IPCS INCHEM Home

    TRICLABENDAZOLE

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

    1.  EXPLANATION

         Triclabendazole is a benzimidazole anthelminthic agent. It is
    used for the control of liver fluke infestation in sheep, goats and
    cattle. Triclabendazole had not been previously evaluated by the
    Joint FAO/WHO Expert Committee on Food Additives.

    2.  BIOLOGICAL DATA

    2.1  Biochemical Aspects

    2.1.1  Absorption, distribution, biotransformation and excretion

    2.1.1.1  Rats

         Following single oral doses of 0.5 or 25 mg/kg bw of
    14C-labelled triclabendazole to rats, excretion was rapid with
    approximately 93% of the dose eliminated in 48 h. At the end of 144
    h, total recovery amounted to 98% of which 88 to 95% was in faeces,
    4 to 10% in urine, less than 0.05% in expired air and up to 1% in
    tissues. There were no differences related to sex or dosage. In a
    bile cannulated rat given 5 mg/kg bw by gavage, biliary excretion in
    49 h was 34% of the administered dose (Muecke, 1981; Hambock, 1983).

         Degradation products were examined using chromatographic
    analysis of excreta from the previous rat study. Faecal metabolites
    were: unchanged drug (6-9% of dose), triclabendazole sulfoxide
    (20-27%), triclabendazole sulfone (3%), 2-benzimidazolone (8-10%),
    4-hydroxy triclabendazole plus minor unknowns (11-12%), unknown
    substances (9-13%) and non-extractable radio-label (16-32%). The
    metabolites in urine were generally more polar in nature;
    2-benzimidazolone was the only identified metabolite. It was
    reported that qualitatively similar metabolites were seen in sheep
    and goats (Hambock, 1983).

    2.1.1.2  Rabbits

         Female rabbits were given single oral doses of 3 or 26 mg/kg bw
    of 14C-labelled triclabendazole. Peak plasma radioactivity was
    reached in 8 h and levels declined rapidly thereafter. A comparison
    of the kinetics following oral and intravenous doses indicated
    extensive absorption from the gastrointestinal tract. Unchanged drug
    was not detected in plasma after the low dose and only small amounts
    were seen after the higher dose. Triclabendazole sulfoxide was the
    main plasma metabolite during the first 24 h, with the sulfone at
    similar or slightly higher levels thereafter. Other metabolites
    (which were not identified) began appearing between 24 and 48 h.

         Within 7 days, 80 to 90% of the radioactivity was eliminated of
    which 66 to 76% was in faeces and 7 to 22% in urine. The greater
    urinary excretion was noted at the higher dose. The sulfoxide and
    sulfone as well as other metabolites were detected in urine, but
    unchanged triclabendazole was not found (Wiegand  et al., 1991a,b).

    2.1.1.3  Dogs

         Dogs received single oral doses of 0.5, 5 or 40 mg/kg bw of
    14C-triclabendazole. Peak plasma radioactivity was achieved at 8 h
    with the lower doses and 24 h at the highest dose, which was
    maintained for 2 to 3 days. By comparison with the kinetics after an
    intravenous dose, approximately 40% of the oral dose was absorbed.
    Unchanged drug was essentially non-detectable in plasma. During the
    first 8 to 12 h, the sulfoxide was present at a greater
    concentration than the sulfone but at later times the sulfone was
    the major metabolite and significant levels were found even after 7
    days. Only 1% of the dose was excreted in the urine (Schutz  et al.,
    1991).

    2.1.1.4  Humans

         Three patients infected with  Fasciola hepatica were given
    single oral doses of 10 mg/kg bw triclabendazole in the form of
    Fasinex tablets. In fasted subjects, peak plasma levels occurred at
    2 h. HPLC analysis showed that parent drug was present at low levels
    with high levels of the sulfoxide metabolite and intermediate levels
    of the sulfone. Unchanged triclabendazole was not detected after 8
    h. Low levels of sulfoxide and sulfone were still present at 24 h,
    the final analysis point. In one patient, administration 1 h after a
    meal resulted in plasma levels approximately 3-fold higher than in
    fasted subjects, suggesting enhanced absorption under these
    conditions (Poltera  et al., 1989).

         Based on studies in experimental animals, the proposed pathway
    of metabolism of triclabendazole is outlined in Figure 1.

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

         The results of acute toxicity studies on triclabendazole are
    summarized in Table 1.

    FIGURE 1

        Table 1.  Acute toxicity
                                                                                  

    Species       Sex      Route              LD50        Reference
                                           (mg/kg bw)
                                                                                  

    Mouse         M+F      oral            >8000          Bathe & Sachsse (1979a)

    Rat           M+F      oral            >8000          Bathe & Sachsse (1979b)
                  M+F      dermal          >4000          Bathe & Sachsse (1979c)
                  M+F      inhalation      >500 mg/m3     Ullman & Sachsse (1979b)
                  M+F      ip              1666           Bathe & Sachsse (1979d)

    Rabbit        M+F      oral             206           Ullman & Sachsse (1979a)
                                                                                  
    
         The major toxic signs were sedation, dyspnea, exophthalmos,
    ruffled fur and curved body position after oral, dermal or
    inhalation exposure. Ataxia was also noted following intraperitoneal
    dosing.

         The oral LD50 in male and female rats of the sulfoxide and
    sulfone metabolites was greater than 5000 mg/kg bw. Toxic signs were
    similar to those induced by triclabendazole (Sarasin, 1982a,b).

    2.2.2  Short-term toxicity studies

    2.2.2.1  Rats

         Groups of 20 male and 20 female Charles River CD rats were fed
    diets containing 0, 10, 100 or 1000 ppm triclabendazole (purity 97%)
    for 13 weeks. The calculated intake of the test material was 0.7,
    6.6 and 68.5 mg/kg bw/day in males and 0.8, 7.9 and 87.3 mg/kg
    bw/day in females.

         There was no effect on survival and there were no overt
    clinical signs. Food and water intake were reduced in 1000 ppm males
    while body-weight gain was depressed in 100 ppm males and 1000 ppm
    males and females. Ophthalmological and hearing tests carried out
    before treatment and at weeks 6 and 13 revealed no treatment-related
    effects.

         Haematology, blood chemistry and urinalysis were performed
    before treatment and at weeks 5 and 12.  Numbers of erythrocytes,
    haemoglobin and haematocrit were reduced in 1000 ppm males and
    females; lymphocytes and therefore total white blood cells were

    reduced in 1000 ppm females. Serum alkaline phosphatase was
    increased in 1000 ppm groups. Cholesterol, albumin and total protein
    were increased at 1000 ppm, particularly in females. Urine volume
    was reduced in 1000 ppm males.

         All animals were autopsied. Organ weights were unaffected.
    Gross examination showed increases in pale kidneys and livers at 100
    and 1000 ppm and in congested lungs at 1000 ppm, but pathology was
    unremarkable. The NOEL was 10 ppm, equal to 0.7 mg/kg bw/day (Hunter
     et al., 1982).

    2.2.2.2  Dogs

         Groups of 6 male and 6 female beagle dogs were fed diets
    containing 0, 10, 100, or 1000 ppm triclabendazole (purity 97.6%)
    for 13 weeks. The calculated intake of the test material was 0.35,
    3.4 or 37 mg/kg bw/day in males and 0.35, 3.5 or 39 mg/kg bw/day in
    females.

         There were no overt clinical signs of toxicity. Food intake was
    unaffected but body-weight gain was markedly depressed in 1000 ppm
    dogs. Ophthalmology was tested before treatment and at weeks 6 and
    13 with no evidence of treatment-related effects. ECG's revealed
    prolongation of the QT interval and QTc value in 1000 ppm males and
    females at weeks 5 and 9 but not at week 13.

         Haematology and blood chemistry were examined before treatment
    and at weeks 5, 9 and 13. Erythrocytes, haemoglobin and haematocrit
    were markedly reduced at 1000 ppm throughout the study, with
    evidence of reticulocytosis at week 9 only. Alkaline phosphatase was
    increased in 100 and 1000 ppm groups; serum GPT and cholesterol were
    increased in 1000 ppm dogs. Urinalysis, performed before treatment
    and at weeks 6 and 13, was unaffected.

         A full necropsy was undertaken on all animals;
    treatment-related effects were seen at the 1000 ppm dose only. Liver
    weight was increased and showed centrilobular hepatocellular pigment
    granules accompanied by cytoplasmic basophilia, glycogen depletion
    and foci of pigmented macrophages. Ovaries and testes were immature
    with lower organ weights - females failing to reach oestrous and
    males showing incomplete spermatogenesis. The NOEL was 10 ppm, equal
    to 0.35 mg/kg bw/day (Taupin, 1981).

    2.2.3  Long-term/carcinogenicity studies.

    2.2.3.1  Mice

         Groups of 80 male and 80 female albino Tif:MAGf mice were fed
    diets containing 0, 3, 15, 60 or 300 ppm triclabendazole (purity
    99.5%) for 2 years. Within each group, animals were designated for

    interim sacrifice at 1 year (10 M and 10 F), for use in clinical
    laboratory measurements (10 M and 10 F) and a further 10 M and 10 F
    for examination of haematological parameters. The calculated intake
    of the test material was 0.29, 1.44, 5.7 or 29.6 mg/kg bw/day in
    males and 0.27, 1.39, 5.35 or 28.7 mg/kg bw/day in females.

         Treated mice showed no overt signs of toxicity and mortality
    was comparable to controls. There were no meaningful effects on food
    and water intake while body-weight gain was slightly elevated in all
    treated male groups, particularly during the first year. However,
    the effect was small (10% or less), not dose-related and was not
    observed in females.

         Ophthalmology, haematology, blood chemistry and urinalysis were
    performed at 6 month intervals. Serum levels of alkaline
    phosphatase, GPT and GOT were increased in the 300 ppm groups during
    the first year and in all treated groups in the second year. Effects
    in the second year were not dose-related and significance was
    achieved only occasionally.

         All animals were subjected to a full necropsy. There were no
    findings attributable to treatment at the interim sacrifice. At the
    end of the study, absolute and relative liver weights were increased
    at 15 ppm and above. Hepatomas were increased in all treated female
    groups, but significance was not reached at the 99% level. The
    incidence of carcinomas and time to appearance of tumours were
    unaffected (Table 2).

        Table 2.  Hepatic tumour incidence in female mice
                                                                                  

    Triclabendazole (ppm)          0         3        15        60        300
    Females in study              80        80        80        80         80
                                                                                  

    Benign hepatoma                7        16        15         9         20
    Hepatocelular carcinoma        1         2         2         2          3
    Hepatoblastoma                 0         0         0         1          0
                                                                                  

    Total hepatic tumours          8        18        17        12         23
                                                                                  
    
         The NOEL was 3 ppm, equal to 0.27 mg/kg bw/day (Basler
     et al., 1988a).

    2.2.3.2  Rats

         Groups of 60 male and 60 female Charles River CD rats were fed
    diets containing 0, 3, 15, 30 or 100 ppm triclabendazole (purity
    99.5%) for 2 years. Additional groups were designated for interim
    sacrifice at 1 year (10 M and 10 F) and for haematology,
    biochemistry and urinalysis investigations (20 M and 20 F). The
    calculated intake of the test material was 0.1, 0.6, 1.2 or 4.0
    mg/kg bw/day for males and 0.2, 0.7, 1.5 or 5.2 mg/kg bw/day for
    females.

         There was no effect on survival and there were no overt toxic
    signs. Food and water intake were unaffected but body-weight gain
    was depressed at 100 ppm, significant only in females. Ophthalmology
    and hearing tests, measured every six months, were also unaffected.

         Clinical laboratory parameters were examined pre-test and at
    weeks 13, 26, 51, 78 and 104. Lymphocyte counts were reduced at
    termination in 30 and 100 ppm groups but the values were reported to
    be within normal variation. Slight decreases in plasma chloride and
    BUN and increases in calcium and protein in 100 ppm males and slight
    increases in protein and decreases in BUN in all treated female
    groups were judged to be of no toxicological significance as the
    variations were small and not consistent throughout the study and
    were reported to be within normal variation. There were no
    alterations in urinalysis.

         A full necropsy was performed on all rats. Kidney weights were
    lower in 100 ppm males at the interim kill but not at the terminal
    sacrifice. At pathology, pancreatic islet cell adenomas were
    increased in 15 and 100 ppm males. The relationship to treatment was
    questionable as statistical significance was not achieved, there was
    no dose relationship and greater numbers of carcinomas were seen in
    control males (Table 3).

        Table 3.  Pancreatic islet cell tumours in male rats (70/group)
                                                                         

    Dose (ppm)         0         3        15        30         100
                                                                         

    Adenomas           3         4        12         4          11
    Carcinomas         6         4         4         2           4
                                                                         

    Total              9         8        16         6          15
                                                                         
    
         The NOEL was 30 ppm, equal to 1.2 mg/kg bw/day (Charnley
     et al., 1986).

    2.2.4  Reproduction studies

    2.2.4.1  Rats

         Groups of 20 male and 20 female Tif:RAIf rats were fed diets
    containing 0, 3, 15 or 75 ppm triclabendazole (purity 97.6%). Dosing
    of the initial generation (P) commenced 62 days prior to mating and
    was continued throughout the second generation (F1) until post
    partum day 35 of the third generation (F2) pups. The calculated
    average intake of test compound was 0.2, 1.1 or 5.5 mg/kg bw/day in
    males and 0.3, 1.4 or 7.4 mg/kg bw/day in females.

         Observations of P and F1 generation adults revealed no overt
    signs of toxicity, no effects on body-weight gain and no influence
    on reproductive parameters.

         Examination of pups, including a range of early developmental
    and behavioural tests, showed no meaningful changes in the F1
    offspring. In the F2 pups, mortality was increased in 15 and 75
    ppm groups during lactation. The increase was significant when
    compared to concurrent controls but not when compared to the F1
    groups. Body weights at weaning were lower at 15 and 75 ppm but
    significance was not achieved. The NOEL was 75 ppm, equal to 5.5
    mg/kg bw/day (Fritz  et al., 1984).

    2.2.5  Special studies on embryotoxicity and teratogenicity.

    2.2.5.1  Rats

         Groups of 25 pregnant Tif:RAIf rats were given gavage doses of
    0, 10, 30 or 100 mg/kg bw/day of triclabendazole (purity 97.6%) as a
    suspension in 0.5% (w/v) carboxymethyl cellulose. Treatment was on
    gestation days 6 to 15 and females were killed on gestation day 21.

         There was no mortality or clinical signs related to treatment.
    Body-weight gain and food consumption were markedly depressed at 100
    mg/kg bw/day with slight reduction in weight gain at 10 and 30 mg/kg
    bw/day. Gross pathology of dams was unremarkable.

         The implantation rate was similar in each group and treatment
    did not influence the number of resorptions or fetal deaths. Live
    fetus weight was reduced at 100 mg/kg bw/day but no external,
    visceral or skeletal malformations were induced. The NOEL was 30
    mg/kg bw/day (Giese  et al., 1981a; Giese, 1987).

         Groups of 20 pregnant Sprague-Dawley rats were given gavage
    doses of 0, 10, 25, 50, 100 or 200 mg/kg bw/kg of triclabendazole
    (purity 100%) as a suspension in water. Treatment was on gestation
    days 8 to 15 and dams were killed on gestation day 21.

         Maternal weight gain was depressed at 100 and 200 mg/kg bw/day
    with no signs of toxicity at lower levels. Uterine and fetal
    examinations revealed no effects on embryo or fetal survival or on
    fetal malformations. The only fetal effect was reduced body weight
    at 100 and 200 mg/kg bw/day. The NOEL was 50 mg/kg bw/day
    (Yoshimura, 1987).

    2.2.5.2  Rabbits

         Groups of 20 pregnant chinchilla rabbits were given gavage
    doses of 0, 3, 10 or 20 mg/kg bw/day of triclabendazole (purity
    unknown) as a suspension in 0.5% (w/v) carboxymethyl cellulose.
    Treatment was on gestation days 6 to 18 with does killed on
    gestation day 28.

         Three low-dose females died and diarrhoea was noted in a few
    animals from each treated group. Maternal body-weight gain during
    the study was similar in all groups but when "corrected" by
    subtracting the weight of uterus and contents, there was a slight
    non-dose related decrease in the treated groups.

         The numbers of implantations, resorptions and fetal deaths were
    similar in each group and fetal body weight was unaffected. Fetal
    examinations showed unossified phalanges of fore and hind limbs at
    10 and 20 mg/kg bw/day. One 20 mg/kg bw/day fetus exhibited
    omphalocele which is rare in this strain of rabbit. The NOEL was 3
    mg/kg bw/day (Giese  et al., 1981b)

    2.2.5.3  Sheep

         Merino ewes were drenched with a single dose of 0, 5 or 10
    mg/kg bw triclabendazole in the third trimester. There were no
    effects on lambing or on the morphology of offspring (Strong & Ryan,
    1981).

         In a series of experiments, merino ewes were drenched with
    doses of 0 or 30 mg/kg bw/day triclabendazole before conception and
    during the first trimester of pregnancy as follows:

         A.   3 treatments during the first 24 days of gestation.

         B.   4 treatments during the first 43 days of gestation.

         C.   2 treatments 2 to 3 weeks before conception plus
              2 treatments during the first 25 days of gestation.

         D.   3 treatments 2 to 4 weeks before conception plus
              1 treatment 7 to 9 days after conception.

         E.   3 treatments 2 to 4 weeks before conception.

         None of the treatment regimes caused clinical signs of toxicity
    in the ewes, nor were there effects on lambing or development of
    lambs (Strong, 1981).

         Groups of 27 to 28 pregnant Merino ewes were drenched with a
    single dose of 0 or 50 mg/kg bw of triclabendazole. Drug
    administration was on days 12, 17, 21, 24 or 28 days after mating.
    There were no effects on lambing performance or development of lambs
    (Strong & Steiger, 1983).

    2.2.5.4  Cattle

         Hereford cows were drenched with a single dose of 24 mg/kg bw
    triclabendazole during the first month of pregnancy. Calving and
    uterine development of offspring were unaffected (Bowen & Ryan,
    1985a).

         Hereford or black poll cows were drenched with a single dose of
    0 or 24 mg/kg bw/day triclabendazole during the second, third,
    fourth and sixth to seventh month of pregnancy. There were no
    difficulties at calving or abnormalities in the calves (Bowen &
    Ryan, 1985b).

    2.2.6  Special studies on genotoxicity

         The results of genotoxicity studies on triclabendazole are
    summarized in Table 4.

        Table 4.  Results of genotoxicity studies on triclabendazole1
                                                                                              

    Test system         Test object         Concentration          Results    Reference
                                                                                              

    Reverse mutation2   S. typhimurium      0.5-1250 g/plate      Negative   Ogorek & Arni,
                        TA98, TA100,                                          1987a
                        TA1535, TA1537,
                        TA1538

    Forward mutation2   Chinese hamster     0.025-0.5 g/ml (-S9)  Negative   Dollenmeier &
                        V79 cells           3.5-70 g/ml (+S9)                Puri, 1988

    Unscheduled         Primary rat         0.3-40 g/ml           Negative   Hertner & Puri,
    DNA-synthesis       hepatocytes                                           1988

    Unscheduled         Human fibroblasts   0.4-60 g/ml           Negative   Meyer & Puri,
    DNA-synthesis                                                             1988

    Nucleus anomaly     Chinese hamster     172-688 mg/kg bw       Negative   Hool et al.,
                        bone marrow         by gavage                         1982

    Sister chromatid    Chinese hamster     173-692 mg/kg bw by    Negative   Hool & Muller,
    exchange            bone marrow         gavage                            1982
                                                                                              

    1    Appropriate positive controls were used.
    2    Both with and without rat liver S9 fraction.
    

    2.2.7  Special studies on irritation and sensitization

    2.2.7.1  Guinea-pigs

         Groups of 10 male and 10 female pirbright guinea-pigs were used
    in an optimization test. The induction phase was carried out by
    administering 10 intracutaneous injections of a 0.1% (w/v)
    suspension in propylene glycol/saline. Epidermal challenge produced
    no reaction but an intradermal challenge resulted in a positive
    sensitization reaction (Ullmann & Sachsse, 1979e)

    2.2.7.2  Rabbits

         Groups of 3 male and 3 female New Zeeland white rabbits were
    used in a patch test. Triclabendazole was suspended in propylene
    glycol/saline and applied for 24 h. The test material was judged to
    be a slight skin irritant (Ullmann & Sachsse, 1979c)

         Groups of 3 male and 6 female New Zeeland white rabbits
    received   0.1 g of triclabendazole instilled into the conjunctival
    sac of the eye. Subsequent examination failed to reveal any eye
    irritation (Ullmann & Sachsse, 1979d).

    2.2.8  Special studies on triclabendazole and fenbendazole in
           combination

         A series of studies was conducted using test material
    containing 50% triclabendazole and 50% fenbendazole that are briefly
    reviewed below.

         Pregnant rats were treated with gavage doses of 0, 10, 40 or
    120 mg/kg bw/day test material during gestation days 6 to 15. At 120
    mg/kg bw/day, dams had a reduced food consumption and there were
    increases in partial abortion of conceptuses and in resorptions.
    Fetotoxicity at the same level included decreased fetal weight,
    reduced ossification, kinked tail, meningo-encephalocele and
    hydrocephaly. Delayed ossification was present in the 40 mg/kg
    bw/day fetuses while there were no adverse findings in the 10 mg/kg
    bw/day group (Giese  et al., 1985).

         In two developmental studies in sheep, pregnant ewes received
    either two doses of 0 or 50 mg/kg bw or a single dose of 0 or 150
    mg/kg bw, during the first month of pregnancy. There were no effects
    on lambing performance and the only adverse effect on offspring was
    grossly misshapen kidneys, with disorganized internal structure, in
    3 of 25 lambs at the higher-dose level (Bowen & Heckenberg, 1985;
    Richards  et al., 1985).

         Mutation assays in  Salmonella typhimurium strains TA98,
    TA100, TA1535 and TA1537 and  Saccharomyces cerevisiae D7 were
    negative, both in the presence and absence of rat liver microsomes
    (Deparade & Arni, 1983; Hool & Arni, 1985). Chromosome aberrations
    in cultured human lymphocytes were increased at 22 and 44 g/ml
    (dose-related), but not at 11 g/ml, only in the presence of a rat
    liver S9 fraction (Strasser & Arni, 1985a). The bone marrow of
    Chinese hamsters revealed an increase in nucleus anomalies (single
    Jolly bodies only) following oral doses of 1000, 2000 or 4000 mg/kg
    bw. While the increases were statistically significant they were
    only slight and non dose-related (Strasser & Muller, 1984).
    Chromosome aberrations were not induced in mouse primary and
    secondary spermatocytes or spermatogonia after oral doses of up to
    2500 mg/kg bw (Strasser & Arni, 1985b; Strasser  et al., 1985).

    2.2.9  Special studies on triclabendazole and levamisole in
           combination

         A series of studies was conducted using test material
    containing 61.5% triclabendazole and 38.5% levamisole that are
    briefly reviewed below.

         Acute studies in male and female rats revealed LD50 values of
    1996 mg/kg bw by the oral route and >2000 mg/kg bw by the dermal
    route (Hartmann & Schoch, 1987a,b). In rabbits, slight and
    reversible eye irritation was observed while the test material was
    judged to be non-irritant to skin (Schoch, 1987a,b).

         Rats were administered 0, 20, 200 or 2000 ppm of the test
    material in the feed for 3 months. Body-weight gain was depressed at
    200 ppm and above and anaemia was apparent at 2000 ppm. Increased
    serum levels of liver enzymes and cholesterol and decreased levels
    of triglycerides were suggestive of hepatocellular damage at 2000
    ppm and, to a lesser extent, at 200 ppm. Necropsy revealed the
    following slight changes at 2000 ppm: chronic lesion of renal
    tubules, spermatic granulomas in the epididymis, fatty change in the
    adrenal cortex, thymic atrophy and skeletal muscle atrophy. There
    were no effects at 20 ppm, equal to 1.4 mg/kg bw/day (Basler
     et al., 1988b).

         Dogs were fed diets containing 0, 20, 60, 240 or 1000 ppm for 3
    months. At 1000 ppm, body weight gain and food intake were reduced
    and half the animals died. The administration of this dose was
    discontinued after 45 days. Anaemia, increased alkaline phosphatase
    and cholesterol were evident at 240 ppm and above. Increases were
    observed in liver weight at 240 ppm and spleen weight at 60 and 240
    ppm. There was increased haematopoiesis of the sternum at 60 ppm and
    above. Survivors in the 1000 ppm group, which were not dosed for the
    previous 45 days, showed at least partial recovery of toxic effects.
    There were no effects at 20 ppm, equal to 0.75 mg/kg bw/day (Monnot,
    1988).

         Pregnant rats were treated with gavage doses of 0, 10, 80 or
    160 mg/kg bw/day during gestation days 6 to 15. Ruffled fur was seen
    at 160 mg/kg bw/day and increased wet bedding was noted at 80 mg/kg
    bw/day and above, suggesting polyuria. Maternal body-weight gain and
    food intake were depressed at 80 and 160 mg/kg bw/day. The only
    fetal effects, seen at 80 and 160 mg/kg bw/day, were decreased fetal
    body weight, increased bipartite sternebrae and reduced
    ossification. There were no adverse effects at 10 mg/kg bw/day
    (Thouin  et al., 1988).

         Pregnant rabbits received gavage doses of 0, 1.5, 30 or 50
    mg/kg bw/day on gestation days 7 to 19. In the 50 mg/kg bw/day
    group, there was reduced body weight gain, one abortion and total
    resorption of conceptuses in one rabbit. The resorption rate was
    slightly increased at 50 mg/kg bw/day but significance was not
    achieved. There were no increased developmental effects in any
    group. No adverse effect was noted up to 30 mg/kg bw/day (Khalil
     et al., 1989).

         Mutation assays in  Salmonella typhimurium strains TA98,
    TA100, TA1535 and TA1537 and Chinese hamster V79 cells gave negative
    results both in the presence and absence of rat liver microsomes
    (Ogorek & Arni, 1987b; Dollenmeier & Puri, 1987). Using isolated rat
    hepatocytes and human fibroblasts there was no evidence of
    unscheduled DNA synthesis in exposed cells (Hertner & Puri, 1987;
    Meyer & Puri, 1987). Micronuclei were not induced in bone marrow of
    mice dosed orally with the test substance (Strasser  et al., 1988).

    3.  COMMENTS

         A range of studies on triclabendazole was submitted for
    assessment, including data on kinetics and metabolism, acute
    toxicity, short-term and long-term toxicity, reproductive and
    developmental toxicity, and genotoxicity.

         Approximately 40-50% was absorbed following the administration
    of single oral doses of radiolabelled triclabendazole to rats and
    dogs. Oral absorption was considerably higher in rabbits but could
    not be quantified in a human study. Peak plasma levels of
    radioactivity were generally achieved within 8 h; elimination
    (primarily in the faeces) was rapid in rats, rabbits, and humans. In
    dogs, peak plasma levels of radioactivity were maintained for 2-3
    days and significant levels persisted for more than 7 days.
    Triclabendazole was rapidly and extensively degraded in rabbits,
    dogs, and humans, the sulfoxide and sulfone being the main
    metabolites found in plasma. In addition to these oxidation
    products, rat excreta contained 4-hydroxytriclabendazole and
    2-benzimidazolone.

         Single oral doses of triclabendazole were slightly toxic (LD50
    > 8000 mg/kg bw) in mice and rats and moderately toxic (LD50 =
    206 mg/kg bw) in rabbits, whose greater sensitivity was probably due
    to a greater bioavailability of oral doses.

         Findings after short-term oral dosing in rats and dogs were
    primarily non-specific. In 3-month studies, decreased weight gain
    was observed at 7 mg/kg bw/day and above in rats and at 37 mg/kg
    bw/day in dogs; anaemia was seen at 68 mg/kg bw/day and 37 mg/kg
    bw/day, respectively. Evidence of hepatotoxicity, for example
    increases in plasma levels of liver enzymes and cholesterol and in
    liver weight, was seen at approximately 70 mg/kg bw/day in rats and
    37 mg/kg bw/day in dogs. Minor non-neoplastic liver lesions were
    observed in a 3-month study in dogs at 37 mg/kg bw/day. The NOELs
    were 0.7 mg/kg bw/day in rats and 0.35 mg/kg bw/day in dogs.

         Hepatomas were seen in female mice given up to 29 mg/kg bw/day
    for 2 years. The incidences of adenomas were higher than in controls
    at all dose levels, but a dose-response relationship was not found.
    Significance at the 99% level, which is widely used to assess the
    significance of tumours that occur at a high background rate, was
    not reached for this common benign mouse tumour. In addition, there
    was no significant increase in the incidence of hepatocellular
    carcinomas at any dose level. The NOEL was 0.27 mg/kg bw/day based
    on increased liver weight at the next highest dose, 1.4 mg/kg
    bw/day. Tumours were not induced in a 2-year dietary study in rats,
    the NOEL being 1.2 mg/kg bw/day based on reduced weight gain at 4
    mg/kg bw/day. Several different  in vitro and  in vivo
    genotoxicity studies were clearly negative. These results suggest
    that triclabendazole has no carcinogenic potential.

         In a two-generation reproduction study in rats, postnatal
    survival and growth were reduced during the lactation period of the
    second generation at 1 mg/kg bw/day and above. However, the
    incidence of these effects was not dose-related and was similar to
    that in the first-generation offspring. In addition, statistical
    significance was not achieved, and it was concluded that the
    findings were not related to treatment. The NOEL was 5.5 mg/kg
    bw/day.

         Developmental studies in rats and rabbits provided no evidence
    of embryotoxicity. Fetotoxicity, in the form of reduced fetal weight
    in rats and decreased ossification in rabbits, was observed at 100
    and 10 mg/kg bw/day, respectively. One rabbit fetus at 20 mg/kg
    bw/day exhibited omphalocele, a rare abnormality in the strain used.
    All the above effects were present only at maternally toxic dose
    levels. Drug treatment during pregnancy in sheep and cattle did not
    affect growth and development of the conceptus. The NOELs were 50
    mg/kg bw/day in rats and 3 mg/kg bw/day in rabbits.

         Special studies with triclabendazole in combination with either
    fenbendazole (developmental and genotoxicity studies) or levamisole
    (acute, subchronic, developmental, and genotoxicity studies) did not
    reveal any synergism between the drugs.

    4.  EVALUATION

         The database in support of the safety evaluation of
    triclabendazole is substantial. The lowest NOEL was 0.27mg/kg
    bw/day, based on increased liver weight in the long-term study in
    mice. Using a safety factor of 100, the Committee established an ADI
    for triclabendazole of 0-3 g/kg bw.

    5.  REFERENCES

    BASLER, W., GRETENER, P., FROEHLICH, E., KRINKE, G., MALINOWSKI, W.,
    CHRISTEN, P., FORMICA, G. & GFELLER, W. (1988a). Lifetime
    carcinogenicity and chronic toxicity study in mice. Unpublished
    Report No. 811708 from CIBA-GEIGY, Switzerland. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    BASLER, W., GRETENER, P., FROEHLICH, E., KRINKE, A.L., MALINOWSKI,
    W. & GFELLER, W. (1988b), 3-month oral toxicity study in rats
    (administration in feed). Unpublished Report No. 861575 from
    CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel,
    Switzerland.

    BATHE, R. & SACHSSE, K. (1979a). Report on acute oral LD50 in the
    mouse of technical CGA 89'317. Unpublished Report No. 791073 from
    CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel,
    Switzerland.

    BATHE, R. & SACHSSE, K. (1979b). Report on acute oral LD50 in the
    rat of CGA 89'317. Unpublished Report No. 790038 from CIBA-GEIGY,
    Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    BATHE, R. & SACHSSE, K. (1979c). Report on acute dermal LD5O in
    the rat of technical CGA 89'317. Unpublished Report No. 791076 from
    CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel,
    Switzerland.

    BATHE, R. & SACHSSE, K. (1979d). Report on acute intraperitoneal
    LD50 in the rat of CGA 89'317. Unpublished Report No. 790039 from
    CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel,
    Switzerland.

    BOWEN, F.L. & HECKENBERG, K. (1985). Reproduction study in sheep:
    triclabendazole plus fenbendazole. Unpublished Report No. 85/12/1060
    from CIBA-GEIGY, Australia. Submitted to WHO by CIBA-GEIGY, AG,
    Basel, Switzerland.

    BOWEN, F.L. & RYAN, K.J. (1985a). A field trial to assess the safety
    of triclabendazole for cows during their first month of pregnancy.
    Unpublished Report No. 85/11/1054 from CIBA-GEIGY, Australia.
    Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    BOWEN, F.L. & RYAN, K.J. (1985b). Field trials to assess the safety
    of triclabendazole for cows during the second to sixth month of
    pregnancy. Unpublished Report No. 85/11/1055 from CIBA-GEIGY,
    Australia. Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    CHARNLEY, B.N., HEYWOOD, R., STREET, A.E., IMM, S.A.,
    GIBSON, W.A., GOPINATH, C., ALMOND, R.H. & DAWE, I.S. (1986).
    Potential tumorigenic and toxic effects in prolonged dietary
    administration to rats. Unpublished Report No. CBG 318/85595
    (811709) from Huntingdon Research Centre, UK. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    DEPARADE, E. & ARNI, P. (1983).  Salmonella/mammalian-microsome
    mutagenicity test. Unpublished Report No. 831517 from CIBA-GEIGY,
    Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    DOLLENMEIER, P. & PURI, E. (1987). Point mutation test with Chinese
    hamster cells V79. Unpublished Report No. 871011 from CIBA-GEIGY,
    Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    DOLLENMEIER, P. & PURI, E. (1988). Point mutation test with Chinese
    hamster cells V79 with CGA 89'317 tech. Unpublished Report No.
    871170 from CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY,
    AG, Basel, Switzerland.

    FRITZ, H., SUTER, H.P., ZAK, F., NAYLOR, D.C. & HESS, R. (1984).
    Report on CGA 89'317: 2-Generation toxicity study in rats.
    Unpublished Report No. 811540 from CIBA-GEIGY, Switzerland.
    Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    GIESE, K. (1987). Amendment No. 1 to Final Report on CGA 89'317
    tech., Teratology study (Seg. II) in rats. Unpublished Report
    amendment No. 802099-1 from CIBA-GEIGY, Switzerland. Submitted to
    WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    GIESE, K., SUTER, H.P. & GFELLER, W. (1985). Report on CGA 89317
    Tech and CGA 50560 Tech (1:1). Teratology study in rats. Unpublished
    Report No. 831213 from CIBA-GEIGY, Switzerland. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    GIESE, K., SUTER, H.P. & HESS, R. (1981a). Report on CGA 89'317
    tech. Teratology study (Seg. II) in rats. Unpublished Report No.
    802099 from CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY,
    AG, Basel, Switzerland.

    GIESE, K., SUTER, H.P. & HESS, R. (1981b). Report on CGA 89'317
    tech. Teratology study in rabbits. Unpublished Report No. 802090
    from CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY, AG,
    Basel, Switzerland.

    HAMBOCK, H. (1983). The metabolic fate of CGA 89317 in sheep, rat
    and the lactating goat. Unpublished Report No. 41/83 from
    CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel,
    Switzerland.

    HARTMANN, H.R. & SCHOCH, M. (1987a). Acute oral toxicity in the rat.
    Unpublished Report No. 861571 from CIBA-GEIGY, Switzerland.
    Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    HARTMANN, H.R. & SCHOCH, M. (1987b). Acute dermal toxicity in the
    rat. Unpublished Report No. 861574 from CIBA-GEIGY, Switzerland.
    Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    HERTNER, TH. & PURI, E. (1987). Autoradiographic DNA-repair test on
    rat hepatocytes. Unpublished Report No. 861580 from CIBA-GEIGY,
    Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    HERTNER, TH. & PURI, E. (1988). Autoradiographic DNA repair test on
    rat hepatocytes (OECD conform) with CGA 89'317 tech. Unpublished
    Report No. 871173 from CIBA-GEIGY, Switzerland. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    HOOL, G. & ARNI, P. (1985).  Saccharomyces cerevisiae D7/mammalian
    microsome mutagenicity test  in vitro. Unpublished Report No.
    840945 from CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY,
    AG, Basel, Switzerland.

    HOOL, G., LANGAUER, M. & MULLER, D. (1982). Nucleus anomaly test in
    somatic interphase nuclei, CGA 89'317, Chinese hamster (test for
    mutagenic effects on bone marrow cells). Unpublished Report No.
    801392 from CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY,
    AG, Basel, Switzerland.

    HOOL, G. & MULLER, D. (1982). Sister chromatid exchange study, CGA
    89'317, Chinese hamster (Test for mutagenic effect on bone marrow
    cells). Unpublished Report No. 820209 from CIBA-GEIGY, Switzerland.
    Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    HUNTER, B., BERRYMAN, E.L., HEYWOOD, R., PRENTICE, D.E., STREET,
    A.E., GIBSON, W.A., SINGH, H. & OFFER, J.M. (1982). CGA 89,317, a
    13-week toxicity study in rats by incorporation in the diet.
    Unpublished Report No. CBG/252/81151 (791817) from Huntingdon
    Research Centre, UK. Submitted to WHO by CIBA-GEIGY, AG, Basel,
    Switzerland.

    KHALIL, S., THONIN, M.H., WEBER H., GRUENDER, G. & BASLER, W.
    (1989). Developmental toxicity (teratogenicity study). Unpublished
    Report No. 881433 from CIBA-GEIGY, Switzerland. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    MEYER, A. & PURI, E. (1987). Autoradiographic DNA-repair test on
    human fibroblasts. Unpublished Report No. 861581 from CIBA-GEIGY,
    Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    MEYER, A. & PURI, E. (1988). Autoradiographic DNA repair test on
    human fibroblasts (OECD conform) with CGA 89'317 tech. Unpublished
    Report No. 871172 from CIBA-GEIGY, Switzerland. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    MONNOT, G. (1988). 13-week dietary administration toxicity study in
    the beagle dog. Unpublished Report No. 380/520 (861576) from
    Hazleton, France. Submitted to WHO by CIBA-GEIGY, AG, Basel,
    Switzerland.

    MUECKE, W. (1981). Distribution, degradation and excretion of CGA
    89317 in the rat. Unpublished Report No. 27/81 from CIBA-GEIGY,
    Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    OGOREK, B. & ARNI, P. (1987a).  Salmonella/mammalian microsome
    mutagenicity test (OECD conform) with CGA 89'317 tech. Unpublished
    Report No. 871171 from CIBA-GEIGY, Switzerland. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    OGOREK, B. & ARNI, P. (1987b).  Salmonella/mammalian microsome
    mutagenicity test. Unpublished Report No. 861582 from CIBA-GEIGY,
    Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    POLTERA, A.A., ROUAN, M.C., LECAILLON, J.B. & DUBOIS, J.P. (1989).
    Kinetics in humans. Unpublished Report No. CRB R37/1989 from
    CIBA-GEIGY, France and Switzerland. Submitted to WHO by CIBA-GEIGY,
    AG, Basel, Switzerland.

    RICHARDS, R.J., BOUVARD, H.R. & STRITTMATTER, J. (1985). Effect on
    reproduction in sheep of triclabendazole/fenbendazole treatments
    given during the first month of pregnancy. Unpublished Report No.
    CRA 154/85T from CIBA-GEIGY, Switzerland. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    SARASIN, G. (1982a). Report on acute oral LD50 in the rat of CGA
    110'752. Unpublished Report No. 811294 from CIBA-GEIGY, Switzerland.
    Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    SARASIN, G. (1982b). Report on acute oral LD50 in the rat of CGA
    110'753. Unpublished Report No. 811295 from CIBA-GEIGY, Switzerland.
    Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    SCHOCH, M. (1987a). Acute dermal irritation/corrosion study in the
    rabbit. Unpublished Report No. 861573 from CIBA-GEIGY, Switzerland.
    Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    SCHOCH, M. (1987b). Acute eye irritation/corrosion study in the
    rabbit. Unpublished Report No. 861572 from CIBA-GEIGY, Switzerland.
    Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    SCHUTZ, H., LECAILLON, J.B. & GODBILLON, J. (1991). Kinetics in dogs
    and rats. Unpublished Report No. CRB R25/1991 from CIBA-GEIGY,
    France and Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel,
    Switzerland.

    STRASSER, F. & ARNI, P. (1985a). Chromosome studies on human
    lymphocytes  in vitro. Unpublished Report No. 840944 from
    CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY, AG, Basel,
    Switzerland.

    STRASSER, F. & ARNI, P. (1985b). Chromosome studies on male germinal
    epithelium of mouse spermatogonia. Unpublished Report No. 840943
    from CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY, AG,
    Basel, Switzerland.

    STRASSER, F., LANGAUER, M. & ARNI, P. (1988). Micronucleus test
    (mouse). Unpublished Report No. 861579 from CIBA-GEIGY, Switzerland.
    Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    STRASSER, F. & MULLER, D. (1984). Nucleus anomaly test in somatic
    interphase nuclei of Chinese hamster. Unpublished Report No. 831518
    from CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY, AG,
    Basel, Switzerland.

    STRASSER, F., PURI, E. & ARNI, P. (1985). Chromosome studies on the
    germinal epithelium of mouse spermatocytes. Unpublished Report No.
    840946 from CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY,
    AG, Basel, Switzerland.

    STRONG, M.B. (1981). Studies on the lambing performance of ewes
    following multiple dosing with CGA-89317 during the first trimester
    of pregnancy. Unpublished Report No. 81/10/881 from CIBA-GEIGY,
    Australia. Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    STRONG, M.B. & RYAN, K.J. (1981) Preliminary field studies with
    CGA-89317 in pregnant ewes. Unpublished Report No. 81/1/845 from
    CIBA-GEIGY, Australia. Submitted to WHO by CIBA-GEIGY, AG, Basel,
    Switzerland.

    STRONG, M.B. & STEIGER, R.F. (1983). Studies on the lambing
    performance of ewes given a single elevated dose of CGA-89317
    (triclabendazole) during the first trimester of pregnancy.
    Unpublished Report No. 83/10/967A from CIBA-GEIGY, Australia.
    Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    TAUPIN, P.J.Y. (1981). CGA 89'317, 13 week dietary toxicity study in
    the dog. Unpublished Report No. 2588--380/6 from Hazleton
    Laboratories Europe, UK. Submitted to WHO by CIBA-GEIGY, AG, Basel,
    Switzerland.

    THOUIN, M.H., SCHOCH, M., SCHMIDT, B & GFELLER, W. (1988).
    Developmental toxicity (teratogenicity) study. Unpublished Report
    No. 861577 from CIBA-GEIGY, Switzerland. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    ULLMANN, L. & SACHSSE, K. (1979a). Report on acute oral LD50 in
    the rabbit of technical CGA 89'317. Unpublished Report No. 791074
    from CIBA-GEIGY, Switzerland. Submitted to WHO by CIBA-GEIGY, AG,
    Basel, Switzerland.

    ULLMANN, L. & SACHSSE, K. (1979b). Report on acute aerosol
    inhalation toxicity in the rat of technical CGA 89'317. Unpublished
    Report No. 791078 from CIBA-GEIGY, Switzerland. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    ULLMANN, L. & SACHSSE, L. (1979c). Report on skin irritation in the
    rabbit after single application of CGA 89'317. Unpublished Report
    No. 790040 from CIBA-GEIGY, Switzerland. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    ULLMANN, L. & SACHSSE, K. (1979d). Report on eye irritation in the
    rabbit after single application of CGA 89'317. Unpublished Report
    No. 790041 from CIBA-GEIGY, Switzerland. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    ULLMANN, L. & SACHSSE, K. (1979e). Report on skin sensitizing
    (contact allergenic) effect in guinea pigs of technical CGA 89'317.
    Unpublished Report No. 791077 from CIBA-GEIGY, Switzerland.
    Submitted to WHO by CIBA-GEIGY, AG, Basel, Switzerland.

    WIEGAND, H., SCHUTZ, H., LECAILLON, J.B. & GODBILLON, J. (1991a).
    Kinetics in female rabbits. Unpublished Report No. CRB R22/1991 from
    CIBA-GEIGY, France and Switzerland. Submitted to WHO by CIBA-GEIGY,
    AG, Basel, Switzerland.

    WIEGAND, H., SCHUTZ, H. & PROBST, A. (1991b). Absorption and
    disposition studies in female rabbits. Unpublished Report No. DM
    12/1991 from CIBA-GEIGY, Switzerland. Submitted to WHO by
    CIBA-GEIGY, AG, Basel, Switzerland.

    YOSHIMURA, H. (1987). Teratogenic evaluation of triclabendazole in
    rats.  Toxicology, 43: 283-287.


    See Also:
       Toxicological Abbreviations
       TRICLABENDAZOLE (JECFA Evaluation)