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    TIABENDAZOLE (THIABENDAZOLE)

    First draft prepared by
    Dr G. Roberts
    Environmental Health Branch
    Department of Health, Housing and Community Services
    Canberra, Australia

    1.  EXPLANATION

          Tiabendazole (also known as thiabendazole) had not been
    previously reviewed by the Committee, but was evaluated at the 1970
    and 1977 Joint FAO/WHO Meetings on Pesticide Residues (FAO/WHO,
    1971, 1978). At the 1977 Joint Meeting, an ADI of 0-0.3 mg/kg bw was
    established. Tiabendazole is a benzimidazole compound used both as a
    broad-spectrum anthelminthic in various animal species and for the
    control of parasitic infestations in humans.

    2.  BIOLOGICAL DATA

    2.1  Biochemical Aspects

    2.1.1  Absorption, distribution, biotransformation and excretion

    2.1.1.1  Mice

          Pregnant Jcl:ICR mice were administered a single gavage dose of
    1000 mg/kg bw of 14C-tiabendazole on gestation day 9. When an
    olive oil vehicle was used, peak plasma radioactivity occurred
    within 30 min and was 5-fold higher than the peak level with an
    aqueous gum arabic vehicle, achieved 6 h after dosing. After 12 h,
    plasma levels were similar with both vehicles and by 72 h they were
    negligible. The time course for levels of radioactivity in the
    conceptus was similar to that in plasma. Over a 3-day period,
    excretion was 74 and 60% in urine and 23 and 18% in faeces for the
    olive oil and aqueous gum arabic vehicles, respectively (Yoneyama
     et al., 1984).

          Pregnant Jcl:ICR mice received single gavage doses of 1300
    mg/kg bw of 14C-tiabendazole on gestation day 11. Use of an olive
    oil vehicle resulted in 7-fold higher peak blood levels than with
    gum arabic. The initial rate of urinary excretion was higher with
    the olive oil vehicle, otherwise elimination kinetics were similar
    for both vehicles. Over 7 days, 60% was recovered in urine and 37%
    in faeces with each vehicle.

          Chromatographic analysis of urine revealed 12 to 15% as parent
    drug, 22 to 24% as 5-hydroxy tiabendazole, 28 to 29% as 5-hydroxy
    tiabendazole glucuronide and 30 to 31% as 5-hydroxy tiabendazole
    sulfate. Additionally, a small amount of N-methyl tiabendazole was
    identified (Tsuchiya  et al., 1987).

          Pregnant Crj:CD-1(ICR) mice were given a single oral dose of
    1000 mg/kg bw of 14C-tiabendazole in olive oil on gestation day
    10. HPLC analysis of 24 h urine revealed the major metabolites as
    unchanged tiabendazole, 5-hydroxy tiabendazole and the glucuronide
    and sulfate conjugates of the latter. An additional 2 minor
    metabolites, eluting between tiabendazole and the 5-hydroxy
    metabolite, were detected but the amounts were too low to enable
    identification (Fujitani  et al., 1991).

    2.1.1.2  Rats

          Following a dose of 100 mg/kg bw, tiabendazole labelled with
    14C in the benzene ring was rapidly absorbed from the
    gastrointestinal tract of rats, with a maximum blood concentration
    two to three hours after treatment. Radio-activity gradually
    disappeared from the blood, and approximately 92% of a dose of 25
    mg/kg bw and 80% of a 100 mg/kg bw dose was excreted in the urine

    and faeces within three days. Most of the drug and its metabolites
    were excreted within the first 24 h. Of the metabolites, 50%
    appeared as the glucuronide of 5-hydroxy tiabendazole and 40% as the
    sulfate ester of the same aglycone. Traces of unchanged tiabendazole
    and 5-hydroxy tiabendazole were also evident (FAO/WHO, 1971).

          Male F344/DuCrj rats were given a single oral dose of 800 mg/kg
    bw tiabendazole. In addition to the major urinary metabolites
    described above, the same 2 minor degradation products as were found
    in mouse urine were also detected. Using mass spectrometry, the new
    metabolites were identified as 2-acetyl benzimidazole and
    4-hydroxytiabendazole (Fujitani  et al., 1991).

    2.1.1.3  Dogs

          Dogs given a single oral dose of 50 mg/kg bw of 14C-labelled
    tiabendazole were found to have maximum plasma levels within two
    hours. Excretion was essentially complete in eight days, with
    approximately 35% of the dose appearing in the urine and 47%
    appearing in the faeces (FAO/WHO, 1971).

    2.1.1.4  Humans

          Sixteen male subjects were administered tiabendazole at dosages
    of 1 to 2 g per person in the form of tablets, wafers, capsules or
    suspension. The lower dose was rapidly absorbed and peak plasma
    concentrations were observed about one hour after treatment. Plasma
    drug levels declined rapidly thereafter and reached essentially zero
    values between 24 and 48 h. Tiabendazole and its metabolic products
    were excreted rapidly in the urine (81-91%) and faeces (2-7%) within
    48 h. Approximately half of the material in the urine was associated
    with compounds identified as the glucuronide and sulfate esters of
    5-hydroxy tiabendazole. In plasma, both unchanged tiabendazole and
    free 5-hydroxy tiabendazole were also found. At the higher dosage
    level, maximum drug levels in plasma appeared three hours following
    dosing. These studies utilized 14C-labelled and unlabelled
    tiabendazole (FAO/WHO, 1971; Robinson, 1965).

          Based on the metabolism studies, the pathway for tiabendazole
    degradation in mammals may be represented as in Figure 1.

    FIGURE 1

    2.2  Toxicological Studies

    2.2.1  Acute toxicity studies

          The results of acute toxicity studies with tiabendazole are
    summarized in Table 1.

        Table 1.  Acute toxicity
                                                                                            

    Species        Sex       Route                  LD50               Reference
                                                 (mg/kg bw)
                                                                                            

    Mouse          M&F       oral                 2400-3810            FAO/WHO, 1971
                   M&F       ip                         430            FAO/WHO,1971
                   M&F       iv                         150            FAO/WHO, 1971

    Rat            M&F       oral                 3330-3600            FAO/WHO, 1971
                   M&F       ip                        1850            FAO/WHO, 1971
                   M&F       iv                         130            FAO/WHO, 1971
                   M&F       inhalation          >397 mg/m3            Gurman et al., 1981

    Rabbit         M&F       oral                      3850            FAO/WHO, 1971
                   M&F       dermal                   >2000            Blaszcak & Auletta,
                                                                       1987

    Sheep          ?         drench                    2000            FAO/WHO, 1971

    Goat           ?         drench                   >2000            FAO/WHO, 1971
                                                                                            
    

          Toxic signs following administration of large doses of
    tiabendazole by oral or intraperitoneal routes were generally
    similar and consisted of lethargy and stupor. The intravenous
    administration of a large dose of tiabendazole hydrochloride
    produced narcosis. Death appeared to be due to respiratory failure.
    Rabbits that survived large oral doses initially lost weight but
    recovered after several days.

    2.2.2  Short-term toxicity studies

    2.2.2.1  Mice

          In an investigation of renal function, Crj:CD-1 (ICR) mice were
    given gavage doses of 0, 250 or 500 mg/kg bw/day tiabendazole
    (purity 98.5%) in olive oil. Groups of 6 to 8 males and females were
    killed after dosing for 1, 3, 5 or 7 days. There was no effect on

    body weight. Water intake was unaffected but urine volume was
    increased in all treated groups, significantly so in males given 500
    mg/kg bw/day.

          There were no meaningful effects on serum creatinine or urea
    nitrogen, urinary glucose or protein or the presence of occult blood
    in urine. Electrophoresis however, revealed relatively high
    molecular weight protein in treated mice, while low molecular weight
    protein was found in all groups. There was a progressive
    dose-related increase in renal lesions including tubular dilatation
    and degenerative desquamation, cell infiltration, fibrosis and
    regeneration of tubular epithelium. Electron microscopy showed
    evidence of glomerular damage such as flattening of the foot
    processes of podocytes and oedematous changes in the mesangium in
    treated mice (Tada  et al., 1989).

          In a 6-week pilot study, groups of 10 male and 10 female
    Charles River CD-1 (HaM/ICR) mice were given 0, 50, 150, 300, 600 or
    900 mg/kg bw/day tiabendazole (purity unknown) via the diet. There
    were no clinical signs or mortality. Food intake and weight gain
    were depressed in males at 600 and 900 mg/kg bw/day. Other
    parameters were not monitored (Bokelman & Zwickey, 1977).

    2.2.2.2  Rats

          Rats (Sprague-Dawley Holtzman, 10 males and 10 females per
    group) were administered tiabendazole by gavage at dosage levels of
    0, 100, 400, 800, 1200 or 1600 mg/kg bw/day. During the 30 day
    experimental period, rats in the 800 mg/kg bw/day group decreased
    their food intake and gradually lost weight. They were slightly less
    active, had ruffled fur and became slightly flaccid; three males and
    three females died during the course of the experiment. All of the
    rats in the 1200 and 1600 mg/kg bw/day groups died during the 30-day
    test period. Rats dosed at 100 and 400 mg/kg bw/day appeared normal
    throughout the test period, although a slight depression in
    body-weight gain was noted in males at 100 mg/kg bw/day and in
    females at 400 mg/kg bw/day. Higher doses produced greater effects
    on body-weight gain. Haematologic studies on rats receiving 800
    mg/kg bw/day showed a mild neutrophilia with concurrent lymphopenia.
    There was also a suggestion of a decrease in red blood cell elements
    at 400 mg/kg bw/day and above. Blood biochemistry showed no
    meaningful changes.

          No gross anatomical changes were noted in rats dosed with 100
    mg/kg bw/day, whereas male and female rats treated with 400 mg/kg
    bw/day showed thymic involution. A slight enlargement of the liver
    was also noted in females at 400 mg/kg bw/day. Animals surviving 800
    mg/kg bw/day showed gross signs indicating starvation; normal body

    fat depots and subcutaneous fat appeared to be depleted. The liver
    and adrenals were slightly enlarged in males and females and the
    thymus was involuted. Microscopic pathology showed bone marrow
    hypoplasia, thymus haemosiderosis and colloid depletion in the
    thyroid at 400 mg/kg bw/day (FAO/WHO, 1971; Robinson, 1964).

          Groups of 12 male and 12 female Albino Crj:CD (SD) rats were
    administered gavage doses of 0, 50, 100, 200 or 800 mg/kg bw/day
    thiabendazole (purity 100%), suspended in 0.5% methylcellulose, for
    28 to 31 days. Severe toxicity was observed at 800 mg/kg bw/day in
    the form of decreased activity, sedation, ataxia, recumbency,
    flaccidity, loss of righting reflex, piloerection, emaciation, rough
    hair coat, alopecia and a high level of mortality. Food intake and
    body-weight gain were depressed at 200 and 800 mg/kg bw/day.

          Laboratory analyses were carried out in week 4. Serum albumin,
    total protein and cholesterol were increased and erythrocytes,
    haemoglobin and haematocrit were decreased at 200 and 800 mg/kg
    bw/day with reticulocytosis and leucocytopenia at the higher level.
    Urinalysis was unchanged. Autopsy revealed changes at all dose
    levels. There was haemosiderosis and increased extramedullary
    haematopoiesis in the spleen at all doses with increased spleen
    weight at 200 mg/kg bw/day and above. Increased thyroid weight and
    follicular cell hyperplasia and decreased thymus weight were seen at
    50 mg/kg bw/day and above. Lymphoid depletion was observed in the
    thymus at 100 mg/kg bw/day and above, in bone marrow at 200 mg/kg
    bw/day and above and in spleen and lymph nodes at 800 mg/kg bw/day.
    Liver weight and centrilobular hepatocytic hypertrophy were
    increased at 100 mg/kg bw/day and above (Usui & Sakaguchi, 1989).

          Groups of 20 male and 20 female Sprague-Dawley Crl:CD (SD) BR
    rats were given gavage doses of 0, 25, 100 or 400 mg/kg bw/day
    tiabendazole (purity not stated), suspended in 0.5% methyl
    cellulose, for 13 weeks. Alopecia was noted in some rats of each
    treatment group. There was no mortality. Body-weight gain was
    reduced at 100 and 400 mg/kg bw/day with lower food intake in 400
    mg/kg bw/day males. Ophthalmology at the end of study was
    unremarkable.

          Clinical laboratory parameters were studied in weeks 6 and 13.
    Decreased erythrocytes, haemoglobin and haematocrit and increased
    cholesterol were induced at 100 and 400 mg/kg bw/day. Urinary levels
    of bilirubin, urobilinogen and nitrite were increased at 400 mg/kg
    bw/day. At 100 and 400 mg/kg bw/day, increased liver weight and
    centrilobular hypertrophy, enlarged thyroids with follicular cell
    hyperplasia and splenic congestion and pigmentation were observed.
    In the kidney, renal calculus and transitional epithelial
    hyperplasia were evident at 100 and 400 mg/kg bw/day with tubular

    degeneration at the highest level. The stomach exhibited acanthosis
    and/or degeneration of non-glandular mucosa at 100 and 400 mg/kg
    bw/day and cytoplasmic rarefaction and necrosis of glandular mucosa
    at 400 mg/kg bw/day. The NOEL was 25 mg/kg bw/day (Kangas  et al.,
    1989).

          Groups of 10 male and 10 female Sprague-Dawley Crl:CD BR rats
    were fed diets containing tiabendazole (purity 99.4%) for 13 weeks.
    Based on food intake the calculated doses were 0, 9, 37, 150 or 302
    mg/kg bw/day. There was no effect on survival or on the eyes at the
    end of study. Alopecia was increased at 150 and 302 mg/kg bw/day.
    Doses of 37 mg/kg bw/day and above were associated with decreased
    body-weight gain and food intake in males; females were similarly
    affected at 150 mg/kg bw/day and above.

          Clinical laboratory analyses were undertaken in weeks 6 and 13.
    At doses of 150 and 302 mg/kg bw/day serum cholesterol was
    increased, glucose, erythrocytes, haemoglobin and haematocrit were
    depressed and there were increased numbers of abnormal erythrocytes.
    Urinalysis was unaffected. Liver weight increases and centrilobular
    hypertrophy, increased thyroid weight and follicular cell
    hypertrophy and bone marrow erythroid hyperplasia were observed at
    37 mg/kg bw/day and above. At 150 and 302 mg/kg bw/day there was
    spleen pigmentation and thymus atrophy with skeletal muscle atrophy
    in females given 302 mg/kg bw/day. The NOEL was 9 mg/kg bw/day
    (Myers & Lankas, 1990).

          Rats (Sprague-Dawley Holtzman, 30 males and 30 females per
    group) were administered tiabendazole, suspended in 1% methocel, by
    gavage for 180 days, at doses of 0, 12.5, 25, 50, 100, 200 or 400
    mg/kg bw/day. All of the animals survived throughout the duration of
    the experiment. At 400 mg/kg bw/day, a depression in body weight was
    observed in both sexes. At 200 mg/kg bw/day, the male rats showed a
    slight depression in weight gain. No clinical signs of toxicity were
    observed. Haematological studies at 400 mg/kg bw/day indicated a
    slight suggestion of a fall of the red blood cell elements,
    neutrophilia and lymphopenia which were not evident at levels below
    this dose. Blood biochemistry studies and urinalysis were normal at
    all dosage levels with a slight polyuria in both male and female
    rats at 400 mg/kg bw/day, which was apparently the result of a
    slight increase in water consumption at this dosage level.

          Gross pathology showed thymic involution in both males and
    females at 400 mg/kg bw/day and in females at 200 mg/kg bw/day.
    There was an increase in liver size at doses of 100 mg/kg bw/day and
    above in males and at 50 mg/kg bw/day and above in females. Males
    dosed with 200 and 400 mg/kg bw/day and females at 400 mg/kg bw/day

    showed an apparent increase in kidney weight. Microscopic
    examination of animals at 100 mg/kg bw/day showed a small incidence
    of haemosiderosis of the thymus. At 200 and 400 mg/kg bw/day, these
    examinations showed considerably more haemosiderosis of the thymus
    and colloid depletion in the thyroid. The NOEL was 25 mg/kg bw/day
    (FAO/WHO, 1971; Robinson, 1964).

    2.2.2.3  Rabbits

          Groups of 5 male and 5 female New Zeeland white rabbits
    received dermal doses of tiabendazole (purity 98.9%) moistened in
    0.9% saline. The drug was applied to the shaved trunk of animals at
    doses of 0, 50, 200 or 1000 mg/kg bw, 6 h/day for 3 weeks. Oral
    ingestion was prevented by use of a collar. Clinical laboratory
    parameters and pathology were investigated at the end of the study.
    There was no evidence of local or systemic toxicity (Cavagnaro &
    Yamamoto, 1989).

    2.2.2.4  Dogs

          Groups of 4 male and 4 female beagle dogs were given capsules
    of tiabendazole (purity 99.4%) at doses of 0, 35, 75 or 150 mg/kg
    bw/day for 14 weeks. Emesis was increased at 75 and 150 mg/kg bw/day
    with salivation at 150 mg/kg bw/day. There were no deaths. During
    the first 2 weeks of treatment, food consumption and body-weight
    gain were decreased in all treated groups. Subsequently, food was
    made available overnight rather than for 1 h per day which led to
    comparable food intake and weight gain in all groups.

          Ophthalmology and ECG examinations were normal throughout the
    study. Red blood cells, haemoglobin and haematocrit were depressed
    at 150 mg/kg bw/day, more so at weeks 4 and 8 than at week 12. Blood
    chemistry and urinalysis were unchanged at any time. Relative but
    not absolute liver weights were slightly increased in all treated
    groups but with no dose-relationship. At 75 and 150 mg/kg bw/day,
    gallbladder cytoplasmic vacuolation was increased in incidence and
    severity. The NOEL was 35 mg/kg bw/day (Batham  et al., 1989).

          Groups comprising two male and two female beagle dogs were
    orally administered tiabendazole for periods of over two years at
    doses of 0, 20, 100 or 200 mg/kg bw/day. No clinical signs or
    morbidity were observed, food and water consumption were normal and
    blood and urine chemistry were normal. A slight retardation in
    body-weight gain was observed at 200 mg/kg bw/day, which was
    accompanied by a slight reduction in total erythrocyte count. At
    this level, changes in haemoglobin concentration and haematocrit
    were also observed.

          No gross pathological observations were noted at the conclusion
    of this test and organ weights appeared normal. A significant
    haemosiderosis was present in dogs at 100 and 200 mg/kg bw/day in
    the spleen, liver, lymph nodes and bone marrow. This was not
    associated with an increase in serum haemoglobin. The NOEL was 20
    mg/kg bw/day (FAO/WHO, 1971; Robinson, 1964)

          Groups of beagle dogs (three males and three females) were
    orally administered tiabendazole in capsules for two years at doses
    of 0, 20, 50 or 125 mg/kg bw/day. At 125 mg/kg bw/day, two of six
    dogs died. One of these dogs had marked liver cirrhosis, seminal
    tubular degeneration, bone marrow atrophy and degenerative renal
    changes. Slight to moderate reduction in haemoglobin and packed cell
    volume occurred. Elevated blood urea nitrogen, serum alkaline
    phosphatase and serum GOT and chronic inflammatory liver changes
    were evident. Urinary albumin was seen more frequently than in
    controls. Inspissated bile entwined in the gall bladder villi was
    also observed in one dog. One dog of this group was sacrificed and
    was found to have pulmonary arteritis of parasitic origin.

          At 50 mg/kg bw/day, growth of male dogs was slightly depressed.
    All six dogs given tiabendazole at 50 mg/kg bw/day survived the
    study and their tissues differed from those of the control dogs in
    that some liver glycogen depletion was observed in three dogs and
    inspissated material was found adhering to the gall bladder mucosa
    in one. Five of six dogs given tiabendazole at 20 mg/kg bw/day
    survived the study. Three of the five showed slight liver glycogen
    depletion. A general impression in this study was of an overall
    appearance of mild chronic inflammatory degenerative renal changes
    in all treated dogs. The NOEL was 20 mg/kg bw/day (FAO/WHO, 1971;
    Woodard, 1964).

    2.2.2.5  Chickens

          Groups of 0.5 week-old male white leghorn chicks (10 to 20 per
    group) were fed tiabendazole in the diet at dosage levels ranging
    from 1 to 10 000 ppm for a period of 2 1/2 weeks. This level
    corresponded to a mean daily intake of tiabendazole ranging from 0.1
    to 1200 mg/kg bw. A gradual decrease in growth appeared to occur
    with concentrations of 100 ppm tiabendazole in the diet. This dose
    corresponded to approximately 13 mg/kg bw/day. Gross pathological
    examination of the chicks at a dietary level of 4000 ppm
    tiabendazole showed them to be normal except for a smaller size
    (FAO/WHO, 1971).

    2.2.2.6  Sheep

          Thirty weanling wethers were employed in a 16-week study at
    doses of 0, 10, 50, 100, 200, 400 or 800 mg/kg bw/day. Tiabendazole
    was administered in gelatin capsules. Two of the four sheep dosed at
    100 mg/kg bw/day did not survive the test period. However, because

    of infection, tiabendazole may not have been directly related to the
    cause of their death. All the animals treated at 200 mg/kg bw/day
    and above died before the end of the test period. No significant
    effects on blood biochemistry or urinalysis were observed. Doses of
    50 mg/kg bw/day and above affected body-weight gain after
    approximately 120 days on the test. Doses of 10 mg/kg bw/day had no
    effect. Food consumption was unaffected at 10 mg/kg bw/day but a
    minor decrease was noted at 50 and 100 mg/kg bw/day and a
    significant decrease at 200 mg/kg bw/day and above. No gross
    pathological changes were observed at doses below 200 mg/kg bw/day.
    Starvation and loss of body weight complicated the interpretation of
    data concerning organ weights at 200 mg/kg bw/day and above. At 200
    to 800 mg/kg bw/day, a moderate hypoplasia of the bone marrow with
    replacement by adipose tissue was observed. Loss of colloid in
    thyroid was evident at 800 mg/kg bw/day, as well as lymphoid atrophy
    at the higher dose levels (FAO/WHO, 1971).

          Five groups of two ewe lambs (10 to 12 weeks old) and eight
    wether lambs (10 to 19 weeks old) were fed diets containing 0, 100,
    320, 1000 or 3200 ppm tiabendazole for periods up to 50 weeks. Sheep
    10 weeks of age tolerated 1000 ppm tiabendazole in the diet for the
    duration of the experiment. This dose corresponded to 30 to 50 mg/kg
    bw/day. The sheep tolerated 3200 ppm in their diet for the first 14
    weeks but thereafter lost weight in the final stages of the
    experiment (FAO/WHO, 1971).

    2.2.2.7  Pigs

          Five groups of four barrows each were given a diet containing
    0, 320, 1000, 3200 or 10 000 ppm tiabendazole for 14 weeks. A
    concentration of 320 ppm was tolerated without observable effects
    for the 14-week period. This concentration corresponded to an intake
    of 15 mg/kg bw/day. The concentration of 10 000 ppm tiabendazole in
    the diet caused reduced weight gain and reduced food consumption
    with no mortality. Gross pathologogical examination revealed no
    abnormal conditions (FAO/WHO, 1971).

    2.2.2.8  Cattle

          Five female holstein calves (seven months old) were fed a diet
    containing 0, 320, 1000, 3200 or 10 000 ppm of tiabendazole for a
    14-week test period. Calves tolerated 3200 ppm tiabendazole in their
    diet without observable effects on growth, food intake or general
    condition. This concentration corresponded to a mean daily intake of
    90 mg/kg bw. At 10 000 ppm tiabendazole, the calves grew normally
    for the first two weeks, but in the following 12 weeks the weight
    gain was about half that observed for the controls. Gross
    examination at the time of autopsy revealed no pathological
    condition and histological examination of several tissues showed no
    changes resulting from the incorporation of tiabendazole in the diet
    (FAO/WHO,1971).

    2.2.3  Long-term/carcinogenicity studies

    2.2.3.1  Mice

          Groups of 50 male and 50 female Charles River CD-1 (HaM/ICR)
    mice were fed diets containing tiabendazole (purity 99.3%) for up to
    2 years. The study was commenced using dietary concentrations of 0
    (three groups), 220, 660 or 2000 ppm in males and 0 (three groups),
    660, 2000 or 5330 ppm in females. From the seventh week the
    concentration of tiabendazole in the feed of the low-dose males and
    females was reduced to 60 ppm in an effort to establish a NOEL. The
    intake of tiabendazole was 5.6-8.3, 63-121 or 184-372 mg/kg bw/day
    in males and 5.7-9.9, 209-368 or 534-1005 mg/kg bw/day in females.

          Mortality was increased in groups given the intermediate and
    high-doses. At 2000 ppm in males and females and 5330 ppm in
    females, myocardial thrombosis was the primary cause of death. The
    reason for decreased survival in 660 ppm males was not apparent.
    When survival reached 20%, the remaining animals of the group were
    sacrificed. Thus 5330 ppm females were killed in week 81, 2000 ppm
    males were killed in week 85, 660 ppm males and 2000 ppm females
    were killed in week 93, 60 ppm males (originally 220 ppm) were
    killed in week 101 and 60 ppm females (originally 660 ppm) were
    killed in week 105. A proportion of each control group was killed at
    each of these sacrifice times.

          Body-weight gain was depressed in 2000 ppm males and females
    and 5330 ppm females. Males given 660 ppm had slightly lower weight
    gain in the early and latter parts of the study. At the lowest dose,
    slightly lower weight gain was noted early in the study, but
    following dosage reduction, no further effect was observed. Food
    consumption showed no meaningful alterations. Ophthalmoscopy
    conducted at termination was unremarkable. Laboratory parameters
    were not studied.

          At autopsy liver weight was significantly increased in 2000 ppm
    males and females and 5330 ppm females. Kidney weight was
    significantly decreased in 5330 ppm females with slight decreases in
    2000 ppm males and females and 660 ppm males. There were no
    pathological lesions associated with the organ weight changes. A
    high incidence of atrial thrombosis was seen in 2000 ppm males and
    females and 5330 ppm females and was judged to be a major cause of
    intercurrent mortality. Tumour incidences were unrelated to
    treatment. The NOEL was 6 mg/kg bw/day (Bagdon  et al., 1980).

    2.2.3.2  Rats

          Groups of Charles River rats (35 of each sex) were fed dietary
    levels adjusted to provide 0, 10, 40 or 160 mg/kg bw/day of
    tiabendazole for up to two years. At the 160 mg/kg bw/day level, a
    reduction of weight gain of about 25%, with concomitant reduction in
    food consumption and slightly reduced haemoglobin and haematocrit
    values were the only changes attributable to compound
    administration. No effects attributable to compound administration
    were noted with respect to survival, time of death in non-survivors,
    incidence or location of neoplasms and histopathological examination
    of the tissues.

          No effect on food consumption or haemograms were seen at either
    10 or 40 mg/kg bw/day. Very slight depression in growth rate was
    observed in male rats at 40 mg/kg bw/day but not at 10 mg/kg bw/day.
    At 10 mg/kg bw/day, the mean absolute thyroid weights of the male
    rats were heavier than the mean thyroid weight of the controls. This
    effect was not observed in the rats given 40 or 160 mg/kg bw/day.
    The NOEL was 10 mg/kg bw/day (FAO/WHO, 1971; Woodard, 1964).

          In a carcinogenicity study, groups of 30 male and 30 female
    F344/DuCrj rats were fed diets containing 0, 500, 1000, 2000 or 4000
    ppm tiabendazole (purity 98.5%) for 2 years. Based on food
    consumption the drug intake was calculated as 21, 43, 90 or 207
    mg/kg bw/day in males and 26, 53, 112 or 237 mg/kg bw/day in
    females.

          There were no signs of toxicity or effects on survival. Food
    intake was lower at 4000 ppm whereas body weight gain was reduced at
    1000 ppm and above, leading to small and poorly developed animals at
    2000 and 4000 ppm. Clinical laboratory parameters were not examined.

          At the end of 2 years, all animals were necropsied. Liver
    microgranulomas and aggregations of foamy cells in the lung were
    increased at 1000 ppm and above. Renal epithelial hyperplasia of
    papilla and pelvis were increased at 2000 and 4000 ppm. Preputial or
    clitoral gland adenoma incidences were higher than control values at
    4000 ppm. The increase was statistically significant (p <0.05) only
    for adenomas in the preputial gland. There were no adverse effects
    at 500 ppm, equal to a NOEL of 20 mg/kg bw/day (Fujii  et al.,
    1991).

    2.2.4  Reproduction studies

    2.2.4.1  Mice

          A five-generation reproduction study utilized 25 male and 25
    female mice given diets containing tiabendazole at concentrations of
    0, 200, 1000 or 5000 ppm. When the mice attained the age of eight
    weeks, they were mated and continued on the same diet. The young

    from these matings, when they were weaned, were maintained on the
    test diet and mated when they reached the age of eight weeks. This
    procedure continued for five complete reproductive cycles. No
    effects were noted at 200 ppm. At 1000 ppm, a slight decrease in the
    weights of weanlings was observed in all five generations. At 5000
    ppm, the number of mice born and weaned per litter was reduced and a
    marked reduction in the average weanling weight of the young was
    observed. The NOEL was 200 ppm, equivalent to 30 mg/kg bw/day
    (FAO/WHO, 1971).

    2.2.4.2  Rats

          A three-generation, two-litter reproduction study (10 male and
    10 female FDRL albino rats per group) at dosages of 0, 20, 40 or 80
    mg/kg bw/day showed no adverse effects on reproduction, lactation or
    histomorphology in the three generations of rats examined. The only
    treatment-related findings were decreased body-weight and decreased
    food consumption in the male rats at all dosage levels in the F0-
    and F2-generations. Slight decreases in final body weights and
    food consumption at the 80 mg/kg bw/day dose level in the F1- and
    F2-generation females were also observed (FAO/WHO, 1971; Vogin,
    1968)

    2.2.5  Special studies on embryotoxicity and teratogenicity

    2.2.5.1  Mice

          A series of developmental studies were undertaken in Jcl:ICR
    mice. Pregnant females were given gavage doses of tiabendazole
    (purity 98.5%) in olive oil at various times during the gestation
    period. Females were killed on gestation day 18.

          Exp. 1: Groups of 39 mice were dosed with 0, 700, 1300 or 2400
    mg/kg bw/day on gestation days 7-15. Maternal weight gain was
    depressed in a dose-related manner with mortality at 1300 mg/kg
    bw/day (5 out of 39) and 2400 mg/kg bw/day (24 out of 39). The
    resorption rate was increased at 1300 and 2400 mg/kg bw/day. At all
    treatment levels, there were reduced fetal weights and increased
    malformations such as cleft palate, fusion of vertebral arches and
    vertebral bodies.

          Exp. 2: Groups of 7-12 mice were given a dose of 2400 mg/kg bw
    on a single day of gestation between days 6 and 15. Mortality was 8
    to 55% in treated groups but there were no data on body weight. In
    each group, resorptions were increased and fetal body weights were
    decreased. Fetal malformations detected were: microcephaly and
    exencephaly (following treatment on gestation days 6 to 8); short or
    absent tail and anal atresia (day 9); open eyelids (days 7, 8, 10,
    13, and 14); reduction deformity of limbs and cleft palate (days 9
    to 12); fusion of vertebral arches and bodies (days 7 to 10, and 13)
    and fusion of ribs (days 7 to 9). The fetal abnormalities were

    judged to be most prominent on gestation day 9. As the types of
    malformation were diverse and primarily related to the timing of
    treatment, it was suggested that tiabendazole was a non-specific
    teratogen.

          Exp. 3: Groups of 21 to 31 mice were given a single dose of 30
    to 2400 mg/kg bw on gestation day 9. Mortality was induced at 1670
    mg/kg bw and above and maternal weight gain was reduced at 1160
    mg/kg bw and above. The resorption rate was increased at 1670 mg/kg
    bw and above while fetal weight was lower at 60 mg/kg bw and above.
    The limb reduction deformity was seen regularly at doses of 480
    mg/kg bw and above; the threshold was calculated as being 360 mg/kg
    bw. Fusion of vertebral arches, vertebral bodies and ribs was
    increased at 240 mg/kg bw and above. Other malformations were not
    consistently increased. There were no treatment-related effects at
    30 mg/kg bw/day (Ogata  et al., 1984).

          Follow-up developmental studies were carried out in groups of
    16 to 20 pregnant female Jcl:ICR mice. Tiabendazole (purity 98.5%)
    was given by gavage in olive oil at doses of 0, 250, 500 or 1000
    mg/kg bw/day on gestation day 9. Females were killed on gestation
    day 18. Treatment at the two highest doses produced similar effects
    to the previous mouse studies.

          Pretreatment with SKF-525A (inhibitor of cytochrome P-450)
    enhanced the rate of resorptions and the incidence of fetal
    malformations. Sodium phenobarbital pretreatment, on the other hand,
    resulted in decreases in the resorption rate and reduced fetal
    abnormalities to control levels. Pretreatment with glutathione,
    cysteine or diethyl maleate (a glutathione-depleting substance) had
    no effect on resorptions. However, the incidence of fetal
    malformations was increased with glutathione or cysteine and reduced
    to control levels by diethyl maleate. Graphs of tissue
    concentrations of tiabendazole against time showed the AUC for both
    maternal blood and fetal tissue was increased by glutathione and
    reduced by diethyl maleate. The overall conclusion was that the
    developmental effects appear to be due to unchanged tiabendazole and
    not to its degradation products (Ogata  et al., 1987; 1989).

    2.2.5.2  Rats

          Two groups of rats (20 male and 20 female) were placed on a
    diet containing 0 or 500 ppm tiabendazole. There were no
    abnormalities among the young from either mating attributable to
    tiabendazole at 500 ppm. It was concluded that these data presented
    no evidence of teratogenecity (FAO/WHO, 1971).

          In a preliminary teratology study, Charles River SD rats (8
    pregnant females per group) were given gavage doses of 0 or 80 mg/kg
    bw/day tiabendazole (purity unknown) on gestation days 8 to 15. Dams
    were killed on gestation day 21. There were no effects on resorption
    rate or on fetal survival, growth or development (Delatour  et al.,
    1974).

          Groups of 20 pregnant female Wistar rats were administered
    gavage doses of 0, 125, 250 or 500 mg/kg bw/day of a commercial
    formulation containing 45% tiabendazole and 55% unknown ingredients.
    Dosing was on gestation days 6-15 and dams were killed on gestation
    day 22. No adverse effects were apparent in females and no
    meaningful effects were reported on the resorption rate, fetal
    viability, growth or development (Khera  et al., 1979).

          In a range-finding study, Sprague-Dawley Crl:CD(SD)BR rats were
    given gavage doses of 0, 50, 100, 200 or 400 mg/kg bw/day
    tiabendazole (purity 99.4%). Groups of 10 pregnant females were
    treated on gestation days 6 to 17 and were killed on gestation day
    20.

          There were no deaths or abortions but all 200 and 400 mg/kg
    bw/day females were killed due to severe body-weight effects.
    Maternal weight gain was also depressed at 50 and 100 mg/kg bw/day.
    Other toxic signs were lethargy and ptosis at 100 mg/kg bw/day and
    above and reduced faeces at 200 mg/kg bw/day and above. Increased
    protein, albumin and cholesterol were observed at the higher doses
    with decreased triglycerides at all dose levels. Resorptions and
    fetal morphology were unaffected but fetal weight was reduced at all
    treatment levels (Lankas & Wise, 1990a).

          Groups of 25 pregnant female Sprague-Dawley Crl:CD(SD)BR rats
    were given gavage doses of 0, 10, 40 or 80 mg/kg bw/day tiabendazole
    (purity 98.9%) suspended in 0.5% methyl cellulose. Drug
    administration was on gestation days 6 to 17 and the dams were
    killed on gestation day 20.

          At 80 mg/kg bw/day, rats showed ptosis and a few animals
    regurgitated a portion of the dose. Food intake and body-weight gain
    were depressed at 40 and 80 mg/kg bw/day. There was no mortality or
    abortions nor were there increases in the resorption rate or in dead
    fetuses. Fetal abnormalities were not produced, but statistically
    significantly decreased fetal weight was noted at 40 and 80 mg/kg
    bw/day. The NOEL was 10 mg/kg bw/day (Lankas & Wise, 1990b).

    2.2.5.3  Rabbits

          Groups of 10 to 32 pregnant female New Zeeland white rabbits
    were dosed by gavage with 0, 100, 200, 400 or 800 mg/kg bw/day
    tiabendazole (purity unknown) suspended in 1% carboxymethyl
    cellulose. Treatment was on gestation days 8 to 16 and does were
    killed on gestation day 29 or 30.

          At 200 mg/kg bw/day and above, does lost weight and the
    resorption rate was increased (not dose-related). Fetal weight was
    decreased at 400 and 800 mg/kg bw/day but fetal morphology was
    unaltered. The NOEL was 100 mg/kg bw/day (Peck, 1966a).

          In a range-finding study New Zeeland white rabbits were given
    gavage doses of 0, 100, 200, 400 or 800 mg/kg bw/day tiabendazole
    (purity 98.9%). Groups of 8 pregnant females were dosed on gestation
    days 6 to 18 and does were killed on gestation day 29.

          At 800 mg/kg bw/day, abnormal faeces were seen and weight loss
    necessitated early sacrifice of this group. Food intake and weight
    gain were lower at 200 and 400 mg/kg bw/day. The implantation rate
    was lower at 400 mg/kg bw/day but resorptions were not increased.
    External fetal examinations were unremarkable (Christian  et al.,
    1989).

          Groups of 18 pregnant female New Zeeland white rabbits were
    administered 0, 24, 120 or 600 mg/kg bw/day tiabendazole (purity
    98.9%) suspended in 0.5% methyl cellulose. The gavage doses were
    given on gestation days 6 to 18 and females were killed on gestation
    day 29.

          At 600 mg/kg bw/day one doe died, four aborted, abnormal faeces
    were increased, food consumption was lower and body weight was lost.
    Weight gain was slightly depressed at 120 mg/kg bw/day. There were
    increased resorptions at 120 and 600 mg/kg bw/day, including total
    resorption of conceptuses in 4 females at 120 mg/kg bw/day. Domed
    head, hydrocephaly and enlarged fontanelles were seen in one fetus
    at 120 mg/kg bw/day and two fetuses at 600 mg/kg bw/day. The NOEL
    was 24 mg/kg bw/day (Hoberman & Lankas, 1989).

          Groups of 18 pregnant female New Zeeland white rabbits were
    given gavage doses of 0, 50, 150 or 600 mg/kg bw/day tiabendazole
    (purity 98.6%) suspended in 0.5% methylcellulose. Treatment was on
    gestation days 6 to 18 and dams were killed on gestation day 28.

          There were no deaths or abortions related to treatment. Food
    intake and body weight gain were reduced at 600 mg/kg bw/day during
    the dosing period only. Resorptions were increased slightly but
    significantly at 600 mg/kg bw/day. At 600 mg/kg bw/day, there were
    increases in the incidences of variation in lung lobation and
    incompletely ossified metacarpals. The NOEL was 150 mg/kg bw/day
    (Lankas & Wise, 1991).

    2.2.5.4  Sheep

          Pregnant ewes tolerated a single dose of 400 mg/kg bw
    tiabendazole at 2.5 to 8 weeks prior to lambing without any effect
    on the birth rate, growth or viability of the lambs. This dose had
    no effect on the ewes throughout the test interval or on viability
    of the lambs to six weeks of age. Miscellaneous tests using 39 ewes
    produced 29 weanling lambs after treatment with tiabendazole at 400
    mg/kg bw, whereas, from a control group of 22 ewes, 13 lambs were
    weaned. Ewes tolerated a single dose of 18 g tiabendazole per animal
    (equal to 235 to 335 mg/kg bw), three to ten days after lambing,
    without any effect on the weight or food intake of the ewes or
    survival and growth of the lambs up to the weaning time of six weeks
    (FAO/WHO, 1971).

    2.2.6  Special studies on genotoxicity

          The results of genotoxicity studies with tiabendazole are
    summarized in Table 2.

        Table 2.  Results of genotoxicity studies on tiabendazole1
                                                                                            

    Test system    Test object        Treatment            Results        Reference
                                                                                            

    Reverse        S.typhimurium      10-5000              negative       MacGregor, 1976
    mutation       TA98, TA100,       g/plate
                   TA1535, TA1537     (+&-S9)2

    Reverse        S.typhimurium      100-2500             negative       Shirasu et al.,
    mutation       TA1535, TA1537,    g/plate (-S9)                      1976a.
                   TA1538, TA98,      10-1000
                   TA100, E.coli      g/plate (+S9)2
                   WP2 hcr-

    Reverse        S.typhimurium      10-2000              negative       Peck, 1977
    mutation       TA98, TA100,       g/plate
                   TA1538             (+&-S9)2
                   TA100, TA1538      10-2000              negative
                                      g/plate (+S9)3
                   TA98               10-500               negative
                                      g/plate (+S9)3
                                      1000-2000            positive
                                      g/plate (+S9)3
                                      1000-2000            negative
                                      g/plate (+S9)3
                                      pure tiabendazole
                                      20-1000              positive
                                      g/plate (+S9)3
                                      concentrated
                                      impurities

    Host           ICR mice,          300-1000             negative       Shirasu et al.,
    mediated       S.typhimurium      mg/kg bw/day for                    1976a
                   G46.               5 days, po

    Rec. assay     B.subtilis         2-1000               negative       Shirasu et al.,
                   H17, M45           g/disc (-S9)                       1976a

    DNA            Rat                60-262               negative       Lankas, 1989
    damage         hepatocytes        g/ml

    Anaphase-      CHO cells          0.06-0.12            negative       Mudry de
    telophase                         g/ml (-S9)                         Pargament
    test                              0.24-0.6             positive       et al., 1987
                                      g/ml (-S9)
                                                                                            

    Table 2. cont'd
                                                                                            

    Test system    Test object        Treatment            Results        Reference
                                                                                            

    Sister         Mouse bone         50-200               negative       Mudry de
    chromatid      marrow             mg/kg bw, ip                        Pargament
    exchange                                                              et al., 1987

    Chromosome     Human              2-50                 negative       Shirasu et al.,
    aberration     fibroblasts        g/ml (-S9)                         1976c

    Chromosome     Rat bone           100-1000             negative       Shirasu et al.,
    aberration     marrow             mg/kg bw, po                        1976d
                                      30-300               negative
                                      mg/kg bw/day
                                      for 5 days, po

    Micronucleus   Mouse bone         125-500              negative       Peck, 1977.
    test           marrow             mg/kg bw, po

    Micronucleus   Mouse bone         50-200               positive       Mudry de
    test           marrow             mg/kg bw, ip                        Pargament
                                                                          et al., 1987

    Dominant       Mice               200-600              negative       Shirasu et al.,
    lethal                            mg/kg bw/day                        1976b,
    test                              for 5 days, po

    Dominant       Mice               125-500              negative       Peck, 1977.
    lethal                            mg/kg bw/day
    test                              for 5 days, po
                                                                                            

    1    Appropriate positive controls were used.
    2    Liver microsomes obtained from Aroclor 1254 pretreated rats.
    3    Liver microsomes obtained from phenobarbital pretreated rats.
    


    2.2.7  Special studies on irritation and sensitization

    2.2.7.1  Guinea-pigs

          Male albino guinea-pigs received 10 intracutaneous injections
    of a 0.1% suspension of tiabendazole in 0.9% saline. Two weeks after
    the induction period an intracutaneous challenge dose failed to
    exacerbate reactions at the injection site (Peck, 1966b).

    2.2.7.2  Rabbits

          There was no evidence of a significant degree of irritation
    when 0.5 g tiabendazole was applied in cold cream at concentrations
    of 10 and 50% (w/w) for 24 h to intact rabbit skin (FAO/WHO, 1971).

          No evidence of irritation was noted other than a very slight
    erythema observed for approximately one hour after application of 1
    ml of tiabendazole as a 12% suspension in sodium carboxymethyl
    cellulose or 10 mg of the dry powder to the conjunctival sac of two
    rabbits (FAO/WHO, 1971).

          Male and female New Zeeland white rabbits received 100 mg of
    tiabendazole powder instilled into the conjunctival sac of the eye.
    At 15 min, there was slight conjunctival injection with a clear
    discharge which returned to normal within 24 h (Merck, Sharp &
    Dohme, undated).

    2.2.8  Special studies on pharmacology

          Oral doses of tiabendazole (4000 mg/kg bw) produced no striking
    acute pharmacological effects on blood pressure or respiration in
    either cats or dogs. Similarly, there were no alterations in the
    electrocardiogram (FAO/WHO, 1971).

    2.3  Observations in humans

          A double blind study was carried out with 100 male volunteers,
    half of them receiving 250 mg tiabendazole/day for 24 weeks and half
    of them a placebo. Each subject was interviewed weekly and any
    potential side effect was recorded. General physical examination and
    laboratory examinations (haematology, cholesterol, glucose, urea,
    alkaline phosphatase, thymol turbidity, bilirubin in serum and
    urinalysis) were carried out before the test and after 4, 12 and 24
    weeks. PBI in serum and ECGs were carried out only at the beginning
    and after 24 weeks. Thirty-six subjects on tiabendazole and 41 on
    placebo completed the study. As tiabendazole has a possible
    influence on the thyroid the values for PBI were evaluated
    carefully. No indication, however, was found of a decrease or
    increase in PBI values due to tiabendazole. Under the conditions of
    the study, tiabendazole was well tolerated at a dosage of 250 mg/day
    during 24 weeks. No effect on any of the parameters studied could be
    clearly ascribed to the drug. The NOEL was 3-4 mg/kg bw/day
    (Colmore, 1965; FAO/WHO, 1978).

          Twenty-three patients with trichinosis received 50 mg/kg bw/day
    up to  3 g daily tiabendoazole for 10 days (total dose 25 to 30 g
    tiabendazole), which was administered twice a day (after breakfast
    and after evening meal). Symptoms of muscle pain and fever subsided
    1 to 3 days after commencing tiabendazole. One woman withdrew due to

    drug-induced rash, fever and proteinuria. Side-effects occurred in
    14/23 treated patients - the most common effects being nausea,
    retching and vomiting in 11/23 subjects, aversion to tablets (3/23),
    exanthema (3/23), impotence (2/23), diarrhoea (1/23), liver damage
    (1/23), fever (1/23) and dizziness (1/23) (Hennekeuser  et al.,
    1969).

    3.  COMMENTS

          Information from a range of studies on thiabendazole was
    available for assessment, including data on kinetics and metabolism,
    acute toxicity, short-term and long-term toxicity, reproductive and
    developmental toxicity, and genotoxicity and observations in humans.

          Toxicokinetic studies revealed rapid absorption after oral
    dosing in mice, rats, dogs, and humans, peak plasma levels occurring
    within 3 h of drug administration. The drug was excreted in the
    urine and faeces. Elimination of tiabendazole and its degradation
    products appeared more rapid in humans than in mice, rats, and dogs,
    but metabolism was similar in mice, rats, and humans. The main
    urinary metabolites were the glucuronide and sulfate conjugates of
    5-hydroxytiabendazole; there were also small amounts of unconjugated
    tiabendazole and the 5-hydroxy derivative. At very high doses, other
    minor metabolites were detected in rat and mouse urine.

          Single oral doses of tiabendazole were slightly toxic
    (LD50 > 2000 mg/kg bw) in mice, rats, rabbits, sheep and goats.
    Where deaths occurred, they appeared to be due to respiratory
    failure.

          Following repeated oral administration of tiabendiazole to
    mice, rats, dogs, chickens, sheep, pigs, and cattle, the most common
    finding was a reduction in food consumption and in body-weight gain.
    The effects on weight gain appeared to be greater than could be
    accounted for by the depressed food intake. Anaemia was seen in rats
    and dogs, and to some extent may have been related to poor
    nutrition. However, the presence of increased haemosiderosis in
    lymphoid tissues and reticulocytosis in some studies was suggestive
    of red cell destruction. The haematological changes occurred at dose
    levels of 100 mg/kg bw/day and above for 3 months in rats and 150
    mg/kg bw/day and above for 3 months in dogs.

          The major target organs for toxicity were the hepatic system,
    thyroid gland, and lymphoid organs. Liver hypertrophy was seen in a
    3-month study in rats at doses of 37 mg/kg bw/day and above, and in
    a 2-year study in dogs minor hepatobiliary changes were observed at
    50 mg/kg bw/day and above. Thyroid follicular cell hyperplasia and
    colloid depletion were noted in a 3-month study in rats at 37 mg/kg
    bw/day and above and in a 16-week study in sheep at 800 mg/kg
    bw/day. The thymus, spleen, lymph nodes, and/or bone marrow
    exhibited lymphoid depletion or atrophy in a 28-day study in rats at
    100 mg/kg bw/day and above and in a 16-week study in sheep at 800
    mg/kg bw/day. Effects on blood cells, the liver, and lymphoid organs
    are commonly observed with benzimidazoles.

          Less common observations included both renal tubular
    degeneration and hyperplasia in one 7-day study in mice at 250 mg/kg
    bw/day and above and in one 3-month study in rats at 100 mg/kg
    bw/day and above. Gastric changes, including mucosal degeneration,
    cytoplasmic rarefaction, and/or necrosis, were produced in a 3-month
    study in rats at 100 mg/kg bw/day and above. Atrial thrombosis was
    present at high incidence in a two-year study in mice at doses of
    200 mg/kg bw/day and above that resulted in the death of the
    affected animals.

          Tumour incidences were not increased in a two-year
    carcinogenicity study in mice. The NOEL was 6 mg/kg bw/day, and
    there was increased mortality at the next highest level, 60 mg/kg
    bw/day.

          The incidence of preputial or clitoral gland adenomas was
    increased at doses above 200 mg/kg bw/day in one of two 2-year
    studies in rats. Statistical significance was achieved only in
    males; the animals also displayed poor development due to severe
    effects on weight gain which suggests that the maximum tolerated
    dose was exceeded. The relevance of these tumours to low-dose
    exposure of humans to tiabendiazole is questionable. The NOEL was 10
    mg/kg bw/day based on depressed weight gain at the next highest
    level, 40 mg/kg bw/day.

          Genotoxicity tests were generally negative. In one of three
     Salmonella typhimurium reverse-mutation assays, positive results
    were obtained in strain TA98 only. Further investigation showed that
    an impurity in some batches was responsible for the mutagenic
    activity. The manufacturer indicated that no positive results had
    been obtained in tests on several hundred further batches. In one
    laboratory, micronuclei were induced in mouse bone marrow and
    abnormal anaphase-telophase figures were increased in cultured
    Chinese hamster ovary cells. The effects were seen only at
    relatively high levels and may be indicative of the tubulin-binding
    activity characteristic of benzimidazoles (Annex 1, reference 97,
    section 3.2.4). A range of other assays for mutation, DNA damage,
    and cytogenetic activity were clearly negative.

          A multigeneration reproduction study in rats showed no adverse
    effects on reproduction parameters up to the highest dose tested, 80
    mg/kg bw/day. In mice, litter size and survival during the lactation
    period were reduced at 750 mg/kg bw/day, but reproduction was
    unaffected at lower doses in a five-generation study. The NOEL was
    30 mg/kg bw/day.

          Developmental toxicity was examined in mice, rats, rabbits, and
    sheep. In a series of studies in mice, embryotoxicity was observed
    at 1300 mg/kg bw/day and above, a dose that also resulted in the
    death of 5 of 39 females. Fetal malformations were produced at 240
    mg/kg bw/day

    and above, the main abnormalities being a reduction deformity of the
    limbs, cleft palate, and fusion of vertebral arches and vertebral
    bodies. Unchanged tiabendazole was implicated as the probable
    embryotoxic and teratogenic agent.

          The only finding in several rat developmental studies was a
    reduction in fetal weight at 40 mg/kg bw/day and above. The NOEL was
    10 mg/kg bw/day.

          In rabbits, abortions occurred at 600 mg/kg bw/day in one study
    on developmental toxicity, but not in the prior range-finding study
    at higher doses or in a repeat experiment in which similar treatment
    levels were used. Embryotoxicity and low incidences of domed head,
    hydrocephaly, and enlarged fontanelles were seen at 120 mg/kg bw/day
    and above in one study, but not in the repeat study at similar dose
    levels. All effects in rabbits were seen only at maternally toxic
    dose levels. The NOEL was 24 mg/kg bw/day.

          No adverse reproductive effects were observed in pregnant ewes
    given doses of 400 mg/kg bw/day.

          In a 24-week study in humans, male volunteers received 250 mg
    of tiabendazole/day; there were no treatment-related effects on a
    range of physical and biochemical parameters. The NOEL was 3-4 mg/kg
    bw/day. In another study, patients with trichinosis were given up to
    3 g of tiabendazole daily for 10 days. Side-effects occurred in 14
    of 23 patients, the most common being nausea, retching, and
    vomiting.

    4.  EVALUATION

          The Committee noted the availability of extensive data in
    support of the safety evaluation of tiabendazole and the
    manufacturer indicated that further studies had been completed or
    were under way. At the 1977 joint FAO/WHO meeting on pesticide
    residues, the study in human volunteers was used to establish an ADI
    of 0-0.3 mg/kg bw. The Committee considered that the investigations
    undertaken as part of this human study were limited in nature, and
    that in view of the availability of a number of recent well
    conducted animal studies, the NOEL should be derived from the animal
    data.

          The overall NOEL was 10 mg/kg bw/day based on reduced weight
    gain in a 2-year dietary study in rats and decreased fetal weight in
    a developmental study in rats. The Committee decided not to use the
    NOEL of 6 mg/kg bw/day from the 2-year study in mice as the next
    administered dose was considerably higher at 60 mg/kg bw/day.

          Using a safety factor of 100, the Committee established an ADI
    of 0-100 g/kg bw for tiabendazole. The Committee noted that the ADI
    provided a safety margin corresponding to a factor of over 1000 with
    respect to the dose required for fetal malformations in mice.

          The Committee asked to see the results from recently completed
    and ongoing toxicological studies in order to update the database on
    tiabendazole.

    5.  REFERENCES

    BAGDON, W.J., BOKELMAN, D.L. & ZWICKEY, R.E. (1980). Lifetime
    carcinogenic study in mice. Unpublished Report No. TT77-014-0 from
    Merck, Sharp & Dohme Research Laboratories. Submitted to WHO by MSD
    Research Laboratory, Lauterbach, Germany.

    BATHAM, P., REID, S. & OSBORNE, B.E. (1989). A 14-week oral toxicity
    study in the beagle dog. Unpublished Report No. 84021 (TT 89-9010)
    from Bio-Research Laboratories, Canada. Submitted to WHO by MSD
    Research Laboratory, Lauterbach, Germany.

    BLASZCAK, D.L. & AULETTA, C.S. (1987). Acute dermal toxicity study
    in rabbits. Unpublished Report No. 4004-86 from Bio/dynamics Inc.,
    USA. Submitted to WHO by MSD Research Laboratory, Lauterbach,
    Germany.

    BOKELMAN, D.L. & ZWICKEY, R.E. (1977). Tiabendazole, six-week pilot
    study in mice. Unpublished Report No. TT77-004-0 from Merck, Sharp &
    Dohme Research Laboratories, USA. Submitted to WHO by MSD Research
    Laboratory, Lauterbach, Germany.

    CAVAGNORO, J. & YAMAMOTO, K.S. (1989). 23 day dermal toxicity study
    in rabbits. Unpublished Report No. HLA 284-161 (TT89-9011) from
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    See Also:
       Toxicological Abbreviations