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    DISULFOTON

    First draft prepared by Dr. S. Caroldi,
    University of Padua,
    Padua, Italy

    EXPLANATION

         Disulfoton was previously reviewed by the Joint Meeting in 1973
    and 1975 (Annex I, 20 and 24).  In 1975 an ADI of 0.002 mg/kg bw was
    allocated. Since then, a number of additional studies have been
    generated, which were evaluated by the 1991 FAO/WHO Joint Meeting.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

    Rats

         Sprague-Dawley rats (3/sex/treatment) were given single oral
    doses of either 0.2 or 1 mg 1-ethylen-14C-disulfoton/kg bw.  Another
    3 rats/sex received 14 daily oral doses of 0.2 mg unlabelled
    disulfoton/kg bw followed by one dose of 0.2 mg labelled disulfoton/kg
    bw.  The primary excretory pathway in both sexes was via urine. 
    Approximately 90% of radioactivity was recovered in urine within 24
    hours of dosing and excretion was practically completed at 72 hours. 
    Less than 2% of radioactivity was found in faeces and less than 1% was
    exhaled as 14CO2.  The present study indicates that disulfoton is
    rapidly absorbed by oral route and rapidly excreted in rats.  Both the
    single dose and multiple dose testing regimens indicate kinetics and
    route of disulfoton excretion are similar in males and females (Lee
     et al., 1985).

    Biotransformation

    Rats

         Urine samples from the rats subjected to the single-dose (0.2 or
    1 mg/kg) and multiple-dose (0.2 mg/kg/day) testing regimens described
    above were analyzed for disulfoton metabolites by thin layer
    chromatography.  The primary metabolite was an unidentified polar
    compound that probably was a product of disulfoton  hydrolysis. 
    Oxidative metabolites identified in the urine were disulfoton sulfone
    (PSSO2), disulfoton oxygen analogue sulfoxide (POSO), and disulfoton
    oxygen analogue sulfone (POSO2).  No consistent differences between
    sexes were observed after either single or multiple doses (Lee
     et al., 1985).  The proposed metabolic pathway of disulfoton in rats
    is shown in Figure 1.

    Chickens

         Fourteen adult White Leghorn hens were administered 10 mg/kg/day
    1-ethylene-14C-disulfoton p.o. for 3 days.  Birds were sacrificed 4
    hours after the last disulfoton dose.  Three sulfonic acid metabolites
    (2-ethyl sulfinyl ethane, 2-ethyl sulfonyl ethane, and 2-ethyl
    thioethane) comprised approximately 58% of the disulfoton residue in
    eggs, heart, breast and thigh muscle, skin, kidney and liver.  Fat and
    gizzard contained 87% and 90% unmetabolized disulfoton, respectively. 
    Minor metabolites found in the tissues included disulfoton oxygen

    analogue, disulfoton sulfone, and disulfoton oxygen analogue sulfone
    (Krautter  et al., 1987)

    Goat

         A lactating goat was administered 1.1 mg/kg/day
    1-ethylene-14C-disulfoton p.o. for 3 days.  The animal was killed 2
    hours after the last disulfoton dose.  Three sulfonic acid metabolites
    (2-ethyl sulfinyl ethane, 2-ethyl sulfonyl ethane, and 2-ethyl
    thioethane) comprised approximately 66% of the disulfoton residues in
    muscle, kidney, liver and fat.  Liver and muscle also contained 34%
    and 18% unmetabolized disulfoton, respectively (Krautter  et al.,
    1988)

    Short term studies

    Rats

         Ten male and 10 female Wistar II albino rats (Winkelmann,
    Borchen) were exposed in dynamic inhalation chambers to 0, 0.5, 1.8,
    or 9.8 mg/m3 of disulfoton (purity 94.4%, dissolved in a 1:1 mixture
    of ethanol and Lutrol and aerosolized into chambers) for 5 daily
    4-hour exposures.  The rats were kept under observation for 14 days
    after the last exposure.  Animals were weighed weekly and both plasma
    and erythrocyte cholinesterase activities were measured before
    starting exposure and after the first, third and fifth exposures and
    72 hours after the last one.  No deaths were observed, except in
    female rats at 9.8 mg/m3 disulfoton (9 out of 10 animals died between
    1-8 days from the beginning of the study).  Symptoms typical for
    cholinergic toxicity were observed in all animals of both sexes from
    1.8 mg/m3.  Body weight and gross pathology were not different among
    groups. Dose-related inhibition of plasma cholinesterase activities
    (80-90% at the highest dose level in surviving rats) and slight
    inhibition of erythrocyte cholinesterase activities (20-30% at the
    highest dose level in surviving rats) were measured in both sexes from
    1.8 mg/m3 (Thyssen 1978).


    FIGURE 1


        Acute toxicity studies

    Table 1.  Acute toxicity of Disulfoton

                                                                                                 

    Species       Sex       Route                LD50          LD50         Reference
                                              (mg/kg bw)     (mg/m3)
                                                                                                 

    Mice           M        oral                  7.0                       Mihail (1978)a
                   F                              8.2
                  M&F       oral                 27                         Iyatomi (1980)b
                  M&F       i.p.                 14                         Iyatomi (1980)b
                   M        s.c.                 20                         Iyatomi (1980)b
                   F                             28
                  M&F       dermal               35                         Iyatomi (1980)b

    Rats           M        oral                  6.2                       Mihail (1978)a
                   F                              1.9
                   M        oral                  9.6                       Iyatomi (1980b)b
                   F                              4.2
                   M        inhalation                            290       Thyssen (1978)c
                   F        (1 hr exp)                             63
                   M        inhalation                      approx 60       Thyssen (1978)c
                   F        (4 hr exp)                      approx 15
                   M        i.p.                  7.5                       Iyatomi (1980)b
                   F                              3.1
                   M        s.c.                  7.7                       Iyatomi (1980)b
                   F                              4.0
                   M        dermal               15.9                       Mihail (1978)a
                   F        (24 hr exp)           3.6
                   M        dermal               22.6                       Iyatomi (1980)b
                   F                              7.3
                                                                                                 

    Table 1 (contd).

                                                                                                 

    Species       Sex       Route                LD50          LD50         Reference
                                              (mg/kg bw)     (mg/m3)
                                                                                                 

    Dogs           F        oral              approx .5                     Mihail (1978)a
                                                                                                 

    a  Test substance; S 276, pure grade 94.4%.  Typical cholinergic symptoms reported.  Pulmonary
       oedemas were observed in necropsied animals.
    b  Test substance; disulfoton pure grade 98.6%. Only LD50s are reported. Details about
       symptoms and pathology are lacking.
    c  Test substance; S 276, pure grade 94.4%. Typical cholinergic symptoms reported. Gross pathology
       negative.
    

         Two subacute inhalation studies were conducted on Wistar TNO/W 74
    albino rats (Winkelmann, Borchen, Germany) (10/sex/dose level) exposed
    in dynamic inhalation chambers to aerosolized concentrations of
    technical disulfoton (purity 94.4%).  In each study exposure was for
    6 hours per day, five days per week for three weeks.  Test compound
    was dissolved to final concentrations in ethanol and polyethylene
    glycol 400 (1:1 mixture).  Controls were exposed to solvent mixture at
    a concentration of 20,000 µl/m3.  In study 1, disulfoton
    concentrations were 0, 0.1, 0.5 and 3.7 mg/m3 air.  Rats were
    observed daily for clinical symptoms and weighed weekly.  Twenty-four
    hours after the last exposure, 5 rats/sex/dose level were subjected to
    haematological tests, clinical chemistry tests and urinalysis. Both
    plasma and erythrocyte cholinesterase activities were measured after
    0, 5, 10 and 15 exposures and brain cholinesterase activity was
    determined at the end of the study. Pathology was performed at the end
    of the study.

         At the highest dose level, all rats showed clinical symptoms
    typical for cholinergic toxicity and 5 female rats died within 12
    exposures. At lower dose levels, behavioural disturbance was detected
    during the last week of exposure soon after the end of each exposure. 
    Body weight, haematological tests, clinical  chemistry tests and
    urinalysis did not show dose-related alterations.  Plasma
    cholinesterase activities were significantly reduced in females at all
    dose levels and in males only at the highest dose level.  At 3.7 mg
    disulfoton/m3, erythrocyte cholinesterase activity was consistently
    reduced throughout the duration of the study in both sexes.  At the
    end of the study brain cholinesterase activities were 48% and 58% of
    control values in males and females, respectively.  Mottled distended
    lungs and ulcer-like foci were observed in animals which died before
    the end of the study, but no toxic effects were detectable in
    surviving rats.  At the highest dose level, increased relative and
    absolute adrenal weights were observed in female rats.  Histopathology
    showed inflammatory changes in the region of the respiratory tract 
    and concurrent bone marrow changes from 0.5 mg disulfoton/m3 in both
    sexes.  In study 2, 10 female and 10 male rats were exposed to a
    concentration of 0.02 mg disulfoton/m3 air (controls exposed to
    solvent/air only).  Also 20 additional female rats were exposed to 3.1
    mg disulfoton/m3 air to confirm the high mortality  rate observed in
    females at the highest dose level in study 1.  The protocol of study
    2 was like that of study 1.  Results at the highest concentration in
    study 2 confirmed toxicity detected at a similar dose level in study
    1.  Three out of 20 rats died before the end of the study.  All
    clinical, biochemical and pathological parameters were unaffected at
    0.02 mg disulfoton/m3 air.  A concentration of 0.1 mg/m3 was the
    NOAEL for inhalation of a disulfoton aerosol with females being more
    sensitive to disulfoton toxicity than males (Thyssen, 1980).

         Nine or ten male and 10 female Fischer 344 rats were exposed in
    dynamic inhalation chambers to aerosolized technical disulfoton
    (purity 97.8%) by the nose-only technique for 6 hours per day, 5 days
    per week for 3 weeks.  The targeted concentrations of disulfoton were
    0.005, 0.05 and 0.5 mg/m3 air which corresponded to analytical
    concentrations of 0.006, 0.07 and 0.7 mg disulfoton/m3 air. 
    Disulfoton was dissolved in a mixture 1:1 of ethanol/polyethylene
    glycol and two control groups were added, exposed to either
    solvent/air or air only.  Rats were observed daily for mortality and
    signs of toxicity and weighed weekly.  No deaths, signs of toxicity
    nor differences in body weight were detected throughout the study.  No
    reduction of brain cholinesterase activity was measured in any group
    at the termination of the study.  The NOAEL could be set at 0.7 mg/m3 
    air based on normal brain cholinesterase activity at the end of the
    study (Shiotsuka, 1988).

         Twelve male and 12 female Fisher 344 rats were exposed in dynamic
    inhalation chambers to aerosolized technical disulfoton (purity 97.8%)
    by the nose-only technique for 6 hours per day, 5 days a week for 13
    weeks at concentrations of 0.015, 0.15 and 1.5 mg disulfoton/m3 air.
    Solutions of disulfoton in vehicle (1:1 ethanol, polyethylene glycol
    400) were prepared weekly and actual concentrations in the chambers
    (checked daily) were 0.018, 0.16 and 1.4 mg disulfoton/m3 air for the
    lowest, mid and highest concentration, respectively.  Disulfoton
    exposure did not produce clinical symptoms nor increase mortality. 
    Feed consumption and body weight were not different among groups. 
    Ophthalmology, clinical chemistry tests, haematological tests and
    urinalysis did not reveal toxic alterations. Slight inhibition of
    plasma, erythrocyte and brain cholinesterase activities were measured
    in both sexes at the highest dose level (at termination of the study,
    brain cholinesterase inhibition was 29% and 28% in males and in
    females, respectively).  Gross pathology and organ weights did not
    show toxic effects related to disulfoton exposure.  A significantly
    increased incidence of inflammation in the nasal turbinate of males
    exposed to the highest disulfoton concentration was detected and
    judged as a topical irritant effect of the test substance.  The NOAEL
    in this study was 0.16 mg disulfoton/m3 for both sexes, based on
    cholinesterase inhibition and histopathological finding detected at
    the next higher dose level (Shiotsuka, 1989).

    Rabbits

         Groups of adult male and female New Zealand rabbits (5/sex/dose
    level) received technical disulfoton (97.8% purity grade, formulated
    with Cremophor EL in saline) dermally (skin not abraded, uncovered
    after application and test substance washed away at the end of each
    exposure period) for 6 hours per day, 5 days per week for 3 weeks. 
    The tested concentrations were 0, 0.4, 1.6, 6.5 mg disulfoton/kg bw. 
    Rabbits were observed for signs of toxicity twice a day (skin was
    evaluated for irritation before the beginning of the study and 24
    hours after the end of each treatment).  Body weights and feed
    consumption were determined weekly.  Cholinergic signs such as muscle
    spasms, dyspnoea and salivation were observed in both sexes at the
    highest dose level and all animals died within 10 days.  Cholinergic
    symptoms and deaths appeared earlier in female rabbits.  Mortality,
    appearance (skin included) and behaviour, feed consumption and body
    weight were not affected by treatment up to 1.6 mg disulfoton/kg
    bw/day.  No dose-related effects were observed in clinical chemistry
    tests (except cholinesterase activities), haematological tests,
    urinalysis, gross pathology, organ weights nor histopathology up to
    1.6 mg disulfoton/kg bw/day.  Marginal inhibition of both plasma and
    erythrocyte cholinesterase activities were determined at 1.6 mg/kg
    bw/day but brain cholinesterase activity was not different from that
    of controls.  The NOAEL can be set at 1.6 mg disulfoton/kg bw/day
    based on normal brain cholinesterase activity measured at this dose
    level (Flucke, 1986).

    Dogs

         Four male and 4 female pure-bred Beagle dogs were treated with
    disulfoton (95.7% purity grade) at concentrations of 0, 0.5, 1 and 2
    ppm (increased to 5 ppm on week 70 and again to 8 ppm on week 73 up to
    the end of the study) equal to 0, 0.155, 0.319 and 1.31 mg/animal/day
    for 104 weeks.  Disulfoton was mixed with the food (50% premix x 2)
    and the food ration (pulverized food + twice as much tap water) was
    administered to all dogs in the form of a mash once daily.  The
    mixture was prepared weekly. The dogs were inspected daily for
    toxicity and weighed weekly.  Body temperature and pupillary reflex,
    patellar reflex, flexor reflex and extensor thrust were tested several
    times throughout the study.  Disulfoton did not affect food and water
    intake nor body weight gain.  No clinical symptoms related to
    disulfoton administration were detectable at any dose level. 
    Ophthalmoscopic examinations, reflexes and results of haematological
    tests, clinical-chemical tests and urinalysis did not show toxicity
    due to disulfoton.  A single dog dosed with 0.5 ppm of disulfoton
    developed interstitial nephritis of both kidneys and was sacrificed on
    week 93.  No other dogs died before the scheduled termination of the
    study. Plasma, erythrocyte and brain cholinesterase activities were
    not reduced in dogs up to 1 ppm disulfoton.  Marginal inhibition of
    plasma and erythrocyte cholinesterases was observed at 2 ppm which was

    further increased by increasing the dose of disulfoton in the diet. 
    At the end of the study plasma and erythrocyte cholinesterase
    activities in dogs dosed with 8 ppm were inhibited 50-60%. In this
    group, brain cholinesterase was reduced 34% and 18% in males and
    females. Neither macroscopic pathology nor histopathology provided any
    evidence of tissue alterations attributable to dietary administration
    of disulfoton.  The NOAEL is 1 ppm disulfoton equal to 0.319
    mg/animal/day (Hoffman & Weischer, 1975)

    Long term studies

    Mice

         Fifty male and 50 female CD1 albino mice were treated with
    disulfoton (98.2% purity grade) at concentrations of 0, 1, 4, 16 ppm,
    equal to 0, 0.137, 0.548, 2.223 mg/kg bw/day for males and 0, 0.18,
    0.73 and 2.3 mg/kg bw/day for females (calculated as average daily
    intake throughout the duration of the study) for 99 weeks.  The mice
    were 4 weeks old at the beginning of the study.  The diets were
    prepared weekly with corn oil as the vehicle (1% by weight) and
    acetone as the solvent and kept in a freezer until presented to the
    mice at one dietary level on consecutive days. Stability and
    homogeneity of disulfoton were acceptable.  The actual content of
    disulfoton in the formulation was checked monthly and showed 77%, 89%
    and 92% of nominal (mean of the 25 determinations) for 1, 4, 16 ppm,
    respectively. Observation for toxicological effects were made twice
    daily (1X/day on holidays).  Weekly observations for abnormalities and
    masses were made and feed consumption and body weights were recorded. 
    Haematology determinations on 10 mice/sex/dose level were performed at
    6 months, 12 months and termination of the study.  Plasma, erythrocyte
    and brain cholinesterase activities were determined at the end of the
    study in controls and in mice treated with the highest dose of
    disulfoton. Pathology was performed on all animals found dead or
    sacrificed at the end of the study.

         In both sexes, food intake and body weight were not influenced by
    disulfoton administration.  Neither sex showed any changes in the
    incidence of clinical signs, or mortality rate at any dose level. At
    the end of the treatment the mortality rate was 42%, 40%, 34%, 44%
    (male) and 54%, 62%, 46%, 54% (female) at 0, 1, 4, 16 ppm disulfoton,
    respectively. Disulfoton had no effects on haematological parameters.
    At termination of the study inhibition of plasma, erythrocyte and
    brain cholinesterase activities in mice at the 16 ppm dose level were
    79%, 56%, 44% (male) and 50%, 82%, 46% (female), respectively. 
    Trivial differences in organ weights were observed between controls
    and dosed mice.  Both neoplastic and non-neoplastic histopathologic
    observations were those of spontaneous or naturally occurring lesions
    of aging albino mice.  No differences in the incidence of neoplastic
    or non-neoplastic lesions were found when treated mice were compared
    to control mice.  Disulfoton showed no evidence of an oncogenic effect
    when added to the diet up to 16 ppm equal to 2.223 and 2.690 mg/kg

    bw/day for males and females, respectively.  The NOAEL for disulfoton
    in the present study was 4 ppm equal to 0.55 and 0.73 mg/kg bw/day in
    males and females, respectively (Hayes, 1983).

    Rats

         Sixty male and 60 female Sprague-Dawley rats were dosed with
    disulfoton (purity 95.7%) at concentrations of 0, 0.5, 1, or 2 ppm for
    104 weeks.  The lowest dose was increased to 5 ppm from week 80 as at
    that time no clear adverse effects were detectable at the next highest
    dose. The average daily intakes were: at 0.5/5 ppm 0.03 mg/kg/day and
    0.02 mg/kg/day (0.009/0.1 and 0.007/0.7 corresponding to the 0.5 and
    5 ppm period), at 1 ppm 0.02 mg/kg/day and 0.01 mg/kg/day and at 2 ppm
    0.04 mg/kg/day and 0.03 mg/kg/day in males and females, respectively. 
    Rats were 4-5 weeks old at the beginning of the study.  Powdered
    standard rat diet and tap water were available  ad libitum.  The test
    compound was formulated 50% in Ultrasil and mixed into the diet
    (prepared every two weeks) up to nominal concentrations.  Analyses of
    concentrations of the test compound in the food were not reported. 
    Haematological tests, clinical chemistry tests, and urinalysis were
    performed several times throughout the study and at the end of the
    study (brain cholinesterase included).  At the end of the study 10
    rats/sex/dose level were necropsied and organ weights were recorded. 
    Histopathology was performed on tumour-bearing animals which died or
    were killed during the study (except some animals which could not be
    investigated as a result of the progressed autolytic state) and at
    termination of the study on 5 animals per sex of the control group and
    the 5 ppm-group.  No significant differences in food and water
    consumption nor body weight were observed between controls and treated
    animals.  No overt signs of toxic effect were observed apart from
    transient muscle twitches seen in some animals after increasing the
    dose to 5 ppm.  At the end of the study mortality rate was 55%, 60%,
    60% and 75% in males and 45%, 38%, 42% and 32% in females at 0, 0.5/5,
    1 and 2 ppm, respectively. Scattered difference of some haematological
    tests, clinical chemistry tests and urinalysis of no biological
    relevance were noted. Trivial inhibition of plasma and erythrocyte
    cholinesterase (20-30%) activities were not consistent throughout the
    study in any group except the 0.5/5 ppm group after increasing the
    dose when inhibitions of similar magnitude (20-40%) were observed in
    both sexes.  No differences of brain cholinesterase activities were
    detectable between controls and treated rats. Autopsy and
    histopathological findings were unremarkable.  Brain cholinesterase
    activity was not inhibited at the end of the study suggesting a NOAEL
    of 2 ppm in the present study, equal to 0.038 and 0.030 mg
    disulfoton/kg bw/day in males and females, respectively. No
    carcinogenicity was noted at 2 ppm disulfoton but final judgement can
    not be drawn from this study as it was not properly designed to
    evaluate this effect (Carpy & Klotzsche, 1975).

         Fifty male and 50 female Fisher 344 rats were treated with
    technical Disulfoton (97.91% purity, containing 29 identified
    impurities) at concentrations of 0, 1, 4 and 16 ppm equal to 0, 0.06,
    0.22, 0.92 mg/kg bw/day for males and 0, 0.08, 0.26 and 1.33 mg/kg
    bw/day for females (calculated as average daily intake throughout the
    duration of the study) for two years.  The rats were 4 weeks old at
    the beginning of the study.  The diets were prepared weekly with corn
    oil as the vehicle (1% by weight) and acetone as the solvent and kept
    in a freezer until presented to the rats at one dietary level on
    consecutive days. The actual content of disulfoton in the formulations
    was checked monthly, results 87%, 90% and 90% of nominal (mean of 25
    determinations) for 1, 4, and 16 ppm, respectively. Homogeneity and
    stability of the diets were acceptable.

         At 16 ppm dose level, feed consumption and body weight were
    reduced.  Increased incidences of clinical signs such as rough coat,
    urine stain, loose stool, tail rash and skin lesions were observed in
    both sexes.  These parameters were not consistently affected in rats
    treated with 1 nor 4 ppm disulfoton.  At the end of the treatment the
    mortality rate was 24%, 24%, 24% and 12% (male) and 12%, 22%, 30% and
    40% (female) at 0, 1, 4 and 16 ppm, respectively.  The historical
    mortality range of female control rats in previous studies was 18-34%
    which suggests that a marginal effect on mortality could have occurred
    in females at the highest dose level.  A trend towards increased total
    white cell counts in 16 ppm female rats was present at 6, 12, 18, and
    24 months.  At termination of the study, decreased serum total
    protein, albumin and cholesterol were observed at 16 ppm in both
    sexes.  Significant differences of other haematological or biochemical
    parameters were observed but considered to be of no biological
    relevance.  Dose-related inhibition of both plasma and erythrocyte
    cholinesterase activities were observed throughout the duration of the
    study ranging between a borderline inhibition in rats treated with 1
    ppm of disulfoton or about 90% inhibition in rats dosed with 16 ppm
    disulfoton. At termination of the study acetylcholinesterase
    inhibition levels in brain were 15%, 53% and 79% in males and 21%, 53%
    and 82% in females at 1, 4, and 16 ppm, respectively. Gross pathology
    did not reveal increases in masses between control rats and those
    receiving disulfoton. Several non-neoplastic changes observed at
    necroscopy were increased in females fed at 16 ppm. These included an
    increase in overall number of external observations, particularly
    those of the skin which histologically appeared as inflammation,
    ulceration, acanthosis, hyperkeratosis and epithelial inclusion cyst,
    and those of the eye (increased vascularization).  Reduction of muscle
    size of the rear limb was confirmed microscopically as skeletal muscle
    atrophy. An increased incidence of lung lesions was mainly
    granulomatous or suppurative inflammation. There was an increase in
    relative organ weight of heart, liver, kidneys and lung in female rats
    and brain in both sexes at 16 ppm.  The forestomach papillomas
    occurred slightly more often in the high-dose groups than in other
    groups and was usually associated with mucosal hyperplasia and
    hyperkeratosis.  An increased incidence of cystic degeneration of the

    Harderian gland was seen in 16 ppm males and in 4 and 16 ppm females
    (a similar increase at the 1 ppm level was not confirmed after
    re-evaluation of specimens by other pathologists).  There were no
    statistically significant differences in the incidence of neoplasms
    between groups.  Disulfoton was not carcingenic for male nor female
    rats consuming up to 16 ppm disulfoton.  The NOEL for disulfoton in
    this study was 1 ppm corresponding to 0.059 mg/kg bw/day for males
    and 0.075 mg/kg bw/day for females (Hayes, 1985).

    Reproduction studies

    Rats

         In a 2-litter, 2-generation study, groups of 26 (F0) male and
    female rats (Sprague-Dawley strain) approximately 6 weeks old
    received Disulfoton (purity 97.8%) admixed in the diet at 0, 1, 3, 9
    ppm.  Homogeneity and stability of disulfoton in the diet were checked
    and found acceptable.  Actual concentrations  of disulfoton in the
    diet were measured monthly and corresponded to 87%, 86% and 88% of
    nominal at 1, 3 and 9 ppm (average percentage throughout the study),
    respectively. Rats of F0 generation were maintained on their
    respective diets for 15 weeks prior to mating. The F1b generation
    received the compound in the diet for at least 13 weeks prior to
    mating to produce F2 generations. F1b rats were maintained on
    treated feed continuously throughout production of F2 generations. 
    Parent rats were observed daily for clinical symptoms.  Weight and
    food consump-tion were measured weekly.

         Sialodacryoadenitis virus infection developed in F0 rats
    (clinical symptoms confirmed by serum analysis and histopathology) but
    did not interfere with the study as it was present in all groups and
    because mating and reproductive parameters and postnatal indices were
    not affected during the time of infection.  Body weight and feed
    consumption were not affected in any group by treatment during
    pre-mating period.  In the 9 ppm females, tremors were occasionally
    observed during production of F1 generation.  Fertility index was
    decreased during production of both F1a and F1b litters and reduction
    of body weight gain and feed consumption was observed during
    lactation.  The gestation length and gestation index were not
    different for control and treated groups. Litter count, litter weight,
    and viability and lactation indices were not affected up to the 3 ppm
    group but growth and survival of 9 ppm group offspring were
    significantly  decreased as compared to those of control in F1a and
    F1b generations.  Acetylcholinesterase activity in brain of F1a pups
    was reduced 0, 24 and 50% in males and 0, 32 and 59% in females at 1,
    3 and 9 ppm, respectively.  No treatment-related clinical signs of
    toxicity were observed in either sex of any dose group during the
    premating period of F1b animals.  Body weight and feed consumption
    were not affected up to 3 ppm but they were both decreased at 9 ppm in

    females, as was feed consumption only for males. Fertility index was
    reduced at 9 ppm during production of both F2a and F2b litters and
    reduction of body weight and feed consumption were occasionally
    observed during gestation and lactation. The gestation length and
    gestation index were not different for control and treated groups. 
    Litter count, litter weight, viability, and lactation indices were not
    affected up to the 3 ppm group (F2a generation) and up to the 1 ppm
    group (F2b generation) but growth and survival of 9 ppm group
    offspring were significantly decreased as compared to those of control
    in both generations. At 3 ppm F2b litters showed a reduction of
    gestation index, viability index (day 4) and mean weight (day 0). 
    Gross pathology and histopathology did not show compound-related
    lesions in examined adults nor pups.  The significant reduction in
    overall reproductive performance was found at 9 ppm in the presence of
    overt parental intoxication. At 3 ppm reduced reproduction was found
    in only one set of litters (F2b). This effect was assumed to be
    related to cholinesterase inhibition which was observed in similarly
    treated F1a litters. The parental NOAEL for toxicity was 3 ppm.  The
    NOAEL for reproductive effects was 1 ppm (Hixson & Hathaway, 1986).

    Special studies on delayed neuropathy

    Hens

         Twenty adult White Leghorn hens were treated orally with 30 mg/kg
    bw of technical disulfoton (97.8% purity) on two separate occasions 22
    days apart.  In preliminary studies 30 mg/kg bw of disulfoton was
    lethal to hens so that in the present study birds were protected with
    atropine (0.5 mg/kg i.m.) and 2-PAM (12.5 mg/kg i.m.).  Controls were
    dosed either with atropine/2-PAM (5 birds) or 500 mg/kg of
    tri-o-cresyl phosphate (TOCP, 10 birds) or not treated (5 birds). 
    Animals were observed daily for toxicity for 42 days.  Body weights
    and feed consumption were recorded twice a week.  Untreated control
    and antidote control birds were normal throughout the  study. 
    Fourteen out of 20 birds dosed with disulfoton showed loss of
    equilibrium, decreased activity, diarrhoea and locomotor ataxia
    typical of cholinergic symptoms, starting soon after the first dosing
    which disappeared within 5 days.  Eight out of 10 TOCP-dosed birds
    showed locomotor ataxia starting between days 12-24 which disappeared
    in 5 hens before termination of the study.  Birds dosed with
    disulfoton did not show histopathological changes suggestive of
    delayed neurotoxicity in peripheral nerves nor in spinal cord.
    TOCP-dosed hens showed axonal degenerations with macrophage
    accumulation in brain and spinal cord.  Disulfoton does not induce
    acute delayed neuropathy after 2 oral 30 mg/kg bw doses  (Hixson,
    1983).

    Special studies on embryotoxicity and teratogencity

    Rats

         Twenty-five female CD rats were treated with technical Disulfoton
    (98.2% purity) at concentrations of 0, 0.1, 0.3 and 1.0 mg/kg/day
    orally by gavage (dissolved in polyethylene glycol 400) on days 6
    through 15 of gestation.   A positive control group (25 females)
    received hydroxyurea at 350 mg/kg in distilled water on days 9, 10 and
    11 of gestation only.  Recovery of disulfoton from dosing solutions
    ranged from 74 to 106% of nominal.  Neither clinical signs nor
    mortality were observed in treated or control groups.  There were no
    significant differences in body weight or feed consumption between the
    groups.  Dose-related inhibition of both plasma and erythrocyte
    cholinesterase activities were measured on day 15 of gestation. The
    inhibition was trivial at 0.1 mg/kg, about 40% at 0.3 mg/kg and 80-90%
    at 1.0 mg/kg (both activities similarly inhibited). Gross pathology
    did not show lesions related to disulfoton administration.  There were
    no significant differences in the number of implantations per litter,
    live, dead and resorbed fetuses per litter or in the average weight of
    live fetuses between groups treated with disulfoton and control. There
    were no statistically significant differences in the incidence of soft
    tissue abnormalities.  Increased incidence of incomplete ossification
    of the sternebrae in fetuses of dams treated with disulfoton at 1.0
    mg/kg was observed. Significant increases were found in several gross,
    soft tissue and skeletal abnormalities in fetuses in the positive
    control group.  Disulfoton is not teratogenic at dosages that result
    in significant inhibition of cholinesterase activity.  The NOAEL for
    embryotoxicity was 0.3 mg/kg;  the NOAEL for maternal toxicity 0.1
    mg/kg (Lamb & Hixson, 1983).

    Rabbits

         Fourteen (22 for the highest dose level only) pregnant New
    Zealand White rabbits were treated by gavage with disulfoton (purity
    97.3%) during gestation days 6-18 at doses of 0, 0.3, 1  or 3 mg/kg
    bw/day.  The highest dose level was reduced to 2 and 1.5 mg/kg bw/day
    in some but not all of the high dose animals due to severe toxic
    response and mortality. On day 29 of gestation, animals were
    sacrificed for examination of their uterine content. Internal,
    external and skeletal exams were performed on the fetuses.  Maternal
    toxicity observed at the highest dose group included muscular tremor,
    increased respiratory rate, unsteadiness/incoordination and mortality
    (59% at the end of the study). Body weight gain was reduced in animals
    dosed with 3/2/1.5 mg/kg and 1 mg/kg disulfoton but only during
    treatment.  Body weight gain was similar to that of controls for all
    treated groups during post-treatment period.  Number of implantations
    and viability, the extent of pre- and post-implantation losses and
    fetal and placental weights were unaffected by treatment.  Three
    malformed fetuses were observed in the 0.3 mg/kg group but no

    malformations were detectable in offspring of animals treated at
    higher doses of disulfoton, therefore fetal survival, development and
    growth  in utero were considered unaffected by treatment.  Disulfoton
    at dosages of 1.5 mg/kg/day produced marked toxicity but survival,
    growth and development of fetuses were unaffected (Tesh, 1982).

         Four New Zealand White rabbits were treated with disulfoton as
    above at concentrations of 0, 0.1, 0.3 and 1 mg/kg bw/day in a
    preliminary study.  No clear signs of toxicity occurred in females up
    to the highest dose (transient reduction of body weight gain during
    treatment).  There was no evidence of any adverse effect of treatment
    upon fetal morphogenesis or growth (Tesh, 1981).


        Special studies on genotoxicity

    Table 2.  Results of genotoxicity assays on disulfoton

                                                                                                                          

    Test system           Test object           Concentration of      Purity     Results         Reference
                                                test substance
                                                                                                                          

    Reversion assay(1)    S. typhimurium        0.1-1000 µg/plate     94.1%      Negative (2)    Inukai & Iyatomi (1976)
                          TA98, TA100,
                          TA1535, TA1537

    Reversion assay(1)    E. coli WP2 hcr       50-20 000 µg/plate    96.5%      Positive (3)    Shirasu et al. (1979)
                          S. typhimurium
                          TA98, TA100,
                          TA1535, TA1537,
                          TA1538

    Reverse mutation      Saccharomyces         1.5-200 µl/well       97.3%      Negative (4)    Jaganath (1981)
    test(1)               cerevisiae
                          S138, S211

    CHO/HGPRT             Chinese hamster       0.03-10 µg/ml         97.0%      Equivocal (5)   Yang (1988)
    mutation assay(1)     ovary cell

    Mitotic non-          Saccharomyces         20-200 µl/ml          97.3%      Negative (6)    Brusick (1981)
    disjunction(1)        cerevisiae D6

    Pol test(1)           E. coli p3478,        625-10 000 µg/plate   97.3%      Negative (7)    Herbold (1983)
                          w3110

    Rec-assay             Bacillus subtilis     3-300 µg/disc         94.1%      Negative (8)    Inukai & Iyatomi (1976)
                          NIG17 Rec+
                          NIG45 Rec-
                                                                                                                          

    Table 2 (contd).

                                                                                                                          

    Test system           Test object           Concentration of      Purity     Results         Reference
                                                test substance
                                                                                                                          

    Rec-assay             Bacillus subtilis     1-100% v/v            96.5%      Negative (9)    Shirasu et al., (1979)
                          H17 Rec+              dissolved in DMSO
                          M45 Rec-

    Sister chromatide     Chinese hamster       0.004-0.1 µl/ml       97.9%      Positive (10)   Putman (1987)
    exchange              ovary cells           (nonact)
                                                0.002-0.2 µl/ml                  Negative (10)
                                                (act)

    Dominant lethal       Male NMRI/ORIG        1 x 5 mg/kg bw        94.9%      Negative (11)   Herbold (1980)
    test                  Kissleg strain mice

    Micro nucleus test    Male/female Bor:      2 x 6                 50%        Negative (12)   Herbold (1981
                          NMRI-mice             2 x 12 mg/kg bw       (pre-mix)
                                                                                                                          
    

    (1)  both with and without metabolic activation

    (2)  Positive control without activation: N-methyl-N-nitro-
         N-nitrosoguanidina 10 µg/plate (TA1535) dexon; 50 µg/plate
         (TA1537 and TA98); N-fluoren-2-yl-acetamide 50 µg/plate (TA98);
         dimethylnitrosamine 1000 µg/plate (TA1535 and TA100;
         furylfuramide 0.02 µg/plate (TA100) gave expected positive
         response. Positive  control with activation: N-fluoren-
         2-yl-acetamide 50 µg/plate (TA98); dimethylnitrosamine 1000 
         µg/plate (TA1535 and TA100) gave expected positive response.

    (3)  Positive control without activation: 2-aminoanthracene 10
         µg/plate (all strains); furylfuramide, 0.05 µg/plate (TA100),
         0.25 µg/plate (WP 2 hcr),  0.1 µg/plate (TA 98); ß-propiolactone,
         50 µg/plate (TA1538) gave expected positive response.  Positive
         control with activation:  2-aminoanthracene, 10 µg/plate (all
         strains) gave expected positive response.  Test compound gave
         positive response with and without  metabolic activation on
         TA1535 strain.

    (4)  Positive control without activation: Quinacrine mustard, 50
         µl/well (S138);  ethyl methanesulfonate, 10 µl/well (S211) gave
         expected positive response.  Positive control with activation:
         Cyclophosphamide 50 µg/well (S211) gave  expected positive
         response.  2-acetylaminofluorene, 10 µg/well (S138) did not give
         positive response.

    (5)  Positive control without activation:  Ethyl methanesulfonate, 0.2
         µg/l gave expected positive response.  Positive control with
         activation:  Benzo(a)pyrene, 4 µg/ml gave expected positive
         response. Disulfoton was  mutagen at concentrations that were
         either insoluble or partially soluble in the medium.   At 
         soluble concentrations disulfoton was not mutagenic in this
         assay.

    (6)  Positive control without activation: Ethyl methanesulfonate (20
         µl/ml) did not induce chromosome aneuploidy and did induce
         mitotic recombination and chromosome deletions.

    (7)  Positive control with and without activation: methyl
         methanesulfonate, 10 µl/plate gave expected positive response.

    (8)  Positive control: Mitimycyn C 0.3 µg/disc gave the expected
         positive response.

    (9)  Positive control: Mitimycyn C 0.1 µg/disc gave the expected
         positive response.

    (10) Positive control without activation: Triethylenemelamine, 0.025
         µg/ml gave the expected positive response. Positive  control with
         activation:  Cyclophosphamide, 2.5 µg/ml gave the expected
         positive response.  Test material gave positive response at 0.1
         µl/ml in the absence of metabolic activation.

    (11) Concurrent positive control not conducted.  Test material
         administered once to mice by oral gavage.

    (12) Positive control (TrenimonR 2 x 0.125 mg/kg bw) gave expected
         positive response.  Test material administered twice (24 hours
         apart) to mice by oral gavage.

    Special studies on metabolites

    Rats

         The sulfone metabolite of disulfoton was administered in a pilot
    study to Fischer 344 rats (10/sex/level) by diet at concentrations of
    0, 0.5, 0.75 or 1 ppm for six weeks to determine its possible effect
    on cholinesterase activity.  There were neither biologically
    significant depression of brain cholinesterase activity at termination
    of the study nor depressions of plasma and erythrocyte cholinesterase
    activities (performed weekly) (Stuart, 1986a).

    Dogs

         Two identical studies were conducted on Beagle dogs to determine
    the effect of disulfon metabolites on cholinesterases.  The oxygen
    analog sulfone metabolite of disulfoton was administered in the diet
    to Beagle dogs (2/sex/level in each study) for 6 weeks at
    concentrations of 0, 0.5, 0.75, and 1 ppm.  Trivial differences were
    observed on plasma and erythrocyte cholinesterase activities
    (determined weekly throughout the study) and on brain cholinesterase
    at termination of the study (Stuart, 1986b, 1986c).

    Cows

         Angus cattle (3/sex/level) were fed diets of alfalfa pellets
    containing a mixture of the disulfoton metabolites sulfoxide, sulfone
    and their oxygen analogs at a ratio of 1:2:1:1:, respectively. The
    study was conducted for 31 days to determine the effect levels for
    cholinesterase inhibition in whole blood. Diet concentrations tested
    were 0 (4/sex), 3.6, 7.2, 10.8, and 18 ppm.  Dose-related inhibition
    of cholinesterase activity was observed at concentrations of 7.2 ppm
    and greater. The NOEL for cholinesterase inhibition was 3.6 ppm
    (Horton  et al., 1975)

         Holstein dairy cows (3/level) were fed alfalfa pellets containing
    a mixture of disulfoton metabolites sulfoxide, sulfone, oxygen analog

    sulfoxide and oxygen analog sulfone at a ratio of 1:2:1:1,
    respectively.  Animals received dietary concentrations of 3.6, 7.2, or
    18 ppm for 28 days.  A single untreated cow served as control.  Blood
    cholinesterase activity was determined before starting the study and
    weekly throughout the duration of the study.  Feed consumption, body
    weight and milk production were also recorded.  All measured
    parameters were affected at the high- and medium-dose levels. A
    trivial reduction of blood cholinesterase activity was noted at the
    low-dose (30% decrease compared to 19% decrease in control).  The NOEL
    for cholinesterase inhibition was 3.6 ppm (Thornton, 1976).

    Special studies on skin sensitization

         Forty male guinea pigs (Pirbright White W 58) were treated with
    technical disulfoton (purity 98.6%) to investigate sensitizing effect
    on skin. The Magnusson and Kligman maximization test was used. 
    Evaluation showed that there were 2 positively reacting animals in the
    test compound group as against one in the control group.  There were
    no indications of a skin sensitizing effect on guinea pigs for
    disulfoton (Flucke, 1983).

    COMMENTS

         Disulfoton was previously evaluated by the JMPR in 1973 and 1975
    and an ADI of 0-0.002 mg/kg bw was allocated.  Disulfoton is rapidly
    absorbed in rats after oral dosing and approximately 90% is excreted
    via the urine within 24 hours. The biotransformation pathway consists
    of hydrolysis and oxidation to metabolites such as disulfoton sulfone,
    disulfoton oxon sulfoxide and disulfoton oxon sulfone.

         Disulfoton has high acute oral toxicity to mice, rats and dogs. 
    It is classified by WHO as "extremely hazardous".

         Cholinesterase inhibition and related clinical effects were the
    only significant findings in long-term bioassays in mice and rats.  In
    a 99-week study in mice at dietary concentrations of 0, 1, 4, or 16
    ppm, the NOAEL was 4 ppm, equal to 0.55 mg/kg bw/day.  At the 16 ppm
    concentration brain acetylcholinesterase inhibition was reported. 
    There was no evidence of carcinogenicity.

         In a long-term study in rats at dietary concentrations of 0, 1,
    4, or 16 ppm the NOAEL was 1 ppm, equal to 0.06 mg/kg bw/day.  At
    higher concentrations clinical signs of toxicity and inhibition of
    plasma, erythrocyte and brain cholinesterase activities were observed. 
    No carcinogenic effect was detected.

         In a 2-year study in dogs at dietary concentrations of 0, 0.5, 1,
    or 2/5/8 ppm, the NOAEL was 1 ppm, equal to 0.03 mg/kg bw/day.  At the
    next highest dose inhibition of brain acetylcholinesterase was
    observed.  Treatment-related histo-pathological changes were not
    found.

         Disulfoton did not cause delayed neuropathy in adult hens.

         Disulfoton was not teratogenic in rats nor rabbits.  In rats
    given 0, 0.1, 0.3 or 1 mg/kg bw/day, the NOAELs for embryotoxicity and
    maternal toxicity were 0.1 and 0.3 mg/kg bw/day respectively.  In
    rabbits given 0, 0.3, 1 or 3/2/1.5 mg/kg bw/day, the NOAELs for
    embryotoxicity and maternal toxicity were 1.5 and 0.3 mg/kg bw/day,
    respectively.

         In a 2-litter 2 generation reproduction study in rats at dietary
    concentrations of 0, 1, 3 or 9 ppm, the NOAEL for toxicity was 3 ppm
    (equivalent to 0.15 mg/kg bw/day), based on signs of maternal toxicity
    at 9 ppm.  The NOAEL for reproductive effects was 1 ppm (equivalent to
    0.05 mg/kg bw/day) based on decreased brain acetylcholinesterase,
    body-weight gain and survival of pups at 3 ppm.

         Although there was one positive reverse mutation assay it was
    concluded, after review of all available  in vivo and  in vitro
    genotoxicity data, that there was no evidence of genotoxicity.

         The human volunteer study reviewed by the 1975 JMPR was reported
    in summary form only and was considered inadequate for the estimation
    of an ADI.

         The ADI was based on the 2-year study in dogs, using a 100-fold
    safety factor.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    4 ppm in the diet, equal to 0.55 mg/kg bw
         Rat:      1 ppm in the diet, equal to 0.06 mg/kg bw
         Dog:      1 ppm in the diet, equal to 0.03 mg/kg bw
         Man:      0.75 mg/man/day, equivalent to 0.01 mg/kg bw

    Estimate of acceptable daily intake for humans

         0-0.0003 mg/kg bw.

    Studies which will provide information valuable in the
    continued evaluation of the compound

         Further observations in humans.

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    See Also:
       Toxicological Abbreviations
       Disulfoton (ICSC)
       Disulfoton (WHO Pesticide Residues Series 3)
       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)