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    ALDICARB

    First draft prepared by M M. Watson
    Ministry of Agriculture, Fisheries and Food
    Harpenden, Hertfordshire, United Kingdom

    EXPLANATION

         Aldicarb was evaluated for acceptable daily intake by the 1979
    and 1982 Joint Meetings (Annex 1, references 32 and 38). An ADI of
    0-0.005 mg/kg bw was allocated by the 1982 Joint Meeting. Since that
    time additional information has become available, including a new
    human volunteer study, and the results of these studies were
    reviewed at the present Meeting. In order to facilitate review of
    the complete database, summaries of information presented in the
    reports of the Joint Meetings of 1979 and 1982 are included in this
    monograph.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical Aspects

    Absorption, distribution, and excretion

         Aldicarb is readily absorbed, distributed widely in the body
    and excreted rapidly in mammals. Radiolabelled aldicarb was
    administered orally to male rats and residues were analyzed over a
    14-day period. Excretion was essentially complete within 4 days
    (greater than 95% of the administered dose). The major
    concentrations of metabolites were observed to have been excreted
    within 24 h of dosing. Four days following acute oral dosing,
    residues were not detected in animal tissues. In dogs, the excretion
    pattern of aldicarb administered subacutely was similar to that
    noted following acute administration in other species. A similar
    urinary excretion pattern was observed when aldicarb sulfone and
    aldicarb nitrile were administerd to lactating dairy cows either
    alone or in combination with one or more aldicarb metabolites.
    Following a single acute administration of aldicarb, approximately
    83% of the dose was eliminated in the urine within 24 h. A minor
    quantity of residue was eliminated in the faeces and small amount of
    residues were observed in milk (less than 3% of the administered
    dose was observed in milk over a 5-day interval). Aldicarb and/or
    aldicarb sulfone administered as a single oral dose to laying hens
    were rapidly excreted in the faeces. Minute quantities of terminal
    residues were observed in eggs on the first day after treatment, but
    the residue level declined rapidly (Knaak  et al., 1966; Andrawes
     et al., 1967, 1977; Dorough & Ivie, 1968; Sullivan, 1968a,b,c;
    Dorough  et al., 1970; Hicks  et al., 1972; Romine, 1973; Sullivan
    & Carpenter, 1974).

         A study in goats was conducted to determine the fate, nature
    and magnitude of aldicarb residues in urine, milk and tissues. Two
    lactating goats received S-methyl-14C-aldicarb administered in
    gelatin capsules at a level equivalent to 2.5 ppm in the feed for
    ten days. A third goat served as the control. The goats were
    sacrificed within 6 to 8 h after the last dose was given. No toxic
    effects were noted during the study. Of the applied dose, 61.2% was
    eliminated in urine, 11.3% in faeces and 1.1% was secreted in milk.
    Only 0.2% of the applied dose was found in the respiratory gases and
    < 0.10% in tissues at the end of the ten-day dosing period
    (Andrawes & Lee, 1986).

    Biotransformation

         The metabolic fate of aldicarb has been studied in a variety of
    vertebrate and invertebrate species. Minor biotransformation
    differences have been found to occur with respect to quantities of

    individual metabolites. The basic metabolic profile of aldicarb in
    all species examined appears to be the same and is shown in Figure
    1. Aldicarb is rapidly oxidized to aldicarb sulfoxide, a relatively
    stable metabolite. Aldicarb sulfoxide is slowly degraded by both
    oxidative and hydrolytic mechanisms yielding the corresponding
    aldicarb sulfone and sulfoxide oxime (Knaak  et al., 1966; Metcalf
     et al., 1966; Andrawes  et al., 1967, 1977; Bull  et al., 1967;
    Dorough & Ivie, 1968; Sullivan 1968a; Dorough  et al., 1970; Hicks
     et al., 1972; Sullivan & Carpenter, 1974; Andrawes & Lee, 1986).

    Effects on enzymes and other biochemical parameters

         As noted with other N-methylcarbamate esters, aldicarb is a
    readily reversible inhibitor of cholinesterase activity and  in
     vitro studies have shown that cholinesterase inhibition induced by
    aldicarb and its oxidative metabolites (aldicarb sulfoxide and
    aldicarb sulfone) can be rapidly reversed by simple dilution.
    Aldicarb sulfoxide was 47 and 25 times more effective in inhibiting
    cholinesterase than aldicarb and aldicarb sulfone, respectively,
    with an insect enzyme preparation, and 23 and 60 times more
    effective, respectively, when using an RBC preparation obtained from
    cows (Metcalf  et al., 1966; Bull  et al., 1967; Chin & Sullivan,
    1968).

    Toxicological studies

    Acute toxicity studies

         The acute toxicity of aldicarb and its metabolites has been
    studied in a variety of mammalian species. A summary of acute
    toxicity data for aldicarb in shown in Table 1 and for the
    metabolites in Table 2.

    Short-term toxicity studies

    Mice

    - Aldicarb

         Groups of 5 mice/sex were fed aldicarb in the diet at dose
    levels of 0, 0.1, 0.3, 0.6 or 1.2 mg/kg bw/day for 7 days. Mortality
    was noted in both males and females at the high dose level. Growth
    was not affected over the course of the study. Liver and kidney
    weights were also unaffected. A dose level of aldicarb equal to 0.65
    mg/kg bw/day for females and 0.75 mg/kg bw/day for males was without
    substantial effects. The NOAEL in this study was 0.6 mg/kg bw/day
    (Weil & Carpenter, 1970e).

    FIGURE 1

        Table 1: Acute toxicity of aldicarb
                                                                                           
    Species       Sex    Route   Vehicle         LD50           Reference
                                                 (mg/kg bw)
                                                                                           

    Rat           M      oral    corn oil        0.84           West & Carpenter (1966b)
    Rat           M      oral    corn oil        0.93           Striegel & Carpenter (1962)
    Rat           M      oral    corn oil        0.67-1.23      Carpenter (1963)
                                                                Nycum & Carpenter (1968b)
    Rat           F      oral    corn oil        0.62-1.07      Carpenter (1963)
    Rat           F      oral    gycerol:
                                 ethanol         1.0            WHO (1966)
    Rat           F      ip      corn oil        0.71           Carpenter (1963)
    Rat           M+F    ip      corn oil        0.44           Carpenter (1963)
    Rat           M      ip      PEG             0.37-0.44      Weil & Carpenter (1970a)
    Rat           M      ip      ethanol         0.57           Johnson & Carpenter (1966b)
    Rat           M      iv      water           0.47           Weil & Carpenter (1970a)
    Rat           M      dermal  corn oil        >10            Field (1979b)
    Rat           F      dermal  DMP             3.2-7.0        WHO (1966)
    Rat           M      dermal  water           38.1-44.9      Weil & Carpenter (1968a)
    Mouse         M      oral    corn oil        0.382          Weil & Carpenter (1972b)
    Mouse         M      oral    corn oil        0.5            Weil & Carpenter (1972c)
    Mouse         F      oral    cotton seed     1.5            Dorough  et al. (1970)
                                 oil
    Mouse         F      ip      cotton seed     0.3            Dorough  et al. (1970)
                                 oil
    Guinea-pig           oral    corn oil        1.0            Nycum & Carpenter (1968b)
    Rabbit               oral    propylene       1.3            Nycum & Carpenter (1968b)
                                 glycol
    Rabbit        M      dermal  corn oil        >10            Field (1979a)
    Rabbit        M      dermal  PEG             5.0            Striegel & Carpenter (1962)
    Rabbit        M      dermal  dry             141->200       Weil & Carpenter (1968a)
    Chicken       M      oral                    9              West & Carpenter (1965)
                                                                                           

    Table 2:  Acute toxicity of aldicarb metabolites
                                                                                                     
    Chemical               Species      Route    Vehicle     LD50          Reference
                           (sex)                             (mg/kg bw)
                                                                                                     
    A. nitrile             rat          oral                 570           West & Carpenter (1966b)
    A. sulfoxide           rat (M)      oral     corn oil    0.49-1.13     Weil & Carpenter (1970a)
                                                                           Nycum & Carpenter (1968b)
    A. sulfone             rat (M)      oral     corn oil    20-25         Weil & Carpenter (1970a)
                                                                           Nycum & Carpenter (1968b)
    A. sulfoxide           mouse (M)    oral     corn oil    0.8-1.6       Nycum & Carpenter (1968b)
    A. sulfone             mouse (M)    oral     corn oil    25            Nycum & Carpenter (1968b)
    A. sulfoxide           guinea-pig   oral     corn oil    0.8-1.8       Nycum & Carpenter (1968b)
    A. sulfone             guinea-pig   oral     corn oil    >50           Nycum & Carpenter (1968b)
    A. sulfoxide           rabbit       oral     corn oil    0.4-1.8       Nycum & Carpenter (1968b)

    Table 2 (cont'd)
                                                                                                     
    Chemical               Species      Route    Vehicle     LD50          Reference
                           (sex)                             (mg/kg bw)
                                                                                                     
    A. sulfone             rabbit       oral     corn oil    75            Nycum & Carpenter (1968b)
    A. sulfoxide           rat (M)      ip       water       0.47          Weil & Carpenter (1970a)
    A. sulfoxide           rat (M)      ip       corn oil    0.71          Johnson & Carpenter (1966b)
    A. sulfone             rat (M)      ip       PEG         21.2          Weil & Carpenter (1970a)
    A. sulfoxide           rat (M)      iv       water       0.47          Weil & Carpenter (1970a)
    A. sulfone             rat (M)      iv       water       14.9          Weil & Carpenter (1970a)
    A. sulfoxide           rabbit       dermal   water       >20           West & Carpenter (1966b)
    A. sulfone             rabbit       dermal   water       >20           West & Carpenter (1966b)
    2-methyl-2-
    (methyl-sulfinyl)
    propanol-1             rat          oral                 11 000        Weil & Carpenter (1969b)
    OH-methyl A            rat          oral                 42.9          Carpenter (1969)
    A. sulfoxide oxime     rat (M)      oral                 8060          Nycum & Carpenter (1968a)
    A. sulfone oxime       rat (M)      oral                 1590          Nycum & Carpenter (1968a)
    A. sulfoxide nitrile   rat (M)      oral                 4000          Nycum & Carpenter (1968a)
    A. sulfone nitrile     rat (M)      oral                 350           Nycum & Carpenter (1968a)
                                                                                                     

    A: aldicarb
    
    Mice

    - Aldicarb/aldicarb metabolites

         Groups of 3 male and 5 female mice were fed a mixture of
    aldicarb and aldicarb sulfone (1:1) in the diet at dose levels of 0,
    2, 6, 18, or 36 mg/kg bw/day for 7 days. No mortality was noted at
    any dose level, but severe cholinergic signs of poisoning were
    observed at the high-dose in males. Depression of growth was
    observed at the two highest dose levels. Kidney weight was depressed
    at the highest dose and liver weight was reduced substantially at 6
    mg/kg bw/day and above in both males and females. The NOAEL in this
    study was 2 mg/kg bw/day (Weil & Carpenter, 1970d)

         Groups of 5 Charles River CD-1 mice/sex were fed aldicarb
    sulfone in the diet at dose levels of 0, 0.15, 0.6, 2.4, 9.6 or 38.4
    mg/kg bw/day for 7 days. Significant body-weight decrease was noted
    at the highest dose but there were no significant organ weight
    changes. Cholinesterase activity was not determined (Weil &
    Carpenter, 1974e).

    Rats

    - Aldicarb

         Groups of 5 rats/sex were fed aldicarb in the diet for 7 days
    at dose levels of 0, 4, 8 or 16 mg/kg bw/day. Mortality was noted
    predominantly at the highest dose at which all males and 2 of 5
    females died. One of 5 males also died at 8 mg/kg bw/day. There was
    a substantial reduction in body-weight gain noted at all dose
    levels. In males, kidney weights were significantly reduced at 8
    mg/kg bw/day and liver weight was depressed at 4 and 8 mg/kg bw/day.
    In females, both liver and kidney weight was significantly depressed
    at all dose levels (Weil & Carpenter, 1970b).

         Groups of 5 rats/sex were fed aldicarb in the diet at dose
    levels of 0, 0.8, 1.6 or 3.2 mg/kg bw/day for 7 days. Growth was
    depressed at 1.6 mg/kg bw/day and above. There was no mortality
    attributable to aldicarb. In males, liver weights were depressed in
    all treatment groups. In females, liver weights were affected only
    at the highest dose, but the liver to body-weight ratio was reduced
    at 1.6 mg/kg bw/day and above. Kidney weights were reduced in males
    at all dose levels and in females only at the highest dose.
    Cholinesterase activity, measured on the day after the conclusion of
    feeding, was normal at the highest dose tested with the exception of
    plasma cholinesterase which was slightly reduced at the highest
    level (Weil & Carpenter, 1969a).

         Groups of 10 CFE rats/sex were fed aldicarb in their diet for
    93 days at dose levels of 0, 0.02, 0.1 or 0.5 mg/kg bw/day. One rat
    per level was killed for cholinesterase (plasma, RBC and brain)
    determinations at 1, 2, 4 and 29 days of dosing. Mortality was
    increased and body-weight and food consumption were decreased at the
    highest level. Histopathology of selected organs was unremarkable
    and there were no compound-related effects noted. There were no
    consistent dose-related effects on the cholinesterase
    determinations, except for plasma cholinesterase depression in both
    sexes after 30 days at the highest level. There was no indication of
    how soon after feeding the cholinesterase determinations were
    performed, which could account for the sporadic results, together
    with the small number of animals sampled at each interval. The NOAEL
    in this study was 0.1 mg/kg bw/day (Weil & Carpenter, 1963).

    Rats

    - Aldicarb/aldicarb metabolites

         Groups of 5 rats/sex were fed diets containing aldicarb at dose
    levels of 0, 0.4, 0.8, 1.6 or 3.2 mg/kg bw/day, or aldicarb
    sulfoxide at dose levels of 0, 0.4 or 0.8 mg/kg bw/day, or aldicarb
    sulfone, at dose levels of 0, 0.4, 1.0, 2.5, 5 or 20 mg/kg bw/day,
    for 7 days. With aldicarb (as with its two major carbamate

    metabolites) there was a significant growth depression at the
    highest dose. There were no effects noted with respect to liver or
    kidney weights. The erythrocyte cholinesterase appeared to be the
    most sensitive parameter with all three materials tested. The
    NOAELs, based on erythrocyte cholinesterase depression or decreased
    body-weight gain over the 7-day treatment period were: aldicarb -
    0.8 mg/kg bw/day; aldicarb sulfoxide - 0.4 mg/kg bw/day; and
    aldicarb sulfone - 2.5 mg/kg bw/day (Nycum & Carpenter, 1968b).

         Groups of 5 rats/sex received in the diet, aldicarb (0.3 mg/kg
    bw/day), aldicarb sulfoxide (0.4, 0.8 or 1.6 mg/kg bw/day), aldicarb
    sulfone (0.6, 5 or 20 mg/kg bw/day), a 1:1 mixture of aldicarb
    sulfoxide and aldicarb sulfone (1.2 mg/kg bw/day) or a control diet.
    At the end of the 7 days of feeding, animals were placed on control
    diets for one day after which they were sacrificed for
    cholinesterase determination and for examination of liver and
    kidney. A second one-week feeding trial was performed to compare the
    data with other strains of rats. Aldicarb sulfoxide was fed to
    groups of 5 male rats at dose levels of 0, 0.4, 0.8 or 1.6 mg/kg
    bw/day and aldicarb sulfone was fed to male rats at dose levels of
    0, 5 or 20 mg/kg bw/day. As might be expected with the protocol
    followed in the study, cholinesterase depression was not observed in
    either plasma, erythrocyte or brain at the conclusion of the study.
    The second trial using both the same and a different strain of rats
    was performed in an effort to explain a slight but non-significant
    inhibition of erythrocyte cholinesterase activity measured in the
    initial study. Over the course of this study, there were no effects
    noted on erythrocyte cholinesterase activity (Weil & Carpenter,
    1970c).

         Groups of 5 rats/sex were fed aldicarb sulfoxide in the diet at
    dose levels of 0, 0.3 or 1.0 mg/kg bw/day and aldicarb sulfone at 0,
    2.4 or 16.2 mg/kg bw/day. Animals were sacrificed at 1, 3, 7, 14, 28
    and 56 days for cholinesterase analyses. Plasma and erythrocyte
    cholinesterase activities were measured at the first three time
    intervals. At the last three time intervals, plasma erythrocyte and
    brain cholinesterase activities were examined. There was no
    mortality, but growth was depressed at the highest dose levels with
    both the sulfoxide and sulfone. Rats administered aldicarb sulfoxide
    at 1.0 mg/kg bw/day had a slight but significant cholinesterase
    depression during the study. There were no effects noted at 0.3
    mg/kg bw/day. Cholinesterase depression was marked with the aldicarb
    sulfone consistently throughout the study at the highest dose level
    of 16.2 mg/kg bw/day (Weil & Cox, 1975).

         Groups of 10 Wistar rats/sex were administered aldicarb
    sulfoxide and aldicarb sulfone in a 1:1 ratio, in drinking water,
     ad libitum, for 29 days. The drinking water levels were 0, 0.075,
    0.3, 1.2, 4.8 or 19.2 mg/litre. Plasma and red blood cell
    cholinesterase levels were determined after 8, 15 and 29 days of
    treatment. Brain cholinesterase was measured at termination. Animals

    were continuously exposed to the test substances in water until
    blood samples were taken or sacrifice was performed. There was no
    mortality and food and water consumption values together with body-
    weight gains were significantly decreased in both sexes at the high-
    dose level when compared to controls. Significant depression of
    plasma, RBC and brain cholinesterase, in both sexes, occurred at the
    highest dose level. The data demonstrate that a level of 4.8
    mg/litre of aldicarb sulfoxide:aldicarb sulfone in water is without
    effect on cholinesterase (plasma, RBC, brain) in either sex. Based
    on the actual concentrations being approximately 80% of the nominal
    concentrations, the NOAEL was roughly 3.8 mg/litre, equivalent to
    0.4 mg/kg bw/day (Mirro  et al., 1982).

         Groups of 15 rats/sex were fed aldicarb sulfoxide in the diet
    at dose levels of 0, 0.125, 0.25, 0.5 or 1 mg/kg bw/day for 6
    months. Animals were sacrificed at 3 months and at the conclusion of
    the study for cholinesterase determinations and for gross and
    microscopic examination of liver and kidneys. There was no mortality
    noted during the course of the study, although growth, especially in
    males, at 0.25 mg/kg bw/day and above was reduced. Cholinesterase
    activity was substantially reduced, at the three highest dose
    levels, especially in plasma and erythrocytes of males. Gross
    examination of liver and kidneys revealed no abnormalities
    attributable to aldicarb. The NOAEL in this study was 0.125 mg/kg
    bw/day (Weil & Carpenter, 1968b).

         In an attempt to resolve the question of cholinesterase
    depression and rapid recovery, groups of 5 rats/sex were fed
    aldicarb sulfoxide for one week or one week plus one day of control
    diets at a dose level of 1 mg/kg bw/day. When the study was
    concluded (within one week), animals were sacrificed at 0 and 24 h
    after the dietary feeding interval (the 24 h animals were fed
    control diets). Cholinesterase depression was noted at the 0 h
    sacrifice in erythrocyte and plasma preparations. Administration of
    a control diet for one day (24 h sacrifice) completely reversed the
    cholinesterase depression noted when animals were sacrificed without
    any recovery interval (Weil & Carpenter, 1970c).

         Groups of 5 rats/sex were fed aldicarb sulfoxide in the diet at
    dose levels of 0, 0.0625, 0.125, 0.25, 0.5 or 1.0 mg/kg bw/day for 3
    and 6 months after which some of the animals were sacrificed
    immediately and others were placed on a control diet for 24 h prior
    to sacrifice and cholinesterase analysis. Cholinesterase activity in
    the brain was unaffected by aldicarb sulfoxide. Plasma and
    erythrocyte cholinesterase was substantially reduced at the 0 h
    sacrifice in both sexes. Males were slightly more sensitive with
    depression being noted at 0.25 mg/kg bw/day and above, while with
    females depression was noted at 0.5 mg/kg bw/day and above. There
    was no cholinesterase depression noted in any of the animals treated
    for either 3 months or 6 months when the animals were allowed to
    recover from cholinesterase depression for a one day recovery

    interval. The NOAEL in this study was 0.125 mg/kg bw/day (Weil &
    Carpenter, 1968b).

         In a series of studies similar to those reported with aldicarb
    sulfoxide, groups of rats were fed aldicarb sulfone at dietary
    concentrations at dose levels of 0, 0.2, 0.6, 1.8, 5.4 or 15.2 mg/kg
    bw/day for 6 months. Animals were sacrificed at 3 and 6 months for
    examination of liver and kidney abnormalities and for evaluation of
    cholinesterase activity. Cholinesterase determinations were made at
    the end of the 3 and 6 month intervals with rats fed continuously
    until sacrifice or rats were allowed to consume a control diet for
    24 h prior to sacrifice and determination of cholinesterase
    activity. There was no mortality over the course of the study. 
    Transient but significant growth depression was noted at the highest
    level in the longer study. There were no effects noted with respect
    to food consumption or on gross and microscopic examinations of
    liver and kidneys. Plasma, erythrocyte and brain cholinesterase were
    significantlv depressed at 5.4 mg/kg bw/day and above. Erythrocyte
    cholinesterase depression was also noted at 1.8 mg/kg bw/day. There
    was no cholinesterase depression noted at 0.6 mg/kg bw/day in any of
    the tissues examined. In the study to evaluate recovery of
    cholinesterase activity, when animals were allowed to equilibrate
    for one day on control diets, all depressed cholinesterase values
    returned to normal. The NOAEL in this study was 0.6 mg/kg bw/day
    (Weil & Carpenter, 1968c).

         Groups of rats were fed aldicarb oxime at dose levels of 0,
    31.25, 62.5, 125, 250, 500 or 1000 mg/kg bw/day for 7 days. There
    was no mortality over the course of the study. Growth was slightly
    reduced at the initiation of the study at dose levels of 125 mg/kg
    bw/day and above, but at the end of one week only the two highest
    dose levels appeared to show a retardation in growth. Gross changes
    were noted in both liver and kidneys at the two highest dose levels
    in both males and females. The NOAEL in this study was 62.5 mg/kg
    bw/day (Weil & Carpenter, 1974b).

         Groups of 5 rats/sex were fed the hydrolytic metabolite of
    aldicarb (2-methyl-2-(methylsulfinyl)propanol-1) for 7 days at dose
    levels of 0, 500 or 1000 mg/kg bw/day. Growth was depressed at both
    dose levels in males but only at the highest dose level in females.
    In females, while growth was depressed within one day of treatment,
    the animals appeared to recover during the rest of the week. There
    was no apparent effect on major organs, although, in females at the
    highest dose level, kidney weights were slightly depressed.
    Cholinesterase activity was not measured (Weil & Carpenter, 1969b).

    Rabbits

    - Aldicarb

         Four groups, each of 5 male rabbits with abraded skin, were
    administered aldicarb 10G formulation at dose levels of 0, 5, 10 or
    20 mg/kg bw/day, for 6 h per day, 5 days per week, for 15 days.
    Water was added periodically during the exposure time to the
    dressing containing the aldicarb treatment, simulating a condition
    of excess perspiration. One additional group was administered 20
    mg/kg bw/day to intact, unabraded skin with no water added to the
    dressing. Animals treated with aldicarb under a dry condition with
    unabraded skin showed normal weight gains and no apparent effects as
    a result of the treatment. Administration of aldicarb under
    conditions where the dressing was wet and the skin abraded resulted
    in reduced body-weight at a dermal dose of 5 mg/kg bw/day and above.
    During the interim where dermal treatment was not applied, recovery
    of growth was extremely rapid. Plasma cholinesterase activity was
    inhibited at the two highest dose levels. There were no other
    adverse effects on haematology or clinical chemical parameters and
    limited organ weight analysis and microscopic examination of several
    major tissues showed no pathological effects attributable to
    aldicarb. Almost identical results were also obtained in a similar
    study in rats (Carpenter & Smyth, 1966; Weil & Carpenter, 1968a).

    Rabbits

    - Aldicarb metabolites

         Aldicarb sulfone (technical and 75 WP) were administered to the
    unabraded, but closely clipped, ventral surface of rabbits (6
    males/group, 5 days/week for 19 applications) at dosages of 4.8
    mg/kg bw/day for 75 WP and 3.5, 7.0 or 14.0 mg/kg bw/day for
    technical aldicarb sulfone. No mortality, skin irritation or
    cholinesterase depression were observed. However, rabbits were
    removed from treatment 19 h prior to sampling for cholinesterase
    analyses, which could account for the lack of cholinesterase
    depression. Body-weight was significantly depressed in the high-dose
    level rabbits. There were no reported treatment-related effects on
    organ weights and necropsy findings were unremarkable (Weil  et
     al., 1977).

    Dogs

    - Aldicarb

         Groups of 2 beagle dogs/sex were fed aldicarb at dose levels of
    0, 0.2, 0.3 or 0.7 mg/kg bw/day for 7 days. There was no mortality
    over the course of the study. Plasma, erythrocyte and brain
    cholinesterase activities, measured one day after conclusion of the
    dietary treatment, were normal. Gross liver and kidney weights and

    organ to body-weight ratios were unaffected by aldicarb in the diet
    (Weil & Carpenter, 1973).

         Groups of 4 beagle dogs/sex were fed aldicarb in the diet for
    five days per week at dose levels of 0, 0.2, 0.3 or 0.7 mg/kg bw/day
    for 100 days. There was no mortality over the course of the study
    and growth was comparable within all dosage groups. A slightly
    decreased testes weight and a slight increase in adrenal weight were
    observed at the highest level in males, but there were no effects in
    females on any of the tissues and organs examined. Microscopic
    analysis did not suggest any abnomalities including tissues where
    gross changes had been seen to occur. Cholinesterase values, as well
    as other clinical chemistry and haematology parameters, were
    unaffected by the presence of aldicarb in the diet, however, the
    animals had been removed from aldicarb exposure for 24 to 48 h prior
    to cholinesterase analyses. The NOAEL in this study was 0.3 mg/kg
    bw/day (Weil & Carpenter, 1974c).

         Groups of 3 beagle dogs/sex were fed aldicarb in the diet at
    dose levels of 0, 0.025, 0.05 or 0.1 mg/kg bw/day, 5 days per week
    for 2 years. There was no mortality over the course of the study and
    growth and food consumption data were comparable to control values.
    Haematology parameters and clinical chemistry values, evaluated at
    five intervals over the course of the study were normal. Plasma and
    erythrocyte cholinesterase, evaluated over the course of the study,
    did not differ from control values. At the conclusion of the study
    brain cholinesterase, while somewhat lower at the high dose level,
    was not statistically different from controls. Gross and microscopic
    examination of tissues and organs showed no lesions which could be
    attributable to the presence of aldicarb in the diet at dose levels
    up to and including 0.1 mg/kg bw/day (Weil & Carpenter, 1966c).

         A two-week range-finding study was conducted in beagle dogs to
    select dose levels for a subsequent one-year dog study. Aldicarb was
    fed to groups of 1 male and 1 female at dietary concentrations of 0,
    1, 3, 10, 30 or 100 ppm. There was no mortality during the study,
    but tremors and slight ataxia were observed at 30 and 100 ppm, and
    soft faeces were noted more frequently in these dogs. Food
    consumption was depressed in all treated males, particularly at the
    highest dose, and slightly depressed in the 100 ppm female. Body-
    weight losses were noted in the 100 ppm group and in the 30 ppm
    male. Red blood cell and plasma cholinesterase inhibition exceeded
    25% at doses of 3 ppm and greater. Brain cholinesterase inhibition
    exceeded 25% for the 30 and 100 ppm group males (no calculation was
    possible in the female groups due to presumed technical error)
    (Hamada  et al., 1985b).

         As a clear NOEL for cholinesterase depression was not
    demonstrated in the first study, a second two-week dietary dose
    range-finding study was conducted to select the dose levels for a
    subsequent one-year dog study. Aldicarb was fed to groups of 1 male

    and 1 female at dietary concentrations of 0, 0.1, 0.3, 1, 3 or 10
    ppm. There was no mortality during the study and no
    treatment-related clinical signs were observed. Body-weight change
    and food consumption were unaffected by treatment. Maximum plasma
    and erythrocyte cholinesterase inhibition occurred immediately
    following the two-hour feeding and lasted approximately 4 h after
    the dosing period. Erythrocyte and plasma cholinesterase inhibition
    (> 25% compared to the mean pre-study value) occurred in the 10 ppm
    group on both days 7 and 14. There was no inhibition of brain
    cholinesterase and no other compound-related effects noted. The
    NOAEL in this study was 3 ppm, equal to 0.096 mg/kg bw/day (Hamada,
    1987b).

         In a five-week study, conducted in order to further investigate
    the cholinesterase inhibition dose response curve, aldicarb (99.7%)
    was fed at dietary concentrations of 0, 0.35, 0.7, or 2 ppm, to 3
    groups of 6 beagle dogs/sex. There were no mortalities nor any
    changes in body-weight gain, food consumption, clinical symptoms or
    gross pathology indicative of a compound-related effect seen during
    the study. Plasma cholinesterase inhibition over 20% when compared
    to the control occurred only in the highest dose group. Red blood
    cell cholinesterase activity inhibition was not observed in any dose
    group and brain cholinesterase activity was not measured. No adverse
    effects were observed at 2 ppm (equal to 0.06 mg/kg bw/day) and the
    NOEL for any symptoms including plasma cholinesterase depression was
    0.7 ppm (equal to 0.02 mg/kg bw/day) (Hamada, 1991).

         In a 52-week oral toxicity study in beagle dogs, groups of 5
    dogs/sex were fed dietary concentrations of 0, 1, 2, 5 or 10 ppm
    aldicarb (95.5%) daily for 52 weeks. The study was designed to
    produce maximum cholinesterase depression by limiting feeding time
    to two hours per day to mimic a bolus administration of aldicarb.
    Erythrocyte and plasma cholinesterase activities were measured from
    blood samples collected approximately 2 h after the daily feeding
    period to minimise dissociation of the carbamate-cholinesterase-
    complex. Aldicarb at up to 10 ppm (equal to 0.241 mg/kg bw/day)
    caused no observable effects other than inhibition of cholinesterase
    activity. Inhibition of erythrocyte and brain cholinesterase
    activity was restricted to dogs receiving 5 or 10 ppm. The NOEL for
    plasma cholinesterase inhibition was 1 ppm, equal to 0.027 mg/kg
    bw/day, while if the changes in the plasma enzyme activity are
    discounted, the NOAEL was 2 ppm, equal to 0.054 mg/kg bw/day
    (Hamada, 1988).

         An inhalation study was conducted to determine the toxicity of
    pyrolysis products of cigarettes made from tobacco pretreated with
    aldicarb. Twelve beagle dogs (two animals/sex/dose), which had been
    initially conditioned prior to commencement of the test to smoking
    10 cigarettes per day via tracheostomy, were exposed to untreated,
    low-level and high-level treated cigarettes on a schedule of two
    successive cigarettes 5 times per day, 5 days per week for a total

    of 19 exposure days. Whole blood cholinesterase was monitored
    throughout the study with samples taken before smoking, after 4 and
    after 10 cigarettes. All effects observed in this study were
    apparently due to inhalation of cigarette smoke. No inhibition of
    cholinesterase was seen in any treatment group (Coate  et al.,
    1982).

    Dogs

    - Aldicarb metabolites

         Groups of 3 beagle dogs/sex were fed aldicarb sulfoxide in the
    diet at dose levels of 0, 0.0625, 0.125, 0.25 or 0.5 mg/kg bw/day 5
    days per week for 3 months. There was no mortality over the course
    of the study. Slight body-weight changes were noted in many of the
    dogs at the highest dose level within the first week of treatment
    but thereafter the body-weight changes were similar to but lower
    than control values. No effects on haematologic and blood chemistry
    parameters were observed. Cholinesterase depression measured 24-48 h
    after the final exposure was not observed in plasma, erythrocytes or
    brain of any of the animals at the conclusion of the study. Gross
    and microscopic examination of tissues and organs did not show any
    adverse effects attributable to the presence of aldicarb sulfoxide.
    The NOAEL in this study was 0.25 mg/kg bw/day (Weil & Carpenter,
    1968b).

         Groups of 3 dogs/sex were fed aldicarb sulfone in the diet at
    dose levels of 0, 0.2, 0.6, 1.8 or 5.4 mg/kg bw/day 5 days per week
    for 90 days. There was no mortality over the course of the study.
    Slight body-weight depression was noted at the highest dose level,
    although the body-weight was not statistically lower than control
    levels. There were no effects noted with respect to biochemical and
    haematologic parameters and gross and microscopic examination of
    tissues and organs revealed no effects attributable to the presence
    of aldicarb sulfone in the diet. Cholinesterase depression was not
    observed, but dogs were removed from treated diet prior to
    cholinesterase determinations. The NOAEL in this study was therefore
    greater than 5.4 mg/kg bw/day (Weil & Carpenter, 1968c).

         In a two-week range-finding study, aldicarb sulfone was fed to
    six groups of 1 male and 1 female beagle dog at dietary
    concentrations of 0, 3, 10, 30, 100 or 300 ppm. There was no
    mortality during the study, but emesis, tremors and decreased food
    consumption were observed in the high-dose group. Inhibition of
    cholinesterase (> 25%) occurred at 10 ppm and over in both sexes
    for plasma cholinesterase, and 100 ppm and over for red blood cell
    and brain cholinesterase (Hamada  et al., 1985a).

         In a one-year feeding study, aldicarb sulfone was administered
    to four groups of 6 beagle dogs/sex at dietary concentrations of 0,
    5, 25 or 100 ppm. In this study, samples for cholinesterase

    determinations were taken approximately two hours after feeding in
    order to measure maximum cholinesterase inhibition. No
    treatment-related clinical signs were seen. Body-weight gain was
    slightly reduced in the high-dose males and females. There was a
    slight decrease in the spleen weights of the mid- and high-dose
    females and in the thyroid/parathyroid weight of the high-dose
    females when compared to respective control values. These changes
    were not seen in the males. Slight treatment-related effects were
    noted in the mandibular lymph nodes of the high-dose males and
    females, and adrenal cortex of the high-dose females. The NOAEL
    based on depression of erythrocyte and plasma cholinesterase
    activity was 25 ppm, equal to 0.54 mg/kg bw/day (Hamada, 1987a).

    Monkeys

         As a result of reports of alleged illness associated with
    consumption of watermelons and cucumbers illegally treated or
    contaminated with aldicarb in 1985, two studies were conducted to
    evaluate the acute toxicity of aldicarb residues in food
    commodities. Two crops were chosen for the studies: bananas as a
    representative of a registered food crop in the USA, and watermelons
    as a representative of a non-registered food crop from the cucurbit
    family. (Suggestions had been made that some possible natural
    component in cucurbits might synergise aldicarb toxicity). Bananas
    were treated with approximately ten times the recommended label rate
    and watermelons were treated at 13.44 kg ai/ha, to ensure adequate
    residues in the fruit. Each study was performed using 3  Cynomolgus
    monkeys/sex, with an additional group of 3 monkeys/sex serving as a
    control (total of 12 animals per study). Following analytical
    determination of actual residues in the two commodities to be
    consumed, (approximately 0.3 ppm in bananas and 5 ppm in
    watermelons), intake of the treated crops was adjusted with control
    fruit to provide a dose of exactly 0.005 mg aldicarb/kg bw. The
    animals were offered the fruit as the first meal of the day, and
    consumed it immediately. Individuals were monitored for clinical
    signs at regular intervals, and plasma and erythrocyte
    cholinesterase activities were measured pre-dose, then at 1, 2, 4,
    6, 12, 18 and 24 hours post-feeding. In both studies, there was no
    evidence of acute cholinergic distress or any signs of over-exposure
    in any animal. Depression of plasma cholinesterase activity was
    evident within 1-4 h after ingestion and reached a maximum of 32 to
    36% at 2 h after feeding (banana trial) and 36 to 37% at 1 h after
    feeding (watermelon trial). Erythrocyte cholinesterase activity was
    not depressed in either study. Rapid recovery of all enzyme activity
    was observed. There was no indication in these studies that
    components in watermelons potentiate aldicarb toxicity (Trutter,
    1987a,b).

    Long-term toxicity/carcinogenicity studies

    Mice

    - Aldicarb

         Groups of 50 B6C3F1 mice/sex (25 of each sex were used as
    controls) were fed aldicarb at dietary concentrations of 0, 2 or 6
    ppm for 103 weeks in a carcinogenicity bioassay. A preliminary
    dietary study (using 10 mice/sex fed dietary concentrations of
    aldicarb of 0, 0.5, 1.0, 2.5, 5, 10, 20 or 40 ppm for 13 weeks)
    showed no significant effects on microscopic examinations of the 0,
    20 and 40 ppm levels. In the long-term carcinogenicity study there
    was no mortality attributable to aldicarb. A variety of benign and
    malignant tumours, occurring at different sites in both control and
    aldicarb-treated mice, were not unusual for this strain of mice and
    were evaluated to be independent of the administration of aldicarb.
    Gross and microscopic examination of tissues, organs and all gross
    lesions was performed and it was concluded that aldicarb was not
    carcinogenic for the B6C3F1 strain of mice of either sex (NIH,
    1979).

         Groups of 44 CD-1 mice/sex were fed aldicarb at dose levels of
    0, 0.1, 0.2, 0.4 or 0.7 mg/kg bw/day for 18 months. Mortality was
    evident in males at the two highest dose levels and in females at
    the three highest dosage levels during the first two and one-half
    months of the study. Following this period, aldicarb was admixed
    with the diet in a different manner which appeared to eliminate its
    acutely toxic effects. (In the early parts of the study, aldicarb
    was mixed in a dry fashion using a finely ground aldicarb
    preparation. At the 2.5 month interval, aldicarb was dissolved in
    acetone and the acetone-aldicarb solution was dispersed in the diet
    at a more uniform rate. It was assumed that consumption of small
    crystalline particles of aldicarb may have led to the high mortality
    during the initial phases of the study). At the high dose level in
    males there was a statistically significant increase in hepatomas
    found predominantly in the survivors at the termination of the study
    and an increase in lymphoid neoplasias which occured in the mice
    that died. None of the male mice surviving at the end of the study
    were found to have lymphoid neoplasias. There were no significant
    increases in any other types of tumours at dose levels of 0.4 mg/kg
    bw/day and below (Weil & Carpenter, 1972c).

         Groups of 50 male CD-1 mice were fed aldicarb at dose levels of
    0, 0.1, 0.3 or 0.7 mg/kg bw/day in an effort to verify the results
    of the previous mouse carcinogenicity bioassay. A group of 150 mice
    were used as concurrent controls with a mouse being sacrificed for
    each treated animal that died during the course of the study. Diets
    were prepared by dissolving aldicarb in acetone and mixing the
    solution with the diet. The aldicarb was the same sample as used in
    the previous study and the duration of the study was approximately

    the same as in the previous trial. There was no mortality observed
    in the study as a result of aldicarb in the diet. At the end of 18
    months cumulative mortality at all dose levels was the same as noted
    in controls. There was no effect of aldicarb on growth in any of the
    groups. An examination of the animals that died during the course of
    the study and those that were sacrificed at the end of 18 months was
    made and the data compared with control values. There was no
    significant association between aldicarb in the diet and the
    formation of tumours, particularly with respect to the incidence of
    hepatomas, lung adenomas, and lymphoid neoplasias. The data were
    evaluated with respect to the mice that died, those that survived
    the test and the total of all animals. It was concluded that the
    administration of aldicarb at levels up to and including 0.7 mg/kg
    bw/day for approximately 18 months did not result in a higher than
    normal incidence of tumours and the inclusion of aldicarb in the
    diet of CD-1 mice did not result in an increased incidence of
    carcinogenic response (Weil & Carpenter, 1974d).

         Groups of C3H/Hej male mice were administered aldicarb
    dissolved in acetone, dermally 3 times a week for 28 months by
    applying a brush full of an acetone solution to the shaved back of
    the mice. For the first 2 weeks, treatment was performed 3 times a
    week using a 0.25% solution in acetone. After 2 weeks this was
    reduced to a twice weekly application. This dosing regimen was
    maintained for 2 months and further reduced thereafter to a
    concentration of 0.125% which was maintained for the rest of the
    study. While there was some aldicarb-induced mortality noted over
    the course of the study this mortality was not substantially
    different from that noted with control applications. There were no
    substantial differences with respect to the incidence or onset of
    tumours. Two growths, a haemangioma and a thymoma, were noted in the
    animals administered aldicarb. Neither of these internal growths was
    accompanied by cutaneous papillomas or carcinomas and were
    considered to be spontaneous growths unrelated to treatment.
    Aldicarb, administered dermally to this sensitive species, did not
    induce any incidence of malignancy (Weil & Carpenter, 1966b).

    Mice

    - Aldicarb metabolites

         Groups of Charles River CD-1 mice (50/sex/group) were
    administered 0, 0.15, 0.6, 2.4 or 9.6 mg aldicarb sulfone/kg bw/day
    via the diet for 18 months. Aldicarb sulfone did not affect tumour
    incidence or produce any pathological alteration in this strain of
    mouse (Woodside  et al., 1977b).

    Rats

    - Aldicarb

         Groups of 20 rats/sex were fed aldicarb for 2 years at dose
    levels of 0, 0.005, 0.025, 0.05 or 0.1 mg/kg bw/day. Additional
    groups of 16 rats/sex were maintained for serial sacrifices at 6 and
    12 months. There was no mortality, attributable to the presence of
    aldicarb. Growth was normal at all dose levels as was consumption of
    food and behavioural characteristics. Results of gross examination
    of liver and kidney weight at 6 months and at one year did not
    differ from control values. Haematologic determinations in the
    highest dose level and control groups were normal. Blood and brain
    cholinesterase activity, measured at 6 and 12 months, were normal.
    Microscopic examination of tissues and organs for histopathologic
    occurrences and neoplasms showed the incidence of lesions to be
    similar in aldicarb-treated and in control groups. An apparent
    no-effect-level in this study is 0.1 mg/kg bw/day (Weil & Carpenter,
    1965).

         Groups of 50 F344 rats/sex (25/sex for controls) were fed
    aldicarb in the diet at dietary concentrations of 0, 2 or 6 ppm for
    103 weeks. A preliminary study used 10 rats/sex, with dietary
    concentrations of 0, 5, 10, 20, 40, 80, 160 or 320 ppm for 13 weeks.
    Microscopic examinations performed on male and female rats of the 0
    and 80 ppm dose levels at the conclusion of the preliminary trial
    showed no significant effects. In the long-term carcinogenicity
    study, there was no mortality attributable to aldicarb in the diet.
    A variety of benign and malignant tumours occurring at different
    sites in both control and aldicarb treated rats were not unusual for
    this strain of rat and were evaluated to be independent of the
    administration of aldicarb. Gross and microscopic examination of
    tissues, organs and all gross lesions was performed and it was
    concluded that aldicarb was not carcinogenic for the F344 strain of
    rat of either sex at dietary concentrations of up to 6 ppm (NIH,
    1979).

    Rats

    - Aldicarb/Aldicarb metabolites

         Groups of 20 rats/sex were fed aldicarb for 2 years at dose
    levels of 0 or 0.3 mg/kg bw/day. In addition, groups of rats were
    fed aldicarb sulfoxide (0.3 or 0.6 mg/kg bw/day), aldicarb sulfone
    (0.6 or 2.4 mg/kg bw/day) or a 1:1 mixture of aldicarb sulfoxide and
    aldicarb sulfone (0.6 or 1.2 mg/kg bw/day). There was no significant
    mortality observed over the course of the study with any of the
    individual chemicals or the mixture of sulfoxide and sulfone. In the
    initial phases of the study, there was a slightly higher mortality
    noted in the high-dose level of aldicarb sulfoxide and in the group
    receiving the combined aldicarb sulfoxide and aldicarb sulfone. A

    slight increase in mortality was also noted at the latter part of
    the study with aldicarb sulfoxide. Growth was slightly depressed at
    the high-dose level of the sulfoxide:sulfone mixture, primarily in
    males. There were no apparent effects on growth with respect to the
    aldicarb, aldicarb sulfoxide or aldicarb sulfone administered alone.
    Haematological values observed at various intervals over the course
    of the study did not differ from controls. Cholinesterase
    determinations were made periodically over the course of the study
    (6, 12 and 24 months). Plasma, erythrocyte and brain cholinesterase
    were examined only at a 24-h interval after animals were removed
    from test diets. There was a slight depression of plasma
    cholinesterase noted in males administered the high-dose level of
    the combination aldicarb sulfoxide and sulfone at the 24-month
    interval. A repeat of the analyses within the final week of the
    study showed a slight depression in all chemical groups with respect
    to plasma cholinesterase. There were no effects noted at any
    interval with respect to red blood cell or brain cholinesterase. The
    plasma cholinesterase depression noted at the 24-month interval was
    limited to male rats. An evaluation of the incidence of tumours
    suggested that there was no statistical difference between treated
    and control groups. Gross and microscopic examination of tissues and
    organs at various periods over the two-year test interval showed
    that these sporadically distributed lesions could not be considered
    to be indicative of damage induced by aldicarb, its major
    metabolites, or the combination of the sulfoxide and sulfone (Weil &
    Carpenter, 1972a).

    Reproduction studies

    Rats

    - Aldicarb

         Groups of rats (8 male and 16 female rats per group) were fed
    aldicarb at dietary concentrations at doses of 0, 0.05 or 0.1 mg/kg
    bw/day for approximately 90 days and mated to initiate a 3-
    generation, one litter per generation reproduction study. Dietary
    administration was continuous throughout the study. In addition to
    the reproduction indices (fertility, gestation, viability and
    lactation) the F3 generation was maintained for an additional
    period and tissues from these animals were histologically examined
    at either weaning or at 90 days of age. In all groups, the
    reproduction indices from the aldicarb-treated animals were similar
    to the control group. Body-weights of both male and female pups at
    weaning were similar to control values as were results of gross and
    microscopic examinations of tissues and organs in the F3 weanling
    and 90-day old animals. In all three generations, with all criteria
    examined, there were no effects of aldicarb on reproduction at a
    dose level of 0.1 mg/kg body-weight (Weil & Carpenter, 1964).

         Groups of rats (10 male and 20 female per group) were
    administered aldicarb in the diet at doses of 0, 0.2, 0.3 or 0.7
    mg/kg bw/day for 100 days prior to pairing and mated to initiate an
    additional 3-generation (one litter per generation) reproduction
    study. Dietary administration was continuous throughout the study. A
    larger group was used for the F2 generation (15 male and 25 female
    rats) as male pups of this generation were maintained on aldicarb
    diets for 148 days and subjected to a (modified) dominant lethal
    (mutagenesis) bioassay where they were mated with groups of
    untreated virgin females for a period of 10 weeks. Each female in
    the group was mated with 2 treated males and allowed to maintain
    pregnancy until day 12 when they were sacrificed and examined. There
    was some mortality over the course of the study which was associated
    with lung infection and not as a result of aldicarb in the diet. At
    the high-dose level, body-weights of both male and female F2 pups
    were lower than the control values. Overall, there were no effects
    on any of the reproduction indices (fertility, gestation, viability,
    or lactation). Gross and microscopic examinations of the parents and
    pups of the high level and control groups showed no effects
    attributable to aldicarb. The dietary dominant lethal mutagenesis
    bioassay showed no statistical differences between the
    aldicarb-treated rats and controls with respect to early or late
    fetal death or any other parameter examined (Weil & Carpenter,
    1974a).

    Rats

    Aldicarb metabolites

         Aldicarb sulfone (99.76% pure) was fed to groups of 10 male and
    20 female rats at dietary concentrations at doses of 0, 0.6, 2.4 or
    9.6 mg/kg bw/day for approximately 100 days. Rats were then mated to
    initiate a three-generation, one litter per generation, reproduction
    study. Dietary administration was continuous throughout the study.
    Male rats fed 9.6 mg/kg bw/day exhibited reduced body-weights. There
    were no differences from the control with regard to fertility,
    gestation survival or viability indices. It was determined that
    aldicarb sulfone, at levels up to and including 9.6 mg/kg bw/day,
    was without adverse effects on reproduction under the conditions of
    this study (Woodside  et al., 1977a).

    Special studies on embryo/fetotoxicity

    Rats

    - Aldicarb

         Using a test protocol where both the reproductive and
    teratologic potential of aldicarb was evaluated, groups of pregnant
    rats were fed aldicarb at dietary concentrations at dose levels of
    0, 0.04, 0.2 and 1.0 mg/kg bw/day. Females from each of the dietary

    groups were assigned to one of three treatment groups: (1) aldicarb
    administered in the diet throughout pregnancy or until pups were
    weaned; (2) aldicarb administered in the diet from day 0 to day 7 of
    gestation; (3) aldicarb administered in the diet from day 5 to day
    15 of gestation. Five or six females from each group were sacrificed
    and examined on day 20 of pregnancy and a similar number of females
    were allowed to bear, nurse and wean the pups. There were neither
    gross manifestations of teratogenicity in any of the pups carried by
    females administered aldicarb at dose levels of up to 1 mg/kg bw/day
    nor was there apparent interference with the reproductive process by
    any of the dosage regimens used in this study. The administration of
    aldicarb at dose levels up to and including 1.0 mg/kg bw/day had no
    apparent effect on the growth of pregnant females during the course
    of the study (Weil & Carpenter, 1966a).

         Pregnant Sprague-Dawley rats were given aldicarb by gavage at
    levels of 0, 0.125, 0.25 or 0.5 mg/kg bw/day on gestational day 6
    through day 15. Maternal toxicity was indicated, at the highest
    dose, by reduced weight gain and food intake during the treatment
    and post-treatment period as well as by the occurrence of three
    maternal deaths and, at the two highest levels, by reduced food
    consumption during treatment. Gestational parameters, including
    ovarian corpora lutea, number of implantations per litter and sex
    ratio were unaffected by treatment. Fetal body-weight per litter was
    significantly reduced at 0.5 mg/kg bw/day. There was no increase in
    the incidence of external or skeletal malformations. A significantly
    increased incidence of dilated lateral ventricles with tissue
    depression was observed only at 0.5 mg/kg bw/day. No increased
    incidence of malformation was observed in the absence of clear
    maternal toxicity nor were these malformations accompanied by more
    severe malformations. The NOEL was 0.125 mg/kg bw/day for maternal
    toxicity and 0.25 mg/kg bw/day for embryo-fetal toxicity and
    teratogenicity (Tyl & Neeper-Bradley, 1988).

    Rats

    - Aldicarb metabolites

         The aldicarb sulfone reproduction study incorporated a
    teratology bioassay. The animals were divided into 4 groups and
    orally dosed with 0, 0.6, 2.4 or 9.6 mg/kg bw/day at one of the
    following time intervals of gestation: 0-20 days, 6-15 days, or 7-9
    days. All animals were sacrificed before parturition (day 20) and
    the fetuses examined for skeletal and visceral changes. Anomalies
    were essentially non-existent and there was no indication of
    structural abnormalities produced under the conditions of the study
    at levels up to and including 9.6 mg/kg bw/day (Woodside  et al.,
    1977a).

    Rabbit

    - Aldicarb

         A range-finding study was conducted with aldicarb in rabbits to
    determine dosage levels of aldicarb for a teratology study. Pregnant
    Dutch belted rabbits (5/dose) were dosed by oral gavage at 0.1,
    0.25, 0.5, 0.75 or 1.0 mg/kg bw/day on days 6 to 27 of gestation.
    Two does in the high-dose group and one doe in the second highest
    group died during the study. Increased incidences of decreased
    defecation (all except low-dose group) and soft stools (two highest
    dose groups) were noted. Maternal body-weight losses or markedly
    decreased maternal body-weight gain during the treatment and
    gestation intervals were observed at 0.25 mg/kg bw/day and greater.
    Of the uterine parameters measured, there was an increase in the
    mean post-implantation loss in the high-dose group. Dosage levels of
    0.1, 0.25 and 0.5 mg/kg bw/day were selected for the definitive
    study (Aldridge  et al., 1983).

         Pregnant Dutch belted rabbits (16/dose) were dosed by oral
    gavage at 0.1, 0.25, or 0.5 mg/kg bw/day on days 7 to 27 of
    gestation. Signs of maternal toxicity in the treated groups included
    small amount of stool, pale kidneys and hydroceles on oviducts. A
    loss in body-weight occurred in the 0.25 and 0.5 mg/kg bw/day dosage
    groups during gestation days 7 to 27. A decline in the number of
    viable fetuses per doe was observed in all treatment groups (8.7,
    5.0, 6.5 and 6.2 for the control, 0.1, 0.25 and 0.5 mg/kg bw/day
    treatment groups, respectively). This can be explained by an
    unusually high number of implantations in the control group (9.8,
    6.1, 7.2 and 7.8 implantations per doe in the control, 0.1, 0.25 and
    0.5 mg/kg bw/day treatment groups, respectively). There was no clear
    dose-effect relationship. There were also no increases in
    post-implantation losses (1.1, 1.1, 0.7 and 1.7 post-implantation
    losses for the control, 0.1, 0.25 and 0.5 mg/kg bw/day treatment
    groups, respectively) these figures falling within the historical
    control range. There was no meaningful difference in any of the
    other developmental parameters nor in the number of developmental
    variations or malfunctions between the control and treatment groups.
    Aldicarb did not produce a teratogenic response when administered
    orally to rabbits by gavage at dosage levels up to 0.5 mg/kg bw/day
    (Leng  et al., 1983).

    Special studies on genotoxicity

         Results of genotoxicity tests are summarised in Tables 3 and 4
    (for  in vitro and  in vivo tests with aldicarb) and Table 5 (for
     in vitro tests with aldicarb metabolites).


    
    Table 3:  Results of in vitro genotoxicity assays on aldicarb
                                                                                                             
    Test System        Test Object           Concentration       Purity   Results     Reference
                                                                                                             

    Ames test          S. typhimurium        50-5000 µg/plate    nk       Negative    Godek  et al. (1980c)
                       TA98,TA100,TA1535,
                       TA1537,TA1538

    Reverse            E. coli WP2           nk                  nk       Negative    Dunkel  et al. (1985)
    mutation assay

    Reverse            S. cerevisiae         nk                  nk       Negative    Guerzoni  et al. (1976)
    mutation assay

    HGPRT forward      CHO cells             1000-5000 µg/ml     nk       Negative    Stankowski  et al. (1985a)
    mutation assay

    SCE                Human                 nk                  nk       Weak        Debuyst & Larebeke (1983)
    mutation assay     lymphocytes                                        Positive

    Cytogenetics       Human                 10-250 µg/ml        nk       Weak        Cid & Matos (1984)
    mutation assay     lymphocytes                                        Positive

    UDS                Rat hepatocytes       0.16-5000 µg/ml     nk       Negative    Godek  et al. (1984a)

    DNA damage         S. typhimurium        > 500 µg/disc       nk       Positive    Rashid & Mumma (1986)
                       TA 1538 uvrB
                       TA 197
                                                                                                             

    nk: not known

    Table 4: Results of in vivo genotoxicity assays on aldicarb
                                                                                                               
    Test System        Test Object           Concentration       Purity   Results     Reference
                                                                                                               

    Micronucleus       Mouse                 0.001-0.01          93.47%   Negative    Ivett  et al. (1984)
    test                                     mg/kg bw

    Micronucleus       ICR mouse             0.1-0.4             99.7%    Negative    Ivett (1990)
    test                                     mg/kg bw

    Dominant           Wistar rat            0.2-0.7             99.2%    Negative    Weil & Carpenter (1974a)
    lethal test                              mg/kg bw
                                                                                                               

    Table 5: Results of in vitro genotoxicity assays on aldicarb metabolites
                                                                                                                  
    Test System        Test Object           Concentration       Purity   Results     Reference
                                                                                                                  

    Ames test          S. typhimurium        50-5000 µg/plate    nk       Negative    Godek  et al. (1980b)
                       TA98,TA100,TA1535,    sulphoxide
                       TA1537, TA1538

    Ames test          S. typhimurium        100-10000 µg/plate  nk       Negative    Godek  et al. (1980a)
                       TA98,TA100,TA1535,    sulphone
                       TA1537, TA1538

    HGPRT forward      CHO cells             500-1500 µg/ml      nk       Negative    Stankowski  et al. (1985b)
    mutation assay                           sulphone

    Cytogenetics       CHO cells             50-500 µg/ml        nk       Negative    San Sebastian  et al. (1984)
    mutation assay                           sulphone

    UDS                Rat hepatocytes       0.1-3000 µg/ml      nk       Negative    Godek  et al. (1984b)
                                             sulphone
                                                                                                                  

    nk: not known


    
    Special studies on skin and eye irritation and sensitization

         Administration of aldicarb to the conjunctival sac of rabbits
    did not produce ocular irritation or corneal damage. Ocular
    irritation studies were performed at doses that were lethal without
    indication of ocular damage. Furthermore, there was no evidence of
    dermal irritation when aldicarb was applied to the shaved, abraded
    backs of rabbits (Striegel & Carpenter, 1962).

         There was no indication of a sensitization reaction induced by
    aldicarb. Male guinea-pigs were administered aldicarb by multiple
    subdermal applications (0.7 mg/kg body-weight) and re-administered
    aldicarb three weeks later by a similar intradermal administration.
    There was no suggestion of sensitization in any of the animals
    tested (Pozzani & Carpenter, 1968a).

         Skin sensitization to aldicarb sulfone (UC 21865, technical) or
    a 75% WP formulation was evaluated in albino guinea-pigs (Hartley
    Strain) using a modified Landsteiner technique. Neither substance
    was determined to be a sensitizer under the conditions of this study
    (Conroy & Carpenter, 1977).

    Special studies on delayed neurotoxicity

    Hens

    - Aldicarb

         Groups of 6 adult chickens were administered aldicarb as a
    single oral dose of 4.5 mg/kg bw or as daily oral doses of 0, 2.25
    or 4.5 mg/kg bw/day for 30 days. A positive control group, treated
    with 100 mg of TOCP, was used to produce typical delayed neurotoxic
    signs of poisoning. While there was some weight loss, which was
    correlated with the dose of aldicarb administered, the only
    neurological effects attributable to aldicarb were acute signs of
    poisoning noted in the first two or three days of treatment. Neither
    ataxia nor hind limb paralysis were noted over the course of the
    study. Aldicarb did not induce a delayed neurotoxic syndrome similar
    to that induced by certain organophosphate esters (Johnson &
    Carpenter, 1966a).

    Hens

    - Aldicarb metabolites

         A group of 40 adult white Leghorn hens were intubated to
    receive 250 mg/kg bw aldicarb sulfone suspended in maize oil. Two
    other groups, each with 10 hens, received either TOCP (500 mg/kg bw)
    or maize oil alone, and served as positive and negative control
    groups respectively. There were no neurological effects other than
    acute cholinergic signs of poisoning in the TOCP dosed group. No

    histological examination was performed, owing to the lack of
    demonstrated neurotoxic signs. Aldicarb sulfone did not cause
    delayed neurotoxic reactions under the conditions of the study
    (Babish & Salerno, 1977).

    Special studies on behaviour

         The effects of acute administration of aldicarb and aldicarb
    sulfoxide on avoidance behaviour in rats was compared to a variety
    of other carbamate esters. Rats were trained and evaluated for their
    ability to avoid electrical shock in standard avoidance behaviour
    tests. Aldicarb and aldicarb sulfoxide were administered by
    intraperitoneal injection and the rats were evaluated for their
    ablity to avoid shocks over a 6 h period following administration.
    The lowest beviourally effective dose was found to be 0.266 mg/kg bw
    which, when compared to the acute ip LD50 value, was noted to have
    a smaller ratio of behaviour effects to acute LD50 than any of the
    other carbamates tested. These data suggest that the level of
    aldicarb needed to produce measurable avoidance is greater (closer
    to a fatal dose and less likely to be achieved at the suggested use
    level) than the chemicals to which it was compared. Additionally,
    the activity over the 6-h period was seen to rapidly decline again
    attesting to the transient nature of the cholinesterase inhibition
    (Johnson & Carpenter, 1966b).

    Special studies on immune responses

         Aldicarb was evaluated for its ability to modulate the immune
    response in two strains of mice. The B6C3F1 mouse was chosen
    because it is the strain used by the US National Toxicology Program
    for immunotoxicology studies, and the hybrid Swiss Webster mouse was
    included because aldicarb had been reported to suppress the splenic
    plaque-forming cell response to sheep red blood cells in an inverse
    dose-response fashion (Olson  et al., 1987). An attempt was made to
    reproduce these findings and to expand the data base using more
    standardised techniques with the B6C3F1 strain. Aldicarb was
    administered in the drinking water  ad libitum for 34 consecutive
    days to female mice of both strains at dosages ranging from 0.1 to
    1000 µg/litre in 10-fold increments (equivalent to 0.04 to 364 mg/kg
    bw/day). Aldicarb had no effects on body-weights or organ weights,
    on numbers or types of circulating white blood cells, or on the
    microscopic pathology of the thymus, spleen, liver, kidneys, or
    lymph nodes. Also unaffected were the number of antibody forming
    cells in the spleen and the amount of circulating antibody in the
    blood. Aldicarb had no effect in either strain on  in vivo host
    resistance to infectious viral challenge, on the capacity of B- and
    T-lymphocytes to respond to nonspecific mitogens, or on the ability
    of T-lymphocytes to recognize genetically different cell types in a
    mixed lymphocyte culture. In this study, subchronic exposure to
    aldicarb in the drinking water of mice had no effect on any measured

    immunological function or toxicological parameter (Thomas  et al.,
    1987).

         In another study, adult female B6C3F1, mice received
    distilled water only or water containing 1.0, 10 or 100 µg/litre of
    aldicarb daily for 34 days. To further develop an immune profile of
    the compound, following aldicarb exposure, the ability of splenic
    natural killer (NK) cells as well as specifically sensitized
    cytotoxic T-lymphocytes to lyse YAC-1 lymphoma and, P815 tumour
    cells, respectively, was evaluated. To complement the functional
    assays, the impact of aldicarb exposure on spleen cell viability,
    splenic cellularity and the percentages and absolute numbers of
    total T-cells, T-suppressor, T-helper and B-cells was evaluated. The
    results of this study demonstrated that aldicarb did not impact upon
    the functional ability of interferon-induced splenic NK cells to
    lyse YAC-1 lymphoma target cells. Aldicarb had no effect on the
    functional capacity of cytotoxic T-lymphocytes to recognize
    allogeneic cells  in vivo and undergo differentiation and lysis of
    these cells in a short-term 51-Cr release assay. The numbers and
    percentages of T-cell subpopulations and B-cells in the spleen also
    were not significantly affected. In addition, aldicarb had no
    significant effect on body-weights, on spleen cellularity or cell
    viability or on absolute weights of lymphoid organs. The absence of
    statistically significant effects on any of these parameters
    indicated that aldicarb did not have adverse effects on the immune
    system of mice (Thomas  et al., 1990).

    Special studies on pesticide antagonistic agents

         Following acute oral administration to rats, aldicarb has been
    shown to induce a strong muscarinic action at excretory, bronchial
    and cardiac nerve sites. A nicotinic effect was also shown to occur
    at myoneural junctions. The parasympathetic signs of poisoning were
    readily reduced following atropine administration. Administration of
    atropine and 2-PAM, alone, or in combination, showed that while
    atropine was a more effective antidote, 2-PAM was also active. While
    it has been shown that aldicarb elicits a strong muscarinic action
    as well as nicotinic action at myoneural sites, the control of signs
    of poisoning from both mechanisms appears to be somewhat difficult
    to achieve. Atropine has been shown to be an effective antidote to
    block the muscarinic effects, but decamethonium, commonly used to
    block the nicotinic effects, has been shown to be somewhat
    ineffective. Additional studies to influence the nicotinic actions
    by such drugs as tubocurare also failed to completely eliminate
    nicotinic activity. Further studies confirmed the therapeutic
    effects of a variety of oximes (P2S and obidoxime) in reducing the
    acute toxic signs of poisoning associated with aldicarb. (Johnson &
    Sullivan, 1968a,b; Natoff & Reiff, 1973).

    Special studies on pesticide interactions

         Aldicarb was administered orally to male rats alone and in
    combination with a series of eight organophosphate esters or one
    carbamate ester, all anti-cholinesterase agents, to examine the
    potential interactive or additive effects. Results of the study,
    using proportions of the acute lethal dose of each material alone
    and in combination with aldicarb, showed a simple additive effect
    with all materials tested. Aldicarb was not found to potentiate the
    acute oral toxicity of other anticholinesterase agents. Further
    studies were reported on the potential interaction of aldicarb with
    alpha-naphthol, aldicarb sulfoxide with aldicarb sulfone and
    aldicarb sulfone with parathion administered orally and aldicarb
    with alpha-naphthol or with carbaryl administered by the
    intraperitoneal route. In no case were any interactions greater tban
    the predicted additive effects (West & Carpenter, 1966a; Weil &
    Carpenter, 1970a).

    Observations in humans

         Groups of 4 adult male volunteers were administered aldicarb
    orally in aqueous solution at dose levels of 0.025, 0.05 or 0.1
    mg/kg body-weight. Clinical signs of poisoning were recorded and
    whole blood cholinesterase activity was measured up to 6 h after
    administration of the sample. Total urine voided was collected and
    aldicarb-excretion patterns for the initial 8 h after dosing were
    evaluated. In addition, spot samples were taken at 12 and 24 h.
    Acute signs of poisoning, typical of anticholinesterase agents, were
    observed at the high-dose level within 1 h after administration of
    aldicarb. There were no signs of poisoning observed at the 0.05
    mg/kg body-weight dose level. Cholinesterase depression was observed
    in all volunteers prodominantly within 1-2 h after treatment. Within
    the first six hours of treatment almost all cholinesterase
    depression and clinical signs of poisoning were diminished.
    Examination of urinary excretion patterns showed that approximately
    10% of the administered dose was excreted as carbamates (toxic
    residues) within the first 8 h interval. Cholinesterase analyses
    confimed the same rapid inhibition and recovery pattern with man as
    had been observed in experimental animals (Haines, 1971).

         In another study, two additional subjects were administered
    aldicarb in water solution at dose levels of 0.05 and 0.26 mg/kg
    body-weight. Acute signs of poisoning were recorded at the higher-
    dose level and atropine was administered to aid recovery. No signs
    of poisoning were recorded with the lower-dose level. Urinary
    excretion of carbamate residues within 24 h accounted for
    approximately 10% of the administered dose (Cope & Romine, 1973).

         A double blind, placebo controlled study has been conducted, in
    which aldicarb was given as a single oral dose to healthy male and
    female subjects. The doses administered were: placebo (22 subjects -

    16 males and 6 females), 0.01 mg/kg bw (8 males), 0.025 mg/kg bw (8
    males and 4 females), 0.05 mg/kg bw (8 males and 4 females) and
    0.075 mg/kg bw (4 males). Subjects were screened before entry by
    general medical history and examination and laboratory tests
    including haematology, clinical chemistry and urinalysis. Clinical
    measurements were made at intervals before and after dosing. These
    included vital signs, (systolic and diastolic blood pressure, pulse
    rate), pulmonary function tests, pupil size, electrocardiographs,
    salivation and clinical signs of nausea, vomiting, diarrhoea,
    sweating, abdominal cramps, involuntary movement and slurred speech.
    Samples were taken for urinalysis, clinical chemistry (including red
    blood cell and plasma cholinesterase activity) and haematology
    evaluation before and after dosing. Urine and blood were collected
    for aldicarb analysis. The results of these latter analyses were not
    reported. There were no clinically significant changes in vital
    signs, pupil size, pulmonary function, ECG's, salivation, clinical
    signs, clinical chemistry (apart from cholinesterase), haematology
    or urinalysis in the study. Cholinesterase activity in red cells and
    plasma was maximally depressed at one hour after dosing and had
    recovered by 8 h in all subjects. The fall in activity was dose-
    related. Only marginal depression of cholinesterase activity (< 20%)
    was seen in erythrocytes from patients treated with 0.01 or 0.025
    mg/kg bw and in plasma at 0.01 mg/kg bw. Depression in
    cholinesterase activity > 20% was seen in erythrocytes at 0.05 and
    0.075 mg/kg bw and in plasma at 0.025, 0.05 and 0.075 mg/kg bw. No
    serious adverse events occurred. The minor adverse events which were
    recorded were similar to those reported in other volunteer studies.
    Only one subject (0.075 mg/kg bw group, actual dose 0.06 mg/kg bw)
    developed symptoms which were reported to be related to aldicarb.
    The NOAEL in this study should be based on depression (> 20%) in
    erythrocyte cholinesterase activity and was thus 0.025 mg/kg bw
    (Nimmo  et al., 1992).

         Fifteen male volunteers participated in a study in Panama to
    evaluate human exposure in a banana plantation where Temik-15G was
    applied under natural conditions. Temperatures ranged from 24 °C to
    32 °C with 80% to 90% relative humidity. The workers used three
    different types of hand-held applicators. Blood samples were taken
    from all volunteers prior to initiating the test and immediately
    following each 6 h working period for estimation of blood
    cholinesterase activity. Samples were obtained in the field and
    analyzed 1-2 h later in the laboratory. Only two workers showed
    greater than 25% reduction in their blood cholinesterase activity
    (29% and 50%). Spontaneous reversibility was evident in both cases.
    The worker with 50% reduction showed 25% recovery within 3 h. Blood
    samples from the other worker indicated 100% recovery 24 h later.
    Results of blood analyses indicated that cholinesterase activity was
    below the normal range (population) in samples collected from six
    workers during the second day of the study. Cholinesterase activity
    in all samples taken during the first and third day of the study
    were within the normal range. No clinical signs of aldicarb-induced

    intoxication were found, although one individual presented symptoms
    of nausea, stomachache and headache (Union Carbide, 1979).

         A series of human exposure episodes was reported occurring as a
    result of a variety of field and glasshouse conditions in an effort
    to assess the potential for human harm from exposure under actual
    occupational conditions. In several instances, slight blood
    cholinesterase depression attested to the actual exposure situation.
    Exposure data, as indicated by cholinesterase depression or urinary
    excretion, suggested that there was no change in the general health
    of workers exposed under any of the working conditions. Although
    there were acute clinical signs of poisoning there was no indication
    that the workers exposed were harmed once removed from exposure
    situation (Williams, 1966; Burrows  et al., 1970; Wakefield  et
     al., 1973; Shrivastava, 1975; Pandey, 1977).

         From 1966 to 1979, 133 cases of apparent over-exposure to
    aldicarb formulations were reported. Of these cases, 40 were
    confirmed aldicarb poisoning episodes where clinical diagnosis
    and/or urinalysis for aldicarb and its metabolites were performed.
    As has been the case with other carbamate insecticides, the acute
    signs of toxicity are rapidly dissipated, although atropine therapy
    and hospitalization have been useful therapeutic regimens (Abdalla,
    1977, 1979). Several deaths have been reported, but all of these
    have been attributed to suicide or gross neglect (Lee, 1984).

         California reported that in 1974, 1975 and 1976 a total of 10,
    14 and 13 cases of human illnesses were reported, respectively. In
    these incidents, people were directly exposed to aldicarb and
    illness was brought on by dermal, inhalation and in one instance,
    ocular exposure. While most illnesses resulted from aldicarb
    exposure in loading or applying the formulated pesticide, some
    illness has been reported from the handling of plants and soils
    treated with aldicarb (Peoples  et al., 1977).

         Several misuses of aldicarb on watermelons and cucumbers have
    been reported in the literature.  Goes  et al. (1980) reported on a
    suspected food-borne intoxication in Nebraska associated with the
    consumption of aldicarb-contaminated hydroponically grown cucumbers.
    Two episodes were reported (April 1977: 9 cases; July 1978: 5
    cases). Neither cholinesterase determinations nor urine residue
    determinations were performed in any of these patients. Four
    cucumbers (two in the supermarket and two in the greenhouse were
    analyzed and aldicarb content was 6.6 and 10.7 mg/kg (supermarket) 0
    and 9.9 mg/kg (greenhouse). No data are available on cucumbers
    actually eaten and no attempts to correlate symptoms and aldicarb
    consumption were made.

         Hirsch  et al. (1987) reported over 300 alleged intoxications
    in Canada following ingestion of aldicarb contaminated cucumbers
    (residue levels up to 26 mg/kg). In only five cases involving 13

    patients, were any remaining portion of the cucumbers consumed still
    available for analyses.

         Goldman (1990) reported on four outbreaks of aldicarb poisoning
    having occurred in California and other states in the USA from 1978
    to 1988.

         Outbreak 1: watermelons, 1985
         Outbreak 2: watermelons, 1987
         Outbreak 3: cucumbers, 1988
         Outbreak 4: cucumbers, 1978 (corresponds to Goes (1980)
                     publication).

         In the first outbreak, 1376 people allegedly became ill due to
    consumption of contaminated watermelons. Of this total, 308 were
    considered by the authors themselves as unlikely (235) or incomplete
    (73). Nevertheless, only 28 cases were supported by positive
    findings of aldicarb residues in the food commodity. All the other
    cases were only supported by self-diagnosis.

         An epidemiological study of potential adverse health effects of
    aldicarb metabolites in drinking water was performed. In two surveys
    conducted on Long Island, New York, the major cohorts were selected
    on the basis of aldicarb levels in their drinking water. Levels of
    contamination were generally 4-12 µg/litre, but a maximum of 400
    µg/litre was reported. Questionnaires to determine water and food
    consumption, symptoms experienced, and diagnosed illnesses were sent
    to 1035 residents of 462 households. Although the initial survey
    indicated a possible association between the incidence of diarrhoea
    and levels of aldicarb in the water, the follow-up study, focusing
    on children, did not confirm this association. No relationship was
    detected between food consumption or water source and adverse health
    symptoms, and self-reported physician-diagnosed illnesses for
    1974-1979 were not significantly related to levels of aldicarb in
    the water (Whitlock  et al., 1982).

         Another survey attempted to relate self-reported symptoms
    suggestive of peripheral neuropathy to aldicarb levels in drinking
    water in Suffolk County, New York. The response rate was less than
    20%. Responses were classified as "probably", "possibly", or
    "vaguely" suggestive of a neurologic syndrome. A significant
    correlation with aldicarb concentration was obtained only by
    combining all three categories of response, including reports of
    just one symptom or of symptoms not forming any cohesive syndrome.
    The authors concluded that further study was needed (Sterman &
    Varma, 1983).

         A pilot epidemiological study by Fiore  et al. (1986)
    evaluated a wide range of clinical immunological parameters in 23
    women exposed to aldicarb in their drinking water and in a
    non-exposed control group. The groups did not differ in any

    immunological parameters except in T8-Lymphocytes: the number was
    considered as elevated in five exposed and in one control.
    Observation of an elevated stimulation assay response to one of the
    large number of antigens (Candida) was not considered as
    toxicologically significant, nor was it attributed to aldicarb
    exposure.

         In a follow-up study, five women of the preceeding group and
    still exposed to aldicarb were examined versus previous control
    women plus women previously exposed but for whom exposure no longer
    occurred (e.g., change in water supply due to addition of a charcoal
    filter). According to the authors, this follow-up study confirmed
    the previous results, except for increased response to Candida
    antigens which was no longer present (Mirkin  et al., 1990).

    

COMMENTS Aldicarb is rapidly absorbed, widely distributed in the body and rapidly excreted. Metabolism appears to be similar in all species studied, aldicarb being rapidly metabolised to aldicarb sulfoxide, which is more slowly degraded to aldicarb sulfone. All metabolites are quickly eliminated from the body, 80-90% being excreted within 24 h. Elimination was complete by the fifth day after dosing and no bio-accumulation was seen. Aldicarb has high acute toxicity in a wide variety of mammalian species. Signs of toxicity are those commonly associated with acetylcholinesterase inhibition by a carbamate insecticide: cholinergic signs of poisoning, which are alleviated rapidly on cessation of exposure. Aldicarb sulfoxide is a more potent inhibitor of acetylcholinesterase than aldicarb itself, while aldicarb sulfone is considerably less toxic than either aldicarb or the sulfoxide. WHO has classified aldicarb as extremely hazardous (WHO, 1992). Short-term and long-term studies have been performed in rats, mice and dogs with aldicarb and aldicarb metabolites, both individually and in combination. Toxicity tests employing mixtures of aldicarb or aldicarb sulfoxide with aldicarb sulfone are of interest because aldicarb sulfoxide and aldicarb sulfone are the terminal residues potentially consumed by humans. Cholinesterase depression is the most significant indicator of toxicity that can be evaluated. However, considerable attention must be paid to the methods of sample collection and determination of cholinesterase activity. Continuous administration of aldicarb to the test animals until collection of samples for analysis is important, as is rapid analysis under carefully controlled conditions. No-effect levels in the various studies which included evaluation of cholinesterase inhibition are summarized in Table 6. No distinction is made in this table for the methods of determining cholinesterase activity. It is now considered inappropriate to use no-adverse-effect levels from many of the earlier repeat-dose studies for the derivation of an ADI, because animals were not dosed for 24-48 h prior to collection of tissue samples for measurement of cholinesterase activity. In the most recent dog studies, which were conducted in a manner designed to maximize detection of cholinesterase depression, the overall NOEL was 0.02-0.03 mg/kg bw/day, but the NOAEL (which discounts inhibition of plasma cholinesterase only) was 0.05-0.06 mg/kg bw/day. Results of repeat-dose studies with aldicarb demonstrate that the method of administering the test material to the test animals can greatly modify the apparent toxicity of aldicarb and its metabolites. Mice, rats and dogs have tolerated daily doses equal to the LD50 incorporated into the diet for 7 days to 2 years. Doses which caused death in less than 2 h when administered as a bolus, caused no death and only moderate cholinesterase depression when given in the diet. Two dietary carcinogenicity studies have been conducted with aldicarb in rats and three in mice. A dermal carcinogenicity study has also been conducted with aldicarb in mice and dietary studies have been carried out with aldicarb sulfone in mice and aldicarb sulfoxide in rats. Aldicarb was not carcinogenic in mice and rats. Two reproduction studies have been conducted in rats with aldicarb and one with aldicarb sulfone. There were no effects on reproductive performance at doses up to 0.7 mg/kg bw/day aldicarb or 9.6 mg/kg bw/day aldicarb sulfone. Aldicarb did not display any teratogenic potential in rats or rabbits in studies which included maternally toxic doses. After reviewing the available genotoxicity data, the meeting concluded that aldicarb, aldicarb sulfoxide and aldicarb sulfone are not genotoxic. In a range of special studies in animals (involving delayed neurotoxicity, behaviour, antagonistic agents and pesticide interactions) aldicarb displayed no results which gave cause for concern. There was no evidence of immuno-toxicity in mice in a number of functional assays of cell-mediated immunity and in host resistance to respiratory infection. Epidemiological studies provided no convincing evidence that aldicarb could significantly alter immunological function in humans. In addition to the above epidemiological studies, studies conducted in 1982 and 1983 attempted to correlate any potential adverse health effects with the occurrence of aldicarb in drinking water. Although the authors concluded that further study was needed, there was no clear evidence that aldicarb contamination of drinking water generally at concentrations of about 4-12 µg/litre, but at a maximum concentration of 400 µg/litre was related to any health effects. The anticholinesterase potential of aldicarb has been extensively investigated in human. These studies revealed the same pattern of rapid cholinesterase inhibition and rapid recovery seen in experimental animals. Transient erythrocyte cholinesterase depression was seen at single doses of 0.05 mg/kg bw, and the NOAEL for cholinesterase depression (discounting changes in plasma enzyme activity) was 0.025 mg/kg bw. A number of poisoning incidents have been reported in the agricultural use of aldicarb, but there has been no indication that the workers exposed were harmed once removed from the exposure source. Although several deaths have been reported, all of these have been attributed to suicide or gross neglect. A number of food-borne aldicarb intoxications have been reported in the literature. These have all been associated with misuse and reliable quantification of the dose of aldicarb involved has always proved difficult, if not impossible. An ADI was allocated using a 10-fold safety factor applied to the NOAEL for depression of erythrocyte cholinesterase activity in human volunteers. TOXICOLOGICAL EVALUATION Level causing no toxicological effect Rat: 0.1 mg/kg bw/day (93-day dietary study) Dog: 0.05 mg/kg bw/day (52-week study) Human: 0.025 mg/kg bw (double-blind, placebo controlled volunteer study) Estimate of acceptable daily intake for humans 0-0.003 mg/kg bw Studies which will provide information valuable in the continued evaluation of the compound Further observations in humans, including information regarding the correlation of blood cholinesterase depression and clinical signs and symptoms. Table 6: Summary of no effect levels in repeat dose toxicity studies which included cholinesterase investigations Species Duration Test Material Dosages* NOAEL** Effects at higher doses Mouse 7 days Aldicarb 0,0.1,0.3,0.6,1.2 0.6 Mortality Mouse 7 days Aldicarb: 0,2,6,18,36 2 Kidney and liver weight A. sulfone reduction, growth 1:1 depression Rat 7 days Aldicarb 0,4,8,16 NE Mortality, growth depression, kidney and liver weight reduction Rat 7 days Aldicarb 0,0.8,1.6,3.2 NE Growth depression, kidney and liver weight reduction Rat 93 days Aldicarb 0,0.02,0.1,0.5 0.1 Mortality, growth depression Rat 2 years Aldicarb 0,0.005,0.025, >0.1 No effects seen 0.05,0.1 Table 6 (cont'd) Species Duration Test Material Dosages* NOAEL** Effects at higher doses Rat 7 days Aldicarb 0,0.4,0.8,1.6,3.2 0.8 Growth depression, A. sulfoxide 0,0.4,0.8 0.4 RBC cholinesterase A. sulfone 0,0.4,1.0,2.5,5,20 2.5 depression Rat 29 days A. sulfoxide: 0,0.0074,0.03, 0.4 Growth depression, A. sulfone 0.12,0.47,1.67 in brain, plasma and RBC 1:1 drinking water cholinesterase depression Rat 6 months A. sulfoxide 0,0.125,0.25,0.5,1 0.125 Growth depression, brain, plasma and RBC cholinesterase depression Rat 6 months A. sulfoxide 0,0.0625,0.125, 0.125 Plasma and RBC 0.25,0.5,1.0 cholinesterase depression Rat 6 months A. sulfone 0,0.2,0.6,1.8, 0.6 Brain, plasma and RBC 5.4,15.2 cholinesterase depression Rat 7 days A. oxime 0,31.25,62.5,125, 62.5 Growth depression, 250,500,1000 minor liver and kidney changes Dog 7 days Aldicarb 0,0.2,0.3,0.7 >0.7 No effects seen Dog 100 days Aldicarb 0,0.2,0.3,0.7 0.3 Minor organ weight changes Dog 2 years Aldicarb 0,0.025,0.05 >0.1 No effects seen 0.1 Dog 2 weeks Aldicarb 0,0.022,0.068, NE Brain, plasma and RBC cholinesterase depression 0.192,0.609,1.42 Dog 2 weeks Aldicarb 0,0.003,0.008, 0.096 Brain, plasma and RBC cholinesterase depression 0.027,0.096,0.28 Dog 5 weeks Aldicarb 0,0.012,0.024, >0.06 No effects seen 0.06 Dog 52 weeks Aldicarb 0,0.027,0.054, 0.054 RBC and plasma 0.131,0.241 cholinesterase depression Table 6 (cont'd) Species Duration Test Material Dosages* NOAEL** Effects at higher doses Dog 3 months A. sulfoxide 0,0.0625,0.125, 0.25 Transient growth 0.25,0.5 depression Dog 3 months A. sulfone 0,0.2,0.6, >5.4 No effects seen 1.8,5.4 Dog 1 year A. sulfone 0,0.11,0.59, 0.11 RBC and plasma 2.25 cholinesterase depression * mg/kg bw/day equivalence, by dietary administration, unless otherwise stated. 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    See Also:
       Toxicological Abbreviations
       Aldicarb (EHC 121, 1991)
       Aldicarb (HSG 64, 1991)
       Aldicarb (ICSC)
       Aldicarb (Pesticide residues in food: 1979 evaluations)
       Aldicarb (Pesticide residues in food: 1982 evaluations)
       Aldicarb (IARC Summary & Evaluation, Volume 53, 1991)