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    PESTICIDE RESIDUES IN FOOD - 1979


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1979





    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, 3-12 December 1979



    CYPERMETHRIN

    IDENTITY

    Common Name:             Cypermethrin (BSI).

    Chemical Name (IUPAC):   [S,R]-alpha-cyano-3-phenoxybenzyl-2,2-dimethyl
                             [1R,1S, cis, trans]-3-(2,2-dichlorovinyl)
                             cyclopropanecarboxylate.

    Synonyms:                WL 43467 (Shell), PP383 (ICI), CCN52(ICI), NRDG
                             149, RIPCORD(R) (Shell), CYMBUSH (R) (SHELL),
                             CYMBUSH (R) (ICI)

    Empirical Formula:       C22H19O3NCl2

    Structural Formula:      CHEMICAL STRUCTURE 1


    Molecular Weight:        416

    Technical Material:      Contains not less than 90% w/w cypermethrin
                             which is a racemic mixture of the 8 isomeric
                             forms with a cis: trans isomer ratio of
                             approximately 40:60

    Physical Form            Technical material is a viscous yellow liquid.

    Density:                 1.12 g/ml at 22C.

    Thermal Stability:       Thermal analysis has shown that at a
                             temperature of 259C slow weight losses occur
                             accompanied by negligible heat of reaction
                             indicating high thermal stability.

    Solubility:              Water 0.009 mg/l. Hexane 103 g/l.  Acetone,
                             cyclohexanone, ethanol xylene and chloroform
                             450 g/l.

    Volatility:              relatively non-volatile

    Vapour pressure:         5  10-6 N/m2 at 70C

    Flash point:             80C

    Formulations:            Currently available in emulsifiable
                             concentrates ranging from 25-400 a.i. g/l.
                             Several formulations for ultra low volume
                             applications containing 8-75 g/l are also
                             available.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, Distribution and Excretion

    Studies were performed in vivo on a wide range of mammalian species
    and in vitro on isolated cell fractions to define the
    pharmacokinetics of cypermethrin.  In general, a wide range of studies
    have shown that cypermethrin is rapidly absorbed, distributed to a
    variety of tissues and organs, metabolised and rapidly excreted from
    the body.  Studies have been performed to evaluate the
    pharmacokinetics in mice, rats, dogs, sheep and cows.

    Mice

    Groups of male mice were orally administered the cis or trans isomers
    of cypermethrin dissolved in methoxytriglycol at dose levels of 7
    mg/kg with the cyclopropyl-14C isomer and 8 mg/kg with the benzyl-14C
    isomer.  Results suggest that the proportion of cypermethrin which was
    readily absorbed following oral dosing was rapidly eliminated in the
    urine of mice.  Absorption from the gastrointestinal tract was more
    rapid with the trans isomer than with the cis as evidenced by high
    radioactivity levels of the cis isomers in the faeces within the first
    few days of the study.  The rate of urinary excretion of cypermethrin
    isomers labelled in acid and alcohol portions of the molecule was very
    similar with the major quantity of radioactivity being eliminated from
    the body within three days.  Tissue residues after three days were
    low.  Adipose tissue was found to retain small quantities of the
    radioactivity in concentrations higher than that noted for most other
    tissues (Hutson, 1978a).

    To evaluate the elimination of cypermethrin and its metabolites from
    animal tissues following oral administration, groups of male mice were
    administered cypermethrin at dose levels approximating 9 mg/kg body

    weight (14C-benzyl, cypermethrin).  In contrast to data from other
    tissues, the rate of elimination of cypermethrin from adipose tissue
    of mice was relatively slow with a half-life of approximately 10-20
    days.  Unchanged cis-cypermethrin was the only chemical residue
    identified in adipose tissue.  There was little change in the residue
    during the last half of the 42-day trial following the relatively
    rapid elimination during the first three weeks suggesting possible
    long term storage and buildup of residue in adipose tissue (Crawford
    and Hutson, 1978a).

    Rat

    Groups of male and female Wistar rats were orally administered
    cypermethrin (14C benzyl, cis-isomer) at the dose level of 2.4 mg/kg
    for females and 1.8 mg/kg for males.  Cypermethrin was administered in
    corn oil solution and animals and tissues were monitored over a period
    of eight days.  Excretion was rapid with both sexes.  There was a
    significant sex difference in the rate of excretion with male rats
    excreting a substantially larger portion of the radioactivity in urine
    than females over the first 24 hour interval.  However, there were no
    substantial differences in the overall rate of elimination by both
    males and females when data were evaluated over the total 8-day period
    of the test.  The residues of radioactivity in the tissue of animals
    of both males and females sacrificed at various periods over the 8-day
    interval showed a small residue in a variety of tissues.  While the
    tissue residue in blood, liver, kidney, etc. was rapidly depleted over
    the test interval, concentrations of cypermethrin in adipose tissue
    were relatively stable over the 8-day trial (Crawford, 1976a).

    Groups of male and female rats were orally administered cypermethrin
    14C-benzyl, trans-isomer) at dose rates of 2.4 mg/kg for males and
    3.0 mg/kg for females.  Again, excretion was rapid with both sexes
    with approximately 95% of the administered dose excreted within 48
    hours.  In contrast to that noted with the cis-isomer, there appeared
    to be no sex differences in the elimination of the trans-isomer.
    Residues in adipose tissue of females was somewhat higher than noted
    in adipose tissue of males.  The observations are consistent with the
    suggestion that the trans-isomer is metabolised faster than the
    cis-isomer (Crawford, 1976b).

    Groups of rats were administered cypermethrin (1:1 cis: trans-isomer
    ratio, 14C-cyclopropyl) at dose rate of 1 mg/kg for males and 2 mg/kg
    for females.  Rapid elimination of cypermethrin was observed with a
    substantial difference noted in the 24-hour urinary excretion in males
    and females.  Females excreted considerably more radioactivity in
    urine over the first 24 hours.  At the end of 72 hours urinary and
    faecal excretion in both sexes was approximately the same.  Small
    quantities of radioactivity were expired as 14CO2 which suggested
    some metabolic breakdown of the cyclopropyl ring. At the end of three
    days, tissue concentrations in liver, kidney muscle, brain, blood,
    skin and remaining carcass were relatively low.  Intestinal content
    was somewhat higher in males than in females ranging from 3 to 9% of

    the administered dose.  Low residue concentrations, which never
    exceeded 1 ppm, were observed in fat (Crawford, 1977).

    The elimination pattern of cyclopropyl- and benzyl-labelled
    cypermethrin appears to be the owns in both males and females. 
    Females absorb and metabolise the trans-isomer faster than males and
    males absorb and metabolise the cis-isomer faster than females
    (Crawford, 1976b).  In a further study to resolve the residual nature
    of the residues of cypermethrin in adipose tissue of rat, Crawford and
    Hutson (1978b) again found that the cis-isomer was relatively stable
    in adipose tissue.  Administration of 14C-benzyl cypermethrin
    (cis-isomer) at a dose of approximately 2 mg/kg to female rats
    resulted in a residue of approximately 0.3 ppm in the fat eight days
    after a single oral dose.  Further studies through 42 days following
    dosing were performed to evaluate the half-life of the cis-isomer in
    fat and the total elimination pattern.  At the end of 42 days,
    residues were observed in fat which were approximately 10% of those
    concentrations noted at eight days.  There was a 90% loss of the
    material from fat over the 8-42 day interval during which time samples
    were taken.  From these data with rats, a half-life of approximately
    20-25 days was estimated with respect to removal of residues from fat
    following a single oral dose.  These half-life values are somewhat
    longer than those noted with the mouse.

    Dogs

    Groups of male beagle dogs were administered 14C-benzyl cypermethrin
    and the individual 14C-benzyl labelled cis- and trans-isomers of
    cypermethrin, orally, at a dose of 2 mg/kg.  Elimination of
    radioactivity from all animals was rapid although differences in data
    from individual dogs precluded a complete evaluation of the rate of
    elimination.  Differences in the rates of elimination of the
    individual dogs in the study may have been due to differences in
    absorption as cypermethrin was given orally in a capsule with no
    solvent.  Tissue residues observed 4 days after oral administration of
    cypermethrin were extremely low.  The vast majority of the excreted
    material was observed in faeces (80%) with urine containing only 11%
    of the administered dose.  As with other species, small residues of
    cypermethrin were observed in fat, approximating 2% of the
    administered dose (this residue was estimated to be 0.3 ppm based upon
    total adipose tissue of the dog) (Crawford, 1979b).

    Sheep

    Sheep were administered cypermethrin dermally (962 mg/animal
    administered in acetone) or orally (without solvent) in gelatin
    capsule at a dose of 4 mg/kg body weight.  Following dermal
    administration, cypermethrin was not readily absorbed (less than 0.5%
    of the administered dose was observed in urine within 24 hours and 2%
    over the six day test interval).  Little radioactivity was found in
    the liver and kidney of dermally-treated sheep.  Tissue residues in
    renal and subcutaneous fat was found to be similar to those noted with

    other animal species and was qualitatively identified as cypermethrin.
    Elimination of cypermethrin from the orally-dosed sheep was rapid with
    61% of the administered dose being eliminated within 48 hours (41% of
    the dose in urine and 20% of the dose in faeces).  The tissue residue
    pattern in sheep following oral administration was similar to that
    noted with other mammalian species.  Low levels of cypermethrin were
    noted in various tissues, including renal and subcutaneous fat
    (Crawford and Rutson, 1977a).

    Cows

    Cypermethrin (1:1, cis:trans-isomer, 14C-benzyl-label) was orally
    administered to lactating cows over a period of three weeks at a
    dietary dosage of 0.2 ppm.  Urine, faeces and milk residues were
    examined over the course of the study and at the conclusion of the
    three week dietary interval, animals were sacrificed and tissue
    residues examined.  Elimination of radioactivity in urine and faeces
    rapidly reached an equilibrium within 2-3 days.  Radioactivity was
    eliminated in the urine and faeces predominantly and accounted for the
    major quantity of cypermethrin residues.  Small quantities of
    radioactivity were noted in milk with a total radioactivity residue
    approximating 0.5% of the administered radioactive cypermethrin.
    Tissue residues were extremely low with notable residues in bile and
    fat as well as in the liver and kidney.  There were no detectable
    residues in muscle, blood or brain.  Analysis of the milk fat showed
    that a high percentage of the radioactivity was present in this
    portion of the milk.  Residues in the milk fat or cream sample were
    reflective of the lipoidal nature of cypermethrin, with residues
    concentrating in fatty tissues (Hutson and Stoydin, 1976).

    In a further study to obtain information on the metabolic distribution
    of cypermethrin in cows, lactating cows were treated for 7 days at a
    dietary concentration of 5 ppm.  Urine, faeces, and milk were analysed
    and at the conclusion of the feeding trial, all animals were
    sacrificed and tissue residues were determined.  As in the previous
    study, elimination occurred rapidly after the onset of dosing with the
    major route of excretion being via urine and faeces.  Tissue residues
    were extremely low with measurable amounts observed in blood, liver,
    kidney, bile and adipose tissue.  Total milk residues amounted to
    approximately 0.2% of the applied cypermethrin, with the largest
    proportion of the residue again found in milk fat (Crawford, 1978).

    Metabolism

    The metabolic fate of cypermethrin was investigated in a variety of
    mammalian species and was determined to be relatively similar in the
    different species.  The major metabolites are derived by cleavage of
    the ester linkage followed by subsequent metabolism of both the acid
    and alcohol fragments and conjugation and excretion of the fragments.

    Studies on the metabolic fate of both cis- and trans-cypermethrin
    administered orally to rats have shown that cypermethrin is rapidly
    cleaved at the ester bond to yield the cyclopropanecarboxylic acid and

    the 3-phenoxybenzyl alcohol moiety.  The latter is rapidly oxidised to
    3-phenoxybenzoic acid and conjugated prior to elimination.  Major
    reactions occurring with the cyclopropanecarboxycyclic acid include,
    in part, oxidation at the methyl groups and apparent lactone
    rearrangement prior to conjugation and elimination.  Hydroxylation of
    the phenoxybenzoyl moiety has been noted to occur in at least two
    positions prior to conjugation and elimination.  Rats and mice
    metabolised cypermethrin in a similar fashion.  In mice, a substantial
    portion of the phenoxybenzoic acid was conjugated with taurine as well
    as with glucuronic acid (Hutson, 1977).  Oxidation has been noted to
    occur in the 4'- position of phenoxybenzoic acid.  Following
    oxidation, the molecule is conjugated as a sulfate and excreted.  A
    portion of unconjugated hydroxylated phenoxybenzoic acid was also
    excreted.  Hydroxylated cypermethrin was observed in mouse faeces
    suggesting that hydroxylation may occur prior to ester cleavage
    (Hutson, 1978b).  Shono, Ohsawa, and Casida (1978), using mouse liver
    microsomal preparations, showed that hydroxylation of the
    phenoxybenzyl moiety at positions other than the 4'- position can
    occur. Small amounts of the 5- and 6-hydroxy phenoxybenzyl derivatives
    were also observed.  Both cis- and trans-isomers were rapidly
    metabolised by cleavage of the ester bond and aromatic hydroxylation
    at the 4'-position of the 3-phenoxybenzyl alcohol moiety.  In rats,
    approximately half of the administered cypermethrin was excreted as
    sulfate conjugates of the hydroxylated phenoxybenzoic acid.
    Phenoxybenzoic acid was also excreted free and conjugated with glycine
    in contrast to the conjugate pattern noted in mice (Crawford and
    Hutson, 1977b, 1978c).  In studies with cyclopropanecarboxylic
    acid-labelled cypermethrin, hydroxylation of the methyl groups on the
    cyclopropane ring occurred to a limited extent.  Oxidation was
    believed to have occurred following ester cleavage.  While most of the
    radioactive metabolites were found in the urinal a small quantity of
    hydroxylated metabolites were eliminated via the
    biliary-intestinal-faecal route suggesting absorption and
    re-distribution through the bile to the faeces.

    In both rats and mice as well as other species, ester cleavage is
    rapid.  There is quantitative and qualitative evidence to suggest that
    the cis-isomer is more stable yielding a larger variety of
    hydroxylated products prior to ester cleavage while the trans-isomer
    yields a wider variety of hydrolytic products which in part are
    oxidised following the ester cleavage.  The acid fragment is
    conjugated predominantly with glucuronic acid an a -glucuronide.
    Conjugated cyclopropanecarboxylic acid derivatives in urine were
    identified as glucuronides have a relative resistance to the action of
    -glucuronidase.  -Glucuronides formed from these acids are generally
    of the ester type readily cleaved by mild acid hydrolysis.  Thus,
    treatment of urine with methanol and sulfuric acid will convert both
    the free acid and the acid glucuronide into a methyl ester.  The
    methyl ester of the carboxylic acid has been shown to be volatile and
    analytical losses may occur with this compound.  The alcohol fragment,
    the alpha-cyano-3-phenoxybenzyl alcohol, is readily oxidised
    metabolically to the benzoic acid, conjugated and excreted.  Alcohol
    conjugates with glucuronic acid are generally ether derivatives,

    stable to acid and enzymatically hydrolysable.  The phenoxybenzyl
    moiety of cypermethrin has been found to form both ester and ether
    -glucuronides.

    Thus, the results of the studies with both rats and mice suggest that
    most of the excreted metabolites of cypermethrin are hydrolysis
    products, although hydroxylation of the intact ester has been
    reported.  Hydroxylation of the methyl groups attached to the
    cyclopropane ring has also been reported.  There was no evidence of
    metabolism at the 2,2-dichlorovinyl moiety.  Evidence exists that the
    cis-isomer is somewhat more resistant than the trans-isomer to
    hydrolysis.  In all cases, only small amounts of hydroxylated
    metabolites with the intact ester bond were observed with the
    cypermethrin.

    The metabolic fate of cypermethrin in dogs was qualitatively similar
    to that observed with other species with the exception being
    conjugation reactions of several metabolites.  As with other species,
    cypermethrin is rapidly metabolised by cleavage of the ester bond and
    by hydroxylation of the phenoxybenzyl moiety at the 4' position.
    Sulfate conjugation of the hydroxylated benzoic acid was reported.
    Additionally, a major urinary metabolite was identified as the
    3-phenoxybenzyl glycine.  Studies on the metabolic fate of
    3-phenoxybenzoic acid in dogs revealed a metabolic pattern of
    oxidation and conjugation similar to that noted with cypermethrin
    (Crawford, 1979a and 1979c).

    In cows, the major urinary metabolite of cypermethrin ( 14C-benzyl)
    was the glutamic acid conjugate of the 3-phenoxybenzoic acid
    (Crawford, 1978).  The cyclopropanecarboxylic acid moiety was
    hydroxylated and/or conjugated with glucuronic acid prior to
    excretion.

    3-Phenoxybenzoic acid has been observed as a major metabolite of
    cypermethrin in all species studied.  Residues of cypermethrin in rat
    skin (<3% of the dose) were noted after oral administration.  Further
    studies to define the skin residue were performed using
    14C-3-phenoxybenzoic acid administered orally to rats as seven
    consecutive daily doses.  The radioactive metabolites in skin were
    identified as predominately 3-phenoxybenzoic acid and a small quantity
    of glyceryl dipalmitate esters of 3-phenoxybenzoic acid (Crawford and
    Hutson, 1979).

    Further studies were performed in rats of the metabolism of
    3-phenoxybenzoic acid and a glucoside conjugate isolated from plant
    tissue.  3-Phenoxybenzoic acid was oxidised at the 4' position of both
    aromatic moieties and to a minor extent at the 6' position of the
    benzoic acid moiety.  Excretion occurred as conjugates, predominantly
    the 4-hydroxy-3-phenoxybenzoic acid-O-sulfate and 3-phenoxybenzoic
    acid.  Additionally, other hydroxylated derivatives and conjugates of
    these oxidation products were observed.  The excretion pattern of the
    glycoside conjugates of 3-phenoxybenzoic acid was qualitatively and

    quantitatively similar to that observed with 3-phenoxybenzoic acid
    suggesting rapid hydrolysis and availability of plant metabolites
    following oral administration (Crawford, 1978).

    Effects on Enzymes and Other Biochemical Parameters

    Preliminary evidence suggested that an increase in the activity of
    certain lysosomal enzymes in peripheral nerves and deficits in
    behavioural functioning tests could serve as indicators of peripheral
    nerve damage.  During Wallerian degeneration, the activity of such
    enzymes as -glucuronidase and -galactosidase as well as other
    enzymes in nerve preparations were shown to be increased significantly
    (Dewar, 1977a).

    Cypermethrin (1:1 cis:trans) was administered to male and female rats
    at dose levels ranging from 25 to 200 mg/kg/day for five consecutive
    days by oral intubation as a 10% W/V solution in DMSO.  A dose related
    functional deficit was observed when the mean slip angle test and the
    landing foot spread test were applied to the animals.  The deficit was
    maximal from 6 to 14 days after the beginning of treatment and
    complete functional recovery occurred within four weeks.  Substantial
    variation in data from the landing foot spread test was noted.  Data
    were inconsistent over the course of the study.  -glucuronidase
    activity was increased in a dose-dependent fashion in both males and
    females.  The results suggest that cypermethrin produced a primary
    axonal degeneration, readily measurable 28 days after treatment as an
    increase in -glucuronidase activity and in deficits in specific
    behavioural-function testing of rats (Dewar, 1977b).

    When further studies were performed on the biochemical indices of
    nerve degeneration to compare results with known degenerating
    compounds (methyl mercury), it was observed that the changes in
    -glucuronidase and -glucuronidase activity were considerably smaller
    and less reproducible than those obtained following methyl mercury
    poisoning (7.5 mg/kg/day for 7 days).  In comparison of central versus
    peripheral nerve damage, there was no evidence that the trigeminal
    nerve was more sensitive to the effects of cypermethrin than the
    sciatic and posterior tibial nerves.  At near lethal doses of
    cypermethrin biochemical changes in the trigeminal nerve were
    consistent with those of Wallerian degeneration.  The changes were
    similar qualitatively to those seen with methyl mercury, but were
    quantitatively much less intense (Dewar and Moffett 1978a).

    Electrophysiological studies were performed to determine whether acute
    or subacute intoxication with cypermethrin produced changes in the
    conduction velocity of slower fibres in peripheral nerves or
    alterations in the maximal motor conduction velocity.  There was no
    evidence to suggest that cypermethrin, at doses that induced severe
    clinical signs of intoxication, including ataxia, had any effect on
    maximal motor conduction velocity or conduction velocity of the slower
    motor fibers in peripheral nerves.  Doses used in the study ranged
    from a single dose of 200 mg/kg to 7 consecutive doses of 150 mg/kg
    followed by 2 doses of 400 mg/kg.  At near-lethal doses there were no

    effects noted on conduction velocity in the slower motor fibers of the
    sciatic nerve and tail or on the maximal conduction velocity, even in
    the presence of clinical signs of acute intoxication and at dose
    levels where previous studies had shown functional degeneration. 
    These electrophysiological findings are reflective of motor function
    which would suggest that the physiological and functional deficits
    observed as a result of acute intoxication may be primarily sensory in
    nature (Dewar and Deacon, 1977).

    SPECIAL STUDIES ON REPRODUCTION

    Dominant Lethal Studies

    Mice

    Groups of male mice (12 mice/group, 36 mice were used as controls)
    were administered a single dose of cypermethrin dissolved in dimethyl
    sulfoxide at dosage levels of 0, 6.25, 12.5 and 25 mg/kg body weight
    or 5 successive daily oral doses of 0, 2.5 and 5.0 mg/kg.  Following
    dosing, each male was caged with 3 virgin females for 7 days.  The
    mating procedure was repeated weekly over an interval of 8 weeks in a
    standard dominant lethal test.

    Females mated to males treated with 5 daily oral doses of 2.5 mg/kg
    and those mated to males receiving a single dose of 12.5 mg/kg showed
    a significant reduction in the incidence of pregnancy during the
    second and third week respectively of the onset of treatment.  This
    did not occur with other either higher or lower dosed groups or at
    other intervals.  In females, mated to males treated daily with doses
    of cypermethrin a significant reduction in foetal implants was
    observed during the second week of mating.  Early foetal deaths were
    increased in the second week at 5 mg/kg.  No such increases occurred
    in any other weekly interval or any other dosed group.  Thus, multiple
    administration of cypermethrin on five successive days induced a
    significant reduction in foetal implants during the second week of
    mating and a marginal increase in early foetal deaths at the same time
    interval.

    To evaluate the potential (noted above) for a dominant lethal effect,
    a second experiment was performed.  Groups of male mice (12
    mice/group, a control group consisted of 36 mice) were administered
    five daily oral doses of cypermethrin at levels of 0, 2.5, 5.0, 7.5
    and 10 mg/kg (in dimethyl sulfoxide).  Following dosing each male was
    mated with three virgin females for four days and subsequently
    provided with virgin females every four days for a period of three
    weeks.  Female mice were examined for evidence of dominant lethality
    13 days after mating.  In addition, 40 males of proven fertility were
    dosed for five successive days at the same dosage levels, 0, 2, 5,
    5.0, 7.5 and 10 mg/kg.  These animals were also mated with four virgin
    females on four successive days for a period of three weeks.  Four
    animals from each group were sacrificed for histological examination
    of the testes and epididymis on days 1 and 7 after the final dosing.

    In contrast to the previous trial, no reduction in foetal implants was
    noted in any of the animals mated with cypermethrin-treated males. The
    number of early foetal deaths was marginally increased at the highest
    dose level in the 12-16 day interval after dosing and in the first 4
    day period after treatment with 7.5 mg/kg males.

    In the groups of animals examined histologically, no abnormalities
    were detected in the testes and epididymis and there were no
    observable histological differences between any of the test groups and
    the controls (Dean et al., 1977).

    Rat

    Groups of rats (30 male and 30 female rats/group) were fed
    cypermethrin in the diet at concentrations of 0, 10, 100 and 500 ppm
    for five weeks after which they were mated to initiate a standard
    three generation, 2-litter per generation, reproduction study.  After
    the selection of the second litter as parents for the following
    generation, the original parents were sacrificed and subjected to
    gross and microscopic examination.  At the conclusion of the study,
    ten animals of each sex at the age of 21 days were also examined
    histologically.  Calculations were made of the indices of fertility,
    gestation, viability and lactation.  There was no mortality over the
    course of the study, and behaviour was not abnormal.  Reduced body
    weight and food intake was seen at various intervals in both males and
    females fed 500 ppm in the diet.  Reduced total weight was observed at
    500 ppm in the F1A litters and reduced total weight and litter size
    were noted at 100 and 500 ppm in the F1B.  No compound related gross
    or microscopic pathological findings were noted in any rats (Hend et
    al., 1978).

    SPECIAL STUDIES ON TERATOGENICITY

    Rat

    Groups of 25 pregnant rats were administered orally from day 6 to day
    15 of gestation at dose levels of 0, 17.5, 35.0 and 70.0 mg/kg/day in
    a standard teratology bioassay.  On day 21 of gestation, the animals
    were sacrificed and gross examination of foetuses were made, including
    skeletal and somatic examinations.  Pre-implantation losses were
    evaluated based on corpora lutes, counts and implantation sites and
    post-implantation losses were evaluated based upon implantation sites
    and viable foetuses.  Foetal somatic and skeletal examinations on day
    21 of gestation showed no teratogenic changes that could be
    attributable to the treatment.  There were no indications of
    embryotoxic or teratogenic events in the study (Tesh et al., 1978).

    Rabbit

    Groups of pregnant rabbits (20 rabbits/group, 30 rabbits were used as
    an additional control group) were administered cypermethrin dissolved
    in corn oil at dose levels of 0, 3, 10 and 30 mg/kg body weight orally

    from day 6 to day 18 of gestation.  On day 28 of gestation the rabbits
    were sacrificed and examination made of live foetuses, dead foetuses,
    resorption sites and corpora lutea.  Live foetuses were maintained for
    24 hours to assess viability. Foetuses were also examined for gross
    somatic and skeletal deformities.

    There was no significant mortality or differences in weight gain
    during the period of gestation.  There were no significant differences
    between control and test groups with respect to pregnancy, foetal
    death and survival.  Although a wide range of skeletal and visceral
    abnormalities were found in the course of the study, there were no
    differences between control and test groups with respect to
    abnormalities.  It was concluded that oral dosing at up to 30 mg/kg
    during the major period of organogenesis resulted in no teratogenic
    effects in the offspring (Dix, 1978).

    SPECIAL STUDIES FOR MUTAGENICITY

    Mice Host-Mediated Assay

    Groups of male mice (2-3 mice per group) were administered
    cypermethrin, orally, at dose levels of 0, 25 and 50 mg/kg in
    dimethylsulfoxide.  The animals were immediately injected
    interperitoneally with a suspension of S. cerevisiae in a standard
    host mediated assay.  After five hours, the mutagenic conversion rates
    in the yeast cells recovered from the treated animals were comparable
    with those of control animals suggesting that, under the terms of this
    assay, there was no evidence to suggest a mutagenic potential (Brooks,
    1976).

    Microorganisms

    The mutagenic potential of cypermethrin on various microorganism
    species including: S. cerevisiae, E. coli WP2 uvr A, and S.
    typhimurium TA-1538 (with and without the use of a rat activation
    system) was examined.  No increase in the mitotic gene conversion was
    recorded in S. cerevisiae, either in the presence or absence of
    microsomal oxidation. Cypermethrin, at concentrations up to 500
    micrograms per plate, did not induce an increased mutation rate with
    E. coli or S. typhimurium TA-1538, in vitro either in the
    presence or in the absence of the microsomal oxidation system (Brooks,
    1976).

    Cypermethrin did not increase the number of revertant colonies of S.
    typhymurium (TA-1535, TA-1537, TA-1538, TA-98 and TA-100) in the
    presence or absence of a mouse liver subcellular activation
    preparation obtained from 6 strains of PCB-treated mice.  Cypermethrin
    was tested at dose levels up to 1 mg/plate (Suzuki, 1977).

    Hamster - Chromosomes

    Groups of Chinese Hamsters (12 males and 12 females/group) were
    administered orally on each of two successive days at a dose rate of

    0, 20 or 40 mg/kg cypermethrin dissolved in dimethylsulfoxide.
    Positive and negative controls consisted of cyclophosphamide (100
    mg/kg) and dimethylsulfoxide alone.  In chromosome preparations of the
    control and cypermethrin-treated hamsters, there were no indications
    of abnormalities.  The cylophosphamide treatment induced a significant
    degree of chromosomal damage (Dean, 1977).

    SPECIAL STUDIES ON NEUROTOXICITY

    Rats

    Cypermethrin, orally administered to rats at high acute dosage levels,
    produced severe clinical signs of poisoning which was accompanied by
    histological evidence of sciatic nerve damage.  Within one day
    following the acute poisoning, neuropathy was evident as axonal breaks
    in the sciatic nerve (Carter and Butterworth, 1976).

    Groups of rats (10 males per group) were utilised in a paired feeding
    study to examine the neurotoxicological effects of high dietary
    levels.  Rats were fed dietary levels of cypermethrin (45:55,
    cis:trans-isomer ratio) for 14 days at dosage levels of 0, 1250, 2500,
    and 5000 ppm.  Growth was monitored and clinical evaluations for
    adverse behaviour were recorded during the course of the study.  Gross
    pathology on tissues and organs and microscopic examination of the
    sciatic nerve were performed at the conclusion of the study.

    At 5000 ppm, mortality was observed with all rats either dying or
    sacrificed in a moribund condition within the first week.  At 2500
    ppm, 6 of 10 rats died before the conclusion of the study.  There was
    no mortality in the low dose group.  Clinical signs of neurotoxicity
    were characterised by an impaired ability to walk and splayed hind
    limbs.  In extreme cases, clinical signs of ataxia and paralysis were
    reported.  Other clinical signs included: hypersensitivity to external
    stimuli, gross disorientation and convulsions, the latter generally
    seen at high dose levels.  The neurotoxic signs of poisoning observed
    in the 1250 ppm group after day three were spontaneously reversed by
    day nine when all surviving animals that were initially affected
    appeared to be normal.  Remission of ataxia at the 2500 ppm group was
    also noted within 11 days of treatment.  Growth reduction was observed
    in all animals in the study.  At the lowest dose level, the rate of
    growth was delayed for the first few days after which time the rate
    was consistent with that of controls for the remainder of the study.
    The absolute body weight of the treated animals was, however,
    significantly lower than the controls at the conclusion of the
    two-week study.  Reduction in body weight was consistent with
    reduction in food consumption.  Ultrastructural changes in the sciatic
    nerve were observed in the two highest dose levels, although the
    number of animals examined was small.  There was some evidence of
    axonal damage in the myelinated nerves primarily at the two highest
    dose groups.  Changes in unmyelinated axons were not observed.  In
    general, the histological and ultrastructural changes in the sciatic
    nerve, accompanied by clinical signs of poisoning, are not readily
    apparent at low doses.  Thus, cypermethrin, at acutely toxic dietary

    levels,induces damage to sciatic nerves, the clinical signs of which
    may be reversible (Glaister et al., 1977a).

    Hamsters

    Groups of male and female Syrian hamsters were orally administered
    doses exceeding the LD50 in an attempt to define clinical signs of
    poisoning and to evaluate the histological damage to the sciatic
    nerve.  At doses of 794 mg/kg and above, all animals showed clinical
    signs of poisoning including tremors, abnormal, irregular movements,
    and an unusual gait.  As noted with rats, axon and myelin degeneration
    was noted in all groups treated.  The lesions included swelling and
    breaks in the axons and clumping of myelin (Butterworth and Clark,
    1977).

    A series of experiments were performed to further evaluate the
    neurotoxic potential following subacute, oral administration to
    Chinese hamsters.  Clinical examination, functional testing and enzyme
    determinations using -galactosidase and -glucuronidase were
    performed.  The functional test consists of measuring the mean slip
    angle where the animal is maintained on an inclined plane that
    steadily increases its angle until the animal can no longer maintain a
    stationary position.  (The average angle of five replicate trials
    constituted the mean slip angle test.)

    Groups of 20 male and 20 female Chinese hamsters were orally
    administered at a dose of 40 mg/kg followed by a dose of 20 mg/kg for
    the following four days.  Fifteen animals in each sex served as
    controls.  There was extensive weight loss in all dosed groups and
    some mortality was observed primarily as a result of the initial
    administration of 40 mg/kg.  There was a loss of fur and a dermal
    ulceration observed in the early parts of the study.  This dermal
    occurrence was transient, disappearing rapidly after the treatments
    were concluded.  There was significant weight loss in the initial
    phase of the study.  However, after the last dose, the surviving
    animals rapidly gained weight at a rate consistent with the control
    animals.  There were no effects noted on the mean slip angle
    experiment and a marginal increase in -galactosidase was observed in
    peripheral nerve.

    A further experiment utilising five male and five female Chinese
    hamsters administered cypermethrin daily for five days at dose levels
    of 0, 5, 10 and 20 mg/kg showed no mortality over the course of the
    study.  There was a slower growth of the animals treated with 20 mg/kg
    which again was reversed at the conclusion of the treatment period.
    Hyperexcitability was noted in one female at the high dose level.
    There were no notable differences in behaviour in any of the animals.
    There was a significant deficit in the mean slip angle test with
    females showing an earlier dose-related deficit than noted in males.
    The females recovered from this deficit earlier than males who showed
    an erratic pattern of recovery.  -galactosidase activity was
    increased at all dose levels three weeks after the onset of the
    experiment.  This increase was statistically significant at the two

    highest dose levels.  Dermal irritation and fur loss was not noted in
    this experiment.

    Sixteen male and sixteen female Chinese hamsters were administered
    five daily doses of 30 mg per kg of body weight or a control of
    dimethyl sulfoxide.  Additionally eight animals of each sex were
    administered five daily doses of methyl mercury (7.5 mg/kg body
    weight) as a positive control.  With cypermethrin, there was no
    mortality and the rate of weight gain was consistent with that of the
    controls.  There was a transient dermal irritation in the majority of
    the animals accompanied by skin ulceration.  This condition
    disappeared at the conclusion of the treatment interval.  One male
    administered cypermethrin had an unusual gait.  There was a slight
    deficit in the inclined plane test which was noted in the early parts
    of the experiment but was absent by the end of the third week.
    Increases in both -glucuronidase and -galactosidase were evident in
    peripheral nerve tissue.  It was concluded that cypermethrin when
    administered at high subacute doses, produced changes in the sciatic
    nerve consistent with Wallerian degeneration.  Biochemical changes
    were evident as increases in -glucuronidase and -galactosidase
    activity and clinically functional deficits were noted (Dewar and
    Moffett, 1978b).

    Hen

    Groups of adult hens were fed cypermethrin at a dosage rate of 1 mg/kg
    for five successive days.  After 3 weeks, the dosing regimen was
    repeated.  Positive (TOCP) and negative control groups were included
    in the study.  There were no signs of delayed neurotoxicity (as
    generally noted with certain organophosphate esters) seen following
    cypermethrin treatment.  TOCP induced the standard clinical and
    histological signs of axon and myelin disruption (Owen and
    Butterworth, 1977).

    Acute Toxicity

    Table 1 contains a summary of the findings of various studies on acute
    toxicities to a number of animals.

    Table 2 illustrates that the cis isomer is more toxic than the trans.



        Table 1.  Acute Toxicity of Cypermethrin to Various Animals

                                                                                                          
    Species          Sex      Route     Vehicle               LD50           Reference
                                                              (mg/kg)
                                                                                                          

    Mouse            M,F      Oral      Corn oil              82             Coombes, Carter et al., 1976
    Mouse            M,F      Oral      Dimethylsulphoxide    138            Coombes, Carter et al., 1976
    Mouse            M,F      Oral      Aq.suspension         779b           Jaggers, 1979
    Mouse            M,F      I.P.      corn oil              485            Combs, Carter et al., 1976

    Rat              M,F      Oral      Corn oil              251-992        Combs, Carter et al., 1976
    Rat              M,F      Oral      Dimethylsulphoxide    303            Combs, Carter et al., 1976
    Rat              M        Oral      Glycerol formal       200-400        Combs, Carter, et al.,1976
    Rat              F        oral      Glycerol formal       app. 200       Combs, Carter et al., 1976
    Rat              M        Oral      Aq.suspension         400-800        Combs, Carter et al., 1976
    Rat              F        Oral      Aq.suspension         app. 400       Combs, Carter et al., 1976
    Rat              F        Oral      Aq.suspension         4123b          Jaggers, 1979
    Rat              M        Oral      Aq.suspension         3000c          Jaggers, 1979
    Rat (3wks)       M,F      Oral      Dimethylsulphoxide    163            Rose and Dewar, 1978
        (6wks)       M,F      Oral      Dimethylsulphoxide    322            Rose and Dewar, 1978
        (12 wks)     M,F      Oral      Dimethylsulphoxide    526            Rose and Dewar, 1978
    Rat              F        I.P.      Aq.suspension         >500b          Jaggers, 1979
    Rat              M,F      I.P.      Propylene glycol      1000-2000b     Jaggers, 1979
    Rat              F        Dermal    Undiluted             >4800b         Jaggers, 1979
    Rat              M,F      Dermal    Xylene                >1600          Combs, Carter et al., 1976

    Syrian
    hamster          M,F      Oral      Corn oil              >400           Combs, Carter et al., 1976

    Chinese
    Hamster          M,F      Oral      Corn oil              203            Combs, Carter et al., 1976

    Guinea pig       M        Oral      Corn oil              app. 500       Combs, Carter et al., 1976
    Guinea pig       F        Oral      Corn oil              >1000          Combs, Carter et al., 1976
    Guinea pig       M        Oral      Aq.suspension         >4000b         Jaggers, 1979

    Table 1.  Continued...

                                                                                                          
    Species          Sex      Route     Vehicle               LD50           Reference
                                                              (mg/kg)
                                                                                                          

    Rabbit           F        Oral      Undiluted             >2400b         Jaggers, 1979
    Rabbit           F        Dermal    Undiluted             >2400b         Jaggers, 1979

    Dom. fowl        M,F      Oral      Dimethylsulphoxide    >2000          Combs, Carter et al., 1976

    Partridge        M,F      Oral      Dimethylsulphoxide    >3000          Combs, Carter et al., 1976
                                                                                                          

    a)  Unless specified, all values refer to data generated using 50:50 cis:trans material.

    b)  Data generated using 40:60 cis:trans material.

    c)  Data generated using 53:46 cis:trans material.



    Table 2.  Effect of Cis:Trans Ratio on Acute Toxicity of Cypermethrin

                                                                                             
                                                                LD50
    Species    Sex     Vehicle               Cis:trans ratio    (mg/kg)    Reference
                                                                                             

    Rat        M,F     Dimethylsulphoxide    cis only           160-300    Brown, 1979a
               M,F     Dimethylsulphoxide    trans only         >2000      Brown, 1979b
               F       Corn oil              cis:trans 90:10    367        Jaggers, 1979
               F       Corn oil              cis:trans 40:60    891        Jaggers, 1979
                                                                                             

    


    Cypermethrin was administered dermally to rats by a single application
    (5000 mg/kg) or 5 consecutive daily doses (2500 or 5000 mg/kg/day).
    Low mortality was observed in the multiple dose groups (20-30%). 
    Toxic signs of poisoning were similar to those described below. 
    Axonal lesions of the sciatic nerve were noted in microscopic
    examination (Okuno et al., 1976).

    The toxic signs noted following acute poisoning with cypermethrin were
    similar in most mammalian species.  In rats this consisted of
    sedation, ataxia, a splayed or ataxic gait and occasional tremors or
    convulsions.  The onset of toxic signs of poisoning were rapid and
    disappeared within several days in survivors.  In dogs, signs of acute
    intoxication included nervousness, inappetance, diarrhea, vomiting,
    tremors and exaggerated ataxia while walking were noted at extremely
    high levels.  A single application of undiluted cypermethrin to rabbit
    eyes produced a mild transient conjunctivitis lasting two days.

    Groups of ten male and ten female guinea pigs were used to assess the
    skin sensitizing potential of cypermethrin.  Two guinea pigs out of
    the 20 exposed to cypermethrin showed a positive skin reaction
    indicating that cypermethrin may have a weak skin-sensitizing
    potential.  Groups of four male and four female rabbits were
    administered cypermethrin dermally in a 24-hour skin test.  A single
    application of cypermethrin was observed to be a moderate irritant to
    rabbit skin (Coombs et al., 1976).

    SHORT TERM STUDIES

    Rat

    Groups of rats (20 male and 20 female rats per group) were fed
    cypermethrin in the diet at concentrations of 0, 75, 150 and 1500 ppm
    for 90 days.  Cypermethrin used in the study was a 44:56
    (cis:trans-ratio) with a purity of 92%.  Random samples were
    chemically analysed periodically during the course of the study.  At
    the conclusion of the study, four animals of each sex were maintained
    on control diets for a one-week recovery period.

    There was no mortality over the course of the study although both
    males and females at 1500 ppm had reduced body weight and food
    consumption in the first month of the study.  After the first month,
    the growth rate was similar to that of controls although the animals
    never achieved the weight noted in the other groups.  At the
    conclusion of the study, hematology, clinical chemistry, urinalysis
    and histopathology were performed on all animals.  With the exception
    of a slight increase in M/E ratio in the bone marrow of female rats
    fed 1500 ppm in the diet, there were no hematological or urinalysis
    effects.  An increased microsomal (smooth endoplasmic reticulum)
    oxidative activity was noted as an increased hepatic aminopyrine
    demethylase activity in both males and females at 1500 ppm and in
    males at 150 ppm.  These adaptive changes in the subcellular portions
    of the liver were substantially reversed within the four week recovery
    period.  Increased liver weight was not noted on gross examination at

    the conclusion of the study.  A slight reduction in pituitary weight
    of males, while statistically significant, was not dose-related.  A
    slight decrease in female kidney weight was dose-dependent and
    significantly different from control values at the highest level.  The
    decrease in kidney weight in males was slight and not significantly
    different from controls in any of the dietary levels.  Gross and
    microscopic (including electron microscopic) examinations of tissues
    and organs showed no significant differences from the observations
    noted in controls.  Examination of the sciatic nerve from animals in
    the control and 1500 ppm dietary group showed no changes which could
    be directly attributable to the presence of cypermethrin in the diet.

    Seven of the sixteen males fed 1500 ppm and two of twelve male
    controls showed slight changes in myelin which may or may not have
    been brought about by histological fixation of the material prior to
    examination.  The condition of the sciatic nerve of females was
    similar to that noted in control females.  There were no effects noted
    in unmyelinated axons in both males and females.  Interim histological
    examination at 30 days, during which time clinical signs of poisoning
    were noted, was not performed in this study (Glaister et al.,
    1977b).

    Groups of rats (6 male and 6 female rats/group, 14 of each sex were
    used as controls) were fed trans-isomer for five weeks at dietary
    concentrations of 0, 30, 100, 300, 1000 and 3000 ppm.  There was no
    mortality observed over the course of the study.  Food intake and
    growth were reduced in the high dosage group.  Alkaline phosphatase
    activity was increased at the two highest dose levels.  Minimal
    changes were observed at the two highest dose levels including several
    hematological parameters (red blood cell count and hemoglobin
    concentration).  Liver, spleen and kidney weights were increased at
    1000 ppm and above with the spleen and at the 3000 ppm level with the
    kidney and liver.  Gross and microscopic histopathologic examination
    of several tissues and organs revealed no cypermethrin-related
    injuries.  Special reference was given to the examination of the
    sciatic nerve which showed no damage (Hend and Butterworth, 1977a).

    Groups of rats (6 male and 6 female rats/group, 10 of each sex were
    used as controls) were fed dietary concentrations of cis-isomer at
    concentrations of 0, 30, 100, 300, 750 and 1500 ppm for five weeks
    following a protocol similar to that described above.  Mortality was
    observed at the 1500 ppm dose occurring at intervals from 4 to 17 days
    from the start of the experiment with all animals displaying
    neurotoxic signs of poisoning.  At the next lower dose group (750 ppm)
    almost all of the animals showed gross neurotoxic signs of poisoning,
    abnormal sensitivity to sound and touch and slight cases of ataxia.
    There was no compound-related mortality at dose levels of 750 ppm or
    below.  Growth was reduced at the 750 ppm over the course of the
    study.  Significant reductions in food intake were also noted at 300
    ppm and above at the initial phase of the study.  Gross examination of
    tissues and organs again revealed a reduction in heart, liver, spleen
    and kidney weights.  Adjustment of the data for terminal body weight
    revealed a statistically significant change in kidney weight at 300

    ppm and above while liver weight was increased at 750 ppm.  Plasma
    protein levels were decreased and urea and potassium concentrations
    were increased in male rats at 750 ppm.  Gross and microscopic
    examinations of tissues and organs showed substantial degeneration at
    1500 ppm and above in both the liver and sciatic nerve.  Liver lesions
    consisted of a coagulative necrosis of hepatocytes occurring in both
    males and females.  The sciatic nerve from both sexes showed swelling
    and breaks in axons with concomitant myelin degeneration and
    vacuolation.  There were no lesions observed in the brain or the
    spinal cord (Hend and Butterworth, 1977b).

    Groups of rats (12 male and 12 female rats/group, 24 of each sex were
    controls) were fed cypermethrin in the diet at dosage levels of 0, 25,
    100, 400, and 1600 ppm for 13 weeks.  After two weeks exposure to 1600
    ppm, both males and females exhibited hypersensitivity and varying
    signs of ataxia.  Mortality was observed with male rats up to the
    fifth week of feeding after which the surviving animals improved
    clinically and appeared normal at the end of the study.  Reductions in
    body weight, growth and food intake were also noted at the 1600 ppm
    dose level.  At the conclusion of the study, small increases in plasma
    urea were noted in both sexes.  Males had a slight increase in plasma
    potassium while females had a slight increase in alkaline phosphatase
    and plasma protein levels at the 1600 ppm dosage group.  Hematological
    abnormalities noted at 1600 ppm at the end of 13 weeks included a
    reduction of hemoglobin, packed cell volume and red blood cell count
    in females and a reduction in kaolin-cephalin clotting time in males.
    There were no effects at dose levels below 1600 ppm.

    Gross and microscopic pathology performed at the conclusion of the
    study showed axonal breaks and vacuolation in the sciatic nerve of
    animals fed 1600 ppm in the diet.  This was especially noted with
    those animals that showed clinical signs of ataxia and died during the
    course of the study.  At the conclusion of the 13-week trial, sciatic
    nerve lesions were not noted in any surviving animals.  An increased
    kidney weight in males fed 400 ppm was observed which was not
    associated with any clinical or pathological signs of abnormality
    (Hend and Butterworth, 1976).

    Dogs

    Groups of beagle dogs (4 male and 4 female dogs/group) were fed
    cypermethrin (1:1 cis:trans-isomeric mixture) in the diet at
    concentrations of 0, 5, 50, 500 and 1500 ppm for 13 weeks.  There was
    no mortality over the course of the study.  However, there were
    significant signs of poisoning observed at the 1500 ppm level which
    included diarrhea, anorexia and tremors as well as ataxia,
    incoordination and hyperesthesia.  On account of these clinical signs,
    two male and two female dogs at the high dose level had to be
    sacrificed before the end of the experiment.  Minor variations were
    observed at various hematological parameters with the kaolin-cephalin
    clotting time observed to be consistently lower throughout the study
    in female dogs at 500 ppm.  There were no other significant
    differences with respect to standard hematological or clinical

    chemistry parameters.  Gross examination of kidneys and organs showed
    no effect on organ weights attributable to the diet.  Microscopic
    examination of tissues and organs revealed a nonspecific focal
    bronchopneumonia in the lungs of the animals surviving 1500 ppm. 
    There were no compound-related changes and no histological
    abnormalities in other tissues examined with the exception of a
    variation in the intensity of the pink colour of the optic disc noted
    on ophthalmologic examination at the conclusion of the study.

    Because of the pink colouration observed in the optic disc, a further
    experiment was undertaken to determine the cause of this occurrence.
    Cypermethrin was fed to two groups of three male dogs at
    concentrations of 0 and 500 ppm for 13 weeks.  Specific ophthalmologic
    examination was made to evaluate the degree of colouration of the
    optic disc.  At the end of 13 weeks, there were no consistent
    differences between the colour of the optic discs of the treated dogs
    and controls.  A no-effect level of 50 ppm was observed in this
    short-term study (Buckwell and Butterworth, 1977).

    LONG-TERM STUDIES

    Rat

    Groups of rats (48 male and 48 female rats/group, 96 of each sex were
    used as controls) were maintained under SPF conditions and fed 1:1
    cis:trans in the diet for 2 years at dosage levels of 0, 1, 10, 100
    and 1000 ppm.  Chemical analyses were made confirming stability of
    cypermethrin in the diet over the test interval.

    There was no mortality over the course of the study attributable to
    cypermethrin in the diet.  General health and behaviour of the
    cypermethrin-fed animals was not different from that of the control
    animals.  Body weight and food consumption data showed a reduction in
    dietary intake and growth in both males and females in those groups
    fed 1000 ppm in the diet.

    Gross morphological changes were noted periodically over the course of
    the study.  At six months, males fed 1000 ppm had a slightly reduced
    testes weight which was not seen thereafter.  Slight changes in the
    gross kidney weight at periodic intervals in the study were not
    accompanied by notable changes in clinical measurements or on
    microscopic examinations.  These changes in kidney weight were
    believed to be unrelated to the presence in the diet.  Liver weight
    increases were noted at 18 months again in those animals maintained at
    the high dose level.  The only clinical chemistry changes noted over
    the course of the study was a slight decrease in the activity level of
    alkaline phosphatase in males at the 2 year interval.  The decrease in
    alkaline phosphatase activity was not dose-related and was not noted
    in females.  Minor fluctuations were seen in various hematological
    parameters over the course of the study but these, too, were not
    compound related nor statistically significant.  These changes are not
    believed to be related to the presence in the diet.  Gross and

    microscopic examination of tissues and organs periodically over the
    course of the study did not suggest adverse somatic effects.

    The kidneys of most animals after 12 months showed chronic nephrosis,
    histologically characterized as tubular dilatations, interstitial
    chronic inflammatory infiltration and glomerular scarring.  In the
    liver, varying degrees of chronic inflammatory infiltration,
    hepatocyte vacuolation and bile duct proliferation were observed.
    These changes were characteristic of ageing processes and were not
    attributable to cypermethrin.  Dermal ulceration was present in a
    number of animals and over the course of the study.

    A portion of the sciatic nerve from 12 animals fed 1000 ppm for one
    year and 12 control animals was histologically examined for signs of
    neurotoxicity.  There were no differences in the incidence of abnormal
    fibres in the control and animals fed for cypermethrin for 12 months
    (Trigg et al., 1977).  Microscopic examination of the sciatic nerve
    from animals sacrificed at the conclusion of the study showed a small
    number of nerve fibers exhibiting slight Wallerian degeneration
    changes.  These degenerative changes increased with age but did not
    appear to be dose-related with respect to severity.  Thus,
    cypermethrin did not induce neuropathy clinically nor did it induce
    histological evidence of nerve degeneration.

    There did not appear to be a significant increase in the incidence of
    tumor formation in either males or females over the course of the
    study.  A large number of pituitary adenomas were reported
    predominantly in females of all dose groups including controls.  This
    occurrence did not appear to be dose-related as similar events were
    recorded in all dose levels.  Based on the reduced body weight
    observed at 1000 ppm in the diet of both males and females, the
    no-effect level is 100 ppm (McAusland et al., 1978).

    Observations in Humans

    Urine obtained from operators spraying cypermethrin in experimental
    trials was analysed for the presence of the chlorinated cyclopropane
    carboxylic acid metabolite.  Using standard gas liquid chromatography,
    the carboxylic acid metabolite was observed in urine of exposed
    workers at levels up to 0.4 g/ml (the limit of detection was
    estimated to be 0.05 g/ml) (Baldwin, 1978).  Studies were carried out
    in the Ivory Coast, Africa where operators sprayed with a hand-held
    ULV apparatus either cypermethrin or a control UW formulation.  The
    cypermethrin sprayers were found to have residues on the exposed parts
    of their bodies.  Medical and electrophysiological examinations showed
    no adverse effects from the exposure.  The rate of dermal exposure of
    the operators during spraying ranged from 1.5 to 46.1 mg/hour.  There
    was a reasonable relationship between the total cypermethrin deposited
    dermally and the excretion in urine.  The levels of the cyclopropane
    carboxylic and acid metabolite in the 24 hour urine were between
    <0.05 and 0.32 mg.  This, together with the finding of 0.6 mg of this
    metabolite in 72 hour urine from one man led to the estimation that

    approximately 3% of the total dermal dose was absorbed and rapidly
    excreted by the operators (Prinsen and van Sittert, 1978).

    COMMENTS

    Cypermethrin is an insecticidally active synthetic pyrethroid
    currently being developed for use in agriculture.  The acute toxicity
    has been studied in a variety of species and the toxic response in all
    species is very similar.  Cypermethrin has a moderately acute oral
    toxicity.  The acute signs of poisoning, in addition to a generalized
    nervous system response, include a neurological involvement in rodents
    where reversible clinical signs of ataxia was accompanied by
    histological and biochemical evidence of peripheral (and possibly
    central) nerve disruption.  Myelin and axon degeneration in the rat
    sciatic nerve was noted following high dose level administration.
    There was no information on the relative sensitivity of humans to the
    nervous system disruption noted in rodent species (see Report Section
    3.5).

    Cypermethrin is readily absorbed, distributed, and metabolised in
    mammals.  Because of the chemical and especially the isomeric
    complexity of the molecule, the metabolic profile with respect to all
    of its isomers is extremely complex.  Cypermethrin is readily cleaved
    at the ester linkage and subjected to oxidative degradation and
    conjugation of the metabolic products.  Elimination from the body
    following acute and subacute administration is rapid.  However, the
    clearance rate from adipose tissue is slow and a half-life in rats and
    mice may range from 10 to 30 days.  The data suggested a potential for
    bioaccumulation in the body following continuous exposure.

    In a wide variety of studies, there was no carcinogenic or mutagenic
    potential as evidenced by short-term bioassays or a long-term chronic
    study.  Reproduction was unaffected and no signs of teratogenic
    potential were noted in two species examined.  Two dominant lethal
    tests were performed, and while data were basically negative, these
    studies did not give full assurance of the lack of a dominant lethal
    effect on male reproduction.  In short-term tests, only younger
    animals were susceptible to the inductive effects of cypermethrin on
    liver metabolizing enzymes.

    The extensive toxicological data base already in existence lent
    assurance to the estimation of an ADI for man.  The lack of data on
    tissue residue storage and release and on the limited human experience
    with cypermethrin were instrumental in making this temporary, pending
    further information.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

    Rat: 100 ppm in the diet equivalent to 5.0 mg/kg body weight
    Dog:  50 ppm in the diet equivalent to 1.25 mg/kg body weight

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN

    0-0.006 mg/kg body weight

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

    Cypermethrin is a recently introduced insecticide recommended as a
    foliar spray for the control of a wide range of insect pests.  In line
    with other members of the pyrethroid group of compounds, it is used at
    lower rates than most other types of chemical insecticides.
    Application rates seldom exceed 250 g/ha.  In most instances a
    considerably lower rate is required.  Several applications, up to two
    per month and up to 7 days before harvesting, may be made during a
    growing season.

    Current recommendations for use on various food crops are summarised
    in Table 3.

    Table 3.  Current dosage rates for use on various crops

                                                                 
                                          Recommendations
    Crop                                  (in active ingredients)
                                                                 

    Alfalfa                               25 g/ha
    Apples                                0.003%-0.0125%
    Brassica leafy vegetables             30-200 g/ha
    Cereals (barley, wheat)               25-200 g/ha
    Cherries                              0.0075%-0.0125%
    Citrus                                0.0025%-0.01%
    Cotton                                50 - 100 g/ha
    Grapes                                30-50 g/ha
    Kiwifruit                             0.01%
    Legume vegetables                     25-200 g/ha
    Lettuce                               50-150 g/ha
    Maize                                 25-200 g/ha
    Pasture                               100 g/ha
    Peaches                               0.002%-0.01%
    Pears                                 0.002%-0.0125%
    Plums                                 0.05%-0.0125%
    Potatoes                              20-150 g/ha
    Rape                                  25-75 g/ha
    Raspberries                           0.0075%-0.015%
    Soya                                  50-250 g/ha
    Strawberries                          0.0075%-0.015%
    Sugar beet                            25-125 g/ha
    Tomatoes                              40-150 g/ha
                                                                 

    Post-harvest uses

    Although cypermethrin may be introduced to control pests of stored
    commodities and for animal health purposes, no data were available for
    evaluation at this meeting.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    Residue data have been obtained from numerous trials carried out on a
    world-wide basis and on the main crops treated.  Some data from
    excessive treatments rates are included where they provide useful
    information, e.g. on the effect of processing.  Treatments were
    generally made using E.C. formulations which are representative of
    current application practice.

    MAIN CROPS

    Apples

    Residue data have been obtained from trials in several countries.  In
    these experiments, dosages covered recommended and higher rates and
    were in the range of 0.0025% - 0.02% (25-200 g/ha), based on a spray
    volume of 1000 l/ha.  Treatments were made on up to 12 occasions.
    Results and details of the trials are summarised in Table 4.

    Residues in whole fruit one week after treatment at recommended rates
    up to 0.02% were usually below 1 mg/kg except when six or more
    applications were made.  Apart from one instance, however, these were
    all less than 1.5 mg/kg.  In the one case, where 2.7 mg/kg was
    reported, the result was considered to be atypical.

    Examination of fruit pulp and peel separately showed that residues
    were located mainly in the peel, the average weight of which was
    10-18% of the whole fruit.  After peeling, levels in 78 samples were
    generally less than 10% of those in whole fruit.

    Pears

    Samples of fruit were analyzed from trials carried out in Europe,
    Canada, Australia and South Africa.  In these experiments, treatment
    rates were between 0.0008% and 0.04% (or 30-400 g/ha).  Between one
    and six treatments were made and fruit harvested at various intervals
    after treatment.  The results obtained were similar to those with
    apples.  Residues in whole fruit, one week after treatment at rates up
    to 0.02% (slightly above the recommended rate of 0.015%), were all
    below 1 mg/kg.  As with apples, analysis of peeled fruit showed that
    cypermethrin residues were mainly in the peel.  In 32 samples,
    residues in the pulp did not exceed 30% of those in whole fruit.



        Table 4.  Residues Following Supervised Trials with Apples (1976-1978)

                                                                                                                                            
                                   Application         Interval
                                                       between                                                                     Ref.
    Varieties        Country      No.      rate        Appl.s       Residues in mg/kg, at intervals (days) after application       (Shell)
                                        kg a.i./ha     (week)
                                           or %                    0      7        12-17     21       28-30    35-42        56
                                                                                                                                            

    Granny Smith     Australia    3     0.02% (to
                                        run off)         382                       0.95               0.45     0.45                   1

    MacIntosh        Canada       3     0.18             2                         0.57                        0.38                   2

    Lobo                          3      0.18            2                         0.47                        0.32

    Northern spy                  8     0.07             9-15
                                                         days                                                  0.13-0.3               3

    MacIntosh                     8     0.07             9-15
                                                         days                                                  0.1-0.251

    Northern Spy                  8     0.05             "                                                                0.2-0.26

    MacIntosh                     8     0.15             "                                                                0.2-2.25

    Richared         France       1     0.15                       0.25   0.19     0.6       0.25                                     4

    Golden
    Delicious                     7     0.05             2-3              0.05                                                        5

    Golden
    Delicious        FRG          6     0.2              2,3,2,3   3.1    1.0      0.6       0.3      0.5                             6
                                                         and 1     3.2    2.7      1.9       1.7      0.81

    James Grieve                  6     0.02%            1,1,1
                                                         4 & 1    1.3    0.96     0.82      0.8      0.67                            7
                                                                                                                                            

    Table 4.  Continued...

                                                                                                                                            
                                   Application         Interval
                                                       between                                                                     Ref.
    Varieties        Country      No.      rate        Appl.s       Residues in mg/kg, at intervals (days) after application       (Shell)
                                        kg a.i./ha     (week)
                                           or %                    0      7        12-17     21       28-30    35-42        56
                                                                                                                                            

    Cox's Orange                  6     0.02%            1,3,4
                                                         4 & 2     0.97   0.75     0.6       0.84     0.31
    Golden
    Delicious                     6     0.02%            1,6,6,
                                                         2 & 2     1.7    1.3      0.93      0.9      0.9
                                  6     0.1              1-3       1.2    1.1      1.0       0.9      0.8                             8
                                  6     0.1              1-3       0.8    0.7      0.7       0.95     0.5
                     Italy        1     0.037            -                                            0.3-0.5                         11

    Strumer          N. Zealand   12    0.008%           2-3              1.1      0.6       0.7               0.53                   12

    Reinette         Portugal     5     0.005%           3                0.19     0.2       0.14                                     13
                                  5     0.0075%          3                0.32     0.1
                                  5     0.01             3                0.6      0.35      0.45

    Granny Smith     S. Africa    1     0.005%           -         0.42   0.36     0.28      0.25                                     14
                     Spain        1     0.024            -         0.06   0.05     0.04                                               10
                                  1     0.048            -         0.1    0.1      0.05      0.06                                     10
                     U.K.         3     0.005%           1-2       0.29   0.45     0.27
                                  3     0.01%            1-2       0.99   0.91     0.52
                                  3     0.005%           1        0.6    0.81     0.64
                                  3     0.01             1        1.1    0.98     0.82
                                  1     0.01             -         1.3    1.2      0.83

    Worcester
    Pearmain         U.K.         2     0.015%                                                                            0.01        15
                                                                                                                                            

    Table 4.  Continued...

                                                                                                                                            
                                   Application         Interval
                                                       between                                                                     Ref.
    Varieties        Country      No.      rate        Appl.s       Residues in mg/kg, at intervals (days) after application       (Shell)
                                        kg a.i./ha     (week)
                                           or %                    0      7        12-17     21       28-30    35-42        56
                                                                                                                                            

    Chivers
    Delight                       2     0.0025%          4                                                               0.02        16
                                        0.005%           4                                                               0.05
                                  2     0.01%            6                                                               0.01

    Laxton Superb                 2     0.01%            6                                                               0.01

    Spartan                       1     0.012%           -         0.36   0.15     0.07      0.05                                     17
                                        0.01             -         0.36            0.12               0.03                <0.01

    Lobo             Sweden       3                      2-4                                                             0.1422    Sweden

    Ribston                       3                      2-4                                                             0.25
                                                                                                                                            

    1  Minimum-maximum residues in three samples.
    2  90 days after treatment.
    


    Peaches

    Residues in whole fruit, less stone, from trees sprayed with
    cypermethrin at recommended rate (0.005%-0.01%) and harvested one week
    after treatment were generally 1 mg/kg or less although in one trial
    in Germany a residue of 1.8 mg/kg was reported in fruit under these
    conditions.  Analysing 43 samples of fruit after peeling and removal
    of the stone showed that levels in the pulp were less than 10% of
    levels found in whole fruit.

    Details of the trials are given in Table 5, which contains data
    relating to some treatments at rates higher than recommended.

    Citrus

    Experiments were carried out in South Africa (oranges), Spain (lemons)
    and Italy (oranges) in which applications of cypermethrin at
    recommended rates up to 200 g/ha were made on 1 or 2 occasions.  Fruit
    was harvested 1 to 39 weeks after treatment, depending on the trial,
    and analysed for residues of cypermethrin.  The results are shown in
    Table 6.

    Residues up to 1.3 mg/kg were found in whole fruit taken within six
    weeks of treatment.  Analysis of peel and pulp showed that the
    residues were largely (90%) percent in the peel and that residues in
    the pulp were normally below the limit of determination, although in
    one series of experiments residue levels up to 0.16 mg/kg were
    reported (4 weeks after treatment at 0.02%).  In some experiments
    samples of orange juice were obtained from treated fruit but residues
    were all less than 0.01 mg/kg.

    Cotton

    Samples of seed were obtained at harvest from trials in several
    countries in which up to 12 applications were made at recommended
    rates (up to 150 g/ha) and also at treatment rates up to 240 g/ha. The
    intervals between the last treatment and harvest varied between 1 day
    and 13 weeks.  The data obtained are given in Table 7 which also
    summarises the trial details.

    The seed from these trials was ginned after harvest and was separated
    in the laboratory into kernels and hulls.  The latter also contained
    adhering linters.

    In 8 samples no residue of cypermethrin was found in the kernels
    (limit of determination of 0.01 mg/kg).  Analysis of hulls, which in
    most instances had adhering linters, showed that any residues present
    were located entirely on the seed surface and its associated fibre.



        Table 5.  Residues Following Supervised Trials on Peaches (1976-1978)

                                                                                                                                       
                           Application
                                 rate       Intervals         Residues in mg/kg, at intervals (days) after application1       (Shell)
    Country              No.   kg a.i./ha    /week/         0-1       6-7       12-14     18-21     28-30     40-43     54      Ref.
                                 or %
                                                                                                                                       

    Australia             3      0.02%       3 & 2                              1.0                                             33
    Canada                3      0.006%      4 & 5                                         0.07                                 34
                          3      0.006%                     0.34      0.15      0.06                                            35
                                 0.1                                            0.052

    France                1      0.005%         -                                                   <0.02                       36
                                 0.0075%                                                            <0.02
                                 0.0125%        -                                                             <0.01
                                 0.0187%                                                                      <0.01
                                 0.015%                               0.5       0.4        0.1      0.15

    Federal Republic
    of Germany            4      0.02%       2              3.2       1.6       1.1        0.65                                 38
                          4      0.01%       3,3 & 2        0.85      0.7       0.5        0.18                                 39
                          4      0.01%       3,3 & 2        3.0       1.8       1.6        0.75
                          5      0.01%       2,3,3 & 2      2.0       1.0       0.85       0.3

    Italy                 1      0.01%          -                                                   0.1                         40
                          1      0.02%                                                              0.5

    Portugal              1      0.005%                               0.08      0.08       0.08                         41
                                 0.0075%                              0.19      0.11       0.09
                                 0.01%                                0.32      0.21       0.14

    Spain                 1      0.15                                           0.15                                            42
                          2      0.195       3                                                                0.03
                          2      0.195       1                                                                          0.04
                                                                                                                                       

    1  Results refer to whole fruit without stone.
    2  Average of ten samples taken from the same site (min.-.max. values: 0.02-0.11 mg/kg).

    Table 6.  Residues of Cypermethrin in Citrus (1976 - 1977)

                                                                                                                      
                                                  Interval                    Cypermethrin
    Crop           Dose Rate      No. of          between                     Residue (mg/kg)                Ref.
    (Country)      (a.i.)         Applications    applications   Intervals                       WHOLE       (Shell)
                                                  (days)         (days)       PULP      PEEL     FRUIT
                                                                                                                      

    LEMONS         150 g/ha       2               27             7            <0.01     2.1      1.1         43
    Verna                                                        14           <0.01     2.0      1.0
                                                                 21           <0.01     2.1      1.1
    (Spain)                                                      58           <0.01     1.1      0.55

                                                                              JUICE
    ORANGES        0.01%          1               -              60           <0.01     0.22     0.14        44
    Moro           0.02%          1               -              60           <0.01     0.44     0.21
    (Italy)
                                                                              PULP

    ORANGES
    Moro           0.005%         1               -              67           0.02      0.91     0.30        45
                   0.01%          1               -              67           0.02      1.2      0.39
                   0.005          1               -              91           0.01      0.69     0.19
                   0.01%          1               -              91           0.02      1.3      0.35
                   0.01%          1               -              27           0.06      1.0      0.36        46
                                                                 43           0.05      1.5      0.48
                                                                 56           0.05      1.3      0.40
                   0.02%          1               -              27           0.16      3.0      1.2
                                                                 43           0.13      3.7      1.3
                                                                 56           0.09      1.9      0.73
                                                                              JUICE
                   0.005%         1               -              1            <0.01     0.50     0.13        47
                                                                 4            <0.01     1.2      0.20
                                                                 8            <0.01     1.0      0.16
                                                                 18           <0.01     0.81     0.21
                                                                 39           <0.01     1.1      0.28
                                                                 68           <0.01     1.3      0.39
    (S. Africa)                                                  96           <0.01     1.3      0.38
                                                                                                                      

    Table 6.  Continued...

                                                                                                                      
                                                  Interval                    Cypermethrin
    Crop           Dose Rate      No. of          between                     Residue (mg/kg)                Ref.
    (Country)      (a.i.)         Applications    applications   Intervals                       WHOLE       (Shell)
                                                  (days)         (days)       PULP      PEEL     FRUIT
                                                                                                                      


    ORANGES        0.01%          1               -              1            <0.01     1.0      0.30        47
    Moro                                                         4            <0.01     0.55     0.22
                                                                 8            <0.01     0.19     0.16
                                                                 18           <0.01     0.83     0.25
                                                                 39           <0.01     0.60     0.16
                                                                 68           <0.01     0.45     0.13
                                                                 96           <0.01     0.45     0.13
                   0.015%         1               -              1            <0.01     2.6      0.58
                                                                 4            <0.01     1.2      0.30
                                                                 8            <0.01     1.0      0.24
                                                                 18           <0.01     1.3      0.25
                                                                 39           <0.01     1.2      0.21
                                                                 68           <0.01     1.8      0.40
                                                                 96           <0.01     0.95     0.22
                   0.01%          1               -              0            <0.01     1.6      0.52
                                                                 1            <0.01     2.9      0.85
                                                                 2            <0.01     2.2      0.65
                                                                 4            <0.01     2.8      0.55
                                                                 9            <0.01     1.8      0.58
                                                                 16           <0.01     1.9      0.72
                   0.005%         2               6-weeks        69           <0.01     <0.01    <0.01
                                                                 114          <0.01     <0.01    <0.01
                                                                 237          <0.01     <0.01    <0.01
                   0.01%          1               -              110          <0.01     <0.01    <0.01
                                                                 155          <0.01     <0.01    <0.01
    (S. Africa)                                                  278          <0.01     <0.01    <0.01
                                                                                                                      

    Table 7.  Residues Resulting from Supervised Trials in Cotton Seed (1975-1977)

                                                                                                                                          
                     Application                      Residues in whole seed (mg/kg) at Intervals (days) after app. lication     Ref.
    Country             rate kg        Intervals                                                                                 (Shell)
                   No.  a.i./ha or     /Week)         1         7-8       13-15     19-20     28-37     44-55     70-91
                                                                                                                                          

    Australia      1    0.0015%        -                                  0.01                0.01                                 10
                   1    0.003%                                            0.05                0.01

    Brazil         4    0.12           1                                                      0.01                                 51
                   4    0.24           1                                                      0.01
                   4    0.12           1                                                                <0.01                      52
                        0.24           1                                                                 0.01

    Columbia       1    0.1                           0.09      0.03      0.01                                                     54
                   5    0.1            3 to 8 days                                  <0.01                                          55
                   2    0.075          12 days                                                          <0.02                      56

    South Africa   12   0.2            1 to 2                                                                      0.01            58
                   11   0.2            1 to 2                                                                      0.02
                   1    0.1            -                                                                          <0.01            10
                        0.2                                                                                       <0.01

    Spain          5    0.1            2,2, 1 & 2                       0.04                                                     59
                   4    0.1            2,2 & 1                                               0.03
                   5    0.2            2,2, 1 & 2                       0.03
                   4    0.2            2,2,1                                                 0.06
                   3    0.1            2                                                      0.03
                   3    0.2            2                                                      0.04
                   3    0.2                                                                             0.02
                                                                                                                                          
    


    The presence of occasional small residues on the fibre and the outside
    of the seed case is to be expected, particularly where applications
    were made after the bolls had opened.  However, the results indicate
    that migration through the seed case to the kernel did not occur even
    after treatment at excessive rates, and that measurable residues in
    kernels are unlikely to be found in practice.

    As a whole, the data suggest that, following treatment according to
    recommendations, seed taken 1 week after a series of applications is
    unlikely to contain more than 0.1 mg/kg cypermethrin on the whole
    seed.

    Leafy Vegetables (Brassicae)

    Trials have been carried out in a number of countries in order to
    obtain residue data on cabbages - including savoy, broccoli, Brussel
    sprouts, cauliflower and kale.  These are described in Table 8.

    The treatments were made according to recommendations (up to 200 g
    a.i./ha or 0.02%) or at slightly higher dose rates.  In most cabbage
    samples as expected, the residue was located mainly in the outer
    leaves, which are normally removed in the field, and the majority of
    the samples examined were received without the "discard" leaves.  In
    one experiment however (New Zealand) whole unstripped cabbages were
    received.  Residues in these samples reaches 3.2 mg/kg but were found
    to be reduced to below 0.1 mg/kg on removal of the outer leaves in the
    laboratory.

    With most of the other brassicae examined, including cauliflower
    heads, residue levels were similar to those in cabbage without discard
    leaves.  But residues in kale from experiments in Germany tended to be
    somewhat higher.

    OTHER CROPS

    Supervised trials were carried out with a number of other crops in
    various locations.  Residue data obtained in these experiments are
    summarized in Table 9 and the following comments.

    Alfalfa

    A single application at a rate equivalent to 0.1 kg a.i/ha was used to
    establish a residue decay curve.

    Beans

    Trials were carried out in South America on soya and on phaseolus
    bean.  Residues in beans (soya and phaseolus) removed from their pods
    were below measurable levels (0.01 mg/kg) four weeks after treatment,
    even where excessive rates (up to 300 g/ha) were used.



        Table 8.  Residues Resulting from Supervised Trials with Various Vegetables (1976/79)

                                                                                                                                             
    Crop                Application           Intervals
    (Country)                   rate          between appl.s           Residues in mg/kg, at intervals/days after application          Ref.
                        No.     kg a.i./ha    (week/             0-1       3-4       7-8       10        14-16       21       28     (Shell)
                                                                                                                                             

    BROCCOLI            3       0.16          3 & 2              0.38      0.28                0.16      0.06                          69
                        1       0.0015        -                  0.11                0.03                <0.01                         10
    (Canada)            1       0.003%        -                  0.3                 0.03                <0.01

    BRUSSELS SPROUTS    3       0.15          1,5                0.55      0.25                0.25                                    70
                        7       0.07          3,3,2,2            0.14      0.1                                                         71
                                              2 & 3              0.12      0.09
                                                                 0.23      0.13
                                                                 0.18      0.18
                        6       0.07          3,3 & 2                                                    0.06
                                                                                                         0.09
                                                                                                         0.1
    (Canada)                                                                                             0.08

    CABBAGES            3       0.07          1,5                0.22      0.11                          0.11                          60
                                                                 0.22      0.12                          0.06
                                                                 0.16      0.27                          0.17
                                                                 0.22      0.27                          0.05
                        3       0.15          1,5                0.43      0.03                <0.01                                   61
    (Canada)            3       0.16          2                  0.15      0.1                 0.02      <0.01                         62

    CABBAGES            4       0.06          2                  1                   0.4                 0.11        <0.01    <0.01    63
    (Germany)           4       0.06          2                  0.1                 0.02      <0.01     <0.01       <0.01

    CABBAGES            1       0.25                                                                                          0.161a   Hungary
                                                                                                                              0.1
    (Hungary)                                                                                                                 0.2
                                                                                                                              0.2
                                                                                                                                             

    Table 8.  Continued...

                                                                                                                                             
    Crop                   Application        Intervals
    (Country)                      rate       between appl.s           Residues in mg/kg, at intervals/days after application        Ref.
                        No.     kg a.i./ha       /week/          0-1       3-4       7-8       10        14-16       21       28     (Shell)
                                                                                                                                             

    CABBAGES            5       0.002%        2                  0.03                <0.01               0.01
                        5       0.006         2                  0.05                0.02                0.02                          66
                        1       0.002%        -                  0.07                0.02                0.02
    (South Africa)      1       0.006%        -                  0.08                0.03                0.02

    CABBAGES            6       0.14          2                  2,11                1,71                1.41                          67
                                                                 0.061b              0.011b              0.011b
                        6       0.14                             0.76      0.6       0.57                0.47                          N.Z.
    (New Zealand)       6       0.28                             1.13      0.82      0.68                0.42

    CABBAGES            1       0.008%        -                                                          0.51                          68
    (U.K.)

    CABBAGES
    (Savoy)             4       0.06          1,1 & 2            0.55                0.4                 0.35        0.15     <0.01    64
    (Germany)           4       0.06          2                  0.3                 0.2                 0.1         0.05     <0.01
                        1       0.005%                                                                               0.02              65
                        1       )0.015%                                                                              0.02
    (Italy)             1       0.03%                                                                                0.02

    CAULIFLOWERS        3       0.16          3 & 2              0.17      0.09                0.01      <0.01                         72
                        3       0.07          1,5                0.23      0.21                          <0.01                         73
                                                                 0.26      0.30                          0.01
                                                                 0.34      0.24                          0.08
    (Canada)                                                     0.3       0.08                          0.11
                        4       0.06          2                  0.03                <0.01               <0.01       <0.01
    (Germany)           3       0.06          2                  0.05                <0.01               <0.01       <0.01    <0.01

    KALE                4       0.06          2                  1,6                 0.85                0.4         0.3      0.25     75
    (Germany)           4       0.06          2                  1,4                 0.9                 0.7         0.5
                        2       0.075+0.04    6.5                1.1                 0.76                0.47        0.13              76
    (U.K.)              2       0.225+0.08    6.5                1.5                 0.95                0.60        0.23

    Table 8.  Continued...

                                                                                                                                             
    Crop                   Application        Intervals
    (Country)                      rate       between appl.s           Residues in mg/kg, at intervals/days after application        Ref.
                        No.     kg a.i./ha       /week/          0-1       3-4       7-8       10        14-16       21       28     (Shell)
                                                                                                                                             

    KALE
    (China)             6       0.005%        4-5 days                               0.85
    (Thailand)
                                                                                                                                             


    NOTE:  The cabbages were analysed without the outer leaves with some exceptions:
    1   whole cabbage
    1a  whole cabbages as specified by CC/PR/153/
    1b  heart only.
    


    Cherries and Plums

    Samples of plums and cherries have been obtained from field
    experiments in Germany in which cypermethrin was applied on several
    occasions (three in the case of cherries, five for plums) at
    approximately the recommended rate and double the recommended rate
    (0.01% and 0.02% respectively).  Under similar conditions, residues in
    plums were found to be somewhat lower than in cherries.

    Grapes

    At recommended rates of up to 80 g/ha and treatments on up to 4
    occasions, residues in grapes harvested one week after the last
    application were at or below 1 mg/kg (Table 9).  In practice, the
    material is generally applied an a prophylactic treatment at 50 g/ha
    and harvest is likely to be more than one week after treatment.

    Lettuce

    Residue data are available from trials carried out in Canada, France
    and Germany at rates generally in the range of 50-70 g/ha (0.005% to
    0.007%, based on 1000 l/ha spray volume).  Residue levels were 1.6
    mg/kg cypermethrin or less in lettuce taken one week after treatment.
    From the glasshouse data available, there was no evidence that levels
    in glasshouse lettuce were substantially different from levels in
    outdoor crops.

    Kiwi Fruit

    Supervised trials were carried out in New Zealand at the recommended
    dose rate and at double rate (Table 9).  The pulp contained 5-10% of
    that which was found in whole fruit.

    Maize

    Residue experiments have been carried out in several countries in
    which cypermethrin has been applied to maize at recommended rates up
    to 150 g/ha.  Green maize (whole plants) were sampled at intervals
    following treatment, and in some instances grain was also sampled at
    the sweet corn stage or when fully mature.

    In green maize following treatments at rates up to 150 g/ha, residues
    were below 1 mg/kg two weeks after treatment and below the limit of
    determination (0.01 mg/kg) after eight weeks.  In grain, no residues
    were found in either sweet corn or mature grain, even in samples taken
    three days after treatment at this rate.

    Pasture

    Supervised trials were carried out in New Zealand in which
    cypermethrin was applied at several times higher than the recommended
    rate.  The residues on the grass increased roughly in proportion to
    the increases in dosage (Table 8).

    Peas

    Trials were carried out on peas in the U.K., Hungary and South Africa.
    No residues were found at dose rates of 15 to 100 g/ha in the peas
    themselves which were sampled between one day and four weeks after
    treatment (limit of determination 0.01 mg/kg).  However, an excessive
    dose rate of 200 g/ha resulted in residues between 0.04-0.07 mg/kg in
    the peas (Table 9).

    Potatoes

    Samples were obtained from residue trials carried out in Europe,
    Cyprus and Canada, with from 1-9 treatments at dosage rates in the
    range of 10 g/ha to 200 g/ha, and intervals between last treatment and
    harvest from 0-8 weeks.  Detectable residues were absent from all
    samples of whole or peeled tubers, even 3-9 days after treatment.
    However, samples from one trial in Italy, obtained three weeks after
    treatment were peeled.  Residues up to 0.05 mg/kg were found in the
    peel, but none was detectable in the peeled potatoes.

    Rape

    Data from supervised trials in Canada, Germany and the U.K. show that,
    where treatments at recommended rates were made more than six weeks
    before harvest, residues in the whole seed were below the limit of
    determination of 0.01 mg/kg.  In one of the replicated Canadian
    experiments, however, residues were found in samples taken six weeks
    after treatment; residues between replicates varied from 0.01 mg/kg to
    0.12 mg/kg.

    Raspberries and Strawberries

    Trials were carried out in Canada and the U.K. in which raspberry
    canes were treated with cypermethrin at rates between 0.005% and
    0.015% (the maximum recommended rate).  Residues in fruit taken 12 or
    more days after treatment were all below 0.5 mg/kg even where multiple
    applications were made.  Residues in strawberries from Canadian
    experiments using cypermethrin at rates of 0.006% or 0.01% on two
    occasions at an interval of 8 or 9 days were also below 0.5 mg/kg when
    harvested three weeks after treatment (Table 9).

    Sugar Beet

    In experiments carried out in France, Germany and the U.K., 1 to 5
    treatments were carried out at rates between 60 g/ha and 200 g/ha
    cypermethrin.  Samples of both roots and tops were taken for analysis
    at intervals up to 17 weeks from the time of treatment.

    Apart from one sample taken two weeks after treatment at 60 g/ha,
    which contained a small residue of 0.02 mg/kg, no residues of
    cypermethrin were found in the root samples.

    In leaves, residues were between 6 and 13 mg/kg immediately after the
    last of 5 applications made at two weekly intervals.  Subsequently
    these declined, reaching 0.02-0.13 mg/kg six weeks after treatment.
    After 11 weeks residues were 0.01 mg/kg or less (Table 9).

    Tomatoes

    In outdoor experiments carried out in Southern Europe, Australia,
    Canada, S. Africa, the Canary Islands and Mexico, tomatoes were given
    foliar treatments at rates between 50 g/ha and 300 g/ha.  Applications
    were made on up to 9 occasions at intervals from 5 days to 3 weeks
    depending on the experiment.  Samples were taken at intervals ranging
    from the day of treatment to six weeks later.  Although some of the
    tomatoes received were green, they were close to ripening
    (approximately 5 cm diameter) and in the condition at which they would
    be picked for export.  The residues (Table 9) did not exceed 0.5 mg/kg
    in any of the samples taken shortly after treatment at the recommended
    rates (up to 0.0% or 100 g/ha assuming use at 1000 l/ha).

    Wheat

    Residue trials have been carried out on wheat in Canada and Brazil,
    with application rates up to 150 g/ha.  In the grain residues did not
    exceed 0.1 mg/kg at harvest two weeks after application.  Residues in
    straw were higher, and the few data obtained suggest that under these
    conditions they may approach 10 mg/kg (Table 9).



        Table 9.  Residues Resulting from Supervised Trials with Various Fruits and Other Crops (1974/79)

                                                                                                                                         
    Crop          Country         Application               Interval
    (Variety)                             rate              between     Residues in mg/kg,at intervals (days) after application
                                No.     kg a.i./ha,         appl.s                                                                 Ref.
                                           or %             (week)      0       2-3     6-7      13-17      21      28-30        (Shell)
                                                                                                                                         

    ALFALFA       Cyprus        1       0.1                             12              5.6      4.7                             10

    BEANS
    (Dried)       Colombia      3       0.15                1                                                       <0.011       87

    CHERRIES      Germany       3       0.02%               1-2         4.5             3.3      0.65       0.6                  18
                                        to run off
                                3       0.02%               1-2         2.7             1.6      1.0        0.39
                                        to run off
                                3       0.02%
                                        to run off          1-2         7.4             5.4      1.5        1.2
                                3       0.01%               1.5-2       0.59            0.47     0.27       0.25    0.2          19
                                3                           1.5-2       1.0             0.6      0.3        0.1     0.1

    GRAPES        Canada
    (Delaware)                  1       0.08                -                                    0.7        0.32                 20
                                                                                                                                 21
    (Elvira)                    4       0.07                4,5 & 3                     0.24
                                                                                        (0.1 to
                                                                                        0.37)
    (Friedamia)                 1       0.006%
                                        to run off                      0.75            0.41     0.25
    (Sauvignon)   France        4       0.075               1                           0.08     0.03       0.02    <0.01        22
    (Alicante)
    (Bouschet)                  1       0.075               -                           0.4      0.28       0.23    0.12         23
                                2       0.075               3                                    0.37
    (Riesling)    Germany       4       0.08                5,4 & 2     0.5             0.2      0.11       0.09    0.05         24
                                4       0.08                5,4 & 2     0.8             0.5      0.1        0.05    0.05
    (Barbera)     Italy         1       0.01%                                                                       0.1          25
                  S. Africa     1       0.0375              -           0.2     0.1     0.18     <0.05      <0.05                S. Africa
                                                                                                                                         

    Table 9.  Continued...

                                                                                                                                         
    Crop          Country         Application               Interval
    (Variety)                             rate              between     Residues in mg/kg,at intervals (days) after application
                                No.     kg a.i./ha,         appl.s                                                                 Ref.
                                           or %             (week)      0       2-3     6-7      13-17      21      28-30        (Shell)
                                                                                                                                         

    GRAPES
    (Waltham
    Cross)                      2       0.0375              2           0.24    0.2     0.19     0.07       <0.05
    (Chemin
    Blane)                      1       0.0375              -           0.1     0.12             <0.05      <0.05
                                2       0.0375              2           0.12    0.07    <0.05    <0.05      <0.05

    KIWI FRUIT    N. Zealand    6       0.01%                           2.2             1.9      1.7        1.3                  N.Zealand
                                6       0.02%                           6.2             3.9      3.4        2.8

    LETTUCE       Canada        6       0.07                1                           <0.012                                   78
                                                                                        0.02
                  France        1       0.15                                                     0.52                            79
                                        0.3                                                      1.1
                  France        1       0.05                            1.2             0.27     0.123                           80
                                1       0.05                            1.1             0.3      0.06                            81
                                1       0.05                            2.2             1.6      0.35
                                1       0.05                            1.8             0.5      0.02
                                1       0.054                           2.4             1.0      0.85                            82
                  Germany       3       0.06                2           4.0             0.25     0.04       0.02    <0.01        83
                                3       0.06                2           1.2             0.06     0.01       <0.01
                                                                                                                                         

    Table 9.  Continued...

                                                                                                                                             
    Crop          Country        Application        Interval
    (Variety)                           rate        between      Residues in mg/kg,at intervals (days) after application
                               No.    kg a.i./ha,   appl.s                                                                            Ref.
                                         or %       (week)       0         2-3      6-7       13-17     21      28-30     42-56       (Shell)
                                                                                                                                             

    MAIZE

    Cobs          Australia    1      0.0015%                    <0.01                                                                10
    Cobs                              0.003%                     <0.01
    Sweet corn    Canada       5      0.07          5 days                 <0.01                                                      84
    Sweet corn                 3      0.075         1                      <0.01    <0.01
    Sweet corn                 6      0.064         5 days                 <0.01    <0.01     <0.01                                   85
                  Germany      1      0.1                        1.9                0.04                                              86
                               1      0.1                        2.7                2.2       0.51      0.05              <0.015
                               1      0.1                        2.9                1.1       0.15              0.05      0.025
                                                                                                                          <0.01
    Leaves        S. Africa    1      0.075                      5.2                3.86                        0.4                   10
    Leaves                     1      0.15                       17                 106                         2.6
    Stalks                     1      0.075                      <0.01              0.086                       <0.01
    Stalks                     1      0.15                       0.05               0.02                        0.06

    PEAS          U.K.         2      0.05          2                                         <0.01                                   88
    w/o pods                   1      0.025         -                                                           <0.01                 89
    Peas          Hungary      1      0.1           -                                                   <0.017
    pods (only)                       -                                                                 0.07
    Peas                       1      0.2                                                               0.04
                                                                                                        0.077
                  Sweden       2      0.08          2                                         <0.01                                   165
                  S. Africa    1      0.015         -            <0.01              <0.016    <0.01                                   10
                               1      0.03          -            <0.01              <0.016    <0.01

    PLUMS         Germany      5      0.02%         1-3          1.0                0.65      0.5                                     90
                               5      0.02%         1-3          0.9                0.75      0.4       0.25
                               5      0.02%         1-3          1.3                1.1       0.7
                               5      0.01%         3,2,3 & 1    0.3                0.29      0.29      0.25    0.11                  91
                               5      0.01%         3,2,3 & 1    0.24               0.15      0.12      0.1
                                                                                                                                             

    Table 9.  Continued...

                                                                                                                                             
    Crop          Country        Application        Interval
    (Variety)                           rate        between      Residues in mg/kg,at intervals (days) after application
                               No.    kg a.i./ha,   appl.s                                                                            Ref.
                                         or %       (week)       0         2-3      6-7       13-17     21      28-30     42-56       (Shell)
                                                                                                                                             

    POTATOES      Canada       4      0.075         2                                         <0.01                                   92
                               4      0.15          2                                         <0.01
                               9      0.072         1                                         <0.01
                               9      0.145         1                                         <0.01
                               4      0.150         2                               <0.017                                            93
                               9      0.15          1                               <0.01                                             94
                  Cyprus       1      0.1                        <0.01     <0.01                                                      10
                  France       1      0.15                                                                                <0.01       95
                  Germany      4      0.090         2                                         <0.01     <0.01   <0.01                 96
                               4      0.2           2                                         <0.01     <0.01   <0.01                 97
                               4      0.2           2            <0.01              <0.0l     <0.01
                               4      0.2           2                                         <0.01     <0.01   <0.01
                  Italy        1      0.04          -                                                   0.058                         98
                               1      0.12          -                                                   0.038

    SOYA BEANS    Brazil       2      0.24          2                                                                     <0.01       99
                               3      0.24          2                                                           <0.01
    dried         Colombia     4      0.3           1,1 week
                                                    & 4 days                                                    <0.01                 100

    SUGARBEET     France       1      0.1           -                                                                     <0.01
    Leaves                                                                                                                after       101
                                                                                                                          17 wks

                               1      0.15                                                                                <0.01
                                                                                                                          after       102
                                                                                                                          17 wks
                  Germany      5      0.06          )2,2,2       1.3                          0.52              0.07      0.05        103
                               5      0.06          )& 1         2.2                          0.1               0.03      <0.01
                               5      0.2           2            12                           4.0               2.3       0.02        104
                                                                                                                                             

    Table 9.  Continued...

                                                                                                                                             
    Crop          Country        Application        Interval
    (Variety)                           rate        between      Residues in mg/kg,at intervals (days) after application
                               No.    kg a.i./ha,   appl.s                                                                            Ref.
                                         or %       (week)       0         2-3      6-7       13-17     21      28-30     42-56       (Shell)
                                                                                                                                             

    SUGARBEET     Germany      5      0.2           2            6.2                          2.3               0.18      0.05
    Leaves                     5      0.2           2            13                           0.73              0.23      0.13
                  U.K.         1      0.2                                                                                 <0.01
                                                                                                                          after
                                                                                                                          15 weeks    105
    RASPBERRIES   Canada       1      0.225         -                                         0.2110                                  114
                               3      0.18          2                                         0.4510                                  115
                               3      0.135         2                                         0.410                                   116
                  U.K.         1      0.005%        1                                         0.1311                                  117
                                      0.015%        1                                         0.2511

    STRAWBERRIES  Canada       2      0.23          9 days                                              0.07                          118
                               2      0.18          90                                                  0.04                          119
                               2      0.18          8 days                                              0.45                          120

    TOMATOES      Australia    9      O.01%         5-7 days     0.3       0.3      0.24      0.14                                    106
                               9      0.02%         5-7 days     0.57      0.57     0.44      0.53
                               1      0.0015%       -            0.02      0.03                                                       10
                  Canada       1      0.15          -            0.13      0.07                                                       107
                               2      0.15          1            0.2       0.05
                  France       1      0.0075%       -                      0.09     0.06      0.04                                    108
                  Italy        1      0.005%        -                                                   0.02                          109
                                      0.015%                                                            0.08
                                      0.03                                                              0.17
                  Mexico       1      0.0075        -            0.02               0.01                                              10
                               1      0.015         -            0.05               0.04
                               1      0.03          -            0.08               0.13
                  Portugal     3      0.075%        11 & 7                                    0.06      0.032                         110
                                                    days
                                                                                                                                             

    Table 9.  Continued...

                                                                                                                                             
    Crop          Country        Application        Interval
    (Variety)                           rate        between      Residues in mg/kg,at intervals (days) after application
                               No.    kg a.i./ha,   appl.s                                                                            Ref.
                                         or %       (week)       0         2-3      6-7       13-17     21      28-30     42-56       (Shell)
                                                                                                                                             

    TOMATOES      S. Africa    4      0.0075%       3,2,2,2                0.17     0.1       0.05                                    111
                               4      0.01%         3,2,2,2                0.27     0.15      0.09
                               4      0 02%         312,2,2                0.27     0.14      0.08
                               4      0:03%         3,2,2,2                0.29     0.2       0.6
                  Spain        7      0.03%         3,2 & 2                                             0.08                          112
                               1      0.075         -            0.16      0.07     0.14                                              10
                                                                 0.16      0.06     0.10
                               2      0.2           1                                         0.1       0.09    0.06                  113
                               3      0.2           1                               0.25      0.2       0.05
                  Canary Is.   2      0.1           1                                         0.25              0.15      0.01        113
                               3      0.1           1                               0.2       0.15      0.06    0.03
                               2      0.15          1                                         0.4               0.3       0.15
                               3      0.15          1                               0.55      0.4       0.2     0.6

    WHEAT         Canada       1      0.14          -                                         0.1       0.07    0.05                  121
                               1      0.15          -                               0.08      0.08      0.08    0.04                  122
                                                                                    0.07      0.05      0.06    0.03
                                                                                    0.07      0.05      0.05    0.04
                                                                                    0.09      0.09      0.06    0.04
                  Brazil       1      0.09                                                    <0.01                       <0.01       123
                               2      0.09          12 days                                   0.04
                               2      0.09          31 days                                   0.03
                               2      0.09          19 days                                                     0.01
                               3      0.09          19 & 12
                                                    days                                      0.04
                                                                                                                                             

     1  +4 week storage, beans were analysed without pods
     2  In 3 samples
     3  10 days after treatment
     4  In glasshouse

    Table 9.  Continued...

     5  The grain contained <0.01 mg/kg
     6  8 days after treatment
     7  In 9 samples
     8  In the peel
     9  24 days after treatment
    10  12-13 days after treatment
    11  19 days after treatment
    


    FATE OF RESIDUES

    GENERAL OBSERVATIONS

    Following applications to crops cypermethrin may degrade to a variety
    of hydrolysis and oxidation products.  The most likely degradation
    products present in crops at harvest following normal agricultural use
    of cypermethrin are the derived amide (compound B), 3-phenoxybenzoic
    acid and 2-(2',2'-dichloro vinyl)-3,3 dimethyl cyclopropane carboxylic
    acid (compound C), the structures of which are shown in Figure 1.  The
    latter two compounds are found in the free state as well as in
    conjugated forms.  However, the evidence indicates that the major
    component of any residue present at harvest will be cypermethrin
    itself.  A number of crop samples obtained from supervised trials
    discussed previously were analysed also to determine compounds B, C
    and phenoxybenzoic acid.  The results of these examinations involving
    some 20 crops showed no residues of Compound B, of Compound C or of
    3-phenoxy benzoic acid in excess of 0.05 mg/kg.

    Following use on animal feed crops, residue may be present in feed at
    levels depending on the crop.  However, since the product is readily
    metabolized by animals, these amounts are unlikely to give rise to
    more than traces of foods of animal origin.

    IN ANIMALS

    Cattle Feeding Studies

    Studies were undertaken to investigate the fate of cypermethrin in
    cattle and whether residues in meat or milk could arise from the use
    of cattle feed containing products made from treated crops.  Two
    experiments were undertaken, both using radiolabelled cypermethrin.

    a.   Low Dietary Intake (0.2 mg/kg)

    Two lactating cows were given feed concentrate containing
    radio-labelled cypermethrin twice daily for a three-week period with a
    feeding level equivalent to 0.2 mg/kg on total daily feed.  The cows
    were milked twice daily and the amount of radioactivity determined at
    each milking.  The total radioactivity present in whole milk was in
    the range of 0.0002 mg/1 to 0.0012 mg/1 in terms of cypermethrin
    equivalents and 60-70% of the amount of radioactivity in the milk was
    present in the cream fraction.  The total radioactivity found in the
    milk amounted to only 0.5% of the radioactivity fed to the animals.
    The remainder of the radioactivity was excreted in the urine (54%) and
    faeces (43%).  The elimination occurred rapidly after dosing and the
    rate of elimination of radioactivity reached its peak (near 100% of
    applied dose) after three days.

    FIGURE 1

    In the urine 3(4-hydroxyphenoxy) benzoic acid-O-sulphate and the
    glutamic acid conjugate of 3-phenoxybenzoic acid were detected in the
    ratio of 1:4.   The free acids were not detectable.  The faeces
    contained the parent compound amounting to approximately 85% of the
    faecal 14C, that is, about 36% of the amount ingested.  At the end of
    the three-week feeding period the animals were slaughtered and samples
    of tissues examined for radioactivity.  Levels were below 0.001 mg/kg,
    in cypermethrin equivalents, in blood, muscle and brain. In
    subcutaneous and renal fats, liver and kidney samples, residues were
    at or below the equivalent of 0.012 mg/kg cypermethrin (Shell R. 124).

    b. High Dietary Intake (5 mg/kg)

    Radiolabelled cypermethrin was fed in the feed concentrate twice daily
    and was given in amount equivalent to 4 mg/kg on total diet over a
    period of 7 days.

    The radioactivity in the milk, urine and faeces was monitored
    throughout the feeding period and showed that the major excretory
    route was via the kidneys.  All the cows were found to be pregnant at
    necropsy and the milk yields throughout the experiment were poor.
    Equilibrium between intake and excretion was reached 3-4 days after
    commencement of feeding, after which levels in whole milk ranged
    between 0.009 mg/l and 0.013 mg/l cypermethrin equivalent to
    radioactivity present.  The cream fraction of the milk contained
    85-90% of the total radioactivity.  Results of experiments carried out
    with 14C-benzyl and 14C-cyclopropyl labels indicate that the residue
    in milk is an ester and contains both the acidic and alcoholic
    functions of the parent compound.

    The major urinary metabolites in cows were identified as the glutamic
    acid conjugate of 3-phenoxybenzoic acid (68%), 3-phenoxybenzylglycine
    (16%), 3-phenoxybenzoic acid (9%). 3(4-hydroxy-phenoxy) enzoic-acid
    and its O-sulphate conjugate appeared to be present in only small
    amounts (1%).

    At the end of the test feeding period the animals were slaughtered and
    tissues were taken for measurement, with the following results,
    radioactivity being expressed as cypermethrin equivalents.

               Muscle                     0.04 mg/kg
               Fat                        0.01-0.10 mg/kg
               Liver and Kidney           0.05-0.13 mg/kg

    These results indicate that the cypermethrin does not accumulate in
    the tissues of the animals.  Even at a high intake, residues are
    mostly in the fat, liver and kidney.  Cereals and components of feed
    (e.g. cotton seed) treated with the highest recommended dose rates
    therefore, are unlikely to result in measurable residues in meat or
    milk of cattle (Shell R. 125).

    IN PLANTS

    Degradation on cotton, lettuce and apples has been studied using
    14C-radiolabelled material with the label in various positions in the
    cypermethrin molecule.  Structures of compounds mentioned are given in
    Figure 1.

    a.    Cotton

    An experiment in which the cis- and trans-isomers of cypermethrin
    were applied in acetone/water solution to cotton leaves using a small
    syringe was carried out on plants grown in pots in the greenhouse.
    Each of the two isomers, which in themselves consisted of a racemic
    mixture of two enantiomeric pairs of stereo isomers, was labelled in
    the cyclopropyl and benzyl rings in separate experiments.  In each
    experiment the rate of application was 10-20 g/g of leaf.  Leaf
    samples were taken for examination immediately after treatment and
    again 42 days later.  The samples were extracted with acetone and the
    examined by chromatographic and radiochemical techniques.

    Forty-two days after treatment 75-85% of the original total applied
    radioactivity was still present in cotton leaves and 90% of this was
    acetone extractable.  Thin-layer chromatography showed that at least
    six components were present in the extracts.  Products identified and
    the approximate proportion present in the extracts were cypermethrin
    (40-50%), 4-hydroxy-cypermethrin (compound A/ 5-8%), 3-phenoxybenzoic
    acid (15%), and an amide (compound B/ 8-20%).  In this preliminary
    study unidentified material accounted for the remaining 20-30% and was
    mainly polar material.  No evidence of an appreciable difference in
    the rate of loss and breakdown of the two isomers was obtained.

    A second experiment was carried out on a larger scale, in which
    cypermethrin was 14C radio-labelled in the benzyl ring and applied at
    the rate of 4 g/g leaf.  Two applications were made 15 days apart and
    leaf samples were taken 5 weeks after the second treatment.  Results
    were qualitatively similar to the first experiment, except that
    smaller amounts of metabolites were found and, in addition, some
    3-(4-hydroxyphenoxy)-benzoic acid was also reported to be present. Due
    to the larger scale of the experiment it was possible to examine the
    polar fraction in more detail.  This was found to consist of at least
    8 compounds which were mainly conjugated forms of 3-phenoxybenzoic
    acids 3-(4-hydroxyphenoxy)-benzoic acid and 3-phenoxybenzyl alcohol.

    When the results from experiments using cypermethrin, separately
    labelled in the nitrile, cyclopropyl and benzyl groups, were compared,
    the properties of the polar products formed differed according to the
    label position.  Thus it was again concluded that, following the
    primary step of hydrolysis of the ester link, further degradation of
    the component parts, including loss of nitrile, oxidation and
    conjugation, took place.  In this work, the cyclopropane carboxylic
    acid (compound C) was identified as a metabolite.

    In a third experiment the cotton was grown in boxes outdoors in
    Seville, Spain.  Cypermethrin, labelled either in the cyclopropane or
    benzyl rings, was applied to separate plants.  The cis and trans
    isomers, in each case, were also applied in separate experiments.
    Three applications were made at rates equivalent to 300 g/ha and
    samples were taken at harvest 15 weeks after the final treatment.

    Seed, fibre, boll cases and leaves were examined separately. All the
    kernel samples separated from the seed cases contained small amounts
    of radioactivity equivalent to 0.07-0.24 mg/kg cypermethrin.  Due to
    the oily nature of the extracts and the small size of the samples, it
    was not possible to fully identify the products present, although it
    was shown the radioactivity was not present in the form of
    cypermethrin itself.  Seed cases freed from lint also contained
    radioactivity equivalent to up to 0.17 mg/kg cypermethrin, which again
    was shown not to be parent insecticide.

    The lint samples contained rather more variable amounts, between 0.08
    and 0.62 mg/kg cypermethrin equivalents, probably depending on the
    degree of opening of the bolls at the time of spraying.  Cypermethrin
    itself was the major compound present (between 50 and 90% of the
    total) but the remainder consisted of polar products.  Foliage and
    boll cases were found to contain the same products as those reported
    from glasshouse experiments.  These included cypermethrin,
    3-phenoxybenzoic acid in free form, the cyclopropane carboxylic acid
    (free) and the amide, Compound A.  The latter in particular was
    present, however, in considerably smaller amounts than found in the
    glasshouse experiment.

    Polar materials were also found in appreciable amounts.  These could
    be hydrolysed by acid to give 3-phenoxybenzoic acid, 3-phenoxybenzyl
    alcohol and 3-phenoxybenzaldehyde.  Unidentified materials in foliage
    amounted to only a small proportion of the total radio-label present.

    In another experiment, abscised cotton leaves were placed with their
    stems immersed in an aqueous solution containing ring
    14C-radiolabelled Compound C for 72 hours.  At the end of this period
    90% of the radioactive material originally present in the solution had
    been taken up by the leaves.  The major proportion (78%) of this
    material was found to be present as sugar conjugates of Compound C.

    Experiments have also been carried out with the degradation products
    3-phenoxybenzoic acid (14C ring-labelled) and
    cis-2-(2',2'-dichlorovinyl)-3,3-dimethyl cyclopropane carboxylic
    acid (14C-C1-label).  In some of these the stems of cotton leaves
    were immersed in aqueous solutions.  There was a rapid uptake of both
    compounds and a rapid conversion to polar products.  These products
    were subsequently shown to be derivatives with various mono- or
    di-saccharide sugar products in the case of the cyclopropane
    carboxylic acid and mainly glucose in the case of 3-phenoxybenzoic
    acid.  Leaves to which 3-phenoxybenzoic acid was applied topically on
    the intact plant showed similar conversions to a mixture of sugar

    conjugates although at a much slower rate than in the case of petiole
    uptake.  Similar experiments with 3-phenoxybenzoic acid have been
    undertaken on vine, tomato, soybeans, pea and broad bean leaves and
    with similar findings, (Shell R. 126, 127, 128, 158, 159 and 160)

    b.    Lettuce

    Experiments were carried out on plants grown in pots in the glasshouse
    and treated with solutions of either the cis- or trans-isomer of
    cypermethrin.  Each isomer was also labelled in either the benzyl or
    cyclopropyl rings.  Details were similar to the first cotton
    experiment, described above, except that samples were taken
    immediately after treatment and 18 days later, and the results were
    qualitatively similar.  Just over 70% of the original applied
    radioactivity was still present 18 days after application and 90% of
    this was extractable with acetone.  But a higher proportion (50-70%)
    of the extracted radioactivity was present as cypermethrin than with
    cotton.  The proportions of other products found were: compound A,
    5-10%; 3-phenoxybenzoic acid, 10-15%; and compound B, 12-15%.  An
    unidentified 11-15% consisted of several minor metabolites.

    An outdoor experiment was also performed on lettuce using cypermethrin
    labelled in the benzyl and cyclopropyl rings.  The two labelled
    materials were applied to different plants as an overall foliar spray
    of a diluted E.C. formulation at a rate equivalent to 300 g/ha.
    Treatments were made on two occasions with an interval of about two
    weeks, and the plants were harvested approximately three weeks after
    the second treatment.  The major part of the residue, which amounted
    to 0.8-1 mg/kg(radioactivity equivalent to cypermethrin) was located
    in the outer leaves and only 10-20% was present in the hearts.  In the
    benzyl labelled experiment, 50% of the radioactivity was present as
    cypermethrin itself and most of the remainder as polar materials which
    individually were in too small amounts for detailed study.  Only 4%
    was not extracted.  In the cyclopropyl labelled experiment, 30% of the
    residue consisted of cypermethrin and 40% as conjugates of Compound C
    of which a glucose ester was identified (Shell R. 126, 129).

    c.  Apples

    Apple trees growing in an outdoor wire-covered enclosure were treated
    with cis-cypermethrin, separately labelled in the benzyl or
    cyclopropyl rings, or with trans-cypermethrin, labelled in the
    benzyl ring.  Leaves were treated on three occasions at intervals of
    25 and 37 days, and harvested four weeks after the last treatment.
    Fruit was treated twice at a 24-day interval and harvested three weeks
    after the second application.

    Examination of the leaves showed that 32-46% of the residue consisted
    of the parent isomer applied.  In addition, 7-15% of the radioactivity
    present was identifiable as compounds A and C, 3-phenoxybenzyl
    alcohol, 3-phenoxybenzaldehyde and 3-phenoxybenzoic acid. Polar
    compounds made up most of the remaining residue.  Sugar conjugates of

    3-phenoxybenzoic acid and the corresponding alcohol, as well as of
    3-(4-hydroxyphenoxy)-benzoic acid, were identified.

    In fruit, results were similar although the quantities present were
    much lower.  Examinations of peel and pulp separately showed that less
    than 2% of the total radioactivity in the fruit was present in the
    pulp.  On the peel 50-77% was present in the form of the parent isomer
    applied.  During the experiment 15% of the cis isomer was converted
    into the trans isomer.  The amounts of metabolites were somewhat
    less than in leaves and accounted, as free compounds, for 3-7% of the
    radioactivity present.  Polar materials from the fruit were present in
    much smaller amounts then in leaves and were not present in sufficient
    quantities to be studied in detail.

    In the experiments with the cis isomer some conversion (30%) into
    the trans isomer occurred, but the reverse change was not observed.
    In some routine examinations of field samples for residues of
    cypermethrin the glc analytical method used results in separation of
    the cis and trans isomers on the chromatograph trace.  No change
    in the relative sizes of the two peaks with different treatment to
    harvest intervals, or between unresolved standard material and the
    test samples, has been observed.  It would, therefore, seem that the
    conversion of cis isomer into trans compensates for the faster
    degradation of the trans isomer (Shell R. 130).

    IN SOIL

    Degradation on soils was studied by adding 14C-labelled cypermethrin
    to three different soils - a clay and a sandy clay from Spain, and a
    sandy loam from the U.K.  Separate experiments were carried out with
    the molecule labelled in the benzyl or the cyclopropyl moiety.  In
    addition, the cis and trans isomers were studied individually
    (Roberts and Standen, 1977).

    The cis isomer was found to degrade at an initial rate equivalent to
    a half life of between 2 and 4 weeks in sandy clay and sandy loam, and
    about 10 weeks in the clay soil.  The trans isomer degraded more
    rapidly than the cis isomer in all three soils, with initial
    half-lives between about one and three weeks.  Degradation was shown
    to proceed by hydrolysis of the ester link and cyano group with loss
    of carbon dioxide to give 3-phenoxybenzoic acid and Compound C, which
    were both present as free compounds.  Subsequent degradation of both
    compounds was shown to occur, since 14 C-radiolabelled carbon dioxide
    was evolved over 22 weeks in amounts equivalent to 24% and 38%,
    respectively, of the total radioactivity initially present as ring
    label.  As indicated by the presence of small amounts of Compounds A
    and 3-(4-hydroxyphenoxy)-benzoic acid, some hydroxylation of the
    aromatic rings also took place.

    Up to 36% of the original radioactivity was found to be difficult to
    extract 16 weeks after the commencement of the experiment.  A study of
    this fraction showed it to be composed of several materials bound to

    soil components.  Examination of the acid hydrolysed material showed
    that 30% or more of the radioactivity was in the form of Compound C.
    Smaller amounts of 3-phenoxybenzoic acid and
    3-(4-hydroxyphenoxy)-benzoic acid were also found.  After 52 weeks
    unchanged parent material accounts for 1.4-10.7% of the radioactivity
    originally applied to the soils.  In one sample of a Spanish soil
    (Brenes) a trace amount of Compound B was also present and in the same
    soil 5.8% of the original radioactivity was present as a cyclopropane
    dicarboxylic acid, Compound D.  In a separate experiment, this latter
    compound was also found, in amounts of 3-13% of the applied
    radioactivity, 8 weeks after application to soils stored in the
    laboratory.  Under waterlogged and anaerobic conditions hydrolytic
    breakdown was found to be somewhat slower than under aeroboic
    conditions.  Breakdown of 3-phenoxybenzoic acid was also slower.

    Compound C has also been shown to be formed from permethrin in soils
    and to be degraded by hydroxylation at the gem-dimethyl groups.
    Subsequent further breakdown has been shown in further studies,
    leading to extensive evolution of CO2 derived from ring and
    chloromethylene carbons (ICI, 132, 133, 134, 135).  These data
    substantially confirm the results obtained with cypermethrin, showing
    that Compound C is unlikely to accumulate in soils following treatment
    with the pesticide.

    In addition to the degradation studies referred to above, studies have
    also been made to determine the rate of loss of cypermethrin from
    soils from field experiments in which very high rates of application
    had been made.  The compound was applied as a diluted 40% EC and was
    partly incorporated to the soil (3-5 cm) after treatment.  Samples
    were generally taken from 0-15 cm depth.  The data obtained (Shell C
    and R. 136 to 140), show that for the same rate applied, the amount of
    residue initially present after treatment varied widely from one trial
    to the other, and that cypermethrin degrades fairly rapidly in soils.
    Only 1-5% of initial residue, if any, could be detected 4-8 months
    after treatment.  The leaching studies with labelled cypermethrin in a
    column containing sandy loam soil show that less than 2% of applied
    radioactivity had been eluted with water at a rate of 2 ml/hr from the
    column over the 45-day period (Hungary, 1979), and that 90% of the
    initial activity was present in the top 2 cm of the soil.  The
    findings from laboratory experiments are in agreement with the results
    of field trials.

    From the above findings, it may be concluded that, even when
    applications have been made to crops at recommended rates, residues of
    cypermethrin itself are unlikely to be present at detectable levels in
    soils at the beginning of the season following that in which
    treatments were made.  It may also be concluded that crops grown in
    plots where treatments with cypermethrin have been made in a previous
    season are unlikely to contain detectable residues.

    IN PROCESSING

    Cypermethrin is a moderately stable and water-insoluble compound. Data
    relating to the effect on residue levels of various treatments given
    to harvested crops are as follows:

    a.  Peeling

    Numerous data show that the residue present in a crop is largely on
    the surface.  Analyses of pulp and peel after peeling apples, pears,
    peaches and citrus fruits (Table 6) show that levels in the pulp were
    below 30%, and in most instances below 10%, of those in whole fruit.

    b.  Juice extraction - citrus

    Data for citrus have shown that residues of cypermethrin in juice
    extracted from treated fruits contained no measurable residues of the
    pesticide (see Table 6).

    C.  Wine making

    Wine has been manufactured from grapes treated with cypermethrin and
    containing up to 0.15 mg/kg pesticide.  No residues (limit of
    determination 0.01 mg/l) were found in the juice after fermentation
    (Shell C., 142).

    d.  Cooking

    Studies were made on the effect of boiling on residue levels in plums,
    and cabbage.  Levels were not substantially reduced by boiling plums
    for 30 minutes or cabbage for 45 minutes.  Residues in the cooked
    commodities were 75-90% of the initial levels and only very small
    amounts were found in the cooking water (Shell C., 143).

    e.  Oil seed processing

    An experiment was carried out with a cotton seed sample deliberately
    treated at the high rate of 300 g/ha and harvested one day after
    treatment.  It contained 0.12 mg/kg cypermethrin on whole seed, with
    adhering linters.  The sample was processed by simulating commercial
    practice in a laboratory specialising in the techniques.  Residues
    were found to be transferred to kernels, which originally did not
    contain any detectable residue in the seed, during the commercial
    mechanical separation process (Shell R., 144).  The residues of
    cypermethrin in the extracted oil at various stages were as follows:

    Crude oil 0.10 mg/l, neutralised oil 0.07 mg/l, bleached oil 0.08 mg/l
    and deodorised oil 0.05 mg/l.  Both the alkali wash and deodorisation
    steps contribute to some losses.  The results from this experiment
    suggest that the two processes together may be expected to remove
    about half of the residue.  Hence, it is possible that residues may
    occasionally occur in oil obtained from seed, treated under practical
    conditions, at levels approaching those in whole seed.

    Photodecomposition

    The photodecomposition of cypermethrin was studied in methanol
    solution under UV light and in the solid phase (3 mg/cm2 on glass)
    under sunlight.  55% of cypermethrin was recovered from the methanol
    solution after two days.  In sunlight there was no detectable loss of
    cypermethrin after 30 hrs.  In both experiments cypermethrin proved to
    be more stable than decamethrin and its behaviour was comparable to
    permethrin (Ruzo et al, 1976, 1977).

    EVIDENCE OF RESIDUES IN FOOD IN COMMERCE OR AT
    CONSUMPTION

    At present no data deriving from national monitoring studies or market
    control are available.

    METHODS OF RESIDUES ANALYSIS

    Several methods have been developed for the analysis of agricultural
    commodities for residues.  These are all based on gas-liquid
    chromatography procedures using equipment commonly found in modern
    analytical laboratories.  Limits of determination of 0.01 mg/kg are
    usually attainable.

    The racemic cypermethrin contains eight possible steric and optical
    isomers which can be partially resolved in the GLC column depending on
    its polarity.  On analysis of the mixture of isomers on OV-225 phase
    three partially resolved peaks with a characteristic pattern are
    obtained.  However with apolar or moderately polar packings (OV-101 or
    OV-17) no resolution of isomers occurs which facilitates the
    quantitation of the residue.  Four methods have been developed by
    Shell.  For cotton and other oil-seed crops, the sample is extracted
    with an acetone/petroleum mixture and the extract subjected to
    clean-up by solvent partition followed by absorption chromatography on
    Florisil.  The appropriate fractions of the eluate are then examined
    by gas-liquid chromatography using electron capture (63Ni) detection
    (Shell R. 147).  For other crops the samples are ground with anhydrous
    sodium sulphate and cypermethrin extracted with acetone and petroleum
    spirit.  The extract is washed with water and the resultant petroleum
    spirit layer separated and cleaned-up by chromatography on a Florisil
    column.  Cypermethrin is eluted with ether/petrol and determined using
    gas-liquid chromatography and a (63Ni) electron-capture detector
    (Shell R. 148).

    Residues in animal tissues are determined by extracting the tissue
    with mixed acetone:hexane, and fat removed by partitioning between
    hexane and acetonitrile.  The extract is cleaned-up by absorption
    chromatography on a column of Florisil and cypermethrin determined in
    the appropriate eluate fractions, by glc using electron-capture
    detection (Shell R. 149).

    Soil samples are mixed with anhydrous sodium sulphate and extracted
    with a mixture of acetone and petroleum spirit.  The extract, which

    contains any cypermethrin present in the soil, is washed with water to
    remove acetone and cleaned up by adsorption chromatography on
    Florisil.  Residues of cypermethrin are determined using GLC with an
    electron-capture detector (Shell R. 150).

    Confirmation of a residue in either soil or crop may be obtained by
    TLC (thin-layer chromatography) on Silica Gel plate eluted with
    toluene without previous saturation followed by further GLC.  ICI have
    also developed basically similar analytical methods for application to
    crop samples.  In their method the crop samples are extracted with 20%
    acetone in hexane and, where necessary, co-extractives removed by
    solvent partition.  Further clean-up is carried out by adsorption
    column chromatography on Silica Gel or Florisil and cypermethrin
    determined by GLC in conjunction with an 63Ni E.C. detector (ICI
    151).

    Recovery experiments have shown that all the methods cited are capable
    of measuring 80% or more of any cypermethrin residue present and that
    they are suitable for regulatory purposes.

    Chapman reported on the applicability of various adsorbent-solvent
    systems for the cleanup of some plant extracts containing
    cypermethrin, fenpropanate, permethrin, and fenvalerate.  Analytical
    methods suitable for the determination of metabolites of cypermethrin
    in crop samples obtained following practical applications in the field
    have been developed using HPLC.  Under normal circumstances the limit
    of determination is 0.05 mg/kg.(Shell R. 161)

    The amide, Compound B, is extracted with a mixture of water and
    acetonitrile from the sample of which the water content is known.
    Clean-up of the extract is performed by solvent partition and
    reversed-phase partition chromatography followed by reversed phase
    HPLC.  Final analysis is carried out with normal HPLC using a UV
    detector (Shell R. 162).

    3-phenoxybenzoic acid may be determined in a similar manner, although
    partition between dilute aqueous alkaline acetonitrile and hexane in
    used to remove parent cypermethrin from free 3-phenoxybenzoic acid.
    Conjugated material is hydrolysed by treatment of the concentrated
    aqueous extract with hydrochloric acid.  The 3-phenoxybenzoic acid is
    converted into the methyl ester which may then be determined directly
    on HPLC.  Alternatively, if further clean-up is required, HPLC may be
    used for this purpose and gas chromatography/mass spectrometry with
    multiple ion monitoring used for the determination (Shell R. 163).

    Compound C may also be extracted from crop samples with a mixture of
    water and acetonitrile and separated from unwanted material by solvent
    partition.  Conjugated Compound C is however retained in the aqueous
    phase which may be concentrated and hydrolysed with hydrochloric acid.
    The liberated compound C may then be extracted with an ether/petroleum
    spirit mixture.  Clean-up of the extracts is performed by reversed
    phase HPLC and Compound C determined by normal phase HPLC.  If
    extracts are insufficiently clean for HPLC they may be treated with

    alpha-cyano-3-phenoxy-benzyl bromide, and the cypermethrin formed
    determined by gas chromatography with electron capture detection
    (Shell R. 164).

    Other experiments have shown that the great majority of samples may be
    stored for long periods in the deep freeze without appreciable loss of
    residues.  Residue levels were determined in crop and soil samples at
    intervals following addition of known quantities of cypermethrin in
    the range of 0.2 mg/kg to 1 mg/kg.  The samples were stored at -18C
    between treatment and extraction for analysis, for periods between 1
    and 54 weeks for crops and 4-49 weeks for soil.  Recoveries of
    cypermethrin added to crops (21 samples) were 85-110%, apart from one
    sample of tobacco which yielded 45% after 6 months storage.  In the
    case of soils (5 samples) recoveries were all between 90 and 110%
    (Shell R. 152).

    Studies have also been carried out on the stability in storage at
    -18C of residues of 3-phenoxybenzoic acid and Compounds B and C. 
    Over three months there was no evidence of loss of 3-phenoxybenzoic
    acid, since the total amounts recovered from the 6 crops used
    (lettuce, potatoes, cabbage, apples, pears and maize grain) were in
    the range of 75-100% and comparable to recovery values of the method
    itself.  With Compound B experiments were carried over three months
    with sweet corn and over five months with apples and cabbage.
    Recoveries were 70%, 75% and 75% respectively.  Cabbage and apples
    treated with Compound C were also stored at -18C for five months.
    Recoveries were 90-95% respectively.  These data, therefore, indicate
    that loss of any of the three degradation compounds mentioned were
    negligible over periods of 3-5 months at 18C.

    NATIONAL MRLs REPORTED TO THE MEETING

    National MRLs and pre-harvest intervals have been established in
    several countries based on local requirements.  The following were
    presented at the meeting:

                                                                      
    Country        Commodity            MRL      Pre-harvest int. (days)
                                                                      

    Argentina      Apples                                 21
                   Cotton                                 20
                   Peaches                                25
                   Tomatoes                                7
                   Soya, Sorghum                          40
                   Sunflower                              30

    Colombia       Cotton                                 35

    Costa Rica     Cotton, Vegetables                     15

                                                                      

                                                                      
    Country        Commodity            MRL      Pre-harvest int. (days)
                                                                      

    Cyprus         Vegetables                             14
                   Top Fruit

    Fed. Rep.
    of Germany     Leafy vegetables                       14
                   Potatoes                               14
                   Maize                                  49

    France         Apples               0.5               14
                   Peaches              0.5               14
                   Vines                0.5               14

    New Zealand    Kiwi fruit           2.0               14
                   Pome fruit           1.0               14
                   Brassicas            1.0               7

    Peru           Cotton                                 15
                   Tomatoes                               15
                   Potatoes                               15

    Spain          Cotton                                 21
                   Potatoes                               21
                   Tomatoes                               21
                   Citrus                                 21

    South Africa   Cotton               0.05              28
                   Grapes               0.05              28
                   Maise                1.5               28
                   Peas                 0.1                7
                   Tomatoes             0.2                4

    Syria          Top fruit                              7-10
                   Vegetables
                                                                      

    Experimental or wider use of cypermethrin in further 43 countries was
    reported where neither preharvest intervals nor MRL's have been yet
    established.

    APPRAISAL

    Cypermethrin is active against a wide range of insects which attack
    crops and can be used at a relatively low dose rate in the range of
    0.02-0.25 kg a.i./ha.  It is a moderately stable and water insoluble
    compound.  The technical material contains not less than 90% w/w
    cypermethrin, which is a mixture of optical isomers, with a cis:trans
    isomer ratio of approximately 40:60.  The maximum concentration of
    residues in/on the treated crops in the range of 0.05-2 mg/kg and
    decreases slowly.

    The majority of residues are in the peel or outer leaves, and in most
    instances the pulp or hearts contain below 10% of those in the whole
    crop.  The trans isomers of cypermethrin degrades slightly faster
    than the cis, which is compensated by the conversion of cis isomer
    into trans during degradation, thus the isomers remain in a constant
    ratio at different times after application in plants.  Degradation in
    crops occurs mainly by hydrolysis of the ester bond followed by
    further hydrolytic and oxidative processes to give a variety of
    products.  Less rapid processes observed were hydrolysis of the
    nitrile group to amide and hydroxylation of the phenoxy ring.  The
    compounds formed were, in turn, also hydrolysed at the ester link.
    However, metabolites have not been detected in crop commodities from
    supervised trials.  At least 90% of the total residue present in plant
    material is extractable with acetone.  Processing of treated crops
    after harvest usually reduces the residue significantly.

    Cattle consuming feed items treated with cypermethrin eliminate the
    residue rapidly.  Equilibrium between intake and excretion is reached
    in 3-4 days.  The total radioactivity found in the milk amounted to
    only 0.5% of the radioactivity fed to the animals and 60-90 of this
    residue was present in the cream fraction.  The residues in the milk
    are esters and contain both acidic and alcoholic moieties of the
    parent compound.  The vast majority of residue in the feed is excreted
    in the urine and faeces in roughly similar proportions.  The main
    metabolite in urine is 3-phenoxybenzoic acid which is present as
    glutamic acid conjugate and glycine derivatives.  The faeces mainly
    contain the intact molecule.

    Cypermethrin does not accumulate in the meat.  Even when fed at a high
    dose rate residues are mostly in the fat, liver and kidney.  The data
    indicate that the feeding of crops treated with cypermethrin following
    the recommended use patterns does not result in measurable residues in
    meat or milk of cattle.  Since the compound may be used for direct
    treatment of animals and data deriving from the latter use are not
    available, recommendations of MRLs for animal products cannot be made
    at present.

    In soils, spray deposits remain in the surface layer.  The rate of
    degradation is dependent on the type of soil and proceeds by
    hydrolysis of the ester link and cyano group finally resulting in
    acids from both parts of the parent compound.  Some hydroxylation of
    the phenoxy aromatic ring occurs.  Subsequent degradation also takes
    place with the breakdown of the carbon rings.  The trans isomer
    degrades more rapidly than the cis.  The results indicate that no
    detectable residue of cypermethrin itself will be present in soil 8-12
    months after treatment and that crops grown in the next season will
    not contain measurable residues of cypermethrin.

    Analytical methods available for the determination of residues in
    various commodities are suitable for regulatory purposes.  The limit
    of determination is typically 0.01-0.02 mg/kg.

    RECOMMENDATIONS

    The following temporary maximum residue limits are recommended based
    on the pre-harvest intervals indicated below.  The limits refer to the
    sum of isomers of the parent compound in the portion of sample to be
    analysed as described by CC/PR.

                                                                       
                                               Pre-harvest interval on
    Commodity           Temporary MRL mg/kg    which recommendation is
                                               based (days)
                                                                       

    Citrus fruits                2                        14
    Peaches                      2                         7
    Pome fruits                  2                         7
    Cherries                     1                         7

    Grapes                       1                         7
    Brassica leafy
    vegetables                   1                         7
    Lettuce                      2                         7
    Plums                        1                         7
    Raspberries                  0.5                      14
    Strawberries                 0.5                      21
    Tomatoes                     0.5                       3
    Rapeseed                     0.2                      42
    Wheat                        0.2                      14
    Cottonseed                   0.1                       7
    Cottonseed oil
    (finished)                   0.2
    Kidney beans, peas,
    soybeans
    (without pods)               0.05                      7
    Maize                        0.05                      7
    Potatoes                     0.05                      7
    Sugar beet (roots)           0.05                     14
    Sweet corn                   0.05                      7
                                                                       

    FURTHER WORK OR INFORMATION

    Required by 1981:

    1.  Pharmacokinetic data on the potential bioaccumulation of
        cypermethrin and/or metabolites in adipose tissue.

    2.  Observations in man, especially those with high level of
        occupational exposure, to evaluate the potential susceptibility of
        man to the neurotoxic syndrome observed in rodents.

    Desirable

    1.  A dominant lethal bioassay.

    2.  Further residue data on kiwi fruit from supervised trials.

    3.  Selective surveys of residues in crops known to have been treated
        under practical circumstances.

    4.  Use patterns for animal health use and residues in animal products
        deriving from the recommended application.

    REFERENCES

    Baldwin, M.K.  The analysis of a Metabolite of WL 43467 in Human Urine
    as an Index of Exposure to that Compound. (1978) Unpublished Report
    from Shell Research Ltd., submitted by Shell International Chemical
    Co.

    Brooks, T.M.  Toxicity Studies with WL 43467. Mutagenicity Studies
    with WL43467 in the Host-Mediated Assay and in Micro-Organisms In
    Vitro.  (1976) Unpublished report from Shell Research Ltd., submitted
    by Shell International Chemical Company.

    Brown, V.K.  Toxicology of WL 43467 Isomers: Acute Toxicity of WL
    43481 in DMSO to rats.  (1979a) Unpublished report submitted by Shell
    International Chemical Company.

      Toxicology of WL43467 Isomers: Acute Toxicity of WL42641 in DMSO to
    Rats.  (1979b) Unpublished report submitted by Shell International
    Chemical Company.

    Buckwell, A.C. and Butterworth, S.T.G. Toxicity Studies on the
    Pyrethroid Insecticide WL 43467. A 13-Week Feeding Study in Dogs.
    (1977) Unpublished Report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

    Butterworth, S.T.G. and Clark, D.G.  Toxicity Studies on the
    Insecticide WL43467:  Acute Oral Toxicity and Neuropathological
    Effects in Syrian Hamsters.  (1977) Unpublished report from Shell
    Research Ltd., Submitted by Shell International Chemical Company.

    Carter, B.I. and Butterworth, S.T.G.  Toxicity of Insecticides.  The
    Acute Oral Toxicity and Neuropathological Effects of WL 43467 to Rats.
    (1976) Unpublished report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

    Chapman, R.A., and Harris, C.R.  Extraction and Liquid-Solid
    Chromatography Cleanup Procedures for the Direct Analysis of 4
    Pyrethroid insecticides in Crops by Gas Liquid Chromatography. J. of
    Chromatography 166. 513-518.

    Combs A.D., Carter, B.I. Hend, R.W., Butterworth, S.G. and Backwell,
    A.C. Toxicity Studies on the Insecticide WL-43467: (1976) Unpublished
    summary of results of preliminary experiments from Shell Research
    Ltd., submitted by Shell International Chemical Company.

    Crawford, M.  The Metabolism of WL 43467 in Mammals (1).  The fate of
    a Single Oral Dose of [14C-Benzyl] WL 43481 (cis-WL 43467) in the
    Rat.  1976a) Unpublished report from Shell Research Ltd., submitted by
    Shell International Chemical Company.

      The Metabolism of WL 43467 in Mammals. The Fate of a Single Oral
    Dose of [14C] WL-42641 (trans-WL43467), in the Rat.  (1976b)
    Unpublished Report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

    Crawford, N.J.  The Metabolism of WL 43467 in Mammals. The Fate of a
    Single Oral Dose of [14C-cyclopropyl] WL 43467 in the Rat. (1977)
    Unpublished Report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

      The Excretion and Residues of Radioactivity in Cows Treated Orally
    with 14C-Labelled WL 43467.  (1978) Unpublished report from Shell
    Research Ltd., submitted by Shell International Chemical Company.

      The Metabolism of Cypermethrin (WL 434671) in Mammals. The Fate of a
    Single Oral Dose of [14C-cyclopropyl] Cypermethrin in the Dog.
    (1979a) Unpublished report from Shell Research Ltd., submitted by
    Shell International Chemical Company.

      The Metabolism of Cypermethrin (WL 43461) in Mammals. The Fate of
    Single Oral Doses of cis- and trans- [14C-benzyl] Cypermethrin in
    the Dog. (1979b) Unpublished report from Shell Research Ltd.,
    submitted by Shell International Chemical Company.

      The Metabolic Fate of the cis- and Trans-isomers of WL 43467
    (Cypermethrin) and of 3-Phenoxybenzoic Acid in Dogs.  (1979c)
    Unpublished report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

    Crawford, M.J. and Hutson, D.H.  The Elimination and Retention of WL
    43467 when administered Dermally or Orally to Sheep.  (1977a)
    Unpublished report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

    Crawford, M.J. and Hutson, D.R.  The Metabolic Fate of the cis- and
    trans- isomers of WL 43467 (Cypermethrin).  Metabolism and
    Elimination of 14C-labelled cis- and trans-isomers in Rats. (1977b)
    Unpublished report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

      The Elimination of Residues from the Fat of Mice Following the Oral
    Administration of [14C-benzyl-] WL 43481 (cis-WL43467).  (1978a)
    Unpublished report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

      The Elimination of Residues from the Fat of Rats Following the Oral
    Administration of [14C-benzyl] WL 43481 (cis-WL 43467).  (1978b)
    Unpublished Report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

      The Metabolic Fate of the cis-and trans-isomers of Cypermethrin
    in the Rat.  Metabolites Derived from the 14C-Labelled Cyclopropyl
    Ring.  (1978c) Unpublished report from Shell Research Ltd., submitted
    by Shell International Chemical Company.

    Crawford, J.V.  A Study of the Metabolism of 3-Phenoxybenzoic Acid and
    its Glucoside Conjugate in Rats.  (1978) Unpublished report from Shell
    Research Ltd., submitted by Shell International Chemical Company.

    Crawford, J.V. and Hutson, D.H.  The identification of Metabolites in
    the Tissues of Rats Treated Orally with 3-Phenoxybenzoic Acid. (1979)
    Unpublished report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

    Dean, B.J.  Toxicity Studies with WL 43467: Chromosome Studies on Bone
    Marrow Cells of Chinese Hamsters After Two Daily Oral Doses of WL
    43467.  (1977) Unpublished report from Shell Research Ltd., submitted
    by Shell International Chemical Company.

    Dean, B.J., van der Paux. C.L. and Butterworth S.T.G.  Toxicity
    Studies with WL 43467: Dominant Lethal Assay in Male Mice After Single
    Oral Doses of WL 43467. (1977) Unpublished report from Shell Research
    Ltd., submitted by Shell International Chemical Company.

    Dewar, A.J.  The Use of Lysosomal Enzyme Measurements as an Indicator
    of Chemically-Induced Peripheral Neuropathy. (1977a) Unpublished
    report from Shell Research Ltd., submitted by Shell International
    Chemical Co.

    Toxicity Studies on the Insecticide WL 43467: Biochemical and
    Functional Studies on the Neurotoxicity of WL 43467 to Rats. (1977b)
    Unpublished report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

    Dewar, A.J. and Deacon, P.A.  Toxicity Studies on the Insecticide WL
    43467:  Electrophysiological Studies on the Neurotoxicity of WL 43467
    to Rats. I. - The Effect on Motor Conduction Velocity in the Sciatic
    and Tail Nerves.  (1977) Unpublished report from Shell Research Ltd.,
    submitted by Shell International Chemical Company.

    Dewar, A.J. and Moffett, B.J. Toxicity Studies on the insecticide WL
    43467:  Biochemical studies on the effect of WL 43467 on the rat
    trigeminal nerve and ganglion. (1978a) Unpublished report from Shell
    Research Ltd., submitted by Shell International Chemical Company.

      Toxicity Studies on the Insecticide WL 43467: Biochemical and
    Function Studies on the Neurotoxicity of WL 43467 to Chinese Hamsters.
    (1978b) Unpublished report from Shell Research Ltd., submitted by
    Shell International Chemical Company.

    Dix, K.M.  Toxicity of WL 43467: Teratological Studies in Rabbits
    given  WL 43467 Orally. (1978) Unpublished report from Shell Research
    Ltd., submitted by Shell International Chemical Company.

    Glaister, J.R., Pratt, I. and Richards, D. PP 383: Effects of High
    Dietary Levels on Clinical Behaviour and Structure of Sciatic Nerves
    in the Rat.  (1977a) Unpublished report from ICI Central Toxicology
    Laboratory submitted by ICI Ltd.

    Glaister, J.R., Gare, C.W., Marsat, G.J., Phillips, C. and Pratt, I.
    PP 383:  90-Day Feeding Study in Rats.  (1977b) Unpublished report
    from ICI Central Toxicology Laboratory submitted by ICI Ltd.

    Hend, R.W. and Butterworth, S.T.G.  Toxicity Studies on the
    Insecticide WL 43467: A Three-month Feeding Study in Rats.  (1976)
    Unpublished report from Shell Research Ltd., submitted by Shell
    International Chemical Co.

      Toxicity Studies on the Insecticide WL 42641: a Five-Week Feeding
    Study in Rats.  (1977a) Unpublished report from Shell Research Ltd.,
    submitted by Shell International Chemical Company.

      Toxicity Studies on the Insecticide WL 43481: A five-Week Feeding
    Study in Rats. (1977b) Unpublished report from Shell Research Ltd.,
    submitted by Shell International Chemical Company.

    Hend, R.W., Hendy, R. and Fleming, D.J. Toxicity Studies on the 
    Insecticide WL  43467: A Three-Generation Reproduction Study in Rats.
    (1978) Unpublished report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

    Hungary.  Information supplied by country delegation to Codex
    Committee on Pesticide Residues on compounds on priority list. (1979).

    Hutson, D.H.  Taurine Conjugation in the Metabolism of
    3-Phenoxybenzoic Acid and the Pyrethroid Insecticide Cypermethrin (WL
    43467).  (1977) Unpublished report from Shell Research Ltd., submitted
    by Shell International Chemical Company. (Published in Xenobiotica, 8
    (1978) 565-571).

      The Elimination of Radioactivity by Mice Following Oral Dosing with
    14C-cis and 14C-trans-WL 43467 (Cypermethrin). (1978a) Unpublished
    report from Shell Research Ltd., submitted by Shell International
    Chemical Company.

      The Metabolites of cis- and trans-Cypermethrin (WL 43467) in
    Mice. (1978b) Unpublished report from Shell Research Ltd., submitted
    by Shell International Chemical Company.

    Hutson, D.H. and Stoydin, G.  The Excretion of Radioactivity from Cows
    fed with Radioactively Labelled WL 43467.  (1976) Unpublished report
    from Shell Research Ltd., submitted by Shell International Chemical
    Co.

    ICI.  (1979) Unpublished reports available to meeting (referred to in
    text by ICI and code numbers 10, 132 to 135 and 151).

    Jaggers, S.  Cypermethrin: Summary and Review of Acute Toxicities in
    Laboratory Species.  (1979) Unpublished report submitted by ICI, Ltd.

    McAusland, H.E., Butterworth, S.T.G. and Hunt, P.F.  Toxicity Studies
    on the Insecticide WL 43467: A Two-year Feeding Study in Rats. (1978)
    Unpublished report from Shell Research Ltd., submitted by Shell
    International Chemical Company.

    New Zealand.  Information supplied by CCPR country delegation on
    compounds on priority list. (1979)

    Okuno Y., Kohda, H. and Kadota, T.  Neurotoxic Effects of S-5602 and
    NRDC 149 by Dermal Application in Rats.  (1976) Unpublished report
    from Sumitomo Chemical Company submitted by Shell International
    Chemical Co.

    Owen, D.E. and Butterworth, S.T.G.  Toxicity of Pyrethroid
    Insecticides: Investigation of the Neurotoxic Potential of WL 43467 to
    Adult Domestic Hens. (1977) Unpublished report from Shell Research
    Ltd., submitted by Shell International Chemical Company.

    Prinsen, G.H. and Van Sittert, W.J. Exposure and Medical Monitoring
    Study of the Pyrethroid WL 43467 After Single Application on Cotton in
    Ivory Coast.  (1978) Unpublished report from Shell International
    Research Maatschappij, B.V., submitted by Shell International Chemical
    Co.

    Roberts, T.R. and Stande, M.E.  Degradation of the Pyrethroid
    Cypermethrin NRDC 149 ( alpha-cyano-3-phenoxybenzyl)  (cis trans
    3(2,2-dichlorovinyl) 2,2-dimethycyclopropane carboxylate and
    Respective cis (NRDC 160) and trans (NRDC 159) Isomers in Soils.
    Poetic. Sci. 8, 305-319 (1977).

    Rose, G.P. and Dewar, A.J.  Toxicity Studies on the Insecticide WL
    43467: The Effect of Age on the Neurotoxicity of WL 43467 to Rats.
    (1978) Unpublished report from Shell Research Ltd., 

    Ruzo, L.O., Holmstead, R.L., Casida, J.E.  Solution photochemistry of
    the potent pyrethroid insecticides alpha-cyano-3-phenoxybenzyl cis
    2,2-dimethyl-3-(2,2dibromovinyl) cyclopropane carboxylate. 
    Tetrahedron Letters 35, 3045/1976.

    Ruzo, L.O., Holmstead, R.L. and Casida, J.E.  Pyrethroid
    Photochemistry: Decamethrin  J. Agr. Food Chem 25, 1385 (1977).

    Shell Chemie. France.  Unpublished Reports.  Referred to by "Shell C"
    and numbers in the text: 2-9, 11, 12, 14, 17-25, 27-30, 34,40, 44, 47,
    55, 56, 60-64, 67-75, 77-86, 90-97, 101-105, 107-109, 112, 114-116,
    118-122 136, 137, 142, 143, 152, 154, 155.

    Shell Research Ltd., England - Unpublished reports referred to by
    "Shell R." and numbers in the text: 1, 13, 15, 16, 26, 31-33, 41-43,
    45, 46, 48-54, 57-59, 65, 66, 76, 87-89, 98-100, 106, 110, 111, 113,
    117 123-130, 138-140, 144, 147-150, 152, 156, 158-160, 162-164.

    Shono, T., Ohsawa, K. and Casida, J.E. Metabolism of trans- and
    cis-Cypermethrin, and Decamethrin by Microsomal Enzymes.  J. Agric.
    Food Chem., 27 (2), 316-325.

    South Africa.  Information on compounds on priority list.  (1979)

    Sweden.  Information on compounds on priority list.  (1979)

    Suzuki, H.  Studies on the Mutagenicity of Some Pyrethroids on
    Salmonella Strains in the Presence of Mouse Hepatic S9 Fraction.
    (1977) Unpublished report from Sumitomo Chemical Co., Ltd., submitted
    by Sumitomo Chemical Co., Ltd.

    Tesh, J.M., Tesh, S.A. and Davies, W.  WL 43467: Effects Upon the
    Progress and Outcome of Pregnancy in Rat.  (1978) Unpublished report
    from Life Science submitted by Shell International Chemical Company.

    Trigg, C.E., Butterworth, S. and Hunt, P.F. Neurotoxicity of
    Pyrethroids: A Study of Teased Nerves from Rats Fed WL 43467 for 12
    Months.  (1977) Unpublished report from Shell Research Ltd., submitted
    by Shell International Chemical Company.
    


    See Also:
       Toxicological Abbreviations