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    BIORESMETHRIN

    First draft prepared by Dr. W. Phang,
    US Environmental Protection Agency,
    Washington, D.C., United States

    EXPLANATION

         Bioresmethrin is a d- trans-isomer of resmethrin which consists
    of four isomers (35% d- trans-isomer, 35% l- trans-isomer, 15%
    d- cis-isomer, and 15% l- cis-isomer).  The Joint Meeting evaluated
    the available toxicological information in 1976 and concluded that
    long-term studies on bioresmethrin were needed before an ADI could be
    allocated (Annex I, 26). Recently, a combined long-term
    feeding/oncogenicity study in rats, a two-generation reproduction
    study in rats, a rat teratology study, a rat metabolism study, a
    rabbit teratology study, and several acute toxicity studies have
    become available. In addition, a mouse oncogenicity study and a
    108-days feeding study in dogs with resmethrin which contains at least
    30% of bioresmethrin were also available. These studies are evaluated
    and summarized.  To facilitate the evaluation of the toxicological
    profile of this compound, sections of the 1977 FAO monograph on
    bioresmethrin are reproduced in their entirety in this monograph
    addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, and excretion

         The absorption, distribution, and excretion of bioresmethrin were
    discussed by the 1976 Joint Meeting (Annex I, 27).  Recently, a rat
    metabolism study on [14C-acid]-d- trans-resmethrin has become
    available; the results are summarized along with the previously
    published information.

         Following oral administration, bioresmethrin is rapidly absorbed
    from the gut and widely distributed in the body within 3 hours. The
    distribution of 3H-bioresmethrin following oral or iv administration
    to rats was monitored with radio-autographic techniques. At 24 hours
    following oral administration, most tissues showed greatly reduced
    residual radioactivity, but concentration in adipose tissue,
    mesenteric skin, testes, epididymus, lacrymal gland, and connective
    tissue was high. The excretion of 3H activity into the bile duct was
    demonstrated with rats surgically cannulated to collect the bile. 
    Shortly after iv treatment, 3H was found in  the bile (50% after 24
    hours and 60% after 72 hours), and a large amount of the radioactivity
    was recovered in the faeces suggesting significant enterohepatic
    circulation (Farebrother, 1973, as cited in Annex I, 27).

         Following oral administration to rats (14C-carboxyl label, 0.87
    mg/kg), bioresmethrin was slowly eliminated from the body with only
    73% of the administered dose accounted for in the accounted for 32% in
    faeces and 41% in urine after 6 days (means from two experiments). 
    After 6 days, the highest residue level was found in fat. The order of
    residue levels seen in various tissues was fat > blood > lung >
    kidney > liver > heart > muscle > spleen >> brain. 
    After two weeks excretion was not complete (Ueda  et al., 1975b).
    Qualitative identification of several metabolites of bioresmethrin was
    performed.  Intact bioresmethrin was not found in the urine or faeces. 
    The most slowly excreted metabolite arose from the alcohol moiety of
    bioresmethrin whereas those arising from the acid moiety were rapidly
    excreted.

         In a recent metabolism study, groups of rats (5/sex/dose)
    received either a high dose (200 mg/kg), a low dose (1 mg/kg), or
    repeated dose (1 mg/kg) of [14C-acid]-d- trans-resmethrin.  At 12
    hours after dosing, the amount of radioactivity eliminated in the
    urine was greater than that in the faeces in all test animals;
    however, at day 1 or later, slightly more radioactivity was eliminated
    in faeces that in the urine.  By day 2 after dosing, essentially all

    radioactivity was eliminated from the body.  Significant amount of
    radioactivity was not detected in any tissue (Ruzo, 1991).

    Biotransformation

         Most of the data on biotransformation of bioresmethrin in the
    laboratory animals were evaluated by the 1975 and 1976 Joint Meetings
    (Annex I, 25, 27).  Most of the information presented in the 1977 FAO
    monograph is reproduced below.

         As shown in Figure 1, the biotransformation of bioresmethrin is
    a complex process with several reactions occurring simultaneously at
    various positions in the molecule. The initial step in the metabolism
    is cleavage at the ester linkage, a reaction found to be catalyzed by
    esterases localized in the liver microsome. Transisomerization was
    reported with bioresmethrin but was apparently limited to the
    isomerization of the metabolites.  In addition, this process was seen
    only when bioresmethrin was administered at low levels.
    Transisomerization was not noted on administration of higher levels by
    ip injection (low dose = 1 mg/kg; high dose = 3 gm/rat over a period
    of 3 days administered 2X/day).  Transisomerization occurred only with
    the acid portion of the molecule as observed in Figure 1 (tE-CAA,
    cE-CDA), which shows the probable metabolic route for both the acid
    and alcohol moieties of bioresmethrin in rats.

          In vitro studies with rat and mouse liver preparations
    suggested mouse liver esterases hydrolyzed bioresmethrin
    ((d)- trans-resmethrin isomer) rapidly relative to the corresponding
     cis-isomers ((d)- or (l)- cis-resmethrin) while microsomal enzymes
    oxidize the (d)- trans-isomer, bioresmethrin, more slowly the
     cis-isomers (Ueda  et al., 1975a). When administered to rats,
    bioresmethrin undergoes a complicated series of reactions involving
    initial ester cleavage and subsequent oxidation with or without
    conjugation of both the acid and alcohol metabolites.

         Bioresmethrin is degraded by ester cleavage and the alcohol
    moiety is oxidized to 5-benzyl-3-furylmethanol (BFA),
    5-benzyl-3-furoic acid (BFCA), 4'-hydroxy BFCA and alpha-hydroxy BFCA
    (alpha-OH-BFCA)  (Figure 1).  The chrysan-themate (acid) moiety
    undergoes oxidation from  trans-chrysanthemic acid (t-CA) to
    2,2-dimethyl-3-(2'hydroxy-methyl-1'-propenyl) cyclopropane carboxylic
    acid (tE-CHA) (oxidative metabolism at the methyl group of the
    isobutenyl side chain  trans (E) to the cyclopropane). This is
    further oxidized through the formyl derivative (CAA) to the
    dicarboxylic acid isomers (tE-CDA and cE-CDA).  It is at the CAA
    oxidation stage where isomerization may occur through the proposed
    aldehyde (cE-CAA) intermediate to (cE-CDA) the  cis-dicarboxylic acid
    (Ueda  et al., 1975b).  This metabolic sequence may also account for

    FIGURE 1

    the consideration of Verschoyle & Barnes (1972) that as a delay in
    signs of poisoning was evident following iv administration,
    bioresmethrin might be converted  in vivo to a toxic metabolite.  The
    presence of (d)- trans-CA, BFA, and BFCA as metabolites, which are
    more toxic than bioresmethrin, may account for their observation and
    conclusions.

         The recent bioresmethrin metabolism study indicated that
    bioresmethrin was metabolized by a combination of hydrolytic,
    oxidative, and conjugative processes.  The results of metabolite
    determinations were consistent with those of the 1975 papers of Ueda
     et al. (Ruzo, 1991).

    Toxicological studies

    Acute toxicity

         Much of the information on the acute toxicity of bioresmethrin 
    had been evaluated by the 1976 Joint Meeting and published in the 
    monograph (Annex I, 27).  Some new data have become available, and 
    they have been summarized along with the published information in
    Table 1.

        Two or more hours after oral administration, the treated animals
    showed signs of aggressiveness and tremors.  The final stages of
    poisoning consisted of convulsive twitching, prostration, coma, and
    death normally between 3 and 24 hours (Annex I, 27).  The recent
    findings in clinical signs also include hypotonicity, slightly arched
    back, and piloerection at 30 minutes after treatment (Audegond,
    1989a,b).

    
    Table 1.  Acute toxicity of bioresmethrin

                                                                                     

    Species   Sex    Route             LC50        LC50     Reference
                                   (mg/kg b.w.)   (mg/L)
                                                                                     

    Rat       m/f    oral              >5000                Audegond, 1989a
               m     oral               8800                Glomot & Chevalier, 1969
               f     oral              >8000                Verschoyle & Barnes, 1972
               f     oral               7071                Wallwork et al., 1970
               f     iv                  340                Verschoyle & Barnes, 1972
               f     iv              106-133                Chescher & Malone, 1971a
               f     ip                >8000                Wallwork & Malone, 1971
              m/f    inh. (4 h)                   >5.3      Hardy et al., 1989
               f     inh. (24 h)                  >872      Wallwork & Malone, 1972
               f     dermal          >10 000                Wallwork et al., 1970

    Rabbit     f     dermal            >2000                Audegond, 1989b

    Mouse      f     oral            >10 000                Wallwork et al., 1970
               m     oral               3100                Ueda et al., 1975b
               m     ip                >1500                Ueda et al., 1975b

    Chicken          oral            >10 000                Wallwork et al., 1970
                                     >10 000                Chester & Malone, 1970a
                                                                                     

    
    Acute toxicity of metabolites

         The data on the acute toxicity of the metabolites of
    bioresmethrin were evaluated in the 1976 Joint Meeting and published
    in the monograph (FAO, 1977).  No new data on the acute toxicity of
    these metabolites are available; therefore, the previously published
    data (Annex I, 27) are reproduced in its entirety in Table 2.

        Table 2.  Acute toxicity of the metabolites of bioresmethrin
              (as cited in Annex 1, 27, animal species not named in
              original)

                                                                              

    Metabolite                                        LD50 (mg/kg/bw)a
                                                      ip            oral
                                                                              

    1)  (+)-trans-resmethrin (bioresmenthrin)         > 1500        3100
        (5-benzyl-3-furylmethyl (+)-trans-
        chrysanthemate)

    2)  (+)-trans-CA (t-CA)                               98         280
        (+)-trans-chrysanthemic acid

    3)  (+)-trans-CDA (tE-CDA)                           408
        (+)-trans-chrysanthemundicarboxylic
        acid

    4)  BFA                                               75         310
        5-benzyl-3-furylmethanol

    5)  BFCA                                              46
        5-benzyl-3-furoic acid
                                                                              
    
    Short-term studies

         New data on short-term studies are not available; however, the
    1976 Joint Meeting had evaluated several short-term studies on rats
    and dogs.  The summaries of these study are published in the monograph
    (Annex I, 27), and they are reproduced below.

    Rats

         Groups of rats (10 males/group) were administered bioresmethrin
    orally by gavage six days per week for 3 weeks at doses of 0, 1000,
    and 2000 mg/kg body weight.  There was no mortality attributable to
    bioresmethrin.  There was a slight reduction in body weights at 2000
    mg/kg.  Haematology was normal with a slight reduction noted in
    haemoglobin content and haematocrit value.  Albumin and BUN were
    increased while SGOT activity was reduced.  At the end of three weeks,
    gross examination of major tissues showed slight effects on liver
    (increased size), reduced thymus weight (both organs affected at 1000
    mg/kg), and reduced prostate (only at the high dose).  Histological
    examination showed only thymic involution without structural changes
    with no effects noted in liver (Glomot, undated, as cited in Annex I,
    27).

         Groups of rats (18/sex/group) were fed bioresmethrin at dietary
    concentrations of 0, 400, 1200, and 8000 ppm (the last dose group was
    fed 4000 ppm for 30 days, and the level was increased thereafter) for
    91 days.  There was no mortality observed in this study.  Food
    consumption was normal, and food conversion was unaffected by
    bioresmethrin.  Growth was reduced at the highest dose level which was
    accompanied by changes in blood chemistry parameters indicating liver
    dysfunction (ASP, SGOT, and urinary nitrogen were increased at 90
    days; glucose content was decreased).  Depression of red blood cell
    count was observed at 1200 ppm although no consistent parallel changes
    were seen in haemoglobin content or packed cell volume.  Urinalyses
    were normal.  Gross and microscopic analyses of tissues and organs
    showed an increase in the liver weight at 4000 ppm and a decrease in
    several other organ weights (spleen, heart, brain, thymus, prostate,
    ovary, and uterus).  At  1200 and 4000/8000 ppm fatty infiltration of
    liver was seen on microscopic examination.  A no-effect level in this
    study is 400 ppm (equivalent to an average daily intake of 32.8 to
    36.1 mg/kg body weight of males and females, respectively) (Wallwork
     et al., 1971, as cited in Annex I, 27).

    Dogs

         Groups of dogs (2/sex/group) were administered bioresmethrin by
    gavage, daily at dose levels of 0 and 500 mg/kg body weight for 7 days
    followed by a dose increase to 1000 mg/kg for an additional 14 days. 
    There were no effects noted in this test with respect to mortality,
    behaviour, body weight changes, haematology, blood chemistry or

    urinalysis parameters or on electrocardiograph measurements.  Short
    term administration for three weeks at an oral dose of 1000 mg/kg was
    uneventful in the parameters measured (Malone & Chesher, 1970, as
    cited in FAO, 1977).

         In a continuation of the above trial, after a two-week interval
    on the control diets, dogs were administered bioresmethrin by gavage
    for 7 days at a dose of 2000 mg/kg body weight.  Again, no significant
    effects were noted in the parameters recorded above (Chesher & Malone,
    1971b as cited in Annex I, 27).

         Groups of dogs (3/sex/group) were administered bioresmethrin
    (gelatin capsule) by gavage daily for 90 days at dose levels of 0, 25,
    80, and 250 mg/kg (the high dose was increased to 500 mg/kg in week
    7).  There was no mortality.  Growth, food consumption, and calculated
    food utilization parameters were normal.  Clinical biochemistry,
    ophthalmological examination, and urinalysis parameters were normal at
    all intervals (30, 60, and 90 days) examined.  In the high dose group,
    reduced RBC count, haemoglobin content, and packed cell volume were
    noted.  BUN was slightly increased only at the high dose after 12
    weeks.  There were no adverse effects noted on gross or microscopic
    examination of tissues and organs (including bone marrow).  The NOAEL
    is 80 mg/kg (equivalent to an average of 1600 ppm in the diet) (Noel
     et al., 1971 as cited in Annex I, 27).

    Long-term/carcinogenicity studies

    Mice

         Groups of Charles River CD-1 mice (75/sex/dose) received
    resmethrin at dietary concentrations of 0, 250, 500, or 1000 for 85
    weeks.  The survival rate of 1000 ppm females was significantly (32%)
    lower (p<0.05) than that of controls from week 63 to the end of the
    study.  In 1000 ppm males decreased survival rate was first found at
    week 81 (31% at the end of the study).

         Terminal body weights of mice from the 1000 ppm groups were
    significantly lower (p <0.05) than those of the controls. Although
    the food consumption data indicated a slight decrease, it was not
    compound-related.  Haematological parameters did not show significant
    changes in the treated animals relative to those of the controls.
    There was a significant increase in absolute and relative adrenal
    weights in 500 ppm (20% and 30% respectively) and 1000 ppm males (31%
    and 50%, respectively). There were increases in the relative liver,
    kidney, and brain weights of 1000 ppm males, but these increases were
    mainly due to a decrease in the terminal body weights.  An increase in
    the incidence of amyloidosis was seen in various tissues of high-dose
    animals relative to that in the controls; however, this increase was
    not considered to have been compound-related since the control males
    and females also had high incidence of amyloidosis.  No increase in

    tumour incidence was found in any treatment group.  The NOAEL was 250
    ppm (equivalent to 38 mg/kg bw/day or 11 mg/kg bw/day).

    Rats

         Groups of Sprague-Dawley rats (50/sex/dose) received
    bioresmethrin (technical grade) at dietary concentrations of 0, 50,
    250, or 1250 ppm for 104 weeks. These dietary concentrations were
    equivalent to 3.0, 14.9, and 76.2 mg/kg/day for male rats and 4.0,
    19.8, and 101.3 mg/kg/day for female rats. Two satellite groups in
    each dose level were included in the study.  Satellite group 1
    consisted of 10 rats/sex/dose and was sacrificed on week 52 of the
    study; satellite group 2 consisted of 20 rats/sex/dose and received
    the test chemical for 104 weeks. An extra control group consisting of
    50 animals/sex was included in the study.

         Bioresmethrin did not affect clinical signs, mortality rate, body
    weights, food consumption, food efficiency, haematological parameters,
    or urinalysis parameters.  However, a statistically significant and
    compound-related decrease in cholesterol levels and an increase in
    alkaline phosphatase levels were observed in 1250 ppm males at various
    examination periods. An increase in the alkaline phosphatase levels
    was also found in males at 250 ppm, but this increase did not always
    show a statistical significance.  During sacrifice at 52 and 104
    weeks, a slight increase in the absolute liver weight in males and
    females at 1250 ppm was found.

         Gross pathology showed an increase in the incidence of paleness
    of the liver in both males and females at 1250 ppm (control, 0/10;
    1250 ppm males, 5/10; 1250 ppm females, 2/10) at the 52 week
    sacrifice.

         Histopathology data indicated an increase in the incidence of
    periportal hepatic cell hypertrophy in 250 ppm females (control, 0/10;
    250 ppm, 2/10) and in 1250 ppm male (3/10) and female rats (3/10) at
    52 week sacrifice.  At 104 week sacrifice, there was also an increase
    in the incidence of periportal hepatic cell hypertrophy in 250 ppm
    females (5/70) and 1250 ppm males (37/70) and females (30/70) relative
    to the controls (0/70).  Most animals which had periportal hepatic
    cell hypertrophy also showed signs of vacuolated hepatocytes at 104
    weeks.  No increase in the incidence of neoplasia was found at any
    site in animals receiving bioresmethrin at dose levels up to 1250 ppm. 
    Based upon the histopathologic findings, the NOAEL was 50 ppm (equal
    to 3.0 and 4.0 mg/kg/day in males and females, respectively (Vallet,
    1990).

    Reproduction study

         Groups of Sprague-Dawley rats (25/sex/group) received
    bioresmethrin (93.5% purity) at dietary concentrations of 0, 0, 80,
    250, 750, and 2250 ppm.  The study began with 3 dose levels: 250, 750,
    and 2250 ppm, but the 2250 ppm group had only 3 live births.
    Therefore, the 80 ppm group was added along with its concurrent
    control group after the birth of F1 pups.  For F0 generation, the
    treatment began 8 weeks prior to mating and continued through mating,
    pregnancy, and lactation periods for females.  For the F1 parental
    animals, one male and one female per litter were selected at the
    weaning and received treatment for approximately 14 weeks and then
    mated.  The treatment groups received biores-methrin throughout the
    experiment. Each male was mated with a female of the same treatment
    group until pregnancy occurred or 3 weeks had elapsed. For F1 and
    F2 generations, only the first litters were produced.  At day 4
    post-partum, each litter was standardized to have 4 males and 4
    females if possible.

         For F0 parental animals, 17/20 pregnant females in the 2250 ppm
    group showed clinical signs of decreased spontaneous activity and
    piloerection immediately before and after parturition.  There was a
    slight decrease in male body weights at 250 ppm from days 22 to 64. 
    A significant decrease in the body weight gain was found in 2250 ppm
    males from the second week of treatment to the scheduled sacrifice. 
    There were decreases in female body weights at 750 ppm during the
    premating period, on days 14 and 21 during the pregnancy period, and
    on days 1 and 4 of the lactation period.  At 2250 ppm, female body
    weight was decreased during the premating and pregnancy periods.  Food
    consumption was decreased in females at 750 and 2250 ppm during the
    lactation period.  No significant difference was found in the
    copulation index, fertility index, or length of pregnancy between the
    treated and the control animals.  Macroscopic examination showed an
    increase in the incidence of liver changes characterized by
    accentuated lobular pattern in 2/25 females at 750 ppm.  In 2250 ppm
    females, 11/25 showed marked lobular pattern, and 7/25 showed paler
    than normal liver.  Microscopically, the hepatic changes were
    associated with steatosis.

         For F1 litter parameters, there was a significant decrease
    (p <0.01) in birth index at 750 and 2250 ppm relative to the controls
    (control, 91%; 750 ppm, 81%; 2250 ppm, 1%).  In the 2250 ppm group,
    only 3 pups were born alive.  The viability index on day 4 post-partum
    was also reduced at 750 ppm (control, 95%; 750 ppm, 55%), and there
    was no survival in the the 2250 ppm group.  The mean pup body weight
    of the 750 ppm group was significantly decreased (p< 0.01) on days 1,
    4 and 7 post-partum).  No compound-related effects on physical and
    behavioural developmental parameters were found in all treated pups;

    the parameters examined included pinna unfolding, hair growth, incisor
    eruption, eye opening, auricular duct opening, surface righting
    reflex, cliff avoidance, and air righting reflexes. Gross pathology
    findings revealed an increase in the incidence of discolored liver in
    pups which died between days 1 and 21 postpartum at 250 ppm (2/16),
    750 ppm (13/109), and 2250 ppm (3/167); at 750 ppm, similar finding
    was also reported for pups, which were not selected as F1 parental
    animals on day 21 post-partum.

         For F1 parental animals, no compound-related clinical signs were
    noted in either males or females.  There was a decrease in the body
    weights of 750 ppm males throughout the treatment period, and this
    decrease was statistically significant between days 1 and 113.  The
    body weight decrease was also seen in females at 750 ppm during the
    premating, pregnancy, and lactation periods. A consistent decrease in
    food consumption was not seen in all treated males. In treated
    females, a slight decrease in food consumption was noted at 750 ppm
    from days 14 to 21 of the pregnancy, and a significant drop in this
    parameter was also reported during the lactation period.  As in the F0
    parental animals, the compound produced no effects on copulation
    index, fertility index, and length of pregnancy. Gross pathology
    showed that 1/23 females at 250 ppm had pale liver associated with
    hepatic steatosis. In the 750 ppm group, 1/16 males and 3/15 females
    also had pale liver associated with hepatic steatosis.

         For the F2 litter parameters, at 750 ppm, there was a decrease
    in the birth index (control, 96%; 750 ppm, 58%), in the viability
    index at birth (control, 94%; 750 ppm, 33%), and in the viability
    index at weaning (control, 76%; 750 ppm, 48%).  The mean pup body
    weight at 750 ppm was decreased relative to that of the controls
    during the lactation period, and the decrease was statistically
    significant (p<0.001) on day 1 of post-partum only.  Bioresmethrin
    did not affect the physical and behavioural developments of the pups. 
    Both gross pathological and histopathological examinations on the pups
    showed no abnormalities.

         At 250 ppm, an increase in the incidence of pale or discolored
    liver associated with hepatic steatosis was found in F1 parental
    females (1/23) and in F1 pups (2/16).  Therefore,  the NOAEL for this
    study is 80 ppm (equivalent to 4 mg/kg/day) (Savary, 1987).

    Special study on developmental toxicity

    Rats

         Groups of pregnant Sprague-Dawley rats (40/group) received
    technical grade bioresmethrin (93.5% purity) by gavage at doses of 0,
    50, 100, and 200 mg/kg/day from gestation days 6 to 15.  On gestation
    day 20, 25 females/group were sacrificed, and the fetuses were

    delivered by caesarean section.  The remaining 15 females/group were
    allowed to deliver normally and to nurse their offspring till weaning.

         The clinical signs, mortality, and number of abortions were
    comparable between the treated and the control dams. There was a
    slight and statistically significant drop in body weight gain in
    c-section dams at 200 mg/kg.  The mean numbers of corpora lutea,
    implantation, resorption, and live fetuses were comparable between the
    treated and the control animals.  The fetal body weights of the
    treated groups were similar to those of the controls.  Fetal
    abnormalities were incidental and not compound-related.

         The results in females which delivered normally did not show any
    treatment-related effects on clinical signs, abortion, or the duration
    of gestation. There was a statistically significant (p <0.001)
    decrease in body weight gain in dams at 200 mg/kg. The mean live
    birth, body weight of the live pups, survival rates, and the rate of
    post-implantation losses were comparable to those of the controls. The
    physical and behavioural development of pups from the treated groups
    were similar to those of the controls.  The physical and behavioural
    developmental parameters examined were pinna unfolding, hair growth,
    incisor eruption, eye opening, auricular duct opening, surface
    righting reflex, cliff avoidance, and air righting reflexes.  The
    NOAEL for maternal toxicity was 200 mg/kg, and no embryotoxic,
    teratogenic, and developmental toxicity effects were found in the
    highest dose tested (200 mg/kg) (Savary  et al., 1988).

    Rabbits

         Groups of artificially inseminated female rabbits (16/group)
    received bioresmethrin by gavage at doses of 0, 15, 60, and 240 mg/kg
    from gestation days 6 to 18. The fetuses were delivered on gestation
    day 28, and dams were sacrificed at that time.  Under the conditions
    of the study, the compound produced no maternal nor developmental
    toxicity at any dose levels.  Based upon the results of this study,
    the pregnant rabbits could have tolerated higher dose levels (Savary,
    1990).

         An older rabbit teratology study on the bioresmethrin had been
    considered by the Joint Meeting in 1976 and published in 1977 FAO
    monograph.  The summary of the study is reproduced in its entirety
    below.

         Groups of pregnant rabbits (4-6 rabbits/group) were administered
    bioresmethrin in doses of 0, 10, 20, 40, and 80 mg/kg by oral gavage
    daily from days 8-16 of gestation.  The does were sacrificed on day 28
    and examined for implantation, live and dead fetuses, resorption
    sites, and abnormalities (after staining a representative number for
    skeletal examination).  There was no apparent effect on parents in the
    study as growth and gestation were unaffected.  There was an increase
    in dead fetuses at the highest dose and a large number of resorption

    sites noted at all treatment levels.  There were a number of deformed
    fetuses observed but the total numbers were not sufficient for
    adequate statistical evaluation.  The deformities included straight
    tail, crossed hind limbs and unilateral union of 6th and 7th ribs at
    the sternal end.  An overall fetal loss was observed at all dose
    levels (primarily  because of the large number of resorption sites
    recorded) (Waldron, 1969, as cited in Annex I, 27).

    Special studies on genotoxicity

         A number of mutagenicity studies have been conducted with
    bioresmethrin.  The results are summarized in Table 3.

    Special studies on skin and eye irritation and sensitization

         A volume of 0.5 ml bioresmethrin (95%) was applied under
    occlusive conditions to the shaven intact skin of 3 male New Zealand
    white albino rabbits for 4 hours.  No evidence of skin irritation was
    found up to 72 hours after application (Audegond, 1989d).

         Three New Zealand white albino rabbits were administered 0.1 ml
    of bioresmethrin (95%) in their conjunctival sac of the right eye. 
    The treated eyes did not appeared to have been washed.  No eye
    irritation was found under the conditions of the test (Audegond,
    1989c).  An older study conducted by Chesher and Malone (1970c) also
    showed that bioresmethrin was not an eye irritant in rabbits (FAO,
    1977).

         Bioresmethrin (95%) was tested for skin sensitization in 10 male
    Hartley albino guinea pigs.  During the induction phase, The animals
    were treated topically with 0.5 ml bioresmethrin daily for 10 days. 
    On day 36, the animals were challenged with 0.5 ml of the test
    substance and later rechallenged with similar volume on day 43.  A
    positive control group of 10 males received 0.06% w/v solution of
    2,4-dinitrochlorobenzene in a similar manner as those treated with
    bioresmethrin.  Bioresmethrin did not produce skin sensitization
    reaction in guinea pigs (Kuhn, 1990).

         In an older study published in the FAO Monograph (Annex I, 27),
    groups of adult guinea pigs (6 males/group) were applied bioresmethrin
    (0.1 ml of a 5% (w/v) formulation) or 2,4-dinitrochloro-benzene (DNCB)
    to the ears for 4 days.  On day 7, 0.2 ml of bioresmethrin or DNCB
    were applied dermally.  Bioresmethrin produced only traces of erythema
    suggesting a low potential for sensitization and irritation (Chesher
    & Malone, 1970b).


        Table 3. Results of genotoxicity assays on bioresmethrin
                                                                                                      

    Test system         Test object         Concentration      Purity    Results       Reference
                                                                (%)
                                                                                                      

    Ames test           S. typhimurium      0.2. 1-5. 10.       92.2     Negativea     Moore, 1981
    (with and           TA1535, TA1537,     50, 100, 250,
    without S9)         TA1538, TA98,       500, 1000,
                        TA100               5000 g/plate

    Ames test           S. typhimurium      30, 100, 300,       97       Negative      Pluijmen et
    (with and           TA98, TA100         1000 g/plate                              al., 1984
    without S9)

    Gene mutation       V79 Chinese         5, 10, 15, 20       97       Negative      Pluijmen et
    assay (with and     hamster cells       g/ml                                      al., 1984
    without S9)

    Micronucleus        Swiss CD 1 mice     300 mg/kg (M)       93.6     Negative      Vannier &
    assay                                   450 mg/kg (F)                              Fournex, 1986

    Metaphase           human               4, 20, 40           93.6     Negative      Allen, Brooker
    chromosome          lymphocytes         g/ml                                      & Howell (1986)
    analysis (with
    and without S9)

    Unscheduled         human               0.125, 0.25,        93.6     Negative      Allen &
    DNA synthesis       epithelioid         0.5, 1, 2, 4,                              Proudlock,
    assay (with         cells               8, 16, 32, 64                              1986
    and without S9)     (HeLa S3)           128 and 256
                                            g/ml
                                                                                                      
    a  The report of this study has serious deficiencies which include lack of information on the source
       of the metabolic activation system and whether the results presented in the report are the
       averages or single determinations.
    

    COMMENTS

         Bioresmethrin was absorbed and distributed rapidly following oral
    administration, and was quickly metabolized by oxidation and
    hydrolysis at various sites in the molecule. Complete elimination of
    bioresmethrin occurred slowly.  The enterohepatic circulation system
    was involved in the elimination.  There is no indication that
    isomerization of bioresmethrin to the (+)- cis-isomer occurs.

         In general, bioresmethrin has low acute toxicity after oral
    administration.  In mammals, the  cis-isomers are generally more
    toxic than the corresponding  trans-isomers.  Some metabolites of
    bioresmethrin are more toxic than the parent compound.

         Short-term studies in rats show that bioresmethrin fed at 1000
    ppm caused a slight increase in liver weight and a reduction in thymus
    weight in rats.  In a 90-day feeding study in rats, at dietary
    concentrations of 0, 400, 1200 or 8000 ppm, bioresmethrin at 1200 ppm
    or above induced an increase in liver weight and fatty liver which was
    accompanied by changes in blood enzyme levels (serum alkaline
    phosphatase and aspartate aminotransferase) indicative of liver
    injury.  In a 90-day gavage study in dogs, bioresmethrin at 250 mg/kg
    bw/day or above reduced the erythrocyte count, haemoglobin content,
    and packed cell volume.

         A carcinogenicity study in mice with resmethrin (containing at
    least 30% bioresmethrin) at dietary concentrations of 250, 500 and
    1000 ppm for 85 weeks did not demonstrate a carcinogenic effect. 
    However, resmethrin decreased survival rate in both male and female
    mice at 1000 ppm and adrenal weights were significantly increased in
    males at 500 and 1000 ppm.  The NOAEL for resmethrin was 250 ppm,
    which was equal to 38 mg/kg bw/day for resmethrin and 11 mg/kg bw/day
    for bioresmethrin.

         In a long-term carcinogenicity study in rats at dietary
    concentrations of 0, 50, 250 or 1250 ppm for 104 weeks, bioresmethrin
    did not produce an increase in the tumour incidence.  However, it
    induced an increase in alkaline phosphatase in males at 250 and 1250
    ppm and a decrease in cholesterol levels in males at 1250 ppm. 
    Bioresmethrin caused an increase in the incidence of non-neoplastic
    liver changes, including pallor and hypertrophy of hepatocytes in
    males at 250 ppm and in males and females at 1250 ppm.  Based upon
    these findings, the NOAEL for chronic toxicity was 50 ppm, equal to
    3.0 mg/kg bw/day.

         In a two-generation reproduction study in rats, at dietary
    concentrations of 0, 80, 250, 750 or 2250 ppm, bioresmethrin did not
    affect reproductive performance at dietary concentrations of 250 ppm
    or less, although reproduction was adversely affected at 750 and 2250
    ppm.  Based on a decrease in parental body weight and hepatotoxicity

    observed at 250 ppm, the NOAEL for this study was 80 ppm, equivalent
    to 4 mg/kg/day.

         Studies on the developmental toxicity of bioresmethrin in rats
    and rabbits failed to elicit effects at doses up to 200 and 240 mg/kg
    bw/day respectively.

         After reviewing all available  in vitro and  in vivo short-term
    assays with bioresmethrin, the Meeting concluded that there was no
    evidence of genotoxicity.

         The ADI was based upon the long-term/carcinogenicity study in
    rats utilizing a safety factor of 100.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat:   50 ppm in the diet, equal to 3.0 mg/kg bw/day
         Dog:   80 mg/kg bw/day

    Estimate of acceptable daily intake for humans

         0-0.03 mg/kg bw

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

         Observations in humans.

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    See Also:
       Toxicological Abbreviations
       Bioresmethrin (ICSC)
       Bioresmethrin (WHO Pesticide Residues Series 5)
       Bioresmethrin (Pesticide residues in food: 1976 evaluations)
       Bioresmethrin (UKPID)