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    DIALIFOS        JMPR 1976

    IDENTITY

    Chemical name

         S-(2-chloro-1-phthalimidoethyl) 0,0-diethyl phosphorodithioate

    Synonyms

         Dialifor (adopted as a common name by the American National
    Standards Institute), AC 14503, Torak(R)

    Structural formula

    CHEMICAL STRUCTURE 1


    Other information on identity and properties

    State:         white crystals (pure)

                   brown crystals (isolated technical)

                   brown liquid (commercial technical)

         Commercial technical dialifos is produced in the form of an
    80% solution of technical dialifos in a xylene-range aromatic
    solvent. This solution is adjusted to a minimum dialifos content of
    72% by weight. Technical dialifos in crystalline form is not an
    item of commerce.

    Melting point:      67C (pure)

    Vapour pressure:    < 10-4 mm Hg 35C

    Solubility:         water 0.18 mg/kg
                        essentially insoluble in vegetable oils,
                        alcohol and glycols
                        soluble in acetone, chloroform, xylene and
                        ethyl ether

    Hydrolytic stability in ethanol/water (2:8) at 25C:

         half life of 119 hours at pH 6
         half life of 2.5 hours at pH 8

    Dialifos is formulated as emulsifiable concentrates in the range 25
    to 50% or as a 50% wettable powder.

    Purity

    TABLE 1. Impurities (maximum levels in commercial technical dialifos
                                                                        
    Compound                                Maximum level (%w/w)
                                                                        
    O,O-diethyl S-(1-phthalimidoethyl
    phosphorodithioate
    ("norchlorodialifos")                   5

    dialifos oxygen analogue                <1

    N-(2-hydroxyethyl) phthalimide          <.3

    N-(2-acetoxyethyl) phthalimide          <.3

    N-(1,2,2-trichloroethyl)phthalimide     1

    N-(1,2-dichloroethyl)phthalimide        1

    N-(2-chlorovinyl)phthalimide            1

    OOO-triethyl phosphorthioate            3

    OOS-triethyl phosphorodithioate         3

    Unidentified                            2
                                                                        

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Effects on enzymes and other biochemical parameters

         The in vitro inhibitory effect of dialifos (technical) on
    rat plasma and erythrocyte cholinesterase was studied. The
    enzyme-inhibitor complex was formed within five minutes and was

 

    stable during the incubation period. Linear reaction rates were
    also demonstrated, confirming the reliability of the electrometric
    assay procedure for cholinesterase activity. The concentration of
    dialifos required to obtain a 50% inhibition of plasma
    cholinesterase was 2.55 g/ml and 0.31 g/ml for erythrocyte
    cholinesterase. The in vitro oxidation of dialifos with a
    peroxide-acetic acid system decreased the 50% inhibition
    concentration to 0.83 g/ml for plasma cholinesterase and 0.015
    g/ml for erythrocyte cholinesterase (Lazanas et al 1966a, 1966b).

         A study was conducted to investigate the effect of dialifos on
    aliphatic esterases in comparison with cholinesterase. Groups of 6
    female rats were fed levels from 0.5 to 50 ppm dialifos
    (technical). Three animals at each dietary level were killed after
    1 and 3 weeks and measurements of the rate of enzymic hydrolysis of
    diethyl succinate and tributyrin by the liver and serum, and
    cholinesterase activity of the brain were conducted. The dietary
    levels producing 50% inhibition of tributyrinase activity of liver
    and serum were 4.7 and 10.3 ppm respectively after 3 weeks. Diethyl
    succinate hydrolysis in the liver and serum was inhibited by 50% at
    dietary levels of 13.5 and 12.5 ppm after 1 week and 16.0 and 12.0
    ppm after 3 weeks respectively. Brain cholinesterase was
    significantly reduced at 50 ppm after 3 weeks. In a preliminary
    study liver and serum cholinesterase were shown to be appreciably
    inhibited after 1 week at dietary levels of 25 ppm. The
    cholinesterase activity of all the tissues was inhibited to a
    lesser extent than the aliesterase activity (DuBois et al, 1969).

    TOXICOLOGICAL STUDIES

    Special studies on antidotes

         The acute oral LD50 of dialifos was determined in groups of
    male rats (1) without antidote; (2) treated with atropine sulphate
    (17.5 mg/kg); (3) treated with 2-PAM (50 mg/kg); (4) treated with
    a combination of atropine sulphate and 2-PAM at 17.5 and 50 mg/kg
    respectively. Antidotes were administered intramuscularly 30
    minutes after dialifos. The LD50 for the groups were 71, 140, 267
    and 177 mg/kg respectively. The onset of symptoms and time of death
    were delayed in the treated groups. Atropine sulphate and 2-PAM
    would appear to be effective antidotes for dialifos (Mastri et al,
    1968).

    Special studies on reproduction

    Rat

         Groups of 8 male and 16 female rats were fed dialifos
    (technical) in the diet at dosage levels of 0, 0.05 and 0.5 mg/kg
    body weight/day and subjected to a standard 2 litter, 3 generation
    reproduction study. The following parameters were measured: body
    weight, mortality, symptoms, hematology, urinalysis, organ weights

    and gross and histopathology of all parental generations after the
    second weaning as well as plasma and erythrocyte cholinesterase
    activities of all parental generations and litters. In addition,
    the following reproduction indices were measured: mating, pregnancy,
    fertility, parturition and lactation. With respect to progeny mean
    litter size, number of stillborn and viable pups and pup body weights
    were recorded. Plasma and erythrocyte cholinesterase depression were
    observed primarily in the female of all parental groups and
    weanlings fed 0.5 mg/kg body weight. There were random non-dose
    related effects in some reproductive parameters of both test groups
    when compared to controls. No compound-related gross or
    histopathological findings were observed. (Arnold et al, 1968).

    Special studies on teratology

    Rabbit

         Groups of 10 pregnant rabbits were administered dialifos
    (technical) via gelatin capsule at dosage levels of 0, 1 and 3
    mg/kg from day 6 to day 18, and 10 and 25 mg/kg from day 6 to day
    16 of gestation. Thalidomide was given at a dosage of 75 mg/kg/day.
    Does were sacrificed on day 29 of gestation. Offspring were placed
    in an incubator for 24 hours to determine viability and then
    sacrificed for skeletal examination. Parental weight loss occurred
    at 3, 10 and 25 mg/kg. Mortality was increased at 10 mg/kg (7/10)
    and 25 mg/kg (10/10). Hemorrhage in the small intestine was
    observed in the two highest dose groups. Litter size was reduced
    and fetal resorption increased at 10 and 25 mg/kg while the
    viability index was decreased at all dosage levels. Four
    abnormalities (3 umbilical hernia, 1 partial acranius) were noted
    at 3 mg/kg, however no abnormalities were observed at 10 mg/kg. The
    thalidomide group showed clubbing of the extremities (30/49)
    (Kennedy et al, 1966). This study was repeated in a similar fashion
    using the same strain of rabbit, administered 0, 1, or 3 mg
    dialifos (technical)/kg from day 6 to day 18 of gestation. No
    adverse effects were observed with respect to maternal body weight,
    survival or behaviour. Number of implantation sites and litter size
    were reduced and the number of resorption sites increased in
    treated groups when compared to corresponding controls. This was
    considered to be due to physical manipulation of these animals
    rather than a possible toxic effect of the test material. The
    viability index was comparable to controls, and no skeletal or
    external abnormalities were found in any of the progeny receiving
    dialifos (Jackson et al, 1966b).

         Groups of 17 female rabbits were treated from day 6 through
    day 18 of gestation with daily doses of either 0, 1.0 or 3.0 mg/kg
    norchlorodialifos via gelatin capsule. Thalidomide was administered
    concurrently at 37.5 mg/kg body weight as a positive control.
    Rabbits were sacrificed on gestation day 29. Young were removed by
    caesarean section and placed in an incubator for 24 hours. They

    were then sacrificed and examined for external skeletal and soft
    tissue abnormalities. At 3 mg/kg the animals lost weight during the
    dosing period. No effect in body weight gain was exhibited at 1
    mg/kg. No deaths or unusual reactions were observed. The number of
    live fetuses and fetal survival were reduced at 3 mg/kg. No
    significant differences were observed in 24 hour viability index
    or fetal body weights between control and norchlorodialifos treated
    animals. No compound-related internal or skeletal abnormalities were
    noted (Ladd et al, 1972).

    Hamster

         Pregnant hamsters were dosed orally with dialifos once on day
    7 or 8 of gestation or several times on days 6-8 or days 6-10 of
    gestation. The total administered dose varied from 100-500 mg/kg.
    On day 15 of gestation the surviving hamsters were sacrificed and
    the fetuses removed. The usual parameters for teratogenicity were
    examined. From the mortality data of the dams it was concluded that
    most of the doses were > LD50.  The lowest single dose of 100
    mg/kg body weight produced malformations in 4/98 fetuses, 3 with
    limb defects and one with umbilical hernia (Robens, 1970).

    Monkey

         Ten pregnant stumptailed macaques were dosed with dialifos
    (technical) at 1 mg/kg body weight (the dose causing ca 25% plasma
    and erythrocyte cholinesterase depression (Vondruska et al, 1968)
    for a period of one week during the critical period of limb
    formation. Nine other pregnant females were administered either 5
    or 10 mg thalidomide/kg as positive controls. Blood samples were
    taken on the 15th, 18th and 21st days of pregnancy and on the last
    dosing day for complete hematology and cholinesterase activity.
    During the 12th week of gestation, fetuses were recovered by
    caesarean section and examined for abnormalities. No hematological
    effects were observed. Plasma and erythrocyte cholinesterase
    activity for monkeys receiving dialifos were reduced to 65 and 62%
    of pre-treatment values. No abortions were observed with dialifos
    and all fetuses were normal. Abortions occurred in four females
    dosed with thalidomide. A total of five fetuses were recovered from
    females treated with thalidomide and all exhibited gross
    deformities of the anterior extremities (Vondruska and Fancher,
    1969).

    Special studies on mutagenicity

         Dialifos was tested for mutagenic activity using a series of
    microbial indicator organisms (Saccharomyces cerevisiae strain
    D4; Salmonella typhimurium strains TA-1535, 1537, 1538) in
    qualitative plate tests with and without metabolic activation.
    Activation was accomplished by the use of tissue homogenates of
    liver, lung and testes from mice, rats and monkeys. The compound
    did not exhibit significant genetic activity in any of the assays
    performed (Brusick, 1975).

    Special studies on neurotoxicity

         Groups of 6 hens were given 0 or 464 mg/kg body weight (oral
    LD 50) of dialifos (technical). Surviving birds were re-dosed with
    the LD50 after 21 days and were observed for an additional 21 days.
    Samples of spinal cord, sciatic nerve and brain were taken for
    histological examination. A positive control group was dosed with
    500 mg/kg body weight TOCP and studied simultaneously with the test
    group. No signs of ataxia were noted and no clinical neurotoxic
    effects were observed. Birds in the positive control group showed
    signs of neurotoxicity approximately 14 days following
    administration of the last dose. Histopathology of nervous tissue
    was not done (Jackson et al, 1968).

    Special studies on potentiation

         An acute potentiation study was conducted in order to
    determine the degree of interaction between dialifos (technical)
    and malathion. The acute oral LD50 values were determined in male
    and female rats separately. Doses corresponding to 1/2, 1/4 and 1/8
    the LD50 of dialifos were administered orally to animals in
    separate groups consisting of 5 male and 5 female rats followed
    four hours later by the corresponding fractions of the LD50 of
    malathion. No potentiation was observed in female rats. However, in
    the case of males, potentiation did occur since 1/8 of the LD50 of
    each compound resulted in an LD40 (Schoenig et al, 1966e).

    Special studies on eye irritation

         Undiluted dialifos when applied directly to the conjunctival
    sac of two rabbits was shown to be mildly irritating in both
    unwashed and washed eyes. When dialifos was applied as a 5%
    suspension in propylene glycol, similar results were observed
    (Schoenig et al, 1966d).

    Special studies on dermal irritation

         When undiluted dialifos was applied to shaved and abraded skin
    of two rabbits, a slight irritating effect was noted after 24
    hours. Mortality precluded a 72-hour reading (Schoenig et al,
    1966d).

    Acute toxicity

    TABLE 2. Acute toxicity of dialifos

                                                                         

    Animal    Sex   Route     Solvent        LD50          Reference
                                             mg/kg bw
                                                                         

    rat       M     oral      propylene      53            Schoenig et al
                              glycol                       1966d

              M     oral      propylene      43            ibid
                              glycol

              M     oral      1% methyl      71            ibid
                              cellulose

              F     oral      propylene      5             ibid
                              glycol

    mouse     M     oral      propylene      39            Schoenig et al
                              glycol                       1966d

              F     oral      propylene      65            ibid
                              glycol

    rabbit    M     oral      propylene      58            ibid
                              glycol

              F     oral      propylene      71            ibid
                              glycol

              F     oral      maize oil      35            Jackson et al
                                                           1966a

              M     dermal    xylene         145           Schoenig et al
                                                           1966d

    dog       M     oral      propylene      97            Schoenig et al
                              glycol                       1966d

    chicken   F     oral      maize oil      464           Jackson et al
                                                           1968

         The impurities of dialifos were isolated. The acute toxicities
    of the impurities and pure compound were compared.

    TABLE 3. Acute toxicity of pure dialifos compared with its
    impurities
                                                                       

                                                 LD50
    Animal    Sex     Route     Solvent        mg/kg bw    Reference
                                                                       

    pure dialifos

    rat       M       oral      propylene      69          Schoenig et al
                                glycol                     1966a

              F       oral      propylene      5           ibid
                                glycol

    impurities

    rat       M       oral      propylene      327         Schoenig et al
                                glycol                     1966b

              F       oral      propylene      218         ibid
                                glycol
                                                                       

    TABLE 4. Acute toxicity of dialifos formulations

                                                                         
                                             LD50
    Animal     Sex   Route        Solvent    mg/kg bw      Reference
                                                                         


    Emulsifiable concentrate - 47%

    rat        M     oral         water      51            Nomura 1970

               F     oral         water      19            ibid

               M     oral         water      62            Ueda 1968

               F     oral         water      21            ibid

               M&F   Inhalation   water      saturated
                     (4 hr)                  vapour(LC50)  Hathaway et al
                                                           1969a

    TABLE 4. (Cont'd.)
                                                                         
                                             LD50
    Animal     Sex   Route        Solvent    mg/kg bw      Reference
                                                                         

    mouse      M     oral         water      99            Nomura 1970
               F     oral         water      90            ibid

               M&F   inhalation   water      saturated
                     (4 hr)                  vapour(LC50)  Hathaway et al
                                                           1969a

    rabbit     M     dermal       water      327           Mastri et al
                                                           1969a





    guinea     M&F   inhalation   water      saturated     Hathaway et al
    pig              (4 hr)                  vapour        1969a
                                             (LC50)

    Wettable Powder - 50%

    rabbit     M     dermal       water      735           Mastri et al
                                                             1969b

    rat        M&F   inhalation              0.5 mg/l      Hathaway et al
                     (2 hr)                  (LC50)        1969b

    mouse      M&F   inhalation   1.0        mg/l          ibid
                     (2 hr)                  LC50)

    guinea     M&F   inhalation   1.0 mg/l   ibid
    pig              (2 hr)                  LC50)

                                                                         

    TABLE 5. Acute toxicity of norchlorodialifos
                                                                         
                                               LD50
    Animal     Sex    Route     Solvent        mg/kg bw     Reference
                                                                         

    rat        M      oral      maize oil      81           Gabriel 1972

               F      oral      maize oil      22

    rabbit     M      dermal    -              > 1000       Gabriel 1972

                                                                         

    Short term studies

    Rabbit - dermal

         Dialifos 4 lbs/gal (0.48 kg/l) emulsifiable solution was
    applied to the clipped backs of groups of 3 male and 3 female
    rabbits at dosages of 0.3, 1, 5 and 25 mg/kg. The test material was
    applied for a period of 6 hours/day, 5 days/week until 22
    applications were made. An untreated control group received no
    dermal application. At dosage levels of 25 and 5 mg/kg, growth was
    depressed with inhibition of plasma, erythrocyte and brain
    cholinesterase activity. A slight acanthosis of the epidermis
    suggesting slight irritation was observed. There was a slight but
    questionable depression of plasma and brain cholinesterase at 1 mg/kg.
    No adverse effects were observed in any of the parameters studies at
    0.3 mg/kg body weight (Mastri et al, 1969c; Mastri et al, 1970).

    Rat and guinea pig - inhalation

         Groups of rats and guinea pigs (6 males and 6 females of each
    species) were exposed for 6 hours/day, 6 days/week for 2 weeks to
    an aerosol of dialifos generated from an acetone solution of a 4
    lb/gal (0.48 kg/1) emulsifiable formulation at concentrations of 0,
    2.8, 7.7 and 20.0 g/liter. Half the animals were sacrificed for
    pathological examination after the last exposure. The remaining
    animals were sacrificed after a further two week observation
    period. Plasma, erythrocyte and brain cholinesterase activities
    were determined only in the rat. Some mortality, ataxia, dyspnea,
    marked plasma and slight erythrocyte cholinesterase depression were
    observed at 20 g/liter. No adverse effects were noted at exposure
    levels of 7.7 and 2.8 g/liter (Hathaway et al, 1969c; Hathaway et
    al, 1970).

    Mouse - oral

         Groups of 5 male and 5 female mice were administered dialifos
    dissolved in lard oil by gavage 7 days a week at dosages of 1, 2.5,
    5 and 10 mg/kg/day for 90 days. Two control groups were used in
    this study, one receiving no treatment, the other an equivalent
    amount of lard oil to the treated groups. One half of the animals
    were sacrificed after 30 days and the remainder at 90 days. The
    following parameters were measured: body weight, hematology, organ
    weights, gross and histopathology. Cholinesterase determinations
    were not conducted. Decreased growth rate and liver necrosis were
    observed in male mice receiving 10 mg/kg body weight. No
    significant effects were observed at 5 mg/kg body weight or less
    (Nomura, 1970).

    Rat - oral

         Dialifos dissolved in lard oil was administered by gavage 7
    days a week at dosages of 1.0, 2.5, 5 and 10 mg/kg/day for males
    and 0.15, 0.375, 0.75 and 1.5 mg/kg/ day for females for 90 days.
    Control groups received either no treatment or an equivalent amount
    of lard oil. One half of the animals were sacrificed at 30 days and
    the remainder at 90 days. Observations on the following parameters
    were made: body weight, hematology, organ weights, gross and
    microscopic pathology. Serum cholinesterase measurements were made
    after 30 days. Serum cholinesterase was depressed at 2.5 mg/kg and
    above in males and 0.375 mg/kg and above in females. At the upper
    dosage levels in both male and female, increased mortality and
    liver necrosis were observed (Nomura, 1970).

         Dialifos was administered orally to groups of 3 male and 3
    female rats at 0, 0.5, 1.0, 2.5, 5.0, 10.0, 25.0 and 50.0 mg/kg/day
    for 14 days. Plasma cholinesterase was inhibited at 0.5 mg/kg/day
    and above, erythrocyte cholinesterase at 1.0 mg/kg and above, and
    brain cholinesterase at 2.5 mg/kg and above. There was increased
    mortality at 10.0 mg/kg and above. Gross pathological findings
    among test animals were comparable to those of controls (Wolf and
    Calandra, 1965).

         Dialifos was fed at dietary levels of 0, 10, 25, 50 and 100
    ppm to groups of 10 male and 10 female rats for 90 days.
    Erythrocyte cholinesterase activity was decreased at all dietary
    levels. Plasma cholinesterase activity was depressed among females
    at all dietary levels and among males at 25 ppm and above. Brain
    cholinesterase activity of males was depressed at 100 ppm while
    among females depression was noted at 25 ppm and above. At 100 ppm,
    body weight gain and food consumption were reduced; a
    compound-related increase in mortality was noted; BUN and serum A/G
    ratios were increased. Hematology, organ weights, gross and
    histopathology revealed no compound-related effects (Wolf et al,
    1966b).

         Groups of 21 male and 21 female rats were fed diets containing
    dialifos at levels of 0, 0.3, 1, 3, 10 and 30 ppm for 13 weeks.
    After 1, 3, 6 and 13 weeks of feeding, 3 rats/sex/groups were
    sacrificed for plasma, erythrocyte and brain cholinesterase
    determinations. The remaining rats were then fed the control diet
    and a similar number of animals sacrificed at 1 and 4 weeks
    post-treatment. Plasma and erythrocyte cholinesterase activities
    were depressed at 10 and 30 ppm while brain cholinesterase was
    depressed at 30 ppm. After 1 week recovery, plasma and erythrocyte
    cholinesterase were still depressed at the upper level. Values for
    all three parameters were normal after a 4 week recovery period.

         Since there was great variability in plasma cholinesterase
    activity after 3 weeks and anomolous results after 13 weeks in
    erythrocyte cholinesterase values, an additional study was
    conducted. Groups of 12 male and 12 female rats were fed as above
    for 13 weeks. Determination of plasma, erythrocyte and brain
    cholinesterase activity was carried out at 3 and 13 weeks. All the
    parameters measured were depressed at 30 ppm. Erythrocyte
    cholinesterase was also decreased at 10 ppm. A no-effect level of
    3 ppm was demonstrated (Wolf et al 1966a; 1966c).

         Norchloro-dialifos was fed to groups of 10 male and 10 female
    rats at dietary levels of 0, 50 and 200 ppm for 90 days. Body
    weight gain and food consumption were decreased among females at
    both test levels. There was a slight decrease in reticulocytes in
    both sexes at 200 ppm. Significant depressions in erythrocyte,
    plasma and brain cholinesterase activities were observed among male
    and female rats from both test groups. No compound-related effects
    were noted with respect to mortality, blood chemistry, urinalysis
    organ weights, gross and microscopic pathology (Smith et al 1972b).

         An additional study was designed in a comparable manner in
    which groups of 9 male and 9 female rats were fed dietary levels of
    norchloro-dialifos of 0, 1, 3 and 10 ppm for 90 days. After 3, 6
    and 13 weeks, 3 rats/sex/group were randomly selected and
    sacrificed for plasma, erythrocyte and brain cholinesterase
    determinations. After 13 weeks decreases in both plasma and
    erythrocyte cholinesterase activities were observed at 3 and 10
    ppm. Brain cholinesterase activity was slightly depressed at 3 ppm
    among males, while females of all groups showed a non-dose related
    decrease (Smith et al 1972a).

    Dog - oral

         Groups of 1 male and 1 female dogs were fed diets containing
    0, 20, 100 and 500 ppm of dialifos for 14 days. Plasma and
    erythrocyte cholinesterase activities were depressed at 20 ppm and
    above. There was food rejection at all levels with weight loss at
    500 ppm (Schoenig et al, 1966a).

 

        Dialifos (technical) was administered in the diet to groups of
    2 male and 2 female dogs at levels of 0, 1, 3, 10, 30 and 100 ppm
    for 98 days. Plasma and erythrocyte cholinesterase activities were
    not depressed when measured at 0, 7, 21, 42 and 90 days at dietary
    levels of 1 and 3 ppm or less respectively. A slight reduction in
    brain cholinesterase activity was noted at the upper dose level.
    Body weight gain, food consumption, hematology, clinical chemistry,
    urinalysis, organ weights, gross and histopathology were within
    normal limits (Baran et al, 1966).

         Groups of 3 male and 3 female dogs were fed dialifos
    (technical) which was incorporated into the diet to give a dose
    level of 0, 50 ,or 200 ppm for 2 years. The upper level was reduced
    to 100 ppm after 21 days. After 1 year, 1 male and 1 female/group
    were sacrificed. Most dogs showed weight loss and symptoms
    associated with cholinesterase depression while receiving 200 ppm.
    Cholinesterase activity was reduced at 50 and 100 ppm in plasma and
    erythrocytes at 6, 12 and 24 months. Brain cholinesterase appeared
    to be slightly depressed at 100 ppm. No compound-related effects
    were observed with respect to food consumption, mortality,
    hematology, clinical chemistry, organ  function tests, organ
    weights, gross and histopathology (Baran et al, 1968).

         Tissue residue studies were performed on body tissues of dogs
    fed dialifos (technical) for 2 years. Samples of muscle, fat,
    liver, kidney and heart of each dog were examined. Barely
    detectable residues of dialifos were found in muscle, liver, kidney
    and heart samples, residues ranging from 0.003 to 0.005 mg/kg.
    Slightly higher levels were detected in the fat samples. These
    averaged 0.022 mg/kg at the 50 ppm and 0.032 mg/kg at the 100 ppm
    feeding levels. The oxygen analogue of dialifos was not detected in
    any of the tissues examined (Ford 1970c).

    Chicken - oral

         Replicate groups of 3 laying hens were fed 0, 0.375 and 1.25
    mg/kg/day of dialifos (technical) for 8 weeks. Erythrocyte and
    plasma cholinesterase activities were determined prior to and at 1,
    2, 4 and 8 weeks following the initiation of treatment.
    Cholinesterase activities were not affected. No toxic symptoms were
    observed and no effect was noted on daily food consumption, body
    weight or egg production (Sedivy 1968c).

    Cattle - oral

         Groups of 3 beef animals (180 kg) were fed 0, 0.1 and, O.2
    mg/kg/day of dialifos for 28 days. One animal of each group was
    sacrificed after 12 days of treatment, and the remaining animals at
    28 days for collection of tissue samples. There was no
    treatment-related effect with respect to plasma or erythrocyte
    cholinesterase activity. Residue levels in fat, kidney, liver and

    muscle were generally less than 0.001 mg/kg. The highest residue
    level detected was 0.003 mg/kg in the fat of animals fed 0.2 mg/kg
    (Taylor, 1969).

         Three beef animals (180 kg) were fed diets containing
    approximately 2.2 mg/kg/day; a fourth animal served as a control.
    At the end of each feeding period of 2, 4 and 8 weeks, one animal
    was sacrificed for tissue residue studies. Plasma and erythrocyte
    cholinesterase determinations were made at weekly intervals.
    Residues in the range of 0.1 to 0.3 mg/kg were found in liver and
    fatty tissues. Lower residues ( <0.1 mg/kg) were detected in
    muscle and kidney. No evidence for the build-up of the residue was
    observed when the feeding period was doubled. The oxygen analogue
    of dialifos was not detected to any significant degree in the
    tissues analysed. Erythrocyte cholinesterase activity was markedly
    inhibited, while plasma inhibition was only slightly affected.
    (Ford 1970a; Sedivy 1968a).

         Four holstein milk cows were administered a daily dose of
    dialifos of 1.35 mg/kg for 21 days. Weekly plasma and erythrocyte
    cholinesterase determinations were made and milk samples collected
    for residue analysis. No overt signs of toxicity were observed and
    milk production was not altered. A marked inhibition of erythrocyte
    cholinesterase was noted. The slight reduction in plasma
    cholinesterase was questionable. An average dialifos residue of 5
    mg/kg was detected in milk samples which quickly disappeared when
    the administration of dialifos was terminated. No oxygen analogue
    was found in any of the samples (Ford 1970b., Sedivy 1968b).

    Long-term studies

    Rat

         Groups of 30 male and 30 female rats were fed dietary levels
    of 0, 0, 20 and 50 ppm of dialifos (technical) for 2 years. After
    6, 12 and 24 months 3 rats/sex/group were randomly selected and
    sacrificed for plasma, erythrocyte and cholinesterase determinations.
    Erythrocyte cholinesterase activity was depressed in all animals of
    both test levels at all examination intervals. Plasma
    cholinesterase activity was decreased among females at both test
    levels while males exhibited depression at 50 ppm after 6, 12 and
    18 months but not at 24 months. Brain cholinesterase activity was
    depressed at the higher intake level. No significant differences
    between treated and control animals were observed with respect to
    body weight gain, food consumption, mortality, hematology, blood
    chemistry, urinalysis, organ weights or gross and histopathology.
    There was no increase on the incidence of tumours in the test
    animals (Wolf et al 1968).

         Dialifos was fed at dietary levels of 0, 1, 3 and 10 ppm to
    groups of 30 male and 30 female rats for 1 year. Five males and 5
    females/group were randomly selected and sacrificed after 3, 6, 9
    and 18 months for plasma, erythrocyte and brain cholinesterase
    determinations as well as gross and histopathological examination.
    Plasma cholinesterase in females and erythrocyte cholinesterase in
    both sexes were decreased at the dietary intake of 10 ppm. Brain
    cholinesterase was not affected. Body weight gain was slightly
    decreased in males fed 10 ppm. There were no compound-related
    effects in mortality, organ weights, gross and histopathology
    (Regna et al 1975).

         A small number of animals from the one year oral toxicity
    study reported above were continued on the appropriate diet for an
    additional year. The small number of surviving animals on test
    makes the interpretation of the data difficult. However, no
    significant changes were noted in body weights, food consumption,
    mortality, behavioural reactions, plasma, erythrocyte and brain
    cholinesterase, gross and histopathology. No evidence of increased
    tumour incidence or production of unusual tumour types was observed
    in the treated animals (Marias et al, 1975).

    OBSERVATIONS IN MAN - ORAL

         Dialifos was administered orally to 3 male and 3 female
    volunteers in gelatin capsules in daily single doses of 0.01 (2
    weeks), 0.03 (4 weeks) and 0.1 mg/kg (10 days) with 2 males and 2
    females receiving placebos. After an appropriate recovery period
    four of the test subjects were used as controls and the 4 control
    subjects became part of the total of 6 test subjects in a second
    study. In this study dialifos was administered orally in gelatin
    capsules 3 times a day to simulate 3 meals a day in dosage levels
    of 0.01 (2 weeks), 0.02 (4 weeks), 0.03 (8 weeks) and 0.05 (4
    weeks) mg/kg. In both studies, plasma and erythrocyte
    cholinesterase, plasma ali-esterases (tributyrinase and diethyl
    succinase) were measured before dosing and at intervals during the
    study and recovery periods. Periodically, other observations were
    made which included hematology, blood pressure, pulse rate, pupil
    size, light reflex, eye accommodation, chest sounds, muscle tone,
    kneejerk, tongue tremor and finger tremor. No significant
    inhibition of any of the enzyme systems tested was observed at
    dosage levels of 0.01, 0.02 and 0.03 mg/kg when given either in single
    or divided daily dose. Plasma cholinesterase and tributyrinase 
    were slightly depressed while no effect was observed
    on erythrocyte cholinesterase or diethyl succinase at 0.05 and 0.1
    mg/kg.  Recovery was essentially complete in 14-21 days. The other
    parameters measured were not affected (Greco et al, 1970).

    COMMENTS

         In mammals dialifos is an acutely toxic organophosphorus ester
    which would appear to be rapidly absorbed as shown by the rapid
    onset of cholinergic symptoms of poisoning. No data were available
    with respect to absorption, metabolism and excretion in animals.

         Teratogenic and reproduction studies indicated no adverse
    effects at doses below those which were toxic to the parents.
    Mutagenic activity was not observed in the microbial indicator
    organisms used in the study. No apparent signs of neurotoxicity
    were observed in hens given large doses of dialifos.

         In several short-and long-term studies in the mouse, rat, dog,
    hen, monkey, cattle and man, dialifos was shown to be an active
    cholinesterase inhibitor. Plasma cholinesterase was inhibited to a
    greater extent than either erythrocyte or brain cholinesterase with
    no marked difference between animal species.

         The major impurity of technical dialifos, 00-diethyl
    S-(1-phthalimidoethyl) phosphorodithioate ("norchlordialifos"), was
    as toxic as dialifos as indicated by acute, short-term and
    teratogenic studies.

         No-effect levels in the rat, dog and man have been established
    on the basis of the most sensitive parameter, the depression of
    plasma cholinesterase activity. The data were sufficient to
    recommend an acceptable daily intake for man.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat            3 ppm in the diet equivalent to 0.15 mg/kg bw

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

         Man            0.03 mg/kg bw/day

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.003 mg/kg bw

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         Dialifos is an acaricide and insecticide used in wettable
    powder and emulsion sprays on citrus, apples, pears, grapes,
    pecans, rapeseed, cotton, potatoes and sugar beets. Dosages, number
    of treatments, and use restrictions vary widely with the target
    pest and the residue tolerances in the country in which it is used.

         A summary of various national use patterns is shown in Table
    6. The table is based primarily on information provided by the
    basic manufacturer of dialifos. Country statements furnished to the
    Meeting indicate that South Africa has cancelled registered uses
    for dialifos, that use in the Netherlands is curtailed because of
    resistance problems, and that Australia has no registered uses but
    has applications for use on some fruits pending.

    
    TABLE 6. National use patterns of dialifos

                                                                             
                   Application           Pre-harvest       Other
    Country        rate (a.i.)           interval (days)   Restrictions
                                                                             

                              Citrus

    U.S.A.         30-60g/100 l          7                 2 treatments per
                                                           year

    Turkey         1.0-1.5 kg/ha         28                2 treatments per
                                                           growing season

    Japan          1.7-3.3 kg/ha         45

                              Grapes

    U.S.A.         1.1 kg/ha             25                one treatment after
                                                           shot-berry stage
                                                           and no more than
                                                           2 per year

    France         0.75-1.0 kg/ha        28                one spray per
                                                           growing season
                                                           (before Aug 1)

                              Apples, Pears

    U.S.A.         60-90 g/100 l         60                not more than 5
                                                           cover sprays
    Netherlands    0.75-1.0 kg/ha*       8 weeks

    TABLE 6. (Cont'd.)
                                                                             
                   Application           Pre-harvest       Other
    Country        rate (a.i.)           interval (days)   Restrictions
                                                                             
    France         1.0 kg/ha             4 weeks
    Germany        1.0 kg/ha             4 weeks
    Italy          1.0 kg/ha             4 weeks
    Belgium        1.0 kg/ha             6 weeks
    Switzerland    1.0 kg/ha             6 weeks

    New Zealand                                            pre-blossom spray
                                                           only (provisional
                                                           registration)
    U.K.           0.06%(high vol.)      3 weeks           not more than 3
                                                           sprays per season
                   1.0 kg/ha(low vol.)

                              Pecans

    U.S.A.         60 g/100 l            --                apply before husk
                                                           split

                              Rapeseed

    Germany        288 g/ha                                apply only during
                                                           flowering
                                                                             
    * Report decreased use because of resistance.

    
         It was also reported that dialifos is used on potatoes (500g/ha)
    and sugar beets (700-750 g/ha) in Europe and on cotton in Turkey and
    Africa at rates of 100-125 g/ha.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Residue data from supervised trials in the U.S.A., Canada, Japan 
    Australia, the Netherlands, Republic of South Africa, West Germany and
    Italy were made available to the Meeting through a submission by the
    basic manufacturer (Hercules, 1976) and country statements. The
    findings are discussed separately by commodity. Unless otherwise
    noted, residue values are for dialifos per se.

    Citrus

         Data from supervised trials in the U.S.A. are summarized in Table
    7 and Figure 1.

    FIGURE 1


    
    TABLE 7. Dialifos residues in citrus fruits (U.S.A., whole fruit basis).

                                                                                                                                            

                                                                 Dialifos, mg/kg

                                   0.025% a.i.spray                                            0.05% a.i. spray
                                   Fruit (no. of treatments)                                   Fruit (no. of treatments)
                                                                                                                                            

    Days after last   Valencia     Pineapple                                   Valencia        Pineapple
    treatment         Oranges(2)   Oranges(3)   Grapefruit (3)   Lemons (3)    Oranges(2)      Oranges(3)    Grapefruit (3)      Lemons (3)
                                                                                                                                            

    3                 0.74         1.4          0.62             0.24          1.2    1.7      1.9           1.2       1.6       0.38

    7                 0.76         0.93         0.63             0.17          1.3    1.8      2.1           1.3       1.6       0.36

    7                 0.69         -            -                -             1.2    -        -             -         -         -

    56                0.58         0.73         0.54             0.08          0.87   1.2      1.4           0.99      1.6       0.24

    84                0.36         0.59         0.64             -             0.61   0.88     1.1           1.1       1.4       -
                                                                                                                                            

    


         In supervised trials with oranges in Japan, residues 90-183 days
    after a single treatment at 1.6-2.0 kg/ha averaged 0.38 mg/kg in the
    peel and 0.01 mg/kg in both whole fruit and juice.

    Grapes

         Decline studies on grapes showed initial deposits of about 2
    mg/kg at the recommended 1.1 kg/ha rate, steady decline for 25-30 days
    to about 0.4 mg/kg, and then a levelling off with little additional
    loss until harvest. The pattern of residue decline coincides with the
    growth of the grape, there being practically no growth dilution over
    the last 20-25 days before harvest. Field trials in W. Germany with
    analyses at the Central Institute for Nutrition and Food Research,
    Holland, were in good agreement with the Californian data (Anon,
    1974). Residues found in several varieties of grape after 35 days are
    shown in Table 8 (Hercules, 1976).

    TABLE 8. Harvest residues of dialifos on grapes, 35 days after
             treatment (California)

                                                                        
                              Residue, mg/kg after treatment at (kg/ha)
                                                                        

    Year     Variety          2.2             1.7                1.1
                                                                        

    1968     Thompson         -               -                  0.98

    1969     Thompson         2.1             -                  0.7

    1971     Emperor          0.5             -                  0.4

    1971     Carignane        0.28            -                  0.25

    1972     Thompson         0.88            0.40               0.34

    1972     Ruby Red         0.55            0.29               0.23

                                                                        

    Apples, pears

         Supervised trials were conducted at 15 locations in Canada and
    the U.S.A. and in South Africa, the Netherlands, and Australia
    (Hercules, 1976; Anon., 1969, 1972). No striking differences were
    noted with respect to geographic location. Both WP and EC formulations
    were used and both high volume and low volume applications made.
    Typical initial deposits from recommended rates were about 2-3 mg/kg
    with a very slow decline rate. Figure 2 shows a composite decline
    curve based on residue values from 9 test locations.

    FIGURE 2

    Pecans

         Analysis of nut meats treated according to label directions
    showed no residues above the limit of detection of the method (0.005
    mg/kg). Residues were found on outer husks, but there was no
    penetration.

    Rapeseed

         Supervised field trials in W. Germany in 1972 showed only trace
    residues (0.01-0.02 mg/kg) in seeds receiving multiple treatments at
    the rate of 270 g/ha. Extraction was by surface stripping, a technique
    which may not be effective in removing residues absorbed into an oily
    seed.

    Sugar beets

         Field trials in Italy in 1973 showed residues averaging 0.09
    mg/kg on roots and 1.17 on tops following 4 applications at 675 g/ha.

    Cotton

         Results from limited trials at 2 locations in the U.S.A. were
    made available. The report contained a total of 4 analyses of treated
    samples. Residues in the range of 0.02-0.06 mg/kg were found on
    undelinted seed.

    Potatoes

         Field trials in the Netherlands showed only trace residues
    (<0.002 to 0.004 mg/kg) in treated potatoes.

    Processed products from treated raw commodities

         Data were made available on some processed food and feed products
    derived from the raw commodities discussed in the previous section.
    The findings are summarized by commodity.

    Citrus pulp

         Two pilot plant studies showed an average concentration factor of
    5.3 in processing oranges to dried pulp. That is, whole oranges
    bearing residue levels at the national maximum residue limit of 3
    mg/kg would contribute residues approximating 16 mg/kg to the
    commercial cattle feed (dried citrus pulp). See also discussion on
    potential transfer to meat, milk, eggs.

    Grape juice and pomace

         Low level residues (maximum 0.02 mg/kg) occurred in juice
    expressed from grapes bearing 1 mg/kg, most of the residue remaining
    in the pomace. There is about a 4 fold concentration factor between
    whole grape and wet pomace.

    Raisins

         The residues found are summarized in Table 9.

    
    TABLE 9. Dialifos residue in raisins

                                                                                               

                 Dosage                        Pre-harvest              Dialifos, mg/kg
                 rate        No. of            interval,
    Year         kg/ha       applications      days             Processed(2)     Unprocessed(1)
                                                                                               

    1968         0.6         2                 62               0.26             0.45

                 1.1         2                 62               0.84             0.91

    1970         1.1         2                 41               -                1.2

    1971         1.1         1                 58               -                1.6

                 1.1+2.2     2                 36               -                4.3

    1973         1.1         3                 40               0.98             -

    1973         1.1         2                 40               0.76             -

    1973         1.1         2                 70               0.20             -
                                                                                               

    (1) Sun dried

    (2) Sun dried, cleaned, fumigated, moisture adjusted

    
    Apple pomace

         U.S. data indicate a concentration factor of about 16 in
    processing from whole apples to dried apple pomace, a commercial
    cattle feed.


         No data were available on edible oils from cottonseed or rapeseed
    or the respective oilseed meals.

    FATE OF RESIDUES

    Potential for residues in meat, milk, poultry, and eggs

         As far as could be determined by the Meeting, there are no
    registered uses for dialifos on primary forage crops. There are a
    number of commodities from which processed by-products or offal may be
    incorporated into animal feeds. This would include dried citrus pulp
    and molasses, grape pomace, apple pomace, rapeseed and cottonseed
    meal, and sugar beet pulp.

         There were sufficient data from controlled feeding experiments
    with cattle and poultry to relate dialifos intake levels to residue
    levels in milk and meat. However, there was only fragmentary
    information available on residue levels in the feed items and on the
    proportions in which these feed items occur in animal rations in
    national use patterns.

         Metabolism studies in ruminants indicate that dialifos is
    metabolized to diethyl phosphorodithioate and phthalic acid
    derivatives. The metabolic pathways are similar to those of phosmet, a
    closely related compound. Some dialifos per se transfers from feeds to
    meat fat and to milk. At a feeding level of 45 mg/kg to lactating
    cows, maximum residues approximating 0.25 mg/kg appeared in milk (fat
    basis). Beef calves were fed at 2, 4 and 10 mg/kg levels. At the
    highest feeding level the tissue residue levels were 0.4 mg/kg.

         A poultry feeding study was also available. Birds were fed at
    levels of 3.7 and 11 ppm in the total feed for up to 8 weeks.
    Residues, if any, found in eggs were negligible. Trace residues
    occurred in tissues.

         National tolerances for dialifos in meat, milk and eggs have been
    established in the U.S. to provide for residues resulting from feed
    uses of citrus pulp and apple and grape pomace.

    In plants

         Studies available on dialifos suggest that the principal route of
    degradation on plants is by hydrolysis to diethyl phosphorodithioate,
    phthalic acid, phthalic acid and phthalimide. The oxon of dialifos has
    been detected at trace levels but was not regarded as a significant
    component of the terminal residue. This is consistent with the known
    metabolic patterns of the related compound phosmet. Photolysis studies
    disclosed similar degradation products after exposure to UV radiation
    or sunlight. Dialifos per se is the residue of concern on crops.
    Radio-tracer studies indicate only a minor tendency to translocate
    from foliar deposits or to be absorbed into fruit pulp. Residues are
    primarily in the peel or rind. Once residues are fixed in the peel or

    on the surface of a fruit, they tend to be extremely persistent, as
    shown in the decline curves (Figures 1 and 2) for citrus and apples.

    In processing and cooking

         No data were available on the effects of cooking. Some limited
    information was provided on the reduction of residues on oranges in
    commercial processing. 23% of the initial residue on oranges was
    removed by washing and an additional 32% loss occurred in the rigorous
    processing to dried citrus pulp. There was no evidence submitted of
    occurrence in food at the time of consumption or findings of dialifos
    in national "total diet" surveys.

    METHODS OF RESIDUE ANALYSES

         A TLC-cholinesterase inhibition method has been described as
    suitable for residues of dialifos and its oxygen analogue in foods
    (Mendoza 1968). However, the method of choice for regulatory purposes
    would be the gas chromatographic (GC) method developed by the basic
    manufacturer. The method is used with either a thermionic or flame
    photometric detector and with alternative clean-up steps for analyses
    of crops, meat and milk. (Pesticides Analytical Manual, Vol. II,
    1967). The method has been validated in government laboratories for
    regulatory purposes on crops, meat, and milk. The estimated limit of
    determination is 0.01 mg/kg in citrus, 0.005 mg/kg in meat and meat
    fat and 0.06 mg/kg in milk fat. The GC method has been validated only
    for dialifos per se, but is said to be capable of detecting the oxygen
    analogue at greatly reduced sensitivity (limit of determination about
    ten times that of dialifos).

         The widely used multi-residue screening method employing
    acetonitrile extraction and Florisil cleanup (Pesticides Analytical
    Manual, Vol. I, 1968) recovers dialifos quantitatively through the
    non-fatty sample clean-up procedure, but only partially by the
    procedure for fatty samples. Dialifos oxygen analogue it not detected
    by either clean-up used with the PAM I method. The behaviour of
    dialifos through the multi-residue method of Storherr for
    organophosphorus insecticides (PAM I, Section 232.2) has not been
    studied. It is known however that the closely related compound phosmet
    is quantitatively recovered through the Storherr (charcoal column)
    method and it is likely that dialifos would be recovered also.

    NATIONAL TOLERANCES REPORTED TO THE MEETING

         National tolerances reported to the Meeting are shown in Table
    10.

    TABLE 10. National tolerances for dialifos reported to the Meeting

                                                                       

                                              Pre-harvest    Tolerance
    Country        Crop                         interval       (mg/kg)
                                                (days)
                                                                       

    Germany        Apples, pears                28             0.5

    Netherlands    "                            56             0.3

    Switzerland    "                            42             0.3

    U.S.A.         Citrus                       7              3
                   Apples, pears                60             1.5
                   Grapes                       25             1
                   Pecans                       -              0.01
                   Meat, fat & meat products
                   of cattle, goats & sheep                    0.15
                   Milk fat                                    0.15
                   Meat, fat and meat
                    by-products of poultry                     0.05
                   Eggs                                        0.01
                                                                      

    * Tolerances are for the sum of dialifos and its oxygen analogue.


    APPRAISAL

         The acaricide/insecticide dialifos has been in use since the late
    1960's on a variety of fruits, nuts, and field crops. It is reported
    to be currently used in ten countries and national maximum residue
    limits have been established in four of these countries.

         The residue of principal concern on harvested crops is dialifos
    per se. It tends to be very persistent but is not appreciably
    translocated or absorbed into fruits. The oxon of dialifos has been
    detected at trace levels but is not a significant residue component.
    The principal route of degradation is by hydrolysis to diethyl
    phosphorodithioate, and phthalic acid, phthalamic acid and
    phthalimide.

         The pesticide exhibits some tendency to transfer from animal
    feeds to meat and milk. Data were available to show residue levels
    expected in some by-product feed items such as dried citrus pulp, but
    not in all. National tolerances have been established in the U.S.A.
    for residues in meat, milk, and eggs to regulate residues in these
    items resulting from the use of treated apple pomace, grape pomace,
    and citrus pulp in animal feeds.

         While there were adequate data available to support the
    recommendations for the maximum residue limits given below, there was
    not sufficient information on residues or national use patterns to
    support recommendations for potatoes, rape, sugar beets, stone fruits,
    berries or cotton.

    RECOMMENDATIONS

         The following maximum residue limits are recommended for the sum
    of dialifos and its oxygen analogue, expressed as dialifos.

                                                    Interval on which
                                                    recommendation is
    Commodity                     Limit, mg/kg      based (days)

    Apple pomace (dried)            40

    Citrus pulp(dried)              15

    Grape pomace (dried)            20

    Citrus                          3                   7

    Raisins                         2

    Apples, pears                   2                   60

    Grapes                          1                   35

    Fat of meat of cattle and
    sheep, milk (fat basis)         0.2

    Eggs, pecans                    0.01*

    Meat and fat of poultry         0.05*

              

    *Level at or about the limit of determination

    FURTHER WORK OR INFORMATION

    DESIRABLE

    1.   Metabolism studies in one or more animal species.

    2.   Further observations in man.

    3.   Additional information on national use patterns and supervised
    residue trials on potatoes, rape, sugar beets and cotton.

    REFERENCES

    Anon                Residues of dialifor when used against red
    1969                spider mites on apples in Holland. 1969 Study.
                        Report of Central Institute for Nutrition and Food
                        Research, Zeist, Holland. Summarized translation
                        by Ir. L. Veegans of Hercules BV, The Hague,
                        Holland. Undated.

    Anon                Report No. 3968. Residues of dialifor when
    1972                used against red spider mites on apples in
                        Holland. 1972 Study. Central Institute for
                        Nutrition and Food Research, Zeist, Holland.
                        Summarized translation by Ir. L. Veegens of
                        Hercules BV, The Hague, Holland. Undated.

    Anon                Report No. R4331. Residues of dialifor in
    1974                grapes. Central Institute for Nutrition and Food
                        Research, Zeist, Holland, February 1974.

    Arnold, D., Kodras, R., Fancher, O.E. Three generation reproduction
    1968                studies in albino rats - AC14503. Report from
                        Industrial Bio-Test Laboratories, submitted by
                        Hercules Incorporated. (Unpublished)

    Baran, J., Fancher, O.E. & Calandra, J.C. 98-day sub-acute oral
    1966                toxicity of AC14503 technical - Beagle dogs.
                        Report from Industrial Bio-Test Laboratories,
                        submitted by Hercules Incorporated. (Unpublished)

    Baran, J., Vondruska, J.F., & Fancher. O.E. Two-year chronic oral
    1968                toxicity of AC14503 - Beagle dogs. Report from
                        Industrial Bio-Test Laboratories, submitted by
                        Hercules Incorporated. (Unpublished)

    Bourke, J.B. et al. The metabolism of Torak. Report of the
    1970                New York Agricultural Experiment Station, Geneva,
                        New York, January 1970. (Unpublished)

    Brusick, D. Mutagenic evaluation of compound X19943-99-1
    1975                Torak. Report from Litton Bionetics, submitted by
                        Hercules Incorporated. (Unpublished)

    DuBois, K.P., Flynn, M., Root, M., & Su, M. Effects of Hercules
    1969                AC14503 on aliesterases and cholinesterase -
                        weanling female Holtzman rats. Report from
                        Toxicity Laboratories - University of Chicago,
                        submitted by Hercules Incorporated. (Unpublished)

    Ford, J.J. Tissue residue studies on beef calves fed a diet
    1970a               containing Torak. Submitted by Hercules Research
                        Center. (Unpublished)

    Ford, J.J. Torak residues in milk - dairy cows. Submitted by
    1970b               Hercules Research Center. (Unpublished)

    Ford, J.J. Tissue residue studies on Beagle dogs maintained
    1970c               for two years on Torak dosed diets. Submitted by
                        Hercules Research Center. (Unpublished)

    Gabriel, K.L. Acute oral and acute dermal toxicity studies
    1972                in rats of Hercules X15260-51-2. Report  from
                        Biosearch, Inc., submitted by Hercules
                        Incorporated. (Unpublished)

    Greco, R.A., Palazzolo, R.J., & Fancher, O.E. Effects of
    1970                AC14503 on plasma and erythrocyte cholinesterase
                        and plasma aliesterase activity in human
                        volunteers. Report from Industrial Bio-Test
                        Laboratories, submitted by Hercules Incorporated.
                        (Unpublished)

    Hathaway, D., Keplinger, M.L., & Fancher, O.E. Acute vapor
    1969a               inhalation toxicity study on Torak 47%
                        emulsifiable concentrate in albino rats, guinea
                        pigs, and mice. Report from Industrial Bio Test
                        Laboratories, submitted by Hercules Incorporated.
                        (Unpublished)

    Hathaway, D., Keplinger, M.L., & Fancher. O.E. Acute dust
    1969b               inhalation toxicity study on Torak 50% wettable
                        powder in albino rats, guinea pigs, and mice.
                        Report from Industrial Bio-Test Laboratories,
                        submitted by Hercules Incorporated. (Unpublished)

    Hathaway, D., Keplinger, M.L., & Fancher, O.E Two-week subacute
    1969c               aerosol inhalation toxicity study on Torak
                        emulsified concentrate - albino rats and guinea
                        pigs. Report from Industrial Bio-Test Laboratories
                        submitted by Hercules Incorporated. (Unpublished)

    Hathaway, D., Keplinger, M.L., & Fancher, O.E. Two-week subacute
    1970                aerosol inhalation toxicity study on Torak
                        emulsifiable concentrate - albino rats and guinea
                        pigs. Report from Industrial Bio Test
                        Laboratories, submitted by Hercules Incorporated.
                        (Unpublished)

    Hercules "Torak" (dialifor) submitted to FAO/WHO by Hercules
    1976                Incorporated, July 30, 1976.

    Jackson, G.L., Fancher, O.E., & Calandra, J.C. Acute toxicity
    1966a               study on technical AC14503 female Dutch belted
                        rabbits. Report from Industrial Bio-Test
                        Laboratories, submitted by Hercules Incorporated.
                        (Unpublished)

    Jackson, G., Kennedy, G., Fancher, O.E., Calandra, J.C. Rabbit
    1966b               teratogenic study AC14503. Report from Industrial
                        Bio-Test Laboratories, submitted by Hercules
                        Incorporated. (Unpublished)

    Jackson, G., Palazzolo, R.J., & Fancher, O.E. Neuro toxicity
    1968                study - chickens - AC14503. Report from Industrial
                        Bio-Test Laboratories, submitted by Hercules
                        Incorporated. (Unpublished)

    Kennedy, G., Jackson, G.L., Fancher, O.E., & Calandra, J.C. Rabbit
    1966                teratogenic study - AC14503. Report from
                        Industrial Bio-Test Laboratories, submitted by
                        Hercules Incorporated. (Unpublished)

    Ladd, R., Jenkins, D.H., Wright, P.L., & Keplinger, M.L.
    1972                Teratogenic study with Norchloro-Torak in albino
                        rabbits. Report from Industrial Bio Test
                        Laboratories, submitted by Hercules Incorporated.
                        (Unpublished)

    Lazanas, J.C., Fancher, O.E., & Calandra, J.C. The in vitro
    1966a               inhibitory effect of AC14503 on cholinesterases -
                        rat plasma. Report from Industrial Bio-Test
                        Laboratories, submitted by Hercules Incorporated.
                        (Unpublished)

    Lazanas, J.C., Fancher, O.E., & Calandra, J.C. Addendum:
    1966b               The in vitro inhibitory effect of oxidized
                        AC14503 on rat plasma and erythrocyte
                        cholinesterase activity. Report from Industrial
                        Bio-Test Laboratories, submitted by Hercules
                        Incorporated. (Unpublished)

    Marias, A.J., Kennedy, G.L., Kinoshita, F.K., Keplinger, M.L.
    1975                Two-year chronic oral toxicity study with Torak
                        technical in albino rats. Report from Industrial
                        Bio-Test Laboratories, submitted by Hercules
                        Incorporated. (Unpublished)

    Mastri, C., Keplinger, M.L., & Fancher, O.E. Study on the efficacy
    1968                of atropine sulfate and 2-PAM C1 as antidotes for
                        AC14503 (technical) intoxication - male albino
                        rats. Report from Industrial Bio-Test
                        Laboratories, submitted by Hercules Incorporated.
                        (Unpublished).

    Mastri, C., Keplinger, M.L., & Fancher, O.E. Acute dermal
    1969a               toxicity study on Torak (Hercules 14503) in male
                        albino rabbits (emulsified concentrate). Report
                        from Industrial Bio-Test Laboratories, submitted
                        by Hercules Incorporated. (Unpublished)

    Mastri, C., Keplinger, M.L., & Fancher, O.E. Acute dermal toxicity
    1969b               study on Torak (Hercules 14503) in male albino
                        rabbits. Report from Industrial Bio-Test
                        Laboratories, submitted by Hercules Incorporated.
                        (Unpublished)

    Mastri, C., Keplinger, M.L., & Fancher, O.E. 30-day subacute
    1969c               dermal toxicity study on Torak emulsifiable
                        concentrate in albino rabbits. Report from
                        Industrial Bio-Test Laboratories, submitted by
                        Hercules Incorporated. (Unpublished)

    Mastri, C., Keplinger, M.L., & Fancher, O.E. 30-day sub-acute
    1970                dermal toxicity study on Torak emulsified
                        concentrate in albino rabbits. Report from
                        Industrial Bio-Test Laboratories, submitted by
                        Hercules Incorporated. (Unpublished)

    Mendoza, C.E., Wales, P.J., Mcleod, H.A., & McKinley, W.P.
    1968                "Enzymatic detection of 10 organophosphorous
                        pesticides and carbaryl on thin-layer
                        chromatograms: An evaluation of indoxyl,
                        substituted indoxyl and 1-naphthyl acetates as
                        substrates for esterases," Analyst, London, 93:
                        34-38.

    Nomura. Torak (C14H17O4NS2PCl) acute toxicity studies
    1970                - male and female mice and rats. Report from
                        Kumamoto University, submitted by Hercules
                        Incorporated. (Unpublished)

    PAM I               Pesticide Analytical Manual Vol. I, 2nd Ed.
    1968                revised; U.S. Department of Health, Education and
                        Welfare, Food and Drug Administration.

    PAM II              Pesticide Analytical Manual Vol. II, revised;
    1967                U.S. Department of Health, Education and Welfare,
                        Food and Drug Administration.

    Reyna, M.S., Kennedy, G.L., Kinoshita, F.K., & Keplinger, M.L.
    1975                1-year chronic oral toxicity study with Torak
                        technical in albino rats. Report from industrial
                        Bio-Test Laboratories, submitted by Hercules
                        Incorporated. (Unpublished)

    Robens, J.F. Teratogenic activity of several phthalimide derivatives
    1970                in the golden hamster. Toxicol. Appl. Pharmacol.
                        16: 24-34.

    Schoenig, G., & Fancher, O.E. Acute oral toxicity of recrystallized
    1966a               AC14503 - albino rats. Report from Industrial
                        Bio-Test Laboratories, submitted by Hercules
                        Incorporated. (Unpublished)

    Schoenig, G., Fancher, O.E., & Calandra, J.C. Acute oral toxicity
    1966b               of column residue from Technical AC14503 male and
                        female albino rats. Report from Industrial
                        Bio-Test Laboratories, submitted by Hercules
                        Incorporated. (Unpublished)

    Schoenig, G., Fancher, O.E., & Calandra, J.C. 14-day subacute
    1966c               oral toxicity of technical AC14503 - mongrel dogs.
                        Report from Industrial Bio-Test Laboratories,
                        submitted by Hercules Incorporated. (Unpublished)

    Schoenig, G., Fancher, O.E., & Calandra, J.C. Acute toxicity
    1966d               studies on technical AC14503 - mice, albino
                        rabbits, dogs, and rats. Report from Industrial
                        Bio-Test Laboratories, submitted by Hercules
                        Incorporated. (Unpublished)

    Schoenig, G., Fancher, O.E., & Calandra, J.C. Acute potentiation
    1966e               of AC14503 with malathion. Report from Industrial
                        Bio-Test Laboratories submitted by Hercules
                        Incorporated. (Unpublished)

    Sedivy, W.E. Study on the effects of Hercules compound 14503 on
    1968a               beef animals. Report from Harris Laboratories,
                        submitted by Hercules Incorporated. (Unpublished)

    Sedivy, W.E. Study on the effects of Hercules compound 14503
    1968b               on dairy cows. Report from Harris Laboratories,
                        submitted by Hercules Incorporated. (Unpublished)

    Sedivy, W.E. Study on the effects of Hercules compound 14503
    1968c               on poultry. Report from Harris Laboratories,
                        submitted by Hercules Incorporated. (Unpublished)

    Smith, P.S., Reyna, M.S., Kennedy, G.L., & Keplinger, M.L.
    1972a               90-day cholinesterase study with Norchloro-Torak
                        in albino rats. Report from Industrial Bio-Test
                        Laboratories, submitted by Hercules Incorporated.
                        (Unpublished)

    Smith, P.S., Reyna, M.S., Kennedy, G.L., & Keplinger, M.L.
    1972b               90-day subacute oral toxicity study with
                        Norchloro-Torak in albino rats. Report from
                        Industrial Bio-Test Laboratories, submitted by
                        Hercules Incorporated. (Unpublished)

    St. John, L.E. et al. Metabolism studies with Torak insecticide
    1971                in a dairy cow. Department of Entomology Pesticide
                        Residue Laboratory, Cornell Univ. J. agr. Fd.
                        Chem. 19 (5): 900-903.

    Taylor, R.E. Cholinesterase and tissue residue study using
    1969                Hercules 14503 on beef animals. Report from Harris
                        Laboratories, submitted by Hercules Incorporated.
                        (Unpublished)

    Ueda, K. Report on acute toxicological test - rats. Report 1968
                        from Tokyo Dental University, submitted by
                        Hercules Incorporated. (Unpublished)

    Vondruska, J.F., Keplinger, M.L., & Fancher, O.E. Status Summary
    1968                - Evaluation of AC14503 upon primate
                        cholinesterase levels in stumptailed monkeys.
                        Report from Industrial Bio-Test Laboratories,
                        submitted by Hercules Incorporated. (Unpublished)

    Vondruska, J.F. & Fancher, O.E. Teratologic study of compound
    1969                AC14503 in stumptailed monkeys. Report from
                        Industrial Bio-Test Laboratories, submitted by
                        Hercules Incorporated. (Unpublished)

    Wolf, C. & Calandra. J.C. 14-day oral toxicity of AC14503
    1965                - albino rats. Report from Industrial Bio-Test
                        Laboratories, submitted by Hercules Incorporated.
                        (Unpublished)

    Wolf, C., Fancher, O.E., & Calandra, J.C. Effects of AC14503
    1966a               on cholinesterase activity in the albino rat.
                        Report from Industrial Bio-Test Laboratories,
                        submitted by Hercules Incorporated. (Unpublished)

    Wolf, C., Fancher, O.E. & Calandra, J.C. 90-day subacute oral
    1966b               toxicity of AC14503 - albino rats. Report from
                        Industrial Bio-Test Laboratories, submitted by
                        Hercules Incorporated. (Unpublished)

    Wolf, C., Fancher, O.E. & Calandra, J.C. Effects of AC14503
    1966c               on cholinesterase activity on the albino rat
                        (Additional determinations). Report from
                        Industrial Bio-Test Laboratories, submitted by
                        Hercules Incorporated. (Unpublished)

    Wolf, C., Keplinger, M.L., & Fancher, O.E. Two-year chronic oral
    1968                toxicity of AC14503 - albino rats. Report from
                        Industrial Bio-Test Laboratories, submitted by
                        Hercules Incorporated. (Unpublished)
    


    See Also:
       Toxicological Abbreviations