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    BIORESMETHRIN     JMPR 1976

    Explanation

         Bioresmethrin was evaluated in 1975 (FAO/WHO 1976b) and a
    monograph covering "Identity" and "Residues in food and their
    evaluation" was published. Toxicological information was not then
    available and therefore no ADI could be recommended. The 1975 Meeting
    indicated that full Toxicological data was required and that the
    following information was desirable.

    1.   Further information on the level and fate of bioresmethrin on
         different classes of raw grains.

    2.   Residue data from supervised trials on other stored commodities,
         including nuts, peanuts, lentils, dried fruit and dried
         vegetables.

    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 bioresmethrin for
         the control of various stored-product pests.

    5.   Improved procedures for the determination of bioresmethrin
         residues in fruit and vegetables as well as stored products.
         Information on many of these topics was received and evaluated by
         the Meeting and the following monograph addendum is provided.

    IDENTITY AND PROPERTIES

         Bioresmethrin was developed under grants from the National
    Research and Development Corporation by scientists at Rothamsted
    Experimental Station in the United Kingdom. At least five principal
    companies have been licenced to manufacture, formulate or distribute
    bioresmethrin insecticides in different parts of the world and for
    different fields of use.

         The effective performance of bioresmethrin and its novelty, being
    the first synthetic pyrethroid with properties comparable to natural
    pyrethrins, has stimulated many independent scientists and government
    research workers to study the chemistry, metabolism, biological
    effects and fate of bioresmethrin. Much of this information is
    available in published literature and in addition the Meeting had
    access to the results of a number of on-going studies.

         Because the (+) cis isomer of bioresmethrin is acutely somewhat
    more toxic than bioresmethrin there is interest in whether this isomer
    could be a significant component of technical bioresmethrin. In the
    manufacturing process the optical isomers of chrysanthemic acid are
    separated by procedures which include crystallisation and it is

    understood that substantially all of the (+) cis isomer is removed
    before the esterification reaction.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, distribution and excretion

         Bioresmethrin is rapidly absorbed (following oral administration)
    from the gut and widely distributed in the body within 3 hours. Whole
    body radioautographic techniques monitored the distribution of
    3H-bioresmethrin following oral or intravenous administration to
    rats. At 24 hours following oral administration, most tissues showed
    greatly reduced residual radioactivity but concentration in fatty and
    other tissues was high (adipose tissue, mesenteric skin, testis,
    epididimus, lachrymal gland and connective tissue). The excretion of
    3H activity into the bile duct was demonstrated with rats surgically
    cannulated to collect the bile. Shortly after iv3 treatment (50%
    after 24 hours and 60% after 72 hours) 3H was found in the bile.
    After iv administration a large amount was recovered in faeces
    suggesting significant enterohepatic circulation (Farebrother, 1973).

         Following oral administration to rats (14C-carboxyl label, 0.87
    mg/kg), bioresmethrin was slowly eliminated from the body with only
    73% of the administered dose accounted for in faeces (32%) and urine
    (41%) after 6 days (means from two experiments). The highest residue
    after 6 days was found in the fat: other tissues contained 0.01 mg/kg.
    Residues were observed in other tissues analyzed following
    administration of bioresmethrin (alcohol label): Fat > blood
    > lung > kidney > liver > heart > muscle > spleen >> brain.
    After two weeks excretion was not complete (Ueda, et al., 1975b).
    Qualitative identification of several metabolites of bioresmethrin was
    performed. No unmetabolized bioresmethrin was excreted. The
    metabolites most slowly excreted (persisting longest in the body)
    arise from the alcohol-labelled bioresmethrin. Those arising from the
    acid moiety are rapidly excreted.

    Biotransformation

         Information on the fate of bioresmethrin in laboratory animals
    was discussed by the 1975 Joint Meeting (FAO/WHO, 1976b). Some of this
    is repeated in the extended discussion which follows.

         The biodegradation of bioresmethrin is a complex phenomenon with
    several reactions occurring simultaneously and taking place at various
    positions in the molecule. The initial step in the metabolism is
    cleavage at the ester linkage, a reaction found to be catalyzed by
    esterases localized in the liver microsome. Transisomerization was
    reported with bioresmethrin but was apparently limited to
    isomerization of degradation products, not observed with the parent
    molecule and seen only when bioresmethrin was administered at low

    levels. Transisomerization was not noted on administration of higher
    levels by ip injection (low dose = 1 mg/kg; high dose = 3 gm/rat over
    a period of 3 days administered 2X/day). Transisomerization occurred
    only with the acid portion of the molecule as observed in Figure 1
    (tE-CAA cE-CDA), which shows the probable metabolic route for both
    the acid and alcohol moieties of bioresmethrin in rats.

         In vitro studies with rat and mouse liver preparations
    suggested mouse liver esterases hydrolyze bioresmethrin
    ((+)-trans-resmethrin isomer) rapidly relative to the corresponding
    cis-isomers ((+)-or (-)-cis-resmethrin) while microsomal enzymes
    oxidize the (+)-trans-isomer, bioresmethrin, more slowly than the
    cis-isomers (Ueda et al., 1975a). When administered to rats
    bioresmethrin undergoes a complicated series of reactions involving
    initial ester cleavage and subsequent oxidation with or without
    conjugation of both the acid and alcohol metabolites.

         Bioresmethrin is degraded by ester cleavage and the alcohol
    moiety is oxidized to 5-benzyl-3-furylmethanol (BFA),
    5-benzyl-3-furoic acid (BFCA), 4'-hydroxy BFCA and alpha-hydroxy BFCA
    (alpha-OH-BFCA). The chrysanthemate (acid) moiety undergoes oxidation
    from trans-chrysanthemic acid (tE-CHA) to
    2,2-dimethyl3-(2'hydroxymethyl-1'-propenyl)cyclopropanecarboxylic acid
    (tE-CHA) (oxidative metabolism at the methyl group of the isobutenyl
    side chain trans (E) to the cyclopropane). This is further oxidized
    through the formyl derivative (CAA) to the dicarboxylic acid isomers
    (tE-CDA and cE-CDA). It is at the CAA oxidation stage where
    isomerization may occur through the proposed aldehyde (cE-CAA)
    intermediate to (cE-CDA) the cis-dicarboxylic acid (Ueda et al.,
    1975b). This metabolic sequence may also account for the consideration
    of Verschoyle and Barnes (1972) that as a delay in signs of poisoning
    was evident following iv administration, bioresmethrin may be
    converted in vivo to a toxic metabolite. The presence of
    (+)-trans-CA,-BFA and BFCA as metabolites, which are more toxic than
    bioresmethrin, may account for their observation and conclusions. The
    metabolic sequence is very similar qualitatively to that observed with
    resmethrin although much less complicated because of the lack of
    isomeric products (Miyamoto et al., 1971) and because of the
    specificity of certain isomers to enzymatic degradation by selected
    routes as mentioned above (Ueda et al., 1975a, b; Abernethy and
    Casida, 1973).

    TOXICOLOGICAL STUDIES

    Special study on teratology

         Groups of pregnant rabbits (4-6 rabbits/group) were administered
    bioresmethrin in doses of 0, 10, 20, 40 and 80 mg/kg by oral gavage
    daily from day 8-16 of gestation. The does were sacrificed on day 28
    and examined for implantation, live and dead fetuses, resorption sites
    and abnormalities (after staining a representative number for skeletal
    examination). There was no apparent effect on parents in the study as

    FIGURE 3

    growth and gestation were unaffected. There was an increase in dead
    fetuses at the highest dose and a large number of resorption sites
    noted at all treatment levels. There were a number of deformed fetuses
    observed but the total numbers were not sufficient for an adequate
    statistical evaluation. The deformities included straight tail,
    crossed hind limbs and unilateral union of 6th and 7th ribs at the
    sternal end. An overall fetal loss was observed at all dose levels
    (primarily because of the large number of resorption sites recorded).
    (Waldron, 1969).

    Special studies on potentiation

         Groups of rats (6 female rats/group) were administered
    bioresmethrin, bioallethrin and/or piperonyl butoxide alone and in
    combinations at doses approximating the acute ip LD50 value. No
    potentiation of the acute toxicity was observed in this study. In all
    cases with bioresmethrin combinations, the observed LD50 values were
    equal to or exceeded the expected value (Wallwork and Malone, 1971).

    Special studies on irritancy and sensitization

         Groups of adult guinea pigs (6 males/group) were tested with
    bioresmethrin (0.1 ml of a 5% (w/v) formulation) or
    2,4-dinitrochloro-benzene (DNCB) (0.1 ml of a (1% w/v) formulation in
    mineral oil) to assess the sensitization properties. The test
    substance was applied to the ears for 4 days. On day 7, 0.2 ml was
    applied dermally and the degree of irritation recorded. As expected,
    the DNCB was an irritant while bioresmethrin showed only traces of
    erythema suggesting a low potential for sensitization and irritation
    (Chesher and Malone, 1970b).

         Instillation of technical bioresmethrin into the eye of rabbits
    (0.1 ml) produced no irritation or corneal damage. A group of six
    rabbits was treated with no indication of ocular hazard (Chesher and
    Malone, 1970c).

    Acute toxicity

                                                                                         
                                            LD50
    Species     Sex     Route               (mg/kg)        Reference
                                                                                     
    Rat         m       oral                8800           Glomot & Chevalier, 1969
                f       oral                >8000          Verschoyle & Barnes, 1972
                f       oral                7071           Wallwork, et al., 1970
                f       iv                  340            Verschoyle & Barnes, 1972
                f       iv                  106-133        Chesher and Malone, 1971a
                f       ip                  >8000          Wallwork & Malone, 1971
                f       inhalation          >872 mg/m3     Wallwork & Malone
                        (24 hr exposure)
                f       dermal              >10000         Wallwork et al., 1970

                                                                                     
                                            LD50
    Species     Sex     Route               (mg/kg)        Reference
                                                                                     
    Mouse       f       oral                >10000         Wallwork et al., 1970
                m       oral                3100           Ueda, et al., 1975b
                f       ip                  5359           Wallwork et al., 1973
                m       ip                  >1500          Ueda et al., 1975b

    Rabbit

    Chicken             oral                >10000         Wallwork et al., 1970
                                                           Chesher & Malone, 1970a
                                                                                     
    
         Signs of poisoning: After 2 or more hours following oral
    administration, tremors occurred; animals were sensitive to each other
    and aggressive. The final stages of poisoning consisted of convulsive
    twitching, prostration, coma, and death normally between 3 and 24
    hours.

         Mode of action: The nervous systems of both vertebrates and
    invertebrates are equally sensitive and respond in a similar manner to
    pyrethins (both natural and synthetic). The uncoordinated tremors of
    the rat are similar to those signs of poisoning generally associated
    with organochlorine pesticides.

    Acute toxicity of metabolites

                                                                     
                                                           LD50
                                                         (mg/kg*)
    Metabolite                                          ip      Oral
                                                                     
    1)  (+)-trans-resmethrin (bioresmethrin)         >1500      3100
        (5-benzyl-3-furylmethyl (+)-trans-
        chrysanthemate)

    2)  (+)-cis-resmethrin 1                           320
        (5-benzyl-3-furylmethyl (-)-cis-
        chrysanthemate)

    3)  (+)-trans-CA (t-CA)                             98      280
        (*)-trans-chrysanthemic acid

    4)  (+)-cis-CA (c-CA)1                             600
        (+)-cis-chrysanthemic acid

    5)  (+)-trans-CDA. (tE-CDA)                        408
        (+)-trans-chrysanthemumdicarboxylic acid

                                                                     
                                                           LD50
                                                         (mg/kg*)
    Metabolite                                          ip      Oral
                                                                     
    6)  BFA                                             75      310
        5-benzyl-3-furylmethanol
    7)  BFCA
        5-benzyl-3-furoic acid                          46
                                                                     
    *LD50 - male mouse 24-hour toxicity following intraperitoneal
              injection.
    1  Cis isomers (numbers 2 and 4) are not metabolites of
       bioresmethrin.
       Cis isomers are metabolites in degradation of resmethrin.
       (Ueda et al., 1975b; Miyamoto, 1975, 1976)

    Short-term studies

    Rat

         Groups of rats (10 males/group) were administered bioresmethrin
    orally by gavage daily, six days per week for three weeks at doses of
    0, 1000 and 2000 mg/kg body weight. There was no mortality
    attributable to bioresmethrin. There was a slight reduction in weight
    at 2000 mg/kg. Haematology was normal with a slight reduction noted in
    haemoglobin content and hematocrit value. Albumin and BUN were
    increased while SGOT activity was reduced. At the end of three weeks
    gross examination of major tissues showed slight effects on liver
    (increased size), reduced thymus weight (both organs affected at 1000
    mg/kg), and reduced prostate (only at the high dose). Histological
    examination showed only thymic involution without structural changes
    with no effects noted in liver (Glomot, undated).

         Groups of rats (18 males and 18 females/group) were fed
    bioresmethrin in the diet at concentrations of 0, 400, 1200 and 8000
    ppm (the latter dose group was fed 4000 ppm for 30 days and the level
    increased thereafter) for 91 days. There was no mortality observed in
    this study. Food consumption was normal and food conversion was
    unaffected by bioresmethrin in the diet. Growth was reduced at the
    highest dose level which was accompanied by changes in blood chemistry
    parameters indicating liver dysfunction (SAP, SGOT, and urinary
    nitrogen increased at 90 days, glucose content reduced). Depression of
    red blood cell count was observed at 1200 ppm although no consistent
    parallel changes were seen in hemoglobin content or packed cell
    volume. Urinalyses were normal. Gross and microscopic analysis of
    tissues and organs showed an increase in liver weight at 4000 ppm and
    a decrease in several other organs (spleen, heart, brain, thymus.
    prostate, ovary and uterus at 1200 and 4000/8000 ppm fatty
    infiltration of liver was seen on microscopic examination. A no-effect
    level in this study would be 400 ppm equivalent to an average daily
    intake of 32.8 to 36.1 mg/kg body weight for males and females
    respectively (Wallwork et al., 1971).

    Dog

         Groups of dogs (2 of each sex/group) were administered
    bioresmethrin by gavage, daily at dose levels of 0 and 500 mg/kg body
    weight for 7 days followed by a dose increase to 1000 mg/kg for a
    further 14 days. There were no effects noted in this test with respect
    to mortality, behaviour, body weight changes, hematology, blood
    chemistry or urinalysis parameters or on electrocardiograph
    measurements. Short-term administration for three weeks at an oral
    dose of 1000 mg/kg was uneventful in the parameters measured (Malone
    and Chesher, 1970).

         In a continuation of the above trial, after a two-week interval
    on control diets, dogs were administered bioresmethrin by gavage for 7
    days at a dose of 2000 mg/kg body weight. Again no significant effects
    were noted in the parameters recorded above (Chesher and Malone,
    1970b).

         Groups of dogs (3 male and 3 female/group) were administered
    bioresmethrin by gavage in gelatin capsule, daily for 90 days at
    dosage levels of 0, 25, 80 and 250 mg/kg (the high dose was increased
    to 500 mg/kg in week 7). There was no mortality. Growth, food
    consumption and calculated food utilization parameters were normal.
    Clinical biochemistry, ophthalmological and urinalysis parameters were
    normal at all intervals (30, 60 and 90 days) examined. In the high
    dose group, reduced RBC count, hemoglobin content and packed cell
    volume values were noted. BUN was slightly increased only at the high
    dose after 12 weeks. There were no adverse effects noted on gross or
    microscopic examination of tissues and organs (including bioresmethrin
    bone marrow). A no-effect level was observed to be 80 mg/kg
    (equivalent to an average of 1600 ppm in the diet) (Noel et al.,
    1971).

    OBSERVATIONS IN MAN

    None.

    COMMENTS

         Bioresmethrin is the common name for the
    (+)-trans-chrysanthemate ester of 5-benzyl-3-furylmethanol, a
    synthetic pyrethroid insecticide. Bioresmethrin is a component of
    another synthetic pyrethroid, resmethrin, whose toxicological
    properties have not been evaluated. Resmethrin consists of a mixture
    of isomers having the empirical formula C22H2603.  The mixture is
    made up of approximately 65% trans-(bioresmethrin, approximately one
    half of this fraction, is the (+)-trans-isomer) and 35%
    cis-isomers.

         In general, the (-)-isomers have low biological activity. The
    (+)-cis-isomer of bioresmethrin is acutely more toxic than
    bioresmethrin. Bioresmethrin is relatively non-toxic on an acute basis

    and readily degradable. In animals, it is absorbed rapidly from the
    gut and translocated partially to the lipid portions of the body.
    Bioresmethrin is excreted slowly, probably owing to its lipophilicity.
    It has been shown to reflect a delay in the onset of acute signs of
    poisoning possibly owing to delay in ester cleavage which results in
    more toxic (hydrolysis) products. Bioresmethrin is metabolised by
    oxidation and hydrolysis occurring at various sites in the molecule.
    There is no evidence for isomerisation of bioresmethrin to the
    (+)-cis-isomer which might result in greater toxicity.

         Several short term toxicology studies in rat and dog are
    available. Bioresmethrin is not a teratogen although at high levels it
    has been shown to induce some fetal abnormalities and fetal mortality.
    Bioresmethrin is nonirritating and does not induce a sensitisation
    reaction. In short term studies at high doses, thymic atrophy was
    noted over a 3 week test period. This was accompanied by increased
    liver size. In rats reduced growth, dysfunction, and fatty
    infiltration of the liver were observed in a 90 day study at dietary
    levels of 1200 ppm and above. In dogs, several hematological
    parameters were affected at dose levels of 250 and 500 mg/kg, as noted
    over a 90 day period. No-effect levels were noted based on short term
    studies only. There were no observations in man available for
    consideration.

         Although short term studies were available along with several
    special studies which did not specifically raise any unusual
    toxicological factors, the absence of data from long term studies
    precluded the Meeting from estimating an ADI for man. In concurrence
    with previous conclusions, the Meeting expressed its need for
    evaluation of long term studies in its consideration of an ADI for
    man. This is especially important in the case of bioresmethrin, owing
    to the fact that this synthetic pyrethroid is the first of a chemical
    class of pesticides projected for extensive use in future. Although
    bioresmethrin effects have been observed only at relatively high dose
    levels in short term studies, the potential for adverse toxicological
    effects in long term studies needs to be evaluated.

    TOXICOLOGICAL EVALUATION

         No ADI for man was allocated.

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         The high potency and broad spectrum activity of bioresmethrin
    could be expected to lead to a wide field of use. Susceptibility to
    rapid degradation by light and the availability of several other
    synthetic pyrethroid insecticides with much superior stability to
    light has however almost completely discouraged interest in
    bioresmethrin for use against pests of fruit, vegetable or forage
    crops.

         In addition to the widespread use of bioresmethrin against pests
    of households and of public health there has been considerable
    interest in its use for the control of insect pests of stored
    products, particularly the lesser grain borer, Rhyzopertha
    domenica, which is not controlled by acceptable rates of
    organophosphorus insecticides.

         The 1975 monograph (FAO/WHO, 1976b) reviewed many scientific
    papers on the properties and usefulness of bioresmethrin against
    stored product pests. Since the preparation of the monograph a number
    of additional studies have been completed.

         Desmarchelier (1976) showed that combinations of pyrethroids,
    which are particularly effective against Rhyzopertha domenica, and
    organophosphorus insecticides which are effective against Tribolium
    castaneum controlled both species for as long as the pyrethroid
    alone controlled Rhyzopertha domenica and the organophosphorus
    compound alone controlled Tribolium castaneum. Bioresmethrin was by
    far the best of the many pyrethroid compounds examined.

         Bengston et al (1976a) reporting extensive field trial to compare
    a range of grain protectant insecticides showed that none of the five
    organophosphorus insecticides evaluated was adequate to control
    Rhyzopertha domenica, which lived and reproduced in all samples
    including those drawn immediately after insecticide application.

         Bengston et al. (1976b) demonstrated, in commercial scale trials,
    the outstanding performance of several organophosphorus grain
    protectants when combined with bioresmethrin. Complete protection was
    obtained against all strains of all species of stored product pests
    and reproduction was completely inhibited for many months.

         The development of organophosphorus- and fumigant-resistant
    strains of many stored product pests (Champ and Dyte, 1975) in most
    countries and in all continents points to the urgency of having
    available acceptable insecticides which have different properties and
    modes of action. Supplies of natural-pyrethrum are not adequate to
    meet the developing emergency.

         Australian authorities have approved the use of bioresmethrin at
    the rate of 2 mg/kg for the control of Rhyzopertha domenica and
    other insect pests of wheat, oats and barley to protect valuable
    stocks of grain and to ensure compliance with the phytosanitary
    requirements of grain-importing countries. It is understood that
    similar action has been taken in a number of other countries.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    Pre-harvest treatments

         No further information on the level or fate of bioresmethrin
    residues on fruit or vegetables has become available. In view of the

    advances which have been made with the development of several other
    pyrethroid insecticides with outstanding efficacy against a wide range
    of pests combined with a high level of stability to light it appears
    unlikely that bioresmethrin will be developed or utilised for
    pre-harvest application.

    Post-harvest treatments

         Extensive commercial scale trials were carried out in Australia
    during 1976 at 20 sites involving 42 silos each containing from 2,000
    to 8,000 tonnes of wheat. The wheat had been placed in storage
    directly from the harvest. The temperature of the grain ranged from
    27 to 39C and the moisture content from 9.2% to 12.0%.
    Pirimiphos-methyl or fenitrothion was applied in the form of a dilute
    emulsion at the rate of 1 litre/tonne to give a deposit of 5 mg/kg of
    pirimiphos-methyl or 10 mg/kg of fenitrothion. Bioresmethrin emulsion
    was added at the same time to give a nominal deposit 1 mg/kg. The
    amount deposited was estimated from the quantity of emulsion used.
    Samples were withdrawn for bioassay and for chemical analysis at
    regular intervals for 9 months. The temperature of the grain was
    recorded over this period. Figure 2 illustrates the rate of decline of
    the bioresmethrin deposit with time (Desmarchelier et al., 1976a). The
    variations in the amount found at any one interval after application
    are not particularly great but are no doubt due to variations in
    temperature, grain moisture and amount of bioresmethrin applied at
    each separate site.

         These data confirm earlier studies under laboratory conditions
    which indicate that the half-life of bioresmethrin in stored grain is
    directly dependent on temperature. At 30-35C the half-life is 8-10
    weeks whilst at 20C it exceeds 26 weeks. This degree of stability is
    greater than that shown by malathion under similar conditions and
    increases the effectiveness of bioresmethrin as a grain protectant
    insecticide. Because the stability is combined with potency against
    the target species it is not necessary to use concentrations above 2
    mg/kg even on grain stored at relatively high temperatures.

    FATE OF RESIDUES

    In animals

         The metabolism of bioresmethrin in the rat and mouse is described
    above ("Biochemical aspects")

    In grain

         One of the questions remaining in doubt at the 1975 Meeting was
    the fate of bioresmethrin on different classes of raw grain.
    Preliminary results of an on-going official study in Australia
    indicate that there is no significant difference in the stability
    (persistence) of bioresmethrin deposits on different types of raw
    grain held at 25C under comparable moisture regimes (Desmarchelier,


    FIGURE 2
    1976b). Twenty kg quantities of barley, oats, rice in husk, husked
    rice, polished rice and wheat were treated under standardised
    conditions with a dilute emulsion of bioresmethrin/piperonyl butoxide
    (1:5) at a rate designed to deposit 7 mg bioresmethrin per kg of
    grain. The amount applied was deliberately high to enable the effects
    of long term storage and processing to be compared and to ensure that
    analytical difficulties would not interfere. The grain was held in a
    constant temperature room at 25C and was sampled after 3 and 6
    months.

         Table 1 compares the level of bioresmethrin found in each type of
    grain after 3 and 6 months in storage.

    TABLE 1. Effect of storage at 25C on bioresmethrin residues on
    various grains
                                                                     

                                                Residue*, mg/kg
                                                after storage for
                                                                     
    Grain                moisture %         3 months       6 months

    Barley               13.0               3.5            1.75

    Oats                 12                 3.5            2.0

    Rice in husk         13                 1.5            1.5

    Husked rice          12.5               3.5            1.5

    Polished rice        12.7               3.5            1.5

    Wheat                11.0               3.5            2.0
                                                                     
    * Original rate of application = 7.0 mg/kg

    In processing and cooking

         The 1975 Meeting indicated that further information on the level
    and fate of residues in food at the point of consumption was
    desirable. Studies involving barley, oats, rice and wheat were
    initiated in Australia and preliminary results were made available to
    the present Meeting (Desmarchelier et al., 1976b). In these tests, a
    portion of the barley, oats, husked rice, milled rice and wheat in the
    storage experiment described above was withdrawn for processing and
    cooking after 3 months. The barley was subjected to a simple malting
    process after which the bioresmethrin content had declined from 3.5
    mg/kg to 1.5 mg/kg. The oats were crushed and were then boiled for 15
    minutes in the smallest quantity of water that would cover the grains.
    The residue level fell from 3.5 mg/kg to 1.5 mg/kg during cooking. The
    husked and the polished rice were likewise boiled in minimal

    quantities of water for 15 minutes after which the residue level had
    declined from 3.5 mg/kg to 2.5 and 2.0 mg/kg respectively. A portion
    of the same husked rice was found to contain only 0.5 mg/kg of
    bioresmethrin after being cooked for 25 minutes.

         The rice in husk, after 6 months storage, was subjected to
    milling, firstly for the removal of husk and then for the removal of
    bran, followed by polishing. Removing the husk reduced the
    bioresmethrin level from 1.5 mg/kg to 0.25 mg/kg. Further milling and
    polishing reduced the residue on the polished rice to 0.1 mg/kg.

         The treated barley which had been in storage for 6 months was
    subjected to a standard commercial malting process. There was no
    reduction of germination and the prepared malt contained only 0.35
    mg/kg of bioresmethrin, a reduction from 1.75 mg/kg on the barley
    before malting. Table 2 summarizes the results.

    METHODS OF RESIDUE ANALYSIS

         The methods available for residue analysis were reviewed in 1975
    (FAO/WHO 1976b). Since then several further papers have been
    published.

         Simonaitis and Cail (1975) used a gas chromatographic method with
    flame ionisation detection for the determination of resmethrin in
    maize, cornmeal, flour and wheat. The minimum detectable concentration
    of resmethrin was 0.2 mg/kg (determined on a standard solution of
    resmethrin) and an average recovery of 83% was achieved on the four
    commodities studied over the range 0.2 to 3.2 mg/kg. Reproducibility
    was claimed to be good. Desmarchelier (1976a) applied four detection
    systems to the determination of pyrethroids on grains. The first was
    that of Andrews (1974), a TLC method for which a minimum detectable
    concentration of 0.06 mg/kg was claimed in the original paper when
    estimating resmethrin in foliage. The second was that of Heath (1972),
    a GLC method used for formulation analysis. No limit of determination
    is quoted. The third was based on the spectrophotometric method of
    McClellan (1964). The limit of determination is given as 0.5 mg/kg
    since below this value background interference from the commodity
    becomes relatively large. The fourth was a mixture of the first and
    third. Recoveries by all four methods on wheat, bran, pollard, flour
    and bread when fortified with 0.5 to 4.0 mg/kg bioresmethrin were
    between 90 and 102%. All four methods gave comparable results for any
    one sample. The limit of detection for methods one and four was 0.2 to
    2.0 g. This could be improved to 0.02 to 0.05 g by purification of
    the commodity extract. The author points out that the two major
    problems with all four of the methods investigated were the relative
    insensitivity and lack of selectivity as compared for example with the
    electron capture GLC of chlorinated compounds and the flame
    photometric detection of phosphorus compounds respectively.


    
    TABLE 2. Fate of bioresmethrin in various grains processed after storage at 25C

                                                                                      

                                     Residue                                Residue
                        Storage      after                                  after
                        period,      storage                                processing
    Grain               (months)     (mg/kg)*     Processing                (mg/kg)*
                                                                                      

    Barley              3            3.5          primitive malting         1.5

    Barley              6            1.75         commercial malting        0.35

    Oats                3            3.5          boil 15 minutes           1.5

    Rice in husk        6            1.5          husked                    0.25
                                                  milled/polished           0.1

    Husked rice         3            3.5          boiled 15 minutes         2.5

                                                  boiled 25 minutes         0.5

    Polished rice       3            3.5          boiled 15 minutes         2.0

    Wheat               3            3.5          bran                      5.5
                                                  shorts                    3.5
                                                  flour                     2.5
                                                  white bread               <0.1
                                                  wholemeal bread           1.0
                                                                                      

    * Original rate of application = 7.0 mg/kg.

    

         A method for the determination of bioresmethrin residues on wheat
    by high-speed liquid chromatography has been developed by Gunew
    (1976). This is claimed to be highly specific and to have a limit of
    determination of 0.02 mg/kg.

         Bioresmethrin is extracted from the wheat sample using 25%
    acetone in hexane with intermittent shaking for 24 hours. The raw
    extract is cleaned up on a column of alumina, and after evaporation of
    the eluate, addition of O-chloroaniline as internal standard, and
    volume adjustment an aliquot is injected into a microparticulate
    silica gel column fitted with a pre-column. A variable wavelength
    spectrophotometer set at 225 nm is used as detector. Use is made of
    peak height ratios to determine the concentration of bioresmethrin in
    the wheat.

    NATIONAL TOLERANCES REPORTED TO THE MEETING

         The Meeting was aware that the following national tolerances had
    been established.

         Australia

              raw grain                                    5 mg/kg

              milled products from grain                   5 mg/kg

              cooked cereal products including bread       0.05* mg/kg

         France

              raw grain                                    4 mg/kg

              *at or about limit of determination

    APPRAISAL

         Following the evaluation of bioresmethrin by the 1975 Joint
    Meeting a number of additional items of information that were
    considered desirable have been made available.

         It appears that bioresmethrin will not be developed for use on
    fruit and vegetable crops or for direct application to livestock.
    However there is an important and major use as a grain protectant
    insecticide on the whole range of stored grain. Extensive information
    on the level and fate of bioresmethrin on several types of raw grain
    and processed cereals has been evaluated and has been published in
    this and the previous (1975) monograph. The new information confirms
    and extends that previously available.

         New methods for the analysis of bioresmethrin residues on raw
    grain have been published. These have not been evaluated for
    regulatory purposes.

         The further information evaluated by the Meeting has confirmed
    the guideline levels recorded previously and has satisfied the needs
    of the Meeting for the information recorded as desirable in 1975 for
    the evaluation of residues in food. No additional guideline levels are
    recorded.

    FURTHER WORK OR INFORMATION

    REQUIRED (before an acceptable daily intake can be allocated)

    1. Long-term studies.

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    See Also:
       Toxicological Abbreviations
       Bioresmethrin (ICSC)
       Bioresmethrin (WHO Pesticide Residues Series 5)
       Bioresmethrin (Pesticide residues in food: 1991 evaluations Part II Toxicology)
       Bioresmethrin (UKPID)