was performed on six males
    and six females at each sacrifice. There was no indication of how dead
    animals were handled or examined, although the report refers to their
    necropsy.

         Early signs of reaction to treatment at 75 ppm (slight
    piloerection, exophthalmia, and fine tremor) disappeared during the
    fourth week of treatment, and no other clinical signs were attributed
    to treatment. A high mortality rate resulted from an infection after
    78 weeks, with the deaths of 55 males and 37 females, evenly
    distributed among the groups. The infection was treated with
    oxytetracycline as three oral doses of 40 mg/kg bw over three weeks.
    There was no treatment-related mortality. Body-weight gain was reduced
    in animals treated at 75 ppm, up to week 20 for females and throughout
    the study for males. Food consumption was unaffected, but conversion
    was reduced in animals treated at 75 ppm, in line with body weight.
    The achieved mean doses were 0.02, 0.2, 2, and about 20 mg/kg bw per
    day. Haematological investigations indicated no effects of treatment.
    Cholinesterase activity was clearly reduced in the plasma,
    erythrocytes, and brain of animals receiving 10 or 75 ppm. The brain
    acetylcholinesterase activity of animals receiving 1 ppm was 20% lower
    than that of controls after one year. There were no other
    toxicologically significant intergroup differences in the composition
    of the plasma or urine. Organ weight analysis after one year indicated
    lower liver, spleen, adrenal, and testis weights in males at 75 ppm
    than in the controls; after two years, the adrenal and liver weights
    of males and females at 75 ppm were lower than those of controls.
    Necropsy of animals that died during the study and of animals killed
    at the scheduled sacrifices indicated no treatment-related changes.
    The distribution of macroscopically observed rumours was unaffected by

    treatment. No microscopic changes were found that were attributed to
    treatment. The incomplete data presentation and the infection that
    occurred in the middle of the study significantly compromise its
    validity (Ministry of Agriculture, Fisheries and Food, 1993a).

         Groups of 50 male Osborne-Mendel rats were fed diets providing
    technical-grade dimethoate at concentrations of 250 or 500 ppm
    (equivalent to 25 and 50 mg/kg bw per day) for 19 weeks; the doses
    were then reduced to 125 and 250 ppm (equivalent to 6.3 and 13 mg/kg
    bw per day),and treatment continued for 61 weeks. Necropsy was
    performed after a further 33-35 weeks without treatment. The same
    dietary concentrations were fed to similar groups of females, except
    that they were reduced only after 43 weeks; the animals were then
    treated at concentrations of 125 or 250 ppm for a further 37 weeks.
    The total treatment period for all animals was 80 weeks, followed by
    up to 35 weeks without treatment. A control group of 10 males and 10
    females was supplemented by similar groups of animals from concurrent
    studies on other pesticides, giving a pooled control group of 50-60
    animals, although the studies were not precisely concurrent. All
    animals were observed daily, and body weights were recorded 'at
    regular intervals until 110 weeks'. The animals were then necropsied
    and, when feasible, tissues were retained for histopathological
    examination. Treatment at 500 ppm was associated with lower
    body-weight gains in males and females during the first 20 weeks of
    treatment. After the reduction to 250 ppm at 19 weeks, the body-weight
    gain of males increased but remained lower than in controls until
    treatment ceased. The body-weight gain of males at the low dose and
    females at the high dose remained lower than that of controls until
    week 80. Clinical signs of inhibition of cholinesterase activity were
    seen in animals at the high dose, particularly during the first week
    of treatment. Conjunctivitis of vital origin was diagnosed in the
    animals at week 38. Animals that survived to termination were said to
    be 'generally in poor physical condition'. More animals at the high
    dose died than matched or pooled controls, although the number of
    matched control males that died during the study (7 of 10) was
    reported to be unusually large. There was no difference in the
    distribution of non-neoplastic or neoplastic changes among the treated
    groups that could clearly be ascribed to treatment. The pathological
    assessment indicated no oncogenic potential (US National Cancer
    Institute, 1976, 1977).

         A review by Reuver (1984) covered several carcinogenicity studies
    in rats and mice, including that of the US National Cancer Institute.
    It was concluded from the studies of Gibel  et al. (1973) and
    Stieglitz  et al. (1974) that dimethoate is highly carcinogenic to
    rats, but insufficient details of these experiments were given,
    precluding assessment. The review of the US National Cancer Institute
    study involved re-reading of the sections; it was again concluded
    that dimethoate is carcinogenic. The basis for the review was not
    described, and the numbers of animals given in the tables shown in the

    review differ from those in the original report. Reuber quoted text
    from the report in reverse order to that in which it was originally
    published. This review did not satisfactorily explain the methods used
    or discuss the discrepancies in the reported incidences and in the
    conclusions from those of the original report. In view of these
    deficiencies, no weight is placed on this publication.

    (d)  Reproductive toxicity

    Mice

         A multigeneration study was undertaken in CF-1 mice fed diets
    containing concentrations of 0, 5, 15, or 50 ppm dimethoate,
    equivalent to 1.4, 4.3 and 14.5 mg/kg bw per day, throughout the
    study. The study was conducted before Good Laboratory Practice came to
    be enforced but was designed according to the recommendations of the
    Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics of
    the Association of Food and Drug Officials of the United States. Each
    generation was mated twice, the first set of litters being discarded
    and the next generation (F1b, F2b, and F3b) being produced from the
    second litters. For each generation, eight males were mated with 16
    females in each group, and males were rotated within their group
    during the mating period. The observations were limited in comparison
    with current practice. After weaning of the F3b generation, the
    parents (F2b) were killed and necropsied; liver, kidneys, and gonads
    were weighed, but no microscopy was performed. All animals of the F3b
    generation were necropsied at death or at weaning, and a wide range of
    tissues from one male and one female from each litter was examined
    microscopically. Organ weighing was restricted. All fetuses that were
    not examined microscopically were retained in 80% alcohol for skeletal
    staining in alizarin red.

         There were no clinical reactions to treatment. Tremors were seen
    in four dams of the F2b generation treated with 50 ppm, three of
    which lost their litters, on one occasion after a weekly change of
    diets; the diets were replaced, as a formulation error was suspected,
    and the condition was not seen again. No treatment-related differences
    in group mean body weights were recorded at any mating. Measurement of
    the food consumption of the F0 generation before mating indicated
    no effect of treatment, but no data were presented and no other
    measurements were carried out. The fertility, gestation, viability,
    and lactation indices were unaffected by treatment, and there was
    no effect on the weights of the pups at weaning. No intergroup
    differences in organ weight or pathological findings were seen that
    were related to treatment. The NOAEL for reproductive toxicity was
    50 ppm (Ribelin  et al., 1965).

         In five generations of CD-1 mice given 60 ppm of dimethoate in
    drinking-water, reproductive performance was significantly altered, as
    indicated by reduced mating success and longer gestation. Litter size
    and weight were not reduced at birth, but pup mortality was increased
    significantly by treatment. The growth rate of the pups was generally
    lower than that of controls. Dimethoate did not show teratogenic
    potential or adverse effects on organ weights or histological
    appearance (Budreau & Singh, 1973).

    Rats

         In a multigeneration study, dimethoate (purity, 96.4%) was
    administered in the diet at fixed concentrations of 0, 1, 15, or
    65 ppm (equal to about 0.08, 1.25 and 5 mg/kg bw per day) to groups of
    28 male and 28 female Sprague-Dawley rats for 10 weeks before the
    first of two matings to produce F1a and F1b animals. The F1
    generation, selected from the F1a litters, was first mated at about
    16 weeks of age to produce F2 pups, which were killed and examined at
    21 days of age. A second mating of the F1a generation was conducted,
    followed by a partial third mating involving animals that had not been
    successful at either of their first two pairings. Administration of
    dimethoate was continued at the same dietary levels throughout
    premating, mating, gestation, and lactation. Treatment at 65 ppm was
    associated in the parent animals with marked reductions in plasma,
    erythrocyte, and brain cholinesterase activities in animals of both
    generations, slightly reduced body-weight gain, increased food intake,
    and reduced water intake. In the F1a pups at 65 ppm at four days of
    age, a reduction in brain acetylcholinesterase activity was seen in
    males but not in females. The parental animals at 15 ppm had a
    significant reduction in brain and erythrocyte acetylcholinesterase
    activity in both generations, but no effect on cholinesterase activity
    was seen in the offspring. Mating performance (as assessed by median
    precoital time and duration of pregnancy) was not affected by
    treatment; however, an effect was seen on the pregnancy rate (Table
    2). These data are clearly indicative of substandard performance at
    65 ppm and also show a possible effect at 15 ppm on the second mating
    of the F1 generation. The Meeting concluded that this information did
    not clarify the possible effect at the intermediate dose. Treatment at
    65 ppm was also associated with a reduction in litter size at birth,
    as shown in Table 3.

    Table 2.  Pregnancy rates of animals treated with dimethoate with
              live pups at birth

                                                                      

    Generation     Mating                 Pregnancy rate (%)
                                                                      

                              Control    1 ppm     15 ppm     65 ppm
                                                                      

    F0            First         93        96         86         89
                  Second        89        93         89         71

                               (100)     (100)      (100)      (96)
    F1            First         96        71         71         63
                  Second        73        67         58         50
                               (100)     (79)       (92)       (75)
                                                                      

    In parentheses, the percentages of animals with implantations
    confirmed at autopsy by Salewski staining of the uteri of
    apparently non-pregnant females

    Table 3.  Litter size at birth of animals treated with dimethoate

                                                                      

    Generation    Mating         Group mean litter size at birth
                                                                      

                            Control    1 ppm     15 ppm     65 ppm
                                                                      

    F0            First      16.4      15.3*     15.3*      14.2**
                  Second     14.9      14.9      14.2       14.3
    F1            First      12.3      11.9      14.6       12.0
                  Second     14.1      13.3      13.1       10.0*
                                                                      

    *    p < 0.05
    **   p < 0.01

         There was also a slight increase in pup mortality during
    lactation in animals at 65 ppm. Changes in litter weight reflected the
    changes in litter size. The mean pup weight at birth was unaffected by
    treatment, but pup body-weight gain was adversely affected by the high
    dietary level. There was a slight delay in attainment of the startle
    reflex in pups born after the first mating of both generations at
    65 ppm, but the mean delay was less than one day and was not apparent
    across all four matings; it was thus probably not related to

    treatment. There was no other effect on pre- or post-weaning
    development. Histopathological examination of tissues associated with
    the reproductive tract did not reveal any treatment-related changes.
    The NOAEL for toxicity was 1 ppm, equivalent to 0.08 mg/kg bw per day,
    on the basis of inhibition of cholinesterase activity at 15 ppm
    (Brooker  et al., 1992). The Meeting discounted the possible adverse
    effect on pregnancy rate at 15 ppm, and this was the NOAEL for
    reproductive performance, equivalent to 1.2 mg/kg bw per day.

    Rabbits

         Three groups of three male rabbits received gelatin capsules
    containing individually calculated doses of a dimethoate formulation
    (composition unspecified) calculated to be one-tenth and one-hundredth
    of the LD50, which was not specified, at an unspecified frequency. A
    six-week preliminary period was followed by six weeks of treatment and
    then by six weeks of respite. Body weights were recorded weekly, and
    semen was collected twice weekly from all animals throughout the
    experimental period. Ejaculate volume was recorded after removal of
    the gel mass. Seminal initial fructose was determined immediately
    after collection, and methylene blue reduction time was recorded. The
    numbers of live, dead, and abnormal sperm were assessed, and sperm
    concentration was determined with a haemocytometer. Data were
    presented in graphs rather than as individual values; there was no
    indication of variation between individual animals. Clinical signs
    were not reported. Body-weight gain was reduced in treated animals,
    and there were indications of reduced libido. The ejaculate volume and
    sperm concentration of treated animals, expressed as a percentage of
    that of controls, decreased during the treatment period, and the
    effect on sperm concentration persisted into the recovery period.
    Treatment increased the numbers of abnormal sperm in a dose-related
    manner; these were greatest at the end of the treatment period but
    declined thereafter. A significant increase in the methylene blue
    reduction time and a decrease in the initial fructose concentration
    were also seen. There was some evidence of recovery from these effects
    during the latter part of the recovery period (Salem  et al., 1988).
    In view of the deficiencies, it was difficult to assess the
    significance of the changes seen, but they should be explained in view
    of the reported reproductive effects of dimethoate.

    (e)  Developmental toxicity

    Mice

         Intraperitoneal administration of dimethoate at 40 mg/kg bw as a
    single dose to mice on the day of mating or on day 9 of gestation or
    for the first 14 days of gestation caused a high incidence of
    embryonal loss (Scheufler, 1975).

         Dimethoate administered orally at doses of 10 or 20 mg/kg bw was
    not teratogenic to CD-1 mice, and these levels were not lethal to the
    dams. Doses of 40 and 80 mg/kg bw induced maternal toxicity (Courtney
     et al., 1985).

    Rats

         Groups of pregnant rats were given 0, 3, 6, 12, or 24 mg/kg bw of
    a dimethoate formulation by gavage daily on days 6-15 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 fetuses were weighed
    and examined for viability and external malformations; live fetuses
    were studied for skeletal and visceral anomalies. Maternal weight was
    decreased significantly in the group receiving 24 mg/kg bw, and clonic
    spasms and muscular tremors were seen. The mean fetal weight was not
    affected by treatment. Treatment with 12 or 24 mg/kg bw was associated
    with an increased number of litters with abnormal fetuses and fetuses
    with wavy ribs. The NOAEL was 6 mg/kg bw of formulated product, equal
    to 2.84 mg/kg bw dimethoate (Khera  et al., 1979).

         Three groups of 25 time-mated CrL:COBS CD (SD) BR rats received
    technical-grade dimethoate (purity, 97.3%) in 1% aqueous methyl
    cellulose (10 ml/kg) at doses of 3, 6, or 18 mg/kg bw per day by
    gavage daily on days 6-15 of gestation; a control group received the
    vehicle alone. Clinical observations were made at regular intervals,
    and food consumption and body weight were recorded. All animals were
    killed on day 20 of gestation and the uterine contents examined for a
    normal range of parameters. One-half of the pups were preserved in
    Bouin's solution for free-hand sectioning and the remainder in
    industrial methylated spirits for subsequent alizarin staining and
    skeletal examination. The doses were chosen on the basis of the
    results of a preliminary study, which was not presented or discussed.
    The signs seen in animals at 18 mg/kg bw per day included salivation,
    hypersensitivity, ataxia, tremor, fur staining, and small, rounded
    faecal pellets. The signs at 3 mg/kg bw per day were confined to
    salivation; in animals at 6 mg/kg bw per day, this was accompanied by
    a low incidence of small, rounded faecal pellets. Food consumption and
    body-weight gain were lower in animals at 18 mg/ kg bw per day than in
    the controls during treatment; similar effects were not seen at the
    two lower doses. Neither litter parameters nor fetal development (as
    indicated by the incidences of visceral or skeletal abnormalities) was
    affected by treatment. The NOAEL for toxic signs depends on the
    interpretation of the significance of the salivation seen in the
    animals at 3 and 6 mg/kg bw per day and on the abnormal faecal pellets
    in the latter group. Although salivation is an expected effect of
    organophosphate pesticides, there was no clear evidence that the
    effect was unduly prolonged (It was described as occurring
    'immediately' after treatment.) and may have been incidental. The

    presence of abnormal faecal pellets may be related to the action of
    this class of compound on the gastrointestinal tract and is unlikely
    to be of toxicological significance (Edwards  et al., 1984a).The
    Meeting concluded that the NOAEL was 6 mg/kg bw per day.

    Rabbits

         Groups of 16 female New Zealand white rabbits (obtained from
    several breeders) were mated with males of proven fertility and
    received technical-grade dimethoate (purity, 97.3%) in 1% aqueous
    methylcellulose (5 ml/kg) at doses of 10, 20, or 40 mg/kg bw per day
    by gavage daily on days 7-19 of gestation; a control group received
    the vehicle alone. The doses were chosen from a preliminary study, the
    results of which were not summarized. After coitus, each animal
    received an injection of luteinizing hormone. Clinical observations
    were made at regular intervals, and food consumption and body weight
    were recorded. All animals were killed on day 29 of gestation, and the
    uterine contents were inspected; a range of parameters for this type
    of study was assessed. After examination  in vivo, the pups were
    killed and dissected. The skinned, eviscerated pups were fixed in
    industrial methylated spirits, and the brain was examined for
    abnormalities by longitudinal sectioning; carcasses were cleared and
    stained by a modified Dawson's technique for skeletal examination.
    There were no clinical signs of reaction to treatment with doses of 10
    or 20 mg/kg bw per day; at 40 mg/kg bw per day, muscle tremors and
    ataxia were seen during the latter part of the treatment period. Food
    consumption was reduced between days 15 and 23 of gestation in animals
    treated at 40 mg/kg bw per day, and the body-weight gain of these
    rabbits was lower than that of controls throughout the treatment and
    particularly between days 15 and 20 of gestation. A slight reduction
    in body-weight gain was seen in animals at 20 mg/kg bw per day. An
    initial reduction in weight gain was seen at the beginning of the
    treatment period in animals at the low dose, but these animals
    subsequently gained more weight than the controls. Treatment had no
    effect on fetal development; litter size and weight were unaffected,
    and pups had no abnormalities that could be ascribed to treatment.
    Although there was a transient reduction in body-weight gain at the
    start of treatment in animals at 10 mg/kg bw per day, the deficit was
    quickly corrected. This dose was therefore the NOAEL (Edwards  et al.,
    1984b).

    Cats

         Four groups of 17 cats were mated and treated with Cygon-4E, a
    commercial insecticide containing 47.3% dimethoate, as single daily
    doses of 0, 3, 6, or 12 mg/kg bw on days 14-22 of gestation. The cats
    were necropsied on day 43 of gestation, and the fetuses were removed,
    weighed, and examined for external malformations. The total number of
    anomalous fetuses in cats at 12 mg/kg bw per day was not significantly
    higher than that in controls. The only treatment-related malformation

    was observed at this dose and consisted of forepaw polydactyly in
    eight of 39 fetuses. A dose-response relationship was not established
    owing to the limited response and the common occurrence of this
    anomaly in cats. The NOAEL was 6 mg/kg bw per day of Cygon-4E, equal
    to 2.8 mg/kg bw per day of dimethoate (Khera, 1979).

    (f)  Genotoxicity

         The regulatory reports evaluated by the Meeting concluded that
    dimethoate does not induce reverse mutation or gene mutation  in
     vitro, nor did it induce micronucleus formation, dominant lethal
    mutation, or chromosomal aberration in mice  in vivo. Dimethoate
    induced unscheduled DNA synthesis  in vitro in two assays using
    different methods of assessing the uptake of tritiated thymidine into
    DNA but not in an assay  in vivo/in vitro. A review of the literature
    on the mutagenic potential of dimethoate revealed a number of positive
    results, notably for reverse mutation in  Salmonella typhimurium
    TA100 and for sister chromatid exchange in mammalian cells  in vitro.
    It was concluded that although dimethoate has mutagenic potential  in
     vitro, mutagenicity does not appear to be expressed  in vivo. The
    results of assays for genotoxicity with dimethoate are summarized in
    Table 4.

    (g)  Special studies

    (i)  Dermal and ocular irritation and dermal sensitization

         The dermal irritation potential of a 400-g/litre emulsifiable
    concentrate formulation of dimethoate was investigated in rabbits.
    Only slight erythema was observed 4 h after application, and the
    effect had resolved by 24 h after treatment (Ministry of Agriculture,
    Fisheries and Food, 1993a).

         The ocular irritation potential of the same formulation of
    dimethoate was also investigated in rabbits. Redness and swelling of
    the conjunctiva were observed, with slight corneal opacity, 1-72 h
    after application. All of the effects had resolved by eight days after
    treatment (Ministry of Agriculture, Fisheries and Food, 1993a).

         Studies to investigate the ocular irritation potential in
    rabbits of 40 and 38.3% dimethoate formulations concluded that the
    formulations were irritating to the rabbit eye. The 'in use' dilution
    of the 40% formulation (0.84%) was not irritating (Ministry of
    Agriculture, Fisheries and Food, 1993a).

         Technical-grade dimethoate (purity, 97.3%) did not sensitize the
    skin of guinea-pigs when tested by the Buehler method (Madison  et al.,
    1984).

        Table 4.  Results of tests for the genotoxicity of dimethoate

                                                                                                                                      

    End-point                     Test system           Concentration             Purity    Results           Reference
                                                                                    (%)
                                                                                                                                      

    In vitro

    5-Methyltryptophan            E. coli               1.6 × 10-3 mol/litre        NR      Positivea         Mohn (1973)
    resistance mutation
    Reverse mutation              S. typhimurium        < 5000 mg/plate             NR      Positive          Moriya et al. (1983)
                                  TA98, TA100,                                              in TA100a
                                  TA1535, TA1537,
                                  TA1538
                                  E. coli WP2hcr        < 5000 mg/plate                     Positivea
    Reverse mutation              S. typhimurium        < 5000 mg/plate             NR      Negativea         Probst et al. (1981)
                                  TA98, TA100,
                                  TA1535, TA1537,
                                  TA1538
                                  E. coli WP2uvrA-      47 nmol/ml                          Initially
                                                                                            positive,
                                                                                            negative
                                                                                            quantitativelya
    Reverse mutation              S. typhimurium        2-200 mg/plate              NR      Positivea         Vishwanath & Jamil
                                  TA100                                                                       (1986)
    Mitotic gene conversion       S. cerevisiae         7 doses, 40-100 mmol        NR      Positive          Fahrig (1974)
    Mitotic gene conversion       S. pombe (ade 6)      1.3-131 mmol                NR      Negative          Gilot-Delhalle et al.
                                                                                                              (1983)
    Gene mutation                 Chinese hamster       1000-3500 mg/ml            97.3     Negative          Johnson et al. (1985)
                                  ovary (hprt)
    Sister chromatid exchange     Cultured human        < 120 ppm                   NR      Positive          Gomez-Arroyo et al.
                                  lymphocytes                                                                 (1987)
    Sister chromatid exchange     Chinese hamster       10, 20, 40, 80 mg/ml        94      Positive          Chen et al. (1981)
    and cell cycle delay          ovary V79 cells       + 10 pg/ml BUdR
                                                                                                                                      

    Table 4.  (Cont'd)

                                                                                                                                      

    End-point                     Test system           Concentration             Purity    Results           Reference
                                                                                    (%)
                                                                                                                                      

    Cytotoxicity                  Chang liver and       50-500 mg/ml               99.8     Positive          Gabliks &
                                  HeLa cells                                                                  Friedman (1965)
    Cytotoxicity                  HeLa cells            2-300 mg/ml                99.8     Positive          Gabliks (1965a)
    Susceptibility to             HeLa cells            2-300 mg/ml for            99.8     Positive          Gabliks (1965b)
    poliovirus infection                                < 108 days
    Unscheduled DNA               SV-40 transformed     100, 1000 mmol              NR      Positive          Ahmed et al. (1977)
    synthesis                     human fibroblast
                                  cell line VA-4
    Unscheduled DNA               Rat hepatocytes       47 nmol/ml                  NR      Negative          Probst et al. (1981)
    synthesis
    Unscheduled DNA               Rat hepatocytes       < 2290 mg/ml                NR      Positive          Ministry of Agriculture,
    synthesis                                                                                                 Fisheries and Food
                                                                                                              (1993a)
    Unscheduled DNA               Rat hepatocytes       NR                          NR      Positive          Ministry of Agriculture,
    synthesis                                                                                                 Fisheries and Food
                                                                                                              (1993a)

    In vivo

    Micronucleus formation        Mouse                 2 equal oral doses          NR      Positive          Rani et al. (1980)
                                  bone marrow           of 51.7 mg/kg bw at
                                                        24-h interval
    Host-mediated                 Mouse;                3 equal oral doses          NR      Positive          Rani et al. (1980)
    mutagenicity                  S. typhimurium        of 155 mg/kg bw
    Dominant lethal               CFLP mice             30, 60 mg/kg bw ip          NR      Negative          Fisher & Scheufler
    mutation                      AB Jena mice          5 × 6 mg/kg bw ip                   Negative          (1981)
                                  DBA mice              3 × 18 mg/kg bw ip                  Negative
    Dominant lethal               NMRI mice             5, 10, 20 mg/kg            96.9     Negative          Becker (1985)
    mutation                                            orally, 5 days
                                                                                                                                      

    Table 4.  (Cont'd)

                                                                                                                                      

    End-point                     Test system           Concentration             Purity    Results           Reference
                                                                                    (%)
                                                                                                                                      

    Dominant lethal               Strain Q mice         10 mg/kg ip + 0.6           NR      Negative          Degraeve & Moutschen
    mutation                                            mg/l drinking-water                                   (1983)
    Chromosomal                   CFLP mice             20-60 mg/kg bw ip           NR      Positive (gaps    Nehéz (1983)
    aberration                                                                              and numerical
                                                                                            changes)
    Chromosomal aberration        Rats                  15, 75, 150 mg/kg bw ip     NR      Negative          Ministry of Agriculture,
                                                                                                              Fisheries and Food
                                                                                                              (1993a)
    Chromosomal aberration        Mice                  50, 100 mg/kg bw            NR      Positive          Bhunya & Behera
                                                                                                              (1975)
    Chromosomal aberration        Hamster               16-160 mg/kg bw ip          NR      Weakly            Dzwonkowska & Hubner
                                                                                            positive          (1986)
    Sex-linked recessive          Drosophila            1 mg/kg feeding             NR      Negative          Woodruff et al. (1983)
    lethal mutation
    Sex-linked recessive          Drosophila            10 or 20 ppm; adult         NR      Positive at       Velásquez et al. (1986)
    lethal mutation                                     feeding                             low dose
                                                        0 or 10 ppm larval                  Negative
                                                        feeding
    Sex-linked recessive          Drosophila            LD50 and half LD50,         NR      Positive          Tripathy (1988)
    lethal mutation                                     larval feeding
    Unscheduled DNA               Rats                  50, 100, 200 mg/kg          NR      Negative          Ministry of Agriculture,
    synthesis                                           bw orally                                             Fisheries and Food
                                                                                                              (1993a)
    Micronucleus formation        CD-1 mice             55 mg/kg bw ip once        97.3     Negative          Sorg (1985)
                                                        or twice 24 h apart
    Metaphase alteration          Rats                  15, 75, 150 mg/kg          97.3     Negative          San Sebastian (1985)
                                                        bw ip
                                                                                                                                      

    ip   intraperitoneally
    a    With and without metabolic activation
             Nineteen cases of allergic, occupational contact eczema and one
    of contact dermatitis have been reported (von Jung, 1989). Exposure
    to dimethoate was cited in four cases: in two male and one female
    gardener and in one female agrochemical technician, 22-69 years of
    age. The results of patch tests with dimethoate in these individuals
    were positive.

    (ii)  Neurotoxicity

         In a preliminary study, the LD50 of dimethoate in hens was
    determined in groups of 10 birds given single oral doses of 0, 30, 45,
    68, 100, or 150 mg/kg bw in water. These doses were selected on the
    basis of the results of a preliminary study in groups of two birds at
    doses between 12.5 and 200 mg/kg bw; both birds at 100 or 200 mg/kg bw
    died. In each of these studies, dosing was followed by a 14-day
    observation period. Body weights were recorded weekly. Surviving birds
    were killed but not necropsied. Neurotoxicity was assessed after a
    single subcutaneous dose of 55 mg/kg bw to 16 birds or 55 mg/kg bw
    orally to 30 birds; a control group of 14 birds was dosed orally, and
    a positive control group of six birds received 500 mg/kg bw of
    tri- ortho-cresyl phosphate (TOCP) as a single oral dose in corn oil.
    All birds were starved overnight before treatment. In an experiment
    conducted before the main study to evaluate the protective
    effectiveness of atropine, it was shown to have no protective value at
    twice the LD50 value. Birds dosed subcutaneously with dimethoate were
    included for comparative biochemical assays. Three birds in the
    treated and negative control groups were used to determine
    cholinesterase and neuropathy target esterase activity 4 and 48 h
    after dosing; these assays were performed for three TOCP-dosed birds
    only 48 h after dosing. Analyses of the formulation used indicated
    satisfactory content and stability over 24 h. Dosing was followed by
    an observation period of 21 days. Birds were assessed daily for ataxia
    by observing their ability to walk and to jump onto and off an
    obstacle. Body weights were recorded weekly. Nervous tissue from three
    TOCP-dosed birds, six negative controls, and six birds dosed orally
    with dimethoate was examined histologically.

         In the study to determine the LD50, toxicity was seen in a
    dose-related manner. Deaths occurred at doses > 45 mg/kg bw, and
    all birds at doses > 100 mg/kg died. Deaths occurred up to three
    days after dosing, and the surviving birds were normal by day 5. The
    LD50 for dimethoate was calculated to be 55 mg/kg bw, with a 95%
    confidence interval of 45-67 mg/kg bw. The body weights of survivors
    were decreased during the week after treatment but subsequently
    increased. The three birds dosed with TOCP that were not sacrificed
    for enzyme assays at 48 h developed signs of delayed neurotoxicity
    after 13 days, although no clinical signs of cholinesterase inhibition
    were seen. All of the birds treated subcutaneously with dimethoate
    died within 48 h, after showing clinical signs of cholinesterase
    inhibition. After oral administration of 55 mg/kg bw dimethoate, all

    birds showed clinical evidence of cholinesterase inhibition. Twelve of
    these birds that survived to termination had recovered by day 6 of the
    observation period, and none showed signs of delayed neurotoxicity; 12
    birds in this group died within 48 h of dosing. Body-weight losses
    of up to 10% were seen in treated birds during the first week of
    observation, but these losses were subsequently recovered. Microscopic
    examination indicated no difference between controls and birds treated
    with dimethoate. Brain acetylcholinesterase activity was markedly
    reduced in both groups treated with dimethoate; this was more marked
    (90% inhibition relative to controls) 4 h after dosing than after 48 h
    (61 and 75% inhibition after subcutaneous and oral administration,
    respectively). Brain neuropathy target esterase activity was slightly
    lower than that in controls in birds treated with dimethoate, but was
    markedly lower in TOCP-treated birds. Spinal cord neuropathy target
    esterase activity was reduced in TOCP-treated birds but was unaffected
    in those that received dimethoate (Redgrave  et al., 1991).

         Groups of nine or 10 white Leghorn hybrid chickens were given
    graded doses of technical-grade dimethoate up to 33 mg/kg bw for three
    days, based on the oral LD50 in Japanese quail, in a study designed
    to accord with the guidelines then current in eastern Germany and
    Poland. Negative and positive controls (TOCP) were used. Antidotes
    (atropine sulfate and obidoxime chloride) were administered to treated
    birds but not to controls. The route of administration was not stated
    but is assumed to have been oral. The precise study design was not
    clear from the translation of the original document but indicated
    administration of a further series of three doses at intervals
    determined by the condition of the birds. Deaths occurred despite use
    of the antidotes. Signs of reaction indicative of cholinesterase
    inhibition were seen from about 60 min after dosing. Although the
    tests indicated that dimethoate has high acute toxicity, there was no
    evidence of delayed neurotoxicity, except in the positive controls
    (Ministry of Agriculture, Fisheries and Food, 1993a).

    (iii)  Immunotoxicity

         A single dose of dimethoate at 75 mg/kg (route unspecified) to
    mice and rats decreased the lymphocyte count to 50% of the value
    before exposure and increased the number of neutrophil granulocytes.
    After 72 h, these parameters had returned to normal. A reduction in
    the thymus cortex, with disrupted lymphocytes, and a reduction in the
    number of rosette-forming cells were observed (Tiefenbach & Lange,
    1980).

         Dimethoate administered to rats at 5-30 mg/kg bw orally or
    15 mg/kg bw intramuscularly, twice a week until death, caused
    hyperplasia in the bone marrow, resulting mainly in granulocyto-
    poiesis. The authors considered the changes to be a direct effect of
    dimethoate (Stieglitz  et al., 1974).

    (iv)  Effects on the heart

         The effects of dimethoate on the heart have been investigated
    in rabbits (Mahkambaeva, 1971), guinea-pigs, and rats (Nadmaiteni &
    Marosi, 1983). After oral administration of 150 mg/kg bw to rabbits,
    the effects observed included bradycardia and increased atrio-
    ventricular and intraventricular conductance, with complete recovery
    after four to seven days. In rats and guinea-pigs, a dose-effect
    relationship was established for heart rate disturbances and
    atrio-ventricular block. An electron microscopic study of the
    myocardium showed no changes.

         In anaesthetized guinea-pigs treated with lethal doses of
    dimethoate, cardiac failure and serious electrocardiographic
    disturbances developed during the early phase of intoxication. The
    toxic cardiac phenomena appeared to be unrelated to the degree of
    cholinesterase inhibition but were correlated with the myocardial
    concentration of dimethoate. Cardiac failure and death were first
    observed at a dose of about 110 mg/kg bw, while a dose of 221 mg/kg bw
    resulted in death in all cases. This investigation addressed the
    direct effect of dimethoate on the myocardium, independently of its
    anticholinesterase action (Marosi  et al., 1985a,b).

    (v)  Studies on metabolites

         Omethoate is the oxygen analogue of dimethoate. Information on
    the absorption, distribution, excretion, metabolism, and toxicity of
    this compound is summarized below, although the original reports were
    not available for detailed evaluation.

          Absorption, distribution, and excretion of omethoate: After oral
    administration of 14C-omethoate at doses of 0.3, 5, or 10 mg/kg bw
    to rats, 96-97% of the radiolabel was eliminated in urine, 1-2% in
    faeces, and 1% in expired carbon dioxide within 48 h. Intravenous
    injection of 0.3 mg/kg bw resulted in a similar, rapid elimination
    pattern. Maximal tissue residues were reached 1 h after
    administration. After 8 h, about 18% of the residual radiolabel was
    found in the body. After two days, < 0.55% of the administered dose
    was found. Quantitative analysis and whole-body autoradiography
    indicated a relatively homogeneous distribution of 14C activity,
    except that a 10-20-fold higher concentration was found in the thyroid
    (Weber  et al., 1978).

         Five male Wistar rats were given 10 mg/kg bw 14C-omethoate
    orally in order to obtain preliminary information on pulmonary
    excretion. In the main study, groups of five males and five females
    received a single intravenous dose of 0.5 mg/kg bw 14C-omethoate, a
    single oral dose of 0.5 mg/kg bw 14C-omethoate, 14 daily oral doses
    of 0.5 mg/kg bw unlabelled omethoate and a single oral dose of
    0.5 mg/kg bw 14C-omethoate on day 15, or a single oral dose of

    10 mg/kg bw 14C-omethoate. Urine and faeces were collected over
    periods up to 48 h after treatment, and blood samples were collected
    until sacrifice 48 h after treatment. Only 0.14% of the administered
    radiolabel was detected in expired air. Comparison of the results
    obtained with intravenous and oral treatment indicated that > 98%
    omethoate had been absorbed from the gastrointestinal tract. Within
    48 h, 88-98% of the administered radiolabel was recovered in the
    excreta, with 95-98% in the urine and 2-5% in the faeces. Excretion of
    the low and the high oral doses was not different in females, but
    males at the high dose group tended to excrete more radiolabel in the
    faeces than those at the low dose. The maximal plasma concentration
    was seen 40-60 min after oral dosing, with an initial half-life of
    about 2 h and terminal half-lives of 13-28 h. Less than 0.05% of the
    administered dose was found in tissues after 48 h (Ministry of
    Agriculture, Fisheries and Food, 1993b).

          Biotransformation of omethoate: Urine was collected from two
    male rats 12, 24, and 48 h after an oral dose of 50 mg/kg bw
    radiolabelled omethoate. The cumulative percentages of administered
    radiolabel excreted over the indicated times were 16, 19, and 30%. The
    metabolites found in a 24-h composite urine sample by ion-exchange
    chromatography were:  O,O-dimethylphosphoric acid (34%), unknown A
    (52%),  O,O-dimethylphosphorothioic acid (9.5%), and unknown B
    (4.5%). After treatment of male rats with dimethoate, 81% of the
    administered dose was excreted in the urine within 24 h, while after
    treatment with omethoate only 19% was excreted (Dauterman  et al.,
    1959).

         In the experiment conducted by the Ministry of Agriculture,
    Fisheries and Food (1993b), the predominant form of excreted
    radiolabel was unchanged parent compound (26-62%), with  N-methyl-
    2-(methylsulfinyl)acetamide accounting for 16-36% and an  O-demethylated
    omethoate for 4-9%. Pretreatment of animals for 14 days with unlabelled
    omethoate followed by a single labelled dose resulted in no significant
    difference from the results obtained after a single administration.

          Effects of omethoate on enzymes and other biochemical parameters:
    Dealkylation of omethoate was proposed to be a significant detoxification
    mechanism on the basis of information from assays in fly heads (Aharoni &
    O'Brien, 1968). Oxidative metabolism of omethoate results in the
    de- N-methyl derivative, which is as toxic as the parent compound
    although less active as a cholinesterase inhibitor (Lucier &
    Menzer, 1970). Kinetic studies indicated that the reaction between
    acetylcholinesterase and omethoate was irreversible and bimolecular.
    Omethoate was 75-100 times more potent than dimethoate in inhibiting
    rat brain acetylcholinesterase activity.

          Acute toxicity of omethoate: The signs of poisoning after a
    single dose of omethoate are typical of cholinergic stimulation, as
    elicited by other organophosphorus esters. The signs appear 5-60 min
    after dosing and include salivation, lacrimation, and tremors. They
    may persist for one to three days (Kimmerle, 1968). The LD50 values
    are summarized in Table 5.

          Short-term toxicity of omethoate: Groups of 50 male and 50
    female BOR:NMRI mice were fed diets containing omethoate (purity,
    97.1%) providing doses of 0, 1, 3, or 10 ppm for four weeks and were
    killed at intervals to investigate brain acetylcholinesterase
    activity. There were no clinical signs of reaction to treatment, and
    food and water intake, mortality, and body-weight gain were also
    unaffected. The cholinesterase activity in plasma was clearly lower
    than that in controls in mice receiving 10 ppm, but the differences
    were smaller and much less consistent in erythrocytes. Plasma and
    erythrocyte cholinesterase activity in mice at 1 and 3 ppm showed no
    consistent differences from controls. Brain acetylcholinesterase
    activity was clearly depressed in animals at 10 ppm. Inhibition of
    brain acetylcholinesterase activity at 3 ppm was inconsistent, but the
    level was up to 30% lower than that in contemporary controls. In
    animals at 1 ppm, brain acetylcholinesterase activity was biologically
    significantly lower than in controls only on day 3 in males (Ministry
    of Agriculture, Fisheries and Food, 1993).

         Groups of 15 male and 15 female rats (30 of each sex as controls)
    were fed diets containing omethoate providing doses of 0, 2.5, 5, 15,
    50, or 150 ppm for four months. Signs of cholinergic stimulation was
    seen at doses > 15 ppm. Cholinesterase activity was depressed in
    females at 50 and 150 ppm and in males at doses > 5 ppm. No effects
    were noted on growth, organ weights, blood parameters, or urinary
    parameters at levels < 50 ppm. Animals at 150 ppm died or had
    depressed body weights and food consumption, and the relative liver
    weight in males was increased (Löser & Lorke, 1967).

         Groups of 15 male and 15 female rats were fed diets containing
    omethoate to provide doses of 0, 0.5, 1.0, 2.0, or 4.0 ppm for three
    months. Clinical signs of cholinergic stimulation were evident in
    animals at 4 ppm. Erythrocyte acetylcholinesterase activity was
    depressed in animals at 2 ppm, but the effect was only slight in
    females. In rats at 4 ppm, the inhibition was 30-50%. No effects were
    noted on growth, food consumption, blood parameters, liver and kidney
    function tests, organ weights, or histological appearance of tissues
    (Löser, 1968).

        Table 5.  Acute toxicity of omethoate in experimental animals

                                                                                                         

    Species             Sex             Route           LD50                  Reference
                                                     (mg/kg bw)
                                                                                                         

    Mouse          Male            Oral                  36          Kimmerle (1968)
    Mouse          Male            Oral                  27          Santi & de Pietri Tonelli (1960)
    Mouse          Male            Intraperitoneal       13          Lucier & Menzer (1970)
    Mouse          Male            Intravenous           23          Kimmerle (1962)
    Rat            Male, female    Oral                 28-65        Kimmerle & Lorke (1967)
    Rat            Male, female    Oral                  50          Ben-Dyke et al. (1970)
    Rat            Male, female    Oral                 22-28        Ministry of Agriculture,
                                                                     Fisheries and Food (1993b)
    Rat            Male            Intraperitoneal       14          Kimmerle (1968)
    Rat            Male            Intraperitoneal       38          Kimmerle (1962)
    Rat            Male, female    Dermal              145-232       Ministry of Agriculture,
                                                                     Fisheries and Food (1993b)
    Rabbit         Male            Oral                  50          Kimmerle (1962)
    Guinea-pig     Male            Oral                  100         Kimmerle (1962)
    Cat            Male            Oral                  50          Kimmerle (1962)
    Chicken        Male            Oral                  125         Kimmerle (1962)
    Chicken        Male            Oral                  100         Levinskas & Shaffer (1965)
                                                                                                         
             Groups of six male and six female beagle dogs received omethoate
    (purity, 97.1%; dissolved in acidulated water) daily for 12 months
    by stomach tube at doses of 0, 0.02, 0.125, or 0.625 mg/kg bw.
    Administration by gavage was chosen due to the reported instability of
    the test material in dietary admixture. The appearance and behaviour
    of the animals were normal, and no clinical signs attributable to
    treatment were observed. All of the animals survived the treatment.
    No significant differences were seen between the control and treated
    groups with respect to reflexes, ophthalmoscopic parameters, body
    temperatures, pulse rate, food and water consumption, mean
    body weight, or haematological, clinical chemical (except for
    cholinesterase activity), or urinary parameters. Clear depression
    of plasma cholinesterase activity was observed only in rats at
    0.625 mg/kg bw, amounting to 25-32% of the control value in males
    and 16-29% in females. The depression remained essentially
    constant throughout the study. A marked depression of erythrocyte
    acetylcholestinerase activity was measured in males (17-40%) and
    females (22-40%) at 0.625 mg/kg bw, which varied only slightly during
    the study. At 0.125 mg/kg bw, only males showed slight (< 28%)
    depression of erythrocyte acetylcholinesterase activity during the
    first third of the study. Brain acetylcholinesterase activity was
    depressed in males at 0.125 mg/kg bw (by 20%) and 0.625 mg/kg bw (39%)
    and in females at 0.625 mg/kg bw (30%). The absolute and relative
    organ weights were not significantly different between the control and
    treated groups. Gross pathological and histopathological examination
    showed no dose-related findings. The NOAEL was 0.62 mg/kg bw for
    somatic effects and 0.02 mg/kg bw for inhibition of erythrocyte
    acetylcholinesterase activity (Hoffmann & Schilde, 1984).

          Long-term toxicity and carcinogenicity of omethoate: Groups of
    50 male and 50 female BOR:CWF1 mice were fed diets containing
    omethoate (purity, 94%) providing levels of 0, 1, 3, or 10 ppm for 24
    months. Appearance, behaviour, and activity were not significantly
    different between the control and treated groups, and total and mean
    daily food consumption were essentially the same in all the animals.
    The body weights of treated males were generally higher than those of
    the controls throughout the experiment, whereas those of the females
    were no different from controls. Mortality and the frequency
    distribution of mortality were comparable in all the groups. The
    mortality rate at 18 months was 12-27% for males and 14-31% for
    females. The absolute and relative organ weights of control and
    treated groups showed no dose-related, significant differences. Gross
    anatomical and histopathological examination 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 gave no indication of treatment-related toxic effects. Neoplastic
    changes were found primarily in the lungs, liver, adrenal cortex,
    and haematopoietic system. Neither the type, site, or frequency
    distribution of tumours by sex and dose level nor the numbers of
    tumour-bearing mice, mice with benign tumours, mice with malignant

    tumours, or mice with both benign and malignant tumours indicated
    effects of treatment. The NOAEL for somatic effects was 10 ppm, equal
    to 2.1 mg/kg bw per day for male mice and 3.1 mg/kg bw per day for
    female mice (Kroetlinger & Löser, 1982).

         Four groups of 50 male and 50 female Wistar rats were maintained
    for 24 months on a diet containing omethoate providing concentrations
    of 0, 0.3, 1,3, or 10 ppm. The control group consisted of 100 males
    and 100 females. Omethoate did not clearly affect behaviour, body
    weight, survival, food intake, or haematological, clinical chemical,
    or urinary parameters. Plasma and erythrocyte cholinesterase
    activities, measured in five males and five females from each group
    at 1, 2, 4, 8, 13, 26, 52, and 78 weeks and at the end of the study,
    were significantly depressed in all animals at 10 ppm. Erythrocyte
    acetylcholinesterase activity was also inhibited in animals of each
    sex at 3 ppm. The suppression of brain acetylcholinesterase activity,
    measured in 10 males and 10 females per group, was dose-related in
    animals at 3 and 10 ppm; it was also significantly affected in females
    at 1 ppm, which can be considered the marginal no-effect level. Gross
    and microscopic examination revealed no diverse effect of omethoate.
    The tumour incidence was not clearly affected by treatment (Bomhard
     et al., 1979).

          Reproductive toxicity of omethoate: Groups of 10 male and 20
    female FB 30 Long-Evans rats were fed diets containing omethoate
    (purity, 94%) to give concentrations of 0, 1, 3, or 10 ppm for about
    10 weeks, after which they were mated to initiate a three-generation
    study of reproductive toxicity with two litters per generation.
    Immediately after birth, the litters were examined for malformations.
    Four days after birth, the litters were reduced to 10. When the
    offspring were three weeks old, they were killed and subjected to
    gross examination. Ten males and 10 female rats of the F3b generation
    at all doses were examined histopathologically four weeks after birth.
    There were no clear effects either on mating performance, pregnancy
    rate, mortality, or the type and distribution of abnormalities. The
    size of the litters of the second generation at 3 and 10 ppm was
    reduced, and in the F2b generation, litter size was reduced at both 3
    and 10 ppm after four days and at 10 ppm only after 28 days. Since
    this effect was observed in only one progeny generation, 3 ppm was the
    NOAEL (Löser, 1981).

         In a two-generation study, omethoate was administered to groups
    of 25 male and 25 female Wistar rats in the drinking-water at levels
    of 0, 0.5, 3, or 18 ppm throughout a 70-day premating period and
    throughout pairing, gestation, and lactation during breeding of a
    single litter in each of the F1 and F2 generations. Reproductive
    performance was adversely affected at 18 ppm, with a reduced
    implantation rate, increased postnatal loss, and retarded pup weight
    gain in both generations and increased precoital time, an increased
    number of non-pregnant females, and increased postimplantation loss in

    the F1 generation. Histopathological examination revealed an
    increased incidence of epithelial vacuolation in the epididymides of
    males treated with 18 ppm. The NOAEL for reproductive effects was
    3 ppm, equivalent to 0.2 mg/kg bw per day. There was no NOAEL
    for general toxicological effects, since erythrocyte and brain
    acetyl-cholinesterase activities were inhibited at the lowest dose
    (Ministry of Agriculture, Fisheries and Food, 1993).

          Developmental toxicity of omethoate: Groups of 20-24 pregnant
    rats were given omethoate orally at doses of 0, 0.3, 1, or 3 mg/kg bw
    on days 6-15 of gestation. The animals were killed on day 20 of
    gestation, and the fetuses were examined for skeletal and tissue
    abnormalities. The fetuses and placentas of the animals at 3 mg/kg bw
    weighed less than those of the controls. Other reproductive parameters
    were unaffected. No teratogenic effect was observed (Machemer, 1975).

         Groups of 14 pregnant New Zealand white rabbits were treated
    daily by gavage with omethoate (purity, 96.8%) dissolved in distilled
    water at doses of 0, 0.1, 0.3, or 1 mg/kg bw on days 6-18 of
    gestation. On day 29 of gestation, the animals were killed and their
    uterine contents examined. Whole-blood cholinesterase activity was
    determined before treatment on day 6 of gestation and 2 h after
    treatment 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 females at 1 mg/kg bw in comparison
    with both the pretreatment level and the control level after
    treatment. There were no treatment-related differences between the
    control and treated groups with respect to corpora lutea count,
    implantations, male and female viable young, early and late
    resorptions, pre- and postimplantation losses, or fetal and placental
    weights. Examination of fetuses at necroscopy on day 29 of gestation
    or after skeletal investigation revealed a number of non-dose-related
    findings of types and incidences previously recorded in this strain of
    rabbit and in the laboratory that performed the study. The NOAEL for
    developmental toxicity was 1 mg/kg bw (Tesh  et al., 1982).

          Genotoxicity of omethoate: Omethoate has been extensively
    tested in assays for mutagenicity  in vitro. Positive results were
    obtained in  Salmonella, in one assay for gene mutation in mammalian
    cells, and in assays for clastogenicity. Omethoate has also been
    extensively tested  in vivo. Negative results were obtained for
    end-points in the bone marrow, liver, and germ cells, but a positive
    result was obtained in a mouse spot test. The results of assays for
    the genotoxicity of omethoate are summarized in Table 6.

          Neurotoxicity of omethoate: Groups of 10 hens were given
    omethoate orally at the LD50 (92 mg/kg bw) with atropine, and and
    five positive controls were given TOCP at 350 mg/kg bw. Although
    several hens treated with omethoate died, none showed clinical signs
    of delayed neurotoxicity. Clinical signs were observed in those
    treated with TOCP (Kimmerle, 1972). Histological examination of
    nervous tissue with haematoxylin and eosin staining showed
    degeneration in the hens treated with TOCP but not in those given
    omethoate (Newman  et al., 1972).

         Groups of two to four hens were treated orally with omethoate
    dissolved in corn oil at doses of 20-300 mg/kg bw, which were four
    to eight times the unprotected LD50, under eserine and atropine
    protection. The omethoate used was a sample that had caused a fatal
    human poisoning accident. The acetylcholinesterase and neurotoxic
    esterase activities of brain homogenates were assayed for 24 h after
    dosing, and pair-dosed birds that survived were observed for signs of
    ataxia for three to four weeks. Hens treated at four times the LD50
    showed no inhibition of neurotoxic esterase at 24 h and no signs of
    ataxia. Those treated at eight times the LD50 did not survive,
    despite treatment with high doses of atropine; however, the neurotoxic
    esterase activity in the brains of the animals that died within 36 h,
    measured immediately after death, was found to be normal. Acute
    cholinergic symptoms in all the birds were correlated with strong
    inhibition of brain acetylcholinesterase activity, but 70% inhibition
    in a bird treated with 20 mg/kg bw of omethoate still did not produce
    detectable signs of acute poisoning.

         The capacity of pure omethoate and of the incriminated sample to
    inhibit neurotoxic esterase and acetylcholinesterase activities were
    measured in hen and human brain tissue  in vitro. As the IC50 for
    acetylcholinesterase in both tissues was 0.08-0.15 mmol/litre, it
    would be virtually completely inhibited at 5 mmol/litre, the
    concentration that caused no detectable inhibition of neurotoxic
    esterase. The activities of both enzymes were also measured in
    cortical tissue samples taken 24 h  post mortem from a 30-year-old
    male farmer who had been acutely poisoned by a commercial formulation
    of omethoate. The neurotoxic esterase activity was within the normal
    range, while acetylcholinesterase activity was strongly inhibited. It
    was concluded that omethoate is extremely unlikely to cause delayed
    neuropathy in humans (Lotti  et al., 1981).

        Table 6.  Results of tests for the genotoxicity of omethoate

                                                                                                                                      

    End-point              Test system            Concentration       Purity            Results                    Reference
                                                                        (%)
                                                                                                                                      

    In vitro

    Reverse mutation     S. typhimurium        0-12 500 µg/plate       95.1       Weakly positive             Herbold (1980)
                         TA98, TA100,                                             in TA98, TA100, and
                         TA1535, TA1537                                           TA1535a Negative in
                                                                                  TA1537a
    DNA repair           E. coli (pol)         0-10 000 µg/plate        96        Negative                    Herbold (1983)
    Gene mutation        Chinese hamster       0-6 mg/ml               97.4       Positivea                   Ministry of Agriculture,
                         ovary cells (hprt)                                                                   Fisheries and Food
                                                                                                              (1993)
    Cell mutation        L5178Y mouse          0-5000 µg/ml            96.9       Negativea                   Bootman & Rees (1982)
                         lymphoma cells
    Sister chromatid     Chinese hamster       0-1000 µg/ml             96        Positive at > 250 µg/ml     Ministry of Agriculture,
    exchange             ovary cells                                                                          Fisheries and Food
                                                                                                              (1993)
    Gene conversion;     S. cerevisiae         0-66.7 µl/ml            96.9       Negative                    Hoorn (1982, 1983)
    reverse mutation                                                              Positive

    In vivo

    Micronucleus         Mouse                 2 × 6 or 12             97.1       Negative                    Herbold (1981)
    formation                                  mg/kg bw
    Dominant lethal      Mouse                 0.5 mg/kg bw            95.4       Negative                    Machemer (1974)
    mutation
    Unscheduled DNA      Wistar rat            0-30 mg/kg bw           96.6       Negative                    Ministry of Agriculture,
    synthesis                                                                                                 Fisheries and Food
                                                                                                              (1993)
    Spot test            C57Bl/6J × T          0-16 mg/kg bw         96.7-97%     Positive                    Ministry of Agriculture,
                         mice                                                                                 Fisheries and Food
                                                                                                              (1993)
                                                                                                                                      

    a     With and without metabolic activation
        3.  Observations in humans

         The results of two studies of dimethoate in humans were
    summarized briefly in the report of the 1963 JMPR (Annex 1, reference
    2). In the first study, 20 volunteers were given daily doses of 2.5 mg
    dimethoate in aqueous solution (corresponding to approximately
    0.04 mg/kg bw) for four weeks. No toxic effect was observed, and there
    were no changes in blood cholinesterase activity. Similar results were
    reported in single subjects who ingested 9 mg (0.13 mg/kg bw) or 18 mg
    (0.26 mg/kg bw) for 21 days (Sanderson & Edson, 1964).

         The results of a number of studies in which human volunteers with
    no occupational exposure to organophosphate pesticides were given
    dimethoate were summarized in Environmental Health Criteria monograph
    No. 90 (WHO, 1989) and are presented in Table 7. The studies of
    volunteers indicate that repeated doses of up to 0.2 mg/kg bw
    dimethoate do not inhibit cholinesterase activity in the blood.

        Table 7.  Results of controlled human trials with dimethoate

                                                                                                                                      

     No. of     Sex      Route         Daily dose          Duration of              Results                          Reference
    subjects                                                exposure
                                                                                                                                      

      20        NR      Oral       0.04 mg/kg                4 weeks     No toxic effects or inhibition of       Sanderson & Edson
                                                                         blood ChE                               (1964)
       2        NR      Oral       0.13 mg/kg                21 days     No toxic effects or inhibition of       Sanderson & Edson
                                   0.26 mg/kg                            blood ChE                               (1964)
       5        M       Oral       0.25 mg/kg                Single      No toxic effects or inhibition of       Sanderson & Edson
                                                             dose        blood ChE                               (1964)
      50        NR      Dermala    2.5 ml                    2 h         No irritation or inhibition of blood    Sanderson & Edson
                                                                         ChE                                     (1964)
      12        M+F     Oral       5 mg (0.068 mg/kg bw)     28 days     No significant change in whole-blood    Edson et al. (1967)
                                                                         ChE
       9        M+F     Oral       15 mg (0.202 mg/kg bw)    39 days     No significant change in whole-blood    Edson et al. (1967)
                                                                         ChE
       8        M+F     Oral       30 mg (0.434 mg/kg bw)    57 days     Inhibition of ChE by day 20 (24%)       Edson et al. (1967)
       6        NR      Oral       45 mg (0.587 mg/kg bw)    45 days     Inhibition of ChE (35%)                 Edson et al. (1967)
       6        M+F     Oral       60 mg (1.02 mg/kg bw)     14 days     Inhibition of ChE (21%)                 Edson et al. (1967)
                                                                                                                                      

    NR, not reported; ChE, cholinesterase
    a    Patch test with 32% liquid formulation
        Comments

    Dimethoate

         Dimethoate is rapidly and extensively absorbed from the gut and
    rapidly excreted. There was no accumulation in fat tissue. In rats and
    humans, up to 90% of radiolabel was found in the urine within 24 h.
    The report of a study with methylcarbamoyl-labelled dimethoate
    indicated that up to 18% of the administered label was excreted in
    expired air. Four metabolites with anticholinesterase activity have
    been identified in rats and humans. One seems to result from thiono
    oxidation, leading to the formation of the oxygen analogue of
    dimethoate, i.e. omethoate; this step was followed by hydrolysis to
    a thiocarboxyl product, said to be the main metabolite in rats and
    humans.

         Data on the acute oral toxicity of dimethoate gave LD50 values
    of about 310 mg/kg bw in rats, 150 mg/kg bw in mice, and 55 mg/kg bw
    in hens. The signs of toxicity were those typical of cholinesterase
    inhibition. WHO has classified dimethoate as 'moderately hazardous'
    (WHO, 1996).

         In short-term and long-term studies at dietary concentrations
    > 75 ppm, there were minor reductions in body-weight gain and food
    consumption. Apart from inhibition of cholinesterase activity,
    dimethoate had no effect on the composition of the blood or urine. The
    liver weights of animals treated at the higher doses tended to be
    lower than those of the control groups: there were, however, no
    microscopic changes, and the effect is unlikely to be of toxicological
    significance. Investigations of toxicity at higher doses were limited
    by effects due to cholinesterase inhibition. The NOAELs were thus
    generally based on reductions in acetylcholinesterase activity in
    the brain or erythrocytes. On the basis of minimal reductions in
    acetylcholinesterase activity of 10-20%, the NOAEL in a 12-month study
    in dogs at doses of 0, 5, 20, or 125 ppm was 5 ppm, equal to 0.2 mg/kg
    bw per day; in rats, the NOAEL in a life-span study at doses of 0, 1,
    5, 25, or 100 ppm was 1 ppm, equal to 0.04 mg/kg bw per day. In mice,
    an NOAEL was not identified, as cholinesterase activity was depressed
    at all doses after 52 weeks of treatment in a life-span study at doses
    of 0, 25, 100, or 200 ppm.

         The results of long-term studies of toxicity and carcinogenicity
    in mice (at 0, 25, 100, or 200 ppm) and rats (at 0, 5, 25, or 100 ppm)
    reported in 1986 and studies reported in 1977 indicate that dimethoate
    is not carcinogenic to rodents.

         In a multigeneration study of reproductive toxicity conducted in
    1989-90 with doses of 0, 1, 15, or 65 ppm, reproductive performance
    of rats was impaired at the high dose. The NOAEL for reproductive
    toxicity appeared to be 15 ppm (equal to 1.2 mg/kg bw per day) and

    that for parental toxicity was 1 ppm (equal to 0.08 mg/kg bw per day)
    on the basis of cholinesterase inhibition, but the Meeting noted that
    there was some indication that reproductive performance may have been
    affected at lower doses. In a multigeneration study conducted in mice
    in 1965 at doses of 0, 5, 15 or 50 ppm, there was no overt effect on
    reproductive capacity, even in the presence of cholinergic toxicity.
    In a poorly reported study in rabbits, sperm numbers and quality were
    adversely affected at doses equivalent to one-tenth and one-hundredth
    of the LD50.

         Studies of developmental toxicity in rats (at 0, 3, 6, or
    18 mg/kg bw per day on days 6-15 of gestation) and rabbits (at 0, 10,
    20, or 40 mg/kg bw per day on days 7-19 of gestation) provided no
    evidence of a teratogenic effect, although maternal toxicity was
    observed at the high dose in rats and at the high and middle doses in
    rabbits.

         After reviewing the data available on mutagenicity, the Meeting
    concluded that although in-vitro studies indicate that dimethoate has
    mutagenic potential, this potential does not appear to be expressed
     in vivo.

         Undiluted dimethoate formulations were irritating to the eye in
    rabbits. Skin irritation was minimal and confined to slight, transient
    erythema. Dimethoate was not a skin sensitizer in guinea-pigs, but a
    32.7% emulsifiable concentrate formulation induced sensitization in
    one of 10 guinea-pigs. In a published paper, dimethoate was cited
    in four human cases of contact dermatitis, and sensitization was
    confirmed in these individuals by patch testing.

         In hens given a single dose of 55 mg/kg bw by subcutaneous
    injection or orally, dimethoate did not induce delayed neurotoxicity.

         In a 39-day study in nine male and female volunteers, the NOAEL
    for cholinesterase inhibition was 0.2 mg/kg bw per day. This NOAEL was
    supported in seven other studies each involving 6-20 volunteers who
    received doses ranging from 0.04 to 1.0 mg/kg bw per day for up to 57
    days.

    Omethoate

         The oral LD50 of omethoate was approximately 25 mg/kg bw
    in rats. Signs of reaction to treatment with omethoate were those
    consistent with cholinesterase inhibition.

         In short-term and long-term studies, the potential toxicity of
    omethoate was limited by the onset of cholinesterase inhibition. In a
    12-month study of toxicity in dogs at doses of 0, 0.025, 0.12, or
    0.62 mg/kg bw per day by gavage, the NOAEL was 0.02 mg/kg bw per day
    on the basis of inhibition of acetylcholinesterase activity. In

    life-span studies in rats (at 0, 0.3, 1, 3, or 10 ppm) anti mice (at
    0, 1, 3, or 10 ppm), there was no evidence of oncogenic potential. The
    study in mice was unsuitable for deriving an NOAEL because acetyl-
    cholinesterase activity was not investigated; the NOAEL in rats was
    0.3 ppm (0.015 mg/kg bw per day) on the basis of inhibition of
    acetylcholinesterase activity.

         In multigeneration studies in rats at 0, 1, 3, or 10 ppm, a
    dietary concentration of 10 ppm was associated with reduced viability
    of pups; there was evidence that this effect extended to animals
    treated at 3 ppm. The NOAEL was 1 ppm (equivalent to 0.05 mg/kg bw per
    day). In a further multigeneration study in rats at doses of 0, 0.5,
    3, or 18 ppm in the drinking-water, there was evidence of epididymal
    vacuolation and fewer pups per dam at the high dose; these pups had
    lower weight gains and were less viable. The precoital time was
    increased and the number of non-pregnant females was greater than
    among controls. The NOAEL for reproductive performance was 3 ppm
    (equivalent to 0.2 mg/kg bw per day), but cholinesterase inhibition
    was detected at the lowest dose of 0.5 ppm. In studies of
    developmental toxicity, there was no evidence of teratogenicity in
    rats given 0, 0.3, 1, or 3 mg/kg bw omethoate per day on days 6-15 of
    gestation or in rabbits given 0, 0.1, 0.3, or 1 mg/kg bw omethoate per
    day on days 6-18 of gestation.

         Omethoate has been extensively investigated for mutagenicity  in
     vitro and  in vivo. The Meeting concluded that it has clear mutagenic
    potential but that the weight of the evidence observed  in vivo was 
    negative; however, the positive result obtained in the mouse spot test
    could not be completely disregarded.

         In studies in hens given single oral doses of 20-300 mg/kg bw,
    omethoate did not induce delayed neurotoxicity.

    Conclusions

         An ADI of 0-0.002 mg/kg bw was established for dimethoate on the
    basis of the apparent NOAEL of 1.2 mg/kg bw per day for reproductive
    performance in the study of reproductive toxicity in rats and applying
    a safety factor of 500. Although a safety factor of 100 would normally
    be used in deriving an ADI from a study of this type, the Meeting was
    concerned about the possibility that reproductive performance may have
    been affected at 1.2 mg/kg bw per day in this study and therefore used
    a higher-than-normal safety factor. No data are available to assess
    whether the effects on reproductive performance were secondary to
    inhibition of cholinesterase. The Meeting concluded that it was
    not appropriate to base the ADI on the results of the studies of
    volunteers since the crucial end-point (reproductive performance) has
    not been assessed in humans.

         This ADI would usually be used only when assessing the intake of
    dimethoate itself. As the use of dimethoate on crops can give rise to
    residues of omethoate, and omethoate has been used as a pesticide in
    its own right, previous Joint Meetings have allocated an ADI to
    omethoate; however, the primary manufacturer is no longer producing
    omethoate. The Meeting noted that omethoate is considerably more toxic
    than dimethoate; however, the levels of residues of omethoate
    resulting from use of dimethoate on crops are likely to be low. The
    Meeting therefore recommended that residues of dimethoate and
    omethoate resulting from the use of dimethoate be expressed as
    dimethoate and be assessed in comparison with the ADI for dimethoate.

         As the primary manufacturer is no longer producing either
    omethoate or formothion, toxicological data on these compounds were
    not made available to the Meeting. The previous ADIs of 0-0.0003 mg/kg
    bw for omethoate and 0-0.02 mg/kg bw for formothion were therefore
    withdrawn.

         There may be a need to re-evaluate the toxicity of dimethoate
    after the periodic review of the residue and analytical aspects of
    dimethoate has been completed if it is determined that omethoate is a
    major residue.

    Toxicological evaluation

    Levels that cause no toxic effect (dimethoate)

         Rat:      1 ppm, equal to 0.04 mg/kg bw per day (two-year study
                   of toxicity and carcinogenicity)

                   15 ppm, equal to 1.2 mg/kg bw per day (reproductive
                   performance in a study of reproductive toxicity)

                   1 ppm, equal to 0.08 mg/kg bw per day (parental
                   toxicity in a study of reproductive toxicity)

                   6 mg/kg bw per day (maternal toxicity in a study of
                   developmental toxicity)

         Rabbit:   10 mg/kg bw per day (maternal toxicity in a study of
                   developmental toxicity)

         Dog:      5 ppm, equal to 0.2 mg/kg bw per day (52-week study of
                   toxicity)

         Human:    0.2 mg/kg bw per day (39-day study of cholinesterase
                   inhibition)

    Estimate of acceptable daily intake for humans

         0-0.002 mg/kg bw (sum of dimethoate and omethoate expressed as
         dimethoate)

    Studies that would provide information useful for continued evaluation
    of the compound

         1.   Further multigeneration study in rats using dimethoate

         2.   Mouse spot test using dimethoate

        Toxicological criteria for estimating guidance values for dietary and non-dietary exposure to dimethoate

                                                                                                                                      

           Exposure                  Relevant route, study type, species                          Results, remarks
                                                                                                                                      

    Short-term (1-7 days)      Oral, toxicity, rat                                LD50 = 310 mg/kg bw
                               Dermal, toxicity, rat                              LD50 > 7000 mg/kg bw
                               Dermal, irritation, rabbit                         Slightly irritating
                               Ocular, irritation, rabbit                         Slightly irritating
                               Dermal, sensitization, human                       Sensitizing

    Medium-term (1-26 weeks)   Repeated dermal, 21 days, toxicity, rabbit         NOAEL > 1000 mg/kg bw per day (highest dose tested)
                               Repeated oral, reproductive toxicity, rat          NOAEL = 1.2 mg/kg bw per day, reproductive toxicity
                                                                                  NOAEL = 0.05 mg/kg bw per day, parental toxicity
                               Repeated oral, developmental toxicity, rat         NOAEL = 6 mg/kg bw per day, parental toxicity.
                                                                                  No evidence of embryotoxicity or teratogenicity
                                                                                  at 18 mg/kg bw per day (highest dose tested)
                               Repeated oral, developmental toxicity, rabbit      NOAEL = 10 mg/kg bw per day, parental toxicity.
                                                                                  No evidence of embryotoxicity or teratogenicity
                                                                                  at 40 mg/kg bw per day (highest dose tested)

    Long term (> 1 year)       Repeated oral, toxicity and carcinogenicity, rat   NOAEL = 0.04 mg/kg bw per day, cholinesterase
                                                                                  inhibition
                                                                                                                                      
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    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: 1987 evaluations Part II Toxicology)