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    DISULFOTON      JMPR 1973

         Disulfoton is a member of the demeton family of insecticides.
    Demeton was reviewed by the 1965 Joint Meeting. The relationship of
    disulfoton to other compounds comprising the demeton family can be
    seen in Table 1 (Table 1 is reproduced in WHO Monograph FAD/RES/73.5a,
    page 4).

    Chemical name

         O,O-diethyl 2-ethylthioethyl phosphorodithioate

    Synonyms

         Thiodemeton

         DisystonR

         S 276

         BAYER 19 639

         M-74 (common name in USSR)

    Structural formula

    CHEMICAL STRUCTURE 1


    Empirical formula

         C8H19O2PS3

    Other information on properties

         Appearance:         colourless, oily liquid
         Molecular weight:   274.4
         Boiling point:      62°C at 0.01 mm Hg
                             82°C at 0.05 mm Hg
                             128°C at 1.0 mm Hg
         Vapour pressure:    0.6 x 10-4 mm Hg at 10°C
                             1.8 x 10-4 mm Hg at 20°C
                             5.2 x 10-4 mm Hg at 30°C
                             14.0 x 10-4 mm Hg at 40°C
         Volatility:         0.9 mg/m3 at 10°C
                             2.7 mg/m3 at 20°C
                             7.5 mg/m3 at 30°C
                             19.7 mg/m3 at 40°C
         Specific gravity:   1.14 at 20°C C
                                      4°

         Solubility:         approximately 1:40 000 in water at room
                             temperature: soluble in most organic solvents
         Minimum purity:     94%
         Impurities:         2-ethylthioethylchloride       max. 0.2%
                             2-ethylthioethanethiol         max. 0.2%
                             bis(2-ethylthioethyl)
                             disulfide                      max. 0.6%
                             O,O S-triethyl
                             phosphorodithioate             max. 2.0%
                             O,O,O S-triethyl
                             phosphorothioate               max. 0.5%
                             sulfotepp                      max. 0.5%
                             3 oligomeric alkyl(thio)
                             phosphates                     max. 1.5%
                             water                          max. 0.5%

         Disulfoton is a member of the demeton family of insecticides.
    Demeton was reviewed by the 1965 Joint Meeting (FAO/WHO, 19G6) and an
    ADI was estimated for man to be 0.0025 mg/kg/day. The relationship of
    disulfoton to the other compounds comprising the demeton family can be
    seen in the monograph of demeton-methyl.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    Biochemical aspects

    Absorption, distribution and excretion

         There are essentially no data available on the absorption of
    disulfoton in mammals. Studies on the metabolism and distribution in
    mammals have been limited to mouse and intraperitoneal administration.

         Following intraperitoneal administration of radio-labelled
    disyston to mice, 30-60% of the radio-activity (depending on the dose

    administered, 5-15 mg/kg) was recovered in the urine over a 96-hour
    period. Approximately 2-3% of the radio-activity was recovered in the
    faeces (March et al., 1957).

    Metabolism

         Two studies on the metabolism of disulfoton were consistent in
    observations that disulfoton is rapidly metabolized by three major
    biochemical reactions. The first reaction is the oxidation of the
    thioether to produce sulfoxides and sulfones; the second reaction is
    the oxidation of the thiono-sulfur moiety to produce the thiol
    analogue; and the third reaction concerns the hydrolytic cleavage of
    the P-S-C linkage of the phosphorothiolate moiety and the P-O-C
    linkage of the ethyl ester moieties. The first two reactions act
    independently but concurrently and are presumably responsible for
    production of toxic metabolites. These oxidations produce increasingly
    effective inhibitors of cholinesterase with the thiol analogue of the
    sulfone being the most active. The rate of conversion of S to S = O is
    considerably more rapid than the oxidation of P = S to P = O which is
    about equal to the conversion of S = O to O = S = O (Bull, 1965; March
    et al., 1957).

         In comparative studies on various species of organisms, it was
    found that the routes of metabolism in insects, plants, and mammals
    are similar. The main differences are in the rates of reaction with
    the reactions being fastest in the animal next in the insects, and
    slowest in the plants. In mammals, the reaction to P = S to P = O
    takes place at an exceptionally fast rate. In addition, no biological
    conversion is known to occur with P(S)O converting rapidly to P(O)S
    esters (Fukuto and Metcalf, 1954).

         The following scheme depicts the metabolism of disulfoton in all
    systems thus far studied:

    CHEMICAL STRUCTURE 2

    Effects on enzymes and other biochemical parameters

         Disulfoton itself has been shown to have little if any effect on
    cholinesterase or any other biochemical parameter in the body.
    However, as noted above, it is rapidly oxidized to highly active in
    vivo and in vitro cholinesterase inhibitors. In the demeton group
    of cholinesterase inhibitors demeton-S is the most active compound to
    mammalian cholinesterase activity. This can be noted in the pI50
    values for rat brain. In contrast demeton-S-methyl sulfone is more
    active than other isomers to purified insect cholinesterase. The
    sulfoxide and sulfone of demeton-S and its sulfoxide have about the
    same cholinesterase inhibiting property (rat brain) while the sulfone
    of demeton-O has considerably less activity (FAO/WHO, 1965). In
    mammals, demeton-S loses part,of its cholinesterase inhibiting
    properties as the molecule undergoes this ether oxidation to the
    sulfoxide and sulfone. This is also partly true with demeton-O
    (although a less active inhibitor than demeton-S) where oxidation to
    the sulfoxide does not change the pI50 value, but the sulfone has a
    significantly reduced pI50 Disulfoton as with other
    organophosphorodithioates is a poor inhibitor of  cholinesterase but
    is rapidly converted to an active inhibitor. This can be seen In Table
    1 which shows the pI50 values of disulfoton and its oxygen analogue
    demeton-S.

         In rat brain, disulfoton sulfoxide is about 10 times more active
    than disulfoton, whereas disulfoton sulfone has about the same
    inhibitory power as disulfoton. Demeton-S however shows a tenfold
    stronger inhibitory power than its sulfoxide and its sulfone. In
    insects, whole weevil and fly head cholinesterases behave differently.
    The whole weevil ChE becomes practically unaffected by disulfoton
    sulfone. Disulfoton sulfoxide is only about three times as active as
    disulfoton. Demeton-S, its sulfoxide and sulfone show about the same
    anticholinesterase activity. In fly head cholinesterase there are no
    great differences in the inhibition by disulfoton compared with
    disulfoton sulfoxide, but disulfoton sulfone is about tenfold more
    active as an inhibitor. Within the demeton group, the inhibitory power
    increases with the oxidation to the sulfoxide and the sulfone
    respectively, although there exist quantitative discrepancies between
    different authors. In general, the demeton-S compounds are better
    inhibitors than the compounds of the disulfoton group.

         As with other cholinesterase-inhibiting organophosphate esters,
    the effects on other biochemical parameters or enzymes were not
    reported.

         Following acute i.p. administration, 5/8 of the LD50 level,
    cholinesterase activity of brain serum and submaxillary gland was
    maximally depressed within a very short period of time (less than six
    hours) to approximately the same level (15-257 of normal) after which
    recovery was initiated but not complete within 72 hours. An induced
    tolerance to the cholinergic stimulation has been observed with
    disulfoton especially with chronic administration (Bombinski and
    DuBois, 1958).

    
    TABLE 1. pI50 - VALUES OF DISULFUTON AND DEMETON-S AND THEIR METABOLITES ON CHOLINESTERASES OF
             INSECTS AND RAT BRAIN

                                                                                                          

                           Insectb          Insectc       Insectd       Insecte       Insecte       Ratf,g
    Compounda              (whole weevil)   (fly head)    (fly head)    (fly head)    (fly head)    brain
                                                                                                          

    Disulfoton             3.62             -             -             4.00          --            3.85

    Disulfoton-S (O)       4.08             -             -             4.15          4.30          4.77

    Disulfoton-S (O)(O)    2.00             -             5.90          5.46          4.92          4.00

    Demeton-S              4.89             5.46          -             5.46          -             6.68

    Demeton-S (O)          5.08             5.82          -             5.82          5.70          5.66

    Demeton-S (O)(O)       4.66             6.22          6.49          6.22          7.70          5.70
                                                                                                          

    a S (O) = Sulfoxide;   S (O)(O) = Sulfone.

    b Bull, 1965.

    c March et al., 1955.

    d Metcalf et al., 1957.

    e March et al., 1957.

    f FAO/WHO, 1965.

    g Bombinski and DuBois, 1958.
    


         Groups of rats (five female Sprague-Dawley strain per group) were
    administered disulfoton intraperitoneally at dose levels of 0, 0.25,
    0.5, 1.0, 1.2, and 1.5 mg/kg/day for 60 days. Mortality occurred at
    the three highest dose levels. No mortality was evident at 0.5
    mg/kg/day or below, although inhibition of growth was observed. At 1
    mg/kg, typical signs of cholinergic stimulation were evident during
    the first days of testing but within 10 days the animals recovered and
    were symptomless thereon. Furthermore, these animals began to gain
    weight and appeared to adapt to the continuous administration of
    disulfoton (Bombinski and DuBois, 1958). A further series of rats was
    treated with disulfoton at levels of 0, 0.25, 0.5, and 1.0 mg/kg daily
    by intraperitoneal administration for 30 days. Cholinesterase data,
    monitored over the course of this experiment, showed that there was an
    initial rapid decrease of brain cholinesterase which was dependent
    upon the daily dose of disulfoton. With the two highest doses, a
    permanent decrease in enzyme activity occurred only during the first
    seven days after which time further treatment resulted in maintenance
    of the enzyme level at a constant subnormal level. The lowest dose
    however induced a permanent decrease of brain cholinesterase activity.
    The serum-ChE showed nearly the same time course and degree of
    depression as the brain cholinesterase, but the cumulative effect of
    the lowest dose between days 7-30 was not marked.

         Clinical cholinergic signs of poisoning, including weight loss,
    evident over the first seven days of treatment at the highest dose
    level disappeared with the result being a symptomless cholinesterase
    depression (Bombinski and DuBois, 1958). Further studies to determine
    the mechanism of this acquired tolerance were reported (Brodeur and
    DuBois, 1964).

         It was observed that the development of tolerance to subacute
    administration of disulfoton was not paralleled by changes in the
    acetylcholine-cholinesterase system. The free acetylcholine level in
    the brain was elevated to approximately the same extent by each
    successive dose throughout the period of treatment. In addition, it
    was believed that the development of tolerance did not involve the
    metabolic conversion of disulfoton to its oxidative anticholinesterase
    analogues (Stavinoha et al., 1972). These authors postulated that the
    development of the tolerance resulting from high repeated
    administration of disulfoton was due to the development of a
    refractoriness of the cholinergic receptors to prolong exposure to
    high levels of acetylcholine. It was further observed that strain
    differences exist in the acquired tolerance to cholinergic
    stimulation.

         Groups of Charles River and Holtzmann rats received a daily
    intraperitoneal injection of 1 mg disulfoton/kg for three, 10, and 24
    days respectively. In each of the three groups the signs of poisoning
    were most severe on the third day. The Holtzmann rats treated for 10
    and 24 days exhibited early signs of adaptation while the Charles
    River rats took longer to adapt. Measurements of cholinesterase
    activity in the brain showed that acetyl cholinesterase activity as

    expected decreased, the amount of depression being dependent on the
    duration of the application while the acetylcholine concentration
    initially increased. In the Holtzmann rat acetylcholine concentration
    returned to the control level after 10 days of injections and was
    still at the control level when measured after 24 days of treatment.
    In the Charles River rats, the acetylcholine concentration of the
    brain was still elevated at the end of the 24-day injection period. In
    an experiment in which disulfoton was added to the diet at
    concentrations of 0, 10, 25, and 50 ppm, it was observed that
    adaptation progressed more slowly than in the intraperitoneal
    injection experiment. The time required for adaptation was longer as
    the amount of disulfoton in the diet was increased, e.g., 1 to 1-1/2
    months at 10 ppm; 2 to 3 months at 25 ppm; and very little adaptation
    was observed at 50 ppm. There was pronounced suppression of weight
    gain at 50 ppm. Acetyl cholinesterase was reduced in relation to the
    dietary concentration although only in one strain at the highest dose.
    The acetylcholine concentration was not different from the control
    level. Choline acetyltransferase activity was not affected (Stavinoha
    et al., 1969).

         Groups of weanling rats (six rats per group) were fed disulfoton
    in the diet at levels of 0, 1, 5, and 25 ppm for seven days. At the
    end of one week the animals were sacrificed for the measurement of the
    hydrolysis of tributyrin and diethylsuccinate by liver and serum and
    for the measurement of cholinesterase in serum, liver and brain.
    Dietary levels of disulfoton producing 50% inhibition of aliesterases
    and cholinesterase over this one week feeding period were obtained by
    analysis of a plot of the logarithm of dietary concentration and
    inhibition of the respective enzymes. There was no significant
    difference in this experiment between the levels of inhibition caused
    by disulfoton and demeton. The liver hydrolysis of tributyrin was the
    most sensitive parameter followed by diethylsuccinate hydrolysis.
    Depression of cholinesterase activity was caused in the brain by 5.2
    ppm disulfoton in the diet; in the liver by 14.5 ppm and the serum by
    6.0 ppm. Depression of liver aliesterase hydrolyzing DES was caused by
    3.5 ppm while in the serum it was calculated to be 8.4 ppm.

         Depression of the enzymes hydrolyzing tributyrin was caused in
    the liver by 0.6 ppm and in the serum by 9.2 ppm disulfoton in the
    diet. Although these authors point out that there is a possible
    relationship of aliesterase inhibition with potentiation, studies (see
    Potentiation Section) show that with a selected series of
    organophosphorus compounds, potentiation was not demonstrated (Su et
    al., 1971).

         Results of a recent study of the inhibited portions of rat brain
    following disulfoton administration is show in Table 2.

         This experiment reveals a severe inhibition of the
    cholinesterases in the hippocampus and caudate nucleus, compared with
    the hypothalamus and medulla. The recovery of cholinesterase activity
    occurred more rapidly in the first two mentioned parts of the brain

    than in the others although at the end of the seven day recovery
    period, activity in the hypothalamus and caudate nucleus is as still
    low (Modek et al., 1971).


    TABLE 2. CHOLINESTERASE ACTIVITYa

                                                                      

    Tissue                Control        Treatmentb          Recoveryc
                                                                      

    Hypothalmus           4.62           1.87                3.27

    Medulla               5.26           1.95                4.00

    Hippocampus           3.19           0.62                1.79

    Caudate nucleus       13.56          2.42                8.65

    Ileum                 2.90           2.38                2.80

    Gastrocnemius         0.48           0.28                0.40
                                                                      

    a mM substrate hydrolyzed/gm protein/h (Modek et al., 1971).

    b Intraperitoneal administration for 10 days at 1.5 mg/kg/day to
      rats.

    c Recovery time = seven days.


    TOXICOLOGICAL STUDIES

    Special studies on mutagenicity

    Mouse. Groups of male mice (12 mice/group) were administered
    disulfoton by intraperitoneal injection at doses of 0, 0.25, and 0.5
    mg/kg. Each male was mated with three virgin females each week for six
    weeks in the standard dominant lethal mutation test. There were no
    abnormalities noted in the data on implantation resorption or on the
    embryo itself. In this study, disulfoton did not exhibit any mutagenic
    effect on male mice (Arnold et al., 1971).

         Disulfoton inhibited growth of three human haematopoietic cell
    lives but had no effect on chromosomes (Huang, 1973).

    Special studies on reproduction

    Rat. Groups of rats (20 females and 10 males/group) were fed dietary
    levels of disulfoton at 0, 2, 5, and 10 ppm over the course of a
    two-litter per generation, three generation reproduction study. There

    did not appear to be a significant effect of disulfoton in the diet on
    reproduction in the rat. Levels up to and including 10 ppm did not
    significantly affect reproduction parameters. At 10 ppm in the F-1-A
    there was a greater than normal mortality of rats at weaning time.
    There was no significant difference in any of the groups in the number
    of pregnancies or in the number of young per treatment groups.
    Histological examination of the F-2-B rats indicated a cloudy swelling
    of the liver cells with a fatty metamorphosis especially in male rats
    on 10 ppm which was not observed in the controls. This was not
    observed in similar F-2-B rats. RBC-cholinesterase depression was
    obvious in all  treatment groups examined. No gross differences were
    observed between dale and female rats. The reduction was dose
    dependent and was more significant in females than males. While
    disulfoton does not appear to have a definitive effect upon
    reproduction parameters, high levels of disulfoton in the diet (10
    ppm) have shown somatic effects and levels of 2 ppm in the diet have
    shown reduction in cholinesterase (Taylor, 1966).

    Special studies on teratogenicity

         Groups of 15 pregnant rabbits were administered disulfoton orally
    in gelatin capsules at doses of 0, 0.1, and 0.2 mg/kg daily from days
    six through 18 of gestation. On day 29 of gestation, the young were
    removed by caesarean section. There were no deaths or unusual
    reactions among the females in any of the groups and the incidence of
    fetal mortality as indicated by resorption sites or abortion was not
    affected by disulfoton. There was no indication of fetal external or
    internal abnormalities and the weights of the fetuses were similar to
    those of the controls. A positive treatment of this test was obtained
    with thalidomide. Disulfoton does not appear to cause any teratogenic
    effects in rabbits (Ladd et al., 1971).

         Demeton while being embryotoxic as a single dose of 5 mg/kg for
    three days on days 7-13 of gestation or as a single dose of 7 or 10
    mg/kg during the same interval. Only a mild teratogenic potential was
    noted (Budreau, 1972; Budreau and Singh, 1973).

    Special studies on neurotoxicity

         Adult hens were orally administered disulfoton at a dose
    estimated to be the LD50 (26 mg/kg) twice at 21 day intervals and
    maintained for a further 21 days. Growth and histological examination
    of the animals indicated there were no signs of delayed neurotoxicity
    while a positive control (TOCP) showed definite signs of poisoning.
    Disulfoton does not induce delayed toxicity or demyelination (Fletcher
    et al., 1971). Hens, protected from acute cholinergic stimulation and
    organophosphorus poisoning by atropine and PAM were orally
    administered disulfoton at levels of up to 0.1 ml/kg. Delayed
    neurotoxic effects were not noted during the six weeks post-treatment
    observation period (Kimmerle, 1961).

    Special studies on the neurotoxicity of metabolite

         Disulfoton sulfoxide was administered intraperitoneally at levels
    up to 0.5 g/kg to hens previously administered PAM and atropine.
    Although mortality was evident at high dose levels there was no
    evidence of delayed neurotoxicity as observed normally with TOCP
    (Hecht and Kimmerle, 1965).

    Special studies on potentiation

         Simultaneous administration of an LD50 dose with eight other
    organophosphate insecticides resulted in a slight additive acute
    toxicity with five compounds and less than additive acute toxicities
    with the other three. None of the combinations resulted in a
    potentiation of the acute toxicity Dubois, 1957 a & b). Further
    studies with organophosphate and a carbamate ester were negative
    (Dubois, 1960). Equitoxic mixtures of disulfoton and phenamiphos (the
    active ingredient of NemacurR, ethyl 4-(methylthio)-m-tolyl
    isopropyl phosphoroamidate) resulted in less than additive toxicity
    (Kimmerle, 1972). A combination of disulfoton and phosphamidon did not
    cause potentiation (Sachsse and Voss, 1971).

         The signs of poisoning caused by disulfoton are typical of those
    produced by anticholinesterase compounds. The signs of poisoning
    consist of excitability, salivation, lacrimation, urination,
    defaecation, and muscular fasciculations. The signs were followed by
    convulsive seizures, prostration, and respiratory failure. As with
    other organophosphorus compounds the occurrence of signs of poisoning
    are indicative of both nicotinic and muscarinic actions of
    acetylcholine indicating that the compound or its active metabolite
    has gained access to both the central and peripheral nervous system.
    The time of onset and duration of signs of poisoning are dependent
    upon the dose. With lethal doses death usually occurred within the
    first 48 hours but upon sublethal administration death was delayed for
    several days. A comparison of the toxicity by disulfoton by various
    routes i.p. and oral) indicate that the compound is well absorbed from
    the GI tract. A considerable sex difference in susceptibility was
    noted in rats in some studies (i.e. Bombinski and DuBois, 1958) with
    the male being five times less sensitive than the females. This was
    not noted with other species. Similar sex differences in
    susceptibility of rats have been noted with other thiophosphates. It
    has been suggested that because the oxygen analogues did not exhibit
    this difference in sex susceptibility that the differences in the rate
    or extent of conversion of thiophosphates to their toxic oxygen
    analogues is presumably responsible for the observed sex difference.

    Special studies on antidotes

         Several studies on the antidotal properties of atropine and PAM
    administered intramuscularly before and after oral administration of
    disulfoton have the distinct therapeutic effects with these materials.
    Atropine in combination with other oximes administered

    intraperitoneally after the appearance of signs of poisoning also
    produced a therapeutic effect (Kimmerle, 1961; Lorke and Kimmerle,
    1968). Atropine, when injected intraperitoneally (100 mg/kg) prior to
    a dose of disulfoton, protected rats from the acute oral effects of
    poisoning of an LD50 dose. Acute administration of two times the LD50
    proceeded by administration of atropine was lethal (Bombinski and
    Dubois, 1958).

         Studies on the antidotal effects of atropine and PAM with
    disulfoton sulfoxide were similar to those reported with disulfoton
    where a significant reduction in acute toxicity was noted with both
    atropine and oximes alone. A more significant protective effect was
    noted with a combination of both atropine and oxime (Hecht and
    Kimmerle, 1965).

    Special studies on inhalation

         Female rats were exposed to concentrations of 0, 0.14, 0.35 and
    0.70 microgram/litre in the air one hour a day for five or 10 days.
    There was no mortality nor any significant decrease in cholinesterase
    activity in brain, serum or submaxillary gland (DuBois and Kinoshita,
    1971).

    Acute Toxicity

    (a) Original compound

                                                                                                   
    Species                  Route         LD50                 Reference
                                           (mg/kg)
                                                                                               

    Rat             M & F    oral          2.3-12.5             Ben-Dykeet al., 1970
                                                                DuBois, 1957; Gaines, 1969
                                                                Kimmerle, 1961, 1962, 1966, 1972
                    M        oral          12.5                 Bombinski and DuBois, 1958
                    F        oral          2.6                  Bombinski and DuBois, 1958

    Guinea Pig      M        oral          10.8                 Bodbinski and DuBois, 1958
                    M        i.p.          7.0                  Bombinski and DuBois, 1958

    Rat             M        i.p.          10.5                 Bombinski and DuBois, 1958
                    F        i.p.          2.0                  Bombinski and DuBois, 1958

    Mouse           M        i.p.          5.5                  Bombinski and DuBois, 1958
                    F        i.p.          6.5                  Bombinski and DuBois, 1958

    Rat             M        dermal        25-50                Ben-Dyke et al., 1970
                                                                Gaines, 1969; Kimmerle, 1962
                                           0.285
                                           (4 hr exposure)      Well et al., 1971

                                                                                               
    Species                  Route         LD50                 Reference
                                           (mg/kg)
                                                                                               

    Rat             M        inhalations   200 g/m3
                                           (1 hr exposure)      Doull, 1957

    Mouse           F        inhalation    58 mg/m3             Doull, 1957
                                           (1 hr exposure
                                                                                               

    (b) Metabolites

                                                                                                 

    Material         Species        Route         LD50                Reference
                                                  (mg/kg)
                                                                                                 

    Disulfoton       Rat            oral          1.7-6.5             Hecht and Kimmerle, 1965;
    Sulfoxide                                                         Kimmerle, 1962;
                                                                      Schrader, 1963; Wirth, 1958

                     Mouse          oral          5.4                 Bombinski and DuBois, 1958

                     Guinea Pig     oral          >3.6                Hecht and Kimmerle, 1965

                     Rabbit         oral          2.5-3.6             Hecht and Kimmerle, 1965

                     Cat            oral          1.0-2.5             Hecht and Kimmerle, 1965

                     Rat            i.p.          5.0                 Hecht and Kimmerle, 1965

                     Rat            dermal        0.195 ml/kg         Hecht and Kimmerle, 1965
                                                  4 hr

                                                  0.075 ml/kg         Hecht and Kimmerle, 1965
                                                  7 day

                                                  0.192 ml/kg         Kimmerle, 1962

                     Rat            inhalation    140 g/m3            Hecht and Kimmerle, 1965
                                                  (1 hr exposure)

    Disulfoton       Rat            oral          5.0-7.5             Schrader, 1963; Wirth, 1958
    Sulfone
                     Mouse          oral          5.6                 Bombinski and Dubois, 1958

    Demeton-S        Rat            oral          1.5-3.5             Klimmer and Pfaff, 1955;
    (isosystox)                                                       Wirth, 1958

                                                                                                 

    Material         Species        Route         LD50                Reference
                                                  (mg/kg)
                                                                                                 

                     Mouse          i.p.          5.6-7.0             Muhlmann and Tietz, 1956;
                                                                      FAO/WHO, 1965

                     Guinea Pig     i.p.          5.5                 FAO/WHO, 1965

    Demeton-S        Rat            oral          1.5-2.0             Schrader, 1963; Wirth, 1958
    Sulfoxide

    Demeton-S        Rat            oral          1.5-2               Schrader, 1963; Wirth,1958
    Sulfone
                                                                                                 

    
    In almost all instances, female rats were more susceptible than males.


    Short-term studies

    (a) Original compound

    Mouse. Groups of mice (12 male and 12 female CF-LP strain per group)
    were fed disulfoton in the diet at levels of 0, 0.2, 1.0 and 5.0 ppm
    for 13 weeks. Food consumption and growth were measured weekly and
    behaviour and mortality were observed daily. At 12 weeks, urinalysis
    haematological examination and blood chemistry including BBC, plasma
    and cholinesterase assays were performed. At the conclusion of the
    study, gross and microscopic examination of tissues was performed. No
    treatment-related changes were observed in growth, urinalysis,
    haematology, or blood chemistry with the exception of cholinesterase
    activity. Cholinesterase activity was reduced in all tissues at 5 ppm,
    especially in females. Gross histological examination indicated a
    slight increase in the liver weight in females at 5 ppm. There were no
    other abnormalities noted on gross or microscopic examination of
    tissues and organs. The no-effect level based upon this study in mice
    is 1 ppm in the diet (Rivett et al., 1972).

    Rat. Groups of rats (13 males and 13 females per group) were fed
    disulfoton in the diet at levels of 0, 1, 2, 5 and 10 ppm for 16
    weeks.

         Food consumption and growth were measured daily for the first two
    weeks every two days for the next month and then weekly until 16
    weeks. At the end of the feeding period, three males and three females
    were sacrificed and tissues examined for gross and microscopic
    changes. Cholinesterase activity in serum, erythrocyte brain and
    submaxillary gland was examined at eight and 16 weeks of feeding.

    There were no effects of disulfoton in the diet at any dose level on
    growth, food consumption, behaviour or mortality over the 16-week
    period. Gross and microscopic examination of all tissues from both
    male and female animals revealed no differences. Cholinesterase
    depression was observed in erythrocyte and brain at levels of 2 ppm
    and above at both eight and 16 weeks and was more marked in female
    than male. Submaxillary gland and serum was less sensitive. A
    no-effect level in this study based upon cholinesterase inhibition is
    1 ppm in the diet (Doull and Vaughn, 1958).

         Groups of rats (25 male and 25 female Wistar strain rats) were
    fed disulfoton in the diet at levels of 0, 0.2, 1.0 and 5 ppm for 90
    days. Body weight and food consumption data were recorded weekly and
    behaviour and mortality was observed daily. Urinalysis, clinical
    chemistry and haematological examinations including RBC and plasma
    cholinesterase activity were made periodically. At the conclusion of
    the study, brain cholinesterase activity was analysed and all animals
    were sacrificed for gross and microscopic examination of tissues and
    organs. There were no significant differences between the controls and
    the treated animals with regard to growth, behaviour, mortality,
    urinalysis, and clinical chemistry. There appear to be no effects of
    the feeding of disulfoton on gross or histological examination of the
    tissues at the conclusion of the study. Cholinesterase was
    significantly depressed (primarily in females) in plasm and red blood
    cells at 5 ppm. In this study, 1 ppm is a no-effect level based upon
    cholinesterase inhibition Motzsche, 1972).

    Dog. Groups of adult mongrel dogs (one male and one female per
    group) were fed disulfoton in the diet at levels of 0, 1, 2, and 10
    ppm for 12 weeks. At all feeding levels, no weight loss, signs of
    poisoning or adverse behaviour were noted. Plasma and RBC
    cholinesterase values were significantly decreased at 2 and 10 ppm
    while 1 ppm caused do significant inhibition (Vaughn et al., 1958).
    After returning to a control diet, the plasma cholinesterase
    inhibition rapidly returned to normal. The RBC cholinesterase remained
    inhibited for over four weeks.

    (b) Metabolites (disulfoton sulfoxide)

    Rat. Groups of rats (10 male rats per group) were administered
    disulfoton sulfoxide orally, five doses per week, for one month at
    dosage levels of 0, 0.215, 0.43, 0.9 mg/kg. Cholinesterase activity
    was significantly depressed at the highest dose level and marginally
    depressed at the middle dose level. At seven days after the initiation
    of the study, cholinesterase depression reached a maximum level and
    thereafter recovered slightly maintaining a constant depressed level
    to the end of the experiment. Seven days after the conclusion of the
    experiment, the cholinesterase values were essentially normal (Hecht
    and Kimmerle, 1965).

         Groups of rats (10 female rats per group) were administered
    disulfoton sulfoxide daily five days per week for nine weeks at dosage
    levels of 0, 0.046, 0.093, 0.186, 0.388 and 0.775 mg/kg/day. Mortality
    was obvious at the highest dose level tested although growth was not
    affected in any of the groups. Haematological and urinalysis were
    normal as was gross pathology. Slight changes in liver epithelial
    cells were noted in several animals at the highest dose level (Hecht
    and Kimmerle, 1965). On the basis of these studies with disulfoton
    sulfoxide with the most sensitive parameter being acetyl
    cholinesterase depression, a level of 0.43 mg/kg administered orally
    five days per week would be considered to be the marginal effect
    level.

    Long-term studies

         Long-term feeding studies on rats and dogs have been initiated
    but data are not available.

    Observations in man

         Five volunteer subjects each received a daily oral dose of 0.75
    mg of disulfoton for 30 days; two persons served as controls. Plasma
    and erythrocyte cholinesterase levels were measured twice weekly
    during the pre-test control period and during the 30-day test period.
    No depression of cholinesterase activity was noted (Rider, 1972).

    Comments

         Disulfoton, a phosphorodithioate insecticide structurally similar
    to demeton, is acutely toxic and produces its primary effect through
    inhibition of cholinesterase activity. Disulfoton.is metabolized by
    thionate oxidation, thioether oxidation, and hydrolysis or oxidative
    cleavage. Thionate oxidation would result in demeton which is further
    degraded. As disulfoton is a fast acting organophosphate, the
    oxidation of the thionate to demeton is apparently very rapid. Demeton
    was evaluated by the Joint Meeting in 1965 and the ADI for man was
    estimated to be 0.0025 mg/kg.

         Toxicological studies showed disulfoton to have no effect on
    reproduction and tests for teratogenicity and mutagenicity gave
    negative results. Disulfoton did not produce delayed neurotoxicity in
    hens nor potentiate the toxicity of several organophosphorus compounds
    although it is an inhibitor of aliesterase activity. In short-term
    studies in rats and dogs a no-effect level was estimated to be 1 ppm
    based upon inhibition of cholinesterase. At higher levels liver damage
    was observed. Studies in man showed that levels of 0.75 mg for 30 days
    was without effect on cholinesterase activity.

         Long-term studies have been reported to be in progress and on the
    basis of short-term studies a temporary ADI was established.

    TOXICOLOGICAL EVALUATION

    Level causing no significant toxicological effect in animals

         Rat:   1 ppm in the diet equivalent to 0.05 mg/kg bw

         Dog:   1 ppm in the diet equivalent to 0.025 mg/kg bw

         Man:   0.75 mg/man/day

    Estimate of temporary acceptable daily intake for man

         0-0.001 mg/kg

    RESIDUES IN FOOD AND THEIR EVALUATION

    Use pattern

         Disulfoton possesses systemic activity and is used to control
    aphids, leafhoppers, thrips, beet flies (mangold fly, spinach leaf
    miner), coffee leaf miner and spider mites. it is formulated as
    granules and liquid concentrate and seed dressing powder (used only on
    cotton). Disulfoton formulations are used on cotton, vegetables,
    potatoes, cereals (chiefly sorghum and rice), coffee, etc. Products
    based on disulfoton are registered in a total of 33 countries, 807
    being used on vegetables including potatoes and 20% on field crops.

    Pre-harvest treatments

         Disulfoton is chiefly applied at sowing or as a top dressing. The
    recommended application rates range from 1 to 4 kg/ha on most crops,
    with pre-harvest intervals of from 30 to 100 days. These recommended
    pre-harvest intervals are not necessarily identical in all countries.

    Post-harvest treatments

         No uses.

    Other uses

         Applied to ornamentals.

    Residues resulting from supervised trials

         A large amount of data are available on residues resulting from
    the application of disulfoton to various crops. Most of them are from
    the United States of America. Results are presented in Table 1.



    
    TABLE 1

                                                                                       

                                      Rate of
    Crop                    No. of    Application   No. of       Days after     Residue
                            trials    kg/ha         treatments   application    PPM
                                                                                       

    Alfalfa                   11      1-1.5           1          7-28           n.d.-0.7
      (Forage)                 4      1               3          7-28           6-30
      (Hay)                    8      1.5             1          3-7            5-15
                               2      1.5             3          7              14, 19
    Beans                     16      1-2             1          80-160         n.d.-0.3
    Broccoli                   7      1-4             1          7-80           n.d.-0.6
    Brussels sprouts           4      1-2             1          7-100          n.d.-0.2
    Barley (grain)             3      1               1          33-104         n.d.
    Cabbage                    8      1.7 oz/         1          35-106         0.01-0.1
                                      1000 ft row
    Cabbage (in furrow)
      5% granules)             6      1               1          28-87          0.1-1.5
    Cotton                     3      1.2             1          28             < 0.3
    Cottonseed                16      1-4             1          30-180         n.d.-0.6
                               4      1-1.5           2          30-120         n.d.-0.2
    Celery                     5      1.2-2.5         1          55-130         n.d.-3
    Coffee                     6      1-4 oz/         1          24-180         n.d.
                                      plant
    Clover                     8      1.5-2           1          3-28           1-7
    Clever (hay)               2      1.5             1          3              8, 17
    Lettuce head or
      leaf                     5      1-2             1          16-62          <0.1
    Maize                     17      1-2             1          30-120         n.d-0.5
                              11      1-2                        20-30          0.2-7
    Oats (grain)               2      1               1          77, 98         n.d.
    Potatoes                   8      1-1.5           1          60-168         n.d-0.3
                              66      2-3             1          50-170         n.d,-0.4
                               8      3-3.5           1          86-180         0.2-2
                              11      3-4.5           2          60-180         0.05-0.3

    TABLE 1 (Cont'd.)

                                                                                       

                                      Rate of
    Crop                    No. of    Application   No. of       Days after     Residue
                            trials    kg/ha         treatments   application    PPM
                                                                                       

    Peanuts                    3      1-2             1          116-148        n.d
    Peanuts (shells)          11      9-14            1          116-168        0.01-0.4
    Peanuts (kernels)          3      16+32           2          70             0.1
    Peas (including pods)     13      1-2             1          28-70          n.d.-0.3
                               2      2               1          28-43          4,9
    Pineapple                 14      1-5             1          7-70           n.d.
    Rice                      12      1-4             1          50-200         n.d,-0.5
    Spinach                    4      1               1          7-21           2-4
                              10      1               1          40-90          n.d.-0.5
    Sorghum                   17      1-1.5           1          30-80          n.d.-0.1
    Sugar beets               11      1               1          98             0.1-0.3
                              11      1               1          51             n.d.-6
                               5      1-2.5           1          160-180        n.d.-0.1
    Soybeans                   2      1,2             1          132            n.d.
    Tomatoes                  10      0.5-6           1 or 2     30-108         n.d.-0.5
    Wheat                     24      0.75-4          1          30-300         n.d.-0.2
                               5      0.25-1          4          30-52          0.01-0.02
    Pecans                     5      1-20            1          88-240         n.d.
    Soil persistence           1      0.5             1          0-366          n.d.
                               1      0.5             1          1-424          6-0.4
                               1      0.5             1          1-181          4-1
                                                                                       

    

    FATE OF RESIDUES

    In plants

         From knowledge of the ready biological oxidation of thioether
    groups and in view of the known conversion of phosphothionates to
    their P=O analogues, the expected metabolites of disulfoton (I) are
    the compounds (II) to (VI):

    CHEMICAL STRUCTURE 3

    Compound (IV) is demeton-S, one of the active ingredients of the
    well-known systemic insecticide SystoxR. Thus the metabolism of
    disulfoton dovetails into the metabolism of demeton-S. However, it
    should be noted that owing to the rapid formation of the sulfoxides,
    the occurrence of (IV) as a metabolite is hardly to be expected.
    Following the formation of these metabolites, further degradation can
    only be by hydrolysis. The plant metabolism of disulfoton was studied
    by the use of 32-p labelled compound (Metcalf et al., 1957, 1959) in
    cotton, lemon, bean and alfalfa plants. Disulfoton was rapidly
    oxidized to produce the sulfoxide (II) and slowly to produce sulfone
    (III). Both those compounds were also oxidized at the thiono-sulfur to
    produce V and VI. These same compounds were identified by Bull (1965)
    working with other plants, e.g., avocado, brussels sprouts, cabbage,
    corn, tomato. The same results were obtained but the proportions of
    various compound differed. These studies we re confirmed by later
    investigations.

         Loeffler (1970b) found II and VI as major metabolites in tobacco.
    Gentry et al., (1970) found that in tobacco the order was: Ill, II,
    VI, V (see also Bowman et al., 1969).

    In soil and water

         Generally, the half-life of disulfoton residues in different
    soils is between 30 and 100 days (Olson, 1964; Loeffler, 1969). Soil
    type and microbial activity seem to have a greater influence on the
    rate of decomposition than the temperature (Henzer et al., 1970).

         Both sulfones were detected as metabolites in the soil (Henzer et
    al., 1970), but the sulfoxides occurred in only minute amounts. Takase
    et al., (1971, 1972) however, found chiefly disyston sulfoxide and
    sulfone as metabolites in different types of soil.

         Disulfoton does not display a strong tendency to leach into the
    soil since approximately 1670, 1970 and 4400 m of theoretical rainfall
    were required to leach the compound 30 cm into sandy loam, silt loam
    and high organic silt loam soils, respectively (Flint et al., 1970).

         No effect on soil micro-organisms was observed (Houseworth and
    Tweedy, 1972), though some reduction of fungal population was observed
    with the high level of 250 ppm in the soil.

         The half-life of disulfoton in water under simulated field
    conditions was 2.9 days (Flint et al., 1970).

    Fate of residues in storage, processing and cooking

         In frozen storage, residues remain unchanged for long periods,
    sometimes for more than two years (Chemagro Rep. 8857).

         The thermal destruction of disulfoton during processing of
    apricots (100°C/2 min) and spinach (120°C/55 min) was investigated by
    Thornburg and reported (Anderson 1959a, b). Loss of residues was 37%
    and 80% respectively.

         The fate of disulfoton in potatoes during processing was
    investigated by Kleinschmidt (1971). Total residues (1.33 ppm) were
    reduced by 35% with lye peeling. Lye peeling plus a single water
    blanching reduced the total residue by 38, 74 and 61% for french
    fries, dehydrated cubes and dehydrated mashed potatoes, respectively.
    On a dry weight basis, overall reduction in residues due to processing
    potatoes into french fries, dehydrated cubes, dehydrated mashed, and
    chips were 77, 81, 89 and 97% respectively. Lye peeling and cooking
    decreased residues of disulfoton by 30% (Zwolinska and Trojanowski,
    1968a).

    Total diet studies and residues in food moving in commerce

         Abbott et al., 1970, found residues of disulfoton only on one
    sample of green vegetables. In 1968, 0.1 ppm of disulfoton was found
    in only one sample of citrus fruit in New Zealand (N.Z. Min. of Agr.
    information, 1973).

    Methods of residue analysis

         Prior to the advent of GLC methods employing phosphorus sensitive
    detectors, residues of disulfoton and its metabolites were determined
    by total phosphorus procedures. GLC methods for the determination of
    disulfoton residues are now available (Thornton and Anderson, 1968;
    Thornton, 1967a, 1967c, 1969; Bowman et al., 1969; Bowman and Beroza,
    1969). The principle of most GLC procedures is oxidation of the
    residues to disulfoton-sulfone (Ill) and/or demeton-S-sulfone (VI). If
    permanganate is used for oxidation, there is usually no transformation
    of P = S to P = O so that it is possible to distinguish between P =
    S-sulfones and P = O-sulfones. This permits conclusions to be drawn as
    to whether the residues present result from application of demeton-S
    or disulfoton. It is possible to distinguish clearly between these and
    related sulfone pairs by using a 1.1 m column packed with 10% DC-200 +
    1% QF -1 on 80/100 mesh Gaschrom Q; at 195°C. The following retention
    times are reported (Wagner, 1973):

         demeton-S-methyl sulfone      3.75 min
         thiometon sulfone             4.75 min
         demeton-S-sulfone             5.0 min
         disulfoton-sulfone            6.15 min

         Confirmatory GLC procedures, using different columns, are also
    available (Olson, 1969; Loeffler, 1970). An interference study for
    disulfoton residue determinations on alfalfa, clover and potatoes was
    carried out by Olson (1970). A great number of organophosphorus
    compounds were mixed with the various sulfone compounds.
    Chromatographic conditions were modified and/or a confirmatory column
    was employed and it was possible to eliminate all interference.
    Numerous multi-residue methods capable of measuring disulfoton and its
    metabolites are reported (Abbott et al., 1970; Storherr et al., 1971;
    Watts, 1969; McCaulley, 1965). The available GLC procedures appear to
    be satisfactory, specific and suitable for regulatory purposes.

    Appraisal

         Disulfoton is an organophosphorus insecticide, possesses systemic
    activity and is used to control aphids, leafhoppers, thrips, beet
    flies, coffee leaf miner and spider mites. It is formulated
    predominantly as granules and for some special uses as a liquid
    concentrate. A seed dressing powder is exclusively used in cotton.
    Disulfoton is used on a great variety of crops, including vegetables,
    potatoes, sugar beets, cotton and cereals. Products based on
    disulfoton are registered in a total of 33 countries. The percentage
    breakdown of the amounts used in the different crop areas is roughly
    80% in vegetables (including potatoes) and 207 in field crops.
    Disulfoton is chiefly applied at sowing or as a side dressing.
    Recommended application rates are from 1 to 4 kg/ha, pre-harvest
    intervals ranging mostly from 30 to 100 days. The minimum purity of
    the technical product is 94%. The impurities have been identified and
    quantified.

    NATIONAL TOLERANCES

    Pre-harvest intervals and tolerances
                                                                         
                                           Pre-harvest
    Country         Crop                   interval              Tolerance
                                           (days)                 (ppm)
                                                                         

    Australia       Potatoes               70                     0.5
                    Vegetables             40                     0.5
                    Cereals                70                     0.5
                    Deciduous fruit        70                     0.5

    Belgium         Deciduous fruit                               0.01
                    Potatoes                                      0.01
                    Vegetables                                    0.01

    Bulgaria                               60

    Canada          Beans                                         0.5
                    Broccoli                                      0.5
                    Brussels sprouts                              0.5
                    Cauliflower                                   0.5
                    Lettuce                                       0.5
                    Peas                                          0.5
                    Potatoes                                      0.2
                    Spinach                                       0.5
                    Tomatoes                                      0.5

    Germany         Beets                  Do not feed tops before
                    Hops                   harvest. Application by
                                           sprinkling method must be
                                           made only up to 1 June at
                                           the latest.
                    Potatoes               Only for seed          0.2
                                           production

    Netherlands     Vegetables,                                   0.01
                    deciduous fruit
                    Potatoes               Only at planting       0.01

    New Zealand     Barley                 56
                    Beans                  56
                    Broccoli               42
                    Brussels sprouts       42
                    Cabbage                42
                    Carrots                56
                    Cauliflower            42
                    Oats                   50
                    Peas                   56

    Pre-harvest intervals and tolerances (cont'd.)

                                                                          

                                           Pre-harvest
    Country         Crop                   interval              Tolerance
                                           (days)                 (ppm)
                                                                          

                    Potatoes               91
                    Turnips                56
                    Wheat                  56

    Poland          Hops                   Apply only at the time
                                           of earthing up.
                    Potatoes               Only for seed production
                    Beets                  Apply up to the six-leaf
                                           stage.
                    For fodder             60

    USSR            Cereals, cotton                               0.35
                    seed oil
                    Fodder                       No residues

    South Africa    Cabbage                42                     0.5
                    Onions (for aerial     90                     0.5
                    plant parts)
                    Potatoes               90                     0.5

    Switzerland     Field crops            42

    United
    Kingdom                                42

    United States   Alfalfa
    of America      (fresh forage)                                5.0
                    (hay)                                         12.0
                    Barley (grain)         60                     0.75
                    (forage or straw)                             5.0
                    Beans (green, Lima,    Application at         0.75
                    snap)                  time of planting
                    (on vines)                                    5.0
                    Beans (dry)            60                     0.75
                    (on vines)                                    5.0
                    Broccoli               14                     0.75
                    Brussels sprouts       30                     0.75
                    Cabbage                42                     0.75
                    Cauliflower            40                     0.75
                    Clover (fresh)         7                      5.0
                    (clover hay)                                  12.0
                    Coffee                 90                     0.3
                    Cotton 
                    (non-irrigated, seed)  28                     0.75

    Pre-harvest intervals and tolerances (cont'd.)

                                                                         

                                           Pre-harvest
    Country         Crop                   interval              Tolerance
                                           (days)                 (ppm)
                                                                         

                    Cotton (irrigated,     28,90                  0.75
                    seed)
                    Hops                                          0.5
                    Lettuce                60                     0.75
                    Maize (field corn,
                    sweet corn,            40,100                 0.3
                    popcorn)(grain)
                    (fodder)                                      5.0
                    Oats (grain)           60                     0.75
                    (forage or straw)                             5.0
                    Peanuts                Application            0.75
                    (peanut hay)           at time of             5.0
                                           planting
                    Peas                   50                     0.75
                    (vines)                                       5.0
                    Pecan                  80                     0.75
                    Pineapples             60                     0.75
                    (foliage)                                     5.0
                    Potatoes               75                     0.75
                    Rice                   100                    0.75
                    (straw)                                       5.0
                    Sorghum (grain)        7                      0.75
                    (fodder and            28                     5.0
                    forage)
                    Soybeans               Do not pasture or use treated
                                           crop for feed food or forage
                    Spinach                Application at         0.75
                                           time of planting
                    Strawberries           Do not use fruit from
                                           treated plantg for food
                    Sugar beets            30                     0.5
                    (tops)                                        2.0
                    Sugar cane             28                     0.3
                    Tomatoes               30                     0.75
                                           resp. application at time
                                           of planting
                    Wheat (grain)          45                     0.3
                    (green fodder          Do not graze           5.0
                    and straw)             treated fields

                                                                          

         Metabolism studies on plants and soil are available, indicating
    the formation of sulfoxides and sulfones of disulfoton and the oxygen
    analogue (demeton-S). The ratio of these metabolites can vary and
    depends on plant variety, soil type and climatic conditions.

         A large number of residue data are available from supervised
    trials, predominantly from the United States of America, but also from
    some European countries and New Zealand.

         Evidence on the fate of residues during storage, processing and
    cooking indicates that residues are stable under deep freeze
    conditions; losses of residues occur during cooking, heating, or
    peeling in the case of potatoes.

         Information on residues in food moving in commerce or from total
    diet studies is scanty. No data are available on the eventual
    carry-over of residues from forage crops into animal tissues, milk or
    eggs. Methods of analysis for disulfoton residues based on GLC with
    phosphorus specific detectors are available and appear to be suitable
    for regulatory purposes, the limit of detection being in the order of
    0.05-0.1 ppm depending on the crop.

         Residues are best determined, following oxidation to
    disulfoton-sulfone and/or demeton-S sulfone, as the sum of parent
    compound and all of its oxydative metabolites, expressed as parent
    disulfoton. By applying-suitable oxidation procedures, a quantitative
    differentiation can be made between the two sulfones. Absence of
    disulfoton-sulfone would indicate that prevailing residues have arisen
    from an application of demeton, in which case residues should be
    expressed as parent demeton.

    RECOMMENDATIONS

         The following tolerances are recommended, the residues being
    determined as disulfoton-sulfone and demeton-S-sulfone and expressed
    as disulfoton.
                                                                      
    Crop                                              Tolerance (ppm)
                                                                      
    Vegetables, including beans, broccoli, 
      brussels sprouts, cabbage, cauliflower,         0.5
      lettuce, potatoes, peas, spinach,
      tomatoes, rice (in husk), sugar beets

    Cereals (except rice) sugar beets, cottonseed     0.2

    Coffee beans, peanuts (kernels),
      pecans, pineapple, soybeans                     0.1a

    Forage crops (green)                              5.0
                                                                     
    a At or about the limit of determination.

    FURTHER WORK OR INFORMATION

    Required before June 1975

    1. Results of the long-term studies now in progress.

    2. Kinetic studies on absorption, distribution, metabolism, and
    excretion in mammals.

    3. Evaluation of liver damage observed in short-term studies.

    4. Data on residues in meat, milk, and eggs after feeding animals on
    crops or feedstuffs treated with disulfoton, in order to determine
    residue limits in foods of animal origin.

    Desirable

    1. Information on residues in food moving in commerce.

    REFERENCES

    Abbott, D.C., Crisp, S., Tarrant, K.R. and Tatton, J. O'G. (1970)
    Organophosphorus pesticide residues in the total diet. Pestic. Sci.
    1: 10-13

    Adams, J.M. (1960) A specific method for the detection of residues  of
    DI-SYSTON and its metabolites in the presence of other cholinesterase
    inhibiting pesticides. 1. Application to cottonseed. Chemagro-Report
    No. 5928

    Anderson, C.A. (1959a) Thermal destruction of DI-SYSTON during 
    processing of spinach. Chemagro-Report No. 4882d

    Anderson, C.A. (1959b) Thermal destruction of DI-SYSTON during the
    processing of apricots. Chemagro-Report No. 4882e

    Anderson, C.A. (1960) Colorimetric determination of DI-SYSTON and 
    SYSTOX residues in plant material. III. Application to potatoes, sugar
    beets, sugar beet tops, cabbage, broccoli, pineapple and alfalfa.
    Chemagro-Report No. 5511

    Anderson, C.A. (1961a) Colorimetric determination of DI-SYSTON and 
    SYSTOX residues in plant material. I. Application to cottonseed.
    Chemagro-Report No. 5339

    Anderson, C.A. (1961b) Colorimetric determination of DI-SYSTON
    residues in plant material. III. Application to Brussels sprouts,
    cauliflower, green beans, lettuce, lilies, peas, pineapple and
    tomatoes. Chemagro-Report No. 6684

    Anderson, C.A. (1962) Colorimetric determination of DI-SYSTON and 
    SYSTOX residues in plant material. Chemagro-Report No. 8544

    Anderson, C.A. (1963) Colorimetric determination of DI-SYSTON residues
    in green coffee beans. Chemagro-Report No. 10 919

    Arnold, D., Keplinger, M.L. and Fancher, O.E. (1971) Mutagenic Study
    with DI-SYSTON in Albino mice. IBT No. E 8920. Unpublished report from
    Industrial Bio-TeSt Laboratoricos Inc.

    Ben-Dyke, R., Sanderson, D.M. and Noakes, D.N. (1970) "Acute Toxicity
    Data for Pesticides (1970)". World Review of Pest Control, 9:
    119-127

    Bombinski, I.J. and DuBois, K.P. Chicago. (1958) "Toxicity and
    Mechanism of Action of Di-Syston". A.M.A Archives of Industrial
    Health, Vol. 17: 192-199

    Bowman, M.C. and Beroza, M. (1969) Rapid GLC method for determining
    residues of fenthion, disulfoton, and phorate in corn, milk, grass,
    and faeces. J.A.O.A.C., 52: 1231-1237

    Bowman, M.C., Beroza, M. and Gentry, C.R. (1969) GLC determination  of
    residues of disulfoton, oxydemetomethyl, and their metabolites in
    tobacco plants. J.A.O.A.C., 52: 157-162

    Brewerton, H.V. and Close, R.C. (1967) Disulfoton residues in potato
    tubers. N.Z. J1. agric. Res., 10: 272-277

    Brodeur, J. and DuBois, K.P., Chicago. (1964) "Studies on the 
    Mechanism of Acquired Tolerance by Rats to 0,0-Diethyl S-2-(ethylthio)
    ethyl phosphorodithioate (Di-Syston)", Arch. Int. Pharmacodyn., 149:
    560-570

    Budreau, C.H. (1972) Teratogenicity and chromotoxicity of three
    organophosphorus insecticides in CF1 mice. Diss. Abs. Int., 33:
    1174B

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    toxicity of Demeton and Penthion in CF1 mouse embryos. Toxicol. Appl.
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    See Also:
       Toxicological Abbreviations
       Disulfoton (ICSC)
       Disulfoton (WHO Pesticide Residues Series 5)
       Disulfoton (Pesticide residues in food: 1978 evaluations)
       Disulfoton (Pesticide residues in food: 1979 evaluations)
       Disulfoton (Pesticide residues in food: 1981 evaluations)
       Disulfoton (Pesticide residues in food: 1984 evaluations)
       Disulfoton (Pesticide residues in food: 1991 evaluations Part II Toxicology)