IPCS INCHEM Home


    PIRIMIPHOS-METHYL       JMPR 1974

    IDENTITY

    Chemical Name

         O-(2-diethylamino-6-methylpyrimidin-4-yl) O,O-dimethyl
         phosphorothioate.

    Synonyms

         PP 511, 'Actellic'(R).

    Structural Formula

    CHEMICAL STRUCTURE 12 


    Other Information on Identity and Properties

         Pirimiphos-methyl is a pale straw coloured liquid. It melts at
    15-18C and decomposes above 100C. It has a vapour pressure of
    approximately 1  10-4 Torr at 30C and a density of 1.157 g/ml at
    20C.

         Pirimiphos-methyl is stable for up to six months at room
    temperature. It is hydrolysed by strong acid or alkali.

         Pirimiphos-methyl is miscible with most organic solvents. Its
    solubility in water is approximately 5 mg/l at 30C.

         Formulated products include emulsifiable concentrates (8%, 25%
    and 50% a.i.), dusts (2% a.i.) and formulations for ultra-low volume
    application (10% a.i. and 50% a.i.). A diluent-free formulation and a
    smoke generator formulation are under development.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, distribution and excretion

         When 0.6 mg/kg of 2-14C-ring-labelled pirimiphos-methyl was
    given to adult male rats, either orally or by intraperitoneal
    injection, 73 to 81% of the dose was excreted in the urine during the
    first 24 hours. This indicates rapid absorption. At the end of 120
    hours after oral dosing, the entire dose could be accounted for by
    excretion of radioactive products in the urine (86% of dose) or faeces
    (15.2% of dose). Similar results were obtained after intraperitoneal
    injection although the excretion was more rapid after oral
    administration.

         Two male beagle dogs given 17-18 mg/kg orally also excreted most
    of the dose in the urine during the first 24 to 48 hours.
    Chromatographic and autoradiographic studies of the urine of dosed
    dogs and rats revealed extensive metabolism by the presence of 9
    radioactive chromatogram spots (Bratt and Dudley, 1970). The
    concentration of label in the abdominal fat of female rats given four
    daily doses of 5 mg/kg of 14C-pirimiphos-methyl revealed that the
    metabolites were stored to some extent in fat: 0.46, 0.69, 1.87 and
    1.00 ppm of pirimiphos-methyl equivalents in fat after 1, 2, 3 and 4
    doses, respectively (Bratt and Jones, 1973).

         In a lactating goat, 91% of the label of a single dose of 0.12
    mg/kg of 2-14C ring-labelled pirimiphos-methyl was excreted (87% in
    urine and 4% in faeces) within 8 days. The milk contained only 0.41%
    of the label, primarily during the first 24 hours. The maximum residue
    in milk was 0.026 ppm pirimiphos-methyl equivalents, and the parent
    insecticide accounted for only 0.003 ppm (Bowker et al., 1973).

         Bullock et al. (1974a) found that the pattern of excretion of
    2-14C labelled pirimiphos-methyl in the cow was similar to that in
    the goat. The label from a single dose of 0.5 mg/kg was quantitatively
    recovered in the urine (85%) and faeces (14%) during the following 7
    days. During the first 3 days, 0.35% of the label was secreted in the
    milk. The milk contained 0.04 ppm of pirimiphos-methyl equivalents of
    which less than 2% was unchanged pirimiphos-methyl and
    phosphorus-containing metabolites. Hydroxypyrimidine hydrolysis
    products or their conjugates constituted the major part of the residue
    in milk.

         Hens given a single oral dose of 14C-pirimiphos-methyl excreted
    more than 70% of the label within 24 hours. When fed for 28 days in
    the diet, at a level of 4 ppm, pirimiphos-methyl itself never exceeded
    0.01 ppm in yolks and whites of eggs although the total concentration
    of metabolites reached equilibrium levels of about 0.028 ppm, mostly
    as water soluble metabolites. Increasing the dietary concentration to
    32 ppm for a 7-day feeding period resulted in residues of 0.007 and
    0.012 ppm of pirimiphos-methyl in the whites and yolks of eggs. In
    muscle, 0.31 ppm and 0.16 ppm of the label was present in hens fed 32
    and 4 ppm respectively; however, the parent insecticide or its oxygen
    analogue was not detected (Green et al., 1973). See also the section
    "Fate of residues in animals."

    Biotransformation

         The metabolism of pirimiphos-methyl in rats (100 mg/kg, p.o.) and
    in one dog (20 mg/kg, p.o.) was studied by thin-layer chromatographic
    separation of urinary metabolites. Twelve metabolites were detected.
    None of these possessed anticholinesterase activity. No parent
    pirimiphos-methyl was detected in the urine. Five of the twelve
    metabolites were identified by comparison with authentic samples. In
    both rats and does, 2-ethylamino-4-hydroxy-6-methylpyrimidine was the
    major urinary metabolite (30% of dose). The next most predominant
    metabolite in the dog was
    4-O(2-diethylamino-6-methylpyrimidinyl)--D-glucosiduronic acid (11%
    of dose), and in the rat an unidentified phosphorus-containing
    product thought to be a dealkylated derivative of either
    pirimiphos-methyl or its oxygen analogue (12% of dose). Other
    identified urinary metabolites included
    2-amino-4-hydroxy-6-methylpyrimidine,
    2-[N-ethyl-N-(2-hydroxyethyl) amino]-4-hydroxy-6-methylpyrimidine,
    and 2-diethylamino-4-hydroxy-6-methylpyrimidine (Bratt and Jones,
    1973).

         These studies indicate that the P-O-C bond of pirimiphos-methyl
    is extensively cleaved and that N-dealkylation and/or conjugation are
    further steps in the metabolism of the pyrimidine leaving group.
    Although the oxygen analogue of pirimiphos-methyl was not detected as
    a urinary metabolite, the fact that cholinesterase inhibition occurs
    in vivo suggests that the oxygen analogue is also formed and may be an
    intermediate step leading to the identified urinary products.

    Effect on enzymes and other biochemical parameters

         The only biochemical effects consistently noted in acute or
    chronic toxicity tests was inhibition of cholinesterase. A group of 36
    male rats were given single oral doses of 1450 mg/kg of
    pirimiphos-methyl. Symptoms were noted and they were sacrificed at
    intervals up to 4 days after dosing for measurements of brain, plasma,
    and red-cell cholinesterase activity. Few signs were noted at 6 hours
    after dosing when cholinesterase inhibition was 0, 35 and 51%
    respectively for brain, red cells and plasma. Clear signs of poisoning
    only became apparent by 24 hours when brain was inhibited by 46% and

    red cell and plasma by 70 and 80% respectively. Recovery of
    cholinesterase activity began to be apparent by 72 hours. Plasma
    cholinesterase activity had completely recovered by 96 hours, but red
    cell and brain remained 47 and 30% inhibited, respectively, at this
    time (Clark, 1970). From these studies it appears that inhibition of
    brain cholinesterase by 40% or more results in obvious signs of
    toxicity.

    TOXICOLOGICAL STUDIES

    Special studies on potentiation

         Tests for potentiation of the acute oral toxicity of combinations
    of pirimiphos-methyl and gamma-BHC were conducted by simultaneous
    administration of one-half LD50 doses of the two compounds to ten
    fasted female rats. Three of the ten animals died during a 14-day
    observation period, suggesting no potentiation. Combinations of
    one-half LD50 doses of pirimiphos-methyl and dichlorovos were tested
    in the same manner and no mortality resulted in ten test rats. Under
    these limited test conditions, there was no evidence of potentiation
    of pirimiphos-methyl with 2 other insecticides that are likely to be
    used in conjunction with it (Parkinson, 1972 a,b).

    Special studies on reproduction

    Rat

         The effect of pirimiphos-methyl on the growth and reproductive
    performance of the rat was assessed by feeding groups of 24 female and
    12 male rats dietary concentrations of 0, 20 and 200 ppm of the
    compound throughout three generations. However, dietary analysis of
    the F0 generation nominally given 20 ppm revealed concentrations of
    pirimiphos-methyl far below the intended levels and so animals treated
    at 20 ppm were reared to produce a fourth (F4B) generation.

         There were no effects among parent animals attributable to the
    feeding of the compound. Mating performance and pregnancy rates were
    reduced at 200 ppm for F1B and F2B generations. At 20 ppm there was an
    effect at 2nd mating of the F1B generation and at both matings of the
    F2B generation. When expressed as an average over all generations,
    there was a dosage related decrease in pregnancy rate. Litter
    parameters, as assessed by total litter loss, litter size, litter and
    mean pup weights, pup mortality and the incidence of abnormalities
    showed no consistent dosage-related trends. Examination of the
    ultimate generation (F3B for 200 ppm dosage group, and F4B for 20 ppm)
    by organ weight analysis and skeletal staining of 10 males and 10
    females from all groups, and by microscopic examination of 10 male and
    10 female pups from controls and from the 200 ppm group, showed no
    difference that could be conclusively related to treatment (Palmer and
    James, 1972).

         The testes of the F1B and F2B male rats were examined
    histopathologically in an attempt to find an explanation for their
    reduced mating performance. However in the testes examined, from rats
    of the control and both treatment groups, the degree of activity and
    maturity of the process of spermatogenesis were comparable (Palmer and
    Cherry, 1972).

    Special studies on skin irritation, sensitization, and effects in
    the eye

         Application of a 50% solution of pirimiphos-methyl in olive oil
    to ears of 6 guinea pigs did not produce erythema when challenge
    applications of 10%, 5% and 1% were applied to shaved skin of their
    flanks 4 days later. This indicated a lack of sensitizing potential.

         Undiluted pirimiphos-methyl was applied to the clipped backs of 4
    female rats and the site of application covered for 24 hours with an
    impermeable dressing. No signs of primary irritation were noted after
    a single such application nor after a second or third application at
    alternate 24-hour intervals.

         One drop of undiluted pirimiphos-methyl was placed in the left
    conjunctival sac of the eyes of 4 albino rabbits. No signs of
    irritation or myosis was noted on frequent observation over the next 7
    days (Clark, 1970).

    Special studies on teratogenicity

    Rat

         Three groups of 18 to 21 virgin female, Alderley Park specific
    pathogen-free rats were mated and fed diets containing 0, 10 or 200
    ppm of pirimiphos-methyl from day 1 to day 20 of pregnancy. On day 20,
    the females were killed and foetuses immediately removed by Caesarean
    section. The uterus was examined for resorptions, foetuses were
    examined for viability and weighed. One third of the foetuses were
    eviscerated and stained with alizarin red for examination of skeletal
    defects. Viscera were fixed and examined for histopathology. Maternal
    rats showed no toxic signs. It was presumed that 200 ppm produced
    cholinesterase inhibition but this was not measured. The only
    significant difference between pirimiphos-methyl and control litters
    was a reduction in mean foetal weight; however, this may have been
    because there were more foetuses per litter in the experimental
    groups. No increased incidence of skeletal abnormalities were observed
    in foetuses from the pirimiphos-methyl treated groups. The only
    significant soft-tissue abnormality was increased hydronephrosis (7,
    17 and 22 foetuses, representing incidence of 6, 17 and 16%) in the
    foetuses examined from dams that received 0, 10 and 200 ppm in the
    diet respectively. The investigators stated that these incidences of
    hydronephrosis were within normal limits for Alderley Park rats and
    they conclude that there was no evidence to suggest teratogenic action
    for pirimiphos-methyl (Hodge and Moore, 1972).

    Rabbit

         Two groups of 16 to 17 pregnant rabbits were given gelatin
    capsules containing pirimiphos-methyl dissolved in corn oil at doses
    of 1 mg/kg and 16 mg/kg daily throughout pregnancy. A group of 16
    controls was given capsules containing corn oil only. Twenty-nine days
    after mating all the foetuses were delivered by Caesarean section. The
    uterus was examined for resorptions and the foetuses for viability.
    One half of the foetuses from each litter were stained with Alizarin
    Red for skeletal examination and the remaining half were fixed in
    Bouin's solution and dissected for soft-tissue examination. Does were
    examined for gross and histological pathology and for blood
    cholinesterase inhibition.

         Three of the experimental does died during the gestational
    period, two receiving 1 mg/kg/day and one receiving 16 mg/kg/day.
    These deaths appeared to be due to causes unrelated to
    pirimiphos-methyl. The does gained weight normally, but at the end of
    4 weeks, the group average of RBC cholinesterase was 19% and 60% less
    than controls in the 1 and 16 mg/kg dosage groups respectively. Data
    on observations of foetuses were reported for 10, 10 and 11 litters
    where implantations occurred in the 0, 1 and 16 mg/kg dosage groups
    respectively. One grossly abnormal foetus was observed in a litter
    from one doe receiving 16 mg/kg/day. No abnormalities were seen in the
    remaining ten foetuses. There was no increase in resorptions in
    experimental groups. Although the foetal weights of the 1 and 16 mg/kg
    dosage groups were less than controls, there were more foetuses/litter
    in these groups so that mean litter weights among the three groups did
    not differ. The ratios of male/female foetuses were 1.0, 1.25 and 1.39
    for the 0, 1 mg/kg and 16 mg/kg dosage groups. The authors state that
    these are "within normal control limits." The only statistically
    significant difference in the occurrence of abnormalities was a higher
    incidence of 14 caudal vertebrae in the pirimiphos-methyl groups,
    which the investigators state were isolated findings. This study
    indicates no teratogenic action of pirimiphos-methyl in rabbits at
    dosages which produce considerable inhibition of blood cholinesterase
    in maternal animals (Gore et al., 1974a).

    Acute toxicity

         Pirimiphos-methyl, 90-94% purity, was administered to animals
    undiluted or, for small doses, in propylene glycol. Single-dose LD50
    values or estimates of LD50's by various routes are shown in Table
    1. In the single-dose dermal test the skin of rats was washed with
    soap and water 24 hours following application. All animals were
    observed for 14 days or longer.


        TABLE 1.  Acute toxicity of pirimiphos-methyl

                                                                             

    Animal         Sex       Route        mg/kg bw                   References
                                                                             

    Rat            F         Oral         2050 (1840-2260)           Clark, 1970

    Rat            F         ip           approx. or equal to 800    Clark, 1970

    Rat            M         ip           approx. or equal to 800    Clark, 1970

    Rat            F         dermal       >2000                      Clark, 1970

    Mouse          M         Oral         1180 (1030-1360)           Clark, 1970

    Guinea Pig     F         Oral         1000-2000                  Clark, 1970

    Rabbit         M         Oral         1150-2300                  Clark, 1970

    Cat            F         Oral         575-1150                   Clark, 1970

    Dog            M         Oral         >1500                      Gage, 1972

    Hen            F         Oral         30-60                      Clark, 1970

    Quail          F         Oral         approx. or equal to 140    Gage, 1971a

    Green Finch              Oral         200-400                    Gage, 1972
                                                                             

    Figures in parentheses are 95% confidence limits.
    
         The toxic signs exhibited after single doses were typical of
    cholinesterase inhibition. In female rats given single oral doses,
    only mild to moderate signs were noted at 12 hours after dosing, but
    marked signs consisting of incontinence, salivation,
    chromolacrymation, fibrillations, fasciculations and prostration were
    present at 24 hours and persisted up to 11 days. No additional toxic
    signs were noted during a 12 week observation period. Six surviving
    hens of 8 dosed with 31 mg/kg were observed for 28 days after dosing
    and no abnormal gait or other neurological signs were observed after
    the initial acute toxic effects had subsided (within 7 days) (Clark,
    1970).

         2-Diethylamino-4-hydroxy-6-methylpyrimidine is a plant metabolite
    of pirimiphos-methyl. It is also formed metabolically in rats and
    dogs. Single-dose, range-finding acute toxicity tests (3 rats per
    dose) indicated the acute oral LD50 in rats to be between 800 and
    1600 mg/kg (Gage, 1971b). This is of the same order of acute toxicity
    as the parent insecticide, but no description of toxic signs was
    provided. Groups of 10 male and 10 female rats were given 100 and 400
    mg/kg of the metabolite, orally, five days a week for two weeks. No
    toxic signs, altered body weights or gross or histopathology were
    noted. There was an approximate 25% increase in reticulocytes and a
    reduction in total leucocytes which could be accounted for by a 30 to
    40% reduction in lymphocytes, particularly in females, which the
    investigators attribute to a "stress response" (Gage, 1971b).

         Atropine sulphate and a mixture of atropine plus
    pyridine-2-aldoxime methane-sulphonate partially counteracted the
    acute oral toxicity of pirimiphos-ethyl in female rats when the
    antidotes were given at intervals at which toxic signs appeared. The
    combination of antidotes was more effective than atropine alone
    (Clark, 1970).

    Short-term studies

    Rat (feeding)

         Repeated daily oral dosing of 10 male and 10 female rats with 200
    mg/kg of pirimiphos-methyl, 5 days a week for 2 weeks produced mild
    signs of poisoning which were first noted after the 7th dose. The
    signs did not progress in intensity with continued dosing; however,
    body weight gain over this period was less than half that of controls.
    An approximate 9% reduction of haemoglobin levels accompanied by
    reticulocytosis was observed in the treated rats. Gross or
    histopathology was not striking but slight to moderate haemopoesis of
    the spleen was observed. When the experiment was repeated at a dose of
    400 mg/kg, signs of poisoning appeared after 2 doses and increased in
    severity as the experiment progressed. Males were more affected than
    females and deaths occurred from the 4th day in males and from the 6th
    in females. Cumulative mortality after 10 doses was 9 of 10 male rats
    and 3 of 10 females (Clark, 1970).

         Four groups of 25 male and 25 female Alderley Park specific
    pathogen-free adult rats were maintained for 90 days on diets
    containing 0, 8, 80 and 360 ppm of pirimiphos-methyl. Haematology and
    plasma and erythrocyte cholinesterase activities were examined on
    individual samples from five male and five female rats in each group
    before, during and at the end of the feeding period. Brain
    cholinesterase activities and organ:body weight ratios were calculated
    for five males and five females in each group at the end of the
    feeding period. Gross and histopathological examinations were
    conducted. Body weight gain in the female rats fed diets containing 80
    and 360 ppm pirimiphos-methyl averaged 18% and 21% less than controls.

    This was apparently due to reduced food utilization as food
    consumption did not differ significantly from controls. Plasma
    cholinesterase was inhibited 65% in males and 80% in females fed 360
    ppm and 40% in males and 60% in females fed 80 ppm, but no inhibition
    was detected at 8 ppm. Erythrocyte cholinesterase was inhibited 20% in
    males and 50% in females only at the highest dietary level. Both
    plasma and erythrocyte cholinesterase returned to normal within one
    week after cessation of dosage. Terminal measurements of brain
    cholinesterase activity revealed inhibition in rats fed 80 and 360 ppm
    with females affected most (about 40% inhibition in the 360 ppm
    group). There was no inhibition in the 8 ppm group. Brain
    cholinesterase was still inhibited at 4 weeks after cessation of
    feeding pirimiphos-methyl. Haematological examinations revealed no
    significant effects on haemoglobin concentration, packed cell volumes,
    mean corpuscular diameter, white cell or platelet counts or clotting
    function. There were no increases in gross or histopathological
    lesions in the pirimiphos-methyl-fed rats over controls (Clapp and
    Conning, 1970).

    Rat (inhalation)

         Four male and 4 female rats exposed by inhalation to a nominal
    vapour-aerosol concentration of 3.5 ppm, 6 hours/day, 5 days/week for
    3 weeks did not result in toxic signs nor reduction in body weight nor
    decreased cholinesterase activities. An increase in alveolar
    macrophages and slight lymphoid hyperplasia was noted (Clark, 1970).

    Rabbit (dermal)

         Daily application of 1000 mg/kg of pirimiphos-methyl to the
    dorsal skin of 6 rabbits for 14 days (application site was washed 1
    hour before each successive dose) resulted in fibrillations after 7 to
    12 applications. Approximately 15% loss of body weight occurred and
    one rabbit died after 14 applications (Clerk, 1970).

    Avian species

         Mallard ducklings and bobwhite quail chicks were fed
    pirimiphos-methyl in their diets for five days and observed for an
    additional 3 days. LC50 values were 633 and 207 ppm for ducklings and
    quail chicks respectively (Fink, 1974a,b). Pirimiphos-methyl in the
    diet of broiler chicks at levels from 4 to 48 ppm did not reduce feed
    efficiencies or growth rate, except for a temporary period at the
    beginning of the study (Graham and Jenkins, 1974). When 0, 4, 12 and
    40 ppm were fed in the diet of laying hens for 28 days there was no
    adverse effect on the hens. Egg production and egg quality were
    considered normal although there was a small, dose-related increase in
    the number of "small" eggs. There was some reduction in the number of
    chicks hatched from eggs from the pirimiphos-methyl fed hens which was
    not significant, although there were significantly greater numbers of
    chicks dead in shell at the 12 and 40 ppm dietary levels (Ross et al.,
    1974).

    Dog

         Groups of four male and four female beagle dogs were dosed orally
    seven days a week for 13 weeks by administration of gelatin capsules
    containing corn oil solutions of pirimiphos-methyl. The dosage rates
    were 0, 2, 10 and 25 mg/kg given as single daily doses about 1 hour
    after feeding the daily ration of complete dry diet. Clinical signs,
    body weight, food and water consumption, electrocardiograms and
    ophthalmic examinations were included among the observations.
    Laboratory investigations included plasma and red cell cholinesterase
    haematology, urinalysis, serum alkaline phosphate (SAP), serum
    glutamic-pyruvic transaminase (SGPT) plasma urea and blood glucose. At
    the end of the dosing period, two dogs of each sex in each dosage
    group were sacrificed and the remaining dogs observed for an
    additional four weeks before sacrifice. Gross and histopathological
    examinations and brain cholinesterase assays were performed. There
    were no deaths. Clinical symptoms were minimal with occasional
    episodes of vomiting and watery stools. Body weight gain was
    significantly reduced in both males and females given 25 mg/kg/day and
    in females given 10 mg/kg/day. The rate of weight gain also tended to
    be less for females given 2 mg/kg/day but this was of borderline
    significance. At the highest dosage level (25 mg/kg) only, there was
    reduced food consumption and a slower heart rate. Plasma and
    erythrocyte cholinesterase activities were significantly depressed
    (20% or more) at all three dosage levels. Plasma cholinesterase
    rapidly returned to normal upon cessation of dosing but reversal of
    red cell inhibition was delayed. At the lowest dosage level,
    significant inhibition of red cell cholinesterase was only observed
    during the latter weeks of the dosing period. Terminal brain
    cholinesterase assays revealed no inhibition in any of the dosage
    groups. Two dogs receiving 25 mg/kg showed very high SGPT and SAP
    levels after three months dosing, while a third showed a less marked
    SGPT increase. Post-mortem examination showed evidence of liver damage
    in these animals. All other biochemical findings were within normal
    limits. Histopathological examination post-mortem showed some bile
    duct proliferation in one dog receiving 10 mg/kg and bile duct
    proliferation together with portal cirrhosis in one dog receiving 25
    mg/kg. After four weeks observation following the cessation of dosing,
    two other dogs receiving 25 mg/kg showed minimal degrees of bile duct
    proliferation. No other histopathological findings or other consistent
    effects were noted (Noel et al., 1970).

         Four groups each consisting of 4 male and 4 female beagle dogs
    were orally dosed once daily, seven days/week, for two years with
    gelatin capsules containing corn oil solutions of pirimiphos-methyl at
    dosage rates of 0, 0.5, 2 or 10 mg/kg/day. Brain cholinesterase
    activities at the end of the dosing period were 81, 78 and 44% of
    control in the 0.5, 2 and 10 mg/kg groups respectively. The mean
    activities in the 0.5 and 2 mg/kg groups were significantly less than
    values for controls at the 1% level of probability, and in the 10
    mg/kg group, brain cholinesterase depression was significant at the
    0.1% level. Red cell cholinesterase was significantly inhibited with

    respect to pre-dosing values, in both the 2 and 10 mg/kg groups from
    the 8th week of dosing, but only occasionally inhibited in the 0.5
    mg/kg group. Plasma cholinesterase was inhibited significantly
    (30-50%) in all 3 groups from the 16th week of dosing. There was also
    a decline in plasma cholinesterase activity in controls during the
    experimental period. However, even with correction for this, 20-25%
    depression was noted in the 0.5 mg/kg group, with only slightly
    greater depressions with the higher dosages. It appears that plasma
    cholinesterase inhibition did not discriminate well among the 3
    experimental groups. One female dog in the 10 mg/kg group died after
    the 400th day after showing few clinical signs. Clinical signs
    consisting of loose stools were observed, in a dose-related frequency
    in excess of controls, only in the 2 highest dosage groups. Vomiting
    was infrequently noted. Dogs in the 10 mg/kg group showed some loss of
    appetite and a reduced rate of weight gain. The 0.5 mg/kg/day dosage
    rate appears to be a no effect level for clinical signs. No
    abnormalities of the eyes, examined by ophthalmoscopy nor in
    electrocardiogram records were observed. No appreciable or consistent
    effects were noted in any of the dosage groups with respect to
    haematology, standard urinalysis values or blood urea, blood glucose,
    serum protein, SAP, SGPT, NA+ or K+ values. No consistent or
    dose-related gross or histopathological changes were observed in post
    mortem studies. However, a statistically significant increase in liver
    weights and liver body weight ratios was seen in the group given 10
    mg/kg/day (Rivett et al., 1973).

    Long-term studies

    Rat

         Four groups of 48 male and 48 female rats were fed
    pyrimiphos-methyl in their diet at levels of 0, 10, 50 and 300 ppm for
    two years. Twenty-four additional animals of each sex were included in
    each dosage group, and were killed at intervals up to one year to
    provide interim data on brain cholinesterase activity and clotting
    function. Eight animals of each sex in each of the dosage groups fed
    for two years were continued on a control diet for 4 to 8 weeks beyond
    the two year feeding period to allow for observation of recovery from
    any treatment-induced effects.

         Rats fed 300 ppm pirimiphos-methyl showed marked plasma
    cholinesterase inhibition (50-80%) and some inhibition of erythrocyte
    and brain cholinesterase activity (30-40%). The only other adverse
    effect noted at this dosage rate was a slight anaemia in female rats.
    Only female rat plasma cholinesterase was consistently inhibited
    (50-65%) at the 50 ppm dietary level. Recovery from inhibited
    cholinesterase, when it occurred, was usually complete by the end of
    an 8-week period on the control diet. Slight (generally <25%)
    transient depression of plasma cholinesterase activity in female rats
    fed 10 ppm was observed. Erythrocyte and brain cholinesterases were
    not depressed at this dietary level. Although cumulative mortality was
    greater than for controls in male rats fed 300 ppm at 54, 60, 66 and

    72 weeks of feeding, thereafter the cumulative mortalities of all
    groups were approximately equal. Body weight gains, weights of major
    organs and incidence of gross or microscopic pathology (including
    tumors), in a comprehensive list of tissues, did not differ between
    the control and experimental groups.

         The results of this study indicate that 10 ppm in the diet of
    rats is an experimental no-adverse-effect level (Gore et al., 1974b).

    OBSERVATIONS IN MAN

         A dose of 0.25 mg/kg/day of pirimiphos-methyl (97.8% purity) was
    taken orally for 28 days by five healthy male volunteers (25-45 years
    of age; 59.7-73 kg body-weight). Blood samples were taken before
    dosing began, on days 1, 3, 7, 14, 21 and 28 during administration,
    and 7 and 14 days after cessation of dosing. Only one subject had a
    plasma cholinesterase depression (on day 28) which exceeded 20%
    (21.5%). Otherwise variations, both above and below pre-dosing values
    were within 12%. Four of the five subjects had red cell cholinesterase
    values that were slightly below either of the pre-exposure values
    during the last 2 weeks of the study. However, the group means for
    each time interval did not differ significantly, and the variations
    noted were within the range of variations found by others for normal
    untreated subjects (Chart et al., 1974).

    COMMENTS

         Pirimiphos-methyl is rapidly absorbed from the gastrointestinal
    tract, metabolised and quantitatively excreted in the urine and faeces
    of several mammalian species.

         The moderate acute toxicity of pirimiphos-methyl is due to its
    inhibition of cholinesterase. After single toxic doses the onset of
    inhibition of cholinesterase and appearance of toxic signs were
    delayed for several hours and persisted for several days. Furthermore,
    subacute and 2-year feeding studies in rats and dogs showed that
    cholinesterase inhibition did not reach equilibrium for several weeks.
    A two-year feeding study in rats provided a no-effect level based on
    cholinesterase inhibition. Pirimiphos-methyl was not teratogenic in
    rats and rabbits although hydronephrosis was noted. A decrease in
    pregnancy rates was noted in a 3-generation reproduction study,
    however cholinesterase activity was depressed at all dosages tested.
    Other parameters of reproduction were not affected. No
    compound-related histopathological effects were detected at dosage
    rates considerably above those that inhibited cholinesterase, except
    that in a 90-day study in dogs liver injury was observed in the
    absence of cholinesterase inhibition.

         In two-year studies in dogs, cholinesterase inhibition in brain
    and plasma was noted at 0.5 mg/kg/day and above. No organ pathology
    was observed in that study, however. Human volunteers who ingested
    0.25 mg/kg/day of pirimiphos-methyl for 28 days had only a slight
    reduction of plasma cholinesterase. Because of the slow decline in
    cholinesterase activity in 2-year studies in the rat, and in the dog,
    there is some question as to whether the experiments in volunteers
    were of sufficient duration to detect maximum effect at the dosage
    tested. Because of this, and because a no-effect level for brain
    cholinesterase inhibition in the two-year dog studies was not clearly
    established, the studies in rats provided the primary basis for
    estimating an ADI.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat: 10 ppm in the diet, equivalent to 0.5 mg/kg bw.

         Man: 0.25 mg/kg bw in 28 day period.

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.005 mg/kg bw

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         Pirimiphos-methyl is a fast-acting broad-spectrum
    organophosphorus insecticide with both contact and fumigant action. It
    shows activity against a wide spectrum of insect pests, including
    ants, aphids, beetles, caterpillars, cockroaches, fleas, flies, mites,
    mosquitoes, moths and thrips. It possesses only limited biological
    persistence on leaf surfaces but gives long lasting control of insect
    pests on inert surfaces such as wood, carpets, sacking and masonry. It
    retains its biological activity when applied to stored agricultural
    commodities including raw grain and nuts.

         Commercial uses of pirimiphos-methyl are now developing in a wide
    variety of outlets, including growing crops, public health and stored
    products. The most important potential use appears to be as a grain
    protectant and for use in the control of insect pests in stored
    products. Such uses will be authorised as soon as appropriate maximum
    residue limits have been recommended.

         When used for the control of stored product pests,
    pirimiphos-methyl is effective as a spray on structural surfaces and
    on the outside of bagged produce and as an admixture treatment. The
    recommended rates of application to bagged grain to control a complex
    of beetles, weevils, moths and mites are normally in the range 250-500
    mg/m2. For admixture with small grains the recommended rate of
    application is 4 mg/kg except where Rhizopertha dominica is present
    when a rate of 6 mg/kg is required.

         Since the widespread development of strains of stored product
    pests resistant to malathion (Pieterse et al., 1972; Waterhouse, 1973)
    there has been considerable interest in pirimiphos-methyl which has
    proved effective against all known strains of malathion-resistant
    stored product insects.

         Pirimiphos-methyl is regarded as more than a replacement for
    malathion. At recommended rates it is effective against a wider
    spectrum of insect pests, having an ability to destroy all forms other
    than eggs and to confer long-term protection. It is effective at lower
    rates of application and for much longer periods than is malathion.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    Pre-harvest Treatments

         The only information received by the Meeting on residues
    resulting from pre-harvest application was provided by Hungarian
    authorities and is summarised in Table 2.

    TABLE 2.  Residues resulting from pre-harvest applications of
              pirimiphos-methyl1

                                                                             

                                                       Interval
                                        Application    after          Residue
    Crop         Pest    Formulation    rate           treatment      mg/kg
                                                                             

    Tomato       aphid   cartridge      1/200 m3       1 day          0.15

                                                       2 days         0.06

                                                       5 days         0.01

    Tomato               50% EC         2 l/ha         1 day          0.11

                                                       2 days         0.24

                                                       5 days         0.1

    TABLE 2.  (Cont'd.)

                                                                             

                                                       Interval
                                        Application    after          Residue
    Crop         Pest    Formulation    rate           treatment      mg/kg
                                                                             

    Cucumber     aphid   10% EC         7.5 l/ha       16 hours       0.11

                                                       24 hours       0.06

                                                       48 hours       0.04

    Green
     pepper              10% EC         7.5 l/ha       16 hours       0.12

                                                       24 hours       0.06

                                                       48 hours       0.04
                                                                             

    1  Glasshouse experiments in 1974. The residue results are the average
        of 3 samples. The limit of the determination was 0.01 mg/kg.


    Post-harvest treatments

    Surface sprays

         Bullock (1973) has summarised the results of studies carried out
    during 1970-1972 to determine the persistence of pirimiphos-methyl on
    stored products. Trials were carried out in Colombia, Malaysia and the
    United Kingdom involving the following bagged small grains: barley,
    oats, rice in husk, milled rice, polished rice. In the period of 1-5
    months after spraying the outside of the bags at rates up to 1000
    mg/m2 the residues of pirimiphos-methyl in the whole grain taken from
    the bag were found normally to be below 0.5 mg/kg and in no case to
    have exceeded 1 mg/kg. The concentration was found to be highest in
    grain sampled from within 2.5  cm of the inside of the bag. These
    results are summarised in Table 3. No residues of the phosphorus
    containing compounds (II) and (III) (Figure 1) were detected (Limit of
    detection: 0.01 mg/kg in each case).

         In most experiments the level of residues found in the grain in
    the bags tended to rise during the first few weeks following
    application and then to remain relatively constant over an interval of
    three months. The level of residues in the grain was roughly
    proportional to the rate of application to the surface of the bags.
    FIGURE 2

    Admixture with small grain cereals

         Bullock (1973 and 1974) reports numerous trials undertaken in
    Australia, Argentina, Guyana, Malaysia, U.K. and the U.S.A. where
    pirimiphos-methyl was admixed with wheat, barley, maize, and rice in
    husk (residues were determined on the rice after milling). The results
    are summarised in Table 4. Mean initial residues of pirimiphos-methyl
    itself in the whole grains of wheat, barley and maize rarely exceeded
    the nominal treatment rate and were frequently in the range of 40-60%
    of the nominal dose. This appears to be a reflection of the method of
    application and suggests that some at least of the nominal dose is
    lost into the atmosphere during application. Higher percentage
    retention of the applied chemical was obtained by treating 5-10% of
    the grain with all the chemical rather than applying it to 50% or more
    of the grain stream entering the storage. Again no residues of the
    phosphorus-containing compounds (II) and (III) were detected.


    TABLE 3.  Residues of pirimiphos-methyl in whole grains
              after spraying bagged grains. (Bullock, 1973)

                                                                            

                                    Interval
                                    between         Range of
                     Application    application     residues
                     Rate           and sampling    found,
    Crop             mg/m2          months          mg/kg         Country
                                                                            

    Barley           400            0-3             0.05-0.33     UK

    Oats             400            2-3             0.07-0.19     UK

    Rice in husk     300            0-3             <0.01-0.08    Colombia

    Milled rice      500            0-5             0.02-0.28     Malaysia

    Treated when
    in husk          1000           0-5             0.01-0.70     Malaysia
                                                                            

    TABLE 4.  Residues of pirimiphos-methyl in whole grains
              after admixture. (Bullock, 1973, 1974)

                                                                            

                                    Interval
                      Nominal       between         Range of
                      admixture     admixture       residues
                      rate,         and sampling    found,
    Crop              mg/kg         (months)        mg/kg         Country
                                                                            

    Wheat             3             0-8             1.0-2.1       Australia

                      4             0-3             1.3-4.6       UK

                      5             1-3             1.7-4.7       USA

                      6             0-12            1.3-3.9       Argentina
                                    0-8             3.0-4.9       Australia

                      10            1-3             4.7-8.4       USA

    Barley            4             0-3             0.03-3.6      UK

                      8             0-3             0.26-4.4      UK

    Maize             5             1-3             2.1-6.9       USA

                      10            1-3             4.7-8.0       USA

    Milled rice       3             0-3             0.21-0.53     Guyana
    treated when
    in husk           4             0-5             0.12-0.26     Malaysia

                      5             0-4             0.16-0.59     Guyana

                      7.5           0-11            0.53-0.98     Guyana

                      8             0-5             0.21-0.85     Malaysia

                                                                            


    Wheat

         The stability of the deposit of pirimiphos-methyl on wheat grains
    is quite remarkable and from the work of Bullock the half life has
    been estimated to be of the order of 9 months. Degradation proceeds
    uniformly and slowly as indicated in the results from a typical trial
    carried out in Argentina on wheat with a moisture content ranging from
    11 to 13% (Table 5).


        TABLE 5.  Pirimiphos-methyl residues in wheat at intervals after admixture-Argentina.
              (Bullock, 1973)

                                                                                                             

    Nominal
    admixture
    rate
    mg/kg          1 Day     1 Month     2 Months    3 Months    4 Months    6 Months    9 Months    12 Months
                                                                                                             

    2              1.60      1.16        1.47        2.06        2.00        0.90        0.80

    3              1.61      1.53        1.30        1.34        1.13        1.96        1.03        0.80

    4              2.04      2.40        1.89        1.79        1.53        1.80        1.66        0.92

    5              2.26      2.79        2.06        2.00        1.93        2.00        1.73        1.31

    6              3.91      3.65        2.62        2.42        2.39        2.14        2.02        1.29

    7              3.90      3.71        3.12        3.06        2.43        2.30        2.20        1.35
                                                                                                             

    Moisture content: low (11-13%)
    

         Bengston et al. (1974) report the results of two extensive trials
    in Australia with five grain protectant insecticides applied to wheat
    having a mean moisture content of 10-12% and a mean temperature of
    29-32C. In these trials the target application rate was 6 mg/kg but
    based on the analyst's determination of the concentrate strength and
    the weight of grain treated (2000 tons per treatment) the calculated
    application rate was 5.5 mg/kg. Analysis by five collaborating
    laboratories showed the concentration of pirimiphos-methyl on samples
    taken 1 week after application to range from 5.5-6.4 mg/kg.
    Representative data summarised in Table 6 show relatively little
    change over a 26 week period notwithstanding the high temperature
    which prevailed throughout.

         Based on this work calculations have been made of the half-life
    of Pirimiphos-methyl deposits on wheat stored in concrete bins at
    30C. When using data from samples taken from within 10 cm of the
    surface and using the rate of disappearance during weeks 1-11, a
    half-life of 43 weeks is obtained. Based on data from weeks 11-26 the
    half-life was 104 weeks. Using data from samples taken 6 metres
    beneath the surface where the mean temperature exceeded 32C a
    half-life of 77 weeks is obtained whether the data from samples
    collected during weeks 1-11 or weeks 11-26 are used. The mean
    half-life from many data is 82 weeks. This compares with a half-life
    for malathion of 3-9 weeks under comparable conditions.

    Barley

         Bullock (1973 and 1974) reports numerous trials where barley was
    treated with pirimiphos-methyl in the United Kingdom by admixture of
    2% Pirimiphos-methyl dust or by the application of dilute emulsion
    designed to deposit from 2-8 mg/kg on the weight of grain.
    Unfortunately moisture and temperature conditions are not stated and
    extensive sampling and analysis has failed to recover more than 25-30%
    of the amount that was supposed to have been applied. Residue analyses
    however fail to show much decline in the level of residues over the
    first three months following spray application. The deposit seems to
    disappear more quickly when the application is made in a manner
    designed to fully cover all grains than when only a proportion of the
    grain receives the spray. Subject to some reservations about the
    residue data, the half-life on barley from these trials appears to be
    at least 30 weeks.

    TABLE 6a.  Pirimiphos-methyl residues in stored wheat from site M
               of two trials in Australia. Samples taken at various
               depths analysed by independent laboratories.
               (Bengston et al., 1974)
                                                                             

    Interval since    Sample                       Analyst
    treatment         depth, m.     A       B        C        D        Mean
                                                                             

    1 week            0.1           5.5     6.6      -        -        6.1
                      0.6           6.4     -        -        -        
                      1.5           4.9     5.8      -        -
                      6.0           5.6     5.6      -        -        5.6
                      Mean          5.3     6.0      -        -

    6 weeks           0.1           5.2     5.2      5.5      5.3      5.3
                      0.6           -       -        -        -        -
                      1.5           4.6     5.1      4.9      4.5      4.8
                      6.0           4.8     5.1      5.3      3.8      4.8
                      Mean          4.9     5.1      5.2      4.5      -

    11 weeks          0.1           5.6     5.1      6.0      4.8      5.4
                      0.6           -       -        -        -        -
                      1.5           5.1     4.5      5.2      3.8      4.7
                      6.0           5.4     4.9      5.8      3.8      5.0
                      Mean          5.3     4.8      5.7      4.1      -

    16 weeks          0.1           5.4     -        -        4.9      5.1
                      0.6           -       -        -        -        -
                      1.5           5.1     -        -        4.3      4.7
                      6.0           5.4     -        -        4.3      4.8
                      Mean          5.3     -        -        4.6      -

    22 weeks          0.1           5.6     4.3      4.8      4.1      4.7
                      0.6           -       -        -        -        -
                      1.5           5.5     4.1      4.1      3.7      4.4
                      6.0           5.2     4.2      4.4      3.6      4.4
                      Mean          5.4     4.2      4.4      3.8      -

    26 weeks          0.1           -       4.2      5.2      -        4.7
                      0.6           -       -        -        -        -
                      1.5           -       3.6      4.6      -        4.1
                      6.0           3.6     3.6      4.4      -        3.9
                      Mean                                              -
                                                                             

    TABLE 6b.  Pirimiphos-methyl residues in stored wheat from site W
               of two trials in Australia. Samples taken at various
               depths analysed by independent laboratories
               (Bengston et al., 1974)

                                                                             

    Interval since    Sample                       Analyst
    treatment         depth, m.     A       B        C        D        Mean
                                                                             

    2 weeks           0.1           -       -        -        -        -
                      0.6           5.6     5.4      4.5      4.5      5.0
                      1.5           6.0     4.9      4.7      4.0      5.0
                      6.0           5.8     4.9      4.4      4.0      4.8

                      Mean                  5.1      4.5      4.2      -

    8 weeks           0.1           -       -        -        -        -
                      0.6           4.4     3.9      4.5      4.0      4.2
                      1.5           4.8     4.5      5.0      4.5      4.7
                      6.0           4.5     3.9      4.7      4.2      4.2

                      Mean          4.6     4.1      4.7      4.2      -

    13 weeks          0.1           -       -        -        -        -
                      0.6           4.2     4.0      -        2.3      3.5
                      1.5           4.8     4.2      -        3.3      4.1
                      6.0           4.2     3.9      -        2.7      3.6

                      Mean                                             -
                                                                             

    TRIAL TERMINATED BECAUSE OF INFESTATION WITH RHIZOPERTHA DOMINICA


    Rice

         Bullock (1973) reports trials in Guyana, Indonesia and Malaysia
    where rice in husk and polished rice were treated by admixture of
    varying amounts of pirimiphos-methyl. In all trials reported the husk
    was removed after varying intervals and the residues on husk and grain
    determined separately. There appears to be some migration of the
    insecticide from the husk to the grain during parboiling prior to
    dehusking. The level of the residue in the husk declines over a period
    of one month to about 30% of its concentration shortly after
    application. Table 7 shows results from Guyana where rice was treated
    in husk. When the rate of application was 20 mg/kg, 55% of the deposit
    was lost from the husk within three days, the level declining to 35%
    of the initial value at the end of one month.

    TABLE 7.  Pirimiphos-methyl admixed with rice paddy and
              analysed at intervals - Guyana. (Bullock, 1973)
                                                                            
                    Interval
    Rate of         between              Before               After
    application,    treatment          Parboiling*          Parboiling*
    mg/kg           and sampling     Husk      Grain      Husk      Grain
                                                                            

    3               3 days           14        0.53       8.4       1.0

                    1 month          4.4       0.21       1.1       0.66

                    2 months         2.4       0.34       2.7       1.0

                    3 months         2.0       0.46       2.0       0.64

    7.5             3 days           34        0.90       5.1       1.8

                    1 month          8.5       0.75       2.0       -

                    2 months         5.2       0.71       6.0       2.3

                    3 months         5.1       0.53       3.4       1.3

                    8 months         12        0.98       4.5       ND

                    11 months        0.59      0.58       1.4       0.38

    19.2            0 days           80        1.2        17        5.6

                    3 days           36        2.1        -         -

                    1 month          28        1.4        8.2       3.2

                    2 months         13        1.8        15        4.9

                    3 months         18        1.3        3.7       2.6
                                                                            

    * Parboiling undertaken for dehusking purposes.
      Moisture content: approximately 14%.

         Bullock (1973) reports extensive trials carried out in Malaysia
    where pirimiphos-methyl was applied to polished rice and to rice in
    husk at various rates and by various methods of application. Polished
    rice appears to retain the initial deposit over a period ranging up to
    7 months. It is not possible to estimate the half-life from these data
    but it can be assumed to be much more than 7 months. Other trials in
    Indonesia confirm this long residual life. Malathion under comparable
    conditions disappeared almost completely within two months. By
    comparison malathion appears not to migrate in significant amounts
    from the husk into the grain of treated paddy.

    Maize

         Bullock (1973) reports trials in the U.S.A. which revealed that
    pirimiphos-methyl deposits on maize remained relatively stable over a
    period of 3 months. When the rate of application was 5-10 mg/kg the
    half-life appeared to be of the order of 3 months but when 20 mg/kg
    was applied no significant change occurred over the three month
    period.

    Peanuts

         Bullock (1973) reports two large scale trials in the U.S.A. where
    pirimiphos-methyl was applied at 20 and 50 mg/kg to undecorticated
    peanuts. Analytical results indicate that the target rate of treatment
    was achieved. Very little change occurred in the level of residues
    during the first month following application. Even at the end of three
    months substantially all of the deposit remained. The data suggest
    that the half-life is of the order of 5 months from the time of
    application. Twelve months after application the residue in the whole
    undecorticated nuts was approximately 20-25% of the original amount
    applied.

    FATE OF RESIDUES

    In stored products

    a) Distribution and degradation

         Residues of pirimiphos-methyl on wheat grains are degraded and
    detoxified by hydrolysis of the phosphorus-ester side chain, to give
    principally the parent hydroxy-pyrimidine (IV), Figure 1, and also the
    related compounds (V) and (VI). At a given temperature, the rate of
    breakdown increases with increasing moisture content of the grains.
    Levels of the N-desethyl phosphorus compound (II) were always
    extremely low (approximately 0.05 mg/kg over a period of 32 weeks in
    wheat grain treated at 4 mg/kg). No residues of the
    chemically-unstable oxygen analogue (III) were detected. The limit of
    detection.was 0.01 mg/kg (Bowker, 1973: See Table 8).

         Radio-autograms of grain sectioned after four months showed that
    the insecticide and its degradation products were concentrated in the
    seed coat so that residues in white flour and bread are likely to be
    lower than in bran and wholemeal products.

         The general pattern of breakdown on stored rice is similar to
    that found on wheat grain. The insecticide and its degradation
    products were concentrated in the husk in which the rate of breakdown
    appeared to be unaffected by the moisture content of the rice (Bowker,
    1973; Bullock, 1973). Representative results are given in Table 9.


    
    TABLE 8.  Effect of moisture on degradation of pirimiphos-methyl residues in wheat
              grain (Bowker, 1973)

                                                                                                         

    Application                                            Pirimiphos-methyl equivalents,
    rate and                                               mg/kg, after interval (weeks)
    moisture
    content             Compound                  0         2         4         8         16        32
                                                                                                         

    4 mg/kg,            I (PP511)                2.16      2.66      2.05      2.66      2.32      2.08
    14% moisture        II + unidentified*       0.04      0.04      0.04      0.06      0.04      -
                        IV, V, VI                <0.01     0.07      0.08      0.17      0.21      0.29
                        TLC baseline             <0.01     <0.01     0.04      0.04      0.08      0.26

    4 mg/kg,
    18% moisture        I                        2.36      2.73      1.12      0.80      0.79      0.38
                        II + unidentified*       0.05      0.03      0.03      0.03      0.03      0.03
                        IV, V, VI                -         0.49      0.56      1.05      0.92      0.66
                        TLC baseline             -         -         0.21      0.03      0.16      0.14

    8 mg/kg,            I                        4.03      5.46      3.80      4.64      5.53      5.37
    14% moisture        II + unidentified*       0.12      0.08      0.08      0.11      0.04      0.10
                        IV, V, VI                -         0.15      0.11      0.16      0.32      0.59
                        TLC baseline             -         -         0.02      0.03      0.04      0.22

    8 mg/kg,            I                        4.44      5.64      2.93      2.84      2.19      1.28
    18% moisture        II + unidentified*       0.69      0.27      0.08      0.09      0.05      0.04
                        IV, V, VI                -         0.98      0.99      1.61      1.89      1.61
                        TLC baseline             -         -         0.41      0.06      0.24      0.27
                                                                                                         

    *  Unidentified compound (minor product).
    

    
    TABLE 9.  Effect of moisture on degradation of pirimiphos-methyl residues in brown rice
              (Bowker, 1973)

                                                                                             

    Application                                  Pirimiphos-methyl equivalents, mg/kg,
    rate and                                     after interval (weeks)
    moisture
    content             Compound                 0         2         4         8         16
                                                                                             

    4 mg/kg,            I (PP511)                2.13      2.31      2.06      2.19      -
    14% moisture        II + unidentified*       <0.01     <0.01     <0.01     0.07      -
                        IV, (V, VI)              0.05      0.11      0.06      0.10      -
                        TLC baseline             0.01      0.07      0.23      0.07      0.02

    4 mg/kg,            I                        1.89      1.99      1.5       1.17      0.76
    18% moisture        II + unidentified*       <0.01     <0.01     <0.01     0.12      <0.01
                        IV, (V, VI)              0.06      0.17      0.34      0.24      0.33
                        TLC baseline             0.01      0.12      0.26      0.27      0.17

    8 mg/kg,            I                        3.7       4.37      4.1       3.73      2.99
    14% moisture        II + unidentified*       <0.01     <0.01     <0.01     0.11      0.09
                        IV, (V, VI)              0.1       0.18      0.11      0.34      0.17
                        TLC baseline             0.03      0.13      0.36      0.23      0.06

    8 mg/kg,            I                        3.11      3.68      1.55      2.3       1.58
    18% moisture        II + unidentified*       <0.01     <0.01     <0.01     0.21      0.11
                        IV, (V, VI)              0.06      0.32      0.10      0.86      0.45
                        TLC baseline             0.02      0.19      1.48      0.43      0.06
                                                                                             

    *  Unidentified compound (minor product)
    

         Pirimiphos-methyl applied as a dust formulation to wheat and
    brown rice is degraded in a similar manner to other organophosphorus
    insecticides used to protect stored grain from infestation (Rowlands,
    1966).

         Degradation is marginally more rapid in contact with the grain
    than in the isolated formulation but whether this additional breakdown
    is caused by factors within the grain or by the associated microflora
    is not known. At higher moisture contents (approximately 18%) less
    pirimiphos-methyl is recovered on analysis but increased levels of the
    hydrolysis product (IV) are obtained suggesting that a more rapid
    degradation of the insecticide occurs. Bowker concludes that grain may
    lack the enzymic activity believed to be present in plants and soil to
    cleave the pyrimidine N-ethyl bonds. It is likely therefore that
    following the treatment of wheat and brown rice with
    pirimiphos-methyl, the major residues during storage will be the

    insecticide itself and the simple hydrolysis product (IV). Under
    optimum conditions, the maximum level of compound (IV) following
    treatment at 4 mg/kg, was found to be 0.17 mg/kg; under poor storage
    conditions with high moisture content grain, 0.62 mg/kg.

         Solutions of pirimiphos-methyl-14C were applied in the
    laboratory to wheat grains of 14 and 18 percent moisture, and also as
    a 2 percept dust, to give levels of 4 mg/kg. Throughout a storage
    period of 6 months, the residues of pirimiphos-methyl were found
    almost entirely in the seed coat and aleurone layer, with only traces
    present in the germ or endosperm. It was also clear that, as with
    malathion but to a greater extent, there was transfer of insecticide
    between grains, possibly in the vapour phase. About 10 percent of the
    total residual radioactivity was bound to lipoprotein material in the
    aleurone region of the grain and was unextractable except by digestion
    of the aleurone protein. By contrast with other organophosphates
    studied, the bound material appeared to be the unchanged pesticide,
    rather than a metabolite. Certainly it was a P=S compound, but
    degradation during the liberation of the bound material complicated
    identification. During the storage period, the pirimiphos-methyl
    available for decomposition decreased by 15 and 50 percent at the 14
    and 18 percent moisture levels respectively. The main products found
    were the free hydroxy-pyrimidine and the N-desethyl pyrimidinol
    (Rowlands et al., 1974).

    b) Toxicity of degradation products

         The hydroxypyrimidines (IV), (V) and (VI) are members of a class
    of compounds known to exhibit low mammalian toxicity and they are also
    products of animal metabolism. It is therefore concluded that
    pirimiphos-methyl itself represents the major toxic residue in stored
    products. Traces of the phosphorus-containing degradation products
    (II) and (III), not exceeding 0.05 mg/kg in total, may also occur.
    They are determined by the preferred analytical method. The acute oral
    LD50 of (II) to the female rat is 800-1600 mg/kg. The oxygen analogue
    (III) is chemically unstable and it has not been possible to undertake
    toxicity tests with it (Gage, 1971b).

    In plants

         In contrast to its fate in stored products pirimiphos-methyl is
    rapidly lost from leaf surfaces during the first 2-3 days after
    spraying, mainly by volatilisation.

         Bowker and Hughes (1974a) identified by a combination of
    thin-layer and gas-liquid chromatography of the compounds or their
    derivatives, all the major extractable metabolites and degradation
    products arising from the interaction of pirimiphos-methyl with
    plants.

         They showed that on plant surfaces, pirimiphos-methyl is lost
    rapidly by vaporisation. Levels of the parent insecticide and the
    major degradation product, compound (II), represent less than 10% of
    the applied material after two to three days. In crops after foliar
    treatment the hydroxypyrimidine (IV), formed by hydrolysis of the
    insecticide, is unlikely to be a significant residue. They found that
    the compound is usually present only in trace amounts and is degraded
    photochemically and bound to plant material.

         These same workers showed that photochemical degradation of
    pirimiphos-methyl on leaf surfaces leads to the formation of compound
    (II) which is not accumulated. When applied to water in which rice
    seedlings were growing, pirimiphos-methyl is not translocated
    significantly into the foliage; in these conditions the hydrolysis
    product (IV) is likely to represent the predominant pyrimidine
    residue. Compounds (V) and (VI) only occur in trace amounts.

    In animals

         Much of the information in this section is also to be found under
    the heading "Absorption, distribution and excretion," but is repeated
    here for convenience.

    Goat

         Bowker et al. (1973) report studies where a single dose of
    radio-labelled pirimiphos-methyl was given orally to a lactating goat
    (0.12 mg/kg bw, equivalent to approximately 6 ppm in the ration). 91%
    of the radio-activity was excreted in the following 8 days: 87% in the
    urine and 4% in the faeces. Only 0.41% of the radio-activity was
    secreted in the milk, primarily during the first 24 hours. The maximum
    residue in the milk was 0.026 mg/kg pirimiphos-methyl equivalents, of
    which pirimiphos-methyl itself represented 0.003 mg/kg.

    Cow

         The pattern of excretion in the cow is very similar to that in
    the goat (Bullock et al., 1974a). When a single dose of radio-labelled
    pirimiphos-methyl was given orally to a cow at 0.5 mg/kg bw
    (equivalent to approximately 17 ppm in the daily diet), the
    radio-activity was quantitatively recovered during the following seven
    days - 85% in the urine and 14% in the faeces. Only 0.37% of the
    radio-activity was secreted in the milk (0.35% during the first three
    days).

         The highest levels of radioactivity in the milk, urine and faeces
    were found during the first day after dosing. The milk contained 0.04
    mg/kg pirimiphos-methyl equivalents, of which approximately 75% could
    be extracted from the fat and protein fraction into organic solvents.
    Pirimiphos-methyl accounted for approximately 12% (i.e. about 0.004 
    ppm), and compound (V) for about 50% of the total radioactivity in the

    milk. The radioactivity was not extracted by organic solvents and
    appeared to be incorporated into natural milk components.
    Approximately 70% of the radio-label in "day 1" urine was
    organo-soluble, the remainder dissolving only in water.

         Four groups of three cows were maintained by Bullock et al.
    (1974b) for 30 days on diets containing 0, 5, 15 and 50 ppm
    pirimiphos-methyl. Residues of pirimiphos-methyl were determined in
    milk samples taken every two days and in samples of kidney, liver,
    heart, fat and muscle taken at the end of the study. None of these
    residues exceeded 0.02 mg/kg. The authors prepared butter from the
    milk of cows dosed at the 110 mg/kg bw rate but found this to contain
    only 0.02-0.04 mg/kg pirimiphos-methyl. In all instances no residues
    of the organophosphorus compounds (II) and (III) could be detected in
    samples of meat, milk or butter. (Limit of detection: 0.01 mg/kg in
    each case).

    Hen

         Green et al. (1973) report that when diets containing 4 ppm
    pirimiphos-methyl were fed to laying hens for 28 days, or when a diet
    containing 32 ppm was fed for 7 days, residues of pirimiphos-methyl
    itself in eggs did not exceed 0.01 mg/kg and no residues of compound
    (III) were detected (Limit of detection: 0.001 mg/kg). The same
    authors using radio-labelled pirimiphos-methyl found that the total
    amount of radio-activity in eggs reached a maximum of 0.03 mg/kg
    pirimiphos-methyl equivalents after 15 days when fed at a
    concentration of 4 ppm in the ration and a maximum of 0.15 mg/kg
    pirimiphos-methyl equivalents at the end of the 32 ppm study. In
    muscle samples taken at the end of the 32 ppm study no residues of
    pirimiphos-methyl or of its P=0 analogue were detected, (Limit of
    detection: 0.001 ppm). Since 86-90% of the radio-activity in eggs is
    present as water-soluble unidentified metabolites and since at no time
    does the concentration of pirimiphos-methyl itself in yolks or whites
    exceed 0.001 mg/kg, Green et al. conclude that pirimiphos-methyl does
    not accumulate in eggs during continuous feeding of the insecticide
    and that at the proposed level of application the residues of the
    pesticide in eggs are negligible.

         Graham and Jenkins (1974), as part of a study of the effect of
    pirimiphos-methyl on the growth rate of broiler chickens, analysed
    muscle, skin and fat samples from birds receiving 4, 8, 16, 32 and 48
    ppm pirimiphos-methyl continuously in rations for 9 weeks. Birds were
    slaughtered within 1 hour of being removed from feed. The only
    residues which appeared were detected in skin and fat. The highest
    level, 0.017 mg/kg, was in the fat of a broiler receiving 48 ppm
    pirimiphos-methyl in the ration. Another had 0.015 mg/kg. All other
    samples contained less than 0.01 mg/kg or residues were not
    detectable.

    In soil

         Pirimiphos-methyl shows very limited persistence and mobility in
    soil.

         Bowker, Riley and Gratton (1972) showed that in a range of soil
    types the half-life of pirimiphos-methyl is less than one month. The
    major soil metabolite is the parent hydroxypyrimidine (IV) together
    with smaller amounts of the related compounds (V) and (VI). The routes
    of metabolism in stored grain, plants and soil are therefore similar.

         The same authors using a descending thick-layer chromatography
    technique, showed pirimiphos-methyl to possess only limited mobility
    in soil: considerably less than atrazine which was used as a standard
    and which itself is recognised as being only moderately mobile.

    In water

         Pirimiphos-methyl in rapidly degraded in water, mainly by
    hydrolysis with loss of the phosphorothionate ester side chain. This
    process is accelerated in the presence of light. Bowker and Hughes
    (1974b) confirmed this and showed that although some volatilisation
    occurs from still water, this is less significant than hydrolysis in
    accounting for loss of the insecticide. In their experiments 50%
    degradation had occurred after one day in sunlight. The major
    degradation product in water is compound (IV). Only trace quantities
    of the P=0 analogue (III) were detected (less than 0.01 mg/l in water
    treated initially with pirimiphos-methyl at 1 mg/l).

    In processing

    Wheat

         Bullock (1973 and 1974) reported many separate experiments which
    demonstrated that residue levels of pirimiphos-methyl are
    significantly reduced during the milling and baking processes. Table
    10 summarises the results of residue trials carried out in the U.K. on
    wheat that had been treated to contain nominally 4 mg/kg
    pirimiphos-methyl.

         Table 11 summarises results of a residue trial reported by
    Bullock (1973) to have been carried out in the U.K. with wheat
    nominally treated to contain 8 ppm pirimiphos-methyl. These data which
    are substantially in agreement with those of Bengston et al. (1974)
    show that there is relatively little penetration beyond the seed coat
    even throughout a storage period of 9 weeks.

    TABLE 10.  Effect of milling and baking on residues in wheat admixed
               with pirimiphos-methyl at 4 mg/kg-UK (Bullock, 1973, 1974)

                                                                            

                 Interval between
    Grain        treatment and                 Residues, mg/kg1
    fraction     sampling (months)     Highest   Lowest    Mean
                                                                            

    Whole        0                     4.2       1.9       2.9   (9)
    grain                              3.0*      -*        3.0*

                 1                     4.1       1.5       2.8   (9)

                 2                     4.1       1.6       2.6   (8)
                                       2.5*      2.4*      2.5*  (3)

                 3                     3.6       1.3       2.3   (7)

    Wholemeal    0                     1.3       0.94      1.1   (3)
    flour
                 1                     2.1       1.1       1.7   (4)

                 2                     2.2       1.2       1.7   (3)
                                       1.5*      1.4*      1.5*  (3)

                 3                     2.1       1.0       1.5   (4)

    White        0                     0.88      0.30      0.52  (6)
    flour                              0.56*     0.53*     0.55* (3)

                 1                     0.77      0.44      0.59  (5)

                 2                     0.64      0.24      0.56  (6)
                                       0.29*     0.24*     0.27* (3)

                 3                     0.67      0.38      0.56  (3)

    Wholemeal    0                     0.72      0.53      0.64  (4)
    bread
                 1                     0.91      0.55      0.79  (4)

                 2                     1.1       0.65      0.93  (4)
                                       0.97*     0.82*     0.88* (3)

                 3                     0.54      0.21      0.49  (3)

    TABLE 10.  (Cont'd.)

                                                                            

                 Interval between
    Grain        treatment and                 Residues, mg/kg1
    fraction     sampling (months)     Highest   Lowest    Mean
                                                                            

    White        0                     0.28      0.19      0.23  (6)
    bread                              0.26*     0.24*     0.25* (3)

                 1                     0.36      0.22      0.30  (5)

                 2                     0.45      0.31      0.36  (8)
                                       0.15*     0.13*     0.14* (3)

                 3                     0.54      0.21      0.43  (3)
                                                                            

    1  All results are from field trials except those marked*
       which are from a small-scale trial. Figures in parentheses are
       the numbers of results upon which the means are based.


    TABLE 11.  Residues of pirimiphos-methyl in whole grains and in milling
               and baking fractions of whole grains treated in a laboratory
               trial in UK at 8 mg/kg. (Bullock, 1973, 1974)

                                                                            

    Interval between                  Residues, mg/kg.1
    treatment and       Whole    White    White     Wholemeal     Wholemeal
    sampling            grain    flour    bread     flour         bread
                                                                            

    0 days              6.0      0.86     0.52      -             -
                        6.0      0.91     0.56      -             -
                        6.0      1.0      0.57      -             -

    9 weeks             4.8      0.47     0.28      3.2           1.7
                        5.2      0.59     0.33      3.0           1.6
                        5.2      0.60     0.30      3.2           1.5
                                                                            

    1  In all cases, no residues of the phosphorus-containing compounds (II)
       or (III) (Figure 1) were detected. (Limit of detection: 0.01 ppm in
       each case.)

         Bengston et al. (1974) report an extensive series of trials in
    which pirimiphos-methyl was applied to wheat at the rate of 6 mg/kg in
    bulk silos in two areas of Australia. Wheat was submitted to two
    separate laboratories, for analysis and for processing, milling and
    baking. The results reported by the two independent laboratories are
    summarised in Table 12. These studies revealed that though a
    significant amount of the pirimiphos-methyl was removed during the
    cleaning process prior to the milling of the wheat, by far the
    greatest separation occurred in the bran. Although the bran
    represented only 25% of the whole grain it contained just over two
    thirds of the entire residue leading to a concentration in the bran of
    250% of that in the whole grain from which the bran was derived. The
    concentration in the flour after milling averaged only 22% of that in
    the whole grain. When the grain was processed into bread and baked
    there was a further 63% reduction in the level of residues according
    to one co-operating laboratory and an almost complete destruction of
    the insecticide reported by the other. Assuming that the amount of
    residue found in the bread would always be as high as the highest
    level reported (0.3 mg/kg) the processing, milling and baking of bread
    from raw grain containing pirimiphos-methyl results in a 93%
    destruction of the original residue. Under practical conditions this
    could well be greater because there is normally a significant delay at
    each stage of the process which would further promote degradation of
    the residue.

    Rice

         Residues of pirimiphos-methyl and its degradation products in
    rice in husk are concentrated in the husk. Bowker (1973) and Bullock
    (1973, 1974) report that parboiling rice to remove the husk results in
    a substantial loss of the insecticide and its degradation products
    from the husk into the water used to soak the rice. Table 13, taken
    from Bullock (1973), shows the results of experiments in Guyana
    designed to determine the lose of residues during the processing of
    rice which had been treated previously while in husk at a nominal rate
    of 5 and 10 mg/kg with pirimiphos-methyl. These results clearly
    demonstrate that the bulk of the residue is in the husk with the
    remainder in the seed coat. Polishing removes virtually all of the
    material deposited in the seed coat although the process of parboiling
    appears to promote the transfer of a small amount of residue into the
    grain itself.


    
    TABLE 12.  Fate of pirimiphos-methyl residues in wheat treated at 6 mg/kg and subjected to
               milling and baking (Bengston et al., 1974).

                                                                                                             

                                                                                       Residues, mg/kg,
                                      Residues, mg/kg, Wheat W                         Wheat M
                                  Laboratory A                Laboratory B                  Laboratory B
    Stage of Processing      1        2        Mean       1        2        Mean       1        2        Mean
                                                                                                             

    Whole grain              4.7      4.8      4.8        4.2      4.2      4.2        4.5      4.5      4.5

    Cleaned grain            3.8      3.8      3.8        -        -        -          -        -        -

    Bran                     10.0     9.9      10.0       8.9      9.3      9.1        11.9     12.7     12.4

    Shorts (pollard)         7.4      7.7      7.6        8.2      8.5      8.3        10.1     10.6     10.4

    Flour                    0.85     0.88     0.9        0.6      0.8      0.7        1.3      1.3      1.3

    Bread                    0.31     0.32     0.3        <0.2     <0.2     <0.2       0.46     0.48     0.47
                                                                                                             
    

    
    TABLE 13.  Effect of milling and polishing on residues in rice admixed with
               pirimiphos-methyl (5 or 10 mg/kg) while in husk - Guyana
               (Bullock, 1973).

                                                                                                

                                                            Residues, mg/kg.
                                            Treated at 5 mg/kg            Treated at 10 mg/kg
                                            Not                           Not
    Sample                                  parboiled    Parboiled        parboiled     Parboiled
                                                                                                

    Dehusked grain                          0.55         0.58             0.72          1.46

    Husks                                   8.7          2.1              9.4           4.95

    Grain polished 1 min.                   0.26         0.31             0.29          0.76

    Polishings from 1st min.                5.9          6.3              9.0           14.0

    Grain polished 2 min.                   0.19         0.29             0.29          0.76

    Polishings from 2nd min.                5.6          6.5              9.4           15.8

    Grain polished 5 mins.                  <0.01        0.28             0.27          0.65

    Polishings from 3rd to 5th mins.        5.3          7.1              9.3           14.9
                                                                                                
    
         Bullock (1973) reports experiments carried out in Indonesia to
    determine the loss of pirimiphos-methyl residues from polished rice
    during cooking. Rice which had been treated by admixture with
    pirimiphos-methyl emulsifiable solution and which contained 1.96 mg/kg
    pirimiphos-methyl was used in the trial. The rice was washed under the
    cold water tap for two minutes before simmering for 20 minutes in 2.5
    times its own weight of tap water. The rice by this time was a soft
    mass. Cold tap water was poured over the grains to separate them and
    the samples were then analysed in the usual manner. A second sample of
    the same batch of rice was treated in the same way and duplicate
    analyses were carried out on each sample. The results which are given
    below show a 74% loss in cooking white rice.
    Residue, mg/kg, before cooking:  1.96; 1.96
                    after cooking:   0.58, 0.50 (mean 0.54); 0.50, 0.47
                                     (mean 0.49).

         No residues of the phosphorus-containing compounds (II) or (III)
    were detected (limit of detection: 0.01 ppm in both cases).

    EVIDENCE OF RESIDUES IN FOOD IN COMMERCE OR AT CONSUMPTION

         Pirimiphos-methyl has not yet been widely used and therefore no
    information is available on residues in food moving in commerce.

    METHODS OF RESIDUE ANALYSIS

         Two methods of residue analysis are available. The more
    sensitive, quicker and preferred method is that of Bullock (1972) in
    which gas chromatography with a phosphorus detector is used. The
    method is suitable for the determination of residues of
    pirimiphos-methyl in crops, it also determines the
    phosphorus-containing metabolites (II) and (III). The limit of
    determination is 0.01 mg/kg in each case. Crop samples are extracted
    with a 20% solution of acetone in n-hexane. A decanted portion of the
    extract is washed with water, and then dried with anhydrous sodium
    sulphate. A portion of the extract is then injected into a gas
    chromatograph equipped with a flame photometric or thermionic
    detector. The peaks obtained at the retention times of
    pirimiphos-methyl and its metabolites (II) and (III) are compared with
    standards. Grain samples are extracted with methanol instead of
    acetone/hexane and oily or fatty materials are subjected to an
    acetonitrile-n-hexane partition before analysis. The oxygen analogue
    (III) has not been detected as a metabolite in any samples analysed in
    the laboratory of the manufacturer, although (as stated above) its
    limit of determination is 0.01 mg/kg.

         Alternatively when GLC is not available, a colorimetric method
    may be used. The colorimetric method reported by Bullock (1969) has
    only been tried on field crop samples. An extract, obtained by
    prolonged maceration or slurrying the sample with n-hexane, is dried
    with anhydrous sodium sulphate, filtered, concentrated down to a small
    volume in a rotary evaporator at low temperature and quantitatively
    transferred to a preparative-layer plate together with a marker spot
    of pirimiphos-methyl. The plate is developed in a mixture of n-hexane
    and acetone and inspected under ultra-violet light. The band opposite
    the marker spot is scraped off and refluxed for one hour with
    concentrated hydrobromic acid to liberate hydrogen sulphide, which is
    swept off in a stream of nitrogen, quantitatively absorbed in alkaline
    zinc acetate and subsequently determined as methylene blue. The limit
    of determination is normally about 0.1 mg/kg with recovery in excess
    of 75%.

         Bullock (1973) reports studies to determine the most effective
    solvent for extracting pirimiphos-methyl and its metabolites from
    "aged" residues in stored grain. Table 14 shows the results of these
    studies indicating the residues of pirimiphos-methyl extractable from
    aged samples by different extraction methods. The samples were ground
    to a fine powder before analysis. The lowest recoveries are almost
    invariably with methanol under reflux. Comparable results are obtained
    with the other solvent systems when extraction is made immediately
    after treatment, but on aged samples cold methanol generally gives
    significantly higher results.

        TABLE 14.  Residues of pirimiphos-methyl extractable from "aged" samples by different
               extraction methods. (Samples ground to fine powder before analysis.)

                                                                                             

                                                 Residues determined (mg/kg) using various
    Sample**              Interval after                   extraction methods*
    (Treatment rate)      treatment              1         2         3         4         5
                                                                                             

    Wheat (4 mg/kg)       0 days                 3.72      3.45      3.82      3.87      2.91

                          1 month                2.92      2.73      2.79      3.01      3.17

                          3 months               1.87      1.73      1.99      2.17      2.04

    Barley (4 mg/kg)      0 days                 3.07      3.12      3.49      3.09      1.90

                          1 month                2.51      2.36      2.17      2.69      2.54

                          3 months               1.53      1.71      1.47      1.84      1.70

    Rice (4 mg/kg)        0 days                 4.10      3.92      4.00      4.07      3.12

                          1 month                2.18      2.40      2.12      2.71      2.60

                          3 months               1.41      1.95      1.84      1.99      1.03
                                                                                             

    *   Extraction methods:  1  Dichloromethane (cold);  2  Acetone (cold);  3  20% Acetone
        in hexane (cold);  4  Methanol (cold);  5  Methanol (1 hour reflux).

    **  The samples had a moisture content of 13-14%.
    
         Bullock also reports studies which show that it is preferable to
    grind aged samples before attempting to extract with either methanol
    or acetone/hexane. Grinding offers no advantage when dealing with
    wheat or rice that has only just been treated but in view of the fact
    that many regulatory analysts will receive samples which have been
    treated three months to three years previously it is obvious that the
    preparation of the sample and the selection of the solvent are of
    critical importance. Table 15 shows results obtained by Bullock. The
    samples were ground in a Moulinex coffee grinder. Later comparison
    with Hobart laboratory grinder showed no significant difference in the
    results and little temperature rise in the grain during grinding.

    TABLE 15.  Effect of grinding on extractability of aged residues
               (Bullock, 1973).

                                                                             

    Sample                                Residues, mg/kg, determined using
    (Treated by   Interval                different extraction solvents
    admixture     after       Original    20% acetone              Methanol
    at 4 mg/kg)   treatment   or ground   in hexane
                                                                             

    Wheat         0 days      Original    3.82                     3.91
                              Ground      3.82                     3.87

                  1 month     Original    2.70                     2.81
                              Ground      3.10                     3.04

                  3 months    Original    1.43                     1.55
                              Ground      1.87                     1.99

    Rice          0 days      Original    4.01                     4.05
                              Ground      4.10                     4.07

                  1 month     Original    2.00                     1.91
                              Ground      2.18                     2.34

                  3 months    Original    1.67                     1.71
                              Ground      1.84                     1.99
                                                                             


         As a check on the loss of residues during grinding Bullock took
    wheat which had been freshly treated with pirimiphos-methyl and
    measured the residue level before and after intense grinding for one
    minute. The analytical results varied by less than 50% which is slight
    by comparison with the loss which would occur if grain treated with
    malathion or dichlorvos were ground in a similar manner. The same
    author reports experiments designed to determine the loss of residue
    from wheat, barley and rice when grain samples were stored at -14C
    while awaiting analysis. Both freshly treated grain and grain which
    had been treated under semi-commercial conditions three months prior
    to sampling were kept under such storage conditions but none of these
    samples showed as much as 5% loss during two months at -14C.

    NATIONAL TOLERANCES

         The information available to the meeting indicates that few
    national tolerances have been established. It is understood that a
    tolerance of 4 mg/kg has been proposed in France for pirimiphos-methyl
    residues in cereals and 2 mg/kg in fruits and vegetables. In the
    Netherlands a tolerance of 0.2 mg/kg has been established for
    pirimiphos-methyl residues in cucumbers, melons, paprika and tomatoes.

    APPRAISAL

         Pirimiphos-methyl is a broad-spectrum organophosphorus
    insecticide with both contact and fumigant action. It shows only
    limited biological persistence on plant surfaces but gives long
    lasting control of insect pests on inert surfaces and retains its
    biological activity when applied to stored agricultural commodities
    including raw grains and nuts.

         The meeting had only limited Information concerning the
    pre-harvest use and performance of this material on crops but
    extensive data were available on its use, performance and fate on a
    variety of small grains and nuts. The recommended rate of application
    to raw cereals is 6 mg/kg.

         Exceptional stability on grain results in an effective half-life
    of up to 80 weeks. Although high temperatures and high moisture levels
    in grain reduce the life of the deposit the effect of these influences
    is much less than with other grain protectants approved or evaluated
    to date.

         Data were available to show that on both wheat and rice the
    deposit resulting from admixture of pirimiphos-methyl with grain is
    almost entirely in the seed coat and husk respectively. Cleaning,
    processing and milling removes the bulk of the applied material. In
    the case of wheat the milling process results in most of the residue
    being separated into the bran where the concentration of
    pirimiphos-methyl can range up to 20 mg/kg. In the case of rice
    substantially all of the deposit is removed during the milling and
    polishing operations. Depending upon the milling process, flour
    prepared from treated wheat may contain significant amounts of
    pirimiphos-methyl but a major proportion of this is destroyed in the
    baking of bread. The small amount of residue remaining in polished
    rice is substantially destroyed in cooking.

         Pirimiphos-methyl and the corresponding hydroxypirimidine are the
    only significant residues detected. Residues of the
    phosphorus-containing metabolites when detected were always extremely
    low (approximately 0.05 mg/kg).

         Extensive data are available on the fate of pirimiphos-methyl in
    plants, domestic animals, hens and their edible tissues, and foods of
    animal origin. In living plants the major phosphorus-containing
    degradation product is the N-desethyl metabolite (II) which is not
    accumulated. The hydroxypyrimidine compound (IV) is the major
    degradation product following root uptake. When fed to domestic
    animals pirimiphos-methyl is rapidly metabolised and excreted, only
    very small quantities being secreted into milk or eggs. Cattle
    receiving pirimiphos-methyl in their ration do not accumulate
    significant quantities in edible tissues, including fat. Such
    organophosphorus residues as are detectable are of the parent
    compound. No residues of the phosphorus-containing metabolites could
    be detected in meat, milk, butter or eggs.

         A GLC method of analysis suitable for the determination of
    residues of pirimiphos-methyl and the phosphorus-containing
    metabolites in plant materials is available, the limit of
    determination being reported to be 0.01 mg/kg. The method appears
    suitable for regulatory purposes. Evidence of the importance of sample
    preparation and method of extraction has been presented.

         No national tolerances have yet been determined.

         In proposing maximum residue limits for pirimiphos-methyl and its
    metabolites on raw grain, milled cereal products and foods prepared
    therefrom, careful consideration has been given to the fact that this
    insecticide is to be used as a grain protectant, that a certain
    concentration must be present on the grain to control infestations and
    prevent damage to stored products and that the compound is
    exceptionally stable under storage conditions. Under practical
    conditions of grain handling and storage it is not possible to apply a
    grain protectant with assurance that the deposit will be absolutely
    uniform. There will always be a natural variation in the level of the
    deposit resulting from fluctuations in the flow of grain and
    insecticide. It is therefore not possible to fix the maximum limit on
    the minimum necessary to control the insect pests. Furthermore
    extensive work has demonstrated that the movement of bulk grain
    results in the segregation of the various components of the bulk with
    a resultant variation in the level of residues throughout the mass.
    Due allowance must be made for the amplitude of these variations and
    the problems of sampling and analysis.

    RECOMMENDATIONS

         The following temporary tolerances are recommended. They refer to
    the sum of pirimiphos-methyl, its oxygen analogue and N-desethyl-
    pirimiphos-methyl, expressed as pirimiphos-methyl.

    TEMPORARY TOLERANCE

                                              mg/kg

    Bran (wheat, rice)                        20
    Wheat, rye, rice (in husk)                10
    Barley, maize, oats                        7
    Wholemeal flour (wheat, rye)               5
    Rice (dehusked), wheat flour (white)       2
    Bread (wholemeal), rice (polished)         1
    Bread (white)                             0.5
    Meat, milk, eggs                          0.05*

                 
    *At or about the limit of determination

    FURTHER WORK OR INFORMATION

    REQUIRED (by 1976)

    1.   Additional studies to clearly establish no-effect level for
         decreased pregnancy rates, and hydronephrosis in offspring.

    2.   Further studies to clarify the liver injury dogs observed in 90
         day studies.

    DESIRABLE

    1.   Longer duration observations in man.

    2.   Information from studies now in progress on other stored
         commodities including nuts, peanuts and dried fruit. The
         information is expected to be available during 1975.

    3.   Information on residues in fruit and vegetables following
         approved uses.

    4.   Further information on the level and fate of residues in food at
         the point of consumption following the use of pirimiphos-methyl
         for the control of various stored product pests.

    REFERENCES

    Bengston, M., Connell, M., Desmarchelier, J., Phillips, M., Snelson,
    J. and Sticka, R. (1974) Evaluation of four new grain protectants.
    Report to Australian Wheat Board. (To be published)

    Bowker, D.M. (1973) Pirimiphos-methyl (PP 511): fate of stored wheat
    and rice grain in the laboratory. ICI Plant Protection Ltd. Report No.
    AR 2457 AR. (Unpublished)

    Bowker, D.M., Griggs, B.F. and Harper, P. (1973) Pirimiphos-methyl (PP
    511): excretion by a goat. ICI Plant Protection Ltd. Report No. AR
    2458 B. (Unpublished)

    Bowker, D.M. and Hughes, H.E. (1974) Pirimiphos-methyl: fate in crops.
    ICI Plant Protection Ltd. Report No. AR 2515 A. (Unpublished)

    Bowker, D.M. and Hughes, H.E. (1974) Pirimiphos-methyl: fate in water.
    ICI Plant Protection Ltd. Report No. AR 2516 A. (Unpublished)

    Bowker, D.M., Riley, D. and Gratton, R.P. (1972) Pirimiphos-methyl:
    fate in soil. ICI Plant Protection Ltd. Report No. TMJ 809 A.
    (Unpublished)

    Bratt, H. and Dudley, L.A. (1970) Pirimiphos-methyl (PP 511):
    Excretion by rats and dogs. Report from ICI Industrial Hygiene
    Research Laboratories. (Unpublished)

    Bratt, H. and Jones, L.A. (1973) Pirimiphos-methyl (PP 511):
    Metabolism in rats and dogs. Report from ICI Industrial Hygiene
    Research Laboratories. (Unpublished)

    Bullock, D.J.W. (1969) Provisional analytical method for the
    determination of PP211 and PP511 residues in vegetables, grain and
    fruit. ICI Plant Protection Ltd. Method No. PAM 310/A.

    Bullock, D.J.W. (1972) Residue analytical method no. 11 for the
    determination of residues of pirimiphos-methyl and its
    phosphorus-containing metabolites in crops (gas chromatographic
    method). ICI Plant Protection Ltd. Method PPRAM-11/A.

    Bullock, D.J.W. (1973) Pirimiphos-methyl: residues in stored grain.
    ICI Plant Protection Ltd. Report No. AR 2472 AR. (Unpublished)

    Bullock, D.J.W. (1974) Pirimiphos-methyl: residues in stored grain
    bread, flour and milled products. ICI Plant Protection Limited. Report
    No. AR 2537 A. (Unpublished)

    Bullock, D.J.W., Day, S., Hemingway, R.J. and Jegatheeswaran, T.
    (1974) Pirimiphos-methyl: residue transfer study with cows. Report
    from ICI Plant Protection Limited. (Unpublished)

    Bullock, D.J.W., Day, S., and Griggs, B.F. (1974) Pirimiphos-methyl:
    metabolism and residue transfer into the meat and milk of a lactating
    cow. ICI Plant Protection Ltd. Report No. AR 2552 A. (Unpublished)

    Chart, S., Foulkes, Caroline A., Gore, G.W. and Williamson, K.S.
    (1974) Erythrocyte and plasma cholinesterase activity in human
    volunteers administered pirimiphos-methyl. Report from ICI Central
    Toxicology Laboratory. (Unpublished)

    Clapp, M.J. and Conning, D.M. (1970) Pirimiphos-methyl (PP511).
    Ninety-day oral toxicity in rats. Report from ICI Industrial Hygiene
    Research Laboratories. (Unpublished)

    Clark, D.G. (1970) The toxicity of PP511
    [O-(2-diethylamino-6-methylpyrimidin-4-yl)
    O,O-dimethylphosphorothioate] Report from ICI Industrial Hygiene
    Research Laboratories. (Unpublished)

    Fink, R. (1974a) Eight-day dietary LC50 - mallard ducks: technical
    pirimiphos-methyl. Report from Truslow Farms Inc. (Unpublished)

    Fink, R. (1974b) Eight-day dietary LC50 - bobwhite quail: technical
    pirimiphos-methyl. Report from Truslow Farms Inc. (Unpublished)

    Gage, J.C. (1971a) Pirimiphos-methyl (PP511): Avian toxicity. Report
    from ICI Industrial Hygiene Research Laboratories. (Unpublished)

    Gage, J.C. (1971b) Pirimiphos-methyl (PP 211) and pirimiphos-methyl
    (PP 511): acute and subacute oral toxicity in the rat of the plant
    metabolite, 2-diethylamino-4-hydroxy-6-methylpyrimidine (R46382). ICI
    Industrial Hygiene Research Laboratory. Report No. HO/IH/R/327.
    (Unpublished)

    Gage, J.C. (1972) Pirimiphos-methyl (PP511): Oral toxicity in the dog
    and in a passerine bird species. Report from ICI Industrial Hygiene
    Research Laboratories. (Unpublished)

    Gore, C.W. Palmer, S. and Pratt, I.S. (1974) Pirimiphos-methyl
    (PP511): teratogenic studies in the rabbit. Report from ICI Central
    Toxicology Laboratory. (Unpublished)

    Gore, C.W., Griffiths, D. and Phillips, C.E. (1974) Pirimiphos-methyl
    (PP511): two year feeding study in the rat. Report from ICI Industrial
    Hygiene Research Laboratories. (Unpublished)

    Graham, C.A. and Jenkins, S.L. (1974) The effect of pirimiphos-methyl
    on the growth rate of broiler chicks. ICI Australia Ltd. Merrindale
    Research Station Report, July 1974.

    Green, T., Monks, I.H. and Phillips, P.J. (1973) Pirimiphos-methyl (PP
    511): sub-acute oral and residue studies in hens. ICI Industrial
    Hygiene Research Laboratories. Report No. HO/IH/P/65B. (Unpublished)

    Hodge, M.C.E. and Moore, S. (1972) Pirimiphos-methyl (PP 511):
    Teratological studies in the rat. Report from ICI Industrial Hygiene
    Research Laboratories. (Unpublished)

    Noel, P.R.B., Mawdesley-Thomas, L.E., Rivett, K.F., Squires, P.F. and
    Street, E. (1970) PP 511: Oral toxicity studies in dogs - initial
    studies and repeated dosage for thirteen weeks. Report from Huntingdon
    Research Centre. (Unpublished)

    Palmer, A.K. and Cherry, C.P. (1972) Effect of PP 511 on reproductive
    function of multiple generations in the rat: histopathological
    examination on testes of F1B and F2B males. Report from Huntingdon
    Research Centre. (Unpublished)

    Palmer, A.K. and James, P. (1972) Effect of PP 511 on reproductive
    function of multiple generations in the rat. Report from Huntingdon
    Research Centre. (Unpublished)

    Parkinson, G.R. (1972a) Pirimiphos-methyl (PP 511): potentiation with
    gamma-BHC. Report from ICI Industrial Hygiene Research Laboratories.
    (Unpublished)

    Parkinson, G.R. (1972b) Pirimiphos-methyl (PP 511): potentiation with
    dichlorvos. Report from ICI Industrial Hygiene Research Laboratories.
    (Unpublished)

    Pieterse, A.H., Schulten, G.G.H. and Kuyken, W. (1972) A study of
    insecticide resistance in Tribolium castaneum in Malawi. J. Stored
    Prod. Res., 8(3):183.

    Rivett, K.F., Edwards, B., Street, E. and Newman, A.J. (1973) PP 511:
    Oral toxicity study in beagle dogs - repeated daily dosage for two
    years. Report from Huntingdon Research Centre. (Unpublished)

    Ross, D.B., Burroughs, Sheila J. and Roberts, Nicholas L. (1974) Egg
    production and hatch-ability in the laying hen following dietary
    inclusion of pirimiphos-methyl at various levels. Report from
    Huntingdon Research Centre. (Unpublished)

    Rowlands, D.G. (1966) The activation and detoxification of three
    organic phosphorothionate insecticides applied to stored wheat grains.
    J. Stored Prod. Res., 2:105-116.

    Rowlands, D.G. et al. (1974) Preliminary report of studies with
    pirimiphos-methyl as a grain protectant. Submission by United Kingdom
    to FAO. (To be published)

    Waterhouse, D. (1973) Background paper presented at the Ninth Session
    of the FAO Working Party of Experts on Pest Resistance to Pesticides
    (Rome, 20 June 1973). (Unpublished)
    


    See Also:
       Toxicological Abbreviations
       Pirimiphos-methyl (Pesticide residues in food: 1976 evaluations)
       Pirimiphos-methyl (Pesticide residues in food: 1977 evaluations)
       Pirimiphos-methyl (Pesticide residues in food: 1979 evaluations)
       Pirimiphos-methyl (Pesticide residues in food: 1983 evaluations)
       Pirimiphos-methyl (Pesticide residues in food: 1992 evaluations Part II Toxicology)