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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION



    TOXICOLOGICAL EVALUATION OF CERTAIN 
    VETERINARY DRUG RESIDUES IN FOOD



    WHO FOOD ADDITIVES SERIES 45





    Prepared by the
    Fifty-fourth meeting of the Joint FAO/WHO
    Expert Committee on Food Additives (JECFA)



    World Health Organization, Geneva, 2000

    CYHALOTHRIN

    First draft prepared by 
    D.W. Renshaw
    Joint Department of Health Ministry of Agriculture, Food and Fisheries
    Food Standards and Safety Group, Department of Health, London, United
    Kingdom

            Explanation
            Biological data
                Biochemical aspects 
                    Pharmacodynamics
                    Absorption, distribution, excretion, and
                    biotransformation
                Toxicological studies
                    Acute toxicity
                    Short-term studies of toxicity
                    Long-term studies of toxicity and carcinogenicity
                    Genotoxicity
                    Reproductive toxicity
                        Multigeneration studies
                        Developmental toxicity
                    Special studies 
                        Neurotoxicity
                        Neurobehavioural effects
                        Immunotoxicity
                    Observations in humans
                Comments 
                Evaluation 
                References 


    1.  EXPLANATION

         Cyhalothrin is a type II pyrethroid insecticide and acaricide.
    Technical-grade cyhalothrin (about 98% pure), which was the material
    used in most of the toxicological studies, consists mainly of four of
    the possible 16 isomers. These four isomers comprise two pairs of
    enantiomers, A and B, in a ratio of 60:40. Within each pair, the
    enantiomers are present in equal amounts.

         Cyhalothrin is used predominantly on cattle and sheep, and to a
    lesser extent on pigs and goats, for the control of a broad range of
    ectoparasites, including flies, lice, and ticks. Cyhalothrin is
    applied topically as a pour-on formulation to cattle at doses of up to
    60 ml (1.2 g) for ticks and 10 ml (0.2 g) for lice or flies, and to
    sheep and pigs at a dose of 5 ml (0.1 g) for all applications.
    Cyhalothrin is also available as a 20% (w/v) emulsifiable concentrate
    for use as a spray or a dip, prepared by dilution to 0.002-0.2%. It is
    applied at a dose of 0.1-4 L per animal, depending on the size of
    animal and the pest for which it is applied. In general, the more
    dilute the spray or dip, the greater the volume applied. A related
    product, lambda-cyhalothrin, contains only the B pair of enantiomers.

         The Committee has not previously evaluated cyhalothrin. It had
    however been evaluated toxicologically by the 1984 Joint FAO/WHO
    Meeting on Pesticide Residues, when an ADI of 0-0.02 mg/kg bw was
    established (JMPR, 1985). It had also been reviewed in an
     Environmental Health Criteria monograph (WHO, 1990).

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Pharmacodynamics

         Type II pyrethroids are characterized by the presence of an
    alpha-cyano group. Their main action is to alter the sodium channels
    in the nerve membrane reversibly, causing persistent prolongation of
    the transient increase in the permeability of the neuronal membrane to
    sodium during excitation (Vijverberg et al., 1982; Narahashi, 1985;
    Aldridge, 1990; Coats, 1990; Vijverberg & van den Bercken, 1990). Type
    II pyrethroids depress resting chloride conductance, thereby
    amplifying any effects of sodium or calcium (Ray, 1991). 

         Cyhalothrin and permethrin have been shown  in vitro to be
    potent inhibitors of mitochondrial complex I but not of complex II,
    III, IV, or V. In isolated mitochondria from rat liver,
    concentration-dependent inhibition of glutamate and succinate stage 3
    respiration was seen (Gassner et al., 1997).

         It has been postulated that type II pyrethroids exert some of
    their effects by binding to the gamma-aminobutyric acid (GABA)
    receptor, but they inhibit this receptor much less than the cyclodiene
    insecticides (Bloomquist et al., 1986). 

         Type II pyrethroids act primarily on the central nervous system,
    whereas type I pyrethroids act mainly on peripheral nerves (Barnes &
    Verschoyle, 1974; Lawrence & Casida, 1982).

    2.1.2  Absorption, distribution, excretion, and biotransformation

         The studies on cyhalothrin summarized in this section date from
    the early 1980s, and many were not conducted in accordance with the
    requirements of good laboratory practice (GLP). They were, however,
    well conducted by the standards of the time and were monitored by a
    quality assurance team. In the studies of Harrison, the batch of
    cyhalothrin used was > 99% pure  cis-Z-cyhalothrin, but individual
    isomers were not measured in either the test material or tissues or
    body fluids.

          Rats 

         Groups of six male and six female Alderley Park Wistar (Alpk/Ap)
    specific pathogen-free (SPF) rats were given a single dose of 1 or 25
    mg/kg bw of 14C-cyhalothrin in corn oil by oral gavage. The
    investigation was conducted with cyhalothrin labelled either at the
    3-phenoxybenzyl side-chain (i.e. the carbon to which the cyanide
    moiety is attached: 14CHCN) or at the 1 position of the cyclopropyl
    moiety. Separate experiments were performed in rats with bile duct
    cannulae. Another group of male and female rats were given a
    subcuta-neous dose of 1 mg/kg bw of 14CHCN-labelled cyhalothrin.

         Approximately 30-40% of the orally administered 14CHCN-labelled
    material was recovered in urine, most of the remainder appearing in
    the faeces. The rate of excretion was unaffected by the dose. Peak
    blood concentrations (approximately 0.6 and 6 g/kg of cyhalothrin
    equivalents at 1 and 25 mg/kg bw, respectively) were reached 7 h after
    dosing. By 48 h, the concentrations had depleted to less than 10% of
    the peak value. In bile duct-cannulated rats, biliary excretion
    accounted for 4.8% of the total excretion in males and 8.9% in
    females, but the amounts excreted in both urine and bile were doubled
    when the cyhalothrin was co-administered with bile. Most of the
    administered material was recovered within 24 h, and only 2-3% of the
    administered radiolabel remained in the carcass after 7 days. The
    radiolabel was distributed mainly to fat. Table 1 shows the
    concentrations in adipose tissues and liver; very little
    (approximately 2-7 g/kg as equivalents) was found in bone, muscle,
    gonads, kidney, lungs, and heart. Elimination of radiolabel was slower
    after subcutaneous administration of 14CHCN-labelled cyhalothrin
    than after oral dosing, and 58% of the radiolabel was still present in
    the carcass 7 days after dosing. With cyclopropyl-labelled
    cyhalothrin, smaller proportions of the administered radiolabel were
    recovered in the urine (18-30%), and the rate of excretion was slower
    than with 14CHCN-cyhalothrin. Peak blood concentrations were
    achieved at 4 h, but these had declined to 10% of the peak values by
    48 h. Only 1-3% of the administered dose remained in the carcass after
    7 days.

         Analysis by thin-layer chromatography (TLC) showed that most of
    the faecal radiolabel consisted of unchanged cyhalothrin (probably
    unabsorbed material). In contrast, no unchanged material was detected
    in urine or bile. Most of the radiolabel in urine (98%) was in the
    form of highly polar compounds. The patterns of metabolites derived
    from the two 14C-labelled forms of cyhalothrin were totally
    different, suggesting that the metabolism involves initial cleavage of
    the ester bond. Of the urinary material derived from
    cyclopropyl-labelled cyhalothrin, 60% could be hydrolysed by
    glucuronidase. Two major urinary metabolites were derived from
    14CHCN-labelled cyhalothrin, representing 75% and 17% of the
    administered dose. Both were polar and resistant to glucuronidase.
    Three biliary metabolites were derived from 14CHCN-labelled
    cyhalothrin, two of which (representing 12% and 67% of the dose) were
    different from the urinary metabolites (Harrison, 1981, 1984a).

        Table 1.  Residues of cyhalothrin equivalents in selected tissues 7 days after 
              dosing

                                                                                      

    Tissue                               Tissue concentration (g/kg as equivalents)
                                                                                      
                                         1 mg/kg bw             25 mg/kg bw
                                                                                      
                                         Males      Females     Males     Females
                                                                                      

    14CHCN-labelled material

    Brown fat                              65          93        870        2 000
    White fat                             340         330       6400       12 000
    Liver                                 320         540        320          540

    14C-Cyclopropyl-labelled material

    Brown fat                              40          54       1600        2 200
    White fat                             160         300       6900       12 000
    Liver                                  21          20        930          740
                                                                                      
    

         In a separate study, groups of six male and six female Alpk/Ap
    rats were given daily doses of 1 mg/kg bw of 14CHCN- or
    14C-cyclopropyl-cyhalothrin by oral gavage in corn oil for 14 days.
    Groups of animals were killed 2, 5, and 7 days after the final dose
    and the radiolabel was measured in various tissues, urine, and faeces.
    Up to 50% of each radiolabelled material was excreted in the urine and
    the remainder in the faeces. Excretion was rapid, over 90% of the
    daily dose being excreted within 24 h and over 90% of the cumulative
    dose being excreted within 7 days of the end of dosing. Most of the
    residue was located in fat, the concentrations in other tissues
    ranging from 20 to 460 g/kg (as equivalents) 2 days after the end of
    dosing. The residue in fat depleted slowly, with an estimated
    half-time of 23 days. The depletion of residues from brown and white
    fat is shown in Table 2. The half-time in white fat was estimated to
    be 30 days. The concentrations of residue found at 2, 5, and 7 days in
    the animals given 14CHCN-cyhalothrin were almost identical to those
    in the animals given 14C-cyclopropyl-cyhalothrin. Analysis by
    high-performance liquid chromatography (HPLC) showed that most of the
    residue in white fat (79%) was in the form of unchanged cyhalothrin
    (Harrison, 1984b).

        Table 2. Depletion of residues from adipose tissues 

                                                                                  

    Tissue       Tissue concentration of radiolabel (g/kg)
                                                                                  
                 2 days                5 days                7 days
                                                                                  
                 CHCN     Cyclopropyl  CHCN    Cyclopropyl   CHCN    Cyclopropyl
                                                                                  

    Brown fat    1900     2300         1100    1000           820     500
    White fat    4200     3600         4400    3500          3300    3400
                                                                                  
    

         The biotransformation of cyhalothrin was examined in groups of
    six male and six female Alpk/Ap rats that were given either daily oral
    doses of 12.5 mg/kg bw of 14CHCN-cyhalothrin for 8 days or daily
    oral doses of 1 mg/kg bw of 14C-cyclopropyl-cyhalothrin for 14 days.
    The major urinary metabolites were analysed by TLC, HPLC, mass
    spectrometry, and nuclear magnetic resonance spectroscopy. Cyhalothrin
    was initially cleaved at the ester bond, breaking the pyrethroid
    structure and therefore presumably detoxifying it. This cleavage
    produced a cyclopropyl carboxylic acid and the phenoxybenzyl cyano
    alcohol, which was subsequently metabolized to
    3-(4'-hydroxyphenoxy)benzoic acid. Cyclopropyl carboxylic acid was
    excreted in the urine, largely as the glucuronic acid conjugate,
    whereas 3-(4'-hydroxyphenoxy)benzoic acid was excreted mainly (~75%)
    as the sulfate conjugate. Small amounts of free
    3-(4'-hydroxyphenoxy)benzoic acid, 3-phenoxybenzoic acid, and
    cyclopropyl carboxylic acid were also found in the urine. It was
    concluded that the metabolism of cyhalothrin in rats proceeded along
    routes similar to those of other type II pyrethroids (Figure 1)
    (Harrison, 1983).

          Dogs 

         Groups of three male and three female beagle dogs were given a
    single oral dose of 1 or 10 mg/kg bw of either 14CHCN- or
    14C-cyclopropyl-cyhalothrin dissolved in corn oil and administered
    in a gelatin capsule. Other groups of dogs were given a single
    intravenous injection of 0.1 mg/kg bw (in ethanol:0.9% saline in a
    3.2:1.2 ratio) of each material. Blood samples and excreta were
    collected over 7 days after dosing and were analysed for radiolabel by
    liquid scintillation counting. Metabolites were measured by TLC, and
    the identities of selected metabolites were confirmed by mass
    spectrometry.

    FIGURE 1

         Excretion was initially rapid, most of the administered doses
    being eliminated within the first 48 h after dosing, but excretion was
    still incomplete at 7 days. After 14CHCN-cyhalothrin was given
    orally, approximately 30% of the administered dose was found in urine
    at 7 days and about 50% in faeces. When 14C-cyclopropyl-cyhalothrin
    was given, the proportion of residue in urine was slightly lower (19%)
    and the amount in faeces higher (68%). The proportions of residue in
    urine and in faeces were approximately equal when the two
    radiolabelled forms of cyhalothrin were given intravenously. A large
    proportion (46-87%) of the faecal residue was in the form of unchanged
    cyhalothrin after oral dosing, but only small amounts (1.4-1.5% of
    faecal radiolabel) were found in faeces after intravenous injection,
    suggesting that the oral dose of cyhalothrin was only partially
    absorbed from the gut lumen, leaving unabsorbed cyhalothrin in the
    faeces.

         Metabolism occurred initially by cleavage of the ester bond to
    give a phenoxybenzyl moiety and a cyclopropane acid moiety. Further
    metabolism of the phenoxybenzyl moiety produced  N-(3-phenoxybenzoyl)
    glycine, 3-(4'-hydroxyphenoxy)benzoic acid and its sulfate conjugate,
    3-phenoxybenzoyl glucuronide, small amounts of various other
    conjugates of these compounds, and a little free phenoxybenzoic acid.
    The cyclopropane acid moiety was extensively metabolized to at least
    11 further metabolites, including 45% as the glucuronide of the
    cyclopropane acid and up to 23% as the free cyclopropane acid (i.e.
    3-( Z-2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclo-propane
    carboxylic acid; see Figure 1 (Harrison, 1984c).

          Humans 

         In a study of three teams of seven pesticide applicators in
    Pakistan, the men were monitored over 15 days while they were using a
    pesticide formulation which contained 10% lambda-cyhalothrin and for a
    further 4 days after they had finished spraying. The men wore typical
    work clothing with no personal protective equipment while spraying
    dwellings to kill mosquitoes as part of a malaria control programme.
    All of the workers underwent four medical examinations, including
    blood sampling, before the study, in the middle of the first week, in
    the middle of the second week, and 4 days after the last spraying, and
    were questioned about adverse effects. Urine samples were collected
    daily. Fifteen men who lived in the treated dwellings were monitored
    for exposure by collection and analysis of 24-h urine samples for 3
    consecutive days after the spraying of their houses. The samples of
    urine and serum were treated enzymically to deconjugate the
    metabolites and were then analysed by gas chromatography with mass
    spectroscopy. The cyhalothrin metabolites measured were
    3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-
    dimethylcyclopropanecarboxylic acid, 3-phenoxybenzoic acid, and
    3-(4'-hydroxyphenoxy)-benzoic acid. The limit of determination for all
    three metabolites was 0.01 g/ml. These metabolites are products of
    cleavage of the ester bond in cyhalothrin, and their presence
    indicates that the initial metabolism of cyhalothrin is similar in
    humans to that observed in other species.

         The average exposure of the workers to lambda-cyhalothrin was
    estimated to be 54 g/person per day (extrapolated from measured
    metabolites in urine). 3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-
    dimethylcyclopropanecarboxylic acid was usually the most abundant
    metabolite in urine. No metabolites were detected in serum samples.
    Most of the inhabitants of treated houses had no detectable residues
    in their urine, although they were measurable in 12 of 44 samples, and
    the measured concentrations were at or close to the limit of
    determination. Most values were not reported, but the highest
    concentration of urinary metabolites was 0.1 mg/person per day
    (Chester et al., 1992). The signs of toxicity found are reported
    below.

    2.2  Toxicological studies

         Most of the toxicological studies of cyhalothrin were performed
    during 1980-84, and some were therefore conducted before GLP was
    widely introduced. The chemical identity of the cyhalothrin used in
    each study is not clearly stated, and, although the purity was
    reported in most cases, the isomers and the isomer ratios were not
    mentioned in most of the reports. The manufacturer has claimed that
    the analysis given in appendices to the report of the inclined plane
    test (see below) is typical of technical-grade cyhalothrin. The
    manufacturer also claimed that measurements made over the last
    15 years have shown little variation in the isomer ratio. Two
    measurements from 1985 gave about 56% for the A isomeric pair and 41%
    for the B isomeric pair, leaving only about 2% for other isomers and
    impurities (Woodward, 2000).

    2.2.1  Acute toxicity

         Acute poisoning of rats with type II pyrethroids such as
    cyhalothrin is typically characterized by progressive development of
    'nosing' and exaggerated jaw opening, increasing extensor tone in the
    hind limbs causing a rolling gait, choreoathetosis (sinuous writhing
    spasms), salivation, incoordination progressing to coarse tremor,
    tonic seizures, apnoea, and death (Barnes & Verschoyle, 1974; Ray,
    1991). This has been called the choreoathetosis/salivation syndrome or
    CS syndrome. In dogs, similar symptoms are seen, but salivation, upper
    airway hypersecretion, and gastrointestinal symptoms are more
    prominent than in rats (Ray, 1991).

         As in poisoning with type I pyrethroids, the plasma noradrenaline
    concentration is increased by type II pyrethroids, but they also
    increase plasma adrenaline and blood glucose concentrations. Type II
    pyrethroids increase cardiac contractility both directly by action on
    cardiac muscle and via circulating catecholamines. They also cause
    repetitive firing and potentiate contraction in skeletal muscle. The
    type II pyrethroids do not produce the repetitive activity in sensory
    nerves that is seen after exposure to type I pyrethroids (Ray, 1991).


        Table 3.  LD50 values for cyhalothrin

                                                                                                           
    Species       Sex   Route              Purity       Vehicle      LD50          Reference
                                           (%)                       (mg/kg bw)
                                                                                                           

    Rat           M     Oral               90/94 cis    Corn oil     240           Nixon & Jackson (1981)
    Rat           M     Oral               92.9         Corn oil     170           Pritchard (1984)
    Rat           M     Oral               90           Oilve oil    51            Ebino et al. (1984a)
    Rat           F     Oral               90/94 cis    Corn oil     140           Nixon & Jackson (1981)
    Rat           F     Oral               92.9         Corn oil     110           Pritchard (1984)
    Rat           F     Oral               90           Olive oil    65            Ebino et al. (1984a)
    Mouse         M     Oral               90/94 cis    Corn oil     37            Nixon & Jackson (1981)
    Mouse         F     Oral               90/94 cis    Corn oil     62            Nixon & Jackson (1981)
    Guinea-pig    M     Oral               90/94 cis    Corn oil     > 5000        Nixon & Jackson (1981)
    Rabbit        F     Oral               89.2         Corn oil     > 1000        Jones (1980)
    Chicken       F     Oral               93.4         Corn oil     > 10 000      Roberts et al. (1982)
    Rat           M     Dermal             90           Undiluted    3600          Ebino et al. (1984d)
    Rat           F     Dermal             90           Undiluted    3700          Ebino et al. (1984d)
    Rabbit        M     Dermal             90/94 cis    Propylene    > 2 ml/kg     Nixon & Jackson (1981)
                                                        glycol
    Rabbit        F     Dermal             90/94 cis    Propylene    > 2 ml/kg     Nixon & Jackson (1981)
                                                        glycol
    Rat           M     Intraperitoneal    90/94 cis    Corn oil     250-750       Nixon & Jackson (1981)
    Rat           M     Intraperitoneal    90           Oilve oil    500           Ebino et al. (1984c)
    Rat           F     Intraperitoneal    90           Oilve oil    420           Ebino et al. (1984c)
    Rat           M     Subcutaneous       90           Oilve oil    > 5000        Ebino et al. (1984e)
    Rat           F     Subcutaneous       90           Oilve oil    > 5000        Ebino et al. (1984e)
                                                                                                           
    

         The acute toxicity of cyhalothrin was investigated in a series of
    studies that complied with GLP (Nixon & Jackson, 1981; Roberts et al.,
    1982; Pritchard, 1984) and also in studies that, although not GLP
    compliant, were accompanied by a suitable quality assurance statement
    (Jones, 1980; Ebino et al., 1984a-e). The LD50 values estimated from
    these studies are listed in Table 3. The LD50 of a wettable
    formulation containing 5% cyhalothrin was 1200 mg/kg bw in male rats
    and 900 mg/kg bw in females when it was administered orally in olive
    oil (Ebino et al., 1981b).

         The signs of toxicity seen in all species and with all routes of
    administration were similar and included subdued behaviour, ungroomed
    appearance, piloerection, salivation, incontinence, and unsteady gait.
    A further account of the signs of acute toxicity in rats receiving
    various oral doses of cyhalothrin is given in the preliminary report
    of the inclined plane test (Denton, 1988), which is described below.

    2.2.2  Short-term studies of toxicity

          Mice 

         In a range-finding study for an assay of dominant lethal mutation
    that complied with GLP, groups of 10 male CD-1 mice were given
    technical-grade cyhalothrin (purity, 89.25%; containing 92.2%
    pyrethroids of which 96.8% was cyhalothrin) at a dose of 0, 5, 10, 20,
    40, or 80 mg/kg bw per day by oral gavage in corn oil for 5 days. At
    the two higher doses, signs of severe toxicity (ataxia and
    convulsions) were observed. One animal at 40 mg/kg bw per day and
    eight at 80 mg/kg bw per day died. Less severe clinical signs were
    seen at 20 mg/kg bw per day, including body-weight loss, ataxia, and a
    rough coat. Only rough coats were seen at 5 mg/kg bw per day (Irvine,
    1981a).

         In a range-finding study for a long-term study of toxicity and
    carcinogenicity, groups of 12 male and 12 female CD-1 mice were fed
    diets containing technical-grade cyhalothrin (purity unspecified) at a
    concentration of 0, 5, 25, 100, 500, or 2000 mg/kg of diet. Over the
    course of the 4-week study, these concentrations gave mean doses of
    cyhalothrin of 0, 0.65, 3.3, 14, 64, and 310 mg/kg bw per day for
    males and 0, 0.80, 4.2, 15, 78, and 290 mg/kg bw per day for females.
    No certificate of compliance with GLP was available for this study,
    but quality assurance systems were in place. 

         Deaths were seen only at the highest dietary concentration, at
    which six males and three females died prematurely. Severe signs of
    toxicity were also seen at this dose, including abnormal gait
    ('walking on toes'), hunched posture, decreased body weight (Student's
     t test,  p < 0.01), and increased respiratory rate. Piloerection
    was observed in several animals in each groups given cyhalothrin at
    > 25 mg/kg and in one control male and one male at 5 mg/kg of diet.
    Haematological changes were seen in males (statistically significant
    in Williams' test:  p < 0.05) but not in females. Animals at 2000
    mg/kg of diet had a decreased total leukocyte count accompanied by a

    lower lymphocyte count and a higher neutrophil count. Those at 100 and
    500 mg/kg of diet also had marginally lowered lymphocyte counts.

         Macroscopic examinations  post mortem revealed no adverse
    effects other than altered organ weights (statistically significant in
    both Student's  t test and Williams' test:  p < 0.05). The weight
    of the kidney relative to body weight was slightly elevated in males
    given 100, 500, or 2000 mg/kg of diet and in females given 2000 mg/kg
    of diet. The relative liver weights were also slightly increased in
    males given 25 or 2000 mg/kg of diet and in females given 2000 mg/kg
    of diet. The heart weights were marginally decreased in females given
    100 or 2000 mg/kg of diet. The activity of aminopyrine- N-demethylase
    in liver was increased in males given 2000 mg/kg of diet and in
    females given 100, 500, or 2000 mg/kg of diet (Student's  t test:
     p < 0.05). Histopathological examination showed minimal
    centrilobular hepatocyte enlargement in two females at 2000 mg/kg of
    diet. Atrophy of the red pulp of the spleen was seen in two of the
    three females at this dose that died. The Committee considered that
    the effect may have been indicative of immunological changes. The NOEL
    was 5 mg/kg of diet, equal to 0.65 mg/kg bw per day, on the basis of
    piloerection at concentrations > 25 mg/kg of diet (Colley et al.,
    1981).

         When liver samples from this study were examined by electron
    microscopy, minimal amounts of smooth endoplasmic reticulum were
    observed in occasional hepatocytes from some mice from each group,
    including controls. Most hepatocytes contained no observable smooth
    endoplasmic reticulum. The incidence of mice with hepatocytes
    containing smooth endoplasmic reticulum was highest in the group given
    cyhalothrin at 2000 mg/kg of diet, consistent with the finding of
    other hepatic effects in this group (Prentice et al., 1981).

          Rats 

         In a range-finding study for an investigation of developmental
    toxicity, groups of 10 female Charles River CD rats were given
    technical-grade cyhalothrin (purity, 89.25%; containing 92.2%
    pyrethroids of which 96.8% was cyhalothrin) at a dose of 0, 10, 20,
    40, or 80 mg/kg bw per day by oral gavage in corn oil for 10
    consecutive days. After treatment, the animals were observed for a
    7-day recovery period. No certificate of compliance with GLP was
    supplied, but suitable quality assurance records had been kept.

         All of the animals given 80 mg/kg bw per day, nine of those given
    40 mg/kg bw per day, and two given 20 mg/kg bw per day had to be
    killed for humane reasons after the first dose, as this caused severe
    toxicity (ataxia and/or collapse). Body-weight loss and reduced food
    intake were seen in the rats given 20 mg/kg bw per day throughout the
    treatment period. Body-weight loss was also seen in the rats given 10
    mg/kg bw per day during the first 5 days of the study. Food intake was
    increased in the groups at 10 and 20 mg/kg bw per day during the

    recovery period. Macroscopic examination of the animals at necropsy
    revealed no treatment-related changes. No NOEL could be identified in
    this study (Killick, 1980).

         In a 28-day range-finding study, groups of 10 male and 10 female
    Charles River CD rats were fed diets containing technical-grade
    cyhalothrin (purity unspecified) at a concentration of 0, 5, 10, 20,
    or 250 mg/kg of diet, equivalent to 0, 0.5, 1, 2, and 25 mg/kg bw per
    day. The study did not comply with GLP. There were no
    treatment-related clinical signs and no deaths. Food intake, food
    efficiency, and body-weight gain were decreased only at the highest
    dose (Student's  t test:  p < 0.05). Gross examination  post 
     mortem revealed no treatment-related effects, and organ weights were
    unaffected by treatment. Electron microscopy of liver samples showed a
    moderate increase in the amount of smooth endoplasmic reticulum in
    hepatocytes of animals at the highest dose, with a decrease in the
    amount of glycogen. An increase in hepatocyte size was noted in the
    centrilobular and mid-zonal regions of the livers of males at this
    dose, which also had increased hepatic activity of
    aminopyrine- N-demethylase (Student's  t test:  p < 0.001). The
    NOEL was 20 mg/kg of diet, equivalent to 2 mg/kg bw per day (Colley et
    al., 1980).

         In a study that complied with GLP, groups of eight male and eight
    female Wistar-derived Alderley Park rats were fed diets containing
    technical-grade cyhalothrin (purity, 89.2%) at a concentration of 0,
    1, 5, 10, 20, or 250 mg/kg of diet, equivalent to 0, 0.1, 0.5, 1, 2,
    and 25 mg/kg bw per day. Full post-mortem examinations were not
    performed, but samples of liver were taken for analysis of
    aminopyrine- N-demethylase activity and electron microscopy. No
    treatment-related clinical signs were reported. The mean body weight
    of males given 250 mg/kg of diet was decreased when compared with that
    of concurrent controls during weeks 1 and 2 of the study (two-sided
     t test:  p < 0.05). Body-weight gain was depressed during week 1
    for males given 250 mg/kg of diet and for females given 10, 20, or 250
    mg/kg of diet (two-sided  t test:  p < 0.05). The absolute weight
    of the liver was reduced in males given 250 mg/kg of diet and in
    females given 20 mg/kg of diet (two-sided  t test:  p < 0.05), but
    the relative weight of the liver was increased in males at 250 mg/kg
    of diet. Both males and females at this dose had increased hepatic
    activity of aminopyrine- N-demethylase and mild proliferation of
    smooth endoplasmic reticulum in hepatocytes. The NOEL was 5 mg/kg of
    diet, equivalent to 0.5 mg/kg bw per day, on the basis of depression
    of body-weight gain, whereas that for hepatic changes was 20 mg/kg of
    diet, equivalent to 2 mg/kg bw per day (Moyes et al., 1984).

         In a 28-day range-finding study, of which full details were not
    available, a dietary concentration of cyhalothrin of 750 mg/kg
    (equivalent to 75 mg/kg bw per day) increased the mortality rate.
    'Characteristic signs of pyrethroid neurotoxicity' were seen at
    dietary concentrations of 250 and 750 mg/kg. Treatment-related effects
    on body weights, food consumption, organ weights, and hepatic activity
    of aminopyrine- N-demethylase were seen at 250 mg/kg of diet. Hepatic

    smooth endoplasmic reticulum proliferation occurred in males fed 20
    and 250 mg/kg of diet. No NOEL could be identified (Lindsey et al.,
    1981).

         In a 90-day study that complied with GLP, groups of 20 male and
    20 female Wistar-derived Alderley Park rats were fed diets containing
    technical-grade cyhalothrin (purity, 89.2%; with a total pyrethroid
    content of 92.2% of which 96.8% was cyhalothrin) at a concentration of
    0, 10, 50, or 250 mg/kg of diet, providing mean doses of 0, 0.56, 2.6,
    and 36 mg/kg bw per day for males and 0, 0.57, 3.2, and 15 mg/kg bw
    per day for females. Blood samples were collected before treatment,
    during week 4 of treatment, and at the end of the study. Urine samples
    were collected before treatment and in weeks 4 and 13. Ophthalmoscopic
    examinations were performed during the week before termination. Full
    post-mortem examinations were performed, and the major organs and any
    grossly abnormal tissues were examined histologically. Liver samples
    were taken for analysis of aminopyrine- N-demethylase activity and
    examination by electron microscopy.

         Treatment with doses < 250 mg/kg of diet had no effect on the
    mortality rate. The body-weight gain of males at the highest dose was
    consistently reduced (two-sided  t test:  p < 0.01) throughout the
    study. Food consumption was slightly reduced in males at 50 and 250
    mg/kg of diet, and this effect was occasionally statistically
    significant (two-sided  t test:  p < 0.05). There were no clearly
    treatment-related haematological effects, although there were small,
    significant, but not dose-related changes in some red blood cell
    parameters (mean corpuscular volume, packed cell volume, haemoglobin,
    mean corpuscular haemoglobin). Plasma alanine and aspartate
    aminotransferase activities and cholesterol concentration were raised
    at 4 weeks in males given 10 or 50 mg/kg of diet, and those at the
    lower dose also had a raised plasma urea concentration (two-sided
     t test:  p < 0.05). At 13 weeks, however, the plasma concentration
    of urea in males at 50 mg/kg of diet was decreased (two-sided
     t test:  p < 0.05). The observed effects on haematological
    parameters, plasma enzyme activity, and concentrations of cholesterol
    and urea were considered to be unrelated to treatment as there were no
    clear dose-response relationships. At 13 weeks, however, the plasma
    triglyceride concentration was reduced and there was a dose-related
    increase in urinary glucose concentration in males at 50 and 250 mg/kg
    of diet (two-sided  t test:  p < 0.05). Ophthalmoscopy revealed no
    treatment-related effects. The results of gross examinations were not
    reported, although the organ weights were recorded. The absolute
    weight of the liver was increased in males at 250 mg/kg of diet, and
    the absolute weight of the lung was decreased in animals given 250
    mg/kg of diet, but the relative weights of these organs were
    unaffected. No treatment-related changes were revealed by optical
    microscopy of organs. Electron microscopy of the liver revealed mild
    proliferation of smooth endoplasmic reticulum in the hepatocytes of
    three males given 50 mg/kg of diet and three males given 250 mg/kg of
    diet. There was a dose-related increased in hepatic
    aminopyrine- N-demethylase activity in males given 50 or 250 mg/kg of
    diet and in females given 250 mg/kg of diet (two-sided  t test:

     p < 0.05). The NOEL was 10 mg/kg of diet, equivalent to 0.56 mg/kg
    bw per day, on the basis of hepatic changes in males at higher doses
    (Lindsey et al., 1981).

          Rabbits 

         In a range-finding study for an investigation of developmental
    toxicity, groups of six mated female New Zealand white rabbits were
    given cyhalothrin (purity, 89.25%) at a daily dose of 0, 20, 30, or 40
    mg/kg bw by oral gavage in corn oil on days 6-18 of gestation. The
    animals were killed on day 18 of gestation. 

         There were no unscheduled deaths and no consistent clinical signs
    of toxicity. Body-weight gain was depressed only at 30 mg/kg bw per
    day, although animals at 40 mg/kg bw per day showed reduced food
    intake. Not all of the animals became pregnant, but in all groups,
    including controls, few of the does had live fetuses. There was no
    dose-response relationship for this effect. Furthermore, not all of
    the pregnant does at 20 and 40 mg/kg bw per day produced live
    offspring. Consequently, there were insufficient numbers of litters to
    allow any meaningful inter-group comparison of litter parameters,
    although no adverse effects were apparent from the limited data
    available. No treatment-related macroscopic changes were seen  post 
     mortem. The apparent NOEL in this limited study was 20 mg/kg bw per
    day on the basis of reduced body-weight gain (Killick, 1981a).

          Dogs 

         In a preliminary study, groups of one male and one female beagles
    were given gelatin capsules containing cyhalothrin (purity
    unspecified) in corn oil at a dose of 0, 2.5, 10, or 30 mg/kg bw per
    day for 4 weeks. After 10 days, treatment with the high dose was
    stopped, and the animals were allowed to recover for 4 days; treatment
    was then resumed at a lower dose of 20 mg/kg bw per day for 4 weeks.
    Blood was taken weekly. Urine samples were collected before dosing and
    during week 4. Ophthalmoscopic examinations were performed on each dog
    before dosing and during week 4. No certificate of compliance with GLP
    was supplied, but suitable quality assurance records were kept.

         None of the dogs died prematurely. Muscular trembling was seen in
    all groups, including controls, but the degree of trembling was more
    marked in animals at the two higher doses. Unsteady gait and
    body-weight loss were observed in dogs given 30 mg/kg bw per day, but
    this effect was not seen after the dose was reduced to 20 mg/kg bw per
    day. Body weight was unaffected by doses up to 10 mg/kg bw per day,
    and only slight fluctuations occurred at 20 mg/kg bw per day. Vomiting
    was seen occasionally at doses > 10 mg/kg bw per day. Dogs at the
    high dose (30 or 20 mg/kg bw per day) had loose stools and increased
    serum alanine and aspartate aminotransferase activities. No
    haematological, ophthalmological, or urinary changes were observed,
    and no gross pathological or organ weight changes were noted  post 
     mortem. Histopathological examination revealed no treatment-related
    effects. No NOEL could be identified in this study owing to the

    finding of an increased frequency of liquid faeces at all doses. The
    LOEL was 2.5 mg/kg bw per day (Chesterman et al., 1983).

         In a 26-week study that complied with GLP, groups of six male and
    six female beagles were given cyhalothrin (purity unspecified)
    dissolved in corn oil inside a gelatin capsule at a dose of 0, 1.0,
    2.5, or 10 mg/kg bw per day. The dogs were examined
    ophthalmoscopically before dosing and during weeks 6, 12, and 24 of
    treatment. Blood and urine samples were taken every 4 weeks. The
    functional integrity of the nervous system was assessed clinically
    before treatment and during week 6. At the end of the treatment
    period, full necropsies were performed on all dogs, and a large
    selection of organs and tissues was examined histologically.

         No deaths occurred during the study. A dose-related increase in
    the incidence of liquid faeces affected all treated groups. At 10
    mg/kg bw per day, the clinical signs seen included vomiting,
    salivation, incoordination, unsteadiness, collapse, muscular spasms,
    and convulsions. Body weight was unaffected by treatment.
    Ophthalmoscopic and neurological examinations revealed no adverse
    effects, and no consistent haematological, serum biochemical, or
    urinary effects were seen. No treatment-related gross effects on organ
    weights or appearance were noted  post mortem, and histopathological
    examination revealed no treatment-related effects. No NOEL could be
    identified in this study owing to the finding of an increased
    frequency of liquid faeces at all doses. The LOEL was 1.0 mg/kg bw per
    day (Chesterman et al., 1981).

         In a 52-week study, groups of six dogs of each sex were given
    lambda-cyhalothrin at a dose of 0, 0.1, 0.5, or 3.5 mg/kg bw per day
    orally in corn oil, but there was lack of agreement between summaries
    of the study about whether the animals were treated by gelatin capsule
    (European Medicines Evaluation Agency, 1999) or by gavage (WHO, 1990).
    The report was not available to the Committee. Clinical signs of
    neurological effects (muscular trembling, unsteadiness, and vomiting)
    were seen in all dogs at the highest dose, but the signs were not
    accompanied by histological changes in the nervous system. The
    European Medicines Evaluation Agency (1999) reported a dose-related
    increased incidence of liquid faeces at all doses, but WHO (1990)
    reported that this effect was seen only at 0.5 and 3.5 mg/kg bw per
    day and that the increased incidence was only slight at 0.5 mg/kg bw
    per day. The incidence of liquid faeces was considered not to be
    toxicologically significant. The NOEL was 0.5 mg/kg bw per day on the
    basis of neurological signs seen at 3.5 mg/kg bw per day. It is
    unclear how this dose relates to a dose of cyhalothrin (WHO, 1990;
    European Medicines Evaluation Agency, 1999).

    2.2.3  Long-term studies of toxicity and carcinogenicity

          Mice 

         In a study that complied with GLP, groups of 52 male and 52
    female CD-1 mice were given diets containing technical-grade
    cyhalothrin (purity unspecified) at a concentration of 0, 20, 100, or
    500 mg/kg for 104 weeks, equal to 0, 1.8, 9.2, and 53 mg/kg bw per day
    for males and 0, 1.8, 11, and 51 mg/kg bw per day for females.
    Satellite groups of 12 mice of each sex were given the same diets for
    52 weeks and then killed. 

         The signs of toxicity observed in animals given high doses were
    piloerection and hunched posture in mice of each sex given 500 mg/kg
    of diet and in males given 100 mg/kg of diet. Males at 500 mg/kg of
    diet also showed emaciation, pallor, hyperactivity, and increased
    fighting activity. The mortality rate was unaffected by treatment.
    Decreased body-weight gain was seen in males at 500 mg/kg of diet
    throughout the study (two-sided Student  t test:  p < 0.05),
    particularly during the first 13 weeks ( p < 0.001). Reduced feed
    use efficiency was seen in the same group over the first 24 weeks of
    the study (not calculated for the rest of the study). Water
    consumption was also slightly increased in males at 500 mg/kg of diet
    (two-sided Student  t test:  p < 0.05).

         The results of haematological tests were unremarkable.
    Statistically significant changes in various parameters were seen at
    various times, but the effects were not consistent or dose-related.
    Urinary analysis revealed no significant differences from control
    values. The serum glucose concentration was slightly reduced
    (two-sided Student  t test:  p < 0.05) in animals given 500 mg/kg
    of diet. During week 100, serum alanine and aspartate aminotransferase
    activities were increased in a dose-related manner, with occasional
    significance ( p < 0.05) for both activities in mice of each sex at
    100 and 500 mg/kg of diet and for alanine aminotransferase activity in
    females at 20 mg/kg of diet.

         Gross examination  post mortem revealed increased incidences
    (not dose-related) of thickening of the forestomach in treated
    females. The ovarian weights were significantly (two-sided Student
     t test:  p < 0.05) decreased at all doses in animals in the main
    group but not in the satellite groups. The effect was not
    dose-related. Other organ weights were unaffected. Histopathological
    examination revealed a variety of non-neoplastic lesions, but none was
    considered to be due to treatment with cyhalothrin. 

         A non-dose-related increase in the incidence of mammary
    adenocarcino-mas was seen in females in the main group, the incidences
    being 1/52 in controls, 0/52 at 20 mg/kg of diet, 7/52 at 100 mg/kg of
    diet, and 6/52 at 500 mg/kg of diet. (The detailed statistical
    analysis of these results was given in an addendum to the report that
    was not available to the Committee.) The incidence of mammary
    adenocinoma in control females in 17 studies performed by the same

    laboratory between 1980 and 1982 ranged from 2% to 12%. No
    preneoplastic changes were found in the mammary glands of mice in the
    main or satellite groups. A re-evaluation of mammary tissues from all
    animals confirmed the original diagnoses of mammary neoplasia. As the
    highest incidence of mammary adenocarcinoma in any group was only
    slightly above the range of historical controls and as there was no
    dose-response relationship, it was concluded that treatment with
    cyhalothrin was unlikely to have caused these tumours. The NOEL was 20
    mg/kg of diet, equal to 1.8 mg/kg bw per day, on the basis of clinical
    signs of toxicity (piloerection and hunched posture) in males at
    higher doses (Colley et al., 1984).

          Rats 

         In a study that complied with GLP, groups of 72 male and 72
    female Alpk/AP SPF rats were fed diets containing technical-grade
    cyhalothrin (purity, 89.25%; containing 92.2% pyrethroids of which
    96.8% was cyhalothrin) at a concentration of 0, 10, 50, or 250 mg/kg
    for 104 weeks, providing mean doses of 0, 0.47, 2.3, and 12 mg/kg bw
    per day for males and 0, 0.55, 2.7, and 14 mg/kg bw per day for
    females. Satellite groups of 10 rats of each sex were given the same
    diets but were killed after only 52 weeks. Blood was taken for
    haematological measurements from 10 rats of each sex in each group at
    4 and 13 weeks and thereafter at 13-week intervals. Blood was taken
    for biochemical analyses and urine for urinary analyses from 12 rats
    of each sex in each group at the same intervals. In weeks 52 and 103,
    ophthalmoscopy was performed on 20 males and 20 females from each
    group.

         No clinical signs were seen that could be attributed to
    treatment. The mortality rate was unaffected. Body-weight gain was
    suppressed in both males and females given 250 mg/kg of diet
    (two-sided Student  t test:  p < 0.05), and the males in this group
    had increased food use efficiency. No consistent, dose-related
    haematological effects were seen, although changes in various
    parameters occasionally achieved statistical significance (two-sided
    Student  t test:  p < 0.05). The volume of urine produced by rats
    fed 250 mg/kg of diet tended to be decreased, but otherwise there was
    no effect on urinary parameters. Ophthalmoscopy revealed no
    treatment-related effects. Blood biochemistry showed intermittent
    effects in rats at 250 mg/kg of diet, consisting of reduced plasma
    concentrations of glucose and triglycerides, reduced plasma alkaline
    phosphatase activity, and increased plasma urea concentration
    (two-sided Student  t test:  p < 0.05). The reduction in plasma
    triglycerides was the most marked finding, especially in females. 

         Long, pointed fibres, thought to originate from the diet, were
    found embedded in the tissues of the palate, nasal turbinates, roof of
    the nasal cavity, and peridontal space. The presence of the fibres
    suggested that the lesions were caused by penetration of the tissue by
    these fibres rather than by cyhalothrin. No treatment-related gross
    lesions were detected  post mortem, but several rats in all groups,
    including controls, had rhinitis and oral lesions (oral granuloma

    formation and erosion of the palate) in response to the presence of
    the fibres in the diet. At the interim kill, the weight of the liver
    (relative to body weight) was increased in rats of each sex given 250
    mg/kg of diet, but this effect was not seen in rats killed at 104
    weeks. The weight of the adrenals (relative to body weight) was
    increased in females at 50 and 250 mg/kg of diet killed at 104 weeks.
    Histopathological examination revealed no treatment-related effect on
    the incidence or severity of any neoplastic or non-neoplastic lesions.
    The NOEL was 50 mg/kg of diet, equal to 2.3 mg/kg bw per day (Pigott
    et al., 1984).

    2.2.4  Genotoxicity

         Cyhalothrin was tested in assays for gene mutation in bacteria,
    cytogenicity in rats  in vivo, dominant lethal mutation in mice, and
    cell transformation. The results of all the assays were negative. The
    assays did not comply with GLP, but they appeared to be of good
    quality and suitable quality assurance records had been maintained.
    The studies are summarized in Table 4. The material tested by Trueman
    (1981) was analysed by reversed-phase HPLC and found to have a
     cis:trans ratio of 97.1:2.9.

         lambda-Cyhalothrin was reported to be non-genotoxic when tested
    for reverse mutation in bacteria, gene mutation in a mouse lymphoma
    cell line, cytogenicity  in vitro, unscheduled DNA damage  in 
     vitro, and micronucleus formation in mice (WHO, 1990). Full reports
    of these assays were not available, but the available details are
    given in Table 5. lambda-Cyhalothrin produced micronuclei in an assay
    in fish (Campana et al., 1999), but the relevance to human health of a
    positive result in this unvalidated assay is not known.

    2.2.5  Reproductive toxicity

         (a)  Multigeneration studies

          Mice 

         Only a brief account of a three-generation study of the effects
    of cyhalothrin on reproduction in mice has been reported. It is
    unclear whether the study was performed in accordance with the
    principles of GLP. Groups of albino Swiss mice were given oral doses
    of '0 (blank control), 2.5 ppm and 5.0 ppm cyhalothrin/kg body weight
    daily' (the meaning of the term 'ppm cyhalothrin/kg body weight' is
    unclear). The F0 generation consisted of groups of four males and
    eight females. No further details of the protocol were available. No
    signs of toxicity or behavioural changes were observed in the parents
    or offspring for up to three generations. Maternal body weights were
    not affected, although F2 generation dams at the low dose had
    increased food intake. The weights of pups of F2 dams treated at the
    high dose were reported to be significantly different from those of
    control pups. Male and female fertility indices, pup live birth and
    survival indices, litter size, and sex ratio were unaffected. The
    meaning of the results was unclear. No NOEL could be identified
    (Deshmukh, 1992).

        Table 4. Assays for genotoxicity with cyhalothrin

                                                                                                 
    End-point        Test object        Concentration       Purity   Results     Reference
                                                            (%)
                                                                                                 

     In vitro 
    Reverse          S. typhimurium     0.16-2500 g/       90.2     Negativea   Trueman (1981)
    mutation         TA1535, TA1537,    plate  S9
                     TA1538, TA98, 
                     TA100

    Cell             Syrian hamster     50-1000 g/ml       NR       Negativeb   Richold et al. 
    transformation                      - S9                                     (1981)
                                        1000-5000 g/ml 
                                        + S9

     In vivo 
    Cytogenicity     Bone marrow,       Single oral dose    89.2     Negativec   Anderson et al. 
                     Wistar-derived     of 1.5, 7.5,15 mg/                       (1983)
                     male rats          kg bw in corn oil 
                                        5 daily oral doses 
                                        of 1.5, 7.5, 15 mg/
                                        kg bw per day

    Dominant         Male CD1  mice     1, 5, 10 mg/kg bw/  89.2     Negatived   Irvine (1981b)
    lethal                              day for 5 days by 
    mutation                            oral gavage  
                                        in corn oil
                                                                                                 

    a   2-Aminoanthracene, 9-aminoacridine, 4-nitroquinoline- N-oxide, and 
         N-methyl- N'-nitro- N-nitrosoguanidine used as positive controls
    b   4-Nitroquinoline- N-oxide and  para-dimethylaminoazobenzene (butter yellow) used 
        as positive controls
    c   Ethyl methanesulphonate used as a positive control
    d   Cyclophosphamide used as a positive control

    Table 5. Assays for genotoxicity with lambda-cyhalothrin

                                                                                              
    End-point         Test object             Concentration       Results     Reference
                                                                                              

     In vitro 
    Reverse           S. typhimurium          < 5000 g/plate     Negative    IPCS (1990)
    mutation          (strains not             S9
                      specified)

    Gene mutation     L51787 mouse            125-4000 g/ml      Negative    IPCS (1990)
                      lymphoma cell            S9
                      line

    Unscheduled       Cultured human          NR                  Negative    IPCS (1990)
    DNA synthesis     HeLa cells

    Cytogenicity      Human lymphocytes       NR                  Negative    IPCS (1990)

     In vivo 
    Micronucleus      Erythrocytes of         0.001-0.05 g/L     Positive    Campana et al. 
    formation         Cheirodon interruptus                                   (1999)
                      interruptus

    Micronucleus      Mice                    < 35 mg/kg bw       Negative    IPCS (1990)
    formation                                 (route not 
                                              specified)a
                                                                                              

    a Cyclophosphamide used as a positive control
    

          Rats 

         Throughout a GLP-compliant three-generation (two litters per
    generation) study, groups of SPF Alpk/AP Wistar-derived rats were
    given diets containing technical-grade cyhalothrin (purity, 89.25%;
    containing 92.2% pyrethroids of which 96.8% was cyhalothrin) at a
    concentration of 0, 10, 30, or 100 mg/kg, providing mean doses of 0,
    0.6, 1.7, and 5.6 mg/kg bw per day for males and 0, 0.7, 1.9, and 6.1
    mg/kg bw per day for females. The F0 generation consisted of groups
    of 15 male and 30 female rats. After 12 weeks on the test diets, these
    animals were mated within their groups to produce a first litter
    (F1a generation). Later, they were mated again to produce a second
    litter (F1b generation). Breeding was repeated with F1 parents (15
    males and 30 females per group) selected from the F1b animals and
    F2 parents (15 males and 30 females per group) selected from the
    F2b animals. At day 36  post partum, all pups not selected as the
    next parental generation were killed and examined externally.
    Approximately half of these were examined by autopsy, with
    histopathological examination of any grossly abnormal tissues. A

    fuller post-mortem examination with histopathology of all major organs
    was performed on five males and five females from each group of the
    F1b and F2b generations and 10 males and 10 females from each of
    the F3b groups.

         No clinical signs of toxicity were found. Minor reductions in
    body-weight gain were seen in the premating period of the F0
    generation of animals of each sex at 100 mg/kg of diet and
    occasionally in females given 30 mg/kg of diet. At other times and in
    other generations, occasional reductions in body-weight gain were seen
    in rats given cyhalothrin at 30 or 100 mg/kg of diet. Male fertility
    was unaffected by treatment. The fertility of F1 females at 30 mg/kg
    of diet was statistically significantly (one-sided  t test:
     p < 0.05) reduced but remained within the range of control values.
    At 100 mg/kg, the litter size of F2 and F3 pups was reduced, the
    effect being statistically significant (one-sided  t test:
     p < 0.05) for the F2a and F3b litters. Small but statistically
    significant decreases (one-sided  t test:  p < 0.05) were seen in
    the percentages of live pups born to animals at 10 mg/kg in the F1b
    generation and to dams at 30 and 100 mg/kg of diet in the F3b
    generation. Post-mortem and histopathological examinations revealed no
    adverse effects that could be attributed to the treatment. The
    occasional effects seen at 10 and 30 mg/kg of diet were considered to
    be incidental, and only the effects at 100 mg/kg of diet were regarded
    as treatment-related. The NOEL was 30 mg/kg of diet, equal to 1.7
    mg/kg bw per day, on the basis of reduced parental body-weight gain
    and reduced litter size (Milburn et al., 1984).

         (b)  Developmental toxicity

          Rats 

         Groups of 24 pregnant Sprague-Dawley-derived rats (CD rats from
    Charles River's SPF colony) were given technical-grade cyhalothrin
    (purity, 89.25%; containing 92.2% pyrethroids of which 96.8% was
    cyhalothrin) at a dose of 0, 5, 10, or 15 mg/kg bw per day by oral
    gavage in corn oil on days 6-15 of gestation. The dams were killed on
    day 20, and the contents of their uteri were examined. No certificate
    of compliance with GLP was supplied, but suitable quality assurance
    records had been kept.

         Body-weight loss, reduced food intake, and signs of neurotoxicity
    (loss of limb coordination in 2 out of 24 rats) were observed in dams
    at the highest dose. The numbers of pregnant animals, pre-implantation
    and post-implantation losses, mean litter weights, and mean weights
    and lengths of fetuses were unaffected by treatment. Abnormalities
    were seen in one litter of a dam at 10 mg/kg bw per day, in which 5 of
    17 fetuses had major defects: four had bilateral agenesis of the
    kidneys, and three had skeletal malformations of the vertebral
    centrae, sternebrae, and/or metacarpals. The effects were considered
    to be incidental and unlikely to be due to treatment. The NOEL was 10
    mg/kg bw per day on the basis of maternal toxicity (Killick, 1981b).

         Six pregnant Wistar-derived rats were given cyhalothrin (purity,
    95.8%) by dermal application throughout the 21 days of gestation at a
    daily dose of 1 ml of 0.02% (w/v; equal to approximately 0.8 mg/kg bw
    per day if completely absorbed) in an aqueous vehicle applied to a
    shaved area of the back. Controls were given the vehicle alone. After
    parturition, six pups were left with each dam. At 90 days of age, 12
    males in the treated group were tested for mating behaviour with
    ovariectomized females that were showing estrus induced by
    subcutaneous injections of 17-estradiol and progesterone. No
    certificate of compliance with GLP was supplied for this study.
    Treated male pups showed a delay in testicular descent, but the age of
    vaginal opening was not affected. The mating behaviour of the males
    was not affected by treatment. No NOEL could be identified (da Silva
    Gomes et al., 1991a).

         In another study which did not appear to conform to GLP, 12
    pregnant Wistar-derived rats were given cyhalothrin (purity
    unspecified) by dermal application throughout the 21 days of gestation
    at a daily dose of 1 ml of 0.018% (w/v; equal to approximately 0.72
    mg/kg bw per day if completely absorbed) in an aqueous vehicle. At
    weaning (21 days) and at 90 days of age, the pups were tested for
    locomotor activity in an open field. At 90 days, training began for
    inhibitory avoidance behaviour. Adult males were also tested for
    motivational response in a 'hole board' test.

         The opening of ears and eyes, the development of fur, and the
    descent of testes were all delayed in treated rats, but the time of
    vaginal opening was not affected. The body weights of the pups of
    cyhalothrin-treated dams were statistically significantly greater
    (Student  t test:  p < 0.05) than those of controls at days 2, 7,
    and 14 of age but not at day 21. Locomotor frequency was increased at
    21 days and decreased at 90 days, but the effects were not
    statistically significant in the Student  t test. No effect was seen
    on inhibitory avoidance behaviour. The results of the hole board test
    showed a decreased motivational response in cyhalothrin-exposed rats.
    No NOEL could be identified (da Silva Gomes et al., 1991b).

          Rabbits 

         Groups of 20 pregnant New Zealand white rabbits were given
    technical-grade cyhalothrin (purity, 89.25%; containing 92.2%
    pyrethroids of which 96.8% was cyhalothrin) on days 6-18 of gestation
    at a dose of 0, 3, 10, or 30 mg/kg bw per day by oral gavage in corn
    oil. The animals were killed and examined on day 28 of gestation. No
    certificate of compliance with GLP was supplied, but suitable quality
    assurance records had been kept.

         The highest dose was toxic to the dams, as indicated by an
    initial body-weight loss followed by a decreased rate of body-weight
    gain. No treatment-related deaths, clinical signs, or gross
    pathological changes were seen in any group of does. There was no
    effect on the incidence of pregnancy or on gravid uterine weight. The
    mean weight of the fetuses of dams at 30 mg/kg bw per day was slightly

    decreased, but the effect was not statistically significant (Wilcoxon
    test). Mean fetal crown-rump length, sex ratio, and the numbers of
    corpora lutea, intrauterine deaths, and implantations were unchanged
    by treatment. There was no increased incidence of any type of fetal
    abnormality in any treated group. The NOEL for maternal toxicity was
    10 mg/kg bw per day (Killick, 1981c).

    2.2.6  Special studies

         (a)  Neurotoxicity

          Rats 

         Groups of rats were given single oral or intraperitoneal doses of
    25-200 mg/kg bw 'cyhalothrin', referred to as 'PP 321, trade mark
    Karate', which are terms associated with lambda-cyhalothrin rather
    than cyhalothrin. Its purity was not reported. It was suspended as an
    emulsion in 'solvents and surface active agents'. After treatment, the
    behaviour of the animals in the open field was monitored, and their
    electroencephalograms were measured while they were moving freely. No
    further details of the protocol were reported. Treated animals were
    found to have limited mobility as a consequence of discoordination of
    the limbs. The reported signs of toxicity were respiratory
    difficulties, tremor, salivation, piloerection, increased reactivity
    to noise and during handling, with vocalization. Analysis of the
    electroencephalograms showed 'changes in amplitudes (depressions in
    majority of cases), in frequency composition (relative increases of
    beta activity) and in repetition of cycles of high and low
    amplitudes'. The results for individual groups were not presented. No
    NOEL could be identified (Zufan et al., 1989).

          Hens 

         In a study that complied with GLP, groups of 10 hens were given
    cyhalothrin (purity, 93.4%) as a single dose of 2500, 5000, or 10 000
    (two groups) mg/kg bw by oral gavage in corn oil. Negative controls
    were given corn oil alone; positive controls received 500 mg/kg bw of
    tri- ortho-cresyl phosphate. The hens were observed for 21 days after
    dosing. The only hens that died during this period were two given
    10 000 mg/kg bw, one in the negative and one in the positive control
    group. The mean body weights of hens in all groups given cyhalothrin
    and the positive controls were reduced. Clinical signs of toxicity
    (ataxia) were seen only in the positive controls. The only
    treatment-related gross change seen  post mortem was muscular atrophy
    in two of the positive control birds. Histopathological examination of
    the cervical cranial, cervical caudal, thoracic, and lumbar spinal
    cord and the proximal and distal sciatic nerve showed morphological
    evidence of axonal damage at all levels of the spinal cord in all the
    positive control birds. There were no consistent or dose-related
    changes in the nerves of any of the groups given cyhalothrin. The NOEL
    was 10 000 mg/kg bw, the highest dose tested (Roberts et al., 1982).

         (b)  Neurobehavioural effects

          Inclined plane test 

         In a preliminary GLP-compliant study, cyhalothrin was
    administered by oral gavage in corn oil to groups of Crl:CD.BR strain
    rats of each sex. Initially, single doses of 50, 100, or 200 mg/kg bw
    were given to groups of two males and doses of 25, 40, or 75 mg/kg bw
    to groups of two females. Later, groups of three rats of each sex were
    given a single dose of 15, 30, or 60 mg/kg bw. Controls received corn
    oil only. The cyhalothrin contained A and B isomer pairs in a 60:40
    ratio and was 95.8% pure, with a total pyrethroid content of 96.4%.
    The other isomers measured were  cis B' (0.2%),  trans D and  cis 
    A' (0.4%), and  trans C (< 0.1%). The contaminants included
    phenoxybenzalde-hyde (0.2%) and
     (Z)3-(2-chloro-3,3,3-trifluoro-1-enyl)-2,2-dimethylcyclopro-pane
    (0.1%). One hour before dosing and again at 30 min, 2 h, 7 h, and 24 h
    after dosing, each rat was placed on a smooth plane with an angle of
    inclination that was gradually increased until the rat could no longer
    maintain its position. For each rat, three measurements were made at
    each time. In the inclined plane test, any decrease in the angle at
    which the rat loses its position (mean slip angle) is regarded as a
    reflection of subtle changes in neuromuscular function.

         Clinical signs of toxicity were seen at all doses tested. At 15
    mg/kg bw, the only clinical sign was soft faeces in females. At 25-40
    mg/kg bw, ungroomed appearance, soft faeces, and piloerection were
    seen. At 50-75 mg/kg bw, there were marked clinical signs, including
    ataxia, writhing, emprosthotonos, high stepping or splayed gait,
    hunched posture, stained snout, salivation, and wasted appearance. At
    100 mg/kg bw, the signs also included vocalization and closure of the
    eyelids. Rats given 60 or 200 mg/kg bw were killed on humane grounds
    after the inclined plane measurements had been made. Only one rat (a
    female at 60 mg/kg bw) died during the study, but all rats given 60 or
    200 mg/kg bw were killed prematurely on humane grounds. Body-weight
    gains were decreased at doses > 50 mg/kg bw. Necropsy of the
    animals showed no consistent gross pathological changes. The result of
    the inclined plane test was uninterpretable, as the clinical signs
    interfered with the conduct of the study: convulsing rats were unable
    to stay on the plane, and rats with soiled fur adhered to it (Denton,
    1988).

          Acute startle response 

         A preliminary study was performed in two phases with groups of
    three male Wistar-derived Alpk:ApfSD rats. The purity of the
    cyhalothrin tested was 97.2%. In phase 1, rats were given a single
    oral dose of 0, 25, 50, or 75 mg/kg bw of cyhalothrin in corn oil, and
    auditory habituation tests were performed 1, 2, and 3 h after dosing.
    Clinical signs of toxicity were seen on day 2 after dosing (the time
    of dosing being the start of day 1) but not on day 1 or day 3, in the
    group given 75 mg/kg bw. The signs included ataxia, subdued behaviour,
    body-weight loss, and stained fur. Rats at this dose had a

    statistically nonsignificant increase in mean response amplitude
    (two-sided Student  t test) but a significant ( p < 0.05) increase
    in the time to maximum amplitude 3 h after dosing.

         In phase 2, rats were given a single oral dose of 0, 75, or 100
    mg/kg bw of cyhalothrin in corn oil, and auditory habituation tests
    were performed on separate groups of animals 3, 5, or 7 h after
    dosing. The signs of toxicity were similar to those seen in phase 1.
    The clearest results in the auditory startle habituation test were
    obtained at 7 h: with both doses tested, the mean response amplitude
    was consistently statistically significantly ( p < 0.05) reduced and
    the time to maximum amplitude was reduced (Brammer, 1998).

         In the main study, groups of 10 male and 10 female Wistar-derived
    Alpk:ApfSD rats were given a single dose of 0, 5, 15, or 75 mg/kg bw
    of cyhalothrin (purity, 97.2%) by oral gavage in corn oil. An auditory
    startle habituation test was performed 7 h after dosing on day 1 and
    on day 8 with an automated recording apparatus. The animals were
    killed after 8 days but were not examined  post mortem. The study was
    performed in accordance with GLP.

         Body-weight gain was reduced in males at the highest dose and in
    females at the two lower doses. Transient clinical signs of toxicity
    were seen at the highest dose. Those seen at day 2 included subdued
    behaviour, ataxia, high-stepping gait, salivation, and tip-toe gait,
    and 'some of these signs' were also seen 7 h after dosing on day 1.
    There were no signs of toxicity from day 3 until the end of the study.

         In the startle response test, there was no effect on time to
    maximum amplitude in either sex on day 1 or day 8. A reduction in the
    mean response amplitude was seen, however, on day 1 in animals of each
    sex at the highest dose. Statistically significant (two-sided Student
     t test:  p < 0.05), but not dose-related, reductions in mean
    response amplitude were also seen on day 1 in females at all doses. No
    effects were seen on day 8.

         The authors reported that the NOEL for this study was 15 mg/kg
    bw, as they dismissed the effects on response amplitude because of the
    absence of a clear dose-response relationship. The Committee disagreed
    with this conclusion. It has been reported that type II pyrethroids
    generally decrease rather than increase the startle response to sound,
    although this is a complex response and at low doses some type II
    pyrethroids give an increased startle response (Hijzen & Slangen,
    1988; Ray, 1991). Thus, although there was a NOEL for a reduced
    response, lower doses may have caused an increased response, which
    would indicate a lower NOEL. The Committee also noted that the startle
    response was not evaluated at the most sensitive time, i.e. the time
    of peak expression of acute toxicity as shown by clinical signs. No
    NOEL could be identified (Brammer, 1999).

          Inhibitory avoidance test 

         Newborn Wistar rat pups were exposed to cyhalothrin (purity
    unspecified) in their mother's milk from birth until weaning at 21
    days of age, and at 97, 104, and 111 days of age they were tested in
    inhibitory avoidance tests. Cyhalothrin was given to nursing dams in
    their drinking-water as a 200-mg/L solution in 400 mg/L sucrose. This
    would be expected to provide a dose of cyhalothrin of approximately 20
    mg/kg bw per day to the dams (assuming that 200-g rats drink about 20
    ml/day). The intake of the pups was not measured, but the treated
    groups consisted of 20 pups and the control group of 15. Control dams
    were given sucrose solution at 400 mg/L. Drink was available
     ad libidum to eight cyhalothrin-exposed dams and six control dams. 

         No clinical signs of toxicity were reported in either the dams or
    the pups. The body weights at weaning and at 90 days of age were not
    affected. The behaviour of the dams was unaffected by treatment
    throughout the 21 days of lactation. The motor activity of the pups at
    weaning was unaffected by the treatment. At 90 days, eight pups
    exposed to cyhalothrin and 11 control pups were chosen (all the males)
    for training and testing in a shuttle box to evaluate inhibitory
    avoidance behaviour. Each rat was trained once by placing it in a
    well-lit box and then opening a door to a dark compartment and giving
    the rat an electric shock to the foot when it entered the dark
    compartment. The test is a measure of the time taken by the rats to
    cross again from the well-lit area to the dark compartment. Each rat
    was tested once at 97, 104, and 111 days of age, receiving no electric
    shock. At all times, there was a reduction in the learning avoidance
    latency of the treated group, but the effect was statistically
    significant (Mann-Whitney U-test:  p < 0.05) only at 97 and 104 days
    of age and not at 111 days. No NOEL could be identified (Moniz et al.,
    1990).

         In a separate study, described above, rats born to dams treated
    dermally with an aqueous solution of cyhalothrin were tested for
    behavioural changes. Inhibitory avoidance behaviour was unaffected by
    the treatment, and there was no consistent effect on locomotor
    frequency. The animals did, however, show a decreased motivational
    response when they were tested as adults in a hole board test. No NOEL
    could be identified for this study because of the production of subtle
    but persistent neurobehavioural effects at the only dose tested. It
    was also difficult to estimate the amount of cyhalothrin received by
    the offspring (da Silva Gomes et al., 1991b).

    2.2.7  Immunotoxicity

         Some pyrethroids have been reported to be potent allergens that
    may cause allergic rhinitis, asthma, or allergic alveolitis (Marrs,
    1993). Cyhalothrin has not been specifically tested for immunotoxicity
    but in a study of toxicity in mice given repeated doses, decreased
    total leukocyte counts, decreased lymphocyte counts, and increased
    neutrophil counts were observed in male but not female mice that had
    consumed feed containing cyhalothrin for 28 days (Colley et al.,

    1981). In the same study, atrophy of the red pulp of the spleen
    occurred in some females given the high dose. Toxicological studies in
    other species did not show alterations in total or differential
    leukocyte counts and showed no histopathological changes in most
    organs potentially involved in immunity (thymus, spleen, lymph nodes,
    bone marrow), as described above. 

         A Magnusson and Kligman maximization test and a Buehler test both
    showed that cyhalothrin is a skin sensitizer in guinea-pigs (European
    Medicines Evaluation Agency, 1999; WHO, 1990). A Magnusson and Kligman
    maximization test with lambda-cyhalothrin, however, showed no skin
    sensitization in guinea-pigs (WHO, 1990).

    2.3  Observations in humans

         Cases of severe poisoning with pyrethroids are rare, but some
    cases, for example in China, have been reported, including a few
    deaths. Absorbed pyrethroids are rapidly detoxified by esterases, so
    that any systemic effects would be of short duration (Marrs, 1993).

         Topical application of pyrethrins or pyrethroids to the skin
    produces local effects unrelated to their systemic action. The
    synthetic pyrethroids have a characteristic irritating effect that is
    not associated with inflammation and appears to be unique to
    pyrethroids. The initial lesions are tenacious, painful pruritus
    (pricking sensation) followed by a local burning sensation with
    blotchy erythema that lasts about 2 days after cessation of exposure;
    when exposure is intense, it is associated with numbness. Later,
    desquamation may occur on the contaminated area of skin. There appear
    to be no lasting ill effects. The condition is produced by all classes
    of pyrethroids although most readily by type II pyrethroids such as
    cyhalothrin. Repeated exposure to systemically toxic doses of
    pyrethroids can produce a different effect: peripheral nerve damage
    can occur subsequent to severe motor symptoms (Aldridge, 1990; Ray,
    1991)

         No clinical or haematological effects were observed in six
    volunteers given a single dose of 5 mg of lambda-cyhalothrin in corn
    oil (equal to 0.05-0.07 mg/kg bw) (European Medicines Evaluation
    Agency, 1999). The route of administration was not reported, but it
    seems likely to have been oral.

         In the study of Pakistani pesticide workers described in section
    2.2, the average exposure of the workers to lambda-cyhalothrin was
    estimated to be 54 g/person per day (extrapolated from measured
    metabolites in urine). Transient signs of toxicity, lasting up to 24
    h, were reported by the workers, which included skin paraesthesia,
    feeling hot, feeling cold, numbness, irritation of the skin, red eyes,
    coughing, and sneezing. Medical examination revealed one case of face
    rash that lasted 2 days (Chester et al., 1992).

         In a study carried out in a village in the United Republic of
    Tanzania, a lambda-cyhalothrin-based insecticide was sprayed inside
    houses and shelters at a coverage of approximately 25 mg/m2. The
    insecticide was supplied as a water-dispersible powder in a soluble
    sachet. Every day for 6 days, 12 spraymen and 3 squad leaders were
    interviewed about symptoms. Each sprayman used up to 62 g of
    lambda-cyhalothrin over 2.7-5.1 h each day. The spraymen wore personal
    protective equipment (rubber boots and gloves, cotton overalls, caps,
    and gauze nose-mouth masks) which left much of the face exposed. One
    sprayman also used a face shield for 3 days. 

         All the spraymen complained at least once of symptoms related to
    exposure to lambda-cyhalothrin. The commonest symptoms were itching
    and burning of the face and nose and throat irritation, frequently
    accompanied by sneezing or coughing. Facial symptoms occurred only on
    unprotected areas, and the worker who wore a face shield was free of
    facial symptoms. All the symptoms had disappeared by the morning after
    the spraying. The number of subjects affected and the duration of
    facial symptoms were proportional to the amount of compound sprayed.
    These parameters were not affected by use of lambda-cyhalothrin in the
    previous 6 months. A sample of occupants was interviewed 1 and 5-6
    days after their houses had been sprayed. One woman who entered her
    house 30 min after the end of spraying complained of periorbicular
    itching, but this lasted only a few minutes. The other inhabitants of
    sprayed houses reported no other insecticide-related adverse effects.
    Furthermore, a squad leader who entered almost every house a few
    minutes after spraying reported no symptoms (Moretto, 1991)

         As part of a field trial conducted in South India,
    electrophysiological tests were conducted on 15 spraymen aged 19-48
    years, before and after exposure to lambda-cyhalothrin (formulation
    and purity unspecified). The tests performed on the subjects comprised
    conduction of the right median, common peroneal, and facial motor
    nerves; conduction of the right median and sural sensory nerves; blink
    response with stimulation of the right supra-orbital nerve and
    recording of R1 and R2 responses from the right orbicularis oculi
    muscle with a pair of surface electrodes; concentric needle
    electromyography of the tibialis anterior; repetitive stimulation of
    the right median nerve at the wrist at 3 and 20 Hz and recording of
    the responses from the abductor pollicis brevis; and multi-modality
    visual, brainstem, auditory and somatosensory evoked potentials. The
    evoked potentials were measured in only six of the subjects, but the
    other measurements were made in all 15 subjects.

         Clinical observation revealed no changes, and facial nerve
    conduction, blink response, responses to repetitive stimulation, and
    visual, auditory, and somatosensory evoked potentials were all normal.
    Six of the 15 subjects had mild changes in peripheral nerve conduction
    parameters (paired  t test:  p < 0.05), but comparison of the mean
    values for the various nerve conduction parameters before and after
    exposure showed no significant difference except for prolongation of
    distal motor latency of the median nerve. Studies of nerve conduction
    12-16 months later in three subjects who had shown abnormalities

    immediately after exposure showed normal rates. The authors concluded
    that occupational exposure to lambda-cyhalothrin can produce
    transient, subclinical electrophysiological changes in the nerves of
    the upper limbs (Arunodaya et al., 1997).

    3.  COMMENTS

         The Committee considered the results of studies on the
    pharmacokinetics, metabolism, acute, short-term and long-term
    toxicity, carcinogenicity, genotoxicity, reproductive toxicity,
    neurotoxicity, and neurobehavioural effects of cyhalothrin and
    observations of effects in humans exposed to this compound. Although
    some of the studies were not fully compliant with codes of GLP, all of
    the pivotal studies were carried out according to appropriate
    standards for study protocol and conduct.

         Oral doses of cyhalothrin were readily but incompletely absorbed
    in the species studied (rats and dogs), and the subsequent metabolism
    was similar, involving initial cleavage of the molecule at the ester
    bond, presumably resulting in detoxification. The metabolites were
    rapidly excreted, some as conjugates, whereas small amounts of
    unchanged cyhalothrin persisted as residues in fatty tissues. Similar
    results were seen in food-producing animals.

         Serum and urine from exposed workers contained the metabolites
    3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-
    dimethylcyclopropanecarboxylic acid, 3-phenoxybenzoic acid, and
    3-(4'-hydroxyphenoxy)benzoic acid. These metabolites are products of
    cleavage of the cyhalothrin molecule at the ester bond, and their
    presence suggests that the initial metabolism of this compound in
    humans is similar to that in the animal species that have been
    investigated. 

         No toxicological studies on metabolites of cyhalothrin were
    available, but the Committee considered it likely that the metabolites
    would be less toxic than cyhalothrin, as none contains an intact
    pyrethroid structure.

         The acute toxicity of cyhalothrin is characterized by effects on
    the nervous system, principally the central nervous system. The signs
    of toxicity are typical of type II pyrethroids and comprise writhing,
    salivation, exaggerated jaw opening, increasing extensor tone in the
    hind legs causing a rolling gait, poor coordination progressing to
    coarse tremor, tonic seizures, and apnoea. The LD50 values after
    oral administration depended on the vehicle used but varied from 37 to
    62 mg/kg bw in mice and from 51 to 240 mg/kg bw in rats. Higher values
    were found in other species or after administration by other routes. 

         In mice that received a dose of 0, 5, 10, 20, 40, or 80 mg/kg bw
    per day orally for 5 days, ataxia and convulsions were seen in those
    given the two higher doses. The dose of 20 mg/kg bw per day caused
    body-weight loss, ataxia, and rough coat. At 5 mg/kg bw per day, the
    only adverse effect was a rough coat. 

         In a 28-day study in mice, cyhalothrin was added to the diet at a
    concentration of 0, 5, 25, 100, 500, or 2000 mg/kg of feed. Atrophy of
    the red pulp of the spleen and an increased mortality rate were seen
    at the highest dose. Adaptive liver changes, including enlarged liver,
    centrilobular hepatocellular hypertrophy, increased activity of
    aminopyrine- N-demethylase, and proliferation of smooth endoplasmic
    reticulum were seen at concentrations of 100 mg/kg of feed and above;
    lowered lymphocyte counts were also seen at these doses. At 25 mg/kg
    of feed, the only effect seen was piloerection. The NOEL was 5 mg/kg
    of feed, equal to 0.65 mg/kg bw per day, on the basis of piloerection
    at higher doses.

         The main effects in five 10-90-day studies of toxicity in rats
    were adaptive changes in the liver similar to those seen in mice. In a
    28-day range-finding study in which rats were fed diets containing
    cyhalothrin at a concentration of 0, 5, 10, 20, or 250 mg/kg of feed,
    only the highest concentration caused adverse effects. These effects
    were characterized by hepatocellular hypertrophy, increased activity
    of aminopyrine- N-demethylase in the liver, and proliferation of
    hepatic smooth endoplasmic reticulum. The NOEL was 20 mg/kg of feed,
    equivalent to 2 mg/kg bw per day. In a 28-day study in rats given 0,
    1, 5, 10, 20, or 250 mg/kg of feed, the activity of hepatic
    aminopyrine- N-demethylase was increased and proliferation of hepatic
    smooth endoplasmic reticulum was seen at the highest dose only. No
    such effect was seen in the liver at doses equivalent to 2 mg/kg bw
    per day or less. Females given 10 mg/kg of feed or more had decreased
    body-weight gain. The NOEL was 5 mg/kg of feed, equivalent to 0.5
    mg/kg bw per day, but this observation was not in line with the
    findings of other short-term studies of toxicity in rats. A third
    28-day study in rats was inadequately reported but showed that
    administration of cyhalothrin at 20 mg/kg of feed (equivalent to 2
    mg/kg bw per day) caused proliferation of hepatic smooth endoplasmic
    reticulum; a NOEL was not identified in this study. 

         A 90-day study was performed in which rats given cyhalothrin at
    0, 10, 50, or 250 mg/kg of feed. Males given the two higher doses
    showed increased activity of hepatic aminopyrine- N-demethylase and
    proliferation of hepatic smooth endoplasmic reticulum. Females at the
    highest dose showed increased activity of hepatic
    aminopyrine- N-demethylase activity. The NOEL was 10 mg/kg of feed,
    equal to 0.56 mg/kg bw per day.

         Groups of dogs received cyhalothrin at a dose of 0, 2.5, 10, or
    30 mg/kg bw per day for 4 weeks or a dose of 0, 1.0, 2.5, or 10 mg/kg
    bw per day for 26 weeks. In the 4-week study, the two higher doses
    caused an increased incidence of vomiting, and the highest dose caused
    body-weight loss, unsteady gait, and increased serum alanine and
    aspartate aminotransferase activities. Muscular trembling was seen in
    dogs in all groups, including the controls, in the 4-week study. In
    the 26-week study, doses of 10 mg/kg bw per day or more caused
    clinical signs including vomiting, salivation, lack of coordination,
    unsteadiness, collapse, muscular spasms, and convulsions. As treatment
    at all doses in both studies increased the prevalence of liquid

    faeces, a NOEL was not identified. The Committee considered it
    possible that the liquid faeces were a consequence of the neurological
    effects of cyhalothrin. The LOEL was 1.0 mg/kg bw per day.

         In a long-term study of toxicity and carcinogenicity in mice,
    cyhalothrin was given in the diet at a concentration of 0, 20, 100, or
    500 mg/kg of feed for 104 weeks. An increased incidence of mammary
    adenocarcinoma was seen in females at the two higher doses. The
    highest incidence (14%) was only slightly greater then the upper limit
    of the range in historical controls (2-12%). The Committee could not
    exclude the possibility that the adenocarcinomas seen in the groups
    given 100 or 500 mg/kg of feed were caused by cyhalothrin. Clinical
    signs of toxicity (piloerection and hunched posture) and increased
    serum activities of aspartate and alanine aminotransferases were seen
    at these doses. The NOEL for these effects was 20 mg/kg of feed, equal
    to 1.9 mg/kg bw per day. 

         In a long-term study of toxicity and carcinogenicity in rats,
    cyhalothrin was given in the diet at a concentration of 0, 10, 50, or
    250 mg/kg of feed for 104 weeks. There was no treatment-related
    increase in the incidence of any type of tumour. Adverse effects found
    at the highest dose included decreased body weight, altered blood
    biochemistry, and an increased weight of the liver relative to that of
    the body in animals of each sex and of the adrenals in females only.
    The NOEL was 50 mg/kg of feed, equal to 2.3 mg/kg bw per day.

         Cyhalothrin was not genotoxic in a range of studies, including a
    test for reverse mutation in  Salmonella, a test for cytogenetic
    effects in the bone marrow of rats treated  in vivo, a test for
    dominant lethal mutation in mice, and an assay of cell transformation
     in vitro. The Committee concluded that cyhalothrin is not genotoxic.
    Furthermore, the Committee considered it likely that the mammary
    adenocarcinomas found in mice in the long-term study were due to a
    non-genotoxic mechanism. 

         A three-generation study of reproductive toxicity was performed
    in rats given cyhalothrin in the diet at a concentration of 0, 10, 30,
    or 100 mg/kg of feed. Adverse effects, including reduced parental
    body-weight gain and reduced litter size, were found only at the
    highest dose. The NOEL for these effects was 30 mg/kg of feed, equal
    to 1.7 mg/kg bw per day. 

         In a study of developmental toxicity, rats received a dose of 0,
    5, 10, or 15 mg/kg bw per day by oral gavage on days 6-15 of
    gestation. Maternal toxicity, characterized by body-weight loss and
    poor coordination, was seen at the highest dose. Embryotoxicity also
    occurred at this dose. Abnormalities were seen in 5 of 17 fetuses in
    one litter from a dam at 10 mg/kg bw per day, but the effect was
    considered not to be due to treatment with cyhalothrin as no
    fetotoxicity was seen at the higher dose. The NOEL for maternal
    toxicity was 10 mg/kg bw per day, and that for developmental toxicity
    was 15 mg/kg bw per day, the highest dose tested. 

         Two studies of developmental toxicity in rats treated by dermal
    administration provided some evidence that cyhalothrin can delay fetal
    development at doses lower than those given orally. However, the
    Committee considered that oral administration is a more relevant route
    and that the NOEL in the study in which this route was used was the
    appropriate one for evaluating developmental toxicity in rats.

         Rabbits studied for developmental toxicity were given a dose of
    0, 3, 10, or 30 mg/kg bw per day by oral gavage. The highest dose
    caused initial body-weight loss in the does, which was followed by
    reduced body-weight gain. There was no significant effect on
    development at any dose. The NOEL for maternal toxicity was 10 mg/kg
    bw per day, and the NOEL for developmental toxicity was 30 mg/kg bw
    per day, the highest dose tested.

         Single oral doses of up to 10 000 mg/kg bw did not induce
    clinical or histopathological signs of neurotoxicity in hens. 

         Various studies of neurobehavioural effects have been performed
    in rats, including a range-finding test of performance on an inclined
    plane, a test for acute auditory startle response, and tests of
    inhibitory avoidance. In the inclined plane test, rats were given a
    single oral dose of 0, 15, 25, 30, 40, 50, 60, 75, 100, or 200 mg/kg
    bw. All of these doses caused soft faeces in at least some of the
    rats, and doses of 25 mg/kg bw or more caused clinical signs of
    neurotoxicity. The results were, however, variable, and no conclusion
    could be reached about neurotoxicity. 

         In the test for acute auditory startle response in which an oral
    dose of 0, 5, 15, or 75 mg/kg bw was given, the highest dose resulted
    in reduced body-weight gain, transient clinical signs, and a reduced
    mean response amplitude in animals of each sex. Statistically
    significant but not dose-related reductions in mean response amplitude
    were also seen at 5 and 15 mg/kg bw in females only. The Committee was
    aware that a biphasic auditory startle response has been reported with
    some other type II pyrethroids, with a reduced response at high doses
    and an increased response at lower doses. A  NOEL for the startle
    response was not identified in this study. 

         In the inhibitory avoidance tests, rats were exposed either
     in utero (dams were given 200 mg/l in drinking-water) or during
    lactation (dams were given 1 ml of a 0.018% solution dermally). The
    doses received by the animals could not be estimated reliably. The
    rats exposed  in utero showed a decreased motivational response when
    tested as adults, but no effects were seen on inhibitory avoidance
    behaviour or locomotor frequency. Animals exposed during lactation had
    a shorter latency in learning avoidance behaviour. There was no NOEL
    in either study, as adverse effects were seen at the only dose tested
    in each study and the doses received by the animals were not known. 

    4.  EVALUATION

         Observations and case reports in humans provided little
    information relevant to the establishment of an ADI for cyhalothrin.
    In most instances, no information on doses was available, the route of
    exposure was dermal, and some studies were of exposure to
    lambda-cyhalothrin rather than cyhalothrin.

         The Committee established a temporary ADI of 0-0.002 mg/kg bw for
    cyhalothrin by applying a 500-fold safety factor to the LOEL of 1.0
    mg/kg bw per day for induction of liquid faeces in dogs in the 26-week
    study. The Committee considered it possible that the liquid faeces
    were a consequence of the neurological effects of cyhalothrin. The
    Committee applied the 500-fold safety factor to account for the
    absence of a NOEL for liquid faeces in dogs and because of the absence
    of a NOEL for neurobehavioural effects. The ADI was made temporary
    because cyhalothrin belongs to a class of substances that are
    characterized by their toxicity to the central nervous system, and
    therefore neurobehavioural effects may be the most sensitive indicator
    of the toxicity of this compound. There was an adequate margin of
    safety between the ADI and the NOELs identified in the studies on
    cyhalothrin, including the NOEL of 0.65 mg/kg bw per day for
    piloerection in the 28-day study in mice.

         The results of studies appropriate for establishing a NOEL for
    neurobehavioural effects in laboratory animals are required for
    evaluation in 2002.

         The Committee noted that the NOEL for toxicological effects other
    than the neurotoxicity related to the pyrethroid structure was 2.3
    mg/kg bw per day for adaptive changes in the livers of rats in the
    long-term study. This suggests that the toxicity of the metabolites
    (none of which has a pyrethroid structure) is no greater than 50% of
    that of the parent drug.

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    See Also:
       Toxicological Abbreviations
       Cyhalothrin (EHC 99, 1990)
       Cyhalothrin (ICSC)
       Cyhalothrin (WHO Food Additives Series 53)
       CYHALOTHRIN (JECFA Evaluation)
       Cyhalothrin (Pesticide residues in food: 1984 evaluations)
       Cyhalothrin (Pesticide residues in food: 1984 evaluations)
       Cyhalothrin (UKPID)