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    PIRIMICARB       JMPR 1978

    Explanation

         Pirimicarb was evaluated by the 1976 Meeting (FAO/WHO, 1977b).
    A temporary ADI for man was established and temporary MRLs were
    recommended for a wide range of fruits and vegetables.

         Additional toxicological and residues data arising from the
    1976 review are summarised in this monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    TOXICOLOGICAL STUDIES

    Special studies on plant metabolites

    Rat

         Groups of 40 rats (20 of each sex) were orally treated with
    daily doses of 12.5 and 50 mg/kg of the plant metabolite carbamate
    (R 34 885) for a period of 14 or 28 days. The control group
    consisted of 10 animals of each sex. The treatment had no effect on
    the clinical condition, behaviour and mean body weight gain. Either
    showed the parameters of the haematological and bone marrow
    examination and the values of the urinalyses any pathological
    alternations. The results gave no evidence of hypochromic anaemia
    as suggested in a previous study. The histopathological examination
    revealed no abnormal findings.

         In a similar experiment designed to study the inhibition of
    the cholinesterase activity of the metabolite groups of 10 rats (5
    males and 5 females) were treated with daily oral doses of 0, 3 and
    12.5 mg/kg for 28 consecutive days. No significant inhibition of
    the enzyme was found in erythrocytes and brain, whereas the plasma
    cholinesterase activity showed a depression of 32% compared to
    control in females after treatment with 28 doses of 12.5 mg/kg
    (Parkinson, 1978a).

         Groups of 40 rats (20 males and 20 females) were orally
    treated with 25 and 100 mg/kg of the plant metabolite 5.6 -
    dimethyl-2-methylamino-pyrimidin-4-yl dimethylcarbamate (R 34 836)
    for 14 or 28 days. Additionally a control group consisting of 10
    animals of each sex was included into the study. The test compound
    had no adverse effect when administered at a dose level of 25
    mg/kg; at 100 mg/kg however 5 male and 6 female animals died during
    the study between two and seven doses with clinical signs of
    cholinesterase inhibition. Some animals at 100 mg/kg lost weight.
    The examination of blood and bone marrow revealed no abnormal
    findings and gave no indication for hypochromic anaemia. The
    results of urinalyses fell into normal limits with the only
    exception of slightly higher urinary protein values in male animals
    treated with 14 and 28 doses of 100 mg/kg respectively. No adverse
    histopathological effects were found at 100 mg/kg.

         To determine the degree of cholinesterase inhibition groups of
    10 rats (5 male and 5 female animals) were orally dosed with 0,
    1.5, 5, 25 and 100 mg/kg of the test compound for 28 days. The
    cholinesterase activity was not affected in erythrocytes and brain,
    the plasma cholinesterase activity however showed inhibition at 25
    mg/kg after 28 days of about 30% in male and about 55% in female
    animals; after 14 days of treatment with 100 mg/kg the depression
    was 40%, after 28 days of treatment 63% in female animals only
    (Parkinson, 1978b).

    Short-term studies

    Rat

         In order to determine a no effect level as regards the growth
    depression particularly in female rats as found in previous long
    term studies, groups of 20 female rats were maintained on diets
    containing 0, 100, 175, 250 and 750 ppm pirimicarb for a period of
    8 weeks. The feeding did not adversely affect the general health
    condition. At 750 ppm reduction of the body weight was observed,
    accompanied by lower food consumption compared to the control
    animals, especially in the first half of the study (Paul et al.,
    1978).

         In a paired feeding study female rats, fed with dietary levels
    of 0, 250 and 750 ppm were paired with rats receiving restricted
    diets at concentrations of 250 and 750 ppm respectively. A
    treatment related growth depression was observed that was slight at
    the 250 ppm dietary level and marked at 750 ppm after ad
    libitum or restricted feeding. The results indicate that the
    growth depression seems not to be due to reduced palatability of
    the supplemented food (Richards et al., 1978).

    Dog

         To define the susceptibility to haemolytic anaemia in the
    beagle strain (Jackson et al., 1977) another study was undertaken
    employing the foxhound an experimental animal. Groups of dogs
    received pirimicarb at dietary levels of 0 (2 animals) and 2 mg/kg
    b.w. (2 animals) over a period of 16 weeks. A third group (6
    animals) was maintained on a diet containing the test compound at
    a level of 25/50 mg/kg The dose level of 50 mg/kg was subsequently
    reduced back to 25 mg/kg as noon an marked haematological changes
    appeared. The treatment was followed by a recovery period from week
    17-23. One dog of the 25/50 mg/kg group was killed after a 2-week
    treatment with 50 mg/kg pirimicarb, showing behavioural changes and
    clinical deterioration as weight loss, inappetence and ataxia.
    Loose faeces were seen in dogs from all treatment groups. At 25
    mg/kg vomiting was observed sporadically. Over the first 4 weeks
    the male animals showed reduced body weight gains. At 50 mg/kg
    usually a few hours after feeding excessive salivation occurred;
    some dogs showed toxic effects as laboured respiration, vomiting,
    bloody faeces and flaccid muscles. The weight loss in some animals

    was accompanied by a slight reduction in food intake. The treatment
    at 50 mg/kg was associated with marked anaemia characterised by
    reduction in haemoglobin, packed cell volume and erythrocyte count 
    and an increase in reticulocytes. The direct Coombs test failed to 
    produce positive results (Jackson and Royle, 1978a). The examination 
    of the bone marrow revealed a tendency to an increased number of 
    normoblasts and towards suppressed activity (hypoplasia). Anaemia, 
    reticulocytosis and bone marrow changes were reversible and normal 
    values were measured after the recovery period. Maximum inhibition 
    of plasma cholinesterase activity of about 50-79% and 80-90% was 
    measured at the 25 mg/kg and the 50 mg/kg dose level respectively. 
    No dose-related alternations as regards the biochemical parameters 
    GOT, GPT, SAP, Glucose and BUN and the common parameters of urinalyses
    were found at any dose level. No abnormal macroscopic findings were 
    detected. Owing to the small number of control animals the 
    significance of various alterations in relative organ weight 
    particularly of the kidney and the spleen can't be determined (Fox, 
    1978).

    Monkey

         Groups of 4 rhesus monkeys (2 of each sex) were orally treated
    with 2 and 25 mg/kg pirimicarb over a period of 91 days;
    additionally 2 monkeys were used as controls. The treatment had no
    effect on mortality, appearance, behaviour and body weight gain.
    The parameters of the haematological examinations and the results
    of urinalyses were within normal limits. There was no evidence of
    haemolytic anaemia and all direct Coombs tests were negative
    throughout the dosing period. The results of clinical chemistry
    with respect to the parameters of Bilirubin, LAP, SGOT, SGPT, SAP,
    total serum protein, plasma glucose, plasma urea showed no abnormal
    alterations. A dose-related inhibition of the cholinesterase
    activity in erythrocytes of 16 and 38% and in plasma of 8 and 74%
    was found at the dose levels of 2 and 25 mg/kg 2 hours after
    dosing. The examination of the bone marrow revealed no pathological
    findings. The few incidental macroscopic findings are not
    attributable to treatment and the organ weights were considered to
    be within normal limits (Heywood et al., 1977).

         In a similar study, groups of 4 rhesus monkeys of each sex
    were orally dosed with 0, 2, 7 and 25 mg/kg pirmicarb for up to 17
    weeks, followed by a recovery period of 8 weeks. The survival,
    appearance and behaviour were not adversely affected by treatment
    and the only clinical effect was loose faeces in animals of all
    treatment groups. At 25 mg/kg a slight reduction In body weight
    gain was observed in the female animals. The results of
    haematological investigations gave no indication of a
    treatment-related anaemia. The parameters of clinical chemistry and
    urinalyses varied within normal limits. The inhibition of the
    cholinesterase activity in erythrocytes was 19, 18 and 31% and in
    plasma it was 23, 35 and 63% at the dose levels of 2, 7 and 25
    mg/kg respectively. The cholinesterase activity measured after 2
    weeks after cessation of treatment was normal. The findings of the

    bone marrow examinations were normal as well as any macroscopic
    post mortem findings. No group differences in organ weights were
    discovered. In the direct Coombs test sporadically positive
    reactions were found (Heywood et al., 1978a). Additional
    serological studies on monkeys confirmed the weak positive
    reactions in the Coombs test in some animals treated with 0, 2, 7 
    and 25 mg/kg pirimicarb (Jackson and Royle, 1978b). As could be 
    demonstrated in a test performed on 30 untreated monkeys isolated 
    positive reactions can occur spontaneously (Heywood et al., 1978b; 
    Jackson and Royle, 1978c).

    COMMENTS

         Previous studies in beagle dogs showed that the oral
    administration of pirimicarb caused haemolytic anaemia at dose
    levels of 10 mg/kg b.w. Concern was expressed by the 1976 Meeting
    regarding the pathogenesis of the condition and the susceptibility
    of other species than beagle dogs. Studies were performed recently
    in the foxhound strain. The same haematologic changes were found
    after oral treatment with 50 mg/kg. However, studies on rhesus
    monkeys with administration of oral daily doses of 25 mg/kg for 17
    weeks did not show my signs of haemolytic anaemia. The toxic
    response of the dog therefore seems to be species specific.

         Significant dose-related cholinesterase inhibition in plasma
    was observed in dogs and monkeys at dose levels of 25 mg/kg and
    above. The additional studies in dog (foxhound) confirm the no
    effect level established at the 1976 Meeting.

         Additionally the results of supplementary rat studies were
    submitted to consider the previously observed growth impairment in
    female rats at 250 ppm in the diet. In one of the presented studies
    a no effect level of 250 ppm was noted. In a corresponding paired
    feeding study a slight reduction in body weight gain at 250 ppm
    compared to the control was observed, suggesting 250 ppm to be the
    borderline of biological effect. Growth impairment was not caused
    by diminished food intake.

         Special studies on two plant metabolites 5,6-dimethyl-2-methyl
    formamido-pyrimidin4-yl dimethyl-carbamate (R 34 885) and
    5,6-dimethyl-2-methylamino-pyrimidin-4-yl dimethylcarbamate (R 34
    836) could not confirm the abnormal haematological findings of
    hypochromic anaemia noted in previous studies which were reported
    at the 1976 Meeting.

         Data on carcinogenicity of pirimicarb were not submitted. New
    data reduced some of the concerns of the previous Meeting and
    allowed a higher value for the temporary ADI.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

              Monkey:   2 mg/kg body weight day

              Rat:      175 ppm in the diet equivalent to 9 mg/kg body
                        weight

              Dog:      1.8 mg/kg body weight day

    Estimate of temporary acceptable daily intake for man

              0-0.01 mg/kg b.w.

    RESIDUES IN FOOD AND THEIR EVALUATION

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Residues data in fruit and vegetables were reviewed at the
    1976 Meeting. Additional data an alfalfa and cereals is reviewed
    below.

    Alfalfa (Medicago sativa)

         At 0.07-0.14 kg ai per ha, pirimicarb controls the blue aphid,
    Acyrthosiphon kondoi and the pea aphid, Acyrthosiphon
    pisum, on alfalfa. The major use of alfalfa is as hay. Freshly
    cut green standing alfalfa is also used as animal feed, cut either
    on an "as needed" basis or for ensilation.

         Seventeen alfalfa residue trials were conducted in seven
    States of the USA during 1975 and 1976, including four aerial
    trials. Samples for residue analysis normally consisted of 0.5-1 kg
    of mature crop derived from 3-4 replicate plots. Samples were
    usually transferred to cold storage at -18C within three hours of
    harvest, prior to analysis by gas chromatography (Edwards et al.,
    1977).

         Residues on green standing alfalfa decay rapidly; 50-75% of
    the initial residue is lost in 1-3 days. One or more days after the
    last application of 0.07-0.14 kg ai per ha, residues of pirimicarb
    plus its two carbamate-containing plant metabolites, II and III
    were less than 50 mg/kg experssed as pirimicarb equivalents on a
    dry weight basis - see Table 1 and Figure 1 (Cox, 1977; Edwards et
    al., 1977).

         During the seven days after spraying, total
    pyrimidine-carbamate residue levels in alfalfa hay, determined on
    a fresh weight basic, did not decrease markedly because moisture
    loss from the cut crop acted as a concentration step. However, when
    calculated on a dry-weight basis, total carbamate residues were

    seen to decrease; although the rate of decay was somewhat lower
    than that found in standing green alfalfa, residue levels in hay
    were still smaller than those on standing green alfalfa determined
    on a dry-weight basis. Residues were consistently below 20 mg/kg in
    hay, on a dry-weight basis, after last spraying at 0.07-0.14 kg ai
    per ha (Table 2) (Cox, 1977; Edwards et al., 1977).

    Cereals (Wheat, Triticum spp., Barley, Hordeum vulgare and
    Oats, Avena sativa)

         At 0.125-0.25 kg ai per ha pirimicarb controls the grain
    aphid, Macrosiphum avenae, on cereals. Spraying is conducted at
    an immature growth stage, normally several weeks before harvest.
    Residue trials have been conducted in Australia, South Africa,
    Canada, Denmark, Germany, the Netherlands and the UK. Approximately
    1 kg samples were normally transferred to a deep freeze within a few
    hours of harvest. Residues of pirimicarb and its two major
    carbamate-contained plant metabolites were usually determined by
    the gas-chromatographic method. As in the case of alfalfa residues
    of pirimicarb on green standing cereals decay rapidly, 50% of the
    initial residue being normally lost within 1-3 days. One day or
    more after the application of 0.25 kg ai per ha, residues of
    pirimicarb plus its two carbamate-containing plant metabolites, II
    and III, were less than 5 mg/kg expressed as pirimicarb equivalents
    - Table 3 and Figure 1 (Dick, 1978; Kennedy, 1978). There was no
    obvious difference between residues on immature ears and stalks
    (Dick, 1978). No residues were detected in grain and straw
    harvested three weeks or more after spraying at 0.125-0.3 kg ai,
    per ha (limit of determination; normally 0.01-0.04 mg/kg). See
    Table 4 (Dick, 1978; Kennedy, 1978).

        TABLE 1. Residues of pirimicarb in green standing alfalfa ("green chop"),
             USA 1975-76

                                                                              

    Application        No. of          Pre-harvest            Total carbamate
    rate             applications      Interval                  residues
    (kg ai/ha)                         (days)                     (mg/kg)
                                                                              

                                                           Range          Mean
                                                                              

    0.07                1-3                0               1.4-26         13
                                           1               1.3-14         6.2
                                           2               0.92-9.7       3.9
                                           3               0.92-6.4       3.7
                                           7               0.48-3.5       2.1
                                                                              

    0.14                1-4                0               6.6-79         27
                                           1               3.1-45         12
                                           2               1.9-46         8.7
                                           3               1.0-27         6.5
                                           7               0.57-11        3.0
                                                                              

    0.28                1-4                0               12-38          29
                                           1               6.8-22         14
                                           2               5.5-14         9.5
                                           3               2.6-11         7.4
                                           7               1.0-5.8        2.6
                                                                              

    * expressed as mg/kg pirimicarb equivalents and on a dry weight basis.

    TABLE 2. Residues of pirimicarb in alfalfa hay, USA 1975-76

                                                                              

    Application       No. of          Pre-harvest              Total carbamate
    rate           applications        interval                   residues
    (kg ai/ha)                           days                      (mg/kg)
                                                                              

                                                           Range          Mean
                                                                              

    0.07                1-3               0-3              0.29-12        3.6
                                          6-7              0.81-5.1       2.3
                                                                              

    0.14                1-4               0-3              0.55-11        2.9
                                          6-7              0.41-7.5       2.3
                                                                              

    0.28                2-4               0-3              1.0-14         5.3
                                          6-7              1.4-8.1        4.2
                                                                              

    * expressed as mg/kg pirimicarb equivalents on a dry weight basis.


    TABLE 3. Residues of pirimicarb in green standing wheat and barley, 1973-78

                                                                              
    Country            Application      Pre-harvest        Total carbamate
                       rate             interval              residues
                       (kg ai/ha)       (days)                 (mg/kg)*
                                                                              
                                                        Range           Mean
                                                                              

    Wheat

    Canada             0.14                1-2          0.89-3.9        2.4
                                             5                          0.76
                                             7          < 0.04-0.98     0.51
                                                                              

    South Africa       0.25                  1          0.84-1.1        0.96
                                             2          0.80-1.0        0.91
                                             4          0.52-0.65       0.60
                                             7          0.27-0.52       0.41

    Germany            0.25                  0          2.5-4.7         3.8
                                             1          0.58-3.4        2.4
                                             3          0.13-2.6        1.6
                                             7          0.04-1.5        0.99

    TABLE 3 (Continued)
                                                                              
    Country            Application      Pre-harvest        Total carbamate
                       rate             interval              residues
                       (kg ai/ha)       (days)                 (mg/kg)*
                                                                              
                                                        Range           Mean
                                                                              


    Australia          (0.025% ai            0                          5.9
                       spray)                2                          3.3
                                             7                          0.33
                                                                              

    South Africa       0.5                   1          2.0-2.6         2.3
                                             2          1.5-2.0         1.7
                                             4          1.3-1.3         1.3
                                             7          0.62-1.0        0.79

    Germany            0.5                   0          2.2-2-4.5       3.1
                                             1          0.47-1.7        1.2
                                           3-4          0.19-1.0        0.48
                                           7-8          0.05-0.21       0.21
                                                                              

    Barley

    Canada             0.14                  1                          2.6

                                             5                          0.51
                                             7                          0.42
                                                                              


    * expressed as mg/kg pirimicarb equivalents on a fresh weight basis.


    TABLE 4. Residues of Pirimicarb in cereal grains and straw, 1968-78

                                                                              
                        Application      Pre-harvest        Total carbamate
    Country             rate             interval               residues
                        (kg ai/ha)       (days)                  (mg/kg)*
                                                                              

                                                          Range        Mean
                                                                              

    1. Wheat grain

    Canada              0.125-0.14            14                       <0.04
                                              23                       <0.04
                                              92                       <0.04

    TABLE 4 (Continued)
                                                                              
                        Application      Pre-harvest        Total carbamate
    Country             rate             interval               residues
                        (kg ai/ha)       (days)                  (mg/kg)*
                                                                              
                                                          Range        Mean
                                                                              

    Denmark             0.125                 33          <0.01        <0.01

    Germany                                13-15          <0.01        <0.01
                                           18-21          <0.01        <0.01

    Holland                                   56          <0.01        <0.01
                                                                              
    Denmark             0.28-0.3              33          <0.01        <0.01

    Germany                                  6-9          <0.01-0.12   0.05
                                           21-22          <0.01        <0.01
                                           39-42          <0.01        <0.01

    Holland                                    7          <0.01        <0.01
                                              14          <0.01        <0.01
                                              56          <0.01        <0.01

    UK                                        70          <0.1**       <0.1**
                                          75-103          <0.01        <0.01
                                                                              

    Barley grain
    Canada              0.14                  14                       0.09
                                              45                       <0.04
                                                                              

    Oat grain

    Canada              0.14               52-71          <0.04        <0.04
                                                                              

    2. Wheat straw

    Germany             0.125              18-21          <0.01        <0.01

    UK                  0.28              75-103          <0.01        <0.01
                                                                              

    Barley straw
    Canada              0.14                  14                       0.26
                                                                              
         * expressed as mg/kg pirimicarb equivalents on a fresh weight basis
        ** determined colorimetrically; limit of determination 0.1 mg/kg
    
    FIGURE 

    FATE OF RESIDUES

    In plants

         Data reviewed by the 1976 Meeting showed that pirimicarb is
    rapidly lost from plants after spraying.  Half of the initial residue
    is lost in 1-3 days. Volatilisation affords the primary means of loss:
    the higher the ambient temperature, the greater the percentage of
    pirimicarb lost by volatilisation (FAO/WHO, 1977b). Pirimicarb also
    undergoes photochemical and metabolic degradation. The major
    carbamate-containing degradation products are compounds II And III
    (Figure 1). Other degradation products include the hydroxypyrimidines
    V, VI and VII, which can be present either free or as conjugates, and
    guanidine and its 1-methyl and III methyl derivatives. A further
    metabolite on cabbages has been characterized by its facile
    degradation to the hydroxypyrimidine V and another metabolic component
    was characterized as re-crystallising with 1,1-dimethylguanidine but
    not susceptible to desorption from charcoal with a solution containing
    a large quantity of 1,1-dimethylguanidine (Teal and Skidmore, 1978).
    Some of the residue is not extracted by conventional techniques, 14%
    of the radioactivity associated with cabbage leaves 3 weeks after
    applying 2 - 14C-labelled pirimicarb was not extracted by maceration
    with methanol (Teal, 1978). In lettuce plants sprayed with 2-
    14C-labelled pirimicarb four weeks prior to harvest, 25% of the
    radioactivity associated with the plants could not be extracted with
    ethanol. Pirimicarb compounds III and VI and the three guanidines
    mentioned above were all shown to be minor constituents of this
    unextracted residue. Approximately 40% of the unextracted
    radioactivity was associated with the cellulose and hemicellulose of
    the plant (FAO/WHO, 1977b).

         The fate of pirimicarb on alfalfa (Davis and Hemingway, 1978a) is
    similar to that reviewed previously on lettuce, cabbage, peach leaves
    and sugar beet leaves.

    In animals

         An oral dose of pirimicarb is rapidly excreted by cows,
    principally in the urine. The biotransformation of pirimicarb in cows
    is similar to that in rat and dog. Only traces of residues are
    transferred to milk and tissues (FAO/WHO, 1977b).

         When a single oral dose of 2-14C-labelled pirimicarb was
    administered to a cow at 1 mg/kg (equivalent to approximately 33 ppm
    in the diet), the radioactivity was quantitatively recovered during
    the following twelve days, principally in the urine (95.6%) but also
    in the faeces (4.3%). Only 0.29% of the radioactivity was recovered in
    the milk. The maximum residue in the milk (0.25 mg/kg pirimicarb
    equivalents) was detected one hour after dosing; 80-90% of the residue
    was due to the hydroxypyrimidines V, VI and VII (Figure 1). Subsequent
    residues were 0.06 mg/kg pirimicarb equivalents or less. The maximum
    residue in fat and meat tissues after twelve days was only 0.04 mg/kg
    pirimicarb equivalents (FAO/WHO, 1977b).

         When 2-14C-labelled pirimicarb was administered to a lactating
    goat for seven days at a rate equivalent to 37 ppm in the diet, 96% of
    the radioactivity recovered in the excreta was in the urine.
    Hydroxypyrimidines constituted the major residues - compound VI 35%,
    compound VII 29% and compound V 2% of the radioactivity in the urine.
    The total radioactive residue in the milk reached plateau levels of 0,
    12 and 0.3 mg Pirimicarb equivalents /kg in the morning and afternoon
    milkings respectively. Hydroxypyrimidines again constituted the major
    components - VI and VII together accounting for more than 56% of the
    radioactivity and V 5%. The goat was sacrificed four hours after
    receiving the last dose. In the tissues the levels of radioactivity,
    in pirimicarb equivalents, were muscle 0.45 mg/kg, fat, 0.18 mg/kg,
    liver 1.8 mg/kg and kidney 2.3 mg/kg. Approximately 50-60% of the
    extractable radioactivity in muscle, liver and kidney was due to the
    hydroxypyrimidines V, VI and VII, the two latter predominating (Davis
    and Hemingway, 1978b). The hydroxypyrimidines V-VII are also major
    metabolites in the rat and dog and are of low mammalian toxicity
    (FAO/WHO,1977b). In no instance were residues of pirimicarb or its
    carbamate-containing metabolites detected in this study. The remainder
    of the radioactivity present in tissues and milk was due to a mixture
    of polar, water-soluble compounds (Davis and Hemingway, 1978b).

         Groups of three barren Friesian cows were maintained for 28-29
    days on diets containing approximately 20, 60 and 200 ppm pirimicarb,
    applied as a spray to pelleted grass nuts. The majority of milk
    samples obtained from the 20 ppm group did not contain detectable
    carbamate residues (ie pirimicarb plus its two carbamate-containing
    metabolites II and III; limit of determination 0.01 mg/kg pirimicarb
    equivalents). Only trace residues were found in milk obtained from the
    60 ppm group - up to approximately 0.02 mg/kg. Milk samples from the
    200 ppm group contained mean residues of 0.07 mg/kg (range 0.02 - 0.13
    mg/kg). Two animals in each group were sacrificed after 28-29 days and
    the third after a further seven days on untreated diet. Total
    carbamate residues in meat tissues were normally non-detectable (ie
    less than 0.01 mg/kg pirimicarb equivalents) at all dose levels. Trace
    residues were detected in a few muscle and fat samples but the total
    carbamate residue was consistently below 0.05 mg/kg in all groups
    (Edwards et al., 1978).

         An oral dose of pirimicarb is rapidly excreted by hens. Only
    traces of residues are transferred to eggs and tissues and the
    hydroxypyrimidines V-VII constitute the major components of these
    residues.

         When a single oral dose of 2-14C-labelled pirimicarb was
    administered at 8 mg/kg to a hen in peak egg production, 88% of the
    administered radioactivity was recovered from the excreta during the
    following three days (Hendley at al., 1978).

         When 2-14C-labelled pirimicarb was administered to two hens in
    full egg production, at a rate equivalent to 6 ppm in the diet for
    fourteen days, total radioactive residues in eggs reached a plateau of

    0.05-0.06 mg pirimicarb equivalents/kg in 5-8 days, when the residue
    in the yolk was approximately twice that in the albumen. The
    hydroxypyrimidines V-VII (Figure 1) constituted approximately 50% of
    the total radioactivity in the yolks, with compounds VI and VII
    predominating (each approximately 20% of the radioactivity in eggs).
    The pyrimidine-carbamates I-IV together represented approximately 8%
    of the total radioactivity in the yolks, the remainder of the
    radioactivity was either not solubilised or was more polar than
    compound VII. The hens were sacrificed three hours after receiving the
    last dose. The tissues contained approximately 0.15 mg/kg (muscle),
    0.35 mg/kg (liver) or 0.02 mg/kg (fat) pirimicarb equivalents. 48-63%
    of the radioactivity in liver and muscle was due to the
    hydroxypyrimidines V-VII, compounds VI and VII again predominating. No
    more than 3.5% of the radioactivity in the tissues was due to the
    pyrimidine-carbamates I-VI (Figure 1). About 25% of the radioactivity
    in the tissues was due to compounds more polar than the
    hydroxypyrimidine VII, including a conjugate or conjugates of VI
    Hendley et al., 1978).

         When a hen in full egg production was given nine daily doses of
    2-14C-labelled pirimicarb at a rate equivalent to 60 ppm in the diet,
    levels of total radioactivity in eggs and tissues were greater than
    those in the equivalent hens dosed at the 6 ppm rate by the expected
    factor of 10 (Hendley et al., 1978).

         Groups of 40 hens in maximum egg production were maintained for
    up to 28 day on diets containing 1.5, 4.6 and 14 ppm total pyrimidine
    carbamates. Approximately 90% of the administered carbamate mixture
    was pirimicarb itself and 10% the carbamate metabolites II and III. No
    residues of either pirimicarb or compounds II and III were detected in
    either yolks or albumen of the eggs or in muscle and skin at sacrifice
    (limits of determination: 0.01 mg/kg for pirimicarb, 0.01-0.02 mg/kg
    for compounds II and III determined jointly). Trace total carbamate
    residues in liver did not exceed 0.05 mg/kg pirimicarb equivalents
    (Edwards and Dick, 1978).

    METHODS OF RESIDUE ANALYSIS

         A gas chromatographic method using a nitrogen-selective detector
    to determine residues of pirimicarb plus its two major carbamate
    containing plant metabolites (II and III, Figure 1) was reviewed by
    the 1976 meeting as the preferred crop residue method (FAO/WHO,
    1977b). With modified extraction procedures, this method is suitable
    for the determination of these residues in products of animal origin.
    Milk and eggs are extracted with a mixture of acetonitrile and
    chloroform. Tissues are extracted with methanol in the presence of
    anhydrous sodium sulphate. Clean-up by solvent partition and
    determination by gas chromatography are as reviewed at the 1976
    Meeting (ICI Ltd., 1978).

         Acetonitrile/chloroform has been shown to be an efficient solvent
    for extracting aged residues of pirimicarb and of the two metabolites

    from milk. Greater than 80% extraction efficiency was obtained. The
    low residue levels in tissues precluded a meaningful extractability
    study but by analogy with studies on the extractability of these
    compounds from a wide range of crop substrates, methanol is considered
    to be the most acceptable extraction solvent for tissues (Edwards et
    al., 1978;). Mean percentage recovery values for samples fortified in
    the range 0.005/0.01-0.01/0.25 mg/kg were 76-92% for milk, 76-98% for
    egg fractions, 80-89% for cow tissues and 62-96% for hen tissues
    (Edwards et al., 1978; Edwards and Dick, 1978).

    APPRAISAL

         Further data on residues of pirimicarb on alfalfa, wheat, barley
    and oats were reviewed, together with information concerning likely
    levels in milk, eggs and meat arising from treated animal feeds.
    Available methods of analysis have been improved and extended to cover
    products of animal origin. The data provided are sufficient to
    recommend additional temporary maximum residue limits for residues of
    pirimicarb in alfalfa, barley, oats, milk, meat and eggs. No data were
    available on residues in other grains each as maize or rice.

    RECOMMENDATIONS

         The following temporary maximum residue limits refer to the sum
    of pirimicarb, its N-formyl(methylamino) analogue (desmethylformanido
    pirimicarb) and desmethyl pirimicarb.

              Commodity           Temporary MRL (mg/kg)

              Alfalfa (green)     50 (dry weight basis)
              Alfalfa hay         20 (dry weight basis)
              Barley              0.05*
              Oats                0.05*
              Eggs                0.05*
              Meat                0.05*
              Milk                0.05*

    * At or about the limit of determination.

    FURTHER WORK OR INFORMATION

    Required (by 1980)

    1.   Carcinogenicity study in an appropriate mammalian species using a
    currently acceptable protocol.

    REFERENCES

    Fox, T. Pirimicarb dietary toxicity study in foxhounds. Unpublished
    (1978)              report from  Hazelton Laboratories Europe Ltd.,
                        No. 1371-72/2, submitted by ICI Ltd.

    Heywood, R., Sortwell, R.J., Pulsford, A.H., Brown, G. and
    (1977)              Street A.E. Pirimicarb preliminary oral toxicity
                        study in rhesus monkeys (repeated dosages for 13
                        weeks). Unpublished report from Huntingdon
                        Research Centre, No. 164/77825, submitted by ICI
                        Ltd.

    Heywood, R., Sortwell, R.J., Pulsford, A.H., Brown, G. and
    1978a               Street, A.E. Pirimicarb oral toxicity study in
                        rhesus monkeys (repeated dosage for 17 weeks,
                        followed by a recovery period of 8 weeks).
                        Unpublished report (final report) from Huntingdon
                        Research Centre, No. 198/78444, submitted by ICI
                        Ltd.

    Heywood, R., Sortwell, R.J., Pulsford, A.H. and Brown, G.
    (1978b)             Pirimicarb comparative data from naive rhesus
                        monkeys (white blood cell counts and Direct Coombs
                        Tests). Unpublished report from Huntingdon
                        Research Centre, No. ICI 219/78445, submitted by
                        ICI Ltd.

    Jackson, J.A., Chart, I.S., Sanderson, J. H. and Garner, R.
    (1977)              Pirimicarb induced immune hemolytic anaemia in
                        dogs. Scand. J. Haematol. 19, 360-366.

    Jackson, J.A. and Royle, G. Pirimicarb: dietary toxicity study
    (1978a)             in foxhounds. "Addendum:  results of additional
                        aerological investigations". Unpublished report
                        from ICI Central Toxicology Laboratory, No.
                        CTL/P/420, submitted by ICI Ltd.

    Jackson, J.A. and Royle, G. Pirimicarb: oral toxicity study in
    (1978b)             rhesus monkeys.  "Addendum: results of additional
                        aerological investigations". Unpublished report
                        from ICI Central Toxicology Laboratory No.
                        CTL/P/421, submitted by ICI Ltd.

    Jackson, J.A. and Royle. G. Pirimicarb: comparative data from
    1978c)              naive rhesus monkeys  (white blood cell counts and
                        Direct Coombs Tests). "Addendum: results of
                        additional haematological and serological
                        investigations". Unpublished report from ICI
                        Central Toxicology Laboratory, No. CTL/P/419,
                        submitted by ICI.

    Kennedy, S.H. Residues data on pirimicarb in cereals: Canada.
    (1978)              ICI Plant Protection Division data (unpublished).

    Parkinson, G.R. Pirimicarb metabolite R 34 885: subacute oral
    (1978a)             toxicity to rats. Unpublished report from ICI
                        Central Toxicology Laboratory, No. CTL/P/402,
                        submitted by ICI.

    Parkinson, G.R. Pirimicarb metabolite R 34 836: subacute oral
    (1978b)             toxicity to rats. Unpublished report from ICI
                        Central Toxicology Laboratory, No. CTL/P/401,
                        submitted by ICI.

    Paul, J.D., Richards, D., Banham, P.B. and Weight, T.M.
    (1978)              Pirimicarb: growth study to determine a no effect
                        level in the female rat. Unpublished report from
                        ICI Central Toxicology Laboratory No. CTL/P/408
                        submitted by ICI.

    Richards, D., Banham, P.B. and Weight. T.M. Pirimicarb paired
    (1978)              feeding study in a female rat. Unpublished report
                        from ICI Central Toxicology Laboratory, No.
                        CTL/P/407, submitted by ICI.

    Teal, G. and Skidmore, M.W. Pirimicarb: metabolism on cabbage plants
    (1978)              in the field, ICI Plant Protection Division Report
                        No. RJ00033A (unpublished).
    


    See Also:
       Toxicological Abbreviations
       Pirimicarb (Pesticide residues in food: 1976 evaluations)
       Pirimicarb (Pesticide residues in food: 1979 evaluations)
       Pirimicarb (Pesticide residues in food: 1981 evaluations)
       Pirimicarb (Pesticide residues in food: 1982 evaluations)