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    FLUBENDAZOLE

    First draft prepared by
    Dr Radovan Fuchs
    Institute for Medical Research and Occupational Health
    University of Zagreb, Croatia

    1.  EXPLANATION


    Flubendazole([5-(4-fluorobenzoyl)-1H-benzimidazole-2-y1]-carbamic
    acid methyl ester) belongs to the group of benzimidazole carbamates.
    Flubendazole is an anthelminthic agent active against a range of
    gastrointestinal parasites in pigs and poultry.

         Flubendazole had not been previously evaluated by the Joint
    FAO/WHO Expert Committee on Food Additives.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution and excretion

         Groups of 18 Wistar rats and 12 multi-mammate rats  (Mastomys
     natalensis) were given an oral dose of 40 mg/kg bw of flubendazole
    as a microsuspension. The same amount of test substance was given
    subcutaneously to 24 Wistar rats and 12 multimammate rats. Groups of
    six rats of both strains were sacrificed by decapitation at 4 and 8
    h and at 24 and 48 h after administration to Wistar rats. Plasma
    levels of flubendazole after oral administration were found to be 81
    and 17 ng/ml at 4 h in the Wistar rats and multimammate rats,
    respectively. The estimated half-life was 6-7 h. At 24 h the
    flubendazole plasma level in the Wistar rats was 5.6 ng/ml. Plasma
    concentrations after subcutaneous injection was very low. Peak
    plasma levels of 7-9 ng/ml were observed after 4-8 h in both
    strains. After 48 h, plasma levels represented 32% of the peak
    level, indicating very slow absorption of the drug from the
    injection site (Michiels  et al., 1980a).

         Groups of male Wistar rats were given oral doses of 10 mg/kg bw
    microcrystalline suspension of 14C-labelled flubendazole. Animals
    were sacrificed at different intervals (0.5, 1, 2, 4, 6, 16 and 24 h
    after administration). Peak plasma levels of unchanged flubendazole
    were observed after 0.5 h and the drug was eliminated with a
    half-life of 6 h. Generally, the concentration of flubendazole in
    blood and plasma was very low, and was almost unchanged at 0.5 h
    (0.27 g/ml) and 24 h (0.18 g/ml) after exposure. After 24 h,
    nearly 50% of the dose was excreted via faeces while 4% of the dose
    was excreted in urine as metabolites. The amount of total
    radioactivity present in the liver, lung, kidney, muscle and fat was
    very low and did not exceed 3.1 g/g of tissue (Michiels  et al.,
    1977a).

         Five male Wistar rats were each given an oral dose of 10 mg/kg
    bw of 14C-labelled flubendazole. Within 4 days, 7% of the dose was
    excreted in urine, and 89% in faeces. After 48 h, 91% of
    administered flubendazole was excreted. Radioactivity in urine was
    due to metabolites while in faeces the radioactivity was mainly due
    to the unchanged drug. The main metabolites identified in urine were
    present mainly in the form of glucuronides and resulted from
    carbamate hydrolysis and reduction of ketone (Meuldermans  et al.,
    1977).

         14C-Labelled flubendazole was given orally to 3 female beagle
    dogs at a dose of 10 mg/kg bw. A total of 88% of the radioactivity
    was excreted within 4 days after administration. The majority of the
    radioactivity (81.5%) was measured in faeces, while only 6.3% was
    found in urine. Radioactivity found in urine was related to

    metabolites of flubendazole. In samples of faeces collected during
    48 h, the radioactivity was almost exclusively due to unchanged
    flubendazone. There are indications that flubendazole may undergo
    enterohepatic circulation (Meuldermans  et al., 1978).

         A group of 2 male and 4 female beagle dogs was treated orally
    with flubendazole at a dose of 22 mg/kg bw. Plasma levels peaked at
    2 to 8 h after dosing (4-5 ng/ml) (Michiels  et al., 1987).

         Eight male beagle dogs were divided into groups of two and were
    given micro-suspensions of flubendazole intramuscularly. Doses of
    2.5 and 25 mg/kg bw were given as single injections or as repeated
    injections for five consecutive days. Blood tests were made during
    42 days after administration. At both doses, three phases in plasma
    concentration-time curves were observed. First there was a fast
    phase, with more rapid release of the drug from the injection site
    than its elimination from the body. A second phase showed faster
    elimination than release from the depot and a third phase showed
    very slow terminal resorption. After a single injection of 2.5 mg/kg
    bw, peak plasma levels appeared after 3-5 days at concentrations up
    to 0.6 ng/ml. With a single injection of 25 mg/kg bw, maximal plasma
    levels up to 2.1 ng/ml were observed 5-7 days after administration.
    Repeated injections for 5 consecutive days gave maximal plasma
    levels at 3-4 days after the last dose; concentrations found were
    2.4 and 13.2 ng/ml for the low and high dose, respectively. The
    elimination half-life for both doses and regimes was estimated to be
    24 h (Michiels  et al., 1980b).

         Pigs were given 14C-flubendazole, labelled in the 2-position
    of the benzimidazole ring at a dose of 1.5 mg/kg bw for five
    consecutive days. A total of 79% of the administered dose was
    excreted within 30 days after the medication period (23% in urine
    and 56% in faeces). The main metabolic pathways were carbamate
    hydrolysis and ketone reduction (Meuldermans  et al., 1982).

    2.1.2  Biotransformation

         Reduction of the ketone functional group and hydrolysis of the
    carbamate moiety are the main biotransformation pathways of
    flubendazole. To some extent, methylation has also been found as a
    relatively minor pathway. In rats and dogs, the urinary metabolites
    are formed exclusively by ketone reduction, carbamate hydrolysis and
    glucuronide and sulfate conjugation (Meuldermans  et al., 1977,
    1978).

         The metabolic pathways of flubendazole in different animal
    species, adapted from Van Leemput,  et al., 1991, is presented in
    Figure 1.

    FIGURE 1

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

         The acute toxicity of flubendazole is summarized in Table 1. In
    some cases the animals exhibited exophthalmus, hypotonia, slight
    sedation, general depression, ataxia, convulsions and pilo-erection.
    Deaths were recorded within the first 24 h after intraperitoneal
    administration of test substance.

        Table 1.  Acute toxicity of flubendazole
                                                                                      

    Species            Sex          Route          LD50         Reference
                                                (mg/kg bw)
                                                                                      

    Mouse              M&F          oral*       >5000           Niemegeers, 1974
                       M&F          oral#       >10 000         Nakaoka et al., 1983a
                       M&F          s.c.*       >5000           Niemegeers, 1986a
                       M&F          s.c.#       >10 000         Nakaoka et al., 1983a
                       M            i.p.#       528             Nakaoka et al., 1983a
                       F            i.p.#       434             Nakaoka et al., 1983a

    Rat                M&F          oral*       >5000           Niemegeers, 1974
                       M&F          oral#       >10 000         Nakaoka et al., 1983b
                       M            i.p.#       435             Nakaoka et al., 1983b
                       F            i.p.#       252             Nakaoka et al., 1983b
                       M&F          s.c.#       >5000           Nakaoka et al., 1983b
                       M&F          s.c.*       >10 000         Niemegeers, 1986b

    Guinea-pig         M&F          oral*       >5000           Niemegeers, 1974
                       M            s.c.*       4679            Niemegeers, 1986c
                       F            s.c.*       4834            Niemegeers, 1986c

    Laying-hen         F            oral        >640            Vanparijs &
                                                                Desplenter, 1982

    Guinea fowl                     oral        >1200           Le Brun, 1983
                                                                                      


    *  vehicle: aqueous suspension with 1% polysorbate 80
    #  vehicle: 0.5% methylcellulose solution
    
    2.2.2  Short-term toxicity studies

    2.2.2.1  Rats

         In a 3-month study flubendazole admixed with the diet at levels
    of 0, 10, 40 or 160 mg/100 g food was given to Wistar rats (10
    rats/sex/dose level). The approximate intakes of flubendazole over
    the period of the study were equal to 0, 8, 30 or 130 mg/kg bw/day
    for males and 0, 9, 40 or 150 mg/kg bw/day for females. No
    treatment-related effects were observed on mortality, behaviour,
    appearance, food consumption, body weight, haematology, serum
    analysis, urinalysis, microscopy, organ weight or histopathology
    (Marsboom, 1975a).

    2.2.2.2  Dogs

         Groups of beagle dogs (3 dogs/sex/group) were given
    flubendazole orally as a powder in gelatin capsules at doses of 0,
    2.5, 10 or 40 mg/kg bw/day, six days per week, over 3 months.
    Control animals received 250 mg lactose only. Observations included
    behavioural changes, food consumption, body weight, ECG, blood
    pressure, haematology, serum analysis, urinalysis, necropsy, organ
    weight and histopathology. Small-sized prostate and congestion of
    cauda of the epididymis were observed in all males at doses of 10
    and 40 mg/kg bw/day.

         Histopathologically some atrophic changes of the prostate were
    noticed at the higher dose groups, but the changes were not
    dose-related. Atresic changes in the ovaries were noted in 2 females
    in the 2.5 mg/kg bw/day group, 1 in the 10 mg/kg bw/day group and 3
    in the 40 mg/kg bw/day group. Atrophic changes of the uterine wall
    and vagina in some dosed females were also observed. According to
    historical control data the changes in the female genital tract were
    considered to be within the normal range for the age of the dogs
    (Marsboom  et al., 1975).

         Subsequent to the above report the histopathological slides
    were evaluated by two independent pathologists. Both experts agreed
    that the atrophic changes were not indicative of a treatment-related
    toxic effect and should be considered as incomplete development in
    sexually immature dogs (Thoonen, 1987; Powell, 1991). Because of the
    lack of conclusive evidence as to the etiology of these changes, the
    Committee concluded that the NOEL in this study was 2.5 mg/kg
    bw/day.

    2.2.2.3  Chickens

         Flubendazole was given to 4 groups of broiler breeder pullets
    (50 F + 5 M/group) over a period of 7 days. The drug was admixed in

    the feed at concentrations of 0, 60, 120 or 180 mg/kg. Four days
    after the end of treatment 10 hens and a cock were removed from the
    groups for blood sampling and necropsy.

         The only significant difference in haematological parameters
    was a lower haematocrit value and red blood cell count in the
    highest-dose group. Clinical biochemistry tests showed significant
    increases in triglycerides and phospholypides at 120 mg/kg,
    decreased aspartic aminotransaminase at 180 mg/kg and decreased
    cholinesterase at 120 and 180 mg/kg. Histopathologically,
    treatment-related effects were observed in the spleen of the
    high-dose group, in reduction of the white pulp area and reduction
    of the number of red blood cells in the red pulp. The NOEL in this
    study was 120 mg/kg, equivalent to 15 mg/kg bw/day (Desplenter &
    Coussement, 1985).

    2.2.3  Long-term/carcinogenicity studies

    2.2.3.1  Mice

         Four groups of 50 male and female Swiss albino mice were fed
    diets containing 0, 5, 10 or 20 mg/100 g flubendazole for a period
    of 18 months. The intake of the drug over the study period was
    equivalent to 7.5, 15 or 30 mg/kg bw/day (data on food consumption
    and body weight were not provided). The mortality rate, clinical
    observations and presence of subcutaneous masses were recorded
    daily. A complete necropsy and histopathological examination were
    performed at termination of the study.

         No treatment-related effects were noted for clinical condition
    or survival. The percent survival for treated groups was comparable
    to the controls, as shown in Table 2.

        Table 2. Survival at 18 months in the long-term study in mice

                                                                                  

          Sex                         Dose mg/kg bw/day
                                                                                  

                      0               7.5         15           30

          M           54%             44%         38%          38%

          F           40%             34%         40%          32%
                                                                                  
    
         The total number of benign and malignant tumours was similar
    for treated and control groups. The most common types of tumours
    were hepato-cellular tumours and alveologenic lung carcinoma. No
    effect of flubendazole was evident histopathologically. The NOEL in
    this study was 30 mg/kg bw/day (Verstraeten,  et al., 1983a).

    2.2.3.2  Rats

         Groups of 50 Wistar rats of each sex were fed diets containing
    0, 10, 20 or 40 mg/100 g flubandezole for 24 months. Drug intake was
    equivalent to 5, 10, or 20 mg/kg bw/day.

         All animals were observed once daily for signs of abnormal
    behaviour and clinical effects. At termination of the study a full
    necropsy was performed and the organs were examined
    histopathologically.

         The mortality rate was very high in all groups of animals
    including the controls at the end of the study. There was no
    statistically-significant difference in mortality rates between the
    groups during the entire period of the study. There were no
    treatment-related effects among the treated and control animals.
    During the study subcutaneous masses in females were noted in
    approximately 20% of the control and 40% of the high-dose animals.
    On necropsy a significantly increased incidence of pale kidneys was
    observed in females at 5 and 20 mg/kg bw/day. However, there was no
    histopathological evidence for dose-related changes in the kidney.
    Flubendazole at concentrations of up to 40 mg/100 g feed for 2 years
    did not show biological or statistical evidence of incidence of
    neo-plasms. The NOEL in this study was 20 mg/kg bw/day (Verstraeten
     et al., 1983b).

    2.2.4  Reproduction studies

    2.2.4.1  Mice

         Groups of 30 female Swiss albino mice were given flubendazole
    in a single dose of 0, 20, 80 or 320 mg/kg bw. The drug was
    administered orally by gavage in microsuspension vehicle. A control
    group of females received vehicle suspension only. All the females
    were mated with untreated males. The animals were controlled daily
    over a period of 360 days. During the experiment the mortality rate,
    incidence of pregnancy, time interval between dosing and birth, and
    number of pups were not affected by treatment.

         By comparing the data from control and treated animals, no
    differences were noted regarding mortality of females, the average
    time interval between dosing and birth of first litters or litter
    size per female. In the high-dose group (320 mg/kg bw) a reduction
    of mean number of pups per female was observed. The NOEL in this
    study was 80 mg/kg bw (Marsboom, 1977a).

    2.2.4.2  Rats

         In a fertility study, Wistar rats (20 animals/sex/dose) were
    given flubendazole admixed in feed. The concentration of the test
    substance in the diet was 0, 2.5, 10 or 40 mg/100 g, equivalent to
    2.5, 10 or 40 mg/kg bw/day. Females were treated with flubendazole
    for 14 days prior to cohabitation with males and during the
    pregnancy period. Males received flubendazole over a period of 60
    days before mating. Untreated animals were mated with treated ones.

         No drug effects were noted regarding food consumption or
    average weight gain of females. All the females were sacrificed on
    the 22nd day post-mating. No drug effects were noted on incidence of
    pregnancy and the percentage of pregnancies was 100% in almost all
    groups. In all females the average number of implantations and
    percentages of live, dead and resorbed fetuses were similar and not
    affected by the treatment. Treatment-related fetal skeletal
    abnormalities were not observed. The NOEL in this study was 40 mg/kg
    bw/day (Marsboom, 1976a).

         Four groups of 20 Wistar rats were given flubendazole admixed
    in feed at concentrations of 0, 2.5, 10 or 40 mg/100 g feed,
    equivalent to 0, 2.5, 10 or 40 mg/kg bw/day from day 16 of gestation
    up to the 3-week-lactation period.

         The average body weight and food consumption were not
    significantly different among the groups. Only one female from the
    40 mg/kg bw/day group died during the time of treatment. The
    pregnancy rate, average duration of gestation and fetal parameters
    were comparable among the treated and control groups. No
    abnormalities were found among offspring in any of the groups in the
    study. The NOEL in this study was 40 mg/kg bw/day (Marsboom, 1976b).

    2.2.4.3  Pigs

         A study was performed on 5 different pig farms. On each farm 16
    sows and 1 boar received flubendazole admixed in the feed, providing
    a dose of 3 mg/kg bw/day. On each farm the same number of
    non-treated animals served as controls. Each boar was mated with 8
    treated and 8 control sows. The treated sows received flubendazole
    diet from estrus till parturition, while boars were treated two
    months prior to the first mating and until all sows were
    successfully bred.

         During the study no differences were observed on conception
    rate of the boars, estrus behaviour or gestation length. Post-partum
    conditions were normal except in 7 sows, which were found to be

    related to dystocia. The number of live and dead piglets among the
    different groups was not statistically different. There were no
    significant differences in abnormalities observed among the piglets
    from any groups except in slightly increased number of
    mummifications. The investigators associated mummifications to the
    endemic occurrence of pseudorabies and parvovirus infections in the
    area where the study was performed. The time interval betwen weaning
    to the next estrus were equal among the groups (De Keyser  et al.,
    1984)

    2.2.5  Special studies on embryotoxicity/teratogenicity

    2.2.5.1  Rats

         Groups of 20 young female Wistar rats were fed diet containing
    flubendazole at concentrations of 0, 2.5, 10 or 40 mg/100 g feed,
    equivalent to 0, 2.5, 10 or 40 mg/kg bw/day, from day 6 to day 15 of
    pregnancy. Parameters measuring body weight, food consumption,
    mortality and pregnancy were recorded. The animals were sacrificed
    on the 22nd day of pregnancy and the fetuses were delivered by
    caesarean section. The number of live, dead and resorbed fetuses was
    recorded, average body weight of pups was measured and the fetuses
    examined for abnormalities.

         During the study none of the animals died and food consumption
    and average body weight were comparable among the groups. The
    percentage of pregnancies in all treated groups was 95% and in the
    control group 90%. All the fetal parameters studied were comparable
    among the treated and control groups. The absence of metacarpal and
    metatarsal bones was noticed in only one fetus from the highest dose
    group. The NOEL in this study was 40 mg/kg bw/day (Marsboom, 1974).

         In a separate study, four groups of 20 female Wistar rats each
    were treated with flubendazole in the diet at concentrations of 0,
    2.5, 10 or 40 mg/100 g feed, equivalent to 0, 2.5, 10 or 40 mg/kg
    bw/day. The study design and parameters studied were the same as
    described in the previous study. There were no changes in any of the
    parameters studied. The NOEL was 40 mg/kg bw/day (Marsboom, 1975b).

         A third study (same experimental design) was carried out in
    order to confirm the results of the previous studies. The test
    substance in this experiment was given orally by gavage at doses of
    0, 2.5, 10 or 40 mg/kg bw/day. All the maternal and fetal parameters
    were comparable among the treated and control groups of animals. The
    NOEL in this study was 40 mg/kg bw/day (Marsboom, 1977b).

         Groups of female Wistar rats (20 animals/group) were given
    flubendazole admixed in a powdered diet at concentrations of 0, 10,
    40 or 160 mg/100 g feed, equivalent to 0, 10, 40 or 160 mg/kg bw/day
    from days 6 to 15 of pregnancy. The same parameters as in the
    previous experiments were studied. Food consumption and average body

    weight were comparable among all groups. During the study no
    mortalities occurred. The percentage of pregnancies was high and
    comparable among the groups. No evidence of embryotoxicity or
    teratogenicity was found. The NOEL in this study was 160 mg/kg
    bw/day (Marsboom, 1978).

         Flubendazole extracted from commercially formulated drug was
    suspended in water and given by gavage to female Sprague-Dawley rats
    (20 animals/group) at doses of 0, 2.5, 10, 40 or 160 mg/kg bw/day
    from day 8 to day 15 of pregnancy. On day 21 of pregnancy the
    animals were sacrificed and the number of implantation sites and
    live fetuses were recorded. The fetuses were further examined for
    malformations.

         During the study period signs of maternal toxicity were not
    observed. The highest dose (160 mg/kg bw/day) was found to be
    embryocidal, resulting in a significant increase in the fetal
    resorption rate. A dose-dependent decrease in fetal body weight
    occurred, which was significant at 40 and 160 mg/kg bw/day. The two
    highest doses induced significant gross, skeletal and internal
    malformations. In the 160 mg/kg bw/day dose group, 16.8% of fetuses
    were grossly malformed. The malformations were described as:
    encephalocele, cranial meningocele, omphalocele, ectrodactyly, club
    foot, anal atresia, spina bifida occulata and tail defects. Skeletal
    malformations affected mainly the vertebrae and ribs, and
    significant malformations were found in 24.6% and 32.6% of fetuses
    in the two highest dose groups. Significant internal malformations
    were observed in 19.8% and 47.7% of fetuses in the 40 and 160 mg/kg
    bw/day group. respectively. The NOEL in this study was 10 mg/kg
    bw/day (Yoshimura, 1987).

    2.2.5.2  Rabbits

         Groups of 20 female New Zeeland white rabbits were orally
    administered 0, 10 or 40 mg flubendazole/kg bw/day from day 6 to day
    18 of gestation. The females were sacrificed on gestation day 28 and
    fetuses were delivered by caesarean section. The animals from all
    doses were necropsied. The fetuses were weighed and examined for
    external anomalies. After incubation of the pups the survival rate
    was calculated. All the fetuses were radiographically examined.
    One-third of the fetuses were examined for visceral anomalies and
    the rest were preserved and used for additional analysis.

         During the study one non-pregnant female in the highest dose
    group died due to infection. The average body weight increase was
    comparable among all groups. No differences were observed in
    pregnancy rate among the groups and no teratogenic effects were
    found among the offspring. The percentage of live, dead and resorbed
    fetuses and survival rate of incubated pups from all groups were not
    significantly different. The NOEL in this study was 40 mg/kg bw/day
    (Marsboom, 1976c).

    2.2.5.3  Pigs

         Flubendazole (5% powder formulation) was admixed in the diet at
    a concentration of 30 mg/kg and given to 6 crossed Landrace-Pietrain
    sows from day 8 to day 50 of pregnancy. Altogether 62 piglets were
    born. No piglets were stillborn and no abnormalities were recorded
    (Marsboom, 1976d).

         In a separate study flubendazole (5% powder formulation)
    admixed in the feed at a concentration of 200 mg/kg, equivalent to 8
    mg/kg bw/day, was given to 20 sows from the first day of mating
    until the day of farrowing. Three sows were withdrawn from the
    experiment after 3 weeks. In the group of 17 sows having successful
    pregnancies 154 live and 8 stillborn piglets were recorded. There
    were no detectable external abnormalities, except for a mild form of
    sprayed legs observed in 2 piglets of one sow. Abnormalities were
    not found in stillborn piglets (Rogiers, 1979).

         A group of 8 sows was given 50 mg flubendazole/kg bw/day
    admixed in the diet from the first day of mating until day 70 of
    pregnancy. Sixty-three piglets of normal weight and 3 stillborn
    piglets were born. No external abnormalities were recorded (Rogiers,
    1980).

    2.2.6  Special studies on eye and skin irritation

    2.2.6.1  Rabbits

         A group of 6 adult New Zeeland rabbits had 0.1 ml of a 50% w/w
    suspension of a 5% premix formulation instilled into the
    conjunctival sac of the left eye. There were no signs of eye
    irritation during the observation time of 21 days (Teuns & Marsboom,
    1987a).

         A flubendazole formulation was applied to intact skin of New
    Zeeland rabbits. The test sites were occluded for 24 h. After
    removal of dressings, the test sites were scored for erythema and
    oedema. A barely perceptible irritation (index 0.63) was noted
    during the first 5 days in the treated animals according to the
    Draize irritation index. This irritation was fully reversible after
    5 days. This study was designed primarily to determine the dermal
    LD50 value (Teuns & Marsboom, 1987b).

    2.2.7  Special studies on genotoxicity

         The genototoxicity of flubendazole is summarized in Table 3.

        Table 3. Results of genotoxicity studies on flubendazole
                                                                                            

    Test system         Test object         Concentration       Results      Reference
                                                                                            

    In vitro

    Repair test         B. subtilis         1-5000 g/disc      Negative     Yamashita &
                                                                             Hattori, 1983

    Ames test +/- S9    S. typhimurium      10-5000 g/plate    Negative     Yamashita &
                        TA1535, TA1537,                                      Hattori, 1983
                        TA1538, TA100,
                        TA98
                        E. coli
                        N/r WP2 trp hcr

                        S. typhimurium      0.5-1000 g/plate   Negative     Jagannath &
                        TA535, TA1537,                                       Brusick, 1978
                        TA1538, TA98,
                        TA100
                        S. cerevisiae D4

    In vivo

    Sex-linked          Drosophila          500 and 2000 ppm    Negative     Vanparys &
                        melanogaster        feeding/3d                       Marsboom, 1982

    Micronucleus        Male Swiss albino   2 oral doses: 40,   Negative     Vanparys &
    test                mice                80, 160,                         Marsboom, 1979
                                            1280 mg/kg bw

                        female Wistar       2 oral doses: 80,   Negative     Vanparys &
                        rats                160, 640 mg/kg bw                Marsboom, 1981

    Dominant            Male Swiss albino   single oral dose:   Negative     Marsboom, 1977c
    lethal              mice                10, 40,
                                            160 mg/kg bw
                                                                                            
    

    2.3  Observations in humans

         Three male volunteers were given single doses of flubendazole
    orally in 100 mg tablets. Flubendazole was mainly excreted in faeces
    (77.3% of the administered dose) within 3 days after intake of the
    drug. Less than 0.1% of the dose was excreted in the urine as
    unchanged drug (Heykants  et al., 1975).

         Three male volunteers were given oral doses of 100 mg
    flubendazole 2 h before meals, 2000 mg flubendazole immediately
    after a heavy meal and 2000 mg flubendazole before a meal. Serum
    concentrations of flubendazole were monitored. The plasma
    concentration was very low, and peak levels after 100 and 2000 mg
    doses taken before meals were 0.35 and 0.74 ng/ml, respectively. In
    the case of flubendazole taken after a heavy meal, the peak plasma
    concentration was markedly higher (4.06 ng/ml), which indicates that
    the presence of food enhances the absorption of flubendazole from
    the gastro-intestinal tract. By calculating the area under the curve
    (AUC) values it was found that the absorption of the drug was not
    dose-dependent. AUC values increased only 1.4-fold after a 20-fold
    increase in dose (Michiels  et al., 1977b).

    3.  COMMENTS

         A substantial database was available for assessment, including
    data on kinetics and metabolism, acute toxicity, short-term and
    long-term toxicity, reproductive and developmental toxicity, and
    genotoxicity.

         The absorption, metabolism, and excretion of flubendazole have
    been studied using radiolabelled drug. Flubendazole is poorly
    absorbed and metabolized in a qualitatively similar way in all
    species studied. More than 50% of the ingested drug is eliminated
    unchanged in the faeces. The absorbed drug is rapidly metabolized,
    so that levels of parent drug in the blood and urine are extremely
    low. The main site of metabolism is the liver, and major metabolic
    pathways are carbamate hydrolysis and ketone reduction. It seems
    probable that flubendazole undergoes enterohepatic circulation.

         Single oral doses of flubendazole were slightly toxic to
    experimental animals, the median lethal dose (LD50) being greater
    than 5000 mg/kg of body weight in mice, rats, and guinea-pigs.

         Flubendazole was given orally in gelatin capsules to dogs at
    doses of 2.5, 10 or 40 mg/kg bw/day, 6 days a week for 3 months.
    Some atrophic changes and congestion of the epididymis were observed
    in the male genital tract at doses of 10 and 40 mg/kg bw/day, and in
    the female genital tract at all doses. The changes in the female
    genital tract were considered to be within normal limits for dogs of
    the age of those used in the study. On histological examination of
    male sex organs, changes in the testes could not be clearly
    associated with flubendazole treatment. The findings in male dogs
    may not be compound-related, but because of the lack of conclusive
    evidence as to the cause of these changes, the Committee concluded
    that the no-observed-effect level (NOEL) was 2.5 mg/kg bw/day.

         Carcinogenicity studies were performed in mice and rats at
    doses up to 30 and 20 mg/kg bw/day respectively; no
    treatment-related effects were observed. There was no
    treatment-related increase in any type of neoplasm. The Committee
    was of the opinion that flubendazole had no carcinogenic potential
    at the highest doses administered in these studies.

         The results from a range of  in vitro and  in vivo
    genotoxicity tests were all negative.

         The Committee considered data from reproduction,
    embryotoxicity, and teratogenicity studies. Studies in mice,
    rabbits, and pigs were negative. Flubendazole was extensively
    studied in segmented reproduction studies in rats, performed as
    required for human drug regulation purposes and accepted by the
    Committee in lieu of a multigeneration reproduction study. In
    several rat developmental

    studies, doses of up to 40 and 160 mg/kg bw/day, given on gestation
    days 6-15, did not produce any embryotoxic or teratogenic effects.
    In a rat teratogenicity study published in 1987, using material
    extracted from a commercial preparation, gross skeletal and internal
    fetal malformations were recorded at doses of 40 and 160 mg/kg
    bw/day. The NOEL in this study was 10 mg/kg bw/day.

    4.  EVALUATION

         An ADI of 0-12 g/kg of body weight was established for
    flubendazole, based on the NOEL of 2.5 mg/kg bw/day in the 3-month
    study in dogs, and a safety factor of 200. This safety factor was
    used by the Committee to take account of the fact that the doses
    were administered only 6 days per week in this study, the precise
    consequences of which could not be assessed.

         The Committee noted that the ADI also provided a safety margin
    corresponding to a factor of about 1000 with respect to the NOEL of
    10 mg/kg bw/day derived from the rat teratogenicity study. The
    Committee considered that further carcinogenicity studies would not
    be required, since the highest dose used in the negative studies
    that it had evaluated exceeded the ADI by a factor of approximately
    2000.

    5.  REFERENCES

    DE KEYSER, H., DONY, J. & ROGIERS, M. (1984). Fertility study with
    flubendazole (R 17889) in pigs. Unpublished results No. V4988 from
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    DESPLENTER, L. & COUSSEMENT, W. (1985). Safety evaluation of
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    levels: haematological, biochemical and histopathological
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    Research and Department of Toxicology, Janssen Pharmaceutica.
    Submitted to WHO by Janssen Research Products Information Service,
    Janssen Pharmaceutica, B-2340 Beerse, Belgium.

    HEYKANTS, J., WYNANTS, J. & SCHEIJGROND, H. (1975). The absorption
    and excretion of flubendazole in man. Unpublished results No. N10250
    from Department of Drug Metabolism, Department of Separation
    Techniques and Department of Clinical Pharmacology Janssen
    Pharmaceutica. Submitted to WHO by Janssen Research Products
    Information Service, Janssen Pharmaceutica, B-2340 Beerse, Belgium.

    JAGANNATH, D.R. & BRUSICK, D.J. (1978). Mutagenicity evaluation of
    flubendazole in the Ames  Salmonella/microsome plate test.
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    Pharmaceutica, B-2340 Beerse, Belgium.

    LE BRUN, J. (1983). Acute toxicity of flubendazole in guinea fowls.
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    Information Service, Janssen Pharmaceutica, B-2340 Beerse, Belgium.

    MARSBOOM, R. (1974). Potential of oral R 17889 for embryotoxicity
    and teratogenic effects in rats. Unpublished results No. 556 from
    Department of Toxicology, Janssen Pharmaceutica N.V. Submitted to
    WHO by Janssen Research Products Information Service, Janssen
    Pharmaceutica, B-2340 Beerse, Belgium.

    MARSBOOM, R. (1975a). Oral toxicity study in Wistar rats (repeated
    dosage for 3 months). Unpublished results No. 567, Janssen
    Pharmaceutica, Research Laboratories 2340 Beerse, Belgium. Submitted
    to WHO by Janssen Research Products Information Service, Janssen
    Pharmaceutica, B-2340 Beerse, Belgium.

    MARSBOOM, R. (1975b). Potential of oral R17889 for embryotoxicity
    and teratogenic effects in rats. Unpublished results No. 572 from
    Department of Toxicology, Janssen Pharmaceutica N.V. Submitted to
    WHO by Janssen Research Products Information Service, Janssen
    Pharmaceutica, B-2340 Beerse, Belgium.

    MARSBOOM, R., HERIN, V., VANDESTEENE, R. & PARDOEL, L. (1975). Oral
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    Laboratories 2340 Beerse, Belgium. Submitted to WHO by Janssen
    Research Products Information Service, Janssen Pharmaceutica, B-2340
    Beerse, Belgium.

    MARSBOOM, R. (1976a). Oral male and female fertility study in Wistar
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    Janssen Pharmaceutica N.V. Submitted to WHO by Janssen Research
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    Belgium.

    MARSBOOM, R. (1976b). Oral embryotoxicity and teratogenicity study
    in Wistar rats. Unpublished results No. 692 from Department of
    Toxicology, Janssen Pharmaceutica N.V. Submitted to WHO by Janssen
    Research Products Information Service, Janssen Pharmaceutica, B-2340
    Beerse, Belgium.

    MARSBOOM, R. (1976c). Oral embryotoxicity and teratogenicity study
    in New Zealand white rabbits (segment II). Unpublished results No.
    692 from Department of Toxicology, Janssen Pharmaceutica. Submitted
    to WHO by Janssen Research Products Information Service, Janssen
    Pharmaceutica, B-2340 Beerse, Belgium.

    MARSBOOM, R. (1976d). Potential of oral flubendazole (R 17889) for
    teratogenic effects in pigs. Unpublished results No. 692 from
    Department of Toxicology, Janssen Pharmaceutica. Submitted to WHO by
    Janssen Research Products Information Service, Janssen
    Pharmaceutica, B-2340 Beerse, Belgium.

    MARSBOOM, R. (1977a). Total reproductive capacity test in female
    mice. Unpublished results No. 773 from Department of Toxicology,
    Janssen Pharmaceutica. Submitted to WHO by Janssen Research Products
    Information Service, Janssen Pharmaceutica, B-2340 Beerse, Belgium.

    MARSBOOM, R. (1977b). Oral embryotoxicity and teratogenicity study
    in Wistar rats (Segment II). Unpublished results No. 755 from
    Department of Toxicology, Janssen Pharmaceutica. Submitted to WHO by
    Janssen Research Products Information Service, Janssen
    Pharmaceutica, B-2340 Beerse, Belgium.

    MARSBOOM, R. (1977c). Dominant lethal test in male mice (single oral
    dose). Unpublished results No. 688 from Janssen Pharmaceutica,
    Research Laboratories. Submitted to WHO by Janssen Research Products
    Information Service, Janssen Pharmaceutica, B-2340 Beerse, Belgium.

    MARSBOOM, R. (1978). Oral embryotoxicity and teratogenicity study in
    Wistar rats (Segment II). Unpublished results No. 820 from
    Department of Toxicology, Janssen Pharmaceutica Submitted to WHO by
    Janssen Research Products Information Service, Janssen
    Pharmaceutica, B-2340 Beerse, Belgium.

    MEULDERMANS, W., HURKMANS, R., SWIJSEN, E. & HEYKANTS, J. (1977). A
    comparative study on the excretion and metabolism of flubendazole
    (R17889) and mebendazole (R17635) in the rat. Unpublished report No.
    V2940 from Department of Drug Metabolism, Janssen Pharmaceutica.
    Submitted to WHO by Janssen Research Products Information Service,
    Janssen Pharmaceutica, B-2340 Beerse, Belgium.

    MEULDERMANS, W., SWIJSEN, E., HENDRICKX, J., LAUWERS, W., BRACKE,
    J., LENAERTS, F., SNEYERS, R. & HEYKANTS, J. (1978). On the
    absorption, excretion and biotransformation of flubendazole in the
    dog. Unpublished report No. N15186 from Department of Drug
    Metabolism and Pharmacology and Analytical Department, Janssen
    Pharmaceutica. Submitted to WHO by Janssen Research Products
    Information Service, Janssen Pharmaceutica, B-2340 Beerse, Belgium.

    MEULDERMANS, W., LEE, I.Y., HENDRICKX, J., SWYSEN, E., LAUWERS, W.,
    PORTER, D. & HEYKANTS, J. (1982). Metabolism of flubendazole in
    swine: Excretion pattern of [2-14C] flubendazole and its
    metabolites and depletion kinetics of drug residues in edible
    tissues. Preliminary report from Department of Drug Metabolism,
    Department of Analytical Research, Janssen Pharmaceutica, and
    Pitman-Moore, Inc., Washington Crossing, NJ., USA. Submitted to WHO
    by Janssen Research Products Information Service, Janssen
    Pharmaceutica, B-2340 Beerse, Belgium.

    MICHIELS, M., HEYKANTS, J. & HENDRICKX, J. (1977a). Distribution of
    flubendazole (R17889) and its metabolites in the Wistar rat.
    Unpublished report No. N12336 from Department of Drug Metabolism and
    Analytical Department, Janssen Pharmaceutica. Submitted to WHO by
    Janssen Research Products Information Service, Janssen
    Pharmaceutica, B-2340 Beerse, Belgium.

    MICHIELS, M., HENDRIKS, J. & HEYKANTS, J. (1977b). The
    pharmacokinetics of mebendazole and flubendazole in animal and man.
     Arch. Internat. Pharmacodinam. Therapie, 256: 180-191.

    MICHIELS, M., HEYKANTS, J., VAN DEN BOSSCHE, H. & VERHOEVEN, H.
    (1980a). A comparative study on the systemic absorption of oral and
    subcutaneous mebendazole, flubendazole and R34803 in two different
    rodents. Unpublished report No. N19702 from Department of Drug
    Metabolism and Department of Comparative Biochemistry, Janssen
    Pharmaceutic. Submitted to WHO by Jansen Research Products
    Information Service, Janssen Pharmaceutical, B-2340, Beerse,
    Belgium.

    MICHIELS, M., PRINSEN, P., HEYKANTS, J. & VAN DEN BOSSCHE, H.
    (1980b). Systemic absorption of intramuscular flubendazole in the
    dog. Unpublished report No. N20709 from Department of Drug
    Metabolism and Department of Comparative Biochemistry, Janssen
    Pharmaceutic. Submitted to WHO by Jansen Research Products
    Information Service, Janssen Pharmaceutical, B-2340, Beerse,
    Belgium.

    MICHIELS, M., MONBALIU, J., WOESTENBORGHS, R., HEYKANTS, J. & MAES,
    L. (1987). Absorption and plasma concentrations of flubendazole in
    the dog after single oral administration at the therapeutic dose
    level of 22 mg/kg as the commercial flubendazole paste (Fflubenol KH
    pasteR). Unpublished report No. V6282 from Department of Drug
    Metabolism and Pharmacology and Animal Health Department, Janssen
    Pharmaceutica. Submitted to WHO by Janssen Research Products
    Information Service, Janssen Pharmaceutica, B-2340 Beerse, Belgium.

    NAKAOKA, A., FURUKAWA, T. & FUKUHARA, K. (1983a). Acute toxicity
    study of flubendazole in mice. Unpublished report No. V5050 from
    Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka,
    Japan. Submitted to WHO by Janssen Pharmaceutica, B-2340 Beerse,
    Belgium.

    NAKAOKA, A., FURUKAWA, T. & FUKUHARA, K. (1983b). Acute toxicity
    study of flubendazole in rats. Unpublished report No. V5049 from
    Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka,
    Japan. Submitted to WHO by Janssen Pharmaceutica, B-2340 Beerse,
    Belgium.

    NIEMEGEERS, C.J.E. (1974) The acute oral toxicity of flubendazole in
    Wistar rats, albino mice and guinea-pigs. Unpublished results No.
    N9208 from Department of Pharmacology, Janssen Pharmaceutica.
    Submitted to WHO by Janssen Research Products Information Service,
    Janssen Pharmaceutica, B-2340 Beerse, Belgium.

    NIEMEGEERS, C.J.E. (1986a). The acute subcutaneous toxicity of
    R17889 in mice. Unpublished results No. N49012 from Department of
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    Research Products Information Service, Janssen Pharmaceutica, B-2340
    Beerse, Belgium.

    NIEMEGEERS, C.J.E. (1986b) The acute subcutaneous toxicity of R17889
    in rats. Unpublished results No. N49023 from Department of
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    Research Products Information Service, Janssen Pharmaceutica, B-2340
    Beerse, Belgium.

    NIEMEGEERS, C.J.E. (1986c) The acute subcutaneous toxicity of R17889
    in guinea-pigs. Unpublished results No. N49024 from Department of
    Pharmacology, Janssen Pharmaceutica. Submitted to WHO by Janssen
    Research Products Information Service, Janssen Pharmaceutica, B-2340
    Beerse, Belgium.

    POWELL, C.J. (1991). Independent report on slides from the
    flubendazole study No. 568. Unpublished results from Department of
    Toxicology St. Bartholomew's Hospital Medical College, University of
    London. Submitted to WHO by Janssen Research Products Information
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    ROGIERS, M. (1979). Potential of oral flubendazole (R17889) for
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    ROGIERS, M. (1980). Potential of oral flubendazole (R17889) for
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    administered during the first 10 weeks of the gestation period.
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    TEUNS, G. & MARSBOOM, R. (1987a). Primary eye irritation study in
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    TEUNS, G. & MARSBOOM, R. (1987b). Acute dermal toxicity study in New
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    Pharmaceutica, B-2340 Beerse, Belgium.

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    VAN LEEMPUT, L., MAES, L., MEULDERMANS, W. & HAYKANTS, J. (1991).
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    VANPARYS, Ph. & MARSBOOM, R. (1979). Micronucleus test in mice.
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    VANPARYS, Ph. & MARSBOOM, R. (1981). Micronucleus test in rats.
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    VANPARYS, Ph. & MARSBOOM, R. (1982). Sex-linked recessive lethal
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     Toxicology, 43: 133-138.


    See Also:
       Toxicological Abbreviations
       FLUBENDAZOLE (JECFA Evaluation)