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    BIFENTHRIN

    First draft prepared by E. Bosshard
    Federal Office of Public Health
    Schwerzenbach, Switzerland

    EXPLANATION

         Bifenthrin is a synthetic pyrethroid insecticide and acaricide
    that was reviewed for the first time by the present Meeting.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, excretion and biotransformation

         Absorption, distribution, excretion and biotransformation of
    bifenthrin was investigated in hens, rats and goats. Alcohol
    (phenyl)- and acid (cyclopropyl)-14C-bifenthrin were utilized.

    Hens

         Laying hens (20/group) were dosed with encapsulated 14C-
    labelled bifenthrin for 10 days at a level equal to 40 ppm. Excreta
    and eggs were collected on specified days and prepared for analysis.
    The hens in the control and treatment groups were sacrificed for
    tissue collection within 24 h of the final dose. Measurable 14C-
    residues were found in all treated group's tissues, excreta, egg
    white and egg yolk. Maximum residues in egg yolk were about 3 ppm,
    in egg white 0.04 ppm. The highest tissue concentration was found in
    fat and liver with values of about 2 ppm. 14C-bifenthrin was
    eliminated primarily via the excreta (Jameson  et al., 1986). 

         White Leghorn laying hens were dosed orally with either acid-
    14C or alcohol-14C-bifenthrin for 10 days with doses of 2 mg/kg
    bw. Residues in livers of acid-14C-bifenthrin treated hens
    consisted mainly of hydroxymethyl-bifenthrin and fatty acid
    conjugates (palmitate, oleate), TFP acid1, hydroxymethyl TFP acid
    and the parent compound. A similar metabolic pattern was identified
    from hens treated with alcohol-14C-bifenthrin. Hydroxylation of
    the 2-methyl group of the cyclopropyl ring is the major metabolic
    pathway in poultry. The presence of fatty acid conjugates of the
    hydroxymethyl-bifenthrin represents a new process in the
    biotransformation of this pyrethroid (Singer  et al., 1987).

         Laying hens were orally dosed with 14C-bifenthrin for 10 days
    at dose levels of 4 mg/animal. Analysis of tissues and eggs from
    treated laying hens showed that unchanged bifenthrin (40-50%) and
    the fatty acid conjugates with palmitic or oleic acid (20-40%) are
    the major constituents of the residues in the tissues. A minor
    metabolite is the unconjugated hydroxymethyl-bifenthrin (Tullman  et
     al., 1987).

                 

    1   Cis, trans-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-
         dimethyl-cyclopropanecarboxylic acid

         The metabolism of bifenthrin in poultry appears to start by
    hydroxylation of the 2-methyl carbon of the cyclopropane ring,
    followed by fatty acid conjugation (Wu, 1987).

    Rats

         Rats were treated with a single oral dose of 5 mg/kg bw alcohol
    (phenyl)-14C-labelled bifenthrin. About 76%-79% of the
    administered radioactivity was eliminated via the faeces and 6-7%
    via urine within the first 48 h. A total of about 90% was recovered
    in excreta after 7 days. Radiocarbon residues in most tissues were
    < 0.1 ppm, except for liver (up to 0.1 ppm), skin (up to 0.4 ppm)
    and fat (up to 1.7 ppm). A significant portion of parent chemical
    was excreted unchanged in the faeces (El Naggar  et al., 1983).

         Excretion of bifenthrin following oral administration of a
    single dose of 2.7 mg/kg bw to female or 5.2 mg/kg bw to male bile
    duct-cannulated rats was investigated in urine, faeces and bile.
    Signs of stress, evidenced by low biliary volume, decreased
    defecation and a high fatality rate as a consequence of
    intoxication, was noticed among the male rats. Therefore the
    bifenthrin dose was reduced in female rats. In female rats an
    average of about 30% of the radioactivity was excreted in bile,
    about 15% in the urine and about 49% in the faeces. In male rats
    excreted radioactivity averaged 19%, 11% and 25% of the 14C-dose
    in bile, urine and faeces, respectively. Over 90% of the excreted
    14C-residue in the bile was in form of polar conjugates and less
    than 1% could be attributed to the parent compound. Total absorption
    of bifenthrin using the sum of average biliary and urinary excretion
    and tissue concentrations determined in this study yields a value of
    about 50% in females and 36% in males, respectively (El Naggar  et
     al., 1991).

         Male and female rats were dosed with 14C-bifenthrin in one of
    the following dose regimens: control (vehicle only), a single low-
    dose of 4 mg/kg bw, multiple low-doses of 4 mg/kg bw/day of non-
    radiolabelled test material over a two-week period, followed by a
    single radiolabelled dose of 4 mg/kg bw or a single high-dose of 35
    mg/kg bw. In a preliminary study total recovery in expired air was
    less than 1% of the dose administered; thus expired air was not
    collected during the definitive study. The majority of the
    radioactivity was found in faeces ranging from about 71%-84% of the
    total dose while 9%-15% of the applied radioactivity was eliminated
    in the urine. After application of low-doses the majority of
    radioactivity in urine and faeces was eliminated within 36 h after
    treatment, whereas after application of the high-dose the majority
    of the applied dose was eliminated after only 72 h.

         Tissues and carcass contained a total of about 3%-5% of the
    dose. Highest residues were found in fat with values of slightly
    more than 1 ppm after low-dose application and 8 and 16 ppm in males

    and females, respectively, after application of the high-dose.
    Residue levels in other organs were in most cases < 0.2 ppm after
    low-dose administration and < 1 ppm after high-dose administration
    (Cheng  et al., 1988).

         Male and female rats were orally dosed with acid- and alcohol-
    14C-labelled bifenthrin at single dose levels of 4 mg/kg bw or 35
    mg/kg bw. Additional groups of rats were dosed once daily with
    unlabelled bifenthrin for 14 days at 4 mg/kg bw/day followed by a
    single low dose of radiolabelled bifenthrin. A majority of 14C-
    radioactivity was excreted in faeces and ranged from about 66%-73%
    (alcohol-14C-label) and 69-83% (acid-14C-label). In the urine,
    elimination ranged from 20-25% and 13-22% for both 14C-labels,
    respectively. Total tissue residues amounted to about 3%. The
    majority of 14C-residue was eliminated within 12-72 h after
    dosing. Analysis of the 14C-residues showed that the parent
    compound was the major product. Faecal metabolites were mainly
    derived from hydroxylated (on either the biphenyl and/or cyclopropyl
    part of the molecule) parent compound. Urinary metabolites were the
    result of hydrolytic and oxidative-hydrolytic processes. Slight sex
    differences and differences between the various dosing regimens were
    observed in metabolite distribution. The amount of parent compound
    eliminated in the excreta was lower in females (17%-26%) than in
    males (25%-44%). Multiple low-doses when compared with a single low-
    dose showed a decrease in the amount of parent chemical within the
    same 14C-label, and a noticable increase in hydrolytical
    degradates indicating a significant inductive effect on esterase
    activities (El Naggar  et al., 1986; Selim, 1986a).

         Female and male rats were dosed with acid-14C and alcohol-
    14C-bifenthrin, respectively, using the following dose regimens:
    single oral low-dose of 5.4 mg/kg bw; single oral high-dose of 36-43
    mg/kg bw depending on sex; multiple oral low-doses of 4.9 mg/kg bw.
    For the multiple oral low-dose regimen, rats were dosed once daily
    with unlabeled bifenthrin for 14 days followed by a single low-dose
    of 14C-labelled chemical on the 15th day. A majority of 14C-
    residues were excreted in faeces and urine within 48-72 h. Faecal
    metabolites were excreted primarily as non-conjugates while urinary
    metabolites were eliminated in both conjugated and non-conjugated
    form. Metabolic profiles appeared to be similar among the three
    dosing regimens, while excretion rate appeared to be slower in high
    dose rats.

         Analyses of metabolite fractions indicated that the major
    faecal metabolites were primarily derived from hydroxylated parent
    compound, such as: hydroxymethyl bifenthrin, 4'-OH bifenthrin, 3'or
    4'-OH-hydroxymethyl bifenthrin. Hydrolytic products related to mono-
    and dihydroxylated intact parent chemical were also detected

    including 4'-OH BP acid1, 4'-OH BP alcohol2, dimethoxy BP acid
    and dimethoxy BP alcohol. Analyses of metabolites from urine
    fractions indicated that the majority of 14C-residues were also
    from hydrolytic or oxidative degradation resulting in metabolites
    such as: 4'-OH BP acid, BP acid, 4'-OH BP alcohol, dimethoxy BP
    acid, 4'-Methoxy BP acid, dimethoxy BP alcohol, BP alcohol, TFP
    acid,  cis- and  trans-hydroxymethyl TFP acid (Wu  et al., 1988).

         14C-labelled bifenthrin was administered orally to female
    rats for 70 days at a dose level of 0.5 mg/kg bw/day. Animals were
    sacrificed daily during the dosing period and radiocarbon levels
    were measured in blood, tissues and organs. Average peak
    concentrations of radioactivity were 9.6 ppm in fat, 1.7 ppm in
    skin, 0.4 ppm in liver, 0.3 ppm in kidney, 1.7 ppm in ovaries, 3.2
    ppm in sciatic nerve, 0.06 ppm in whole blood and 0.06 ppm in
    plasma. Analyses were extended for an additional 85 days following
    cessation of dosing (depuration phase). Half-lives of 51 days (fat),
    50 days (skin), 19 days (liver), 28 days (kidney), and 40 days
    (ovaries and sciatic nerve) were estimated from 14C-depuration.
    Plasma concentrations of radioactivity were similar from days 21 to
    70 (0.04-0.06 ppm) and decreased to 0.01 ppm at 78 days and to <
    0.01 ppm thereafter. Whole blood levels were similar to plasma
    indicating no specific accumulation. Analysis of fat revealed that
    parent chemical accounted for a majority (65%-85%) of the 14C-
    residues in fat. Three metabolites accounted for the remaining
    radiocarbon residues (Hawkins  et al., 1986).

         Bifenthrin was administered once orally to male rats at dose
    levels of 4 or 35 mg/kg bw using alcohol-14C-labelled compound.
    Mean peak concentrations of 14C in blood of about 0.6 and 3 g/ml
    for the low- and high-dose, respectively, were reached 4-6 h after
    dosing. Twenty-four hours after dosing about 0.2 g/ml and 2 g/ml
    were measured in the plasma at the two dose levels, respectively
    (Selim  et al., 1986b).

         Male rats were given either a single oral low dose of 4 mg/kg
    bw or a high-dose of 35 mg/kg bw of alcohol-14C-bifenthrin. Plasma
    samples were analyzed for parent compound and metabolites. The major
    products found were parent compound, the hydrolysis product BP
    alcohol and the oxidized hydrolysis product, BP acid each
    representing about 20-30% of the total radioactive residues (Tullman
    and Robinson, 1986).

         Bifenthrin (aqueous emulsion) was dermally administered to a
    shaved area on the back of rats at a dose of 36 g/rat. A mean of
    about 4% of the administered dose remained on the washed dosed skin

                             

    1 BP acid = 2-methyl-3-phenylbenzoic acid
    2 BP alcohol = 2-methyl-3-phenylbenzyl alcohol

    site following treatment. Concurrently a mean of about 97% of the
    dose was recovered in the skin wash. After a contact time of 24 h,
    19% of the dose was recovered on the skin and about 73% in the skin
    wash. Radioactivity in the residual carcass was less than 2%. About
    1.4% was excreted in the urine and 1.8% in the faeces 24 h post-
    dose. Thus dermal absorption is low (Braun  et al., 1990).

         Rats were treated dermally with single doses of 49.2, 514 or
    5253 g 14C-labelled bifenthrin/rat (proposed dosage levels: 0.05,
    0.5 and 5.0 mg/rat). The average amount of test material
    eliminated in the urine and faeces within 24 h was less than 1% of
    the applied dose. Measurable amounts of 0.01 g/ml were only
    detected in blood 4 h after application of the highest dose of 5253
    g bifenthrin. Twenty-four hours after application the concentration
    had increased to 0.02 g/ml. The amount of bifenthrin present in the
    carcasses, 24 h after application, corresponded to about 0.4% for
    the highest dose group and 0.8% for the other dose groups. Average
    amounts absorbed into and through the skin 24 h after application
    varied between 45 and 71% for the different dose groups (Craine  et
     al., 1986).

    Goats

         Lactating goats were orally dosed with 14C-labelled
    bifenthrin for 7 con-secutive days at a dose level of 2 mg/kg
    bw/day. About 90%-98% of the 14C-residue in milk samples were
    found to be the parent compound. Milk also contained about 4-5 minor
    degradates (El Naggar  et al., 1984).

         Analysis of tissues and milk from goats administered 14C-
    labelled bifenthrin at dose levels of 2 mg/kg bw/day for seven
    consecutive days showed the parent compound to be the major product
    in milk, contributing about 75%-82% of total 14C-residues (ca. 1
    ppm). Fat contained 78%-80% (ca. 1.7 ppm) parent compound, muscle
    74%-88% (ca. 6.2 ppm), heart 77% (ca. 0.4 ppm), kidney 16%-22% (0.1
    ppm) and liver 19%-44% (0.8 ppm). Biphenyl acid was the major
    metabolite identified in kidney and liver amounting to 42% (0.2 ppm)
    and 31% (0.6 ppm), respectively, and was a minor metabolite in milk.
    Biphenyl alcohol was detected in milk, fat, kidney and liver at
    lower levels (< 1-3%). Other metabolites, including 4'-hydroxy-
    bifenthrin, hydroxymethyl-bifenthrin, hydroxymethyl-TFP acid3 and
    BP aldehyde4 were detected in minor amounts. A majority of the
    14C-residues were isolated as organosoluble, non-conjugated
    products. Certain hydrolytic and intact ester metabolites of the
    parent chemical were found to be conjugated with polar and nonpolar
    substrates (El Naggar  et al., 1986a).

                 
    3   Cis, trans-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2-methyl,
          trans-hydroxy-methyl-(1-14C)-cyclopropanecarboxylic acid
    4  2-Methyl-3-phenylbenzaldehyde

         Lactating goats were orally dosed with acid (cyclopropyl)-14C
    or alcohol (phenyl)-14C-bifenthrin at 2 mg/kg bw/day for 7
    consecutive days. 14C-Residues from acid-14C and alcohol-14C
    were comparable. Steady state concentration in milk was reached
    within 4 days from the beginning of dosing and ranged from about
    0.8-1.5 ppm. Maximum residues in liver, fat, kidneys and heart were
    3.9 ppm, 2.8 ppm, 1.0 ppm and 0.6 ppm, respectively. About 40%-52%
    of the dose was excreted in faeces and 8%-17% in the urine (Predmore
     et al., 1984).

    Toxicological studies

    Acute toxicity studies

         The predominant clinical signs in the animal species tested
    were clonic convulsions, tremors and oral discharge. The results are
    summarized in Table 1. Bifenthrin has moderate acute toxicity and is
    classified as moderately hazardous by WHO (WHO, 1992).

    Table 1:  Acute toxicity of bifenthrin
                                                                       
    Species    Sex   Route     LD50       Reference
                               (mg/kg bw)
                                                                       

    Mouse      M,F   oral      43           Freeman (1983)

    Rat        M,F   oral      56           Freeman  et al. (1982)
                                            Freeman  et al. (1983a)
    Rabbit     M,F   ip        799          Freeman  et al. (1986)
                     dermal    > 2000       Freeman  et al. (1983b)
                                                                       

    Irritation and sensitization

         Instillation of 0.1 ml in the eyes of rabbits caused slight
    irritation reactions (Freeman  et al., 1983c). No irritation was
    observed after dermal application on abraded and intact skin of
    rabbits (Freeman  et al., 1983d). After dermal treatment of guinea-
    pigs with undiluted material no sensitization reaction was noted
    (Freeman  et al., 1983e).

    Short-term toxicity studies

    Mice

         Two sequential 28-day dietary studies were conducted with
    groups of mice (Swiss Webster 10/sex/group). In the first study
    bifenthrin was administered in the diet at concentrations of 0, 50
    (500), 100, 200 or 300 ppm. Since there were no significant
    treatment-related adverse effects in the 50 ppm group, it was

    changed to a dietary concentration of 500 ppm for the last 2 weeks
    of the study. Therefore a second study was initiated with dosage
    levels of 0, 500, 600, 750 or 1000 ppm. Tremors and clonic
    convulsions were the most consistent clinical signs of intoxication
    noted in males and females of the 750 and 1000 ppm groups prior to
    death. Tremors were also prevalent in males and females surviving
    dietary treatment of 500 and 600 ppm.

         In the 1000 ppm, 7/10 males and all females died. Deaths
    occurred also at 750 and 600 ppm in females only. No consistent
    influence on body-weight was noticed among the treatment groups.
    Food consumption was depressed in males at 1000 and 750 ppm during
    most of the study and in females in all dose groups in the first
    study week. Changes in mean organ weights were slight and showed no
    dose-response relationship. The NOAEL was 300 ppm equal to 69 mg/kg
    bw/day for males and 84 mg/kg bw/day for females (Rand  et al.,
    1983a).

    Rats

         In a 28-day range-finding study, groups of rats (Sprague-
    Dawley, 10/sex/group) were fed dietary levels of 0, 50, 100, 200,
    300 or 400 ppm. All rats in the 400 ppm group died by day 15 of the
    study. Clinical signs consisting of clonic convulsions and tremors
    were observed at dose levels of 200 ppm and higher. Deaths occurred
    also at 300 ppm (6/10 males and 1/10 females). No further results
    are recorded for the study group at 400 ppm. Body-weight gain was
    reduced in the 300 ppm dose group and at 200 ppm in males at the
    beginning of the study. Food consumption was depressed at 200 and
    300 ppm particularly during the first study weeks. Changes in the
    organ weights usually did not follow a dose-related pattern with the
    exception of an increase in adrenal weight and depressed testes
    weight in males at 300 ppm. At 300 ppm in males relative organ
    weights of the brain and kidney were elevated; in females at this
    dose level an elevation of the relative brain, kidney and liver
    weights were observed. No other parameters were investigated. The
    NOAEL was 100 ppm equal to about 11 mg/kg bw/day (Rand  et al.,
    1983b).

         Tehnical bifenthrin (90%  cis/10%  trans-isomer) was
    continuously administered in the diet of rats (Sprague-Dawley:
    15/sex/dose) for at least 90 days at concentrations of 0, 12, 50,
    100 or 200 ppm. For this study only a summary report was available.
    An additional 10 animals in the control and 200 ppm group were
    observed for a period of 28 days without treatment to discover
    reversibility or appearance of delayed effects. The only significant
    treatment-related effect consisted of tremors in all test animals of
    the 200 ppm group. This effect was reversible and was not observed
    during the 28-day post treatment period. The treatment did not cause
    effects on mortality, body-weight development, food consumption,
    ophthalmologic examination, haematology, clinical chemistry, organ

    weights or gross and histopathological examination. The NOAEL in
    this study was 100 ppm equivalent to 5 mg/kg bw/day (Rand  et al.,
    1984).

    Rabbits

         Technical bifenthrin was applied to the shaved skin of rabbits
    (New Zeeland white; 6/sex/group) for at least 6 h/day at dosages of
    0, 25, 50, 100 or 500 mg/kg bw/day for 21 consecutive days. One
    female at 500 mg/kg bw/day died on day 19 most probably due to
    ingestion of the test material. The other animals at 500 mg/kg
    bw/day showed tremors and loss of muscle control as the most
    consistent sign of intoxication. The treatment did not influence
    body-weight gain, food consumption, values of haematology and
    clinical chemistry with the exception of an increased platelet count
    in males at 500 mg/kg bw/day and elevated kidney- and liver-weights
    in females at this dose level. The NOAEL in this study was 100 mg/kg
    bw/day (De Prospo  et al., 1984).

    Dogs

         In a 13-week subchronic oral capsule study, groups of dogs
    (beagle: 4/sex/dose) were treated with technical bifenthrin (purity
    88.4%) at levels of 0, 2.5, 5.0, 10 or 20 mg/kg bw/day. There were
    no treatment-related effects on survival, food consumption,
    ophthalmologic examination, haematology, clinical chemistry, organ
    weights, gross and microscopic pathology. Compound-related tremors
    were observed at doses of 5 mg/kg bw/day and above. Signs of ataxia
    and languid appearance were noted at 20 mg/kg bw/day with single
    findings at 10 and 5 mg/kg bw/day. Less frequent or isolated signs
    of compound-related effects included salivation, lacrimation or
    mydriasis. Slightly reduced body-weight gain was observed at 20
    mg/kg bw/day in females. The NOAEL in this study was 2.5 mg/kg
    bw/day (Serota  et al., 1984).

         In a 52-week oral capsule study, groups of dogs
    (beagle;4/sex/dose) were treated with technical bifenthrin (purity
    88.4%) at dose levels of 0, 0.75, 1.5, 3.0 or 5.0 mg/kg bw/day. No
    treatment-related effects concerning survival, food consumption,
    ophthalmology, haematology, clinical chemistry, urinalysis, organ
    weights, gross pathology and histopathology were observed. Dose-
    related tremors appeared at doses of 3 and 5 mg/kg bw/day after 15
    weeks of treatment disappearing again following 29 weeks of
    treatment. The body-weight gain was decreased in males at 5 mg/kg
    bw/day. The NOAEL in this study was 1.5 mg/kg bw/day (Serota  et
     al., 1985).

    Long-term toxicity/carcinogenicity studies

    Mice

         In a lifetime feeding study technical bifenthrin (purity 88.4%)
    was administered continously over at least 20 months in the diet of
    mice (Swiss Webster; 50/sex/dose) at concentrations of 0, 50, 200,
    500 or 600 ppm (these levels refer to concentrations of pure
    bifenthrin). The treatment did not affect significantly the survival
    rate of the animals although single early deaths after 1-2 weeks of
    study occurred at 500 and 600 ppm. The predominant clinical sign of
    toxicity consisted of tremors occurring at 500 and 600 ppm. Single
    males at 200 ppm exhibited also minimal clinical signs of toxicity.
    Body-weight gain was reduced in all dose groups in males and in the
    500 and 600 ppm group in females, but no distinct dose-effect
    relationship was observed. A treatment-related depression in food
    consumption was observed in the first week of the study only in the
    two highest dose groups. The treatment did not affect the
    haematological parameters and organ-weights. Histopathological
    examination revealed an increase in urinary bladder tumours in high-
    dose males. The tumours were originally described as leiomyosarcoma
    of the urinary bladder wall by the study author with incidences of
    2/48 (4%), 6/50 (12%), 8/50 (16%), 7/50 (14%) and 14/49 (29%), in
    the control, 50, 200, 500 and 600 ppm groups respectively. The
    tumours were also noted in females including one control animal, but
    no dose-effect relationship was present. The data have been
    reassessed by a panel of pathologists who concluded that the tumours
    were of vascular origin. The panel reported incidences of 10, 14,
    16, 16, and 27% in control through the high-dose group,
    respectively. So far lesions of this morphology have only been
    reported infrequently in the literature probably due to variations
    in diagnoses. They are described only in the mouse and predominantly
    in males. The historical control incidence is not known,
    furthermore, no lesions of this morphological type have been
    reported in the human urinary bladder. According to the reassessment
    of the histological data the tumours occurring in the submucosa of
    the mouse bladder are of low malignant potential (slow growth, no
    metastasis). Statistical analysis of the data produced equivocal
    results leading to the conclusion of the study reviewers (Butler  et
     al., 1991) that the results do not provide persuasive evidence of
    a compound-related effect. Although the statistical analysis of the
    tumour data does not indicate unambiguous significance of the
    increase in incidence of bladder tumours, the lack of such
    significance being used as the only criterion to rebut tumorigenic
    potential is not sufficient to exclude a possible tumorigenic
    potential of the compound. In addition, an increased incidence of
    liver hyperplasia/adenoma/carcinoma was observed in the high dose
    males. A significant trend was noted for carcinoma incidence which
    occurred in 0/49, 0/50, 1/50, 2/49 and 2/49 at 0, 50, 200, 500 and
    600 ppm respectively. The NOAEL in this study was 50 ppm equal to
    7.6 mg/kg bw/day concerning clinical effects in males and 200 ppm

    equal to 37 mg/kg bw/day in females, respectively (Geiger  et al.,
    1986).

    Rats

         In a two-year feeding study in rats (Sprague-Dawley;
    50/sex/dose) technical bifenthrin (purity 88.4%) was administered at
    dietary concentrations of 0, 12, 50, 100 or 200 ppm. The treatment
    did not influence mortality, parameters of clinical chemistry,
    urinalysis, organ weights, gross and microscopic examination.
    Numerous instances of tremors were observed in all males and females
    of the 200 ppm group between day 4 through about day 30, in single
    animals and at single instances also in the other dose groups. Due
    to the low number of animals and incidences and the lack of a dose-
    relationship, the tremors observed at lower dose levels are not
    considered treatment-related. A treatment-related decrease in body-
    weight gain was observed in females at 200 ppm. Erythrocyte counts
    were reduced in males at 200 ppm. In this study, bifenthrin did not
    show any tumorigenic potential. The NOAEL in this study was 100 ppm
    equal to 4 mg/kg bw/day in males and 7.5 mg/kg bw/day in females
    (McCarty  et al., 1986).

    Reproduction studies

    Rats

         Only a summary report was available for evaluation of this
    study. Bifenthrin (technical) was administered in the diet at
    concentrations of 0, 30, 60 or 100 ppm to groups of rats
    (25/sex/group) over two consecutive generations. The dietary levels
    represent concentrations of bifenthrin after correcting for purity.
    There was no influence on mortality. At 100 ppm tremors were
    observed in lactating dams of the P1 and F1 generation. Females
    of the P1 generation showed reduced body-weight gain on days 7 and
    14 of the lactation period. Food consumption was depressed in the
    F1 group at 100 ppm in the males during a single week of exposure.
    The treatment did not have any effects on the reproductive
    performance or litter size, litter weight or survival of the
    progeny. Changes in organ weights at 100 ppm consisted of an
    elevation of the brain weights of P1 females. No histomorphologic
    alterations were observed in tissues from parental or weanling
    animals. A NOAEL of 60 ppm equivalent to 3 mg/kg bw/day is proposed
    (DeProspo  et al., 1986).

    Special studies on delayed neurotoxicity

    Rats

         Groups of rats (COBS/Wistar; 3 males/dose group) were orally
    treated with dose levels of 0, 1, 3, 10 or 30 mg/kg bw/day for 5
    consecutive days. Parameters investigated included alertness,

    locomotor activity, apathy, tremor and abnormal gait. Rats at 30
    mg/kg bw/day showed tremor, abnormal gait, respiratory depression
    and signs of CNS depression (apathy, paralysis). Deaths occurred
    after developing convulsions. No effects were recorded during the 7-
    day period after termination of dosing with 1, 3 and 10 mg/kg bw/day
    (Algate  et al., 1985).

         The minimum effective dose of 30 mg/kg bw/day which caused
    neurological signs such as paralysis as determined in the Irwin
    dose-range test (Algate  et al., 1985) was used in a tilting-plane
    test. The test compound was administered orally to groups of rats
    (5/sex) on two consecutive days. The tilting-plane test (parameter:
    angle of inclination at which the animals began to slide down a
    tilted platform) was performed every second day from days 2-16 of
    the study. The results did not reveal impairment of performance by
    the treatment and this gave no indication of a delayed neurotoxic
    effect (Algate  et al., 1985).

    Hens

         In a neurotoxicity study, female domestic hens were orally
    treated with a single dose of 5000 mg/kg bw followed by a repeat
    dose after 21 days in birds showing negative response at this dose
    level (LD50 > 5000 mg/kg bw). The second dose was followed by a
    22-day observation period. Clinical signs of toxicity consisting of
    unsteadiness and trembling appeared within about 22 h after dosing.
    Some mortalities occurred in all groups. Surviving birds had
    recovered from the clinical signs a few days after second dosing.
    The treatment did not produce clinical signs of delayed
    neurotoxicity. No histological examination of the nervous tissue was
    performed (Roberts  et al., 1984).

    Special studies on embryotoxicity and teratogenicity

    Rats

         In a teratogenicity study, groups of rats (25
    females/dose/group) were orally treated (gavage) on days 6 through
    15 of gestation with doses of 0, 0.5, 1 or 2 mg/kg bw/day.
    Estimation of dose levels were based on a previous pilot teratology
    study, where doses of 2.5 mg/kg bw/day resulted in the death of some
    dams (DeProspo  et al., 1983b). An aqueous aspirin suspension (250
    mg/kg bw/day) served as positive control. Tremors were observed as
    the predominant sign of toxicity among animals receiving 2 mg/kg
    bw/day. Body-weight gain did not differ between the different
    groups. No treatment-related effects were observed concerning the
    reproduction parameters (pregnancy, number of corpora lutea,
    implantations, resorptions or litter size). Malformations occurred
    only sporadically in all groups and without dose relationship. The
    study did not reveal any teratogenic activity of bifenthrin at the
    dose levels tested . The NOAEL in this study was 1 mg/kg bw/day for

    maternotoxicity and > 2 mg/kg bw/day for embryo fetotoxicity
    (Freeman  et al., 1984b).

    Rabbits

         In an oral teratology study groups of rabbits (20
    females/dose/group) were treated with doses (stomach tube) of 0,
    2.7, 4 or 8 mg/kg bw on days 7 through 19 of gestation. The
    recommended dose levels were estimated from a previous dose range
    finding study (DeProspo  et al., 1983a). Observations of tremors
    were noted for most of the animals receiving 8 mg/kg bw/day and head
    and fore limb twitching were observed during the second half of the
    dosing period among most of the animals receiving 4 or 8 mg/kg bw.
    The application of the test material did not affect the body-weight
    of the dams, the reproduction parameters, viability or body-weight
    of the pups, nor the incidence of external and visceral anomalies.
    The study therefore gave no indication for a teratogenic potential
    at the dose-levels administered. The NOAEL was 2.7 mg/kg bw/day for
    maternotoxicity and > 8 mg/kg bw/day for embryo-fetotoxicity
    (Freeman  et al., 1984a).

    Special studies on genotoxicity

         Based on the results of genotoxicity essays given in Table 2,
    the Meeting concluded that bifenthrin was unlikely to present a
    genotoxic hazard.

    COMMENTS

         After oral administration of bifenthrin to rats the compound
    was absorbed and eliminated mainly via faeces (70-80% within 48 h).
    Urinary excretion amounted to 5-10% of the administered doses.
    Biliary excretion was shown to range from 20-30%. Hydrolysis and
    hydroxylation were the majors steps in the biotransformation.

         Bifenthrin has moderate acute toxicity and is classified as
    moderately hazardous by WHO (WHO, 1992).

         Following dietary administration to rats for 90 days at
    concentrations of 0, 12, 50, 100 or 200 ppm bifenthrin, tremors were
    the only treatment-related effect occurring at 200 ppm. The NOAEL
    was 100 ppm, equivalent to 5 mg/kg bw/day.

         In a 13-week oral toxicity study in dogs at doses of 0, 2.5,
    5.0, 10 or 20 mg/kg bw/day administered in capsules, the NOAEL of
    2.5 mg/kg bw/day was based on the occurrence of tremors at 5.0 mg/kg
    bw/day and higher. In a one-year oral toxicity study in dogs at
    doses of 0, 0.75, 1.5, 3.0, or 5.0 mg/kg bw/day administered in
    capsules, the NOAEL of 1.5 mg/kg bw/day was based on the appearance
    of the same clinical signs.

         In a lifetime feeding study with mice at dietary concentrations
    of 0, 50, 200, 500 or 600 ppm over at least 20 months, a NOAEL
    (based on tremors at 200 ppm in males and 500 ppm in females) was 50
    ppm, equal to 7.6 mg/kg bw/day in males, and 200 ppm, equal to 37
    mg/kg bw/day, in females. Treatment at 600 ppm equal to 103 mg/kg
    bw/day caused an increased incidence of submucosal tumours
    (hemangiomas) in the urinary bladder in male animals. This finding
    was of marginal statistical significance, but tumorigenic potential
    for bifenthrin in mice cannot be excluded.

         In a two-year feeding study with rats at concentrations of 0,
    12, 50, 100 and 200 ppm, the NOAEL was 100 ppm equal to 4 mg/kg
    bw/day in males and 7.5 mg/kg bw/day in females. Higher dose levels
    caused tremors and a reduction in body-weight gain. Bifenthrin was
    not carcinogenic in rats.

         In a multigeneration study in rats at dietary concentrations of
    0, 30, 60 or 100 ppm, the NOAEL was 60 ppm equivalent to 3 mg/kg
    bw/day, based on changes in brain weight at 100 ppm. Reproduction
    was not impaired by treatment.

         In a teratogenicity study in rats at gavage dose levels of 0,
    0.5, 1 or 2 mg/kg bw/day, the NOAEL was 1 mg/kg bw based on the
    occurrence of tremors at 2 mg/kg bw in the dams. There was no
    evidence of teratogenicity.

         In a teratogenicity study in rabbits at gavage dose levels of
    0, 2.7, 4 or 8 mg/kg bw/day, the NOAEL was 2.7 mg/kg bw/day. Doses
    of 4 and 8 mg/kg bw/day caused tremors and twitching. No
    teratogenic, foetotoxic or embryotoxic effects were found.

         After reviewing the available genotoxicity data, the Meeting
    concluded that bifenthrin was unlikely to present a genotoxic
    hazard.

         The results of the long-term studies in rats and mice and a
    series of studies designed to evaluate genotoxicity indicated that
    bifenthrin is unlikely to pose a carcinogenic hazard to humans.

         An ADI was allocated on the basis of the NOAEL of 1.5 mg/kg
    bw/day in the one-year study in dogs using a 100-fold safety factor.
    This result was supported by the same NOAEL in the rat teratology
    study, although in the latter study gavage, rather than dietary
    administration, was used.


    
    Table 2.  Results of genotoxicity assays on bifenthrin
                                                                                                          
    Test system         Test object         Concentration            Results        Reference
                                            (purity)
                                                                                                          

    Ames assay          S. typhimurium      75 - 7500 g/plate       negative       Haworth (1983)
                                             activation
                                            (techn. mat.)

    Ames assay          S. typhimurium      8 - 5000 g/plate        precipitation
                                            5000 g/plate            at negative    Kennelly  et al. (1988)
                                             activation (88.4%)

    Mouse lymphoma      L 5178 Y mouse      non-activated:
    assay               lymphoma cells      0.018 - 0.24 l/ml       positive1      Kirby (1983)
    (TK +/- locus)                          activated:
                                            0.0075 - 0.1 l/ml
                                            (88.3%)

    Mouse lymphoma      L 5178 Y mouse      15.8 - 500 g/ml         negative       Kennelly (1986)
    assay               lymphoma cells       activation
    (HGPRT locus)                           (purity not specified)

    CHO/HGPRT           Chinese hamster     without activation:      negative
    mutation assay      ovary cells         250 - 1000 g/ml
                                            with activation:         inconclusive2  Thilagar (1984a)
                                            20 - 50 g/ml (88.3%)

    CHO/HGPRT           Chinese hamster     10 - 100 g/ml
                        ovary cells          activation             negative       Heidemann  et al. (1989)
                                            (90.6%)

    Chromosome          Chinese hamster     1000 - 10 000 g/ml      negative       Thilagar (1984b)
    aberration assay    ovary cells          activation
                                            (techn. mat.)

    DNA repair          rat primary         0.01 - 2.0 l/ml         positive3      Thilagar (1983a)
    test (UDS)          hepatocytes         (techn. mat.)

    Table 2 (cont'd)
                                                                                                          
    Test system         Test object         Concentration            Results        Reference
                                            (purity)
                                                                                                          

    DNA repair          rat primary         0.5 - 2.5 l/ml          negative       Thilagar (1983b)
    test (UDS)          hepatocytes         (techn. mat.)

    DNA repair          rat primary         1 - 100 g/ml            negative       Fautz  et al. (1989)
    test (UDS)          hepatocytes         (90%)

    Sister chromatid    Chinese hamster     1 - 60 g/ml             negative       Heidemann (1989)
    exchange            ovary cells (CHO)    activation
                                            (90.6%)

    Transformation      BALB/3T3            3 - 100 g/ml            negative       Putman (1983a)
    test                mouse embryo        without activation
                        cells               (techn. mat.)

    5 day               rat                 3, 10, 30 mg/kg          negative       Putman (1983b)
    Cytogenetics                            oral
    assay (in vivo)                         (techn. mat.)

    Recessive lethal    Drosophila          50 and 100 g/ml         negative       Benson (1984)
    assay (in vivo)     melanogaster        (88.4%)
                                                                                                          

    1    After metabolic activation: positive answer at the highest concentration of 0.1 l/ml without
         metabolic activation in most concentration positive, no distinct dose-effect relationship.

    2    In the activation system at the lowest dose of 20 g/ml postive response; no dose-response relationship.

    3    Slightly positive answer at the highest dose level of 2 g/ml.


    
    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:   50 ppm, equal to 7.6 mg/kg bw/day (20-month feeding
                        study)

         Rat:     100 ppm, equal to 4 mg/bw/day (two-year feeding study)
                  1 mg/kg bw/day (teratogenicity study)
                  60 ppm, equivalent to 3 mg/kg bw/day (multi-generation
                        reproduction study)

         Rabbit:  2.7 mg/kg bw/day (teratogenicity study)

         Dog:     1.5 mg/kg bw/day (one-year study)

    Estimate of acceptable daily intake for humans

         0-0.02 mg/kg bw

    Studies which will provide information valuable in the continued
    evaluation of the compound

         Observations in humans.

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    Associates for FMC Corp., Princeton, NJ, USA. Submitted to WHO by
    FMC Corporation.

    Thilagar, A., Brauninger, R.M., Bullock, W.L., Karten, P.V., &
    Malloy, A.V. (1983b). Unscheduled DNA synthesis in rat primary
    hepatocytes: FMC 54800 technical. FMC Report No. A83-1043.
    Unpublished report prepared by Microbiological Associates for FMC
    Corp., Princeton, NJ, USA. Submitted to WHO by FMC Corporation.

    Thilagar, A., Bullock, W.L., Karten, N.S., Kott, S., & Malloy, A.V.
    (1984a). CHO/HGPRT Mutation assay in the presence and absence of
    exogenous metabolic activation: FMC 54800 technical. FMC Report No.
    A83-1144. Unpublished report prepared by Microbiological Associates
    for FMC Corp., Princeton, NJ, USA. Submitted to WHO by FMC
    Corporation.

    Thilagar, A., Bullock, W.L., Karten, N.S., Kott, S., Kumaroo, P.V.,
    & Malloy, A.V. (1984b). Chromosome aberrations in Chinese hamster
    ovary (CHO) cells: FMC 54800 technical. FMC Report No. A83-1105.
    Unpublished report prepared by Microbiological Associates for FMC
    Corp., Princeton, NJ, USA. Submitted to WHO by FMC Corporation.

    Tullman, R.H. & Robinson, R.A. (1986). Analysis of FMC 54800
    residues in plasma from rats dosed orally with 14C FMC 54800.
    Unpublished report No. P-1448 from FMC Corp., Princeton, NJ, USA.
    Submitted to WHO by FMC Corporation.

    Tullman, R.H., El Naggar,S.F., Barge, M., Curle, E.M., Robinson,
    R.A., & Tullman, R.H. (1987). Nature of the residue livestock.
    Metabolism of FMC 54800 in the laying hen. Nature of the residue in
    adductor muscle, abdominal fat and egg yolk. Unpublished report No.
    P-1840 from FMC Corp., Princeton, NJ, USA. Submitted to WHO by FMC
    Corporation.

    WHO (1992). The WHO recommended classification of pesticides by
    hazard and guidelines to classification 1992-1993 (WHO/PCS/92.14).
    Available from the International Programme on Chemical Safety, World
    Health Organization, Geneva, Switzerland.

    Wu, J. (1987). Nature of the residue: livestock. Metabolism of FMC
    54800 in the laying hen. Nature of the nonextractable residue in
    liver. Unpublished report No. P-1840 from FMC Corp., Princeton, NJ,
    USA. Submitted to WHO by FMC Corporation.

    Wu, J., Barge, M., Cuirle, E.M., & Robinson, R.A. (1988). Metabolism
    of 14C-bifenthrin (FMC 54800) in rats - analyis and quantitation
    of metabolites in excreta. Unpublished report No. PC-0093 from
    Xenobiotic Laboratories, Inc., Princeton, NJ, USA. Submitted to WHO
    by FMC Corporation.


    See Also:
       Toxicological Abbreviations
       Bifenthrin (UKPID)