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    CHLORPYRIFOS-METHYL     JMPR 1975

    IDENTITY

    Chemical name

         O,O-Dimethyl 0-3,5,6-trichloro-2-pyridyl phosphorothioate

    Synonyms

         DOWCOR 214, ENT 27520, OMS 1155, RELDANR, DOWRELDANR 
         ZERTELLR

    Structural formula

    CHEMICAL STRUCTURE 1


    Other information on identity and properties

    (Brust, 1969; Kenaga, 1971)

         Molecular weight      :   322.6

         State                 :   Granular crystalline solid

         Colour and odour      :   White/mild mercaptan

         Melting point         :   45.5-46.5C

         Vapour pressure       :   7.40  10-7mm Hg at 0C

                                   4.22  10-5mm Hg at 25C

                                   1.8  10-4mm Hg at 35C

         Solubility (g/100g    :   Acetone               640
         at 23C)
                                   Acetonitrile          680

                                   Benzene               520

                                   Carbon disulfide      430

                                   Carbon tetrachloride  280

                                   Chloroform            330

                                   Diethyl ether         480

                                   Ethanol                30

                                   Methanol               30

                                   n-Octanol              20

                                   Hexane                 23

                                   Water              0.0004

                                   The compound readily dissolves in
                                   dimethylformamide, N-methylpyrrolidine,
                                   tetrahydrofuran, xylene, methylene
                                   chloride and 1,1,1-trichloroethane.

         Stability             :   Chlorpyrifos-methyl is reported to be
                                   hydrolyzed by water, the rate being
                                   dependent on temperature and pH.
                                   Half-lives at 25C vary from 22.7 to
                                   9.4 days in tap water and buffered
                                   distilled water within the Ph range
                                   4.2-8.0.
                                   This hydrolysis is enhanced by traces
                                   of copper ions due to chelation
                                   (Meikle, 1973). The major products of
                                   hydrolysis are
                                   3,5,6-trichloro-2-pyridinol and
                                   O,O-dimethyl phosphate.
                                   Photodecomposition of evaporated
                                   chlorpyrifos-methyl in humid air is
                                   also reported, with the formation of
                                   3,5,6-trichloro-2-pyridinol,
                                   hydroxylated pyridinol derivatives and
                                   oxidation products of quinone
                                   structures (Smith & Taylor, 1972).

         Purity                :   The crystalline compound is stated to
                                   be 99.8%  0.1%.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, distribution and excretion

         When 2,6 C14 ring labelled chlorpyrifos-methyl was administered
    as a single oral dose (16 mg/kg) to rats, the radioactivity was
    rapidly absorbed and excreted. After 72 hours, 90-93% of the
    radioactivity was eliminated from the body, 83-85% in urine, 7-9% in
    faeces and 0.23-0.43% in respired air. Maximum blood levels (2.4-3.7%)
    were reached five hours after treatment. The maximum amount of the
    dose remaining in the tissues by 72 hours was 0.65-1.3 ppm. Individual
    tissue levels were low (less than 1 ppm). Urinary metabolites were
    shown to be 3,5,6 trichloro-2-pyridinol and unidentified activity at
    the origin by thin layer chromatography. The possibility of urinary
    conjugates was not studied (Branson and Litchfield, 1971a).

         The distribution of a single oral dose of C14 labelled
    chlorpyrifos-methyl in the body of the young rat was investigated by
    whole body autoradiographic techniques. Whole body autoradiograms were
    taken at 0.5, 1, 3, 5, 7, 24, 72 and 120 hours after treatment. The
    highest level was found initially in the blood. The dispersion in the
    various tissues reached a peak at three hours. Residues were extremely
    low in fat, liver, kidney and intra-intestinal faeces 72 hours after
    administration and completely eliminated from the body by 120 hours
    (Nakajima et al., 1974).

    Biotransformation

         The metabolism of 2,6 C14 ring labelled chlorpyrifos-methyl was
    studied in sheep and rats using radioactive counting,
    mass-spectroscopy, infrared spectroscopy, column, thin-layer and gas
    liquid chromatography techniques. Two ewes were dosed orally with 100
    mg/kg by gelatin capsule. Recoveries of radioactivity after four days
    were 69.2% in urine, 12.5% in faeces and 2% in tissues. No C14O2 was
    detected. Radioactivity in the urine was shown to be the glucuronide
    of 3,5,6 trichloro-2-pyridinol 41.6%, o-methyl-o-trimethylsily-o-(3,
    5,6 trichloro-2 -pyridyl) phosphorothionate 38% and three minor
    unknown fractions 5.2%. In the faeces, 34% of the faecal radioactivity
    consisted of parent compound and 55.3% made up primarily of
    o-methyl-o-hydrogen-(3,5,6 trichloro-2-pyridyl) phosphorothionate and

    3,5,6 trichloro-2-pyridinol. The three fractions found in the urine
    were present in the plasma. Detectable amounts of radioactivity (0.32
    to 11.8 ppm) were found in the tissues after 96 hours, the highest
    level being found in visceral fat (Branson and Litchfield, 1971; Bakke
    and Price, 1975).

         Ten male rats were given a single oral dose (10 mg) of 2,6 C14
    ring labelled chlorpyrifos-methyl. After 48 hours the radioactivity in
    the urine consisted of three components, the glucuronide of 3,5,6
    trichloro-2-pyridinol (68.6%), o-methyl-o-hydrogen-o (3,5,6
    trichloro-2-pyridyl) phosphorothionate (17.8%) and 3,5,6
    trichloro-2-pyridinol (13.8%). Faecal metabolites were not
    characterized. No respiratory C14O2 was detected (Bakke and Price,
    1975).

         The principal metabolite of chlorpyrifos-methyl has been shown to
    be 3,5,6-trichloro-2-pyridinol. The metabolism of this metabolite in
    rats was summarized by FAO/WHO (1973) when the pesticide chlorpyrifos
    was evaluated. It was rapidly absorbed and excreted primarily in the
    urine and faeces. Small tissue residues (<0.3 ppm) were present and
    occurred mainly in biological systems involved with urinary excretion,
    i.e. liver, kidney and blood. Residues of the pyridinol in fat were
    trivial, which is consistent with its much greater polarity (FAO/WHO,
    1973; Smith et al., 1970).

         In a similar study in sheep a single oral dose 2,6 C14 ring
    labelled 2,5,6 trichloro-2-pyridinol was shown to be rapidly absorbed
    and excreted in the urine and faeces. The only radioactive component
    detected in the plasma and urine was the glucuronide of the pyridinol
    and in faeces the unchanged pyridinol. No C14O2 was detected in
    respired air. Residues in tissues after 96 hours were mainly in the
    digestive and excretory tracts and was non-detectable in fat, muscle,
    heart and other tissues (Bakke and Price, 1975).

    TOXICOLOGICAL STUDIES

    Special studies on carcinogenicity

         Rat

         Chlorpyrifos-methyl was administered to groups of Sprague-Dawley
    CD strain rats at dietary levels of 0, 0.1 and 1.0 mg/kg/day for 104
    weeks. There were no overt signs of reaction to the test compound.
    Body weight gain, food consumption, efficiency of food utilization
    were comparable between groups and within normal limits. The changes
    observed on gross and histopathological examination were those
    consistent with the age and strain of rat employed. There was no
    compound-related effect an the incidence of spontaneous tumours
    (Hunter et al., 1974b).

    Special studies on neurotoxicity

         Chlorpyrifos-methyl was administered orally to adult hens at 4860
    mg/kg body weight and were observed for 21 days. Survivors were given
    an intramuscular injection of atropine (10 mg/kg) and PAM (50 mg/kg)
    and redosed with 4455 mg/kg chlorpyrifos-methyl and observed for a
    further 21 days. No signs of ataxia were detected. The birds were not
    examined histologically for nervous systems lesions. TOCP was used as
    a positive control (Ross et al., 1975).

    Special studies on reproduction

         Rat

         In a three generation reproduction study (two litters per
    generation) three groups of 10 male and 20 female rats received
    chlorpyrifos-methyl at dietary levels of 0, 1.0 or 3.0 mg/kg body
    weight/day. No treatment related effects on behaviour, survival, body
    weight gain or food consumption were observed in parental animals.
    Fertility, gestation, viability and lactation indices were comparable
    to control values. Pup weights of the second litter, third generation
    were significantly less than control at 0, 4 and 21 days postpartum.
    There was no effect on sex ratio. In adults of third generation,
    plasma cholinesterase activity was decreased in both sexes at both
    dosage levels. Erythrocyte cholinesterase depression was observed at 1
    mg/kg in females and in both sexes at the highest dose level. Brain
    cholinesterase activity was not affected. Gross and histopathological
    examination of control and high dose parental animals of the third
    generation did not reveal any treatment related abnormalities
    (Thompson et al., 1975).

    Special studies on teratogenicity

         Mouse

         Chlorpyrifos-methyl was administered orally to mice at dosage
    levels of 0, 20, 100 and 250 mg/kg body weight/day from day 7 through
    day 13 of gestation. Animals were sacrificed on day 18 and pups
    removed by caesarean section. No significant differences between the
    control and treated groups were observed in regard to number of
    implants and number of deaths. Body weights were lower in both males
    and females at 250 mg/kg. An increased incidence of cleft palate and a
    delay of ossification of the cervicovertebral body was observed at 250
    mg/kg. When pregnant mice were dosed with a single oral dose of 1000
    mg/kg on the seventh or eleventh day of pregnancy, there was no effect
    on mortality or body weights of the foetuses. Skeletal abnormalities
    were observed (exencephalia, cleft palate, liberation of bone fragment
    of cervicovertabral arch) in a few cases especially on treatment on
    seventh day of gestation. No control data was presented in the 1000
    mg/kg body weight study. In a further study, pregnant mice were
    treated as before with 0, 20, 100 and 250 mg chlorpyrifos-methyl/kg

    body weight/day on day 7 through day 13 of gestation. Females were
    allowed to deliver their pups. Body weights at birth and after three
    weeks were dose dependent, being lower on the higher treatment. No
    significant morphological abnormalities were detected (Esaki et al.,
    1973).

         Pregnant rats received 0, 20, 100 and 250 mg/kg body weight of
    chlorpyrifos-methyl from day 9 to day 15 of gestation. On day 20
    animals were laparotomized and embryos removed. No reproductive or
    teratogenic effects were observed. In a similar study the pregnant
    rats were allowed to deliver their progeny. Body weight at birth
    tended to be higher in the treated groups but no differences observed
    when weaned at four weeks. No teratogenic effects related to treatment
    were noted (Esaki et al., 1973).

         Chlorpyrifos-ethyl was administered to pregnant rats at 0, 50,
    100 or 200 mg/kg body weight/day on days 6 through 15 of gestation.
    Animals were killed on day 21 of gestation and foetuses removed by
    caesarean section. No significant effects were observed in the number
    of corpora lutea per pregnant female, the number of resorption sites
    or the number of live foetuses. No dose-related effects were observed
    in the incidence of runts, subcutaneous oedema and dilated renal
    pelvis. Evidence of delayed ossification of sternabrae was observed at
    all treatment levels with an increase in lumbar spurs at the high dose
    level. The administration of 200 mg chlorpyrifos-methyl/kg body weight
    for 10 days caused a significant decrease in plasma and red blood cell
    cholinesterase activity in maternal blood as well as in a homogenate
    of foetal tissues (Schwetz et al.  1973;Schwetz, 1974a, b).

    Acute toxicity
                                                                                                

                                               LD50
    Species     Sex     Route     Solvent      (mg/kg)     Reference
                                                                                            

    Rat         M       oral      CMC          3 733       Hasegawa at al., 1973a
                F       oral      CMC          3 597                  "
                M       oral      corn oil     2 472                  "
                F       oral      corn oil     1 828                  "
                M&F     oral      corn oil     1 700       Davis and Collins, 1975
                M       oral      corn oil     2 140       Litchfield and Norris, 1969
                F       oral      corn oil     1 090                  "
                M       oral      corn oil     2 140       Olson, 1964a
                F       oral      corn oil     1 630             "
                F       oral      corn oil     >1 000      Olson et al., 1963
                F       oral      corn oil     3 600       Esaki et al., 1973
                M&F     dermal    CMC          >4 827      Hasegawa et al., 1973a
                M&F     dermal    corn oil     >3 713                 "

                                                                                            

                                               LD50
    Species     Sex     Route     Solvent      (mg/kg)     Reference
                                                                                            




    Mouse       M       oral      corn oil     2 254                  "
                F       oral      corn oil     2 032                  "
                M       oral      arachis oil  1 122       WHO, 1966
                F       oral      corn oil     2 440       Esaki et al., 1973
                M&F     dermal    CMC          >2 856      Hasegawa at al., 1973a

    Cavy        M       oral      corn oil     2 250       Olson, 1964a

    Rabbit      M&F     oral      corn oil     approx.
                                               2 000             "

    Chicks      M       oral      corn oil     >7 950      Olsen, 1964a
                        (capsule)

    Chicken     F       oral      corn oil     4 860       Ross et al., 1975
                        (capsule)
                M&F     oral      corn oil     7 532       Ross and Roberts, 1974
                        (gavage)
                        oral      corn oil     8 000                  "
                        (capsule)
                                                                                            
    
         Undiluted chlorpyrifos-methyl was applied directly to
    conjunctival sac of rabbits. There were signs of conjunctival
    irritation which subsided after 24-48 hours. No corneal injury was
    discernible (Olson and Taylor, 1964b).

         No significant skin reaction occurred when undiluted
    chlorpyrifos-methyl was applied to shaved and abraded skin of the
    rabbit for prolonged periods (Olson and Taylor, 1964b; United States
    Army, 1973).

         Cholinesterase activity was reduced by 90% and all animals died
    within 24 hours when rats were treated orally with chlorpyrifos-methyl
    (4 g/kg) and subcutaneously with various levels of atropine sulfate.
    Rats were treated with a sublethal oral dose of chlorpyrifos-methyl in
    conjunction with subcutaneous injections of atropine sulfate and PAM
    (25, 50 and 100 mg/kg) and glutathione (100, 300, 500 and 700 mg/kg)

    or combinations of each. Symptoms of anticholinesterase activity were
    observed and total blood, erythrocyte, plasma and brain cholinesterase
    levels determined. The antidotes were effective especially at the
    upper dose levels in reducing the toxic symptoms. The combination of
    atropine sulfate with PAM or glutathione was more effective than
    atropine sulfate alone (Hayashi et al., 1973).

         Chlorpyrifos-methyl was administered to groups of rats at 5 x
    LD50 (8.5 g/kg). At first signs of anticholinesterase activity one
    group was given atropine sulfate (17.5 mg/kg) intramuscularly and a
    further group atropine sulfate (17.5 mg/kg) and PAM (50 mg/kg)
    intramuscularly. A further administration of antidote was given to all
    rats seven hours after treatment. All treated rats died within 24
    hours, untreated controls died within eight hours (Davies and Collins,
    1975).

    Short-term studies

         Avian species

         Mallard ducks, bobwhite and Japanese quail were fed various
    levels of chlorpyrifos-methyl for five days and observed for a further
    three days. The following LC50 values were determined.

         Bobwhite quail - 1835 ppm, Japanese quail ->5000 ppm, mallard
    duck - 2500-5000 ppm. Body weight and food consumption were reduced
    for bobwhite and Japanese quail at 2500 and 1250 ppm respectively and
    at 5000 ppm for the mallard duck. In a similar study, mallard ducks
    were fed graded levels of chlorpyrifos-methyl for five days. Whole
    blood cholinesterase activity was inhibited at dietary levels of 78
    ppm and greater. Brain cholinesterase was not affected at the highest
    level tested (Shellenberger, 1970).

         Mouse

         Chlorpyrifos-methyl was administered orally to mice at 0, 100,
    250, 500 and 1000 mg/kg body weight/day for 14 days. No effect on
    mortality or significant changes in body weight at 100 and 250 mg/kg
    were observed. After four doses, there was 100% mortality at 1000
    mg/kg. At 500 mg/kg, 40% mortality occurred in 14 days and a
    noticeable decrease in body weight (Esaki et al., 1973).

         Groups of male and female mice were fed standard diets containing
    0, 0.5, 1, 5, 10, 20, 30, 40 and 100 ppm for a period of six months.
    No differences were observed in mortality, food intake, body weight
    gain, organ weights and urinalysis. Haematological, biochemical and
    pathohistological parameters were considered normal in groups given
    less than 40 ppm. Plasma and erythrocyte cholinesterase activities
    were lower at dosage levels greater than 20 ppm. Brain cholinesterase
    was decreased in males given 40 and 100 ppm and in females given 40
    ppm (Hasegawa et al., 1973c).

         Rat

         Chlorpyrifos-methyl was administered orally to rats at 20, 100
    and 500 mg/kg body weight/day for 14 days. No significant effect on
    mortality or body weight gain was shown. At 500 mg/kg hypertrophy of
    the liver and heart were observed (Esaki et al., 1973).

         Groups of female rats were fed chlorpyrifos-methyl in the diet
    for 14 days at 0, 1.6, 6, 25, 95, 500 and 2130 mg/kg body weight/day.
    Plasma and red blood cell cholinesterase was depressed at 6 mg/kg and
    in brain at 95 mg/kg. Organ to body weight ratios of liver, kidney and
    spleen were not significantly different from control but brain to body
    weight ratio was increased at 2130 mg/kg. No compound-related gross or
    histopathological lesions were observed (United States Army, 1973).

         Groups of six male and female rats consumed in their diet 0,
    0.08, 0.8, 8.0, 40, 80 and 160 mg chlorpyrifos-methyl/kg body
    weight/day for 90 days. Plasma cholinesterase activity was depressed
    in males at 8 mg/kg and above and in females at 0.8 mg/kg and above.
    The incidence of erythrocyte and brain cholinesterase depression was
    significantly increased at 8.0 mg/kg/day and above for both male and
    female. Liver weight to body weight ratio of male rats was increased
    at 40, 80 and 160 mg/kg. Apart from small aggregates of lymphocytes
    and plasma cells in the periportal areas of the liver, no changes were
    noted in gross or histopathology (Steinberg, 1971).

         Chlorpyrifos-methyl was fed at dietary levels of 0, 0.5, 1, 5,
    10, 20, 30, 40 and 100 ppm to groups of male and female Wistar rats
    for six months. No significant differences were noted in mortality,
    food intake, weight gain, organ weights and urinalysis.
    Haematological, biochemical and pathological findings were not
    affected at 40 ppm or less. Serum and erythrocyte cholinesterase
    activity was decreased at 30 ppm and above at one, three and six
    months (Hasegawa et al., 1973b).

         Groups of five male and five female rats received 0, 0.2, 1.0 and
    5.0 mg chlorpyrifos-methyl/kg body weight/day by stomach tube daily,
    six days/week, for six weeks. Plasma cholinesterase activity was
    depressed in females at 5 mg/kg. Erythrocyte and brain cholinesterase
    activities were not significantly reduced. Growth, haematology, blood
    chemistry and liver microsomal mixed function oxidase activities were
    not affected (Coulston and Griffin, 1975).

         Dog

         Groups of dogs (two males and two females/group) were fed
    chlorpyrifos-methyl in the diet for 92 days at dose levels of 0, 0.3,
    1, 3 and 10 mg/kg body weight/day. No treatment-related effects were
    observed in behaviour, food consumption, body weight, hematology,

    clinical chemistry, urinalysis, organ weight: body weight ratios,
    gross and histopathology. Plasma cholinesterase activity at all test
    levels was depressed after one, four and 12 weeks of treatment.
    Inhibition of erythrocyte cholinesterase activity was evident at 1.0,
    3.0 and 10.0 mg/kg body weight/day. The activity of brain
    cholinesterase was not affected (Sparschu et al., 1971).

         A supplemental study was conducted in which groups of dogs (two
    males and two females/group) were fed chlorpyrifos-methyl in the diet
    at dose levels of 0, 0.03 and 0.1 mg/kg body weight/day for 125 days.
    There was no significant depression of plasma or erythrocyte
    cholinesterase activity. Behaviour was normal and body weight and food
    consumption considered to be within normal limits (Humiston et al.,
    1972).

         Groups of dogs (seven males and seven females/group) were fed
    chlorpyrifos-methyl at dietary levels of 0, 0.03, 0.1, 1.0 and 3.0
    mg/kg/day for 104 weeks with an interim sacrifice of three males and
    three females/group at 26 weeks. No significant effects were observed
    with respect to mortality, behaviour, food and water consumption,
    ophthalmology, haematology, blood biochemistry, organ to body weight
    ratio or gross and histopathology at either 26 or 104 weeks. Treated
    animals gained less weight than controls due to some weight loss
    during the latter part of the study. Body weights, however, were
    considered within normal limits. Cholinesterase activity was depressed
    in red blood cell and plasma at 3.0 mg/kg and in plasma at 1.0 mg/kg.
    There was no reduction in brain cholinesterase activity at 26 or 104
    weeks (Rivett et al., 1974).

         Monkey

         Chlorpyrifos-methyl was administered by stomach tube daily, six
    days/week for six months to five groups of rhesus monkeys, three male
    and three female group at dose levels of 0, 0.1, 0.2, 1.0 and 5.0
    mg/kg body weight/day. Plasma cholinesterase was depressed in those
    animals receiving 1.0 and 5.0 mg/kg. Inhibition of erythrocyte
    cholinesterase was evident at 5.0 mg/kg. Brain cholinesterase was not
    affected at any test level. No treatment related effects were noted in
    growth, haematology, blood chemistry, mixed function oxidase activity
    of the liver, relative organ weights, gross or histopathology
    (Coulston and Griffin, 1975).

         Cow

         Groups of four cows were fed for 42 days silage corn which had
    been sprayed 83 days previously with chlorpyrifos-methyl. The diets
    contained 0, 0.35, 0.87 and 1.85 ppm chlorpyrifos-methyl and 0, 0.44,
    0.79 and 1.75 ppm 3,5,6 trichloro-2-pyridinol. Residue intakes

    amounted to 0.009, 0.022 and 0.054 mg chlorpyrifos-methyl and 0.012,
    0.020 and 0.051 mg 3,5,6 trichloro-2-pyridinol/kg body weight. No
    adverse effects were observed in silage intake, milk production, blood
    cholinesterase activity or body weight gains. Urine, faeces and milk
    contained trace amounts of chlorpyrifos-methyl and 3,5,6
    trichloro-2-pyridinol. One week after treated feed withdrawn these
    residue were not detectable (Johnson et al., 1974).

    Long-term studies

         Rat

         Groups of 55 male and 55 female rats were administered
    chlorpyrifos-methyl in the diet at 0, 0.03, 0.1, 1.0 and 3.0 mg/kg
    body weight/day for 104 weeks. After five weeks of treatment five
    males and five female/group were sacrificed for cholinesterase
    determination. Twenty-six weeks after treatment 10 males and 10
    females/group were killed for interim study and the size of each group
    was reduced to 30 males and 30 females after 52 weeks. Red blood cell
    cholinesterase activity was depressed in both sexes at 1.0 and 3.0
    mg/kg/day. Plasma cholinesterase activity was reduced consistently in
    females at 1.0 and 3.0 mg/kg/day; males showing little effect during
    the first year after which it was significantly depressed at 3.0
    mg/kg/day. Brain cholinesterase levels were not affected.
    Chlorpyrifos-methyl produced no significant effect on behaviour,
    mortality, body weight gain, food consumption and efficiency of food
    utilization. Haematologic, blood biochemical and urinalysis
    determinations were within normal limits and revealed no abnormal
    changes. No effect attributable to treatment was observed in organ
    weights or on gross and histopathologic examination. Tumour incidence
    was comparable between groups (Hunter et al., 1974a).

    Observations in man

         Fourteen male volunteers were divided into two treatment groups
    of five men each and a control group of four men. Chlorpyrifos-methyl
    was administered by gelatin capsule in a single daily dose of 0, 0.03
    and 0.1 mg/kg body weight/day for four weeks. Plasma and erythrocyte
    cholinesterase activities were not depressed at levels tested.
    Haematology, blood chemistry, urinalysis, blood pressure, pulse and
    ophthalmology were not affected by treatment (Coulston et al., 1975).

    COMMENTS

         In mammals, chlorpyrifos-methyl is rapidly absorbed and
    metabolized the principal metabolite being
    3,5,6-trichloro-2-pyridinol. The parent compound and metabolite are
    excreted primarily in the urine and faeces and are not stored to any
    extent in the body. This metabolite has also been shown to occur in
    plants.

         Teratogenic studies in the rat revealed no adverse effects at
    dietary intake levels of up to 250 mg/kg. In an inadequately conducted
    and reported study in the mouse there appeared to be a tendency for a
    weak teratogenic response at 250 mg/kg. No compound-related
    abnormalities were noted at 100 mg/kg.

         No adverse effects were noted in the reproductive capacity of the
    rat over three generations at dietary levels of up to 3 mg/kg.
    Mutagenic studies have not been reported.

         No apparent clinical evidence of neurotoxicity was observed in
    hens given a large dose of chlorpyrifos-methyl. Histological
    examination of nervous tissue was not conducted. In various short- and
    long-term studies in the rat, dog, mouse, monkey, mallard duck,
    bobwhite and Japanese quail, chlorpyrifos-methyl was shown to be an
    active cholinesterase inhibitor. Plasma cholinesterase activity was
    inhibited to a greater extent than either erythrocyte or brain
    cholinesterase.

         In the long-term study and specific tumorigenic study in the rat,
    no compound-related effect or increase in tumour incidence was
    observed.

         No effect levels were demonstrated in the rat, dog, monkey and
    man on the basis of the most sensitive parameter plasma cholinesterase
    inhibition. The no-effect level in man was confirmed by two
    independent studies. The data were considered sufficient to allocate
    an acceptable daily intake.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat:      0.1 mg/kg
         Dog:      0.1 mg/kg
         Monkey:   0.2 mg/kg
         Man:      0.1 mg/kg

    Estimation of acceptable daily intake

         0-0.01 mg/kg

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         Registration of chlorpyrifos-methyl for insect control in fruit,
    vegetable and cereal plants and in grain storage is recorded from the
    following countries: Egypt, France, Japan, Korea, and Turkey. In these
    countries it is marketed as dusts and/or granules and as emulsifiable
    concentrates containing 2-3% a.i. and 25-40% a.i. respectively.

         As a relatively new chemical chlorpyrifos-methyl is marketed as a
    broad-spectrum organophosphorus insecticide of relatively low toxicity
    and persistence, although it shows reasonably good stability in
    stored, dry products such as grains (Schulten, 1973) and dried fruits
    (Soderstrom and Armstrong, 1974). In these products it controls a wide
    range of beetles, weevils, moths and mites, including several such
    species which may have developed resistance towards other
    insecticides, e.g. malathion. Using spray techniques or admixing
    procedures to treat the stored grain products, chlorpyrifos-methyl is
    usually applied at the rate of 5-10 mg a.i. per kg.

         In several of the countries mentioned, chlorpyrifos-methyl is
    approved for wider uses in agriculture and horticulture against pests
    of economic importance connected to fruit and vegetable growing
    (Nakayama et al., 1973). In laboratory tests it is further found to be
    effective against a wide range of household pests, including spiders,
    houseflies, cockroaches, house crickets etc, (Snetsinger, 1972).

         A number of recommended practical applications is listed in Table
    1.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Data on chlorpyrifos-methyl residues resulting from a number of
    the above uses have been presented by the originating company (Kenaga,
    1975). The data derived from field trials and controlled experimental
    work under a variety of geographical and climatic conditions is as
    follows.

    In plants

    Cereal plants and grass

         Leuck et al. (1975) found chlorpyrifos-methyl to be relatively
    non-persistent in field trials where coastal bermuda grass and corn
    were sprayed once with 0.56, 1.12 and 2.24 kg a.i. per ha (see Table
    2). In both crops and at all three levels chlorpyrifos-methyl
    diminished rapidly at rates corresponding to half-lives of about two
    to three days. The hydrolysis product, 3,5,6-trichloro-2-pyridinol,
    was more persistent and in some cases actually increased up to a
    maximum during the first few days after application. Thereafter the
    pyridinol disappeared following a first order scheme with estimated
    half-life values of 9-12 days.


    
    TABLE 1.  Some use patterns of chlorpyrifos-methyl on plants and grain

                                                                                                                           

                                               Insecticide use               Use rate             Method and number
    Country        Formulation                 principal pest/crop           (active ing.)        of applications
                                                                                                                           

    Australia      Emulsifiable concentrate    Wheat                         5.0 mg/kg

    Egypt          Emuls. conc., 24% (w/v)     Spodoptera littoralis and     0.9 kg/ha or         Foliar broadcast spray
                                               S. exigua on vegetables       90 g/litre
                                               and clover

    France         Emuls. conc., 24% (w/v)     Stored grain pests            2.5 mg/kg

    Japan          Dust, 2% (w/w)              Rice stemborer                0.6-0.8 kg/ha        Max. 4 applic. per season
                   Micro-granule, 3% (w/w)     Rice stemborer                0.9-1.2 kg/ha        Broadcast appl. Max. 4 x
                                                                                                  per season
                   Granule, 5% (w/w)           Rice stemborer                1.5-2.0 kg/ha        Submerged appl. Max. 4 x
                                                                                                  per season
                   Emuls. conc., 25% (w/v)     Rice stemborer                0.1-0.375 kg/ha      Max. 4 sprays/season:
                                                                                                  rice and cabbage
                                               Diamondback moth, Pieria
                                               rapae, aphids on tobacco                           Max. 2 sprays/season:
                                               Cutworm on cabbage,                                chinese cabbage and
                                               chinese cabbage, radish                            radish

    Korea          Granule, 3% (w/w)           Rice stemborer, plant         0.9-1.2 kg/ha        2-3 appl. per season
                                               hopper, leaf hopper on
                                               rice.
                                               Tobacco cutworm, mole
                                               cricket on tobacco and
                                               vegetables

    TABLE 1. (Cont'd)

                                                                                                                           

                                               Insecticide use               Use rate             Method and number
    Country        Formulation                 principal pest/crop           (active ing.)        of applications
                                                                                                                           

    Korea          Emuls. conc., 25% (w/v)     Rice stemborer, plant         0.25-0.35 kg/ha      2-3 appl. per season
                                               hopper, leaf hopper on
                                               rice
                                               Tobacco cutworm, mole
                                               cricket on tobacco and
                                               vegetables

    Sudan          Emuls. conc., 24% (w/v)     Pests of apricots

    Turkey         Emuls. conc., 24% (w/v)     Spodoptera litteralis and     0.9 kg/ha            Foliar broadcast spray
                                               Heliothis obsoleta in
                                               cotton and vegetables
                                               Aphids on melons

    USA            Emuls. conc.                Wheat                         5-10 mg/kg
                                                                                                                           
    

         Johnson et al. (1974) in an earlier experiment sprayed corn in
    the dent stage with chlorpyrifos-methyl at the same dosage rates. In
    this case, the corn was harvested and ensiled for forage purposes one
    day after the treatment (Table 2). The initial losses of
    chlorpyrifos-methyl from the time of application through harvesting
    and ensiling amounted to 62-79%. After the ensiling, however, residues
    became relatively stable and they disappeared only slowly with
    formation of the pyridinol. From the first day until the eighty-third
    day, on average for the three treatments, 60% of the
    chlorpyrifos-methyl disappeared while the pyridinol increased 421%.


        TABLE 2.  Residues of chlorpyrifos-methyl and pyridinol in grass and corn

                                                                                                

                                                                  Residues (mg/kg)
                                                                                                
                         Treatment     Days after
    Crop                 kg/ha         treatment      Chlorpyrifos-methyl   Trichloro-2-pyridinol
                                                                                                

    Bermudagrass,          0.56             0                 5.5                   1.07
    coastal                                 7                 0.1                   0.73
    (Leuck et al., 1975)                   21                <0.01                  0.32

                           1.12             0                12.5                   2.21
                                            7                 0.21                  1.81
                                           21                 0.01                  0.58

                           2.24             0                28.4                   4.48
                                            7                 0.45                  4.08
                                           21                 0.09                  1.24

    Corn, growing          0.56             0                 2.2                   0.11
    (Leuck et al., 1975)                    7                 0.11                  0.17
                                           21                 0.03                  0.09

                           1.12             0                 8.2                   0.41
                                            7                 0.29                  0.54
                                           21                 0.07                  0.21

                           2.24             0                20.4                   0.78
                                            7                 1.43                  1.38
                                           21                 0.20                  0.60

                                                                                            

    TABLE 2.  (Cont'd.)

                                                                                                

                                                                  Residues (mg/kg)
                                                                                                
                         Treatment     Days after
    Crop                 kg/ha         treatment      Chlorpyrifos-methyl   Trichloro-2-pyridinol
                                                                                                

    Forage corn,           0.56             0                 2.22                  0.11
    ensiled at day 1                        1                 0.75                  0.13
    (Johnson et al.,                       27                 0.51                  0.48
    1974)                                  55                 0.47                  0.49
                                           83                 0.34                  0.70
                                          125                 0.34                  0.27

                           1.12             0                 8.20                  0.41
                                            1                 1.92                  0.34
                                           27                 1.42                  1.09
                                           55                 1.27                  1.40
                                           83                 0.72                  1.74
                                          125                 0.77                  0.35

                           2.24             0                20.40                  0.78
                                            1                 4.08                  0.69
                                           27                 2.98                  2.50
                                           55                 2.31                  2.28
                                           83                 1.64                  3.34
                                          125                 1.80                  1.13
                                                                                                
    

         Kubota (1975) has reported on field trials with growing rice. As
    shown in Table 3, residues at the time of harvest were not detectable
    or at most insignificant when spraying was carried out 4-17 days
    before harvest.

    Stored grain products

         White and LaHue (1974), in their experiments showing effective
    protection against several grain insects, e.g. rice weevil, lesser
    grain borers, flour beetle, sawtooth grain beetle, and foreign grain
    beetle, also followed the dissipation of chlorpyrifos-methyl in stored
    wheat, sorghum and maize. Wheat at 79C and containing 14.6% moisture
    was treated with 4.8, 6.6 and 10.4 mg/kg chlorpyrifos-methyl. The
    residue half-life was >6 months, 2-3 months and <1 month,
    respectively. Maize and sorghum tested under similar conditions at
    about 6-7 mg/kg had a residue half-life of about 2-3 months (Table 4).


        TABLE 3. Residues of Chlorpyrifos-methyl in rice*

                                                                                                       

                        Application
                                         

                     Rate                         Days after       Number of
    Formulation     (kg/ha)      Frequency      last treatment      samples         Residues, mg/kg
                                                                                                       

    3% dust          1.2             2              35-42              8        <0.005-<0.005(n.d.)

                                     4              14-42              8        <0.005-<0.005(n.d.)

                                     6              11                 8        <0.005-<0.005(n.d.)


    5% granule       2               2              53-57              8        <0.005-<0.005(n.d.)

                                     4              53-57              8        <0.005-<0.005(n.d.)

                                     6              17-32              8        <0.005-0.012


    25% e.c.         0.30-0.375      2              32-53              8        <0.005-<0.005(n.d.)

                                     4              24-53              8        <0.005-<0.005(n.d.)

                                     6              4-32               8        0.005-0.013
                                                                                                       

    * From Kubota (1975).

    TABLE 4. Residues of chlorpyrifos-methyl in stored grains in the United States of America*

                                                                                                     

                                                   Residue, mg/kg

    Grain               0 days    5 days    1      2      3      4      5      6      8      9 months
                                                                                                     

    Wheat (26C,        4.8       4.6       3.5    3.0    2.8    3.3    -      3.3    -      -
    14.6% moisture)     6.6       5.5       5.0    2.8    3.2    -      -      1.6    -      -
                        10.4      6.2       4.1    2.6    2.3    -      -      4.4    -      -

    Corn
    (13.6% moisture)    6.70      -         -      -      -      3.2    2.5    2.3    1.9    1.8

    Sorghum             -         -         -      -      3.5    3.3    2.7    2.6    2.2    1.9
                                                                                                     

    * From White and LaHue (1974).
    

         In laboratory experiments, Bulla and LaHue (1975) tested the
    disappearance rates of chlorpyrifos-methyl on the same three grains,
    kept for six months at 80F in covered glass jars with regulated
    moisture contents from 10 to 16%. With overall half-life rates varying
    from one to six months they found a decreasing persistence in the
    sequence: maize > wheat > sorghum. Grains containing 14 or 16%
    moisture degraded chlorpyrifos-methyl about 1.5-2 times faster than
    those containing 10 or 12%.

         In similar Australian experiments under commercial conditions,
    Deahl and Tucker (1974) found that chlorpyrifos-methyl at initial
    concentrations of 5.0 and 6.2 mg/kg declined at rates corresponding to
    half-lives of the order of three to five months (see Table 5). The
    average half-life at 31C was 15-16 weeks with indications of a
    reduced breakdown at lower temperatures (Desmarchelier, 1975a).

         From these extensive trials, Desmarchelier et al. (1975b and c)
    also reported the rate of loss of residues of chlorpyrifos-methyl on
    white wheat containing 11% moisture at 25C when stored in glass jars.
    These tests indicate that under the laboratory conditions stated,
    chlorpyrifos-methyl decays at a predictable first-order rate,
    irrespective of concentration or age of the residues.

         Morel and Galet (1975) report tests conducted in France on wheat
    containing 15.2% moisture and 2.35 and 1.17 mg/kg chlorpyrifos-methyl
    which was stored for various periods of time at 25C for residue
    analyses. Under these conditions half-lives of chlorpyrifos-methyl
    were estimated to be about six weeks. Residue levels six months after
    treatment were in the range of 0.2-0.4 mg/kg.

    Apples and peaches

         Residue levels on apples and peaches have been established under
    Japanese conditions following spraying at recommended dosage rates,
    i.e. about 1-1.5 kg/ha. The results of these trials are shown in Table
    6 which indicates levels in apples below 0.3-0.5 mg/kg if harvested
    about two weeks after the last treatment. The results for peaches do
    not show signs of penetration of residues through the peel into the
    fruit pulp.

    Vegetable plants

         Residue data from experiments with chlorpyrifos-methyl
    applications on vegetable plants are shown in Tables 7 and 8. The
    experiments derive from different geographical regions and cover
    mostly foliar applications on the following crops: artichoke, beans,
    cabbage, chinese cabbage, eggplant, lettuce, pepper, radish, tea and
    tomatoes.

    TABLE 5. Residues of chlorpyrifos-methyl during silo-storage, Australia*

                                                                            

                                    Residue, mg/kg after interval (weeks)
                                                                           
                   Depth of
    Treatment      silo         1       6       11      16      22      26
                                                                            

    6.2 mg/kg      0.1 m        4.5     3.1     2.3     2.1     1.9     1.5

    (Queensland    1.5 m        3.4     3.6     2.1     2.3     1.8     1.5

    experiment)    6.0 m        3.2     3.0     2.4     2.2     2.0     -
                                                                            

    Average                     3.7     3.2     2.3     2.2     1.9     1.5
                                                                            


                                                           

                                         3       8       13
                                                           

    5.0 mg/kg       0.1 m                4.1     3.9     1.8

    (N.S. Wales     1.5 m                4.1     3.7     2.4

    experiment)     6.0 m                3.3     3.1     2.4
                                                           

    Average                              3.8     3.6     2.2
                                                           

    * From Deahl and Tucker (1974).

    
    TABLE 6. Residues of chlorpyrifos-methyl in apples and peaches, Japan*

                                                                                        

                   Preharvest    Number of       Number of           Range of
    Application    interval      applications    samples             results (mg/kg)
                                                                                        

    Apples

    1.25-1.5       10 days       1-2            6                   0.22-0.353
    kg/ha          20 days       1-2            7                   0.201-0.310
                   30 days       1-2            4                   0.174-0.186

                   10 days       4              9                   0.182-0.798
                   20 days       4              6                   0.128-0.225
                   30 days       4              4                   0.162-0.257

                   10 days       6              4                   0.489-0.936
                   20 days       6              7                   0.152-0.333
                   30 days       6              4                   0.250-0.478


    Peaches                                                     Peel             Pulp
                                                                                        

    0.9 kg/ha      21 days       2              6              <0.03-0.26       <0.005
                   30 days       2              8              <0.03-0.05       <0.005

                   21 days       4              6              <0.03-0.11       <0.005
                   30 days       4              8              <0.03-0.05       <0.005

                   21 days       6              6              <0.03-0.10       <0.005
                   30 days       6              8              <0.03-0.06       <0.005
                                                                                        

    * From Kubota (1975).

    TABLE 7.  Residues of chlorpyrifos-methyl in vegetables, Europe/Near East

                                                                                              

                                   Preharvest       Number of        Residues      Country and
    Crop          Dosage rate      interval       applications       (mg/kg)       reference
                                                                                              

    Artichoke     48 g/100 l       7 days               2            0.05          France1
                                                                     (aver.)

                                   14 days              2            0.03
                                                                     (aver.)


    Beans         1.2 kg/ha        0 days               1            0.32          Turkey2
                                   7 days               1            0.01
                                   14 days              1            0.02


    Beans,        48 g/100 l       7 days               5            <0.02         France1
    french                                                           (aver.)
                                   14 days              3            <0.02
                                                                     (aver.)

    Eggplant      1.2 kg/ha        0 days               1            0.06          Turkey2
                                   7 days               1            0.01
                                   14 days              1            0.01


    Lettuce       48 g/100 l       7 days               4            0.78          France1
                                                                     (aver.)
                                   14 days              2            0.04
                                                                     (aver.)

    Pepper        1.2 kg/ha        0 days               1            2.28          Egypt3
                                   1 day                1            0.58
                                   2 days               1            0.25
                                   3 days               1            0.20
                                   5 days               1            0.09
                                   7 days               1            0.10
                                   9 days               1            0.04

    TABLE 7. (continued)

                                                                                              

                                   Preharvest       Number of        Residues      Country and
    Crop          Dosage rate      interval       applications       (mg/kg)       reference
                                                                                              
    Tomato        0.1% until       3 days               1            1.90          England4
                  run-off          6 days               1            0.90
                  (greenhouse)     9 days               1            0.40
                                   13 days              1            0.09

                  1.2 kg/ha        0 days               1            0.31          Turkey2
                                   7 days               1            0.04
                                   14 days              1            0.05

                  48 g/100 l       7 days               6            0.21          France1
                                                                     (aver.)
                                   14 days              6            0.04
                                                                     (aver.)
                                                                                              

    1 Hascouet (1974).
    2 Hollick and Collison (1972a).
    3 Hollick and Collison (1972b).
    4 Wirth et al. (1971).

    TABLE 8. Residues of chlorpyrifos-methyl in vegetables, Japan*

                                                                                                                       

               Dosage                   Preharvest    Number of     Number of                 Range of
    Crop       rate                     interval      treatments    samples                   residues (mg/kg)
                                                                                                                       

    Cabbage    0.45 kg/ha               7 days        2            8                         <0.002-0.002
                                        14 days       2            8                         <0.002

                                        7 days        4            8                         <0.002
                                        14 days       4            8                         <0.002

    Chinese    0.25 kg/ha               14 days       4            2                         <0.005
    cabbage
               0.375 kg/ha              7 days        2            7                         0.027-0.220
                                        14 days       2            7                         <0.005-0.100

                                        7 days        4            7                         0.036-0.175
                                        14 days       4            5                         0.039-0.056

               0.50 kg/ha               7 days        2            4                         0.019-0.025
                                        14 days       2            4                         0.004-0.006

    TABLE 8. Residues of chlorpyrifos-methyl in vegetables, Japan*

                                                                                                                       

               Dosage                   Preharvest    Number of     Number of                 Range of
    Crop       rate                     interval      treatments    samples                   residues (mg/kg)
                                                                                                                       
    Chinese                             7 days        4            4                         0.001-0.002
    cabbage                             14 days       4            4                         0.003-0.007

    Eggplant 0.75 kg/ha                 3 days        2            4                         0.002-0.003
                                        7 days        2            4                         0.001
                                        14 days       2            4                         <0.002

                                        3 days        4            4                         0.002-0.004
                                        7 days        4            4                         0.001
                                        14 days       4            4                         <0.002

    Pepper,    0.50 kg/ha               3 days        2            4                         0.011-0.171
    green                               7 days        2            4                         0.004-0.028
                                        14 days       2            4                         <0.002-0.012

    Pepper,                             3 days        4            4                         0.013-0.129
    green                               7 days        4            4                         0.003-0.060
    (cont'd)                            14 days       4            4                         <0.003-0.021

                                                                                  Leaves                  Root
                                                                                                                      

    Radish     0.2-0.3 kg/ha            7 days        2            4             0.024-0.324             <0.002-0.069
                                        28 days       2            4             0.003-0.009             0.005-0.008

                                        7 days        3            2             0.109                   <0.001-0.003
                                        28 days       3            4             0.024-0.130             <0.001-0.001

                                        7 days        4            4             0.040-0.299             <0.002-0.081
                                        28 days       4            4             0.003-0.010             0.013-0.020

                                        7 days        6            2             0.075                   <0.002-0.002
                                        14 days       6            4             0.019-0.040             0.002-0.003

    Tea        0.50 kg/ha               7 days        1            6                         <0.001-0.065
                                        14 days       1            6                         <0.001-0.047
                                        21 days       1            6                         <0.003
                                        27 days       1            6                         <0.003
                                        7 days        2            6                         <0.001-0.026
               0.75 kg/ha               7 days        1            7                         <0.001-0.091
                                        14 days       1            6                         <0.001-0.056
                                        21 days       1            6                         <0.001-0.047
                                        7 days        2            6                         <0.003-0.085
                                                                                                                       
    * From Kubota (1975).
             The levels of chlorpyrifos-methyl residues on these crops at the
    time of harvest, i.e. from 7 to 14 days after the last treatment are
    generally at or below 0.1 mg/kg.

    FATE OF RESIDUES

    In plants

         Residues of chlorpyrifos-methyl in or on plants are assumed to
    behave similarly to chlorpyrifos Of  FAD/WHO, 1973) without
    translocation in plants to any significant extent.

         The principal hydrolysis product of chlorpyrifos-methyl in
    plants, animals and soil, 3,5,6-trichloro-2-pyridinol, may or may not
    be taken up by plants depending on pH. The free pyridinol, which is
    the predominant form of the compound below pH 6.0, is essentially
    insoluble in water. In radio-labelled studies, soil and nutrient
    culture experiments have shown its uptake by plants to be
    insignificant (Smith et al., 1967). At or above pH 7, the pyridinol is
    readily converted to a salt in which form water solubility (4.4 g/100
    ml at 25C for the sodium salt) as well as rate of absorption by the
    plant are enhanced compared with the free pyridinol. Although still at
    very low levels, the sodium salt of the pyridinol enters the plant
    more than five times as fast as the free pyridinol. It undergoes
    metabolism with the liberation of chloride and the formation of
    several unidentified water soluble decomposition products.

    In cereal-products

         Residues of chlorpyrifos-methyl in treated grains have been
    followed from the time of application through milling and baking
    procedures in several experiments (see Table 9). Bulla and LaHue
    (1975) fractionated wheat containing 6.3 mg/kg chlorpyrifos-methyl and
    found that most of the residues after three and six months of "ageing"
    were still concentrated in the outer grain fractions, such as "red
    dog" and bran. The residues in flour were reduced to below 10% of the
    original concentration (i.e. to 0.53 and 0.39 mg/kg, respectively).
    Bread baking reduced the remaining residues further by about 60%.

         Similar results have been found by Bengtson et al. (1975) who
    after 11 and 22 weeks of ageing also found considerable reduction from
    grain residues to milled flour and baked bread, the latter showing
    below 0.25 mg/kg residual chlorpyrifos-methyl.

         Morel and Galet (1975) analysed wheat which was milled from 6 to
    17 weeks after treatment of commercially stored grains with 1.6-1.8
    mg/kg of chlorpyrifos-methyl. The distribution of residues in various
    milled fractions is shown in Table 9. About 90% of the residues
    remained in the outer bran and course middlings.


    
    TABLE 9.  Chlorpyrifos-methyl residues in milled wheat fractions and bread

                                                                                                                 

                                               Residues, mg/kg, in
                                                                             
                                                                                                Bread
                                                                                                            
    Ageing                                               Pollard
    period     Whole wheat      "Red dog"      Bran      (or middling)   Flour          Wholemeal       White
                                                                                                                 

    USA (Bulla and LaHue, 1975)

    3 months   6.3 mg/kg*       6.5            5.0                       0.53                           0.21
    6 months   6.3 mg/kg*       3.3            3.0                       0.39                           0.16


    France (Morel and Gallet, 1975)

    6 weeks                                    4.3       1.4             0.26
    9 weeks    1.6-1.8 mg/kg*                  2.96      1.46            0.22
    14 weeks                                   3.92      1.60            0.29
    17 weeks                                   3.55      1.61            0.23


    Australia (Bengtson et al., 1975 and Desmarchelier, 1975a)

    6 weeks    6.7-6.9 mg/kg    -              7.6-8.8   2.6-3.2         0.38-0.38      1.11-1.17       0.25-0.28
    11 weeks   3.6 mg/kg        -              9.3       9.0             0.6            -               0.2
    11 weeks   2.0 mg/kg        -              5.2       4.6             <0.10          -               <0.12
    22 weeks   1.8 mg/kg        -              6.6       3.6             0.4            -               0.13
                                                                                                                 

    * Treatment levels.
    

    In animals and animal products

    Insects

         Although direct studies have not been carried out with
    chlorpyrifos-methyl to the same extent as for its ethyl analogue,
    chlorpyrifos (cf. FAO/WHO, 1973), there is evidence that the general
    metabolic pathways in living organisms are closely parallel for the
    two compounds, e.g. the principal metabolic products in some insects
    (tobacco budworm, cf. Whitten and Bull, 1974) are
    3,5,6-trichloro-2-pyridinol mad O,O-dimethyl phosphate produced by
    microsomal oxidase activity which apparently is indicated also
    catalyses the formation of the P=O analogue of chlorpyrifos-methyl.
    Soluble, non-oxidative hydrolytic enzyme systems are likewise
    believed to act in detoxification mechanisms through O-dealkylation
    (see Figure 1).

         Absorption studies in these insects suggest that the slightly
    higher toxicity of chlorpyrifos-methyl compared to chlorpyrifos is
    probably connected with a faster rate of absorption of the former.

    Cow

         In their previously mentioned studies of chlorpyrifos-methyl in
    ensiled forage corn, Johnson et al. (1974) fed silage corn containing
    0.35, 0.87 and 1.87 mg/kg chlorpyrifos-methyl and 0.44, 0.79 and 1.75
    mg/kg 3,5,6-trichloro-2-pyridinol to cows for 42 days. This dietary
    residue intake was equivalent to an average of 0.09, 0.022 and 0.054
    mg chlorpyrifos-methyl and 0.012, 0.20 and 0.051 mg of the pyridinol
    per kg of body weight per day, respectively.

         Residue analyses showed no trace of the P=O analogue of
    chlorpyrifos-methyl in any samples including milk, urine and faeces.,
    The principal excretory route for chlorpyrifos-methyl was by means of
    the faeces. Only at the 0.054 mg/kg day dosage did a trace of
    chlorpyrifos-methyl (0.001-0.002 mg/kg) appear in the milk with none
    in the urine. The principal excretory route for the pyridinol was via
    the urine. Some excretion of the pyridinol occurred also in the faeces
    (up to 0.36 mg/kg and in the milk (up to 0.008 mg/kg) at the 0.054
    mg/kg/day rate. These studies did not include analyses of animal meat
    or fat.

    In soils

         Regoli et al. (1974) studied the aerobic degradation of
    ring-labelled C14-chlorpyrifos-methyl in the laboratory at 1 mg/kg in
    two soils (silty clay loam and loam containing 4.2% and 0.8% organic
    carbon respectively) incubated at 15, 25 and 35C and with moisture
    at 32% or 100% of field capacity for up to 428 days. All incubations
    were conducted in closed, aerated containers so that a balance of
    radioactivity added to each sample could be drawn.

    FIGURE 1

         An overall average of 100.4% recovery of added activity was
    obtained for samples over the entire study and it was found that the
    major metabolite in soil was 3,5,6-trichloro-2-pyridinol which is
    further degraded to CO2 followed by lesser amounts of
    3,5,6-trichloro-2-methoxy-pyridine. The authors speculated whether the
    methoxy-compound is formed through direct methylation of
    chlorpyrifos-methyl or from the pyridinol through microbial activity,
    but the former route, involving subsequent conversion of the
    methoxypyridine to the pyridinol seems more likely as no other
    decomposition-products could be traced.

         The breakdown of chlorpyrifos-methyl to
    3,5,6-trichloro-2-pyridinol is a rapid process if conditions are
    favourable for microbial and hydrolytic activity. The time required
    for 50% breakdown ranged from 1.5 to 2.0 days in the high organic soil
    at 25-35C and 100% moisture to 33.3-17.7 days in the low organic soil
    at 15C and 32% moisture. The calculated times required for 90%
    degradation ranged from 20 to 30 days under favourable conditions to
    500-1600 days under less favourable. Thus in practice
    chlorpyrifos-methyl could hardly persist in soils and give rise to
    traceable carry-over during crop rotations.

         Hamaker (1974) studied the soil adsorption of
    C14-chlorpyrifos-methyl by analysing both the soil and the
    supernatant from slurries of soil in 1 mg/l solutions (one part of
    soil:four parts of solution). The soils contained organic carbon
    ranging from 0.28 to 5.76%.

         The adsorption by these soils ranged from 46 to 99% after 24
    hours and the average distribution ratio between soil organic carbon
    and water was found to be 3300 after four hours and 4600 after 24
    hours. This is less by one-third than in the case of chlorpyrifos but
    still represents a strong adsorption to soil.

         The hydrolysis product (3,5,6-trichloro-2-pyridinol) is absorbed
    to a smaller degree than the parent compound showing a distribution
    ratio of 714 between soil and water. In the conclusions of the author,
    however, this still represents a sufficiently strong adsorption to
    make leaching of the compound from soils an unlikely process.

         Kubota (1975) has reported on both field trials and laboratory
    tests determining residue disappearance from rice paddy soils over
    periods of 30 days (Table 10). The half-life periods in the field
    tests varied from five to about 20 days, while the half-life was less
    than three days when chlorpyrifos-methyl was applied directly to the
    soil in the laboratory.

         A DOWCO 214 formulation applied to bacterial cultures in amounts
    corresponding to normal soil application showed no influence on the
    bacterial activity measured as the O2-uptake under incubation of
    Azotobacter vinelandii (MacRae and Celo, 1974). Neither was the
    nitrogen fixation of this strain as measured by the reduction of
    acetylene to ethylene affected, even at concentrations 100 times the
    practical application rates (Wood and MacRae, 1974).

    TABLE 10.  Disappearance of chlorpyrifos-methyl in Japanese soils*

                                                                          

    Formulation/    Dosage       Days after     Number of     Range of
     treatment      rate         application    samples    residues (mg/kg)
                                                                          

    3% dust         1.8 kg/ha    0 days         4          1.98-2.94

                                 10 days        4          0.41-1.47

                                 20 days        4          0.10-0.33

                                 30 days        4          <0.05-0.17


    3% dust         0.18 kg/ha   0 days         4          0.171-0.236

                                 10 days        4          0.121-0.183

                                 20 days        4          0.059-0.089

                                 30 days        4          0.007-0.014


    96% DOWCO 214   5 mg/kg      0 days         4          4.02-4.10
    (laboratory
    test)                        3 days         4          0.82-1.47

                                 10 days        4          0.26-0.39

                                 30 days        4          0.06-0.31
                                                                          

    * From Kubota (1974).


    METHODS OF RESIDUE ANALYSIS

    Gas-chromatographic methods for the determination of
    chlorpyrifos-methyl and its principal metabolite,
    3,5,6-trichloro-2-pyridinol, have been described in numerous
    modifications, mostly varying in the detailed procedures of extraction
    and clean-up (Deahl and Tucker (1974), Desmarchelier (1975b) for
    grains; Hollick and Collison (1972a and b) for various vegetables;
    Johnson et al. (1974) for corn, milk, urine and faeces; Kubota (1975)
    for a variety of vegetables, rice and soils; McKellar et al. (1970,
    1971a, b and c) for grains, grass, bovine tissues land milk; Regoli et
    al. (1974) for soils; Wirth et al. (1971) for tomatoes).

         Of the two compounds, the pyridinol which usually appears as a
    hydrolytic product and mostly in non-fatty tissues is of less
    importance in the analysis for regulatory purposes. The determination
    of the P=O analogue of chlorpyrifos-methyl may or may not be included
    by the above procedures (cf. for instance Johnson et al. (1974)), but
    it is usually not encountered in animal or plant tissues.

         Generally speaking, the principle of determination is based on
    extraction with dichloromethane (from wet media), acetone or methanol
    (from wet media and soils) or hexane (from dry or fatty tissues)
    followed by partitioning procedures (acetone: CH2Cl2 and/or hexane:
    acetonitrile) with eventual further clean-up on florisil, silica gel
    or alumina.

         The final determination of chlorpyrifos-methyl (and its oxygen
    analogue) is made from acetone solution by GLC utilizing a phosphorus
    specific detector of the FPD- or AFID types. For the pyridinol
    metabolite the determination is made according to McKellar and
    Dishburger (1970) on GLC with a nickel (Ni63) EC-detector after
    derivatization with N,O-bis(trimethylsilyl)acetamide.

         The analytical sensitivities reported as limits of determination
    for these methods range from 0.001 to 0.02 mg/kg of
    chlorpyrifos-ethyl, about 0.01 mg/kg of the O-analogue and 0.001-0.05
    mg/kg of the pyridinol in various substrates and with recoveries of
    85.9-100.4% for all the compounds.

         The general work chart for the analysis of chlorpyrifos (FAO/WHO
    (1973) page 192) also seems to apply for the analysis of
    chlorpyrifos-methyl and the general scheme should be adaptable for
    regulatory purposes as part of a multiresidue analysis system.

    NATIONAL TOLERANCES REPORTED TO THE MEETING

                                                                        

    Country         Crop                       Tolerance, mg/kg (PHI)
                                                                        

    Japan           Rice                           0.03 (60 days)

                    Chinese cabbage,
                    radish                         0.03 (30 days)

                    Cabbage                        0.03 (7 days)

                    Tobacco                        0.03
                                                                        

    APPRAISAL

         Chlorpyrifos-methyl is an organophosphorus insecticide of
    relatively low toxicity and with broad spectrum effects against a
    number of insects of great economic interest as well as several
    species of household insects. Since its introduction it has gained
    particular and fairly wide interest as a potential grain protectant.

         Information on the chemical and physical properties of
    chlorpyrifos-methyl has been presented to the Meeting. The compound is
    available in crystalline form with a purity of 99.8%. It is relatively
    easily hydrolysed with the formation of 3,5,6-trichloro-2-pyridinol
    which is also the major metabolite in plants, animals and soils.

         It is registered and marketed in some countries as dusts,
    granules and emulsifiable concentrates for pre-harvest agricultural
    and horticultural purposes and for post-harvest grain treatments.
    Recommended dosage rates vary from 0.1 to 2.0 kg/ha under field
    conditions and from 2.5 to 10 mg/kg in grain storage.

         Residue data from supervised trials and experimental tests with
    chlorpyrifos-methyl in several countries have been made available by
    the manufacturer in support of registrations, including the
    establishment of tolerances. These data include residue levels and
    disappearance rates in several vegetable crops, fruits and cereal
    plants as well as stored grain products, including wheat, corn and
    sorghum grains.

         While generally of low persistence, chlorpyrifos-methyl is
    relatively stable and evidences prolonged protection against insects
    in grains and stored, dried products. The half-life of
    chlorpyrifos-methyl in stored wheat averages three to five months
    under practical conditions, but at higher moisture levels and higher
    temperatures the rate of decomposition increases. Conversely at low
    temperatures and low humidities the effective life is expected to be
    prolonged.

         Evidence of the fate of residues during the milling, processing
    and baking of cereals is demonstrated in several trials. Residues in
    grains are to a great extent confined to the outer layers and
    concentrated in bran and milling offals. Correspondingly they are
    diminished to low levels (10% of the original deposits or lower) in
    flour and further reduced to half of this in baked bread.

         Feeding trials with cows indicate that both chlorpyrifos-methyl
    and its pyridinol moiety may give rise to trace amounts (below 0.01
    mg/kg) in milk, but that the main excretory route for the parent
    compound is via the faeces and for the metabolite via the urine.

         Residue studies on meat products, fat or eggs are not available.

         Several soil studies have been made on chlorpyrifos-methyl which
    confirms that hydrolysis to 3,5,6-trichloro-2-pyridinol is a fairly
    rapid process under normal conditions and that total residues of
    chlorpyrifos-methyl could hardly persist in soils or give rise to
    traceable carry-over in crop rotation. Neither run-off nor leaching of
    the compounds from the site of application is likely to occur.

         Specific gas-chromatographic methods of analysis are available
    for the determination of chlorpyrifos-methyl and
    3,5,6-trichloro-2-pyridinol. The analytical procedure is closely
    parallel to that for the ethyl analogue, chlorpyrifos, and should be
    adaptable for regulatory purposes as part of multiresidue analysis.

         Residues of chlorpyrifos-methyl may occur as its main metabolite,
    3,5,6-trichloro-2-pyridinol. The amounts of this, however, are
    generally low in relation to the original deposits.

    RECOMMENDATIONS

         The following maximum residue limits based on the parent compound
    are recommended. They are not likely to be exceeded when following
    good agricultural practices. Determination of the level of
    chlorpyrifos-methyl parent compound will adequately control the amount
    of total residue resulting from the use of this insecticide.

                                                                        

                                        Maximum      Pre-harvest interval
                                        residue      on which
                                        limit        recommendations
     Commodity                          mg/kg        are based (days)
                                                                        

    Bran                                 20

    Raw grains (wheat, corn, sorghum)    10

    Flour, wholemeal bread               2

    Apples, peaches                      0.5               14

    Tomatoes                             0.5               3-5

    White bread                          0.5

    Artichoke, beans, cabbage,
    chinese cabbage, eggplant,           0.1               7-14
    lettuce (outdoor), peppers,
    radish, tea (green)

    Rice (pre-harvest treatment)         0.1               21

    Milk                                 0.01
                                                                        

    FURTHER WORK OR INFORMATION

    REQUIRED (before additional maximum residue limits can be
    recommended)

         1.   Information on residues in animal tissues, fat and eggs
              following feeding of chlorpyrifos-methyl residues in animal
              feeds.

    DESIRABLE

         1.   Appropriate mutagenic study.

         2.   Neurotoxicity study with histological examination of nervous
              tissues.

         3.   Information on evidence of residues in commerce.

         4.   Further information on residue disappearance in practical
              grain storage at low temperatures and low humidities.

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    See Also:
       Toxicological Abbreviations
       Chlorpyrifos-methyl (PDS)
       Chlorpyrifos-methyl (Pesticide residues in food: 1979 evaluations)
       Chlorpyrifos-methyl (Pesticide residues in food: 1991 evaluations Part II Toxicology)
       Chlorpyrifos-methyl (Pesticide residues in food: 1992 evaluations Part II Toxicology)