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    PESTICIDE RESIDUES IN FOOD - 1981


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    EVALUATIONS 1981







    Food and Agriculture Organization of the United Nations
    Rome

    FAO PLANT PRODUCTION AND PROTECTION PAPER 42

    pesticide residues in food:
    1981 evaluations

     the monographs

    data and recommendations
    of the joint meeting
    of the
    FAO panel of experts on pesticide residues
    in food and the environment
    and the
    WHO expert group on pesticide residues

    Geneva, 23 November-2 December 1981

    FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS
    Rome 1982

    PERMETHRIN

    Explanation

         Permethrin was first evaluated in 1979 when a temporary ADI was
    proposed and recommendations were made for MRLs in a wide range of raw
    agricultural commodities.* In 1980, the Meeting considered post-
    harvest uses of permethrin as a grain protectant insecticide and
    recommended MRLs for cereal grains and milled cereal products.

         In 1979 further information was required or desired on potential
    bioaccumulation of the compound and/or its metabolites; observations
    in humans to evaluate possible susceptibility to neurological effects
    noted in rodents; results of additional supervised residue trials on
    oranges and other citrus varieties in representative citrus-growing
    countries; results of additional residue trials on spinach and other
    leafy vegetables, meat, milk and eggs; information on world-wide good
    agricultural practices (i.e. authorized national use patterns);
    information on any future changes in manufacturing processes that
    substantially alter the ratio of cis : trans isomers in the technical
    grade product; characterization studies on the photodecomposition
    products; selected surveys of residues in crops known to have been
    treated under practical circumstances.

         A number of other matters, outstanding in 1979, were dealt with
    at the 1980 Meeting.

         Information has been provided to enable the Meeting to consider
    each of these topics and several questions that arose at the 13th
    Session of CCPR.

    Information on identity and properties

         The 1979 Meeting listed as Required "Information on any future
    changes in manufacturing processes which substantially alter the ratio
    of cis- and trans- isomers in the technical grade product". There has
    been no change since 1979 in the material sold by the four principal
    manufacturers and it is not anticipated that there will be a change in
    the foreseeable future. Material of approximately 40:60 cis:trans
    isomer ratio is produced most readily by the manufacturing procedures
    being used by most of the major manufacturers internationally.

         The Meeting recognized that there are at least two manufacturers
    producing permethrin with a 25:75 cis:trans ratio and information on
    the properties, fate and residues of such isomeric mixture has been
    received. The Meeting is therefore able to consider the consequences
    of such isomeric mixtures being applied to livestock and starch grain.

              
    *  See Annex II for FAO and WHO documentation.

         In this review, as in 1979 and 1980, the term "permethrin" refers
    to material which is nominally 40:60 () cis:trans permethrin, unless
    otherwise indicated.

         Permethrin (25:75) contains not less than 93% of permethrin with
    a cis:trans isomer ratio of approximately 25:75. The Meeting received
    details of the composition and concentration of impurities in the
    technical material together with relevant specifications and methods
    of analysis.

         Rickett (1981) reviewed the available information on the
    mechanisms and conditions required to obtain isomerization of
    permethrin. The following conclusions have been drawn:

    1.   Interconversions of permethrin isomers involve fission of the 1,3
         bond of the cyclopropane ring via a triplet excited state with
         energy greater than 60 kcal -1.

    2.   In solution, the rate of isomerization is solvent-dependent and
         is fastest in water. The rate can generally be increased by
         adding triplet sensitizers, such as benzophenone or acetone.

    3.   Isomerization is always accompanied by degradation of the
         permethrin. Under field conditions, degradation is a much faster
         process and so isomerization is not of practical significance.

    4.   In the absence of light, no isomerization takes place.

    5.   When changes is isomer ratios are observed under dark conditions,
         these can be explained usually by the lower stability of the
         trans isomer to hydrolysis.

         Rickett and Knight (1976) studied the photostability of the cis-
    and trans- isomers of permethrin and reported that when trans-
    permethrin (NRDC 147), cis-permethrin (NRDC 167) and two samples of
    the racaemic mixture of varying cis:trans ratio (NRD 143) were coated
    onto glass plates at 1g/m2 and exposed to continuous irradiation of
    44 000 lux, degradation of cis/trans isomers occurred, tending towards
    and equilibrium value of 40:60. This was accompanied by racemization.

         Photodegradation in hexane solution produced similar
    interconversion. The rate of degradation was markedly reduced when air
    was excluded from the solution. A gas chromatography method for
    measuring the enantiomeric purity of the acid moiety is described.

         Morgan (1979) studied the fate of the two optical isomers
    following application of a 25:75 mixture to the hair of cows.

         Permethrin (0.1%) was applied to three Friesian cows at a nominal
    rate of 0.5 l per animal, using a knapsack sprayer. Analysis of hair
    samples collected 1, 7, 14 and 21 days after treatment showed no
    significant change in the 25:75 cis/trans isomer ratio of permethrin.

    DATA FOR THE ESTIMATION OF ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, distribution, biotransformation and excretion

         Studies have been performed  in vivo on a wide range of
    mammalian species in order to define better the pharmacokinetics of
    permethrin. An oral dose of the compound is quickly absorbed and
    extensively metabolized to polar materials, which are rapidly
    excreted. Only very small amounts of chemical are taken up by adipose
    tissue, and then principally as the less rapidly hydrolysed cis-
    isomer of permethrin. On cessation of exposure, permethrin is
    eliminated promptly from fat tissues.

    Rat

         Orally-administered permethrin was taken up rapidly by rats.
    After a single dose of 10 mg/kg of 14C-labelled permethrin, a peak
    level of radioactivity in blood was observed within 1.5 h, after which
    it declined. The half-life of elimination of radioactivity from blood
    was approximately 7 h. More than 80% of the orally-administered
    radioactivity was excreted in urine and faeces in 48 h, and at least
    92% was excreted after 7 days. Differences were noted in the pattern
    of excretion of the two isomers: 79 to 82% of the radiolabelled dose
    of the more readily hydrolysed trans isomer was excreted in the urine
    within 12 days, but only 52 to 54% of the cis isomer was excreted in
    the same time.

         The major metabolites of permethrin in the rat are excreted in
    the urine and are derived from ester cleavage. There are the cis and
    trans isomers of 3-(3,3-dichlorovinyl)-2,2-dimethylcyclopropane
    carboxylic acid (DCVA), 3-phenoxybenzoic acid and 3-(4-hydroxy-
    phenoxy)benzoic acid. These are all excreted principally as polar
    conjugates. Hydroxylation at other positions in the 3-phenoxybenzyl
    moiety and of the methyl groups attached to the cyclopropane rings
    represent only minor routes of metabolism. Only a small proportion of
    orally administered permethrin is excreted unchanged (6% in the case
    of cis, 3% in the case of trans) and then only in the faeces (FAO/WHO,
    1980).

         In a bioaccumulation study, female rats were dosed orally with
    40:60 cis:trans 14C-cyclopropyl-labelled permethrin daily at
    0.8 mg/kg bw/day for up to 21 days. This dose level is equivalent to
    approximately 20 ppm in the diet. Groups of three rats were sacrificed

    weekly. At the end of three weeks, dosing was terminated and groups of
    three animals sacrificed after a further one or two weeks. The highest
    mean level of radioactivity found in liver during the dosing period
    was 0.22 g permethrin equivalents/g, and this declined to a non-
    detectable level within a week of cessation of dosing (limit of
    determination: 0.08 g permethrin equivalents/g). Levels of
    radioactivity in kidney and brain were below 0.08 g/g throughout the
    study. The highest levels of radioactivity found were in adipose
    tissues - up to 0.72 g permethrin equivalents/g. These declined to a
    non-detectable level (< 0.08 g/g) within two weeks after cessation
    of dosing (Bratt  et al 1977).

         Another group of rats was dosed orally with 40:60 cis:trans
    14C-methylene-labelled permethrin daily at a dose level of 1 mg/kg
    bw/day for up to eleven weeks. Levels of radioactivity in adipose
    tissue reached a plateau of approximately 1 to 2 g permethrin
    equivalents/g after three weeks. Approximately 87% of the
    radioactivity in the fat was due to permethrin, present principally as
    the cis isomer. The half-life of the material in adipose tissue was
    about 18 days and elimination was complete within 7 weeks of the
    termination of dosing. Plateau levels of 0.2 to 0.7 g permethrin
    equivalents/g in liver and kidney declined to below 0.08 g/g within a
    week of cessation of dosing. Levels of radioactivity in muscle
    remained below 0.08 g/g throughout the study (Bratt  et al 1977).

         Studies to demonstrate the differences and similarities in
    absorption or distribution between the cis- and trans- isomers of NRDC
    143, utilizing whole body and radiography in male rats, have been
    described (Fairbrother 1977). Following single oral administration of
    14C-labelled cis and trans isomers in maize oil, the trans isomer
    was better absorbed from the gut than the cis isomer (the blood level
    being about 5 times higher 2 h after dosing). Both isomers tended to
    remain in the blood; tissues with high blood volumes had the highest
    levels of radioactivity. Radioactivity persisted in storage and depot
    fat, the cis isomer being taken up more than the trans. Both isomers
    were seen in the meninges, but only cis isomer appeared in small
    amounts in CNS tissue. Both isomers provided higher levels of
    radioactivity 6 h after dosing. Both isomers were excreted in the
    urine, but higher concentrations of the cis isomer were found in the
    bile. Although the tissue levels as measured by radiometry suggested
    that the thymus contained activity, at no time was activity detected
    by autoradiography.

         The residence time in the body and the metabolic fate of both the
    acid and alcohol moieties of (1R, trans)-, (IRS, trans)-, (IR, cis)-
    and (IRS, cis)- permethrin were elaborated after these esters were
    administered to male albino Sprague-Dawley rats at dosages ranging
    from 1.6 to 4.8 mg/kg (Gaughan  et al 1977). These trans- and cis-
    isomers of permethrin and of their metabolites were almost completely

    eliminated from the body within a few days. About 3 and 6% of the
    trans- and cis-permethrin doses were excreted in the faeces without
    metabolism, due either to incomplete absorption from the G.I. tract or
    to enterohepatic circulation. Metabolites retaining the ester linkage
    further established the greater  in vivo lability of the ester
    linkage in the trans- compared with cis-permethrin. The cis- compound
    yielded four faecal metabolites, which resulted from hydroxylation at
    the 2'-phenoxy, 4'-phenoxy, of 2-trans-methyl position or at both
    of the latter two sites. Other significant metabolites were
    3-phenoxybenzoic acid (free and glucuronide and glycine conjugates),
    the sulphate conjugate of 4'-hydroxy-3-phenoxybenzoic acid, and
    sulphate conjugate of 2'-hydroxy-3-phenoxybenzoic acid (from cis-
    permethrin only), the trans- and cis-dichlorovinyldimethylcyclopropane
    carboxylic acids (free and glucuronide conjugates) and the 2-trans-and
    2-cis-hydroxymethyl derivative of each of the aforementioned trans and
    cis acids 1 (free and glucuronide conjugates).

         Figure 1 illustrates the metabolic pathways for trans-permethrin
    and cis-permethrin after oral administration to rats. This figure
    depicts the products originating from the (1R)-esters, but the same
    products, in nearly the same proportions, result from administration
    of the (IRS)-esters. As the rate of mouse microsomal metabolism of
    trans-permethrin and cis-permethrin by esterase, oxidase and combined
    esterase and oxidase systems is quite similar for the (1R)- and (1S)-
    and (1RS)-ester (Soderung and Casida 1976), it was suggested by
    Gaughan  et al (1977) that it is also likely that (1S, trans)-
    permethrin and (1S,cis)-permethrin were also metabolized by the
    pathways shown in Figure 1.

    FIGURE 1

         The metabolism of the (1R, trans)- and (1R, cis)-ester of the
    active isomers of permethrin following oral administration of 0.5 to
    2.9 mg/kg to male Sprague-Dawley rats was examined using compounds
    labelled with 14C in the acid or alcohol moieties (Elliot  et al 
    1976). Preliminary results indicated that the organochlorine moiety of
    (1R,trans)-and (1R, cis)-permethrin and the (1R, trans)-dichlorovinyl
    acid was rapidly and almost completely eliminated from the body and
    only traces remained in the fat and liver 4 days after oral
    administration.

         This ease of elimination is associated with the increased
    polarity of the products, which results from rapid  in vivo 
    glucuronidation of the dichlorovinyl acids and, to a lesser extent,
    hydroxylation of one of the germinal dimethyl groups. It appeared that
    at least some of the hydroxylated acids underwent minor degrees of
    conjugation. Much less hydroxylated derivative was formed from the
    (1R, trans)-dichlorovinyl acid itself than from the (1R, trans)-
    permethrin, indicating that permethrin was hydroxylated to some extent
    before hydrolysis. The predominant sites of hydroxylation in the
    dichlorovinyl acid appear to be the 2-cis position for (1R, trans)-
    permethrin and the 2-trans position for (1R, cis)-permethrin.
    (Presumably these methyl groups are sterically favoured at the
    hydroxylation site of the microsomal oxidase system.) Neither the
    parent isomer nor any metabolites of permethrin remained for an
    unusual period or in an unexpected locations in the organs examined.
    Four days after treatment, the residues of permethrin and its
    metabolites in tissues, determined as the total radiocarbon by
    combustion, were below 0.01 ppm permethrin equivalents in blood, bone,
    brain, fat, heart, kidney, liver, lungs, muscle, spleen and testes.
    The largest persistence was for products derived from the 3-phenoxy-
    benzyl alcohol in the fat, liver and kidney. Figure 2 illustrates the
    structures and relative proportions of the metabolites of (1R, trans)-
    and (1R, cis)-permethrin, of (1R,trans)dichlorovinyl acid and of
    3,phenoxybenzyl alcohol.

    FIGURE 2

    Mouse

         Groups of 10 male and 10 female mice were fed permethrin in the
    diet for 4 weeks at dosage levels of 0, 20, 500 and 4 000 ppm to
    compare residue concentrations in adipose tissue with data obtained
    from animals fed similar concentrations for 80 weeks. Residue levels
    were consistently higher in females than in males. The residue levels
    in peritoneal adipose tissue were essentially the same as those seen
    in animals fed for over 80 weeks. There was a rapid build-up to
    equilibrium levels in mice within 4 weeks of dietary exposure (FAD/WHO
    1980).

    Dog

         Dogs were dosed orally with 40:60 cis:trans 14C-methylene-
    labelled permethrin daily at 1 mg/kg bw/day for 10 days. This dose
    level is equivalent to approximately 40 ppm in the diet. Levels of
    radioactivity in adipose tissue 24 h after termination of dosing did
    not exceed 6 ug permethrin equivalents/g. Radioactivity in the fat was
    present as permethrin (Bratt and Slade 1977).

    Cow

         When cows received a single oral dose of 40:60 cis:trans
    14C-labelled permethrin (either cyclopropyl- or methylene-labelled)
    at 2.5 mg/kg bw, equivalent to approximately 80 ppm in the diet,
    levels of radioactivity in milk reached a maximum of 0.13 g
    permethrin equivalents/g after 1 to 2 days. These declined to less
    than 0.02 g/g after 7 days. Levels of radioactivity in the fat were
    0.12 to 0.18 g permethrin equivalents after 7 days. By 14 days these
    had declined to 0.05-0.06 g/g, indicating that the small residues in
    fat are also not maintained on cessation of dosing (Bewick and Leahey
    1976).

         Radiocarbon from 14C-acid- and 14C-alcohol-labelled preparations
    of trans- and cis-permethrin administered orally to lactating Jersey
    cows for 3 consecutive days at approximately 1.0 mg/kg was largely
    eliminated from the body within 12 or 13 days after the initial
    treatment (Gaughan  et al 1978a). Milk and fat residues were
    relatively low. Total 14C-permethrin equivalents in milk were
    consistently below 0.3 g/g and declined to less than 20% of their
    highest values during the 10 days following cessation of exposure.
    Residues recovered from fat and milk were higher when cis-permethrin,
    rather than trans-permethrin, was administered and consisted almost
    entirely (>85%) of unmetabolized permethrin, as well as trace levels
    of cis-permethrin hydroxylated at the methyl group trans to the
    ester functionality. Major excreted metabolites (each 8 to 28% of
    the administered radiocarbon) from both isomers were: the esters
    hydroxylated at the trans-methyl group; the acid moieties hydroxylated
    at the cis-methyl group and the corresponding gamma-lactones;

    3-phenoxybenzyl alcohol; the glutamic acid conjugate of
    3-phenoxybenzoic acid. Additionally, 13 excreted metabolites of trans-
    permethrin and 10 of cis-permethrin were tentatively identified. Total
    14C-permethrin equivalents in blood reached a transient peak shortly
    after each dose and dropped to insignificant levels within 2 to 4 days
    after the last dose. Figure 3 illustrates the metabolic pathways to
    convert trans- and cis-permethrin into more polar derivatives for
    excretion. The permthrin isomers, although fat-soluble materials, were
    rapidly metabolized and excreted by cows so that relatively little of
    these compounds appeared in milk or were retained in tissues for more
    than a few days.

    FIGURE 3

         Table 1 lists the radiocarbon recovery in excreta, milk, tissues,
    organs and gut contents 12 or 13 days after treatment of three daily
    doses of (14C)acid- or (14C)alcohol-trans-and cis-permethrin at
    approximately 1 mg/kg for each dose.

    TABLE 1.  Radiocarbon recovery in excreta, milk, tissues, organs and
              gut contents 12 or 13 days after initiating a treatment
              schedule consisting of three daily doses of (14C)acid- or
              (14C)alcohol-trans- and cis-permethrin at 1 mg/kg for
              each dose
                                                                        

                             Recovery of administered radiocarbon(%)
                                                                        
    Sample                          Trans                    Cis
                             Acid      Alcohol        Acid      Alcohol
                                                                        

    Urine                    38.98      46.71         28.46      22.22
    Faeces                   51.60      57.24         60.06      75.85
    Carbon dioxide1          <0.01      <0.01         <0.01     
    <0.01
    Milk                      0.03       0.44          0.26       0.18
    Fat                       0.15       0.40          1.59       0.64
    Liver                     0.03       0.04          0.08       0.06
    Muscle                    0.01       0.04          0.03       0.11
    Skin                      0.01       0.07          0.04       0.06
    Other tissues             0.04       0.02          0.03       0.04
    Gut contents             <0.01       2.83          0.15       0.05
                                                                        

    Total                    90.85     107.79         90.70      99.21
                                                                        

    1  Collected for 6 days only (includes bile). (Gaughan et al 1978).

         Studies in which non-radiolabelled permethrin was administered to
    cows support the finding that permethrin itself, rather than its polar
    metabolites, consistitutes the predominant part of the small residues
    present in milk and fat. Groups of three cows were maintained for 28
    to 31 days on diets containing 40:60 cis:trans permethrin at 0.2, 1.0,
    10, 50 and 150 ppm in the diet. Two of the cows were then sacrificed
    and the third returned to control diet for a further 8 to 9 days
    before sacrifice. Permethrin itself constituted more than 80% of the
    residue determined in the milk. Mean plateau levels were below
    0.01 g/g at the 0.2 and 1.0 ppm dietary inclusion rates, 0.02 g/g at
    the 10 ppm rate, 0.1 g/g at the 50 ppm rate and 0.3 g/g at the
    150 ppm rate. Milk was analysed for DCVA, 3-phenoxybenzyl alcohol and
    3-phenoxybenzoic acid. The highest metabolite residue detected in the
    milk was 0.03 g/g at the 150 ppm dose rate. In all cases, residue

    levels in milk did not accumulate over the period of the study and
    they declined rapidly, on returning animals to untreated diet, to
    below 0.01 g/g within five days (Edwards and Iswaran 1977; Swaine and
    Sapiets 1981 a,b).

         Permethrin itself constituted more than 85% of the residue
    determined in adipose tissue (Table 2). Levels in peritoneal fat were
    somewhat higher than those in subcutaneous fat, but were still small
    (Tables 2 and 3). The small residues in adipose tissue declined
    noticeably on cessation of exposure (Table 2).

    TABLE 3.  Residues in fat of cows receiving permethrin at
              rates up to 150 ppm in the diet
                                                                        

    Nominal                  Residues (g/g) of permethrin in
    dietary inclusion                                                   
    level (ppm)              Peritoneal fat      Subcutaneous fat
                                                                        

       0.2                  <0.01-0.04           <0.01
       1.0                   0.01-0.02           <0.01
      10                     0.02-0.25           <0.01-0.09
      50                     0.46-1.1             0.10-0.42
     150                     2.8 -6.2             0.96-4.3
                                                                        

         Permethrin itself was also the major component of the small
    residues determined in adductor, pectoral and cardiac muscle. The
    residue levels present were approximately 0.1 to 0.2% of corresponding
    dietary inclusion levels. As found separately by Leahey  et al 
    (1977) in the goat (see below), DCVA, 3-phenoxybenzyl alcohol and
    3-phenoxybenzoic acid were major constituents of the residues in liver
    and kidney. As with milk and fat residue levels in muscle, liver and
    kidney, residues declined rapidly on cessation of exposure of the
    animals to permethrin (Edwards and Iswaran 1977; Swaine and Sapiets
    1981 a,b).

    Goat

         Cis-(IRS) and trans-(IRS)-permethrin, radiolabelled with 14C in
    either the acid or alcohol moiety, were rapidly metabolized and
    excreted after oral administration to lactating Nubian and Nubian-
    Saanen cross goats (Ivie and Hunt 1980). In these studies, each of
    four goats received 10 successive daily oral doses of one of the four
    (14C)-permethrins; each dose ranged from 0.2 to 0.3 mg/kg bw/day,
    depending on the 14C label and isomer given. Twenty six metabolites
    of the permethrin isomers were fully or partly characterized by TLC or
    GLC/MS, and several others (enclosed by brackets in Figure 4) although
    not isolated are logical intermediates in the pathways defined. In the

        TABLE 2.  Residues of permethrin and three major metabolites in tissues of cows receiving
              permethrin at 150 ppm in the diet
                                                                                                             

                                                                     Residue (g/g) of
    Tissue            Feeding                                                                                
    analysed          regime1          Permethrin       Cis +           3-BPAlc          3-PBAcid
                                                        Trans DCVA
                                                        (I and II)      (III)            (IV)
                                                                                                             

    Muscle            Treated          0.10-0.27        0.04-0.14       0.01-0.12       <0.01-0.05

                      Treated plus     0.03-0.07       <0.03           <0.01            <0.01
                      recovery

    Subcutaneous      Treated          2.9 -4.3         0.14-0.33       0.08-0.24        0.04-0.06
    fat
                      Treated plus     0.96-1.2        <0.01            0.05             0.03-0.04
                      recovery

    Peritoneal        Treated          5.4 -6.2         0.16-0.32       0.20-0.29        0.02-0.05
    fat
                      Treated plus     2.8 -3.1         0.09            0.08-0.10       <0.01
                      recovery

    Liver             Treated          0.01-0.03        0.18-0.26       0.72-1.1         0.36-0.57
                      Treated plus    <0.01            <0.01            0.01-0.08        0.03-0.08
                      recovery

    Kidney            Treated          0.16-0.43        0.37-0.49       0.72-0.91        0.19-0.39
                      Treated plus     0.04-0.05       <0.01            0.02-0.05       <0.01
                      recovery
                                                                                                             

    1  Treated - indicates the animals received treated diet for 28-29 days and were then slaughtered.
       Treated plus recovery - indicates the animals received treated diet for 28 days and were
       then returned to untreated diet for a further 8 days before slaughter.
    
    FIGURE 4

    goat, permethrin was rapidly and extensively degraded via hydrolytic,
    oxidative and conjugative reactions, e.g., through hydrolysis of the
    ester linkage, hydroxylation of the cis- or trans-methyl of the
    germinal dimethyl group and hydroxylation of the 4'-position of the
    phenoxybenzyl moiety. Certain of these products were further oxidized
    and/or conjugated with glycine, glutamic acid, glucuronic acid, or
    other unidentified compounds before excretion.

         Unmetabolized permethrin and certain ester metabolites were found
    in faeces, milk and fat from the treated goats, but only metabolites
    arising from ester hydrolysis were found in the urine.

         The patterns of radiocarbon elimination and tissue retention
    by these goats were reported earlier by Hunt and Gilbert (1977) and
    are briefly summarized in Table 4. Urine was the major route of
    radiocarbon excretion in goats treated with (14C-acid) or
    (14C-alcohol) preparations of trans-permethrin, but most of the
    administered radiocarbon was eliminated via the faeces in cis-
    permethrin-treated goats.

    TABLE 4.  Summary of radiocarbon elimination and residue retention by
              lactating goats orally treated for 10 consecutive days with
              (14C) alcohol- or (14C)Acid-labelled cis-(1RS)or
              trans-(1RS)-permethrin isomers1, 2
                                                                        

                          Radiocarbon eliminated     Tissue residues
    Label and isomer          cum % dose                 (ppm)3, 4
                                                                        
                        faeces  urine    milk      liver    kidney   fat
                                                                        

    (14Cacid)-c-per     67.5    25.8     0.66      0.12     0.05     0.23
    (14C-alc)-c-per     51.7    36.4     0.53      0.13     0.05     0.24
    (14C-acid)-t-per    15.0    72.1     0.17      0.04     0.03     0.02
    (14C-alc)-t-per     12.3    79.4     0.24      0.01     0.03     0.02
                                                                        

    1  Data summarized from Hunt and Gilbert (1977).
    2  Goats treated with 10 successive daily oral doses of the
       appropriate (14C) per isomer  (0.2-0.3 mg/kg per d.).
    3  Tissues taken 24 h after last dose.
    4  Other edible tissues contained lower residues.

         Total radioactive residues in milk reached a plateau after
    3 days of 0.02 to 0.05 g permethrin equivalents/g and <0.01 g/g
    respectively for the cis- and trans-isomers. Unmetabolized permethrin
    was a major component of the radioactivity in the milk. The goats were
    sacrificed 24 h after receiving the final dose. Of the edible tissues
    analysed for radiocarbon 24 h after the final permethrin doses, fat,
    kidney and liver contained the highest residues. Radiocarbon retained

    by the tissues and that secreted into the milk were appreciably higher
    in goats treated with cis-permethrin than with trans-permethrin (Table
    4, Hunt and Gilbert 1977). Total radioactivity of the fat of the
    animals receiving the cis-isomer was ten times higher than those
    receiving the more easily hydrolysed trans-isomer and was due mainly
    to unmetabolized permethrin (Hunt and Gilbert 1977; Ivie and Hunt
    1980).

         In another study, goats were orally dosed with 40:60 cis:trans-
    14C-labelled permethrin (cyclopropyl or methylene-labelled) at a rate
    equivalent to approximately 10 ppm in the diet for 7 days. Total
    radioactive residues in the milk reached a plateau of 0.02-0.03 g
    permethrin equivalents/g after 5 days. Of this radioactivity, 30 to
    50% was associated with the butterfat fraction of the milk in which
    total radioactive residues were 0.13-0.27 g permethrin equivalents/g.
    The animals were sacrificed 4 h after receiving the final dose, when
    levels of radiocarbon in meat tissues were as shown in Table 5. Where
    alcohol-labelled permethrin was used, approximately 70% of the
    radioactivity in kidney was due to 3-phenoxybenzoic acid plus
    3-(4-hydroxyphenoxy)benzyl alcohol. A further 15% was due to
    3-phenoxybenzoic acid plus 3-(4-hydroxyphenoxy)benzoic acid. Where
    acid-labelled permethrin was used, approximately 10 to 15% of the
    label in liver and kidney was due to the cis and trans DCVA,
    principally the trans isomer (Leahey  et al 1977).

         It is important to compare the metabolic fate of permethrin in
    the species noted above. With reference to previously published
    studies on the fate of (14C)-permethrin in mammals, specifically rats
    (Elliott  et al 1976; Gaughan  et al 1977) and lactating cattle
    (Gaughan  et al 1978a) the following similarities and differences
    between goats and these mammals were noted by Ivie and Hunt (1980).

    1)   In each of the three species, a greater percentage of an
    administered cis-permethrin dose was eliminated in the faeces than was
    a trans-permethrin dose, a pattern that appears to be most pronounced
    in goats and least in cattle. It was suggested that trans-permethrin
    was absorbed more rapidly than cis-permethrin from the G.I. tract, or
    alternatively, isomer differences in the rates of biliary excretion of
    permethrin and/or its metabolites may account for the above
    observations.

    2)   Although retention of permethrin by tissues and its excretion
    into milk of mammals was minimal, cis-permethrin and its metabolites
    in rat, lactating goat and lactating cattle were retained by tissues
    to a more significant degree than was trans-permethrin.

    3)   Primary metabolism of permethrin in rats involves attack at five
    major sites, including ester cleavage, hydroxylation at the cis- or
    trans-methyl of the germinal dimethyl moiety, and hydroxylation at the
    2' or 4'- position of the phenoxybenzyl moiety. Ester cleavage and

        TABLE 5.  Total radiolabelled residues in tissues of goats receiving 14C-labelled permethrin daily orally for 7 to 10 days
                                                                                                                                      

    Material            Dose level   Duration of       Period between          Total residue (g permethrin equivalents/g)in
    administered        (ppm in      administration    last date and                                                                  
                        diet)        (days)            sacrifice (hours)       Fat            Muscle         Liver          Kidney
                                                                                                                                      

    Permethrin            -10             7                   4                <0.01          <0.014         0.12-0.34      0.31-0.41
    40:60 cis:trans

    Permethrin             -6            10                  24                 0.01-0.03     <0.01          0.01-0.04      0.03
    trans-isomer

    Permethrin             -6            10                  24                 0.22-0.25     <0.01          0.12-0.13      0.05
    cis-isomer
                                                                                                                                      
        4'-hydroxylation are the major routes of metabolism. Cattle and goats
    metabolize permethrin similarly, with the exception that
    2'-hydroxylation apparently does not occur in these ruminants.

    4)   Ester metabolites of permethrin were eliminated primarily through
    the faeces of rats, cattle and goats, in contrast to cattle which
    eliminated large quantities of ester metabolites of both cis-
    permethrin and trans-permethrin in faeces.

    5)   In each species, conjugation of permethrin metabolites before
    urinary excretion was extensive. Rats, cattle and goats eliminated the
    acid moiety in urine primarily as conjugates with glucuronic acid. The
    alcohol moiety was excreted, mostly as phenoxybenzoic acid glucuronide
    or 4'-hydroxyphenoxybenzoic acid-sulphate in rats, but amino acid
    conjugates of phenoxybenzoic acid comprised most of the excreted
    products in cattle and goats. Although conjugation of phenoxybenzoic
    acid with glycine was preferred in goats, conjugation with glutamic
    acid was favoured in cattle.

         The metabolic fate of permethrin in the goat is similar to that
    in the cow. Radioactivity deriving from the oral administration of the
    cis-isomer of permethrin is excreted mainly in the faeces, whereas
    that deriving from the more readily hydrolysed trans-isomer is
    excreted mainly in the urine. Radioactivity in faeces is due
    principally to permethrin and, in the case of cis-isomer, to
    4'-hydroxypermethrin. the predominant urinary metabolites are DCVA and
    3-phenoxybenzoic acid, which are excreted mainly as polar conjugates
    (Ivie and Hunt 1980).

         The major products of the metabolism of permethrin in the cow are
    similar to those in the rat. The most notable differences are that in
    the cow a greater percentage of the administered radioactivity is
    excreted in faeces as intact ester metabolites, notably as 4'-
    hydroxypermethrin. In cow urine, the major degradation product derived
    from the alcohol part of the molecule is 3-phenoxybenzoic acid,
    whereas in rats it is 3-(4-hydroxyphenoxy) benzoic acid. DCVA is the
    major urinary metabolite derived from the acid part of the molecule in
    both rats and cows. In all cases, the major urinary metabolites are
    excreted as polar conjugates (FAO/WHO 1980).

    Hen

         Radiocarbon from 14C-carbonyl- and 14C-methylene-labelled
    preparations of (1RS)-trans- and (1RS)-cis-permethrin administered to
    laying hens for three consecutive days at 10 mg/kg for each dose was
    largely eliminated from the body within 1 day after the last dose, a
    portion as 14CO2 (Gaughan  et al 1978b). The excreta contained all
    and the eggs most of the following compounds: the unmetabolized
    pyrethroids; cis-permethrin hydroxylated at the 4'-position, at the
    methyl group trans to the carboxyl, and at both of these sites; the

    di-chlorovinyl phenoxybenzoic acid and their 4'-hydroxy derivatives;
    sulphate, glucuronide, taurine and other conjugates of these alcohols
    and acids (Figure 5). Residues of unmetabolized trans- and cis-
    permethrin in fat were 0.15 and 0.93 ppm respectively, at 7 days after
    the last dose, and in eggs they reached peak levels of 0.3 and 1.2 ppm
    respectively, at 3 to 4 days after the last dose. Almost half of the
    residues in eggs were unmetabolized trans- and cis-permethrin in the
    yolk and the remainder was a great variety of metabolites in the yolk
    and white, including most of those also detected in the excreta.

         The preference in hydroxylation site based on identified
    metabolites is the same with hens and rats, e.g., phenoxy > cis-
    methyl > trans-methyl with cis-permethrin, In contrast, with cows,
    both trans- and cis-permethrin have the same preference order of
    trans-methyl > cis-methyl = phenoxy.

         Metabolites detected in hens, but not in rats or cows, are the
    cis isomer of trans-hydroxy permethrin sulphate, the trans isomer of
    cis-hydroxy-phenoxybenzyl alcohol-sulphate and Cl2CA-taurine isomers.

         Both hens and rats extensively utilize glucuronic acid and
    sulphate conjugates in excretion of permethrin metabolites, while
    glutamic acid conjugates are most significant in cows

    Trout

         The distribution and metabolism of the cis- and trans-permethrin
    isomers were studied in rainbow trout to evaluate the role of these
    parameters in the differential toxicity of permethrin to fish and
    mammals (Glickman  et al 1981). Both (14C)-permethrin geometrical
    isomers were readily taken up and eliminated by rainbow trout and
    there appeared to be little difference in the rate of uptake of the
    two geometric isomers. Elimination half-lives for (14C)-permethrin
    residues in trout tissues, with the exception of fat, were in the
    magnitude of hours. High concentrations of a polar metabolite
    (glucuronide conjugate of 4'-hydroxypermethrin) were found in bile
    within 4 h of cis- and trans-permethrin exposure. Urine contained a
    small amount of a polar metabolite that was resistant to hydrolysis by
    beta-glucuronidase but was cleaved to some extent by aryl-sulphatase.
    The relative absence of permethrin hydrolysis products in trout bile
    and the small amount of radioactivity excreted in urine suggested that
    the ability of rainbow trout to hydrolyse permethrin  in vivo was
    minimal. The inability of the rainbow trout to hydrolyse permethrin
    rapidly may result in an overall low rate of detoxification, which was
    suggested to be a possible factor in the trout's sensitivity to the
    compound, particularly the trans-isomer. However, it was also noted
    that detoxification may not be the sole factor, as the trout may be
    more sensitive physiologically than mammals to permethrin (Glickman
     et al 1981).

    FIGURE 5

    Figure 5. Metabolic pathways for (1 RS)-trans- and 
    (1 RS)-cis-permethrin in hens showing abbreviations used for 
    metabolites. Numbers in parentheses are percentage amounts of 14C
    for each product derived from  trans- and  cis-permethrin as
    follows: E = products in excreta from the first 3 days of the treatment
    schedule relative to total administered 14C (see Table I);
    Y = products in egg yolk at days 5 and 6 of the treatment schedule
    relative to total 14C content of yolk (see Table III). Ester
    products are averages for 14C acid and 14C alcohol preparations
    and cleavage products are based on either 14C acid or 14C
    alcohol preparations, as appropriate.

    Effects on enzymes and other biochemical parameters

         Carp liver microsomal esterases hydrolysed trans-permethrin much
    more extensively than cis-permethrin, and the same relationship exists
    for rainbow trout liver microsomes, although they appeared to be less
    active (Glickman  et al 1979). There was a strong preference with
    both isomers and microsomal mixed-function oxidases of both species
    for hydroxylation at the 4'-position of the alcohol moiety as opposed
    to other sites. The methyl group trans to the carboxyl was usually
    hydroxylated more extensively than the cis-methyl group, the greatest
    specificity being with carp microsomes acting on cis-permethrin. The
    bile of rainbow trout exposed  in vivo to 14C-alcohol-labelled
    trans-permethrin contained little or no permethrin but instead
    consisted mainly of conjugates cleaved by beta-glucuronidase but not
    by aryl-sulphatase (Glickman  et al 1979).

         The rates of permethrin hydrolysis in rainbow trout and mouse
    tissues  in vitro were estimated in a recent study (Glickman and Lech
    1981). Mouse liver, kidney and plasma, incubated at 37C, hydrolysed
    trans-(14C)-permethrin approximately 166, 38 and 59 times faster,
    respectively, than the same rainbow trout tissues incubated at 12C.
    At an incubation temperature of 37C, trout liver microsomes
    hydrolysed trans-permethrin approximately 45 times slower than mouse
    liver microsomes. When the total capacity of trout and mouse tissues
    to hydrolyse trans-permethrin ions were compared on a whole body
    basis, mice hydrolysed trans-permethrin 184 times faster than rainbow
    trout (Glickman and Lech 1981),

    TOXICOLOGICAL STUDIES

    Acute toxicity

         (1RS 3RS)-permethrin has an acute oral LD50 of 490 mg/kg for
    male and female mice and >5 000 mg/kg for male and female rats
    (Miyamoto 1976). Various laboratories and even the same laboratory
    (Kadota 1976) reported the rat oral LD50 values of (1RS, 3RS)-
    permethrin to range from about 450 to >5 000 mg/kg. (See Table 6).

         The individual isomers of permethrin have mouse oral LD50
    values as follows: 1R,3S-3 150 mg/kg; 1R, 3R-about 96 mg/kg; 1S,3R and
    1S,3S- >5 000 mg/kg (Miyamoto 1976). The (+)-cis-permethrin is more
    toxic than the trans-isomer (perhaps due to the easier hydrolysability
    of (+)-trans) (Miyamoto 1976). The toxicity of isomer mixtures
    approximates that expected if there is no potentiating effect of one
    isomer component with another (Ruzo and Casida 1977).

        TABLE 6.  Acute toxicity of permethrin in animals
                                                                                         

    Compound       Species     Sex       Route      LD501,2          Reference
                                                    (mg/kg)
                                                                                         

    Racemic3       Mouse       M         Oral       490              Miyamoto 1976
                               F         Oral       490              "
    (+)-trans                  M         Oral       3100             "
                               F         Oral       3200             "
    (+)-cis                    M         Oral       107              "
                               F         Oral       85               "
    (-)-trans                  M         Oral      >5000 (0)         "
                               F         Oral      >5000 (0)         "
    Racemic        Rat         M         Oral      >5000 (20)        "
                               F         Oral      >5000 (0)         "
                               M,F       Dermal    >4000             Kadota 1976
                               M,F       Dermal    >2000             "

                   Acute Inhalation Toxicity4                        Miyamoto 1976

                                                    LC50 mg/m3       Minimum Toxic Dose
                                                                     (mg/m3)

    Racemic        Mouse       M,F                 >685              140
                   Rat         M,F                 >685              140
                                                                                         

    1  Compound dissolved in corn oil; 0.1 ml/10 g bw and 0.5-1 ml/100 g bw administered
       by stomach tube to dd mice and Sprague-Dawley rats respectively;

    2  Figures in paretheses indicate the % mortality at the highest dose;

    3  The trans, cis ratio of the racemic mixture was 3:2;

    4  Experimental conditions: solvent: kerosene; 3 h exposure, air flow 50 l/min.
    
         The effect on the rat acute oral toxicity of changing the
    cis/trans ratio from 80% to 20%/80% in six stages was assessed. The
    LD50 values for the 80% cis/80% trans mixture gave a value of
    approximately 6 000 mg/kg (See Table 7)

         The test demonstrated that the high the cis content the greater
    the toxicity, both in terms of symptoms and mortality. Where the cis
    content was >50%, acute toxic symptoms comprising muscular tremors
    were seen with doses of 250 mg/kg or less. When the cis-content was
    < 40%, no toxic symptoms were seen after oral doses of 250 mg/kg
    (Wallwork  et al 1975).

        TABLE 7.  Acute oral toxicity of permethrin1
                                                                               

    Species   Permethrin cis/trans ratios   Formulation    Sex     LD50 (mg/kg)
                                                                               

    Rat               24/75                 maize oil       M        1 479
                      80/20                 "               F          224.5
                      60/40                 "               F          445.3
                      50/50                 "               F        1 000
                      40/60                 "               F        1 260
                      30/70                 "               F        1 684
                      20/80                 "               F        6 000

    Mouse             25/75                 "               F        2 690
                      25/75                 "               M        2 394

    Chick             25/75                 "               M       >4 000
                                                                               

    1  References - Wallwork and Malone, 1975; Wallwork et al 1975.
    
         The symptoms of permethrin poisoning in mice and rats include
    hypersensitivity, tremor and motor ataxia, sometimes with fibrillation
    and salivation (Miyamoto 1976; Ruzo and Casida 1977; Wallwork and
    Malone 1975; Wallwork  et al 1975).

         The subcutaneous and dermal toxicities are very low as compared
    with the oral toxicity. Permethrin does not cause eye or skin
    irritation or skin sensitizing effects (Ruzo and Casida 1977; Wallwork
    and Malone 1975; Wallwork  et al 1975).

    Short-term studies

    Rat

         Racemic permethrin was administered to 20 males and 20 females SD
    strain rats at dietary concentrations of 375, 750 and 1 500 ppm for 24
    weeks. A slight increase of liver weight was often accompanied by
    liver hypertrophy and fatty change. At a higher level (3 000 ppm)
    there was a slight hypertrophy of hepatoparenchymal cells. These
    effects were considered neither indicative nor suggestive of
    tumorigenicity (Miyamoto 1976).

         In another study, groups of 18 male and 18 female weanling rats
    were fed diets containing 0, 200, 600, 2 000 and 4 000 ppm 21Z73 for
    90 consecutive days. At 90 days, groups of 20 (10 males and 10
    females/group) rats were sacrificed, while the surviving animals were

    offered unmedicated diet for a further 36 days, this being the
    recovery phase. The no-effect level for 21Z73 in the rat was
    determined as 2 000 ppm (equivalent to 175 mg a.i./kg/day) (Williams
    1976).

    Special studies on neurology

         Groups of 10 male and 10 female Sprague-Dawley rats were given a
    diet containing 21Z73 for 21 days at doses of 0, 4 000, 6 000 and
    9 000 ppm. The permethrin contained 24.4% cis and 74.6% trans isomer.
    Severe trembling and abnormal gait appeared in all groups, and the
    animals lost weight. No consistent abnormality was found on detailed
    histological examination of the brain, spinal cord, dorsal root
    ganglia, sciatic and sural nerves, and of terminal motor and sensory
    innervation in proximal (thigh) and distal (lumbrical) muscles from
    half the animals in the control and 6 000 ppm groups, and from all
    animals (term survivors and those dying prematurely) in the 9 000 ppm
    group.

         It was concluded that the clinical disorders produced in the rat
    by 21Z73 were due to a pharmacological effect and not to an anatomical
    lesion (Dayan 1980).

    Special studies on teratogenicity

         Pregnant ICR mice were treated p.o. with racemic permethrin at
    dose levels of 15, 50 and 100 mg/kg/day during days 7 to 12 of
    gestation. Pups were obtained by caesarean section prior to the
    termination of the gestation period and external as well as skeletal
    abnormalities were examined. No significant treatment-related effects
    were found (Miyamoto 1976).

    Special studies on mutagenicity

    Bacteria

         Racemic, (+)-trans-, (+)-cis-, (-)-trans and (-)-cis-permethrin
    dissolved in DMSO were all tested at 10 mg/plate in  Escherichia 
     coli W3623 and W3102 as well as  Salmonella typhimurium TA 1535 and
    1538 strains and were found to be non-mutagenic (Miyamoto 1976).

         In the host-mediated assay (Legator and Malling 1971) both
    (+)-trans-permethrin at dose levels of 3 000 and 600 mg/kg, p.o.
    and (+)-cis-permethrin at dose levels of 54 and 21 mg/kg were
    non-mutagenic (Miyamoto 1976). Table 8 summarizes the system in which
    permethrin was found to have no mutagenic activity (Ruzo and Casida
    1977).

        Table 8   Systems in which permethrin shows no mutagenic activity.
                                                                                                                                                

                                                                                            Metabolic
                                                                                Permethrin  activation    Positive control
    Method                       Species            Strain                      amount      system        and amount                  References
                                                                                                                                                

    Bacterial assays,            Escherichia        W3623trpA: W3102trpE        10.000 a b    No        N-MethyI-N'-nitro-N
     reversion of                coli                                                                   nitrosoguanidine (100);       Miyamoto,
     tryptophan requirement                                                                             4-nitroquinoline N-           1976
                                                                                                        oxide (10)a

                                                                                                        N-Methyl-N'-nitro-N-
                                                    WP2                         1-1000        Yes       nitrosoguanidine (2)          d
                                                                                                        N-Methyl-N'-nitro,N,-         Miyamoto,
    Bacterial assays,            Salmonella                                                             nitrosoguanidine (100);       1976
     reversion of                typhimurium        TA1535:TA1538               10,000a,b     No        4-nitroquinoline-N-
     histidine requirement                                                                              oxide (10)a
                                                                                                        N-Methyl-N'-nitro-N-
                                                    TA 1535                     1-1000a,b     Yes       nitrosoguanidine (2)          d
                                                                                                        9-Aminoacridine (100)         d
                                                    TA1537                      1-1000a,b     Yes       4-o-Tolylazo-o-
                                                    TA 1538. TA98               1-1000a,b     Yes       toluidine (25)                d
                                                                                                        Benzo(a)pyrene (20)           d
                                                    TA 100                      1-1000a,b     Yes       N-Methyl-N'-nitro-N-
    Bacterial assays inhibition  E. coli            W3623 (wild); W3623polA;    10,000        No        nitrosoguanidine (100)        Miyamoto,
     zone of DNA-repair                             W3623uvrA; W3623recA                                (100)                         1976
     deficient mutant as         S. typhimurium     TA1978 (wild); TA1538uvrB   10,000        No        (100)
     compared with wild strain   Bacillus subtilis  H17 (wild); M45recA         10,000        No        Streptozotocin (20)
    Host-mediated bacterial      S. typhimurium     G46                         600 and 3000
     assays, reversion of        -mouse                                         (1R,3S)
     bacterial histidine                                                        21 and 54
     requirement                                                                (1R,3R)                 Ethylmethane sulfonate (620)  g
                                                                                                                                                

    Table 8   (con't)
                                                                                                                                                

                                                                                            Metabolic
                                                                                Permethrin  activation    Positive control
    Method                       Species            Strain                      amount      system        and amount                  References
                                                                                                                                                
    Cultured lymphomal           Mouse              L5178Y/TK+/-                30-125        No        2-Acetylaminofluorene (50)    g
     cells                                          L5178Y;TK+/-                16-94         Yes       Trimethylphosphate (679)      i
    Dominant lethal system       Mouse              Charles River CDI           452
                                                                                                                                                

    a  In g plate.
    b  Tests on racemic mixture and each individual isomer (1R.3S; 1R,3R: 1S.3R: 1S.3S)
    c  Tests on racemic mixture.
    d  Data of G. P. Schoenig (FMC Corporation), unpublished results.
    e  In mg kg oral dose.
    f  In g/ml.
    g  Data of D. Clive (Wellcome Research Laboratories), unpublished results.
    h  In mg kg. 5 daily oral doses to male mice.
    i  Data of B. C. Chesher. J. C. Malone. and M. J. Parker (Wellcome Research Laboratories), unpublished results.
        Special studies on interaction

         The organophosphorus pesticides profenofos, sulprofos, O-ethyl-O-
    (4-nitrophenyl) phenylphosphonothioate (EPN) and S,S,S-tributyl
    phosphorotrithioate (DEF) administered intraperitoneally to mice at
    0.5 to 5 mg/kg strongly inhibited the liver microsomal esterase(s),
    hydrolysing trans-permethrin. Topically applied profenofos, sulprofos
    and DEF was much less effective in synergizing the toxicity of trans-
    permethrin than that of cis-permethrin to cabbage looper larvae and
    house fly adults (Gaughan  et al 1980).

         Data reviewed by the 1979 Meeting showed that permethrin produces
    symptoms indicative of an effect on the nervous system in laboratory
    animals. These are manifested clinically by tremoring and ataxia.
    These effects are seen only at comparatively high dose levels and are
    reversible in those animals that survive high doses. It is only at
    lethal or near lethal doses that signs of pathological changes in the
    nervous system are observable, with sparse axonal degeneration in the
    sciatic nerves of some animals. In a long-term study, no histological
    changes were seen in sciatic nerves of rats receiving the high dietary
    level of 2 500 ppm permethrin, equivalent to approximately 125 mg
    permethrin/kg bw/day daily for two years. Hens receiving a dose of
    1 000 mg/kg/day for 5 successive days, and then for another 5 days
    three weeks later, and hens receiving the maximum practical single
    oral dose of approximately 9 000 mg/kg, showed neither clinical nor
    histopathological evidence of neurotoxicity (FAO/WHO 1980; ICI 1981).

    OBSERVATIONS ON HUMANS

         The 1979 Meeting noted that there was no information on the
    relative sensitivity of humans to the peripheral neuropathy noted in
    rodent species at very high dose levels. No cases of misuse leading
    to acute poisoning in humans have been reported to the major
    manufacturers during several seasons of use worldwide. Some laboratory
    workers handling natural and synthetic pyrethroids have noticed a
    transient sensation in the periorbital area of the face. In a clinical
    survey, three subjects who had moderate exposure to permethrin did not
    develop these symptoms, which were only found after exposure to other
    pyrethroids. Neurological signs and electrophysiological studies in
    arms and legs of these subjects were normal (LeQuesne  et al 1980).

         A survey was conducted in Sweden of 45 subjects handling conifer
    seedlings, which were dipped in an EC formulation of 40:60 cis:trans
    permethrin that had been diluted with water to 1 to 2% of active
    ingredient. One of the subjects mentioned itching of the skin. None
    reported burning sensations or paraesthesia in the face. Symptoms were
    more marked among subjects handling seedlings treated with WP
    formulations of 25:75 cis:trans permethrin or of fenvalerate
    (Kolmodin-Hedman  et al 1981).

         Two volunteers were dosed orally with about 2 and 4 mg permethrin
    in order to establish whether "CVA" is a major metabolite in humans,
    excreted largely in urine as the unconjugated acid and easily
    hydrolysable conjugates, and that therefore a gas chromatographic
    analysis of "CVA" concentration in urine could be used to estimate the
    amount of absorbed permethrin. The two subjects were shown to excrete
    18% and 35% of the theoretical yield of metabolite after a dose of
    2 mg, and 39% and 32% after 4 mg. Most of the urinary elimination was
    seen during the first 12 h after dosing (Cridland and Weatherley
    1977).

         An estimate of permethrin (NRDC 143; OMS 182) absorbed by people
    employed in a field trial of the insecticide in Kuduna, Nigeria, 7-11
    June, has been reported (Cridland and Weatherley 1977). Before the
    trial, samples of urine from trial personnel were analysed for CIVA
    and creatinine content. By comparison with results from the volunteer
    study, using creatinine as a biological internal standard, it was
    possible to estimate that not more than 2 mg permethrin was absorbed
    by any person handling the insecticide in any 12-h period.

    RESIDUES IN FOOD

    USE PATTERN

         Permethrin was first evaluated at the 1979 Meeting, when MRLs
    were recommended for a wide range of commodities on a temporary basis.
    These recommendations took account of residue levels on crops
    immediately after spraying. For the 1981 Meeting, further information
    was required on world-wide good agricultural practices (i.e.
    authorized national use patterns). The PHIs that can be recommended
    between countries are varied. They tend to be shorter in those
    countries in which the majority of the potential use of permethrin
    will arise. It was agreed that the Meeting should recommend MRLs to
    cover the full worldwide spectrum of good agricultural practices.
    Permethrin residues on growing crops decline slowly. They tend to be
    rather more variable than for some other compounds. Therefore, the
    Meeting agreed to support the process used by the 1979 Meeting, which
    took account of permethrin residue levels immediately after spraying.

         Permethrin is a photostable synthetic pyrethroid. It possesses an
    extremely high level of activity against Lepidoptera. It is also
    effective against Hemiptera, Diptera and Coleoptera. It is a stomach
    and contact insecticide, with very little fumigant activity.
    Permethrin is extremely fast-acting. It is effective against all
    growth stages, particularly larvae. It also has significant repellent
    action. Permethrin controls many insect strains that have developed
    resistance to organophosphorus and organochlorine insecticides. It is
    of low mammalian toxicity and yet it is effective against insects at
    extremely low rates of application. Unlike earlier pyrethroids, it is
    sufficiently photo-stable to be of wide-ranging practical use in
    agriculture. It represents a major advance in the insecticide field.

         Permethrin is not plant systemic. It has very little fumigant or
    translaminar activity. Usually, best results are obtained with good
    spray cover, and repeat applications are normally made every 7 to 10
    days. However, where conditions are conducive to a rapid build-up of
    insect infestations, re-spraying may be needed after as little as 3
    days (for example, when controlling  Spodoptera littoralis on leaf
    brassicae in the Far East). Where a range of rates is quoted for
    worldwide use, the higher values are required more frequently in those
    climates where infestation pressure is greatest.

         The major uses arise in the Americas, Africa and parts of the Far
    East, i.e. in hot, often humid conditions, where the pressure of
    insect attack is frequently high. Cotton dominates the market
    potential for permethrin. Soybeans are also very important in the USA
    and Brazil. However, cotton seed and soybeans contain negligible
    residues when these crops are sprayed as recommended. Smaller, but
    still very important, uses in hot countries are those on horticultural
    vegetables and on fruit. These include the human foodstuffs that can
    contain noteworthy residues - leafy vegetables, solanaceous fruits,
    pip fruits and stone fruits.

         Not more than 5% of the potential world usage of permethrin is
    associated with Western Europe. There, main outlets are on
    horticultural vegetables, top fruit and vines. Typically, use rates of
    50 g a.i./ha are effective on leaf brassicae, whereas 100 g a.i./ha is
    often needed under the more severe conditions of the Americas, Africa
    and the Far East.

         In 1979, the group of manufacturers noted the relatively slow
    rate at which permethrin residues decline on the sprayed parts of
    crops. A table showing "half-lives" of 3 to 29 days was provided. To
    persons labelling a product, this slow rate of residue decline
    provides altogether different problems from those which pertain when
    residues decline quickly. One example of the latter is the compound
    pirimicarb. During the first 2 to 3 days after spraying, pirimicarb
    levels decline dramatically on many crops. Volatilization is mainly
    responsible. This tends to mask other effects that will be present,
    including inter-site differences in residue levels or the effects of
    photochemical and/or enzymatic degradation. After these first few
    days, the rate of residue decline becomes less marked. Thus one can
    apply a pre-harvest withholding interval (PHI) of 2 to 3 days in
    anticipation of obtaining a substantial decrease in residue levels
    routinely on those parts of the crop that are exposed to the spray. In
    contrast, permethrin is not volatile. It is comparatively photo-
    stable. Residue levels decline slowly. In the absence of a dominant
    route of rapid degradation, permethrin residue levels tend to be
    somewhat more variable. Undoubtedly, inter-site differences in spray
    practice, in weather and even in varieties may contribute to this.
    Whatever the reasons, this slow rate of residue decline reduces the
    value of a PHI in yielding a substantial reduction in residue levels
    on exposed crop parts.

         Because of this slow rate of residue decline, and because use
    patterns worldwide were still evolving, the 1979 JMPR took account of
    residue levels immediately after spraying when proposing MRL values.
    Permethrin application is relevant only to crop parts that are sprayed
    directly, and are of no consequence to situations in which the edible
    part is protected and where residues are negligible (e.g. root
    vegetables). Therefore, attention has been focused upon residues in
    crops such as vegetables and top fruit.

         A survey of crops and of PHIs recommended on them nationally are
    summarized in Table 9. Countries that have imposed a PHI of 7 days or
    more tend to be ones with more moderate climates and lesser problems
    of insect infestation. They are mainly European, but include Brazil,
    Peru and Uruguay. Conversely, countries allowing shorter PHIs, or
    which do not specify a PHI, on vegetables and on fruit tend to be
    those with more severe climates and with greater problems of insect
    control. These include the USA, many parts of Latin America, Africa
    and the Far East - the countries in which the major potential uses
    arise. Noteworthy are the comments received on the PHIs needed on
    vegetables in the USA. On lettuce and leaf brassicae, major pests
    include loopers, diamondback moth and imported cabbageworm. The crop
    yields and quality relate directly to the presence (or absence) of
    insects. The cleaner the crop, the higher the number of heads that can
    be marketed. Therefore, growers demand a high level of insect control,
    which permethrin is capable of giving. Many fresh vegetables are
    harvested continuously, on a 1 to 3 day schedule. Many crops go to
    processors, who demand standards such that the produce from an entire
    field can be discarded if any insects or insect parts are found in any
    part of the harvested crop. Permethrin has the quality of causing
    loopers to roll into a ball and fall from the plant. There is a need
    for an insecticide treatment close to harvest, which permethrin can
    fulfill. A similar picture pertains on tomatoes. Fresh market outlets
    are supplied on short notice. Growers who sell through brokers often
    have to commit field to pre-designated standards of yield and quality
    in a crop which is harvested continuously. The US Environmental
    Protection Agency has recognized these needs when granting clearances
    (as Section 18 Emergency Exemptions) on a wide range of crops (FAO/WHO
    1979).

         Information on the full range of use patterns is less well-
    documented for parts of the Third World. However, it is hard to
    believe that USA is the only country in which continuous harvesting
    occurs soon after spraying. Clearly, if a crop has to be re-sprayed
    every 3 to 7 days, a PHI of more than a few days is not practical.

        TABLE 9  Uses of permethrin reported to the Meeting as approved by national governments
                                                                                               

    Country or Area          Crop                                         PHI
                                                                          (days)
                                                                                               

    Algeria                  Apple, pear, brassicae, aubergine, pepper,
                             tomato, cotton                               None specified

    Argentina                Pea, pepper, tomato                          1
                             Alfalfa, cotton,maize                        7
                             Apple, apricot, nectarine, peach,)
                             pear, plum, quince, soyabean     )           21
                             Sunflower, sorghum               )

    Australia                Broccoli, Brussels sprout, cabbage,          2
                             cauliflower, tomate, maize

    Austria                  Cabbage, cauliflower, cucumber,              None specified
                             gherkin, maize, plum, spinach,
                             turnip, vines

    Belgium                  Aubergine, cabbage, cucumber,                2 (under glass)
                             endive, lettuce, melon, pepper,
                             tomato                                       7 (outdoors)

    Bolivia                  Aubergine, pepper, tomato, cotton            Non specified

    Brazil                   Cabbage, cauliflower                         3
                             Tomato, cotton                               7
                             Coffee                                       30
                             Maize                                        45
                             Soybean                                      60

    Canada                   Apple, pear, grape                           (pre-bloom)
                             Sweet corn                                   1
                             Cabbage, cauliflower, Brussels sprout        3
                             Broccoli                                     7

    Canary Islands           Tomato                                       15

    Chile                    Apple, cherry, damson, peach,                None specified
                             pear, plum, beans, potato,
                             cabbage, maize

    Colombia                 Aubergine, pepper, tomato, cotton            None specified

    Costa Rica               Cotton                                       None specified
                                                                                               

    TABLE 9  (con't)
                                                                                               

    Country or Area          Crop                                         PHI
                                                                          (days)
                                                                                               

    Cuba                     Aubergine, tomato, cotton,                   None specified
                             chilli pepper                                

    Cyprus                   Cucumber                                     5
                             Beans, pepper, tomato                        14

    Czechoslovakia           Apple                                        21
                             Cereals                                      28

    Denmark                  Pea, beetroot, potato                        14

    Dominican Republic       Brassicae, pepper, tomato, cotton,           None specified
                             oilseed rape

    Democratic Republic of   Aubergine, cucumber, pumpkins,               4
    Germany                  pepper, tomato
                             Potato                                       14
                             Brassicae, lettuce, spinach, carrot,         21
                             radish, sugarbeet, swede, turnip
                             Flax, cereals, oilseed rape                  None specified

    France                   Grape, apple, pear, lettuce, cabbage         15
                             Grain crops                                  40

    Federal Republic of      Cabbage                                      7
    Germany                  Apple, pear, hops                            14
                             Oilseed rape                                 56

    Guatemala                Cotton, brassicae, potato, maize             None specified


    Guernsey                 Aubergine, cucumber, pepper,                 None specified
                             tomato (under glass)
                             Pea, brassicae, aubergine, cucumber,         None specified
                             pepper, tomato (outdoors)

    Hong Kong                Cabbage, watercress, onion                   None specified

    Hungary                  Apple, pear, apricot, peach, maize           None specified

    Indonesia                Soybean, cabbage, pepper, oil palm,          None specified
                             cotton
                                                                                               

    TABLE 9  (con't)
                                                                                               

    Country or Area          Crop                                         PHI
                                                                          (days)
                                                                                               

    Iran                     Pistachios, cotton                           7

    Israel                   Pumpkin                                      10

    Jordan                   Apple, pear, brassicae, aubergine,           None specified
                             okra, pepper, tomato, alfalfa,
                             cotton

    Malaysia                 Citrus, brassicae, aubergine, pepper,        None specified
                             tomato, oil palm, cocoa, coconut

    Mexico                   Cotton, lettuce, broccoli, Brussels          None specified
                             sprouts, cabbage, cauliflower, maize

    Morocco                  Apple, pear, brassicae, aubergine,           None specified
                             cotton

    Netherlands              Mushrooms                                    2
                             Aubergine, cucumber, honeydew melon,         3
                             pepper, tomato, courgette
                             Apple, pear, brassicae, beans, pea,     )
                             horseradish, potato, fennel, leek       )    7
                             onion, radish, sugarbeet, swede,        )
                             turnip, grape, cherry, plum, strawberry )
                             currant,gooseberry,blackberry,raspberry,)
                             rutabaga, potato, fodder beet,poppy seed)
                             Lettuce, endive, fennel                      21

    New Zealand              Greenhouse fruit and vegetables              2
                             Brassicae, beans, tomato (outdoor))
                             and fruit trees other than citrus )          3
                             Maize, outdoor fruit and vegetables          7
                             Fodder crops, pome fruit                     14
                             Citrus fruit, grape                          28

    Nicaragua                Brassicae, aubergine, tomato, cotton,        None specified
                             maize

    Pakistan                 Cotton                                       None specified

    Peru                     Beans, potato, tomato, alfalfa,              7
                             cotton, maize
                                                                                               

    TABLE 9  (con't)
                                                                                               

    Country or Area          Crop                                         PHI
                                                                          (days)
                                                                                               

    Philippines              Banana, rice, mango, cabbage,                None specified
                             cauliflower, tomato

    Poland                   Cucumber, tomato (under glass)               2
                             Pea, brassicae                               None specified

    Portugal                 Tomato                                       2

    El Salvador              Cotton                                       None specified

    South Africa             Apple, pear                                  14
                             Cotton, maize                                None specified

    Spain                    Citrus, potato, tomato, cotton               15

    Syria                    Cotton, brassicae, aubergine, okra,          None specified
                             pepper, tomato

    Taiwan                   Cabbage, rice                                None specified

    UK                       Cucumber, pepper, tomato,                    None specified
                             aubergerine, mushroom (fogging indoors).

                             Apple, pear, cherry, plum, pea,              None specified
                             brassicae, lettuce, celery, courgette,
                             potato, carrot, swede, turnip, sugarbeet,
                             grass, cereals, blackcurrants,
                             redcurrants, gooseberry, raspberry,
                             strawberry.

    Uruguay                  Apple, peach, plum, pea, beans,              20
                             soybean, tomato, onion, sorghum,
                             quince

    USA                      Cotton                                       14

    USSR                     Apple, cotton                                None specified

    Venezuela                Cotton                                       None specified
                             Cabbage, pepper, tomato, onion               7

    Yugoslavia               Broccoli, Brussels sprout, cabbage,
                             cauliflower, tomato, maize                   2
                                                                                               
    
         One may wish to entertain applying a PHI for toxicological
    reasons or owing to knowledge of good agricultural practice. In view
    of the slow rate of residue decline, a PHI of 2 to 3 weeks would be
    the minimum required to effect a substantial and consistent decline in
    residue levels, for toxicological reasons. A few governments have set
    PHIs of 2 to 3 weeks; presumably, they must consider that such PHIs
    are capable of being observed within the limitations of good
    agricultural practice within their countries. Other governments have
    set lower PHIs based on a knowledge of good agricultural practice
    within their country and of the toxicological and residues data on the
    compound. Still other governments have not specified a PHI on the
    label.

    Post-harvest treatments

         In trials in Australia (Halls 1981) permethrin (25:75, cis:trans)
    was applied at rates in the range 0.5 to 5.0 mg /kg to wheat of
    moisture content 9.5 - 10.5 held in small silos at temperatures that
    ranged, due to seasonal effects, from 25C through 10C and back to
    23C over a period of 9 months. There was little detectable
    degradation of any of the treatments, as indicated in Table 10.

         Halls and Periam (1980) reported studies in which two permethrin
    (25:75, cis:trans) liquid grain protectant formulations were applied
    to wheat, which was then stored for 9 months in metal silos in the UK.
    Residue analysis on wheat samples taken at monthly intervals showed no
    degradation of the permethrin. There was no detectable degradation of
    permethrin by the processes of milling or baking over the storage
    period, except possibly in the case of the baking of wholemeal bread
    from wheat stored for 6 months or more. The results are given in Table
    11. The trials were continued and the results reported later (Halls
    1981) indicated that there was no significant degradation 15 months
    after treatment.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         At the 1979 Meeting, residues data were reviewed from supervised
    trials on kale and spinach sprayed in the Federal Republic of Germany
    in 1977 at 22.5 to 30 g a.i./ha. Having regard to the use pattern data
    reviewed at the 1979 Meeting and to the higher use rates that could be
    needed under conditions of greater insect pressure in countries
    outside of Western Europe, additional trials on kale and spinach were
    conducted in the UK in 1980 at a rate of 100 g a.i./ha. Allowing for
    these differences in application rates, there is good agreement within
    the total data now available. At the 100 g a.i./ha rate, residues
    during the first three days after spraying were in the range 1.5 to
    4.1 mg/kg on spinach and 1.1 to 3.6 mg/kg on kale (Table 12). The 1979
    Meeting noted that the rate of decline in permethrin residue levels on
    growing crops is fairly small, with half-life periods ranging from

        TABLE 10.  Residues of permethrin, piperonyl butoxide and fenitrothion detected on wheat after indicated periods
               of storage in Australia
                                                                                                                   

                   Target                                    Residue analysis (mg/kg)
    Compound1      application                                                                                     
                   rate (mg/kg)
                                    Initial     1 month     2 months   3 months   6 months    8 months    9 months
                                                                                                                   

    PM                 0.5           0.38        0.35         0.38        0.28      0.39        0.39      0.36
    PB                10.0           3.9         4.5          4.4         5.0       5.7         3.8       -
    FEN               12.0           7.2         7.2          7.7         6.9       6.9         4.3       4.3
                                                                                                                   

    PM                 1.0           0.93        0.99         0.88        0.89      0.80        0.75      0.75
    PB                10.0           7.9         4.6          4.1         5.5       6.7         4.0       -
    FEN               12.0           8.9         7.6          6.6         8.0       7.0         5.8       5.2
                                                                                                                   

    PM                 2.0           1.90        2.00         2.05        1.59      1.64        1.60      1.68
                                                                                                                   

    PM                 2.0           1.82        1.76         1.95        2.02      1.88        1.75      2.15
    PB                10.0           4.2         3.4          3.0         4.0       4.0         3.5       -
                                                                                                                   

    PM                 5.0           4.5         4.4          4.9         4.5       5.0         3.6       2.6
                                                                                                                   

    PM                 5.0           5.1         5.8          6.0         5.1       5.9         5.6       4.5
    PB                10.0           5.6         7.3          6.9         6.6       6.4         5.9       -
                                                                                                                   

    1  PM = permethrin, PB = piperonyl butoxide, FEN = fenitrothion, - = not analysed.

    TABLE 11.  Permethrin residues on milling fractions and bread made from freshly treated wheat and from wheat after three,
               six or nine months' storage1
                                                                                                                                   

    Target
    application         Sampling                                                                First-        Total
    rate                period                Wholemeal    Wholemeal              Fine          reduction     white       White
    (mg/kg)             (months)    Wheat     flour        bread        Bran      offal         flour         flour       bread
                                                                                                                                   

                        0           0.82      0.80         0.52         4.40      nd1           nd            0.27        0.19

                        3           0.96      0.65         0.67         3.70      approx. 1     nd            nd          0.15

    2.0
                        6           0.95      0.83         0.47         2.90      0.74          0.12          0.17        0.06
                                                           (25:75)3                                                       (23:77)3

                        9           1.09      0.78         0.24         4.00      1.04          0.12          0.25        0.12
                                                                                                                                   

                        0           1.74      1.60         0.95         10.20     nd            nd            0.55        0.51

                        3           2.04      2.25         1.20         10.30     2.40          nd            0.42        0.30

    5.0
                        6           2.32      2.19         0.68         5.90      1.79          0.23          0.34        0.18
                                                           (25:75)3                                                       (23:77)3

                        9           2.14      2.21         0.64         8.00      2.60          0.23          0.60        0.20
                                                                                                                              

    1  Analytical results are subject to confidence limits of  20%;
    2  nd = not detectable (<0.05 mg/kg);
    3  cis:trans isomer ratio

    TABLE 12.  Permethrin residue levels on kale and spinach, UK 1980
                                                                                                                                  

                                                                                  Harvest       Lowest        Highest     Mean
    Crop                Formulation    Rate           Volume     No. of           interval      residue       residue     residue
                                       (g a.i./ha)    (l/ha)     applications     (days)        (mg/kg)       (mg/kg)     (mg/kg)
                                                                                                                                  

    Spinach             25% EC         100            500        1                0                                       4.1 (1)1

                                                                                  3             1.5           3.6         1.9 (5)

                                                                                  7                                       0.81(1)

                                                                                  14                                      0.26(1)

    Kale                25% EC         100            500        3                0                                       3.6 (1)

                                                                                  3             1.1           3.9         2.7 (5)

                                                                                  7                                       3.9 (1)

    (var. acephala)                                                               14                                      1.3 (1)
                                                                                                                                  

    1  Number of samples used for calculating mean.
        about one to three weeks, depending upon the crop. In the UK trials in
    1980, permethrin had an initial half-life of ten days on kale and
    three days on spinach (FAO/WHO 1980; Swaine 1981a).

         Supervised trials, involving ULV applications to grapefruit and
    tangerine were conducted in Spain in 1980, and involving high volume
    applications to oranges, lemon and grapefruit in the USA in 1981. The
    1979 Meeting noted that in orange, residues were found almost
    exclusively in the peel; in edible flesh levels did not exceed
    0.01 mg/kg. Similar results have now been found in grapefruit, lemon
    and tangerine, in which levels in the edible flesh did not exceed
    0.05 mg/kg. Residues on the whole fruit at the use rate normally
    recommended (50 g a.i./ha) were within the MRL of 0.5 mg/kg
    recommended by the 1979 Meeting (FAO/WHO 1980; Swaine 1981b,
    c). Permethrin levels in orange, lemon and grapefruit juice were below
    0.05 mg/kg at the use rate normally recommended and did not exceed
    0.07 mg/kg at twice that rate (Table 13) (Swaine 1981c). Information
    received, from New Zealand, Canada and The Netherlands concerning
    residues on apple, grape, orange, kiwi fruit, boysenberry, cabbage,
    sweet corn, Brussels sprouts, tomato and cucumber included in Table
    14, confirm recommendations made previously. Other limited data on
    avocado and cranberry were also received.

    FATE OF RESIDUES

    Photochemical degradation

         One of the major drawbacks in the use of natural pyrethrins and
    early synthetic pyrethroids as agricultural insecticides was their
    susceptibility to degradation in light and air. Introduction of the
    dichlorovinyl group into the acid part of the molecule in place of the
    isobutenyl group, common in many early pyrethroids, removes one
    possible site of photodegradation.

         Deposits of permethrin on glass exposed to daylight near a window
    indoors persisted for longer than 3 weeks. Out of doors exposed to UV
    and visible light but shielded from wind and rain with temperatures
    reaching up to 50C, deposits lasted for about 10 days. Other
    experiments comparing the stability of films exposed near a window
    indoors showed 60% undecomposed permethrin after 20 days. Permethrin
    remained effective on plywood for more than 12 weeks and under a
    sunlamp for more than 26 days. Permethrin formulations also showed
    improved stability on plant leaf surfaces, persisting for 10 to 20
    days (Elliott  et al 1973 a,b).

         Photolysis of permethrin in various solvents with artificial
    light and on soil in sunlight results primarily in cyclopropane ring
    isomerization and ester cleavage to 3-phenoxy-benzyl alcohol and
    3-(2,2, dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCVA)

        TABLE 13.  Permethrin residues in Citrus, 1980-81
                                                                                                                                                

                                                                No.           Harvest    Residue levels(mg/kg) in
    Crop          Country   Formulation  Rate         Volume    of            interval                                                          
                  Year                   (g a.i./ha)  (l/ha)    applications  (days)     Whole                                   Reference
                                                                                         fruit     Flesh     Peel      Juice
                                                                                                                                                

    Orange        USA       24% EC       45           4700      1             0          <0.05     <0.05     0.25      <0.05     Swaine
                  1981                                                        3          0.07      <0.05     0.15      <0.05     1981c
                                                                              7          <0.05     <0.05     0.07      <0.05

                                         90           4700      1             0          0.18      <0.05     0.40      <0.05
                                                                              3          0.13      <0.05     0.40      <0.05
                                                                              7          0.12      <0.05     0.38      <0.05
                                                                                                                                                

    Lemon         USA       24% EC       45           4700      1             0          0.13      <0.05     0.19      <0.05     Swaine
                  1981                                                        3          0.08      <0.05     0.23      <0.05     1981c
                                                                              7          0.10      <0.05     0.23      <0.05

                                         90           4700      1             0          0.42      <0.05     0.57      <0.05
                                                                              3          0.22      <0.05     0.31      <0.05
                                                                              7          0.13      <0.05     0.48      <0.05
                                                                                                                                                

    Grapefruit    USA       24%          45           4700      1             0          0.06      <0.05     0.11      <0.05     Swaine
                  1981                                                        3          <0.05     <0.05     0.14      <0.05     1981c
                                                                              7          <0.05     <0.05     0.21      (0.05

                                         90           4700      1             0          0.13      0.05      0.28      0.07
                                                                              3          0.10      <0.05     0.42      <0.05
                                                                              7          0.07      <0.05     0.27      <0.05
                                                                                                                                                

    TABLE 13.  (con't)
                                                                                                                                                

                                                                No.           Harvest    Residue levels(mg/kg) in
    Crop          Country   Formulation  Rate         Volume    of            interval                                                          
                  Year                   (g a.i./ha)  (l/ha)    applications  (days)     Whole                                   Reference
                                                                                         fruit     Flesh     Peel      Juice
                                                                                                                                                

    Grapefruit
                  Spain     25% EC       50           3.3       2             0          0.08      <0.01     0.26      Swaine
                  1980                                                        3          0.15      <0.01     0.48      1981b
                                                                              7          0.12      <0.01     0.39
                                                                              14         0.11      <0.01     0.35

                                         100          3.3       2             0          0.17      0.01      0.52
                                                                              3          0.18      0.01      0.53
                                                                              7          0.14      <0.01     0.45
                                                                              14         0.12      0.01      0.39
                                                                                                                                                

    Tangerine     Spain     25% EC       50           3.3       2             0          0.49      0.01      1.4       Swaine
                  1980                                                        3          0.23      <0.01     0.86      1981b
                                                                              7          0.21      0.02      0.73
                                                                              14         0.29      <0.01     1.0

                                         100          3.3       2             0          0,18      <0.01     0.65
                                                                              3          0.13      <0.01     0.47
                                                                              7          0.44      <0.01     1.7
                                                                              14         0.52      <0.01     1.8
                                                                                                                                                

    TABLE 14.  Permethrin residues in various crops
                                                                                                                                                

                                       Application                       Residues (mg/kg) at intervals(days) after application
    Crop          Country      Year    No.   Rate           Formulation                                                                         
                                             (g a.i./100 l)              0-1         3       6      9       14       21      28         41
                                                                                                                                                

    Apple         New Zealand  1980    11    5              EC           0.33                0.36           0.31     0.21
                                       11    7.5            EC           0.25                0.7                     0.32
                                       7     2.5            EC                                      0.05    0.06     0.05    N.D.
                                       8     2.5            EC                               0.24           0.04             0.16
                                       7     3.75           EC                               0.19           0.16             0.16       0.11

    Avocado       New Zealand  1980    6     2.5            EC           0.09                0.07           0.06             0.04

    Grape                              7     2.5            EC                       0.46           0.37    0.26     0.19

    Orange                             1     5              EC           0.12skin                                            0.09skin
                                                                         nd pulp                                             nd pulp
                                                                         0.07total                                           0.05total

                                       1     10             EC           nd pulp                                             nd pulp
                                                                         0.15 Total                                  0.07 total

                                                                                                                                                
                                                                         0          7          14          28        42        56        84
                                                                         (a) (b)    (a) (b)    (a)  (b)    (a) (b)   (a) (b)   (a) (b)   (a) (b)
                                                                                                                                                

    Kiwi fruit    New Zealand          6     1.5            EC           0.34 1.71             0.29 1.43
                                       5     25             EC                      0.5  -     0.56 4.22              0.16 -   0.16 -    0.08
                                       6     2.5            EC                      0.15 -     0.11 0.34   0.08 0.26  0.03 -   nd   -
                                       7     2.5            EC                      0.25 -     0.34 2.45   0.17 1.21  0.16 -   0.07 -    0.06 -
                                       6     3.0            EC           0.5  2.51             0.41 2.05
                                       6     4.4            EC           2.5  12.5  2.5  12.5  1.9  9.6    1.7  8.8
                                                                                                                                                

    TABLE 14.  (con't)
                                                                                                                                                

                                       Application                       Residues (mg/kg) at intervals(days) after application
    Crop          Country      Year    No.   Rate           Formulation  0          7          14          28        42        56        84
                                             (g a.i./100 l)              (a) (b)    (a) (b)    (a)  (b)    (a) (b)   (a) (b)   (a) (b)   (a) (b)
                                                                                                                                                

    Boysenberry                        2     2.5            EC             0.26       0.15       0.12        0.07
                                       2     2.5            EC             0.65       0.58       0.34        0.14
                                       2     3.75           EC             0.29       0.32       0.22        0.12

                                                                         1        2           4         6        9       14        45
                                                                                                                                                

    Brussels      Canada       1976    4     70             EC                                                            0.09
    sprout                                   70             EC                                                            0.09
                                             70             EC                                                                      0.05

    Cranberry     Canada       1977    2     70             EC                                                                      0.12(60days)
                                                                                                                                    0.15(" )
                                                                                                                                    0.08(")

    Tomato        Netherlands  1978    2     76             Smoke                 0.58
                                                            gener.               (0.36-0.75)

                               1979    1     -              "                     0.11
                               August                                            (0.06-0.17)
                               1979    1     -              "                    <0.01
                               October

    Cucumber                   1979    1     -              "                    <0.01
                               October
                                                                                                                                                

    TABLE 14.  (con't)
                                                                                                                                                

                                       Application                       Residues (mg/kg) at intervals(days) after application
    Crop          Country      Year    No.   Rate           Formulation                                                                         
                                             (g a.i./100 l)              1        2           4         6        9       14        45
                                                                                                                                                

    Cabbage       New Zealand  1980    1     25             EC           0.55                 0.43               0.22     0.17
                                       1     50             EC           0.54                 0.78               0.36     0.22
                                       1     100            EC           0.39                 0.61               0.44     0.55

    Sweet corn                 1980    1     50             EC           2.7 nd               2.84 nd            1.04 nd  0.54 nd
                                                                         foliage              foliage            foliage  fol.
                                                                         cob                  cob                cob      cob

    Pasture                    1980    1     250            EC          39       13           7         6        4        3
                                             500            EC          45       24           9         9        7        3
                                             750            EC          69       44          29        29       12       10
                                             1000           EC          97       56          35        23       19       15
                                             1500           EC         114       77          56        54       25       24
                                                                                                                                                
        (See Figure 6). The photolysis of cis and trans isomers of permethrin
    has been studied using material 14C-labelled in the carbonyl or
    methylene moieties. Both permethrin isomers decomposed under
    artificial light (peak outlet lambda 290-320nm) slightly faster in
    hexane than in methanol. In each solvent, the cis isomer
    photodecomposed approx. 1.6 times faster (T1/2 43 to 58 min) than the
    trans isomer. The reacon involved extensive isomerization of the
    cyclopropane ring, i.e. interconversion of the trans and cis isomers.
    This probably occurred via a triplet energy state forming the
    diradical intermediate (cleavage of cyclopropane ring), as the
    reaction proceeded in the presence of phenoxybenzaldehyde and
    benzophenone acting as photosensitizer, and was efficiently quenched
    by 1,3-cyclohexadiene. The isomerization rate increased in the order
    methanol < hexane < water, and at equilibrium after 1 to 4 h
    irradiation the more thermodynamically stable trans isomer constituted
    65 to 70% of the isomer mixture.

         Together with the isomerization reaction, ester cleavage was
    the major photoreaction in methanol, hexane, water and 2% aqueous
    acetone. The major degradation products were DCVA and 3-phenoxybenzyl
    alcohol. Other products formed in trace amounts in water included the
    monochloropermethrin derivative, and the corresponding monochlorovinyl
    acid, formed by reductive dechlorination. Permethrin and
    monochloropermethrin do not undergo epoxidation at the dichlorovinyl
    or chlorovinyl substituent under normal photooxidative conditions.
    Photo oxidation to decarboxylated molecules was negligible with
    permethrin (Holmstead  et al 1977, 1978).

         Exposure of the permethrin isomers on Dunkirk Silt Loam soil for
    48 days resulted in approx. 55% loss in sunlight and approx. 35% loss
    in the dark. The amount of radioactivity unextractable by 1:1 methanol
    and ether was approx. 65% in the dark and approx. 18% in the light.
    The unextractable radioactivity appears to be due to microbial
    activity rather than to chemical reactions, but irradiation increased
    the amount.

         On/in the soil, relatively little isomerization at the
    cyclopropane ring was encountered as compared with the photolysis in
    solution. There was little difference in the amount of the DCVA
    detected in the dark or light, and 3-phenoxybenzyl alcohol was the
    major cleavage product of the alcohol moiety. Other products detected
    in trace amounts were essentially the same as those in solutions
    (Holmstead  et al 1978).

    In soil

         The residues of permethrin in an organic soil and in vegetables
    grown in soil treated with a granular formulation of permethrin were
    studied by means of gas chromatography (Belanger and Hamilton 1979).
    Permethrin persisted in the soil for the initial 28 days and then

    FIGURE 6

    declined slowly during the rest of the season. Permethrin did not
    translocate into the edible parts of the vegetables but was present in
    the root system of onion and lettuce. Carrot and lettuce yields were
    not significantly different from those of controls, but onion yields
    were substantially decreased in the presence of permethrin.

         Six soils, fortified with permethrin at 1 mg/kg, were incubated
    for 16 weeks at temperatures alternating between 20C for 15 h and
    10C for 9 h. Initially, and at 4-week intervals, soils were sampled
    and analysed. In five of the soils, degradation of permethrin was
    rapid, resulting in half-lives of approximately 3 weeks. In the other
    soil very little degradation occurred, recovery after 16 weeks being
    greater than 75%. Sterilization of the two soils in which degradation
    was rapid greatly reduced the rate, indicating that microbial
    degradation was the chief factor involved (Williams and Brown 1979).

    On processing

         The 1979 Meeting recommended an MRL of 20 mg/kg in dried tea.
    Data are now available on residue levels in the final beverage
    produced from tea leaves containing permethrin at four different
    levels (in the range approximately 0.5 to 20 mg/kg). An aliquot sample
    (5 g) of tea was brewed with 200 cm3 of boiling water, allowed to
    cool and filtered. Only very low levels of permethrin were present in
    the beverage (0.02-0.08 mg/kg) (Table 15). The residue level in the
    beverage, expressed as a percentage of the corresponding residue level
    in the dried tea, increased from 0.4%, when leaves containing
    approximately 20 mg/kg were used, to 0.8% when leaves containing
    approximately 3 mg/kg were used to prepare the beverage (Swaine
    1981d). This pattern of data is consistent with the known low
    solubility of permethrin in water.

    TABLE 15.  Permethrin residues in tea and tea leaves
                                                                        

    Permethrin residues (mg/kg)      Residue level in beverage  100%
                                                               
    Tea leaves     Tea (beverage)    Residue level in leaves
                                                                        

    18                0.08                    0.4
    10                0.06                    0.6
    2.6               0.02                    0.8
    0.43             <0.01                    -
                                                                        

    NATIONAL MAXIMUM RESIDUE LIMITS

         The national maximum residue limits summarized in Table 16 have
    been reported to the Meeting, in addition to those noted in 1979 and
    1980.

    TABLE 16.  Additional national MRLs reported to the Meeting
                                                                        

                                                                mg/kg
    Australia

    Celery                                                      5
    Kiwi fruit                                                  2
    Rape seed, sunflower seed                                   0.2
    Fat of meat, linseed, soybeans, mung beans and navy beans   0.1
    Sweet corn                                                  0.05 *
    Beans                                                       0.5
    Water                                                       0.3

    Brazil

    Cotton                                                      0.5
    Tomato                                                      0.3
    Cabbage and cauliflower                                     0.1
    Maize                                                       0.1
    Soybean, coffee                                             0.01

    France

    Apple, pear, grape, lettuce and cabbage                     1
    Vegetables (other than lettuce and cabbage)                 0.5
    Wheat                                                       0.5

    Hungary

    Fruit, vegetables                                           1

    Netherlands

    Kiwi fruit                                                  2
    Other fruit and vegetables                                  1
    Meat and meat products, mushroom, potato                    0.05
    Milk and milk products                                      0.05

    New Zealand

    Bush and core fruit                                         1
    Beans                                                       0.5

    South Africa

    Sorghum                                                     0.5
    Beans                                                       0.1
                                                                        

    EVALUATION

    COMMENTS AND APPRAISAL

         Permethrin was evaluated by the 1979 and 1980 JMPR, which
    considered extensive toxicological data on the compound. The 1979
    Meeting required data on the potential bioaccumulation of the compound
    and/or its metabolites, as well as observations in humans to evaluate
    possible susceptibility to neurological effects noted in rodents,
    before a full ADI for permethrin could be established.

         The present Meeting considered pharmacokinetic studies on a wide
    range of mammalian species. These indicated that permethrin is rapidly
    absorbed and metabolized to more polar materials that are excreted.
    Only small amounts of permethrin are taken up by adipose tissue and
    these are principally of the less-rapidly hydrolysed cis-isomer. On
    cessation of exposure, permethrin is promptly eliminated from adipose
    tissue.

         Information from observations in humans was also available to the
    Meeting. This indicated that permethrin did not appear to cause the
    transient abnormal facial sensations that are caused by exposure to
    other synthetic pyrethroids. No other cause for concern was indicated.

         Further studies on teratogenicity, mutagenicity and neurotoxicity
    were also evaluated, none of which indicated cause for particular
    concern.

         The Meeting was of the view that the requirements of the previous
    JMPR had been satisfied. However, the Meeting was made aware that
    there were in existence at least three further long-term studies,
    which were said to suggest possible carcinogenic risk from permethrin.
    These studies were not available to the Meeting. In the absence of
    these data, the present Meeting felt unable to do other than to extend
    the temporary ADI established by the 1979 JMPR.

         Residue trials on orange, lemon, grapefruit and tangerine provide
    a basis for proposing maximum residue limits in citrus fruit. These
    studies confirm that the residue is confined wholly within the peel
    and that no residue is detected in flesh or juice.

         Data from additional trials on kale and spinach, taken in
    conjunction with the information considered in 1979, have enabled the
    Meeting to confirm the recommendations for MRLs in spinach and to
    propose a higher limit for kale. Information from trials on
    boysenberry (dewberry), apple, pear, tomato and cucumber confirmed the
    recommendations previously made for MRLs on dewberry and pome fruit.

         Extensive information on the use patterns needed and approved for
    the use of permethrin in 49 countries show the great diversity in the
    pre-harvest interval (PHI). They tend to be much shorter in those
    countries in which the majority of the potential use of permethrin
    will arise than in countries with a temperate climate and a consequent
    lesser threat from insect pests of crops. The slow rate of dissipation
    of permethrin residues from plants reduces the significance of a
    withholding period between treatment and harvest. The Meeting
    considered this feature in conjunction with the low rate of
    application and resulting low concentration of residues, and came to
    the conclusion that it was appropriate to recommend MRLs based on the
    minimum interval between application and harvest.

         The Meeting was informed that the largest proportion of the
    permethrin used world wide consists of a 40:60 ratio of cis:trans
    isomers. It is recognized that products based on a 25:75 ratio of
    cis:trans isomers are available. Until information becomes available
    from significant usage of such materials in general agriculture/animal
    husbandry, the Meeting will confine its recommendations to permethrin
    products based principally on the 40:60 ratio (cis:trans isomer) of
    permethrin. Data are available on the fate of permethrin on plants
    both in the greenhouse and outdoors. Photolysis of permethrin in
    various solvents with artificial light and on soil in sunlight
    results primarily in cyclopropane ring isomerization and ester
    cleavage to 3-phenoxybenzyl alcohol and 3-'2,2-dichlorovinyl)-2,
    2-dimethylcyclopropane carboxylic acid (DCVA). These compounds are
    also the major metabolites of permethrin on plants. Photoelimination
    of carbon dioxide is a negligible route of photochemical degradation
    of permethrin.

         Questions were raised during the 13th Session of CCPR concerning
    the appropriateness of the MRL for permethrin in dry manufactured tea.
    Studies have shown that irrespective of the level of residue in the
    tea, very little is leached out during the brewing of the beverage.
    The Meeting felt that the recommendation should stand.

         At the 13th Session of CCPR (1981) the Netherlands commented that
    the limits for permethrin on gherkins and squash should preferably be
    0.5 mg/kg, in line with those for cucumbers. The Meeting concurs that
    the information in the 1979 monographs support this view and
    recommendations were amended accordingly.

         A number of national authorities have established additional MRLs
    for permethrin. These were noted. Further studies in the fate of
    permethrin in soil indicate that it is degraded in biologically active
    soils and that the residue is not taken up into crops grown in such
    treated soil.

         The Meeting noted the omission of a recommendation for soybean
    oil from the 1979 Evaluations, though the decision was recorded on
    page 413.

    Level causing no toxicological effect

         Rat  :  100 ppm in the diet, equivalent to 5.0 mg/kg bw/day

    Estimate of temporary acceptable daily intake for man

         0 - 0.03 mg/kg bw

    RECOMMENDATIONS OF RESIDUE LIMITS

         The following maximum residue limits, determined and expressed as
    total permethrin isomers excluding metabolites are recommended:

    Commodity                MRL (mg/kg)

    Citrus fruits            0.5
    Kale                     5
    Gherkins                 0.5
    Squash                   0.5
    Soybean oil1             0.1

    1  Omitted from the 1979 recommendations

    FURTHER WORK OR INFORMATION

    Required (by 1982)

         Reports of carcinogenicity studies not yet made available to the
    JMPR.

    Desirable

    1.   Mutagenicity studies on the metabolite 3-(2,2-dichlorovinyl)-2,2-
         dimethylcyclopropane carboxylic acid.

    2.   Results from further studies of residues in lettuce following
         approved use patterns.

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    See Also:
       Toxicological Abbreviations
       Permethrin (EHC 94, 1990)
       Permethrin (HSG 33, 1989)
       Permethrin (ICSC)
       PERMETHRIN (JECFA Evaluation)
       Permethrin (Pesticide residues in food: 1979 evaluations)
       Permethrin (Pesticide residues in food: 1980 evaluations)
       Permethrin (Pesticide residues in food: 1982 evaluations)
       Permethrin (Pesticide residues in food: 1983 evaluations)
       Permethrin (Pesticide residues in food: 1984 evaluations)
       Permethrin (Pesticide residues in food: 1987 evaluations Part II Toxicology)
       Permethrin (JMPR Evaluations 1999 Part II Toxicological)
       Permethrin (UKPID)
       Permethrin (IARC Summary & Evaluation, Volume 53, 1991)