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    PESTICIDE RESIDUES IN FOOD - 1982


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1982





    Data and recommendations of the joint meeting
    of the FAO Panel of Experts on Pesticide Residues
    in Food and the Environment and the
    WHO Expert Group on Pesticide Residues
    Rome, 23 November - 2 December 1982

    Food and Agriculture Organization of the United Nations
    Rome 1983


    CHLORPYRIFOS

    CHEMICAL STRUCTURE 1

    Explanation

         Chlorpyrifos was reviewed by the Joint Meetings of 1972, 1974,
    1975, 1977 and 1981 (FAO/WHO 1973, 1975, 1976, 1978, 1982)1/. An ADI
    of 0-0.001 mg/kg bw was established, based on plasma cholinesterase
    depression in humans. Additional reports on the toxicity of
    chlorpyrifos have been submitted, including a two-year chronic
    feeding/oncogenicity study in mice, a teratology study in mice, and a
    delayed neurotoxicity study in hens. These studies have been reviewed
    and summarized in this monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    TOXICOLOGICAL STUDIES

    Special Study on Teratogenicity

         Groups of 40-47 pregnant CF-1 mice were given 0, 1, 10 or
    25 kg bw/day of chlorpyrifos by gavage on days 6 through 15 of
    gestation. Administration of 25 mg/kg/day of chlorpyrifos resulted in
    severe maternal toxicity. Additional groups of 35-41 pregnant mice
    were gavaged with 0, 0.1, 1.0 and 10 mg chlorpyrifos/kg bw on days 6
    through 15 of gestation, due to the maternal toxicity at 25 mg/kg body
    weight. On day 18 of gestation all pregnant animals were sacrificed
    and foetuses delivered by caesarean section. Maternal observations
    included cageside observations; body, liver and gravid uterine
    weights; food and water consumption; number and position of live,
    dead, and resorbed foetuses and evidence of implantation sites. Foetal
    body weights, crown-rump measurements, external alterations, together
    with visceral and skeletal alterations, were similarly determined for
    all foetuses. Separate groups of pregnant mice were also examined for
    clinical evidence of cholinesterase depression during selected periods
    of gestation, including ChE measurements of plasma and erythrocytes,
    as well as the ChE of a foetal homogenate on gestation day 15.

              

    1/  See Annex 2 for WHO and FAO documentation.

         Evidence of maternal toxicity (including cholinesterase
    inhibition, decreased body weight, decreased food and water
    consumption and death) was observed among pregnant mice given 25 mg/kg
    of chlorpyrifos. Plasma and erythrocyte cholinesterase levels were
    significantly reduced among maternal mice at 1 mg/kg or greater and in
    foetuses at dose levels of 10 mg/kg or greater.

         Foetotoxicity, as evidenced by increased occurrence of minor
    skeletal variants (i.e. delayed ossification of skull bones and
    sternebrae) and decreased foetal body weight measurements, was noted
    at the 25 mg/kg dose level.

         Reproduction performance (as determined by implantation sites,
    resorption sites and live young) was not affected by chlorpyrifos at
    any dose level administered. Some malformations (exencephaly) were
    observed among litters of mice given 1 mg/kg chlorpyrifos; however, a
    dose-related teratogenic response was not observed nor repeated in the
    additional mice given the same dose. No evidence of teratogenic
    response was observed among mice given 0.1, 1, 10 or 25 mg/kg of
    chlorpyrifos, during the critical period of organogenesis (Deacon
     et al 1979).

    Special Study on Neurotoxicity

    Chicken

         Groups of adult hens (av. 14.5 months) were administered
    chlorpyrifos orally at dosage levels of 0, 25, 50, 100, 200 or
    400 mg/kg bw, and the oral LD50 estimated to be 50 mg/kg bw. Separate
    groups of non-fasted adult hens (av. 17 months) were given single oral
    doses of 0, 50 and 100 mg chlorpyrifos/kg bw. A positive control
    (TOTP, 232 mg/kg) was also used. Ten birds comprised each test group.
    Atropine sulphate (30 mg/kg) was given to all birds prior to
    administration of TOTP or chlorpyrifos. At the conclusion of the study
    (21-24 days), all surviving hens were sacrificed and subjected to
    gross and microscopic examinations. Axon and myelin degeneration were
    assessed in the sciatic nerve and spinal cord.

         There was no mortality in any group. Body weight was slightly,
    but not statistically, depressed in the positive control (TOTP). There
    were dose-dependent, acute cholinergic effects observed for the
    chlorpyrifos treated groups. Symptoms included transient signs of
    ataxia, CNS depression and paralysis, which recovered to normal within
    2 to 4 days post-treatment. There were no signs of delayed
    neurotoxicity observed with chlorpyrifos. The positive control animals
    (TOTP) displayed delayed gross symptoms beginning on day 10 and
    continued through to sacrifice. There were slight to severe signs of
    ataxia in all birds, with partial paralysis in a few. Histologic
    evaluation revealed no evidence of neurotoxic effects in either the
    chlorpyrifos treated group or the negative control (atropine sulphate

    only). Evidence of delayed neurotoxicity was apparent in the TOTP
    group with the observation of swollen, degenerate, fragmented and
    demyelinated axons in the spinal cord, plus swollen neurollemma
    sheaths and vacuolation of the sciatic nerve. Based on the results of
    this study, it was concluded that chlorpyrifos does not induce delayed
    neurotoxic reactions in adult white leghorn hens when administered as
    a single acute oral dose (Rowe  et al 1978).

    Special Study for Carcinogenicity

    Mouse

         Groups of CD-1 mice (56 male and 56 female/mice/group) were fed
    chlorpyrifos in the diet at dosage levels of 0, 0.5, 5 and 15 ppm for
    105 weeks. These dose levels were approximately equivalent to 0, 0.05,
    0.5 and 1.5 mg/kg/day over the entire treatment period. The animals
    were examined daily for mortality and adverse physical/behavioural
    condition. Periodic evaluation of food consumption and body weights
    were performed. At the conclusion of the study, or at death, organ
    weights and gross and microscopic examination of tissues and organs of
    all animals were performed. All mice were killed by CO2 inhalation
    and exsanguination via the axillary blood vessels. Peripheral blood
    smears were prepared from tail blood from all survivors at terminal
    sacrifice.

         There were no unusual behavioural changes and no significant
    effects on food consumption, body weight gain or mortality. Absolute
    and relative organ weights of selected organs were varied and
    unrelated to dose. Relative liver weights for both male and female
    mice were significantly decreased (p <0.05) at the low- and mid-dose,
    but not at the high dose. Histological examination revealed a
    significant difference between control and mid-dose males for the
    incidence of hyperplastic nodules of the liver. There was also a
    significant increase in the incidence of spindle cell hyperplasia of
    the adrenal gland for male mice at the low and mid-dose levels, and in
    female mice at the low dose only. Lesions observed in the lung
    included a significant increase of alveologenic adenomas in mid-dose
    male mice only. The histologic changes identified appear to be
    spontaneous in nature and without a demonstrated dose-response.
    Furthermore, type A and B nodules of the liver parenchyma, as well as
    the alveologenic carcinomas of the lung, occurred with equal frequency
    between treatment and control group animals. There were no other
    significant lesions or statistically increased hyperplastic and/or
    nodular lesions. The results of this study demonstrate that
    chlorpyrifos is not oncogenic in mice at dietary levels up to and
    including 15 ppm for a period of 105 weeks (Warner  et al 1980).

    COMMENTS

         The Meeting evaluated substantial new data submitted on
    chlorpyrifos, including a mouse teratology study, a mouse
    carcinogenicity study and a hen neurotoxicity study. Chlorpyrifos was
    not teratogenic to mice at doses up to and including 25 mg/kg bw/day,
    although severe maternal toxicity and foetotoxicity were evident at
    that dose. It was also determined that 15 ppm of chlorpyrifos was not
    oncogenic when administered in the diet of mice for 105 weeks. A
    single acute oral dose of 100 mg/kg bw (twice the LD50) did not
    induce a delayed neurotoxic response in hens. However, the Meeting
    reiterated previously expressed JMPR opinions that a delayed
    neurotoxicity study in hens requires multiple dosing, such that doses
    are repeated 21 days apart for a total of two acute oral doses. In
    this context, the present study may not fully address the delayed
    neurotoxic potential of chlorpyrifos relative to residues in food.

         Chlorpyrifos is recognized to be an active cholinesterase
    inhibitor in several mammalian species, including humans. In all
    species evaluated, plasma ChE or pseudo-cholinesterase was inhibited
    at lower administered dose levels of chlorpyrifos than were RBC or
    brain ChE (where determined). Chlorpyrifos was reviewed by the Joint
    Meeting in 1972 (FAO/WHO 1973), which determined that chlorpyrifos
    inhibited the plasma ChE in humans at 0.03 mg/kg bw, but not at
    0.014 mg/kg bw (Coulston  et al 1972). This served as a basis for the
    ADI (0.0015 mg/kg), which was subsequently rounded off to 0.001 mg/kg
    bw at the recommendation of the Joint Meeting of 1977 (FAO/WHO 1978).
    However, appropriate statistical evaluation of the human
    cholinesterase determinations in the Coulston  et al study (1972)
    (Park 1972) demonstrated 0.03 mg/kg to be a threshold level for
    inhibition of plasma ChE, which was without statistical significance
    when compared to current controls. Based upon repeated daily doses for
    a period of 21 days, it was concluded by Coulston  et al and Park
    that a dose of 0.03 mg chlorpyrifos/kg bw has no significant
    toxicological effect in humans. This conclusion is supported by the
    evidence from studies in other mammalian species at comparable dose
    levels (McCollister  et al 1971a,b; Coulston  et al 1971).

         These same investigators determined that erythrocyte
    cholinesterase activity was inhibited at comparable levels in
    different species (e.g. 0.1 mg/kg for rat, dog and humans, and
    0.08 mg/kg for monkey). Except for ChE depression, these levels were
    without significant effects noted on mortality, behaviour, food
    consumption growth, haematology, clinical chemistry, urinalysis, or
    gross and microscopic examination of selected tissues (where
    determined).

         The Meeting accordingly increased the ADI from 0.001 to
    0.01 mg/kg body weight, based on the level causing no inhibition of
    RBC cholinesterase and not on the plasma cholinesterase.

    TOXICOLOGICAL EVALUATION

    Level Causing no Toxicological Effect

    Rat: 0.1 mg/kg bw/day

    Dog: 0.1 mg/kg bw/day

    Man: 0.1 mg/kg bw/day

    Estimate of Acceptable Daily Intake for Man

    0 - 0.01 mg/kg bw.

    FURTHER WORK OR INFORMATION

    Desirable

         Data on the inhibition, reactivation and ageing of cholinesterase
     (in vitro).

    REFERENCES

    Coulston, F., Goldberg, L., Abraham, R., Benitz, K.F., Griffin, T.B.
    1971     and Norvell, M. Final report on safety evaluation and
             metabolic studies on Dowco 179 (IN 151). Report from Insp.
             Exp. Pathol. Toxicol., Albany Medical College, submitted to
             the World Health Organization by Dow Chemical Company.
             (Unpublished)

    Coulston, F., Goldberg, L. and Griffin, T. Safety evaluation of
    1972     Dowco 179 in human volunteers. Summary and tables 33 and 34,
             reviewed by JMPR 1972. Report from Albany Medical College,
             Albany, New York, submitted to the World Health Organization
             by Dow Chemical Company. (Unpublished)

    Deacon, M.M., Murray, J.S., Pilney, M.K., Dittenber, D.A., Hanley,
    1979     T.R. Jr. and John, J.A. The effects of orally administered
             chlorpyrifos on embryonal and foetal development in mice.
             Report from Dow Chemical Company submitted to the World
             Health Organization by Dow Chemical Company. (Unpublished)

    McCollister, S.B., Kociba, R.J., Gehring, P.J. and Humiston, C.G.
    1971a    Results of two-year dietary feeding studies on DowcoR 179
             in beagle dogs. Report T35.12.44793-18, from Dow Chemical
             Company, submitted to the World Health Organization by Dow
             Chemical Company. (Unpublished)

    1971b    Results of two-year dietary feeding studies on DowcoR179 in
             rats. Report NBT35.12-44793-21, from Dow Chemical Company
             submitted to the World Health Organization by Dow Chemical
             Company (Unpublished)

    Park, C. Analysis of plasma and red blood cell cholinesterase levels
    1972     in humans ingesting DOWCO 179. Report from Dow Chemical
             Company submitted to the World Health Organization by Dow
             Chemical Company. (Unpublished)

    Rowe, L.D., Warner, S.D. and Johnston, R.V. Acute delayed
    1978     neurotoxicologic evaluation of chlorpyrifos in White Leghorn
             hens. Report from Dow Chemical Company submitted to the
             World Health Organization by Dow Chemical Company.
             (Unpublished)

    Warner, S.D., Gerbig, C.G., Strebing, R.J. and Molello, J.A. Results
    1980     of a two-year toxicity and oncogenicity study of
             chlorpyrifos administered to CD-1 mice in the diet. Report
             from Dow Chemical Company, submitted to the World Health
             Organization by Dow Chemical Company. (Unpublished)

    CHLORPYRIFOS

    Explanation

         Chlorpyrifos was evaluated in 1972, 1974, 1975 and 1977 (FAO/WHO
    1973, 1975, 1976, 1978)1/. Use patterns for chlorpyrifos have
    undergone significant changes since 1972 with less emphasis on
    previous animal applications, the development of "spot-on" animal
    treatments and the emergence of more feed uses. At the 1982 meeting of
    the CCPR, a question was raised concerning the recommended limit in
    milk in view of these changing use patterns.

         New information was made available to the Meeting on a survey of
    international uses on dairy cattle, residues in meat from "spot-on"
    treatment, residues in meat and milk from ingestion of treated feed,
    metabolic fate in lactating goats, an improved method of analysis for
    milk and cream and national maximum residue limits.

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

    In Animals

         A survey of uses of chlorpyrifos in animals was conducted by Dow
    Chemical Co. in each geographic region in late 1981. This survey was
    aimed specifically at clarifying whether dairy cattle are treated with
    chlorpyrifos and, if so, whether such use is likely to lead to
    residues greater than 0.1 mg/kg on a fat basis in milk or milk
    products in international trade. Table 1 summarizes recommendations
    for treatment of cattle with chlorpyrifos in each country where it has
    been used.

              

    1/  See Annex 2 for FAO and WHO documentation.

        Table 1.  Survey of Uses of Chlorpyrifos in Cattle: A. Developed Countries
                                                                                                                           

    Country          Product               Use                                 Comment
                                                                                                                           

    Australia        DURSBAN 1/24E         For ticks and lice in cattle,       Do not use on lactating cattle or in
      all states     250 g/litre           as dip at 1 litre/1 000 litres      dairy cows later than 3 weeks before
      1970-71                              of water (0.025% a.i.), or as       calving. Do not spray later than 3
                                           spray at 200 ml/200 litres          weeks before slaughter, or dip later
                                           using at least 5 litres per         than 3 days before slaughter of meat
                                           animal.                             animals.

      all states     DURSBAN JS            For louse control in cattle,        Do not use in lactating dairy cattle
      1977           50% a.i. w/v          apply as a "one-shot" treatment     or in dry dairy cows within 3 weeks
                                           using 3 ml/100 kg bw (1.5 g         before calving. Do not use later than
                                           a.i./100 kg bw) as spot-on to       21 days before slaughter for meat
                                           rump.                               animals.

    New Zealand      DURSBAN 10E           For cattle lice control, use        Do not use on dairy cows "in milk".
      1971?          License No. 1454      62.5 - 125 ml/100 litres of         Treat dairy cows not later than 3
                                           water                               weeks before calving. Treat beef
                                                                               cattle not later than 3 weeks before
                                                                               slaughtering.

      1977?          DURSBAN JS            For control of cattle lice, use     Do not use on dairy cows "in milk".
                     (400 g a.i./litre)    15-30 ml/100 litres, of water       Spray no later than 3 weeks before
                     License No. 2941      applied as a saturating spray,      calving for dry dairy cattle or
                                           or 2 ml/50 kg live weight (1.6      before slaughter for meat animals.
                                           g/100 kg bw) as a spot-on           Apply spot-on no later than 5 weeks
                                           treatment.                          before calving or slaughter.

      1978           Ridlice               For cattle, ectoparasites as        Do not use on lactating dairy cattle
                     50% a.i. w/v          one-shot application, use 3 ml/     or within 5 weeks before calving or
                     License No. 3485      100 kg bw (1.5 g a.i./100 kg bw)    slaughter.
                                           as spot-on to top of rump.
                                                                                                                           

    Table 1.  (con't)
                                                                                                                           

    Country          Product               Use                                 Comment
                                                                                                                           

    U.S.A.           DURSBAN 24E           For control of fever ticks in       For use under supervision of qualified
      1972           2 lb a.i./gal2/       beef cattle, use 1 ounce of         state or federal personnel responsible
                     23.7% a.i., w/v       product in 8 gallons of water       for quarantine programmes. Withdrawal
                     EPA Reg No.           (0.025% a.i.), and apply 3/4 to     period of 2 weeks before slaughter.
                     464-450               1 gallon as spray treatment; or     No more than 6 applications at 21-day
                                           use 1/2 gallon of product per       intervals per season.
                                           500 gallons of water (0.025%
                                           a.i.) for dip treatment.2/

    U.S.A.
      1979           DURSBAN 44            For lice control in beef cattle     Do not treat dairy cows during
                     43.2% a.i. w/v        and non-lactating dairy cattle,     lactation. Do not treat dry dairy cows
                     EPA Reg. No.          apply to back as a "spot-on"        or replacement heifers within 60 days
                     464-542               treatment using 2 ml/100 lb bw      before freshening. Do not slaughter
                                           (2 g a.i. 100 kg bw) or 16 ml       meat animals for 14 days after initial
                                           maximum per animal.                 treatment, or after a second treatment
                                                                               applied 45 days or more after the first
                                                                               treatment. Do not slaughter for 21
                                                                               days after second treatment applied
                                                                               30 days after first treatment.
    Canada
      Temp. 1979     DURSBAN 44            Temporary registration for louse    Do not treat within 14 days before
      Expired 1980   43.2% a.i.            control in beef cattle              slaughter.

    Argentina        DURSBAN 24E           Control of ticks on cattle by       Do not slaughter cattle within 3
      1969           240 g a.i./litre      spraying and dipping using 336      weeks of treatment.
                     Reg. No. 1307         g a.i./1 000 litres of water.

      1975           DURSBAN 18A           Dip or spray treatment for          Preslaughter interval of 2 days for
                     180 g a.i./litre      cattle.                             meat animals (previously 2 weeks)
                                                                                                                           

    Table 1.  (con't)
                                                                                                                           

    Country          Product               Use                                 Comment
                                                                                                                           

    Brazil           DURSBAN 1E            Tickicide for cattle as spray       Withdrawal period of 14 days after
      1969, 1973     13% a.i. w/v          or dip at 1:500 - 1:300             treatment.
                     Reg. No. 973          dilution

      1975           DURSBAN 24E           Control of ticks on cattle by       Preslaughter limitation of 14 days
                     240 g a.i./litre      spraying and dipping at             after treatment. Also 48 hours
                     NBR 96/75             1:1 000 - 1:600 dilution            limitation on use of milk after
                                                                               treatment.

    Colombia         DURSBAN 24E           Control of ticks on cattle by       Do not slaughter cattle within 3
      1972           240 g a.i./litre      spraying and dipping using          weeks of treatment.
                                           336 g a.i./1 000 litres of water.

    Costa Rica       DURSBAN 24E                          "                                   "
      Expired        240 g a.i./litre
      1976           Reg. No 255

    Dominican        DURSBAN 24E                          "                                   "
    Republic         240 g a.i./litre
      1975

    Ecuador          DURSBAN 24E                          "                                   "
      1975           240 g a.i./litre

    El Salvador      DURSBAN 24E           Control of ticks on cattle by       Do not slaughter cattle within 3
      1975           240 g a.i./litre      spraying and dipping using          weeks of treatment.
                                           336 g a.i./1 000 litres of
                                           water.
                                                                                                                           

    Table 1.  (con't)
                                                                                                                           

    Country          Product               Use                                 Comment
                                                                                                                           

    Mexico           DURSBAN 24E                          "                                   "
      1969           240 g a.i./litre
                     Reg.No. 0-0480-015

    Nicaragua        DURSBAN 24E                          "                                   "
      1975           240 g a.i./litre

    Panama           DURSBAN 24E                          "                                   "
      1975           240 g a.i./litre
                     Reg.No. 15130

    Trinidad         DURSBAN 24E                          "                                   "
      1972           240 g a.i./litre

    Venezuela        DURSBAN 24E                          "                    Not to be used for 20 hours before
      1972           240 g a.i./litre                                          milking or 15 days before slaughter
                                                                               of meat animals.
                                                                                                                           

    1/   Trademark of The Dow Chemical Company;

    2/   1 gallon = 3.8 litres;

    3/   1 lb (16 oz) = 0.45 kg.
             Labels approved recently in Australia, New Zealand and the U.S.
    recommends a one-shot "spot-on" treatment rather than dipping or
    spraying. Limitations specify withdrawal intervals prior to slaughter
    of meat animals, and state that the product is not to be used on dairy
    cattle during lactation, nor within a stated interval prior to
    freshening or calving.

         In Canada, temporary approval expired in 1980 for use of
    chlorpyrifos to control lice in cattle and pigs. In Europe, only one
    recommendation was noted, as a dip for sheep using a mixture of
    chlorpyrifos and gamma HCH (Rycovet 365 Dip, Glasgow, June 1978).

         Recommendations for chlorpyrifos in Latin America generally do
    not differentiate between beef animals and dairy animals. However, the
    use of these products has been declining steadily, and the total sold
    in 1981 amounted to less than 40 000 kg active ingredient for the
    entire region. Records of Dow Chemical Co. indicate that less than
    1 000 kg was sold in Brazil in each of 1979, 1980 and 1981, and none
    was sold in Venezuela in 1981.

         Although it is difficult to estimate how much chlorpyrifos is
    actually used in lactating animals, the rate of milk production under
    present agricultural practice in developing countries is inadequate
    even for local consumption. Thus, it is highly unlikely that minor use
    of chlorpyrifos in cows in certain Latin American countries would
    result in residues in milk products in international trade.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    In Meat

         Cattle were treated once with DURSBAN 44 Insecticide at the rate
    of 2 ml/100 lb of body weight (equivalent to 20 mg chlorpyrifos per
    kg bw) applied as a "spot-on" to the top midline just posterior to the
    withers. Groups of three cattle each were sacrificed the day after
    treatment and at 7-day intervals through 35 days after application.
    The maximum residue of chlorpyrifos was 1.4 mg/kg in fat at 7 days
    after treatment (Table 2). Residues in muscle were much lower than in
    fat, and did not exceed 0.6 mg/kg chlorpyrifos at any sampling. Thus
    residues from "spot-on" treatment are not likely to exceed the
    recommended limit of 2 mg/kg for chlorpyrifos in carcase meat on a fat
    basis (McKellar and Dishburger 1976).

        Table 2.  Summary of Average Residues of Chlorpyrifos and 3,5,6-Trichloro-2-Pyridinol in Tissues of Cattle1/
                                                                                                                                           

    Days from                                     Average Residue Found, mg/kg (range, mg/kg)
    Treatment                     Chlorpyrifos                                             3,5,6-Trichloro-2-Pyridinol
    to Sampling   Muscle       Liver         Kidney        Fat                 Muscle         Liver          Kidney         Fat
                                                                                                                                           

       1          0.02         0.01          0.07          0.28                ND             0.74           0.52           0.10
                  (0.01-0.03)  (0.01)        (0.06-0.08)   (0.03-0.46)                        (0.52-0.97)    (0.45-0.56)    (<0.05-0.18)

       7          0.04         0.04          0.12          1.1                 0.09           1.0            0.86           0.19
                  (0.01-0.06)  (0.01-0.08)   (0.09-0.18)   (0.95-1.4)          (<0.05-0.15)   (0.67-1.5)     (0.46-1.4)     (0.08-0.24)

       14         0.01         0.02          0.11          0.80                ND             0.59           0.52           0.07
                  (ND-0.01)    (0.02-0.03)   (0.08-0.16)   (0.61-0.99)                        (0.47-0.69)    (0.48-0.58)    (0.06-0.08)

       21         0.01         0.01          0.08          0.05                ND             0.42           0.29           0.14
                  (0.01)       (<0.01-0.01)  (0.06-0.10)   (ND-0.14)                          (0.31-0.53)    (0.14-0.57)    (0.09-0.24)

       24         0.01         ND            0.07          0.47                ND             0.20           0.10           <0.05
                  (0.01)                     (0.03-0.09)   (0.34-0.71)                        (0.11-0.27)    (0.06-0.13)    (ND-0.05)

       35         ND           ND            0.03          0.20                ND             0.13           0.05           ND
                                             (0.01-0.05)   (0.02-0.34)                        (0.05-0.23)    (0.04-0.07)
                                                                                                                                           

    1/   All animals received a single treatment of Dursban spot-on (M-4110) at a rate of 2 ml/45 kg body weight.
         Values corrected for control and recovery. ND = No detectable differences between treated and control samples.
             Groups of three cattle were fed chlorpyrifos for 30 days at
    levels of 3, 10, 30 and 100 ppm on a daily, dry matter intake basis.
    Residues of chlorpyrifos were mainly in the fat, reaching maxima of
    4.70 mg/kg in renal fat at 100 fed and 1.09 mg/kg in renal fat at
    30 ppm fed. The residues of chlorpyrifos declined to less than 2 mg/kg
    in fat within 7 days after discontinuation of feeding 100 ppm in the
    total diet of the cattle for 30 days (Table 2).

         The oxygen analogue of chlorpyrifos was shown to be unstable in
    liver and kidney, and no residue was found in any tissue at any
    feeding level. The pyridinol metabolite was not detected in muscle at
    feeding levels of 3 and 10 ppm chlorpyrifos, but was present in liver
    and kidney at all feeding levels, reaching maxima of 2.61 mg/kg in
    liver at 100 ppm fed and 1.67 mg/kg in liver at 30 ppm fed (Dishburger
     et al 1977).

    In Milk

         Lactating cows were fed a complete ration containing chlorpyrifos
    at levels from 0.3 to 30 ppm for 2 weeks at each level. At 30 ppm in
    the total diet, maximum residues of chlorpyrifos were 0.01 mg/kg in
    milk and 0.10 mg/kg in cream. The oxygen analogue was not detected in
    any sample of milk or cream at any dietary level of chlorpyrifos. The
    pyridinol metabolite was detected at 0.01 mg/kg in milk of cows fed
    30 ppm chlorpyrifos, but does not concentrate in fat. Thus, residues
    resulting from ingestion of feedstuffs containing chlorpyrifos
    residues amounting to no more than 10 - 15 mg/kg in the total diet
    should not exceed the current recommendation of 0.1 mg/kg for
    chlorpyrifos in milk on a fat basis (McKellar  et al 1976).

    FATE OF RESIDUES

    In Animals

         An additional metabolic study has been conducted using 14C-ring
    labelled chlorpyrifos in lactating goats. The material was
    administered via capsule twice daily at doses equivalent to 16 and
    25 ppm in the daily feed for 10 days. The majority of the total 14C
    activity was recovered in the urine (80.3%), with small amounts in the
    faeces (3.6%), gut (0.9%) tissues (0.8%) and milk (0.1%).

         Most of the radioactivity in the urine was excreted as the
    -glucuronide conjugate of 3,5,6-trichloro-2-pyridinol with small
    amounts of free pyridinol metabolite. About 75% of the 14C activity
    in the fat was chlorpyrifos (0.1 mg/kg) with most of the remaining
    14C activity hydrolysable to the pyridinol metabolite. The results of
    this study validate the methodology used in earlier animal residue
    studies (Glas 1981).

    METHODS OF RESIDUE ANALYSIS

         The analytical method used for analysis of beef tissues from the
    "spot-on" treatment, was the procedure developed in 1972 for
    determination of chlorpyrifos residues in chicken tissues and eggs.
    Analysis is by gas chromatography using flame photometric detection.
    The validated lower level of sensitivity is 0.01 mg/kg chlorpyrifos in
    muscle, liver, kidney and fat of beef animals, as well as the chicken
    muscle, liver, kidney and eggs (McKellar and Dishburger 1976; Wetters
    1972).

         An improved analytical method for the determination of
    chlorpyrifos in milk and cream has lower limits of detection at 0.01
    and 0.05 mg/kg in these matrices, respectively. The samples are
    extracted with hexane, the extract partitioned into acetonitrile,
    cleaned up on deactivated silica gel and analysed by gas
    chromatography with flame photometric detection (Jeffries 1980).

    NATIONAL MAXIMUM RESIDUE LIMITS

         Maximum residue limits reported to the Meeting for chlorpyrifos
    in foods of animal origin are summarized in Table 3. The Codex MRLs
    included for comparison are in terms of chlorpyrifos alone, since the
    pyridinol hydrolysis product is of low mammalian toxicity and is
    excreted rapidly in the urine and faeces of animals (FAO/WHO 1973b,
    p. 162 and 194).

         U.S. tolerances include its pyridinol metabolite, expressed as
    chlorpyrifos, and were increased recently to include the estimated
    contribution from ingestion of feedstuffs treated with chlorpyrifos.
    The tolerances in feedstuffs, which do not exceed 15 mg/kg in any
    case, also represent maximum total residues of chlorpyrifos and its
    pyridinol hydrolysis product, expressed as chlorpyrifos, without
    differentiation as to the contribution due to each component (U.S.
    Code of Federal Regulations 1982).

    APPRAISAL

         New information on current uses of chlorpyrifos on animals and on
    residues in milk from ingestion of treated feed indicate that such
    uses should not result in residues in excess of the proposed CCPR MRLs
    of 2 mg/kg in carcase meat of cattle (for fat-soluble pesticides, a
    portion of carcase fat is analysed and the MRLs apply to carcase fat)
    and of 0.1 mg/kg in milk and milk products (both on a fat basis).
    Because chlorpyrifos residues in whole milk from cows fed up to

    Table 3.  Maximum Residue Limits for Chlorpyrifos1/ in
              Food Products of Animal Origin
                                                                        

    Cattle

       Codex         2.0 mg/kg in carcase meat (carcase fat).
       Australia     2.0 mg/kg in fat of meat of cattle.
       Canada        1.0 mg/kg (temporary) in meat and meat by-products
                     (fat basis) and in fat, liver and kidney.
       New Zealand   1.5 mg/kg in meat fat in any food.
       U.S.          2.0 mg/kg in fat, meat and meat by-products.

    Eggs

       Codex         0.01 mg/kg (on shell-free basis).
       U.S.          0.1 mg/kg.

    Goats

       U.S.          1.0 mg/kg in fat, meat and meat by-products.

    Pigs

       Australia     0.1 mg/kg in fat of meat of pigs.
       U.S.          0.5 mg/kg in fat, meat and meat by-products.

    Horses

       U.S.          1.0 mg/kg in fat, meat and meat by-products.

    Milk

       Codex         0.1 mg/kg (on a fat basis) including milk products.
       Switzerland   0.005 mg/kg in whole milk.
       U.S.          0.5 mg/kg in fat (reflecting 0.02 mg/kg in whole
                     milk).

    Poultry

       Codex         0.1 mg/kg in carcase meat (carcase fat).
       U.S.          0.5 mg/kg in fat, meat and meat by-products.

    Sheep

       Codex         0.2 mg/kg in carcase meat (carcase fat).
       New Zealand   1.5 mg/kg in meat fat in any food.
       U.S.          1.0 mg/kg in fat, meat and meat by-products.
                                                                        

    Table 3.  (con't)
                                                                        

    Turkeys

       Codex         0.2 mg/kg in carcase meat (skin and carcase fat).
       U.S.          0.2 mg/kg in fat, meat and meat by-products.
                                                                        

    1/   Tolerances in Canada and the U.S. include residues of
         3,5,6-trichloro-2-pyridinol expressed as chlorpyrifos.

    30 mg/kg in the total diet reached the measurable level of 0.01 mg/kg
    and, in consideration of the current CCPR approach to the
    establishment of limits for fat-soluble pesticides in milk, the MRL
    for milk should be changed to 0.01 mg/kg for chlorpyrifos (the limit
    of determination) in whole milk, from which the MRL for milk products
    containing more than 2% fat would be calculated on a fat basis,
    assuming 4% fat in raw milk.

    RECOMMENDATIONS

         The recommended maximum residue limit for milk and milk products
    on a fat basis is deleted and replaced with a new maximum residue
    limit for milk. The limit applies to chlorpyrifos only.

                  Commodity           Limit (mg/kg)

                  Milk                       0.01*

              

    *    at or about the limit of determination.

    REFERENCES

    Dishburger, H.J., McKellar, R.L., Pennington, J.Y. and Rice, J.R.
    1977     Determination of residues of chlorpyrifos, its oxygen
             analogue, and 3,5,6-trichloro-2-pyridinol in tissues of
             cattle fed chlorpyrifos. Journal of Agricultural Food Chem.
             25(6): 1325-1329.

    Glas, R.D. The metabolic fate of 14C-chlorpyrifos fed to lactating
    1981     goats. Report GH-C 1408R, Dow Chemical Co, (Unpublished)

    Jeffries, T.K. Determination of residues of chlorpyrifos in milk and
    1980     cream. Method ACR 80.5. Dow Chemical Co. (Unpublished)

    McKellar, R.L. and Dishburger, H.J. Determination of residues of
    1976     chlorpyrifos and 3,5,6-trichloro-2-pyridinol in tissues of
             cattle receiving a single treatment of DURSBAN spot-on.
             Report GH-C-930, Dow Chemical Co. (Unpublished)

    McKellar, R.L., Dishburger, H.J., Rice, J.R., Craig, L.F. and
             Pennington, J. Residues of chlorpyrifos, its oxygen
             analogue, and 3,5,6-trichloro-2-pyridinol in milk and cream
             from cows fed chlorpyrifos. Journal of Agricultural Food
             Chem. 24(2): 283-286.

    U.S. Code of Federal Regulations. Title 40: Section 180.342 for
    1982     chlorpyrifos tolerances in raw agricultural commodities;
             Section 193.85 for chlorpyrifos tolerances in processed
             foods; Section 561.98 for chlorpyrifos residues in processed
             feeds.

    Wetters, J.H. Determination of residues of 0,0-diethyl 0-(3,5,6-
    1972     trichloro-2-pyridyl) phosphorothioate in chicken tissues and
             eggs by gas chromatography with flame photometric detection.
             Method ARC 72.3. Dow Chemical Co. (Unpublished)


    See Also:
       Toxicological Abbreviations
       Chlorpyrifos (ICSC)
       Chlorpyrifos (PDS)
       Chlorpyrifos (WHO Pesticide Residues Series 2)
       Chlorpyrifos (WHO Pesticide Residues Series 5)
       Chlorpyrifos (Pesticide residues in food: 1977 evaluations)
       Chlorpyrifos (Pesticide residues in food: 1981 evaluations)
       Chlorpyrifos (Pesticide residues in food: 1983 evaluations)
       Chlorpyrifos (JMPR Evaluations 1999 Part II Toxicological)