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    THIODICARB

    EXPLANATION

         Thiodicarb is a non-systemic carbamate insecticide with a
    relatively narrow spectrum of activity closely related to its first
    metabolite, methomyl. It is specific against Lepidopterous pests,
    controlling larvae at different stages as well as eggs in many
    instances.

         Thiodicarb was reviewed for the first time by the Joint Meeting
    in 1985.

    IDENTITY

    CHEMICAL NAME

         3,7,9,13-tetramethyl-5,11-dioxa-2,8,14-trithia-4,7,9,12-
    tetraazapentadeca-3,12-diene-6,10-dione

         IUPAC - Dimethyl N,N'-thiobis-[O-(methylcarbamoyl)
    thiolacetohydroxamate]

         CAS - Ethanimidothioic acid, N,N'-[thiobis[(methylimino)-
    carbonyloxy]]bis, -dimethyl ester (CAS Registry No. 59669-26-0)

    SYNONYMS

         Dimethyl N,N'[thiobis[(methylimino)carbonyloxy]]bis
    [ethanimidothioate]

         LARVIN(R); NIVRAL(R); SEMEVIN(R)

    EMPIRICAL FORMULA

         C10H18N4O4S3

    STRUCTURAL FORMULA

    CHEMICAL STRUCTURE 5

    OTHER INFORMATION ON IDENTITY AND PROPERTIES

    MOLECULAR WEIGHT:   354.5

    PHYSICAL STATE
    AND COLOUR:         crystalline powder, white to light tan

    ODOUR:              slightly sulfurous

    DENSITY (g/ml):     1.4424 at 20C

    VAPOUR PRESSURE:    4.3  10 -5 at 20C
     (mm Hg)            1.1  10 -4 at 35C
                        2.1  10 -4 at 40C
                        3.2  10 -4 at 45C
                        4.2  10 -4 at 50C
                        5.2  10 -4 at 55C

    MELTING POINT:      173-174C

    FLAMMABILITY:       generates a flammable vapor space (methanol)

    REACTIVITY:         stable in light and ambient conditions. At
                        elevated temperatures (e.g. above 100C), the
                        product decomposes into the following principal
                        degradation products; carbon dioxide, acetonitrile
                        and dimethyl disulfide. The decomposition process
                        is catalyzed by Lewis-acid type heavy metal salts.

                        Can be hydrolyzed under acid- or base-catalyzed 
                        conditions. The principal degradation product from
                        the hydrolysis of thiodicarb is methomyl.

    OXIDIZING OR
    REDUCING ACTION:    Neither the product nor any of the accompanying
                        impurities have the tendency to act as an
                        oxidizing or reducing agent.

    pH:                 1 g/100 ml H2O produces a pH of 6.65 at 21.5C

    SOLUBILITY
    (wt. %):            Xylene                 0.1      at      50C
                                               0.4      at      68C
                                               1.0      at      92C
                                               2.5      at      106C
                                               5.0      at      119C

                        Pyridine               1.2      at      25C
                                               6.4      at      45C
                                               13.4     at      60C

                        Dichloromethane        10.2     at      0C
                                               11.4     at      5C
                                               16.1     at      30C

                        Acetone                0.8      at      25C

                        Acetonitrile           2.0      at      25C

                        Ethyl acetate          0.2      at      25C

                        Ethyl ether            0.1      at      25C

                        Methanol               0.3      at      25C

                        Tetrachloroethylene    0.1      at      25C

                        Water (distilled)      35 ppm   at      25C

    OCTANOL/WATER
    PARTITION
    COEFFICIENT:        1.65 (Log P by reverse phase TLC technique)

    STORAGE
    STABILITY:          Minimum storage life is typically in excess of 2
                        years.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, excretion, and biotransformation

         Thiodicarb, which essentially consists of two methomyl moieties
    joined through their amino nitrogen by sulfur, is rapidly degraded to
    S-methyl-N-[(methylcarbamoyl)oxy]thioacetamide (methomyl) in the rat
    stomach. Over 30% of an oral dose of 16 mg thiodicarb per kg. b.w. was
    converted to methomyl in the gut within 15 minutes. Only 40% of the
    oral dose was found in the rat gut at 15 minutes, indicating that the
    compound had been rapidly absorbed. Approximately 26% of the
    radioactivity in the administered dose was found in other body
    fractions, with the remainder of the dose (34%) apparently lost as
    volatiles (Andrawes et al., 1977).

         In rats given radiolabelled thiodicarb as a single oral dose of
    40 mg/kg b.w., 80% of the administered dose was eliminated within 48
    hours. After 4 days, 48% of the dose had been eliminated in the
    respiratory gases, 32% in the urine, and 4.5% in the faeces; 11% of

    the dose remained in the carcass, due to incorporation of
    radiolabelled carbon dioxide and acetic acid metabolites into natural
    products (Andrawes et al., 1977; Andrawes & Bailey 1979a; Feung
    et al., 1980).

         Thiodicarb is degraded in the stomach not only to methomyl but
    also to some other unstable intermediates, including methomyl
    methylol, methomyl oxime, methomyl sulfoxide, and methomyl sulfoxide
    oxime, which are subsequently converted to acetonitrile and carbon
    dioxide and primarily eliminated by respiration and in the urine.
    Acetonitrile is the only metabolite retained to some extent in body
    tissues and fluids; a very small fraction of the acetonitrile is
    further degraded to carbon dioxide, acetic acid, and to acetamide,
    which is suspected of being a mouse and rat carcinogen (Weisburger
    et al., 1969; Fleischman et al., 1980). The ultimate metabolic
    fate of methomyl in animals depends on its isomeric configuration. In
    the rat the stable and predominant form is the syn isomer, which is
    metabolized primarily to CO2, while partial conversion from the syn
    isomer to the anti isomer leads primarily to acetonitrile, most of
    which is respired unchanged (Huhtanen & Dorough 1976).

         A proposed metabolic pathway for thiodicarb in animals is shown
    in Figure 1.

         In the cow, metabolites of a single oral dose of thiodicarb are
    excreted in different proportions when compared to the rat, although
    there are no substantial differences in the metabolic pathways
    involved. During the initial 3-day period following administration of
    radiolabelled thiodicarb (16 mg/kg) or methomyl (4 mg/kg) to rats,
    31-32% of the administered dose was found in the urine. Only 5% of a
    dose of thiodicarb (7.02 mg/kg) administered to a cow was excreted in
    the urine during the same period. In rats, approximately 40-50% of the
    dose was recovered as CO2 and/or acetonitrile from respired gases
    during a 72 hour period, while similarly the cow eliminated 66% of the
    applied dose in respired gases. The CO2:acetonitrile ratio in
    respired air was 4- to 16-fold higher in the cow than in the rat. The
    higher CO2:acetonitrile ratios in cows may represent a species-
    specific tendency toward reduced formation of the anti methomyl
    stereoisomer (Andrawes et al., 1977; Andrawes & Bailey, 1979b;
    Khasawinah & College, 1978).

    FIGURE 1

         Andrawes (1983) reported that oral administration of radiolabeled
    acetonitrile to rats resulted in elimination of 65% of the applied
    dose in expired air, with less than 1% expired as 14CO2. In a
    similar study however, Huhtanen & Dorough (1976) found that in rats
    9.1% of a dose of acetonitrile was eliminated as CO2 in respiratory
    gases.

         Two lactating Holstein cows/group were given approximately 0.004,
    0.4, 1.4, or 4 mg 14C-thiodicarb per kg b.w. daily for 21 days. Milk
    and urine were collected twice daily, and blood and faeces were
    collected at 3- to 4-day intervals. One cow at each dosage level was
    sacrificed 12 hours after the last treatment, and tissues (liver,
    kidney, lung, spleen, heart, brain, ovary, udder, tongue, foreleg
    muscle, hindleg muscle, neck muscle and omental fat) were collected
    for analysis. The remaining 4 cows (1 at each dosage level) were kept
    for an additional 7 days after termination of treatment. During this
    post-treatment phase, milk and urine were collected twice daily as
    before, and blood and faeces were collected daily. The same tissues
    were collected after 7 days post-treatment. The radioactivity found in
    all samples (i.e., tissue, milk, blood, urine and faeces) was dose
    dependent. The concentration of acetonitrile in milk approached peak
    levels within 7 days in all dose groups. The acetonitrile levels
    appeared to remain nearly constant through the rest of the 21-day
    treatment period, then declined sharply during the 7-day post-
    treatment phase. Following 21 days of treatment, tissue levels of 14C
    residues were highest in liver and lowest in adipose tissues. Seven
    days after termination of dosing, radioactivity levels were lower in
    all tissues except liver. The authors concluded that the predominant
    end-products of thiodicarb catabolism were acetonitrile, acetamide,
    and carbon dioxide. Acetamide, which is believed to be produced by
    hydrolysis of acetonitrile, was found in trace amounts (< 0.01 ppm)
    in milk at the highest feeding level. Approximately 24% of the
    aqueous-extractable urinary-radioactivity was identified as acetamide
    (Feung et al., 1980).

         In a cow given a single dose (7.02 mg/kg b.w.)14C-acetyl
    thiodicarb, 66, 11.4, 5.0, and 4.6% of the administered radioactivity
    was eliminated, during 72 hours post-treatment, in respired air,
    faeces, urine and milk, respectively, while 10.1% was retained in the
    tissues (Khasawinah & College, 1978).

         In a study using mature White Leghorn laying chickens, no
    carbamate residues were found in tissues or eggs after 21 days of oral
    administration of thiodicarb at dosages of 15.4, 28.6 and 102 ppm in
    the diet. Acetonitrile, detected in the eggs and tissues (except fat)
    at the 102-ppm level, corresponded to 0.2 ppm (egg yolk and whites),
    0.5 ppm (liver), and 0.2-0.3 ppm (muscle). The level in eggs was
    directly proportional to the dosage level administered. Acetamide was
    not detected in egg yolks, but was found in egg whites (0.07 ppm), in
    liver (0.06 ppm) and in muscle (0.01 ppm), when administered at 102
    ppm thiodicarb (Andrawes & Bailey, 1980).

         Based on the available data that 5.72% of the administered
    syn-methomyl is converted to acetonitrile, a maximum of 5.72% of the
    administered 14C-thiodicarb could therefore be available for
    conversion to acetamide, since thiodicarb is metabolized predominantly
    to syn-methomyl. On a weight-percent basis, the maximum acetamide
    that could occur from ingestion of thiodicarb residues is 1.9% of the
    administered dose (53:1 thiodicarb:acetamide on a weight-to-weight
    basis) (Andrawes & Bailey, 1979a & 1979b; Huhtanen & Dorough, 1976).

    Effects on enzymes and other biochemical parameters

         The most significant biochemical effect of thiodicarb and its
    carbamate metabolites is the ability to reversibly inhibit
    acetylcholinesterase (ChE), a capability in common with other methyl
    carbamate esters. The methylcarbamate-acetylcholinesterase complex
    dissociates rapidly, and the acetylcholinesterase enzyme is released
    unaltered. The transient nature of acetylcholinesterase inhibition by
    thiodicarb makes it difficult to assay accurately, since inhibition is
    reversed by sample dilution and by adding substrate (butyrylcholine or
    acetylcholine) during assay procedures. Therefore, the assay procedure
    must be very rapid and use less than optimal amounts of substrate. The
    automated colorimetric method of Humiston & Wright (1967) is suitable
    for such determination.

         Groups of Fischer 344 rats (10 males and 10 females per group)
    were administered thiodicarb in the diet at dosage levels of 0, 1, 3,
    10, or 30 mg/kg b.w./day for 28 days. Rats were observed for mortality
    and clinical symptoms of toxicity. Food consumption was determined
    weekly and plasma- and erythrocyte-ChE measurements were analyzed on
    days 0, 15, and 29. Brain ChE was determined on day 29.

         Body weight and food consumption were significantly reduced in
    females at > 10 mg/kg, b.w. Males were not similarly affected.
    There was no mortality. Plasma and erythrocyte ChE were significantly
    depressed in high-dose males and females. Plasma ChE recovered to
    normal values by day 29, while red blood cell (RBC) ChE remained
    significantly depressed in both sexes at > 30 mg/kg b.w./day. Brain
    ChE was not depressed at any level (Mirro & DePass, 1982).

    Toxicological studies

    Special study on reproduction

    Rat

         Groups of Fischer 344 rats (20 female and 10 male rats/group)
    were administered thiodicarb (purity 99+%) in the diet, at dosage
    levels of 0, 0, 0.5, 1.0, 3, or 10 mg/kg b.w., in a three-generation
    reproduction study. Each generation produced only one litter per

    generation. The routine indices of fertility, gestation,
    survivability, viability, and lactation were determined for all
    generations, as well as selected gross and histopathological
    evaluations for F2a and F3a generations. Rats were mated on a 1-male-
    to-2-females ratio when approximately 100 days of age. Dams and pups
    were observed daily for appearance and behaviour. Litter size was
    reduced to 10 on day 4 postpartum. Brother-sister matings were
    avoided.

         There were no compound-related effects on any of the reproductive
    parameters measured, except for an initial transitory body-weight
    depression in F0 males. Gross and microscopic analyses were
    reportedly unremarkable. Thiodicarb was without adverse effects on
    reproduction at doses up to and including 10 mg/kg b.w. (Woodside
    et al., 1979c).

    Special studies on teratogenicity

    Mouse

         In a pilot study using pregnant Charles-River CD-1 mice,
    thiodicarb (technical grade) administered orally from days 6 through
    16 of gestation, at dosage levels of 0, 20, 60, 100, 150, 200, 300, or
    400 mg/kg b.w., produced excessive maternal toxicity (body-weight
    depression and mortality) at doses greater than 200 mg/kg b.w.
    (Dangler & Rodwell, 1979).

         Groups of Charles-River CD-1 mice (25 mated females/group) were
    administered thiodicarb (technical grade) via oral gavage at dosage
    levels of 0, 50, 100, or 200 mg/kg b.w. from days 6 through 16 of
    gestation. Mating was accomplished on a 1-female-to-1-male schedule at
    94 days of age. Day of copulation was also considered day 0 of
    gestation. Animals were observed routinely for appearance, behaviour
    and body-weight changes. Pups were delivered by Caesarean-section on
    day 17 of gestation. All foetuses were weighed, sexed, examined for
    external malformations, and subsequently subjected to visceral or
    skeletal examination.

         Six females in the high-dose group died during the study. Body
    weights were unaffected by treatment. There was no evidence of
    maternal or foetal toxicity at doses > 100 mg/kg b.w. and no
    teratogenic effects at doses > 200 mg/kg b.w. (Janes et al.,
    1980).

    Rat

         In a pilot teratology study using pregnant Charles-River CD COBS
    rats, thiodicarb (technical grade), administered orally at dosage
    levels of 0, 20, 40, 80, 120, or 160 mg/kg b.w. on days 6-19 of

    gestation, produced mortality at doses > 40 mg/kg b.w. There were
    no reported adverse effects on reproduction or foetal development
    (Ziemke & Rodwell, 1979).

         Groups of Charles-River CD COBS rats (25 mated females/group)
    were administered thiodicarb (technical grade) via oral gavage at
    dosage levels of 0, 10, 20, or 30 mg/kg b.w. on gestation days 6-19.
    Females were mated 1-to-1 with males at 13 weeks of age. Day of
    copulation was also considered day 0 of gestation. Animals were
    observed routinely for appearance, behaviour, and body-weight changes.
    Pups were delivered by Caesarean-section on gestation-day 20. All
    foetuses were weighed, sexed, measured, and examined for external
    malformations. One-third of the foetuses were fixed for visceral
    examination and the remaining two-thirds of the foetuses were
    subjected to skeletal examination. Early and late resorptions, number
    of implantations and corpora lutea, and the number and location of
    viable and non-viable foetuses, were recorded.

         Clinical observations, apparent at 20 and 30 mg/kg b.w. within 4
    hours after treatment, included inactivity, tremors, and clear oral
    discharge. There was no mortality. Maternal body weights determined
    on days 0, 6, 9, 12, 16, and 20 were significantly decreased at
    > 20 mg/kg b.w, and mean foetal body-weights were significantly
    reduced at > 10 mg/kg b.w. No teratogenic effects were produced,
    although delayed maturation of foetuses (reduced ossification),
    associated with maternal toxicity, was observed. There was no evidence
    of visceral or skeletal anomalies attributable to thiodicarb at doses
    up to and including 30 mg/kg b.w. (Tasker et al., 1979).

         Groups of Fischer 344 rats (10 mated females/group) were
    administered thiodicarb (purity 99+%) in the diet via 2 separate
    dosing regimens: from day 0 to day 20 of gestation or from day 6 to
    day 15 of gestation. Dose levels in each dosing schedule included 0,
    0.5, 1.0, 3, or 100 mg/kg b.w. A positive control group received
    625 mg/kg b.w. of aspirin via gavage on gestation day 10. Females were
    mated with males on a 1-to-1 schedule in order to achieve 10 pregnant
    females per dose. All pups were delivered by Caesarean-section on
    gestation day 20 and examined for visceral and skeletal abnormalities.

         Maternal body-weight gains determined on days 0 and 12 of
    gestation were reduced in all treatment groups. However, these changes
    were extremely variable at doses of 0.5-3.0 mg/kg b.w. (only two
    measurements were included) and they were not considered to be
    biologically significant except at the highest dose administered where
    the body weights were uniformly depressed. Foetal body weight and
    length were also significantly reduced in the high-dose group that was
    administered thiodicarb throughout gestation (days 0-20). The aspirin-
    exposed foetuses were similarly affected. Thiodicarb did not adversely
    affect the number of implantations, resorptions, live foetuses per
    litter, or pre-implantation losses. Resorption frequency was increased

    in high- dose females given thiodicarb from days 6 through 15 of
    gestation. The increase was based on the percentage of affected
    litters as well as the resorptions per litter. Aspirin demonstrated
    the same response. The incidences of visceral anaomalies were not
    increased in either the aspririn or thiodicarb groups when compared to
    controls. Skeletal variations were similar among all groups except for
    an increased incidence of bilobed thoracic vertebral centra and poorly
    ossified sternebrae (on a percentage of live-foetuses-per-litter
    basis) in the 100 mg/kg b.w. group administered thiodicarb throughout
    gestation. This effect was suggestive of delayed maturity in foetuses
    derived from dams which demonstrated significant maternal toxicity
    (i.e. decreased weight gain and decreased foetal size). This effect is
    also known to occur spontaneously (at similar frequencies) in other
    rat strains. The aspirin group exhibited several skeletal variations
    (e.g. split/missing vertebral centra, extra vertebrae, extra ribs and
    fused/wavy ribs), demonstrating the sensitivity of the study.
    Thiodicarb was not teratogenic at any dose administered but it was
    maternally toxic at 100 mg/kg b.w. (Woodside et al., 1979b).

    Special studies on carcinogenicity (See also "Long-term studies")

    Mouse

         Groups of Charles-River COBS CD-1 mice (80/sex/group) were
    administered thiodicarb (analytical grade, 99+% purity) in the diet
    for 24 months at dosage levels of 0, 0, 1.0, 3, or 10 mg/kg b.w./day.
    Animals were 42 days old at the start of the study. The mice were
    examined daily for mortality and adverse physical/behavioural
    condition. Routine evaluation of food consumption and body weights
    were performed. At the conclusion of the study, or at death, organ
    weights and gross and microscopic examination of tissues and organs of
    all animals were performed. All were anesthetized with methyoxyflurane
    and killed by cervical dislocation.

         Mortality in high-dose mice was increased over controls in males
    during the last 2 months of the study and in females during months 17
    and 18.

         Body weights and food consumption were not affected by treatment.
    There were no significant differences among treatment and control
    groups for the incidence of neoplasms or the identification of non-
    neoplastic lesions occurring in dead animals, or interim- and final-
    sacrifice animals. However, the overall incidence among control and
    treatment groups of hepatocellular neoplasms was much greater than
    reported in the literature for this strain of mouse (Table 1).

    Table 1.  Hepatocellular neoplasms in mice treated with thiodicarb
              and in 2 control groups
                                                                        

                                  Dose (mg/kg b.w.)
                                                                        

                        0         0         1         3         10
                                                                        

    Males
     Adenoma            18/80     19/76     22/78     24/78     24/80
     Carcinoma          37/80     25/76     29/78     32/78     26/80

    Females
     Adenoma            2/80      5/77      2/78      2/76      1/75
     Carcinoma          1/80      3/77      3/78      1/76      3/75
                                                                        

         Furthermore, there was no decrease in time-to-tumour for the
    observation of hepatocellular neoplasms (Table 2).

    Table 2.  Time-to-tumour (hepatocellular neoplasms) for male mice
              treated with thiodicarb and for 2 control groups
                                                                        

                                       Dose (mg/kg b.w.)
                                                                        

                          0         0         1         3         10
                                                                        

    Animals which
     died or were         6/53      10/49     12/51     22/48     13/54
     moribund

    Animals at 18-
     month interim        16/20     15/20     16/20     15/20     13/20
     sacrifice

    Animals surviving
     24 months            4/7       6/8       6/7       4/10      4/6
     (terminal kill)
                                                                        

         The other most frequently occurring neoplasm was alveologenic
    tumour of the lungs. As with hepatocellular neoplasms, there was no
    compound-related response within the incidence of this tumour type
    (Table 3).

    Table 3.  Alveologenic tumours in mice treated with thiodicarb and
              in 2 control groups
                                                                        

                                       Dose (mg/kg b.w.)
                                                                        

                             0         0         1         3       10
                                                                        

    Males
     Alveologenic
     tumours                 23/80     23/76     31/78     15/78   22/80

    Carcinoma                1/80      0/76      0/78      1/78    0/80

    Females
     Alveologenic
     tumours                 19/80     13/78     19/78     17/77   13/75

    Carcinoma                2/80      0/78      0/78      0/77    0/75
                                                                        

         The principle non-neoplastic lesions observed in all control and
    treated groups included: lymphocytic infiltration or hyperplasia of
    numerous tissues, generalized amyloidosis, hyaline degeneration of
    sternal cartilage, haemosiderosis of various organs, subacute
    sialoadenitis, glomerulosclerosis, and renal cystic tubular dilation.
    These effects were not compound-related. Thiodicarb was not
    carcinogenic to CD-1 mice at dietary doses up to and including 
    10 mg/kg b.w. (Woodside et al., 1980a).

    Special studies on mutagenicity

         Thiodicarb was evaluated in a series of mutagenicity assays
    including the Ames, dominant-lethal, micronucleus, reverse-mutation,
    mitotic-crossing-over, and DNA-damage test methods. It was negative
    for mutagenic potential in all tests except for a positive response in
    the mitotic gene conversion assay using Sacharomyces cerevisiae.
    (See Table 4 for details.)

        Table 4.  Results of mutagenicity assays on thiodicarb
                                                                                                           

    Test                Test                Concentration       Purity        Results         Reference
    System              Object              of thiodicarb
                                                                                                           

    Ames test           S. typhimurium      1, 10, 100,         Unknown       Negative        Jagannath &
    *                   TA98                500, and                                          Brusick, 1978
                        TA100               1000 g/plate
                        TA1535
                        TA1537
                        TA1538

    Micronucleus        Mouse, bone         5 and 10            Technical     Negative        Naismith &
    test                marrow              mg/kg               grade         (1)             Matthews,
                                                                                              1979a

    Dominant            Rat                 0, 0.5, 1,          Analytical    Negative        Woodside
    lethal                                  3 &                 grade         (2)             et al., 1979c
                                            10 mg/kg            (99+%)

    Reverse             S. cerevisiae       2.5, 6.2,           Technical     Negative        Naismith &
    mutation                                25, 62, &           grade         (3)             Matthews,
                                            250 g/ml                                         1979b

    Mitotic             S. cerevisiae       2.5, 6.2,           Technical     Negative        Naismith &
    crossing                                25, 62, &           grade         (3)             Matthews,
    over                                    250 g/ml                                         1979e

    Mitotic             S. cerevisiae       2.5, 6.2,           Technical     (4)             Naismith &
    gene                                    25, 62, &           grade                         Matthews,
    conversion                              250 g/ml                                         1979c

    Primary             E. coli             0.001, 0.01,        Technical     Negative        Naismith &
    DNA                 W3110               0.1, 1, and         grade         (5)             Matthews,
    damage*             p3478               10 mg/ml                                          1979d

    Chromosomal         Chinese hamster     10, 15, 20,         Technical     Negative        Ivett &
    aberrations         ovary (CHO)         30 g/ml            91.48%                        Brusick,
                        cells*              w/o activ.                                        1985
                                            10, 20, 30,
                                            40 g/ml
                                            w/activation

    Unscheduled         Rat primary         0.5, 1.0, 2.5,      Technical     Negative        Cifone &
    DNA synthesis       hepatocytes         5.0, 10.0,          91.48%                        Brusick,
                                            25.0, 50.0,                                       1985a
                                            100.0, 250.0
                                            g/ml
                                                                                                           

    Table 4.  (Con't)
                                                                                                           

    Test                Test                Concentration       Purity        Results         Reference
    System              Object              of thiodicarb
                                                                                                           

    Mouse lymphoma      L5178Y (TK+/-)      5, 8, 10,           Technical     Positive        Cifone &
    forward mutation                        & 12 g/ml          91.48%        (6)             Brusick,
    assay*                                                                                    1985b
                                                                                                           

    *    With and without metabolic activation
    (1)  The positive control (TEM) gave the expected response at 0.5 ml/kg.
    (2)  The positive control (TEM) gave the expected response at 0.25 mg/kg.
    (3)  The positive control (NQO) gave the expected response at 10-6 M.
    (4)  Increase in the heteroallelic trp 5-12/trp 5-27 diploid strain D7 at
         25 g/ml.
    (5)  The positive controls (ethylmethane sulfonate and diethylnitrosamine)
         gave the expected response.
    (6)  The test material induced repeatable increases in the mutant frequency,
         with and without metabolic activation.
    
    Special studies on neurotoxicity

         Although the Meeting considers the testing of methyl carbamates
    for potential neurotoxicity to be inappropriate (Annex 1, FAO/WHO,
    1985b, para. 2.8), the manufacturer conducted 2 separate studies, both
    of which were negative.

    Chicken

         In a preliminary acute oral toxicity study using 10- to 14-month-
    old White Leghorn hens, the LD50 for thiodicarb was calculated to be
    582 mg/kg b.w. When atropine sulfate (15 mg/kg b.w.) was administered
    15 minutes prior to dosing only 2/5 hens died after 5 days at a dose
    of 830 mg/kg b.w. (Schwartz & Stevens, 1978).

         Hens protected with 15 mg/kg b.w. atropine sulfate were
    administered single doses of 660 mg/kg b.w. thiodicarb via oral
    intubation. Vehicle (corn oil) and positive (TOCP) control groups were
    also employed. A dose of 750 mg/kg b.w. TOCP in corn oil was used.
    There were 10 hens in each control group and 40 in the thiodicarb
    group. Hens were observed daily for pharmacologic and toxicologic
    effects, including neurologic evaluation of leg weakness, gait, and
    walking ability. On day 21 all positive controls and 10 test-group
    birds were necropsied, perfused with 10% neutral buffered formalin,
    and examined histologically. On day 22 eight new positive controls
    were added to the study and the existing 30 treated birds were
    re-dosed a second time with 660 mg/kg b.w. thiodicarb.

         The vehicle controls provided no evidence of toxicity, while the
    positive control group displayed clinical and microscopic symptoms of
    delayed neuro-toxicity (increased number of swollen axons per cervical
    spinal cord cross-section). Although some signs of neurological
    impairment were initially displayed in the thiodicarb group, these
    were not evident after 4 days in study and were not confirmed upon
    histologic examination (Becci et al., 1979).

         Due to the marginal response in thiodicarb-treated birds, the
    entire study was repeated using 30 White Leghorn hens (8-12 months
    old) dosed orally with 660 mg/kg b.w. thiodicarb (analytical grade).
    There were 10 hens in each of the negative (corn oil) and positive
    (TOTP) control groups. Thirty minutes prior to dosing, each group
    received 25 mg/kg b.w. atropine sulfate via gavage. A dose of
    1200 mg/kg b.w. TOTP was employed in the positive control group.

         A total of 13/30 thiodicarb hens died on test, with no mortality
    in either control group. Thiodicarb and the negative control group
    provided no evidence of delayed neurotoxicity. In the TOTP group, 9/10
    birds demonstrated lesions in the sciatic nerve and spinal cord,
    consisting of axonal degeneration, necrosis, and demyelination (Myer
    et al., 1980).

    Special studies on skin and eye irritation

    Rabbit

         Thiodicarb is not irritating to the skin. When applied to the
    shaved backs of rabbits, thiodicarb produced only slight erythema in a
    few cases (Mallory et al., 1982i; Wentz & Wolfe, 1979).

         Thiodicarb was applied to the shaved, intact skin of rabbits, 5
    times a week for 3 consecutive weeks, at 4 dosage levels up to
    4 g/kg/day. Mortality, behaviour, food consumption, body weight, and
    gross and microscopic histopathology were unaffected by treatment.
    Localized erythema and edema occurred in all treated groups.
    Thiodicarb treatment was reported to produce a dose-related macrocytic
    anaemia (Conroy et al., 1979b; Gallo & Stevens, 1980).

         In a second dermal toxicity study in rabbits, using
    2000 mg/kg/day as the highest dosage level, all criteria were
    unaffected by treatment. Groups of 10 male and 10 female New Zealand
    White rabbits were treated dermally with thiodicarb 5 days per week
    for 3 consecutive weeks at dosage levels of 0, 250, 500, 1000, or
    2000 mg/kg (2 control groups were utilized in this study). Thiodicarb
    was administered to both intact and abraded dermal surfaces. There
    were no effects in the study attributable to thiodicarb. The
    occurrence of macrocytic anaemia, observed in the first study, was not
    confirmed (Schardein, 1982).

         Thiodicarb applied to the conjunctival sacs of rabbits did not
    damage the cornea, but resulted in temporary eye irritation (Cameron &
    Wolfe, 1979; Mallory et al., 1982a). In monkeys, thiodicarb caused
    no eye irritation or damage (Weatherholtz, 1982). Methomyl was mildly
    irritating to the skin of guinea-pigs and was a mild irritant to the
    eye (Kaplan & Sherman, 1977). Methomyl oxime was not irritating to the
    skin and was moderately irritating to the eye (Myers et al., 1984).

    Special studies on dermal sensitization

         The potential for thiodicarb to produce skin sensitization was
    tested in guinea-pigs and human subjects. Guinea-pigs, given multiple
    intradermal injections of thiodicarb in a modified Landsteiner
    procedure, showed minimal sensitization reactions to a challenge
    injection two weeks later (Conroy et al., 1979a & c). Repeated
    application (via a modified Buehler method) of thiodicarb to the
    shaved backs of guinea-pigs did not cause allergic sensitization
    (Field, 1979b). In a similar test with human subjects, thiodicarb
    produced no sensitization by repeated contact (Kamphake et al.,
    1980). Methomyl was not a sensitizer when administered to guinea-pigs
    (Kaplan & Sherman, 1977).

    Acute toxicity

         The acute toxicity of thiodicarb and its metabolites in several
    animal species is summarized in Table 5.

    Short-term studies

    Mouse

         Groups of Charles River CD-1 mice (5 males and 5 females per
    group) were administered thiodicarb in the diet for 7 days at dietary
    levels of 0, 15, 45, or 90 mg/kg b.w./day. Growth and mortality were
    unaffected. In male mice, at the two highest dosage levels, an
    increased absolute kidney weight was observed (Homan et al., 1977).

         Groups of ICR-JCL (SPF) mice (10 per sex per group) were fed
    thiodicarb (92.5% purity) in the diet for 4 weeks at dosage levels of
    0, 30, 100, or 300 ppm (equal to 0, 4.2, 13.7, and 40.8 mg/kg b.w./day
    for males and 0, 3.8, 12.3, and 36.3 mg/kg b.w./day for females).
    There was no mortality during the study. Body weight, food consumption
    and organ weights (brain, heart, liver, spleen, kidney, testes, and
    ovaries) were unaffected by treatment (Yoshida et al. 1983a).

        Table 5.  Results of acute toxicity assays of thiodicarb and its metabolitea
                                                                                                                                  

                                               Solvent       LD50              LC50           Reference
    Chemical       Species  Sex   Route        (vehicle)     (mg/kg b.w.)*     (mg/L)**
                                                                                                                                  

    Thiodicarb     Mouse    both  Oral         corn oil      226                              Myers et al., 1977b
                                                             (148-346)

                   Rat      M     Oral         corn oil      74.8-129                         Hallory et al.,1982b;1982e;1982g
                                                             (52.9-186)                       Myers et al.,1982b;1982c;1982d;1982e

                            F     Oral         corn oil      50-136                           Mallory et al., 1982b;1982e;1982g
                                                             (34.9-192.1)                     Myers et al.,1982b;1982c;1982d;1982e

                            M     Oral         0.25% methyl  46.5-83                          Mallory et al., 1982c;1982f;1982h
                                               cellulose or  (33.4-108)                       Myers et al.,1982b;1982c;1982c;1982d
                                               water

                            F     Oral         0.25% methyl  39.1-55                          Mallory et al., 1982e;1982f;1982h
                                               cellulose or  (29.4-65.5)                      Myers et al., 1982b;1982c;1982d
                                               water

                            both  Oral         corn oil      74.6-215                         Mallory et al., 1982b;1982e;1982g
                                                             (59.6-268.8)                     Myers et al., 1982b;1982c;1982d;1982e

                            both  Oral         0.25% methyl  49.4-97                          Mallory et al., 1982c;1982f;1982h
                                               cellulose or  (39.4-138.2)                     Myers et al., 1982b;1982c;1982d
                                               water

                   Guinea-  M     Oral         corn oil      160                              Myers et al., 1977c
                   pig                                       (94.3-271)

                   Rabbit   both  Oral         capsule       > 400                            Myers et al., 1979a

                            both  Oral         corn oil      556                              Myers et al., 1979a
                                                                                                                                  

    Table 5.  (Con't)
                                                                                                                                  

                                               Solvent       LD50              LC50           Reference
    Chemical       Species  Sex   Route        (vehicle)     (mg/kg b.w.)*     (mg/L)**
                                                                                                                                  

                   Chicken  F     Oral         corn oil      582-660                          Myer et al., 1980
                                                                                              Schwartz & Stevens, 1978

                   Monkey   both  Oral         capsule       467.2                            Weatherholtz et al., 1983
                                                             (329.6-662.1)

                   Rat      M     Dermal                     2540                             Field 1979a
                                  4 hr.                      (1120-5750)                      Koehler & Dorman 1979
                                  intact                                                      Myers et al., 1975;1979a
                                  skin

                   Rabbit   both  Dermal                     > 6310                           Lemen et al., 1979;
                                  24 hr.                                                      Mallory et al., 1982d;
                                  abraded                                                     Myers et al., 1978b;1979a
                                  & intact
                                  skin

                   Rat      both  I.P.                       23 (15.9-33.1)                   Matthews 1979b

                   Mouse    both  I.P.                       34 (21.9-52.7)                   Matthews 1979a
                                                                                                                                  

    Table 5.  (Con't)
                                                                                                                                  

                                               Solvent       LD50              LC50           Reference
    Chemical       Species  Sex   Route        (vehicle)     (mg/kg b.w.)*     (mg/L)**
                                                                                                                                  

                   Rat            Inhalation                 > 2.0                            Myers et al., 1975
                                  148 min.
                                  aerosol in
                                  DMSO

                                  Inhalation                 > 0.2             Myers et al., 1979a
                                  360 min.
                                  aerosol in
                                  DMSO

                            both  Inhalation                 0.1155-0.220      Dickey et al., 1979
                                  240 min.                                     (0.1094-       Myers et al., 1977a
                                  dust                                         0.320)

                                  Inhalation                 > 2.4             Myers et al., 1978a
                                  60 min.
                                  dust

                                  Aqueous                                      1.04           Myers et al., 1982a
                                  aerosol

    Methomyl       Rat      M     Oral         corn oil      14.1-47.6                        Kaplan & Sherman 1977;
                                               peanut oil    (8.0-72.7)                       Myers et al., 1976a;1981
                                               PEG 400

                            F     Oral         corn oil      12.3-48.5                        Kaplan & Sherman 1977;
                                               peanut oil    (7.6-70.2)                       Myers et al., 1979b;I981
                                                                                              Weil & Carpenter 1978
                                                                                                                                  

    Table 5.  (Con't)
                                                                                                                                  

                                               Solvent       LD50              LC50           Reference
    Chemical       Species  Sex   Route        (vehicle)     (mg/kg b.w.)*     (mg/L)**
                                                                                                                                  

                   Guinea-  M     Oral         acetone       15***                            Kaplan & Sherman 1977
                   pig                         peanut oil

                   Japanese       Oral         water;CMC     34                               Kaplan & Sherman 1977
                   Quail

                   Dog      M                  capsule       30***                            Kaplan & Sherman 1977

                   Monkey   both  aqueous      40***                                          Kaplan & Sherman 1977
                   (Rhesus)

                   Chicken  F     Oral         acetone/      28                               Kaplan & Sherman 1977
                                               water

    Hydroxymethyl  Rat      M     Oral         corn oil      200                              Myers et al., 1978c
    methomyl                                                 (123-326)

                                  Oral         corn oil      238                              Myers et al., 1979b
                                                             (156-363)

    Methomyl       Rat      M     Oral         corn oil      453                              Myers et al., 1978a
    sulfoxide                                                (296-692)

                   Oral                        corn oil      476                              Myers et al., 1979b
                                                             (311-727)
                                                                                                                                  

    Table 5.  (Con't)
                                                                                                                                  

                                               Solvent       LD50              LC50           Reference
    Chemical       Species  Sex   Route        (vehicle)     (mg/kg b.w.)*     (mg/L)**
                                                                                                                                  

    Methomyl       Rat      M     Oral         corn oil      794                              Myers et al., 1976b
    oxide                                                    (486-1300)

                                  Oral         corn oil      1000                             Myers et al., 1979b
                                                             (636-1572)

                            both  Oral         water         350                              Myers et al., 1984
                                                             (311-394)

    Acetonitrile   Rat      M     Oral         water         246                              Pozzani et al., 1955
                                                             (160-378)

                            F     Oral         water         234                              Pozzani et al., 1955
                                                             (203-270)

                                  Oral         water         38/0                             Smyth 1947

    Methomyl       Rat      M     Dermal       water         > 200 X                          Kaplan & Sherman 1977
                                  intact &                   5 days
                                  abraded
                                  skin 6 h

                   Rabbit   M     Dermal       water         > 5000                           Kaplan & Sherman 1977
                                  intact
                                  skin 24 h
                                                                                                                                  

    Table 5.  (Con't)
                                                                                                                                  

                                               Solvent       LD50              LC50           Reference
    Chemical       Species  Sex   Route        (vehicle)     (mg/kg b.w.)*     (mg/L)**
                                                                                                                                  

                            M     Dermal       water         800-951                          Myers et al., 1981
                                  intact
                                  & abraded
                                  skin 24 h

                            F     Dermal       water         566-1130                         Myers et al., 1981
                                  intact
                                  & abraded
                                  skin 24 h

    Methomyl       Rat      M     Dermal       corn oil      > 1000                           Myers et al., 1976b
    oxime                         intact
                                  skin 4 h

                                  Dermal       water         > 2000                           Meyers et al., 1984
                                  intact
                                  skin 24 h

    Acetonitrile   Rat            i.p.                       0.95 ml/kg                       Rogers 1959
                                                             (0.58-1.54)

                   Rat            i.v.                       1.68 ml/kg                       Rogers 1959
                                                             (0.08-3.21)

                   Rabbit         Dermal                     1.26 ml/kg                       Carpenter et al., 1958

    Methomyl       Rat      M     Inhaltion    water                           76 mg/l        Kaplan & Sherman 1977
                                  of aqueous
                                  aerosol
                                  4 h
                                                                                                                                  

    Table 5.  (Con't)
                                                                                                                                  

                                               Solvent       LD50              LC50           Reference
    Chemical       Species  Sex   Route        (vehicle)     (mg/kg b.w.)*     (mg/L)**
                                                                                                                                  

    Methomyl       Rat            Inhalation   water                           > 0.82         Myers et al., 1976b
    oxime                         of                                           mg/1
                                  aqueous
                                  aerosol
                                  4 h
                                                                                                                                  

    *    95% confidence limits (the widest range from each set of studies) are given in parentheses.
    **   Because particles of thiodicarb are not of respirable size, the material was ground to a dust
         for these tests.
    ***  Minimum lethal dose.
             Groups of ICR-JCL (SPF) mice, (28 per sex per group) were fed
    thiodicarb (92.5% purity) in the diet for 13 weeks at dosage levels of
    0, 30, 150, or 600 ppm (equal to 0, 3.8, 18.9, and 76.5 mg/kg b.w. for
    males and 0, 4.3, 21.5, and 85.0 mg/kg b.w. for females). Mortality,
    food consumption, body weight, water consumption, urinalysis,
    haematology, and clinical chemistry were determined. Cholinesterase
    levels were determined in plasma, red blood cells (RBC) and brain at
    study termination, as were organ weights, gross pathology, and
    histopathology. Brain ChE was stated to be depressed in 150-
    and 600-ppm females and in 600-ppm males. Also reported were
    significantly-increased relative liver weights in high-dose females.
    There were no other compound-related effects reported. However,
    individual animal data, gross pathology, or histopathology were not
    submitted. Therefore, a no-observed-effect level cannot be assessed
    from these data as presented to the 1985 Joint Meeting (Yoshida
    et al., 1983b).

    Rat

         Groups of Harlan-Wistar rats (5 per sex per group) were fed
    thiodicarb in the diet for 7 days at dosages of 0, 5, 25, or 100 mg/kg
    b.w./day. Limited effects were noted on body weight and food
    consumption, which were decreased in high-dose males. Relative kidney
    weights were also reportedly increased in all treated males (Woodside
    et al., 1975).

         Groups of Wistar rats (5 per sex per group) were administered
    thiodicarb in the diet at dosages of 0, 0, 18.5, 48.6, or 128 mg/kg
    b.w./day for 7 days. Observations were made on mortality, food
    consumption, body weight, and gross liver and kidney changes. Body
    weights were reduced in all treated groups compared to controls.
    Relative liver weights and absolute kidney weights were reduced in
    high-dose rats (Woodside et al., 1978).

         In a preliminary 13-week study 4 groups of Fischer 344 rats
    (5 per sex per group) were administered thiodicarb in the diet at
    dosage levels of 0, 5, 15, or 45 mg/kg b.w./day. One additional group
    per sex received 90 mg/kg b.w./day for 80 days. Observations included:
    mortality, food and water consumption, organ weights, and ChE activity
    (RBC, plasma and brain). Blood samples for ChE measurements were
    obtained via cardiac puncture. At necropsy, the brain was removed,
    weighed, and submitted for ChE assay. Relative liver, adrenal, and
    spleen weights were increased in all treated males, and relative
    spleen weights were increased in mid- and high-dose females. Body
    weights were reduced throughout the study in all treated males. ChE
    activity was unaffected at any dose level, except for increased RBC
    ChE activity in high-dose males and females (Woodside et al.,
    1979a).

         Groups of Fischer 344 rats (10 males and 10 females per group)
    were administered thiodicarb (99% purity) in the diet at dosage levels
    of 0, 0, 1.0, 3.0, 10 or 30 mg/kg b.w./day for 13 weeks. Observations
    included mortality, clinical observations, food and water consumption,
    body weight, organ weights, haematology, clinical chemistry,
    urinalysis, ChE activity (plasma, RBC and brain-at-germination), and
    gross and microscopic analysis. At both 10 and 30 mg/kg b.w./day, body
    weight and water consumption decreased significantly among females,
    with slight increases in males at the same dose levels. At 30 mg/kg
    b.w., relative spleen weights were increased significantly in males,
    while relative kidney weights were increased in high-dose females.
    Urine volume was increased in males and decreased in females at the
    high-dose level. Specific gravity of urine was also decreased in high-
    dose females. Other clinical parameters were unaffected by treatment
    except for decreased mean haemoglobin concentrations in high-dose
    males. ChE activities were comparable among all groups except for a
    significantly-increased RBC ChE in high-dose males. Gross and
    microscopic analyses were unremarkable and typical of changes
    associated with 4-month-old Fischer 344 rats. A NOEL was demonstrated
    at 3 mg/kg b.w. (Homan et al., 1978b).

    Dog

         Groups of 9-month-old Beagle dogs (4 per sex per group) were fed
    thiodicarb in the diet at targeted dosages of 0, 15, 45, or 90 mg/kg
    b.w./day for 13 weeks. However, due to mortality at the highest dose,
    the level was reduced to 76 and 86 mg/kg b.w. for females and males,
    respectively. Animals were examined routinely for physical/behavioural
    changes, food and water consumption, body-weight changes, haematologic
    and blood chemistry parameters, and urinalysis. Organ weights, gross
    necropsy and histologic effects were examined at terminal sacrifice.
    ChE activities (plasma and RBC) were determined pre- treatment and on
    days 28, 63, 79, and 93 of the study. Brain ChE was determined at
    sacrifice.

         Two females died in the high-dose group, and dose-related
    cholinergic symptoms were observed in both sexes in the mid- and high-
    dose groups. Symptoms included anorexia, vomiting, and loose stools.
    However, ChE activity was unaffected throughout the study. Food
    consumption decreased in high-dose females. Water consumption
    increased in both sexes in the high-dose groups. Body weight was
    decreased in females at the mid- and high-dose levels but there was no
    effect on males. Urine volume was increased in mid- and high-dose
    males. Decreases in RBC count, packed cell volume, and haemoglobin
    were noted in both sexes in the mid- and high-dose groups, while
    reticulocyte counts were increased in both sexes of the high-dose
    groups only. These changes, together with bone-marrow hyperplasia,
    decreased mean-corpuscular haemoglobin concentrations, and congested
    spleen in high-dose groups, are suggestive of compensatory
    haematopoiesis and anaemia. Relative liver weights and serum GPT

    levels were increased in both sexes at the high dose. However, males
    at the high dose demonstrated cloudy swelling, vacuolation and
    degenerative liver effects. All treated groups produced evidence of
    focal and diffuse inflammation of the liver. A clear NOEL was not
    demonstrated in this study (Homan, et al., 1978a).

         Groups of Beagle dogs, 6-7 months old (6 per sex per dose) were
    administered thiodicarb in the diet at dosage levels of 0, 5, 15, or
    45 mg/kg b.w./ day for 26 weeks. Animals were observed routinely for
    survival, clinical appearance, food consumption, body-weight change,
    ChE activity, haematologic and clinical chemistry parameters, and
    urinalysis. Organ-weight changes and gross and microscopic pathologic
    examinations were performed at terminal sacrifice. Cholinesterase
    activity was twice determined pretreatment and once each on fasted and
    non-fasted samples during weeks 8, 17, and 26. Brain ChE was
    determined at sacrifice.

         Thiodicarb did not affect body weight, food consumption,
    urinalysis, organ weights, or gross or microscopic pathological
    examination of tissues. Among the male dogs, there was a dose-related
    increase in the combined incidence of soft stools, mucoid stools, and
    diarrhoea. These were not evident in females. Treatment-related
    changes in haematology included significantly-decreased haematocrit,
    haemoglobin, and RBC levels in high-dose males and females. Dogs
    receiving the highest dose had significantly-elevated levels of serum
    GPT, plasma ChE, and RBC ChE as well as significantly-decreased levels
    of calcium, total protein and globulin, with correspondingly-increased
    albumin-to-globulin ratio. There were no treatment-related effects
    reported at 15 mg/kg b.w./day (Wolfe 1981).

    Long-term study

    Rat

         Six groups of Fischer 344 rats (120 rats per sex per dose) were
    administered thiodicarb (analytical grade, 99+% purity) in the diet at
    dosage levels of 0, 0, 0.5, 1, 3, or 10 mg/kg b.w. for 24 months.
    Animals were 50 days of age when dosing began, and housed 3 per cage
    for males and 5 per cage for females. Rats were examined daily for
    mortality and adverse physical or behavioural changes. Food and water
    consumption and body-weight changes were determined routinely. Interim
    sacrifices were performed at 6, 12, and 19 months, utilizing 10 to 20
    rats per sex. Haematology, clinical chemistry, and urinalysis
    determinations were made prior to each scheduled sacrifice. Organ
    weights and gross and microscopic evaluations were also performed at
    each sacrifice and on dead or moribund animals (excluding organ
    weights). Limited ophthalmological examinations were also performed.

         Mortality was increased in high-dose males, but not females, from
    the 15th to the 21st months. At termination of the study, mortality in
    control males exceeded that in the high-dose males. Food consumption
    was unaffected in treated rats, although sporadic decreases were
    occasionally observed. Body weights were depressed in high-dose males
    from the 15th to 20th months and in high-dose females from the 3rd to
    the 21st months. An outbreak of sialodacry-oadenitis virus was
    discovered at about the 18th month, which had contributed to a
    generalized debilitated condition and to weight loss in all animals
    for approximately 2-3 weeks. Haematological parameters were
    unremarkable except for reduced erythrocyte counts, hematocrits and
    haemaglobin levels in males fed > 1 mg/kg thiodicarb at the 12th
    month, but not at 19 or 24 months. ChE activity (plasma, RBC, and
    brain), determined after 48 hours on the control diet, was unaffected.
    However, the time delay between compound administration and ChE
    measurement is considered excessive for a carbamate and therefore this
    result is not meaningful. The only change in ChE activity, consistent
    with other thiodicarb-feeding studies, was a significant increase in
    RBC ChE at 24 months in high-dose males. Clinical chemistry and
    urinalysis determinations were not affected by treatment except for
    transient reduction in urine volume at 12 months in females given
    > 3 mg/kg. Although sporadic differences were observed at various
    sacrifice intervals, there were no dose-related effects on absolute or
    relative organ-weights.

         There were no significant pathologic changes attributable to
    thiodicarb at 6, 12, or 19 months, and no carcinogenic response at any
    dose throughout the study. High-dose males presented evidence at 24
    months of an increased incidence of pituitary cysts, while high-dose
    females demonstrated haemosiderosis of the mediastinal lymph nodes.
    Hepatocellular hyperplasia and interstitial prostatitis were increased
    in treated males, although not significantly at the high dose; their
    incidence was not dose-related, and there was not a significant
    increase in liver neoplasms. High-dose males had an increased, but not
    significant, incidence of epithelial hyperplasia and epithelial
    thymomas. Mononuclear cell leukemia and interstitial cell adenomas
    (in males) occurred spontaneously in all groups, in general agreement
    with this strain of rat.

         A NOEL of 3 mg/kg b.w. was established with no evidence of
    oncogenic potential at doses up to and including 10 mg/kg b.w.
    (Woodside et al., 1980b).

    COMMENTS

         Thiodicarb is rapidly absorbed, metabolized, and excreted, and
    has not been demonstrated to accumulate in animal tissues. It is
    degraded to methomyl, which is converted to the "oxime" (methyl
    hydroxythioacetimidate) and ultimately to acetonitrile, carbon

    dioxide, acetic acid, and acetamide. The ultimate metabolic fate in
    animals depends on the isomeric configuration of methmyl (SYN or
    ANTI).

         The acute oral toxicity (LD50) in rats is 66-120 mg/kg b.w.,
    depending on the vehicle used. In monkeys an oral LD50 is 467 mg/kg
    b.w.

         Thiodicarb causes reversible cholinesterase inhibition. Long-term
    feeding and oncogenicity studies in rats and mice have revealed no
    oncogenic potential in either species, and a NOEL of 3 mg/kg b.w. for
    non-oncogenic effects was determined. No adverse reproduction or
    teratogenic effects in rats or mice have been demonstrated.

         Thiodicarb was not mutagenic in a wide variety of assays.
    However, it was positive in the mitotic gene conversion assay using
    Saccharomyces cerevisiae.

         In two short-term feeding studies in dogs, thiodicarb
    demonstrated adverse liver effects in 90 days at doses > 15 mg/kg
    b.w., while in a 6-month study at doses up to 45 mg/kg b.w. no adverse
    effects were observed at 15 mg/kg b.w. Considering the conflicting
    information concerning liver effects in dogs, the Meeting required the
    submission of the results from an ongoing 1-year dog study by 1987.
    Therefore, a temporary ADI was allocated.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Rat: 60 ppm in the diet, equivalent to 3 mg/kg b.w.

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN

         0-0.01 mg/kg b.w.

    FURTHER WORK OR INFORMATION REQUIRED (by 1987)

    l.   Submission of ongoing 1-year dog feeding study known to be in
         progress.

    2.   Information on possible effect on maternal body-weight gain
         demonstrated in a rat teratology study.

    DESIRED

    1.   Observations in man, including monitoring of acetamide in the
         urine.

    REFERENCES

    Andrawes, N.R., College, P.R. & Bailey, R.H. Short-term fate of orally
    (1977)    administered UC 51762 in the rat. File No. 23509. 
              Unpublished report from Union Carbide Agricultural Products
              Company, Inc. Submitted to WHO by the Union Carbide
              Agricultural Products Co., Inc.

    Andrawes, N.R. & Bailey, R.H. Metabolism of acetyl-l-l4C-LARVIN(R) in
    (1979a)   the rat. File No. 26925. Unpublished report from Union
              Carbide Agricultural Products Company. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

    Andrawes, N.R. & Bailey, R.H. Metabolism of acetyl-1-l4C-methomyl in
    (1979b)   the rat. File No. 26945. Unpublished report from Union
              Carbide Agricultural Products Company. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

    Andrawes, N.R. & Bailey, R.H. Fate of acetyl-1-14C-thiodicarb in laying
    (1980)    chickens under continuous feeding conditions. File No.
              26414. Unpublished report from Union Carbide Agricultural
              Products Company. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Andrawes, N.R. Acetonitrile metabolism in the rat. File No. 32291.
    (1983)    Unpublished report from Union Carbide Agricultural Products
              Company, Inc. Submitted to WHO by Union Carbide Agricultural
              Products Company, Inc.

    Becci, P.J., Schwartz, C.S., & Parent, R.A. Evaluation of UC 51762 No.
    (1979)    40-488 as a potential delayed neurotoxic agent following
              oral administration to hens protected by atropine sulfate.
              Report No. 6065. Unpublished report from Food and Drug
              Research Laboratories. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Cameron, J.T. & Wolfe, G.W. Acute eye irritation study in rabbits.
    (1979)    Project No. 400-616. Unpublished report from Hazleton
              Research Laboratories, Inc. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Carpenter, C.P., Pozzani, U.C., Weil, U.C., Palm, P.E. & Nair, J.H.
    (1958)    The toxicity of acetonitrile. Part II. Special report No.
              21-100. Unpublished report from Mellon Institute. Submitted
              to WHO by Union Carbide Agricultural Products Company Inc.

    Cifone, M.A. & Brusick, D.J. Evaluation of thiodicarb in the rat
    (1985a)   primary hepatocyte unscheduled DNA synthesis assay.
              Unpublished report No. 20991 from Litton Bionetics, Inc.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Cifone, M.A. & Brusick, D.J. Mutagenicity of thiodicarb in a mouse
    (1985b)   lymphoma mutation assay. Unpublished report No. 20989 from
              Litton Bionetics, Inc. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Conroy, W.J., DePass, L.R., Homan, E.R., Weil, C.S., Geary, D.L. &
    (1979a)   Frank, F.R. Dermal sensitization potential in guinea pig.
              Special report No. 42-61. Unpublished report from the Mellon
              Institute. Submitted to WHO by Union Carbide Agricultural
              Products Company, Inc.

    Conroy, W.J., DePass, L.R., Homan, E.R., Weil, C.S., Geary, D.L., &
    (1979b)   Frank, F.R. UC 51762, 16-dose rabbit dermal study. Special
              report No. 42-52. Unpublished report from Mellon Insititute.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Conroy, W.J., DePass, L.R., Homan, E.R., Weil, C.S., & Webb, G.A.
    (1979c)   Dermal sensitization potential in the guinea pig. Special
              report No. 42-26. Unpublished report from Mellon Institute.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Dangler, T.L. & Rodwell, D.E. Pilot teratology study in mice. Report
    (1979)    No. 369-030. Unpublished report from International Research
              and Development Corporation. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Dickey, C.L., Nachreiner, D.J., DePass, L.R., Gad, S.C., Weil, C.S.,
    (1979)    Geary, D.L. & Frank, F.R. Acute and 9-day dust inhalation
              study on rats with UC 51762 technical. Special Report No.
              42-63. Unpublished report from Mellon Institute. Submitted
              to WHO by Union Carbide Agricultural Products Company, Inc.

    Feung, C.S., College, P.R. & Chancey, E.L. Studies on the disposition
    (1980)    of 14C-thiodicarb in lactating cows. File No. 27350.
              Unpublished report from Union Carbide Agricultural Products
              Company, Inc. Submitted to WHO by Union Carbide Agricultural
              Products Company, Inc. 

    Field, W.E. Acute dermal toxicity in rats. Project No. CDC-UC-012-79.
    (1979a)   Unpublished report from CDC Research, Inc. Submitted to WHO
              by Union Carbide Agricultural Products Company, Inc.

    Field, W.E. Skin sensitization in guinea pigs. Project No. CDC-UC-003-
    (1979b)   79. Unpublished report from CDC Research, Inc. Submitted to
              WHO by Union Carbide Agricultural Products Company, Inc.

    Fleischman, R.W., Baker, J.R., Hagopian, M., Wade, G.G., Hayden, D.W.,
    (1980)    Smith, E.R., Weisburger, J.H. & Weisburger, E.K.
              Carcinogenesis bioassay of acetamide, hexanamide, adipamide,
              urea and phi-tolylurea in mice and rats. J. of Environ.
              Pathol. and Toxicol., 3, 149-170.

    Gallo, M.A. & Stevens, K.R. Evaluation of LARVIN(R) (UC 51762) in 21
    (1980)    day dermal toxicity study in rabbits. Project No. 02413-090.
              Unpublished report from Foster D. Snell. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

    Homan, E.R., Weil, C.S., & Cox, E.F. Seven-day feeding study of UC
    (1977)    51762 in mice. Special report No. 40-7. Unpublished report
              from Mellon Institute. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Homan, E.R., Fowler, E.H., Reid, J.B., & Cox, E.F. Thirteen-week oral
    (1978a)   toxicity study of UC 51762 in dogs. Special report No.
              41-98. Unpublished report from Mellon Institute. Submitted
              to WHO by Union Carbide Agricultural Products Company, Inc.

    Homan, E.R., Maronpot, R.R., Reid, J.B., & Cox, E.F. Thirteen-week
    (1978b)   oral toxicity study of UC 51762 in rats. Special report No.
              41-63. Unpublished report from Mellon Institute. Submitted
              to WHO by Union Carbide Agricultural Products Company, Inc.

    Huhtanen, K. & Dorough, H.W. Isomerization and Beckman rearrangement
    (1976)    reactions in the metabolism of methomyl in rats. Pesticide
              Biochem. Physiol. 6, 571-583.

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    (1967)    determination of cholinesterase activity. Tox. Appl.
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    (1985)    thiodicarb in an in vivo cytogenetic assay measuring
              chromosomal aberration frequencies in Chinese hamster ovary
              (CHO) cells. Unpublished report No. 20990 from Litton
              Bionetics, Inc. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Jagannath, D.R. & Brusick, D. Mutagenic evaluation of CHF 41-43 (UC
    (1978)    51762) by the Ames Salmonella/microsome plate test.
              Project No. 20838. Unpublished report from Litton Bionetics,
              Inc. Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Janes, J.M., Rodwell, D.E., & Jessup, D.C. Teratology study in mice.
    (1980)    No. 369-032. Unpublished report from International Research
              and Development Corporation. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Kamphake, J., Ragsdale, W.E., Weber, E.M., & Carabello, F.B. Repeated
    (1980)    insult patch test - human volunteers. Report No. 80-0589-
              70,73. Unpublished report from Hilltop Research, Inc.
              Submitted to WHO by Union Carbide Agricultural Products
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    (1977)    (methylamino)-carbamoyloxy ethamidothioate. Toxicol. Appl.
              Pharmacol., 40, 1-17.

    Khasawinah, A.M. & College, P.R. Fate of single oral dose of 14C-
    (1978)    acetyl UC 51762 in a lactating cow - metabolism into natural
              products. File No. 25257. Unpublished report from Union
              Carbide Agricultural Products Company, Inc. Submitted to WHO
              by Union Carbide Agricultural Products Company, Inc. 

    Koehler, S. & Dorman, N. Clinical safety evaluation of LARVIN(R) UC
    (1979)    51762 powder and LARVIN(R) 500 flowable. Study No. 2177.
              Unpublished report from Food and Drug Research Laboratories.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Lemen, J.K., Wolfe, G.W., & Voelker, R.W. Acute dermal administration
    (1979)    in rabbits. Project No. 400-614. Unpublished report from
              Hazleton Research Laboratories, Inc. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

    Mallory, V.T., Naismith, R.W., & Matthews, R.J. LARVIN(R) technical;
    (1982a)   primary eye irritation test in rabbits. Report No. PH 421-
              UC-004-82. Unpublished report from Pharmakon Research
              Laboratories, Inc. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Mallory, V.T., Naismith, R.W., & Matthews, R.J. LARVIN(R) - analytical
    (1982b)   standard; acute oral toxicity study in rats (14 Day). Report
              No. PH 402-UC-010-82. Unpublished report from Pharmakon
              Research Laboratories, Inc. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Mallory, V.T., Naismith, R.W., & Matthews, R.J. LARVIN(R) - analytical
    (1982c)   standard; acute oral toxicity study in rats (14 Day). Report
              No. PH 402-UC-011-82. Unpublished report from Pharmakon
              Research Laboratories, Inc. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Mallory, V.T., Naismith, R.W., & Matthews, R.J. LARVIN(R) - technical;
    (1982d)   acute dermal toxicity test in rabbits. Report No. PH 422-UC-
              005-82. Unpublished report from Pharmakon Research
              Laboratories, Inc. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Mallory, V.T., Naismith, R.W., & Matthews, R.J. LARVIN(R) - technical
    (1982e)   lab preparation; acute oral toxicity test in rats. Report
              No. PH 402-UC-008-82. Unpublished report from Pharmakon
              Research Laboratories, Inc. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Mallory, V.T., Naismith, R.W., & Matthews, R.J. LARVIN(R) - technical
    (1982f)   lab preparation; acute oral toxicity test in rats. Report
              No. PH 402-UC-009-82. Unpublished report from Pharmakon
              Research Laboratories, Inc. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Mallory, V.T., Naismith, R.W., & Matthews, R.J. LARVIN(R) - technical
    (1982g)   pilot plant - batch 34; acute oral toxicity test in rats.
              Report No. PH 402-UC-006-82. Unpublished report from
              Pharmakon Research Laboratories, Inc. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

    Mallory, V.T., Naismith, R.W., & Matthews, R.J. LARVIN(R) - technical
    (1982h)   pilot plant - batch 34; acute oral toxicity test in rats.
              Report No. PH 402-UC-007-82. Unpublished report from
              Pharmakon Research Laboratories, Inc. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

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    (1982i)   irritation study in rabbits. Report No. PH 420-UC-002-82.
              Unpublished report from Pharmakon Research Laboratories,
              Inc. Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

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    (1979a)   Report No. PH 405-UC-001-79. Unpublished report from
              Pharmakon Research Laboratories, Inc. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

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    (1979b)   Report No. PH 404-UC-001-79. Unpublished report from
              Pharmakon Research Laboratories, Inc. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

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    (1982)    for 28 days. Report No. 45-19. Unpublished report from Union
              Carbide Bushy Run Research Center. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Myer, J., Dean, W.P., & Jessup, D.C. Acute delayed neurotoxicity study
    (1980)    in hens. Report No. 369-047. Unpublished report from
              International Research and Development Corporation.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

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    (1975)    UC 51762 in rats and rabbits. Special report No. 38-55.
              Unpublished report from Mellon Institute. Submitted to WHO
              by Union Carbide Agricultural Products Company, Inc.

    Myers, R.C., Weil, C.S., & Cox, E.F. Acute oral LD50 study UC 45650
    (1976a)   (S-methyl O-(methylcarbamoyl)acetothiohydroximate) in rats.
              Special report No. 39-40. Unpublished report from Mellon
              Institute. Submitted to WHO by Union Carbide Agricultural
              Products Company, Inc.

    Myers, R.C., Weil, C.S., & Cox, E.F. Acute toxicity study of S-methyl
    (1976b)   acetothiohydroximate UC 52702 in rats and rabbits. Special
              report No. 39-25. Unpublished report from Mellon Institute.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Myers, R.C., Carpenter, C.P., & Cox, E.F. Acute inhalation LD50 study
    (1977a)   of UC 51762 in rats. Special report No. 40-61. Unpublished
              report from Mellon Institute. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Myers, R.C., Carpenter, C.P., & Cox, E.F. Acute LD50 study of UC 51762
    (1977b)   in mice. Special report No. 40-6. Unpublished report from
              Mellon Institute. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Myers, R.C., Carpenter, C.P., & Cox, E.F. Acute oral LD50 study in
    (1977c)   guinea pigs. Special report No. 40-142. Unpublished report
              from Mellon Institute. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Myers, R.C., Homan, E.R., Carpenter, C.P. & Cox, E.F. Miscellaneous
    (1978a)   toxicity studies. Special report No. 41-25. Unpublished
              report from Mellon Institute. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Myers, R.C., Homan, E.R., & Cox, E.F. Acute dermal toxicity of UC
    (1978b)   51762 in rabbits. Special report No. 41-93. Unpublished
              report from Mellon Institute. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Myers, R.C., Homan, E.R., & Webb, G.A. Acute oral LD50 study of
    (1978c)   1-methylthioacetaldehyde-O-(hydroxymethyl carbamoyl) oxide
              (UC 58614) in rats. Special report No. 41-133. Unpublished
              report from Mellon Institute. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Myers, R.C., DePass, L.R., Homan, E.R., Weil, C.S., & Frank, F.R. UC
    (1979a)   51762 technical; range-finding toxicity studies. Special
              report No. 42-19. Unpublished report from Mellon Institute.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Myers, R.C., Homan, E.R., Weil, C.S., & Frank, F.R. Miscellaneous
    (1979b)   toxicity studies. Special report No. 42-27. Unpublished
              report from Mellon Institute. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Myers, R.C., DePass, L.R., & Frank, F.R. Methomyl technical; acute
    (1981)    toxicity and irritancy study. Report No. 44-75a. Unpublished
              report from Union Carbide Bushy Run Research Center.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Myers, R.C., DePass, L.R., & Frank, F.R. Acute toxicity and irritancy
    (1982a)   studies. Report No. 45-24. Unpublished report from Union
              Carbide Bushy Run Research Center. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Myers, R.C., DePass, L.R., & Frank, F.R. LARVIN(R) - analytical
    (1982b)   standard; acute oral toxicity study in rats. Report No.
              45-152. Unpublished report from Union Carbide Bushy Run
              Research Center. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Myers, R.C., DePass, L.R., & Frank, F.R. LARVIN(R) - technical lab
    (1982c)   preparation; acute oral toxicity study in rats. Report No.
              45-151. Unpublished report from Union Carbide Bushy Run
              Research Center. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Myers, R.C., DePass, L.R., & Frank, F.R. LARVIN(R) - technical pilot
    (1982d)   plant - batch 34; acute oral toxicity study in rats. Report
              No. 45-151. Unpublished report from Union Carbide Bushy Run
              Research Center. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Myers, R.C., Weil, C.S., & Frank, F.R. LARVIN(R) - technical; acute
    (1982e)   oral toxicity study in rats. Report No. 45-40. Unpublished
              report from Union Carbide Bushy Run Research Center.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Myers, R.C., Slesinski, R.S. & Frank, F.R. Methomyl oxime: acute
    (1984)    toxicity and irritancy study. Project report 47-185.
              Unpublished report from Union Carbide Bushy Run Research
              Center. Submitted to WHO by Union Carbide Agricultural
              Products Company, Inc.

    Naismith, R.W. & Matthews, R.J. UC 51762 technical; micronucleus test.
    (1979a)   Report No. PH 309-UC-001-79. Unpublished report from
              Pharmakon Research Laboratories, Inc. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

    Naismith, R.W. & Matthews, R.J. UC 51762 technical; mitotic crossing
    (1979b)   over in Saccharomyces cerevisiae. Report No. PH302-UC-001-
              79. Unpublished report from Pharmakon Research Laboratories,
              Inc. Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Naismith, R.W. & Matthews, R.J. UC 51762 technical; mitotic gene
    (1979c)   conversion in Saccharomyces cerevisiae. Report No. PH304-
              UC-001-79. Unpublished report from Pharmakon Research
              Laboratories, Inc. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Naismith, R.W. & Matthews, R.J. UC 51762 technical; primary DNA
    (1979d)   damage. Report No. PH 305-AM-002-79. Unpublished report from
              Pharmakon Research Laboratories, Inc. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

    Naismith, R.W. & Matthews, R.J. UC 51762 technical; reverse mutation
    (1978e)   in Saccharomyces cerevisiae. Report No. PH 303-UC-001-79.
              Unpublished report from Pharmakon Research Laboratories,
              Inc. Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Pozzani, U.C., Nair, J.R., & Carpenter, C.P. The toxicity of
    (1955)    acetonitrile. Special report No. 18-34. Unpublished report
              from Mellon Institute. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Rogers, L.D. Intraportal injection of acetonitrile. Report No. 22-2.
    (1959)    Unpublished report from Mellon Institute. Submitted to WHO
              by Union Carbide Agricultural Products Company, Inc.

    Schardein, J. 21-Day dermal toxicity study in rabbits. Report No.
    (1982)    369-053. Unpublished report from International Research and
              Development Corporation. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Schwartz, C.S. & Stevens, K.R. Acute oral LD50 in hens. Report No.
    (1978)    6064. Unpublished report from Food and Drug Research
              Laboratories. Submitted to WHO by Union Carbide Agricultural
              Products Company, Inc.

    Smyth, H.F. Range-finding toxicity test of acetonitrile. Special
    (1947)    report No. 10-23. Unpublished report from Mellon Institute.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Tasker, E.J., Rodwell, D.E., & Jessup, D.C. Teratology study in rats.
    (1979)    Report No. 369-029. Unpublished report from International
              Research and Development Corporation. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

    Weatherholtz, W.M. LARVIN(R) - technical; fourteen-day eye irritation
    (1982)    study in monkeys. Project No. 400-648. Unpublished report
              from Hazleton Research Laboratories. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

    Weatherholtz, W.M., Rendon, F., & Gluck, S.E. Dose rangefinding study
    (1983)    in monkeys. Project No. 400-694. Unpublished report from
              Hazleton Research Laboratories. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Weil, C.S. & Carpenter, C.P. Miscellaneous toxicity studies. Special
    (1978)    report No. 34-88. Unpublished report from Mellon Institute.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Weisburger, J.H., Yamamoto, R.S., Glass, R.M., & Frankel, H.H.
    (1969)    Prevention by arginine glutamate of the carcinogenicity of
              acetamide in rats. Toxicol. Appl. Pharmacol., 14,
              163-175.

    Wentz, K.L. & Wolfe, G.W. Primary skin irritation study in rabbits.
    (1979)    Project No. 400- 617. Unpublished report from Hazleton
              Research Laboratories. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Wolfe, G.W. Subchronic toxicity study in dogs. Project No. 400-626.
    (1981)    Unpublished report from Hazleton Research Laboratories.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Woodside, M.D., Weil, C.S., & Cox, E.F. Seven-day feeding study of UC
    (1975)    51762 in rats. Special report No. 38-136. Unpublished report
              from Mellon Institute. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc.

    Woodside, M.D., DePass, L.R., Reid, J.B., & Cox, E.F. Seven-day
    (1978)    feeding study of UC 51762 in rats. Special report No.
              41-100. Unpublished report from Mellon Institute. Submitted
              to WHO by Union Carbide Agricultural Products Company, Inc.

    Woodside, M.D., DePass, L.R., Weil, C.S., Geary, D.L., & Frank, F.R.
    (1979a)   UC 51762; dimethyl N,N'-(thiobis((methylimino)carbonoyloxy))
              bis-(ethanimidothioate) inclusion in the diet of rats for
              thirteen weeks. Special report No. 42-125. Unpublished
              report from Mellon Institiute. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Woodside, M.D., DePass, L.R., Weil, C.S., Geary, D.L., & Frank, F.R.
    (1979b)   UC 51762; rat teratology studies. Special report No. 42-48.
              Unpublished report from Mellon Institute. Submitted to WHO
              by Union Carbide Agricultural Products Company, Inc.

    Woodside, M.D., DePass, L.R., Weil, C.S., Geary, D.L., & Frank, F.R.
    (1979c)   UC 51762 technical; inclusion in the diet of rats for three
              generations and dominant lethal mutagenesis studies. Special
              report No. 42-165. Unpublished report from Mellon Institute.
              Submitted to WHO by Union Carbide Agricultural Products
              Company, Inc.

    Woodside, M.D., DePass, L.R., Weil, C.S., Geary, D.L., & Frank, F.R.
    (1980a)   UC 51762; chronic oncogenicity feeding study in mice.
              Special report No. 43-10. Unpublished report from Mellon
              Institute. Submitted to WHO by Union Carbide Agricultural
              Products Company, Inc.

    Woodside, M.D., DePass, L.R., Weil, C.S., Geary, D.L., & Frank, F.R.
    (1980b)   UC 51762; chronic toxicity and oncogenicity feeding study in
              Fischer 344 rats. Special report No. 43-18. Unpublished
              report from Mellon Institute. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.

    Yoshida, A., Maita, K., Saito, T., & Miyaoka, T. LARVIN(R): 4-weeks
    (1983a)   range-finding study in mice. Unpublished report from The
              Institute of Environmental Toxicology. Submitted to WHO by
              Union Carbide Agricultural Products Company, Inc.

    Yoshida, A., Takahashi, K., Kosaka, T., & Miyaoka, T. Thiodicarb: 3
    (1983b)   month oral sub-chronic toxicity study in mice (study I).
              Unpublished report from The Institute of Environmental
              Toxicology. Submitted to WHO by Union Carbide Agricultural
              Products Company, Inc.

    Ziemke, K.A. & Rodwell, D.E. Pilot teratology study in rats. Report
    (1979)    No. 369-028. Unpublished report from International Research
              and Development Corporation. Submitted to WHO by Union
              Carbide Agricultural Products Company, Inc.
    


    See Also:
       Toxicological Abbreviations
       Thiodicarb (Pesticide residues in food: 1986 evaluations Part II Toxicology)
       Thiodicarb (JMPR Evaluations 2000 Part II Toxicological)