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    PIRIMICARB         JMPR 1976

    IDENTITY

    Chemical name

         2-dimethylamino-5,6-dimethylpyrimidin-4-yl
    dimethylcarbamate.

    Synonyms

         PPO62, APHOX(R), PIRIMOR(R), FERNOS(R).

    Structural Formula

    CHEMICAL STRUCTURE 1


    Other information on identity and properties

         Primicarb is a colourless, crystalline solid. It melts at
    90.5C.

         Vapour pressure (torr):

                   1.58 x 10-5 at 25C

                   3.0 x 10-5 at 30C

                   4.4. x 10-5 at 35C

                   1.8 x 10-5 at 65C

                   Solubility (g per 100 ml at 25C).

                   Water                     0.27

                   Methanol                 23

                   Ethanol                  25

                   Acetone                  40

                   Xylene                   29

                   Chloroform               32

         Pirimicarb is stable at temperatures up to 37C for at least
    two years.

         Pirimicarb forms stable salts with both organic and
    inorganic acids. It is decomposed by prolonged boiling with acids
    or alkalis to 2-dimethylamino-5,6-dimethyl-4-hydroxypyrimidine
    and dimethylamine. The hydroxypyrimidine is stable in boiling
    acid and alkaline solutions and forms stable salts with both
    acids and bases.

    Purity

         Not less than 95% pure, usually 98%. Impurities contain a
    maximum of 1.3% of other pyrimidine carbamates. Formulated
    products include a 50% ai. dispersible grain, 25% and 50%
    dispersible powders, a 10% ai smoke generator, a 5% ai ultra-low
    volume formulation and a 5% ai emulsifiable concentrate.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption Distribution and Excretion

         Pirimicarb is rapidly absorbed, distributed, metabolized and
    excreted in mammals. In studies with dogs and rats administered
    subacute doses of 14C-labelled pirimicarb (ring or carbonyl
    position), excretion was rapid. In dogs, within one day 74-86% of
    the administered dose of ring labelled pirimicarb was eliminated,
    primarily in the urine. Over the following 3 days, minor
    quantities were released. In total, from 86 to 94% of the
    administered ring labelled dose was recovered (79-88% in urine,
    6-7% in feces). With carbonyl (C=0) labelled pirimicarb, only
    15-26% of the dose administered to dogs was recovered,
    predominantly in urine. The unrecovered product (14CO2) was
    believed to be eliminated rapidly in expired air as suggested by
    studies where rats were administered 14C-carbonyl-pirimicarb by

    FIGURE 1

    oral gavage or intraperitoneal injection. Over 50% of the
    administered dose was expired as 14CO2 within 5 hours following
    administration by either route (Fletcher et al., 1971e).

    Further studies on the absorption, tissue distribution and
    excretion in rats following oral or ip injection again suggested
    the same pattern of rapid absorption, degradation of the
    carbamate ester to CO2 and minor (15%) elimination of
    radioactivity in the urine (Daniel and Bratt, 1968). There was
    essentially no storage in the body of animals (rats) sacrificed 8
    days after treatment. Measurement of abdominal fat from rats
    orally administered pirimicarb (50 mg/IC9) and sacrificed 24
    hours after treatment (either a single application or up to 4
    daily treatments) showed no accumulation of pirimicarb in adipose
    tissue (Fletcher and Bratt, 1972).

         Pirimicarb administered to a lactating cow at a dose of 1
    mg/kg was rapidly excreted in the urine (96%) and feces (4%). A
    trace of material (<0.3% of the recovered dose) was observed in
    milk with a maximum occurring within one hour of treatment
    (Hemingway et al., 1976). Pirimicarb is not expected to
    accumulate in the body following repeated exposures (Fletcher and
    Bratt, 1972).

    Biotransformation

         Qualitative identification of the urinary metabolites from
    rats and dogs administered pirimicarb by oral gavage or
    intraperitoneal injection showed the same series of products. The
    major metabolites were identified as the hydroxy pyrimidine
    (pyrimidinol) derived from pirimicarb with modifications of the
    alkyl substituents of the aromatic moiety. A proposed metabolic
    scheme for the degradation of pirimicarb is seen in Figure 1
    (only a few of the many compounds proposed have been isolated).
    As expected oxidative and hydrolytic mechanisms act on various
    components of the molecule, namely the carbonyl ester, the
    N(CH3)2 of both the ring and carbamate moiety and the CH3
    groups of the 5 and 6 positions of the pyrimidine nucleus.
    Quantitative determination of isolated metabolites from the urine
    of rats, dogs and a lactating cow show essentially the same
    pattern of metabolism. The following four metabolites were
    recovered from urine:

                                                                  
    Metabolite                              % of dose administered
                                                                  

                                            Rat       Dog       Cow

    2-dimethylamino-5,6-dimethyl            16.3      6.4       10
    -4-hydrozypyrimidine (I)

                                                                  

    Metabolite                              % of dose administered
                                                                  

                                            Rat       Dog       Cow

    2-methylamino-5,6-dimethyl              40.9      20.7      41
    -4-hydroxypyrimidine (V)

    2-amino-5,6-dimethyl                    12.9      16.5      21
    -4-hydroxypyrimidine (VI)

    2-dimethylamino-6-hydroxymethyl         5.7       1.8       -
    -5-methyl-4-hydroxyprimidine
    (VII)
                                                                  

    The major metabolites in milk of a lactating cow were also I, V and VI
    above in a similar ratio. Conjugation of hydroxypyrimidines was not
    evident in these studies. There were few aglycones recovered following
    treatment of urinary products with glucuronidase and chromatographic
    characterization of organic soluble products. It was assumed that the
    metabolites predominated in the tautomeric pyrimidone configuration,

    CHEMICAL STRUCTURE 2


    restricting conjugation. Small quantities of the hydroxypyrimidine
    were recovered as conjugates but the major products were passed as
    unconjugated metabolites in the urine of rats and dogs (Fletcher et
    al., 1971e).

         Two products were identified as degradation products in plants
    which were not found in dog or rat urine, the 2-formyl (methylamino)
    (R-34885,II) and the 2-methylamino (demethyl-pirimicarb, R34836, III)
    derivatives containing the intact carbamate. While these were isolated
    from plants and not animals, the probability exists that they are
    formed in mammals as transitory products since the carbamate is labile
    and subject to rapid cleavage. The identification of the 2-methylamino
    (V) and the 2-amibo (VI) hydropyrimidine derivates of pirimicarb in
    rat and dog urine suggest the same sequence of metabolism and
    breakdown in animals as plants with quantitative differences in the
    final products.

    Effects on Enzymes and other biochemical parameters

         Pirimicarb is an anticholinesterase agent and, as other
    N-methyl-and N,N-dimethylcarbamates, elicits a parasympathomimetic
    response in certain animals. Evaluation of reversible cholinesterase
    inhibition by carbamate esters is difficult. Using an automated delta
    pH method the following I50 values for some pirimicarb metabolites
    were obtained (Table 1).

    TABLE 1. Inhibition of cholinesterase by Pirimicarb metabolites

                                                                
    Metabolite                              I50
                                            Molarity X 106
                                                                

    2-Methylamino-5,6-dimethyl-4-
    pyrimidinyl dimethylcarbamate (III)     4.54

    2-amino-5,6-dimethyl-4-
    pyrimidinyl dimethylcarbamate (IV)      4.34

    2-dimethylamino-5,6-dimethyl
    -4-hydroxypyrimidine (I)                14.9 X 103

    2-methylamino-5,6-dimethyl
    -4-hydroxypyrimidine (V)                4.25 X 103

                                            (Fletcher et al., 1971e)

         Using a female cat, a time course study of cholinesterase
    depression was run following acute poisoning by intravenous injection
    of a dose of 20 mg/kg. Rapid in vivo depression of pretreatment
    plasma cholinesterase activity was obtained which persisted for more
    than 4 hours, long after clinical signs of poisoning had stopped.
    These results are summarized in Table 2.

    TABLE 2. Symptoms and plasma cholinesterase depression in a cat
             poisoned with pirimicarb

                                                                     
    Time           Signs of Poisoning            Plasma Cholinesterase
                                                 (% Inhibition)
                                                                     

    5 min.         salivation, trembling         72
    15 min.        salivation, fibrillation      72
    30 min.        reduced fibrillation          73
    1 hr.          none                          72
    2 hr.                                        75
    4 hr.                                       73
                                                                     
                                                 (Clark, 1967b)

         An attempt was made to resolve questions raised on the
    reliability of the routine automated procedure used for the
    determination of blood cholinesterase activity. The original method
    used extended substrate incubation times and large dilutions. Both of
    these factors are known to be responsible for enhancing spontaneous
    reactivation of the carbamoylated enzyme. In an attempt to demonstrate
    that the N,N-dimethylcarbamoylated cholinesterase is sufficiently
    stable to be measured by techniques not normally employed, a shortened
    incubation time (5.5 min. instead of 23 min) and reduced dilution were
    used. Acetylcholine concentrations were not changed. With these
    modifications a comparison of the method used routinely, a radiometric
    (14C-acetylcholine) method and a modified automated delta Ph method
    was made to evaluate cholinesterase depression in vivo in rats.

         Rats were orally administered pirimicarb at 30 mg/kg and blood
    removed after 1 hour. Dogs were administered pirimicarb at 30 mg/kg
    dose and blood was sampled at one hour after treatment.

         Cholinesterase depression was similar in all methods of assay
    employed. In rats, male and female, plasma measured 50% inhibition by
    all methods. In dogs, a comparison of the radiometric
    14C-acetylcholine method with the automated delta Ph method showed no
    inhibition of plasma cholinesterase at 4 mg/kg. In addition, plasma
    cholinesterase from treated animals was found to be stable over a 24
    hour interval at 4-5C with no loss in inhibition spontaneously
    regenerated activity).

         From the foregoing study, it was concluded that a stable
    carbamoylated enzyme analogous to a phosphorylated enzyme may be
    formed with pirimicarb and the reduced activity can successfully be
    measured by an automated delta Ph method. It was concluded that the
    K3 step was slow and a stable intermediate was formed. The conclusion
    of this study is that the method used in most studies to measure
    cholinesterase activity did not underestimate the inhibition and give
    misleading results (Litchfield, 1968).

         In vitro studies in part confirmed these conclusions
    especially with respect to pseudocholinesterase enzymes. The reaction
    of pirimicarb and horse serum cholinesterase yielded a stable N,N-
    dimethylcarbamoylated enzyme having a k3 of 5 X 10-4min-1. 
    However, with acetylcholinesterase (eel or RBC) the k3 is higher (3.7
    X 10-2 min-1 and 0.9 X 10-2 min-1 respectively) and the spontaneous
    reactivity is much greater. Thus, the use of plasma or serum
    cholinesterase to assay pirimicarb inhibition would show adequate
    values for the interaction of enzyme and inhibitor while the use of
    RBC as other-acetylcholinesterase sources would be expected to give
    misleading values especially where extended assay times or large
    dilutions were a factor (Main, A.R. personal communication).

    TOXICOLOGICAL STUDIES

    Special study on reproduction

    Rat

         Groups of rats (12 male and 24 female rats/group) were fed
    pirimicarb in the diet at 0,250 and 750 ppm and mated to begin a
    3-generation, 2-litter per generation standard reproduction study. At
    the conclusion of the study, tissues from 10 rats of each sex from the
    F3b generation were examined microscopically. Four offspring were
    observed to be malformed at birth (3 litter mates of the second
    generation F2a - 250 ppm and one 750 ppm F2a fetus). Reduced body
    weight of the parents (specifically females but often males as well)
    was noted at both treatment levels. Growth of pups prior to weaning
    was not affected by pirimicarb in the diet although a reduced growth
    was seen thereafter in all three generations. The basic reproduction
    indices normally measured (fertility, gestation, lactation and
    viability) were not affected. Evaluation of parturition data suggests
    no effects on the ability to maintain pregnancy. No adverse effects on
    reproduction were observed with pirimicarb. Because malformations were
    observed in only 4 fetuses of 2665 treated it was concluded that these
    were not as a result of pirimicarb in the diet (Fletcher and Sotheran,
    1971).

    Special studies on carcinogenesis

         Groups of mice (50 of each sex per group; SPF, Alderly Park
    strain) were fed pirimicarb in the diet at levels of 0, 300 and 1500
    ppm for 80 weeks. Mortality was reported to be a result of endemic
    respiratory disease. The clinical condition of the mice at autopsy
    confirmed a high incidence of respiratory disease. A slight body
    weight reduction was noted only at the high dose level. No effects
    were noted on food consumption or on gross and microscopic analysis of
    most tissues and organs. The incidence of pulmonary tumors was
    significantly higher in both treated groups than controls used in the
    study. (When the incidence of pulmonary lesions was compared with a
    large group of control mice examined in the laboratory over an 8-year
    interval, the data did not show a significant increase in pulmonary
    tumors as a result of pirimicarb in the diet. The controls used in
    this study apparently had an extremely low incidence of lung lesion).
    There was no evidence of excessive lymphoma or leukemia noted in the
    study and detailed examination of the CNS did not indicate pirimicarb
    to be a carcinogen in mice (Palmer and Samuels, 1974).

         Groups of rats (48 males/group) were fed pirimicarb in the diet
    at dose levels of 0,750 and 2,500 ppm for 2 years. Because of
    respiratory infection, an antibiotic (oxytetracycline and sodium
    sulphadimidine were administered in drinking water as needed.
    Mortality was heavy after the 40th week predominantly as a result of
    respiratory infection. Growth was reduced at 2,500 ppm but not at 750
    ppm. An increased incidence of reticulum cell lymphoma was observed in

    the study. It was concluded that this incidence was as a direct result
    of the accompanying pulmonary infection. However, the infiltration
    pattern of the tumor was mainly perivascular. A statistical treatment
    of the tumor incidence did not confirm a relationship of tumor
    incidence to the presence of pirimicarb in the diet.

         In another study using a different strain, groups of rats (48
    males/group) were fed diets for two years similar to those described
    above. Again, an outbreak of respiratory disease within one year
    limited the surviving animals at the conclusion of the study. However,
    in contrast to the previous study, no reticulum cell lymphoma was
    observed. The incidence of tumors was not different from controls. It
    was concluded that pirimicarb did not produce an increased incidence
    of tumors in male rats.

         A third study was initiated from those animals discarded from the
    three generation reproduction study. Groups of rats (24 of each
    sex/group) previously exposed in utero and fed prior to weaning were
    fed pirimicarb in the diet at dosage levels of 0 and 750 ppm for 2
    years. Again, respiratory infection reduced survival of rats in this
    study (rats were also treated with antibiotics to control the
    infection). There was no difference relating to survival between the
    control and treated groups. Growth of both sexes was reduced by
    pirimicarb in the diet. Gross and microscopic analyses did not
    indicate an increased incidence of tumors in the pirimicarb fed rats.
    Based on lifetime exposure to pirimicarb from conception, there is no
    carcinogenic effect noted in the rat (Samuels et al., 1975). However,
    the undercurrent respiratory infection noted in all four long term
    studies aimed at examining lung lesions precludes definitive
    conclusions on this problem.

    Special studies on teratology

    Mouse

         Groups of mice (25 mated females/group) were fed pirimicarb in
    the diet at dosage levels of 0,40 and 500 ppm throughout pregnancy
    (day 0 to day 18 of gestation). There were no parental deaths and no
    abortions occurred. On sacrifice at day 18, fetuses were removed and
    uteri examined for resorptions. Implantation was slightly reduced in
    both pirimicarb groups. The mean litter weight and fetal weights were
    reduced at the high dose level. There was no effect on the sex ratio
    of fetuses.

         No abnormalities were observed on gross examination or on
    skeletal examination following clearing and alizarin straining
    (Fletcher et al., 1971d).

    Rat

         Groups of rats (18-21 females/group) were fed pirimicarb in the
    diet at dosages of 0, 250 and 750 ppm throughout pregnancy. Parental
    growth was reduced at the high dose level. Total weight was also

    reduced at the high dose level. No abnormalities were noted in the
    treatment group attributable to pirimicarb in the diet (Fletcher et
    al, 1971f).

    Rabbit

         Groups of pregnant rabbits (16 does/group) were administered
    pirimicarb orally by gavage daily from day 1 to day 28 of gestation at
    doses of 0,1.25, 2.50 and 5.0 mg/kg. Administration of 2.5 and 5 mg/kg
    produced a maternally toxic response noted as a reduction of weight
    gain. This was also reflected in reduced fetal weights which occurred
    at the upper two dose levels. There were no teratogenic effects noted
    on gross examination of tissue, or on skeletal examination of cleared,
    stained fetuses. Pirimicarb has no teratogenic potential in rabbits. A
    slight increase in the size of the brain of some litter mates was not
    considered to be hydrocephalus and was not dose dependent (Hodge,
    1974). On the basis of studies in three species, it appears that
    pirimicarb has little teratological potential.

    Special studies on mutagenesis

    Mouse

         Groups of mice (15 males/group) were administered pirimicarb
    orally for 5 days by intubation at dosage levels of 0, 10 and 20
    mg/kg. Two positive controls of 150 mg/kg or 100 mg/kg of ethyl
    methanesulphonate (EMS) were administered either by a single ip
    injection on the day before mating or by oral administration 5 days
    prior to mating. Each male was mated to two virgin females at weekly
    intervals for 8 weeks in a dominant lethal mutagenesis study. In an
    evaluation of pregnancy, implantation and early and late death of
    fetuses, pirimicarb treatment did not show differences from control
    values. In contrast, EMS resulted in reduced pregnancy,
    preimplantation loss and increased early death, judged to be a
    significant mutagenic occurrence. There are no indications from this
    study that pirimicarb would induce mutations in mice (McGregor, 1974).

    Special studies on sensitization

         Groups of guinea pigs (4 males/test group, 3 males as controls)
    were treated on the ear for 3 days with a 10% (w/v) solution of either
    technical or formulated pirimicarb. Four days later the animals were
    challenged by applying doses of 0, 0.1, 1.0 and 10% solutions to the
    shaved flank skin. Traces of erythema were noted but a primary
    sensitization reaction was not observed (Parkinson, 1974c).

    Special studies on inhalation toxicity

         Pirimicarb has been recommended for use under enclosed glasshouse
    conditions. Studies were performed on the acute inhalation toxicity
    following exposure of rats to smoke generated in an enclosed chamber
    at doses up to 300 mg/m3. Mortality was observed as were acute signs

    of poisoning following a 6 hour exposure. Rats exposed to 75 mg/m3
    for 6 hours showed clinical signs of poisoning while at a level of 15
    mg/m3 no signs of poisoning over the 6 hour test exposure were
    observed (Riley, 1972a). Rats exposed to 15 mg pirimicarb/m3, 6 hours
    a day, 5 days/week for 3 weeks did not exhibit toxic signs of
    poisoning. A slight plasma cholinesterase depression was observed
    (Riley, 1972b). Acute inhalation studies on rats using a 50%
    dispersible powder formulation showed that exposure for one hour at a
    dust concentration of 20,000 mg/m3 caused no acute signs of
    poisoning although plasma and RBC cholinesterase depression was noted
    (Riley, 1972c). Rats exposed daily 5 days/week for 3 weeks (6
    hours/day) to a "saturated vapor" of pirimicarb (air passed through
    technical pirimicarb was not analyzed for the presence of pirimicarb)
    did not display signs of poisoning or even of exposure (Clark, 1967b;
    Riley, 1973).

    Special studies on neurotoxicity

         Four adult hens, administered a single oral dose of 25 mg
    pirimicarb/kg by gavage, displayed cholinergic signs of poisoning but
    no clinical indication of a delayed neurotoxic response (Clark,
    1967b).

         Four adult hens were administered pirimicarb by oral intubation
    at a dose level of 25 mg/kg. They were observed for 21 days,
    re-treated with the same dose and again observed for 21 days. No signs
    of delayed neurological ataxia were observed (Fletcher, 1971a).

    Special studies on potentiation

         Groups of female rats (10 rats/group) were administered
    pirimicarb alone and in combination with carbaryl or azinphos-methyl
    orally by gavage. Slight changes in the projected LD50 values were
    noted with azinphos-methyl when the materials were administered in
    combination. No such changes were noted with carbaryl combinations.
    There was no potentiation of the acute effects noted with simultaneous
    oral administration of carbaryl while a slight potentiation of acute
    toxicity was noted with azinphos-methyl (Parkinson, 1975d).

    Special studies on plant metabolites

         Groups of rats (10 male and 10 female rats/group) were
    administered the plant metabolite 2-formylmethylamino pirimicarb
    (R.34885, II) by gavage daily for 10 days at doses of 25 mg/kg/day.
    Males developed a slight hypochromia, while a hypochromic anemia was
    observed in females. No other toxic signs were observed. There was no
    intubution of plasma, RBc or brain cholinesterase. Increased
    hemopoietic activity was noted in the spleen (Fletcher et al., 1971a).

         Groups of rats (10 male and 10 female rats/group) were
    administered the plant metabolite 2-methylaminopirimicarb (R.34836,
    III) by gavage daily for 10 days at doses of 100 mg/kg/day. Acute
    signs of poisoning were noted immediately after each daily dose. These

    signs abated within 2 hours. Plasma cholinesterase depression was
    observed only in females. Hematological examination revealed
    hypochromic anemia in females while males showed reticulocytosis and
    slight hypochromia. No change in clotting time was seen. Increased
    hemopoietic activity was seen in the spleen of males and females.
    Changes in the thymus were also observed (Fletcher et al., 1971b).

    Special studies on antidotes

         Groups of female rats were administered pirimicarb by
    subcutaneous injection (150 mg/kg - 2 X LD50). When signs of
    poisoning were observed, atropine alone or in combination with P2S
    was administered by S.C. injection. Atropine alone or in combination
    with P2S was an effective antidote while P2S alone was not effective
    in reducing the acute toxic effects (Clark, 1967b).

    Eye and skin irritation

         Technical pirimicarb and a 50% dispersible powder formulation
    produced a slight occular irritation when administered to the
    conjunctival sac of rabbits. One drop of a 5% solution or a suspension
    of 25% (w/v) of technical pirimicarb in propylene glycol or 50% (w/v)
    formulated product, instilled in the conjunctival sac, resulted in
    slight pain, redness and transient slight corneal opacity. Pirimicarb
    was classified as a mild irritant graded as 3-4 m a scale of 8 (Clark,
    1967b; Fletcher, 1971b; Ferguson and Parkinson, 1973). Technical
    pirimicarb applied to the intact or abraded skin of rabbits was
    non-irritating when administered as a 25% suspension in propylene
    glycol (Fletcher, 1971b; Parkinson, 1972). When a paste was made of a
    50% dispersible powder formulation, pirimicarb was irritating
    especially to abraded skin. No reaction was observed with intact,
    undamaged skin (Parkinson, 1972). Technical pirimicarb (5% in
    propyleneglycol) applied to the shaved back of rats repeatedly for 24
    hours under a plastic film was not irritating to the skin (Fletcher,
    1971b; Clerk 1967a).

    Acute Toxicity

    TABLE 3. Acute toxicity of pirimicarb

                                                                        
                                           LD50
    Species      Sex     Route            (mg/kg)        Reference
                                                                        

    Rat          F       oral (fasted)    68             Clark, 1967a
                              (fed)       147-210        Clark, 1967a
                 F       oral             101-147        Clark, 1967b;
                                                         Parkinson, 1975
                 F       oral             165-221*       Parkinson, 1972b
                         dermal           >500           Clark, 1967b

    TABLE 3. (Cont'd.)

                                                                        

                                           LD50
    Species      Sex     Route            (mg/kg)        Reference
                                                                        

                 M&F     ip               25-50          Clark, 1967b
                 F       SC               75             Clark, 1967b

    Mouse        F       oral             107            Clark, 1967b

    Dog          M&F     oral             100-200        Clark, 1967b

    Rabbit               dermal           >500           Clark, 1967b

    Hen                  oral             25-50          Clark, 1967b

    Rat                  inhalation       approx.        Riley, 1973
                                          300 mg/m3 
                                                                        

    * pirimicarb stored at 37C for up to 6 months showed no change in
      acute toxicity value suggesting stability over this time interval.

    Signs of poisoning: Within a few minutes of receiving a toxic oral 
         dose, signs of poisoning in a rat were observed including:
         salivation, chromolacrymation, urination, defecation, miosis and
         muscular fibrillations leading to fasciculations and death within
         30 minutes. These are all typical signs of cholinergic
         stimulation normally seen with parasympathomimetic agents.


    Short term studies

    Rabbit - dermal

         Groups of rabbits (4 of each sex/group) were administered
    pirimicarb dermally at a dose of 500 mg/kg for a 24 hour duration. The
    skin was washed and the treatment repeated daily for 14 days. No
    toxicity was observed and the animals appeared normal (Fletcher,
    1971c).

    Rat

         Groups of rats (10 male and 10 female rats/group) were
    administered pirimicarb daily by gavage at doses of 0 and 50 mg/kg for
    10 days. A slight growth depression was noted but no mortality or
    cumulative effects were seen. Hematology was normal and gross
    examination of tissues and organs at the conclusion of the study
    showed no adverse effects (Clark, 1967b).

        TABLE 4. Acute toxicity of metabolites or impurities
                                                                                      
                                                           LD50
    Compound*                    Species   Sex   Route   (mg/kg)       Reference
                                                                                      
    pirimicarb                   Rat       F     oral    800-1600      Lefevre and
    phenol (I)                                                         Parkinson, 1974
    (R.31805)

    N-methyl-N-formyl            Rat       F     oral    50-100        Lefevre and
    pirimicarb (II)                                                    Parkinson, 1974
    (R.34885)

    N-demethyl pirimicarb        Rat       F     oral    200-400       Lefevre and
    III)                                                               Parkinson, 1974
    (R.34836)

    N-di-demethyl                Rat       F     oral    79            Parkinson, 1974a
    pirimicarb (IV)
    (R.35140)

    N-demethyl phenol (V)        Rat       F     oral    2000-2500     Lefevre and
    (R.34865)                                                          Parkinson, 1974

    N-di-demethyl phenol (VI)    Rat       F     oral    >2500         Parkinson, 1974a
    (R.31680)

    N,N-dimethyl                 Rat       F     oral    1455          Parkinson, 1975a
    guanidine HCl

    methyl guanidine SO4         Rat       F     oral    1105          Parkinson, 1975a

    guanidine HCl                Rat       F     oral    1105          Parkinson, 1975a

    2-(dimethyl-amino)-          Rat       F     oral    158           Parkinson, 1974b
    6-methyl-4-pyrimidinyl
    dimethylcarbamate
    (R.42488)

    2-(dimethyl-amino)-5,        Rat       F     oral    Zeta 1000     Parkinson, 1975b
    6 dimethyl-4-pyrimidinyl
    diethylcarbamate
    (R.32444)

    2-(dimethyl-amino)-5,6-      Rat       F     oral    Zeta 800      Parkinson, 1975c
    dimethyl-4-pyrimidinyl
    ethylmethylcarbmate
    (R.33160)
                                                                                      

    * See figure 1 for structural definition of the numbered products.
             Groups of rats (25 males and 25 females/group) were fed
    pirimicarb in the diet for 90 days at dosage levels of 0, 250 and 750
    ppm. A separate group of rats was administered pirimicarb by gavage,
    daily at a dose of 25 mg/kg. There was no effect on growth, food
    consumption or mortality in the dietary groups. Mortality was evident
    in the rats dosed by gavage although the survivors showed normal
    growth over the 90 day interval. Hematology parameters were
    unaffected. A slight decline in plasma cholinesterase was observed in
    the rats treated by gavage and at sporadic intervals in the 750 ppm
    group. RBC and brain activity was normal. Gross and microscopic
    analysis of tissues and organs examined at the conclusion of the study
    was normal. Bone marrow cytology was not performed (Griffiths and
    Conning, 1968).

         A no-effect level of >750 ppm in the diet but lower than
    25 mg/kg body weight administered by gavage was evidenced in this
    study.

    Dog

         Groups of dogs (4 male and 4 female beagle dogs/group) were fed
    pirimicarb in the diet at dosage levels of 0, 4, 10 and 25 mg/kg for
    90 days. Growth was not affected over the course of the study although
    one of the male dogs at the highest level died during the course of
    study. While the cause of death was not completely diagnosed, it was
    probably related to anemia as the animal showed marked erythropoietic
    hyperplasia and the presence of numerous nucleated red blood cells. A
    macrocytic anemia was observed in two other dogs (one high and one
    intermediate dose) at the conclusion of the study. Although hematology
    parameters were not unusual an increased number of nucleated red blood
    cells was observed in peripheral blood. Bone marrow examination showed
    an increased nucleated cell count and reduced m/e ratio at all dose
    levels. This abnormal count dropped slightly after a 28 day recovery
    period, but was not down to normal. Serum folate, iron and vitamin
    B12 levels were normal, suggesting that the hemolytic anemia was not
    related to this type of deficiency.

         Cholinesterase measurements showed depression of plasma enzymes
    at the upper two dose levels. Brain and RBC cholinesterase activity as
    measured by the delta pH method was unaffected by pirimicarb.

         Gross and microscopic examinations of tissues and organs
    indicated hemopoiesis in the spleen and lymph nodes of dogs showing
    hematological signs of anemia. No effects on tissues and organs (other
    than on bone marrow observations of all treated animals or on the
    tissues and organs of the dog that died) were observed. A no-effect
    level was not defined in this study. Delayed maturation of red blood
    cells as evidenced by the presence of abnormal levels of nucleated red
    blood cells was observed in all treated animals (Conning et al.,
    1968).

         Groups of dogs (4 beagle dogs of each sex/group) were fed diets
    containing pirimicarb at dose levels of 0,0.4, 1.8 and 4.0 mg/kg body
    weight for 90 days (the 4.0 mg/kg dose was maintained for 180 days).
    There was no mortality and growth was unaffected by pirimicarb in the
    diet. Clinical chemistry, hematology and urinalysis parameters were
    normal. Bone marrow cytological examination again showed the presence
    of nucleated red blood cell precursors at the highest dose tested. The
    occurrence of these juvenile cells in marrow was not accompanied by
    anemia as was evident In the previous study. Gross and microscopic
    examination of other tissues and organs showed evidence of spleenic
    hemopoiesis at the high dose level over the 6 month test. Other
    tissues and organs were not affected. Plasma and brain cholinesterase
    values were also normal (Conning et al., 1969).

         In special studies to evaluate the hemolytic anemia observed in
    dogs, four dogs (two male and two female) were fed pirimicarb in the
    diet at levels of either 25 or 50 mg/kg for up to 110 weeks. Two of
    the four dogs (1 male at 50 mg/kg and 1 female at 25 mg/kg) developed
    anemia while two (1 female at 50 mg/kg and 1 male at 25 mg/kg) were
    normal over the entire period. Peripheral blood showed changed in the
    size and shape of red cells and the presence of some nucleated red
    blood cells was observed. No abnormalities were seen in the white cell
    series or platelets. Bone marrow samples showed a marked erythroid
    hyperplasia. Attempts made to reduce the anemia with high therapeutic
    doses of Vitamin B12, folic acid and folinic acid were negative. Red
    blood cells from the anemic dogs were able to be agglutinated by
    specific antigamma globulin serum while cells from normal dogs were
    not. Free antibody was demonstrated in the sera of anemic dogs. The
    antibody reacted with cells of the individual from which it was
    removed and also with cells of normal-in-appearance (non-anemic)
    pirimicarb-treated dogs. The antibody did not react with cells of
    normal, untreated dogs. The presence of antibody and the demonstrated
    effects of anemia were reversible (within 6 weeks) upon withdrawal of
    the pirimicarb treatment. The pirimicarb treatment appears to have
    been responsible for inducing changes in red blood cells of dogs
    treated at higher levels. However, only some of the dogs responded
    further in producing antibody that reacts with the altered cell
    inducing anemia (Garner et al., 1972). In a further study to evaluate
    a threshold of response of susceptible animals to pirimicarb, the two
    susceptible dogs when allowed to recover from the induced-anemia were
    fed levels of 1-2 mg/kg. One of the two dogs became anemic when
    exposed for 14 weeks to 2 mg/kg. The other animal remained normal.
    Further immunological studies using the susceptible dogs showed IgG
    binding to cells of non-anemic dogs exposed to pirimicarb and
    suggested that pirimicarb does not inhibit the IgG binding. It was
    concluded that the antibody is not produced in direct relation to
    pirimicarb alone, but possibly to a toxicant-red cell complex or to a
    change induced by the toxicant (Jackson et al., 1974).

         Groups of dogs (4 male and 4 female/group) were fed pirimicarb in
    the diet for two years at dosage levels of 0, 0.4, 1.8 and 4.0 mg/kg
    body weight. There were no effects on behaviour, growth or food
    consumption over the course of the two years. Blood chemistry
    including blood and brain cholinesterase and urinalysis parameters
    were unaffected. Hematology was normal. The M/E ratio was decreased at
    the high level of feeding at the conclusion of the study. There were
    no unusual findings in bone marrow analysis although a slight increase
    in a nucleated red blood cell content was evident at 4 mg/kg. Serum
    iron and folio acid levels were unaffected by pirimicarb. Gross and
    microscopic analysis of tissues and organs showed no effects
    attributed to pirimicarb. Based on the data submitted a no-effect
    level is 1.8 mg/kg body weight (Fletcher et al., 1971c.).

    Long term study

    Rat

         Groups of rats (48 males and 48 females/group) were fed
    pirimicarb in the diet at dosage levels of 0, 250, 500 and 750 ppm for
    two years. There were no effects noted on survival. Growth was reduced
    in females at all dose levels. There were no effects noted in males.
    Total food intake of females was reduced. (Food conversion ratios
    (ratio of food consumed to body weight gain) were reduced primarily in
    the two higher dose groups).

         No effects were noted on hematological parameters including
    cholinesterase activity. Plasma cholinesterase was slightly reduced in
    females. No effects were seen with RBC or brain cholinesterase. Gross
    and microscopic examination of tissues and organs revealed only
    reduced spleen weight of 750 ppm females. No other adverse effects
    attributable to pirimicarb in the diet were noted. There was no
    over-all increase in tumor incidence. An increase in the number of
    localized astrocytomas in the high dosed males but not in the females
    was not considered to be significant. Because of this slight effect
    noted in males, a special study using males was initiated and is
    summarized in the special study on carcinogenesis. A definitive
    no-effect level wan not noted in this study, as dietary conversion
    calculations do not support a firm conclusion of inappetance as a
    basis for reduced growth. The marginal reduction of growth in females
    suggests that a no-effect level is slightly below 250 ppm (Fletcher et
    al., 1972).

    OBSERVATIONS IN MAN

         Cholinergic signs of poisoning accompanied by depression of
    plasma (but not RBC) cholinesterase activity were observed in men
    occupationally exposed to pirimicarb in the manufacture of formulated
    products. In the course of investigating various procedures for safe
    manufacturing conditions, it was observed that substantial vapor
    toxicity was apparent as pirimicarb apparently volatalized at high
    (65C) temperatures and was inhaled by workers. Signs of exposure and

    depression of plasma cholinesterase activity were recorded both of
    which rapidly diminished with no apparent latent effects (Bagness et
    al., 1975).

    COMMENTS

         Pirimicarb, an N,N-dimethylcarbamate ester, is rapidly absorbed
    and metabolised in mammals by oxidative and/or hydrolytic pathways.
    Only a few of the many potential metabolites have been isolated. Those
    products containing an intact carbamate structure are as acutely toxic
    as the parent molecule. Where cleavage of the ester groups occurs, the
    acute toxicity is decreased markedly. With the exception of two
    products observed on leaf surfaces (the N-formyl (methylamino) and
    N-methylamino analogues of pirimicarb) and not in animal studies, all
    other products identified are common to both metabolic pathways. It is
    possible that these two are also produced as transitory products in
    mammals. Pirimicarb is rapidly excreted from the body and neither
    pirimicarb nor its metabolites accumulate in any tissue or organ. In
    short term rat studies with the two carbamate plant metabolites,
    administered at high doses, hypochromic anemia was observed. The
    significance of this occurrence was not defined.

         Pirimicarb is moderately toxic following acute administration to
    various animal species. Enzyme kinetic studies on the in vivo and
    in vitro inhibitory properties suggest that pirimicarb is a
    rapidly reversible inhibitor of acetylcholinesterase as compared with
    its effects on pseudo-cholinesterase. However, the stability of
    inhibited (carbamoylated) plasma cholinesterase allowed an estimate to
    be made of in vivo cholinesterase depression.

         In several species no effects on reproduction (including
    teratogenicity) were observed. A mutagenic response was negative as
    evidenced by a mouse dominant lethal study. Pirimicarb did not induce
    a delayed neurotoxic response, as generally noted with TOCP, in hens.
    Short and long term studies in several animal species were performed.
    In one long term study in the rat an increased number of astrocytomas
    were noted in males, but this was not confirmed in two subsequent
    studies. In a specific carcinogenic study in mice, a significant
    increase in the incidence of pulmonary tumours was observed. However,
    it was believed that the differences were due to an abnormally low
    control value, thus negating the full evaluation of the study. None of
    these studies was entirely adequate for evaluating the carcinogenic
    potential, as chronic respiratory infection in each rat study limited
    survival and a full interpretation of the data.

         In short term studies with dogs, a dose dependent effect
    manifested as hemolytic anemia changes was observed at high levels of
    pirimicarb fed in the diet. Anemia did not occur in all dogs exposed
    at high doses, and there was a suggestion of a sensitisation reaction.
    In studies on the mechanism of action of pirimicarb with respect to
    the hemolytic anemia, it was observed that an abnormal condition in
    red blood cells was associated with the presence of pirimicarb. Also,
    the presence of an increased number of a certain type of nucleated red

    blood cells in bone marrow cytological examination, even in the
    absence of anemia, suggested interference in a late stage of
    development of erythrocytes induced by relatively high levels of
    pirimicarb and complicated the full interpretation of the data. It was
    suggested that hemolysis is caused by induction of a specific antibody
    to the red blood cell following high level administration of
    pirimicarb.

         In a two year study with dogs of the same colony, no anemia was
    observed although a dose dependent occurrence of nucleated red blood
    cell precursors in the bone marrow was noted. At the low dose levels,
    no effects on hematological or other parameters examined were
    observed. Thus, in a susceptible species the effects noted over a
    short term high level exposure were not cumulative and were not
    manifested in a two year study. A similar hematological condition was
    not reported in rodents exposed to pirimicarb in several long and
    short term studies.

         In a long term study with rats, growth depression was observed,
    primarily at high levels. Marginal depression of growth was observed
    in females (but not males) at the lowest dose level tested.
    Calculation of food consumption was made with respect to growth. It
    was concluded that growth depression may be related to inappentance
    rather than being a specific toxicological effect.

         In workers known to be occupationally exposed certain effects on
    plasma cholinesterase activity were observed but no adverse long term
    effects were noted.

         The Meeting, in considering the toxicological properties of
    pirimicarb, concluded with respect to the marginal growth depression
    observed in rat species that a no-effect level would be slightly below
    the lowest dose level tested.

         The adverse effects on hematological parameters noted in the dog
    were dose dependent and a no-effect level could be seen.

         The carcinogenic potential of pirimicarb in rodents could not be
    fully evaluated although the studies performed gave little concern to
    the Meeting that pirimicarb was a potent carcinogen in the species
    tested.

         In consideration of both the long and short term studies in
    several species a no-effect level was agreed upon from the data of the
    2 year dog study.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Dog: 1.8 mg/kg bw/day

    Estimate of temporary acceptable daily intake for man

         0 - 0.004 mg/kg bw.

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         Pirimicarb is a fast-acting, selective aphicide with contact,
    translaminar and, more particularly, fumigant actions. It has proved
    effective on all of the crops on which it has been tried against all
    aphids including organophosphorus-resistant strains, except for
    multiresistant strains of the damson hop aphid, Phorodon humuli.

         Pirimicarb is harmless to useful parasites and predators, with
    the exception of hoverflies. It is also of very low toxicity to bees.
    This specificity makes pirimicarb a valuable chemical for use in
    integrated control programmes.

         It is active at rates as low as 0.125 kg ai/ha, depending on the
    efficiency of crop spray cover and the species of aphid present.
    Normal rates of commercial application are 0.25 kg ai/ha; but rates as
    high as 0.50 kg ai/ha are recommended for some outlets. Applied as a
    smoke, pirimicarb is normally effective at 15 mg/m3.

         Pirimicarb possesses only limited persistence on crops.
    Re-treatment may therefore be necessary after 10-14 days in those
    situations where the potential for re-infestation remains high.
    Pre-harvest withholding intervals range from zero for root crops, and
    crops where the edible portion is protected from the spray, to seven
    days for leafy vegetables.

         Pirimicarb was first synthesised in 1965. It was first registered
    for use on peaches in Western Europe in 1969. It is now registered
    world-wide for use on a wide range of crops, including fruit,
    vegetables and cereals.

         Use patterns in the Netherlands, South Africa, New Zealand and
    Australia are summarized in Table 5.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Pirimicarb has a half-life of one to three days on most crops.

         Residue trials have been conducted on a wide range of crops in
    numerous countries since 1967. The results of these studies are
    reported by Manley (1972) and by Edwards and Dick (1976). They are
    summarized in Tables 6-10. Total pyrimidine carbamate residues have
    been studied, i.e. residues of pirimicarb and its two major
    carbamate-containing metabolites on plants (the N-demethyl and
    N-formyl (methylamino) analogues of pirimicarb, III and II, Figure I).
    II is also commonly known as desmethyl-formamido-pirimicarb.


    
    TABLE 5. Use pattern in various countries

                                                                                                            

    Country          Crop                         Formulation    Rate               Pre-harvest Interval
                                                                 ai.
                                                                                                            

    Netherlands      Cucurbits (Eggplant,         10% smoke      10 g/700m3         3 days
                                cucumber,         generator
                                gherkin,
                                melon)

                     Pepper                       50% WP         25 g/100 l         3 days
                     Tomato

                     All other consumption        10% smoke      10 g/700 m3        1 March-31 Oct - 1 week
                     crops under glass            generator                         1 Nov-28 Feb - 2 weeks

                     All fruits & vegetables      50% WP         25 g/100 l         7 days
                     with the exception of
                     endive and lettuce under
                     glass and parsley and
                     celery

                     Sugarbeet, potatoes          50% WP         0.25 Kg/ha         -

                     Cereals                      50% WP         0.25 Kg/ha         4 weeks

    South Africa     Wheat                        WP             125 g/ha           7 days

                     Peaches                      WP             25 g/100 l         21 days

    New Zealand      Potatoes                                    250 g/220 l/ha     Nil

                     Brassicas                                   250 g/200 l/ha     3 days

    Australia        Vegetables, fruits and hops                                    2 days
    

    Leafy Vegetables (Tables 6 and 7)

         The highest initial residues after spraying edible crops are
    found in leafy vegetables. Lettuce contained total carbamate residues
    of up to 20 mg/kg immediately after spraying at recommended use rates,
    with the highest values occurring after indoor applications. However
    decay rates are normally rapid (half-lives of 1-3 days outdoors) so
    that after seven days in the outdoor situation or fourteen days
    indoors total pyrimidine carbamate residues are normally less than
    1 mg/kg.

    Cucurbits and solanaceous fruits (Table 6)

         A short pre-harvest withholding interval (e.g. 1-3 days) is
    normally required in solanaceous fruits and cucurbits. Pirimicarb
    residues in these crops can vary with the method of application and
    with whether the crop is grown indoors or outside. Nevertheless after
    recommended pre-harvest withholding intervals, total pyrimidine
    carbamate residues are below 1 mg/kg and usually below 0.5 mg/kg. An
    exception is chili peppers, grown outdoors, where residues are below 2
    mg/kg after seven days.

         Treatments with a smoke generator in the greenhouse give rise to
    lower residues than corresponding spray treatments (Table 6).

    Root crops and legumes (Table 8)

         Pirimicarb does not move from the leaves into the storage organs
    (roots and tubers) of root crops. Therefore root crops and tubers do
    not normally contain significant pyrimidine carbamate residues after
    spraying. Where residues are detected, these are due either to the
    root being wholly or partly exposed to the spray (e.g. kohlrabi and
    carrots) or to residues being transferred from the foliage during
    sampling and/or sample preparation. Similarly, detectable residues are
    not expected in peas and beans where the edible portion of the crop is
    protected by pods. The low residues which sometimes occur,
    <0.1 mg/kg, probably arise from inadvertent contamination during
    sample preparation.

         Runner and French beans exposed to the spray contained residues
    up to 1.4 mg/kg immediately after spraying but decay was generally
    rapid (half-life less than 1 day) so that total pyrimidine carbamate
    residues after seven days were normally less than 0.5 (mg/kg).

    Fruit (Table 9)

         Residues in fruit are lower than in leafy vegetables. Levels are
    generally below 2 mg/kg, even immediately after application. These
    decay rapidly, with half-lives of 1-2 days. After seven days, total
    pyrimidine carbamate residues are normally below 0.5 mg/kg and


        TABLE 6. Residues of Pirimicarb And Its Two Major Carbamate-Containing Metabolites In Leafy
             Vegetables, Cucurbits and Solanaceous Fruit From supervised Trials With Sprays Or
             Smoke Generators

    SPRAY USES
                                                                                                  

    Crop                Country        Application    No. of         Pre-harvest    Total carbamate
                                       Rate           Applications   Interval       Residues Range
                                       kg ai/ha                      (Days)         (mg/kg)
                                                                                                  

    Brussels sprouts    Netherlands    0.14           1              3-4            0.11-0.13
                        U.K.           0.28           1              3              <0.14
                                       0.28           3              3              0.28

                        U.S.A.         0.14           5-9            3              0.03-0.10
                                       0.28           5-9            3              0.05-0.32

    Broccoli            U.S.A.         0.14           2-5            1              <0.05-0.71
                                       0.28           2-5            1              <0.10-0.96

    Cabbage (green)     Australia      0.25*          1              7              0.21
                        Germany        0.30           1-2            7              0.57
                        New Zealand (  0.28           1              7-8            0.11-0.30
                        U.K.        (
                        U.S.A.         0.14           2-5            3              <0.05-0.08
                                       0.28           2-5            3              <0.05-0.18

    Cabbage (savoy)     Germany        0.30           1              1-10           0.01
                        Japan          0.50*          4              7-8            0.02-0.78

    Cauliflower         Germany        0.30           1              7              0.03
                                                                                    (whole)

                        U.S.A.         0.14           1-7            3              <0.05
                                       0.28           1-7            3              <0-05-0.275

    Celery (outdoor)    Netherlands    0.25           1              7              0.22-0.97
                        U.K.           0.28           1              7              0.18

    TABLE 6. (Cont'd.)

    SPRAY USES

                                                                                                  

    Crop                Country        Application    No. of         Pre-harvest    Total carbamate
                                       Rate           Applications   Interval       Residues Range
                                       kg ai/ha                      (Days)         (mg/kg)
                                                                                                  

    (indoor)            Netherlands    0.25           1              7              4.1

    Endive              Netherlands    0.28           1              7              <0.10

    Lettuce (outdoor)   Australia      0.28           1              0              7.5
                                                                     2              1.4
                                                                     5              0.23
                                                                     9-16           ND**
                                       0.56           1              0              19.6
                                                                     2              2.4
                                                                     5              0.33
                                                                     9              0.38
                                                                     13-16          ND

                        Germany        0.50           1              7              <0.01-0.05

                        U.K.           0.25*          1              7              <0.18-0.56

                        U.S.A.         0.14           3-7            1              <0.05-0.44
                                       0.28           3-9            1              <0.05-0.97

    (indoor)            U.K.           0.25*          1              13-14          <0.18-0.47

    Parsley (outdoor)   Netherlands    0.25           1              15             0.15-0.65
    (indoor)                           0.25           1              15             4.7

    Onions (salad)      U.K.           0.16*          1              0              0.04-0.39
    Spinach             U.K.           0.50           1              7              <0.01-0.03

    TABLE 6. (Cont'd.)

    SPRAY USES

                                                                                                  

    Crop                Country        Application    No. of         Pre-harvest    Total carbamate
                                       Rate           Applications   Interval       Residues Range
                                       kg ai/ha                      (Days)         (mg/kg)
                                                                                                  

    Cucumbers           Canada         0.28           1              3              0.04-0.13

                        U.K.           0.28           1              2              <0.10-0.34

    Aubergines          U.S.A.         0.28-0.42      7              3              <0.01

    Gherkins            Germany        0.3-0.5        1-3            2-3            0.01-0.05

                        U.K.           0.25*          1              3              0.45

    Peppers (outdoor)   Canada         0.14           3              3              0.05
    (Bell)              U.S.A.         0.14           3-6            1              0.05-0.34
                                       0.28           4              1              0.05-0.43

    (indoor)            Canada         0.28           1              2              0.14

                        France     (
                        Netherlands(   0.25*          1              3              <0.12-0.16

    Peppers (outdoor)   U.S.A.         0.14           2-10           7              0.05-0.83

    (chili)                            0.28           1-10           7              <0.05-1.26

    Tomatoes            Australia      0.25*          1              2              0.08

                        Canada         0.19+0.28      2              2              0.04
                                       0.28           1              3              0.28

                        Germany        0.50           1-2            1              <0.01-0.04

    TABLE 6. (Cont'd.)

    SPRAY USES

                                                                                                  

    Crop                Country        Application    No. of         Pre-harvest    Total carbamate
                                       Rate           Applications   Interval       Residues Range
                                       kg ai/ha                      (Days)         (mg/kg)
                                                                                                  

                        Japan          0.50*          2-4            1              0.10-0.61

                        U.K.           0.25*          2              2              <0.01-0.37

                        U.S.A.         0.28           7              3              <0.01

    SMOKE GENERATOR USES

                                                                                                  

    Crop                Country        Application    No. of         Pre-harvest    Total carbamate
                                       Rate           Applications   Interval       Residues Range
                                       mg ai/m3                      (Days)         (mg/kg)
                                                                                                  

    Cucumbers           Germany        30             3              1              0.29-0.32
                        Netherlands    20             1              0              0.32
                                       15             1              1              0.03

                        U.K.           15             1              0              0.05-0.19

    Endive              Netherlands    12             1-2            13-14          0.02.-0.14

    Lettuce             Germany        14             3              14             0.46

                        Netherlands (  15             1              14             0.02-0.85
                        U.K.        (

    Gherkins            Germany        15-17          3              0              0.11

    TABLE 6. (Cont'd.)

    SMOKE GENERATOR USES

                                                                                                  

    Crop                Country        Application    No. of         Pre-harvest    Total carbamate
                                       Rate           Applications   Interval       Residues Range
                                       mg ai/m3                      (Days)         (mg/kg)
                                                                                                  

                        Netherlands    14             1              1              0.02

    Tomatoes            Germany        14-16          3              0              0.01-0.08

                        Netherlands    13             1              1              0.01-0.02

                        U.K.           15             1              0              0.08-0.09
                                                                                                  

    * Rate in g a.i./l

    ** Not detectable

    

    consistently below 1 mg/kg. Pirimicarb does not penetrate the skin of
    fruit and hence can if necessary be removed by peeling (Edwards and
    Dick 1976; Manley 1969).

    
    TABLE 7. Decline of pirimicarb residues on cabbages (New Zealand)

                                                                                   

    Application           Residues in mg/kg, at intervals (days) after application
           rate                                                                     
    No.    kg a.i./ha     1         3         7         10        14       21
                                                                                   

    1      0.30           0.47      0.38      0.30      0.14      0.13     <0.06

    1      0.50           0.49      0.39      0-30      0.24      0.20     <0.06

    2      0.28           0.44      0.18      0.19

    2      0.56           0.88      0.39      0.18
                                                                                   
    
    Cereals and seed crops (Tables 9 and 10)

         Wheat grain analysed in husk contained total pyrimidine carbamate
    residues of 1-3 mg/kg on day after application (Table 10). Half-lives
    varied between one and seven days. No residues were detected in
    dehusked grain 7 days after spraying.

         Very low residues (<0.1 mg/kg) were detected in oil seed rape
    seven days after application of pirimicarb.

    FATE OF RESIDUES

    In Plants

         Pirimicarb is rapidly lost from plants on which it has a
    half-life of 1-3 days. Volatilisation affords the primary means of
    loss: the higher the ambient temperature, the greater the percentage
    of pirimicarb lost by volatilisation (Manley, 1969; Bewick and Leahey,
    1976; Davis and Hemingway, 1976; Hemingway and Davis, 1976).

         Pirimicarb also undergoes photochemical and metabolic
    degradation.

         The major carbamate-containing degradation products are compounds
    II and III. (Figure 1). Compound IV is only a minor
    carbamate-containing degradation product. Other minor degradation
    products include the water soluble hydroxypyrimidines I, V, and VI,


        TABLE 8. Residues of Pirimicarb And Its Two Major Carbamate Containing Metabolites In Root
             Vegetables And Legumes From Supervised Spray Trials

                                                                                                       

    Vegetable           Country        Application     No. of           Pre-harvest     Total Carbamate
                                       Rate            Applications     Interval        Residues Range
                                       kg ai/ha                         (Days)          (mg/kg)
                                                                                                       

    Beetroot            U.K.           0.25*           1                0               0.02

    Carrots
    (submerged)         U.K.           0.28            1                0               0.02-0.04

    (tops of roots
    exposed)            U.K.           0.25*           1                7               0.11

    Kohlrabi (roots)    Germany        0.25            1                0               <0.01-0.23
                                       0.25            2                0-10            <0.01

    (leaves)            Germany        0.25            1                7               0.09-0.11
                                       0.25            2                1-10            <0.01

    Parsnips            U.K.           0.25*           1                0               <0.01

    Potatoes            Netherlands    0.25            1                0               <0.01
                        (aerial)

                        New Zealand (  0.28            1                0               <0.01
                        U.K.        (

                        U.S.A.         0.14            1-7              0               <0.01
                                       0.28            1-7              0               <0.01

    Radish              Japan          0.25*           2-4              0               <0.01

    Sugar beet          Germany        0.30            1-2              0               <0.01-0.02
      (roots)
      (leaves)          Germany        0.30            1-2              7-8             0.12-0.70

    TABLE 8. (Cont'd.)

                                                                                                       

    Vegetable           Country        Application     No. of           Pre-harvest     Total Carbamate
                                       Rate            Applications     Interval        Residues Range
                                       kg ai/ha                         (Days)          (mg/kg)
                                                                                                       

    Turnips             U.K.           0.25*           1                0               0.04

    Beans (broad)       Germany        0.30            1                0               0.09

    Beans (runner/      Germany        0.30            1                7               0.05
           French)
                        U.K.           0.25*           1                7-8             <0.06.0.55
                                       0.50            1                0               0.89-1.4

    Peas                Australia      0.28            4                0               0.06

                        Germany        0.30            1                0               0.10

                        Netherlands    0.25            1                0               0.03

                        U.K.           0.16*           1                0               <0.01
                                       0.50            1                7               0.06-0.67
                                                                                                       

    * indicates rate in terms of g ai per litre.

    TABLE 9. Residues Of Pirimicarb And Its Two Major Carbamate Containing Metabolites In Fruit, Cereals
             And Seed Crops From Supervised Spray Trials

                                                                                                       

    Crop               Country          Application    No of            Pre-harvest     Total carbamate
                                        Rate           Applications     Interval        Residue Range
                                        g ai/l                          (Days)          (mg/kg)
                                                                                                       

    Apples             Canada           0.25           1                7               0.01-0.60
                       U.K.             0.16           2                7               0.09-0.37

    Blackcurrants      U.K.             0.16           1                7               0.01-0.08

    Oranges            Australia        0.25           1                7               <0.01 (whole fruit)
                                                                                        <0.02 (flesh)
                                                                                        0.32 (peel)

    Peaches            Australia        0.25           1                7               0.05

                       Italy (          0.25           1-3              5-6             <0.10-0.27
                       Spain (          0.50           1-3              5-6             0.20-0.36

    Plums              Canada           0.14*          1                7               0.36
                                        0.28*          1                7               0.38

                       U.K.             0.25           1                7               0.06-0.11

    Raspberries        U.K.             0.16           1                7               0.02-0.09

    Strawberries       Australia        0.25           1                0               1.5
                                        0.25           1                7               0.23

                       U.K.             0.25           1                7               0.07-0.09

    Wheat (in husk)    Australia        0.25*          1                7               0.33

                       Germany          0.25*          1-2              7               0.04-1.5

    TABLE 9. (Cont'd.)

                                                                                                       

    Crop               Country          Application    No of            Pre-harvest     Total carbamate
                                        Rate           Applications     Interval        Residue Range
                                        g ai/l                          (Days)          (mg/kg)
                                                                                                       

                       South Africa     0.25*          1-2              7               0.27-0.52

    (de-husked)        Netherlands      0.125*         1                7               <0.02

    Oil seed rape      Australia        0.28-          1-4              7               <0.10
                       Czechoslovakia   0.35*

                                                                                                       

    * indicates rate in terms of kg a.i./ha

    

    and guanidine and its 1-methyl and 1,1 dimethyl derivatives. This
    pattern of degradation has been shown to take place in part or
    completely on peach and sugar beet leaves (Manley, 1969), lettuce
    (Hemingway and Davis, 1976) and cabbage (Davis and Hemingway, 1976).
    The rate of degradation varies with crop type and weather conditions.
    Thus in lettuce, seven days after application of pirimicarb 71% of the
    radioactivity remaining was present as pirimicarb and the carbamates
    II and III, whilst in cabbage the figure was 32%.

         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 by refluxing with ethanol and was termed
    `bound'. Pirimicarb, compounds III and V and the three guanidines
    mentioned above were all shown to be minor constituents of the bound
    residue. Approximately 40% of the bound residue was associated with
    the cellulose and hemicellulose of the plant (Teal and Skidmore,
    1976).

         When pirimicarb was introduced systemically into broad bean
    plants by stem injection, its half-life was less than one day. Again
    products II and III were formed initially. However these and
    pirimicarb were subsequently degraded, the carbamate groups being
    quantitively eliminated as measured by the evolution of 14CO2 from
    plants treated with 14C-carbonyl-labelled pirimicarb (Manley, 1969).

         Spraying of potatoes with 2-14C-labelled pirimicarb at 0.42 kg
    ai/ha resulted in very low residues of radioactivity in the tubers
    (less than 0.05 mg/kg pirimicarb equivalents). More than 80% of this
    low residue was present as unextractable materials or as a complex
    mixture of water-soluble materials closely associated with plant
    sugars and pigments (Bowker et al, 1975).

         When pirimicarb sprayed at rates up to 5 kg ai per hectare, ie
    20-40 times normal use rates, total pyrimidine carbamate residues in
    "follow-up" crops at harvest extremely small - of the order of the
    limit of determination of the analytical method or below (Edwards et
    al, 1974 and 1975). Total radiolabelled residues in "follow-up" crops
    at harvest as a result of applying 2-14C-labelled pirimicarb at 0.5
    kg ai per hectare were also small - up to 0.14 mg/kg pirimicarb
    equivalents. In lettuce, which contained the highest radioactive
    residue, approximately 50% of the activity was due to a combination of
    pirimicarb, compound III, the hydroxypyrimidines I, V and the three
    guanidines (Hughes and Leahey, 1974; Leahey and Benwell, 1976).

    In animals

         An oral dose of pirimicarb is rapidly excreted by cows,
    principally in the urine. Only traces of residues are transferred to
    milk and tissues.

    TABLE 10. Pirimicarb Residues on Wheat (South Africa) at Intervals
              after Application
                                                                        

                                                     Residues, mg/kg
    Application                   Days
    rate           No. of         after                         Demethyl-
    g a.i./ha      Applications   Application    Pirimicarb     pirimicarb
                                                                        

    250                1              1          2.3            0.4
                                      2          1.7            0.3
                                      4          0.4            0.2
                                      7          0.2            <0.2
                                     55          <0.1           <0.2

    125                1              1          0.7            0.4
                                      2          0.6            0.3
                                      4          0.2            0.2
                                      7          <0.1           <0.2
                                     55          <0.1           <0.2

    250                1              1          2.5            0.5
                                      2          1.6            0.2
                                      4          0.3            <0.2
                                      7          0.2            <0.2
                                     55          <0.1           <0.2

    125                1              1          0.8            0.4
                                      2          0.6            0.2
                                      4          0.1            <0.2
                                      7          <0.1           <0.2
                                     55          <0.1           <0.2

    250                1              1          2.5            0.4
                                      2          2.3            0.4
                                      4          0.4            <0.2
                                      7          0.3            <0.2
                                     55          <0.1           <0.2

    125                1              1          0.6            0.3
                                      2          0.6            0.3
                                      4          0.1            <0.2
                                      7          <0.1           <0.2
                                     55          <0.1           <0.2
                                                                        

    Results are the average of 3 determinations
    Recovery pirimicarb 105% at 1 mg/kg
               demethyl-pirimicarb 78% at 1 mg/kg
    Results not corrected for recovery
    Limit of detection pirimicarb            0.1 mg/kg
                       demethyl-pirimicarb   0.2 mg/kg

         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 radioactive residue in the milk (0.25 mg/kg
    pirimicarb equivalents) was detected one hour after dosing; 80-90% of
    this residue was due to the hydroxypyrimidines I, V and VI (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 (Hemingway et al 1976). See also
    "Biotransformation".

    In soil

         Pirimicarb is extensively degraded in soil. Degradation occurs
    most rapidly in less acid soils. In soils of pH6.5 and above,
    pirimicarb has a half-life of up to 7 weeks under aerobic conditions.
    The rate of degradation in more acid soils was considerably enhanced
    by air drying. Although less important than soil pH, a higher organic
    matter content also appears to enhance the rate of degradation of
    pirimicarb (Hill et al 1975a; Hill and Stevens 1975).

         The principal route of degradation in soil is by hydrolysis of
    the carbamate moiety from the pyrimidine ring. N-dealkylation of the
    2-dimethylamino group has also been observed. Cleavage of the
    pyrimidine ring has been demonstrated by the loss of 14CO2 from
    soils treated with 2-14C-labelled pirimicarb. Hydrolysis of the
    carbamate moiety results from both biological and chemical soil
    activity whereas pyrimidine ring cleavage is mediated only by
    biological activity. Several fungi and actinomycete cultures are
    capable of metabolising pirimicarb (Hill et al 1975a; Hill and Arnold,
    1974; Manley et al 1972).

         Compounds I, III and V (Figure 1) are all major soil metabolites.
    Minor degradation products include the carbamates II and IV and the
    hydroxy pyrimidine VI (Hill et al, 1975a). Compound I is the major
    product of photochemical degradation of pirimicarb on the soil surface
    (84% of the residue recovered after 20 days) (Leahey and Benwall,
    1974).

         After two years, more than 70% of the radioactivity resulting
    from the application of 2-14C-labelled pirimicarb to acid soils was
    not extracted by refluxing with acetone: water (5:1). Almost all of
    this bound residue was associated with the fulvic acid fraction of the
    soil. Up to 60% of the bound residue was due to pirimicarb plus the
    hydroxypyrimidines I and V (Hill et al 1975b).

         Pirimicarb and its soil degradation products are of low mobility
    in soil; lower than atrazine which is recognized as being only
    moderately mobile (Riley et al 1974). There is no significant
    concentration of pirimicarb in "run-off" water or eroded soil (Gouman
    and Hale, 1975).

    In water

         Pirimicarb undergoes rapid photochemical degradation in water:
    over 50% of the applied pirimicarb is degraded in 24 hours at pH5-9.
    There is no significant loss of pirimicarb by volatilisation from
    water. Degradation products include the pyrimidine carbamates II-IV,
    the hydroxypyrimidines I, V and VI, 1,1-dimethylguanidine and
    1-methylguanidine. Only traces (<1%) of guanidine itself have been
    detected (Bowker and Griggs, 1974; Lincoln and Hemingway 1974).

    In washing and cooking

         Residues of pirimicarb and its two major carbamate metabolites II
    and III on lettuce were reduced by 38-49% by washing with cold water.
    In addition, during cooking approximately 60% of the pirimicarb and
    52-65% of the carbamate-containing metabolite residues were
    transferred from Brussels sprouts and cabbage into the cooking water.
    There was no detectable conversion to other products during the
    washing or cooking processes (Edwards et al, 1976).

    In storage

         There was no loss of residue from deep-frozen samples fortified
    with pirimicarb. Details are given in "Methods of residue analysis".

    EVIDENCE OF RESIDUES IN FOOD IN COMMERCE OR AT CONSUMPTION

         Monitoring of pirimicarb residues in the Netherlands has shown
    that residues in imported grapes and in all but one sample of
    home-produced endive were within the national tolerance of 1 mg/kg.

    METHODS OF RESIDUE ANALYSIS

         A gas-chromatographic method using a nitrogen-selective detector
    to detect residues of pirimicarb plus its two major
    carbamate-containing degradation products (II and III, Figure 1) is
    the preferred residue method (Zweig 1975).

         Crop samples are macerated with choloroform in the presence of
    anhydrous sodium sulphate. The extract is subjected to a solvent
    partition clean-up during which
    5,6-dimethyl-2-formylmethylamino-4-pyrimidinyl dimethylcarbamate (II)
    is hydrolysed to 5,6-dimethyl-2-methylamino-4-pyrimidinyl
    dimethylcarbamate (III). The dried extract in ethyl acetate is
    evaporated to dryness and taken up into acetone, and an aliquot of

    this solution is injected into a gas chromatograph fitted with a
    nitrogen detector. The size of the peaks obtained at the retention
    times of pirimicarb and of compound III are used to calculate residue
    levels by comparison with peaks obtained by injection of standard
    solutions of the two compounds (ICI Plant Protection Ltd., 1972).

         Some crop extracts may contain co-extracted interfering
    compounds. These can be removed by cleanup on a column of silica gel,
    prior to gas-chromatographic determination (Edwards and Dick, 1976).

         The limit of determination for pirimicarb and for compound III in
    crops is normally 0.01 mg/kg. Under the conditions of chromatography
    described in the method, retention times for pirimicarb and compound
    III were found to be 0.7 and 1.5 minutes respectively (ICI Plant
    Protection Ltd, 1972).

         Methanol may be used as the extraction solvent instead of
    chloroform. For crops containing a high percentage of water (i.e.
    normal 'green' crops), chloroform and methanol are equally efficient
    (Manley, 1969; Edwards and Dick, 1975). However for crops of very low
    water content (e.g. dry leaf tea, cured tobacco and oil seed rape), it
    is essential to use methanol to extract residues of pirimicarb and
    compounds II and III completely (Edwards and Dick, 1976).

         Hydrolysis of compound II to compound III in 0.1 M hydrochloric
    acid during the solvent partition cleanup was shown to be complete
    (Cox, 1973).

         A colorometric method, involving hydrolysis to dimethylamine, is
    also available for determining residues of pirimicarb metabolites II
    and III in crops (Zweig, 1975). Crop samples are macerated with
    chloroform and the extract washed successively with 0.1M sodium
    hydroxide, water and a slightly acid phosphate buffer (ph 4.3). The
    chloroform is evaporated under reduced pressure and the residue steam
    distilled with 1 M sodium hydroxide, liberating dimethylamine which
    is absorbed in 0.1 M hydrochloric acid and determined
    absorptiometrically as the yellow-brown copper dimethydithiocarbamate
    complex at 436nm. Where troublesome emulsions occur at the washing
    stages, the sample is extracted with acetone. Emulsifying agents are
    removed by solvent partition; pirimicarb and its carbamate-containing
    metabolites are then extracted into chloroform which is treated as the
    chloroform extract obtained above.

         Residues of the dimethyl dithiocarbamate fungicides (thiram and
    ziram) interfere with the determination of pirimicarb and the two
    metabolites by this method. Where interfering residues are present, a
    chloroform extract obtained as described in the preceding paragraph is
    subjected to thin layer chromatography alongside a marker spot on
    silica gel GF 254. The developed chromatogram is viewed under
    ultra-violet light, the primicarb band is removed and steam distilled,
    and the determination completed, as described above (ICI Plant
    Protection Ltd. 1969). The limit of determination of the method is

    normally 0.7 mg/kg pirimicarb or pirimicarb equivalents. Recoveries in
    excess of 70% are normally obtained (Bullock, 1969). The determination
    of residues of pirimicarb and compound II and III is not affected by
    the presence of residues of the ethylene bisdithiocarbamate fungicides
    (e.g. maneb and zineb), nor by the presence of residues of carbaryl,
    as none of these compounds is hydrolysed to dimethylamine.

    TABLE 11. Stability Of Pirimicarb Residues In Crops Stored At -14C

                                                            
                             Mean residues, mg/kg
    CROP                                                     

                     Initially        After           After
                                      3               6.5
                                      months          months
                                                            

    Apples           0.92             0.94            0.86

    Potatoes         1.00             0.79            0.81

    Lettuce          0.97             1.04            0.94

    Cucumbers        0.91             1.05            0.81

                                                            


         Pirimicarb residues are stable at -14C. Samples of apples,
    potatoes, lettuces and cucumbers were spiked with pirimicarb at
    1 mg/kg, stored at -14C for up to six months and analysed for
    pirimicarb by the gaschromatographic method described above (see Table
    11). Statistical analysis of the individual residue figures and of the
    determined recovery values showed that there were no significant
    differences among the residue values due either to storage time or to
    crop (Edwards and Atreya, 1974).

    NATIONAL TOLERANCES REPORTED TO THE MEETING

    The following national tolerances have been established for residue of
    pirimicarb plus its two major carbamate containing metabolites, II and
    III (Table 12).

    TABLE 12. National tolerances reported to the Meeting

    Country             Crop                              Tolerance mg/kg

    Australia           Vegetables,                        1
                        fruit and hops                     0.5
    Hungary             All crops                          0.5
    Japan               Fruit and vegetables               0.3

    TABLE 12. (Cont'd.)

    Country             Crop                              Tolerance mg/kg


    New Zealand         All crops                          0.5
    Switzerland         Fruit and vegetables               1
    USA                 Potatoes                           0.1
    Venezuela           All crops                          0.5
    Netherlands         Fruit and vegetables               1.0
                        Grain                              0.05
                        Potatoes                           0.05

    APPRAISAL

         Pirimicarb is a fast acting, selective aphicide which is now
    registered in a number of countries for use on fruit, vegetables and
    other crops. It has proved effective on all crops on which it has been
    tried against all aphids including organophosphorus-resistant strains,
    with the exception of multi-resistant strains of Phorodon humuli.
    It is harmless to useful parasites and predators, with the exception
    of hoverflies, and has a very low toxicity to bees.

         In addition to its contact and translaminar actions pirimicarb is
    effective as a fumigant. Technical pirimicarb is not less than 95%
    pure and is normally 98% pure; the impurities contain up to 1.3% of
    other pyrimidine carbamates. It is formulated as a 50% dispersible
    powder and a 50% dispersible pellet or grain, as a ULV formulation and
    in a 10% smoke generator. The usual rates of application are 0.25 kg
    a.i./ha as a crop spray and 15 mg/m3 as a smoke.

         Pirimicarb possesses only limited persistence on crops and the
    pre-harvest withholding intervals range from zero for root crops, and
    others where the edible portion is protected from the spray, to seven
    days for leafy vegetables.

         Pirimicarb is rapidly lost from plants; it has a half-life of 1-3
    days. Most of the loss is by volatilisation, the extent of which
    increases with rise in the ambient temperature, but there is some
    photochemical and metabolic degradation. There are two major
    metabolites containing the carbamate moiety, the N-formyl(methylamino)
    (II) and 2-methylamino (III) analogues of pirimicarb, which occur in
    plants. Minor degradation products include a third carbamate, 2-amino
    pirimicarb, the water-soluble 2-dimethylamino-, 2-methylamino- and
    2-amino-hydroxypyrimidines and the corresponding guanidines. The
    recommended residue methods for pirimicarb also estimate the two major
    carbamate-containing metabolites.

         Use of radio-labelled material shows that some part (25% in one
    experiment) of the pesticide may become bound to plant materials (i.e.
    not extractable with organic solvents) but, as far as can be judged,
    the more toxic carbamate compounds are not major constituents of this.
    Within the plant (stem injection of broad beans), metabolic products
    II and III are formed initially but subsequently degraded. Transfer to
    the tubers of sprayed potatoes is small. Follow-up crops grown on
    heavily sprayed land contain only very small amounts (at the
    analytical limit) of determinable residue. Washing heavily treated
    lettuce with cold water reduces residues of pirimicarb by about 38%
    and cooking Brussels sprouts and cabbage gives a 60% reduction.
    Pirimicarb is concentrated in the skin of apples and the residues are
    reduced below the level of detection on peeling.

         The transfer of residues of pirimicarb from animal feed to the
    milk and meat of cows appears to be very small.

         In soil there is substantial hydrolysis of the carbamate moiety
    from the pyrimidine ring and photochemical degradation on the soil
    surface also very largely produces the hydroxypyrimidine V. Pirimicarb
    and its degradation products are of low mobility in soil and there is
    no significant concentration of pirimicarb in run-off water or eroded
    soil.

         Pirimicarb is rapidly degraded photochemically in water exposed
    to bright sunlight (50% in 24 hours at pH 5 to 9) but decomposition is
    slow in the dark.

         Adequate methods of analysis are available for regulatory
    purposes. A gas-chromatographic method using a nitrogen selective
    detector to detect residues of pirimicarb plus its two major carbamate
    degradation products II and III (II is converted to III during the
    clean-up process) is the preferred method. The limit of determination
    of pirimicarb and compound III in crops by this method is 0.01 mg/kg.
    Total carbamate can also be determined by a colorimetric method for
    which the limit of determination is 0.1 mg/kg and the pesticide
    recovery better than 70%. Modifications of clean-up etc. are available
    for both methods to deal with particular problems (Zweig, 1975).

         Although little information is yet available on the residue of
    pirimicarb in food moving in commerce, numerous results from
    supervised residue trials on crops growing in a number of countries
    enable recommendations to be made for certain groups of crops. Because
    the maximum residue limits recommended for many leafy vegetables are
    the same it would be reasonable to have a single recommendation for
    this group.

    RECOMMENDATIONS

         The following temporary maximum residue limits are recommended.
    They refer to the total residue of pirimicarb, its
    N-formyl(methylamino) analogue (desmethylformamido-pirimicarb) and
    desmethyl-pirimicarb expressed as pirimicarb.

    Commodity                    Temporary Maximum       Note:
                                 Residue Limit
                                 (mg/kg)                 Pirimicarb has
                                                         a half-life of
    Chili peppers                      2                 1-3 days on
                                                         plants; leafy
    Apples                             1                 commodities
    Bell peppers                       1                 are harvested
    Broccoli                           1                 7 days after
    Brussels sprouts                   1                 application,
    Cabbage                            1                 root crops are
    Cauliflower                        1                 harvested 0-3
    Celery                             1                 days after
    Cucumber                           1                 application
    Eggplant                           1
    Endive                             1
    Gherkins                           1
    Lettuce                            1
    Parsley                            1
    Tomatoes                           1

    Blackcurrants                      0.5
    Beans (with pod)                   0.5
    Kohlrabi                           0.5
    Onions                             0.5
    Peaches                            0.5
    Plums                              0.5
    Raspberries                        0.5
    Strawberries                       0.5
    Peas                               0.2
    Rapeseed                           0.2
    Beans (without pod)                0.1
    Beetroot                           0.05*
    Citrus fruits                      0.05*
    Parsnips                           0.05*
    Potatoes                           0.05*
    Radishes                           0.05*
    Sugar beet                         0.05*
    Turnips                            0.05*
    Wheat                              0.05*
   
    FURTHER WORK OR INFORMATION

    Required (by 30 June 1978)

    1)   Studies on other species, primarily primate, to define the range
         of species' susceptibility to the hematologic changes noted in
         the dog.

    * At or about the limit of determination.

    2)   Definition of the susceptibility to hemolytic anemia in the
         inbred beagle strain used in toxicological studies.

    3)   Studies to fully define the reduced growth noted in several
         rodent dietary studies.

    4)   Immunological studies when appropriate in animals species other
         than the clog to define further the significance (and possible
         range of occurrence) of the hemolytic anemia.

    5)   Significance of hypochromic anemia associated with rats fed high
         levels of plant metabolites.

    Required (by 1980)

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

    Desirable

    1.   Survey of industrially exposed individuals by immunological (or
         serological) techniques to define the potential occurrence of
         antibodies following pirimicarb exposure.

    2.   More information on residues in grains other than wheat, e.g.,
         barley, oats, rice, maize.

    REFERENCES

    Bagness, J.E., Hamer, C.M. and Willis, G.A., Pirimicarb
    1975                Operational Experience During Formulation.
                        Unpublished report from ICI Plant Protection
                        Division submitted to the World Health
                        Organization by ICI Ltd.

    Bewick, D.W. and Leahey, J.P. Pirimicarb : Identification
    1976                Of Material Volatilised From The Surface Of A
                        Treated Lettuce Plant, ICI Plant Protection Ltd.
                        Report No. TXJ1289A (Unpublished).

    Bowker, D.M. and Griggs, B.F. Pirimicarb : Fate In Water.
    1974                ICI Plant Protection Ltd. Report No. AR2492A
                        (Unpublished).

    Bowker,D.M., Griggs, B.F. and May, M.S. Pirimicarb Fate In
    197e                Potatoes. ICI Plant Protection Ltd. Report No.
                        AR2491 AR (Unpublished).

    Bullock, D.J.W. A Colorimetric Method Of Analysis for Residues Of
    1969                PP062 In Food Crops, ICI Plant Protection Ltd.
                        Report No. AR2091 AR (Unpublished).

    Clark, D.G., The Influence of Feeding on the Oral Toxicity of
    1967a               PP 062 and PP159. Unpublished report from ICI
                        Central Toxicology Laboratory, submitted to the
                        World Health Organization by ICI Ltd.

    Clark, D.G., The Acute Toxicity of Technical PP062, Dispersible
    1967b               Powder (J.F.2130) and PP062 Granules (J.F. 2148).
                        Unpublished report from ICI Central Toxicology
                        Laboratory submitted to the World Health
                        Organization by ICI Ltd.

    Cox, J.H. Determination of Pirimicarb and Metabolites In Potato
    1973                Tubers, ICI America Inc. Report (Unpublished).

    Conning, D.M., Garner, R. and Griffiths, D., Ninety Day Oral
    1968                Toxicity of PP062 - Beagle Dogs (Part 1).
                        Unpublished report from ICI Central Toxicology
                        Laboratory, submitted to the World Health
                        Organization by ICI Ltd.

    Conning, D.M., Garner, R. and Griffiths, D., Ninety Day Oral
    1969                Toxicity of PPO62 - Beagle Dogs (Part 2).
                        Unpublished report from ICI Central Toxicology
                        Laboratory, submitted to the World Health
                        Organization by IGI Ltd.

    Daniel, J.W. and Bratt, H., Absorption and Excretion by Rats of
    1968                the Carbamate Insecticide, PP062. Unpublished
                        report from ICI Central Toxicology Laboratory,
                        submitted to the World Health Organization by ICI
                        Ltd.

    Davis, J.A. and Hemingway, R.J. Pirimicarb : Fate On Cabbage. IGI
    1976                Plant Protection Division Report No. TMJ1348A
                        (Unpublished).

    Edwards, M.J. and Atreya, N.C. Pirimicarb : Storage Stability
    1974                of Residues In Deep Frozen Crop Samples. ICI Plant
                        Protection Ltd. Report No. TMJ1090A (Unpublished).

    Edwards, M.J. and Dick, J.P. Pirimicarb : Crop Extractability
    1975                Study, ICI Plant Protection Ltd. Report No.
                        TMJ1166A (Unpublished).

    Edwards, M.J. and Dick, J.P. Pirimicarb Residue Summary Residues
    1976                In Crops From Field Trials 1973-1975. ICI Plant
                        Protection Division Report No. TMJ1360B (Un
                        published).

    Edwards, M.J. Dick, J.P. and Hayward, G.J. Pirimicarb Effect of
    1976                Washing and Cooking upon Residues in Lettuce and
                        Brassicae Crops. ICI Plant Protection Division
                        Report No. TMJ1346A (Unpublished).

    Edwards, M.J., Dick, J.P. and White D. Pirimicarb : Soil Residue
    1974                Carry Over Study On Lettuce And Radish. ICI Plant
                        Protection Ltd. Report No. AR2565A (Unpublished).

    Edwards, M.J., Dick, J.P. and White D. Pirimicarb : Soil Residue 
    1975                Carry Over Study On Carrots, ICI Plant Protection
                        Ltd. Report No. TMJ1155A (Unpublished).

    Ferguson, D.R. and  Parkinson, G.R., Pirimicarb (PP062)
    1973                Eye Irritation of Technical Grade Pirimicarb and
                        50% Dispersible Powder Formulation (JF 2538,
                        `Pirimor') Unpublished report from ICI Central
                        Toxicology Laboratory, submitted to the World
                        Health Organization by ICI Ltd.

    Fletcher, K., Pirimicarb (PP062) : Neurotoxicity in Hens.
    1971a               Unpublished report from ICI Central Toxicology
                        Laboratory, submitted to the World Health
                        Organization by ICI Ltd.

    Fletcher, K., Pirimicarb (PP062) : Irritancy Tests. Unpublished
    1971b               report from ICI Central Toxicology laboratory,
                        submitted to the World Health Organization by ICI
                        Ltd.

    Fletcher, K., Pirimicarb (PP062) : Subacute Toxicity on Rabbit
    1971c               Skin. Unpublished report from ICI Central
                        Toxicology laboratory, submitted to the World
                        Health Organization by ICI Ltd.

    Fletcher, K. and Sotheran, J., Pirimicarb (PP062): Three
    1971                Generation Reproduction Study in Rats. Unpublished
                        report from ICI Central Toxicology Laboratory,
                        submitted to the World Health Organization by ICI
                        Ltd.

    Fletcher, K., Garner, R., Parkinson, G.R. and Pratt, I.S.
    1971a               Pirimicarb (PP062) Subacute Oral Toxicity of the
                        Plant Metabolite, Demethylformamidopirimicarb.
                        Unpublished report from ICI Central Toxicology
                        Laboratory, submitted to the World Health
                        Organization by ICI Ltd.

    Fletcher, K., Garner, R., Parkinson, G.R. and Pratt, I.S.,
    1971b               Pirimicarb (PP062) Subacute Oral Toxicity of the
                        Plant Metabolite, Demethylpirimicarb. Unpublished
                        report from ICI Central Toxicology Laboratory,
                        submitted to the World Health Organization by ICI
                        Ltd.

    Fletcher, K., Garner, R., Litchfield, M.H. and Watson, M.,
    1971c               Pirimicarb (PP062): Two Year Feeding Study in
                        Beagle Dogs. Unpublished report from ICI Central
                        Toxicology Laboratory, submitted to the World
                        Health Organization by ICI Ltd.

    Fletcher, K., Hodge, M.C.E. and Kinch, D.A., Pirimicarb (PP062) :
    1971d               Teratological Studies in the Mouse. Unpublished
                        report from ICI Central Toxicology Laboratory,
                        submitted to the World Health Organization by ICI
                        Ltd.

    Fletcher, K. Forshaw, A.M. and Monks, I.H., Pirimicarb (PP062):
    1971e               Excretion and Metabolism in the Dog and Rat.
                        Unpublished report from ICI Central Toxicology
                        Laboratory, submitted to the World Health
                        Organization by ICI Ltd.

    Fletcher, K., Kinch, D.A. and Hodge, M.C.E. Pirimicarb (PP062) :
    1971f               Teratological Studies in the Rat. Unpublished
                        report from ICI Central Toxicology Laboratory,
                        submitted to the World Health Organization by ICI
                        Ltd.

    Fletcher, K. and Bratt, H., Pirimicarb (PP062). Accumulation Study
    1972                in Rats. Unpublished report from ICI Central
                        Toxicology Laboratory, submitted to the World
                        Health Organization by ICI Ltd.

    Fletcher, K., Clapp, M.J.L., Garner, R., Litchfield, M.H. and
    1972                Wilson, J., `Pirimicarb', (PP062): Two Year
                        Feeding Study in the Rat. Unpublished report from
                        ICI Central Toxicology Laboratory, submitted to
                        the World Health Organization by ICI Ltd.

    Garner, R., Phillips, C.E., and Slack, P., Pirimicarb (PP062)
    1972                Pirimicarb Anaemia (A Chemically-Induced
                        Autoimmune Haemolytic Anaemia). Unpublished report
                        from ICI Central Toxicology Laboratory, submitted
                        to the World Health Organization by ICI Ltd.

    Gowman, M.A. and Hale, S.W. Pirimicarb : Loss From Soil In
    1975                Run-Off Water and Eroded Soil. ICI Plant
                        Protection Ltd. Report No. TMJ1102A (Unpublished).

    Griffiths, D. and Conning, D.M., Ninety Day Oral Toxicity
    1968                of PP062 - Albino Rats. Unpublished report from
                        ICI Central Toxicology Laboratory, submitted to
                        the World Health Organization by ICI Ltd.

    Hemingway, R.J. and Davis, J.A. Pirimicarb : Fate on Lettuce.
    1976                ICI Plant Protection Division Report No. TMJ1324A
                        (Unpublished).

    Hemingway, R.J. Davis, J.A. and Cleverly, B.A. Pirimicarb:
    1976                Ercretion and Metabolism of a Single Oral Dose
                        Administered to a Cow. Unpublished report No.
                        AR2663A from ICI Plant Protection Division,
                        submitted to the World Health Organization by ICI
                        Ltd.

    Hill, I.R. and Arnold, D.J. Pirimicarb Metabolism by Micro-Organisms
    1974                Isolated from Soil. ICI Plant Protection Ltd.
                        Report No. TMJ1119A (Unpublished).

    Hill, I.R., Arnold, D.J., Minns, E.C. and Greaves, R. Pirimicarb :
    1975a               Laboratory Studies Of The Degradation Of Single
                        Applications Of The Pesticide In Soil In the
                        Absence Of Plants. ICI Plant Protection Ltd.
                        Report No. AR2555A (Unpublished).

    Hill, I.R., Harvey, B.R. and Arnold, D.J. Pirimicarb Extraction And
    1975b               Fractionation Of 'Bound' Residues In Soil. ICI
                        Plant Protection Ltd. Report No. AR2579A
                        (Unpublished).

    Hill, I.R. and Stevens, J.E. Pirimicarb : Losses of Radioactivity
                        From 14C-Pirimicarb Treated Soils, During Air
                        Drying. ICI Plant Protection Ltd. Report No.
                        TMJ1143A (Unpublished).

    Hodge, M.C.E., Pirimicarb (PP062): Teratological Studies in
    1974                the Rabbit. Unpublished report from ICI Central
                        Toxicology Laboratory, submitted to the World
                        Health Organization by ICI Ltd.

    Hughes, H.E. and Leahey, J.P. Pirimicarb : Uptake of Pirimicarb And
    1974                Its Metabolites From Soil By Rotational Crops. ICI
                        Plant Protection Ltd. Report No. AR2553A
                        (Unpublished).

    ICI Plant Protection Ltd. Residue Analytical Method No. 15 for
    1972                The Determination Of Residues Of Pirimicarb And
                        Its Two Major Metabolites In Crops
                        (Gas-chromatographic Method) (Unpublished).

    ICI Plant Protection Ltd. Provisional Analytical Method No. 306/A For
                        The Determination Of Pirimicarb Residues In Fruits 
                        Vegetables And Grain (Unpublished).

    Jackson, J.A., Chart, I.S., and Sanderson, J.H., A Pirimicarb -
    1974                Induced Haemolytic Anemia in Dogs. Report of a
                        Special Study. Unpublished report from ICI Central
                        Toxicology Laboratory, submitted to the World
                        Health Organization by ICI Ltd.

    Leahey, J.P. and Benwell, M. Pirimicarb : Photodegradation On A
    1974                Soil Surface. ICI Plant Protection Ltd. Report No.
                        AR25504 (Unpublished).

    Leahey, J.P. and Benwell, M. Pirimicarb ; Uptake From Soil And 
                        Metabolism In Lettuce And Carrots, ICI Plant
                        Protection Division Report No. TMJ1331A
                        (Unpublished).

    Lefevre, V.K. and Parkinson, G.R., Pirimicarb (PPO62;
    1974                2-dimethylamino-5, 6-Dimethylpyrimidin-4-yl
                        Dimethylcarbamate): Acute Oral Toxicities of Plant
                        and Mammalian Metabolites. Unpublished report from
                        ICI Central Toxicology Laboratory, submitted to
                        the World Health Organization by ICI Ltd.

    Lincoln, B.A. and Hemingway, R.J. Pirimicarb : Fate In Water. ICI
    1974                Plant Protection Ltd. Report No. TMJ1116A
                        (Unpublished).

    Litchfield, M.H., The Measurement of Blood Cholinesterase Activity
    1968                in Animals Dosed with 4,5
                        Dimethyl-2-dimethylamino-6-pyrimidinyl Dimethyl
                        Carbamate (PP062): Unpublished report from ICI
                        Central Toxicology Laboratory, submitted to the
                        World Health Organization by ICI Ltd.

    Manley, C.A.        Pyrimidine Insecticides : The Fate of Pirimicarb
    1969                On Surfaces And Within The Plant ICI Plant
                        Protection Ltd. Report No. AR2109A (Unpublished),
                        18-19 and Figure 14.

    Manley, C. A.       Residue Summary : Pirimicarb In Crops. ICI
    1972                Plant Protection Ltd. Report No. TMJ585/2
                        (Unpublished).

    Manley, C.A., Hill, I.R., Harper, P. Black L. and Brooks J.R.
    1972                Pirimicarb : Fate In Soil. ICI Plant Protection
                        Ltd. Report No. TMJ788AR (Unpublished).

    Main, A.R.          Personal communication.
    1976

    McGregor, D.B.,     Dominant Lethal Study in Mice of ICI PP062.
    1974                Unpublished report from ICI Central Toxicology
                        Laboratory, submitted to the World Health
                        Organization by ICI Ltd.

    Palmer, S. and Samuels, D.M., Pirimicarb: 80 Week Carcinogenic
    1974                Study in Mice. Unpublished report from ICI Central
                        Toxicology Laboratory, submitted to the World
                        Health Organization by ICI Ltd.

    Parkinson, G.R., Pirimicarb (PP062): Irritation Studies of Technical
    1972a               and Formulated Material on Normal and Wounded
                        Rabbit Skin. Unpublished report from ICI Central
                        Toxicology Laboratory, submitted to the World
                        Health Organization by ICI Ltd.

    Parkinson, G.R., Pirimicarb (PP062): Acute Oral Toxicity Following
    1972b               Storage at 37C for Three and Six Months.
                        Unpublished report from ICI Central Toxicology
                        Laboratory, submitted to the World Health
                        Organization by ICI Ltd.

    Parkinson, C.R., Pirimicarb Metabolites (R.31680 and R.35140):
    1974a               Acute Oral Toxicity. Unpublished report from ICI
                        Central Toxicology Laboratory, submitted to the
                        World Health Organization by ICI Ltd.

    Parkinson, G.R., Pirimicarb Impurity (R.42488): Acute Oral
    1974b               Toxicity. Unpublished report from ICI Central
                        Toxicology Laboratory, submitted to the World
                        Health Organization by ICI Ltd.

    Parkinson, G.R., Pirimicarb: Skin Sensitization. Unpublished report
     1974c              from ICI Central Toxicology Laboratory, submitted
                        to the World Health Organization by ICI Ltd.

    Parkinson, G.R., Oral Toxicities of Three Guanidine Compounds.
    1975a               Unpublished report from ICI Central Toxicology
                        Laboratory, submitted to the World Health
                        Organization by ICI Ltd.

    Parkinson, G.R., Pirimicarb Impurity (R.32444): Acute Oral
    1975b               Toxicity. Unpublished report from ICI Central
                        Toxicology Laboratory, submitted to the World
                        Health Organization by ICI Ltd.

    Parkinson, G.R., Pirimicarb Impurity (R.33160) : Acute Oral
    1975c               Toxicity. Unpublished report from ICI Central
                        Toxicology Laboratory, submitted to the World
                        Health Organization by ICI Ltd.

    Parkinson, G.R., Pirimicarb: Potentiation Studies With
    1975d               Azinphos-methyl and Carbaryl. Unpublished report
                        from ICI Central Toxicology Laboratory, submitted
                        to the World Health Organization by ICI Ltd.

    Riley, R.A. Pirimicarb (PP062): "Pirimor" Smoke Generators:
    1972a               Acute Inhalation Studies. Unpublished report from
                        ICI Central Toxicology Laboratories submitted to
                        the World Health Organization.

    Riley, R.A., Pirimicarb (PP062): `Pirimor' Smoke Generators.
    1972b               Subacute Inhalation Studies. Unpublished report
                        from ICI Central Toxicology Laboratory, submitted
                        to the World Health Organization by ICI Ltd.

    Riley, R.A., Pirimicarb (PP062): Acute Inhalation Toxicity of
    1972c               `Pirimor' 50% Dispersible Powder. Unpublished
                        report from ICI Central Toxicology Laboratory,
                        submitted to the World Health Organization by ICI
                        Ltd.

    Riley, R.A., Pirimicarb (PP062) Acute Inhalation Toxicity.
    1973                Unpublished report from ICI Central Toxicology
                        Laboratory, submitted to the World Health
                        Organization by ICI Ltd.

    Riley, D., Coutts, J., Stevens, J.E. and Newby, S.E. Pirimicarb :
    1974                Leaching in Soil ICI Plant Protection Ltd. Report
                        No. AR2556A (Unpublished).

    Samuels, D.M., Hodge, M.G.E. and Palmer, S.M., Pirimicarb - Three
    1975                Two Year Feeding Studies to Assess, Carcinogenic
                        Potential. Unpublished report from ICI Central
                        Toxicology laboratory, submitted to the World
                        Health Organization by ICI Ltd.

    Teal, G. and Skidmore, M.W. Pirimicarb Investigation Of The Bound
    1976                Residues On Lettuce. ICI Plant Protection Division
                        Report No. TMJ1323A (Unpublished).

    Zweig, G. Analytical Methods For Pesticides, And Plant Growth
    1975                Regulators. Academic Press, VII:399.
    


    See Also:
       Toxicological Abbreviations
       Pirimicarb (Pesticide residues in food: 1978 evaluations)
       Pirimicarb (Pesticide residues in food: 1979 evaluations)
       Pirimicarb (Pesticide residues in food: 1981 evaluations)
       Pirimicarb (Pesticide residues in food: 1982 evaluations)