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    UKPID MONOGRAPH




    ESFENVALERATE




    SA Cage MSc M Inst Inf Sci
    SM Bradberry BSc MB MRCP
    S Meacham BSc
    JA Vale MD FRCP FRCPE FRCPG FFOM

    National Poisons Information Service
    (Birmingham Centre),
    West Midlands Poisons Unit,
    City Hospital NHS Trust,
    Dudley Road,
    Birmingham
    B18 7QH


    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom. The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information
    Service.


    ESFENVALERATE

    Toxbase summary

    Type of product

    Insecticide

    Toxicity

    Dermal and inhalational exposures are associated usually with no or
    only mild adverse effects. Following substantial ingestion, patients
    may develop coma, convulsions and severe muscle fasciculations and may
    take several days, occasionally weeks, to recover.

    Fatalities have occurred rarely after pyrethroid exposure, usually
    following ingestion (He et al, 1989). No known fatalities have been
    reported specifically after esfenvalerate exposure although fatalities
    have occurred following exposure to fenvalerate (which contains
    esfenvalerate) (He et al, 1989).

    Features

    Dermal exposure

         -    Tingling and pruritus with blotchy erythema on the face or
              other exposed areas, exacerbated by sweating or touching.
              Systemic toxicity may ensue following substantial exposure
              (see below).

    Ocular exposure

         -    Lacrimation and transient conjunctivitis may occur.

    Inhalation

    Brief exposure:
         -    Respiratory tract irritation with cough, mild dyspnoea,
              sneezing and rhinorrhea.

    Substantial and prolonged exposure:
         -    Systemic toxicity may ensue - see below.

    Ingestion

         -    May cause nausea, vomiting and abdominal pain. Systemic
              toxicity may ensue following substantial ingestion (see
              below).

    Systemic toxicity

         -    Systemic symptoms may develop after widespread dermal
              exposure, prolonged inhalation or ingestion. Features
              include headache, dizziness, anorexia and hypersalivation.
         -    Severe poisoning is uncommon. It usually follows substantial
              ingestion and causes impaired consciousness, muscle
              fasciculations, convulsions and, rarely, non-cardiogenic
              pulmonary oedema.

    Chronic exposure

         -    Long-term exposure is no more hazardous than short-term
              exposure.

    Management

    Dermal

    1.   Remove soiled clothing and wash contaminated skin with soap and
         water.
    2.   Institute symptomatic and supportive measures as required.
         Topical vitamin E (tocopherol acetate) has been shown to reduce
         skin irritation if applied soon after exposure (Flannigan et al,
         1985), but it is not available as a pharmaceutical product in the
         UK.
    3.   Symptoms usually resolve within 24 hours without specific
         treatment.

    Ocular

    1.   Irrigate with lukewarm water or 0.9 per cent saline for at least
         ten minutes.
    2.   A topical anaesthetic may be required for pain relief or to
         overcome blepharospasm.
    3.   Ensure no particles remain in the conjunctival recesses.
    4.   Use fluorescein stain if corneal damage is suspected.
    5.   If symptoms do not resolve following decontamination or if a
         significant abnormality is detected during examination, seek an
         ophthalmological opinion.

    Inhalation

    1.   Remove to fresh air.
    2.   Institute symptomatic and supportive measures as required.

    Ingestion

    1.   Do not undertake gastric lavage because solvents are present in
         some formulations and lavage may increase risk of aspiration
         pneumonia.
    2.   Institute symptomatic and supportive measures as required.

    3.   Atropine may be of value if hypersalivation is troublesome,
         0.6-1.2 mg for an adult, 0.02 mg/kg for a child.
    4.   Mechanical ventilation should be instituted if non-cardiogenic
         pulmonary oedema develops.
    5.   Isolated brief convulsions do not require treatment but
         intravenous diazepam should be given if seizures are prolonged or
         recur frequently. Rarely, it may be necessary to give intravenous
         phenytoin or to paralyze and ventilate the patient.

    References

    Box SA, Lee MR.
    A systemic reaction following exposure to a pyrethroid insecticide.
    Hum Exp Toxicol 1996; 15: 389-90.

    Flannigan SA, Tucker SB, Key MM, Ross CE, Fairchild EJ, Grimes BA,
    Harrist RB.
    Synthetic pyrethroid insecticides: a dermatological evaluation.
    Br J Ind Med 1985; 42: 363-72.

    He F, Wang S, Liu L, Chen S, Zhang Z, Sun J.
    Clinical manifestations and diagnosis of acute pyrethroid poisoning.
    Arch Toxicol 1989; 63: 54-8.

    Lessenger JE.
    Five office workers inadvertently exposed to cypermethrin.
    J Toxicol Environ Health 1992; 35: 261-7.

    O'Malley M.
    Clinical evaluation of pesticide exposure and poisonings.
    Lancet 1997; 349: 1161-6.

    Substance name

         Esfenvalerate

    Origin of substance

         Esfenvalerate is the most biologically active isomer [S,S] of
         fenvalerate                        (IPCS, 1990c).

    Synonyms/Proprietary names

         Asana
         Fenvalerate alpha
         Fenvalerate A alpha
         Halmark
         OMS 3023
         Sumi Alpha
         Sumicidin A alpha                  (RTECS, 1997)

    Chemical group

         Type II synthetic pyrethroid

    Reference numbers

         CAS            66230-04-4          (Pesticide Manual, 1997)
         RTECS          CY1576367           (RTECS, 1997)
         UN             NIF
         HAZCHEM CODE   NIF

    Physicochemical properties

    Chemical structure
         IUPAC name:  (S)-alpha-cyano-3-phenoxybenzyl
          (S)-2-(4-chlorophenyl)-3-methylbutyrate

    CHEMICAL STRUCTURE 1

         C25H22ClNO3                               (Pesticide Manual, 1997)

    Molecular weight
         419.9                              (Pesticide Manual, 1997)

    Physical state at room temperature
         Solid (crystals). Technical grade is a viscous liquid or solid at
         23°C.                              (Pesticide Manual, 1997)

    Colour
         The crystals are colourless. Technical grade is yellow brown.
                                            (Pesticide Manual, 1997)

    Odour
         NIF

    Viscosity
         NIF

    pH
         NIF

    Solubility
         Low solubility in water: 2 x 10 -6 g/L at 25°C
         Acetone >474 g/L at 25°C
         Chloroform >882 g/L at 25°C
         Ethyl acetate >540 g/L at 20°C
         Dimethylformamide >570 g/L at 25°C
         Methanol 55-79 g/L at 25°C
         Xylene > 516 g/L at 25°C           (Pesticide Manual, 1997)

    Autoignition temperature
         NIF

    Chemical interactions
         NIF

    Major products of combustion
         Combustion and/or pyrolysis may lead potentially to the
         production of compounds such as acrolein, formaldehyde, hydrogen
         cyanide and hydrogen chloride (Hartzell, 1996).

    Explosive limits
         NIF

    Flammability
         Burns with difficulty.             (HSDB, 1997)

    Boiling point
         151-167°C (technical grade)        (Pesticide Manual, 1997)

    Density
         1.26 at 4-26°C                     (Pesticide Manual, 1997)

    Vapour pressure
         2 x 10-7 Pa at 25°C              (Pesticide Manual, 1997)

    Relative vapour density
         NIF

    Flash point
         256°C                              (Pesticide Manual, 1997)

    Reactivity
         NIF

    Uses

         Esfenvalerate is a potent insecticide by contact and ingestion,
         and has a very broad range of activity (Pesticide Manual, 1997).

    Hazard/risk classification

         NIF

    INTRODUCTION

    Pyrethrins were developed as pesticides from extracts of dried and
    powdered flower heads of  Chrysanthemum cinerariaefolium. The active
    principles of these (see Fig. 1) are esters of chrysanthemumic acid
    (R1 = CH3) or pyrethric acid (R1 = CH3O2C) (both cyclopropane
    (three membered ring) carboxylic acids), with one of three
    cyclopentanone alcohols (cinerolone, R2 = CH3; jasomolone, R2 =
    CH2CH3; or pyrethrolone, R2 = CHCH2), giving six possible
    structures. These natural pyrethrins have the disadvantage that they
    are rapidly decomposed by light.

    FIGURE 1

    Once the basic structure of the pyrethrins had been discovered,
    synthetic analogues, pyrethroids, were developed and tested. Initially
    esters were produced using the same cyclopropane carboxylic acids,
    with variations in the alcohol portion of the compounds.

    The first commercial synthetic pyrethroid, allethrin, was produced in
    1949, followed in the 1960s by others including dimethrin,
    tetramethrin and resmethrin. 3-Phenoxybenzyl esters were also found to
    be active as pesticides (e.g phenothrin, permethrin). Synthetic
    pyrethroids with this basic cyclopropane carboxylic ester structure
    (and no cyano group substitution) are known as type I pyrethroids. In
    animal studies type I pyrethroids have been shown generally to produce
    a typical toxic syndrome (see below).

    The insecticidal activity of synthetic pyrethroids was enhanced
    further by the addition of a cyano group at the benzylic carbon atom
    to give alpha-cyano (type II) pyrethroids. In animal studies type II
    pyrethroids have been shown generally to produce a typical toxic
    syndrome (see below).

    Despite the lack of the cyclopropane ring, similar insecticidal
    activity was found in a group of phenylacetic 3-phenoxybenzyl esters.
    This led to the development of fenvalerate, an
    alpha-cyano-3-phenoxy-benzyl ester, and other related compounds such
    as fluvalinate. These all contain the alpha-cyano group and hence are
    type II pyrethroids.

    Animal studies suggest that the two structural types of pyrethroids
    give rise generally to distinct patterns of systemic toxic effects.
    Type I pyrethroids produce in animals the so-called "T (tremor)
    syndrome", characterized by tremor, prostration and altered "startle"
    reflexes. Type II (alpha-cyano) pyrethroids produce the so-called "CS
    (choreoathetosis/salivation) syndrome" with ataxia, convulsions,
    hyperactivity, choreoathetosis and profuse salivation being observed
    in experimental studies.

    These observations are consistent with some differences in the
    mechanisms of toxicity between type I and type II pyrethroids (see
    below) but the division of reactions by chemical structure is not
    exclusive. Some compounds produce a combination of the two syndromes,
    and different stereoisomeric forms can produce different syndromes
    (Dorman and Beasley, 1991). The classification into "T" and "CS"
    syndromes is not used clinically.

    All pyrethroids have at least four stereoisomers, with different
    orientation of the substituents on the cyclopropane ring (or the
    equivalent part of the phenylacetate). The isomers have different
    biological activities, as discussed below (see Mechanisms of
    toxicity). Different isomers may have separate common names,
    reflecting their commercial importance (Aldridge et al, 1978).
    Esfenvalerate is one of the isomers of fenvalerate and is produced
    separately since it is a more potent insecticide than the racemic
    mixture.

    Further details are given in the pyrethroid generic monograph.

    EPIDEMIOLOGY

    In 1989-1990, world-wide annual production of pyrethroids was at least
    2000 tonnes (IPCS, 1989a; IPCS, 1989b; IPCS, 1989c; IPCS, 1990a; IPCS,
    1990b; IPCS, 1990c; IPCS, 1990d; IPCS, 1990e; IPCS, 1990f) including
    approximately 1000 tonnes of fenvalerate (IPCS, 1990c) though specific
    data for esfenvalerate were not identified.

    In spite of their long history of use, there are relatively few
    reports of pyrethroid, and specifically esfenvalerate, toxicity. Less
    than ten deaths have been reported from ingestion or occupational
    (primarily dermal/inhalational) pyrethroid exposure (He et al, 1989;
    Peter et al, 1996) with three deaths from fenvalerate (which contains
    esfenvalerate) ingestion and one from combined fenvalerate/dimethoate
    poisoning (He et al, 1989).

    MECHANISMS OF TOXICITY

    In neuronal cells the generation of an action potential by membrane
    depolarization involves the opening of cell membrane sodium channels
    and a rapid increase in sodium influx. The closure of sodium channels
    begins the process of action potential inactivation. Delayed sodium
    channel closure thus increases cell membrane excitability.

    Pyrethroids modify the gating characteristics of voltage-sensitive
    sodium channels in mammalian and invertebrate neuronal membranes
    (Eells et al, 1992; Narahashi, 1989) to delay their closure. They are
    dissolved in the lipid phase of the membrane (Narahashi, 1996) and
    bind to a receptor site on the alpha sub-unit of the sodium channel
    (Trainer et al, 1997). This binding is to a different site from local
    anaesthetics, batrachotoxin, grayanotoxin, and tetrodotoxin
    (Narahashi, 1996).

    The interaction of pyrethroids with sodium channels is highly
    stereospecific (Soderlund and Bloomquist, 1989), with the 1R and 1S
     cis isomers binding competitively to one site and the 1R and 1S
     trans isomers binding non-competitively to another. The 1S forms do
    not modify channel function but do block the effect of the 1R isomers
    (Ray, 1991).

    The prolonged opening of sodium channels by the neurotoxic isomers of
    pyrethroids produces a protracted sodium influx which is referred to
    as a sodium "tail current" (Miyamoto et al, 1995; Soderlund and
    Bloomquist, 1989; Vijverberg and van den Bercken, 1982). This lowers
    the threshold of sensory nerve fibres for the activation of further
    action potentials, leading to repetitive firing of sensory nerve
    endings (Vijverberg and van den Bercken, 1990) which may progress to
    hyperexcitation of the entire nervous system (Narahashi et al, 1995).
    At high pyrethroid concentrations, the sodium "tail current" may be
    sufficiently great to depolarize the nerve membrane completely,
    generating more open sodium channels (Eells et al, 1992) and
    eventually causing conduction block.

    Only low pyrethroid concentrations are necessary to modify sensory
    neurone function. For example, when tetramethrin was added to a
    preparation of rat cerebellar Purkinje neurons, only about 0.6-1 per
    cent of sodium channels needed to be modified to produce:

    (i)    Repetitive discharges in nerve fibres and nerve terminals;

    (ii)   An increase in discharges from sensory neurons (due to membrane
           depolarization); and

    (iii)  Severe disturbances of synaptic transmission (Narahashi, 1989;
           Narahashi et al, 1995; Song and Narahashi, 1996).

    These effects on sodium channels are common to all pyrethroids
    although specific effects of type II pyrethroids, such as
    esfenvalerate, have been clarified in experimental studies. These show
    that type II compounds:

    (i)    Cause depolarization of myelinated nerve membranes without
           repetitive discharges (Dorman and Beasley, 1991; Vijverberg and
           van den Bercken, 1982);

    (ii)   Are associated with a decrease in action potential amplitude
           (Dorman and Beasley, 1991);

    (iii)  Stabilize a variety of sodium channel states by reducing
           transition rates between them (Dorman and Beasley, 1991; Eells
           et al, 1992; Narahashi, 1989), causing a greatly prolonged open
           time (Vijverberg and van den Bercken, 1982), and producing
           stimulus-dependent nerve depolarization and block (Soderlund
           and Bloomquist, 1989);

    (iv)   May act post-synaptically by interacting with nicotinic
           acetylcholine and GABA receptors (Dorman and Beasley, 1991;
           Eells et al, 1992); and

    (v)    Produce effects on cultured neurons that are largely
           irreversible after washing cells with a pyrethroid-free
           solution (Song et al, 1996).

    In addition, type II pyrethroids, such as deltamethrin, enhance
    noradrenaline (norepinephrine) release (Clark and Brooks, 1989).

    In human investigations, maximal conduction velocity in sensory nerve
    fibres of the sural nerve showed some increase in subjects exposed to
    pyrethroids, but there were no abnormal neurological signs, and other
    electrophysiological studies were normal in the arms and legs (Le
    Quesne et al, 1980). He et al (1991) assessed nerve excitability using
    an electromyograph and pairs of stimuli at variable intervals. They
    showed a prolongation of the "supernormal period" in the median nerve
    in individuals who had been exposed to pyrethroids occupationally for
    three days. The "supernormal period" was even more prolonged two days
    after cessation of exposure. (Note: the "supernormal period" is the
    period for which the action potential induced by a second stimulus is
    greater than the action potential produced by an initial stimulus).

    Pyrethroids are some 2250 times more toxic to insects than mammals.
    This can be explained in terms of differences in their potency as
    neuronal toxins and differences in rates of detoxification between
    invertebrates and vertebrates (Narahashi, 1996; Narahashi et al, 1995;
    Song and Narahashi, 1996).

    The sensitivity of invertebrate neuronal sodium channels to
    pyrethroids is ten times greater than in mammals (Song and Narahashi,
    1996). Furthermore, invertebrates typically have body temperatures
    some 10°C lower than mammals and  in vitro studies show tetramethrin
    to be more potent at evoking repetitive neuronal discharges at lower
    temperatures (Song and Narahashi, 1996). In these experiments it was
    noted that the recovery of sodium channels from tetramethrin
    intoxication after washing was some five times faster in mammals than
    invertebrates. In addition pyrethroid hepatic metabolism
    (detoxification) is faster in mammals. Finally small insect size
    increases the likelihood of end-organ (neuronal) toxicity prior to
    detoxification (Song and Narahashi, 1996).

    TOXICOKINETICS

    In addition to the important differences between invertebrates and
    vertebrates outlined above, the low toxicity of pyrethroid
    insecticides in mammals is due to poor dermal absorption (the main
    route of exposure) and metabolism to non-toxic metabolites (Bradbury
    and Coats, 1989).

    Absorption

    Dermal

    Based on excretion studies involving other pyrethroids (Nassif, et al,
    1980; Chester et al, 1987; Eadsforth et al, 1988; IPCS, 1989c; Woollen
    et al, 1991; Woollen et al, 1992; Chester et al, 1992) dermal
    absorption of esfenvalerate is likely to be low (less than 1.5 per
    cent) though there are no human data specific to esfenvalerate.

    Oral

    Between 19 and 57 per cent of orally administered cypermethrin
    (another type II pyrethroid) was absorbed in human studies (Woollen et
    al, 1991; Woollen et al, 1992). There are no data specific to
    esfenvalerate.

    Metabolism

    Pyrethroids are hydrolyzed rapidly in the liver to their inactive acid
    and alcohol components (Hutson, 1979; Ray, 1991), probably by
    microsomal carboxylesterase (Hutson, 1979). Further degradation and
    hydroxylation of the alcohol at the 4' position then occurs, and
    oxidation produces a wide range of metabolites (Hutson, 1979; Leahey,
    1985).

    There is some stereospecificity in metabolism, with  trans-isomers
    being hydrolyzed more rapidly than the  cis-isomers, for which
    oxidation is the more important metabolic pathway (Soderlund and
    Casida, 1977). Although the alpha-cyano group reduces the
    susceptibility of the molecule to hydrolytic and oxidative metabolism
    (Hutson, 1979; Soderlund and Casida, 1977), the cyano group is
    converted to the corresponding aldehyde (with release of the cyanide
    ion), followed by oxidation to the carboxylic acid, sufficiently
    rapidly for efficient excretion by mammals (Leahey, 1985). Other
    differences in the chemical structure of pyrethroids have less effect
    on rates of metabolism (Soderlund and Casida, 1977).

    The pattern of metabolites varies between oral and dermal dosing in
    humans (Wilkes et al, 1993). For example, following dermal dosing with
    cypermethrin (another type II pyrethroid) the ratio of  trans/cis 
    cyclopropane acids excreted was approximately 1:1, compared to 2:1
    after oral administration. Such measurements might be useful in
    determining the route of exposure (Woollen, 1993; Woollen et al, 1991;
    Woollen et al, 1992).

    Animal studies have shown that pyrethroid hydrolysis is inhibited by
    dialkylphosphorylating agents such as organophosphorus insecticides
    (Abou-Donia et al, 1996; He et al, 1990; Hutson, 1979), and urinary
    excretion of unchanged pyrethroid was higher in sprayers using a
    methamidophos/ deltamethrin or methamidophos/fenvalerate mixture than
    from those using the pyrethroid alone (Zhang et al, 1991).

    Experiments with chickens (Abou-Donia et al, 1996) showed that
    pyrethroid (permethrin) toxicity was also enhanced by pyridostigmine
    bromide and by the insect repellent N,N-diethyl-m-toluamide (DEET).
    The authors hypothesized that competition for hepatic and plasma
    esterases by these compounds led to decreased pyrethroid breakdown and
    increased transport of the pyrethroid to neural tissues.

    Elimination

    Pyrethroids are excreted mainly as metabolites in urine but a
    proportion is excreted unchanged in faeces. An overview of human
    pyrethroid elimination data is included in the generic pyrethroid
    monograph though there are no human data specific to esfenvalerate.

    After occupational exposure, deltamethrin and fenvalerate metabolites
    were detectable in urine: deltamethrin was detectable for up to 12
    hours, whereas fenvalerate was still detectable after 24 hours (Zhang
    et al, 1991). In another study fenvalerate metabolites were still
    present in the urine of workers five days after packaging the
    pyrethroid (He et al, 1988).

    CLINICAL FEATURES: ACUTE EXPOSURE

    Occupationally, the main route of pyrethroid absorption is through the
    skin; inhalation is much less important (Adamis et al, 1985; Chen et
    al, 1991; Zhang et al, 1991). Inhalation is more likely when
    pyrethroids are used in confined spaces (Llewellyn et al, 1996). The
    use of protective clothing can reduce dermal exposure (Chester et al,
    1987). The physical formulation also affects exposure, with inhalation
    being more important for dust and powder formulations, and dermal
    exposure more important for liquids (Llewellyn et al, 1996).

    Dermal exposure

    This is the most common route of pyrethroid exposure. Adverse effects
    manifest primarily as peripheral neurotoxicity with reversible
    hyperactivity of sensory nerve fibres (paraesthesiae), though erythema
    and pruritus are also described (see below).

    Peripheral neurotoxicity

    Paraesthesiae have been reported frequently, particularly after the
    inappropriate handling of fenvalerate (which contains esfenvalerate)
    (Le Quesne et al, 1980; Knox and Tucker, 1982; Kolmodin-Hedman et al,
    1982; Tucker and Flannigan, 1983; Knox et al, 1984; Flannigan and
    Tucker, 1985a; He et al, 1988; He et al, 1989; Chen et al, 1991; Zhang

    et al, 1991; Advisory Committee on Pesticides, 1992; Kolmodin-Hedman
    et al, 1995). Paraesthesiae occur most commonly on the face (He et al,
    1991). It seems probable that paraesthesiae are related to the
    repetitive firing of sensory nerve endings in contaminated skin
    (Aldridge, 1990) and not to inflammation as there is little effect on
    neurogenic vasodilatation (Flannigan and Tucker, 1985b). The symptoms
    are exacerbated by sensory stimulation (heat, sun, scratching)
    (Aldridge, 1990), sweating or application of water and may prevent
    sleep (Tucker and Flannigan, 1983).

    In two studies, paraesthesiae were reportedly more severe after
    deltamethrin and flucythrinate exposure, less after cypermethrin and
    fenvalerate, and least after permethrin exposure (Aldridge, 1990;
    Flannigan and Tucker, 1985a). Ten of 52 workers handling fenvalerate
    (which contains esfenvalerate) developed paraesthesiae compared to
    none handling permethrin (Kolmodin-Hedman et al, 1982).

    Paraesthesiae generally start 30 minutes to two hours after exposure
    and peak after about six hours. Recovery is usually complete within 24
    hours (Aldridge, 1990; He et al, 1989; Knox and Tucker, 1982; Knox et
    al, 1984; Tucker and Flannigan, 1983).

    Dermal toxicity

    When used at recommended doses in the treatment of scabies and lice,
    pyrethroids only rarely produce adverse effects. Pruritus is the
    side-effect reported most frequently (Brandenburg et al, 1986;
    DiNapoli et al, 1988), although this may also be caused by the skin
    infestation being treated.

    Skin irritation during occupational pyrethroid exposure may occur in
    up to ten per cent of workers (Kolmodin-Hedman et al, 1982) and may be
    influenced by the ratio of stereoisomers used in the pyrethroid
    formulation. In addition to pruritus, erythema, burning and blisters
    have been reported (Brandenburg et al, 1986; Kalter et al, 1987; IPCS,
    1990b; Kolmodin-Hedman et al, 1995).

    There are no reports of dermal toxicity specific to esfenvalerate,
    though there are several involving fenvalerate, which contains
    esfenvalerate.

    Fenvalerate produced more symptoms than permethrin in planters
    handling treated conifer seedlings (Kolmodin-Hedman et al, 1982).
    Symptoms were more severe from permethrin formulations containing a
    higher proportion of the  trans isomer. The most common symptoms
    were: itching (ten per cent of 52 workers exposed to fenvalerate, two
    per cent of 45 workers exposed to permethrin with a  trans/cis ratio
    60/40, none of 42 workers exposed to permethrin with a  trans/cis 
    ratio 75/25); burning (ten per cent, none, 12 per cent respectively);
    blisters (eight per cent, none, ten per cent respectively) and a "dry
    feeling in the face" (12 per cent, after 75/25  trans/cis permethrin
    exposure only).

    Allergic reactions to pyrethroids are uncommon. Lisi (1992) assessed
    230 volunteers for irritant or delayed contact sensitivity reactions
    to a range of pyrethroids. Two (non-atopic) patients had irritant
    reactions to five per cent resmethrin and a further two had positive
    patch tests to one per cent fenvalerate. There were no positive
    reactions to allethrin, deltamethrin, fenothrin or permethrin.

    Ocular exposure

    Symptoms of mild eye irritation have been reported following
    occupational pyrethroid exposure (Kolmodin-Hedman et al, 1982; IPCS,
    1990d; Lessenger, 1992) though there are no reports specific to
    esfenvalerate.

    Inhalation

    Inhalational pyrethroid exposure typically is occupational and
    produces symptoms and signs of pulmonary tract irritation. The
    frequency and severity of symptoms may vary with the ratio of
    different stereoisomers in a formulation, being more prevalent with a
    higher proportion of the  trans isomer. Systemic effects may occur
    following more substantial exposure (He et al, 1989) and are described
    below. There are no reports of inhalational toxicity specific to
    esfenvalerate exposure, but several involving fenvalerate, which
    contains esfenvalerate.

    Nineteen per cent of 52 workers handling fenvalerate-treated seedlings
    and 13 per cent of 42 workers handling permethrin ( trans/cis 75/25)-
    treated seedlings but only two per cent of 45 workers handling
    permethrin ( trans/cis 60/40)-treated seedlings complained of
    increased nasal secretions during a six hour exposure (Kolmodin-Hedman
    et al, 1982).

    Cough and dyspnoea were reported in six and four per cent of 52
    workers exposed to fenvalerate and eight and two per cent of 42
    workers exposed to permethrin  trans/cis 75/25 but none of 45 workers
    exposed to permethrin  trans/cis 60/40 (Kolmodin-Hedman et al, 1982).

    Ingestion

    Pyrethroid ingestion typically gives rise to nausea, vomiting and
    abdominal pain within minutes. In one series (He et al, 1989)
    involving some 344 cases, vomiting was a prominent feature in 56.8 per
    cent. The Chinese literature includes a case of erosive gastritis with
    haematemesis following ingestion of 900 mL deltamethrin solution
    (concentration not given) (Poisindex, 1996). In another case,
    permethrin/pyrethrins accidentally sprayed directly into the mouth
    resulted in a burning sensation which commenced several hours after
    exposure, and only gradually improved over five months, with
    persistent disordered taste sensation (Grant, 1993).

    Substantial pyrethroid ingestion may give rise to neurological
    features and other systemic effects as discussed below.

    Systemic effects

    Systemic effects generally have occurred after inappropriate
    occupational handling of pyrethroids. This may involve using too
    concentrated solutions, prolonged exposure, spraying against the wind
    or using unprotected hands or mouth to unblock congested sprayers (He
    et al, 1989). Most reported cases have involved dermal, inhalational
    and sometimes also oral exposure to fenveralate, deltamethrin or
    cypermethrin with systemic features occurring between four and 48
    hours after spraying (He et al, 1989). Intentional ingestion may also
    produce systemic effects (He et al, 1989; Peter et al, 1996). Most
    patients recover over two to four days with only seven fatalities
    among 573 cases in one review (He et al, 1989). Four of the seven
    fatalities developed convulsions (two of these had ingested
    fenvalerate), one patient died from non-cardiogenic pulmonary oedema,
    one from "atropine intoxication" and one death followed exposure to a
    fenvalerate/ organophosphorus pesticide combination.

    A further death has been reported recently in a patient who became
    comatose within ten hours of 30 mL deltamethrin ingestion and died
    from aspiration pneumonia complicated by renal failure (Peter et al,
    1996).

    Gastrointestinal toxicity

    As discussed above gastrointestinal irritation is common following
    pyrethroid ingestion. Vomiting was a prominent symptom also in 16 per
    cent of  occupational cases (He et al, 1989) in whom ingestion was
    not suspected, but where exposure involved deltamethrin, cypermethrin
    or fenvalerate. In this review, which included occupational exposures,
    anorexia occurred in 45 per cent of 573 cases of acute pyrethroid
    poisoning (He et al, 1989).

    Neurotoxicity

    He et al (1989) described dizziness in 60.6 per cent, headache in 44.5
    per cent, fatigue in 26 per cent, increased salivation in 20 per cent
    and blurred vision in seven per cent of 573 cases of acute pyrethroid
    poisoning (229 occupational and 344 accidental exposures to
    fenvalerate, deltamethrin or cypermethrin).

    Limb muscle fasciculations, coma and convulsions may complicate severe
    acute pyrethroid poisoning, and have occurred as soon as 20 minutes
    after ingestion (He et al, 1989). "Convulsions" was the stated cause
    of death in four of seven fatalities among 573 cases of acute
    fenvalerate, deltamethrin or cypermethrin poisoning (He et al, 1989)
    but further details were not given.

    An electromyelogram (EMG) in one case of acute pyrethroid poisoning
    (not specified) showed repetitive muscle discharges without
    denervation potentials (He et al, 1989).

    Cardiovascular toxicity

    Palpitation was reported in 13.1 per cent of 573 cases of acute
    pyrethroid poisoning involving oral, inhalational and dermal exposure
    to fenvalerate, deltamethrin or cypermethrin (He et al, 1989). An
    electrocardiogram (ECG) showed ST and T wave changes in eight of 71
    patients. Other ECG abnormalities included sinus tachycardia,
    ventricular ectopics and (rarely) sinus bradycardia (He et al, 1989).
    All ECG changes resolved over 2-14 days.

    Pulmonary toxicity

    Chest tightness has been described following accidental or deliberate
    ingestion of fenvalerate, deltamethrin or cypermethrin (He et al,
    1989).

    Non-cardiogenic pulmonary oedema has been reported rarely following
    substantial fenvalerate ingestion, usually in association with severe
    neurological complications and may contribute to a fatal outcome (He
    et al, 1989).

    Musculoskeletal toxicity

    A case of acute polyarthralgia after skin exposure to flumethrin
    (another type II pyrethroid) has been reported recently (Box and Lee,
    1996).

    Haemotoxicity

    Among 235 cases of occupational or accidental acute pyrethroid
    poisoning in whom a full blood count was performed, 15 per cent showed
    a leucocytosis (He et al, 1989); this was probably a non-specific
    response.

    Nephrotoxicity

    Urinalysis among 124 patients with acute pyrethroid poisoning
    (involving oral, dermal and inhalational exposure to fenvalerate,
    deltamethrin or cypermethrin) showed three patients with haematuria
    (He et al, 1989).

    CLINICAL FEATURES: CHRONIC EXPOSURE

    Dermal exposure

    Few long-term adverse effects from pyrethroids have been reported
    (IPCS, 1990d; Chen et al, 1991, He, 1994). There is no confirmed
    evidence that repeated exposure to pyrethroids leads to permanent
    damage to sensory nerve endings (Vijverberg and van den Bercken,
    1990). There are no data specific to chronic esfenvalerate exposure.

    One hundred and ninety-nine workers employed in a pyrethroid packaging
    plant over four to five months on two occasions (winter and summer
    sessions) were observed for cutaneous effects (He et al, 1988). Work
    involved transferring pyrethroid emulsions (deltamethrin 2.5 per cent,
    fenvalerate 20 per cent and (to a lesser extent) cypermethrin 10 per
    cent) in xylene, from large containers to fill some 50,000 100 mL
    bottles daily. Gloves (and gauze masks) were used in winter only with
    no protective measures in summer. One hundred and forty of 199 (70 per
    cent) workers complained of "abnormal facial sensation" with burning,
    tingling, itching, tightness or numbness. Symptoms were more prevalent
    (p<0.05) in summer, occurring in 92 per cent of summer workers (n=87)
    compared to only 54 per cent of winter workers (n=112). Red miliary,
    mildly pruritic papules were found in 14 per cent of all workers,
    mainly on the face and chest and again were more prevalent (p<0.05)
    in summer. This was probably due to increased sweating during summer
    months (which tends to exacerbate cutaneous symptoms), but may also
    have been contributed to by the absence of protective measures during
    summer (He et al, 1988). The symptoms described in this study are
    identical to those following acute pyrethroid exposure and did not
    last more than 24 hours once subjects were away from the work
    environment. This suggests there are no true  chronic effects from
    repeated pyrethroid exposure.

    Inhalation

    The 199 workers described above were exposed to estimated fenvalerate
    and deltamethrin ambient air concentrations of 0.012-0.055 mg/m3 and
    0.005-0.012 mg/m3 respectively. Sixty-four (32 per cent) complained
    of sneezing and increased nasal secretions but these symptoms were
    only present at work, again suggesting no difference in effect between
    chronic or acute pyrethroid exposure. Systemic symptoms of dizziness,
    fatigue and nausea were mild and reported by only 14, nine and ten per
    cent of workers respectively.

    MANAGEMENT

    Dermal exposure

    Decontamination

    Clothes contaminated with esfenvalerate should be removed, and
    contaminated skin washed with soap and water (He, 1994).

    Specific measures

    Topical alpha tocopherol (vitamin E) to treat paraesthesiae
    As paraesthesiae usually resolve in 12-24 hours, specific treatment is
    not generally administered or required. However, the topical
    application of  dl-alpha tocopherol acetate (vitamin E) has been
    shown to reduce the severity of skin reactions to fenvalerate (IPCS,
    1990c; Tucker et al, 1984; Tucker et al, 1983), and other pyrethroids
    including flucythrinate, permethrin and cypermethrin (Flannigan and
    Tucker, 1985a). The reaction to cypermethrin was completely inhibited

    by vitamin E (Flannigan et al, 1985). Vitamin E appears to be useful
    both prophylactically and therapeutically (Flannigan and Tucker,
    1985a). In a controlled human volunteer study, a commercial vitamin E
    oil preparation produced 98 per cent inhibition of the cutaneous
    symptoms from fenvalerate when applied immediately (Flannigan et al,
    1985). At four hours the inhibition was only 50 per cent (Advisory
    Committee on Pesticides, 1992). The mechanism of the effect of topical
    vitamin E has not been clarified, although some  in vitro studies
    suggest vitamin E may block the pyrethroid-induced sodium "tail
    current" in neuronal membranes (Song and Narahashi, 1995).

    Vitamin E is not included in the British National Formulary but is
    available from health food or alternative medicine sources.

    Other agents to treat paraesthesiae

    Various other topical therapies have been tested for treatment of
    pyrethroid-induced paraesthesiae: in clinical trials mineral oil, corn
    oil and "A&D ointment" (Tucker et al, 1984; Tucker et al, 1983) were
    almost as effective as Vitamin E cream (but the oils may lead to
    defatting of skin). Butylated hydroxyanisole and an industrial barrier
    cream (Tucker et al, 1984) and topical indomethacin (Flannigan and
    Tucker, 1984), were of little therapeutic benefit and in two studies
    zinc oxide paste exacerbated paraesthesiae (Tucker et al, 1984; Tucker
    et al, 1983) .

    Ocular exposure

    Irrigate the affected eye with lukewarm water or 0.9 per cent saline
    for at least ten minutes. A topical anaesthetic may be required for
    pain relief or to overcome blepharospasm. Ensure no particles remain
    in the conjunctival recesses. Use fluorescein if corneal damage is
    suspected. If symptoms do not resolve following decontamination or if
    a significant abnormality is detected during examination, seek an
    ophthalmological opinion.

    Inhalation

    Removal from exposure is the priority. Mild symptoms of rhinitis
    respond to oral antihistamines. Other symptomatic and supportive
    measures should be dictated by the patient's condition.

    Ingestion

    Gut decontamination

    Gastric lavage should be avoided since solvents present in some
    esfenvalerate formulations may increase the risk of aspiration
    pneumonia.

    Systemic toxicity

    Most patients exposed to pyrethroids require only simple supportive
    care. Systemic toxicity is rare but in such patients the presence of
    excess salivation, muscle fasciculations and pulmonary oedema may
    present diagnostic difficulty since similar features are typical also
    of severe organophosphorus pesticide poisoning. Measurement of the red
    cell cholinesterase activity (which is reduced in acute
    organophosphorus poisoning but not in pyrethroid intoxication) allows
    clarification but may not be available rapidly.

    Isolated brief convulsions do not require treatment but intravenous
    diazepam 5-10 mg should be given if seizures are prolonged. Rarely it
    may be necessary to give intravenous phenytoin, or to paralyze and
    ventilate the patient. Diazepam is useful also in the treatment of
    muscle fasciculations. The role of atropine is discussed below.

    Several experimental studies have investigated the role of
    pharmaceuticals in the management of the neurological complications of
    severe pyrethroid poisoning. However, these should be interpreted with
    caution, not only because they usually have involved high-dose
    parenteral pyrethroid administration, but also because there is
    considerable interspecies variation with regard to therapeutic
    efficacy (Casida et al, 1983; Vijverberg and van den Bercken, 1990).

    Atropine for hypersalivation and pulmonary oedema

    In experimental studies atropine sulphate (25 mg/kg subcutaneously)
    reduced hypersalivation produced by oral fenvalerate or cypermethrin
    (each at a dose exceeding the LD50), but did not increase survival
    (Hiromori et al, 1986).

    Intravenous atropine (0.6-1.2 mg in an adult) may be useful to control
    excess salivation but care should be taken to avoid excess
    administration. In a review of pyrethroid poisoning cases reported
    from China (He et al, 1989), 189 of 573 patients were treated with
    atropine which led to an improvement in salivation and pulmonary
    oedema in a few severe cases, but eight patients developed atropine
    intoxication following intravenous administration of 12-75 mg. One
    patient, probably misdiagnosed as having acute organophosphorus
    insecticide poisoning, died of atropine intoxication after a total
    dose of 510 mg, and one patient acutely intoxicated with a
    fenvalerate/dimethoate mixture could not be revived despite a total
    atropine dose of 170 mg.

    Atropine and ethylcarbamate

    In a French study a combination of intravenous atropine 3 mg/kg and
    ethylcarbamate 1000 mg/kg effectively protected rodents against the
    lethal effects of intravenous deltamethrin, increasing the LD50 by a
    factor of 3.48 (Leclercq et al, 1986).

    Diazepam and phenobarbital for convulsions

    In mice (n=10) pre-treatment with intraperitoneal diazepam (1 mg/kg),
    but not phenobarbital (10-30 mg/kg), significantly increased the time
    to onset of convulsions caused by the intracerebroventricular
    administration of deltamethrin (p<0.005) and fenvalerate (p<0.05)
    (Gammon et al, 1982). Under the same conditions diazepam was not
    effective in preventing permethrin- or allethrin-induced seizures.

    Propranolol and procainamide for tremor

    Pre-treatment with intravenous propranolol or procainamide (each 15
    µmol/kg) reduced the severity of tremor or writhing induced in rats by
    the intravenous administration of deltamethrin (10 µmol/kg) (Bradbury
    et al, 1983).

    Ivermectin and pentobarbital for choreoathetosis

    In rodents administered 2 mg/kg intravenous deltamethrin,
    pre-treatment with 4 mg/kg intravenous ivermectin reduced
    choreoathetosis from 3.9 to 3.2 (as graded on a scale of 1-4) 
    (p = 0.023), and reduced salivation by 72 per cent. Pentobarbital (15
    mg/kg i.p.) reduced choreoathetosis produced by 1.5 mg/kg intravenous
    deltamethrin from 3.0 to 1.3 (p = 0.004). An equi-sedative dose of
    phenobarbital produced a non-significant fall to 2.4 (p = 0.11)
    (Forshaw and Ray, 1997).

    Mephenesin and methocarbamol

    The skeletal muscle relaxant mephenesin 22 µmol/kg prevented all motor
    symptoms induced in rats by the intravenous administration of
    deltamethrin (10 µmol/kg) (n=4-20 in different treatment groups)
    (Bradbury et al, 1983).

    Mephenesin has a short half-life in vivo, but intraperitoneal
    methocarbamol (a mephenesin derivative) (400 mg/kg intraperitoneally
    followed by 200 mg/kg whenever tremor was observed) significantly
    (p<0.01) reduced mortality in rats administered more than the oral
    LD50 of fenvalerate, fenpropathrin, cypermethrin or permethrin (n=10
    in each treatment group) (Hiromori et al, 1986).

    There are insufficient data to advocate a clinical role for
    methocarbamol in systemic pyrethroid toxicity.

    Sodium-channel blockers (local anaesthetics)

     In vitro studies suggest local anaesthetics may be useful as
    antagonists of the effect of deltamethrin on sodium channels
    (Oortgiesen et al, 1990). The relevance to human poisoning is not
    known.

    MEDICAL SURVEILLANCE

    Avoiding dermal and inhalational exposure via adequate self-protection
    and sensible use is the most important requirement to reduce adverse
    effects from occupational use of esfenvalerate.

    OCCUPATIONAL DATA

    Maximum exposure limit

    International Standards Organization (ISO) limits for natural
    pyrethrins are: long-term exposure limit (8 hour TWA reference period)
    5 mg/m3; short-term exposure limit (15 min reference period) 10
    mg/m3 (Health and Safety Executive, 1995).

    OTHER TOXICOLOGICAL DATA

    Endocrine toxicity

     In vitro studies show that several pyrethroids interact
    competitively with human skin fibroblast androgen receptors and with
    sex hormone binding globulin (Eil and Nisula, 1990). A possible anti-
    androgenic effect of pyrethroids in humans was suggested following an
    outbreak of gynaecomastia in refugees exposed to fenothrin, but there
    was insufficient evidence to confirm this (Eil and Nisula, 1990).

    Animal studies evaluating other endocrine effects of pyrethroids have
    produced conflicting results (Akhtar et al, 1996; Kaul et al, 1996).

    Immunotoxicity

    In oral dosing studies in rodents, several pyrethroids suppressed the
    cellular immune response (Blaylock et al, 1995; Tulinská et al, 1995)
    or produced thymus atrophy (Madsen et al, 1996). The significance of
    these immunological studies to man is not known.

    Carcinogenicity

    The International Agency for Research on cancer has concluded there is
    inadequate evidence to assess the carcinogenicity of fenvalerate,
    which contains esfenvalerate (IARC, 1991).

    Reprotoxicity

    Animal studies show that esfenvalerate crosses the rat placenta
    poorly, with less than 0.07 per cent of the maternal dose reaching the
    conceptus (Reprotox, 1997).  In vivo oral administration of 25, 50 or
    100 mg/kg bodyweight/day fenvalerate had no effects on fertility
    (DOSE, 1997). There are no human data regarding the reprotoxic effects
    of esfenvalerate.

    Genotoxicity

    Data regarding the potential genotoxicity of pyrethroids provide
    conflicting results (Puig et al, 1989; Barrueco et al, 1992; Herrera
    et al, 1992; Dolara et al, 1992; Barrueco et al, 1994; Surrallés et
    al, 1995), though toxicity reviews of  in vitro and  in vivo data
    for most compounds, including esfenvalerate (Advisory Committee on
    Pesticides, 1992), conclude there is insufficient evidence for them to
    be considered genotoxic or mutagenic.

    Tests with fenvalerate (which contains esfenvalerate) showed no
    genotoxicity in  Salmonella typhimurium TA97, TA98 TA100, TA104,
    TA1535, TA1537, TA1538 with and without metabolic activation. For
     Drosophilia melanogaster sex-linked recessive lethal assay,
    sex-chromosome loss and nondisjunction assays were negative (DOSE,
    1997).

    Fenvalerate caused sister chromatid exchanges and chomosomal
    aberrations in mouse bone marrow and induced polychromatic
    erythrocytes, micronuclei and sperm abnormalities in mice  in vivo 
    (DOSE, 1997).

     In vivo oral fenvalerate at 20, 50 or 100 mg/kg/day gave negative
    results in a dominant lethal assay (DOSE, 1997).

    Fish toxicity

    Esfenvalerate is toxic to fish. It is more toxic at cooler
    temperatures, and thus more toxic to cold than warm water fish, but
    the toxicity of pyrethroids is little affected by pH or water hardness
    (Mauck et al, 1976).

    LC50 (96 hr) for fathead minnow is 690 ng/L esfenvalerate (DOSE,
    1997).

    EC Directive on Drinking Water Quality 80/778/EEC

    Maximum admissible concentration (any pesticide) 0.1 µg/L (EC
    Directive, 1980).

    AUTHORS

    SA Cage MSc M Inst Inf Sci
    SM Bradberry BSc MB MRCP
    S Meacham BSc
    JA Vale MD FRCP FRCPE FRCPG FFOM

    National Poisons Information Service (Birmingham Centre),
    West Midlands Poisons Unit,
    City Hospital NHS Trust,
    Dudley Road,
    Birmingham
    B18 7QH
    UK

    This monograph was produced by the staff of the Birmingham Centre of
    the National Poisons Information Service in the United Kingdom. The
    work was commissioned and funded by the UK Departments of Health, and
    was designed as a source of detailed information for use by poisons
    information centres.

    Date of last revision
    28/1/98

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    See Also:
       Toxicological Abbreviations
       Esfenvalerate (ICSC)
       Esfenvalerate (JMPR Evaluations 2002 Part II Toxicological)