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    MONOCROTOPHOS     JMPR 1975

    Explanation

         Monocrotophos was evaluated by the Joint Meeting in 1972
    (FAO/WHO, 1973), an acceptable daily intake was established and
    recommendations were made for maximum residue limits in a number of
    raw agricultural commodities. The Meeting expressed a desire for
    further information on the incidence of residues in apples and pears.

         Some delegations at the 8th Session of the Codex Committee on
    Pesticide Residues were of the opinion that the maximum residue limit
    proposed for monocrotophos in apples and pears was too high (Alinorm
    76/24, para. 149). After re-examination of the data available to the
    1972 Meeting and evaluation of new data, this Monograph Addendum
    confirms the necessity for the previously proposed limit for apples
    and pears. An increased limit for tomatoes is also recommended.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Biotransformation

         It has been shown that monocrotophos and also dicrotophos are not
    hydrolysed to the corresponding carboxylic acid by an amidase from
    sheep liver which readily hydrolysed dimethoate in this way (Chen and
    Dauterman, 1972).

         The metabolism and degradation of monocrotophos has been reviewed
    recently together with that of several vinyl phosphate insecticides
    (Beynon et al., 1973).

    TOXICOLOGICAL STUDIES

    Special studies on mutagenicity

         Mouse

         Groups of fertile male CFI mice (12 per group) aged 10-12 weeks
    were treated with a single oral dose of 0, 1, 2, 4 mg/kg of
    monocrotophos (99% pure). A control group was dosed orally with
    dimethyl sulphoxide. Treated and control males were mated with
    untreated females for 8 consecutive weeks and 13 days after mating the
    females were killed and examined for evidence of dominant lethal
    mutations. The number of pregnancies, foetal implantations and early
    foetal deaths did not significantly differ from, those in the control
    group at any week interval or over the whole 8 weeks (Dean, 1973).

    Micro-organism

         Technical (77.3% in hexylene glycol), analytical grade (greater
    than 99% pure) azodrin and trimethylphosphate (TMPO) have been
    examined for mutagenic activity in one strain of S. cerevisiae, 3
    strains of S. marcescens and 4 strains of S. typhimurium using a
    host-mediated assay (Carworth Farm Strain (CF1) mice) and direct
    exposure in vitro; both positive (EMS, NTG) and negative (HOH)
    control were used. Mutation rates expressed as revertants to
    prototrophy were not detected in the host-mediated assay with
    technical azodrin at the highest level tested (8 mg/kg). No mutagenic
    effects in the two bacterial systems tested were detected. However,
    technical and analytical grade azodrin and TMPO at high concentrations
    all caused substantial increases in the conversion frequency at both
    adenine and tryphophen loci (Dean et al., 1974).

    OBSERVATIONS IN MAN

         Groups of healthy male volunteers (3 groups, 6 per group), 18-26
    years old and randomly selected from a student population were given
    gelatin capsules containing 0, 0.25 mg (3.6 g/kg bw) and 0.40 mg
    (5.9 g/kg bw) monocrotophos (purity <99% dissolved in 2 mg/ml in 90%
    maize oil and 10% acetone mixture) each day for a period of 30 days.
    Plasma and erythrocyte ChE activities were measured prior, during and
    for 12 days after exposure. The plasma ChE activity of the 0.25
    mg-group reached a stable level of 87% of its initial value after two
    weeks while that of the 0.40 mg-group showed a decline to 78% of its
    initial activity after 28 days and to 77% on the 29th day. Neither
    group showed a decline in the average activity of erythrocyte ChE.
    Liver functions (GOT, GPT and alkaline phosphatase) showed no
    significant changes (Verberk, 1972).

    Comments

         Monocrotophos was previously evaluated in 1972 and an ADI of
    0-0.0003 mg/kg body weight was estimated. Additional data was reviewed
    with respect to mutagenesis, biotransformation and its effect on man.
    In vivo and in vitro studies with mice and micro-organisms reflect
    the lack of mutagenic potential. An extensive study with human
    volunteers demonstrated no significant cholinesterase depression over
    a 30 day test period. A slight depression of plasma cholinesterase was
    rapidly reversed on cessation of exposure. Based on the slight plasma
    cholinesterase depression in human studios, rapid recovery of enzyme
    activity, lack of erythrocyte cholinesterase depression and additional
    evidence of safety based on negative mutagenic potential, the Meeting
    reconsidered and increased the ADI for man.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat: 0.5 ppm in the diet equivalent to 0.025 mg/kg bw

         Dog: 0.5 ppm in the diet equivalent to 0.0125 mg/kg bw

         Man: 0.006 mg/kg bw

    Estimate of acceptable daily intake for man

         0-0.0006 mg/kg bw

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         Although the quantity of monocrotophos used annually has
    increased considerably, there does not appear to be any significant
    increase in the field of usage beyond that evaluated by the Joint
    Meeting in 1972.

         The usefulness of monocrotophos as a spray for deciduous crops,
    particularly apples, has resulted in it becoming one of the most
    widely used insecticides for apples and pears in Australia and Italy.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    Apples

         The extensive data examined by the Joint Meeting in 1972 revealed
    that following the application of 0.04% monocrotophos spray 4 weeks
    before harvest, residues on apples ranged from, <0.01 to 1.5 mg/kg.
    It was noted at the time that the upper figures, however, were derived
    from experiments in which the spray was applied by hand, which usually
    requires somewhat higher volume. It was considered that in practical
    conditions of use, 1.0 mg/kg would be the highest level likely to
    occur.

         The extensive data have been re-examined and a selection of the
    results are included in Table 1.

         From the data summarized in Table 1, it is quickly apparent why
    the Meeting recommended that a maximum residue limit of at least 1
    mg/kg would be required to cover residues resulting from the approved
    use of monocrotophos on apples. It should be emphasized that all these
    data were collected from supervised trials in which the insecticide
    was applied by hand spraying.

         Since these data were generated, the recommendations for use have
    not greatly changed. The spray concentration remains 0.025-0.04%
    active ingredient and the interval between last treatment and harvest,
    4 weeks. However, it has become apparent that in Australia most of the
    monocrotophos used is applied by air-blast sprayers and not hand
    equipment as in most previous trials. Machine-spraying leads to the
    use of lower volumes per tree and hence smaller amounts of total
    product applied.

         New residue data, summarized in Table 2, have been developed from
    commercial orchards where monocrotophos is applied by air-blast
    machine as in Australia. Table 2 also includes some additional data
    from Italy on residues resulting from machine spraying which were not
    available when the original information was reviewed in 1972.

         The new data indicate that residues from machine spraying will be
    lower than where hand equipment is used, and the Australian data are
    considered to give better guidance on residue levels likely to arise
    in commercial practice in Australia than the higher levels reported in
    the 1972 monographs. As may be seen, the new data indicate lower
    residue levels than the old data and would seem to be compatible with
    a maximum residue limit of 0.5 mg/kg for apples. However, in the case
    of Italy, the higher levels reported in the 1972 monographs which are
    summarized in Table 1, are still regarded as representative of much of
    current commercial practice and these suggest that for apples a
    maximum residue limit of 1 mg/kg is still needed.

         It is interesting to note that in the 1975 Australian trials
    (Table 2), the level of residues found in the peeled fruit and in the
    whole fruit were similar. This is not unexpected in view of the
    systemic properties of this insecticide.

    Pears

         In assessing the data in 1972, the Meeting came to the conclusion
    that the level of monocrotophos residues in pears treated in
    accordance with good agricultural practice was such that a maximum
    residue limit of 1 mg/kg was appropriate. This deduction has been
    questioned by some delegates of the Codex Committee on Pesticide
    Residues and the Meeting therefore re-examined the extensive data
    available to the Meeting in 1972.

         A summary of the information examined in 1972 is set out in Table
    3. It is clear that the residues resulting from, the application of
    monocrotophos sprays at or below approved rates are at least equal to
    and often exceed 0.5 mg/kg when fruit Y harvested 4 weeks after the
    last application. As far as can be judged from, these data, the
    half-life of the residue in mature fruit is not much less than 4
    weeks. This is to be expected in view of the systemic properties of
    monocrotophos.


    
    TABLE 1.  Monocrotophos residues in apples resulting from hand spraying

                                                                                                                                               

                                                                        Residues mg/kg after pre-harvest interval (weeks)
                                    Spray         No. of
    Country        Variety        Concn, %     Applications      2       3       4       5       6       7       8       9       10      12
                                                                                                                                               

    Australia      Jonathan         0.04            7           1.9     1.0     0.7
                   Prince Alfred    0.04            2                                                                                   0.19
                      "                             3                                                                   0.94
                      "                             4                                           1.2
                      "                             5           2.1
                   Democrat         0.04            1           1.9     0.7     0.96    0.68    0.94    0.99    0.67    0.46
                   Granny Smith     0.04            1                           0.92    0.86    0.70    0.46    0.44    0.55
                   Unknown          0.04         Unknown                                1.3                                     0.25
                   Golden Delic.    0.04            "           0.84
                   Jonathan         0.04            "                           0.19
                   Granny Smith     0.04            "           0.09                    <0.01
                   Jonathan         0.04            "
                      "             0.04            "                                                   0.34
                      "             0.02            4                                                                   0.18
                      "                             6                                   0.51
                      "                             9           1.8
                      "             0.038           2                                                                                   0.26
                      "                             3                                                   0.48
                      "                             4                           0.48
                      "                             5           2.1
                   Rome Beauty      0.038           5                           1.5

    Italy          Star King        0.025           2                           0.95
                   Democrat                         2                           1.0
                   Abbondanza                       2                           0.8
                   Star King                        2                           1.0
                   Abbondanza       0.05            5                           0.5
                   Unknown          0.03            4           0.25    0.2     0.19            0.18
                                                                                                                                               

    TABLE 2.  Monocrotophos residues in apples resulting from mechanical spraying

                                                                                                                                               

                                                                               Interval                           Monocrotophos residues
                                                                                between         Pre-harvest                 mg/kg
                                                  Spray         No. of        treatments        interval          Whole fruit    Peeled fruit
    Country          Year      Variety           concn. %    applications       (weeks)         (weeks)               (1)             (2)
                                                                                                                                               

    Australia        1975      Granny Smith      0.038           3-4            3-4                3                  0.14            0.13
        "            1975          "               "              "              "                 5                  0.12            0.08
        "            1975          "               "              "              "                 3                  0.43            0.36
        "            1975          "               "              "              "               3 1/2                0.66            0.54
        "            1973          "               "              4             4, 4 & 9           4                  0.13            0.12

    Italy            1970      Imperatone        0.025            2              3                 4                  0.11              -
        "            1970      Golden
                               Delicious           "              "              "                 "                  0.53            0.40
        "            1970      Stark
                               Delicious           "              "              "                 "                  0.37              -
                                                                                                                                               

    (1) Average weight of whole apple 150g.

    (2) The peel accounted for 17% of the weight of the apples
    

         In order to ascertain the effect of the application method on
    residue levels, the results of trials carried out in Italy using hand
    application methods (Table 3) were compared with data obtained from
    other Italian trials where the insecticide was applied with mechanical
    equipment (Table 4). The amount of residue remaining after mechanical
    application cannot be judged to be lower than that found in fruit
    sprayed by hand.

         In order to confirm these observations, further trials were
    carried out in Australia in 1975 using standard spray concentration
    and a minimum number of applications applied at intervals consistent
    with normal practice in the area. At least half of the data indicate
    residues at or above 0.5 mg/kg in fruit harvested 3 to 7 weeks after
    the last treatment. (Table 4).

         Once again the residue studies indicate that the residue is
    distributed relatively evenly through the whole fruit, the peeled
    fruit containing substantially similar amounts of residue to the
    un-peeled.

         On the basis of the data from these supervised trials, the
    previously recommended maximum residue limit for monocrotophos on
    pears must be confirmed.

    Tomatoes

         Because of the dependence of tomato growers on organochlorine
    insecticides for the control of Heliothis and other lepidopterous
    pests, there is an urgent demand for an alternative insecticide which
    is environmentally acceptable. Because of its efficacy against
    Heliothis and other lepidoptera, there has been considerable interest
    in the use of monocrotophos for the control of these pests on
    tomatoes.

         The 1972 Meeting evaluated extensive data, then available, and
    recommended a maximum residue limit of 0.5 mg/kg for monocrotophos on
    tomatoes. Examination of the data published in the 1972 monograph
    (FAO/WHO 1973) indicates that it is only possible to keep within this
    limit if the tomato crop is not sprayed within 4 weeks of harvest.

         Since tomatoes flower and fruit over a long period and since
    fruit at every stage from bud to fully ripe fruit can be found on the
    vine at one time, it is not possible to utilise monocrotophos in a
    manner which would protect the crop against insect damage without
    possibly producing residues in excess of the 0.5 mg/kg maximum residue
    limit. The Meeting, therefore, re-examined the data submitted in 1972
    and considered this in conjunction with results of supervised residue
    studies which have since became available. A summary of a
    representative selection of these data is set out in Table 5.


    
    TABLE 3.  Monocrotophos residues in pears resulting from hand spraying

                                                                                                                                               

                                                                   Residues (mg/kg) after pre-harvest interval (weeks)
                               Spray         No. of
    Country        Variety     concn. %    applications     1       2       3       4       5       6       7       8       9       10      12
                                                                                                                                               

    Australia                  0.04             7          0.2     0.2     0.2     0.1
    Australia                  0.04             4                  0.54
        "                      0.03             4                          0.76
        "                      0.04             3                                  0.61

    Italy                      0.01             2                                  0.60
        "                      0.01             2                                                          0.08
        "                      0.028            1                  0.24
        "                      0.056*           1                  0.35
        "                      0.028            1                  0.25
        "                      0.056*           1                  0.29
        "                      0.025            2                                  0.15
        "                      0.025            4          0.99    0.72    0.54    0.47            0.54
                                                                                                                                               

    * Above recommended dosage.

    TABLE 4. Monocrotophos residues in pears resulting from mechanical spraying

                                                                                                                                  

                                                                   Interval                         Monocrotophos residues
                                                                   between       Pre-harvest                mg/kg
                                        Spray          No. of      treatments    interval         Whole fruit     Peeled fruit
    Country/Year       Variety          concn. %    Applications   (weeks)       (weeks)             (1)              (1)
                                                                                                                                  

    Australia 1975     Packhams         0.038           3-4          3-4           7                 0.50           0.48 (2)
                          "                                                        2                 0.76           0.50 (2)
                          "                                                        3 1/2             0.51           0.46 (2)
                          "                                                        4 1/2             0.26           0.23 (2)
                          "                                                        6                 0.20           0.14 (2)

    Italy 1970         Passacrassana    0.025           3            2             4                 0.28           0.17 (3)
                                                                                   4                 0.21             -
                                                                                   4                 0.18             -
                                                                                   4                 0.18
                                                                                                                                  

    (1) Average weight of a whole pear 130g.
    (2) The peel accounted for 15% of the weight of the pears.
    (3) The peel accounted for 22% of the weight of the pears.
    


         The most noticeable feature of the data is the slight decline in
    the level of residues between the 1st and 28th day after application.
    This is perhaps not unexpected in view of the systemic properties of
    the insecticide and the growth pattern of the crop.

         On the other hand, the data indicate that the number of
    applications has very little bearing on the level of residues
    resulting from the treatment. The level of residues resulting from 19
    successive applications to not significantly higher than that
    resulting from 3 applications of the same concentration of spray.
    Tomatoes grown under a standard regime of monocrotophos sprays were
    submitted for residue analysis both before and after washing with
    water. Generally, though a measurable amount of residue is removed by
    washing, it is only a small proportion of the total. In view of the
    fact that monocrotophos is moderately soluble in water, this result
    would be surprising were it not for the knowledge that the bulk of the
    residue is located well within the fruit. Such residues are
    accumulated by the systemic uptake of spray deposited not only on
    fruit but on leaves and stem also.

    Evidence of residues in food in commerce or at consumption

         As discussed earlier in this monograph addendum, and as indicated
    in Tables 2 and 4, there is every indication that residues resulting
    from approved application of monocrotophos to apples and pears are
    distributed throughout the fruit and would not be removed by washing
    or peeling in preparation for consumption.

         Likewise, in the case of tomatoes the residue is not
    significantly decreased by washing in preparation for eating and it
    must therefore be concluded that the bulk of the monocrotophos
    residues present in raw agricultural commodities will remain, at the
    time of consumption, in foods which are not cooked.

         In Australia in 1973 a survey was carried out in one district
    where monocrotophos is used by most of the apple and pear growers.
    Fruit delivered to the packing-house by growers was sampled at random
    for analysis for monocrotophos residues. In none of the samples were
    residues of monocrotophos found to be above 0.5 mg/kg. The data
    indicate that most of the fruit contained no more than 0.15 mg/kg.

    APPRAISAL

         The 1972 Joint Meeting proposed a temporary maximum residue limit
    for monocrotophos in apples and pears of 1 mg/kg, with a comment that
    further data would be desirable.


    
    TABLE 5.  Monocrotophos residues in tomatoes

                                                                                                                                               

                                                               Monocrotophos residues (mg/kg) after pre-harvest intervai (days)
                       Dosage rate       No. of
    Country               kg/ha       applications     1        3        5        7        10       14       21       28       35       42
                                                                                                                                               

    South Africa          0.2              3                                                       0.14
                           "               2                                                                         0.13
                           "               1                                                                                           0.02
                          0.4              3                                                       0.64
                           "               2                                                                         0.51
                           "               1                                                                                           0.02
                          0.47             3                                                                <0.01
                           "               6                                     0.06
                          0.94             3                                                                0.08
                           "               6                                     0.34
                          0.2              2                                                                                           <0.01
                                           3                                                                         0.01

    U.S.A.                1.0              3          1.5      1.1               0.07     1.1      0.44     0.33
                          1.0              19         1.86     1.15              1.28     0.90
                          2.0              19         2.80     3.03              1.91     1.02
                          1.0              7          0.51     0.30              0.22     0.31
                          0.8              7          0.59     0.57              0.46     0.54

    Australia             0.06% ai         5                                     1.2
                            "              6                                     1.4
                          0.05% ai         3                                     0.42
                            "              4                                     0.36
                            "              5                                     1.1
                            "              6                                     1.1
                            "              7                                     1.6
                          1.2              7                                                       0.12
                            "              8                                     0.25
                            "              9                            0.37
                          3.3              4                   1.1               0.82              0.79     0.31

    TABLE 5.  (Continued)

                                                                                                                                               

                                                               Monocrotophos residues (mg/kg) after pre-harvest intervai (days)
                       Dosage rate       No. of
    Country               kg/ha       applications     1        3        5        7        10       14       21       28       35       42
                                                                                                                                               

    Puerto Rico           1.25             5                                                                         0.35

    Switzerland           0.02% ai         1          0.45              0.16              0.16              0.17     0.12
                            "              1          0.38     0.10              0.07              0.05     0.04

    Guatemala             1.0              10                                                                        0.67
                          0.6              5                                                                                           0.03
                                                                                                                                               

    TABLE 6.  Monocrotophos residues in tomatoes before and after washing

                                                                                                                    

                       Dosage rate       No. of            Pre-harvest          Monocrotophos residues (mg/kg)
    Country               kg/ha          Applications      interval (days)      Before washing     After washing
                                                                                                                    

    Puerto Rico           1.25              5                  27                   0.29                0.25
        "                  "                5                  27                   0.40                0.28

    U.S.A.                1.0               5                  23                   0.14                0.09
        "                  "                5                  23                   0.24                0.15
        "                  "                5                  25                   0.30                0.17
        "                  "                5                  25                   0.21                0.17
        "                  "                5                  30                   0.08                0.12
        "                  "                5                  30                   0.12                0.16
                                                                                                                    
    

         The original data on which the proposed maximum residue limit was
    based were developed from supervised trials in Australia and Italy,
    the two countries employing monocrotophos on pome fruit. Although in
    the meantime the use recommendation has not greatly changed, it has
    become apparent that in Australia the majority of the monocrotophos is
    applied by air-blast sprayers and not hand equipment as used in the
    supervised trials. The use of machine spraying leads to the
    application of smaller volumes and hence smaller amounts of total
    product applied. New residue data have been developed to cover this
    use in Australia.

         These new data have been examined alongside the raw data
    available in 1972 and some additional data from Italy which were not
    available to the 1972 Meeting.

         The new data indicate that residues resulting from machine
    spraying will be somewhat lower than those resulting from the use of
    hand-held equipment but the difference is only slight. Although the
    new data are considered to give better guidance on residue levels
    likely to arise in commercial practice in Australia, the somewhat
    higher levels found following hand spraying and reported in the 1972
    monograph are still regarded as representative of much current
    commercial practice in Italy.

         The data clearly indicate that, owing to the systemic nature of
    the insecticide, there is relatively little loss of residue from fruit
    in the 4 weeks which elapses between application and harvest. Because
    of the substantial variation in the level of residues resulting from
    comparable application procedures, the Meeting judged that it would be
    unwise to recommend maximum residue limits lower than the 1 mg/kg
    recommended in 1972. Among numerous results from many supervised
    trials, there were certainly enough data to indicate that in
    commercial practice there could well be a significant number of lots
    with residues well above 0.5 mg/kg.

         Because of increasing interest in the use of monocrotophos for
    the control of insect pests of tomatoes, the Meeting re-examined the
    data submitted in 1972 and considered new data which had since become
    available. It is obvious that monocrotophos could not be used
    effectively in controlling pests of tomatoes without a substantial
    proportion of samples having residues above 0.5 mg/kg. The Meeting
    therefore recommended that the maximum residue limit on tomatoes be
    increased from 0.5 mg/kg to 1 mg/kg.

    RECOMMENDATIONS

         The previously recommended maximum residue limits for apples and
    pears are confirmed, and the limit for tomatoes is amended.

    MAXIMUM RESIDUE LIMITS

         Commodity                     Limit mg/kg

         Apples, pears, tomatoes       1

    FURTHER WORK OR INFORMATION

    Desirable

         As FAO/WHO 1973a, p. 45, excluding item 2.

    REFERENCES

    Beynon, K. I., Hutson, D. H. and Wright, A. N. (1973) The metabolism
    and degradation of vinyl phosphate insecticides. Res. Rev., 47: 55-142

    Chen, P. R. S. and Dauterman, W. C. (1972) Studies of the toxicity of
    dimethoate analogues and their hydrolysis by sheep liver amidase.
    Pest. Biochem. Physiol., 1:340-

    Dean, B. J. (1973) Toxicity studies on Azodrin: dominant lethal assay
    in male mice after a single oral dose of Azodrin. Unpublished report
    from the Shell Tunstall Research Laboratory, Sittingbourne. Submitted
    to WHO by Shell Co.

    Dean, B. J., Doak., Somerville, H. A and Whitebread, C. (1974)
    Toxicity studies with Azodrin: effect of AzodrinR on micro-organisms
    in the host mediated assay and in vitro. Unpublished report from the
    Shell Tunstall Research Laboratory, Sittingbourne. Submitted to WHO by
    Shell Co.

    Verberk, M. M. (1972) Cholinesterase inhibition in man caused by 30
    days administration of monocrotophos. Unpublished report from the
    Coronal Laboratory, University of Amsterdam. Submitted to WHO by Shell
    Co.
    


    See Also:
       Toxicological Abbreviations
       Monocrotophos (HSG 80, 1993)
       Monocrotophos (ICSC)
       Monocrotophos (WHO Pesticide Residues Series 2)
       Monocrotophos (Pesticide residues in food: 1991 evaluations Part II Toxicology)
       Monocrotophos (Pesticide residues in food: 1993 evaluations Part II Toxicology)
       Monocrotophos (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)