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    OXFENDAZOLE

    First Draft prepared by
    Dr. Radovan Fuchs
    Institute for Medical Research and
    Occupational Health, University of Zagreb, Yugoslavia

    1.  EXPLANATION

         Oxfendazole is an anthelmintic used for the treatment of
    gastrointestinal parasitism in cattle, sheep and horses. 
    Oxfendazole has not been previously evaluated by the Joint FAOP/WHO
    Expert Committee on Food Additives.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution and excretion

         Oxfendazole, fenbendazole and febantel are three metabolically
    related anthelmintics. Fenbendazole and oxfendazole are
    metabolically interconvertible, and febendazole is a prodrug of them
    both. Oxfendazole and fenbendazole both undergo further metabolic
    oxidation and carbamate hydrolysis.

         Using 14C-oxfendazole it was shown that systemic exposure to
    total drug equivalents is the same in rats and calves for equivalent
    doses. Systemic exposure in the rat occurs within 24 hours while in
    the feeder calf it occurs slowly over 168 hours (Tomlinson et al.,
    1986).

         Plasma concentration in rats as a function of time after oral
    administration of 3H-oxfendazole is the same as after intravenous
    administration, indicating complete absorption of the oral dose.
    Between 0-12 hours after intravenous injection of 6 mg/kg b.w. of
    3H-oxfendazole to rats, the t´ of free extractable material in
    the plasma was 360 minutes. In the same experiment, t´ decreased
    to 160 minutes during the 12-24 hour interval. The apparent volume
    of distribution for the drug, based on chloroform extractable
    tritium, was estimated to be 85 ml/rat or 607 ml/kg b.w. (Tomlinson,
    1974a).

         In rats, the plasma metabolite pool is composed of 29%
    oxfendazole, 71% sulfone analogue and 1% thioether analogue. In
    calves, although the metabolites are the same as those found in
    rats, the plasma metabolite pool consists of 20% oxfendazole, 46%
    sulfone analogue and 20% thioether analogue (Tomlinson et al.,
    1986).

         Oxfendazole is excreted in urine and faeces (Tomlinson, 1974a;
    Tomlinson et al., 1986). In rats, recovery of the dose after oral
    administration averaged 40-50% within 48 hours (Tomlinson, 1974a).
    In calves, 14-20% of the dose was recovered in urine, a considerably
    lesser amount, and much more was eliminated via faeces (Tomlinson et
    al., 1986). In rats, oxfendazole or its metabolites may be cycled
    through the enterohepatic path as many as four times before being
    eliminated from the body (Tomlinson, 1974a). Both in rats and in
    calves the major residue burden was located in the liver and major
    identifiable metabolites were the same (Matin et al., 1977). Of the
    residue present in liver, a significant portion cannot be extracted
    into organic solvents. At 0.5 hours and 24 hours
    post-14C-oxfendazole administration, 41% and 93% respectively of

    the residue was protein bound (Tomlinson et al., 1986). Studies in
    cattle have shown that besides liver, milk from treated animals
    (Tomlinson, 1977) contained oxfendazole, its thioether, its sulfone
    and protein bound materials (liver only). The same metabolites were
    found in the livers of treated sheep (Tomlinson, 1974b).

         A metabolic scheme may be found on page 23.

    2.2  Toxicological studies

    2.2.1  Acute studies

        Table 1. Acute studies on oxfendazole
                                                                                  

    Species     Sex      Vehicle              LD50           Reference
                                            (mg/kg b.w.)
                                                                                  

    Mouse       M&F      distilled water     > 6400          Hallesy, 1973

    Rat         M&F      distilled water     > 6400          Hallesy, 1973b
                                                             Chester & Bidlack,
                                                             1987a

                                                             Chester & Bidlack,
                                                             1987b

    Dog         F        gelatine capsule    > 1600          Hallesy, 1973c

    Sheep       F        water                > 250          Braemer & Bidlack,
                         suspension                          1976

    Cattle      M&F      water purified      > 112.5         Bidlack, 1977
                                                                                  
    
         The gastrointestinal tract and bone marrow were the primary
    organ systems affected by the drug. Clinical signs, pathologic
    changes, and in some cases mortality were seen in rats, dogs, sheep,
    and cattle treated with a single high dose of oxfendazole.

    2.2.2  Short-term studies

    2.2.2.1  Mice

         Groups composed of 10 male and 10 female Swiss Webster mice
    were fed diets containing 0, 25, 50, 100, or 200 ppm oxfendazole
    (equivalent to 0, 3.75, 7.5, 15, or 30 mg/kg b.w./day) for 3 months.
    No signs of toxicity were observed in any of the treated groups
    (Hallesey & Shott, 1984).

         Groups of Swiss Webster mice (5 animals/sex/dose) were fed diet
    containing oxfendazole at concentrations of 0, 5000, 10 000, or 50
    000 ppm (equivalent to 0, 750, 3000, or 7 500 mg/kg b.w./day) for 1
    month. Data concerning clinical observations, body weight gain, food
    intake, clinical pathology, gross pathology and histopathology were
    recorded. No clinical signs of drug-related toxicity were observed.
    Increase of SGOT and SGPT were observed in intermediate and
    high-dose females. A dose-related significant increase of the ratio
    of liver weight to body weight was found in all treated animals.
    Significant increase in liver weight compared to controls was
    observed in intermediate and high-dose animals only. The ratio of
    testes weight to body weight in males receiving 20 000 and 50 000
    ppm of oxfendazole was significantly lower than that in controls.
    Histopathological observations included changes in testes of
    intermediate and high-dose groups. Those changes were described as
    mild to moderately severe hypospermatogenesis with desquamation of
    sperm precursors. Hepatocytic vacuolation was a common finding in
    all groups of animals, control group included (Hallesy & Bidlack,
    1987a).

         An additional study on oxfendazole subchronic toxicity was
    conducted on Swiss Webster mice. Five groups of animals composed of
    5 male and female mice were fed diets containing oxfendazole at
    concentrations of 0, 250, 500, 1000, or 2000 ppm (equivalent to 0,
    37.5, 75, 150, or 300 mg/kg b.w./day) for 3 months. During the study
    there were no clinical signs of toxicity. Body weight and food
    intake were not affected by the treatment. Changes attributed to
    treatment consisted of increased liver weight in males and females
    receiving 1000 or 2000 ppm and in female mice receiving 500 ppm
    oxfendazole in diet. Histopathologically, hepatocytic vacuolation
    was seen in all mice including controls, although the vacuolation
    was more severe in male mice fed diets containing 500, 1000, or 2000
    ppm of the drug. Male animals from the highest group dose had
    testicular changes described as hypospermatogenesis with sloughing
    of sperm precursors (Hallesy & Bidlack, 1987b).

    2.2.2.2  Rats

         Groups of 5 male and female Sprague-Dawley (COX-SD) rats were
    given doses of 0, 5, 20, 80, or 160 mg/kg b.w./day oxfendazole by
    gavage for 14 consecutive days. The test material was homogenized in
    2% aqueous starch.

         Reduction in body weight was observed in animals dosed at
    160 mg/kg b.w./day during the first week of treatment, but at the
    end of the observation period (28 days) the animals showed normal
    weights compared to the controls and other groups. Four out of 5
    females of the 160 mg/kg b.w./day group were found dead at times up
    to and including the 14th day of the study. At the 80 and 160 mg/kg
    b.w./day doses, neutrophil counts were depressed during dosing, but
    at the end of the 2-week recovery period the neutrophil levels of
    the surviving rats had returned to normal values. Pathology was not
    performed on all of the animals in this study and the cause of death
    was not ascertained in every rat necropsied (Hallesy et al., 1976a).

         Groups of Sprague-Dawley (COX-SD) rats (6 animals/sex/group)
    were given doses of 0, 11, 33, or 100 mg/kg b.w./day oxfendazole by
    gavage for 14 consecutive days. During the dosing period 4 out of 12
    from the high-dose group died. Decreased weight gain was seen in
    females of the intermediate-dose group and in males and females from
    the high-dose group. Haematology and clinical chemistry were studied
    after 2 weeks of treatment. Decreased haemoglobin and haematocrit
    levels in females given 100 mg/kg b.w./day, and decreased numbers of
    neutrophils in females given 33 or 100 mg/kg b.w./day and in males
    given 100 mg/kg b.w./day were seen. No changes in clinical chemistry
    values in treated rats were observed when compared to controls.
    Decreased terminal body weight for high-dose rats, decrease in
    splenic and testicular weight and increased liver weight for
    intermediate-dose and high-dose rats were noted. Numerous gross
    alterations were noted, which included thymic atrophy, pronounced
    hepatic pallor, increased alimentary tract fluids and red-brown foci
    in the glandular stomach. Histopathologically, lymphoid atrophy and
    inhibition of maturation of bone marrow myeloid and erythroid
    elements in intermediate and high-dose rats were observed.
    Inhibition of spermatogenesis and inflammatory lesions in lungs of
    high-dose animals were also seen. Hepatocytic vacuolation was
    observed in some animals of all dose groups (Hallesy et al., 1977b).

         In a 3-month study oxfendazole incorporated into the diet at 0,
    200, 600, and 2000 ppm was given to Long-Evans rats
    (15 rats/sex/dose level). Thirteen rats out of 30 died by the end of
    the first week of dosing due to toxic effects. This group was
    terminated and an additional two groups receiving 50 and 100 ppm of
    oxfendazole in the diet (10 rats/sex/dose level) were placed on
    test. The approximate daily intakes of oxfendazole over the period

    of the study were 0, 3.8, 7.3, 16.5, and 53.8 mg/kg b.w./day for
    males and 0, 3.8, 7.7, 17.2, and 49.9 mg/kg b.w./day for females. By
    the end of the study, 24 out of 30 rats receiving 600 ppm of
    oxfendazole in feed died. In this group perioral and mandibular
    alopecia with encrustation, priapism, and enlarged clitoris were
    observed. Elevation of SGPT and SAP levels was observed in the 600
    ppm group. SAP was slightly elevated in both sexes of the 200 ppm
    group and in females of the 100 ppm group. Hepatocytic hypertrophy,
    vacuolation and hepatocytic necrosis were seen in the 600 ppm group.
    Other pathological changes consisted of testicular atrophy, splenic
    necrosis or atrophy, abscesses and bone marrow hyperplasia or
    diffuse atrophy. In the 200 ppm group only slight hepatocytic
    hypertrophy was observed. In the 100 and 50 ppm groups no
    microscopic changes related to treatment were observed (Killeen &
    Rapp, 1974a).

    2.2.2.3  Dogs

         Groups of 2 male and female beagle dogs were given 0, 11, 33,
    or 100 mg/kg b.w./day oxfendazole by gavage for 2 weeks. A slight
    decrease in body weight was observed in male dogs given 33 mg/kg
    b.w./day and in male and female dogs from the 100 mg/kg b.w./day
    group. None of the haematological or plasma chemistry parameters was
    affected by the treatment. No meaningful changes were seen in
    urinalysis values after 2 weeks of dosing. Histological changes
    attributed to oxfendazole treatment were seen in dogs from all
    treated groups; reduced myeloid maturation was seen in bone marrow.
    Reduction of splenic lymphoid tissue and thymic atrophy were seen in
    males but not in females (Hallesy et al., 1976b).

         In a second 2-week study on beagle dogs groups of 4 males and
    females were given oxfendazole at doses of 0, 3, 6, and 11 mg/kg
    b.w./day by gavage. No drug-related effects were seen in the animals
    killed after the dosing period (half) or in remaining dogs observed
    for 3 weeks after dosing. In this study a different suspension
    formulation of oxfendazole was used than that used in the previous
    study (Hallesy et al., 1977a).

         Groups of 3 male and female beagle dogs were given 0, 1.5, 3.0,
    and 6.0 mg/kg b.w./day of oxfendazole orally in hard shell gelatin
    capsules for 3 months. No changes related to oxfendazole treatment
    were observed in body weight, gross pathology, or histopathology in
    any of the groups at the end of the study when the dogs were killed
    (Killeen & Rapp, 1974b).

    2.2.2.4  Cattle

         Hereford heifers and bulls from 6 to 8 months old were used in
    the study. Groups consisting of 3 male and female animals were used.
    Oxfendazole was injected intraruminally at doses of 0, 4.5, 13.5,
    22.5, and 112 mg/kg b.w. Oxfendazole was prepared as a 22.5% drug

    suspension. The highest dose (112 mg/kg b.w., corresponding to 25
    times intended field use level) was given as a single dose, whereas
    the other dose groups were treated 3 times over an 8-day period.
    Body weights, haematological and clinical chemistry values were not
    altered by the treatment. No treatment-related gross or microscopic
    pathological changes were observed. In only one male and one female
    animal digestive disturbances described clinically as non-productive
    eructation were seen in the highest dose group. The inflammatory
    reactions noted at the injection site in all groups, including
    control, were attributed to contaminants introduced during
    intraruminal injections (Glock et al., 1987).

    2.2.3  Long-term/carcinogenicity studies

    2.2.3.1  Mice

         Fifty CD-1 mice of each sex were randomly assigned to each of
    three treatment groups. Oxfendazole was administered in the diet at
    concentrations of 100, 300, or 1000 ppm, which was equivalent to
    dose levels of 15, 45, or 150 mg/kg b.w./day respectively. A control
    group of 100 animals of each sex received the same diet without
    oxfendazole. An additional 10 mice of each sex per group were
    included for haematological evaluation. The animals were treated for
    78 weeks. Clinical observations and presence of palpable masses were
    recorded weekly, while body weight and food intake were recorded
    weekly for the first 4 months and monthly thereafter. Blood samples
    for haematological evaluation were obtained during the 6th and 12th
    months of treatment from the designated animals. A complete necropsy
    and histopathological examination was performed at study
    termination.

         No treatment-related effects were noted on clinical condition
    or survival. Mean body weights for treated males were often lower
    than those for controls during the first year of the study.
    High-dose females had significantly higher body weights than
    controls during the first year. Food intake was higher for all
    treated groups during the first year. No biologically significant
    haematological effects were noted. A slightly higher proportion of
    high-dose males had malignant neoplasms compared to controls. This
    included a higher incidence of broncho-alveolar and hepatocellular
    carcinomas. However, the difference was not statistically
    significant. In females the proportion of high-dose animals with
    either benign or malignant neoplasms was slightly higher than in the
    control group, but the difference was not statistically significant.
    Increased incidences of hepatocytic hypertrophy and hepatocytic
    vacuolation were observed in high-dose animals. Results were highly
    significant for hepatocytic hypertrophy in males and hepatocytic

    lipid vacuolation in females. The incidence of focal hepatocytic
    necrosis was also slightly greater in high-dose mice compared to
    controls. No other histopathological changes attributed to
    oxfendazole were observed. The NOEL was 300 ppm, equivalent to
    45 mg/kg b.w./day (DePass & Bidlack, 1987c).

    2.2.3.2  Rats

         Four groups consisting of 25 male and female Sprague-Dawley
    weanling rats were fed diets containing 0, 10, 30, or 100 ppm
    oxfendazole for one year. The daily intake of the drug over the
    studied period was equal to 0.65, 2.0, and 6.6 mg/kg b.w./day for
    males and 0.76, 2.4, and 7.8 mg/kg b.w./day for females,
    respectively. Body weight and food intake were measured weekly for
    the first 13 weeks, and monthly thereafter. Clinical observations
    and tissue masses were recorded at least weekly. Blood samples for
    haematology and serum chemistry evaluations were collected from an
    untreated group of 10 males and 10 females prior to the start of the
    study and from 10 designated males and females from each of the 4
    groups at 4 intervals during the study. Eye examinations were
    performed on each animal prior to the first dose and during study in
    the 3rd, 6th, 9th and 12th months. Animals that were found dead, in
    moribund condition, or killed at study termination received complete
    necropsy examinations.

         No drug effect was noted on clinical or ophthalmological
    condition or on food intake. Increased body weight gain was observed
    in the high-dose female group during the first 6 months. In both
    sexes a drug-related increase in BUN was seen. Treatment-related
    increase in SAP was also observed in treated animals of both sexes.
    Changes in creatinine, GOT, cholesterol, triglyceride measurements,
    and several haematological parameters were observed several times
    during the study. Those changes were not considered to be of
    biological importance since their occurrence was inconsistent in
    respect to dose levels, time interval and the sex of the animals.
    The liver weight of high-dose animals was significantly higher
    compared to other groups and in males a slight reduction of
    accessory sex organs in high-dose animals was observed.
    Histopathological changes were seen in the livers of intermediate-
    and high-dose animals and are described as discoloration and
    centrilobular hepatocytic lipid vacuolation. Those changes, although
    present in all treated animals when compared to control animals,
    were not outside the range of physiological values and historical
    data of the laboratory. The NOEL in this study was 10 ppm, equal to
    0.65 and 0.76 mg/kg b.w./day in males and females, respectively
    (DePass & Bidlack, 1987a).

         Groups of 50 Sprague-Dawley rats of each sex were fed
    oxfendazole-containing diet for at least 105 weeks (2 years). Drug
    concentration in food was 10, 30, or 100 ppm. A control group of 100
    animals of each sex received the same diet without oxfendazole. Drug
    intake was calculated to be, on average, 0.7, 2, or 7 mg/kg b.w./day
    for males and 0.9, 2.5, or 8.8 mg/kg b.w./day for females.

         A statistically significant decrease in body weight in response
    to increasing dose was noted at several intervals, mostly during the
    early part of the study. At some intervals, the treated males
    appeared to have higher intake of food than the controls. However,
    these observations seemed to be biologically insignificant. Tissue
    masses were noted across all treatment groups. Approximately 40% of
    the control and low-dose females had masses. Intermediate and
    high-dose females had approximate tissue mass incidences of 35% and
    25%, respectively. In males, there was a 10% incidence in the
    control and intermediate-dose and 6% incidence in the high-dose.
    There was no treatment-related mortality and the survival times were
    not significantly different among the groups, including controls.
    There were no treatment-related effects on clinical conditions or
    haematology. Oxfendazole at concentrations of up to 100 ppm daily
    for 105 weeks did not offer biological or statistical evidence of an
    increased incidence of neoplasms. Hepatocellular lipid vacuolation
    was present in the livers of intermediate and high-dose animals and
    was found to be dose-related. The NOEL in this study was 0.7 mg/kg
    b.w./day in males and 0.9 mg/kg b.w./day in females (DePass &
    Bidlack, 1987e).

    2.2.3.3  Dogs

         Four groups composed of 5 male and female beagle dogs were
    given 0, 1.5, 4.5, and 13.5 mg/kg b.w./day oxfendazole daily for one
    year. A suspension of the drug was administered orally at a dose
    volume of 0.1 ml/kg b.w.. Eye examinations, haematology and serum
    chemistry assessments were conducted prior to the first dose and
    during the study during the 3rd, 6th, 9th, and 12th months of
    dosing.

         There were no toxic signs or effects on food intake, body
    weight, clinical condition, ophthalmological parameters or serum
    chemistry. Decreasing trends were observed for erythrocyte count,
    haemoglobin, and haematocrit measurements for male dogs at all time
    intervals, but the values were within the physiological range. After
    12 months of dosing, the animals were killed for pathological
    examination. Liver weight to body weight ratios showed a
    statistically significant increase in response to increasing dose in
    the four groups, but absolute liver weights only slightly exceeded
    those of the control animals. No other gross or microscopic changes
    which might be related to treatment were observed. The NOEL in this
    study was 13.5 mg/kg b.w./day (DePass & Bidlack, 1987b).

    2.2.4  Reproduction studies

    2.2.4.1  Rats

         In a 2-generation study, 30 Sprague-Dawley rats/sex/dose were
    given oxfendazole incorporated into feed. The concentration of the
    test substance in the diet was 0, 10, 30, or 100 ppm. The females
    received the drug 2 weeks prior to cohabitation with treated males
    and until the end of the breeding period. Drug intake was calculated
    to be in a range of 0.9-1.0, 2.8-3.1, and 2.8-10.4 mg/kg b.w./day
    respectively.

         No drug effect was noted on the clinical condition, mean body
    weight or average daily food intake of treated rats. No drug effect
    was noted for incidence of pregnancy, length of gestation, live
    litter size or gestation index. The changes attributed to
    oxfendazole treatment consisted of increased mean liver weight and
    liver weight to body weight ratios, liver pallor and increased
    incidence of hepatocytic vacuolation in high-dose females.

         High pup mortality from postpartum days 7 to 14 was noticed in
    all dose groups of the F1 generation including controls. Male F1
    pups born to high-dose dams weighed less at first observation and
    had a decreased rate of growth compared to male pups from control
    dams. No treatment-related anomalies were seen. Pups from
    intermediate- and high-dose litters had liver changes similar to
    those found in their parents. No drug-related effects were noted on
    live litter size or survival index for second generation litters.
    However, the proportion of pregnancies in high-dose dams was
    significantly lower than in controls. Liver changes as previously
    described were noted in intermediate- and high-dose parents of the
    second generation. Initial second generation pup weights were lower
    for intermediate and high-dose litters. No gross or microscopic
    changes were noted in second generation offspring. The NOEL for this
    study was 10 ppm, equal to 0.9 mg/kg b.w./day (DePass & Bidlack,
    1987d).

    2.2.4.2  Cattle

         Three groups consisting of 33 mixed-breed first calf heifers
    were estrus-synchronised using fenprostalene and were intraruminally
    treated with oxfendazole. The drug was administered prior to
    artificial insemination, at weekly intervals from day 14 through day
    42 of gestation and at approximately 60-day intervals to the end of
    gestation. The dose levels applied were 0, 4.5, and 13.5 mg/kg
    b.w./day. Heifers which did not become pregnant were naturally bred
    at subsequent estrus periods.

         Conception rates, length of gestation, time to become pregnant,
    service period and weight gains of heifers during gestation and
    lactation were unaffected by oxfendazole treatment. During the study
    1 low-dose and 1 high-dose dam, and 2 high-dose calves died.
    Pathological changes in those cases suggested that the deaths were
    not associated with oxfendazole treatment.

         Oxfendazole did not cause anatomic abnormalities, decreased
    birth weight or changes in average daily weight gain in calves. The
    NOEL in this study was 13.5 mg/kg b.w./day (Miller et al., 1987).

    2.2.5  Special studies on genotoxicity (see also Section 2.2.7 in
           fenbendazole monograph and 2.2.5.1 in the febantel
           monograph)

        Table 2. Genotoxicity studies on oxfendazole
                                                                                  

    Test system    Test object     Concentration        Result       Reference
                                                                                  

    Ames test1     S.typhimurium   0.5-5000 µg/ml       Negative     Mourot, 1990
                   TA97a, TA98,
                   TA100, TA102
                                                                                  

    1. With and without S9
    
    2.2.6  Special studies on eye and skin irritation

    2.2.6.1  Rabbits

         Groups of 6 male New Zealand white rabbits had 100 mg
    oxfendazole powder instilled into the conjunctival sac of the left
    eye. There were no signs of irritation at any time during
    observation (Hallesy & Hill, 1977).

         In a separate study, oxfendazole as a 2.265% w/v aqueous
    suspension was applied into the conjunctival sac of 5 New Zealand
    white and 1 Californian rabbit (6 animals) at a dose of 0.1 ml. No
    irritation or corneal damage was seen in any of the animals
    (Reynolds & James, 1977).

         The oxfendazole formulation was applied to intact and abraded
    skin of 6 New Zealand white rabbits. The test sites were occluded
    for 4 hours. After removal of dressings test sites were scored for
    erythema and oedema. Twenty-four and 48 hours after washing the
    scoring was repeated. No evidence of erythema or oedema was seen in
    any of the rabbits (Hallesy & Hill, 1976).

    2.2.6.2  Guinea-pigs

         Female Hartley albino guinea-pigs were used in a dermal
    sensitization study. The test was performed on 3 groups of animals:
    a positive control group (2,4-dinitrofluorobenzene), a vehicle
    control group and an oxfendazole-treated group, consisting of 20
    animals each. It was found that neither vehicle nor oxfendazole
    produced contact sensitization in guinea-pigs (Hallesy & Hill,
    1978).

         In a separate study, oxfendazole produced no sensitizing
    effects and no primary irritation when tested on Dunkin-Hartley
    guinea-pigs. In this study dinitrochlorobenzene was used as a
    positive control (Harper & James, 1977).

    2.2.7  Special studies on teratogenicity (see also Section 2.2.5 of
           the monograph on Fenbendazole)

    2.2.7.1  Mice

         Groups of 25 mated female Swiss Webster (COX.SW) mice were fed
    powdered diet containing concentrations of 0, 200, 600, or 2000 ppm
    oxfendazole corresponding to 0, 34, 108, or 360 mg/kg b.w./day. The
    animals were exposed to the drug from gestation day 6 through day 15
    and the females were killed on gestation day 18.

         Food intake was not affected among the groups during the
    treatment, although the body weight gains for high-dose mice were
    less than those for other groups. The diet containing 2000 ppm was
    found to be fetotoxic for mice. In this group decreased litter size,
    average fetal weight, and mean gestation survival index were
    observed. Viable fetuses from this group were found only in 2 out of
    22 pregnancies, and most of the fetuses had been resorbed, resulting
    in an increase of the mean resorption index (p 0.01). Because of the
    small number of fetuses available (3 alive and 1 dead) the
    interpretation of probable teratogenic effects was not possible.

         The maternal parameters were comparable between the control and
    low-dose or intermediate-dose groups. Various external, skeletal,
    and visceral changes were observed in fetuses from the control, low-
    and intermediate-dose groups. Among the abnormalities, only the
    incidence of pelvic cavitation was increased in low- and
    intermediate-dose groups compared to controls. The incidence was
    found to be 8% in treated animals and 0% among the controls. Since
    similar changes with an incidence of 6 to 7% occur in untreated mice
    as well (Palmer, 1972), those changes are not of reliable
    importance. The NOEL in this study was 600 ppm, corresponding to
    108 mg/kg b.w./day (Hallesy et al., 1974a).

    2.2.7.2  Rats

         Groups of 25 mated female Sprague-Dawley rats were given
    oxfendazole by gavage daily at doses of 0, 10, 20, or 60 mg/kg
    b.w./day. The treatment lasted from the 6th to 15th days of
    pregnancy. On the 20th day of gestation, the females were killed.

         Evidence of fetotoxicity characterized by decreased litter size
    and fetal weight, a high incidence of total litter resorption, as
    well as an increased resorption index and a higher percentage of
    male fetuses were seen in the group receiving 60 mg/kg b.w./day.
    Maternal parameters for the 10 and 20 mg/kg b.w./day groups were
    comparable to the control animals. Fetal changes were observed in
    the 20 and 60 mg/kg b.w./day groups and were typical of those
    produced by delayed development and included delayed maturation of
    ossification centres. The NOEL in this study was 10 mg/kg b.w./day
    (Hallesy et al., 1974b).

         The potential embryotoxicity of oxfendazole, the principal
    metabolite of fenbendazole, was evaluated in Wistar rats. Sexually
    mature virgin female Wistar rats were mated with fertile males, to
    provide 4 groups of 20 pregnant animals. Dams were evaluated for
    presence of sperm and the day on which sperm was detected was
    designated gestation day one. Dams in these groups received doses of
    0, 5, 6, 7.5, 10, 15, or 20 mg/kg b.w./day oxfendazole via stomach
    tube in a 2% starch mucilage vehicle at the rate of 10 ml/kg
    b.w./day on gestation days 7-16. Rats were observed daily, and
    weighed weekly. Doses were based on the most recent body weight.
    Food intake was monitored continuously. All dams were sacrificed on
    gestation day 21 and fetuses were delivered by caesarean section.
    Each dam received a gross necropsy and organs were weighed. The
    uterus was opened and number and placement of live and dead fetuses
    and resorptions were determined. Implantation sites and  corpora
     lutea were counted. The fetuses from the control, 7.5, and
    10 mg/kg b.w./day groups were examined externally for abnormalities
    and then about 50% were processed for Alizarin red staining to
    evaluate skeletal abnormalities and the remainder were processed
    with Bouin's solution for evaluation of soft tissue abnormalities.

         No treatment-related effects were observed in the dams. A
    significant increase in resorptions, and decrease in live fetuses as
    well as a reduction in fetal weight was reported for the 20 mg/kg
    treatment group. Examination of the control, 7.5, and 10 mg/kg
    fetuses revealed no treatment-related malformations (Kramer &
    Baeder, 1973).

         The teratogenicity of a series of oxfendazole metabolites and
    the parent were evaluated using the rat. Only the parent was found
    to have teratogenic activity at a dose of 21 mg/kg (Delatour et al.,
    1982b).

         In the literature, oxfendazole was reported to produce
    teratogenic activity when administered orally to rats from day 8
    through day 15 of gestation at 15.75 mg/kg b.w./day or on days 12
    and 13 at 31.5 mg/kg b.w./day. Increased incidences of external and
    skeletal abnormalities were reported accompanied by substantial
    embryolethality (12-39%) (Delatour et al., 1977, 1981, 1984).

    2.2.7.3  Rabbits

         Groups of 15 inseminated New Zealand white rabbits were dosed
    orally with 0, 0.025, 0.125, or 0.625 mg/kg b.w./day of oxfendazole
    from days 6 to 18 of pregnancy. The animals were killed on day 29 of
    gestation.

         There was no overt maternal toxicity nor any effect on litter
    size, fetal weight, resorption, corpora lutea, gestation survival
    index, resorption index or implantation index. Minor changes
    including abnormal carpal and tarsal flexion and low incidence of
    gall bladder hypoplasia or aplasia were seen in fetuses from treated
    animals. Although greater numbers of high-dose fetuses had minor
    skeletal variations, the incidence of those changes was not
    significantly different from that of the controls. Based upon the
    historical control data and current controls those changes were
    considered to be spontaneous and not relevant to oxfendazole
    treatment. The NOEL was 0.625 mg/kg b.w./day (Thunen et al., 1981).

    2.2.7.4  Sheep

         Groups of 27-29 estrus-synchronized ewes were treated orally
    with oxfendazole on the 12th, 17th or 23rd day of gestation. Two
    dose levels were used: 7.5 and 22.5 mg/kg b.w. Double control groups
    (water and vehicle) consisting of 12-14 animals were included in the
    study. Altogether 248 ewes were used in the experiment. About 24
    hours after the first spontaneous deliveries each ewe was given an
    intramuscular injection of dexamethasone. All the lambs that died
    were submitted to autopsies, while the animals which reached a
    commercial weight were examined at the slaughterhouse. It was found
    that oxfendazole administered to pregnant ewes on the 12th or 23rd
    day was not related to embryotoxic properties regardless of the dose
    applied. On the other hand the birth rate was significantly lower in
    the group which received 22.5 mg/kg b.w. of the drug at gestation
    day 17. Weight of lambs was comparable among all the groups. Clear
    evidence of teratogenic activity of oxfendazole was seen in the
    group which was treated with 22.5 mg/kg b.w. on day 17 of gestation.
    Malformations were seen on backbone, ribs, face and organs. No
    effects were observed in animals which received 7.5 mg/kg b.w. at
    any time. The NOEL in this study was 7.5 mg/kg b.w. (Delatour,
    1976).

         In a field study using 5 merino ewes, oxfendazole was given to
    the animals on day 17 of gestation in a single oral dose of 10 mg/kg
    b.w. No adverse effects were observed in lambs in this study. The
    NOEL was 10 mg/kg b.w. (Lloyd, 1978).

         Groups of pregnant Clun-Forest ewes were given a single oral
    dose of oxfendazole formulated as 2.265% w/v aqueous suspension.
    Eight animals per group received the drug on day 14, 17, or 20 of
    gestation at a dose of 10 or 15 mg/kg b.w. The control group did not
    receive treatment. There were no differences associated with
    oxfendazole treatment between the dosed groups and the controls.
    Clinical and autopsy examination revealed no oxfendazole-associated
    abnormalities among the lambs. The NOEL in this study was 15 mg/kg
    b.w. (Piercy et al., 1977).

    2.2.7.5  Pigs

         In a field study, oxfendazole was given orally to sows during
    pregnancy 4 times at 7-day intervals. A control group consisting of
    12 animals did not receive any treatment, while 18 animals were
    treated with oxfendazole at a dose of 4.5 mg/kg b.w./day and 18
    animals received 13.5 mg/kg b.w./day between the 12th and the 37th
    days of pregnancy. No clinical signs of toxicity in the pregnant
    sows were observed and there were no drug-related anatomical or
    behavioural abnormalities in the newborn pigs. The NOEL was
    13.5 mg/kg b.w./day (Morgan, 1982).

    2.2.7.6  Cattle

         Groups of 15 Hereford-Angus heifers were dosed orally with
    13.6 mg/kg b.w. of oxfendazole prepared as 2.265% w/v aqueous
    suspension. The drug was administered on days 11, 15, 19, 23, 27,
    31, 35, and 39 of gestation. Control animals received a placebo
    preparation at the same time intervals.

         No signs of clinical toxicity were seen after dosing in either
    group of animals. All heifers were killed between day 79 and day 104
    of gestation and fetuses were examined. No gross abnormalities were
    found in any of the fetuses and there were no significant
    differences in fetal weight or length among the groups. No
    anatomical abnormalities were found in any fetus. The NOEL was
    13.6 mg/kg b.w. (Piercy et al., 1978b).

         In a separate study 12 pregnant Hereford-Angus heifers were
    treated with oxfendazole as described in the previous study. No sign
    of anatomical abnormality related to oxfendazole treatment was
    found. The NOEL was 13.6 mg/kg b.w. (Piercy et al., 1978a).

    2.2.7.7  Horses

         A group of 15 mares was bred with stallions which received
    single oral doses of 20 mg/kg b.w. of oxfendazole. On day 26
    following breeding the mares received a suspension of oxfendazole
    orally at a dose of 20 mg/kg b.w. Pregnant mares were re-treated
    with the same dose on days 180 and 280 of gestation. Two out of 15
    mares required rebreeding at a second heat period. All mares
    maintained pregnancy and delivered healthy foals free of any
    teratologic effects (Herschler et al., 1979).

    2.2.8  Special studies on mode of action of benzimidazoles

          In vitro turbidimetric techniques and competitive
    colchicine-binding studies demonstrated the inhibitory power of
    benzimidazoles on the polymerization of tubulin into microtubules.
    The difference in the sensitivity of host and parasites to the
    effects of benzimidazoles may be due to difference in the structure
    of microtubules in their cells (Davis & Gull, 1983). However, the
    selective toxicity of those compounds for parasites is not absolute,
    since the toxic effects are observed in mammals as well and are for
    the most part antimitotic (reviewed in McKellar & Scott, 1990). The
    differences in efficiency between members of this class of drugs
    against groups of parasites probably reflects differences in
    bioavailability of the drugs within the host animal.

    2.3  Observations in man

         No information available.

    3.  COMMENTS

         The results of toxicological studies, including pharmacokinetic
    studies on rats, cattle, and sheep; carcinogenicity studies on mice
    and rats; mutagenicity, embryotoxicity, and teratogenicity studies
    on mice, rats, rabbits, sheep, cattle, pigs, and horses; studies on
    eye and skin irritation in rabbits and guinea pigs; reproduction
    studies on rats; and short-term and long-term studies on mice, rats,
    and dogs, were considered by the Committee.

         Pharmacokinetic data have demonstrated very good absorption of
    orally administered oxfendazole (100% in rats, 77% in cattle, and
    85% in sheep). The results showed that, after administration of the
    drug, the plasma metabolite pool was composed of oxfendazole,
    oxfendazole sulfone, and fenbendazole. There was very little
    difference between the various animal species, apart from
    quantitative differences in the plasma metabolite pool. Oxfendazole
    is excreted in urine and faeces. The compound and its metabolites
    can undergo enterohepatic circulation.

         The genotoxic potential of the compound was tested in an Ames
    test using only four strains of  Salmonella typhimurium; this gave
    negative results both with and without metabolic activation.

         Carcinogenicity studies were performed in mice and rats. Mice
    received a diet containing oxfendazole in doses up to 1000 mg/kg
    over a period of 78 weeks. Except for hepatocytic lipid vacuolation,
    no effects related to oxfendazole treatment were observed. The NOEL
    for this study was 300 mg/kg in the diet, equivalent to 45 mg/kg
    b.w./day.

         In the rat carcinogenicity study, animals received oxfendazole
    in the diet at concentrations of up to 100 mg/kg for 2 years. The
    only dose-related effect was seen in animals receiving 30 and
    100 mg/kg, which showed hepatocellular lipid vacuolation; this was
    the earliest sign of compound-related effects seen in the liver in
    this study. The NOEL was 10 mg/kg in the diet, equal to 0.7 mg/kg
    b.w./day in males and 0.9 mg/kg b.w./day in females.

         The Committee noted that two different strains of mice were
    used in the range-finding and carcinogenicity studies. It was
    concluded, however, that this difference was not of great
    significance since Swiss mice were used in both studies. There was
    no evidence of any carcinogenic effect in rats. However, the
    Committee was of the opinion, based on the range-finding 90-day
    study in rats, that higher doses could have been used.

         In a two-generation reproduction study in rats in which
    oxfendazole was administered in the diet, no effect was observed on
    mating behaviour or fertility, maternal behaviour, length of
    gestation, live litter size, gestation index (number of
    fetuses/female), or survival of offspring. However, the proportion
    of pregnancies in the second-generation females receiving 100 mg/kg
    was significantly lower than in controls. The NOEL in this study was
    10 mg/kg in the diet, equal to 0.9 mg/kg b.w./day.

         Oxfendazole did not produce irritation when tested in the
    rabbit eye or skin, or sensitization effects in guinea pig skin.

         The Committee considered data from embryotoxicity and
    teratogenicity studies of oxfendazole conducted on mice, rats,
    rabbits, sheep, cattle, pigs, and horses.

         A dose of 360 mg/kg b.w./day was fetotoxic in mice. The NOEL in
    mice was 108 mg/kg b.w./day.

         Results were reported from three teratogenicity studies in
    sheep given doses of oxfendazole ranging from 7.5 to 22.5 mg/kg b.w.
    on days 12, 14, 17, 20, or 23 of gestation. The sheep fetus was most
    susceptible to the induction of teratogenic effects on day 17, when
    the NOELs ranged from 7.5 to 15 mg/kg b.w.

         A teratogenicity study was performed in New Zealand rabbits at
    doses up to 0.625 mg/kg b.w./day administered on days 6-18 of
    gestation. No signs of maternal toxicity or effects on reproduction
    indices were reported. A number of minor soft tissue and skeletal
    changes were seen in fetuses from treated animals, but these were
    thought not to be treatment related, and the study gave a NOEL of
    0.625 mg/kg b.w./day. While the Committee recognized that rabbits
    may be relatively sensitive to benzimidazole-related toxic effects,
    it believed that the doses used in this study were not high enough
    to enable the teratogenic potential of oxfendazole in the rabbit to
    be adequately explored.

    4.  EVALUATION

         A temporary ADI of 0-4 µg/kg b.w. was established for
    oxfendazole, based on a NOEL of 0.7 mg/kg b.w./day from the
    carcinogenicity study in rats and the use of a safety factor of 200.

         The Committee noted that if the NOEL for teratogenicity in
    sheep had been used as the basis for establishing the temporary ADI
    together with a safety factor of 2000, the value obtained would have
    been of the same order as that derived from the carcinogenicity
    study in rats.

         A temporary ADI was established because of concern that
    sufficiently high doses had not been used in the carcinogenicity
    study in rats and the teratogenicity study in rabbits and the lack
    of genotoxicity data.

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    TOMLINSON, R.V., BERRY, P. & BOWEN, L. (1986)  Comparison of
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    See Also:
       Toxicological Abbreviations
       OXFENDAZOLE (JECFA Evaluation)