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    CYFLUTHRIN

    EXPLANATION

         This chemical has not been previously evaluated by the WHO
    Expert Group.

         Cyfluthrin is a synthetic pyrethroid insecticide that is marketed
    under the trade name "Baythroid". The technical grade compound is
    described by the sponsor as "a mixture of four diastereoisometric
    enantiomer pairs".

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical Aspects

    1.  Absorption, distribution, and excretion

         Male and and female rats were divided into four groups (4-5
    rats/sex/group) and treated according to the following protocol:

         Group A:   single i.v. dose of 0.5 mg/kg.
         Group B:   single oral dose of 0.5 mg/kg.
         Group C:   14 consecutive oral doses of 0.5 mg/kg (Unlabeled),
                    followed by a single oral dose of
                    0.5 mg/kg of the radiolabelled test substance.
         Group D:   single oral dose of 10 mg/kg.

    Excreta and tissue samples were collected to assess absorption,
    elimination, and distribution of the test compound.

         After i.v. administration, the plasma half-life [t(1/2)] of
    elimination was found to be biphasic, with a t(1/2) for the rapid
    phase of about 2 hours, and a t(1/2) for the slow phase of about
    20 hours. Elimination in the male was slightly faster than in the
    female, consequently the Area Under the Curve (AUC) for females was
    larger than for males. About 60% of the administered dose was
    eliminated in the urine in the first 24 hours, with only an additional
    5% eliminated over the next 24 hours, approximately 20% of the
    administered dose was eliminated in the feces in the first 24 hours;
    an additional 3-4% was eliminated after 48 hours. Only a trace amount
    of radiolabel was recovered in expired air. The ratio of urinary/fecal
    metabolites was about 2.9 in males and 2.3 in females.

         The apparent volume of distribution was calculated to be 18% for
    males and 16% for females, which is consistent with distribution
    primarily to the extracellular fluid compartment. Six to 7% of the
    administered dose was recovered from the bodies of rats sacrificed 48
    hours after the i.v. dose. The GI tract accounted for about 0.7% of
    the dose. The remainder of radioactivity was distributed among all
    tissues, with the highest relative concentrations occurring in the
    following tissues (in descending order): fat, ovaries, adrenal, liver,
    and spleen. The lowest relative distribution was recorded for the
    brain, suggesting that the test material does not readily penetrate to
    that compartment. With the exception of the relatively high recovery
    from ovaries, no difference in tissue retention between males and
    females was apparent.

         A single oral administration of 0.5 or 10 mg/kg had little effect
    on elimination. The t(1/2) of absorption was calculated to be about
    0.5 hours, and was independent of dose. Elimination was also biphasic,
    with a rapid t(1/2) of about 2-3 hours, and a slow phase of about 9-12
    hours. The ratio of urinary/fecal metabolites in males was about 3.0
    in the low dose group, and about 2.0 in the high dose group. For
    females these values were 1.6 in the low dose group and 1.2 and 2.2 in
    two different high dose groups. Distribution to tissues was similar to
    that observed after i.v. administration, however only about 2% of the
    administered dose was retained after 48 hours.

         The multiple dose experiment yielded results essentially similar
    to those obtained after a single dose, however excretion in the female
    was found to be monophasic, with a t(1/2) for elimination of about 6
    hours. The ratio of urinary/fecal excretion was higher in males (2.8)
    than in females (1.8) (Klein et al., 1983).

         The second study group of 1-5 male rats was administered single
    doses of 0.5 mg/kg and 10 mg/kg orally, and 0.5 mg/kg i.v. and
    intraduodenally. A group of 5 females was also administered a single
    oral dose of 0.5 mg/kg.

         Recovery of radiolabel in excreta was similar to the observed in
    the previous study, as about 55-70% of an administered dose was
    eliminated in the urine within 48 hours, and about 25-35% was
    eliminated in the feces over this time period. Cannulation of bile
    ducts indicated that about 34% of an administered dose was excreted
    into the bile, and about 12% was recovered in feces. The study authors
    concluded that a small amount of material excreted into the bile was
    reabsorbed by enterohepatic circulation. About 1-1.5% of an
    administered oral dose was retained in the body (excluding GI tract),
    with no effect of dose on the percentage retained. About 5% was
    retained after i.v. administration, and about 0.5% was retained after
    intraduodenal administration.

         The study authors concluded that the "excretion behaviour of the
    radioactivity shows a marked dependency on the route of
    administration". The present reviewer cannot agree with this
    conclusion, as the differences between the groups were modest, at
    best. The only group which appeared to be significantly different was
    the intraduodenal group, which excreted about 1/2 as much label via
    the feces as other test groups.

         Animals were administered 10 mg/kg orally, than sacrificed at
    various times in order to assess the time course of distribution and
    elimination of radiolabel. At 1.5 hours after administration, 38% of
    the administered dose was retained in the body (excluding the GI
    tract). This value rapidly declined so that after 24 hours only 4.2%
    remained, and by 10 days only 0.23% of the administered dose remained
    in the body. The half-lives of absorption and elimination were similar
    to those obtained in the previous study.

         At initial measurements (1.5 hours), the greatest relative amount
    of radiolabel was found in plasma, liver and kidney. By the end of
    10 days, 0.2% of the administered dose remained in the body, with the
    greatest relative amounts found in fat, liver, sciatic nerve and
    adrenal glands. The elimination from tissues was biphasic, with a
    t(1/2) for the rapid phase that ranged from 2.1 hours (adrenal) to
    7.5 hours (sciatic nerve). For the majority of tissues the slow phase
    t(1/2) was between 51 and 87 hours, however fat and sciatic nerve had
    somewhat longer half-lives for this phase, 101 and 113 hours,
    respectively.

         The study report noted that 5 minutes after an i.v. injection,
    the distribution of radiolabel was "essentially a representation of
    the distribution of blood in the body". Four hours after an oral dose
    of 10 mg/kg, a similar pattern was noted, with the distribution of
    label related to regional blood flow and excretion routes. By 24 hours
    after an oral dose, "high concentrations are evident in all fatty
    tissues and in skin", with intermediate shadings in tissues such as
    liver and kidney, and light shadings in remaining tissues (Weber and
    Suwelak, 1983).

         In a study to assess the effect of the formulation vehicle on the
    rate of absorption, male Wistar rats (14/dose) were given a single
    dose by gavage of 10 mg/kg as a 0.2% solution in Lutrol (polyethylene
    glycol 400) or a 0.1% emulsion in Cremophor EL/distilled water. Two
    rats from each group were sacrificed 0.5, 1, 2, 4, 6, 16 and 24 hours
    after treatment. Blood was sampled by cardiac puncture, and stomachs
    were removed and analysed for contents.

         It was found that absorption was much more rapid with the
    Cremophor EL/distilled water emulsion, as cyfluthrin was detected in
    the blood after 30 minutes and reached a peak concentration within
    1 hour. In contrast, cyfluthrin could not be detected in the blood of
    rats treated with the Lutrol solution until after 4 hours, and peak
    concentrations were not obtained until after 6 hours. Predictably,
    concentrations of cyfluthrin in the stomach were higher in rats tested
    with Lutrol than in rats treated with Cremophor EL/distilled water;
    this effect was most apparent at early time points (Eben et al.,
    1982).

    2.  Biotransformation

         Groups of male rats (number unspecified) were administered a dose
    of 10 mg/kg, and urine was collected over 0-8 hours and from
    8-24 hours after administration. As an initial analysis by thin-layer
    chromatography revealed no difference in metabolites between animals,
    urine samples were pooled by collection time for identification of
    metabolite structures. It was found that about 60% of the urinary
    radioactivity was excreted in a conjugated form (glucuronide or

    sulfate), and was tentatively identified as conjugate(s) of
    4'-hydroxy-3-phenoxy-4-fluourobenzoic acid. After acid hydrolysis, a
    second major metabolite (about 40% of excreted radioactivity) was
    tentatively identified as conjugate(s) of 3-phenoxy-4-fluorobenzoic
    acid (Ecker, 1982).

         A second study was conducted to more fully characterize the
    metabolic pathway for cyfluthrin. Excreta were collected from animals
    treated as described above in the study by Klein et al. (1983). The
    major metabolite was identified as a conjugate of 4'-hydroxy-
    3-pheoxy-4-fluorobenzoic acid (FCR3145), which accounted for about
    40-50% of recovered urinary radioactivity from rats given sample or
    multiple doses of 0.5 mg/kg. A slight sex difference was noted, as
    females tended to excrete more of this metabolite (about 5% of
    recovered radioactively) in the feces in an Unconjugated form than did
    males. Males and females given the high dose of 10 mg/kg excreted
    about 35% of recovered activity as the urinary conjugate of FCR3145,
    whereas females excreted about 5% more of recovered activity as free
    (unconjugated) FCR3145, compared to males. A greater percentage of
    radioactivity was recovered in the feces as unmetabolized parent
    (FCR1272) after repeated oral doses (12-16%, as compared to <1% for
    single low doses) or after a single high dose (17-19%) (Ecker, 1983).

         A proposed metabolic pathway is described in Figure 1.

    3.  Effects on enzymes and other biochemical parameters

         See "Special Studies on Neurotoxicity" for a description of
    studies assessing the effects of cyfluthrin on neurotoxic esterage
    activities.

         A published literature review paper discussed the mechanism of
    toxicity of the pyrethroid class of insecticides in the vertebrate
    nervous system. Although this paper did not specifically address
    cyfluthrin, the mechanism of toxicity of this compound is likely to be
    similar to that of other members of this class of insecticides.
    Structure-activity studies of a number of pyrethroid insecticides
    suggest that these chemicals bind to a receptor with a specific chiral
    formation.

         The reviewed literature suggest that the pyrethroids interfere
    with the sodium channel of nerve cell membranes, causing channels that
    are open to remain open, resulting in n delay in re-polarization of
    the nerve. The alpha-cyano pyrethroids (of which cyfluthrin is a
    member) appear to be much more potent in this regard, and also differ
    somewhat from other pyrethroids in that repeated stimulation of

    peripheral myelinated nerves in the presence of an alpha-cyano
    pyrethroid results in a gradual depolarization of the nerve membrane
    with resultant suppression of the action potential. In contrast, these
    compounds cause long-lasting trains of repetitive firing in afferent
    sensory nerves, and this phenomenon is thought to account for facial
    paresthesias observed in humans following exposure to alpha-cyano
    pyrethroids. No anticholinesterase activity was noted with these
    compounds (Vijverberg and Van den Bercken, 1982).

    TOXICOLOGICAL STUDIES

    A.  Special Studies

    Special Studies on Carcinogenicity

    Mice

         See under "Long-term Studies".

    Rats

         See under "Long-term Studies".

    Special Studies on Neurotoxicity

    Hens

         Cyfluthrin was tested for acute delayed neurotoxicity in the
    White Leghorn hen in several experiments. These experiments produced
    symptoms of excitation and behavioural disorders, and mortality, in
    birds given single or multiple oral doses as high as 5000 mg/kg.
    Systematic histopathologic examinations did not reveal any evidence of
    treatment-related lesions to nerve tissues, nor was any effect on
    neuropathic target esterage (NTE) activity noted. Exposures by
    inhalation or dermal routes also failed to produce evidence of
    neurotoxicity (Thyssen et al., 1981; Hixson, 1981; Thyssen and Mohr,
    1980; Pauluhn and Kaliner, 1983; Flucke and Eben, 1985;
    Sacchse, 1986).

    Rats

         In a short-term study deigned to detect morphological changes in
    the nervous system in rats, a group of 50 male Sprague-Dawely rats was
    administered by gavage a dose of 80 mg/kg of technical cyfluthrin
    (95% purity) for 5 consecutive days, at which time the dose was
    lowered to 40 mg/kg for treatment over days 6-14 due to the onset of
    symptoms of toxicity. A group of 25 male rats served as a vehicle
    control group. At the end of the 14-day treatment period rats were
    observed for 3 months without additional treatments. Ten treated rats
    and 5 control rats were sacrificed 1 day, 5 days, and 1, 2, and 3
    months after the final dose of test chemical. Rats were perfused with
    formalin, and after preparation of tissues, examined by light
    microscopy for changes in central and peripheral nervous tissue, and
    in skeletal muscle. In addition, 2 rats from the treated group and 1
    control rat were assessed at each time point (except at 2 months) for
    changes in these tissues visible by electron microscopy.

         During treatment, all rats displayed symptoms of abnormal gait
    and most (47/50) were noted to have excess salivation. These symptoms
    were not evident by 5 days after the end of treatment. Body weight
    gain was lower in treated rats than in control rats during the 14-day
    treatment period, however little difference in weight gain was
    apparent during the 3-month observation period.

         At the initial sacrifice, 6/8 treated rats were noted to have
    "single fiber degeneration associated with axonal swelling and
    myelinic fragmentation" of sciatic nerve. No changes were noted in
    other nerve tissues, and no changes were noted in any control rats.
    The incidence of fiber degeneration decreased over time, so that at
    5 days and 1 month after treatment 3/8 rats were noted with this
    lesion, and at 2 months 2/9 were observed with this lesion.
    By 3 months, no rats were noted to have any significant lesions of the
    nervous system.

         Examination of sciatic nerve sections under electron microscopy
    revealed "dilatation of neurotubules accompanied by proliferation of
    neurofilaments and degeneration of mitochondria" in treated rats
    examined at 1 day, 5 days and after 1 month. A similar lesion was
    reported in the femoral nerve of a single male in 5 days. No
    significant lesions were noted at 3 months, nor were changes reported
    in other tissues. These findings were not noted in control rats. The
    study authors concluded that the findings were treatment-related, but
    reversible after withdrawal of treatment (Oikawa et al., 1983a).

         In another short-term study, male and female Wistar rats
    (5/sex/dose) were treated with 0 or 60 mg/kg/day by gavage for
    14 days. A supplementary group of 5 male rats was treated with
    50 mg/kg/day for 14 days. Behaviour, appearance and body weights were
    recorded over the treatment period. At the end of treatment, rats were
    sacrificed and perfused with 10% formalin. Brain, spinal column,
    sciatic nerve and femoral muscle were removed and processed for
    examination under light microscopy.

         Treated rats Were noted to have disturbances in gait, tremor and
    salivation from day 2 until sacrifice. Four male rats treated with
    60 mg/kg died over days 5-8. Body weight gain was similar in control
    and treated females, however weight gain was diminished in treated
    males. Gross examination of tissues at necropsy did not reveal any
    significant difference between control and treated rats. The only
    significant finding reported after microscopic examination of tissues
    was small, fresh hemorrhage of the brain in the 4 male rats that died
    during the treatment. The study authors concluded that this finding
    was the result of "a terminal cardiovascular disorder with necrosis of
    the vascular walls" (Heiman and Kaliner, 1983). The present reviewer
    is of the option that this finding is apparently related to treatment,
    and unlikely to be of spontaneous origin.

         In a 5-month study, male and female Wistar rats (15/sex/dose)
    were given daily doses by gavage that ranged from 30 to 80 mg/kg/day.
    The dose was varied intermittently with the purpose of inducing
    symptoms of acute toxicity after each dose. For the most part, doses
    of 60 or 80 mg/kg were given. Rats were observed daily for changes in
    appearance or behaviour, and body weights were recorded weekly. At the
    end of the treatment period, rats were sacrificed and examined for
    grossly-visible changes, and selected organ weights were recorded.
    Samples of liver were assessed for mixed-function oxidase (MFO)
    activity, however the biological fraction measured was not specified.
    Liver, kidney, adrenal, brain, spinal cord, and sciatic nerve from
    5 males and females of the control and treated groups were processed
    for microscopic examination.

         Rats were observed to exhibited the characteristic symptoms of
    acute toxicity of this compound: uncoordinated gait, tremor and
    excessive salivation. It could not be determined from the submitted
    data whether males and females were equally affected. Body weight gain
    was decreased by about 20-25% in treated males, however weight gain in
    females was not affected by treatment. Two control males and 2 control
    females died during the treatment period, and 8 treated males and 2
    treated females died over this interval. No effect on MFO activity was
    evident. No treatment-related gross lesions were noted. Decreases in
    liver and kidney weights were noted in treated miles, however these
    changes were likely related to decreased body weight gain in these
    animals. Microscopic examination did not reveal any treatment-related
    lesions. However, in the opinion of the reviewer, this study may be
    criticized by the failure to perform histological examinations of rats
    that died on test. Therefore, this study does not confirm or refute
    the findings of the previous study regarding lesions of the brain
    noted in male rats that died during treatment (Thyssen and Vogel,
    1982).

         In a study to assess the effect of treatment on neuromuscular
    function, groups of 10 male Wistar rats were given single oral doses
    (method not specified) of 0-1.0 mg/kg of cyfluthrin. Diazepam
    (5 mg/kg) was administered as a positive control, and cyfluthrin
    administered over a range of 0-1.0 mg/kg served as a reference
    chemical. After treatment with the test chemical, rats were observed
    at various intervals after treatment to determine their ability to
    retain their grip on a tilted plane. The experimental variable was the
    angle of the plane at which rats lost their grip.

         A dose-related, statistically significant decrease in the angle
    at which rats lost their grip was noted after treatment with
    cyfluthrin. This effect was maximal after 5 hours, and the apparent
    NOEL was 0.01-0.03 mg/kg. The positive control diazepam and reference
    chemical cypermethrin also produced similar results (Polacek, 1984).

    Special Studies on Embryotoxicity/Teratogenicity

    Rats

         Female BAY:FB30 rats (25/group) were mated and administered doses
    of technical cyfluthrin ("approx. 85%" purity) of 0, 3, 10, or
    30 mg/kg by gavage over days 6-15 of presumed gestation. All doses
    were administered in Lutrol at a constant volume of 5 ml/kg body
    weight. Animals were observed for signs of toxicity, and were weighed
    periodically. On day 20 of gestation, rats were sacrificed by CO2
    asphyxiation, and uteri were removed to assess the effect of treatment
    on fetal development. Approximately 1/3 of the fetuses in each litter
    were examined for visceral defects by a modified Wilson technique, and
    the remainder were cleared and stained for evaluation of skeletal
    defects.

         Rats in the mid and high dose groups were reported to have "a
    high stepping gait from the second week of application. Individual
    animals in the top dosage group were occasionally ataxic or exhibited
    decreased motility". No mortalities were recorded.

         No effect of treatment on maternal weight gain was apparent.

         No effects on litter size, resorption frequency, fetal body
    weights, or placental weight were apparent. Similarly, no evidence of
    a treatment-related effect on the incidence of malformations or
    skeletal variations was noted in this study. The study authors
    concluded that "neither...embryotoxic damage nor a specific
    teratogenic effect was established".

         The gait disturbances were considered to be treatment-related. In
    an addendum to the study report, this phenomenon was described as
    typical of the pyrethroid class of insecticides. Although this sign is
    considered to be evidence of cyfluthrin toxicity, the authors felt
    that the effect could not be considered as evidence of a delayed
    neurotoxicity syndrome (Schluter, 1982).

         A second teratology study was conducted in outbred female Wistar
    (KFM-Han) rats (25/group). Rats were administered doses of technical
    cyfluthrin (93.4% purity) of 0, 1, 3, or 10 mg/kg by gavage. Doses
    were administered in 1% Cremophor EL at a volume of 10 ml/kg. Rats
    were observed twice/day for mortality and signs of toxicity. Body
    weights were recorded daily, and food consumption was recorded on days
    6, 11, 16 and 21 of gestation. On day 21 of presumed gestation, dams
    were sacrificed by CO2 asphyxiation, and ovaries and gravid uteri
    were removed by caesarean section for assessment of potential
    developmental effects. About 1/3 of the live fetuses in each litter
    were fixed and examined by the Wilson technique, whereas the remaining
    2/3 were cleared and stained for examination of skeletal effects.

         No treatment-related signs or mortalities were noted. Mean weight
    gain in high dose dams was slightly lower than in controls, as was the
    group mean body weight gain corrected by subtraction of the weight of
    uterine contents. The study authors concluded that this finding could
    not be attributed to the test article, since the major difference in
    weight gain in this group occurred over days 0-6, before initiation of
    treatment. Food consumption also tended to be lower in the high dose
    group during this period.

         At study termination, the numbers of pregnant rats were 25 in the
    control, 25 in the low dose, 22 in the mid dose and 24 in the high
    dose group. One mid dose dam was found to have aborted all fetuses,
    and one high dose dam had total resorption of a litter. At necropsy,
    no effect of treatment on pre- or post-implantation loss, litter size,
    fetal viability, or fetal body weight was apparent. No effect of
    treatment on the incidences of malformations or fetal variations was
    apparent. The study authors concluded that the only effect of
    treatment was a slight reduction in maternal food consumption in the
    high dose group, and "all other recorded parameters showed no evidence
    of effects upon the development of dams and fetuses" (Becker, 1983).

    Rabbits

         Groups of female Himalyan rabbits, strain CHBB:HM (15/dose) were
    given doses of 0, 5, 15 or 45 mg/kg/day of technical cyfluthrin (95.0%
    purity) by gavage over days 6-18 of presumed gestation. All doses were
    administered in a 0.5% Cremophor EL emulsion at a constant volume of
    5 ml/kg body weight. Rabbits were observed for clinical signs of
    toxicity, and were weighed periodically during gestation. On day 29 of
    gestation, rabbits were sacrificed by "a single intrapulmonary
    injection of T61 ad us. vet.", and uteri were examined to assess the
    effects of treatment on fetal development. Fetuses were weighed, then
    dissected and examined for visceral abnormalities. Fetuses were then
    processed and stained for skeletal examinations.

         No signs of toxicity were observed in does during gestation that
    were attributable to treatment, and no mortalities were recorded. No
    effect of treatment on maternal body weight gain was apparent. Of the
    15 rabbits/dose that were mated, 15, 15, 13 and 14 rabbits of the
    control, low, mid and high dose groups, respectively, were found to
    have been fertilized at necropsy. Of the rabbits that were fertilized,
    2 high dose rabbits aborted (on gestation days 25 and 28), and a third
    high dose animal had complete resorption of its litter. All other dose
    groups carried fetuses through day 29, therefore the effects noted in
    the high dose group were likely treatment-related.

         No effect of treatment on fetal body weight, placenta weights or
    litter size was noted. The incidence of resorptions appeared to be
    dose-related: 0.6, 0.7, 1.4 and 1.8 resorptions per litter for
    control, low, mid and high dose does. However, the only change that
    was statistically significant was in the mid dose group;
    interpretation is further complicated by the statistically significant
    higher implantation rate in this group. A higher incidence of
    arthtogryposis (persistent flexure or contracture of a joint) was
    noted in treated litters than in control, with fetal incidences of 0,
    2.4%, 2.2% and 4.3% and litter incidences of 0%, 6.796, 15.4% and 9.1%
    for the respective dose groups. The study authors noted that this
    finding is the most common spontaneous malformation in this strain of
    rabbits, with an average fetal incidence of 0.76%. Other data
    available to this reviewer (submitted by the sponsor to the U.S. EPA)
    indicate that the historical control range of fetal incidences for
    this finding is 0-5.4%, and that of litters is 0-33%. Therefore, it is
    concluded that the test material had no effect of treatment on the
    incidences of visceral or skeletal abnormalities. Based on the 2
    abortions and single incidence of total resorption in the high dose
    group, the study authors concluded that NOEL for embryo and maternal
    toxicity was the mid dose, 15 mg/kg (Roetz, 1983).

    Special Studies on Mutagenicity

         Cyfluthrin did not have any mutagenic properties when tested in a
    number of  in vivo and  in vitro systems, which included assessments
    of gene mutations (bacteria and mammalian cells), DNA damage (bacteria
    and mammalian cells), and clastogenic effects ( in vitro and
     in vitro mammalian cells).

         Summary results are presented in Table 1.

    Special Study on Reproduction

    Rats

         Groups of male and female Wistar (BOR:WISW) rats were fed diets
    containing 0, 50, 150 or 450 ppm of technical cyfluthrin (90.8%
    purity). Ten males and 20 females were assigned to each test group.
    The study was conducted for three generations with two litters
    produced from each generation: F1a and F1b litters from F0 parents;
    F2a and F2b litters from F1b parents; and F3a and F3b litters from F2b
    parents. Each male was mated with two females. The following
    parameters were assessed: fertility, litter size, fetal viability
    during gestation and lactation, fetal birth weight, and parental
    weight gain. F2b parental animals and F3b pups were sacrificed and
    examined for changes in organ weight and gross or microscopic
    appearance.


        Table 1.  Summary of Special Studies on Mutagenicity for Cyfluthrin
                                                                                                                          

    Test System           Test object        Concentration of      Purity        Results          Reference
                                             Cyfluthrin Used
                                                                                                                          

    CHO/HGPRT             Chinese hamster    0-10 ug/ml            94.7%         Negative(1)      Yang & Louie,
    gene mutation         ovary cells,                                                            1985
    assay (with           CHO-K1-BH4
    and without
    activation

    Ames test (with       S. typhimurium     0-24000 ug/plate      83.65         Negative(2)      Herbold, 1980a
    and without           TA98, TA100,
    activation)           TA1535, TA1537

    Unscheduled           Primary            0-5000 ug/ml          94.7%         Negative(3)      Curren, 1985 DNA
    synthesis             hepatocytes
                          from male
                          S-D rats.

    DNA repair            B. subtilis        100-10000             95%           Negative(4)      Moriya & Ohta,
    assay (with           H17 and M45        ug/disk                                              1982
    and without           (rec +/-)
    activation)

    Mouse                 NMRI mice          0. 7.5 and            83.6%         Negative(5)      Herbold, 1980b
    micronucleus                             15 mg/kg (2 doses)
    test
                                                                                                                          

    (1) The positive controls, EMS and BaP, gave the expected positive results.
    (2) The positive controls, endoxan and trypaflavin gave the expected positive results.
    (3) The positive control, DMBA, gave the expected positive result.
    (4) The positive control, mitomycin C, gave the expected positive result.
    (5) This study is unacceptable as the doses did not produce any toxicity.
                                                                                                                          

    Table 1.  Summary of Special Studies on Mutagenicity for Cyfluthrin (cont'd)
                                                                                                                          

    Test System           Test object        Concentration of      Purity        Results          Reference
                                             Cyfluthrin Used
                                                                                                                          

    DNA repair            B. subtilis        200 ug/disk           95%           Negative(6)      Nagane et al.
    assay (with           NIG17 & NIG45                                                           1982
    and without           (rec +/-)
    activation)

    Ames test (with       S. typhimurium     0-25000 ug/plate      95%           Negative(7)      Moriya &
    and without           TA98, TA100,                                                            Ohta, 1982
    activation)           TA1535, TA1537,
                          TA1538;
                          E. coli WP2

    Ames test (with       S. typhimurium     0-5000 ug/plate       95%           Negative(8)      Nagane et al.,
    and without           TA98, TA100,
    activation)           TA1535, TA1537,
                          TA1538;
                          E. coli WP2

    Reverse mutation      S. cervevisiae     0-10000 ug/ml         95%           Negative(9)      Rabenold &
    (with and without     S138 & S211a                                                            Brusick, 1982a
    activation)
                                                                                                                          

    (6) The positive control, AF-2, gave the expected positive response.
    (7) The positive controls, AF-2, ENNG, 2-NF, 9-AA and 2-AA gave the expected positive results.
    (8) The positive controls, B-propiolactone, 9-AA, 2-NF, AF-2, and 2-AAF gave the expected positive results.
    (9) The positive controls, quinacrine mustard, EMS, and sterigmatocystin gave the expected positive results.
                                                                                                                          

    Table 1.  Summary of Special Studies on Mutagenicity for Cyfluthrin (cont'd)
                                                                                                                          

    Test System           Test object        Concentration of      Purity        Results          Reference
                                             Cyfluthrin Used
                                                                                                                          

    Mitotic cross-over,   S. cerevisiae      0-10 mg/ml            95%           Negative(10)     Rabenold &
    reverse mutation      strain D7                                                               Brusick, 1982b
    and gene conversion
    (with and without
    activation)

    Dominant lethal       NMRI mice          0, 30 and 60          83.6%         Negative(11)     Herbold, 1980c
    study                                    mg/kg (1 dose)

    In vitro              CHL Chinese        3.3 x 10-5            93.7%         Negative(12)     Sasaki et al.,
    cytogenetics          hamster lung       to 3.3 x 10-3 M                                      1986
    (with and without     cells
    activation)

    Sister chromatid      Chinese hamster    3-40 ug/ml            Technical     Negative(13)     Putnam, 1985
    exchange              ovary cells        (-activation)
    (with and without     (ATCC #CCL 61)     63-1000 ug/ml
    activation)           (+activation)

    DNA repair            E. coli strains    0-1000 ug/plate       95.0%         Negative(14)     Herbold, 1981
    (with and without     (K 12) p3478
    activation)           W 3110
                                                                                                                          

    (10) The positive controls, EMS and sterigmatocystin, gave the expected positive results.
    (11) The study is unacceptable as no positive control was tested.
    (12) The positive controls, Mitomycin C and BaP, gave the expected positive results.
    (13) The positive controls, TEM and cyclophosphamide, produced the expected positive responses.
    (14) The positive control, MMS, produced the expected positive response.
                                                                                                                          
    
         No effect of treatment on appearance, behaviour, or survival was
    noted. Parental body weight gain was consistently decreased in the
    high dose (450 ppm) dose group, but was not affected in the other
    treatment groups. Based on food consumption and body weights, the mean
    compound intake was calculated by the study authors to be; 0, 3, 7,
    11.8, and 39.6 mg/kg/day for the respective male treatment groups and
    0, 5.4, 15.4, and 50.2 mg/kg/day for females.

         No effect of treatment on fertility or incidence of stillborn
    pups was evident. No consistent effect of treatment on birth weight or
    litter size at birth was apparent. A decrease in the lactation index
    (survival of pups over days 5-28 of lactation) was noted in high dose
    pups in all matings, and in addition a decrease in the viability index
    (number of pups surviving from birth through 5 days of lactation) was
    noted in mid and high dose pups from the F3a and F3b matings. Weight
    gain of pups over 28 days of lactation was consistently, suppressed in
    the mid and high dose groups. At necropsy, decreased absolute liver
    and kidney weights were noted in mid and high dose parental rats,
    however no effect on relative organ weights was apparent, and the
    effect on absolute organ weight was likely related to decreased body
    weight gain in these animals. The study authors concluded that "50 ppm
    FCR 1272 administered in the feed ration is the no observable effect
    level in regard to reproduction" (Loser and Eiben, 1983).

    B.  Acute Toxicity

         Technical cyfluthrin possesses a moderate order of acute
    toxicity. Tetrazepam, a centrally-acting benzodiazepine muscle
    relaxant, provided partial protection against the lethal effects of an
    oral dose, however complete protection could not be obtained
    regardless of dose or route of administration (Heimann, 1983a).

         Combination studies of cyfluthrin with methamidophos, dichlorvos,
    or propoxur did not reveal any evidence of synergism with these
    organo-phosphate insecticides (Heimann, 1983b; Flucke, 1984a; Flucke,
    1984b).

         The results of acute toxicity studies are summarized in Table 2.

         Technical cyfluthrin was shown to cause moderate irritation to
    the eye (Flucke and Thyssen, 1980). Technical cyfluthrin does not
    appear to cause skin sensitization (Mihail, 1981a; Mihail, 1981b).

        Table 2.  Acute Toxicity Studies With Cyfluthrin*
                                                                                        
    Species    Sex    Route           LD50         LC50      Reference
                                      (mg/kg)      (g/L)
                                                                                        
    Mouse      M      oral            291          -         Flucke & Thyssen, 1980
               F                      609

               M      s.c.            >2500        -         "
               F                      >2500        -         "

    Rats       M      oral            869          -         "
               F      (fed)           1271

               M      oral            590          -         "
               F      (fasted)        1189

               M      i.p.            66           -         "
               F                      104

               M      inhalation                   > 1089    "
               F      (1 hr exp)                   > 1089    "

               M      inhalation                   469-592   "
               F      (4 hr exp)                   469-592   "

               M      dermal          >5000                  "
               F      (24-hr exp)     >5000                  "

    Hen        F      oral            4500                   Sachsse & Zbinden, 1985
                      (PEG veh.)

    Hen        F      oral            >5000                  Sachsse & Zbinden, 1985
                      (cremophor/
                      water veh.)

    Hen        F      inhalation                   >596      Pauluhn & Kaliner, 1983
                      (4 hr exp.)

    Rabbit     M      oral            >1000                  Flucke & Thyssen, 1980

    Dog        M      oral            > 100                  "

    Sheep      M/F    oral            1000                   Hoffmann, 1981
                                      (approx.)
                                                                                        
    *    Technical cyfluthrin was tested in these studies.

    
    C.  Short-Term Studies

    Rats

         Groups of male and female Wistar rats (20/sex/dose) were
    administered doses of 0, 5, 20, or 40 (80) mg/kg/day of technical
    cyfluthrin (85% purity) by gavage for 28 consecutive days. A high dose
    of 80 mg/kg/day was administered during weeks 1 and 3, and
    40 mg/kg/day was given during weeks 2 and 4. The high dose was lowered
    after the first week due to toxicity in treated males, however as
    these symptoms disappeared after 1 week at the lower dose, the high
    dose was again raised in the 3rd week. A group of rats from each dose
    group was maintained on control diets without additional treatment for
    6 weeks in order to assess recovery. Rats were observed daily for
    changes in appearance or behaviour, and body weights were recorded
    weekly. Clinical chemistry studies were conducted at the end of the
    28-day treatment interval and at the end of the 6-week recovery
    period. At the end of the treatment period, one-half of the surviving
    rats in each treatment group were sacrificed, and the remaining
    animals were sacrificed after the 6 week recovery period. Animals were
    examined for grossly visible lesions, changes in organ weights, and
    microscopic changes. A standard set of tissues and organs was
    examined.

         Physical examinations of high-dose rats revealed symptoms of
    acute toxicity characteristic of this chemical: uncoordinated
    movements, salivation, ataxia, hyperkinesis, etc. The symptoms were
    described as most severe during weeks 1 and 3 (when a high dose of
    80 mg/kg/day was administered), and minimal during weeks 2 and 4 (when
    the high dose was lowered to 40 mg/kg/day). Only "minimal" behaviour
    disorders were noted in high dose males for the first 7 days of the
    recovery period. Six high dose males died, 5 during the first week of
    treatment, and one other on day 21. A single high dose female died on
    day 26. No deaths were noted during the recovery period. Mean body
    weights were decreased by about 10% in high dose males, whereas body
    weights were not affected by treatment in females. During the recovery
    period, the weight gain deficit noted in high dose males during
    treatment was not apparent, and these animals were apparently able to
    recover from the slight retardation of weight gain. No effect of
    treatment on hematology parameters was noted, and no
    toxicologically-relevant changes in serum enzyme activities or
    electrolyte concentration were apparent. The results of urinalysis
    were considered to be normal. Similarly, no changes in these
    parameters were apparent at the end of the recovery period.

         At necropsy, increased absolute and relative adrenal and liver
    weights were noted in high dose male and female rats sacrificed after
    the 28-day treatment period. At the end of the recovery period, the
    only significant changes noted were decreases in absolute and relative
    liver weights, and slight, dose related increases in the absolute and
    relative adrenal weights in high dose females.

         No treatment-related gross lesions were reported at either
    sacrifice. Microscopic examinations similarly did not reveal any
    treatment-related lesions (Flucke and Schilde, 1980).

         In a subchronic feed study, groups of male and female Wister rats
    (30/sex/dose) were fed diets containing 0, 30, 100, or 300 ppm of
    technical cyfluthrin (84.2% purity) for 3 months. Rats were observed
    daily for changes in appearance or behaviour, and body weights were
    recorded weekly. Clinical chemistry studies were conducted after 1 and
    3 months of treatment, and additional enzyme induction studies were
    conducted after 1 week, 1 month and 3 months of treatment. At the end
    of the treatment period, surviving rats in each treatment group were
    sacrificed, and examined for grossly-visible lesions, change sin organ
    weights, and microscopic changes. A standard set of tissues and organs
    was examined. Animals that died during treatment were necropsied, and
    tissues were prepared for microscopic examination if suitable.

         No effect of treatment on appearance or behaviour was noted, nor
    was any effect on survival apparent. No treatment-related changes in
    food consumption or body weight gain were noted, and average compound
    intake was calculated to be 2.2, 7.4 and 22.5 mg/kg/day for the
    respective treatment groups. No significant effects were noted in
    hematology, serum chemistry or urinalysis studies. A slight increase
    in liver microsomal enzyme activity was noted after 1 week of
    treatment, however no changes were apparent after 3 months of
    treatment.

         At final necropsy, no grossly-visible lesions or
    treatment-related changes in organ weights were noted. Microscopic
    examinations also did not reveal any treatment-related toxicity. The
    study authors concluded the the highest dose tested of 300 ppm was
    without adverse effects (Loser and Schilde, 1980).

         In another subchronic feeding study, male and female
    Sprague-Dawley rats (28/sex/dose) were fed diets containing 0, 100,
    300, or 1000 ppm of technical cyfluthrin (95% purity) for 3 months.
    Twenty rats from each group were scheduled for sacrifice after
    3 months of treatment, and the remaining 8 rats from each group were
    maintained on control diets for 1 additional month prior to sacrifice.
    Test diets were analysed periodically to insure stability and
    homogeneity. Rats were observed daily for changes in appearance or
    behaviour, and body weights were recorded weekly. Clinical chemistry
    and urinalysis studies were conducted after 3 months of treatment, or
    after the 1 month recovery period, surviving rats in each treatment
    group were sacrificed, and examined for grossly-visible lesions,
    changes in organ weights, and macroscopic changes. A standard set of
    tissues and organs was examined. Animals that died during treatment
    were necropsied, and tissues were prepared for microscopic
    examination.

         Most high dose rats displayed symptoms of toxicity within the
    first few weeks of treatment that included abnormal gait and excess
    salivation. The number of rats that displayed these symptoms decreased
    over the treatment period, so that by the end of 3 months, no abnormal
    symptoms were noted. No effect of treatment on survival was apparent.
    Body weight gain was retarded in high dose males and females, and was
    about 10% less than control body weight gain by the end of treatment.
    Some rebound in weight gain was apparent in high dose females during
    the recovery period, however body weights of high dose males remained
    depressed. The observed effects on weight gain were apparently related
    to decreased food consumption. No effect of treatment on hematology or
    urinalysis parameters was noted. Serum chemistry studies revealed the
    following: increased BUN in mid and high dose males and high dose
    females, increased SGOT in high dose males, and dose-related decreases
    in blood glucose levels in male sand females, statistically-
    significant in mid and high dose males and high dose females.
    Paradoxically, SGPT activity appeared to be decreased in treated males
    and females. No significant changes in serum chemistry values were
    apparent at the end of the recovery period.

         At necropsy, alterations in organ weight were noted in high dose
    rats at both sacrifices that were likely related to weight gain
    deficits; otherwise no treatment-related effect on organ weights was
    apparent. No treatment-related gross changes were noted. The only
    significant finding after histopathologic examinations of rats
    sacrificed at 3 months was an increased incidence of single fiber
    degeneration of the sciatic nerve in 5/20 high dose males and
    3/20 high dose females, as compared to an incidence of 0 in the
    control, low and mid dose groups. In the 1 month recovery group, the
    incidence of this finding was 1/8 high dose males, and 0/8 in all
    other groups. The study authors concluded that the dose without
    adverse effects was 100 ppm, equal to 6.2 mg/kg/day (Oikawa and
    Iyatomi, 1983b).

         In a short-term inhalation study, male and female Wister rats
    (10/sex/dose) were exposed to atmospheres containing aerosols of
    0, 10, 50, or 250 g/L technical cyfluthrin nominal concentrations
    (0, 2.3, 11.5 and 69.6 g/L analytical) for 6 hours/day  5 days/week 
    3 weeks (total of 15 exposures). The solvent used in the generating
    system (and the control atmosphere) was a 1:1 mixture of ethanol and
    polyethylene glycol 400 (Lutrol), and the reported purity of the test
    material was 85.3%. Analysis of particle size showed that >90% of the
    particles were <3 m in diameter, and were within the range the study
    authors considered respirable. Exposure of rats was restricted to the
    head/nose region. Rats were observed daily for changes in appearance

    or behaviour, and body weights were recorded weekly. Rectal body
    temperatures were measured after 1, 5, 10 and 15 exposures. Clinical
    chemistry and urinalysis studies were conducted on 5 rats/sex/dose
    after the last exposure. At the end of the treatment period, surviving
    rats in each treatment group were sacrificed, and examined for
    grossly-visible lesions and changes in organ weights. Five
    rats/sex/dose were examined for microscopic changes.

         Signs of ungroomed coat, abnormal gait, and increased salivation
    were noted in mid and high dose rats. A single unscheduled death was
    noted in the high dose female group, and was likely related to
    treatment although a detailed necropsy was not possible due to severe
    autolysis. Body weight gain was retarded in all treatment groups, as
    treated rats either lost body weight or failed to gain weight during
    the treatment period. Body temperatures appeared to be consistently
    lowered after treatment (as compared to mean pre-treatment values),
    however the effect was not consistent throughout the treatment period,
    and is of uncertain toxicological significance. Hematology, serum
    chemistry and urinalysis studies did not reveal any significant
    effects. No evidence of induction of liver drug metabolism enzymes was
    apparent.

         At necropsy, no treatment-related gross lesions were noted, and
    slight organ weight alterations were likely related to effects of
    treatment on body weight gain. Microscopic examinations revealed
    treatment-related increases in inflammation of trachea and in the
    incidence of emphysema in high dose males and females. The study
    authors concluded that the no effect-concentration could not be
    determined due to effects on body weight gain in all treatment groups.

         As effects were noted at all concentration levels, the study was
    repeated with aerosol concentrations of 0, 2, 10 and 50 g/L nominal
    concentrations (0, 0.4, 1.4 and 10.5 g/L analytical). All other
    aspects of the study protocol were unchanged, however clinical
    chemistry studies were not repeated.

         Behavioral changes were noted only in the high dose rats during
    the final week of treatment, and decreased body weight gain was
    observed only in high dose rats. At sacrifice, no treatment-related
    gross lesions were noted, and absolute and relative liver weights were
    decreased in mid and high dose males. No treatment-related lesions
    were noted after microscopic examinations. The study authors concluded
    that an aerosol of 0.4 g/L was without significant toxic effect
    (Thyssen and Mohr, 1980).

         In a subchronic inhalation study, male and female Wistar rats
    (10/sex/dose) were exposed to atmosphere containing aerosols of
    0, 0.5, 3.0, or 20 g/L of technical cyfluthrin nominal concentrations
    (0, 0.09, 0.71 and 4.52 g/L analytical) for 6 hours/day  5 days/week
     13 weeks (total of 63 exposures). The solvent used in the generating
    system (and the solvent control atmosphere) was a 1:1 mixture of
    ethanol and polyethylene glycol 400 (Lutrol), and the reported purity
    of the test material was 94.9%. Analysis of particle size showed that
    >85% of the particles were <5 m in diameter, and were within the
    range that the study authors considered respirable. Rats were observed
    daily for changes in appearance or behaviour, and body weights were
    recorded weekly. Clinical chemistry and urinalysis studies were
    conducted on all rats after 6 weeks of treatment and at study
    termination. At the end of the treatment period, surviving rats in
    each treatment group were sacrificed, and examined for grossly-visible
    lesions and changes in organ weights. A standard set of tissues was
    examined for microscopic changes.

         Signs of "non-specific disturbed behaviour" were observed in all
    high dose males and all mid and high dose females. Dose-related
    decreases in body weight gain of about 10-20% were noted in all male
    treatment groups, and slight decreases of about 5% were observed in
    mid and high dose females. No effect of treatment on hematology, serum
    chemistry, or urinalysis parameters was apparent. Alterations in the
    absolute weights of several organs were noted in mid and high dose
    males and females, and were probably related to decreased weight gain
    in these groups. No treatment-related lesions were revealed by
    microscopic examinations. The study authors concluded that the lowest
    concentration tested, 0.09 g/L was without toxic effect (Pauluhn and
    Mohr, 1984). The present reviewer disagrees with this conclusion, as
    body weight gain was decreased in all male treatment groups. Since
    control and test chemical animals were similarly restrained and
    exposed, in the reviewer's opinion the body weight decrease in low
    dose males was not likely to be due to the exposure paradigm.

    Rabbits

         In a short-term study, male and female White New Zealand rabbits
    (6/sex/dose) were exposed by dermal application to 0 (solvent only),
    50 or 250 mg/kg of technical cyfluthrin (83.5% purity). The skin of 3
    rabbits/sex/dose was abraded prior to application of the test
    chemical. Animals were exposed for 6 hours/day  5 days/week  3 weeks
    (total of 15 exposures) to a total applied volume of 0.5 ml/kg. At the
    end of each 6-hour application, treated skin was washed. Rats were
    observed daily for changes in appearance or behaviour, and body
    weights were recorded weekly. The application site was examined for
    signs of skin irritation. Clinical chemistry and urinalysis studies
    were conducted on all rats prior to the initiation of treatment and at
    study termination. At the end of the treatment period, surviving rats

    in each treatment group were sacrificed, and examined for
    grossly-visible lesions and changes in organ weights. A selected
    number of tissues from control and high dose rabbits, along with
    testes from mid dose rabbits, were examined for microscopic changes.

         No changes in appearance or behaviour were reported, and all
    rabbits survived the treatment period. No toxicologically-significant
    effect on weight gain was apparent. No local skin reactions were noted
    that were related to treatment. Hematology, serum chemistry and
    urinalysis studies were not affected by treatment. No alterations in
    organ weights, or treatment-related gross or microscopic lesions were
    noted (Flucke and Vogel, 1980).

    Dogs

         In a subchronic toxicity study, male and female beagle dogs
    (6/sex/dose) were fed diets containing 0, 65, 200, and 600 ppm of
    technical cyfluthrin (90.8% purity) for 6 months. Treatment was
    initiated in November 1979, and terminated in May, 1980. Dogs were
    initially offered a total of 300 grams of food for about 20 hours/day
    (330 grams/day over weeks 20-26). Test compound intake was calculated
    to 0, 2.0, 6.5, and 19.9 mg/kg/day for the respective treatment groups
    in week 26 (male and female combined). Tap water was available
     ad libitum. Food consumption was measured daily. Dogs were examined
    daily for signs of toxicity, and reflexes, pulse and body temperature
    were determined before treatment initiation, and after 4, 7, 13, and
    26 weeks of treatment. Body weights were determined weekly.
    Ophthalmoscopic examinations were conducted before treatment
    initiation, and after 4, 7, 13, and 26 weeks of treatment. Blood was
    sampled at the same times as the detailed physical examinations for
    measurement of hematology and clinical chemistry parameters. Urine was
    also collected on this schedule.

         At termination, dogs were anesthetized and sacrificed by
    exsanguination. Standard necropsy techniques were followed, and the
    standard set of tissues was collected for evaluation.

         Signs of uncoordinated gait and stiff movements of the hind limbs
    were noted in high dose dogs beginning with week 21 of treatment. By
    the end of treatment, 5/6 high dose males and 3/6 high dose females
    were observed on one or more occasions with these signs. No
    treatment-related deaths were noted. Decreased body weight gain was
    noted in mid and high dose males and females, and although not
    strictly dose-related, these changes did appear to be related to
    treatment. No effect of treatment on food consumption was apparent. No
    treatment-related effects were revealed by ophthalmoscopic
    examinations. Hematology, serum chemistry and urinalysis studies were
    considered to be within normal limits. At necropsy, no treatment-

    related effects on organ weights or gross or microscopic pathology
    was apparent. No lesions of the nervous system were noted to
    correlate with the observed physical signs. The study authors
    concluded that the lowest dose tested, 65 ppm (equal to about
    2 mg/kg/day), was the NOEL for this study (Hoffman and Kaliner, 1981).

         Groups of beagle dogs (6/sex/dose) were fed diets containing
    0, 40, 160, and 640 ppm of technical cyfluthrin (90.8% purity) for
    12 months. Treatment was initiated in January 1982, and terminated in
    January, 1983. Dogs were initially offered a total of 300 grams of
    food for about 20 hours/day. The amount of food offered was gradually
    increased over the course of the study so that by week 27 dogs were
    given 430 grams food/day. Tap water was available  ad libitum. Food
    consumption was measured daily. By study termination, test compound
    intake was equal to about 1.4, 5.1, and 22.9 mg/kg/day (both sexes)
    for the respective dose groups. Dogs were examined daily for signs of
    toxicity, and were given a complete physical examination before
    treatment initiation, and after 6, 13, 26, 39 and 52 weeks of
    treatment. Body weights were determined weekly. Ophthalmoscopic
    examinations were conducted before treatment initiation, and after
    5, 13, 29, 39 and 52 weeks of treatment. Blood was sampled at the same
    times as the detailed physical examinations for measurement of
    hematology and clinical chemistry parameters. Urine was also collected
    on this schedule.

         At termination, dogs were anesthetized and sacrificed by
    exsanguination. Standard necropsy techniques were followed, and the
    standard set of tissues was collected for evaluation. Only tissues
    from control and high dose dogs were evaluated for histopathological
    changes.

         Clinical examinations revealed in two high dose males a syndrome
    characterized by clumsy, stiff movements of the hindquarters and a
    reluctance to move. These observations were noted during week 36 in
    one dog and in week 37 in another. These findings were not noted at
    subsequent examinations, even though "the dogs continued to be
    closely observed for a repetition of this movement". Other
    treatment-related findings in high dose dogs included increased
    tendency to vomit, and "pasty to liquid feces". Clinical observations
    in the low and mid dose groups did not reveal any treatment-related
    changes. No mortalities were recorded in the study, and
    ophthalmoscopic examinations did not reveal any treatment-related
    changes.

         A decrease in mean body weight of about 5-10% relative to control
    was noted in high dose males. This effect was most apparent in the
    second half of the study. Body weights in other treatment groups were
    not affected by treatment. A treatment-related effect on food
    consumption was not evident, and water consumption was also normal.

         No effect of treatment on hematology, clinical chemistry or
    urinalysis parameters was apparent.

         At necropsy, no treatment-related lesions were noted after gross
    examination. The absolute and relative weight of spleen was increased
    by abut 70% in high dose females, and was noted in most dogs in that
    group. Other organ weights were normal. No microscopic changes were
    noted in any tissue that were considered to be treatment-related.
    Congestion of the spleen was noted in a single high dose female,
    however spleens from other high dose females were not similarly
    affected. Microscopic examinations of the sciatic nerve similarly did
    not reveal any evidence of injury to correlate with observed physical
    signs.

         The study authors concluded that the NOEL for this study was
    160 ppm, equal to 5.1 mg/kg/day, based on decreased weight gain and
    disturbances in the gait of males fed diets containing 640 ppm
    (Hoffman & Schilde, 1983).

    D.  Long Term Studies

    Mice

         Groups of CF1/W74 SPF mice (50/sex/dose) were fed diets
    containing 0, 50 ppm, 200 ppm or 800 ppm of technical cyfluthrin
    (90.8% purity) for 23 months. Treatment was conducted from November,
    1980 to October, 1982. Control or test diets and water were offered
     ad  libitum. The dietary intakes of test compound were equal to
    11.6, 45.8, and 194.5 mg/kg/day in males and 15.3, 63.0, and
    259.9 mg/kg/day in females. The results of analyses of the test
    material or of test diets were not presented. Animals were examined
    twice/day for abnormalities of behaviour and appearance. Body weights
    and food consumption were determined weekly.

         Blood was sampled at 0, 6, 12, 18 and 23 months from
    10 mice/sex/dose for assessment of hematology and clinical chemistry
    parameters. A standard battery of test/examinations was conducted.
    Urinalyses were not performed. The fluoride content of bones and teeth
    was determined for 5 mice/sex/dose after 23 months of treatment.

         Mice that died on test, moribund animals, and all mice surviving
    to 23 months were subjected to complete necropsies. Mice were
    anesthetized with ether and sacrificed by exsanguination. Animals were
    dissected, and organs were weighed. The standard set of tissues was
    examined for microscopic changes.

         No effect of treatment on clinical signs was apparent. Survival
    was somewhat lower in mid and high dose females (74% and 68%
    mortality, respectively vs. 52% control), however mortality incidence
    did not appear to be related to dose and the differences were not
    statistically significant at study termination. Mean body weights were
    reduced in high dose females in a doze-related, statistically
    significant manner. Mean body weights in treated males were
    occasionally significantly different from control, however the changes
    did not appear to be related to dose. Food intake was not affected by
    treatment.

         No toxicologically significant effect of treatment on hematology
    parameters was apparent. Although occasional statistically significant
    differences were noted between control and treated group, the effects
    were not dose related. Statistically significant increases in serum
    alkaline phosphatase activity were noted in all treated males after
    6, 12, and 18 months of treatment. This effect was not strictly
    dose-dependant, however all treated groups were consistently elevated
    over the first 18 months of treatment. At study termination, however,
    there was little apparent difference between control and treated
    groups, and the highest individual values were recorded in the control
    group. SGPT was slightly elevated in high dose males after 6 and
    18 months of treatment, but not after 12 months. The reported high
    values in controls at study termination prevented any meaningful
    comparison with treated mice at this time point. Clinical chemistry
    studies in the females did not reveal any treatment-related effects.
    No effect of treatment on the fluoride content of teeth or bones was
    noted.

         At necropsy, no effect of treatment on absolute or relative organ
    weights was noted.

         After gross and microscopic examinations, no toxicologically
    significant differences in the incidences of neoplastic or
    non-neoplastic lesions were noted. No dose-related changes in the
    histology of the liver were noted that correlated with the apparent
    increases in serum ALP or SGPT activities. The study authors concluded
    that cyfluthrin was negative for oncogenic effects in mice, and the
    NOEL was 200 ppm based on slight alterations in body weight gain at
    800 ppm (Suberg and Loser, 1983a).

    Rats

         Groups of male and female Wistar [SPF] rats (65/sex/dose) were
    fed diets containing 0, 50 ppm, 150 ppm or 450 ppm of technical
    cyfluthrin (90.8% purity) for 2 years. Treatment was initiated in
    September 1980 and concluded in September 1982. Control or test diets
    and water were offered  ad libitum. The dietary concentrations were
    equal to 2.0, 6.2, and 19.2 mg/kg/day in males and 2.7, 8.2, and

    25.5 mg/kg/day in females based on average food consumption on body
    weights over the course of the study. The test material and test diets
    were analysed periodically to insure stability. Animals were examined
    twice/day for abnormalities of behaviour or appearance. Body weights
    were recorded weekly through study week 27, biweekly from week 27 to
    week 74, and then weekly until study termination. Food consumption was
    measured weekly.

         Blood was sampled at 6, 12, 18, and 24 months from
    10 rats/sex/dose for an assessment of hematology and clinical
    chemistry parameters. Serum protein electrophoresis was performed on
    blood sampled at 12 months. A standard battery of tests/examinations
    was conducted, and in addition on study day 7, 5 rats/sex/dose were
    sacrificed for measurement of mixed function oxidase activities and
    liver cytochrome P450 content. After 12 and 24 months of treatment,
    the fluoride content of bones and teeth was determined. Urine was
    collected on the same schedule as blood for standard urinalysis
    determinations.

         Ten rats/sex/dose were sacrificed after 12 months of treatment,
    of which 5/sex/dose were perfused with 10% buffered formalin prior to
    gross examination and dissection. All other rats that died on test,
    moribund animals, and all rats surviving to 2 years were subjected to
    complete necropsies. Rats were anesthetized with ether and sacrificed
    by exsanguination. Animals were dissected, and organs were weighed
    (except for animals perfused with formalin). The standard set of
    tissues was examined for microscopic changes.

         No effect of treatment on clinical signs or mortality was
    apparent. Survival in all groups was greater than 80% at study
    termination, mean body weights were significantly decreased throughout
    the study by about 8-10% in males and females fed the high dose
    (450 ppm) diet, and were significantly decreased by about 5% in mid
    dose (150 ppm) males during the first year of treatment. Food
    consumption was not affected by treatment.

         No effect of treatment on hematology parameters was apparent. The
    results of clinical chemistry studies were essentially unremarkable,
    although increases in alpha-1-globulin in mid and high dose females
    (measured at 12 months) was statistically significant and appeared to
    be dose-related. However, corresponding changes in other globulin
    bands or in the A/G ratio were not noted, therefore the study authors
    considered this finding to be of questionable toxicological
    significance. No effect of treatment on urinalysis parameters was
    apparent. Measurement of MFO activities after 7 days of treatment
    suggested an induction of N-demethylase activity in the high dose
    groups. Activity in high dose males was increased by about 30%
    compared to controls but was not statistically significant, whereas
    activity in high dose females was increased by about 70% (p<0.01).

    O-Demethylase activity was not affected, nor was cytochrome P450
    content. No treatment-related changes in the fluoride content of teeth
    and bones were noted after 12 months, however by 24 months dose
    related increases were noted in the bones of mid and high dose males
    and high dose females.

         At necropsy, organs weights were altered in a manner related to
    body weight changes. Absolute weights of several organs were slightly
    decreased in high dose males and females, however relative organ
    weights were not affected in a dose-related manner. No effect of
    treatment on the incidence of microscopic lesions was apparent. The
    total number of tumors, the distribution of specific tumor types, and
    the number and distribution of chronic lesions were not affected by
    treatment. The study authors concluded that cyfluthrin is not
    oncogenic in the rat. The NOEL for chronic toxicity was 50 ppm, equal
    to 2.0 and 2.7 mg/kg/day in males and females, respectively, based on
    decreases in body weight gain in the mid and high dose groups (Suberg
    and Loser, 1983b).

    Observations in Humans

         Examinations of laboratory workers revealed that cyfluthrin
    caused a topical skin effect, characterized by a stinging sensation in
    the affected areas. Areas most commonly affected were the face, and
    mucosal tissues (e.g. prepuce). It was noted that this chemical
    adheres strongly to skin and is not washed off by soap and water, so
    that it is possible to contaminate various parts of the body with
    cyfluthrin present on the hands (Flucke and Lorke, 1979).

    COMMENTS

         Cyfluthrin has not been previously evaluated by the WHO Expert
    Group, but was evaluated by the FAO Panel in 1986.

         Adequate data were submitted to characterize the rates of
    absorption and elimination of cyfluthrin. Approximately 60-70% of an
    oral dose is eliminated via the urine, and the remainder via the
    feces. No potential for bioaccumulation is known. Cyfluthrin is
    readily metabolized, and is excreted as a glucuronide or sulphate
    conjugate.

         Special studies on carcinogenicity, mutagenicity, teratogenicity,
    and reproductive toxicity demonstrated no effects.

         Long-term feeding studies on mice, rats and dogs did not reveal
    any evidence of organ-specific toxicity. The only significant effects
    noted in these studies were retardation of weight gain and alterations
    of organ weights secondary to body weight effects.

    TOXICOLOGICAL EVALUATION

    LEVELS CAUSING NO TOXICOLOGICAL EFFECTS

          Mouse:    200 ppm, equivalent to 30 mg/kg bw/day
          Rat:      50 ppm, equal to 2 mg/kg bw/day
          Dog:      160 ppm, equal to 5.1 mg/kg bw/day

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0-0.2 mg/kg bw.

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
    EVALUATION OF THE COMPOUND

         Observations in man.

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    Loser, E. and Eiben, R., 1983. FCR 1272 Multigeneration study on rats.
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    Mihail, F., 1981a. FCR 1272. Test for sensitizing effect on guinea
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    Moriya, M. and Ohta, T., 1982. FCR 1272. Microbial mutagenicity study.
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    Nagane, M., Hatanaka, J., and Iyatomi, A., 1982. FCR 1272.
    Mutagenicity test on bacterial system. Unpublished report no. 213 from
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    toxicological study-morphological effects on the nervous system of
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    Bayer AG, Leverkusen, FRG.

    


    See Also:
       Toxicological Abbreviations
       Cyfluthrin (ICSC)
       Cyfluthrin (WHO Food Additives Series 39)
       CYFLUTHRIN (JECFA Evaluation)
       Cyfluthrin (UKPID)