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    LEPTOPHOS         JMPR 1975

    Explanation

         Leptophos was evaluated with regard to data on residues in food
    by the 1974 Joint Meeting (FAO/WHO, 1975). Arising from the
    requirements of that Meeting for further information, data were
    obtained on residues from supervised trials in Canada, Japan, India
    and New Zealand on a large number of crops including fruit, small
    grains, rice, maize, sugar beet, potatoes, sunflower seed, rape seed,
    flax seed, tea, tobacco and some vegetable crops. Such information was
    required by the 1974 Joint Meeting from countries other than the
    United States of America.

         Some information became available on residues in waste of
    agricultural crops which may be used as animal feed e.g. sugar beet
    leaves, straw and chaff of cereal crops, including rice and maize
    fodder.

         Additional data became available on the fate of leptophos
    residues in apples, cabbage, tobacco and soil from studies with 14C
    phenyl-and 14C-phenoxy labelled leptophos. Data on the fate of
    leptophos residues during processing of cotton seed and sunflower seed
    were also provided: some of the by-products of this processing may be
    used in animal feed. New data were obtained from model studies with
    14C leptophos in a simple food chain in which water, Daphnia magna
    and the common bluegill, were included.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    Biochemical Aspects

    Absorption, distribution and excretion

         Leptophos is rapidly absorbed and eliminated from the body
    following acute oral administration (Kennedy et al., 1970). Within 96
    hours following an oral dose of 0.8 mg/kg, rats were found to have
    eliminated ring (probably phenyl) labelled leptophos in the urine
    (80-88% of the dose) and faeces (11-12% of the dose). Small quantities
    were noted in several tissues. Within 24 hours 75 to 81% of the
    recovered radioactivity (ranging from 98-103% of the dose) was
    observed in urine. In two further studies on the excretion of
    leptophos following acute oral dosing, it was again observed that
    there was rapid elimination via urine and faeces (Kennedy and
    Keplinger, 1971, 1972). Using phenoxy-labelled leptophos results were
    extremely variable. Urinary excretion in both males and females varied
    from 8-85% of the recovered dose while in the faeces a range of 8-84%
    of the excreted dose was noted within 96 hours. These studies using a
    total of four rats of each sex showed extremes in biological variation
    with some animals excreting more in urine than faeces and others

    reversing the trend. In one instance a possible sex difference in
    excretion was suggested. In all studies, rapid excretion was observed
    with the major quantity eliminated within 24 hours. Tissue levels
    contained little radioactivity after 96 hours. Skin and fat, where
    analysed, showed levels of 1% of an acutely administered oral dose. In
    adipose tissue, the major residue was leptophos with traces of the
    phenol observed (Tarka, 1973).

         In studies with rats administered leptophos as a single oral dose
    ranging from 0.2 to 0.5 mg/kg or in five consecutive doses, recovery
    of all radio-labelled material was rapid; within five days of the
    final dose with a urine:faeces ratio of 80:20. Tissue concentrations
    at five days following the last dose (in the multiple dosed animals)
    were very low with the highest being liver (<0.25% of the dose
    administered). No attempt was made to characterize the tissue
    metabolites (Badie and Whitacre, 1975).

         In mice, rapid elimination was again noted following oral
    intubation. Differences in elimination were noted with different
    14C-positional isomers. The phenyl-label elimination pattern was
    notably slower than the phenoxy-labelled elimination. In all cases
    rapid elimination was observed predominantly in the urine (90-96% of
    the recovered dose) with minor mounts noted in faeces (Holmstead et
    al., 1973).

    Biotransformation

         Characterization of radio-labelled components in rat and mouse
    urine and tissues was performed in conjunction with several
    14C-distribution studies (Kennedy et al., 1970a; Kennedy and
    Keplinger, 1971a; Tarka, 1973; Holmstead et al., 1973; Badie and
    Whitacre, 1975). In three studies, no intact leptophos was observed in
    urine which was known to contain considerable radioactivity. In
    contrast, leptophos was observed in faeces. Leptophos is apparently
    metabolized and excreted in urine as several components, the structure
    of several of which were suggested. In mice following oral
    administration of 25-50 mg/kg, small (1-2%) quantities of leptophos
    and the oxon were observed in faeces. Other components in urine
    included: O-methyl phenyl phosphonate (a major component in rat),
    O-methyl phenyl phosphonothioic acid (a major component in mice);
    leptophos phenol, and phenyl phosphonic acid. The major rat metabolite
    in urine differs from the major mouse metabolite in urine possibly
    reflecting species differences in metabolism. Small quantities of
    materials in urine (designated unknown) were found to chromatograph
    with known standards of O-(4-bromo-2, 5-dichlorophenyl)
    phenyl-phosphonic acid. Impurities found in leptophos, including the
    desbromo derivative, the desbromo monochloro derivative and the
    S-methyl isomeride were not reported in these studies.

         Studies in plants indicated that leptophos was slowly absorbed
    following a foliar treatment with the major quantity found to remain
    on the leaf surface (Holmstead et al., 1973). Studies with several
    leaf types (bean - lettuce) showed that residues diminished rapidly on
    both types of surfaces (Schroeder, 1971). The primary mechanism by
    which leptophos was lost was presumed to be by volatilization.
    Qualitatively, leptophos was metabolized to products similar to those
    found with the mouse. Phenyl phosphonate derivatives were also
    recovered from plant surfaces,

         In vitro studies using artificial sources of sunlight to
    degrade leptophos in acetone solution resulted in rapid degradation to
    a desbromo derivative followed by dehalagenation to a
    desbromo-deschloro leptophos which was reported to rearrange to a
    stable aryl ring structure (Schwemmer, 1971). As a solid, leptophos
    degrades slowly by photolysis in sunlight (March and Fukuto, 1975).
    Several products which were isolated include: desbromo leptophos;
    leptophos oxon; phenyl phosphonic acids, chlorinated phenol and traces
    of the S-methyl isomeride (although this latter and possible other
    products may have originated as impurities in the technical material
    used). A flow diagram of the suggested metabolic scheme is seen in
    Fig. 1.

    Effects on enzymes and other biochemical parameters

         Leptophos is a weak anticholinesterase agent as demonstrated by
    several short-term studies although it is metabolized to the oxon
    which is a relatively potent inhibitor. Leptophos oxon has also been
    demonstrated to be an inhibitor of the mipafox-sensitive esterase
    found in hen brain that is sensitive to inhibition by compounds known
    to induce delayed neurotoxicity (Johnson, 1975). The bimolecular rate
    constant was found to be 106 and 1  105 Mole-1 for brain and RBC
    cholinesterase respectively. Brain cholinesterase was inhibited by
    leptophos and leptophos oxon. Following 30 minute preincubation, I50
    values for both compounds were 2  10-4M. and 2  10-7M. respectively
    calculated. I50 values for the desphenoxy derivative and the phenol
    were <10-3M. (Hassan, 1975).

    Bioaccumulation

         The biological fate of leptophos was studied using a model
    terrestrial-aquatic ecosystem (Sanborn and Metcalf, 1975). In this
    model environment, leptophos was observed to bioaccumulate in higher
    animal species. In comparison with several other organophosphates,
    leptophos was the most stable and showed a tendency towards
    persistence and bioaccumulation.

    FIGURE 1

         In further studies of the biomagnification of leptophos, it was
    observed that an apparent equilibrium was established in fish exposed
    to leptophos for periods of time. After about one week of exposure
    during which time leptophos accumulates there is no additional
    build-up in tissues. These data also suggest that ingestion of
    leptophos - contaminated invertebrates by fish does not increase the
    fish residue suggesting that biomagnification is not a significant
    factor (Sleight and Macek, 1973; Johnson, 1973).

    TOXICOLOGICAL STUDIES

    Special studies on the metabolites

    Leptophos oxon

    Rat

         Groups of rats (25 males and 25 females/group) were subdivided
    into two categories: individually housed (10 rats of each sex per
    group) and group housed (15 rats of each sex per group). These groups
    were fed a control diet and one containing leptophos oxon for 28 days.
    The leptophos oxon diet was increased at weekly intervals from 200 ppm
    to 300 ppm to 500 ppm and finally to 800 ppm. Growth (as evidenced by
    body weight) was reduced in the latter stages of the test in females
    while food consumption was normal. Spleen weight in males and females
    was reduced at 7, 21 and 28 days. Cholinesterase activity of RBC and
    brain was depressed at all test intervals. Plasma cholinesterase was
    depressed in females at all intervals while in males the depression
    became evident after 14 days. No effects were noted on survival,
    haematology, blood chemistry, urinalyses or on microscopic examination
    of tissues and organs (Plank et al., 1971).

         Groups of female rats (15 rats/group) were fed leptophos oxon for
    four weeks at dose levels of 0, 1, 5, 10 and 20 ppm. Measurements of
    red blood cell and plasma cholinesterase activity were made at 14 and
    28 days. Plasma cholinesterase was unaffected while erythrocyte
    cholinesterase was depressed at 10 ppm and above at 14 days. At the 28
    day interval reduction of activity was not significant (Smith et al.,
    1971).

         Groups of rats (15 males and 15 females/group) were fed leptophos
    oxon for 90 days at dose levels of 0, 25, 50 and 500 ppm. Inhibition
    of plasma cholinesterase activity was noted at all dose levels in
    females while males were affected at 500 ppm only at the 84 day test
    interval. Inhibition of erythrocyte and brain cholinesterase activity
    was similar in both sexes and was notable only at 500 ppm. No effects
    were noted on mortality, growth, food consumption, haematology
    parameters, clinical chemistry parameters, urinalyses, and on gross
    and microscopic examination of organs and tissues (Plank et al.
    1971c).

    Leptophos phenol

    Rat

         Groups of rats (25 of each sex/group) were divided into two
    subgroups and housed individually (10 of each sex/group) or housed
    together (15 of each sex/group). The sexes were not mixed. Two dietary
    groups were used; a control and a test group which received a dietary
    level of leptophos phenol of 3500 ppm for one week. This was increased
    to 5000 ppm for the second week, to 8000 ppm for the third week and
    finally to 13 000 ppm for the fourth week. There were no effects on
    food consumption, growth, haematology, blood chemistry including
    cholinesterase or on growth and microscopic examination of tissues and
    organs (Plank et al,, 1971a).

         Groups of rats (15 males and 15 females/group) were fed leptophos
    phenol at dietary levels of 0, 300, 1000 and 10 000 ppm (3000 ppm for
    days 1-49) for 90 days. At 10 000 ppm there was a significant increase
    in liver weight in females. In males a decreased spleen weight was
    noted at all doses tested (none was significantly different from
    control values although the decrease was evident in ratios calculated
    from body and brain weight data). No effects were observed on
    survival, food consumption, growth, haematology, blood chemistry,
    urinalyses or on gross or microscopic examination of tissues or organs
    (other than the gross effects on liver and spleen). A report of the
    microscopic examination of liver and spleen indicated no abnormalities
    (Plank et al., 1971b).

    Special studies on mutagenicity

    Mouse

         A dominant lethal study was conducted where groups of male mice
    (8 mice/group) were administered a single oral or intraperitoneal dose
    of 0, 15 or 30 mg leptophos/kg. The males were mated with three
    females per week for six weeks during the normal period of
    spermatogenesis. Positive control studies were performed with methyl
    methane-sulfonate. There were no effects of leptophos on mating
    performance or on reproduction parameters including preimplantation
    loss, early resorption or embryo viability. Leptophos under the
    conditions of this test did not induce mutagenic changes in male
    germinal cells (Arnold et al., 1971).

    Special studies on neurotoxicity

    Chickens

         Groups of white leghorn hens (6 hens/group) were orally
    administered leptophos at doses of 100, 200 and 400 mg/kg on day 0 and
    14. Observations on clinical conditions were made and at the
    conclusion of the study (day 28) survivors were sacrificed and nervous
    tissue examined microscopically for indications of myelin disruption.

         No clinical signs of delayed neurotoxicity were noted in this
    study following the first dosing. Three hens of six tested at the high
    level died 6-14 days after the second dose. These hens had lost a
    considerable portion of their body weight before death. At 200 mg/kg
    one of six died and one other showed clinical signs of ataxia.
    Microscopic examination of H & E and Luxol Fast Blue stained sections
    of nerve did not reveal myelin degeneration (Stephens et al., 1969).

         Groups of white leghorn hens (10 hens/group) were administered
    leptophos orally at doses of 0, 5, 10, 15, 30, 50, 75, 100 and 200
    mg/kg at days 0 and 21. A positive control was also used in this study
    (Tri-o-Cresyl phosphate, 500 mg/kg - orally at day 0). A number of
    animals showing clinical signs of ataxia were sacrificed at day 42.
    Gross and microscopic examination of brain, spinal cord and sciatic
    nerves were performed. Examinations were made of H & E stained
    sections and tissues embedded in ParaplastR and stained with Luxol
    Fast Blue - Holmes Silver Nitrate. Both light and electron microscopic
    examinations were made in this study.

         A positive delayed neurological condition was clinically evident
    in this study with both TOCP and leptophos. Loss of body weight is
    generally observed clinically in animals with delayed peripheral
    ataxia and this was observed with the TOCP group in 6 of 10 hens
    weighed at day 18. In the leptophos groups, weight loss was noted in 1
    of 10 hens at 75 mg/kg, in 3 of 10 at 100 mg/kg, in 5 of 10 hens at
    200 mg/kg. This weight loss was accompanied by signs of peripheral
    neuritis in various hens of the three upper group levels (3 hens at 75
    mg/kg, 5 hens at 100 mg/kg and the majority of hens at 200 mg/kg).
    Light and/or electron microscopic sections of nerve tissue and muscle
    preparations indicated retrograde degeneration of 8 of 10 TOCP hens
    and 5 of 10 hens at 200 mg/kg. No other positive signs of degeneration
    were observed. At acute oral dose levels of 75 mg/kg and above,
    leptophos was shown to induce a clinical neuropathy in hens (Fletcher
    et al., 1975).

         Other studies have confirmed that, at high acute oral doses,
    leptophos will induce delayed neurotoxicity and clinical signs of
    neuropathy (Abou-Donia et al., 1974; Abou-Donia and Preissig, 1975;
    Kimmerle, 1972). In male chickens, 2 of 9 tested were ataxic between
    9-13 days after oral dosing with 180 mg/kg. No neurotoxic effects were
    noted at dose levels below 180 mg/kg. Further studies showed that 200
    mg/kg and above resulted in ataxia. A 30% formulation of emulsifiable
    concentrate administered to hens by oral or IV injection resulted in
    positive clinical neuropathy at dose levels above 100 mg/kg.

    Special studies on reproduction

    Rat

         In two studies, groups of rats (8 males and 16 females/group
    there - were two control groups of 8 males and 16 females each) were
    fed leptophos in the diet at levels of 0, 10, 30, 40 and 60 ppm and
    subjected to a standard three generation, two litter per generation
    reproduction study. After two litters of the first generation were
    born, the 60 ppm level was discontinued because of pup mortality. A
    second study was initiated at 0 and 5 ppm. The 5 ppm dose was changed
    after one generation to the 40 ppm level (noted above) and maintained
    at this level for two further generations.

         Parental body weight and reproductive performance was similar in
    the 60 ppm group to the control group. Reproductive indices, including
    mating, pregnancy, fertility and parturition showed no differences
    with respect to control and all treated rats. Survival data on pups
    including viability and lactation indices were significantly decreased
    at 60 ppm but were similar to control values at 40, 30 and 10 ppm.
    Mean body weight data for pups at weaning at all dose levels
    (including 60 ppm) were similar. A no-effect level for rat
    reproduction is 30 ppm (Haley et al., 1973, 1972).

    Special studies on teratogenecity

    Rabbit

         Groups of pregnant New Zealand rabbits (10-13 rabbits per group)
    were administered leptophos orally from day 6 to day 18 of gestation
    at dose levels of 0, 1 and 3 mg/kg. Thalidomide was administered over
    this same period at a dose of 37.5 mg/kg to a group of rabbits
    designated as a positive control. No effects were noted on the growth
    of does. Skeletal or somatic abnormalities were noted with
    thalidomide. Leptophos at a dose of 3 mg/kg administered orally to
    rabbits during organogenesis elicited no teratological response (Ladd
    et al., 1971).

         Signs of poisoning are typical of acute parasympathomimetic
    stimulation seen by other anticholinesterase organophosphates. These
    include: hypoactivity, tremors, muscular weakness, ruffed fur,
    diarrhoea, exophthalmia, haemorrhagic conjunctivitis and salivation.


    
    Acute Toxicity

                                                                                                                

                                                                      LD50
    Species          Sex          Formulation              Route      (mg/kg)              Reference
                                                                                                                

    Rat              M      Tech (white mass)              Oral       31.6        Wazeter, 1965
                     M      Tech (white powder)            Oral       59.0           "     1966
                     M      Tech (98.5% white powder)      Oral       54.5           "     1968
                     M      Tech (90% brown granule)       Oral       37.1           "     1968a
                     M      Tech (99.6% white powder)      Oral       56.6           "     1971
                     M      Tech (90% white crystal)       Oral       44.7           "     1970
                     M      Tech (90% grey granule)        Oral       52.8           "     1971a
                   M & F    Tech (94%)                     Oral       20.0        Kretchmar et al., 1971
                   M & F    Tech (90%)                     Oral       90.5        Mastri et al., 1969
                   M & F    (1 day old) Tech 90%           Oral       12.0        Kretchmar et al., 1971a
                   M & F    (5 day old) Tech 90%           Oral       15.0        Kretchmar et al., 1971a
                     F      Tech (98.5% white powder)      Oral       24.3        Wazeter, 1968
                     F      Tech (90% brown granule)       Oral       26.1           "     1968
                     F      Tech (99.6% white powder)      Oral       40.1           "     1971
                     F      Tech (90% grey granule)        Oral       42.9           "     1971a

    Rabbit         M & F    Tech (90% white crystal)       Dermal     10 000         "     1970
                   M & F    Tech (90% brown powder)        Dermal     800            "     1968a
                                                                                     "     1968b

    Chicken          F      Tech                           Oral       225         Fletcher et al., 1975
                                                                                                                

         Technical leptophos is an eye irritant when instilled into the conjuctival sac of rabbits (Wazeter, 1968b, 1970).
    Leptophos is not an irritant when tested on normal or abraded rabbit skin (Wazeter, 1970).

    Acute toxicity formulations

                                                                      LD50
    Species          Sex          Formulation              Route      (mg/kg)              Reference
                                                                                                                

    Rat              M      3 EC (yellow oil)              Oral       271         Wazeter, 1970a
                     M      30 EC (yellow oil)             Oral       271            "     1970a
                     M      29.5 EC                        Oral       400         Mastri et al., 1969a
                     M      35.7 EC                        Oral       735            "     1969a
                     M      5 G                            Oral       2 263       Wazeter, 1971b
                     M      50 WP (grey powder)            Oral       121            "     1971c
                     M      2 EC (yellow liquid)           Oral       178            "     1971d
                     M      3 EC (34.7%)                   Oral       121            "     1971e
                     M      3% Dust (grey dust)            Oral       1 780          "     1971i
                     M      3 ULV (32.1%)                  Oral       192            "     1970b
                     M      5 G                            Inhal      26.9 mg/L   Wazeter, 1971b
                     M      3 ULV (32.1%)                  Inhal      200 mg/L       "     1970b
                   M & F    3 EC                           4 hr
                                                           Inhal      2.7 mg/L    Hathaway et al., 1968
                     M      3% dust                        4 hr
                                                           Inhal      33 mg/L     Wazeter, 1971i
                     M      50 WP                          Inhal      19 mg/L        "     1971c
                     M      2 EC                           Inhal      200 mg/L       "     1971d
                     M      3 EC                           Inhal      200 mg/L       "     197le
                     F      29.5 EC                        Oral       218 mg/L    Mastri et al., 1969a
                     F      36.7 EC                        Oral       327 mg/L       "     1969a

    Rabbit         M & F    2.7 EC                         Dermal     2 000       Wazeter and Goldenthal, 1973
                                                                                                                

    Leptophos formulations are an eye irritant when instilled into the conjunctival sac (Wazeter, 1971b, 1971c, 1971d, 1971e, 1971i). However, one
    formulation tested (3 ULV - 32.1% leptophos) was not an eye irritant (Wazeter, 1970b). Leptophos fomulations are not a skin irritant when tested
    on normal or abraded rabbit skin (Wazeter, 1971b, 1971c, 1971d, 1971e, 1971i).

    Acute toxicity - metabolites and possible contaminants

                                                                                                              

                                                                    LD50
         Compound                  Species     Sex       Route      (mg/kg)                Reference
                                                                                                              

    Leptophos oxon                   Rat       M & F     Oral       119           Mastri et al., 1969b
                                     Rat       M & F     Oral       43            Kretchmar et al., 1972

    Phenylphosphonic
         acid                        Rat         M       Oral       2 480         Mastri et al., 1969b
                                                                    2 241             "          1969c

    S-methyl isomeride               Rat         F       Oral       735           Kretchmar et al., 1972a
    O.O-bis 
    (2,5-di-chloro-4-brom-phenyl)
    phenylphosphono-thioate          Rat         M       Oral       4 640         Wazeter, 1971f
    O.O-dimethyl
    phenyl-phos-phonothioate         Rat         M       Oral       287               "    1971g
    O-methyl phenyl
    phosphonic acid                  Rat         M       Oral       3 690             "    1971h
    O-(2,3-dichloro-4-bromophenyl)   Rat         M       Oral       59.5          Wazeter and Goldenthal, 1972
    phenylphos-phonothioate          Rat         F       Oral       37.5          Wazeter and Goldenthal, 1972
    Leptophos phenol                 Rat       M & F     Oral       2 654         Mastri et al., 1969b
                                                                                                              
    

    Antidotal studies

         Administration of atropine sulfate and 2-PAM alone and in
    combination resulted in an increase in the LD50 value suggesting that
    these agents might be successful in antidotal therapy (Kretchmar et
    al., 1971). The combination of atropine and 2-PAM was no more
    successful than the administration of either agent alone.
                                                                    

         Antidote                    LD50 (mg/kg)     (95% C.L.)

                                                                    

         None                        20.0               (11.8-34.0)

         Atropine Sulfate (IM)
         10 mg/kg 1.5 & 5 hr
         after poisoning             54.0               (41.2-70.7)

         2-PAM
         1.5 hr after poisoning      38.5               (33.8-43.9)

         Atropine + 2-PAM            40.0               (27.6-58.0)
                                                                    


    Short-term studies

    Rat

         Groups of rats (2 males and 2 females/group) were administered
    leptophos by oral intubation of 10 days at dose levels equivalent to
    dietary intakes of 0, 3, 10, 30 and 100 ppm. Mortality was evident at
    100 ppm. At the conclusion of the study the animals were sacrificed
    and cholinesterase determinations run using brain, plasma and red
    blood cells.

         No depression of plasma cholinesterase was noted. The RBC and
    brain cholinesterase activity was depressed at 30 ppm and above in all
    surviving animals (Wazeter, 1968c).

         Groups of rats (10 males and 10 females/group) were fed dietary
    levels of leptophos of 0, 100, 250 and 500 ppm for 28 days. A second
    series of female animals (10 rats/group) were fed levels of 0, 50 and
    75 ppm for 14 days in a cholinesterase depression range-finding test.

         A dose-dependent depression of cholinesterase activity was
    observed in all tissues at all dose intervals and times tested in the
    initial high level study. Activity of the most susceptible
    cholinesterase source (female RBC) was slightly depressed 32% and 22%
    at 75 and 500 ppm respectively after seven days of feeding. The plasma
    cholinesterase activity in the initial study was not inhibited until
    the two week test interval after which it steadily declined (Plank, et
    al., 1970).

         Groups of rats (10 male and 10 female rats/group were fed
    leptophos in the diet at dose levels of 0, 1, 5 and 10 ppm for 90
    days. Growth, food consumption and behaviour were not affected by
    leptophos. No changes were noted in haematology, blood, clinical
    chemistry or urinalysis parameters measured. Cholinesterase activity
    in RBC, plasma and brain were normal at 90 days of testing as were the
    40 day examinations of RBC and plasma cholinesterase. Gross and
    microscopic examination of tissues and organs showed no
    leptophos-related lesions (Wazeter, 1969).

    Dog

         Groups of dogs (four male and four female beagle dogs/group) were
    fed leptophos in the diet for 90 days at dose levels of 0, 10 and 30
    ppm. Behaviour, growth and food consumption were not affected over
    this test interval. No effects were noted on haematology parameters on
    blood, clinical chemistry on urinalyses or on gross and microscopic
    analyses of tissues and organs. A no-effect level was 30 ppm (Lindberg
    et al., 1969).

         Groups of beagle dogs (4 males and 4 female/group) were fed
    leptophos in the diet at dosage levels of 0, 10, 20, 30 and 60 ppm for
    two years (the 60 ppm group had been fed a diet containing 5 ppm for
    180 days which was then increased to 60 ppm for the remainder of the
    study. No mortality occurred over the course of the study and growth,
    food consumption and behaviour was normal at all levels. No
    leptophos-related effects were noted on haematology parameters,
    clinical chemistry values (including blood and brain cholinesterase
    values) or on gross and microscopic examination of tissues and organs.
    Leptophos in the diet at 60 ppm had no effect on any parameter
    recorded in this study (Hartke et al., 1971).

    Chicken

         Groups of white leghorn chickens (4 male and 20 females/group)
    were fed leptophos in the diet at dosage levels of 0, 0.03, 0,10, and
    0.30 ppm for four weeks. Eggs were collected and incubated during the
    latter 14 days of treatment. The chicks were observed for 14 days
    post-hatching having been fed the leptophos diet corresponding to the

    parent. There were no treatment related differences in body weight or
    egg production and size of eggs. Egg hatchability, chick viability,
    and growth was not affected by leptophos. No abnormal behaviour or
    signs of poisoning were observed in this study in either adults or
    chicks (Perkins and Singh, 1971). Analysis of tissue residues
    (including eggs and adipose tissue) did not indicate the presence of
    residues of leptophos, the oxon, the phenol or a photo-product
    (Suzuki, 1971).

    Steer

         Groups of steers (three steers/each treatment group and one
    steer/control group) were fed leptophos in the diet at levels of 0,
    15, 45 and 150 ppm for four weeks. At 28 days the control and two each
    of the treatment groups were sacrificed. The remainder were allowed to
    consume normal untreated food for a further 14 days after which they
    were sacrificed. Daily observations showed no abnormal behaviour or
    toxic signs of poisoning. No gross or microscopic lesions were
    observed at the conclusion of the study. Depression of the whole blood
    and plasma cholinesterase was evident at the higher dose levels over
    the 28 day feeding interval. After seven days on a control ration the
    depressed values returned to normal. Tissue residues of leptophos and
    the oxon were low in liver, kidney, muscle and brain. In fat,
    leptophos was present after 28 days in measurable levels which were
    dose dependent. Following the 14 day recovery intervals, these
    residues in fat were considerably reduced (Perkins and Singh, 1971a).

    Cow

         Groups of lactating dairy cows (three cows/group fed leptophos
    and one cow/control group) were fed leptophos in the diet at
    calculated dose levels of 0, 5, 15 and 50 ppm (actual values fed as
    assessed by chemical analysis were 0, 3.2, 10.0 and 37.4 ppm) for 28
    days and maintained for a further 14 days on control diets to measure
    residue reductions and recovery of normal values. Appearance,
    behaviour and general condition were normal over the study. Body
    weights of several animals tested with leptophos were reduced over the
    study. Milk production was reduced in the low and intermediate group
    but not at the high level of leptophos. Cholinesterase depression was
    not noted in this study (Fink, 1971). Traces of leptophos were noted
    in fat at the conclusion of the 28 day feeding interval at levels
    ranging from 0.2 to 0.5 ppm in the high (37.4 ppm) dose level. After
    two weeks, these residues were reduced to 0.2 ppm (Suzuki, 1971a).

    Long-term studies

    Mouse

         Groups of Swiss white mice (65 males and 65 females/group) were
    fed leptophos in the diet for 18 months at dose levels of 0, 50, 100
    ppm to assess a carcinogenic potential in mice. Two positive control

    groups were fed N-nitrosodiethylamine at levels of 10 ppm (50 males
    and 50 females) and 40 ppm (15 males and 15 females). After six
    months, the mice of the high positive control group and 15 of each sex
    in the leptophos group were sacrificed and subjected to gross and
    microscopic examination for tumour formation. At 18 months all
    remaining animals were sacrificed and 10 animals of each sex (or
    group) were examined.

         The positive control sacrificed at six months (40 ppm) showed
    definitive evidence of lung adenoma or carcinoma. At 18 months, the
    positive control (10 ppm) again showed a positive response to the
    carcinogen. No evidence of lung lesions was noted at 100 ppm leptophos
    in the diet. There were no leptophos-related lesions or tumours in any
    of the tissues and organs examined in this study (Smith et al., 1973).

    Rat

         Groups of Charles River albino rats (50 males and 50
    females/group) were fed leptophos in the diet for two years at
    concentrations of 0, 10, 20, 30 and 60 ppm (the 60 ppm were initially
    fed 5 ppm for the first seven months). Mortality was unaffected by
    leptophos in the diet (although at the conclusion of the study very
    few animals in all groups were alive). Food consumption and growth
    were similarly not affected. There were no differences from control
    values in the haematology, blood chemistry or urine parameters
    examined. Gross and microscopic examination of tissues and organs
    failed to indicate any pathologic disorders noted in controls.
    Cholinesterase activity measured in brain over the first 90 days
    showed no reduction in activity at any dose tested. Erythrocyte
    cholinesterase activity was depressed at all levels tested. A
    significant reduction (below 25%) was noted at the 60 ppm level. A
    no-effect level based on RBC cholinesterase depression is 30 ppm
    (Smith et al., 1971a).

    Comments

         Leptophos, an anticholinesterase organophosphonothioate ester
    recommended for use in agriculture as an insecticide, has a moderate
    acute oral toxicity. Leptophos is rapidly absorbed, metabolized and
    excreted within 24 hours following single acute oral dosing in
    animals, primarily via the urine. No tissue residues were observed
    except for adipose tissue which maintains traces of leptophos for
    extended periods following acute dosing. The metabolism of leptophos
    includes oxidative and hydrolytic processes, generally resulting in
    less toxic products (except the oxon and the dichlorodesbromo
    derivatives). All materials noted as field residues have been found as
    metabolites in animals.

         Leptophos (and its metabolites) is a relatively persistent
    pesticide. Artificial environmental studies using model systems
    suggest that leptophos may bioaccumulate in the food chain.

         Sufficient toxicological data have been reported including long
    and short-term studies with rodents and dogs, reproduction studies
    (including teratogenesis and mutagenesis studies); and carcinogenesis
    studies. The only significant adverse toxicological parameters
    reported in these studies have been esterase depression, pup mortality
    in the reproduction study at high levels and delayed neurotoxicity in
    hens. Short-term studies on the metabolites have shown no substantial
    toxicological effect on rodents except for esterase depression with
    the oxon metabolite.

         Based on the no-effect level observed in two year studies in rats
    and dogs and the no-effect level in acute avian studies for delayed
    neurotoxicity, a temporary ADI was estimated. An exceptionally high
    safety factor was used to allocate the ADI reflecting concern over the
    positive neurotoxicity results. There was less concern over the
    significant delayed neurotoxicity as a factor in evaluating the
    toxicological hazard of food residues than in its evaluation of
    delayed neurotoxicity as a hazard to occupationally exposed
    individuals. The occurrence of the delayed neurotoxicity was, however,
    considered to be highly significant in the toxicological evaluation of
    leptophos. It was decided that delayed neurotoxicity should be
    considered as an additional toxicological parameter, showing a
    dose-response relationship, which permits an evaluation to be made of
    a no-effect level.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat: 30 ppm in the diet equivalent to 1.5 g/kg bw

         Dog: 60 ppm in the diet equivalent to 2.1 mg/kg bw

         Hen: 50 mg/kg (based on delayed neurotoxicity)

    Estimate of temporary acceptable daily intake

         0-0.001 mg/kg bw

    RESIDUES IN FOOD AND THEIR EVALUATION

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    Residues in crops

         Extensive data were obtained on residues from supervised trials
    in which crops were treated according to recommended dosage rates and
    pre-harvest intervals. In most trials separate residue figures were

    given for the parent leptophos and the metabolites leptophos-oxon,
    desbromo-leptophos and the phenol. Leptophos residues consisted mainly
    of the parent compound with much lower levels of the metabolites
    mentioned, as in the trials recorded in the 1974 monograph of
    leptophos. In the following tables therefore, a single figure is shown
    referring to the sum of leptophos, its oxygen analogue and
    desbromo-leptophos expressed as leptophos.

         In a number of trials "apparent" oxon residues were found. As
    explained in the 1974 monograph, these consist of bis-(2-ethylhexyl)
    phthalate, a component of plastic laboratory equipment. In the
    following Tables these apparent oxon residues are omitted.

    Comments on the data

         Apples. Residue data from Canada (three locations in Quebec and
    one in Ontario) show considerable residue levels, up to 2 mg/kg, after
    a pre-harvest interval of 6-10 weeks. Further data on apples are given
    in the section "Fate of residues".

    Vegetables

         Beans. After pre-harvest intervals of 37-40 days residues in
    beans were either not detectable (Canada) or very low, at or below
    0.02 mg/kg (Japan).

         Brassicas. No detectable residues were found in broccoli,
    cabbage or cauliflower after pre-harvest intervals of about 60 days,
    but still considerable residues after intervals of 25-30 days. These
    data confirm those available from the United States of America at the
    1974 Joint Meeting.

         In supervised trials in Japan residue levels in the edible part
    of Chinese cabbage after a pre-harvest interval of 14-31 days were in
    the range 0.1-0.2 mg/kg.

         Celery. Residue levels were very low, 0.01-0.02 mg/kg in three
    locations in Ontario after a pre-harvest interval of 61 days. In other
    trials residues ranged from 0.02-0.05 mg/kg after a similar interval
    and levels up to 0.5 mg/kg were found after an interval of 42 days.

         Lettuce. Residue levels in Canadian trials after a pre-harvest
    interval of 21-30 days were slightly lower than in the experiments
    evaluated at the 1974 Joint Meeting from the United States of America.
    After normal trimming for market, residues did not exceed 0.5 mg/kg.

         Onions, peas, potatoes. Residues were low after the normal
    pre-harvest intervals for these crops. In green onions residues were
    at or below 0.1 mg/kg after a pre-harvest interval of about 60 days
    and in peas <0.01 mg/kg after 30 days. In the vines however, residues
    ranged from 1.1-10.7 mg/kg 22-30 days after treatment. In potatoes in
    New Zealand no detectable residues were found after 21 days. This is
    in conformity with the United States of America data evaluated by the
    1974 Joint Meeting.

    Cereal crops

         Wheat, oats and barley. Residue levels were below 0.1 mg/kg
    after a pre-harvest interval of 60 days in most of the trials; in some
    trials levels reached about 0.5 mg/kg in these crops.

         Maize. Residues in kernels and forage were generally low (0.05
    mg/kg or below) in Canadian experiments, as in the United States of
    America data evaluated by the 1974 Meeting.

         Rice. After pre-harvest intervals of about 30 days residue
    levels in inhulled rice ranged from 0.1-0.5 mg/kg and in leaves and
    straw from 6 to 20 mg/kg.

         Sugar beet. Data from residue trials in Canada and Japan were
    evaluated. After a pre-harvest interval of about 50 days, residues in
    the roots did not exceed 0.05 mg/kg and those in the tops ranged from
    <0.02-0.5 mg/kg.

    FATE OF RESIDUES

    In plants

         Data were obtained from three new studies on the fate of
    leptophos residues in apples, cabbage and tobacco carried out with
    14C-phenoxy- and 14C-phenyl-leptophos. The results generally agreed
    with those of the trials evaluated by the 1974 Joint Meeting.

         In the experiment on apples it was shown that the parent
    leptophos was the principal residue 6 and 14 days after treatment,
    with approximately 10% of the extractable radioactivity as
    leptophos-oxon. Less than 1% of 14C was unextractable from the apple
    pulp. Fourteen days after treatment, about half of the total
    14C-phenyl residue remained on the surface of the apples and up to
    20% of this surface residue remained at the origin during TLC on
    silica gel.

         Only small mounts of 4-bromo-2,5-dichlorophenol, phenylphosphonic
    acid, O-methyl phenylphosphonothioate and methyl phenylphosphonate
    were extracted from the apple tissue (Whiteacre and Schnur, 1974).

        TABLE 1.  Nature of 14C compounds extracted from the surface of
              apples treated with 14C-phenoxy and C-phenyl-leptophos

                                                                                      

                                           % of total surface radio carbon

                                    14C-phenyl                   14C-phenoxy
                                                                                       

    Metabolites                  Days after treatment         Days after treatment
                                                                                       
                                 0        6        14         0        6        14
                                                                                       

    leptophos                    98.6     80.0     77.8       98.4     89.6     92.3

    leptophos oxon               1.4      1.7      2.0        1.4      1.0      1.5

    4-bromo-2,5-dichlorophenol   -        -        -          <0.01    <0.01    <0.01

    polar compounds
    at origin of                 <0.01    18.2     20.2       1.6      9.0      6.2
    TLC plate
                                                                                       

    Total                        100.0    99.9     100.0      101.4    99.6     100.0
                                                                                       
    
         In the experiment on cabbage (Diaz, 1974) it was shown that on
    this crop also, the parent leptophos is the principal residue 4, 7 and
    14 days after treatment; only small amounts of leptophos oxon and free
    4-bromo-2,5-dichlorophenol were present. A small amount of 4-bromo-2,
    5-dichlorophenol was conjugated; no significant amounts of O-methyl
    phenylphosphonothioate, methyl phenylphosphonate or phenylphosphonic
    acid were found.

    In soil

         A new study was carried out on the behaviour and fate of
    14C-phenoxy-and 14C-phenyl-leptophos in soil (Rieck, 1974), giving
    additional information on the mount of "bound" residue (not
    extractable with normal extraction procedures). Columns of a sandy
    loam soil consisting of a one inch depth of treated soil on top of a
    four inch depth of untreated soil were kept under aerobic and
    anaerobic conditions and watered to 80% of field capacity. Two columns
    were analysed initially and the others were watered with half inch
    depth of water at weekly intervals and the leacheate collected. Soil
    columns were analysed after 15, 30, 60, 90 and 120 days.

         It was found (Table 2) that the bound radiocarbon (defined as
    unextractable by 24 hours soxhlet extraction with 80% methanol)
    increased with time at all soil depths. The radioactivity in the top
    2.5 cm (treated) section decreased with time from 92% of the total to
    42% after 120 days. The total 14C in the levels below this remained
    fairly constant during the experiment.


    TABLE 2.  Distribution of total and bound radioactivity in aerobic
              sandy loam soil

                                                                         

                    14C-leptophos equivalent on dry weight basis,*
                                   found at depth
                                                                         
               0 - 2-1/2 cm        2-1/2 - 7-1/2 cm     7-1/2 - 12-1/2 cm
                                                                         
    Time
    (days)     total    bound      total    bound       total    bound
                                                                         

     0         9.16     0.02       0.23     0           0.05     0.0

     15        8.33     0.39       0.06     0           0.14     0.02

     30        6.33     0.69       0.13     0.06        0.04     0.03

     60        5.24     0.98       0.19     0.09        0.09     0.05

     90        4.75     1.47       0.20     0.14        0.07     0.07

     120       4.19     1.84       0.19     0.14        0.04     0.04
                                                                         

    *  to calculate in terms of percentage of the amount applied, move
       the decimal point one place to the right.

         Under the conditions of the experiment the downward movement of
    leptophos and its metabolites was insignificant. The only
    14C-labelled compounds extractable from the lower layers were parent
    leptophos, 4-bromo-2,5-dichlorophenol and methyl phenylphosphonate.
    The total leacheate collected during the study contained only 0.46% of
    the total activity applied to the upper soil layer.

    In storage and processing

    Sunflower and cotton seed

         The nature and magnitude of residues in processed fractions of
    sunflower seed were evaluated in three studies in Canada, In one study
    the seed processed had a parent leptophos residue of 0.06 mg/kg. The
    meal, crude oil and refined oil fractions showed residues of 0.03,
    0.18 and 0.20 mg/kg parent compound respectively. No residues were
    determined in the hulls, soapstock or finished oil. In another study
    in which the crop was treated with 0.3 kg/ha the residue in the seed
    was 0.19 mg/kg. No residues were measured in the hulls, meal, crude
    oil, refined oil, finished oil or soapstock.

         In a similar study in Australia on the processing of cotton seed,
    in which the crop was treated with 0.9 kg/ha, after 78 days the level
    in the seed was 6.33 mg/kg total leptophos residue. The following
    residues were found in the processed fractions.

                                                                   

                        mg/kg                              mg/kg
                                                                   

         seed           6.3            refined oil         32.4

         hulls          2.62           finished oil        0.07

         meal           0.13           soapstock           3.70

         crude oil      40.0
                                                                   

    Tea

         Tea was brewed for 3-10 minutes according to a standard
    procedure. In one study in which tea was treated with 1.3 kg
    leptophos/ha and harvested and brewed (three minutes brew) on the same
    day, the brew contained 0.05 mg/kg leptophos and 0.07 mg/kg of
    4-bromo-2,5-dichlorophenol. In a brew of tea harvested 3-7 and 14 days
    after treatment no leptophos or metabolites except up to 0.02 mg/kg of
    the phenol were found. Sun-dried tea harvested at 0 and 7 days after
    treatment and brewed for three minutes showed no residues of leptophos
    or its metabolites, except 0.06 mg/kg of the phenol in the brew at day
    0 and 0.01 mg/kg of the phenol in the brew after seven days.


    
    TABLE 3. Leptophos: Residues, include the parent compound and the main metabolites, leptophos oxon and desbromo-leptophos.

                                                                                                                                               

                                        Application
                                                                             Residues in mg/kg, at intervals (days) after application
                                                                                                                                            
                                        rate kg a.i./
       Crop      Country      Year  No.  ha or g/100 l  formulation  0/1        7/8        14/16      21       28/30   35/37      57/63      Ref.
                                                                                                                                               

    Fruit crops

    Apple        New Zealand  1972  11   46 g/100 l        wp 45%    2.65       1.95       2.02       2.08             2.28                  V143
                              1972  11   60 g/100 l        wp 45%    3.71       4.16       1.89       1.66             1.83                  V143

                 New Zealand  1972  11   46 g/100 l        wp 45%    2.82       1.45       1.45       1.43     1.78                          V144
                              1972  11   60 g/100 l        wp 45%    2.69       1.56       2.23       1.35     1.69                          V144

                 Australia    1971/ 8    60 g/100 l        wp 45%    1.55       1.28       2.27                1.50                          V144
                 (Tasmania)   1972
                                    8    60 g/100 l        wp 45%    2.52       4.28       2.90                3.80                          V144

                 Australia    1972  8    60 g/100 l        wp 45%    4.06-7.29  5.50-9.03  4.33-6.85           3.56-4.18                     V144
                 (Tasmania)

                 Australia    1972  5    60 g/100 l        wp 45%    0.51-2.54             1.77-1.82                                         V144
                 (NSW)

                 Australia    1970  5    90 g/100 l        wp 45%                          0.36-0.66                                         V73
                 (NSW)        1970  5    120 g/100 l       wp 45%                          0.65-0.93                                         V73

                 Australia    1971  4    120 g/100 l       wp 45%                                                                 0.30-0.48  V173
                 (Tasmania)

                                    6    120 g/100 l       wp 45%                                                                 0.65-0.83  V173

                 Canada       1973  4    110 g/100 l       wp 45%               1.51                                                         V178

    TABLE 3. (continued)

                                                                                                                                               

                                        Application
                                                                             Residues in mg/kg, at intervals (days) after application
                                                                                                                                            
                                        rate kg a.i./
       Crop      Country      Year  No.  ha or g/100 l  formulation  0/1        7/8        14/16      21       28/30   35/37      57/63      Ref.
                                                                                                                                               

    Apple        Canada       1973  3    72 g/100 l        wp 45%                                                                 0.76       V178
    (cont'd)
                 Canada       1973  4    2 kg/ha           wp 40%                                              3.83                          V178

                                         rate
                                         kg a.i./ha                  21/25     28/32     35/38      42/50     53/58     63/67     70/80   
                                                                                                                                               
    Vegetables

    Beans        Canada      1974  1         1            EC 32%                        <0.01                                            Braun
                                                                                                                                         et al.,
                                                                                                                                         1975
                                   1         2            EC 32%                        <0.01                                              "

    Broccoli     Canada      1974  1         1            wp 45%                                                       0.08                 "
                                   1         2            wp 45%                                                       0.13                 "

    Cabbage      Canada      1974  1         1            wp 45%                                                       <0.01                "
                                   1         2            wp 45%                                                       <0.01                "
                 Canada      1974  8         0.6          EC                  0.71                                                       V 176
                                                                              0.06
                                                          EC        0.23                           0.15                                  V 190

    Carrots      Canada      1974  1         0.5          EC 32%                        0.07                 0.02                0.01    Braun
                                                                                                                                         et al.,
                                                                                                                                         1975

    TABLE 3. (continued)

                                                                                                                                               

                                        Application
                                                                             Residues in mg/kg, at intervals (days) after application
                                                                                                                                            
                                        rate
       Crop      Country     Year  No.  kg a.i./ha     formulation  21/25     28/32     35/38      42/50     53/58     63/67     70/80
                                                                                                                                               

    Carrots                         1         1            EC 32%                        0.10                 0.03                0.02
    (cont'd)                        1         2            EC 32%                        0.12                 0.03                        Braun
                                                                                                                                          et al.,
                                                                                                                                          1975

                 Canada       1974  2         0.5          EC 32%              0.16                 0.06                          0.13    Braun
                                                                                                                                          et al.,
                                    2         1            EC 32%              0.32                 0.06                          0.05       "
                                    2         2            EC 32%              0.34                 0.11                          0.14       "

                 Canada       1974  1         1            EC                                                           0.07              V 210
                                    1         1            EC                                                           0.05              V 210
                                    1         2            EC                                                           0.33              V 210
                                    1         2            EC                                                           0.07              V 210

    Cauliflower  Canada       1974  1         1            wp                                                           <0.01            Braun
                                                                                                                                          et al.,
                                                                                                                                          1975
                                    1         2            wp                                                           <0.01               "


                                                                     0/14      21/23     28/30      35/40     42/46     49/56     63/
                                                                                                                                               
    Vegetables

    Celery       Canada       1974  1         0.5          wp                                                 0.10      <0.01             Braun
                                                                                                                                         et al.,
                                                                                                                                         1975

    TABLE 3. (continued)

                                                                                                                                               

                                        Application
                                                                            Residues in mg/kg, at intervals (days) after application
                                                                                                                                  
                                        rate
       Crop      Country      Year  No.  kg a.i./ha     formulation  0/14      21/23     28/30      35/40     42/46     49/56     63/
                                                                                                                                               

    Celery                          1         1            wp                                                 0.20      0.02                 "
    (cont'd)
                                    1         2            wp                                                 0.40      0.04                 "

    (Stalks)     Canada       1974  1         1            EC                                                           0.01              V 208
                                    1         2            EC                                                           0.02              V 208
                                    1         1            EC                                                           <0.03             V 208

                                    1         2            EC                                                           <0.03             V 208

    Lettuce      Canada       1974  1         0.5          EC                  0.20      0.01                                             Braun
    (outdoors)                                                                                                                            et al.,
                                    1         1            EC                  0.37      0.12                                                "
                                    1         2            EC                  0.25      0.04                                                "

    Onions       Canada       1974  1         0.5          EC                                       0.04                <0.01                "
    (green)
                                    1         1            EC                                       0.08                0.02                 "
                                    1         2            EC                                       0.27                0.07                 "
                                    2         0.5          EC                                       0.08                0.02                 "
                                    2         1            EC                                       0.27                0.03                 "
                                    2         2            EC                                       0.42                0.09                 "

    Peas
    (Pods)       Canada       1974  1         1            EC                            0.01                                                "
                                              2            EC                            0.01                                                "

                 Canada       1974  2         1            EC                  0.02                                                       Braun
                                                                                                                                          et al.,
                                              2            EC                  0.03                                                       1975

    TABLE 3. (continued)

                                                                                                                                               

                                         Application
                                                                             Residues in mg/kg, at intervals (days) after application
                                                                                                                                   
                                         rate
       Crop      Country      Year  No.  kg a.i./ha     formulation  0/14      21/23     28/30      35/40     42/46     49/56     63/
                                                                                                                                               

    Peas
    (cont'd)

    (Vines)      Canada       1974  1         1            EC                            2.06                                             Braun
                                                                                                                                          et al.,
                                                                                                                                          1975
                                              2            EC                            1.10                                                "
                                    2         1            EC                  10.65                                                         "
                                              2            EC                  7.48                                                          "

    Rutabaga     Canada       1974  1         0.5          EC                                       0.01                <0.01                "
                                    1         1            EC                                       0.01                0.01                 "
                                    1         2            EC                                       0.02                <0.01                "
                                    2         0.5          EC                            <0.01                0.01                           "
                                    2         1            EC                            0.04                 0.02                           "
                                    2         2            EC                            0.06                 0.02                           "

    TABLE 3. (continued)

                                                                                                                                               

                                            Application
                                                                                                 Pre-harvest interval in days
                                                                                                                                                
                                            rate
       Crop        Country      Year   No.  kg a.i./ha     formulation    7            14            21
                                                                                                                                               

    Cabbage
    Chinese        Japan        1971   1         0.35         EC 34%                 0.09-0.10                                                Miyagi,
                                                                                                                                              1971
                                       3         0.35         EC 34%                 0.09-0.10
                                       1         0.35         EC 34%                               0.08-0.10
                                       3         0.35         EC 34%                               0.10-0.12
                                       1         0.50         EC 34%                 0.06-0.07
                                       3         0.50         EC 34%                 0.06-0.08
                                       1         0.50         EC 34%                               0.05-0.06
                                                                                                   0.12-0.14

                 Japan          1970   1         0.35         EC 34%                 0.08-0.09                                                Miyagi,
                                                                                                                                              1971
                                       3         0.35         EC 34%                 0.09-0.09

                                       1         0.35         EC 34%                               0.09

                                       3         0.35         EC 34%                               0.08-0.10

                                       1         0.5          EC 34%

    TABLE 3. (continued)

                                                                                                                                               

                                           Application
                                                                                                Pre-harvest interval in days
                                                                                                                                               
                                            rate
       Crop       Country      Year   No.  kg a.i./ha     formulation    7            14            21
                                                                                                                                               

    Cabbage                           3         0.5          EC 34%
     (cont'd)                         1         0.5          EC 34%
                                      3         0.5          EC 34%

    Potatoes      New Zealand  1972   1         0.44         wp 45%    <0.05        <0.05         <0.05

                  Japan        1972   2         0.35                                <0.005        <0.005                                     V 142

                                      3                                             <0.005        <0.005


                                                                              Residues in mg/kg, at intervals (days) after application
                                                                                                                                               

                                                                    21/24     28/30     35/40     42/46     49/46     63/72     75/90     Ref.
                                                                                                                                               

    Field crops

    Barley       Canada      1973   1       0.5                               2.17                                                        V 173
    Grain                                                                     0.64
    Grain       Canada      1973   1       0.5                                                                        0.11
    Straw                                  0.5                                                                        0.12

    TABLE 3. (continued)

                                                                                                                                               

                                         Application
                                                                             Residues in mg/kg, at intervals (days) after application
                                                                                                                                               
                                         rate 
       Crop      Country     Year   No.  kg a.i./ha   formulation    21/24     28/30     35/40     42/46     49/46     63/72     75/90     Ref.
                                                                                                                                               

    Grain        Canada                     1.0                                                                        0.14                V 155
    Straw                                   1.0                                                                        0.62
    Oats         Canada      1973   1       0.5
    Grain                                                                                                              <0.01               V 159
    Stubble                                                                                                            <0.01
    Wheat        Canada      1973   1       0.5                                0.37
    Grain                           1       0.36                     0.03                                                                  V 173
    Bran                                                             0.04
    Flour                                                            <0.01
                 Canada      1970   1       0.5
    Grain                                                                                                              <0.01               V 113
    Straw                                                                                                              0.01
    + chaff
                 Canada      1970   1       1

    Grain                                                                                                              <0.01               V 113
    Straw                                                                                                              0.17
    + chaff

    Wheat        Canada      1972   1       0.5
    Grain                                                                                                              0.72                V 155
    Straw                                                                                                              0.28
                             1972   1       1
    Grain                                                                                                              0.24
    Straw                                                                                                              1.32
    Maize
    Sweetcorn    Canada      1974   1       1            EC

    TABLE 3. (continued)

                                                                                                                                               

                                        Application
                                                                            Residues in mg/kg, at intervals (days) after application
                                                                                                                                             
                                        rate 
       Crop      Country     Year   No.  kg a.i./ha   formulation    21/24     28/30     35/40     42/46     49/56     63/72     75/90     Ref.
                                                                                                                                               
    Maize
    (cont'd)
    Cobs                                                                                                               <0.01     <0.01     Braun
                                                                                                                                          et al.,
    Forrage                                                                                                            <0.01     <0.01     1975
                                    1       2            EC
    Cobs                                                                                                               <0.01     <0.01
    Forrage                                                                                                            <0.01     <0.01
                                    2       1            EC

    Cobs                                                                                                     <0.01               <0.01

    Forrage                                                                                                  <0.01               0.31

                                    2       2            EC

    Cobs                                                                                                     <0.01               <0.01

    Forrage                                                                                                  <0.01               0.02

                                                                               28/33                                             75/92

    Fieldcorn
    forrage      Canada      1974   1       0.5          EC                                                                      0.06      V 158

    Forrage                         1       1            EC                                                                      0.04

    Sunflower   Canada      1973   1       1            EC                                                                                V 155

    Hulls                                                                     0.01

    TABLE 3. (continued)

                                                                                                                                               

                                        Application
                                                                            Residues in mg/kg, at intervals (days) after application
                                                                                                                                               
                                        rate 
       Crop      Country     Year   No.  kg a.i./ha   formulation    21/24     28/33     35/40     42/46     49/56     63/72     75/92     Ref.
                                                                                                                                               

    Sunflower    Canada
    (Cont'd)
    Meal                                                                       0.03

    Crude oil                                                                  0.18

    Refined oil                                                                0.20

    Finished oil                                                               <0.01

    Sunflower
    seed         Canada      1972   1       0.5          EC                                                                      <0.01     V 174

    Rape seed    Canada      1973   1       0.5          EC                    0.11                                                        V 183

                                    1       1            EC                    <0.01

                                            0.5          EC                    0.19                                                        V 177

                                            0.5          EC                    0.22

                                            0.25         EC          0.07

                                            0.4          EC          0.04

    Flax seed    Canada      1973   1       0.5                                0.09                                              0.07      V 174

    TABLE 3. (continued)

                                                                                                                                               

                                        Application
                                                                            Residues in mg/kg, at intervals (days) after application
                                                                                                                                               
                                        rate 
       Crop      Country     Year   No.  kg a.i./ha   formulation      0         3         7         15       20        30                 Ref.
                                                                                                                                               

    Rice         Japan       1973   5       0.35         EC

    Unhulled                                                                                                 0.20                       Niigata,
                                                                                                                                        1973
    Straw                                                                                                    15.0-16.8
                                    6       0.35         EC

    Unhulled                                                                                                 0.21
    Straw                                                                                                    15.9-16.7
                                    6       0.35         EC

    Unhulled                                                                                                           0.32
    Straw                                                                                                              16.9-17.3
                                    5       0.35         EC

    Unhulled                                                                                                 0.11
    Straw                                                                                                    22.4-23.3
                                    6       0.35         EC

    Unhulled                                                                                                 0.08
    Straw                                                                                                    30.5-31.7
                                    6       0.35         EC

    Unhulled                                                                                                           0.03-0.05
    Straw                                                                                                              6.15-8.33
                                    5       0.8       dust 2%

                                                                                                                                               
                                        Application
                                                                            Residues in mg/kg, at intervals (days) after application
                                                                                                                               
                                        rate 
       Crop      Country     Year   No.  kg a.i./ha   formulation      0         3         7         15       20        30               Ref.
                                                                                                                                               
    Rice (cont'd)

    Unhulled                                                                                       0.11
    Straw                                                                                          7.20-7.80
                 Japan       1973   6       0.8       dust 2%                                                                           Niigata,
                                                                                                                                        1973

    Unhulled                                                                                                 0.10
    Straw                                                                                                    7.20-7.40
                                    6       0.8       dust 2%

    Unhulled                                                                                                 0.15-0.16
    Straw                                                                                                    11.6-12.4
                                    5       0.8       dust 2%

    Unhulled                                                                                       0.12
    Straw                                                                                          4.15-5.30
                                    6       0.8       dust 2%

    Unhulled                                                                                                 0.08-8.09
    Straw                                                                                                    9.4-10.8
                                    6       0.8       dust 2%

    Unhulled                                                                                                 0.10
    Straw                                                                                                    11.6
                                    5       0.6-0.8   dust 2%

    Unhulled                                                                             0.11
    Straw                                                                                1.59-2.82
                                    6       0.6-0.8   dust 2%

    TABLE 3. (continued)

                                                                                                                                               

                                        Application
                                                                            Residues in mg/kg, at intervals (days) after application
                                                                                                                                               
                                        rate 
       Crop      Country     Year   No.  kg a.i./ha   formulation      0         3         7         15       20        30                 Ref.
                                                                                                                                               

    Rice (cont'd)
    Unhulled                                                                                       0.10
    Straw                                                                                          10.2-10.3

                 Japan       1973   6       0.6-0.8   dust 2%                                                                    Niigata,
                                                                                                                                 1973
    Unhulled                                                                                                 0.20
    Straw                                                                                                    13.6
                                    5       0.6-0.8   dust 2%

    Unhulled                                                                                       0.11
    Straw                                                                                          11.2-11.9
                                    6       0.6-0.8   dust 2%
    Unhulled                                                                                                0.07-0.08
    Straw                                                                                                   10.3-10.9
                                    6       0.6-0.8   dust 2%

    Unhulled                                                                                       0.09-0.10
    Straw                                                                                          19.3-19.7

    Tea (dry
    manuf.)      India       1973   2       1.3          EC          93.4      1.77      3.57      0.29                          V 203
                 Assam
                            *1973  2       1.3          EC          77.3      0.11      3.67      0.23
                            *1973  1       1.3          EC                              2.80-3.77
                            1973   1       1.3          EC                              1.36-1.94


    TABLE 3. (continued)

                                                                                                                                               

                                        Application
                                                                            Residues in mg/kg, at intervals (days) after application
                                                                                                                                               
                                        rate 
       Crop      Country     Year   No.  kg a.i./ha   formulation    30/33     38/45     50/52     75/80                                   Ref.
                                                                                                                                               

    Sugarbeet    Canada      1973   1       0.5          EC

    Roots)                                                           0.05      0.05                                              V 170
         )
    Tops )                                                           0.09      0.07                                              V 170

    Roots                    1973   2       0.5          EC                              <0.02
    Roots                           2       1.0          EC                              <0.02

    Roots                           2       1.0          EC                              <0.02

    Roots)                          1       1.0          EC                              <0.02     0.04
    Tops )                                                                               <0.02     <0.02

                 Japan       1972   3       0.35         EC                                                                      Hokkaido,
    Roots                                                                      <0.02     <0.02                                   exp. sta.
                                                                                                                                 1972

    Tops                                                                       0.43-0.59 0.17-0.30
                             1972   5       0.35

    Roots                                                            0.01                <0.01
    Tops                                                             1.36-1.72           0.66-0.84
                             1972   3       0.35

    Roots                                                            <0.01               <0.01
    Tops                                                             0.59-0.61           0.25-0.27

    TABLE 3. (continued)

                                                                                                                                               
                                        Application
                                                                            Residues in mg/kg, at intervals (days) after application
                                                                                                                                               
                                        rate 
       Crop      Country     Year   No.  kg a.i./ha   formulation    30/33     38/45     50/52     75/80                                   Ref.
                                                                                                                                               
    Sugarbeet
    (cont'd)
                             1972   5       0.35
    Roots                                                            0.01                <0.01

    Tops                                                             0.93-1.02           0.34-0.39

                 Japan       1971   3       0.35                                                                                 Hokkaido,
    Roots                                                            <0.01               <0.01                                   exp. sta.
                                                                                                                                1972
    Tops                                                             0.59-0.66           0.34-0.39
                                    5       0.35
    Roots                                                            0.01                0.01

    Tops                                                             1.75-1.87           0.93-0.98
                             1971   3       0.35

    Roots                                                            <0.01               <0.01

    Tops                                                             0.64-0.69           0.26-0.32
                                    5       0.35

    Roots                                                            <0.01               <0.01

    Tops                                                             1.17-1.20           0.39-0.46
                                                                                                                                               

    * Sun-dried.
    

         In a 10 minutes brew of sun-dried tea harvested seven days after
    treatment no residues of parent leptophos, leptophos-oxon or
    desbromoleptophos was found. The levels of the phenol ranged between
    <0.01 mg/kg and 0.06 mg/kg.

    In a food chain

         Data were obtained in two model studies (Anonymous, 1973;
    Johnson, 1975) with 14C-leptophos in a simple food chain in which
    water, Daphnia magna and the common blue gill (Lepomis macrochirus
    rafinesque) were included.

         Daphnia magna accumulated leptophos rather rapidly from the
    water. In less than four hours leptophos in daphnia reached a constant
    level about 1500 times that in the surrounding water. Blue gills
    feeding on Daphnia magna exposed to leptophos reached a plateau about
    1/10 of that in the daphnia.

         It is obvious that the most significant route of accumulation of
    leptophos residues by fish will be by direct uptake from water.

         Blue gills exposed to leptophos in water only (not in the food)
    contained mean 14C residues in the tissues of 0.179 mg/kg, about 750
    times the mean concentration of 14C-leptophos in the water, after
    10-42 days' exposure. When blue gills were exposed to both aqueous and
    dietary 14C-leptophos for 10-28 days the residue level was almost
    identical (0.170 mg/kg, about 770 times the concentration in the
    water).

         When Daphnia were transferred to insecticide-free water, their
    leptophos level decreased by 50% in about 19 hours. The bio-transfer
    rate of leptophos in the Daphnia-blue gill food chain was only 6.5% of
    that of DDT, a typical bioaccumulating compound.

    APPRAISAL

         Leptophos was evaluated with regard to agricultural data by the
    1974 Joint Meeting (FAO/WHO,1975). Arising from the list of
    requirements, information was obtained on residues from supervised
    trials in various areas on fruit crops (apples and pears), small
    grains, rice, sugar beet, potatoes and on some vegetable crops.

         Some information became available on residues in waste of
    agricultural crops which may be used for feeding purposes, e.g. sugar
    beet leaves, straw and chaff of cereal crops, including rice.

         Additional data were obtained on the fate of leptophos residues
    in apples, cabbage, lettuce and tomatoes from studies with 14C-phenyl
    and 14C-phenoxy-labelled leptophos. Additional data became available
    on the fate of 14C-phenoxy- and 14C-phenyl-labelled leptophos in
    soil. It was shown in this study that the bound fraction increases
    with time at all soil depths. The total 14C in the upper 2.5 cm layer
    decreased with time from 92% of the applied radioactivity to 42% after
    120 days; the total 14C in the lower layers was fairly constant
    during that period.

         New data were obtained from model studies with 14C-labelled
    leptophos in a simple food chain which included water, Daphnia magna
    and the common blue gill. Daphnia magna accumulated leptophos rather
    rapidly from the water; in less than four hours leptophos plateaued in
    Daphnia to levels about 1500 times the level in the surrounding water.
    Blue gills feeding on Daphnia magna exposed to leptophos reached a
    plateau one-tenth of that of the daphnids.

         When Daphnia were transferred to insecticide-free water, their
    leptophos level decreased by 50% in about 19 hours.

         The bio-transfer rate of leptophos in the Daphnia-blue gill food
    chain was less than one-tenth of that of DDT, which is recognized as a
    bioaccumulating compound.

         The new data available confirm the limits recorded at the 1974
    Joint Meeting on cabbage, broccoli, lettuce, tomatoes, potatoes,
    cotton seed and maize.

         In the light of the temporary ADI established at the present
    Meeting these limits are now recommended as temporary maximum residue
    limits, and replace the guideline levels recorded in the 1974
    monograph. Additional temporary maximum residue limits are
    recommended.

    Recommendations

         The maximum residue limits refer to the sum of leptophos, its
    oxygen analogue and desbromo-leptophos, expressed as leptophos.

                                                                           

                                         Maximum        Pre-harvest
                                         residue        interval on which
    Commodity                            limit          recommendation
                                         mg/kg          is based
                                                                           

    Apples, pears                        2              42-60

    Broccoli, Brussels sprouts,
    cabbage                              2              28-50

    Lettuce                              2              28 (outdoor)

    Tomatoes                             2              7

    Cotton seed oil (crude)              1              28

    Raw cereals (wheat, oats,
    barley)                              0.5            60

    Rice (hulled)                        0.5            30

    (Cont'd)
                                                                           

                                         Maximum        Pre-harvest
                                         residue        interval on which
    Commodity                            limit          recommendation
                                         mg/kg          is based
                                                                           

    Cotton seed, cotton seed meal        0.2            28

    Carrots                              0.2            60

    Potatoes                             0.1            21

    Maize, fieldcorn (kernels)           0.05           7

    Sweet corn (kernels and cobs,
    husks and silk removed)              0.05           3-7

    Sunflower seed                       0.05           100

    Sugar beet (roots)                   0.05           50-60

    Sugar beet (tops)                    0.5
                                                                           


    FURTHER WORK OR INFORMATION

    REQUIRED (before 30 June 1978)

    1.   Studies on the kinetics of accumulation of leptophos in storage
    depots of two species, preferably non-rodent to investigate the
    potential buildup in man to ultimate threshold levels.

    2.   Studies on the species variation for delayed neurotoxicity with
    leptophos to assess its ultimate effect on man.

    3.   Epidemiological studies on people in exposed occupations in
    agriculture or industry.

    4.   Further long-term low-level feeding studies in a species
    susceptible to the delayed neurotoxic syndrome.

    5.   Residue data on the major crops for which national tolerances or
    use recommendations exist, e.g., tea, vegetables not included in the
    recommendations, and citrus fruits.

    6.   Residues in those parts of agricultural commodities which are
    used either as such or as agricultural waste for animal feed.

    DESIRABLE

    1.   Improved methodology for assessing the delayed neurotoxic
    syndrome.

    2.   Studies on the mechanism of neurotoxic action of leptophos.
    Further investigations into mechanism of action of TOCP and other
    neurotoxic agents as compared to leptophos.

    3.   Data on current use patterns in countries outside the United
    States of America and Canada and on residue levels resulting from
    those uses.

    REFERENCES

    Anonymous. (1973) Exposure of 14C-leptophos to daphnia magna and
    bluegill sunfish (lepomis macrochiris). Accumulation, distribution,
    elimination and bio-concentration in the food chain. Unpublished
    report from Bionomics, Inc., submitted to FAO by Velsicol Chemical
    Corporation.

    Abou-Donia, M.B., Othman, M.A., Tantawy, G., Khalil, A.Z. and Shawer,
    M.F. (1974) Neurotoxic effect of leptophos. Experimentia, 30:63-64.

    Abou-Donia, M.B. and Pressig, S. (1975) Studies on delayed
    neurotoxicity produced by leptophos. Proc. Fed. Amer. Soc. Exptl.
    Biol., 34:810.

    Arnold, D., Kennedy, G., Keplinger, M.L. and Fancher, O.E. (1971)
    Mutagenic study with Phosvel (VCS-506) in albino mice. Unpublished
    report from Industrial Bio-Test Laboratories, Inc. submitted to the
    World Health Organization by Velsicol Chemical Corporation.

    Badie, M. and Whitacre, D.M. (1975) Metabolism of 14C-leptophos and
    14C-4-bromo-2,5-dichlorophenol in rats: A multiple dosing study.
    Unpublished report submitted to the World Health Organization by
    Velsicol Chemical Corporation.

    Braun, E., McEwen, F.L., Frank, R. and Ritcey, G. (1975) Residues of 
    leptophos and its metabolites following application to various crop
    plants. J. Agr. Food Chem., 23(1):90-95.

    Braun, E., McEwen, F.L., and Frank, R. (1974) Residues of
    chlorpyriphos and leptophos in three field tested vegetable crops.
    Canad. J. Plant Sci., 55:133-137.

    Diaz, L.I. (1974) Radiotracer study of leptophos on cabbage. Velsicol
    Chem. Corp. Lab. rep. 194. (Unpublished)

    Dorough, H.W. (1974) Fate of phosvel-14C in burley tobacco. Progress
    report of Department of Entomology, University of Kentucky, Lexington,
    provided to Velsicol. (Unpublished)

    Fink, R.J. (1971) Continuous feeding and residue study - cows with
    technical Phosvel (VCS-506). Unpublished report from Hazleton
    Laboratories, submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Fletcher, D., Jenkins, D.H., Kinoshita, P.R., Gordon, D.E. and
    Keplinger, M.L. (1975) Neurotoxicity study with technical leptophos in
    chickens. Unpublished report from Industrial Bio-Test Laboratories,
    Inc., submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Haley, S., Plank, J.B., Wright, P.L. and Keplinger, M.L. (1972) Three
    generation reproduction study with VCS-506 in albino rats. Unpublished
    report by Industrial Bio-Test Laboratories, Inc. submitted to the
    World Health Organization by Velsicol Chemical Corporation.

    Haley, S., Kennedy, G.L. and Keplinger, M.L. (1973) Three-generation
    reproduction study with VCS-506 in albino rats. Unpublished report
    from Industrial Bio-Test Laboratories, Inc., submitted to the World
    Health Organization by Velsicol Chemical Corporation.

    Hartke, K., Lindberg, D.C., Wright, P.L. and Keplinger, M.L. (1971)
    Two-year chronic oral toxicity study with VCS-506 technical in beagle
    dogs. Unpublished report from Industrial Bio-Test Laboratories, Inc.,
    submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Hassan, A. (1975) Personal communication to the World Health
    Organization. 

    Hathaway, D., Keplinger, M.L. and Fancher, O.E. (1968) Acute aerosol
    inhalation toxicity study on VCS-506, 3 EC. Unpublished report from
    Industrial Bio-Test Laboratories, Inc., submitted to the World Health
    Organization by Velsicol Chemical Corporation.

    Hokkaido. (1972) Phosphel residue analysis on sugar beet. National
    Hokkaido. Agr. Exp. Sta. Residue data provided to Velsicol.
    (Unpublished)

    Holmstead, R.L., Fukuto, T.R. and March, R.B. (1973) The metabolism of
    O-(4-bromo-2,5-dichlorophenyl) O-methyl phenylphosphonothioate
    (leptophos) in white mice and cotton plants. Archives of Environmental
    Contamination and Toxicology. Vol. 1, No. 2, 133-147.

    Johnson, B.T. (1973) Leptophos accumulation through a simple food
    chain. Unpublished report from the United States Department of the
    Interior, submitted to the World Health organization by Velsicol
    Chemical Corporation.

    Johnson, M.K. (1975) The delayed neuropathy caused by some
    organophosphorus esters: Mechanism and challenge. CRC Critical Reviews
    in Toxicology, June.

    Kennedy, G. and Keplinger, M.L. (1971) Absorption, distribution, and
    excretion study with Phosvel in albino rats. Unpublished report from
    Industrial Bio-Test Laboratories, Inc., submitted to the World Health
    organization by Velsicol Chemical Corporation.

    Kennedy, G. and Keplinger, M.L. (1971a) Characterization of 14C in
    excreta of rats following oral administration of Phosvel. Unpublished
    report from Industrial Bio-Test Laboratories, Inc. submitted to the
    World Health Organization by Velsicol Chemical Corporation.

    Kennedy, G. and Keplinger, M.L. (1972) Absorption, distribution, and
    excretion study with VCS-506 in albino rats. Unpublished report from
    Industrial Bio-Test Laboratories, Inc., submitted to the World Health
    Organization by Velsicol Chemical Corporation.

    Kennedy, G., Keplinger, M.L. and Fancher, O.E. (1970) Distribution and
    excretion study of VCS-506 in albino rats. Unpublished report from
    Industrial Bio-Test Laboratories, Inc., submitted to the World Health
    Organization by Velsicol Chemical Corporation.

    Kennedy, G., Keplinger, M.L. and Fancher, O.E. (1970a)
    Characterization of 14C in urine of rats following oral
    administration of 14C-VCS-506. Unpublished report from Industrial
    Bio-Test Laboratories, Inc., submitted to the World Health
    Organization by Velsicol Chemical Corporation.

    Kimmerle, G. (1972) Acute neurotoxicity studies in hens. Unpublished
    report from Farbenfabriken Bayer, submitted to the World Health
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    Kretchmar, B., Mastri, C. and Keplinger, M.L. (1971) Study of the
    efficacy of atropine sulfate and 2-PAM as antidotes for VCS-506
    intoxication in albino rats. Unpublished report from Industrial
    Bio-Test Laboratories, Inc., submitted to the World Health
    Organization by Velsicol Chemical Corporation.

    Kretchmar, B., Mastri, C., Keplinger, M.L. and Fancher, O.E. (1971a)
    Acute oral (intragastric) toxicity studies with VCS-506 in one day old
    and five day old albino rats. Unpublished report from Industrial
    Bio-Test Laboratories, Inc., submitted to the World Health
    Organization by Velsicol Chemical Corporation.

    Kretchmar, B., Mastri, C. and Keplinger, M.L. (1972) Acute oral
    toxicity study with oxon of VCS-506 in albino rats. Unpublished report
    from Industrial Bio-Test Laboratories, Inc., submitted to the World
    Health Organization by Velsicol Chemical Corporation.

    Kretchmar, B,, Mastri, C. and Keplinger, M.L. (1972a) Acute oral range
    finding toxicity study with S-isomeride in female albino rats.
    Unpublished report from industrial Bio-Test Laboratories, Inc.,
    submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Ladd, R., Jenkins, D.H., Wright, P.L. and Keplinger, M.L. (1971)
    Teratogenic study with Phosvel in albino rabbits. Unpublished report
    from Industrial Bio-Test Laboratories, Inc., submitted to the World
    Health organization by Velsicol Chemical Corporation.

    Lindburg, D., Vondruska, J.F. and Fancher, O.E. (1969) Ninety-day
    subacute oral toxicity of VCS-506 in beagle dogs. Unpublished report
    from Industrial Bio-Test Laboratories, Inc., submitted to the World
    Health Organization by Velsicol Chemical Corporation.

    March, R.B. and Fukuto, T.R. (1975) Reports on studies on the
    photolysis and metabolism of Phosvel. Unpublished report from the
    University of California, submitted to the World Health Organization
    by Velsicol Chemical Corporation.

    Mastri, C., Keplinger, M.L. and Fancher, O.E. (1969) Acute oral
    toxicity study on VCS-506 technical in albino rats. Unpublished report
    from Industrial Bio-Test Laboratories, Inc., submitted to the World
    Health Organization by Velsicol Chemical Corporation.

    Mastri, C., Keplinger, M.L, and Fancher, O.E. (1969a) Acute oral
    toxicity study on two formulations of VCS-506 E.C. in albino rats.
    Unpublished report from Industrial Bio-Test Laboratories, Inc.,
    submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Mastri, C., Keplinger, M.L. and Fancher, O.E. (1969b) Acute oral
    toxicity on four metabolites of VCS-506 in albino rats. Unpublished
    report from Industrial Bio-Test Laboratories, Inc., submitted to the
    World Health Organization by Velsicol Chemical Corporation.

    Mastri, C., Keplinger M.L. and Fancher, O.E. (1969c) Acute oral
    toxicity study on phenylphosphonic acid in albino rats. Unpublished
    report from industrial Bio-Test Laboratories, Inc., submitted to the
    World Health Organization by Velsicol Chemical Corporation.

    Miyagi. (1971) Phosphel residues on chinese cabbage. Miyagi Pref. Agr.
    Exp. Sta. and Aichi Pref. Agr. Exp. Sta. Residues data provided to
    Velsicol.

    Niigata. (1973) Phosphel residue analysis on rice. Niigata Pref. Agr.
    Exp. Sta. and Shizuoka Pref. Agr. Exp. Sta. Data provided to Velsicol.
    (Unpublished)

    Perkins, C.T. and Singh, V.K. (1971) Chicken toxicity and residue
    study. Unpublished report from Bio/Toxicological Research
    Laboratories, Inc., submitted to the World Health organization by
    Velsicol Chemical Corporation.

    Perkins, C.T. and Singh, V.K. (1971a) Beef animal feeding study.
    Unpublished report from Bio/Toxicological Research Laboratories, Inc.,
    submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Plank, J., Keplinger, M.L. and Fancher, O.E. (1970) Cholinesterase
    study of VCS-506 in albino rats. Unpublished report from International
    Research and Development Corporation submitted to the World Health
    Organization by Velsicol Chemical Corporation.

    Plank, J.B., Keplinger, M.L. and Fancher, O.E. (1971) Twenty-eight day
    target organ study with VCS-506 oxon metabolite in albino rats.
    Unpublished report from Industrial Bio-Test Laboratories, Inc.,
    submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Plank, J.B., Keplinger, M.L. and Fancher, O.E. (1971a) Twenty-eight
    day target organ study with VCS-506 phenol metabolite in albino rats.
    Unpublished report from Industrial Bio-Test Laboratories, Inc.,
    submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Plank, J.B., Wright, P.L., Keplinger, M.L. and Fancher, O.E. (1971b) 
    Ninety-day subacute oral toxicity, study with VCS-506 Phenol
    metabolite in albino rats. Unpublished report from Industrial Bio-Test
    Laboratories, Inc., submitted to the World Health Organization by
    Velsicol Chemical Corporation.

    Plank, J.B., Wright, P.L., Keplinger, M.L. and Fancher, O.E. (1971c)
    Ninety-day subacute oral toxicity study with VCS-506 oxon metabolite
    in albino rats. Unpublished report from Industrial Bio-Test
    Laboratories, Inc., submitted to the World Health Organization by
    Velsicol Chemical Corporation.

    Rieck, C.E. (1974) Soil metabolism of 14C-leptophos. Report of Agr.
    Dept., University of Kentucky, Lexington, provided to Velsicol.
    (Unpublished)

    Sanborn, A. and Metcalf, R.L. (1975) The fate of leptophos (Phosvel)
    in a terrestrial-aquatic ecosystem. Unpublished report from the
    University of Illinois submitted to the World Health Organization by
    Velsicol Chemical Corporation.

    Schroeder, C. (1971) The radiocarbon distribution of 14C labelled
    Phosvel in lettuce and green beans. Unpublished report from WARF
    Institute submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Schwemmer, B. (1971) UV photolysis of leptophos in solution.
    Unpublished report submitted to the World Health Organization by
    Velsicol Chemical Corporation.

    Sleight, B.H. and Macek, K.J. (1973) Exposure of 14C-leptophos to
    Daphnia magna and bluegill sunfish (Lepomis macrochirus):
    Accumulation, distribution, elimination, and bioconcentration in the
    food chain. Unpublished report from Bionomics, Inc. submitted to the
    World Health Organization by Velsicol Chemical Corporation.

    Smith, P.S., Plank, J.B., Wright, P.L. and Keplinger, M.L. (1971)
    Twenty-eight day cholinesterase study with VCS-506 oxon metabolite in
    female albino rats. Unpublished report from Industrial Bio-Test
    Laboratories, Inc. submitted to the World Health Organization by
    Velsicol Chemical Corporation.

    Smith, P.S., Plank, J.B., Wright, P.L. and Keplinger, M.L. (1971a)
    Two-year chronic oral toxicity study with VCS-506 technical in albino
    rats. Unpublished report from Industrial Bio-Test Laboratories, Inc.
    submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Smith, P.S., Reyna, M.S., Kennedy, G.L. and Keplinger, M.L. (1973)
    Eighteen-month carcinogenic study with VCS-506 technical in Swiss
    white mice. Unpublished report from Industrial Bio-Test Laboratories,
    Inc. submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Stephens, J.L., Jenkins, D.H. and Fancher, O.E. (1969) Demyelination
    study-chickens, VCS-506 Technical. Unpublished report from industrial
    Bio-Test Laboratories, Inc. submitted to the World Health Organization
    by Velsicol Chemical Corporation.

    Suzuki, H. (1971) Phosvel-chicken feeding study. Unpublished report
    from Velsicol Chemical Corporation submitted to the World Health
    Organization by Velsicol Chemical Corporation.

    Suzuki, H. (1971a) Phosvel-dairy cattle feeding study. Unpublished
    report from Velsicol Chemical Corporation submitted to the World
    Health Organization by Velsicol Chemical Corporation.

    Tarka, S.M. Jr. (1973) Identification of radioactivity in the fat of
    rats administered 14C-phenoxy-labelled leptophos. Unpublished report
    submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Wazeter, F.X. (1965) Acute oral toxicity (LD50) in the albino rat.
    Unpublished report from International Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation. 

    Wazeter, F.X. (1966) Acute oral toxicity (LD50) in male albino rats.
    Unpublished report from International Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Wazeter, F.X. (1968) Comparative acute oral toxicity in male albino
    rats. Unpublished report from International Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Wazeter, F.X. (1968a) Acute toxicity studies in the albino rabbit.
    Unpublished report from International Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Wazeter, F.X. (1968b) Acute toxicity study in the rabbit. Unpublished
    report from International Research and Development Corporation
    submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Wazeter, F.X. (1968c) Ten-day subacute oral toxicity study in rats for
    analysis of plasma, erythrocyte and brain cholinesterase activity.
    Unpublished report from International Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Wazeter, F.X. (1969) Ninety-day feeding study in albino rats.
    Unpublished report from International Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Wazeter, F.X. (1970) Acute toxicity studies in rats and rabbits.
    Unpublished report from International Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Wazeter, F.X. (1970a) Acute oral toxicity (LD50) in the male albino
    rat. Unpublished report from international Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Wazeter, F.X. (1970b) Acute toxicity studies in rats and rabbits.
    Unpublished report from International Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Wazeter, F.X. (1971) Acute oral toxicity (LD50) in male and female
    albino rats. Unpublished report from International Research and
    Development Corporation submitted to the World Health Organization by
    Velsicol Chemical Corporation.

    Wazeter, F.X. (1971a) Acute oral toxicity (LD50) in male and female
    albino rats. Unpublished report from International Research and
    Development Corporation submitted to the World Health Organization by
    Velsicol Chemical Corporation.

    Wazeter, F.X. (1971b) Acute oral toxicity (LD50) in male and female
    albino rats. Unpublished report from International Research and
    Development Corporation submitted to the World Health Organization by
    Velsicol Chemical Corporation.

    Wazeter, F.X. (1971c) Acute toxicity studies in rats and rabbits.
    Unpublished report from International Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Wazeter, F.X. (1971d) Acute toxicity studies in rats and rabbits.
    Unpublished report from International Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Wazeter, F.X. (197le) Acute toxicity studies in rats and rabbits.
    Unpublished report from International Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Wazeter, F.X. (1971f) Acute oral LD50 in albino rats. Unpublished
    report from International Research and Development Corporation
    submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Wazeter, F.X. (1971g) Acute oral LD50 in albino rats. Unpublished
    report from International Research and Development Corporation
    submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Wazeter, F.X. (1971h) Acute oral LD50 in albino rats. Unpublished
    report from International Research and Development Corporation
    submitted to the World Health Organization by Velsicol Chemical
    Corporation.

    Wazeter, F.X. (1971i) Acute toxicity studies in rats and rabbits.
    Unpublished study by International Research and Development
    Corporation submitted to the World Health Organization by Velsicol
    Chemical Corporation.

    Wazeter, F.X. and Goldenthal, E.I. (1972) Acute oral toxicity (LD50)
    in male and female albino rats. Unpublished report by International
    Research and Development Corporation submitted to the World Health
    Organization by Velsicol Chemical Corporation.

    Wazeter, F.X. and Goldenthal, E.I. (1973) Acute dermal toxicity
    (LD50) in male and female albino rabbits. Unpublished report from
    International Development Corporation submitted to the World Health
    Organization by Velsicol Chemical Corporation.

    Whitacre, D.M. and Schnur, P.D. (1974) Metabolic fate of 14C-labelled
    leptophos on apples. Velsicol Chem. Corp. Lab. rep. No. 195.
    (Unpublished)
    


    See Also:
       Toxicological Abbreviations
       Leptophos (PDS)
       Leptophos (WHO Pesticide Residues Series 4)
       Leptophos (Pesticide residues in food: 1978 evaluations)