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    MOXIDECTIN

    First draft prepared by
    Dr K. Woodward, Veterinary Medicines Directorate,
    Ministry of Agriculture, Fisheries and Food, Addlestone,
    Surrey, England

    Explanation

    Biological data
         Biochemical aspects
         Absorption, distribution, and excretion
         Biotransformation

    Toxicological studies
         Acute toxicity studies
         Short-term toxicity studies
         Long-term toxicity/carcinogenicity studies
         Reproductive toxicity studies
         Special studies on embryotoxicity and/or teratogenicity
         Special studies on genotoxicity
         Special studies on skin irritation
         Special studies on eye irritation
         Special studies on dermal sensitization
         Special studies on pharmacodynamic effects

    Comments

    Evaluation

    References

    1.  EXPLANATION

         Moxidectin had not been previously reviewed by the Committee.
    Moxidectin is an antiparasitic drug that is used to control a range of
    internal and external parasites in sheep, cattle and deer. Its
    chemical structure is shown in Figure 1, page 1.

         Moxidectin is synthesized from an intermediate nemadectin,
    F-alpha. The constitution of the final product is at least 90%
    moxidectin with not more than 4% as F-alpha and related minor
    components. The remainder is made up of reaction products from the
    production process, with the total content of moxidectin-related
    compounds being not greater than 9% (American Cyanamid, 1994a,b).

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution, and excretion

         Pharmacokinetic studies have been conducted with 14C-labelled
    moxidectin.

    2.1.1.1  Rats

         Groups of Sprague-Dawley rats (2/sex/group) were given single
    oral doses of 1.5 mg/kg bw 14C-moxidectin in corn oil, and urine,
    faeces and expired air were examined at 24, 48 and 72 h post-dosing.
    Approximately 92% and 95% of the radioactivity was eliminated in
    faeces in males and females, respectively. Less than 0.7% was found in
    urine and no radioactivity was detected in expired air (Wu, 1991a).

         In a separate study, groups of 5 male and 5 female rats were
    given single doses of 1.5 mg/kg bw or 12 mg/kg bw 14C-moxidectin in
    corn oil by gavage. A third group of 15 male and 15 female rats was
    given oral doses of 1.5 mg/kg bw/day 14C-moxidectin for 7 days. In
    animals given single oral doses of moxidectin, 75-80% of the
    radioactivity was found in faeces and less than 1% in urine. Residues
    of moxidectin were 20 fold higher in fat than in other tissues and in
    the 7-day repeat-dose study there was no evidence of bioaccumulation.
    The depletion half-lives in fat, muscle and kidney/liver were 11.5,
    3.9 and 2.4 days, respectively (Wu, 1991b).

    2.1.1.2  Sheep

         Eight sheep were given single oral doses of 14C- or
    2H-moxidectin at a dose of 0.2 mg/kg bw. The total recovery of the
    administered dose was 52% in faeces and less than 1% in urine
    (Afzal, 1991a).

         After oral, i.v. or s.c. administration of 0.2 mg/kg bw
    14C-moxidectin to sheep, the tmax for total 14C in blood after
    oral dosing was 9 h with a Cmax of 9 g/kg moxidectin equivalents.
    The elimination half-life was 19.5 h. The latter was similar to the
    t1/2 after i.v. administration (26 h). Based on the relative AUCs
    for oral and i.v. dose groups, about 23% of the oral dose was
    absorbed. With s.c. dosing, the tmax was 8 h with a Cmax of
    12 g/kg equivalents. Average absorption of the s.c. dose was 76%
    (Afzal, 1991b).

         After oral doses of 0.2 mg/kg bw moxidectin, highest levels of
    residues were found in fat at 7, 14 and 21 days post-dosing
    (Berger, 1991; DeLay, 1991a).

         High levels of moxidectin were found in fat in a 14C study
    after oral and s.c. administration to sheep (Wu, 1990a; Wu, 1990b).

         Similar results were obtained in a preliminary study where sheep
    were given 2 s.c. injections, each of 0.2 mg/kg bw, 10 days apart
    (DeLay 1991a,b; DeLay, 1994; Mortimer, 1994).

    2.1.1.3  Deer

         Twenty red deer were treated with 0.5 mg/kg bw moxidectin as a 5%
    pour-on solution. Animals were sacrificed 7, 14, 21 or 28 days after
    treatment. Highest levels of residues were found in fat at 7
    (126 g/kg) and 28 days (31 g/kg), whereas levels in other tissues
    were low at day 7 (< 24 g/kg) (DeLay, 1993).

    2.1.1.4  Cattle

         A group of 3 cattle received a single s.c. injection of a mixture
    of 14C- and 2H-moxidectin at a dose of 0.2 mg/kg bw. Up to 58% of
    the dose was recovered in the faeces and 3% or less in urine. The
    highest levels of residues were found in fat (900, 635 and 275 g/kg
    at days 7, 14 and 28, respectively), with 109, 77 and 31 g/kg in
    liver, 42, 38 and 13 g/kg in kidney, and 21, 10 and 4 g/kg in muscle
    at days 7, 14 and 28, respectively. The half-lives for clearance from
    tissues were 12-14 days for fat, and 9-12 days for liver, kidney and
    muscle (Zulalian, 1991a).

         After s.c. administration of 0.2 mg/kg bw 14C-moxidectin to
    cattle, the Cmax in serum occurred 8 h after dosing with peak serum
    levels of 60 g/kg moxidectin equivalents. The elimination half-life
    was 56 h based on parent moxidectin, and 76 h based on radiolabel.
    There were no significant differences when i.v. doses of 0.2 mg/kg bw
    were given (Zulalian, 1991b).

         Several other studies have also demonstrated that fat is the
    target tissue for residues of moxidectin after topical or s.c.
    administration (DeLay, 1992a-d; Garces, 1992; Miller 1989; Rooney
    1991a). Similar findings were made in calves (Rooney, 1991b), and
    relatively high levels have been found at s.c. injection sites
    (Rooney, 1991c).

         Moxidectin was excreted in the milk of cattle given a s.c.
    injection of 0.2 mg/kg bw. Concentrations were 103 g/kg and 132 g/kg
    at the morning and afternoon milking the day after treatment, 23 g/kg
    on day 7, < 10-12 g/kg on day 21, and < 10 g/kg on day 22 after
    administration (Garces, 1994; Rooney, 1992).

    2.1.2  Biotransformation

    2.1.2.1  Rats

         After single oral doses of 1.5 or 12 mg/kg bw, or 1.5 mg/kg
    bw/day for 7 days, 85-99% was recovered in faeces, the major component
    being the parent drug (85%). Six minor metabolites were found in the
    liver and faeces. These were the 23-keto derivative, some
    monohydroxylated compounds, the C-14 hydroxymethyl and the C-4
    hydroxymethyl compounds. These metabo-lites were also noted after
    moxidectin was incubated  in vitro with rat liver microsomes
    (Wu, 1991b).

    2.1.2.2  Sheep

         In sheep given oral doses of moxidectin, the faecal metabolites
    and those found in the liver were qualitatively similar. The major
    faecal metabolite was the 9-monohydroxylated derivative of moxidectin,
    largely C-29/C-30 (Afzal 1991a).

    2.1.2.3  Cattle

         Five metabolites were identified in liver, kidney and muscle of
    cattle given moxidectin by topical application. Of these, two were
    identified as the C-29/C-30 metabolites and the C-14 hydroxymethyl
    derivative (Wu, 1992).

         In another study, faecal and tissue residues were found to be
    qualitatively similar. Six metabolites were identified as
    monohydroxylated and dihydroxylated derivatives of moxidectin. The
    main component was the C-29/C-30 hydroxymethyl derivative (Zulalian,
    1991).

    2.2  Toxicological studies

    2.2.1  Acute toxicity studies

         The results of acute toxicity studies with moxidectin are
    summarized in Table 1. Moxidectin was moderately toxic after oral and
    i.p. administration to rats and mice. It was somewhat less toxic after
    s.c. administration to these species, and of low toxicity to rabbits
    after dermal application to intact skin using a 24-h occlusive
    dressing.

         In the oral studies in mice, the main clinical signs were
    decreased activity; surviving animals had fully recovered by day 4. No
    gross abnormalities were seen in animals that died or in those killed
    at day 14. Similar findings occurred in mice given i.p. doses of
    moxidectin.

         In rats given oral doses of moxidectin, decreased activity,
    prostration, tremors, chromodacryorrhea, decreased respiration,
    diarrhoea, hypersensitivity to touch and sound, and epistaxis
    occurred. Congestion of the liver, kidneys and lungs were observed in
    animals that died, but animals which were sacrificed at the end of the
    14-day observation period showed no abnormalities. Similar signs and
    effects were noted in rats given i.p. doses of moxidectin.

         No overt signs of toxicity were noted in rabbits treated dermally
    with moxidectin.

    Table 1.  Acute toxicity of moxidectin
                                                                        

    Species      Sex         Route       LD50            Reference
                                         (mg/kg bw)
                                                                        

    Mouse        M & F       oral        84              Fischer, 1990a
                 F           oral        42              Fischer, 1990a
                 F           oral        50              Fischer, 1990b
                 M & F       i.p.        86              Fischer, 1990b
                 M & F       s.c.        263             Fischer, 1990c

    Rat          M & F       oral        106             Fischer, 1990d
                 M & F       i.p.        394             Fischer, 1990e
                 M & F       s.c.        >640            Fischer, 1990f
                 M & F       inhal.      3.28 mg/l       Hershman, 1991
                                         (5 h LC50)

                                                                        

         Cattle treated with up to 10-fold (2 mg/kg bw) the recommended
    therapeutic dose (0.2 mg/kg bw) by s.c. injection showed only mild
    depression and ataxia, which soon resolved. No adverse effects were
    seen at 3-fold (0.6 mg/kg bw) or 5-fold (1.0 mg/kg bw) the therapeutic
    dose (Goodale, 1989; Rooney, 1989a; Rooney 1989b).

         Dermal doses of 12.5 mg/kg bw (25 times the therapeutic dose)
    were not toxic to cattle (Epperson, 1993). Similar findings were
    observed in calves (Kieran & Cobb, 1992).

         No adverse effects were seen in lambs given 0.4 mg/kg bw or
    1.0 mg/kg bw (2- and 5-fold the therapeutic dose) by oral drench
    (Kieran & Cobb, 1991). The NOEL in sheep was 2.0 mg/kg bw (10-fold the
    therapeutic dose) after s.c. injection; doses above this produced
    salivation, diuresis, tremors, prostration and ataxia (Guerino, 1991).

    2.2.2  Short-term toxicity studies

    2.2.2.1  Mice

         Groups of CD-1 mice (5/sex/group) were given for 28 days 0, 34,
    75, 100, 125 or 150 mg/kg dietary moxidectin, equal to 0, 6.9, 18, 23,
    24 or 32 mg/kg bw/day.

         Signs of toxicity included tremors, hypersensitivity to touch,
    and urine-stained fur in mice given 18, 23 and 24 mg/kg bw/day.
    Mortality was high in the three highest dose groups (80-100%; all mice
    given the highest dietary level died). In the group given 18 mg/kg
    bw/day, 1 animal died but there were no deaths in the lowest dose
    group.

         No effects on haematology were noted in any of the dosed groups
    and there were no effects on absolute or relative organ weights. No
    gross or microscopic changes were observed in any of the treated
    animals. The NOEL in this study was 6.9 mg/kg bw/day (Fischer, 1989a).

    2.2.2.2  Rats

         Groups of Sprague-Dawley rats (5/sex/group) were given 0, 100,
    200, 400 or 600 mg moxidectin/kg of diet, equal to 0, 12, 23, 26 or
    31 mg/kg bw/day, for 28 days. Signs of toxicity were observed from day
    1 of the study in animals given the three highest doses. These
    included ataxia, tremors, salivation, piloerection and diuresis. At
    the lowest level, hypersensitivity to touch was noted in males on day
    2 (5/5) and 3 (1/5) of the study.

         All the animals in the two highest dose groups died by day 8, and
    2 female rats given 23 mg/kg bw/day died during the course of the
    study. There were no mortalities in the lowest dose group. Food
    intakes and body-weight gains were unaffected in the lowest dose group
    but were significantly depressed in the three highest dose groups.

         There were no effects on relative or absolute organ weights in
    any group attributable to moxidectin intake. At the two highest dose
    levels and in animals which died at the 23 mg/kg bw/day level, diffuse
    atrophy of the liver, kidneys, heart, spleen, adrenals, thyroid,
    testes, ovaries and epididymis occurred, which is typical of changes
    often seen in anorexic animals. There were no abnormalities in animals
    given the lowest dose level, nor in surviving rats given 23 mg/kg
    bw/day moxidectin. A NOEL was not identified in this study because
    hypersensitivity to touch was noted in several rats in the lowest
    dose group at days 2 and 3 (Fischer, 1988).

         Groups of Sprague-Dawley rats (10/sex/group) were given diets
    containing 0, 25, 50, 100 or 150 mg moxidectin/kg of feed, equal to
    0, 1.9, 3.9, 7.9 or 12 mg/kg bw/day, for 13 weeks. Signs of toxicity
    in animals given the highest dose included hypersensitivity to touch,
    lethargy, aggressive behaviour, tremors and urine-stained fur. At the
    7.9 mg/kg bw/day level, hypersensitivity to touch began on day 5 but
    cleared by day 14. No overt signs of toxicity were seen in rats given
    the two lowest doses. At the highest dietary level, 3 females died or
    were sacrificed in moribund condition.

         Food intake was reduced in animals given the highest dietary
    level of moxidectin for the first 2 weeks of the study. There was no
    effect on food intakes in any of the other groups when compared with
    control values. Body weights were depressed for the first 6 weeks in
    rats given the highest dose level, and were decreased for the
    remainder of the study. Body weights were also depressed in females
    given 7.9 mg/kg bw/day.

         Haematological values, clinical chemistry and urinalyses were
    unaffected by moxidectin treatment.

         Females given the highest dietary level had significantly
    increased absolute kidney and adrenal weights, and increases in
    relative kidney, liver, heart and adrenal weights. Significant
    increases in absolute and relative adrenal weights in females, and
    testes weights in males occurred at 7.9 mg/kg bw/day. These changes
    are probably related to decreases in body weight. No changes in organ
    weights occurred at the two lowest dietary intake levels.

         No gross or microscopic abnormalities were observed in any of the
    treatment groups. The NOEL in this study was 3.9 mg/kg bw/day
    (Fischer, 1989b).

    2.2.2.3  Dogs

         Groups of pure-bred beagle dogs (2/sex/group) were given diets
    containing 0, 20, 80 or 160 mg moxidectin/kg of feed, equivalent to
    0, 0.5, 2 or 4 mg/kg bw/day, for 28 days. At the highest dose, dogs
    developed anorexia, ataxia, prostration and diarrhoea. After day 5
    they were returned to a control diet for 2 days and then resumed for
    the remainder of the study on a diet containing 50 mg/kg of feed,
    equivalent to 1.25 mg/kg bw/day.

         Body weight and food consumption were depressed in dogs given the
    two highest doses, but these increased or remained stable after week
    1. In the two highest doses, tremors, a languid appearance, mydriasis,
    ataxia, emesis, prostration, dehydration, sensitivity to touch, slight
    salivation, no or few faeces and an inability to hold the head in the
    normal position were observed, but these effects resolved in the
    high-dose dogs after moxidectin intake was reduced. There were no
    signs of toxicity seen in those given the lowest dose.

         No haematological changes occurred and ophthalmoscopic
    examinations gave normal results. There were no gross abnormalities at
    necropsy but relative and absolute testes weights were reduced in dogs
    given the two highest doses. Histopathological examination revealed
    reductions in spermatogenetic activity in males given the two highest
    doses. In animals given 2 mg/kg bw/day, there was a slight decrease in
    colloid in the thyroid. The NOEL in this study was 0.5 mg/kg bw/day
    (Schulze, 1989a).

         In a 90-day study, groups of pure-bred beagle dogs (4/sex/group)
    were fed diets containing 0, 10, 30 or 60 mg moxidectin/kg of feed,
    equal to 0, 0.3, 0.9 or 1.6 mg/kg bw/day, for 90 days  At the highest
    dose, lacrimation, tremors, salivation, slight ataxia and a languid
    appearance were noted. Dose-dependent reductions in absolute body
    weights and food consumption were noted in dogs given the two highest
    doses. No other signs were noted and there were no deaths during the
    test period.

         No abnormalities in haematological parameters, ophthalmoscopic
    examinations or urinalyses were seen. Organ weights were comparable
    with controls except in the high-dose females (decrease in absolute
    heart weights) and high-dose males (slight decreases in absolute
    pituitary and pituitary to brain weight ratios). No microscopic
    abnormalities were seen. The NOEL in this study was 0.3 mg/kg bw/day
    (Schulze, 1989b).

         Groups of pure-bred beagle dogs (6/sex/dose) were given diets
    containing 0, 10, 20 or 45 mg moxidectin/kg of feed, equivalent to
    0, 0.26, 0.52 or 1.15 mg/kg bw/day, for 52 weeks. No signs of toxicity
    occurred and body weights remained comparable to controls throughout
    the study. There were no abnormalities in haematological parameters,
    clinical chemistry or urinalyses, and ophthalmoscopic examinations
    were normal. No gross or microscopic abnormalities were seen at
    necropsy. The NOEL in this study was 1.15 mg/kg bw/day
    (Schulze, 1991).

    2.2.3  Long-term toxicity/carcinogenicity studies

    2.2.3.1  Mice

         Groups of CD-1 mice (65/sex/group) were given diets containing
    0, 15, 30 or 60 mg moxidectin/kg of feed, equal to 0, 2.5, 5.1 or
    12 mg/kg bw/day, for 2 years. After 9 weeks on the study, the highest
    dose was reduced to 50 mg/kg of feed (7.9 mg/kg bw/day) because of
    increased mortality in this group.

         In the high-dose group, hunched-posture, decreased activity,
    tremors, laboured breathing and coldness to the touch were observed.
    During the last 13 weeks of the study, females in this group died or
    were sacrificed in extremis and 10 surviving females in this group
    were killed 2 days before scheduled sacrifice. No increase in

    mortality was seen in males in this group. No other clinical signs
    were evident in any of the other animals in all treated groups.

         Body weights were slightly reduced in high-dose males during
    weeks 0-8, probably because of reduced food intake. There were no
    haematological abnormalities in treated animals at 12, 18 or 24 months
    and no gross or microscopic changes were observed at termination.
    There was no increased incidence of any tumour type. The NOEL in this
    study was 5.1 mg/kg bw/day (Goldenthal, 1992).

    2.2.3.2  Rats

         Groups of Sprague-Dawley Crl:CD BR rats (65/sex/group) were given
    diets containing 0, 15, 60 or 120 mg moxidectin/kg of feed, equal to
    0, 0.8, 3.2 or 9.8 mg/kg bw/day, for 2 years. After 8 weeks on the
    study, the highest dose was reduced to 100 mg/kg (5.1 mg/kg bw/day)
    because of increased mortality in this group.

         During weeks 1-8, 4 of the high-dose females were found dead or
    were sacrificed in extremis. Signs of toxicity in this group included
    hunched posture, tremors, hyperactivity, rough haircoat, urine-stained
    fur, and hypersensitivity to external stimuli. These signs ceased when
    the dose was reduced to 5.1 mg/kg bw/day. No signs of overt toxicity
    were noted in the other treatment groups. Before the dose was reduced,
    high-dose females had body weights significantly lower than controls
    but these became similar to control values when the dose was reduced.

         After the 2-year treatment period, there were no abnormalities in
    haematological parameters, clinical chemistry or urinalyses. There
    were no adverse findings on ophthalmoscopic examination of treated
    rats. At termination, there were no gross or microscopic changes
    observed and there was no increased incidence of any tumour type. The
    NOEL in this study was 5.1 mg/kg bw/day (Zoetis, 1992).

    2.2.4  Reproductive toxicity studies

    2.2.4.1  Rats

         In a pilot single-generation (two litters) study, groups of COBS
    CD Sprague-Dawley derived rats (25/sex/group) were given diets
    containing 0, 25, 50 or 125 mg moxidectin/kg of feed, equal to 1.8,
    3.9 or 9.8 mg/kg bw/day for a 9-week period prior to mating and
    through gestation and lactation to produce the F1a litters. The
    dietary levels were reduced to 0, 5, 10 or 15 mg/kg, equal to 0, 0.4,
    0.8 or 1.1 mg/kg bw/day, for the F1b litter.

         At the highest dietary level, parental animals showed reductions
    in weight gains, a decrease in the number of live pups at birth and an
    increase in the number of dead pups at birth. All the live F1a pups
    died on days 0-4 of lactation.

         No adverse effects were seen in animals given the two lower dose
    levels of moxidectin. Mating, fertility, gestation length and numbers
    of pups born alive were comparable with controls. However, all the
    F1a pups died during lactation.

         No adverse effects were noted in parental animals following the
    reductions in doses for the F1b litter. Gestation length and litter
    size were also unaffected. At the mid-dose level, there was a
    reduction in pup survival rate at days 4-21, while in the high-dose
    group, mean pup weights were reduced at days 4, 7, 14 and 21 of
    lactation and pup survival at days 0-14 and 4-21 of lactation was
    lower than in controls. There were no effects on pups in the lowest
    dose group.

         Gross examination of the parental animals and of the F1b pups
    from treated rats showed no adverse effects. The NOEL in this study
    was 0.4 mg/kg bw/day for the F1b animals (Schroeder, 1991).

         In a 3-generation (2 litters) study in COBS CD Sprague-Dawley-
    derived rats, groups of 25 males and 25 females were given diets
    containing 0, 1, 2, 5 or 10 mg moxidectin/kg of feed, equal to 0,
    0.07, 0.15, 0.41 or 0.83 mg/kg bw/day for a 70-day period prior to
    mating. Randomly selected offspring (F1b and F2b) were
    selected to produce the ensuing generations, while randomly selected
    offspring of the F1b, F2b and F3b generations were sacrificed
    and examined for gross abnormalities. Selected tissues from these
    animals (reproductive organs, pituitary and gross lesions from
    parental animals) were subject to microscopic examination.

         No excess mortality was seen in any of the parental generations
    (P1, F1 or F2). No adverse effects were seen in the 0.07, 0.15
    or 0.41 mg/kg bw/day treatment groups with respect to growth, food
    consumption, maternal weight changes during gestation and lactation,
    reproductive performance or fertility indices. Pup weights, sex
    distribution and pup survival were comparable with controls.

         At the highest dietary level, slight reductions in weight were
    seen in males during the pre-mating (F2), mating and post-mating
    periods (F1 and F2). Significant reductions in pup survival
    indices were noted for days 0-21 for the F1a litters, and for days
    0-4 for the F2a litters. Other parental and neonatal parameters were
    unaffected by compound administration.

         Gross examination of the P1, F1 and F2 parental animals and
    of selected F1b, F2b and F3b animals showed no compound-related
    effects while microscopic examination of primary and secondary sex
    organs revealed no abnormalities. The NOEL in this study was 0.4 mg/kg
    bw/day (Schroeder, 1992).

    2.2.4.2  Dogs

         As part of a target species safety study, adult male beagle dogs
    were given oral doses of 9 g moxidectin/kg bw, once every 30 days for
    4 consecutive months. Semen quality, breeding ability and performance
    were unaffected and there were no gross or microscopic adverse effects
    seen at necropsy (Rooney, 1993a).

    2.2.4.3  Cattle

         There were no effects on ovulation, folliculogenesis, post-
    ovulation or pregnancy in estrous cycling cows when animals were
    given 0.6 mg moxidectin/kg bw by s.c. injection (Wang, 1991c).

         No effects were noted in bulls given 3-fold the therapeutic dose
    (0.6 mg/kg bw) of moxidectin by s.c. injection; semen quality was
    normal as was palpation of the seminal vesicles and testes. The
    circumference of the scrotum was normal (Wang, 1992).

    2.2.5  Special studies on embryotoxicity and/or teratogenicity

    2.2.5.1  Rats

         Groups of 25 pregnant Crl:CD Sprague-Dawley BR rats were given
    gavage doses of 0, 2.5, 5, 10 or 12 mg/kg bw/day moxidectin in corn
    oil from days 6-16 of gestation, when the animals were killed by
    carbon dioxide asphyxiation. No deaths occurred in this study, but the
    12 mg/kg bw/day dose resulted in urine-stained fur, and chromo-
    dacryorrhea. The 10 and 12 mg/kg bw/day doses resulted in
    significant decreases in maternal body weights and decreases in food
    consumption. In the post-dosing period (16 to 20 days of gestation),
    significant increases in food consumption and body weights occurred in
    these animals. However, the body weights were still reduced compared
    with controls, even after a correction for gravid uterine weights was
    made.

         Administration of 10 and 12 mg/kg bw/day resulted in significant
    increases in the total number of fetuses with abnormalities, typified
    by increased incidences of cleft palate and wavy or incompletely
    ossified ribs. No other effects were seen and it is likely that these
    abnormalities were due to embryotoxic effects or maternal toxicity.
    There was no evidence of teratogenic effects and the NOEL in this
    study was 5 mg/kg bw/day (Lochry, 1989).

    2.2.5.2  Rabbits

         Groups of 18 pregnant Hra:(NZ)SPF rabbits were given gavage doses
    of 0, 1, 5 or 10 mg/kg bw/day moxidectin in corn oil from days 7-19 of
    gestation, when the animals were sacrificed. No deaths occurred in
    this study, but 1 control and 1 high-dose rabbit died as a result of
    gavage accidents. Two low-dose animals and 1 high-dose animal aborted
    during the course of the study, which was not considered to be
    compound-related and the incidence was within the range for historical
    controls.

         Dose-related decreases in body weights occurred at 5 and
    10 mg/kg bw/day, accompanied by decreases in feed intake, but
    pregnancy rates in all treated groups were similar to control values.
    There were no effects on numbers of corpora lutea, implantations or
    resorptions when compared to control values, and fetal body weights
    and sex ratios were similar in all groups.

         There was no increased incidence of external, soft tissue or
    skeletal abnormalities in any dosed group when compared with controls.
    On the basis of maternal effects demonstrated by depression in
    body-weight gains, the NOEL in this study was 1 mg/kg bw/day. There
    was no evidence of teratogenicity up to the highest dose employed in
    this study (Hoberman, 1989).

    2.2.5.3  Dogs

         As part of a target animal safety study, a group of 24 pregnant
    beagle dogs was given orally 9 g/kg bw moxidectin (3-fold the
    therapeutic dose) from day 12 of gestation until day 42 of lactation.
    There were no effects on the outcome of pregnancy and no abnormalities
    were seen in pups from treated dogs (Rooney, 1993b).

    2.2.5.4  Cattle

         No adverse effects were seen in cattle when moxidectin, as a
    single s.c. injection, was given in the first, second or third
    trimester of pregnancy to a total of 135 animals, using a dose of
    0.6 mg/kg bw (3-fold the recommended therapeutic dose) (Wang, 1991a).

         No adverse effects were noted in another study where 15 pregnant
    cows were given a single s.c. injection of 0.2 mg/kg bw during the
    first, second or third trimester of pregnancy (Wang 1991b).

    2.2.5.5  Sheep

         The outcome of pregnancy was unaffected when a group of 20
    animals was given a single s.c. injection of 0.4 mg/kg bw moxidectin
    (2-fold the therapeutic dose) at unspecified periods of pregnancy
    (Parker, 1994). Similar findings were made in other studies
    (Cobb, 1994).

    2.2.5.6  Horses

         Breeding and pregnant mares received oral doses of 1.2 mg/kg bw
    moxidectin (3-fold the therapeutic dose) every 2 weeks during
    gestation, or for various periods post-foaling. Moxidectin treatment
    did not affect the outcome of pregnancy (American cyanamid, 1993).

    2.2.6  Special studies on genotoxicity

         The results of genotoxicity studies with moxidectin are
    summarized in Table 2. Moxidectin was not mutagenic in the Ames test,
    in a forward mutation assay with E. coli, or in a test using mammalian
    cells  in vitro. A negative result was obtained in an  in vivo study
    for chromosome aberrations in rat bone marrow cells. It did not induce
    UDS in primary rat hepatocytes.

    2.2.7  Special studies on skin irritation

         Only mild signs of skin irritation were seen in New Zealand white
    rabbits exposed to moxidectin for periods of up to 72 h (Fischer,
    1990 g,h).

    2.2.8  Special studies on eye irritation

         Moderate signs of eye irritation were noted when moxidectin
    (0.1 g) was instilled into the conjunctival sac of New Zealand white
    rabbits. The irritation resolved 48-72 h after treatment
    (Fischer, 1990i).

    2.2.9  Special studies on dermal sensitization

         No evidence of skin sensitization was seen when male Hartley
    guinea-pigs were exposed to moxidectin using the Buehler method. The
    positive control, 1-chloro-2,4-dinitrobenzene gave the expected
    positive response (Ventura, 1990).

    2.2.10  Special studies on pharmacodynamic effects

         In a radioligand binding study, moxidectin stimulated the
    t-butyl-bicyclophosphorothionate binding to rat cortical membranes in
    a similar manner to ivermectin. In another study, the drug stimulated
    the binding of flunitrazepam to rat brain membranes. Such studies
    suggest that moxidectin has activity at the GABA-A receptor in a
    manner similar to ivermectin, and this may contribute to its mode of
    action against parasites. However, it is known that ivermectin has
    more than one mechanism of action and this is also likely to be true
    of moxidectin (Ingle & Wood, 1990).

         Moxidectin was investigated in a variety of screening tests for
    pharmacodynamic action. It had no CNS effects, nor any effects on
    motor activity, blood pressure, heart rate or respiration rate, and
    did not cause haemolysis of sheep red blood cells. It did induce weak
    contractions or relaxation of tracheal smooth muscle but these were
    not antihistamine or anticholine smooth muscle induced effects. It
    also increased GI motility in guinea-pig isolated ileum (Ingle, 1990).
        Table 2.  Results of genotoxicity studies on moxidectin
                                                                                              

    Test system      Test object            Concentration       Results     Reference
                                                                                              

    Ames test1       S. typhimurium
                     TA98, TA100,           50-300 g/          neg.        Traul 1990a
                     TA1535, TA1537,        plate
                     TA1538

    Reverse
    mutation         E. coli                50-2000 g/         neg.        Traul 1990a
    assay1           WP2 uvrA-              plate

    Forward
    mutation         CHO (HGPRT locus)      0.01-15 g/ml       neg.        Traul 1990b
    assay1

    In vivo

    cytogenetics     Rat bone marrow        0-150 mg/kg         neg.        Sharma 1990
    assay                                   bw

    UDS              Primary rat            0.1-30 g/ml        neg.        Curren 1990
                     hepatocytes
                                                                                              

    1    Both with and without rat liver S9 fraction.
    

    3.  COMMENTS

         The Committee considered data from pharmacodynamic,
    pharmacokinetic, metabolism, acute and short-term toxicity,
    carcinogenicity, genotoxicity, reproductive toxicity and
    teratogenicity studies.

         The pharmacokinetics and metabolism of moxidectin were studied in
    rats, sheep and cattle. After oral administration to sheep, about 20%
    of the dose was absorbed. The drug, which is very lipophilic, was
    found at high levels in fat, but at much lower levels in other
    tissues. It was excreted in the milk. After oral administration to
    rats, the major compound recovered in faeces was the parent drug,
    while small amounts of hydroxylated metabolites were found in liver
    and faeces. Hydroxylated metabolites were observed in sheep and cattle
    given oral doses of the drug.

         Orally administered moxidectin was found to be moderately toxic
    with LD50 values of the order of 50-100 mg/kg bw.

         In a 28-day oral toxicity study in mice in which moxidectin was
    administered in the feed, signs of toxicity included tremors and
    hypersensitivity to touch. All mice given the highest dose of 32 mg/kg
    bw/day died. The NOEL in this study was 6.9 mg/kg bw/day.

         Rats given up to 31 mg moxidectin/kg bw/day in a 28-day feeding
    study developed ataxia, tremors, salivation, piloerection and
    diuresis. At 23 mg/kg bw/day and above, dose-related diffuse atrophy
    of the liver, kidneys, heart, spleen, adrenals, testes, epididymis and
    ovaries was seen. A NOEL was not identified in this study because
    hypersensitivity to touch was noted in the lowest-dose group (12 mg/kg
    bw/day) at days 2 and 3. Similar findings were noted in a 13-week
    feeding study in rats, in which the NOEL was 3.9 mg/kg bw/day.

         In a 28-day toxicity study in dogs given up to 4 mg of
    moxidectin/kg bw/day in the feed, animals given the highest dose
    developed anorexia, ataxia, prostration and diarrhoea until the dose
    was reduced to 1.25 mg/kg bw/day. The NOEL was 0.5 mg/kg bw/day. In a
    90-day feeding study in dogs, lacrimation, tremors, salivation and
    slight ataxia were noted in animals given the highest dose of
    1.6 mg/kg bw/day. No major histopathological changes were observed in
    this study. The NOEL was 0.3 mg/kg bw/day. No signs of toxicity were
    noted in a 52-week feeding study in dogs. The NOEL was 1.15 mg/kg
    bw/day, the highest dose used.

         A pilot single-generation reproductive toxicity study was
    performed in rats, in which moxidectin was administered at doses of up
    to approximately 10 mg/kg bw/day for a 9-week period before mating and
    during gestation and lactation. None of the offspring of animals in

    the highest-dose group survived. Survival rates were decreased in the
    progeny of animals given lower doses, but there were no findings which
    could be attributed to effects on fertility. The NOEL in this study
    was 0.4 mg/kg bw/day. In a three-generation reproductive toxicity
    study in rats given doses of up to 0.83 mg/kg bw/day for a 70-day
    period before mating, there were no effects on mortality or on
    fertility except at the highest dose, where slight reductions in male
    body weights and significant reductions in pup survival were seen. The
    NOEL was 0.4 mg/kg bw/day.

         In a teratogenicity study in rats dosed at 10 or 12 mg
    moxidectin/kg bw/day, there was evidence of both materno- and
    fetotoxicity, as shown by increased incidences of cleft palate and
    wavy or incompletely ossified ribs. There was no evidence of
    teratogenic effects, and the NOEL in this study was 5 mg/kg bw/day. In
    a teratogenicity study in rabbits, there was evidence of materno-
    toxicity at 5 and 10 mg/kg bw/day, but no evidence of fetotoxicity
    or teratogenicity. The NOEL in this study, based on maternal effects,
    was 1 mg/kg bw/day.

         In a long-term toxicity/carcinogenicity study in CD-1 mice,
    moxidectin was administered in the diet at concentrations equal to
    0, 2.5, 5.1 or 12 mg/kg bw/day for 2 years. After 9 weeks, the highest
    dose was reduced to 7.9 mg/kg bw/day because of toxic effects that
    included deaths, hunched posture, decreased activity, tremors and
    laboured breathing. There were no effects on haematological parameters
    and no increases in the incidence of any types of tumour were
    observed. The NOEL was 5.1 mg/kg bw/day.

         A 2-year toxicity/carcinogenicity study was conducted in
    Sprague-Dawley rats which were given moxidectin in the diet at
    concentrations equal to 0, 0.8, 3.2 or 9.8 mg/kg bw/day. After 8
    weeks, the highest dose was reduced to 5.1 mg/kg bw/day because of
    signs of toxicity that included hunched posture, tremors,
    hyperactivity, urine-stained fur and hypersensitivity to external
    stimuli. At the end of the 2-year period there was no evidence of
    toxicity and no increased incidence of any type of tumour. The NOEL
    was 5.1 mg/kg bw/day. The Committee concluded that moxidectin has no
    carcinogenic potential.

         Moxidectin has been tested in bacterial mutation assays, in a
    forward mutation assay in Chinese hamster ovary cells, in a test for
    UDS in primary rat hepatocytes, and in an  in vivo cytogenetic assay
    in rat bone marrow. All gave negative results, and the Committee
    concluded that moxidectin had no genotoxic potential.

    4.  EVALUATION

         The Committee concluded that the most relevant effects for the
    toxicological evaluation of moxidectin were those observed in the
    90-day study in dogs, where the NOEL was 0.3 mg/kg bw/day. Based on
    this NOEL and using a safety factor of 200 to account for the
    uncertain sensitivity of the test system used to assess the
    neurotoxicity of moxidectin (Annex 1, reference 119, section 2.2), the
    Committee established an ADI of 0-2 g/kg bw for moxidectin. The ADI
    was rounded to one significant figure, consistent with accepted
    rounding procedures (Annex 1, reference 91, section 2.7). This ADI
    provides an adequate margin of safety for the effects noted in the
    reproductive toxicity studies in rats.

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    Unpublished report No. PD-M Volume 28-49. Submitted to WHO by American
    Cyanamid Company, Princeton, NJ, USA.
    


    See Also:
       Toxicological Abbreviations
       MOXIDECTIN (JECFA Evaluation)