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    EDIFENPHOS           JMPR 1976

    IDENTITY

    Chemical name

    O-ethyl SS-diphenyl phosphorodithioate

    Synonyms

    EDDP, SRA 7847, Bayer 78418, Hinosan(R)

    Structural formula

    CHEMICAL STRUCTURE 1


    C14H15O2PS2. Molecular weight 310.4

    Other information on identity and properties

    Physical and chemical properties

         Physical state:          the technical product has a yellow to
                                  light brown colour.

         Boiling point:           154° at 0.01 mm Hg.

         Specific gravity:        1.23 at 20°/4°C.

         Vapour pressure:         10-4 to 10-2 mm Hg at 20-100°C.

         Solubility:              insoluble in water, soluble in acetone
                                  and xylene.

         Stability:               half-life values: 49 hours at 25°C and 
                                  pH 9; 1135 hours at 25°C and pH 7.

    Composition of the technical product

         The technical product contains a minimum of 87% of edifenphos.
    The main impurities are:

         SSS-triphenyl phosphorotrithioate       max 7%

         OO-diethyl S-phenyl phosphorothioate    max 3.5%

         diphenyl sulphide                       max 2.5%

         toluene                                 max 1.5%

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, Distribution and Excretion

         Edifenphos is rapidly absorbed following acute oral
    administration to rats. Within 8 hours of dosing the major part of
    an 35S-dose was absorbed. Within 72 hours of the administered dose,
    96% in rats and > 97% in mice was excreted in the urine and feces.
    There were no significant sex differences noted in rats, while in
    mice females excreted somewhat more in the feces than corresponding
    males. Apart from this no sex differences in absorption and
    excretion were noted. Tissue residues (35S-labelled) in both rats
    and mice were extremely low at 72 hours. Residues in tissues
    following acute or sub-acute (10-daily) doses were generally low
    and associated with tissues concerned with distribution and
    excretion. Of the 6 tissues examined at various intervals after
    dosing (from 1 to 72 hours) the following sequence reflects tissue
    distribution: liver > kidney > lung > heart >> blood = brain.
    This same qualitative relationship of tissue distribution was
    reflected over the time for maximum tissue clearance (Ueyema, et
    al., 1976).

         Absorption of a single oral dose of edifenphos (0.12 mg/kg
    b.w.) in a lactating cow was slow than seen with the rat, mouse,
    dog and even lactating goat. In the cow, the blood residue reached
    a maximum 20 hours after a single oral dose. Thirty percent of the
    administered dose was excreted during the first day after dosing
    and another 30% during the following 4 days. Twenty seven percent
    of the dose was excreted in the feces in 5 days and < 3% was
    observed as a residue in milk (not above 0.09 mg/kg edifenphos
    equivalents at any time). In a study where a cow was administered

    5 consecutive oral daily doses of edifenphos (0.12 mg/kg. b.w.),
    blood levels of edifenphos (expressed as equivalents) increased from
    0.05 mg/kg after the first application to 0.2 ppm after the fifth.
    A residue plateau was not observed during this time. In urine and
    milk, the increase of total residues was less pronounced and seemed
    to level off after the third application at a concentration of 4 and
    0.18 mg/kg respectively (Pither and Gronberg, 1975). Residues in the
    tissues at slaughter, 20 hours after the last dose, ranged from 0.13 to
    0.67 mg/kg edifenphos equivalents.

    Biotransformation

         Qualitative determination of the fate of edifenphos in rats
    and dogs was reported following a single oral dose. No edifenphos
    was observed in urine but rather the hydrolysis products were
    observed both free and conjugated. A difference was observed
    between male and female rats where two unidentified products were
    observed in female urine that were not seen in males. (Eben and
    Kimmerle, 1972). In contrast, no such differences with respect to
    sex were noted in another study using a 35S-labelled product. In
    rats, dogs, mice and goats, a similar pattern of metabolic
    breakdown was reported. The metabolic pathway followed in animals,
    rice plant and the rice blast fungus, together with photochemical
    and weathering reactions, are illustrated in Figures 1(a) and 1(b).


         All radioactivity in the urine of rats and mice consisted of
    conjugated or water soluble metabolites. The major metabolite in
    rats was the des-S-phenyl hydrolysis product while in mice the
    mono-S-phenyl phosphorothioate was prevalent (further dealkylation
    of the major rat metabolite). In feces, small (< 2%) quantities of
    edifenphos were noted as well as diphenyl disulfide (Ueyama et al.,
    1976).

         Metabolism in other animals, plants and fungi is discussed in
    the section "Fate of residues".

    Effects on Enzymes and Other Biochemical Parameters

         Rabbits were orally administered edifenphos and liver function
    tests performed at various times (up to 7 days) after poisoning. No
    effects were noted on SGPT or SDH activity or BSP retention
    following a dose of 50 mg/kg, while there were effects reported at
    100 mg/kg (Kimmerle and Lorke, 1967).

         A single oral application of edifenphos to rats (150 mg/kg)
    increased liver weight 24 hours after the treatment. While no
    changes were observed in body weight, relative liver weight changes
    were observed at lower doses (> 25 mg/kg) within 24 hours. One
    week after treatment the highest treatment group still showed an
    increased relative liver weight while other groups appeared to have
    recovered. In this study, changes in liver size were not reflected
    in changes in certain liver function tests (SGOT activity, SGPT

    activity, Cholesterol content and glucuronidase activity). Slight
    changes were noted at 24 hours in the A/G ratio, S-protein content,
    certain drug metabolizing enzyme assays (EPN detoxication but not
    aniline hydroxylation or aminopyrine demethylation) and, as expected,
    cholinesterase activity. Within 7 days these liver changes had
    recovered and values were normal. Gross and microscopic examination
    did not suggest a pathological condition.

         Cholinesterase depression measured at 24 hours after treatment
    was dose dependent and sensitivity was as follows: RBC>plasma>
    brain. At 7 days after treatment, recovery of plasma cholinesterase
    was complete while RBC and brain continued to show a reduction at
    the higher dose levels (Anonymous, 1976b).

         Acute signs of poisoning reflect acute depression of
    cholinesterase activity. Within 3 hours of following oral
    intubation of edifenphos (25-50 mg/kg - male rats) significant
    depression of whole blood cholinesterase was observed. After a dose
    of 10 mg/kg the enzyme activity was not depressed. At higher levels
    the effects were persistent, lasting for three days. All enzyme
    activity was normal 7 days following acute exposure (Kimmerle /
    Lorke, 1967).

         In vitro studies with rat brain also demonstrated the
    sensitivity of this cholinesterase source to edifenphos with an I50
    of 1.05 x 10-6 being noted. In vivo inhibition following
    poisoning was rapid and the duration of recovery was long with full
    recovery not seen until 2-3 weeks after treatment. While there was
    an obvious sex difference seen in acute toxicity, the recovery of
    cholinesterase activity did not reflect a sex difference. The rate
    of recovery of cholinesterase (brain, serum or submaxillary gland)
    following an LD50 dose was the same in both males and females.

         In addition to its effects on acetylcholinesterase, edifenphos
    was found to be an effective inhibitor of aliesterase activity.
    Dietary administration of edifenphos at levels resulting in 50%
    inhibition of liver and serum aliesterase activity in rats are seen
    in Table 1. A dietary level of 5 ppm for one week reduced esterase
    activity (those hydrolyzing tributyrin) by 50% in the liver.

    TABLE 1. Dietary Levels (ppm) Inducing-50% Aliesterase
                                                                   
                                  Inhibition in Rats
    Substrate                Male                      Female
                        Liver     Serum           Liver         Serum
                                                                   
    Tributyrin          4.9       8.4             5.4           9.5

    Diethylsuccinate    18.4      10.2            11.5          7.4
                                                                   
                                  (Chen, et al. 1972)

    FIGURE 1

    FIGURE 2

         Cholinesterase depression in rats was observed following acute
    inhalation exposure to aerosolized edifenphos. Plasma and RBC
    cholinesterase depression was seen following exposure to 30 mg/m3
    for 4 hours (threshold level). No depression was noted at an
    exposure concentration of 9 mg/m3 for 4 hours (Kimmerle, 1975b).

    TOXICOLOGICAL STUDIES

    Special Studies on Teratology

         Groups of rats (20 mated females/group) were administered
    edifenphos by oral gavage at doses of 0, 5, 15 and 30 mg/kg body
    weight from day 6 to 15 of gestation. All animals were sacrificed
    and pups delivered by Caesarean Section. Increased mortality
    reduced growth and an unhealthy appearance were observed at the two
    highest dose levels. At the highest dose level, 3 litters were
    resorbed. There were no abortions and with the exception of the 3
    resorbed litters, the numbers of implantations, fetuses and
    resorptions did not differ from control values. The weights of
    fetuses were not different from controls and the nature and
    frequency of somatic and skeletal variations were within normal
    limits. There were no malformations and no indications of a
    teratogenic potential was noted in this study (Lorke, 1971).

         Groups of rabbits (11-13 mated does/group) were administered
    edifenphos by oral gavage at dose levels of 0, 3, 6 and 12 mg/kg
    body weight from day 6 to 18 of gestation. On day 29 of gestation,
    the does were sacrificed and Caesarean Section performed. There was
    no mortality although the two highest dose levels resulted in
    reduced growth (the highest level treatment showed a significant
    weight loss). In the 6 mg/kg group one doe aborted and one resorbed
    all fetuses. Implantation recorded for the two highest doses was
    reduced. However, the significance of this was not apparent as
    treatment did not begin until 6 days after fertilization and
    edifenphos treatment should not have affected this parameter. There
    were no differences in the number of fetuses in the 0 and 3 mg/kg
    dose while the upper two doses had fewer fetuses. The weight of
    fetuses and placenta of the treated group did not differ from
    control values. Malformations were not observed on gross or
    skeletal examination of fetuses. As suggested with rats, edifenphos
    did not induce a teratological response in rabbits (Machemer,
    1976).

    Special Studies on Reproduction

         Groups of rats (10 males and 20 females/group) were fed
    edifenphos in the diet at concentrations of 0, 5, 15 and 150 ppm
    and mated to begin a standard 3 generation, 2 litter per
    generation, reproduction study. Reproductive indices included:
    fertility, gestation, viability and lactation measured for all 6
    litters. There was no mortality observed and the highest dietary
    concentration did not affect fertility. Litter size was reduced and
    in one instance the litter weight was reduced at the 150 ppm level.

    Slight effects (not statistically significant) were noted on
    viability and lactation indices in the high dose group. Histological
    examination of the F3b generation gave no indication of adverse
    effects on the major tissues and organs. A no effect-level in this
    study would be 15 ppm (Loser, 1976).

         Groups of rats (20 females/group) were fed edifenphos in the
    diet at dosage levels of 0, 5, 15 and 50 ppm, mated and subjected
    to a standard 3 generation, 2 litters per generation, reproduction
    study, In combination with the study, additional groups of 5
    females from the P and F1b and 10 females from the F2b were
    sacrificed at day 20 of gestation for an examination of fetuses for
    any teratological events. Additionally, offspring of 5 female rats
    from individual groups of the F1b, F2b and 10 females from the P3b
    were maintained after weaning at the same dietary concentrations of
    edifenphos listed above for periods ranging from 1 to 6 months.
    These short term studies were designed to evaluate growth and
    development of rats exposed initially in utero and thereafter for
    short periods to dietary levels of edifenphos.

         Growth of parental generations was unaffected by the presence
    of edifenphos in the diet. Slight reduction of male food intake and
    body weight at 50 ppm was noted in the first parental generation.
    The reduced food consumption was observed in the F2 and F3 parents
    accompanied by slight reduction of growth. The reduced growth was
    predominant in those animals fed after weaning for prolonged
    periods.

         There were no significant differences noted in the
    reproduction indices over the course of the three generations.
    Edifenphos did not affect the ability of the rats to reproduce,
    maintain pregnancy, deliver, nurse and wean normal sized litters
    over the course of three generations. A teratological examination
    of fetuses delivered by Caesarean Section prior to term did not
    show any abnormalities related to somatic or skeletal defects. In
    the first generation the 50 ppm dosed group reflected a slight
    retardation in the degree of bone ossification not always noted in
    the two lower doses or the controls. There were no significant
    differences in implants, resorptions, live fetuses or in the weight
    of fetuses.

         In those weanlings from the F1b, F2b and F3b litters that were
    maintained on diets containing edifenphos for 1 to 6 months after
    weaning, growth was not substantially affected. Slight reductions
    of growth were noted at 50 ppm accompanied by reduced food intake.
    Hematological examinations made at the conclusion of each time
    interval were normal. Liver function tests including SGOT and SGPT
    activity and cholinesterase determinations using plasma, RBC and
    brain were normal. Gross and microscopic examination of tissues and
    organs of the animals maintained after weaning showed only on
    consistent event attributable to edifenphos in the diet. An
    enlarged kidney in the 50 ppm group fed for 3-6 months was
    accompanied by changes (saccular necrosis) in the tubular

    epithelium noted on microscopic examination. No dose related
    changes were noted in a variety of tissues and organs that could be
    attributable to edifenphos in the diet (Anonymous, 1976a).

    Special Study on Mutagenicity

    Mice

         A dominant lethal study using male mice was performed with
    edifenphos. Groups of mice (12 males/group) were administered
    edifenphos by a single intraperitoneal injection at doses of 0, 50
    and 100 mg/kg. A positive control (MMS, methyl methansulfonate, 100
    mg/kg) was included in the study. The males were mated with three
    untreated virgin females. The females were changed weekly for 6
    consecutive weeks to evaluate maturation of male mouse germ cells.
    One week after breeding, the females were sacrificed and examined
    for implantation sites, resorption sites and embryos.

         There were no deaths as a result of treatments with
    edifenphos. Except for a slight reduction in the mating index at
    week 6 in the 100 mg/kg dose group, there was no effect on the
    ability to mate or fertilise the females. There were no
    dose-related effects noted with respect to implantation, resorption
    or embryo viability. There was no increase in pre-implantation loss
    or mutuation rate although the positive control showed a
    significant increase in early resorptions, attesting to the species
    susceptibility. Edifenphos did not demonstrate a mutagenic
    potential by the dominant lethal test in mice (Arnold, et al.
    1971).

    Microorganisms

         When examined in vitro with various strains of
    microorganisms (B. subtilis, E. coli and S. typhimurium
    edifenphos did not induce a mutagenic response. In two studies with
    the aid of a B. subtilis strain lacking the recombination
    repair system, S. typhimurium and E. coli with either a
    histidine or tryptophane deficiency, edifenphos, examined for its
    ability to induce mutations, was found to be negative. Positive and
    negative controls were used in these assays to assure sensitivity
    to the mutagenic activity and to provide a baseline of operation.
    In addition, liver homogenates (fortified with cofactors necessary
    for microsomal oxidation) were used to activate, if possible,
    edifenphos to an active mutagen. In studies with reversion colonies
    in combination with a microsomal activation system, edifenphos did
    not induce mutations (Shirasu et al., 1976a; 1976b; Yatomi, 1975).

         A host mediated assay was performed where groups of 5 mice
    were orally administered two doses of 0, 50 or 100 mg edifenphos/kg
    (within 24 hours). After the second dose, a microbiological test
    system of S. typhimurium was injected into the peritoneal
    cavity, removed after 3 hours and examined for revertant colonies.

    In this assay, edifenphos was negative although a positive control
    of dimethylnitrosamine (50 mg/kg, oral administration) induced
    reversion at a substantial rate (Shirasu. et al., 1976a).

    Special Studies on Potentiation

         Oral administration of equitoxic doses (LD50) of edifenphos
    with fenthion or propoxur did not result in potentiation of the
    acute toxicity of the combination. (Kimmerle, 1967).

         A greater than additive toxicity, observed with a combination
    of malathion and edifenphos, suggested a potentiating effect with
    these two pesticides (Kimmerle and Lorke, 1967). Further studies on
    toxic interaction of two organophosphorus pesticides were
    undertaken where rats fed 0, 5 or 25 ppm edifenphos in the diet
    were administered malathion by ip injection at a sublethal dose
    (400 mg/kg). The increased mortality observed in the two groups fed
    edifenphos suggested a significant potentiating effect on malathion
    toxicity (Chen, et al., 1972).

    Special Studies on Antidotes

         Following acute oral administration of edifenphos to male
    rats, antidotal administration (ip injection) of atropine (50
    mg/kg) alone or in combination with 2-PAM or BH6 (50 or 20 mg/kg,
    respectively) resulted in a slight reduction in the acute toxicity
    (less than 2 fold) (Kimmerle and Lorke, 1967).

    Special Studies on Neurotoxicity

         Edifenphos was administered to hens by oral intubation or
    intraperitoneal injection at dose levels up to 1000 mg/kg. The
    surviving animals were examined for 42 days with no signs of
    delayed neurotoxicity (Kimmerle and Lorke, 1967).

         Groups of hens were administered edifenphos by oral intubation
    at the LD50 level (547 mg/kg body weight) together with atropine,
    50 mg/kg administered by ip injection. Delayed neurotoxic signs of
    poisoning were not seen, but were observed in all hens treated
    orally with TOCP (350 mg/kg). The hens were observed for 3 weeks
    and sacrificed (Kimmerle, 1971). Histological examination of
    portions of the central and peripheral nervous system of the
    edifenphos-treated hens was negative with respect to axon or myelin
    disruption. The TOCP-treated hens showed axon and neuron
    degeneration in the spinal cord (brain and peripheral nerve were
    not affected) (Spicer, 1971a).

         In an effort to evaluate the relationship of delayed
    neurotoxicity and copper imbalance in hens, an examination of
    several organophosphates inducing a delayed neurotoxicity was made.
    Edifenphos as one of the negative compounds did not induce
    neurotoxicity and did not increase copper and ceruloplasmin levels

    as did several of the positive neurotoxic agents (Kimmerle and
    Loser, 1974).

         Groups of hens (8 hens/group) were fed edifenphos in the diet
    for 30 days at concentrations of 0, 100, 250, 500 and 1000 ppm.
    Growth was depressed at 500 ppm and above. Whole blood
    cholinesterase was depressed after 30 days only in the highest dose
    group. Animals allowed to recover on control diets for a 4 week
    period recovered body weight and cholinesterase depression was
    reduced. Neurotoxic clinical signs were not observed (Kimmerle,
    1969). Histological examination of brain, spinal cord and
    peripheral nerve showed no evidence of myelin degeneration (Spicer,
    1971b).

    Acute Toxicity

    
    TABLE 2. Acute toxicity of edifenphos

                                                                                    
                                              LD50
    Species       Sex   Route                 (mg/kg)     Reference
                                                                                    

    Rat           M     oral                  119-340     Kimmerle, 1967;
                                                          Kimmerle & Lorke, 1967;
                                                          Thyssen & Kimmerle, 1974

                        ip                    48-81       Kimmerle & Lorke, 1967;
                                                          Thyssen & Kimmerle, 1974;
                                                          Chen, et al., 1972

                        dermal
                        (24 hour exposure)    184-413     Kimmerle, 1972a Thyssen &
                                                          Kimmerle, 1974

                        (4 hour exposure)     1,230       Kimmerle & Lorke, 1967

                        (7 hour exposure)     600         Kimmerle & Lorke, 1967

                  F     oral                  63-150      Kimmerle & Lorke, 1967;
                                                          Thyssen & Kimmerle, 1974

                        ip                    26-55       Thyssen & Kimmerle, 1974;
                                                          Kimmerle & Lorke, 1967;
                                                          Chen, et al., 1972

                        dermal
                        (24 hour exposure)    86-135      Kimmerle, 1972a,
                                                          Thyssen & Kimmerle, 1974

    Mice          M     oral                  392         Thyssen & Kimmerle, 1974

    TABLE 2. (Cont'd.)
                                                                                    
                                              LD50
    Species       Sex   Route                 (mg/kg)     Reference
                                                                                    

    Mice          F     oral                  218-295     Kimmerle & Lorke, 1967;
                                                          Thyssen & Kimmerle, 1974

    Guinea Pig          oral                  350-400     Kimmerle & Lorke, 1967

    Rabbit        F     oral                  250-400     Kimmerle & Lorke, 1967;
                                                          Thyssen & Kimmerle, 1974

    Cat                 oral                  >250        Kimmerle & Lorke, 1967
                                                                                    
    
    Note -- In some instances the range of values is reflective of
    differences in solvents used in the test. The lower values were
    obtained with Lutrol while the higher values were obtained with
    ethanol: propylene glycol mixtures. In all cases there appears to be a
    significant sex difference with females more susceptible than males.

    Signs of poisoning were typical of cholinergic stimulation (tremors,
    salivation, labored respiration, etc.) appearing 2-3 hours after acute
    poisoning and persisting for up to 2 days with rats and up to a week
    with mice and rabbits.

    Inhalation Toxicity

         Acute aerosol inhalation toxicity tests (both static and dynamic
    flow) were performed with groups of rats using various exposure times.
    Edifenphos technical or a 50% EC formulation (Hinosan(R)) was used in
    several studies. Data expressed as the technical product do not show
    significant differences in toxicity between the two forms of
    edifenphos. No indication of particle size distribution was given in
    these data.

    Dynamic tests

    Results of dynamic tests are given in Table 3.
        TABLE 3. Inhalation toxicity of edifenphos (dynamic tests)
                                                                        

                     Exposure    LD50
    Species    Sex   Time        (mg/m3)        Reference
                                                                        

    Rat        M     1 hour      >898-1310      Thyssen & Kimmerle, 1974;
                                                Kimmerle, 1972b;
                                                Kimmerle & Lorke, 1967

    TABLE 3. (Cont'd.)

                                                                        

                     Exposure    LD50
    Species    Sex   Time        (mg/m3)        Reference
                                                                        

                     4 hour      362 - 775      Thyssen & Kimmerle, 1974;
                                                Kimmerle, 1972b.,
                                                Kimmerle, 1975b;
                                                Kimmerle & Lorke, 1967

               F     1 hour      > 1017-1046    Thyssen & Kimmerle, 1974;
                                                Kimmerle, 1972b

                     4 hour      230 - 320      Thyssen & Kimmerle, 1974;
                                                Kimmerle, 1975b;
                                                Kimmerle, 1972b
                                                                        
    
    Static Tests

         Groups of rats, mice, rabbits and guinea pigs were exposed to
    static concentrations of edifenphos ranging from 108 to 398 mg/m3 for
    up to 4 hours. In the 1 hour exposure, no toxicity was recorded (only
    one dose level was tested) but mice exhibited toxic signs of exposure.
    In the 4 hour exposure the susceptibility of rats, rabbits and mice
    was the same with 7/10 rats, 2/3 rabbits and 12/20 mice dying at a
    concentration of 269 mg/m3. Only 1/5 guinea pigs died at this
    exposure. No deaths were reported at a concentration of 101 mg/m3 for
    the 4 hour exposure (Kimmerle & Lorke, 1967).

         Edifenphos did not induce a primary dermal irritation when
    applied to the skin of rabbits' ears for up to 24 hours or to the
    conjunctival sac of rabbits. The 50 EC formulation of Hinosan(R)
    irritated both the conjunctiva and skin (1 hour exposure). The primary
    irritation was attributed to the formulation ingredients and not
    technical edifenphos (Kimmerle and Lorke, 1967; Thyssen and Kimmerle,
    1974).

    Toxicity of metabolites

         Acute toxicities of edifenphos metabolites to rats are shown in
    Table 4.


        TABLE 4. Acute toxicity of edifenphos metabolites to rats

                                                                  

    Compound                   Route                  LD50
                                                      (mg/kg)
                                                                  

    O-ethyl S-phenyl           oral       M           >500
    S-(4-hydroxyphenyl)-                  F           >1000
    phosphorodithioate

    SS-diphenyl                oral       M           1000-2000
    phosphorodithioate                    F           1000-2000

    O-ethyl S-phenyl           oral       M           1000-2000
    phosphorothioate                      F           616

    O-ethyl S-phenyl           oral       M           approx. 1000
    S-(3-hydroxyphenyl)                   F           approx. 500
    phosphorodithioate
                                                                  

                               (Lamb & Matzkanin, 1976)
    
    Short-term studies

    Mice

         Groups of ICR mice (10 males and 10 females/group) were fed
    edifenphos in the diet for 3 months at dosage levels of 0, 3, 10, 30,
    100, 300 and 1000 ppm. In general, growth was not affected by dietary
    edifenphos. Food consumption, behaviour, physical condition and
    mortality were unaffected. Plasma cholinesterase depression was noted
    at 30 ppm with RBC and brain depressed only at 1000 ppm. Hematology,
    urinalysis and clinical chemistry parameters were normal. On gross
    examination of tissues and organs, spleen and liver enlargement was
    observed at 1000 ppm. Microscopic examinations showed no abnormalities
    in spleen although liver and adrenal changes were noted at 300 ppm and
    above. In liver, hypertrophy of hepatocytes and deposition of
    phospholipid were observed. Adrenal hypertrophy and pigment deposition
    were noted at the two highest doses (Imamichi, et al., 1973b). A
    no-effect level of 10 ppm was observed equivalent to 1.53 mg/kg body
    weight.

    Rats

         Groups of rats (10 males and 10 females/group) were exposed to
    edifenphos by inhalation at concentrations of 0, 4 (range of 3-15), 10
    (8-12) and 27 (24-30) mg/m3 air for 12 weeks, 5 days/week for 6
    hours/day. The range of particle size was 0.5 to 1.5 µ with 97% of the
    particles having a mean mass diameter of 1 µ (a fully respirable

    particle). There was no mortality although females exposed to 27
    mg/m3 were observed to be adversely affected. Growth was normal at
    all levels of exposure as were clinical chemistry, hematology and
    urinalysis parameters. Cholinesterase (brain, plasma and RBC) activity
    was depressed at 10 mg/m3 and above. No effects were noted at 4
    mg/m3. Gross and microscopic analysis of tissues and organs were not
    affected by edifenphos in the diet. Female adrenal weight was
    increased at the highest dose level but no abnormalities were detected
    on microscopic examination (Kimmerle, 1975; Mohr, 1975).

         Groups of rats (10 males and 10 females/group) were fed
    edifenphos in the diet for 3 months at dosage levels of 0, 3, 10, 30,
    100, 300 and 1000 ppm. There was no mortality during this study but
    growth was inhibited at 1000 ppm in both males and females. In
    contrast to the reduced growth, food consumption was normal at all
    dose levels. Several hematological parameters were affected at 1000
    ppm, namely reduced RBC count, hemoglobin content and hematocrit value
    primarily in males. Liver function was reduced at 1000 ppm (SGOT), 100
    ppm (SGPT) and at 30 PPM (SAP) predominantly in males, with the
    reduction not as marked in females. Urinalysis parameters were
    unaffected. Cholinesterase depression was noted at 300 ppm in males
    (brain and RBC) and 100 ppm in females (brain and RBC), plasma was
    depressed in females at 10 ppm. Gross examination revealed enlarged
    liver (1000 ppm) and kidney (300 ppm). Microscopic examination of
    tissues showed hypertrophy and fatty degeneration of hepatocytes at
    100 ppm and above. No pathological changes were noted in liver at 30
    ppm. At 100 ppm and above, kidney and adrenal changes were noted. At
    high levels a toxic nephritis was observed and the kidney and adrenal
    glands were hypertrophic. In the male, kidney degeneration was
    prevalent while in the females the adrenal was damaged. Gross changes
    noted in brain, pituitary and thyroid of males at high dose levels
    were not accompanied by pathological changes (Imamichi, 1973a).

         Groups of rats (15 males and 15 females/group) were fed
    edifenphos in the diet at dosage levels of 0, 1, 2, 5, 10 and 150 ppm
    for 3 months. Growth was affected by edifenphos and there were no
    differences in behaviour, mortality or appearance. Food consumption in
    the highest dose group was slightly reduced. Hematological
    examinations were normal at 1 and 3 months as were liver function and
    urinalysis tests measured at the same time intervals. Cholinesterase
    depression was observed in the highest dose group (in both RBC and
    plasma) within one week of initiation of the feeding trial. The
    depression was constant and there was no indication of a cumulative
    effect relating to edifenphos. Gross and microscopic analysis of
    tissues and organs, performed at the conclusion of the study, showed
    no dose-related gross change and no significant microscopically
    observable alteration (Loser, 1972; Urwin and Newman, 1972).

         Groups of rats (10 males/group) were administered edifenphos by
    oral intubation, daily for 14 days at dose rates of 0, 12.5, 50 and
    100 mg/kg. Mortality was not reported but a slight decrease in average
    body weight was reported at 100 mg/kg. A significant increase in

    absolute and relative liver weight was reported at all dose levels at
    24 hours. The livers had recovered to normal size within 7 days of the
    end of treatment. Cholinesterase was depressed at all levels with the
    following order of sensitivity: RBC > plasma > brain. One week after
    treatment RBC and brain cholinesterase activity were depressed at all
    dose levels. Liver function tests were slightly affected (SGOT
    reduced) but were normal within 7 days. EPN detoxication by liver
    microsomes was stimulated at all dose levels (aniline hydroxylase and
    aminopyrine demethylase were unaffected) and recovery was not complete
    at 7 days. Microscopic examination of liver, adrenals and kidney
    showed no adverse effects (Anonymous, 1976c).

         Groups of rats (15 females/group) were administered edifenphos
    orally (0, 5, 10, 20, 33.5 and 50 mg/kg) or by intraperitoneal
    injection (0, 1.75, 3.5, 7, 10, 11.5 and 17.5 mg/kg), daily 5 weeks
    per week for 60 days. Oral administration of 50 mg/kg daily resulted
    in no mortality or cumulative toxicity although signs of poisoning
    were seen. No signs of poisoning were evident at 10 mg/kg/day
    following oral dosing. With daily ip injections, no substantial
    mortality (1/15 deaths) was observed at 7 mg/kg (11/15 died at 11.5
    mg/kg). Signs of poisoning were not evident at 3.5 mg/kg. These
    results suggest a minimal cumulative toxicological effect (Kimmerle
    and Lorke, 1967).

    Dog

         Groups of dogs (2 male and 2 female/group, controls had 3 of each
    sex) were fed edifenphos in the diet at dosage levels of 0, 3, 10 and
    30 ppm for 90 days. There was no mortality over the course of the
    study and growth, food consumption, behaviour and general appearance
    were normal. Clinical chemistry, hematology and urinalysis values were
    normal at one and 3 months (except for a slight increase of SDH
    activity at only one month in both males and females at 30 ppm). Blood
    cholinesterase activity was depressed in both plasma and RBC (to the
    same extent in both enzyme sources) at the highest dose. As with
    rodent studies, there was no evidence of cumulative activity over the
    3 month interval. Gross and microscopic examination of tissues and
    organs revealed no adverse effects of edifenphos in the diet. A slight
    increase in the absolute and relative weight of the spleen at 30 ppm
    was not accompanied by microscopic lesions (other than minimal)
    congestion and probable hemosiderin deposition) (Loser, 1969; Spicer
    and Urwin, 1971).

         Groups of dogs (4 male and 4 female/group) were fed edifenphos in
    the diet for two years at dose levels of 0, 7, and 20 ppm. A fourth
    group was fed a diet containing 60 ppm for 1 year after which the
    concentration was increased to 80 ppm for 5 months and raised to 120
    ppm for the remaining 7 months of study. There was no mortality and
    behaviour and physical appearance were normal and unaffected by
    edifenphos in the diet. Growth and food consumption was normal at the
    20 ppm level although it was slightly depressed at the high dose
    regime. At the high level food consumption was slow, diet rejection

    was observed and body weight gain depressed. There was no effect noted
    on ophthalmological examination, urinary or hematology parameters or
    on reflex testing. Some liver function test parameters were abnormal
    (data showed SAP increased although SGPT was normal). This change was
    accompanied by an increased gross and relative liver weight noted at
    the time of sacrifice. Cholinesterase activity was depressed in the
    high dose group in both plasma and RBC of males and females. Brain
    cholinesterase was unaffected at any dose level. Gross and microscopic
    examination of tissues and organs did not suggest an adverse effect of
    edifenphos fed in the diet at concentrations up to and including 120
    ppm. The inductive effect noted on the liver (increased organ weight
    accompanied by increased phosphatase activity) was attributed to an
    adaptation reaction noted with many drugs and chemicals. Microscopic
    examination of liver did not show changes attributable to the presence
    of dietary edifenphos which would account for the increased liver
    weight. A no-effect level was observed to be 20 ppm equivalent to a
    daily intake of 0.58 mg/kg body weight (Hoffmann, 1976; Gallagher and
    Practice, 1976).

    Long Term Studies

    Rat

         Groups of rats (50 male and 50 female rats/group, 100 of each sex
    were used as controls) were fed edifenphos in the diet at
    concentrations of 0, 2, 5, 15 and 150 ppm for two years. Mortality was
    unaffected during the two years. Growth, behaviour and physical
    appearance were normal in all groups. Hematology, blood chemistry and
    urinalysis parameters were normal. A slight decrease in alkaline
    phosphatase at 150 ppm was considered to be within the normal range
    for the animals. Cholinesterase depression was observed in plasma and
    RBC of both sexes at 150 ppm. Brain cholinesterase was depressed only
    in females at 150 ppm. Gross and microscopic examinations were
    performed on surviving animals. No abnormal, dose-related events were
    recorded in the gross examination. A slight increase in adrenal size
    of males at 15 ppm and above was not reflected in changes observed
    under microscopic examination. Histopathological examination of
    tissues and organs revealed luminal deposits of calcium salts in the
    medulary tubules of male rats fed 15 and 150 ppm diets accompanied in
    the high dose group by an increased incidence of glomerulonephrosis in
    males. These changes were not noted in females. A complete examination
    of tumours was performed revealing no indication of carcinogenic
    potential. The frequency of both benign and malignant tumors was
    typical of the rat strain used in the study. A no-effect dietary
    level, based on the microscopic examination observing slight kidney
    changes, was 5 ppm equivalent to 0.30 mg/kg body weight (Loser, 1976;
    Offer and Prentice, 1976).

    COMMENTS

         Edifenphos, an organophosphorus ester, is used in agriculture as
    a fungicide to control rice diseases. Following oral administration it
    is rapidly absorbed, distributed, metabolised and excreted in mammals.

    The well defined metabolic sequence observed in plants and animals
    appears to be the same. In metabolism studies and other studies in
    several species of animals there were no indications of any
    culminative effects.

         Biochemical parameters affected by acute and subacute
    administration of edifenphos include cholinesterase depression and
    changes in certain liver enzyme values reflecting changes in basic
    liver function. Edifenphos is not a potent cholinesterase inhibitor.
    However, the recovery of depressed enzyme activity is not rapid
    suggesting that regeneration of cholinesterase activity is dependent
    on enzyme synthesis rather than reversal of an enzyme-inhibitor
    complex. A sensitive biochemical parameter was aliesterase activity of
    liver and serum with a level of 5 ppm of edifenphos in the diet
    showing 50% inhibition. In special studies for teratogenic and
    mutagenic potential, no effects of edifenphos were noted on several
    species. At high levels, reproduction was slightly impaired but at
    levels that did not affect maternal well-being reproduction parameters
    were unaffected. Edifenphos appeared to potentiate the acute effects
    of malathion as might be expected from the data on depression of
    aliesterase activity. There is no evidence that edifenphos would
    induce a delayed neurotoxic response in hens.

         Edifenphos is moderately toxic on acute exposure to a variety of
    mammalian species with signs of poisoning typical of
    parasympathomimetic agents. The acute signs of poisoning, although
    modified slightly by atropine and reactivators, were not completely
    controlled.

         In all cases, the acute toxicity of metabolites was greatly
    reduced with respect to the acute toxicity of the parent compound. In
    both short and long term studies in rats and dogs, the most sensitive
    parameters affected were cholinesterase depression, liver enlargement
    and deposits of kidney salts in males on long term studies. Based on
    short term studies in mice and dogs and long term studies in rats a
    no-effect level was suggested and a temporary ADI for man was
    recommended. The dietary studies in rat (both short term and long
    term) showing liver and serum aliesterase depression and kidney salt
    build-up in males were used as a basis for evaluating the no-effect
    level. While 5 ppm was a level causing 50% inhibition of aliesterase
    activity the significance of this effect was unclear and has been
    taken to suggest "exposure" rather than "toxicological effect".

         The liver involvement noted in many studies precluded
    consideration of a finite ADI until a specific carcinogenic study is
    performed using a species susceptible to liver changes that might
    relate to hepatic carcinoma. As these changes noted in this study
    resemble those effects seen with other compounds including chlorinated
    hydrocarbons, such studies are required. The lack of carcinogenic
    potential noted in the 2 years, on a limited number of rats, was
    reassuring that the compound is not a potent carcinogen in this
    species. However, it was considered in the 2 year rat study that the

    highest dose level and the small group size were not sufficient to
    fully evaluate the potential for carcinogenicity.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:         10 ppm in the diet equivalent to 1.53 mg/kg bw

         Dog:           20 ppm in the diet equivalent to 0.58 mg/kg bw

         Rat:           5 ppm in the diet equivalent to 0.25 mg/kg bw

    Estimate of temporary acceptable daily intake for man

         0 - 0.003 mp/kg bw

    RESIDUES IN FOOD AND THEIR EVALUATION

         Edifenphos is an organophosphorus compound with a fairly
    selective action against rice blast caused by Piricularia oryzae,
    one of the major rice diseases. It has both a protective and curative
    action against the fungus attack. There is some evidence that the
    compound interferes with chitin formation in the fungal cell wall, a
    process which dose not occur in higher plants. This mode of action may
    therefore explain the selective action of the fungicide.

         The compound is also effective against a few other fungus
    diseases of rice, e.g. ear blight caused by Cochliobolus
    miyabeanus, Hormodendrum and against some insect pests, e.g. leaf
    hoppers.

    USE PATTERN

         Edifenphos is authorised or recommended and sold in various
    countries in Asia including Japan, in Central and South America and in
    Europe, e.g. Italy. The product is marketed as emulsifiable
    concentrates with various concentrations of edifenphos and as a dust.
    In most countries two to four treatments are applied at dosage rates
    of 300-800 g a.i./ha, with a pre-harvest interval of 21 days. The
    recommended preharvest interval in Italy is 60 days.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Residue data are available from supervised trials carried out in
    Japan and in some South American countries, namely Colombia, Mexico,
    Peru and El Salvador. A summary of these data is given in Table 5.

    FATE OF RESIDUES

         The metabolic and other reactions of edifenphos exposed to
    plants, animals, fungi, soil, light and water are shown in Figures
    1(a) and 1(b) taken from Umeda (1972) with some modifications.


    
    TABLE 5. Residues of edifenphos (parent compound) in rice resulting from supervised trials

                                                                                                                                               

                                      Application                                  Residues in mg/kg, at intervals (days) after application
    Crop       Country       Year           rate       Formulation                                                                             
                                      no    kg ai./ha                   7          13/16      20/23      25/27      30/34      36/39      40/42
                                                                                                                                               

    Rice       Japan         1967     2     0.36       EC 30%                                 <0.02
    hulled                            3     0.36       EC 30%                      <0.02
                                      4     0.36       EC 30%           <0.02
                                      3     0.6        dust 1.5%                   <0.02
                                      4     0.6        dust 1.5%        <0.02

                             1969     4     0.6        dust 1.5%                              <0.01
                                      5     0.6        dust 1.5%                   0.015
                                      3     0.6        dust 1.5%                              <0.01
                                      4     0.6        dust 1.5%                   < 0.01
                                      3     0.75       dust 1.5%                              <0.01
                                      4     0.75       dust 1.5%                   0.01

    Rice       Japan         1969     2     0.36       EC 30%                                                                             <0.01
    polished                          3     0.45       dust 1.5%                              <0.01
                                      4     0.75       dust 1.5%                                                               <0.01
                                      4     0.75       dust 1.5%                                         <0.01
                                      3     0.75       dust 1.5%                                                    <0.01
                                      3     0.75       dust 1.5%                                                    <0.01
                                      3     0.75       dust 2.5%                              0.01
                                      3     0.5        dust 2.5%                              0.01
    Rice
    (in husk   Peru          1969     2     0.5        EC                                                                                 0.07
    (straw                                                                                                                                0.15

    (in husk   Colombia      1969     2     0.5        EC                          0.1
    (straw                                                                         0.25

    (in husk   El Salvador   1969     2     0.5        EC                                     0.45
    (straw                                                                                    1.4

    TABLE 5. (Cont'd.)

                                                                                                                                               

                                      Application                                  Residues in mg/kg, at intervals (days) after application
    Crop       Country       Year           rate       Formulation                                                                             
                                      no    kg ai./ha                   7          13/16      20/23      25/27      30/34      36/39      40/42
                                                                                                                                               

    (in husk   Mexico        1969     2     0.5        EC                                                           0.2
    (straw                                                                                                          0.05
                                                                        15/20      21/25      26/30      31/35      36/40      41/50      51/60
                                                                                                                                               
    Rice       Japan         1970     2     0.45       EC                                                           <0.01      <0.01
    hulled                            4     0.45       EC                                                           <0.01
                                      2     0.2-0.45   EC                                     <0.01                            <0.01
                                      4     0.2-0.45   EC                                     <0.01
                                      2     0.45                                   <0.01                 <0.01
                                      4     0.45                                   <0.01

    (hulled                  1973     2     0.3-0.45   EC                                                                      0.02
    (straw                                                                                                                     0.62

    (hulled                  1973     3     0.3-0.45   EC                                                           0.01
    (straw                                                                                                          0.32

    hulled                   1970     2     0.6        dust                                                                    0.03       0.03
                                      4     0.6        dust                                                                    0.01
                             1971     3     0.75       dust             0.03                  0.01
                                      4     0.75       dust             0.02

                             1970     2     0.6-0.8    dust                                                         <0.01      0.01
                                      4     0.6-0.8    dust                                                         <0.01

                             1970     2     0.6-0.8    dust                                                         <0.01      <0.01
                                      4     0.6-0.8    dust                                                         <0.01

    Rice       Japan         1970     2     0.6        dust                        0.01                                                   0.01
    hulled                            4     0.6        dust                        0.02
                                      2     1          dust                                              0.01       0.01
                                      4     1          dust                                              0.01

    TABLE 5. (Cont'd.)

                                                                                                                                               
                                      Application                                  Residues in mg/kg, at intervals (days) after application
    Crop       Country       Year           rate       Formulation                                                                             
                                      no    kg ai./ha                   15/20      21/25      26/30      31/35      36/40      41/50      51/60
                                                                                                                                               

    (hulled                  1972     2                                                                             <0.01                 <0.01
    (straw                                                                                                          0.48                  0.26

    (hulled                  1972     3     1          dust                                              <0.01
    (straw                                                                                               0.93

    (hulled                  1972     2     1          dust                                                         <0.01
    (straw                                                                                                          0.18

    (hulled                           3     1          dust                                   0.02                             <0.01
    (straw                                                                                    3.81                             0.24

    (hulled                  1973     2     1          dust                                                                    <0.01
    (straw                                                                                                                     0.67

    (hulled                  1973     3     1          dust                                                         0.01
    (straw                                                                                                          0.74

    (hulled                  1973     2     1          dust                                                                    <0.01
    (straw                                                                                                                     0.72
    (hulled                           3     1          dust                                                         0.1
    straw)                                                                                                          2.12

    Rice
    (hulled    Japan         1972     2     1          dust                                                                    0.01
    (straw                                                                                                                     2.31
    (hulled
    (straw                            3     1          dust                                                         0.02
                                                                                                                    5.31

    (hulled                           3     1          dust                                                                    <0.01
    (straw                                                                                                                     3.79
                                                                                                                                               
    

    In plants

         Extensive data are available on absorption, translocation,
    accumulation and metabolism in the rice plant. (Ishizuka et al 1973,
    1974; Nitokuno 1971; Takase et al 1973; Tomizawa et al 1972; Uesugi et
    al 1972, Ueyama et al 1973, Umeda et al 1972).

    Absorption and translocation

         Izhizuka et al (1973, 1974) found that when edifenphos was
    sprayed on rice leaves 60% was lost from the surface in five days and
    75% in ten days. It was shown that about 70% of the edifenphos applied
    had penetrated the leaf tissue within two hours.

         Only small quantities were translocated from the site of
    application, and translocation from roots to shoots was also slight.
    Hence the loss of edifenphos was mainly from the leaf surfaces by
    volatization and decomposition, rather than by metabolism inside the
    plant.

         When the flag leaf of a rice plant was painted with 32P-labelled
    edifenphos some translocation of the chemical to the lower part of the
    leaf and to the ears was observed (Ishizuka et al 1973, 1974; Nitokuno
    1971; Umeda 1972). Since no complex of edifenphos with
    photosynthesized plant products was found, it appears that edifenphos
    is translocated without prior metabolism. The concentration of
    edifenphos in plant parts is in the order: leaves and stems >> husks
    >> hulled rice.

    Metabolism

         Takase et al (1973) studied the metabolic fate of edifenphos
    after spraying rice plants at various growth stages. The
    hexane-soluble components, which were analysed throughout the
    experimental period, consisted, mainly of edifenphos parent compound
    (83.2-89.3% of the radioactivity in the fraction). The major
    components in the water soluble fraction were identified as O-ethyl
    S-phenyl phosphorothioate (metabolite VII, Figure 1(a)) and
    SS-diphenyl phosphorodithioate, (III) each representing about 30% of
    the total 32p in the water-soluble fraction. With the lapse of time,
    ethyl phosphate (XV) was formed.

         Ueyama (1973) detected nine metabolites after applying
    35S-labelled edifenphos to rice leaves. Three were identified as
    metabolites IV, VIII and XII (Figures 1(a) and 1(b)). It is probable
    that the formation of VIII and XII involved the exchange of phenylthio
    and ethoxy radicals between molecules of edifenphos.

         A high proportion of S-phenyl phosphorothioate (V) and small
    amounts of O-ethyl S-phenyl phosphorothioate (VII) were found among
    the water-soluble metabolites. Results are shown in Table 6.


    
    TABLE 6. Toluene extracted metabolites in and on rice plants treated with 35S-edifenphos (after Ueyama)
                                                                                                                                     

                                                 Metabolites, 35S counts expressed as edifenphos equivalents, mg/kg
    Growth stage      Part of    Period after
    at application    Plant      application               Identified*                             Not-identified      
                                                 I         IV        VIII      XII       A         B         C         E         F
                                                                                                                                     

    Tillering         leaf       1 hour          35        4.3       2.9       1.1       0.72                                    1
                      blade

                                 6 hour          18        1.1       1.2       0.59      0.02                                    0.33
                                 1 day           20        2.8       1.1       1.4       0.05                                    0.46
                                 3 day           17        1.1       0.73      0.16      0.26                                    1.2
                                 7 day           1.2       0.26      1.5       0.13      0.07      trace     trace
                                 15 day          0.79      0.22      -         0.18      <0.01               0.01

    Tillering         leaf       1 hour          0.73      trace     3.3       -         trace
                      sheath     6 hour          0.84      trace     1.0       trace     trace
                                 1 day           0.79      trace     0.33      0.33      trace
                                 3 day           0.65      trace     0.36      -         0.02
                                 7 day           0.04      0.01      0.05      0.04      <0.01                                   trace
                                 15 day          trace     -         trace

    Heading           leaf       1 hour          42        10        1.2       trace     0.27                0.05      0.05      0.33
                      blade      6 hour          31        8.2       3.2       trace     0.27                0.13      0.13      0.89

                                 1 day           9.8       2.5       1.1       0.12      0.06                0.01      0.03      0.15

                                 3 day           7.8       1.6       0.55      trace     0.03                0.02      0.12      0.29

                                 7 day           3.2       0.19      -                   0.02                <0.01     0.03      0.37

                                 15 day          0.40      0.38      -                   0.18                0.24                0.30
                                                                                                                                     

    * For identities of numbered metabolites, see Figures 1(a) and 1(b) (I = parent compound)

    
    In animals

         Pither and Gronberg (1975) administered 0.12 mg/kg of edifenphos
    as a single oral dose and as a daily dose for 5 days to dairy cows.
    Results are described above ("Evaluation for acceptable daily intake -
    - Absorption, distribution and excretion").

         Strankowski et al (1976) identified metabolites of 14C ring-
    labelled edifenphos in the muscle, liver, kidney, fat, milk and urine
    of dairy cows. Methyl phenyl sulfone (XI, Figure 1(b)) was the
    principal metabolite in both milk and tissues representing 95% of the
    organo-soluble radio-carbon in the milk and from 70% (kidney) to 99%
    in the tissues. Small amounts of metabolites Xa, XIa, XIb, together
    with other minor metabolites were also found (Table 7).

    TABLE 7. Distribution of edifenphos and its metabolites in the
             tissues and milk of dairy cows (Strankowski, 1976).

               Residue, % of total radioactivity in organic extract,
               as metabolite no.*
                                                                   

    Tissue     I      IX     X      Xa     XI     XIa    Xlb    XIIa
                                                                   

    muscle     -      -      -      -      85     2      -      -

    fat        -      1      -      -      99     -      -      -

    liver      <1     <1     <1     4      84     <1     <1     <1

    kidney     <1     -      <1     2      70     2      9      <1

    milk       -      -      1      3      93     1      1      -
                                                                   

    * For identities of numbered metabolites see Figure 1(b),
      (I = edifenphos).


         Hermann and Gronberg (1976) administered 3 mg/kg 14C-edifenphos
    orally to laying hens. After 96 hours 76% of the activity had been
    excreted. Methyl phenyl sulfone (XI) was the only metabolite detected
    in all the tissues and in egg, but a second metabolite was found in
    kidneys and was identified as either IX, XII or XIII (Figure 1(b)).
    The total radiocarbon residues at intervals of 6-72 hours after dosing
    are given in Table 8.

    TABLE 8. Total radiocarbon from 14C-edifenphos in tissues of
             laying hens

                             Radioactivity expressed as edifenphos,
                             mg/kg*, after interval, hours
                                                                      

    Tissue                   6           24          48           72
                                                                      

    Muscle (breast)          0.66        0.73        0.57         0.21

    Muscle (thigh)           0.69        0.75        0.59         0.19

    Skin                     0.79        0.74        0.58         0.21

    Fat                      0.97        1.00        0.80         0.30

    Liver                    1.72        1.45        1.17         0.51

    Kidney                   1.83        1.29        0.96         0.39

    Gizzard                  0.72        0.76        0.56         0.21

    Heart                    0.82        0.89        0.66         0.26
                                                                      

    * Values are mean figures of single analyses of tissues from each of
    four hens.


         Ueyama and Takas (1975) determined the residue levels in goat
    milk after administration of edifenphos at the rate of 1 mg/kg/day for
    ten consecutive days. No edifenphos could be detected in the milk.
    After a single oral dose of 10 mg/kg, 0.0006-0.0008 mg/kg in
    edifenphos could be detected within 24 hours.

         Lamb and Roney (1976a) exposed crayfish to 14C-edifenphos
    concentrations of 10 µg/l (i.e. 10-8) for 14 days and determined 14C
    residues during the exposure period and a 28 day withdrawal period.
    14C residues, expressed as edifenphos, accumulated to a maximum level
    of 0.2 mg/kg. About half of the accumulated 14C was lost within 7
    days of withdrawal.

         The same authors (1976b) exposed Channel catfish (Ictalurus
    punctatus) continuously for 28 days to 10-12 µg/l of 14C
    ring-labelled edifenphos. 14C residues accumulated to a maximum of 1.2
    mg/kg edifenphos equivalents in ten days, representing an accumulation
    factor of 104-117. The non-edible portions (head, viscera and scales)
    contained 75% of the extractable residues. The acetonitrile fraction
    (81% of the total extractable residue) consisted of edifenphos 44%,

    metabolite VI (Figure 1(a)) 10%, VII 19% and VIII 27%. During the
    withdrawal period about 50% of the accumulated 14C residues were
    excreted in five hours and about 85% within four days.

    In fungi

         Uesugi and Tomizawa (1971) studied the metabolism of edifenphos
    in mycelia of the rice blast (Pericularia oryzae) with 32P-, 35S-
    and non-labelled edifenphos. The main metabolic pathway consists in
    the hydrolysis of one P-S linkage, followed by that of the other P-S
    or the ethyl ester bond, finally yielding phosphoric acid. Another
    hydroxylated intermediate, metabolite II (Figure 1(a)) was also found.

         No significant differences in route or rate of metabolism were
    found between susceptible and resistant strains of the fungus.

    In storage, processing and cooking

         The residue is mainly located on the rice husk, hence during
    milling and polishing most of the residue is removed. Takase et al
    (1973) estimated the distribution of 32P-labelled edifenphos in
    milling fractions (Table 9).

         The residues at harvest in the husks consisted largely of
    edifenphos metabolites, although small quantities of the parent
    compound were found (Table 10).

         Residues of edifenphos from foliar application (0.63 kg/ha, 2
    applications) were found primarily in straw and seed hulls 37 days
    after the second application. The residue in the hulls ranged from
    0.02-0.29 mg/kg. Trace amounts were found in the bran, but no residue
    was detectable in the milled and polished rice (Chemagro, 1971).

    On exposure to light

         A marked degradation of 35S-edifenphos by UV light was found on
    irradation in aqueous or hexane solution or as a thin film. In hexane,
    the formation of water-soluble degradation products was low. The
    metabolites III, VIII, XV and XVI were identified (Murai et al, 1976).

    In water and soil

         Shaw (1976b) and Shaw and Murphy (1976) studied the hydrolysis of
    14C ring-labelled edifenphos at concentrations of 1 and 10 mg/kg in
    aqueous solutions buffered at pH 3, 6 and 9 and at temperatures of 25,
    35 and 45 degrees C. The hydrolysis followed first order kinetics and
    its rate increased with temperature and with increasing pH. The same
    major hydrolysis products were formed under all conditions, namely
    compounds VII and XII (Figure 1(a) and (b)) with traces of II, III,
    IV, VI, VIII and XIV.


    
    TABLE 9. Distribution of 32P-labelled edifenphos and its metabolites in milling fractions of rice

                                                                                                                               

                                  Radioactivity (32P) expressed as edifenphos, mg,/kg
                                                                                                                               

    Number of treatments                  1                        2                        3                        1

    Pre-harvest interval,days            13                        1                       24                        8
                                                                                                                               

    Milling fraction              Hexane-    Water-        Hexane-    Water-        Hexane-    Water-        Hexane-    Water-
                                  soluble    soluble       soluble    soluble       soluble    soluble       soluble    soluble
                                                                                                                               

    husks                         0.11       0.04          0.17       0.12          0.28       0.14          2.13       0.34

    hulled rice                   trace      0.02          trace      0.01          0.06       0.03          0.31       0.05

    polished rice                 0.01       0.01          0.01       0.01          trace      trace         trace      -

                                                                                                                               
    

    TABLE 10. Distribution of radio-activity from 32P-edifenphos in rice
              husk.

                                                                        

                                  Residue, % of total radio-activity
                                                                        

                                  3 applications,      1 application,
    Compound*                     latest 24 days       8 day pre-harvest
                                  pre-harvest          harvest
                                                                        

    Unknown

    Water-soluble metabolite      9.6                  13.4

      III                         10.9                 19.4

      VII                         37.6                 29.1

      XV, XVI                     41.8                 28.1
                                                                        

    * For identities of metabolites, see figures 1(a) and 1(b).
    
         Shaw (1976a) incubated 14C ring-labelled edifenphos in pond
    water (pH 8.3) containing soil for 62 days after irradiation with UV
    light and sunlight, with alternating 12-hour periods of light and
    darkness. In these conditions the half-life of edifenphos was 16.8
    hours. The main products were compounds VII and XIV and one or more of
    compounds IX, XII and XIII. Traces of II, III, IV, X and XI were also
    found. These products were found in both the water and the bottom
    sludge.

         Flint and Shaw (1975) estimated the half-life of edifenphos in an
    outdoor simulated pond system at 20°C. Under these conditions the
    half-life was 29 hours in the water and about 60 hours in the bottom
    sludge.

         Edifenphos is almost immobile when applied to soil. Leaching and
    soil adsorption were inversely correlated and the latter was
    proportional to the soil organic matter content.

         When columns of sand and sandy loam soil containing edifenphos at
    a level equivalent to 0.5 kg/ha were eluted with water at a rate
    representing 200 mm of irrigation in two days, no edifenphos was found
    in the eluate (Bayer, 1974 a, b). The half-life of edifenphos was
    about 23 days in the sandy loam (pH 5.2, organic carbon 0.57% and
    particles < 20 µ 19.5%), but only 6-8 days in the sand (pH 6.8,
    organic bound carbon 2.50% and particles < 20 µ 10.1%). In further
    laboratory experiments simulating the flooded soil conditions
    associated with rice growing (Nitokuno, 1972), edifenphos was degraded
    rapidly during the first 24 hours. The half-life was about 19 hours in
    a clay soil and 2 1/2 days in a silt loam. Subsequent degradation was
    slower in both soil types.

         Tomizama (1975) reports similar results obtained in a laboratory
    degradation experiment. Under the anaerobic conditions of the
    experiment about half the edifenphos was degraded during the first 3 -
    5 days. From the sixth day onwards the rate of degradation was
    considerably slower.

         Studies by McNamara (1976) and McNamara and Close (1976) were
    made on the persistence and degradation of 14C ring-labelled
    edifenphos in loam and silt loam under aerobic conditions and in loam
    under anaerobic conditions. The half-lives were 1 day in the aerobic
    silt loam and 3 days in loam under both aerobic and anaerobic
    conditions. The organo-soluble radioactivity decreased to 10-20% of
    that applied within 21 days in all samples. In aerobic soils the
    decrease was mainly due to volatilization and binding to the soil. In
    aerobic loam about 20% of the total radioactivity was lost by
    volatilization in 14 days, and in silt loam 35% in 21 days.

         In aerobic soil the main organo-soluble radioactive residues were
    edifenphos, its initial hydrolytic products III and VII, and
    derivatives of thiophenol (XIII): diphenyl disulphide XII,
    benzenesulphonic acid XIV, methyl phenyl sulphoxide X and methyl
    phenyl sulphone XI. The two major terminal metabolites were X and XI.

         In anaerobic loam the metabolic pathway proceeded via thiophenol
    (XIII) to diphenyl disulphide XII, and benzenesulphonic acid XIV. Only
    small amounts of methylated products were found.

    In a model ecosystem

         Edifenphos was fairly rapidly degraded in a model ecosystem, the
    half-life being 60 hours. The main metabolic features were the
    conversion of edifenphos to compounds IV and VII and the rapid
    oxidation of the diphenyl disulphide released from these compounds. It
    was found that sulphur atoms derived from the diphenyl sulphide were
    incorporated into sulphuric acid and then into cell constituents,
    (Tomizawa and Kazano, 1975).

    METHODS OF RESIDUE ANALYSIS

         Vogeler (1968) developed a gas-chromatographic method for the
    determination of edifenphos residues in rice, using an alkali
    thermionic or flame photometric detector. The rice sample is macerated
    and extracted with acetone and the filtrate evaporated to dryness. The
    residue is cleaned up by acetonitrile - petroleum ether partition and
    by chromatography on a Florisil column. Recoveries from control
    samples fortified with 0.05-1 mg/kg ranged from 70-80%. The limit of
    determination is about 0.05 mg/kg. Thornton (1971) checked several
    organophosphorus compounds which are authorised or recommended for use
    on rice for interference with Vogeler's method. They were tested at
    levels equivalent to the highest recommended dose rate on rice in the
    USA. The compounds tested were dichlorvos, fensulfothion, fenthion,
    malathion, naled, parathion, parathion-methyl, phorate and TEPP. None
    showed any interference.

         Takase et al (1971) described a modified gaschromatographic
    method for the analysis of edifenphos in rice. Extraction is with
    acetonitrile and the residue is cleaned up by partitioning into
    acetonitrile and n-hexane followed by TLC on alumina. The residue is
    determined with a flame photometric detector. Recoveries of added
    levels of 0.1 to 0.2 mg/kg ranged from 96-102%. The limit of
    determination is 0.005 mg/kg or lower.

         Stanley (1972) adapted and modified the Vogeler method to
    determine edifenphos residues in milk and cattle tissues. For milk the
    method involves initial blending with acetone, followed by separation
    of edifenphos from the aqueous solution by partitioning into
    chloroform. Clean-up is by partition between Skellysolve B and
    acetonitrile and chromatography on a Florisil column. Animal tissues
    are extracted with acetonitrile, partitioned with Skellysolve B, and
    cleaned up on a Florisil column. The edifenphos parent compound is
    determined by gas chromatography with a thermionic detector. The limit
    of determination of edifenphos in milk is 0.002 mg/kg and in cattle
    tissues 0.02 mg/kg.

         Recoveries from milk spiked with 0.005-0.5 mg/kg ranged from 77
    to 110%, and in various cattle tissues spiked with 0.05-0.1 mg/kg from
    82 to 118%.

         Sandie and Gronberg (1975) adapted the Stanley (1972) method for
    the analysis of edifenphos in poultry and eggs. For poultry tissues
    the method involves extraction, partition between acetonitrile and
    hexane, and gas chromatography with a thermionic detector. Eggs are
 

    extracted with acetone, and clean-up is by successive aqueous
    acetone-chloroform and acetonitrile - hexane partitions, followed by
    silica gel chromatography. Recoveries were 84-107% from tissues at
    levels of 0.05 and 0.1 mg/kg and 86-97% from eggs at 0.01 mg/kg. The
    limits of determination were 0.01 mg/kg in poultry tissues and
    0.001 mg/kg in eggs.

         Minor (1976) examined possible interferences by other
    organophosphorus pesticides in the determination of edifenphos in
    cattle and poultry tissues and eggs by the methods of Sandie and
    Gronberg (1975) and Stanley (1972). He found that edifenphos could be
    adequately separated from all the 25 organophosphorus pesticides with
    a USA tolerance in milk if the Stanley Florisil column and the Sandie
    and Gronberg silica gel column were used successively in the clean-up
    procedure.

    NATIONAL TOLERANCES

         National tolerances reported to the meeting are given in Table
    11. They refer to the parent compound only.

    TABLE 11. National tolerances reported to the Meeting

                                                                    

    Country        Commodity         Tolerance,      Recommended
                                     mg/kg           pre-harvest
                                                     interval, days
                                                                    

    Italy          rice, hulled      0.05            60

    Japan          rice, hulled      0.03            21

    Mexico         rice, hulled                      20

    U.S.A.         rice, hulled      0.1*
                   rice, hulls       0.3
                                                                    

    * temporary tolerances valid until May 1977


    APPRAISAL

         Edifenphos is an organophosphorus compound with a rather
    selective action against the rice blast caused by Piricularia
    oryzae, one of the major rice diseases, against which it shows both

    a protective and curative action. There is some evidence that the
    compound interferes with the formation of chitin in the fungus
    cell-wall, a process which does not occur in higher plants. This may
    therefore explain the selective action of the fungicide. Edifenphos is
    also effective against a few other rice diseases and some insect
    pests, e.g. leafhoppers.

         The pesticide is used on an extensive scale on rice, as EC
    formulations and as a dust, in Asian countries including Japan, in
    Central and South America and in some mediterranean countries, e.g.
    Italy. In most countries 2 - 4 treatments are applied at 300 - 800 g
    ai/ha, generally with a pre-harvest interval of 21 days.

         Extensive data were obtained on the fate of edifenphos residues
    in soil, water, rice plants and livestock animals such as cattle,
    goats and poultry. Degradation pathways in plants, soil and animals
    are similar, although there are quantative differences.

         In a study with 35S labelled edifenphos on rice, nine
    metabolites were found in a toluene extract from leaves: the three
    main products were OO-diethyl S-phenyl phosphorothioate, SSS-triphenyl
    phosphorotrithioate and diphenyl disulphide. A large proportion of
    S-phenyl phosphorodithioate and small amounts of O-ethyl S-phenyl
    phosphorothioate were found as water-soluble metabolites. In a study
    with 32p-labelled edifenphos, SS-diphenyl phosphorodithioate was
    identified as another major water-soluble metabolite.

         In a cattle feeding study with ring-labelled 14C-edifenphos it
    was shown that methyl phenyl sulphone was the principle metabolite
    both in milk and in animal tissues such as muscle, liver and kidney:
    in milk it amounted to about 93% of the radioactivity extracted. The
    parent compound, together with m- and p-hydroxyphenyl methyl sulphone
    and p-hydroxyphenyl methyl sulphoxide were found, but only in small
    amounts.

         After administering a single dose of 14C-labelled edifenphos
    orally to laying hens (3 mg/kg), 76% of the radioactivity was excreted
    in 96 hours. A single metabolite, methyl phenyl sulphone, was
    identified in all tissues and eggs.

         More than half of the residue from spraying edifenphos onto rice
    leaves was dissipated in five days. Only small quantities were
    translocated from the site of application. Translocation of edifenphos
    from the roots to the shoots was also only slight.

         Residues in rice at harvest are rather low. After the recommended
    pre-harvest interval of 21 days, the residues of edifenphos and its
    main metabolites in hulled rice following an application of
    32P-labelled edifenphos to rice plants were of the order of 0.03 and
    0.06 mg/kg edifenphos equivalents of water-soluble and hexane-soluble
    metabolites respectively. Only traces were found in polished rice. In
    the rice husks the residues were about 0.15 and 0.3 mg/kg edifenphos
    equivalents of water-soluble and hexane-soluble 32P respectively.

         Gas-chromatographic methods of analysis with alkali flame or
    flame photometric detection are available. Recoveries in rice were
    70-80% and the limit of determination ranged from 0.005 to 0.05 mg/kg
    edifenphos parent compound. Nearly all organophosphorus pesticides
    registered and/or recommended for use on rice were checked for
    interference. None of the compounds interfered when tested at levels
    that would be reached by treatments at the highest recommended
    dosages, provided appropriate clean-up procedures were used. These
    methods should be suitable for or adaptable to regulatory purposes.

         Some of the GLC methods mentioned are suitable for the analysis
    of edifenphos residues in cattle tissues, milk, poultry and eggs. The
    limit of determination is 0.01 - 0.02 mg/kg parent compound.
    Recoveries at levels of 0.01 - 0.1 mg/kg ranged from about 80 to 100%.

    RECOMMENDATIONS

         The following temporary maximum residue limits are recommended.
    They refer to the parent compound edifenphos only.

    Commodity                 Limit, mg/kg

    Rice (in husk)              0.2

    Rice (hulled)               0.05

    Rice (polished)             0.01*

    FURTHER WORK OR INFORMATION

    Required (by 1979)

    1.   Further studies to examine the hepatic involvement observed in
         several animal species.

    Desirable

    1.   Observations in man (relative to occupational exposure).

    2.   More information on residues of edifenphos and its main
         metabolites on rice in husk at harvest.

    3.   A method of residue analysis suitable for edifenphos together
         with its main metabolites.

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    1971                Phosphorodithiolate (Hinosan) by Mycelial Cells of
                        Pyricularia Oryzae. Agric. Boil. Chem. 35
                        (6):941-949.

    Uesugi, Y. Tomizawa, C. and Murai, T. Degradation of
    1972                Organophosphorus Fungicides. Environ. Toxicol.
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    Ueyama, I., Uesugi, Y., Tomizawa, C. and Murai, T. Metabolic
    1973                Fate of O-Ethyl S,S-Diphenyl Phosphorodithiolate
                        (Hinosan) in Rice Plant. Agr. Biol. Chem.
                        37(7):1543-1551.

    Ueyama, I. and Takase, I. Metabolic Behaviour of O-Ethyl
    1975                S,S-Diphenyl Phosphorodithiolate (edifenphos) in
                        Female Goat. Agr. Biol. Chem. 39(9):1719-1727.

    Ueyama, I., Takase, I. and Tomizawa, C. The Metabolism of Edifenphos
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                        1046 from Nithon Tokushu Noyaku Seizo Co. .td.
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                        Sciences, submitted to the WHO by Bayer A.G.

    Umeda, Y. Anti-Blast Fungicide "Hinosan" and its Biological
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                        Pest. Inform. No. 10, 85-88.

    Umeda, Y. Hinosan, a Fungicide for Control of Rice Blast.
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    Urwin, C. and Newman, A.J. Pathology Report of SRA7847/3
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                        from Huntingdon Research Centre, submitted to the
                        WHO by Bayer A.G.

    Vogeler, K. Caschromatographische Methods zur Bestimmung von
    1968                Hinosan-Rückständen in Reis. Pflanzenschutz
                        Nachr., Bayer 21 (3):321-325.

    Yatomi, A. Mutagenicity Test on Bacteria. Unpublished report
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                        WHO by Bayer A.G.
    


    See Also:
       Toxicological Abbreviations
       Edifenphos (Pesticide residues in food: 1979 evaluations)
       Edifenphos (Pesticide residues in food: 1981 evaluations)