IPCS INCHEM Home

    ALBENDAZOLE

    1.  EXPLANATION

         Albendazole belongs to the benzimidazole class of anthelmintic.
    Other members of this group most closely related to albendazole are
    fenbendazole and oxfendazole. Albendazole is currently used in a
    number of countries as a human and veterinary anthelmintic. This is
    the first occasion on which albendazole has been evaluated by the
    Joint FAO/WHO Expert Committee on Food Additives.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

         The degradation of albendazole was shown to follow similar
    pathways in rats, mice, humans, cattle and sheep. See Fig. 1 for the
    proposed metabolic pathways.

         Male Charles River CD mice were given a single gavage dose of
    14C-ring labelled albendazole. The dose of 13.2 mg/kg bw was
    suspended in 1% carboxymethylcellulose. Over a 72 h period, 20.5% of
    the administered radioactivity was recovered in the urine. Using TLC
    and autoradiography it was revealed that the sulfoxide (C) and
    metabolites G and E accounted for 81% of the label. Low levels of
    parent drug (ABZ), the sulfone (A), and metabolites F, I and J were
    also detected (see Figure 1) (Parish  et al., 1979a).

         The parent compound was virtually undetectable in the plasma of
    Sprague Dawley males and females given a single gavage dose of 10.6
    mg/kg bw albendazole in an aqueous suspension. Rapid metabolism let to
    the appearance of the sulfoxide and subsequently the sulfone
    derivatives in plasma. Both metabolites decreased to very low levels
    at 18 h (Delatour  et al., 1984; Souhaili-el Amri  et al., 1988).
    Daily dosing at 10.6 mg/kg bw in males for a period of 10 days
    resulted in lower plasma levels of sulfoxide and higher levels of the
    sulfone. Albendazole induces certain hepatic drug-metabolising
    enzymes, which may be responsible for enhancing the degradation of
    sulfoxide to sulfone following repeated administration (Souhaili-el
    Amri  et al., 1988).

         Female Sprague Dawley rats were given a single gavage dose of
    14C-ring labelled albendazole. The dose was 13.25 mg/kg bw suspended
    in 1% carboxymethylcellulose. Over a 72 h period, 31% of the
    administered radioactivity was recovered in the urine. Using TLC and
    autoradiography it was shown that the sulfoxide, metabolite G, the
    2-amino sulfone and metabolite E accounted for 89% of the radiolabel.
    Low levels of the parent drug, the sulfone, and metabolites D, F, H
    and J were also found. Similar doses of the sulfoxide and sulfone
    derivatives resulted in the urinary excretion of 73.0 and 42.7% of the
    dose, respectively. The urinary metabolites were qualitatively similar
    to those observed after albendazole administration (Parish & Gyurik,
    1979).

    FIGURE 1

         Sheep bearing permanent ruminal and abomasal cannulae were given
    a single oral dose of 10 mg/kg bw albendazole as a 2.5% formulation.
    Albendazole was absorbed unchanged from the rumen. Once in the body it
    was rapidly degraded, and sulfone metabolites were detected in plasma,
    the former achieving the greater level. All 3 compounds were present
    in the abomasum. Presumably albendazole was passed through the
    stomachs while the metabolites were secreted or diffused into this
    organ. Non-detectable levels of all 3 compounds were reached in plasma
    and rumen at 96 h and in abomasum at 120 h (Marriner & Bogan, 1980).

         Sheep were given a single oral dose of 10 mg/kg bw 14C-ring
    labelled albendazole. Animals were killed 1, 2, 4, 6 or 8 days after
    treatment. On day 1, the label in liver was mainly in the form of the
    sulfoxide and sulfone metabolites. These compounds were progressively
    converted to the 2-amino sulfone which was the primary residue on day
    8. Low levels of albendazole were detected up to day 2; other
    degradation products were metabolites E, G and J. Over 72 h, pooled
    urine samples, the sulfoxide and 2-amino sulfone accounted for 60-70%
    of the urinary radioactivity. Low levels of albendazole, the sulfone
    and 6 other metabolites were also found (Parish  et al., 1977a;
    Colman  et al., 1977).

         Steers were given a single oral dose of 7.5 mg/kg bw of an
    albendazole formulation. Albendazole could not be detected in plasma.
    Metabolism to the sulfoxide and sulfone was rapid; these compounds
    were present in plasma for up to 40 h (Prichard  et al., 1985).

         Calves were given a single oral dose of 20 mg/kg bw 14C-ring
    labelled albendazole. Animals were killed 1 to 12 days after
    treatment. In liver obtained on day l, the radioactivity was mainly as
    albendazole, the sulfoxide and sulfone. Albendazole disappeared by day
    6 while the sulfoxide and sulfone were progressively converted to
    2-amino sulfone through day 12. Low levels of metabolites G and J were
    also found. A limited examination of kidney tissue revealed a similar
    metabolic profile (Kraeer  et al., 1977).

         Calves were given a single oral dose of 20 mg/kg bw 14C-ring
    labelled albendazole. Over a 7 day period, 47% of the administered
    radioactivity was recovered in the urine. The sulfoxide, sulfone and
    2-amino sulfone accounted for 70% of this radiolabel. Low levels of
    albendazole, metabolites B, D, E, G, H and J were also found (Parish
     et al., 1977b; 1979b).

         Human volunteers were given a single oral 400 mg dose of
    albendazole. The parent sulfide was not detected in blood by HPLC.
    Peak sulfoxide concentrations were achieved after 2.4 h and decayed
    biphasically with a long terminal half-life. Analysis of 24 h urine by
    TLC revealed the presence of the sulfoxide, the sulfone and their
    amino derivatives and metabolites B, E and G (Rossingnol &
    Maisonneuve, 1984).

         The above findings were confirmed in other similar studies.
    Additionally, it was demonstrated that urinary recovery over a 24 hour
    period accounted for up to 0.88% of the dose. Limited information
    suggested biliary excretion was very low. Thus it appears that the
    oral absorption of the albendazole is somewhere around 1%. When
    ingested with a high fat content meal the absorption of albendazole
    was shown to be 4.6 times higher, on average, in 6 volunteers
    (Marriner  et al., 1986; Lange  et al., 1988).

    2.2  Toxicological studies

    2.2.1  Acute studies

    Findings in dead rats included urinary staining of abdomen, bloody
    discharge around nose, chromodacryorrhea and intestinal hemorrhage. 
    Necropsy of dead rabbits showed intestines containing fluid and
    dilated with gas. Toxic signs in other species were not reported.

    2.2.2  Short-term studies

    2.2.2.1  Mice

         In 2 separate experiments, groups of 10 male and 10 female
    Charles River CD1 mice were fed diets containing albendazole for 90
    days.  Drug levels in food were adjusted so that animals received
    doses of 0, 5, 10, 20, 40 or 80 mg/kg bw/d in study 1 and 0, 200, 400,
    800 or 1600 mg/kg bw/d in study 2.

         All females and 5/10 males of the 1600 mg/kg group died
    spontaneously or were killed in a moribund condition. From week 9, ear
    lesions involving thickening and/or encrustation of the tips were
    observed in 2/10 males and 2/9 females at 800 mg/kg and 5/5 males in
    the 1600 mg/kg group. Food consumption was generally decreased in
    males given 400 mg/kg or more but weight gain was depressed only at
    1600 mg/kg.

         Hematology was measured at the end of the study. Hemoglobin,
    hematocrit and erythrocyte levels were reduced at 800 mg/kg or more
    and a decreased leucocyte counts was observed in males of these
    groups. Gross post mortem examinations revealed increases in absolute
    and relative liver weights from 40 mg/kg and greater in males and 80
    mg/kg and greater in females (Daly & Rinehart, 1980a, 1980b).

    2.2.2.2  Rats

         Groups of 15 to 20 male and female Charles River Sprague Dawley
    rats were given gavage doses of 0, 4, 25, 48 or 168 mg/kg bw/d of
    albendazole in 0.5% Tween 80 for 4 weeks.

    
                                                                                  

    Species           Sex      Vehicle          LD50 (mg/kg bw)   Reference
                                                                                  

    Mouse             M        0.75% methocel   over 3000         Macko  et al.,
                                                                  1975a
    Rat               M&F      2% tragacanth    1320              Walker, 1976a
    Rat               M&F      1% methocel      2400              Braun & Killeen,
                                                                  1975
    Hamster           M&F      2% tragacanth    over 10000        Walker, 1976b
    Guinea-pig        M&F      2% tragacanth    900               Walker, 1976c
    Rabbit            M&F      2% tragacanth    500-1250          Walker, 1976d
                                                                                  
    
         Toxic signs were produced in the 2 highest dose groups which
    included diarrhea, piloerection, nasal swelling with blood stained
    nasal discharge and death (7/30 rats at 48 mg/kg and 39/40 rats at 168
    mg/kg died). Body weight gain was depressed at 48 mg/kg with weight
    loss at 168 mg/kg while food consumption was markedly reduced at 168
    mg/kg and slightly reduced at 48 mg/kg.

         Hematology, blood chemistry and urinalysis were measured after 1
    and 4 weeks of treatment, except in the high dose rats which exhibited
    marked overt toxicity. Hemoglobin, hematocrit, erythrocyte and
    leucocyte counts were reduced at 48 mg/kg.

         At autopsy, adrenal size was increased at 48 and 168 mg/kg,
    particularly in females. Testes were soft with reduced size and weight
    in 48 mg/kg males which survived 4 weeks. Testes size was not affected
    at the highest dose presumably due to early death of these males.
    Histopathology examination revealed hypoplasia in testes, bone marrow,
    spleen and lymph nodes in 48 and 168 mg/kg groups.

         An additional group of 5 males and 5 females was given 48 mg/kg
    bw/d of albendazole for 4 weeks, followed by withdrawal of treatment
    for 4 weeks. All drug-related changes were reduced in severity during
    the latter period indicating that the effects were reversible (Simon,
    1979a).

         Groups of 20 male and 20 female Long Evans rats were fed diets
    containing albendazole for 91 days. Drug levels in food were adjusted
    so that animals received doses of 0, 2, 10 or 30 mg/kg bw/d. The
    control and high dose groups included an additional 10 males and 10
    females for laboratory studies.

         There were no signs of toxicity and no effects on body weight,
    food consumption and ophthalmology parameters. Hematology, blood
    chemistry and urinalysis were studied after 1 and 3 months of
    treatment. Gross pathology and organ weights were examined in all rats
    while histopathology was carried out on 15 males and 15 females from
    control and high dose groups.  Meaningful changes related to treatment
    were not observed (Killeen & Rapp, 1975a).

         Groups of 100 male and female Charles River CD rats were fed
    diets containing albendazole.  The initial groups (F0) received doses
    of 0, 1, 2.5 or 5 mg/kg bw/d for 60 days and then throughout mating,
    gestation and post-natal periods. Similar size groups of F1 animals
    received 0, 5, 30 or 45 mg/kg bw/day. The treatment was intended to be
    for 2 years but excessive mortality necessitated termination of the
    study after 26 weeks.

         There were no untoward effects in F0 rats. In the F1 animals,
    92/100 males and 99/100 females of the 45 mg/kg bw/day group died by
    week 25. Prior to death these rats developed swollen cervical glands,
    followed by swelling of paws and the genital area, scabbing in the
    cervical area and emaciation (reduced weight gain and food intake).

         Hematology was measured after 3 and 6 months of treatment. 
    Hemoglobin, hematocrit, erythocyte and leucocyte counts were decreased
    and reticulocytes increased in 45 mg/kg rats at 3 months. At 6 months,
    similar but slight hematological changes were seen in 30 mg/kg bw/day
    rats. Segmented neutrophils were particularly affected and this was
    confirmed by differential bone marrow counts in control and 30 mg/kg
    rats. Blood chemistry and urinalysis were studied after 3 months of
    treatment. In the 45 mg/kg bw/day group, plasma cholesterol was
    increased in males and females, potassium was increased in males, and
    albumin, plasma and erythrocyte cholinesterase were decreased in
    females. Urinary protein was increased in 30 and 45 mg/kg bw/day
    males.

         Post mortems were carried out on all unscheduled deaths and
    approximately 60% of animals surviving to 26 weeks. Numerous gross
    alterations were noted in the high dose group including discoloration
    and/or nodules in the lungs, heart, lymph nodes, spleen, pancreas,
    liver, adrenal and kidney. Some of these organs were also enlarged or
    showed adhesions. Additionally, thymic tissue was often absent and
    testes were small and flaccid.

         Histopathology, performed on selected tissues in 5 males and 5
    females from 0, 30 and 45 mg/kg bw/day groups, identified a number of
    instances where bacterial colonization in lungs, spleen, kidneys and
    heart was associated with necrosis without the usual acute
    inflammatory response. The liver showed centrilobular cloudy swelling,
    vacuolation or necrosis and lymphoid tissues such as bone marrow,
    spleen and thymus showed hypocellularity or other changes suggestive

    of atrophy. All the above lesions were seen at 45 mg/kg while, at 30
    mg/kg, only the thymic and minor hepatic effects were noted (Daly &
    Hogan, 1982).

         The remaining rats were used to further evaluate effects on
    hematological parameters. Control and 5 mg/kg group animals were
    continued on the same treatment level while rats from the 30 mg/kg
    group were now given 0 or 20 mg/kg bw/d albendazole. Group sizes were
    20 to 25 males and females and dosing was continued for 4 months.
    Hematology was studied monthly. The 5 mg/kg rats were still
    unaffected. The red and white cell effects induced at 30 mg/kg were
    essentially normalized within a month of reducing the dose to 0 or 20
    mg/kg. However, differential bone marrow counts at day 81 revealed a
    persistent depression of the myeloid line in the 20 mg/kg group. Gross
    post mortem examination of all animals showed no remarkable effects
    (Daly & Hogan, 1981).

    2.2.2.3  Dogs

         Groups of 4 to 5 male and female beagle dogs were given gavage
    doses of 0, 4, 16, 48 or 168 mg/kg bw/d of albendazole in 2% Tween 80
    for 4 weeks. Toxic signs, in a few dogs at the 2 highest dose levels,
    included diarrhea and vomiting with cardio-pulmonary disturbances in
    1 dog. Death ensued in 1/10 dogs at 48 mg/kg and 6/10 dogs at 168
    mg/kg, mainly in females. Heart rates showed marked increases in some
    168 mg/kg females prior to death. Food intake was reduced at 48 mg/kg
    and above and weight gain was depressed at 16 mg/kg and above.

         Hematology, blood chemistry, urinalysis and ophthalmology were
    studied after 1 and 4 weeks of treatment. Leucocyte counts were
    decreased in a few dogs at 48 and 168 mg/kg and alkaline phosphatase
    was increased from 16 mg/kg. Necropsy revealed lower absolute
    testicular weight in 48 and 168 mg/kg males but no pathological
    alterations (Simon, 1979b).

         Groups of 4 male and female beagle dogs were given 0, 2, 10 or 39
    mg/kg bw/d albendazole in capsules for 91 days. Ophthalmology,
    hematology, blood chemistry and unrinalysis were studied after 1 and
    3 months; organ weights, gross and histopathology were examined in all
    dogs. There were no toxic signs or effects on body weight and food
    intake. No treatment-related effects were found (Killeen & Rapp,
    1975b).

         Groups of 6 male and 6 female beagle dogs were given 0, 5, 30 or
    60 mg/kg bw/d albendazole in capsules for 6 months.

         Food intake was decreased in 30 and 60 mg/kg females, while
    weight gain was lower in 60 mg/kg males and females. Laboratory
    studies included hematology and blood chemistry monthly, urinalysis
    bimonthly and ophthalmology at termination. Hemoglobin, hematocrit and
    erythrocyte counts were slightly reduced at 60 mg/kg and leucocyte
    counts, particularly neutrophils, were reduced at 30 and 60 mg/kg.

         Autopsy on all dogs revealed decreased absolute and relative
    testes and uterine weights and slight increases in relative liver and
    kidney weights at 60 mg/kg. The incidences of small nodules in the
    stomach were increased in all treated groups but microscopically they
    were shown to be normal, submucosal lymphoid follicles. Sternal bone
    marrow showed hypocellularity in 4/6 females in the 60 mg/kg group.
    The NOEL was 5 mg/kg bw/day. (Daly & Hogan, 1980).

    2.2.3  Long-term/carcinogenicity studies

    2.2.3.1  Mice

         Groups of 100 male and 100 female Charles River CD-1 mice were
    fed diets containing albendazole for 25 months. Drug levels were
    adjusted to provide doses of 0, 25, 100 or 400 mg/kg bw/d. Additional
    groups of 25 males and 25 females were given control and high dose
    treatments and used for hematology measurements.

         There were no toxic signs or effects on food intake and body
    weight. Hematology was studied after 3, 6 , 12, 18 and 24 months in
    the main groups and monthly in the ancillary groups. Erythrocyte and
    leucocyte counts were decreased and platelets were increased at 400
    mg/kg, particularly in females.

         A complete gross post-mortem examination was carried out on all
    mice. Full histopathology was undertaken on control and high dose
    mice. In intermediate groups, 6 major organs and grossly abnormal
    tissues were examined routinely. Flaccid or small testes, testicular
    tubular degeneration, oligospermia, and aspermia in epididymides were
    increased in 400 mg/kg males. Centrilobular hepatocytic vacuolation
    was increased in groups given 100 and 400 mg/kg. Eye opacities were
    noted in all groups; however, microscopically, cataracts were slightly
    increased only in 400 mg/kg males. The relationship of these ocular
    findings to treatment is questionable as the bulk of the cataracts
    were unilateral and such abnormalities are commonly obtained following
    repeated blood collection from the orbital sinus.

         The incidence of endometrial stromal polyps appeared to be
    increased over concurrent controls (Table 1) but a statistical
    evaluation of the results did not reveal significant differences
    between groups, and all incidences were within the historical control
    range for this laboratory based on 2 studies with 2 control groups in
    each. The NOEL was 25 mg/kg bw/d. (Daly & Knezevich, 1987a; Sauer,
    1985, 1987b; Selwyn 1987).

    
    Table 1: Tumor incidence in mice
                                                                                   

    Dose (mg/kg bw/d)   0       0        25       100    400    Historical Controls
                                                                                   

    Endometrial stromal tumors

    Polyps              3/98    5/99     3/98     5/98   7/99   Range 0/55-8/47
    Sarcomas            0/98    0/99     1/98     2/98   0/99   Cumulative 29/780
    Total               3/98    5/99     4/98     7/98   7/99
                                                                                   
    
    2.2.3.2  Rats

         Groups of 100 male and 100 female Sprague Dawley CD rats were fed
    diets containing albendazole. The initial groups (F0) received doses
    of 0, 1, 2.5 or 5 mg/kg bw/d for 60 days and then through mating,
    gestation and post-natal periods. Similar size groups of F1 animals
    received 0, 3.5, 7 or 20 mg/kg bw/d for 28 months. Additional groups
    of 25 males and 25 females were given control and high dose treatments
    and used for hematology measurements. An interim sacrifice of 10 males
    and females per group was made after 12 months.

         Treatment-related effects were not observed in F0 animals. In the
    F1 animals, mortality was slightly increased after 24 months in 20
    mg/kg males. There were no other toxic signs or effects on body weight
    and food consumption. Ophthalmology, hematology, blood chemistry and
    urinalysis parameters were studied after 3, 6, 12, 18 and 24 months of
    treatment. In the 20 mg/kg group, total leucocyte and neutrophil
    counts were decreased at 24 months, serum cholesterol was increased in
    females throughout the study and in males at some sampling times.

         A complete gross post-mortem examination was carried out on all
    rats. Full histopathology was undertaken on control and high dose
    rats. In intermediate groups, 8 major organs and grossly abnormal
    tissue were examined routinely. The 20 mg/kg animals showed increased
    incidences of flaccid testes, degeneration/atrophy of germinal and
    relative liver weights in males and hepatic fatty metamorphosis in
    males and females.

         Compared to concurrent controls, the incidences of
    endometrial/cervical tumors and skin histiocytic sarcomas showed an
    apparent increase in certain groups of rats (see Table 2 below).
    Statistical evaluation of the findings did not reveal significant
    differences between groups and in fact all frequencies were within the
    historical control range for this laboratory. The NOEL was 7 mg/kg/d.
    (Daly & Knezevich, 1987b; Sauer, 1985, 1987a; Selwyn, 1987).

    
    Table 2: Tumor incidence in rats
                                                                                   

    Dose (mg/kg/d)      0      0       3.5      7        20      Historical Controls
                                                                                   

    Endometrial/cervical tumors

        Polyps          3/99   5/99    9/98     9/99     10/91   Range 1/69-7/58*
        Sarcomas        0/99   3/99    0/98     4/99     3/91    Cumulative 120/1864
        Total           3/99   8/99    9/98     11/99    13/91

    Skin histiocytic sarcomas

        Males           1/100   2/100  4/98     4/100    6/100   Range 0/116-6/110**
                                                                 Cumulative 32/1190
        Females         0/100   4/100  0/100    1/96     5/100   Range 1/112-11/119
                                                                 Cumulative 40/1188
                                                                                   

    *    based on 18 studies
    **   based on 14 studies.
    
    2.2.4  Reproduction studies

    2.2.4.1  Rats

         Groups of Long Evans rats were fed diets containing 0, 30, 75 and
    150 ppm albendazole for 3 successive generations, commencing 64 d
    before the initial mating. Each parental group consisted of 12 males
    and 24 females, which were bred to produce 2 litters each. Offspring
    from the second litters were selected to serve as parents of the
    subsequent generations. Drug intake was calculated to be, on average,
    2.3, 5.8 and 11.6 mg/kg bw/d.

         There were no toxic signs or effects on body weight, food
    consumption, mating, fertility, pregnancy rates, gestation length,
    litter size and weight. During lactation, pup survival and/or weight
    gain was depressed, but only in F1a and F2a litters given 11.6 mg/kg.
    The NOEL was 5.8 mg/kg bw/d. (Schroeder & Rinehart, 1980).

         Groups of 20 male Sprague Dawley CD rats were given gavage doses
    of 0, 1, 10 or 30 mg/kg bw/d albendozale in 0.5% gum tragacanth, from
    60 days prior to mating to the end of the breeding period. Males were
    mated 1 to 1 with untreated females. Half the dams were killed on
    gestation day 13, the remainder were allowed to deliver naturally and
    rear pups to weaning.

         In males treated with 30 mg/kg, weight gain was lower and 4
    animals died or were killed moribund. Toxic signs were piloerection
    and bloody nasal discharge at 30 mg/kg and dried blood around the nose
    at 10 mg/kg. The ability to impregnate females was unaffected, despite
    the finding in the 30 mg/kg group of reduced testicular size, together
    with focal testicular hypoplasia in 8/10 rats. In the 10 mg/kg group,
    there were a few hypoplastic seminiferous ducts reported in 4 of the
    5 rats examined.

         Uterine examinations on gestation day 13 showed fewer
    implantations (not significant) at 30 mg/kg with no effect on
    resorptions. In females allowed to deliver, weight gain was lower
    during gestation in 30 mg/kg dams, probably reflecting the reduced
    litter size and weight. Postnatal growth, physical and behavioral
    development were unremarkable. The NOEL was l mg/kg bw/day. (Boutemy,
    1980).

    2.2.5  Special studies on genotoxicity

        Table 3:  Results of genotoxicity assays on albendazole
                                                                                  
    Test system         Test object        Concentration   Result     Reference
                                                                                  
    Ames test (1)       S.typhimurium      1-10,000 µg/    Negative   Jagannath,
                        TA1535, TA1537     plate                      1980a
                        TA1538, TA98,
                        TA100

    Ames test (2)       As above           As above        Negative   Jagannath,
                                                                      1980b

    Ames test (2, 3)    As above           As above        Negative   Jagannath,
                                                                      1981

    Ames test (1)       S.typhimurium      0.5-1000 µg/    Negative   Mourot,
                        TA97a, TA98,       plate                      1988
                        TA100, TA102

    CHO chromosome      Chinese hamster    0.047-1.5µg/ml  Negative   Galloway,
    aberration          ovary cells                                   1981
    assay

    Transformation      BALB/3T3 mouse     10-100 µg/ml    Negative   Schechtman,
    assay               cells                                         1982
                                                                                  
    (1)With and without rat liver S-9 fraction
    (2)With and without calf and rat liver S-9 fraction
    (3)Substance tested was 2-amino sulphone metabolite.
        2.2.6  Special studies on eye and skin irritation

         Groups of rabbits had 100 mg albendazole powder instilled into
    the conjunctival sac or 500 mg albendazole applied, under occlusion,
    to abraded and non-abraded skin. There were no primary irritant
    effects at any site (Macko  et al., 1975b).

    2.2.7  Special studies on teratogenicity

    2.2.7.1  Mice

         Groups of 21 to 26 pregnant Charles River CD-1 mice were given
    gavage doses of 0, 2, 5, 10 or 30 mg/kg bw/d albendazole in 0.5%
    methylcellulose. Treatment was on gestation days 6 to 15 and females
    were killed on gestation day 18.

         There was no overt maternal toxicity or effect on resorption
    incidence, fetal weight and external, visceral and skeletal
    development of fetuses (Killeen & Rapp, 1975c).

    2.2.7.2  Rats

         Groups of 25 pregnant Charles River CD rats were given gavage
    doses of 0, 5, 20 or 40 mg/kg bw/d albendazole in 0.5%
    methylcellulose. In each group 19 rats were treated on gestation days
    16 to 20 and 6 were treated from gestation day 16 to lactation day 20.
    All dams were allowed to litter naturally.

         There was no maternal toxicity or effect on gestation or
    parturition. At 40 mg/kg, litter size and weight were reduced at birth
    and remained depressed during lactation. A total of 6, 17, 4 and 55
    pups died in the 0, 5, 20 and 40 mg/kg groups, respectively. Small
    lungs and kidneys and anasarca in the 40 mg/kg pups were possibly
    related to treatment, but an unequivocal conclusion was not possible
    in view of the low number of control pups examined. The authors
    concluded that developmental and behavioral characteristics were
    unrelated to albendazole treatment, but detailed supporting data were
    not provided. The NOEL was 20 mg/kg bw/day. (Johnson, 1981).

         A series of studies was carried out at Biodynamics in Long Evans
    rats. A similar protocol was used in each study, which included dosing
    on gestation days 6 to 15; sacrifice of dams on gestation day 20;
    maternal observations for overt toxicity, weight gain and uterine
    parameters; fetal examination for size, weight, and external, visceral
    and skeletal abnormalities.

    Study A Groups of 20 pregnant rats were given gavage doses of 0, 2,
    5, 10 or 30 mg/kg bw/d albendazole in 0.5% methylcellulose. Maternal
    weight gain and survival were lower at 30 mg/kg. At this dose, there
    was a high incidence of resorptions, surviving fetuses showed reduced
    size, weight and multiple gross, visceral and skeletal malformations.
    Limb abnormalities such as micromelia, ectromelia, curved femur and
    microfetalis were also seen in other treated groups. However, the
    incidences were low, they were not dose-related and they were observed
    only in 1 or 2 litters per group (Killeen & Rapp, 1975e; Christian,
    1984, 1987a.).

    Study B Groups of 19-20 pregnant rats were given gavage doses of 0,
    0.5, 2, 5 or 10 mg/kg bw/d albendazole in 0.5% methylcellulose.
    Fetuses of the 10 mg/kg group revealed reduced size and weight,
    retarded skeletal ossification and increased incidences of micromelia
    and microfetalis (which included shortened long bones in fore and hind
    limbs) (Killeen & Rapp, 1976; Christian, 1984, 1987a).

    Study C Groups of 30 to 60 pregnant rats were fed diets containing
    29% freeze dried liver, obtained from cattle 48 hours after a single
    oral dose of 0 or 27.5 mg/kg bw albendazole. Drug intake was
    calculated to represent 0.42 mg/kg bw/d albendazole equivalents. The
    only possible treatment-related observation was shortened limb bones
    in 2/248 treated fetuses from 2 different litters. These effects were
    not seen in 460 controls and the authors noted that they were an
    infrequent finding at Biodynamics (Hogan & Rinehart, 1977).

         A re-evaluation of these affected fetuses failed to confirm the
    above description. The apparent defects were described as artifacts
    caused by poor staining (Christian, 1987b).

    Study D Groups of 20 to 22 pregnant rats were fed diets containing
    10, 20 or 30% freeze dried liver, obtained from cattle 12 days after
    a single oral dose of 0 or 16.5 mg/kg bw albendazole. Drug intake was
    calculated to be approximately 0.02, 0.04 and 0.06 mg/kg bw/d
    albendazole equivalents. In the group given 30% exposed liver,
    resorptions were increased, 9 of which were in 1 female. If data from
    this rat were eliminated there were no significant effects. The
    overall NOEL for studies A to D was 5 mg/kg bw/day. (Schroeder &
    Rinehart, 1978).

         Groups of pregnant Sprague Dawley rats were given gavage doses of
    0, 5.3, 6.0, 6.62, 8.83, 10.6 or 13.25 mg/kg bw/d albendazole or 9 of
    its animal metabolites at equimolar or higher doses. Treatments were
    on gestation days 8 to 15 and dams were killed on gestation day 21.
    The results were presented in summary form only.

         Skeletal abnormalities were increased at dose levels of 6.62
    mg/kg and greater with increases in resorptions and external
    malformations and decreased fetal weight at 8.83 mg/kg albendazole and
    above. The major malformations were craniofacial and bone defects.

    Qualitatively similar findings were obtained with equimolar amounts of
    albendazole sulfoxide while the other metabolites A, B, E, F, G, J, I
    and H (section 2.1) were all ineffective. The concomitant
    administration of SKF-525-A, a microsomal oxidation inhibitor, almost
    completely suppressed the embryotoxic and developmental effects of
    albendazole. The NOEL was 6 mg/kg bw/day. (Martin, 1980).

         Groups of pregnant Sprague Dawley rats were given diets
    containing albendazole or 40% freeze dried liver, obtained from cattle
    24, 48 or 96 hours after a single oral dose of 0 or 20 mg/kg bw
    albendazole. Drug levels in food were adjusted to provide 0, 12, 24 or
    36 mg/kg bw/d but doses given through incorporation of liver could not
    be estimated. Treatment of rats was on gestation days 8 to 15 and dams
    were killed on gestation day 21. Albendazole doses of 24 and 36 mg/kg
    produced virtually 100% embryolethality, the single live fetus was
    small and had skeletal abnormalities. There were no effects at other
    exposure levels. The NOEL was 12 mg/kg bw/day. (Grannec, 1980).

    2.2.7.3  Rabbits

         Groups of 15 pregnant New Zealand White rabbits were given gavage
    doses of 0, 2, 5, 10 or 30 mg/kg bw/d albendazole in methylcellulose.
    Treatment was on gestation days 7 to 19 and does were killed on
    gestation day 30.

         Maternal mortality was increased at 30 mg/kg but body weight
    comparisons were not meaningful due to wide variation within groups.
    The 30mg/kg group showed a reduction in implants, due largely to 2
    does with corpora lutea but no implants, and increases in resorptions
    and ectrodactyly. Fetal size and weight were depressed at 10 and 30
    mg/kg. The NOEL was 5 mg/kg bw/day. (Killeen & Rapp, 1975d).

    2.2.7.4  Sheep

         In two separate experiments, groups of 15 to 44 Dorset Horn Cross
    and Clun mated ewes were given a single dose of 0, 7.5, 10, 15 or 20
    mg/kg bw albendazole by oral drench. Overall, there were 71, 43, 44,
    43 and 42 animals in the 0, 7.5, 10, 15 and 20 mg/kg groups,
    respectively. Treatment was on gestation day 17 and ewes were allowed
    to deliver naturally.

         There was no overt maternal toxicity but premature delivery was
    noted in more ewes of the 20 mg/kg group than in the others. All
    premature lambs in this group were stillborn, consequently the number
    of live lambs was reduced at 20 mg/kg, as was survival of the lambs to
    post partum day 55. Some lambs were sacrificed in extremis or because
    they were considered commercially unviable, thus the total post partum
    loss was 22/123, 4/67, 11/73, 12/73 and 39/61 in the 0, 7.5, 10, 15

    and 20 mg/kg groups, respectively. Post-mortem examination of these
    lambs revealed increased incidences of prognathia, scoliosis, spina
    bifida and reduced tail at 20 mg/kg and displaced, poorly developed or
    absent kidneys at 15 and 20 mg/kg. The NOEL was 10 mg/kg bw/d. (Tesh
    & Harper, 1977).

         The data shown in Table 4 indicates a relationship between
    teratogenesis and peak plasma concentration of albendaxole sulfoxide.
    Data from Bogan & Marriner (1984).

    
    Table 4.  Relationship between plasma albendazole sulfoxide
                   and teratogenesis
                                                                       

    Species        Albendazole Dose  Peak Plasma   Teratogenic
                   (mg/kg bw)        Albendazole
                                     (mg/ml)
                                                                       
                                                                        
    Sheep              10            2.50          Yes
    Cattle             10            0.57          No(1)
    Rabbit             30            8.82          Yes
    Rat                10            6.6           Yes
    Mouse              30            n.a.(3)       No
    Man           400 mg/person      0.16          No(2)
                                                                       

    (1)  Embryotoxic but not teratogenic
    (2)  No intentional studies performed
    (3)  Not available
    
    2.2.8  Special studies on mode of action of benzimadoles

         Benzimadazoles bind with tubulin and inhibit its polymertisation
    to microtubules. A comparison of inhibitory concentrations for some
    benzimadazoles in nematodes and mammalian cells reveals a selective
    action (reviewed in Sharma & Abuzar, 1983).

    2.3  Observations in man

         Albendazole has been used in 80 countries for 6 years to treat
    gastrointestinal parasitic infections in man at a recommended dose
    rate of 400 mg/person. There are a number of published reports on the
    use of albendazole in man (see Marriner  et al., 1986; Lange  et al.,
    1988).

         In field trials in Nigeria, it was reported that 17 nulliparous
    women aged between 16 and 18 years were inadvertently given a single
    dose of 400 mg albendazole in the first trimester of pregnancy without
    any adverse effects on the mother or child (A.B.C. Nwosu, 1985).

    3.  COMMENTS

         Comprehensive toxicological data on albendazole were submitted
    including the results of studies on its metabolism, carcinogenicity,
    genotoxicity, effects on reproduction and teratogenicity, and
    short-term studies.

         Pharmacokinetic studies, although not specifically designed to
    measure the extent of absorption, suggested that about 20-30% of
    ingested albendazole was absorbed in mice and rats, about 1% in humans
    and 50% in cattle. In all the species studied, oral dosing produced
    very low plasma levels of unchanged drug, because of rapid first-pass
    metabolism in the liver. The primary metabolic reactions were the
    oxidation of the sulfide moiety of albendazole to the sulfoxide and
    sulfone, followed by cleavage of the carbamate moiety to form the
    2-amino-sulfone. This last compound was found to be the main residue
    in the livers of sheep and cattle. The degradation of albendazole
    followed similar pathways in rats, mice, cattle, sheep and humans.

         In a study in mice in which albendazole was administered in the
    diet for 25 months, anemia, leukopenia and testicular degeneration
    were noted at 400 mg/kg bw/day. Hepatocellular vacuolation was
    produced at 100 and 400 mg/kg bw/day, endometrial stromal polyps was
    slightly higher than in concurrent controls, but statistical
    significance was not achieved and all incidences were within the
    laboratory historical control range. The NOEL was 25 mg/kg bw/day. 
    
         In a 28-month study in the rat in which the compound was given 
    in the diet, the highest dose of 20 mg/kg bw/day caused mortality, 
    neutropenia, hypercholesterolemia, testicular degeneration and 
    hepatic fatty metamorphosis. The incidence of endometrial/cervical 
    tumors and histiocytic carcomas in the skin showed an apparent 
    increase in certain treated groups. However, when compared with 
    those for the controls, these findings were not statistically 
    significantly different and were within the laboratory historical 
    control range. The NOEL was 7 mg/kg bw/day. 

         Questions had been raised regarding the statistical analyses of
    the mouse and rat carcinogenicity studies and the use of historical
    controls in the examination of the tumor incidence. The studies were
    reviewed and were determined to be satisfactory. The statistical
    analysis of both rodent carcinogenicity studies was also reviewed and
    found to have been conducted in accordance with currently acceptable
    procedures.

         Albendazole did not produce bacterial mutations, chromosomal
    aberrations or morphological transformations in cultured mammalian
    cells. The 2-aminosulphone metabolite did not produce bacterial
    mutations.

         A three-generation reproduction study in which the compound was
    administered in the diet was conducted in rats. There were no effects
    on fertility or reproduction indices. The only findings were
    reductions in pup postnatal survival and growth at 11.6 mg/kg bw/day.
    The NOEL was 5.8 mg/kg bw/day.

         Male rats were treated by gavage in a fertility study. Overt
    toxic effects and testicular hypoplasia were noted at 10 and 30 mg/kg
    bw/day. Fertility indices were not affected. Litter size and weight
    were reduced at 30 mg/kg bw/day, the former effect being probably due
    to a lower implantation rate. The NOEL was 1 mg/kg bw/day.

         In a perinatal and postnatal study in rats in which albendazole
    was administered by gavage, there was decreased survival and growth
     in utero and during lactation in the pups of females given 40 mg/kg
    bw/day group. There was also some evidence of retarded organ
    development in the offspring of this group. The NOEL was 20 mg/kg
    bw/day.

         In a teratology study in mice in which albendazole was
    administered by gavage, there were no adverse effects at dose levels
    up to 30 mg/kg bw/day.

         Several teratology studies were conducted in the rat in which the
    compound was administered either by gavage or by dietary exposure.
    Embryotoxic, fetotoxic effects and external malformations were
    produced at doses of 8.8 mg/kg bw/day and above. Skeletal
    malformations, in particular limb defects, which were seen at doses of
    6.62 mg/kg bw/day, constituted the most sensitive indicator of
    developmental toxicity. The NOEL was 5 mg/kg bw/day. When administered
    in equimolar amounts, qualitatively similar findings were obtained
    with albendazole sulphoxide, while eight other metabolites of
    albendazole did not show any effects.

         In rabbits, the toxic dose to the dams of 30 mg/kg bw/day was
    associated with embryotoxicity and partially or totally missing
    digits. Fetal growth retardation was observed at doses of 10 mg/kg
    bw/day and above. The NOEL was 5 mg/kg bw/day.

         A teratology study was conducted in sheep using a single oral
    dose of albendazole on day 17 of pregnancy. Premature delivery,
    fetotoxic effects and postnatal death were produced at 20 mg/kg bw and
    malformations were increased at 15 and 20 mg/kg. The NOEL was 10 mg/kg
    bw/day.

         Dogs were dosed for six months by the administration of the
    compound in capsules. They showed neutropenia at 30 mg/kg bw/day and
    above. At 60 mg/kg bw/day there was also anemia, decreased body,
    testicular and uterine weights, and bone marrow hypocellularity. The
    NOEL in this study was 5 mg/kg bw/day.

         Albendazole has been used in 80 countries to treat
    gastrointestinal parasitic infections in humans at a dose rate of 400
    mg/person, and there are a number of published reports on its use. In
    field trials in Nigeria, an unpublished report noted that 17
    nulliparous women aged between 16 and 18 years were inadvertently
    given a single dose of 400 mg albendazole during the first trimester
    of pregnancy without any apparent adverse effects on the mother or the
    neonate.

         Some of the effects observed in general toxicity studies with
    albendazole may be explained by one of the biological actions of the
    benzimadazoles, which is to interfere with tubulin polymerization and
    thus inhibit spindle formation and mitosis.

         The most significant toxicological manifestation resulting from
    treatment with albendazole was its teratogenic activity, limb defects
    in the rat being the most sensitive indicator of developmental
    toxicity.

         A NOEL of 5 mg/kg bw/day was reported in several studies in rats,
    rabbits and dogs. Although for males in the rat fertility study the
    figure was 1 mg/kg bw/day, it was noted that the next highest dose
    used in the study was 10 mg/kg bw/day. In addition, in the
    multigeneration reproduction study in rats, there was no effect on
    fertility at 11.6 mg/kg bw/day, which was the highest dose used, and
    the reported NOEL was 5.8 mg/kg bw/day, based on depression of weight
    gain in pups.

         An ADI of 0-0.05 mg/kg bw was established for albendazole based
    on a NOEL of 5 mg/kg bw/day and using a safety factor of 100.

         A safety factor of 100 was chosen for this compound after taking
    into consideration poor absorption in humans, rapid metabolism, the
    lack of teratogenic potential of most metabolites, the use of the drug
    in humans and the identity of residues in food.

    4.  EVALUATION

         Level causing no toxicological effect

         Rat, rabbit, dog equal to 5 mg/kg bw/day.

         Estimate of acceptable daily intake

         0-0.05 mg/kg bw.

    5.  REFERENCES

    BOGAN, J.A. & MARRINER, S.E. (1984). Pharmacodynamic and toxicological
    aspects of albendazole in man and animals. In: Fock, M. (Ed.).
    Albendazole in helminthiasis. Royal Society of Medicine International
    Congress and Symposium Series No. 61. London, Royal Society of
    Medicine, pp. 13-21.

    BOUTEMY, C. (1980). Expert study of the action of the compound
    albendazole on the fertility of the male rat, per os. Unpublished
    study No. 2477 RSR from IFM Research Center. Submitted to WHO by
    SmithKline and French.

    BRAUN, W.G. & KILLEEN, J.C. (1975). Acute oral toxicity in rats,
    compound No. SK&F 62979. Unpublished project No. 2605-75 from
    Biodynamics Incorporated. Submitted to WHO by SmithKline and French.

    CHRISTIAN, M.S. (1984). Review of albendazole rat teratogenicity
    studies. Unpublished report from Argus International. Submitted to WHO
    by SmithKline and French.

    CHRISTIAN, M.S. (1987a). Review of reported "micropodia" in
    albendazole rat teratogenicity studies. Unpublished report from Argus
    International. Submitted to WHO by SmithKline and French.

    CHRISTIAN, M.S. (1987b). Review of developmental toxicity
    (embryo-fetal toxicity/teratogenicity) and reproductive toxicity
    studies of albendazole in mice, rabbits and rats. Unpublished report
    from Argus International. Submitted to WHO by SmithKline and French.

    COLMAN, W., TOWNER, C., TOWNER, D. & SOKOLEK, J. (1977). Metabolic
    fate of albendazole in sheep tissues. Unpublished report from
    Applebrook Research Centre. Submitted to WHO by SmithKline and French.

    DALY, I.W. & HOGAN, G.K. (1980). A six-month oral toxicity study with
    albendaxole in dogs. Unpublished project No. 790-2371 from Biodynamics
    Incorporated. Submitted to WHO by SmithKline and French.

    DALY, I.W. & HOGAN, G.K. (1981). A toxicity study of albendazole in
    rats. Unpublished project No. 80-2449 from Biodynamics Incorporated.
    Submitted to WHO by SmithKline and French.

    DALY, I.W. & HOGAN, G.K. (1982). A long-term oral dietary toxicity
    carcinogenciity study of albendazole in rats. Unpublished project No.
    79-2383 from Biodynamics Incorporated. Submitted to WHO by SmithKline
    and French.

    DALY, I.W. & KNEZEVICH, A.L. (1987a). A long-term oral (dietary)
    carcinogenicity study of albendazole in mice. Unpublished project No.
    80-2480 from Biodynamics Incorporated. Submitted to WHO by SmithKline
    and French.

    DALY, I.W. & KNEZEVICH, A.L. (1987b)  A long-term oral
    toxicity/carcinogenicity study of albendazole in rats. Unpublished
    project No. 80/2448 from Biodynamics Incorporated. Submitted to WHO by
    SmithKline and French.

    DALY, I.W. & RINEHART, W.E. (1980a). A three month dose range finding
    study with albendazole in mice. Unpublished project No. 79-2368 from
    Biodynamics Incorporated. Submitted to WHO by SmithKline and French.

    DALY, I.W. & RINEHART, W.E. (1980b). A three month feeding study of
    albendazole in mice. Unpublished project No. 79-2423 from Biodynamics
    Incorporated. Submitted to WHO by SmithKline and French.

    DELATOUR, P., GARNIER, F., BENOIT, E. & LONGIN, Ch. (1984). A
    correlation of toxicity of albendazole and oxfendazole with their free
    metabolites and bound residues.  J.Vet.Pharmacol.Therap., 7, 139-145.

    GALLOWAY, S.M. (1981). Mutagenicity evaluation of albendazole (SK&F
    62979) in an  in vitro cytogenetic assay measuring chromosome
    aberration frequencies in Chinese hamster ovary (CHO) cells.
    Unpublished project No. 22000 from Litton Bionetics. Submitted to WHO
    by SmithKline and French.

    GRANNEC, C. (1980). Albendazole: relay embryotoxicity. Thesis for
    D.Vet.Sci. Claude Bernard University, Lyons. Submitted to WHO by
    SmithKline and French.

    GYURIK, R.J.  et al., (1981). Metabolism of albendazole in cattle,
    sheep, rats and mice.  Drug Metabolism and Disposition 9, 503.

    HOGAN, G.R. & RINEHART, W.E. (1977). A segment II teratologic relay
    toxicity study in rats of liver obtained from calves treated with
    albendazole. Unpublished project No. 76-1443A from Biodynamics
    incorporated. Submitted to WHO by SmithKline and French.

    JAGANNATH, D.R. (1980a). Mutagenicity evaluation of albendazole (SK&F
    62979) in the Ames Salmonella/microsome plate test. Unpublished
    project No. 20988 from Litton Bionetics. Submitted to WHO by
    SmithKline and French.

    JAGANNATH, D.R. (1980b). Mutagenicity evaluation of albendazole (SK&F
    62979) in the Ames Salmonella/microsome preincubation plate test. 
    Unpublished project No. 20998 from Litton Bionetics. Submitted to WHO
    by SmithKline and French.

    JAGANNATH, D.R. (1981). Mutagenicity evaluation of SK&F 81038 in the
    Ames Salmonella/microsome plate test. Unpublished project No. 20988
    from Litton Bionetics. Submitted to WHO by SmithKline and French.

    JOHNSON, D.E. (1981). Perinatal and postnatal study in rats.
    Unpublished report No. 483-001 from International Research and
    Development Corporation. Submitted to WHO by SmithKline and French.

    KILLEEN, J.C. & RAPP, W.R. (1975a). A three month oral toxicity study
    of SK&F 62979 in rats. Unpublished project No. 75-1109 from
    Biodynamics Incorporated. Submitted to WHO by SmithKline and French.

    KILLEEN, J.C. 6 RAPP, W.R. (1975b). A three month oral toxicity study
    of SK&F 62979 in dogs. Unpublished project No. 75-1110 from
    Biodynamics Incorporated. Submitted to WHO by SmithKline and French.

    KILLEEN, J.C. & RAPP, W.R. (1975c). A segment II mouse teratology
    study of SK&F 62979. Unpublished project No. 74-1096 from Biodynamics
    Incorporated. Submitted to WHO by SmithKline and French.

    KILLEEN, J.C. & RAPP, W.R. (1975d). A teratology study of SK&F 62979
    in rabbits. Unpublished project No. 75-11234 from Biodynamics
    Incorporated. Submitted to WHO by SmithKline and French.

    KILLEEN, J.C. & RAPP. W.R. (1975e). A segment II rat teratology study
    of SK&F 62979. Unpublished project No. 74-1947 from Biodynamics
    Incorporated. Submitted to WHO by SmithKline and French.

    KILLEEN, J.C. & RAPP, W.R. (1976). A segment II rat teratology study
    of SK&F 62979. Unpublished project No. 75-1274 from Biodynamics
    Incorporated. Submitted to WHO by SmithKline and French.

    KRAEER, P., TOWNER, D. & SOKOLEK, J. (1977). Metabolic fate of
    albendazole in cattle tissues. Unpublished report from Applebrook
    Research Center. Submitted to WHO by SmithKline and French.

    LANGE, H., EGGERS, R. & BIRCHER, J. (1988). Increased systemic
    availability of albendazole when taken with a fatty meal.
    Eur.J.Clin.Pharmacol., 34, 315-317.

    MACKO, E., HORNER, E., DeVAN, J. & WHITE, R. (1975a). Local
    irritation, skin sensitivity and acute toxicity studies using SK&F
    62979. Unpublished report from SmithKline and French Laboratories.
    Submitted to WHO by SmithKline and French.

    MACKO, E., HORNER, E., DeVAN, J. & WHITE, R. (1975b). Local
    irritation, skin, sensitivity and acute toxicity studies using SK&F
    62979. Unpublished report from SmithKline and French Laboratories.
    Submitted to WHO by SmithKline and French. 

    MARRINER, S.E. & BOGAN, J.A. (1980). Pharmacokinetics of albendazole
    in sheep.  Am.J.Vet.Res., 41, 1126-1129.

    MARRINER, S.E., MORRIS, D.L., DICKSON, B. & BOGAN, J.A. (1986).
    Pharmacokinetics of albendazole in man.  Eur.J.Clin.Pharmacol., 30,
    705-708.

    MARTIN, D. (1980). Albendazole: embryotoxic study of ten metabolites.
    Thesis for D.Vet.Sci. Claude Bernard University, Lyons. Submitted to
    WHO by SmithKline and French.

    MOUROT, D. (1988). Albendazole: Ames test with and without metabolic
    activation. Unpublished report from Laboratoire National des
    Médicaments Vétérinaires. Submitted to WHO by SmithKline and French.

    NWOSU, A.B.C. (1985). Albendazole field trials in Nigeria. Unpublished
    report submitted to WHO by SmithKline and French.

    PARISH, R.C., CHOW, A.W., GYURIK, R.J. & ZABER, B. (1977a). The
    isolation and characterization of radioactive metabolites from the
    urine of sheep treated orally with 14°C-labelled SK&F 62979
    (Albendazole). Unpublished report from Applebrook Research Center.
    Submitted to WHO by SmithKline and French.

    PARISH, R.C., CHOW, A.W. & GYURIK, R.J. (1977b). The isolation and
    characterization of radioactive metabolites from the urine of steers
    treated orally with 14°C; labelled SK&F 62979 (Albendazole).
    Unpublished report from Applebrook Research Center. Submitted to WHO
    by SmithKline and French.

    PARISH, R.C., CHOW, A.W., GYURIK, R.J. & ZABER, B. (1977c). The
    isolation and characterization of radioactive metabolites from the
    urine of sheep treated orally with 14°C-labelled SK&F 62979
    (Albendazole). Unpublished report from Applebrook Research Center.
    Submitted to WHO by SmithKline and French.

    PARISH, R.C. & GYURIK, R. (1979). Urinary excretion and identification
    of metabolites from urine of Sprague-Dawley rats orally dosed with
    albendazole - 14°C albendazole sulfoxide - 14°C and albendazole
    sulfone - 14°C. Unpublished report No. A-4003-78 from Applebrook
    Research Centre. Submitted to WHO by SmithKline and French.

    PARISH, R.C., GYURIK, R. & BRUNER, E. (1979a). The isolation and
    quantitation of metabolites from urine of Charles River mice treated
    orally with 14°C-labelled SK&F 62979 (Albendazole). Unpublished report
    No. A-4006-78 from Applebrook Research Center. Submitted to WHO by
    SmithKline and French.

    PARISH, R.C., GYURIK, R.J. & BRUNER, E. (1979b). The isolation and
    quantitation of radioactive metabolites from the urine of steers
    treated orally with 14°C-labelled SK&F 62979. Unpublished report from
    Applebrook Research Center. Submitted to WHO by SmithKline and French.

    PRICHARD, R.K., HENNESSY, D.R., STEEL, J.W. & LACEY, E. (1985).
    Metabolite concentrations in plasma following treatment of cattle with
    five anthelmintics.  Res.Vet.Sci., 39, 173-178.

    ROSSIGNOL, J.F. & MAISONNEUVE, H. (1984). Albendazole: a new concept
    in the control of intestinal helminthiasis.  Gastroenterol.Clin.Biol.,
    8, 569-576.

    SAUER, R.M. (1985). Pathology Working Group report on albendazole in
    Sprague-Dawley rats and CD-1 mice. Unpublished report from Pathco
    Incorporated. Submitted to WHO by SmithKline and French.

    SAUER, R.M. (1987a). Pathology Working Group report on albendazole in
    Sprague-Dawley rats. Unpublished report from Pathco Incorporated.
    Submitted to WHO by SmithKline and French.

    SAUER, R.M. (1987b). Pathology Working Group report on albendazole in
    CD-1 mice. Unpublished report from Pathco Incorporated. Submitted to
    WHO by SmithKline and French.

    SCHECHTMAN, L.M. (1982). Activity of T1709 in the in vitro mammalian
    cell transformation assay in the presence of exogenous metabolic
    activation. Unpublished project No. T1709.109 from Microbiolobical
    Associates. Submitted to WHO by SmithKline and French.

    SCHROEDER, R.E., & RINEHART, W.E. (1978). A segment II teratologic
    relay toxicity study in rats on liver obtained from cattle treated
    with albendazole. Unpublished project No. 77-1825 from Biodynamics
    Incorporated. Submitted to WHO by SmithKline and French.

    SCHROEDER, R.E. & RINEHART, W.E. (1980). A three-generation
    reproduction study with albendazole in rats. Unpublished project No.
    77-2019 from Biodynamics Incorporated. Submitted to WHO by SmithKline
    and French.

    SELWYN, M.R. (1987). Statistical analysis for oral carcinogenicity
    studies of albendazole in mice and rats. Unpublished study from
    Statistics Unlimited Inc. Submitted to WHO by SmithKline and French.

    SHARMA, S. & ABUZAR, S. (1983). The benzimadozole anthelmintics -
    chemistry and biological activity.  Prog. Drug Res., 27, 85-161.

    SIMON, J.C. (1979a). 4-week sub-acute oral toxicity study in rats.
    Unpublished study No. 2206 TSR from IFM Research Center. Submitted to
    WHO by SmithKline and French.

    SIMON, J.C. (1979b). Sub-acute toxicity study in dogs. Unpublished
    study No. 2204 TSC from IFM Research Center. Submitted to WHO by
    SmithKline and French.

    SOUHAILI-EL AMRI, H., FARGETTON, X., BENOIT, E., TOTIS, M. & BATT,
    A-M. (1988). Inducing effect of albendazole on rat liver
    drug-metabolising enzymes and metabolite pharmacokinetics.
     Toxicol.App.Pharmacol., 92, 141-149.

    TESH, J.M. & HARPER, J.A. (1977). Albendazole (SK&F 62979): effects of
    single oral administration upon pregnancy in sheep. Unpublished report
    No. 77/SAF210/205 from Life Science Research. Submitted to WHO by
    SmithKline and French.

    WALKER, T.F. (1976a). The acute oral toxicity of SK&F 62979
    (Albendazole) in the rat. Unpublished report No. B 335A from
    SmithKline and French Laboratories. Submitted to WHO by SmithKline and
    French.

    WALKER, T.F. (1976b). The acute oral toxicity of SK&F 62979
    (Albendazole) in the hamster. Unpublished report No. B 335C from
    SmithKline and French Laboratories. Submitted to WHO by SmithKline and
    French.

    WALKER, T.F. (1976c). The acute oral toxicity of SK&F 62979
    (Albendazole) in the guinea pig. Unpublished report No. B 335B from
    SmithKline and French Laboratories. Submitted to WHO by SmithKline and
    French.

    WALKER, T.F. (1976d). The acute oral toxicity of SK&F 62979
    (Albendazole) in the rabbit. Unpublished report No. B 335D from
    SmithKline and French Laboratories. Submitted to WHO by SmithKline and
    French.


    See Also:
       Toxicological Abbreviations
       ALBENDAZOLE (JECFA Evaluation)