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    CARBOPHENOTHION                  JMPR 1972

    IDENTITY

    Chemical names

    S-(4-chlorophenylthiomethyl) diethyl phosphorothiolothionate;
    S-(4-chlorophenylthiomethyl) 0,0-diethyl phosphorodithioate

    Synonyms

    Trithion(R), Garrathion(R), R-1303, ENT 23708, nephocarp.

    Empirical formula

    C11H16O2Cl PS3

    Structural formula

    CHEMICAL STRUCTURE 1

    Physical and chemical properties

    State: off-white to light amber coloured liquid

    Boiling point: 82C at 0.01 mm Hg

    Vapour pressure: 3  10-7 mm Hg at 20C

    Specific gravity: 1.265 - 1.285 at 20C

    Molecular weight: 342.85

    Refractive index: 1.590 - 1.597

    Solubility: slightly soluble in water (<0.04 g/l at 20C), Miscible
    with most organic solvents (hydrocarbons, alcohols, ketones, esters)

    Stability: stable to hydrolysis but oxidized to the phosphorothiolate

    Purity: technical material about 95%

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, distribution and excretion

    Studies on absorption and distribution of carbophenothion in mammals
    are not available. Following intraperitoneal administration to mice,
    greater than 75% of the administered dose was excreted in the urine
    within 24 hours. During the following 16 hours only 4-7% of the dose
    was excreted. Carbophenothion is apparently rapidly eliminated from
    the body (March et al., 1957).

    Biotransformation

    The metabolism of carbophenothion is qualitatively the same in mice,
    insects and plants, the principal products being oxidative. Although
    the transformation of carbophenothion to oxidative and hydrolytic
    components has been postulated, little data are available on the
    quantitative degradation in mammals. Oxidative metabolism of
    carbophenothion has been shown to result in a substantial increase in
    anticholinesterase activity except for the sulphone of the
    phosphorodithioate. A quantitative difference in animal and plant
    metabolites was the presence of an unidentified product on the surface
    of plants which appeared to a minor degree in the internal parts and
    was found as a minor component in mouse urine and in vitro tests
    with mouse liver. The component is probably the phosphorodithioate
    sulphoxide analogue (March et al., 1957). Five oxidative products of
    carbophenothion have been identified (see figure 1).

          S                             O
    (EtO) PSCH SC H pCl           (EtO) PSCH SC H pCl
         2    2  6 4                   2    2  6 4
    carbophenothion               oxygen analogue

    (5  10-4M)                 (2  10-6M)

          S    O                        O    O
    (EtO) PSCH SC H pCl           (EtO) PSCH SC H pCl
         2    2  6 4                   2    2  6 4
    carbophenothion sulphoxide    oxygen analogue sulphoxide

    (8  10-6M)                 (2  10-7M)

          S    O                        O    O
    (EtO) PSCH SC H pCl           (EtO) PSCH SC H pCl
         2    2O 6 4                 2    2O 6 4
    carbophenothion sulphone      oxygen analogue sulphone

    (1  10-4M)                 (1  10-8M)

    Figure 1 - Oxidative products of carbophenothion

    The number in parenthesis under the oxidative products in Figure 1 is
    the I50 value for housefly head cholinesterase (March et al.,
    1957).

    Results of studies on the metabolism of carbophenothion in lettuce
    have shown a typical pattern of oxidative metabolism resulting in the
    sulphoxide and sulphone analogues of the phosphorothioate and
    phosphorodithioate. Exposure of carbophenothion to UV light resulted
    in the appearance of the phosphorodithioate sulphoxide analogue
    (Menzies, 1969).

    TOXICOLOGICAL STUDIES

    Special studies on neurotoxicity

    Groups of White Leghorn hens (10 hens/group) were fed carbophenothion
    in the diet at levels of 0, 10, 31.6 and 100 ppm for seven weeks. TOCP
    was fed at 500 ppm as a positive control. Egg production was affected
    at 100 ppm. Clinical signs of ataxia were evident in TOCP-fed hens but
    were absent in animals fed all levels of carbophenothion. Histological
    examination of nerve tissue showed slight evidence of demyelination in
    TOCP treated hens but none with carbophenothion (Lobdell and Johnston,
    1964).

    Special studies on potentiation

    Groups of dogs (1 male and 1 female/group) were fed carbophenothion (1
    ppm) in the diet in combination with parathion (1 ppm),
    methylparathion (5 ppm), EPN (20 ppm), demephion (2 ppm), or malathion
    (100 ppm) for 45 days. No evidence of greater than additive depression
    of cholinesterase activity was observed (Horn, 1957).

    Carbophenothion in combination with five other organophosphates
    (parathion, methylparathion, EPN, demephion and malathion) when
    administered orally to rats did not show signs of potentiation of
    acute toxicity (Horn, 1957; Shaffer and West, 1960).

    Special studies on reproduction

    Groups of rats (20 male and 20 female per group) were fed
    carbophenothion in the diet and subjected to a standard
    three-generation (2 litter per generation) reproduction study at
    dosage levels of 0 and 20 ppm. At 20 ppm carbophenothion had an effect
    on reproduction in all three generations. In the F0 generation a
    reduced mean pup birthweight was observed and fewer young were alive
    at weaning. In the F1b generation, an increased number of stillbirths
    was observed in two litters and fewer young were alive at weaning in
    the second (but not the first) litter. In the F2b generation, an
    increase in stillbirths was again observed in two litters, a decreased
    number of live births and again fewer pups were alive at weaning.
    Foetal resorption was an apparent factor in three of 10 females
    examined which had borne less than two litters. An examination of
    stillborn pups for teratological effects of carbophenothion was
    negative (Johnston and Scott, 1966).

    Acute toxicity

    Acute toxicity to carbophenothion in some animal species is summarized
    in Table 1.



        TABLE 1 Acute toxicity to carbophenothion in different animal species
                                                                                                       
    Species        Sex            Route          LD50           Reference
                                                                                                       
    Rat            M              Oral           17-91          Gray, 1954; Elsea, 1955a,b; Horn, 1957;
                                                                Shaffer and West, 1960; Hagan et al.,
                                                                1961; Hayes, 1971

                   F              Oral           10             Hayes, 1971

                                  Oral           7-30           Edson et al., 1963

                   M              Dermal         54             Hayes, 1971

                   F              Dermal         27             Hayes, 1971

    Mouse          M              Oral           106-218        Elsea, 1955b; Gray, 1954

    Dog            M and F        IM             Approx.        Beliles, 1966
                                                 40

    Rabbit                        Dermal         800            Edson et al., 1963

    Duck           M              Oral           121            Tucker and Crabtree, 1970
                                                                                                       
    

    A dose of 25 mg/kg administered to the eye of rabbits resulted in
    death in one-third and signs of acute poisoning in the survivors
    (Gray, 1954).

    Signs of poisoning are typical of organophosphorus esters and include
    salivation, lacrimation, diarrhea, miosis, tremors and other signs of
    cholinergic stimulation.

    Rats exposed to carbophenothion vapours at a dose of 1.04 mg/l for one
    hour exhibited depression which subsided within one hour after
    treatment (Bullock and Kamienski, 1971).

    Atropine and PAM have been shown to be effective therapeutic agents
    for acute poisoning by carbophenothion. Repeated administration with
    both materials was necessary to insure complete survival of poisoned
    animals (Elward and Meydins, 1964). Following acute IM administration
    of carbophenothion, atropine and PAM administered IM were effective in
    temporarily alleviating signs of poisoning. A return of toxic signs
    was evident 2-4 hours after the administration of atropine and PAM
    (Beliles, 1965).

    Dogs were administered carbophenothion by IM injection at a dose
    approximately five times the calculated LD50. This was followed by
    atropine alone or in combination with PAM (atropine was administered
    twice daily after signs of poisoning occurred and PAM administered
    once). All dogs administered atropine alone died, although death was
    delayed. One of six dogs receiving atropine and PAM survived.
    Mortality in the dogs administered atropine and PAM was delayed.
    Atropine plus PAM was a more effective therapeutic agent than atropine
    alone. Signs of toxicity and mortality following lethal doses of
    carbophenothion were alleviated with the two agents in combination
    (Beliles, 1966).

    Short-term studies

    Rat

    Groups of rats (25 males and 25 females/group) were fed
    carbophenothion in the diet for 90 days at dosages of 0, 5, 10, 22, 46
    and 100 ppm. Clinical signs of toxicity, cholinergic stimulation, were
    evident at 46 and 100 ppm. Growth of females was reduced at 100 ppm.
    RBC cholinesterase inhibition was evident at levels of 10 ppm and
    above, especially in females. Brain and plasma cholinesterase was
    inhibited at 22 ppm and above. No effects were observed on survival,
    food consumption and gross histological examination of tissues
    (Fogleman, 1956; Lehman, 1965).

    Dog

    Groups of mongrel dogs (2 males and 2 females/group) were administered
    carbophenothion orally by gelatin capsule, 6 days/week for 90 days, at
    levels of 0.02, 0 04, 0.08, 0.25 and 0.80 mg/kg/day. Dogs at 0.25 and
    0.80 mg/kg/day showed plasma cholinesterase depression and did not
    receive the total dosage. At 0.02 mg/kg/day plasma cholinesterase was

    depressed slightly, while at 0.04 mg/kg inhibition was more apparent.
    RBC cholinesterase was normal at all treatment levels (Fogleman, 1956;
    Lehman, 1965). Groups of purebred beagle dogs (3 males and 3 females/
    group) were fed carbophenothion in the diet for two years at dosages
    of 0, 5, 20 and 80 ppm. Erythrocyte and brain cholinesterase activity
    were depressed at 80 ppm. Plasma cholinesterase activity was depressed
    at all feeding levels at all examination intervals except the initial
    one. At 20 and 80 ppm, the groups were distinguishable from controls
    chiefly on the basis of decreased body-weight gain (in 80 ppm
    females), greater degree of irritability and nervousness and increased
    mean relative adrenal weight (in 80 ppm females). No effects were
    noted on mortality, physical condition, food consumption, behaviour,
    haemograms, clinical chemistry tests, urinalysis, neurological
    examinations and gross or histological examination of tissues
    (Johnston, 1967).

    Cow

    Groups of two lactating dairy cows were administered 0, 1, 3, 10 and
    30 ppm of carbophenothion in the diet, 7 days/week, for 120 days. The
    1 ppm group was changed to 20 ppm on day 23 of the study. A similar
    group, receiving 15 ppm, was added to the study on day 70 and
    continued for 50 days. Clinical signs of toxicity were evident at 30
    ppm. Blood cholinesterase activity was significantly depressed at 20
    and 30 ppm. Appearance and behaviour, food consumption and whole blood
    cholinesterase activity were unaffected at 15 ppm and below (Weir,
    1958).

    Long-term studies

    Rat

    Groups of rats (25 males and 25 females/group) were fed
    carbophenothion in the diet for two years at dosage levels of 0, 5, 20
    and 80 ppm. Although considerable mortality was observed in all groups
    in this study, there was no relationship to the dietary intake. Rats
    at 80 and 20 ppm feeding levels displayed tremors, loose stools and
    hair loss as well as behaviour changes, including nervousness and
    irritability. Females at 80 ppm showed reduced growth during the
    second year of study. At 80 ppm, at 100 weeks of feeding, a gradual
    lowering of hemoglobin became evident. RBC, plasma and brain
    cholinesterase activity was inhibited at 80 and 20 ppm but not at 5
    ppm. Cholinesterase inhibition in brain, RBC and plasma was more
    evident in females than males. At 80 ppm females showed an increased
    adrenal weight and ratio of organ to body-weight. Gross and
    histological examinations showed no compound-related effect other than
    the increased adrenal gland weight. Analyses of the incidence of
    tissue mass showed no differences from control values. There were no
    differences in respect to the frequency of neoplasm occurrence
    (Johnston, 1967).

    OBSERVATIONS IN MAN

    The effects of carbophenothion noted on man are limited to several
    acute poisoning incidents (Hearn, 1961) and a one-month subacute
    administration to humans. Typical signs of cholinergic stimulation in
    humans were obvious following ingestion of contaminated flour. This
    poisoning was controlled with atropine and PAM. Five people were
    administered carbophenothion at a dose of 0.8 mg/kg/day for 30 days.
    There were no effects reported on plasma or RBC cholinesterase
    activity (Rider et al., 1972).

    COMMENT

    Carbophenothion is rapidly excreted and is probably metabolized via
    oxidative and hydrolytic pathways.

    The compound does not induce demyelination and is not potentiated by
    those organophosphates tested.

    Cholinesterase depression was shown to occur in a rat reproduction
    study, conducted at a dose level known to induce maternal
    cholinesterase depression. Reduced pup weights, increased resorption
    rate and postpartum mortality in pups was shown to occur in a
    reproduction study in rats conducted at a dose level known to induce
    maternal cholinesterase depression.

    Plasma cholinesterase depression was the most sensitive criterion of
    effect in both short- and long-term studies in rats and dogs.

    A study in man did not result in plasma cholinesterase depression at
    0.8 mg/kg/day. The meeting considered that the data available were
    insufficient to enable an ADI to be based on this experiment. However,
    the 0.8 mg/kg/day level was borne in mind when the study in dogs was
    considered in the light of the apparent extreme difference in
    sensitivity between man and dog. A no-effect level was not
    demonstrated in dog at the lowest dose utilized (5 ppm or 0.125
    mg/kg/day). In rat, 5 ppm (0.25 mg/kg/day) is a no-effect level with
    regard to plasma cholinesterase depression.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

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

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN

    0 - 0.005 mg/kg

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

    Carbophenothion is a non-systemic organophosphorus insecticide and
    acaricide used for pre-harvest treatments on deciduous fruits, citrus
    fruits, small fruits, vegetables and field crops, and for ectoparasite
    control on cattle and sheep. It is also used as a cereal seed
    dressing.

    It is available as various strengths of emulsifiable concentrates,
    wettable powders and dusts. Recommended treatment levels are as
    follows:

    1) Deciduous fruit  - 1.25 lb to 2.0 lb a.i. per acre with pre-harvest
                        intervals of 30 days.

    2) Citrus fruit     - 2.5 lb to 5.0 lb a.i. per acre. Pre-harvest
                        intervals vary from 0 to 30 days depending on
                        amount of a.i. used per acre.

    3) Vegetable crops  - 1.0 lb a.i. per acre; 7 days pre-harvest
                        interval except for spinach (21 days).

    4) Field crops      - 1.0 lb a.i. per acre; 21 days pre-harvest
                        interval.

    5) Cattle           - 0.02% spray, no pre-slaughter interval.

    6) Sheep            - 0.026% tip spray; 0.062% saturation spray or
                        plunge dip - 14 day pre-slaughter interval.

    Specific uses include the control of greenbug on sorghum (Ward et
    al., 1970) and the control of castor white fly (Radha, 1971).

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    Table 2 gives typical results of analysis for residues of
    carbophenothion following controlled application at stated rates to
    various fruit and vegetable crops (Stauffer Chemical Co., 1972). The
    data on citrus fruits refers to residues on whole fruits; evidence was
    presented showing that practically all of the residue was retained on
    the peel with only very small amounts (0.02 ppm or less) appearing in
    the pulp or juice.

    Tables 3 and 4 show residues of carbophenothion found in some tissues
    of cattle and sheep at different intervals after treatment.

    Table 5 gives results obtained from the analysis of milk from cows fed
    carbophenothion at various concentrations to simulate feeding of
    treated forage (Stauffer Chemical Co., 1972).

    TABLE 2 Carbophenothion residues in various crops
                                                                       
    Crop                Pre-harvest         Rate                Residue
                        interval            (% a.i.)            (ppm)
                        (days)
                                                                       
    Oranges             0                   0.03                0.80
                        7                   0.03                0.67
                        14                  0.03                0.55
                        21                  0.03                0.47
                        28                  0.03                0.38

    Grapefruit          0                   0.03                1.4
                        7                   0.03                1.1
                        14                  0.03                0.85
                        21                  0.03                0.65
                        28                  0.03                0.53

    Lemons              0                   0.12                4.0
                        7                   0.12                3.3
                        14                  0.12                2.5
                        21                  0.12                2.2
                        28                  0.12                1.9

    Limes               0                   0.03                0.95
                        7                   0.03                0.79
                        14                  0.03                0.65
                        21                  0.03                0.53
                        28                  0.03                0.43

    Apples              0                   0.03                0.73
                        2                   0.03                0.30
                        12                  0.03                0.46
                        14                  0.03                0.88
                        19                  0.03                0.36
                        26                  0.03                0.29
                        29                  0.03                0.37

    Pears               33                  0.06                0.41

    Peaches             14                  0.03                0.70
                        27                  0.03                0.15
                        29                  0.03                0.67

    Prunes              28                  0.04                0.24
                        29                  0.04                0.47
                        29                  0.04                0.42

    Apricots            21                  0.03                0.78

    TABLE 2 (cont'd)
                                                                       
    Crop                Pre-harvest         Rate                Residue
                        interval            (% a.i.)            (ppm)
                        (days)
                                                                       
    Nectarines          14                  0.03                0.52-0.66
                        37                  0.03                0.33-0.42

    Green alfalfa       0                   0.25                70
                        10                  0.25                20
                        20                  0.25                5.5

    Alfalfa hay         0                   0.25                70
                        10                  0.25                25
                        20                  0.25                8

    Soybean hay         0                   0.25                70
                        10                  0.25                25
                        20                  0.25                8

    Brussels            0                   0.9 kg/ha           0.91
    sprouts             7                   0.9 kg/ha           0.28

    Cauliflower         0                   1.2 kg/ha           0.56
                        4                   1.2 kg/ha           0.06

    Broccoli            0                   1.2 kg/ha           2.65
                        4                   1.2 kg/ha           0.33

    Sugar beet          7                   1.2                 3.9
    (tops)              11                  1.2                 2.5
                        18                  1.2                 0.6

    Sugar beet          0                   0.25                0.01
    (roots)             8                   0.25                0.02
                        17                  0.25                0.02

    Spinach             2                   4 oz/acre           26.4
                        5                                       11.2
                        10                                      3.8
                        15                                      0.70
                        2                   8 oz/acre           63.4
                        5                                       25.8
                        10                                      12.5
                        15                                      1.7
                        0                   12 oz/acre          36
                        4                                       14
                        22                                      1.56
                        29                                      0.16
                        2                   16 oz/acre          95
                        5                                       32.2
                        10                                      15.1

    TABLE 2 (cont'd)
                                                                       
    Crop                Pre-harvest         Rate                Residue
                        interval            (% a.i.)            (ppm)
                        (days)
                                                                       
    Spinach (cont'd)    15                                      2.4

    Olives              66                  0.06                0.08
                        88                  0.06                0.04
                        119                 0.06                0.02

    Olive oil           66                  0.06                0.16
                        88                  0.06                0.06
                        119                 0.06                0.02
                                                                       

    Potatoes            )
    Rape seed           )  Observed residues all below the
    Walnuts (shelled)   )  limit of determination (0.02 ppm)
    Pecans (shelled)    )


    Information was also available (Stauffer Chemical Co., 1972) regarding
    residues occurring in milk and cream from three cows spray-treated
    with 0.02% carbophenothion; no residues above the limits of
    determination were observed (<0.005 ppm for milk and <0.05 ppm for
    cream).

    FATE OF RESIDUES

    In animals

    Fat samples of cattle treated with carbophenothion have been examined
    for the presence of carbophenothion, its sulphoxide and sulphone and
    the corresponding oxygen-analogue compounds. The parent compound and
    lesser amounts of its sulphoxide and sulphone were found (Table 6),
    but the oxygen-analogues were not observed (Meyding and Browne, 1962).
    In all cases the amounts of the oxygen-analogue, its sulphoxide and
    sulphone were below 0.005 ppm.

    In plants

    Carbophenothion was applied to field-growing lettuce, and samples were
    removed at various times after spraying and analysed for
    carbophenothion and its oxidative metabolites. Carbophenothion
    persisted in growing lettuce for 21 days. Five oxidation products
    appeared within 4 hours of spraying and persisted for up to 21 days.
    The results indicate that the principle route of oxidation involved
    thioether oxidation to form the sulphoxide and then the sulphone,
    followed by phosphorothionate oxidation to form the thiophosphate
    sulphone (Coffin, 1964). (See also Figure 1). In these experiments the
    amount of parent carbophenothion decreased rapidly from 7.0 ppm to 1.2
    

        TABLE 3 Carbophenothion residues in cattle tissues1
                                                                                       

    Tissue              Treatments            Days since last treatment
                        (No.)       1         3         7/8       21        36        43
                                                                                       

    Perirenal fat       1           -         -         0.13      0.09      -         -

    Subcutaneous fat    1           -         -         0.09      0.10      -         -

    Omental fat         1           -         -         0.17      0.15      -         -

    Perirenal fat       2           -         -         0.63      0.20      -         -

    Subcutaneous fat    2           -         -         0.19      0.14      -         -

    Omental fat         2           -         -         0.41      0.24      -         -

    Perirenal fat       3           1.65      0.69      0.71      0.19      0.25      ND

    Subcutaneous fat    3           0.62      0.61      0.37      0.10      0.14      0.04

    Omental fat         3           1.12      0.74      0.47      0.25      0.31      0.02

    Liver               3           0.019     <0.01     ND2       ND        ND        ND

    Kidney              3           0.048     0.03      <0.01     ND        ND        ND

    Skeletal muscle     3           0.036     0.01      ND        ND        ND        ND
                                                                                       

    1  Residues found in the tissues of cattle following 1, 2 or 3 weekly spray exposures
       to a 0.1% active ingredient suspension. Values represent net corrected ppm of
       carbophenothion (Meyding and Browne, 1962).

    2 ND = not detected

    TABLE 4 Carbophenothion residues in sheep tissues1
                                                                           

    Tissue                                  Days after treatment
                                1           3           10          14
                                                                           

    Fat         unshorn         0.39        0.66        0.55        0.61
                shorn           0.90        0.68        0.29        0.29

    Muscle      unshorn         0.054       0.072       0.047       0.042
                shorn           0.049       0.086       0.032       0.026

    TABLE 4 (continued)
                                                                           

    Tissue                                  Days after treatment
                                1           3           10          14

    Kidney      unshorn         *2          0.036       0.045       *
                shorn           0.014       0.020       0.020       *

    Liver       unshorn         *           0.019       0.014       0.011
                shorn           0.01        0.011       *           0.014
                                                                           

    
    1 Residues found in various tissues of sheep resulting from plunge-dips
      in a vat containing 0.05% carbophenothion (Meyding and Patchett, 1964).
      Values given in ppm carbophenothion.

    2 * = <0.01 ppm

    
    TABLE 5 Carbophenothion residues in milk (ppm carbophenothion)
                                                                                                          
    Duration of
    treatment                   Treatment level (ppm in diet)
    (days)            0    1    3                   10                  20                  30
                                                                                                          
    0                 *1   *    *                   *                   *                   0.0014  *

    7                 *    *    *                   0.0023, 0.0029      0.0101              0.0215, 0.0170

    14                *    *    0.0015, 0.0015      0.0028, 0.0024      0.0085, 0.0052      0.0210, 0.0149

    28                *    -    0.0015, 0.0024      0.0086, 0.0058      0.0103, 0.0104      0.0171

    49                *    -    0.0036, 0.0031      0.0058, 0.0047      0.0123, 0.0146      0.0141

    70                *    -    0.0033, 0.0011      0.0054, 0.0048      0.0115, 0.0088      0.0187
    (mean)            *    *    0.0015              0.0045              0.0102              0.0178
                                                                                                          

    1 * = less than 0.001 ppm.

    TABLE 6 Carbophenothion and metabolites in cattle fat
                                                                                                         
    Fat tissue      Treatments      Days since          Carbophenothion     -sulphoxide         -sulphone
                    (no.)           last treatment                     (ppm)
                                                                                                         
    Perirenal       3               7                   0.563               0.318               0.058

    Omental         3               7                   0.368               0.107               0.026

    Subcutaneous    1               8                   0.197               0.068               0.046
                                                                                                         


    TABLE 7 Effect of storage and heat processing on carbophenothion residues
                                                                                         
                                            Heat                          Storage
    Food                Initial level       processed           Ambient             100F
                        (ppm)                                   temp.(1 yr)
                                                                                         
    Spinach             0.76                17%                 71%                 83%

    Apricots            0.76                35%                 84%                 84%
                                                                                         
    
    ppm in the first three days and then more slowly to less than 0.1 ppm
    at 21 days. The total residue declined more steadily from 8.3 ppm
    to 0.1 ppm over the same period.

    Evidence of residues in food in commerce or at consumption

    Some limited information was available on residues of carbophenothion
    occurring in food in commerce. Duggan et al. (1971) have presented
    results of analyses from 1963 to 1969 of nearly 7 000 samples of U.S.
    domestic and imported large fruits (apples, pears, oranges, peaches).
    Of the few samples shown to contain residues of carbophenothion (less
    than 1% of those examined), only 25 samples contained more than 0.1
    ppm and one sample contained more than 1 ppm. No measurable amounts of
    carbophenothion have been observed in various published total diet
    studies.

    Elkins et al. (1972) studied the effect of storage and heat
    processing on the residue level of carbophenothion in canned spinach
    and apricots. The results, shown in Table 7, are expressed in terms of
    percentage reduction in the residue level.

    METHODS OF RESIDUE ANALYSIS

    Carbophenothion and its five oxidative metabolites are extracted from
    non-fatty materials with aqueous acetonitrile, and from fat and oil
    with hexane followed by partitioning in aqueous acetonitrile. The
    residues are partially separated from crop extractives by an alumina
    shakeout, a partition into chloroform, and an activated carbon
    shakeout. The residues are oxidized to the sulphones with potassium
    permanganate, further isolated and separated by liquid-solid
    chromatography on silica gel H, and determined by gas-liquid
    chromatography on OV-1 or QF-1 columns with flame photometric
    detection in the phosphorus mode (Buxton, 1971 and Storherr et al.,
    1971). These procedures should be suitable for regulatory purposes.
    Bowman and Beroza (1970, 1971) published conditions for the gas
    chromatography of organophosphorus pesticides, including
    carbophenothion, using a flame photometric detector. A method based on
    the extraction procedure of McLeod et al. (1967) in conjunction with
    the T.L.C. enzymatic inhibition technique of Mendoza et al. (1968)
    has been proposed by Mendoza et al. (1970). The presence of
    carbophenothion in whole wheat flour could be detected down to 0.5
    ppm. Carbophenothion and its five oxidative metabolites have been
    determined by gas chromatography using a 5 ft column of 10% DC 200 and
    the sulphur mode of the microcoulometric detector (Burke, 1965). A
    method has been proposed for the detection and quantitative
    determination of organothiophosphorus pesticides, including
    carbophenothion, by in situ fluorimetry after separation on silica
    gel layers. Yellowish-green fluorescent spots are obtained when the
    plate is sprayed with a 3-hydroxyflavone, such as robinetin, after
    bromination. Linear calibration curves up to 4 mg per spot of the
    pesticide have been obtained and a relative standard deviation of
    approximately 4% can be expected at the 1.0 g level. Visual and
    instrumental detection limits are around 0.04 g per spot for certain
    pesticides (Frei et al., 1971).

    A thin-layer chromatographic procedure has been described for
    separating and detecting carbophenothion and 16 other
    cholinesterase-inhibiting pesticides on aluminum oxide and silica gel.
    The detection of the anticholinesterase activity is based on the
    hydrolysis of indophenyl acetate by bee brain cholinesterase. Limits
    of detectable cholinesterase inhibitors are at the subnanogram level,
    and the time required for detection is about 40 minutes (Winterlin
    et al., 1968). A detection limit of 5 ng was obtained by Gardner
    (1971) using a combined two-dimensional TLC - esterase method.
    Patchett and Batchelder (1960) describe a two-phase hydrogen
    peroxide-acetic acid-benzene system to oxidize carbophenothion to
    strong cholinesterase inhibitors, which are subsequently determined by
    measuring their inhibition of cholinesterase in human blood plasma.
    The method is sensitive to 0.01 g of carbophenothion and will detect
    0.005 ppm residue in crops having low background values.

    Villeneuve et al. (1970) investigated the separation and detection
    of 13 organophosphorus pesticides, including carbophenothion, using a
    combined TLC-GLC method. The separation of carbophenothion using a
    silica gel microcolumn was investigated by Leoni (1971). A routine TLC
    method for the determination of residues of organophosphorus
    pesticides, including carbophenothion, has been proposed by Mees and
    Antoine (1971). The procedure uses both silica gel and polyamide
    coated plates.

    Table 8 shows examples of national tolerances as reported to the Joint
    Meeting.

    TABLE 8
                                                                    
    Examples of national tolerances as reported to the meeting

    Country                  Commodity                     Tolerance
                                                           ppm
                                                                    
    Australia      Fruit and vegetables                    1
                   Fat of meat of cattle and sheep         1

    Belgium        Fruit and vegetables                    0.5

    Canada         Cherries, eggplants, peppers,
                   pimentos, plums, prunes, tomatoes       0.5
                   Apples, crabapples, onions,
                   pears, quinces                          0.8

    Federal
    Republic
    of Germany     Rape, citrus fruit (without peel)       0.05

    Netherlands    Fruit and vegetables                    0.05

    TABLE 8 (cont'd)
                                                                    
    Examples of national tolerances as reported to the meeting

    Country                  Commodity                     Tolerance
                                                           ppm
                                                                    
    U.S.A.         Almond hulls                            10
                   Alfalfa (green and hey),
                   clover (green and hay),
                   sugarbeet (root and tops)               5
                   Citrus fruit                            2
                   Apples, apricots, snap beans,
                   lima beans, garden beets (root and
                   tops), melons                           0.8
                   Cherries, cucumbers, eggplant, figs,
                   grapes, nectarines, olives, onions
                   (dry bulb and green), peaches,
                   pears, peas, peppers, plums,
                   quinces, pimentos, soybeans,
                   spinach, strawberries, summer
                   squash, tomatoes                        0.8
                   Fat of meat of cattle, goats,
                   pigs and sheep                          0.2
                   Dry beans, pecans, walnuts              0.1
                                                                    

    APPRAISAL

    Carbophenothion is a non-systemic organophosphorus insecticide and
    acaricide used for pre-harvest treatments on deciduous, citrus and
    small fruits, field crops, vegetables and for ectoparasite control on
    cattle and sheep; it also has uses as a cereal seed dressing. The
    pesticidal action is fairly persistent and residues are comprised
    mostly of the parent compound together with its sulphoxide and, to a
    lesser extent, its sulphone; the corresponding oxygen analogues are
    rarely detected in animal tissue but have been observed as minor
    components on treated vegetables. Following treatment of animals, the
    bulk of the residue is contained in the fatty tissues. Residue data
    was available following supervised trial treatments of fruit,
    vegetables and animals, but no information was given regarding
    foodstuffs moving in commerce. No residues have been observed in total
    diet studies. Available multi-residue gas chromatographic procedures
    should be suitable for application for regulatory purposes.

    RECOMMENDATIONS

    TEMPORARY TOLERANCES

    Temporary tolerances apply to the total residue, comprising
    carbophenothion, its sulphoxide and sulphone together with their
    corresponding oxygen analogues, if present, expressed as
    carbophenothion.

                                                      ppm

    Lemons                                            5

    Spinach                                           2

    Fat of meat of cattle and sheep                   1

    Grapefruit, limes, oranges, prunes,
    apricots, nectarines, peaches                     1

    Broccoli, Brussels sprouts, cauliflower,
    apples, pears                                     0.5

    Olive oil                                         0.2

    Olives, sugar beet                                0.1

    Milk and milk products (fat basis)                0.1

    Potatoes, rape seed                               0.02*

    Walnuts and pecans (shelled)                      0.02*

    * at or about the limit of determination

    FURTHER WORK OR INFORMATION

    REQUIRED (by 30 June 1976)

    1.   Further studies to substantiate the marked species difference in
         sensitivity to plasma cholinesterase depression.

    2.   An adequate reproduction study.

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    See Also:
       Toxicological Abbreviations
       Carbophenothion (ICSC)
       Carbophenothion (Pesticide residues in food: 1976 evaluations)
       Carbophenothion (Pesticide residues in food: 1977 evaluations)
       Carbophenothion (Pesticide residues in food: 1979 evaluations)
       Carbophenothion (Pesticide residues in food: 1980 evaluations)
       Carbophenothion (Pesticide residues in food: 1983 evaluations)