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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 92





    RESMETHRINS -- RESMETHRIN BIORESMETHRIN CISRESMETHRIN
                        
                        






    This report contains the collective views of an international
    group of experts and does not necessarily represent the
    decisions or the stated policy of the United Nations Environment
    Programme, the International Labour Organisation, or the World
    Health Organization

    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation,
    and the World Health Organization

    World Health Organization Geneva, 1989

        The International Programme on Chemical Safety (IPCS) is a joint
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    of the biological action of chemicals.

    ISBN 92 4 154292 6

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    ENVIRONMENTAL HEALTH CRITERIA FOR RESMETHRINS

    INTRODUCTION

    1.    SUMMARY
          1.1    Identity, physical and chemical properties, analytical
                 methods
          1.2    Production and uses
          1.3    Residues in food
          1.4    Environmental fate
          1.5    Kinetics and metabolism
          1.6    Effects on experimental animals and in vitro test
                 systems
          1.7    Effects on the environment

    2.    IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
          2.1    Identity
          2.2    Physical and chemical properties
          2.3    Analytical methods

    3.    SOURCES OF ENVIRONMENTAL POLLUTION AND ENVIRONMENTAL LEVELS
          3.1    Industrial production
          3.2    Use patterns
          3.3    Residues in food
          3.4    Fate and residues in domestic animals

    4.    ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
          4.1    Photodegradation
          4.2    Degradation in soil
          4.3    Degradation on plants

    5.    KINETICS AND METABOLISM
          5.1    Metabolism in mammals
          5.2    Enzymatic systems for biotransformation

    6.    EFFECTS ON THE ENVIRONMENT
          6.1    Aquatic organisms
          6.2    Terrestrial organisms

    7.    EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
          7.1    Acute toxicity
          7.2    Short-term exposure
                 7.2.1    Oral administration
                 7.2.2    Inhalation
                 7.2.3    Dermal application
          7.3    Primary irritation and sensitization
          7.4    Long-term exposure and carcinogenicity

          7.5    Mutagenicity
          7.6    Reproductive effects, embryotoxicity, and teratogenicity
          7.7    Immunotoxicity
          7.8    Neurotoxicity
          7.9    Mechanism of toxicity (mode of action)
          7.10   Potentiation

    8.    EFFECTS ON MAN

    9.    EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
          9.1    Human health risks
          9.2    Effects on the environment

    10.   CONCLUSIONS

    11.   RECOMMENDATIONS

    12.   PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    APPENDIX

    

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR ALLETHRINS AND
    RESMETHRINS

    Members

    Dr L.A. Albert-Palacios, National Institute of Biological Resources
        Research, Xalapa, Veracruz, Mexicoa

    Dr V. Benes, Institute of Hygiene and Epidemiology, Prague,
        Czechoslovakia

    Dr A.H. El-Sabae, Faculty of Agriculture, Alexandria University,
        Alexandria, Egypt

    Dr Y. Hayashi, National Institute of Hygienic Sciences, Tokyo, Japan

    Dr S. Johnson, US Environmental Protection Agency, Hazard Evaluation
        Division, Washington DC, USA

    Dr S.K. Kashyap, National Institute of Occupational Health, Ahmedabad,
        India (Vice-Chairman)

    Dr J.H. Koeman, Agricultural University, Wageningen, Netherlandsa

    Dr Yu. I. Kundiev, Research Institute of Labour, Hygiene and
        Occupational Diseases, Kiev, USSR (Chairman)

    Dr J.P. Leahey, ICI Agrochemicals Division, Jealotts Hill Research
        Station, Bracknell, Berkshire, United Kingdom (Rapporteur)

    Dr M. Matsuo, Sumitomo Chemical Co. Ltd, Takarazuka Research Center,
        Takarazuka, Hyogo, Japan

    Dr G.U. Oleru, College of Medicine, University of Lagos, Lagos,
        Nigeria

    Observers

    Mr J.-M. Pochon, International Group of National Associations of
        Agrochemical Manufacturers, Brussels, Belgium

    Dr L.M. Sasynovitch, Research Institute of Hygiene and Toxicology of
        Pesticides, Polymers and Plastics, Kiev, USSR

                 

    a  Invited but unable to attend.

    Secretariat

    Dr Z.P. Grigorevskaja, Centre for International Projects, Moscow, USSR

    Dr K.W. Jager, International Programme on Chemical Safety, World
        Health Organization, Geneva, Switzerland (Secretary)

    Dr J. Sekizawa, National Institute of Hygienic Sciences, Tokyo, Japan
        (Rapporteur)

    NOTE TO READERS OF THE CRITERIA DOCUMENTS

        Every effort has been made to present information in the criteria
    documents as accurately as possible without unduly delaying their
    publication. In the interest of all users of the environmental health
    criteria documents, readers are kindly requested to communicate any
    errors that may have occurred to the Manager of the International
    Programme on Chemical Safety, World Health Organization, Geneva,
    Switzerland, in order that they may be included in corrigenda, which
    will appear in subsequent volumes.

        A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Palais des
    Nations, 1211 Geneva 10, Switzerland (Telephone no. 7988400 -
    7985850).

    ENVIRONMENTAL HEALTH CRITERIA FOR RESMETHRINS

        A WHO Task Group on Environmental Health Criteria for Allethrins
    and Resmethrins met in Moscow from 16 to 20 November 1987. The meeting
    was convened with the financial assistance of the United Nations
    Environment Programme (UNEP) and was hosted by the Centre for
    International Projects of the USSR State Committee on Science and
    Technology. On behalf of the USSR Commission for UNEP (UNEPCOM), Dr
    M.I. Gunar opened the Meeting and welcomed the participants. Dr K.W.
    Jager welcomed the participants on behalf of the Heads of the three
    IPCS cooperating organizations (UNEP/ILO/WHO). The group reviewed and
    revised the draft Environmental Health Criteria and Health and Safety
    Guides and made an evaluation of the risks for human health and the
    environment from exposure to allethrins and resmethrins.

        The first drafts of the documents were prepared by Dr J. Miyamoto
    and Dr M. Matsuo of Sumitomo Chemical Co. Ltd, with the assistance of
    the staff of the National Institute of Hygienic Sciences, Tokyo,
    Japan. Dr I. Yamamoto of the Tokyo University of Agriculture and Dr M.
    Eto of Kyushu University, Japan, assisted in the finalization of the
    draft.

        The second draft was prepared by Dr J. Sekizawa of the National
    Institute of Hygienic Sciences, Tokyo, incorporating comments received
    following the circulation of the first draft to the IPCS contact
    points for Environmental Health Criteria documents.

        The help of the Sumitomo Chemical Company Ltd, Japan and Roussel
    Uclaf, France in making their toxicological proprietary information on
    allethrins and resmethrins available to the IPCS and the Task Group is
    gratefully acknowledged. This enabled the Task Group to make its
    evaluation on the basis of more complete data.

        The efforts of all who helped in the preparation and finalization
    of the documents are gratefully acknowledged.

        Partial financial support for the publication of this criteria
    document was kindly provided by the United States Department of Health
    and Human Services, through a contract from the National Institute of
    Environmental Health Sciences, Research Triangle Park, North Carolina,
    USA -- a WHO collaborating Centre for Environmental Health Effects.
    The United Nations Environment Programme (UNEP) generously supported
    the costs of printing.

    NOTE: The proprietary information contained in this document cannot
          replace documentation for registration purposes, because the
          latter has to be closely linked to the source, the
          manufacturing route, and the purity/impurities of the
          substance to be registered. The data should be used in
          accordance with paragraphs 82-84 and recommendations paragraph
          90 of the Second FAO Government Consultation (1982).

    INTRODUCTION

    SYNTHETIC PYRETHROIDS -- A PROFILE

    1.  During investigations to modify the chemical structures of natural
        pyrethrins, a certain number of synthetic pyrethroids were
        produced with improved physical and chemical properties and
        greater biological activity. Several of the earlier synthetic
        pyrethroids were successfully commercialized, mainly for the
        control of household insects. Other more recent pyrethroids have
        been introduced as agricultural insecticides because of their
        excellent activity against a wide range of insect pests and their
        non-persistence in the environment.

    2.  The pyrethroids constitute another group of insecticides in
        addition to organochlorine, organophosphorus, carbamate, and other
        compounds. Pyrethroids commercially available to date include
        allethrin, resmethrin, d-phenothrin, and tetramethrin (for insects
        of public health importance), and cypermethrin, deltamethrin,
        fenvalerate, and permethrin (mainly for agricultural insects).
        Other pyrethroids are also available including furamethrin,
        kadethrin, and tellallethrin (usually for household insects),
        fenpropathrin, tralomethrin, cyhalothrin, lambda-cyhalothrin,
        tefluthrin, cyfluthrin, flucythrinate, fluvalinate, and biphenate
        (for agricultural insects).

    3.  Toxicological evaluations of several synthetic pyrethroids have
        been performed by the FAO/WHO Joint Meeting on Pesticide Residues
        (JMPR). The acceptable daily intake (ADI) or temporary ADI has
        been estimated by the JMPR for cypermethrin, deltamethrin,
        fenvalerate, permethrin, phenothrin, cyfluthrin, cyhalothrin, and
        flucythrinate.

    4.  Chemically, synthetic pyrethroids are esters of specific acids
        (e.g., chrysanthemic acid, halo-substituted chrysanthemic acid,
        2-(4-chlorophenyl)-3-methylbutyric acid) and alcohols (e.g.,
        allethrolone, 3-phenoxybenzyl alcohol). For certain pyrethroids,
        the asymmetric centre(s) exist in the acid and/or alcohol moiety,
        and the commercial products sometimes consist of a mixture of both
        optical (1R/1S or d/1) and geometric (cis/trans)-isomers.
        However, most of the insecticidal activity of such products may
        reside in only one or two isomers. Some of the products (e.g.,
        d-phenothrin, deltamethrin) consist only of such active isomer(s).

    5.  Synthetic pyrethroids are neuropoisons acting on the axons in the
        peripheral and central nervous systems by interacting with sodium
        channels in mammals and/or insects. A single dose produces toxic
        signs in mammals, such as tremors, hyperexcitability, salivation,
        choreoathetosis, and paralysis. The signs disappear fairly
        rapidly, and the animals recover, generally within a week. At

        near-lethal dose levels, synthetic pyrethroids cause transient
        changes in the nervous system, such as axonal swelling and/or
        breaks and myelin degeneration in sciatic nerves. They are not
        considered to cause delayed neurotoxicity of the kind induced by
        some organophosphorus compounds. The mechanism of toxicity of
        synthetic pyrethroids and their classification into two types are
        discussed in the Appendix.

    6.  Some pyrethroids (e.g., deltamethrin, fenvalerate, flucythrinate,
        and cypermethrin) may cause a transient itching and/or burning
        sensation in exposed human skin.

    7.  Synthetic pyrethroids are generally metabolized in mammals through
        ester hydrolysis, oxidation, and conjugation, and there is no
        tendency to accumulate in tissues. In the environment, synthetic
        pyrethroids are fairly rapidly degraded in soil and in plants.
        Ester hydrolysis and oxidation at various sites on the molecule
        are the major degradation processes. The pyrethroids are strongly
        adsorbed on soil and sediments, and hardly eluted with water.
        There is little tendency for bioaccumulation in organisms.

    8.  Because of low application rates and rapid degradation in the
        environment, residues in food are generally low.

    9.  Synthetic pyrethroids have been shown to be toxic for fish,
        aquatic arthropods, and honey-bees in laboratory tests. But, in
        practical usage, no serious adverse effects have been noticed,
        because of the low rates of application and lack of persistence in
        the environment. The toxicity of synthetic pyrethroids in birds
        and domestic animals is low.

    10. In addition to the evaluation documents of FAO/WHO, there are
        several reviews and books on the chemistry, metabolism, mammalian
        toxicity, environmental effects, etc. of synthetic pyrethroids,
        including those by Elliot (1977), Miyamoto (1981), Miyamoto &
        Kearney (1983), and Leahey (1985).

    1.  SUMMARY

    1.1  Identity, Physical and Chemical Properties, Analytical Methods

        Resmethrin was first produced in 1967 and marketed in 1969.
    Chemically, it is an ester of chrysanthemic acid (CA),
    2,2-dimethyl-3-(2,2-dimethylvinyl) cyclopropanecarboxylic acid and
    5-benzyl-3-furylmethyl alcohol (BFA). It is a racemic mixture of 4
    optical isomers: [1R, trans]-, [1R, cis]-, [1S, trans]- and
    [1S, cis]-isomer. The composition ratio in technical products is
    roughly 4:1:4:1. The [1R, trans]-isomer is called bioresmethrin and
    the [1R, cis]-isomer is cismethrin. Among the isomers, the
    [1R, trans]-isomer has the highest insecticidal activity followed by
    the [1R, cis]-isomer.

        Technical grade resmethrin is a colourless waxy solid with a
    melting point of 43-48C and a boiling point of 180C at 0.01 mmHg.
    The specific gravity is 1.050 at 20C. The vapour pressure is
    1.1  10-8 mmHg at 30C. It is insoluble in water (< 1 mg/litre at
    30C), but soluble in organic solvents, such as hexane, kerosene, and
    xylene. It is not stable in air, light, or in alkaline media. The
    n-octanol/water partition coefficient is 2.9  103 for resmethrin
    and 6.2  104 for bioresmethrin.

        Analysis of environmental samples and determination of residues
    can be carried out by a high-performance liquid chromatograph equipped
    with a UV-detector (206 nm) detecting levels as low as 0.05 mg/kg. A
    gas chromatograph with flame ionization detector is used for the
    analysis of technical products.

        Vapourized resmethrin can be efficiently recovered for analysis by
    using Porpak C18 or Chromosorb 102 sorbents as the trap.

    1.2  Production and Uses

        It is estimated that about 20-30 tonnes of resmethrin are produced
    and used per year. Resmethrin is used mainly for the control of
    household and public health insects. It is formulated as an aerosol,
    oil formulation, or emulsifiable concentrate. Formulations are also
    prepared containing other insecticides and/or synergists.

        Bioresmethrin is used on stored grain and for the control of white
    fly in greenhouses, as well as for household and public health insect
    control.

    1.3  Residues in Food

        Resmethrin on treated crops (tomato, lettuce) degraded so that
    residues were negligible after 3 days on tomato and < 0.1 mg/kg after
    7 days on lettuce. Bioresmethrin on stored grain was fairly stable, a
    residue of 4 mg/kg declining to 1.1 mg/kg over a period of 6 months.
    White bread made from treated grain does not contain any residues of
    resmethrin, but residues may occur in wholemeal bread.

        When the cis- and trans-isomers of radiolabelled resmethrin
    were given orally to White Leghorn laying hens at a dose level of
    10 mg/kg, more than 90% of the radioactivity was eliminated in the
    excreta 24 h after treatment. Residues in the egg white and yolk, and
    in the body tissues were low, the highest levels occurring in the
    liver and kidney.

        Lactating Jersey cows treated orally with radiolabelled resmethrin
    at 10 mg/kg body weight rapidly absorbed, metabolized, and excreted
    the chemical. The cis-isomer was eliminated primarily in the faeces
    and the trans-isomer was eliminated mainly in the urine. Tissue
    residues 48 h after treatment were low (< 1 g/g) except in the liver
    and kidney, and only very low levels of radioactivity were secreted in
    the milk.

    1.4  Environmental Fate

        Resmethrin is rapidly photodegraded on silica gel plates, as a
    thin film on glass plates, and in aqueous solution. In sunlight,
    aqueous solutions have a half-life of 47 min (pure water) and 20 min
    (sea water). A range of photoproducts is formed from ester cleavage
    and oxidation reactions.

        Resmethrin is also very rapidly degraded in soil, 2% of the
    applied parent compound remaining after 16 days. Complete
    mineralization to carbon dioxide is a very important degradation
    process (38% after 16 days).

        Rapid degradation occurs on plants (tomato, lettuce, and wheat).
    After 5 days, no resmethrin is detected on plants and a very complex
    mixture of, at least, 31 break-down products is formed. The alcohol
    formed by ester cleavage, benzaldehyde, phenylacetic acid, benzoic
    acid, and benzyl alcohol were identified as break-down products, each
    being present at low levels (3% of the total residue).

    1.5  Kinetics and Metabolism

        When rats were administered 14C-(alcohol labelled)-[1RS
    trans]-resmethrin orally at the rate of 500 mg/kg body weight, the
    radiocarbon was eliminated slowly in the urine (36%) and faeces (64%)
    within 3 weeks. More than 50% of the 14C dose was secreted in the
    bile in 72 h and enterohepatically circulated. The major metabolic
    reactions were ester cleavage, oxidation at the trans-methyl of the
    isobutenyl group to alcohol, aldehyde, and carboxylic acid and at the
    4'-,alpha-, and 4-positions of 5-benzyl-3-furylmethyl alcohol (BFA),
    and conjugation.

        Rats fed 14C-(acid- or alcohol-labelled) bioresmethrin or
    cismethrin at the rate of 1 mg/kg eliminated 5-benzyl-3-
    furancarboxylic acid (BFCA), 4'-hydroxy-BFCA, and alpha-hydroxy-BFCA
    together with 2-trans- hydroxymethyl- and 2-carboxyl derivatives of
    chrysanthemic acid (CA). Cis/trans-isomerized CA derivatives were
    also found. The residual metabolites in the body were derived from the
    alcohol moiety of bioresmethrin.

    1.6  Effects on Experimental Animals and In Vitro Test Systems

        Resmethrin and bioresmethrin were weakly toxic for animals when
    examined by various routes of exposure (the oral LD50 of resmethrin
    ranged from 690 mg/kg for the mouse to >5 000 mg/kg for the rat). The
    oral LD50s for bioresmethrin were 225 mg/kg for the rabbit,
    480-10 000 mg/kg for the mouse, and 8800 mg/kg for the rat. Cismethrin
    was moderately toxic for the mouse (oral LD50: 152-160 mg/kg).

        Signs of poisoning were tremors, hyperactivity, and convulsion
    (T-syndrome). Resmethrin belongs to the Type I pyrethroid group.

        The acute toxicity (oral and intraperitoneal) of the metabolites
    (e.g., CA, BFA, BFCA) was examined in mice and rats; CA and BFA were
    more toxic than the parent compound in mice though toxic signs were
    different. The acute toxicity (oral LD50) of the metabolites in rats
    ranged from 997 mg/kg to > 4640 mg/kg, which is within the same range
    of acute toxicity as the parent compound. While technical grade
    resmethrin was found to be a slight irritant to the skin, it did not
    cause sensitization and photochemical irritation in guinea-pigs and
    New Zealand White rabbits.

        Resmethrin was applied twice weekly, for 3 weeks, to the skin of
    New Zealand White rabbits by fixing a piece of cotton cloth treated
    with resmethrin (0.247 mg/cm2) over skin that had been pre-treated
    with liquid, imitating sweat, or with resmethrin (10 g), or had not
    been pre-treated. No significant changes were noted in body weight and
    organ weight ratios on day 24 or in the clinical chemistry in any of
    the groups up to day 24. No significant compound-related dermal
    effects were observed.

        When Sprague-Dawley or Long-Evans rats were fed resmethrin in the
    diet at levels of up to 6000 mg/kg for 14 days, mortality was observed
    at the highest dose level, and tremor and reduced body weight and food
    consumption were noted at levels of 1500 mg/kg or more. The maximum
    no-observed-adverse-effect dietary level was 188 mg/kg for Long-Evans
    rats.

        When Long-Evans rats were given resmethrin in the diet at levels
    of up to 750 mg/kg (male) and up to 2400 mg/kg (female) for 90 days,
    all females died at 2400 mg/kg and tremor and reduced body weight were
    noted at 750 mg/kg. The maximum no-observed-adverse-effect dietary
    level was 75 mg/kg for both female and male rats.

        When rats were fed bioresmethrin in the diet at levels of up to
    8000 mg/kg for 91 days, body weight was reduced at the highest level,
    and was accompanied by changes in blood chemistry indicating liver
    dysfunction. The no-observed-adverse-effect level in this study was
    400 mg/kg diet, which corresponds to 32.8 mg/kg body weight and
    36.1 mg/kg body weight for males and females, respectively.

        Dogs (males and females) were administered bioresmethrin at levels
    of up to 500 mg/kg body weight for 90 days. A no-observed-adverse-
    effect level was observed of 80 mg/kg body weight.

        Technical resmethrin was administered via inhalation to Wistar
    rats for 6 h/day on 5 days of each week, for a period of 90 days, at
    nominal exposure levels of 0.1, 0.3, or 1.0 g/m3. The no-observed-
    adverse-effect level was at 0.1 g/m3.

        Rats and rabbits inhaled aerosolized resmethrin formulations for
    5 h/day on 5 consecutive days at levels of 2.9-3.2 mg active
    ingredient/litre of air. Though clinical signs including rapid
    breathing and nasal discharge were observed, there were no
    compound-related effects on body weight and histopathological
    findings, immediately and 7 and 14 days after exposure. No indication
    of toxic effects other than irritation were observed in any of the
    tests.

        No oncogenic effects were seen when CD-1 mice were fed 0, 250,
    500, or 1000 mg resmethrin/kg basal diet for 85 weeks.

        Wistar rats fed resmethrin at levels of 0, 500, 2500, or
    5000 mg/kg basal diet for 112 weeks did not show any signs of
    oncogenicity and a no-observed-adverse-effect level of 500 mg/kg was
    established for chronic toxicity. When resmethrin was administered to
    Sprague-Dawley rats at dietary levels of 500, 1500, or 5000 mg/kg for
    24 weeks, tremors, decreased body weight, and increased liver and
    kidney weights were observed at 5000 mg/kg. A no-observed-adverse-
    effect level of 1500 mg/kg was established.

        Dogs fed resmethrin for 6 months showed increased liver weights at
    30 mg/kg body weight per day, but did not show any adverse effects at
    10 mg/kg body weight per day.

        Resmethrin, bioresmethrin, and cismethrin were tested for
    mutagenicity and/or chromosomal effects in several short-term test
    systems, such as Escherichia coli and Salmonella reverse mutation
    tests, primary DNA damage tests in eukaryotes and prokaryotes, and
    chromosomal effects in Chinese hamster cells or mouse bone marrow
    cells. Negative results were obtained with all tests.

        In a teratogenicity study, pregnant Long-Evans rats were
    administered resmethrin in the diet at levels of 188 or 1500 mg/kg,
    from day 6 to day 16 of gestation. Though mortality, tremor, and
    decreased food and water consumption were noted in the dams at
    1500 mg/kg, gross abnormalities of the fetal skeleton and soft tissues
    were not observed in the treated animals.

        Resmethrin was administered orally (by gavage in corn oil) at
    levels of 0, 20, 40, or 80 mg/kg body weight to female Sprague-Dawley
    rats during the period of major organogenesis. Resmethrin was not
    teratogenic at levels up to and including 80 mg/kg. The
    no-observed-adverse-effect level for fetotoxicity was 40 mg/kg.

        ICR mice were given (+),-[trans, cis]-resmethrin orally at
    levels up to 100 mg/kg body weight. Sprague-Dawley rats received
    levels up to 50 mg/kg body weight during the period of major
    organogenesis. Embryo- and fetotoxicity and teratogenicity were not
    observed in this study.

        In another study, resmethrin was administered to New Zealand White
    rabbits by oral intubation at dose levels of 0, 10, 30, or 100 mg/kg
    body weight on day 6 to day 18 of gestation. Resmethrin was not
    teratogenic at levels up to and including the 100 mg/kg dose.

        In a 3-generation reproduction study, Sprague-Dawley rats were fed
    resmethrin in the basal diet at 0, 500, 800, or 1250 mg/kg. A decrease
    in pup weight and a slight increase in the number of pups cast dead
    were observed at the 500 mg/kg.

    1.7  Effects on the Environment

        In laboratory studies, resmethrin is highly toxic for fish with
    96-h LC50 values of 0.3-5.5 g/litre. Among the isomers, cismethrin
    is the most toxic for fish. However, under field conditions, it has
    been shown that the hazard is significantly reduced because of the
    rapid degradation and low water solubility of the compound. Resmethrin
    is less toxic for arthropods with 48-h LC50 values of 2-25 g/litre.
    Both bioresmethrin and cismethrin are harmless for birds.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1  Identity

    Chemical formula: C22H26O3

    Chemical structure:

    CHEMICAL STRUCTURE 1


        Resmethrin was first produced in 1967 by Elliott et al. (1967). It
    is prepared by the esterification of [1RS, 3RS or 1RS, cis,
    trans]-2,2-dimethyl-3-(2,2-dimethylvinyl)cyclopropanecarboxylic acid
    or chrysanthemic acid with 5-benzyl-3-furyl-methyl alcohol.

        Resmethrin is thus a mixture of 4 stereoisomers (see Fig. 1). The
    cis:trans isomer ratio is reported to be 1:4 and the optical ratio
    of 1R:1S is 1:1 (racemic). Thus, its composition will be roughly
    4:1:4:1 of isomers (1), (2), (3), and (4).

        Bioresmethrin is the [1R,trans]- or (1) isomer and cismethrin is
    the [1R,cis]- or (2) isomer (Table 1).

    2.2  Physical and Chemical Properties

        Some physical and chemical properties of resmethrins are given in
    Table 2.

        Resmethrin is decomposed rapidly on exposure to air or light and
    in alkaline media (Elliot, 1976; FAO/WHO, 1976; Martin & Worthing,
    1977; Meister et al., 1983; Puchalski, 1983; Worthing & Walker, 1983;
    Devaux & Bolla, 1986).

    2.3  Analytical Methods

        Methods for the determination of residues, analysis of
    environmental samples, and product analysis for both resmethrin and
    bioresmethrin are summarized in Table 3. Procedures for extraction,
    partition, and cleanup are listed together with analytical equipment
    and conditions, minimum detectable concentrations, and percentage
    recovery.

        Technical grade resmethrin can be analysed by dissolving the
    product and dicyclohexyl phthalate (an internal standard) in acetone
    and injecting the solution in a gas chromatograph equipped with a
    flame ionization detector (FID) (Murano, 1972).


    FIGURE 1



        Table 1.  Chemical identity of resmethrins of various stereoisomeric compositions
                                                                                                                      

    Common name/            CAS Index name (9CI)                          Stereoisomeric     Synonyms and
    CAS Registry No./                                                     compositiond       trade names
    RTECS Registry No.a     Stereospecific nameb,c
                                                                                                                      

    Resmethrine             [5-(phenylmethyl)-3-furanyl]methyl            (1):(2):(3):(4)    Benzofuroline,
    10453-86-8               2,2-dimethyl-3-(2-methyl-1-propenyl)         =4:1:4:1           Benzylfuroline,
    GZ1310000                cyclo-propanecarboxylate (9CI)                                  Chrysron, Chryson,
                                                                                             Synthrin, For-Syn,
                            5-benzyl-3-furylmethyl [1RS, cis, trans]-                        NIA17370, NRDC104,
                             2,2-dimethyl-3-(2,2-dimethylvinyl)-                             SBP-1382, ENT27474,
                             cyclopropanecarboxylate                                         FMC17370, RU 48440,
                                         or                                                  Pynosect, Pyretherm;
                            5-benzyl-3-furylmethyl [1RS, cis, trans]-                        Premgard
                             chrysanthemate

    Bioresmethrine          same as resmethrin                            (1)                d-trans-Resmethrin,
    28434-01-7                                                                               (+)-trans-Resmethrin,
    GZ1310500               5-benzyl-3-furylmethyl [1R, trans]-                              NRDC107, RU 11484,
                            chrysanthemate

    Cismethrin              same as resmethrin                            (2)                (+)-cis-Resmethrin,
    35764-59-1                                                                               NRDC119
    GZ1430000               5-benzyl-3-furylmethyl [1R, cis]-
                             chrysanthemate
                                                                                                                      

    Table 1 (contd).
                                                                                                                      

    Common name/            CAS Index name (9CI)                          Stereoisomeric     Synonyms and
    CAS Registry No./                                                     compositiond       trade names
    RTECS Registry No.a     Stereospecific nameb,c
                                                                                                                      

    (-)-trans-resmethrin    same as resmethrin                            (3)                --

    GZ 1410000              5-benzyl-3-furylmethyl
                             [1S, trans]-chrysanthemate

    (-)-cis-resmethrin      same as above                                 (4)                --
    GZ 1420000

                            5-benzyl-3-furylmethyl
                             [1S, cis]-chrysanthemate
                                                                                                                      

    a  NIOSH (1983).
    b  (1R), d, (+) or (1S), 1, (-) in the acid part of resmethrin signifies the same stereospecific conformation,
       respectively.
    c  Chrysanthemic acid is a name of the acid that forms the acid part of resmethrin.
    d  Numbers in the parentheses identify the structures shown in the figures of stereoisomers.
    e  ISO common name: Common names for pesticides and other agrochemicals approved by the Technical Committee
       of the International Organization for Standardization.

    


        The sampling efficiency for vapourized pesticides (chlordane,
    chlorpyrifos, diazinone, propoxur, and resmethrin) was examined using
    five trapping solid sorbents, i.e., polyurethane foam, dispo plugs,
    Chromosorb 102, Porpak C18, Carbowax 20M on Gas Chrom Q, and Tenax GC
    (Roper & Wright, 1984). Resmethrin was determined using HPLC. The
    sampling efficiency of Porpak C18 was best (94%) for resmethrin;
    however, that of Chromosorb 102 was best (95%) when means of the 5
    sorbents with the different insecticides were compared.

        Table 2.  Some physical and chemical properties of resmethrins
                                                                                             

                                 Resmethrin           Bioresmethrin          Cismethrin
                                                                                             

    Physical state               waxy solid           Viscous oil                --
                                                      (liquid or solid)

    Colour                       colourless           practically                --
                                                      colourless

    Relative molecular mass      338.48               338.48                   338.48

    Melting point (C)           43-48                30-35                      --

    Boiling point                180C (0.01 mmHg)    180C (0.01 mmHg)          --

    Water solubility (30C)      < 1 mg/litre         < 0.3 mg/litre             --

    Solubility in organic        solublea             soluble                  soluble
    solvents

    Density (20C)               1.050                1.050

    Vapour pressure (mmHg)       1.1  10-8 (30C)    1.4  10-4 (25C)          --

    n-Octanol/water              2.9  103            6.2  104
    partition coefficient
                                                                                             

    a  Methanol (81 g/kg), hexane (220 g/kg), xylene (> 1 kg/kg), kerosene (10%).
       Very soluble in methylene chloride and aromatic petroleum hydrocarbons.

    


        Table 3.  Analytical methods for resmethrina
                                                                                                                                                

    Sample             Sample preparation                        Determination           Limit       % Recovery              Reference
                                                                                     of      fortification
               Extraction   Partition        Clean-up          GC or HPLC              detection   level (mg/kg)
               solvent                   Column      Elution     condition, detector,    (mg/kg)
                                                                 carrier, flow,
                                                                 column,
                                                                 temperature, R.T.
                                                                                                                                                

    Residue
    analysis

    Apple      n-hexane/    extraction   silica      CH2Cl2      HPLC UV-206 nm,         0.05        37 (0.1), 60 (1.0)      Baker &
    Pear       acetone      solvent/     gel                     25 cm ODS, propane      0.05        44 (0.1), 72 (1.0)      Bottomley (1982)
    Cabbage    (1/1)        H2O                                  2-ol, 1 ml/min          0.05        34 (0.1), 57 (1.0)
    Potato                                                                               0.05        54 (0.1), 80 (1.0)

    Corn       pentane      CH3CN/       Florisil    EtOAc/      FID-GC, N2 86           0.2         80-87.5 (0.2-3.2)       Simonaitis &
    Cornmeal                pentane                  pentane     ml/min, 1.83 m,                     75-86.2 (0.15-2.56)     Cail (1975)
    Flour                                            (3 + 97)    10% UC-W 98,                        80-88.7 (0.16-2.71)
    Wheat                                                        245C, 5.5 min                      79.6-86.2 (0.16-2.55)

    Wheat      n-hexane                                          CI-MS/GC, m/e 171,      0.04        97 (0.2)                Cave (1981)
    (grain)                                                      methane, 20 ml/min,                 98 (1.0)
                                                                 1.5 m, 5% OV-101,                   92 (2.0)
                                                                 230C, ca. 2.5 min

    Rice       petroleum                                         colorimetric                        96 (0.7)                Desmarchelier
    (cooked)   ether                                             method, 680 nm                      93 (0.8)                (1980)
               acetone                                                                               93 (0.8)
               acetone/
               petroleum
               ether
               (2/8)
                                                                                                                                                

    Table 3.  (cont'd).
                                                                                                                                                

    Sample             Sample preparation                        Determination           Limit       % Recovery              Reference
                                                                                     of      fortification
               Extraction   Partition        Clean-up          GC or HPLC              detection   level (mg/kg)
               solvent                   Column      Elution     condition, detector,    (mg/kg)
                                                                 carrier, flow,
                                                                 column,
                                                                 temperature, R.T.
                                                                                                                                                

    Environmental
    analysis

    Dish            n-hexane     n-hexane/    HPTLC     benzene/     dual-wavelength                      88-98 (300 g)    Uno et al. (1982)
    Apple                        CH3CN                  CCl4         densitometry                         97 (300 g)
    Spinach                                             (1 + 1)      lambda1 = 370 nm;                    98 (300 g)
    (dislodgeable                                       Rf = 0.44    lambda2 = 230 nm
    residue)

    Product
    analysis

    Technial acetone                                                 FID-GC, H2 40
    grade                                                            ml/min, 1 m, 2%                                        Murano (1972)
                                                                     DEGS, 190C,
                                                                     3.9 min
                                                                                                                                                

    a  HPLC = high-performance liquid chromatography; FID = Flame ionization detector; MS = mass spectrometry;
       CC = column chromatography; GC = gas chromatography; UV = ultraviolet; HPTLC = high-performance thin-layer
       chromatography; RT = retention time; CI = chemical ionization.

    


    3.  SOURCES OF ENVIRONMENTAL POLLUTION AND ENVIRONMENTAL LEVELS

    3.1  Industrial Production

        Resmethrin was first put on the market in 1969 and bioresmethrin,
    in 1973. No information is available to the general public on
    production volume. However, it has been estimated to amount to 20-30
    tonnes yearly (Miyamoto, personal communication, 1986).

    3.2  Use Patterns

        Resmethrin is mainly used in aerosol formulations, but also in oil
    formulations and emulsifiable concentrates, for the control of
    household and public health insects. It is also used in combination
    with other insecticides (e.g., tetramethrin, malathion).

        Resmethrin is currently used for mosquito control (by aerial
    application) in the USA, and it can also be used for the control of
    white fly in greenhouses.

        Bioresmethrin is mainly used as a post-harvest treatment to
    control pests in stored grain (mostly in Australia). Bioresmethrin is
    also widely used for white fly control in greenhouse-grown vegetables,
    mostly in European countries. It is also used in aerosol formulation
    for the control of household and public health insects, in combination
    with synergists and/or other insecticides. It has been used in France
    for cattle shed treatment (Battelle, 1982).

    3.3  Residues in Food

        Resmethrin residues on tomatoes and lettuce after greenhouse
    treatment decreased very rapidly resulting in negligible residues on
    tomatoes after 3 days and < 0.1 mg/kg on lettuce after 7 days (Burr,
    1983a,b).

        Field trials have been carried out with bioresmethrin on fruit and
    vegetable crops, e.g., tomatoes and cucumbers. Tomato fruits were
    treated with 14C-labelled bioresmethrin (1.25 mg/kg). The fruit was
    harvested 7-72 h after application and amounts of the compound in the
    flesh and skin, and on the skin surface were measured. At 72 h, 0.2%
    of the applied compound was detected in the flesh, 4.65% in the skin,
    and 15.5% on the surface (Buick & Flanagan, 1973).

        There are many reports of residue studies, especially on
    post-harvest treatment of grain for storage (FAO/WHO, 1976/1977).

        Residues in the stored grains, e.g., wheat, have also been
    determined. For example, wheat was treated with bioresmethrin at the
    rate of 4 mg/kg and maintained in an unaerated silo at 24C or in an
    aerated silo at 14C, for 6 months. At the end of 6 months, the
    residue levels had declined to only 1.1 mg/kg (unaerated) and
    1.9 mg/kg (aerated) (Bengston et al., 1975).

        Wheat was treated with bioresmethrin (4 mg/kg) and subjected to
    milling and baking processes. When it was used with 20 mg piperonyl
    butoxide/kg, 4.0 mg bioresmethrin remained per kg flour, but no
    residues were detected in bread (Ardley, 1975). In another study, some
    stability of residues during baking were demonstrated, residues of
    2.9 mg/kg in wheat resulted in residues of 1 mg/kg in wholemeal bread
    (Desmarchelier, 1980).

    3.4  Fate and Residues in Domestic Animals

        White Leghorn laying hens were given the cis- and trans-
    isomers of resmethrin, labelled with radiocarbon in either the
    alcohol or acid moiety, at a dosage of 10 mg/kg body weight. With each
    isomer and label position, more than 90% of the radiocarbon was
    eliminated in the excreta within 24 h of the treatment. Radiocarbon
    residues in the egg white and yolk fractions were low with peak levels
    observed, respectively, 1 and 4-5 days after treatment. Radiocarbon
    residues in tissues were low in birds sacrificed 12 h after treatment.
    The highest levels were found in the liver and kidney (Christopher
    et al., 1985).

        Resmethrin labelled with radiocarbon in either the acid or alcohol
    moiety and administered orally to lactating Jersey cows at 10 mg/kg
    body weight was rapidly absorbed, metabolized, and excreted. The
    cis-isomer was eliminated primarily in the faeces, but the
    trans-isomer was eliminated primarily in the urine. Tissue residues
    48 h after treatment were low (< 1 mg/kg), except in the liver,
    ovary, and kidney, and were generally higher with the alcohol-labelled
    compounds. Only very low levels of radiocarbon were secreted in the
    milk. Unmetabolized resmethrin appeared in trace amounts in tissues
    and as the major residue in milk and faeces. The major metabolites
    from both isomers arise from ester hydrolysis and subsequent oxidation
    of the hydrolysed products. They include: chrysanthemic acid (free and
    conjugated with glucuronic acid), chrysanthemumdicarboxylic acid,
    5-benzyl-3-furoic acid (free and conjugated with glucuronic acid or
    glycine), and 5-(alpha-hydroxybenzyl)-3-furoic acid (Ridlen et al.,
    1984).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Photodegradation

        The photodegradation pathways of resmethrin are summarized in
    Fig. 2.

        On irradiation with a sunlamp, trans- and cis-isomers of
    14C-resmethrin (5) labelled in the carboxy (acid or phenyl (alcohol)
    group decomposed on silica gel plates with a half-life of about
    160-190 min. After 420 min irradiation of 14C-bioresmethrin, only 5%
    of the recovered radioactivity was resmethrin, 45% was ester
    photoproducts, 14% was non-ester photoproducts, and 32% was not
    identified. The photoproduct found in the largest amount was
    5-hydroxy-3-oxo-4-phenyl-1-cyclopentenylmethyl trans-chrysanthemate
    (10) (about 24% of the applied 14C), which originated from the cyclic
    ozonide-type peroxide intermediates (8,9) formed by oxidation of the
    furan ring. A relatively large (about 5%) amount of trans-
    chrysanthemic acid (17) was formed. In addition, small amounts of the
    R and S isomers of trans-epoxyresmethrin (6) (about 1.5% each),
    5-benzyl-5-hydroxy-2-oxo-2,5-dihydro-3-furylmethyl trans-
    chrysanthemate (11) (about 3%) and 2-benzyloxy-5-oxo-2,5-dihydro-
    3-furylmethyl trans-chrysanthemate (12) (about 1%) were
    detected with the acid- and alcohol-labelled preparations, and benzyl
    alcohol (14) (about 2%), benzoic acid (16) (about 1.5%), and
    phenylacetic acid (13) (about 1%) were found with the alcohol-labelled
    preparation. The photoproduct distribution was greatly dependent on
    the supporting material or medium. Oxidation at the furan ring
    occurred predominantly on silica gel plates, while epoxidation at the
    isobutenyl substituent proceeded to a greater extent on a filter paper
    or in water. When exposed to sunlight for 10 h, cismethrin on silica
    gel plates (1.7 mg/cm2) gave a large amount of cis-chrysanthemic
    acid (17) but not trans-acid, together with smaller amounts of
    5-hydroxy-3-oxo-4-phenyl-1-cyclopentenylmethyl cis-chrysanthemate
    (10), 5-benzyl-5-hydroxy-2-oxo-2,5-dihydro-3-furylmethyl
    cis-chrysanthemate (11), benzaldehyde (15), and phenylacetic acid
    (13). The photodecomposition rates were compared for residual deposits
    (14 g/cm2) of bioresmethrin, trans-tetramethrin, and
    S-Bioallethrin on silica gel plates under sunlight or a sunlamp.
    S-Bioallethrin was the most stable of these compounds, and
    trans-tetramethrin was more persistent than bioresmethrin (Ueda
    et al., 1974).

        Resmethrin and structurally related 5-benzyl-3-furylmethyl
    derivatives undergo rapid oxidation when exposed to sunlight or a
    sunlamp, either in aqueous medium or as a thin film on glass or silica
    gel. One major photodecomposition route involves epoxidation at the
    isobutenyl substituent to give the R- and S-epoxides. Formation of the
    other major photoproducts is initiated by oxidation of the furan ring
    to a cyclic ozonide-type peroxide (Holmstead et al., 1977).

    FIGURE 2

        In contrast, there was a 10% loss in the original weight of
    resmethrin after 24 h compared with losses of 29% and 41% for
    tetramethrin and allethrin, respectively, when exposed as a thin film
    (500 mg/38.5 cm2) on glass to an incandescent lamp (Abe et al.,
    1972).

        The photodegradation of aqueous solutions (sterile water and
    artificial sea-water) of resmethrin by natural sunlight has also been
    investigated. The half-life was estimated to be 47 min in water and
    20 min in sea water. The major degradation product was chrysanthemic
    acid (Watson, 1984).

    4.2  Degradation in Soil

        The degradation under aerobic conditions of 14C-resmethrin
    applied to soil at rates equivalent to 0.12 and 1.7 kg/ha has been
    studied. The compound degraded very rapidly, so that less than 2% of
    the applied 14C-resmethrin remained after 16 days. Complete
    mineralisation to 14CO2 was a very important metabolic process
    (38% of the applied radioactivity in 16 days). The radioactivity
    remaining in the soil after 16 days was a complex mixture of more than
    11 products resulting from ester cleavage and oxidation reactions
    (Kaufman, 1986).

    4.3  Degradation on Plants

        Tomato and lettuce plants were treated with 14C-resmethrin, under
    greenhouse conditions; wheat was similarly treated in the field. The
    radioactivity was applied by spraying an aqueous suspension at a
    concentration equivalent to 0.5 g/litre. The applied resmethrin
    degraded very rapidly so that 55-82% had degraded within 2 h and no
    unchanged resmethrin remained after 5 days. A very complex mixture of
    degradation products were formed on the plants (up to 31 individual
    compounds). No individual component in the mixture of products formed
    exceeded 10% of the amount applied at any sampling interval up to 15
    days after treatment. The alcohol formed by ester cleavage and
    benzaldehyde (15), phenylacetic acid (13), benzoic acid (16), and
    benzyl alcohol (14) were identified as degradation products. These
    compounds were each present at levels < 3% of the radioactive residue
    (Mumma, 1985).

    5.  KINETICS AND METABOLISM

    5.1  Metabolism in Mammals

        Metabolic pathways for resmethrin in mammals are summarized in
    Fig. 3.

        When 14C-[1RS,trans]-resmethrin (19) labelled in the alcohol
    moiety was administered orally to Sprague-Dawley rats at 500 mg/kg,
    the radiocarbon was rapidly absorbed from the gastrointestinal tract
    and it took 3 weeks for the complete elimination of the radioactivity
    in the urine (36% of the dose) and faeces (64%). A negligible amount
    (less than 0.1%) of the radiocarbon was expired as 14CO2. The
    radiocarbon was not completely excreted, even after 2 weeks, in rats
    given an intravenous dose of 50 mg/kg; notably, appreciable amounts of
    14C were found in faeces. The results of another study indicated that
    the excretion of 14C via the bile duct was very rapid and that more
    than 50% of the total dose was recovered from the bile within 72 h.
    The urinary metabolites were mainly 5-benzyl-3-furancarboxylic acid
    (20) (BFCA) in the free form (28% of the urinary 14C), the
    glucuronide form (2%), and unknown conjugated (18%) forms. Other
    significant metabolites present in the urine were hydroxy derivatives
    of BFCA, such as alpha-(4-carboxy-2-furyl)-benzyl alcohol (21)
    (alpha-OH-BFCA) (11%), 5-benzoyl-3-furancarboxylic acid (22)
    (alpha-keto-BFCA) (1%), 5-benzyl-4-hydroxy-3-furancarboxylic acid (23)
    (2%), and 5-(p-hydroxybenzyl)-3-furancarboxylic acid (24)
    (4'-OH-BFCA) in the free form (3%), the sulfate form (12%) and the
    glucuronide (2%) form (Miyamoto et al., 1971) (Fig. 3).

        Ueda et al. (1975b) elucidated the metabolic fates of the acid and
    alcohol moieties of bioresmethrin (19) and cismethrin (25) in rats
    after a single oral dose (acid- and alcohol-labelled moieties) at
    1 mg/kg. The predominant metabolites from the alcohol moiety were
    BFCA, 4'-OH-BFCA, and alpha-OH-BFCA. The metabolites in the body were
    derived from the alcohol moiety of bioresmethrin. On the other hand,
    the isobutenyl group of the acid moiety was oxidized at either the
    cis- or trans-methyl group of cismethrin, but only at the
    trans-methyl group of bioresmethrin. The major metabolites from the
    acid moiety were the hydroxymethyl (28, 29) or dicarboxylic acid
    derivatives (30, 31) of chrysanthemic acid (26, 27) (CA). The aldehyde
    intermediates of CA were not found. The major dicarboxylic acid
    derivatives of CA were metabolites receiving oxidation at the
    trans-methyl group of the isobutenyl moiety. Although the
    trans-methyl group was predominantly oxidized in both isomers, the
    cis-methyl group of the cis-isomer was also oxidized (32). An
    anticipated metabolic pathway involves epimerization at C-3 of the
    cyclopropane group leading to isomerized forms of dicarboxylic acid
    derivatives of CA. The aldehyde derivatives of CA are the most likely
    compounds for isomerization, because these derivatives readily undergo
    cis- trans-isomerization under the alkaline conditions (Ueda et
    al., 1975b).

    FIGURE 3

    5.2  Enzymatic Systems for Biotransformation

        When 14C alcohol-labelled cismethrin, bioresmethrin, and
    5-benzyl-3-furylmethyl alcohol (BFA) (18) were incubated with rat
    liver S-9 homogenates or microsomes, a proportion of the radioactive
    compounds was covalently bound to proteins. The covalent binding was
    greater with phenobarbital-pretreated rats, and dependent on a
    NADPH-generating system. When a S-9 homogenate was used, the bound
    compounds were twice as high for cismethrin as for bioresmethrin and
    BFA. Inversely, when microsomes were used, more covalent binding
    occurred with bioresmethrin and BFA than with cismethrin. The
    inhibition of esterases by tetraethyl pyrophosphate (TEPP) in a S-9
    homogenate did not alter the amount of covalent binding to the three
    compounds, whereas malathion inhibited this binding. However,
    treatment of a S-9 homogenate with piperonyl butoxide greatly reduced
    covalent binding. Covalent binding was inhibited when the microsomes
    were incubated with carbon monoxide or modified by thermal
    denaturation. It is suggested that oxidative metabolism was
    responsible for the covalent binding (Hoellinger et al., 1985).

        When four resmethrin isomers ([1R,trans]-, [1S,trans]-,
    [1R,cis]-, and [1S,cis]-) were incubated with mouse and rat
    microsomes in 50 mmol/litre tris-HCl buffer (pH 7.4) at 37C for 1 h,
    microsomal esterases readily cleaved the trans- but not the
    cis-isomers. The ester linkage also appeared to undergo oxidative
    cleavage when esterase attack was minimal. Ester metabolites were
    detected in significant amounts only with [1R,cis]-resmethrin, in
    which case oxidation had occurred at the isobutenyl moiety, with or
    without oxidation at the benzylfuryl methyl group. Most of the
    in vitro metabolites were identical with those in the excreta of
    rats given resmethrin orally. The preferred site of oxidation in the
    isobutenyl moiety varies with the resmethrin isomer and microsomal
    source. Mouse microsomes predominantly oxidized the trans-methyl
    group of both [1R,trans]- and [1S,trans]-resmethrin, the
    selectivity, however, being the greatest with [1S,trans]-resmethrin.
    Rat microsomes were relatively nonselective in attacking the
    isobutenyl methyl groups of [1R,trans]-resmethrin (Ueda et al.,
    1975a).

        Plasma-esterases were equally active in hydrolysing cismethrin and
    bioresmethrin (3.2-3.4 nmol benzylfurylmethanol/min per g) whereas
    liver microsomal esterases hydrolysed bioresmethrin 10 times more
    rapidly than cismethrin (White et al., 1976).

    6.  EFFECTS ON THE ENVIRONMENT

        Data on the acute toxicity of resmethrin for aquatic and
    terrestrial non-target organisms are summarized in Tables 4 and 5,
    respectively.

    6.1  Aquatic Organisms

        Resmethrin is highly toxic for fish, and the toxicity is
    negatively correlated with temperature (Mauck et al., 1976); the LC50
    value for bluegill is 2.3 times greater at 22C than at 12C, as shown
    in Table 4. The influence of both water hardness and pH on toxicity
    ranged from slight to negligible. By keeping resmethrin solution at
    12C for 1 week, the toxicity for bluegill decreased 2-fold at each pH
    value as the resmethrin solution aged.

        Among the 4 isomers, the 1R, cis-isomer is most toxic for fish,
    followed by the 1R, trans-, 1S, cis- and 1S, trans-, as observed
    in pyrethroids. Contrary to other pyrethroids, resmethrin is less
    toxic for arthropods than for fish, as shown in Table 4. The 48-h
    LC50 values for arthropods are in the range of 2-25 g/litre
    (Nishiuchi, 1981).

        Laboratory studies have shown that resmethrin is highly toxic for
    fish but, because of the low water solubility of the compound and
    rapid environmental degradation (photochemical and microbial), it
    would be expected that, under field conditions, the toxic impact would
    be greatly reduced. Such a reduction in toxic effects has been
    confirmed in field studies carried out in the USA (Sjogren, 1985;
    Norwood, 1986; Pierce, 1986).

        In one of these studies, ponds were sprayed with resmethrin
    formulations at the expected field rate for adult mosquito control
    (0.01 kg/ha). Residue analysis confirmed that resmethrin levels fall
    rapidly (1.1 ppb at zero time nondetectable after 96 h). Caged fish
    showed good survival (82-100% for bluegill, 73-100% for goldfish) in
    resmethrin-treated ponds. However, one fish species in this study
    (white sucker) was susceptible (8% survival) when piperonyl
    butoxide-synergised resmethrin was used, though good survival was
    noted for this species with unsynergised resmethrin. In a second
    study, synergised resmethrin was applied to a mangrove-fringed pond at
    2-day intervals. The first two applications were at the normal field
    rate, but the third was at 10 times this rate. In this study, both
    fish species used to monitor fish survival (sheepshead minnow,
    fingerling snook) showed good survival (100% at the normal rate and
    88% at the 10-fold rate).



        Table 4.  Acute toxicity of resmethrin for non-target aquatic organisms
                                                                                                                                                

    Species             Size      Parameter     Concentration    Formulation   System     Temperature   pH     Hardness (mg    Reference
                                                (g/litre)                                   (C)              CaCO3/litre)
                                                                                                                                                

    Fish

    Carp (Cyprinus                48-h LC50             44       technical     static         25                               Nishiuchi (1982)
    carpio)

    Killifish           adult     48-h LC50            300       technical     static         25                               Miyamoto (1976)
    (Oryzias            adult     48-h LC50             16       (+)-trans-    static         25                               Miyamoto (1976)
    latipes)            adult     48-h LC50              8       (+)-cis-      static         25                               Miyamoto (1976)
                        adult     48-h LC50       > 10 000       (-)-trans-    static         25                               Miyamoto (1976)
                        adult     48-h LC50           3500       (-)-cis-      static         25                               Miyamoto (1976)

    Rainbow trout                 96-h LC50            2.2       technical     static         12                               Marking & Mauck
    (Salmo gairdneri)                                                                                                          (1975)

    Coho salmon                   96-h LC50           1.50       technical     static         12                               Mauck et al.
    (Oncorhynchus                                                                                                              (1976)
    kisutch)                      96-h LC50          0.277       technical     flow-          12                               Mauck et al.
                                                                               through                                         (1976)

    Steelhead trout               96-h LC50          0.450       technical     static         12                               Mauck et al.
    (Salmo gairdneri)                                                                                                          (1976)
                                  96-h LC50          0.275       technical     flow-          12                               Mauck et al.
                                                                               through                                         (1976)
    Yellow perch                  96-h LC50           2.36       technical     static         12                               Mauck et al.
    (Perca flavescens)                                                                                                         (1976)
                                  96-h LC50          0.513       technical     flow-          12                               Mauck et al.
                                                                               through                                         (1976)
                                                                                                                                                

    Table 4.  (cont'd).
                                                                                                                                                

    Species             Size      Parameter     Concentration    Formulation   System     Temperature   pH     Hardness (mg    Reference
                                                (g/litre)                                   (C)              CaCO3/litre)
                                                                                                                                                

    Arthropods

    Daphnia pulex                 3-h LC50          15 000       technical     static         25                               Nishiuchi (1982)
                                  3-h LC50          50 000       technical     static         25                               Miyamoto (1976)
                                  3-h LC50        25 000 -       (+)-trans-    static         25                               Miyamoto (1976)
                                                    50 000
                                  3-h LC50        25 000 -       (+)-cis-      static         25                               Miyamoto (1976)
                                                    50 000
                                  3-h LC50        > 50 000       (-)-trans-    static         25                               Miyamoto (1976)
                                  3-h LC50        > 50 000       (-)-cis-      static         25                               Miyamoto (1976)

    Moina macrocopa               3-h LC50          14 000       technical     static         25                               Nishiuchi (1982)

    Sigara substriata   0.59 cm;  48-h LC50              2       technical     static         25                               Nishiuchi (1981)
                        6.1 mg

    Micronecta sedula   0.32 cm;  48-h LC50            3.3       technical     static         25                               Nishiuchi (1981)
                        1.8 mg

    Cloeon dipterum     0.93 cm;  48-h LC50            4.5       technical     static         25                               Nishiuchi (1981)
                        5.6 mg

    Orthetrum           2.3 cm;   48-h LC50            7.3       technical     static         25                               Nishiuchi (1981)
    albistylum          0.62 g
    speciosum

    Eretes sticticus    1.5 cm;   48-h LC50             25       technical     static         25                               Nishiuchi (1981)
                        0.2 g

    Sympetrum           2.1 cm;   48-h LC50             10       technical     static         25                               Nishiuchi (1981)
    frequens            0.56 g
                                                                                                                                                

    Table 4.  (cont'd).
                                                                                                                                                

    Species             Size      Parameter     Concentration    Formulation   System     Temperature   pH     Hardness (mg    Reference
                                                (g/litre)                                   (C)              CaCO3/litre)
                                                                                                                                                

    Fish (contd).

    Bluegill (Lepomis             96-h LC50           2.62       technical     static         12                               Mauck et al.
    macrochirus)                                                                                                               (1976)
                                  96-h LC50          0.750       technical     flow-          12                               Mauck et al.
                                                                               through                                         (1976)
                        0.8 g     96-h LC50           5.46       technical     static         22        7.5       40-48        Mauck et al.
                                                                                                                               (1976)
                        0.8 g     96-h LC50           4.28       technical     static         17        7.5       40-48        Mauck et al.
                                                                                                                               (1976)
                        0.8 g     96-h LC50           2.33       technical     static         12        7.5       40-48        Mauck et al.
                                                                                                                               (1976)
                        0.8 g     96-h LC50           2.53       technical     static         12        6.6       10-13        Mauck et al.
                                                                                                                               (1976)
                        0.8 g     96-h LC50           2.54       technical     static         12        7.8      160-180       Mauck et al.
                                                                                                                               (1976)
                        0.8 g     96-h LC50           2.06       technical     static         12        8.2      280-320       Mauck et al.
                                                                                                                               (1976)
                        0.8 g     96-h LC50           2.29       technical     static         12        6.5       40-48        Mauck et al.
                                                                                                                               (1976)
                        0.8 g     96-h LC50           2.46       technical     static         12        9.5       40-48        Mauck et al.
                                                                                                                               (1976)
                        0.8 g     96-h LC50           2.89       technical     static         12        6.5       40-48        Mauck et al.
                                                                                                                               (1976)
                        0.8 g     96-h LC50           2.70       technical     static         12        7.5       40-48        Mauck et al.
                                                                                                                               (1976)
                        0.8 g     96-h LC50           3.13       technical     static         12        8.5       40-48        Mauck et al.
                                                                                                                               (1976)
                        0.8 g     96-h LC50           2.68       technical     static         12        9.5       40-48        Mauck et al.
                                                                                                                               (1976)
                                                                                                                                                
    


    6.2  Terrestrial Organisms

        Acute toxicity data show that both resmethrin and bioresmethrin
    (Table 5) are harmless for birds, as are other pyrethroids.

        In addition, a study has been carried out to assess the effects of
    resmethrin on reproduction in the Mallard duck and Bobwhite quail. The
    birds were given 12, 60, or 300 mg resmethrin/kg diet for 22 weeks. No
    effects on reproduction were seen in either species at these dose
    levels (Roberts et al., 1985a,b).

        Table 5.  Acute toxicity of resmethrin and bioresmethrin or non-target terrestrial
              organisms
                                                                                             

    Species           Compound         Size    Application   Toxicity    Reference
                                       (days)                (mg/kg)
                                                                                             

    Bird
    Quail             Resmethrin       14      diet          LC50        Hill et al.
    (Coturnix                                                > 5000      (1975)
    coturnix
    japonica)

    Mallard                            10      diet          LC50        Hill et al.
    (Anas                                                    > 5000      (1975)
    platyrhynchos)

    Chicken           Bioresmethrin            oral          LD50        Chesher &
                                                             > 10 000    Malone (1970a)
                                                                         Wallwork
                                                                         et al. (1970)
                                                                                             

    
    7.  EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS

    7.1  Acute Toxicity

        Acute toxic signs produced in experimental animals by exposure to
    resmethrins include tremor, hyperexcitability, convulsive twitching,
    prostration, and coma.

        LD50 data on resmethrin isomers administered orally and by other
    exposure routes are summarized in Tables 6 and 7, respectively.

        These data show that resmethrins are weakly toxic, except for
    cismethrin, the acute oral toxicity of which is moderate in the mouse.

        The results of acute toxicity tests of the resmethrin metabolites
    are given in Table 8.

        Acute (1 h) inhalation studies were performed with 3 aerosol
    formulations of resmethrin and 2 blank formulations. Groups of 20 male
    rats and 4 male rabbits inhaled the active ingredient at concentration
    levels of 12-13.7 mg/litre (value based on the weight loss from each
    spray can). In addition, 10 exposed and 10 control rats were tested
    for conditioned avoidance performance immediately following exposure.
    Laboured breathing was seen generally in the animals. Several rabbits
    died in both the resmethrin-treated and the blank-formulation groups.
    In the rats, there were no effects on body weight, or gross or
    histopathological lesions. However, the conditioned avoidance latency
    in the resmethrin-treated rats was significantly greater than that in
    the unexposed controls (Macko et al., 1979).

    7.2  Short-term Exposure

    7.2.1  Oral administration

        Groups of 6 Sprague-Dawley rats from each sex were administered
    resmethrin in the diet at concentrations of 0, 310-323, 630-660,
    1230-1250, 1423-2670, or 1680-5100 mg/kg, for 14 days. Five out of 6
    rats died at the highest exposure level in both sexes. Tremor was
    observed and body weight gain and food utilization were reduced at
    levels of 1230-1250 mg/kg or more. A significant increase in the
    hepatic organ-to-body weight ratios was noted in all groups of females
    and in groups of males fed 630-660 mg/kg or more. Compound-related
    histopathological changes were not observed in any of the tissues and
    organs examined. The maximum no-observed-adverse-effect dietary level
    was 310 mg/kg for male rats only (Swentzel et al., 1977).

        Table 6.  Acute oral toxicity of resmethrin isomers
                                                                                                

                                                     LD50 (mg/kg
    Compound                 Animal           Sex    body weight)    Reference
                                                                                                

    Resmethrin               rat               M        > 5000       Miyamoto (1976)
                             rat               F        > 5000       Miyamoto (1976)
                             rat               M          1244       Gaines & Linder (1986)
                             rat               F          1721       Gaines & Linder (1986)
                             rat (weanling)    M          1987       Gaines & Linder (1986)
                             rat               ?        > 2500       Worthing & Walker (1983)
                             rat               -           960       Volkov et al. (1979)
                             mouse             M           690       Miyamoto (1976)
                             mouse             F           940       Miyamoto (1976)

    Bioresmethrin            rat               M          8800       Glomot & Chevalier (1969)
                             rat               F        > 8000       Verschoyle & Barnes (1972)
                             rat               F          7071       Wallwork et al. (1970)
                             rat               -           840       Kholmatova (1984)
                             rat               -           990       Volkov et al. (1979)
                             rat               -           675       Kagan et al. (1986)
                             mouse             M           590       Miyamoto (1976)
                             mouse             F           800       Miyamoto (1976)
                             mouse             M          3100       Ueda et al. (1975b)
                             mouse             F         10000       Wallwork et al. (1970)
                             mouse             -           520       Kholmatova (1984)
                             mouse             -           480       Kagan et al. (1986)
                             rabbit            -           225       Kholmatova (1984)

    Cismethrin               mouse             M           152       Miyamoto (1976)
                             mouse             F           160       Miyamoto (1976)

    [1S,-trans]-resmethrin   mouse             M           500       Miyamoto (1976)
                             mouse             F           600       Miyamoto (1976)

    [1S,-cis]-resmethrin     mouse             M          3700       Miyamoto (1976)
                             mouse             F          5000       Miyamoto (1976)

                                                                                                
    


        Table 7.  Acute toxicity of resmethrins via other than oral exposure
                                                                                                                                

                                                                  LD50             LC50
    Compound            Animal      Sex      Route                (mg/kg           (mg/m3)       Reference
                                                                  body weight)
                                                                                                                                

    Resmethrin          rat         M        dermal               2500                           Gaines & Linder (1986)
                        rat         F        dermal               2500                           Gaines & Linder (1986)
                        rabbit      -        dermal               2500                           Green (1977)
                        rat         -        inhalation                            > 9490        Jackson & Hardy (1984)
                                             (4-h exposure)
                        rat         -        inhalation                            > 12 000      Macko et al. (1979)
                                             (1-h exposure)
                        rabbit      -        inhalation                            > 12 000      Macko et al. (1979)
                                             (1-h exposure)
                        dog         -        inhalation                            > 420         Macko et al. (1979)
                                             (4-h exposure)
    Bioresmethrin       rat         F        dermal               > 10 000                       Wallwork et al. (1970)
                        rat         F        intravenous          340                            Verschoyle & Barnes (1972)
                        rat         F        intravenous          106-133                        Chesher & Malone (1971b)
                        rat         F        intraperitoneal      > 8000                         Wallwork & Malone (1971)
                        rat         F        inhalation                            > 872         Wallwork & Malone (1972)
                                             (24-h exposure)
                        mouse       M        intraperitoneal      > 1500                         Ueda et al. (1975b)
                        mouse       F        intraperitoneal      > 5359                         Wallwork et al. (1970)

    Mixture of          rat         M,F      inhalation                            > 1500        Miyamoto (1976)
    bioresmethrin                            (4-h exposure)
    & cismethrin        mouse       M,F      inhalation                            > 1500        Miyamoto (1976)
                                             (4-h exposure)
                                                                                                                                

    Table 8.  Acute toxicity of metabolites of resmethrin
                                                                                                                      

      Metabolite                                       Nob      Animal    LD50 (mg/kg)        Reference
                                                                          ip        oral
                                                                                                                      

    (bioresmethrin), (5-benzyl-3-furyl-                         mouse     > 1500a   3100a     Miyamoto (1975-1976)
    methyl (+)-trans-chrysanthemate)                   (1)                                    Ueda et al. (1975b)

    1R or (+)-cis-resmethrin (5-benzyl-3-furyl-        (2)      mouse     320a                Miyamoto (1975-1976)
    methyl (+)-cis-chrysanthemate)                                                            Ueda et al. (1975b)

    d,1-cis,trans-chrysanthemic acid                   (17)     rat                 2443      Reagan & Becci (1985a)

    d,1-trans-chrysanthemic acid                       -        rat                 1598      Reagan & Becci (1985b)

    (+)-trans-chrysanthemic acid, (+)-trans-CA         (26)     mouse     98a       280a      Miyamoto (1975-1976)
    (t-CA)                                                                                    Ueda et al. (1975b)

    (+)-cis-chrysanthemic acid, (+)-cis-CA (c-CA)      (27)     mouse     600a                Miyamoto (1975-1976)
                                                                                              Ueda et al. (1975b)

    d-trans-chrysanthemic acid                         (26)     rat                 983       Reagan & Becci (1985c)

    (+)-trans-chrysanthemumdicarboxylic acid,          (30)     mouse     408a                Miyamoto (1975-1976)
    (+)-trans-CDA (tE-CDA)                                                                    Ueda et al. (1975b)

    5-benzyl-3-furylmethanol (BFA)                     (18)     mouse     75a       310a      Miyamoto (1975-1976)
                                                                                              Ueda et al. (1975b)
                                                                                                                      

    Table 8.  (cont'd).
                                                                                                                      

      Metabolite                                       Nob      Animal    LD50 (mg/kg)        Reference
                                                                          ip        oral
                                                                                                                      

    5-benzyl-3-furoic acid (BFCA)                      (20)     mouse     46a                 Miyamoto (1975-1976)
                                                                                              Ueda et al. (1975b)

    5-benzyl-3-furoic acid (BFCA)                      (20)     rat                 997       Reagan & Becci (1985d)

    ethyl chrysanthemate                               -        rat                 > 4640    Stauffer Chemical Co.
                                                                                              (1984)
                                                                                                                      

    a  Toxicity for male mice, 24 h after intraperitoneal injection or oral administration.
    b  Chemical identification numbers used in Table 1 and Fig. 2.

    
        The same authors fed groups of 6 Long-Evans rats of each sex
    resmethrin in the diet at concentrations of 0, 61-90, 148-180,
    297-386, 584-669, 1080-1375, or 1266-2532 mg/kg body weight per day
    for 14 days. Mortality was observed in the groups fed 1080 mg/kg or
    more. Tremor was observed at levels of 386 mg/kg or more (females only
    at 386 mg/kg). The terminal body weight and food utilization were
    significantly lower in the groups fed 1080 mg/kg or more compared with
    the controls. A significant increase in the hepatic organ-to-body
    weight ratios was noted at levels of 297 mg/kg or more.
    Compound-related histopathological changes were not observed in any of
    the tissues and organs examined. The maximum no-observed-adverse-
    effect dietary level was 148 mg/kg body weight per day for male and
    180 mg/kg body weight per day for female rats (Swentzel et al., 1977).

        In a third study by Swentzel et al. (1977), groups of 8-20
    Long-Evans rats of each sex were fed resmethrin in the diet at
    concentrations equivalent to 0, 22, 66, 211, or 679 mg/kg body weight
    per day for males and of 0, 3, 7, 22, 67, 219, 724, or 2400 mg/kg body
    weight per day for females, for 90 days. All the females fed the
    highest level died. Tremor was observed at levels of 679 mg/kg or
    more. The mean terminal body weight was significantly lower in the
    group given 679-724 mg/kg than in the control group. A significant
    increase in the hepatic and renal organ-to-body weight ratios was
    noted in males fed 211 or 679 mg/kg; while, in females fed 219 or
    724 mg/kg, only an increase in the hepatic ratio was observed. No
    significant differences were observed in clinical chemistry values
    (serum glutamic oxaloacetic transaminase (SGOT), serum glutamic
    pyruvic transaminase (SGPT), total lactate dehydrogenase (LDH),
    alkaline phosphatase (AP), gamma-glutamyl trans-peptidase (GGTP),
    total bilirubin, total protein, blood-urea nitrogen (BUN)) between
    test and control animals. Compound-related histopathological changes
    were not observed in any of the tissues and organs examined. The
    maximum no-observed-adverse-effect dietary level was 67 mg/kg body
    weight per day for female and 66 mg/kg body weight per day for male
    rats.

        Groups of rats (10 males/group) were administered bioresmethrin
    orally by gavage, daily, 6 days/week for 3 weeks at doses of 0, 1000,
    or 2000 mg/kg body weight. Body weights were slightly reduced at
    2000 mg/kg. A slight reduction was noted in haemoglobin content and
    hematocrit value. Biochemical examination revealed an increase in
    albumin and blood-urea nitrogen concentrations and a decrease in
    serum-glutamic oxaloacetic transaminase (SGOT) activity. Increased
    liver size and reduced thymus weight were observed at 1000 mg/kg.
    Reduced prostate weight was noted only at the high dose.
    Histopathological examination revealed thymic involution (Glomot,
    unpublished report).a

              

    a  GLOMOT, R. (undated) Etude de la toxicit chronique de 3 semaines
       chez le rat du RU11484 (NRDC 107) (Unpublished report of Roussel
       Uclaf submitted to WHO by Wellcome Foundation Ltd).
        Wallwork et al. (1971) reported a study in which groups of rats
    (18 males and 18 females/group) were fed bioresmethrin in the diet at
    concentrations of 0, 400, 1200, or 8000 mg/kg over 91 days. The group
    receiving the highest dose was fed 4000 mg/kg for 30 days and
    thereafter 8000 mg/kg. Body weights were reduced at the highest dose
    level and there were changes in blood chemistry parameters indicating
    liver dysfunction (an increase in serum-alkaline phosphatase (SAP),
    SGOT, and urinary nitrogen and a decrease in glucose content). The red
    blood cell count was depressed in the group receiving 1200 mg/kg. An
    increase in liver weight and a decrease in the weights of several
    other organs, such as the spleen and thymus, were observed at
    4000 mg/kg. Fatty infiltration of the liver was noticed at 1200, 4000,
    and 8000 mg/kg. The no-observed-adverse-effect level in this study was
    400 mg/kg, equivalent to an average daily intake of 32.8 and
    36.1 mg/kg body weight for males and females, respectively.

        Bioresmethrin was administered to groups of dogs (2 of each
    sex/group) by gavage, daily, at dose levels of 0 or 500 mg/kg for 7
    days followed by an increased dose of 1000 mg/kg for a further 14
    days. No effects were noted on mortality, behaviour, body weight,
    haematology, blood chemistry, urinalysis, or electrocardiograms
    (Malone & Chesher, 1970).

        Groups of dogs (3 males and 3 females/group) were administered
    bioresmethrin in gelatin capsule by gavage, daily for 90 days, at
    dosage levels of 0, 25, 80, or 250 mg/kg body weight (the highest dose
    was increased to 500 mg/kg body weight in week 7). There were no
    effects on mortality, body weight, food consumption, ophthalmology, or
    urinalysis. Red blood cell count, haemoglobin content, and packed cell
    volume values were reduced at the highest dose level. Blood-urea
    nitrogen was slightly increased at the highest dose after 12 weeks. No
    adverse effects were observed on gross or histopathological
    examination. The no-observed-adverse-effect level was 80 mg/kg body
    weight, equivalent to an average of 1600 mg/kg diet (Noel et al.,
    1971).

        In summary, the no-observed-adverse-effect level for resmethrin as
    determined in the 90-day study on rats was 66 mg/kg body weight per
    day, whereas that for bioresmethrin was 33 mg/kg body weight per day
    in the 91-day study on rats and 80 mg/kg body weight per day in the
    90-day study on dogs.


    7.2.2  Inhalation

        Short-term inhalation studies were performed using three
    resmethrin formulations and one blank formulation. Aerosol spray
    formulations (frequency median diameter of the particles: 1.5-2.0 m,
    volume median diameter 10-18.5 m) were introduced into the top of a
    pyramid-shaped sealed chamber and dispersed for 30-second intervals
    every 30 min. Groups of 25 male rats, 10 female rats, and 4 male
    rabbits were exposed to the inhalations 10 times a day, over a period
    of 5 h, for 5 consecutive days. Daily active ingredient concentrations
    of each formulation in the chamber were 2.9-3.2 mg/litre, based on the
    weight loss from each spray can. The clinical signs included increased
    preening, ruffled pelt, rapid breathing, and slight nasal discharge.
    All signs disappeared overnight, but recurred after each daily
    exposure. In rats, there were no effects on body weight. No gross or
    histopathological lesions related to exposure to the formulations were
    observed in rats necropsied immediately after the last 5-h exposure
    and 7 and 14 days after exposure. No indication of toxic effects,
    other than irritation, was observed in any test (Macko et al., 1979).

        When ICR mice and Sprague-Dawley rats were exposed to [1R,
    trans, cis]-resmethrin (at concentrations of 0, 23, 47, or
    210 mg/m3) for 4 h/day, 5 days/week over 4 weeks, no toxic effects
    were observed on behaviour, food intake, haematology, clinical
    biochemistry, mortality, or histopathology (Miyamoto, 1976).

        When groups of 16 male and 16 female Wistar rats were exposed
    through inhalation for 6 h/day on 5 days of each week, over a period
    of 90 days, to technical resmethrin at target exposure levels of 0.1,
    0.3, or 1.0 g/m3, the no-observed-adverse-effect level was
    established at 0.1 g/m3. At 0.3 g/m3, there were minor effects on
    some clinical pathology parameters and also signs of irritation.
    However, microscopic pathological examination did not reveal any
    treatment-related changes in the lungs or other organs of rats exposed
    at this level. At 1 g/m3, there were clinical signs indicative of
    irritation, minor neurobehavioural changes, a reduced rate of weight
    gain, and some changes in clinical pathology parameters. Microscopic
    examination at this level showed minimal changes in the larynx, liver,
    and thyroid, but these were reversible during the recovery period.
    There were no treatment-related lung changes (Coombs et al., 1985).

    7.2.3  Dermal application

        Resmethrin was applied twice a week for 3 weeks to the shaved skin
    of 4 groups of 10 male New Zealand White rabbits. Cotton cloth treated
    with resmethrin at 0.247 mg/cm3 was applied over 1 ml of liquid
    (imitating sweat) to rabbits in the first group. In the second group,
    cotton cloth treated with resmethrin was applied without the sweat,
    and in the third group, the cotton cloth was fixed to skin that had

    been pretreated with 10 g of technical grade resmethrin. In the fourth
    group, untreated cotton cloth was fixed over skin pre-treated with
    pyrax powder containing 1% resmethrin at the rate of 1 g/kg of body
    weight. The 3 control groups received cotton cloth treated with
    acetone, cotton cloth treated with acetone over 1 ml of the sweat, and
    untreated cotton cloth over 1 g pyrax powder/kg, respectively. No
    significant changes were noted, on day 24 of the test, in rabbit body
    weights and organ-to-body weight ratios of liver, lung, kidney,
    testis, and spleen. Average dermal irritation scores for
    resmethrin-treated rabbits were not significantly higher than those
    for the control groups and did not increase during the test. No
    significant trends compared with the controls were seen in clinical
    chemistry values (serum-glutamic oxalo-acetic transaminase,
    serum-glutamic pyruvic transaminase, lactic dehydrogenase, alkaline
    phosphatase, blood-urea nitrogen) on days 5, 12, 19, and 24 of the
    test. There were no compound-related lesions of the skin or of any of
    the other tissues and organs examined at the termination of the study
    (Swentzel et al., 1977).

    7.3  Primary Irritation and Sensitization

        Technical grade resmethrin was found to be a slight irritant in
    rabbits in a 24 day dorsal/ventral rabbit ear test. Dermal irritation
    was evident on both intact and abraded skin at 72 h and up to 7 days.
    Resmethrin did not cause sensitization reactions in guinea-pigs, or
    photochemical irritation in New Zealand White rabbits. Repeated daily
    applications of 0.1 g of the technical grade compound to one ear of
    each of 5 New Zealand White rabbits were carried out for 30
    consecutive days as well as applications of compound-impregnated
    cotton sateen cloth (0.247 mg/cm2) with artificial sweat for 24 days.
    In this study, resmethrin did not produce acne-form dermatitis
    (Swentzel et al., 1977).

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

        Instillation of technical bioresmethrin into the eye of 6 rabbits
    (0.1 ml) did not produce any irritation or corneal damage, or any
    indication of ocular hazard (Chesher & Malone, 1970c).

    7.4  Long-term Exposure and Carcinogenicity

        When [1R, trans, cis]-resmethrin was fed to Sprague-Dawley
    rats (male and female) at dietary levels of 500, 1500, or 5000 mg/kg
    for 24 weeks, toxic symptoms, such as tremors and decreased body
    weight, increased liver and kidney weights and an increase in alkaline
    phosphatase activity were observed at 5000 mg/kg. The no-observed-
    adverse-effect level was 1500 mg/kg (77.7 mg/kg per day for males and
    86.6 mg/kg per day for females) (Miyamoto, 1976).

        Resmethrin fed to Wistar rats at dosage levels of 0, 500, 2500, or
    5000 mg/kg in the basal diet over a 112-week period, was determined
    not to be oncogenic up to, and including, 5000 mg/kg, which was the
    highest dose tested. The no-observed-adverse-effect level of 500 mg/kg
    for toxic effects, was the lowest effect level for hypertrophy of
    hepatocytes, which was not considered a definite toxic response
    (Knickerbocker et al., 1980; Hess et al., 1982).

        Cox et al. (1979a) fed CD-1 outbred albino mice with 0, 250, 500,
    or 1000 mg resmethrin/kg basal diet for an 85-week period. No
    oncogenicity was observed at any doses up to and including 1000 mg/kg.

        When Beagle dogs were administered 0, 10, 30, or 300 mg
    resmethrin/kg body weight for 6 months, the no-observed-adverse-effect
    level was 10 mg/kg per day. On day 57 of the study, the highest dose
    level was increased from 100 mg/kg per day to 300 mg/kg per day.
    Increased liver weights were noted at 30 mg/kg body weight per day
    (Gephart et al., 1980).

        An acceptable daily intake (ADI) was established by the USA EPA at
    0.125 mg/kg body weight per day based on no-observed-adverse-effect
    levels in long-term toxicity studies. A food additive tolerance has
    been established by the US EPA, permitting resmethrin residues of up
    to 3 ppm, in or on food commodities, resulting from use in food
    handling areas (US Environmental Protection Agency, 1983).

    7.5  Mutagenicity

        Saccharomyces cerevisiae D4 and five strains of Salmonella
    typhimurium (TA1535, TA1537, TA1538, TA98, and TA100) were used to
    evaluate the mutagenic potential of resmethrin. The compound was
    tested in the absence or presence of liver microsomal enzyme
    preparations from rats pre-treated with Aroclor 1254. Resmethrin was
    not mutagenic to any of the indicator organisms under both conditions
    (Swentzel et al., 1977).

        Resmethrin, bioresmethrin, and cismethrin were tested for
    mutagenicity in several test systems. Miyamoto (1976) and Suzuki
    (1975) used the Escherichia coli and S.typhimurium reverse
    mutation tests. Garret et al. (1986) summarized results of point/gene
    mutations in prokaryotes or eukaryotes, primary DNA damage in
    prokaryotes or eukaryotes, chromosomal effects in Chinese hamster
    ovary cells, mouse bone marrow, and cardiac blood cells of the mouse.
    Pluijmen et al. (1984) used reverse mutation tests in S.typhimurium
    TA98 or TA100, or mutagenicity tests with V79 Chinese hamster cells to
    test seven synthetic pyrethroids including resmethrin, bioresmethrin,
    and cismethrin. They all gave negative results.

        Bioresmethrin was also tested in a metaphase chromosome analysis
    of cultured human lymphocytes, an autoradiographic assessment of
    unscheduled DNA synthesis in mammalian cells, and a mouse micronucleus
    test. They also gave negative results (Allen et al., 1986; Allen &
    Proudlock, 1986; Vannier & Fournex, 1986).

    7.6  Reproductive effects, Embryotoxicity, and Teratogenicity

        Three groups of 30 pregnant Long-Evans rats were administered
    resmethrin in the diet at concentrations of 0, 188, or 1500 mg/kg from
    day 6 to day 16 of gestation. The dams showed tremors and decreased
    food and water consumption at 1500 mg/kg and 2 dams died; the lower
    fetal weight seen at this dose and the resorption of embryos and
    fetuses in 15 out of 30 dams were probably due to maternal toxicity.
    No gross abnormalities of fetal skeletons and soft tissues were
    observed in the treated groups. Thus, the consumption of resmethrin in
    ground feed was not teratogenic at 188 and 1500 mg/kg (Swentzel
    et al., 1977).

        In a 3-generation study, Sprague-Dawley rats were fed resmethrin
    in the diet at 0, 500, 800, or 1250 mg/kg (Schwartz et al., 1979c). A
    slight increase in the number of pups cast dead and a decrease in pup
    weights were noted at the 500 mg/kg level. A no-observed-adverse-
    effect level of < 500 mg/kg was established for pups cast dead and
    reduced pup weights at 21 days.

        Sprague-Dawley female albino rats were given resmethrin in corn
    oil, by gavage, at dose levels of 0, 20, 40, or 80 mg/kg during the
    period of major organogenesis (days 6-15 of gestation). Resmethrin was
    not teratogenic in rats at levels up to, and including, 80 mg/kg. The
    no-observed-adverse-effect level for fetotoxicity was 40 mg/kg (Machi
    et al., 1979).

        Pregnant New Zealand White Minnikin rabbits were given resmethrin
    by oral intubation at 0, 10, 30, or 100 mg/kg body weight per day on
    days 6-18 of gestation (Becci et al., 1979). On day 29 of gestation,
    all animals were killed for examination. No teratogenic effects were
    seen at dose levels up to and including 100 mg/kg.

        When [1R, trans, cis]-resmethrin was administered orally to
    female ICR mice (10, 30, or 100 mg/kg, daily) and Sprague-Dawley rats
    (10, 20, or 50 mg/kg daily) during the period of gestation, to examine
    maternal and embryotoxic effects, no significant adverse effects, such
    as abortion, resorption of fetuses or embryos, external or skeletal
    abnormalities of pups, and abnormalities in growth or organ
    differentiation, were observed at any doses (Miyamoto, 1976).

        Groups of pregnant rabbits (4-6 rabbits/group) were administered
    bioresmethrin at doses of 0, 10, 20, 40, or 80 mg/kg, by gavage,
    daily, from day 8 to day 16 of gestation. The does were sacrificed on
    day 28 and examined for implantation, live and dead fetuses,
    resorption sites, and abnormalities. There was no apparent effect on
    parents in the study as growth and gestation were unaffected. There
    was an increase in the numbers of dead fetuses at the highest dose and
    a large number of resorption sites were noted at all treatment levels.
    A number of deformed fetuses were observed, but the total numbers were
    not sufficient for an adequate statistical evaluation. The deformities
    included straight tail, crossed hind limbs, and unilateral union of
    6th and 7th ribs at the sternal end. An overall fetal loss was
    observed at all dose levels (primarily because of the large number of
    resorption sites recorded) (Waldron, 1969).

    7.7  Immunotoxicity

        The influence of various pesticides on the humoral and cellular
    immune response to fluorescein-labelled ovalbumin has been analysed.
    Resmethrin was administered intragastrically in corn oil as a single
    dose (one half of LD50) before primary immunization. Control groups
    included animals treated with corn oil alone, or immunosuppressed with
    methotrexate. Booster immunizations and test bleedings were scheduled
    to follow at weekly intervals. The cellular immune response was
    quantified by redness and swelling, histological examination, and by
    differential temperature measurements of the foot pads after antigen
    challenge. The concentration, binding affinity, and heterogeneity of
    the serum antibody were determined by fluorescence polarization
    measurements. Resmethrin gave an early, sometimes very marked,
    stimulation of the cellular immune response (Danliker et al., 1979).

    7.8  Neurotoxicity

        The neurotoxicity of resmethrin was evaluated in three short-term
    dietary studies on Sprague-Dawley rats designed to examine the gross
    and histopathological changes to the central and peripheral nervous
    system. Resmethrin was not neurotoxic when administered at 1250 mg/kg
    for 32 weeks, 5000 mg/kg for 30 days, or 12 640 mg/kg for 7 days (Cox
    et al., 1979b; Schwartz et al., 1979a,b).

        In order to better characterize the behavioural effects of
    pyrethroid insecticides, comparisons were made of the effects of
    cismethrin and deltamethrin exposure on motor activity and the
    acoustic startle response in male Long-Evans rats (Crofton & Reiter,
    1984). Acute dose effect, acute time course, and 30-day
    repeated-exposure determinations of 1 h motor activity were made using
    figure-eight mazes. The acoustic startle response to a 13-kHz, 120-dB,
    40-msecond tone was measured at each of three background white noise
    levels (50, 65, and 80 dB). Deltamethrin (0, 2, 4, 6, or 8 mg/kg) or
    cismethrin (0, 6, 12, 18, or 24 mg/kg) was administered orally in
    0.2 ml corn oil/kg. Both compounds produced similar dose-dependent
    decreases in motor activity. The time course of onset and recovery for
    this decreased activity was rapid (1-4 h). No cumulative effects on
    motor activity were found of a 30-day exposure to 2 mg deltamethrin/kg
    per day or 6 mg cismethrin/kg per day. The effects of cismethrin and
    deltamethrin on the acoustic startle response differed. Deltamethrin
    produced a dose-dependent decrease in amplitude and an increase in
    latency, and cismethrin produced an increase in amplitude and no
    change in latency. The differential effects of cismethrin (Type I
    pyrethroids) and deltamethrin (Type II pyrethroids) on the acoustic
    startle response may be related to the contrasting effects previously
    shown with neurophysiological and/or neurochemical techniques (see
    Annex).

        The isolated rat neurohypophysis, which shows a calcium-dependent
    hormone release when depolarized in vitro, was used as a model
    system to investigate the effects of the pyrethroids deltamethrin and
    resmethrin on mammalian nervous tissue (Dyball, 1982). Both compounds
    inhibited neurohypophysial hormone release in response to electrical
    stimulation, deltamethrin being more potent than resmethrin.
    Deltamethrin reduced the hormone content of the neurohypophysis.
    Resmethrin did not reduce stored hormone significantly and its effects
    on release were dose dependent. They could be mimicked by raising the
    Na+ of the medium, but not by lowering the Ca2+. Resmethrin did not
    have any effects on the release of hormone following depolarization of
    the tissue with a raised K+. The results are consistent with the
    suggestion that the compounds do not act on the potential-dependent
    secretion process but rather on the mechanism linking depolarization
    of the secretory terminals with the arrival of action potentials,
    possibly by interfering with sodium-channel activation and
    inactivation.

        The neurological effects of four synthetic pyrethroids resmethrin,
    permethrin, cypermethrin, and deltamethrin were investigated in the
    rat to establish whether there is a correlation between the
    clinical-functional status of the animal and peripheral nerve damage,
    as measured biochemically (Rose & Dewar, 1983). Neuromuscular
    dysfunction was assessed by means of the inclined plane test and
    peripheral nerve damage by reference to -glucuronidase and
    -galactosidase activity increases in nerve tissue homogenates from

    treated and control animals. A transient functional impairment was
    found in animals treated with any one of the four pyrethroids tested
    and, in all cases, this was maximal at the end of the 7-day dosing
    regimen (resmethrin doses of 500-2000 mg/kg per day). Significant
    increases in -glucuronidase and -galactosidase were found, 3-4 weeks
    after the start of dosing in the distal portion of the
    sciatic/posterior tibial nerves of animals treated with permethrin,
    cypermethrin, or deltamethrin; however, no changes were found in
    resmethrin-treated animals. Thus, it is concluded that there is no
    direct correlation between the time-course of the neuromuscular
    dysfunction and the neurobiochemical changes. This suggests that these
    pyrethroids have at least two distinct actions, a short-term
    pharmacological effect and, at near-lethal dose levels, a more chronic
    neurotoxic effect that results in sparse axonal nerve damage.

        Resmethrin (30 mol/litre)-induced release of transmitters was not
    affected by manipulation of the Na+ current with either choline or
    tetrodotoxin agents, which readily reversed the effects of
    veratridine, deltamethrin, and cypermethrin (Doherty et al., 1986).
    Resmethrin (I50: 2.2 mol/litre) inhibited the ATP-dependent uptake
    of Ca2+ but deltamethrin and cypermethrin were much less effective.
    Resmethrin also displaced Ca2+ from crude synaptosomal membranes. The
    release-promoting effects of resmethrin in rat brain in vitro are
    better explained by its effects on Ca2+ rather than by a specific
    effect on the Na+ channel. In contrast, deltamethrin and
    cypermethrin promote transmitter release by a Na+ dependent process.

        Glickman & Casida (1982) discussed species and structural
    variations affecting pyrethroid neurotoxicity. They concluded that the
    mammalian nervous system, or at least the brain, appears to lack sites
    sensitive to bioresmethrin and to a lesser extent to [1R,
    trans]-permethrin, yet small structural changes restore the toxicity
    (e.g., [1R,trans]-ethano-resmethrin and [1R, cis]-resmethrin. The
    authors reported that birds and mammals in general respond to cis-
    but not to trans-resmethrin in contrast to insects, crustaceans, and
    fish, which are highly sensitive to both isomers. Furthermore, common
    green lacewing larvae are very tolerant to pyrethroids, suggesting
    possible involvement of nerve insensitivity in addition to
    detoxification in this species. These examples of insensitivity may be
    associated with modified sites of action or perhaps an increased
    stabilization of nerve membranes making them more resistant to
    pyrethroid-induced excitation.

    7.9  Mechanism of Toxicity (Mode of Action)

        Cismethrin is toxic for both insects and mammals. Bioresmethrin is
    about 50 times less toxic than cismethrin and produces few symptoms in
    mice and rats, even at extremely high doses. The poisoning syndrome of
    cismethrin and bioresmethrin was characterized by whole body tremors
    (T-syndrome) and both compounds were therefore classified as Type I
    pyrethroids (Verschoyle & Aldridge, 1980; Lawrence & Casida, 1982,
    Annex).

        Tremors started when the concentrations of cismethrin and
    bioresmethrin in the brain were 0.5-1 mg/kg and 4-5 mg/kg,
    respectively. At death, brain levels of cismethrin were 3.9-5.1 mg/kg,
    and those of bioresmethrin were 23-35 mg/kg. As liver microsomal
    esterases hydrolysed bioresmethrin 10 times more rapidly than
    cismethrin, the lower toxicity of bioresmethrin was partly attributed
    to its faster metabolism and intrinsically lower toxicity at the
    critical site of action in the nervous system (White et al., 1976).

        Cismethrin given intravenously produced repetitive activity, after
    external stimulation, in the spinal cord of rabbit (Carlton, 1977). As
    gamma-aminobutyric acid (GABA) blockers, such as bicuculline and
    picrotoxin, produced convulsions similar to those of cismethrin, the
    effects of the compounds on dorsal root potentials were examined in
    the rat. Bicuculline reduced the amplitude of the potential to 67% of
    the control values, but cismethrin enhanced the potential to 142% of
    the control values. The convulsions associated with cismethrin
    poisoning, therefore, are not produced by an antagonism of
    GABA-mediated inhibitory transmission (Smith, 1980).

        Administration of cismethrin into the lateral ventricle of the
    brain or into the spinal cord causes signs similar to those observed
    after intravenous administration. The onset of tremors after
    intraventricular administration of cismethrin was delayed for about 15
    min while, after intraspinal injection, the symptoms occurred within
    2-5 min, indicating that cismethrin may act directly on the spinal
    cord rather than in the brain (Gray et al., 1980b).

        After intravenous administration of [14C]-alcohol-labelled
    cismethrin or bioresmethrin to rats, the parent pyrethroid was rapidly
    cleared from the blood and liver, and both isomers rapidly entered the
    central nervous system (CNS) reaching peak concentrations within 2-5
    min. Cismethrin concentrations in the brain exceeding 3.5 nmol/g were
    associated only with animals showing tremors. These levels of
    cismethrin were maintained for up to 30 min, but bioresmethrin was
    depleted more rapidly, possibly due to brain metabolism. It is
    concluded that the low toxicity of bioresmethrin is possibly because
    of its inability to interact with the site of action in the CNS and to
    its rapid metabolism in the liver (Gray et al., 1980a).

        Cismethrin produced repetitive firing in the flight muscles and
    uncoupling of motor unit activity in the housefly (Miller & Adams,
    1977), and repetitive firing in a cercal sensory nerve of the
    cockroach (Gammon et al., 1981). On the basis of the
    electrophysiological effects and symptomatology in insects as well as
    in mammals, cismethrin is classified as a Type I pyrethroid,
    characterized by a mainly peripheral nervous system action (Gammon et
    al., 1981).

    7.10  Potentiation

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

    8.  EFFECTS ON MAN

        Although the resmethrins have been used for many years, no data
    have been reported on their toxicity for human beings.

    9.  EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

    9.1  Human Health Risks

        Resmethrin, consisting of four stereo-isomers, is an effective
    insecticide mainly used to control household insects and other public
    health insects, with applications in the food handling and storage
    areas.

        Bioresmethrin and cismethrin are composed of a selected isomer(s).
    As with resmethrin, bioresmethrin is used to control household insects
    and other public health insects. In addition, bioresmethrin is used as
    a post-harvest insecticide to control stored grain pest. Human
    exposure to the resmethrins will be mainly via inhalation, when the
    formulations are sprayed in the form of a mist, though the use in food
    handling and storage areas as well as post-harvest treatment may
    result in dietary residues. Air levels following conventional
    household aerosol spraying with the resmethrins are not expected to
    exceed 0.5 mg/ms.

        The only significant potential dietary exposure will result from
    the use of resmethrin on stored grain. Residues of up to 4 mg/kg might
    be present in grain, but this would be reduced to zero in white bread.
    However, reduced residues may be present in wholemeal bread. A food
    additive tolerance has been established by the US Environmental
    Protection Agency (US EPA) permitting resmethrin residues of up to
    3 mg/kg (3 ppm), in or on food commodities, resulting from use in food
    handling areas. An ADI was established by the US EPA at 0.1250 mg/kg
    body weight per day, based on no-observed-adverse-effect levels in
    long-term toxicity studies. No data are available on occupational
    exposure to the resmethrins. Although the resmethrins have been used
    for many years, no data have been reported concerning their toxicity
    for human beings. Thus, to determine the potential toxicity for human
    beings, extrapolation from animal data and in vitro studies has been
    used.

        The result of short-term studies on experimental animals suggest
    that resmethrins are weakly toxic when administered by various routes
    of exposure (oral LD50 of resmethrin: 690 mg/kg (mouse) - >
    5000 mg/kg (rat); those of bioresmethrin: 225 mg/kg (rabbit),
    480-10 000 mg/kg (mouse), 8800 mg/kg (rats)). Cismethrin showed
    moderate toxicity for the mouse (oral LD50 152-160 mg/kg). The acute
    toxicity of resmethrin metabolites were in the same range in the rat,
    but somewhat more toxic in the mouse.

        While technical grade resmethrin is a slight skin irritant, it is
    not a sensitizer.

        Resmethrins are not mutagenic in a variety of test systems,
    including gene mutations, DNA damage and DNA repair, and chromosomal
    effects.

        Resmethrin was not carcinogenic for mice or rats, when fed at
    dietary levels of up to 1000 mg/kg for 85 weeks and 5000 mg/kg for 112
    weeks, respectively.

        Resmethrin was not teratogenic in the rat, mouse, or rabbit, up to
    dose levels of 100 mg/kg body weight. A level of 40 mg/kg body weight
    appeared to be the no-observed-adverse-effect level for fetotoxicity
    in the rat.

        Resmethrins at near lethal doses are likely to cause
    hyperactivity, tremors, and convulsions and have been classified as
    Type I pyrethroids.

        For resmethrin, a no-observed-adverse-effect level was established
    in a 90-day rat study to be 66-67 mg/kg body weight per day, whereas,
    in another 2-year rat study, the lowest effect level appeared to be
    500 mg/kg diet, corresponding to 25 mg/kg body weight per day. In a
    6-month feeding study on dogs, the no-observed-adverse-effect level
    was 10 mg/kg body weight per day.

        In a 90-day inhalation study on rats, a no-observed-adverse-effect
    level was established of 0.1 g/m3.

        The no-observed-adverse-effect level for bioresmethrin in a 9-day
    feeding study on the rat was 33-36 mg/kg body weight per day; and in a
    90-day study on dogs, it was 80 mg/kg body weight per day.

        In a 24-week feeding study on rats, the no-observed-adverse-effect
    level for [1R, trans, cis]-resmethrin was 1500 mg/kg diet
    corresponding to 75 mg/kg body weight.

    9.2  Effects on the Environment

        Resmethrins are used mainly indoors for the control of household
    insects and also for stored grain protection. They are also used in
    greenhouses and can be used outdoors for mosquito control. However,
    under outdoor conditions, rapid photodegradation and microbial
    degradation in the soil ensure that residues will not persist to any
    extent in the environment.

        In laboratory studies, resmethrins have been shown to be very
    toxic for fish (96-h LC50 values: 0.3-5.5 g/litre) but less toxic
    for Daphnia and aquatic insect larvae. However, under field
    conditions the low water solubility of the resmethrins and their ready
    degradation greatly alleviate the effects that might be predicted from
    the laboratory studies. The toxicity of resmethrins for birds is low
    (LD50 > 5000 mg/kg) and they do not produce any effects on avian
    reproduction.

    10.  CONCLUSIONS

        General population: Under recommended conditions of household
    and other public health use, the exposure of the general population to
    resmethrins is negligible and is unlikely to present a hazard. Under
    recommended conditions of use in food handling and storage areas as
    well as in post-harvest treatment, the exposure of the general
    population to resmethrins in the diet is unlikely to exceed the ADI
    established by the US EPA.

        Occupational exposure: With reasonable work practices, hygienic
    measures, and safety precautions, the use of resmethrins is unlikely
    to present a hazard to those occupationally exposed to it.

        Environment: With recommended application rates, it is unlikely
    that resmethrins or their degradation products will attain levels of
    environmental significance. In spite of the fact that resmethrins are
    highly toxic for fish, this is only likely to cause a problem in the
    case of spillage or over-spraying.

    11.  RECOMMENDATIONS

    -   In order to fully assess the potential dietary exposure from
        current uses of resmethrins, it is suggested that the degradation
        pathway on stored grain be studied, and the terminal residues on
        grain and bread be defined.

    -   It is considered that resmethrin, despite its high octanol-water
        partition coefficient, is very unlikely to bioaccumulate in
        non-target species, because of its ready degradation. However,
        experimental confirmation of this in fish might be useful.

    -   A further multigeneration reproduction study to define a
        no-observed-adverse-effect level should be considered.

    -   Over many years of use, no adverse effects have been reported as a
        result of human exposure to resmethrins, but it is still necessary
        to maintain observations on human exposure.

    -   The labelling of resmethrins for household use should include
        adequate instructions for use and storage and, where appropriate,
        a warning of flammability.

    -   Efforts should be made to obtain a more precise estimate of the
        total global usage of resmethrins.

    12.  PREVIOUS EVALUATION BY INTERNATIONAL BODIES

        The Joint FAO/WHO Expert Committee on Pesticide Residues (JMPR)
    discussed and evaluated bioresmethrin at its meetings in 1975 and 1976
    (FAO/WHO, 1976, 1977). An acceptable daily intake (ADI) has not been
    established.

        The Pesticide Development and Safe Use Unit, Division of Vector
    Biology and Control, WHO, has classified bioresmethrin as a technical
    product unlikely to present an acute hazard in normal use, and
    resmethrin and cismethrin as slightly hazardous (WHO, 1986). A Data
    Sheet on bioresmethrin (No. 34) has been issued (WHO/FAO, 1978).

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    APPENDIX

        On the basis of electrophysiological studies with peripheral nerve
    preparations of frogs (Xenopus laevis; Rana temporaria, and Rana
    esculenta), it is possible to distinguish between 2 classes of
    pyrethroid insecticides: (Type I and Type II). A similar distinction
    between these 2 classes of pyrethroids has been made on the basis of
    the symptoms of toxicity in mammals and insects (Van den Bercken et
    al., 1979; WHO, 1979; Verschoyle & Aldridge, 1980; Glickman & Casida,
    1982; Lawrence & Casida, 1982). The same distinction was found in
    studies on cockroaches by Gammon et al. (1981).

        Based on the binding assay on the gamma-aminobutyric acid (GABA)
    receptor-ionophore complex, synthetic pyrethroids can also be
    classified into two types: the alpha-cyano-3-phenoxy-benzyl
    pyrethroids and the non-cyano pyrethroids (Gammon et al., 1982; Gammon
    & Casida, 1983; Lawrence & Casida, 1983; Lawrence et al., 1985).

    Pyrethroids that do not contain an alpha-cyano group (allethrin,
    d-phenothrin, permethrin, tetramethrin, cismethrin, and
    bioresmethrin) (Type I: T-syndrome)

        The pyrethroids that do not contain an alpha-cyano group give rise
    to pronounced repetitive activity in sense organs and in sensory nerve
    fibres (Van den Bercken et al., 1973). At room temperature, this
    repetitive activity usually consists of trains of 3-10 impulses and
    occasionally up to 25 impulses. Train duration is between 10 and 5
    milliseconds.

        These compounds also induce pronounced repetitive firing of the
    presynaptic motor nerve terminal in the neuromuscular junction (Van
    den Bercken, 1977). There was no significant effect of the insecticide
    on neurotransmitter release or on the sensitivity of the subsynaptic
    membrane or the muscle fibre membrane. Presynaptic repetitive firing
    was also observed in the sympathetic ganglion treated with these
    pyrethroids.

        In the lateral-line sense organ and in the motor nerve terminal,
    but not in the cutaneous touch receptor or in sensory nerve fibres,
    the pyrethroid-induced repetitive activity increases dramatically as
    the temperature is lowered, and a decrease of 5C in temperature may
    cause a more than 3-fold increase in the number of repetitive impulses
    per train. This effect is easily reversed by raising the temperature.
    The origin of this "negative temperature coefficient" is not clear
    (Vijverberg et al., 1983).

        Synthetic pyrethroids act directly on the axon through
    interference with the sodium channel gating mechanism that underlies
    the generation and conduction of each nerve impulse. The transitional
    state of the sodium channel is controlled by 2 separately acting
    gating mechanisms, referred to as the activation gate and the
    inactivation gate. Since pyrethroids only appear to affect the sodium
    current during depolarization, the rapid opening of the activation
    gate and the slow closing of the inactivation gate proceed normally.
    However, once the sodium channel is open, the activation gate is
    restrained in the open position by the pyrethroid molecule. While all
    pyrethroids have essentially the same basic mechanism of action, the
    rate of relaxation differs substantially for the various pyrethroids
    (Flannigan & Tucker, 1985).

        In the isolated node of Ranvier, allethrin causes prolongation of
    the transient increase in sodium permeability of the nerve membrane
    during excitation (Van den Bercken & Vijverberg, 1980). Evidence so
    far available indicates that allethrin selectively slows down the
    closing of the activation gate of a fraction of the sodium channels
    that open during depolarization of the membrane. The time constant of
    closing of the activation gate in the allethrin-affected channels is
    about 100 milliseconds compared with less than 100 microseconds in the
    normal sodium channel, i.e., it is slowed down by a factor of more
    than 100. This results in a marked prolongation of the sodium current
    across the nerve membrane during excitation, and this prolonged sodium
    current is directly responsible for the repetitive activity induced by
    allethrin (Vijverberg et al., 1983).

        The effects of cismethrin on synaptic transmission in the frog
    neuromuscular junction, as reported by Evans (1976), are almost
    identical to those of allethrin, i.e., presynaptic repetitive firing,
    and no significant effects on transmitter release or on the
    subsynaptic membrane.

        Interestingly, the action of these pyrethroids closely resembles
    that of the insecticide DDT in the peripheral nervous system of the
    frog. DDT also causes pronounced repetitive activity in sense organs,
    in sensory nerve fibres, and in motor nerve terminals, due to a
    prolongation of the transient increase in sodium permeability of the
    nerve membrane during excitation. Recently, it was demonstrated that
    allethrin and DDT have essentially the same effect on sodium channels
    in frog myelinated nerve membrane. Both compounds slow down the rate
    of closing of a fraction of the sodium channels that open on
    depolarization of the membrane (Van den Bercken et al., 1973, 1979;
    Vijverberg et al., 1982b).

        In the electrophysiological experiments using giant axons of
    crayfish, the Type I pyrethroids and DDT analogues retain sodium
    channels in a modified open state only intermittently, cause large
    depolarizing afterpotentials, and evoke repetitive firing with minimal
    effect on the resting potential (Lund & Narahashi, 1983).

        These results strongly suggest that permethrin and cismethrin,
    like allethrin, primarily affect the sodium channels in the nerve
    membrane and cause a prolongation of the transient increase in sodium
    permeability of the membrane during excitation.

        The effects of pyrethroids on end-plate and muscle action
    potentials were studied in the pectoralis nerve-muscle preparation of
    the clawed frog (Xenopus laevis). Type I pyrethroids (allethrin,
    cismethrin, bioresmethrin, and 1R, cis-phenothrin) caused moderate
    presynaptic repetitive activity, resulting in the occurrence of
    multiple end-plate potentials (Ruigt & Van den Bercken, 1986).

    Pyrethroids with an alpha-cyano group on the 3-phenoxybenzyl alcohol
    (deltamethrin, cypermethrin, fenvalerate, and fenpropanate)
    (Type II: CS-syndrome)

        The pyrethroids with an alpha-cyano group cause an intense
    repetitive activity in the lateral-line organ in the form of
    long-lasting trains of impulses (Vijverberg et al., 1982a). Such a
    train may last for up to 1 min and contains thousands of impulses. The
    duration of the trains and the number of impulses per train increase
    markedly on lowering the temperature. Cypermethrin does not cause
    repetitive activity in myelinated nerve fibres. Instead, this
    pyrethroid causes a frequency-dependent depression of the nervous
    impulse, brought about by a progressive depolarization of the nerve
    membrane as a result of the summation of depolarizing after-potentials
    during train stimulation (Vijverberg & Van den Bercken, 1979;
    Vijverberg et al., 1983).

        In the isolated node of Ranvier, cypermethrin, like allethrin,
    specifically affects the sodium channels of the nerve membrane and
    causes a long-lasting prolongation of the transient increase in sodium
    permeability during excitation, presumably by slowing down the closing
    of the activation gate of the sodium channel (Vijverberg & Van den
    Bercken, 1979; Vijverberg et al., 1983). The time constant of closing
    of the activation gate in the cypermethrin-affected channels is
    prolonged to more than 100 milliseconds. Apparently, the amplitude of
    the prolonged sodium current after cypermethrin is too small to induce
    repetitive activity in nerve fibres, but is sufficient to cause the
    long-lasting repetitive firing in the lateral-line sense organ.

        These results suggest that alpha-cyano pyrethroids primarily
    affect the sodium channels in the nerve membrane and cause a
    long-lasting prolongation of the transient increase in sodium
    permeability of the membrane during excitation.

        In the electrophysiological experiments using giant axons of
    crayfish, the Type II pyrethroids retain sodium channels in a modified
    continuous open state persistently, depolarize the membrane, and block
    the action potential without causing repetitive firing (Lund &
    Narahashi, 1983).

        Diazepam, which facilitates GABA reaction, delayed the onset of
    action of deltamethrin and fenvalerate, but not permethrin and
    allethrin, in both the mouse and cockroach. Possible mechanisms of the
    Type II pyrethroid syndrome include action at the GABA receptor
    complex or a closely linked class of neuroreceptor (Gammon et al.,
    1982).

        The Type II syndrome of intracerebrally administered pyrethroids
    closely approximates that of the convulsant picrotoxin (PTX).
    Deltamethrin inhibits the binding of [3H]-dihydropicrotoxin to rat
    brain synaptic membranes, whereas the non-toxic R epimer of
    deltamethrin is inactive. These findings suggest a possible relation
    between the Type II pyrethroid action and the GABA receptor complex.
    The stereospecific correlation between the toxicity of Type II
    pyrethroids and their potency to inhibit the [35S]-TBPS binding was
    established using a radioligand, [35S]-t-butyl-bicyclophosphoro-
    thionate [35S]-TBPS. Studies with 37 pyrethroids revealed an absolute
    correlation, without any false positive or negative, between mouse
    intracerebral toxicity and in vitro inhibition: all toxic cyano
    compounds including deltamethrin, [1R,cis]-cypermethrin,
    [1R,trans]-cypermethrin, and [2S, alphaS]-fenvalerate were
    inhibitors, but their non-toxic stereoisomers were not; non-cyano
    pyrethroids were much less potent or were inactive (Lawrence & Casida,
    1983).

        In the [35S]-TBPS and [3H]-Ro 5-4864 (a convulsant
    benzodiazepine radioligand) binding assay, the inhibitory potencies of
    pyrethroids were closely related to their mammalian toxicities. The
    most toxic pyrethroids of Type II were the most potent inhibitors of
    [3H]-Ro 5-4864 specific binding to rat brain membranes. The
    [3H]-dihydropicrotoxin and [35S]-TBPS binding studies with
    pyrethroids strongly indicated that Type II effects of pyrethroids are
    mediated, at least in part, through an interaction with a
    GABA-regulated chloride ionophore-associated binding site. Moreover,
    studies with [3H]-Ro 5-4864 support this hypothesis and, in addition,
    indicate that the pyrethroid-binding site may be very closely related
    to the convulsant benzodiazepine site of action (Lawrence et al.,
    1985).

        The Type II pyrethroids (deltamethrin, [1R,cis]-cypermethrin and
    [2S, alpha2]-fenvalerate) increased the input resistance of crayfish
    claw opener muscle fibres bathed in GABA. In contrast, two
    non-insecticidal stereoisomers and Type I pyrethroids (permethrin,
    resmethrin, allethrin) were inactive. Therefore, cyanophenoxybenzyl
    pyrethroids appear to act on the GABA receptor-ionophore complex
    (Gammon & Casida, 1983).

        The effects of pyrethroids on end-plate and muscle action
    potentials were studied in the pectoralis nerve-muscle preparation of
    the clawed frog (Xenopus laevis). Type II pyrethroids (cypermethrin
    and deltamethrin) induced trains of repetitive muscle action
    potentials without presynaptic repetitive activity. However, an
    intermediate group of pyrethroids (1R-permethrin, cyphenothrin, and
    fenvalerate) caused both types of effect. Thus, in muscle or nerve
    membrane the pyrethroid induced repetitive activities due to a
    prolongation of the sodium current. But no clear distinction was
    observed between non-cyano and alpha-cyano pyrethroids (Ruigt & Van
    den Bercken, 1986).

    Appraisal

        In summary, the results strongly suggest that the primary target
    site of pyrethroid insecticides in the vertebrate nervous system is
    the sodium channel in the nerve membrane. Pyrethroids without an
    alpha-cyano group (allethrin, d-phenothrin, permethrin, and
    cismethrin) cause a moderate prolongation of the transient increase in
    sodium permeability of the nerve membrane during excitation. This
    results in relatively short trains of repetitive nerve impulses in
    sense organs, sensory (afferent) nerve fibres, and, in effect, nerve
    terminals. On the other hand, the alpha-cyano pyrethroids cause a
    long-lasting prolongation of the transient increase in sodium
    permeability of the nerve membrane during excitation. This results in
    long-lasting trains of repetitive impulses in sense organs and a
    frequency-dependent depression of the nerve impulse in nerve fibres.
    The difference in effects between permethrin and cypermethrin, which
    have identical molecular structures except for the presence of an
    alpha-cyano group on the phenoxybenzyl alcohol, indicates that it is
    this alpha-cyano group that is responsible for the long-lasting
    prolongation of the sodium permeability.

        Since the mechanisms responsible for nerve impulse generation and
    conduction are basically the same throughout the entire nervous
    system, pyrethroids may also induce repetitive activity in various
    parts of the brain. The difference in symptoms of poisoning by
    alpha-cyano pyrethroids, compared with the classical pyrethroids, is
    not necessarily due to an exclusive central site of action. It may be
    related to the long-lasting repetitive activity in sense organs and
    possibly in other parts of the nervous system, which, in a more
    advance state of poisoning, may be accompanied by a
    frequency-dependent depression of the nervous impulse.

        Pyrethroids also cause pronounced repetitive activity and a
    prolongation of the transient increase in sodium permeability of the
    nerve membrane in insects and other invertebrates. Available
    information indicates that the sodium channel in the nerve membrane is
    also the most important target site of pyrethroids in the invertebrate
    nervous system (Wouters & Van den Bercken, 1978; WHO, 1979).

        Because of the universal character of the processes underlying
    nerve excitability, the action of pyrethroids should not be considered
    restricted to particular animal species, or to a certain region of the
    nervous system. Although it has been established that sense organs and
    nerve endings are the most vulnerable to the action of pyrethroids,
    the ultimate lesion that causes death will depend on the animal
    species, environmental conditions, and on the chemical structure and
    physical characteristics of the pyrethroid molecule (Vijverberg & Van
    den Bercken, 1982).

    


    See Also:
       Toxicological Abbreviations
       Resmethrins (HSG 25, 1989)