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    ANTHELMINTHIC AGENTS

         The Committee considered doramectin, which belongs to the
    avermectin class of compounds, and moxidectin, which belongs to the
    milbemycin class of compounds. Doramectin and moxidectin share a
    number of structural similarities with each other and with abamectin
    and ivermectin. Ivermectin was previously evaluated at the thirty-
    sixth and fortieth meetings of the Committee (Annex 1, references 91
    and 104). The structures of these compounds are shown in Fig. 1.

         The Committee also considered the benzimidazoles febantel,
    fenbendazole and oxfendazole, which were previously evaluated at the
    thirty-eighth meeting (Annex 1, reference 97).

         Figure 1. Chemical structures of doramectin, ivermectin,
    abamectin and moxidectin

    CHEMICAL STRUCTURE 1

    DORAMECTIN

    First draft prepared by
    Dr G. Roberts
    Toxicology Evaluation Section
    Department of Human Services and Health
    Canberra, Australia

    Explanation

    Biological data
         Biochemical aspects
         Absorption
         Metabolism
         Pharmacological effects

    Toxicological studies
         Acute toxicity studies
         Short-term toxicity studies
         Reproductive toxicity studies
         Special studies on neonatal toxicity
         Special studies on embryotoxicity and teratogenicity
         Special studies on genotoxicity
         Special studies on permeability of blood-brain barrier
         Special studies on pharmacology

    Comments

    Evaluation

    References

    1.  EXPLANATION

         Doramectin is the fermentation product of a specific strain of
     Streptomyces avermitilis that has close structural similarities with
    abamectin and ivermectin. It is used as an endoparasitic agent in
    non-lactating cattle. Doramectin had not been previously reviewed by
    the Committee.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

    2.1.1  Absorption

    2.1.1.1  Rats

         Groups of 5 Long-Evans rats were administered single doses of
    doramectin as follows:

         A - 3 mg/kg bw given over a 2-hour period in the diet
         B - 5 mg/kg bw in methyl cellulose vehicle
         C - 5 mg/kg bw in sesame oil vehicle

         Peak drug levels were achieved in 3 h for groups A and B, and at
    7 h for group C. Maximum levels were 0.06, 0.06 and 0.36 g/ml,
    respectively. The areas under the plasma concentration-time curves
    (AUC) were 1.65, 1.71 and 9.69 g-h/ml for groups A, B, and C,
    respectively (Pfizer, 1987a).

    2.1.2  Metabolism

         Doramectin labelled with tritium in the 5-position was
    administered as a single dose to Sprague-Dawley rats (2 males given
    5 mg/kg bw in propylene glycol:glycerol by gavage), a beagle dog
    (1 female given 3.5 mg/kg bw in sesame oil by gavage) and cattle
    (5 males given 0.2 mg/kg bw subcutaneously). The liver and faeces from
    each species and the fat of cattle were sampled for characterization
    of metabolites by liquid chromatography (Pfizer, 1992a).

         In a second experiment, 2 male and 2 female cattle were given a
    single s.c. injection of 0.2 mg/kg bw 3H-doramectin. Metabolites in
    liver and fat were analyzed by liquid chromatography (Pfizer, 1993a).

         As shown in Table 1, the metabolites detected in liver and faeces
    from each species were similar in nature indicating comparable
    degradation pathways in rats, dogs and cattle.

        Table 1.  Percent of tritium radiolabel recovered from sample.
                                                                                                             

                                                                                           24-hydroxymethyl-
                       Total         Unchanged     3"-O-desmethyl     24-hydroxymethyl     3"-O-desmethyl
                       recovered     doramectin    doramectin         doramectin           doramectin
    Sample                (%)           (%)           (%)                (%)                  (%)
                                                                                                             

    Rat liver             37            18            12                  3                    2
    Rat faeces            na            22            19                 14                   16

    Dog liver             51            28            12                 nd                   nd
    Dog faeces            46             6             8                  5                    4

    Cattle liver          95            70             9                 nd                    7
    Cattle faeces         75            24            14                 5                     4
    Cattle fat *          79            68            nd                 nd                   nd

    Cattle liver          82            49            5.7                3.6                  6.6
    Cattle fat #          82            75            nd                 nd                   nd
                                                                                                             

    na   not available
    nd   not detected
    *    8% of radioactivity was associated with mixed fatty acid esters of 24-hydroxymethyl
         doramectin but structural identification was not pursued.
    #    6% of radioactivity was identified as the 2-epimer of doramectin.
    
         The metabolism of doramectin in mammals is presented in Figure 1.

    Figure 1. Metabolic pathway of doramectin in mammals

    CHEMICAL STRUCTURE 2

    2.1.3  Pharmacological effects

         Avermectins induce rapid, non-spastic paralysis in nematodes and
    arthropods. One common feature of avermectins appears to be the
    modulation of trans-membrane chloride ion (Cl-) channel activity in
    nematode nerve cells, and in both nerve and muscle cells of
    arthropods. These Cl- channels may be gated by a variety of
    neurotransmitter receptors including gamma-aminobutyric acid (GABA),
    glutamate and acetylcholine (Kass  et al, 1984; Duce & Scott, 1985;
    Zufall  et al, 1989). Activation of the Cl- channels by avermectins
    leads to an increase in Cl- conductance which results in a changed
    membrane potential and this causes inhibition of electrical activity
    in the target nerve or muscle cell. GABA is also a major inhibitory
    neurotransmitter in the mammalian CNS and avermectins do have
    intrinsic activity on the mammalian GABA receptor/Cl- channel
    complex.

         Avermectins have been reported to bind to glycine receptor/Cl-
    channel complexes which are restricted to the CNS in mammals
    (Graham  et al, 1982). Penetration of the blood brain barrier by
    avermectins is extremely poor and this may account for the wide margin
    of safety exhibited by these compounds following administration to
    mammals.

    2.2  Toxicological Studies

    2.2.1  Acute toxicity studies

         The results of acute toxicity studies with doramectin are
    summarized in Table 2.

         Clinical signs of toxicity were similar in both mice and rats and
    by both routes of administration, the most common being decreased
    activity and respiration, hunched position, shakiness, weakness,
    tremors, ataxia and weight loss.

         Doramectin was applied to normal and abraded skin of 3 New
    Zealand white rabbits (0.5 g under an occlusive patch) for 24 h.
    Slight erythema was observed 24 and 48 h post-dose at 1 of 3 intact
    sites and 2 of 3 abraded sites. There was no edema at any site and all
    sites appeared normal 72 h post-dose.

        Table 2.  Results of acute toxicity studies with doramectin.
                                                                                              

    Species
    (strain)            Route     Vehicle1      Sex       LD50 in mg/kg bw2       Reference
                                                                                              

    Mouse               po        aqueous       M&F       > 2000(0/3)             Pfizer, 1988a
    (CD-1)
                        po        oil           F         250(0/3)-500(3/3)       Pfizer, 1992b

                        po        oil           F         75(0/5)-200(5/5)        Pfizer, 1994a

                        ip        aqueous       M         700(0/3)-1000(2/3)      Pfizer, 1988a

                        ip        oil           M         100(0/3)-250(3/3)       Pfizer, 1992b

    Rat                 po        aqueous       M         1000(0/3)-2000(3/3)     Pfizer, 1988a
    (Sprague-Dawley)                            F         500(0/3)-1000(2/3)      Pfizer, 1988a

                        po        oil           M         50(0/3)-100(2/3)        Pfizer, 1992b
                                                F         100(1/3)-200(3/3)       Pfizer, 1992b

                        ip        aqueous       M         >300(1/3)               Pfizer, 1988a

                        ip        oil           M         50(0/3)-100(3/3)        Pfizer, 1992b
                                                                                              

    1    aqueous vehicle was 0.1% aqueous methylcellulose; oil vehicle was sesame oil.
    2    figures in brackets represent mortality incidences.
             Doramectin powder (18.8 mg) was instilled into the conjunctival
    sac of one eye in each of 3 New Zealand white rabbits. Slight corneal
    and conjunctival reddening, chemosis and iritis were seen within 1 h
    of dosing. The changes subsided within 6 h and all eyes were normal by
    48 h post-dose (Pfizer, 1991a).

         A comparison of the acute toxicity of different ivermectins in
    mice is given in Table 3.

        Table 3.  Acute oral toxicity of doramectin in comparison with abamectin, ivermectin
              and moxidectin in female CD-1 mice (Pfizer, 1994a).
                                                                                              

    Dose in mg/kg bw1       Doramectin     Abamectin      Ivermectin     Moxidectin
                                                                                              

    Maximum
    "asymptomatic" dose     25                            5              255

    Minimum
    "symptomatic" dose      75                            25             5025

    Minimum
    lethal dose2            200(5/5)       75(5/5)        75(1/5)        75(4/5)

    LD50 dose               75-200         25-75          >75            25-75
                                                                                              

    1 -  vehicle was sesame oil
    2 -  figures in brackets represent mortality incidences.
             Signs of CNS toxicity were similar after dosing with each
    compound and included gait abnormalities with splayed hind limbs,
    intermittent tremors, ataxia and decreased, irregular or laboured
    respiration (Pfizer, 1994a).

    2.2.2  Short-term toxicity studies

    2.2.2.1  Mice

         Groups of CD-1 mice (10/sex/dose) were administered doramectin
    (purity 94.1%) in the diet for 43 days. Target doses were 0, 10, 20,
    40, or 60 mg/kg bw/day on days 1 to 14; 0, 10, 20, 80 or 100 mg/kg
    bw/day on days 15 to 28; and 0, 100, 200, 400 or 600 mg/kg bw/day
    on days 29 to 43.

         Toxic signs included lethargy, hunched posture and tremors at 400
    and 600 mg/kg bw/day, and hunched and ungroomed appearance in some
    mice at 100 and 200 mg/kg bw/day. A number of animals given 400 and
    600 mg/kg bw/day were sacrificed moribund and the remaining mice in
    these groups were killed on day 33. There were no effects on body
    weight or food consumption. Relative liver weights were slightly
    higher in most treated groups but the changes were minor and not
    dose-related. Clinical laboratory parameters and pathological
    examinations were not carried out.

         Plasma drug levels were dose-related, although non-linear, up to
    100 mg/kg bw/day, and reached a plateau at higher doses. Drug levels
    ranged from 0.23 g/ml at 10 mg/kg bw/day to 3.9 g/ml at 600 mg/kg
    bw/day. An unidentified degradation product, represented a
    progressively greater fraction of drug-related material at doses of
    100 mg/kg bw/day and above (Pfizer, 1994b).

         Groups of CD-1 mice (10/sex/group) were fed doramectin (purity
    94.1%) in the diet for 92 days. Target doses were 0, 100, 200 or
    300 mg/kg bw/day. Actual doramectin intake was 83-121, 154-191 or
    221-322 mg/kg bw/day. Tremors, hunched posture, unkempt appearance and
    lethargy were observed at the mid- and high-dose groups and resulted
    in death or moribund sacrifice of 9 mice at 300 mg/kg bw/day and 3
    mice at 200 mg/kg bw/day. The remaining animals in these two groups
    were killed on day 12 or 19, respectively. Body-weight gain was
    depressed in association with reduced food consumption at 200 mg/kg
    bw/day and above.

         Serum creatinine and BUN were slightly increased at 100 mg/kg
    bw/day with no effects at higher doses, presumably due to early
    culling of mice in these groups. Haematological parameters were
    unaffected. All treated groups had increased liver weights and
    hypertrophy of centrilobular hepatocytes, with multinucleate
    non-proliferative liver cells at 100 mg/kg bw/day only. Dead and
    moribund animals showed lymphocyte lysis in lymphoid organs, cellular
    depletion of bone marrow and necrosis of the adrenal cortex which may
    have resulted from stress and weight loss.

         Satellite groups of 3 mice/sex/dose were used to determine plasma
    drug levels. In the 100 mg/kg bw/day group, concentrations reached a
    plateau at 2.8 g/ml by day 45. Doramectin levels were not markedly
    different at higher doses with peaks of 3.6 g/ml and 2.7 g/ml at 200
    and 300 mg/kg bw/day, respectively. An unidentified degradation
    product was present at levels proportional to both dose and duration
    of treatment (Pfizer, 1994c).

    2.2.2.2  Rats

         Groups of Long-Evans rats (3/sex/group) were given 0, 2.5, 5 or
    10 mg/kg bw/day doramectin (purity unspecified) in the diet for 14
    days. There were no overt signs of toxicity and no effects on body
    weight, haematology, serum chemistry, urinalysis, liver or kidney
    weight. Examination of a limited number of organs revealed no
    pathological changes. Mean plasma drug levels at day 10 were
    approximately 0.05, 0.06 and 0.17 g/ml with increasing doses
    (Pfizer, 1987b).

         In a 1-month study, groups of Long-Evans rats (10/sex/group) were
    fed doramectin (purity 95.3%) in the diet at dose levels of 0, 5, 10
    or 20 mg/kg bw/day. There were no clinical signs of toxicity and no
    effects on food intake or body-weight gain. Ophthalmology,
    haematology, serum chemistry and urinalysis were unaffected. Liver
    weight was slightly increased in males given 20 mg/kg bw/day but
    pathological examination was unremarkable. Plasma drug levels were
    proportional to the dose; maximum concentrations achieved were 0.28,
    0.76 and 1.79 g/ml, respectively. The NOEL in this study was 10 mg/kg
    bw/day (Pfizer, 1988b).

         Groups of Long-Evans rats (10/sex/group) were fed a diet
    containing doramectin (purity 94.1%) at levels intended to give 
    target doses of 0, 20, 40, 60 or 80 mg/kg bw/day for 38 days.
    Chromorhinorrhea, chromodacryorrhea and urogenital staining were seen
    at 40 mg/kg bw/day and above. Whole body tremors were also present at
    the two highest doses and resulted in the sacrifice of 2 rats at
    60 mg/kg bw/day and all rats at 80 mg/kg bw/day. Body-weight gain and
    food consumption were lower at 60 mg/kg bw/day and above. Serum
    5'-nucleotidase was increased at 80 mg/kg bw/day with elevated levels
    of BUN at 40 mg/kg bw/day and above. Liver weights were higher in the
    40 and 60 mg/kg bw/day groups but with no dose relationship. Organs
    were not examined for pathology.

         Satellite groups of 3 rats/sex/dose were used for plasma drug
    determinations. Doramectin concentrations were progressively increased
    throughout the study at each dose, and levels were dose-related up to
    60 mg/kg bw/day with no further increase at 80 mg/kg bw/day. Highest
    levels were 0.89, 3.52, 3.78 and 3.54 g/ml at the 4 doses,
    respectively (Pfizer, 1993b).

         Groups of Long-Evans rats (5/sex/group) were administered by
    gavage doses of 0, 2, 5 or 10 mg/kg/bw/day doramectin (purity 92.1%)
    in sesame oil for 38 days. Three females in the 10 mg/kg bw/day group
    were sacrificed after showing hunched appearance, ataxia, tremors and
    urine stains. There were no effects on body weight, food consumption,
    haematology, serum chemistry or urinalysis. Some rats given 5 and
    10 mg/kg bw/day had increased liver weights but pathological
    examination of a limited number of organs was unremarkable. Plasma
    drug levels were similar on days 10 and 38 and were dose-related;
    approximate levels were 0.5, 1.6 and 3.0 g/ml in the low-, mid- and
    high-dose groups, respectively (Pfizer, 1989a).

         Groups of Long-Evans rats (10/sex/dose) were fed doramectin
    (purity 89.7%-94.1%) in the diet at target doses of 0, 30, 40 or
    50 mg/kg bw/day, for 92 days. Based on food consumption, actual
    doramectin intake ranged from 16-32, 11-49 and 14-59 mg/kg bw/day,
    respectively. Thus systemic exposure to doramectin was similar in each
    treated group which was reflected in the toxicological findings.

         Clinical signs, noted in all treated animals, included
    chromorhinorrhea, chromodacryorrhea, urine stains and tremors. Seven
    rats at 30 mg/kg bw/day, all rats at 40 mg/kg bw/day, and 19 rats at
    50 mg/kg bw/day died or were sacrificed moribund. Body-weight gain was
    markedly reduced in all treated groups in association with diminished
    food intake. Ophthalmological examinations were unchanged. All treated
    groups showed decreased leucocytes, erythrocytes, haemoglobin and
    haematocrit, and increased BUN. Serum levels of ALAT and ASAT were
    increased and protein decreased in some animals given 40 and 50 mg/kg
    bw/day. Urinalysis was unaffected.

         At necropsy, animals which failed to survive the treatment period
    showed minimal body fat and a few had stomach erosions. Apparent
    increases in relative kidney and testes weights in treated groups were
    probably due to the lower body weights. Pathological changes, observed
    in all treated groups, comprised kidney nephrosis with protein
    accumulation in the corticomedullary junction, hepatocyte atrophy with
    occasional necrotic cells and haemosiderosis, lymphoid depletion in
    thymus, spleen and mesenteric lymph node, bone marrow atrophy, and
    lipid depletion in the adrenal cortex.

         Satellite groups of 5 rats/sex/dose were treated in order to
    determine plasma drug levels. Doramectin plasma concentrations
    increased during the course of the study in the 30 and 40 mg/kg bw/day
    groups, attaining levels of 4.6 and 5.8 g/ml, respectively. A maximum
    level of 4.1 g/ml was achieved by day 16 in rats given 50 mg/kg
    bw/day (Pfizer, 1994d).

         Groups of Long-Evans rats (20/sex/dose) were selected from the
    F1 offspring in a multigeneration reproductive toxicity study in
    which doramectin was administered by gavage at doses of 0, 0.1, 0.3 or
    1.0 mg/kg bw/day. Thus the animals had received secondary exposure in
    utero and during lactation, and direct exposure for 3 to 4 weeks
    post-weaning. Subsequently, the respective groups were administered
    gavage doses of 0, 0.5, 2 or 8 mg/kg bw/day doramectin (purity 92.5%)
    in sesame oil for 3 months.

         There were no overt signs of toxicity, mortality or treatment-
    related ocular lesions. Initial body weights of the 8 mg/kg bw/day
    group were lower which may be attributed to the prior in utero
    or neonatal exposure to doramectin. During the course of the study
    proper, treated groups gained more weight than controls. Food
    consumption, haematology, serum chemistry and urinalysis were
    unaffected. Liver and kidney weights were increased at 8 mg/kg bw/day
    but there were no concomitant pathological alterations.

         Satellite groups of 3 rats/sex/dose were used for plasma drug
    determinations. Doramectin levels were dose-related with mean levels
    of 0.07, 0.4 and 2.5 g/ml on day 3, and 0.1, 0.7 and 3.2 g/ml on day
    87, in the low-, mid-, and high-dose groups, respectively. The NOEL in
    this study was 2 mg/kg bw/day (Pfizer. 1990a).

    2.2.2.3  Dogs

         Groups of beagle dogs (1/sex/group) were fed doramectin (purity
    unspecified) in the diet at dose levels of 0, 0.5, 1 or 2 mg/kg bw/day
    for 14 days. There were no signs of toxicity or effects on body
    weight, haematology, serum chemistry or urinalysis. Dogs were not
    sacrificed. Plasma drug levels increased during the course of the
    study attaining concentrations of approximately 0.045, 0.07 and
    0.26 g/ml, respectively on day 8 (Pfizer, 1987c).

         Groups of beagle dogs (1/sex/group) were given gavage doses of
    0, 1, 2 or 4 mg/kg bw/day doramectin (purity 92.1%-93.3%) in sesame
    oil for 29 days. Body weight was depressed in both animals
    administered 4 mg/kg bw/day and the male showed salivation, mydriasis,
    tremors, ataxia and decreased heart rate prior to sacrifice on day 16.
    All drug-treated dogs exhibited mydriasis. There were no effects on
    haematology, serum chemistry, urinalysis, organ weight or pathological
    examinations. Plasma drug levels were proportional to the dose,
    highest concentrations achieved were approximately 0.4, 1.2 and
    3.0 g/ml, respectively (Pfizer, 1989b).

         Groups of beagle dogs (3/sex/group) were administered doramectin
    (purity 95.3%) in the diet at doses of 0, 1, 2 or 4 mg/kg bw/day for
    36 days. Apart from mydriasis in two dogs given 4 mg/kg bw/day, there
    were no clinical signs of toxicity. Body weight was depressed in the
    4 mg/kg bw/day group during the first 3 weeks but returned to baseline
    thereafter. Haematology, serum chemistry, urinalysis, organ weights
    and pathology were unaffected. Plasma drug levels increased with
    duration of dosing, reaching maximum concentrations of 0.21, 0.5 and
    0.88 g/ml, at the low-, mid- and high-dose groups, respectively. The
    NOEL was 2 mg/kg bw/day. (Pfizer, 1988c).

         Beagle dogs (4/sex/group) were given gavage doses of 0, 0.5, 1 or
    2 mg/kg bw/day doramectin (purity 92.5%) in sesame oil for 91 days. A
    slow pupillary light reflex was noted in all treated animals and
    mydriasis was diagnosed in 1, 2, and 5 dogs given 0.5, 1, and 2 mg/kg
    bw/day, respectively. One animal given 2 mg/kg bw/day showed anorexia,
    tremors and ataxia and was sacrificed on day 23. No effects were
    observed on body weight, haematology, serum chemistry, urinalysis,
    organ weight or pathology. Plasma drug levels were dose-related but
    were higher on day 30 than on day 90. The levels were approximately
    0.29, 0.5 and 1.2 g/ml on day 30 and 0.24, 0.3 and 0.6 g/ml on day
    90, at the 3 respective doses (Pfizer, 1989c).

         Beagle dogs (3/sex/dose) were given gavage doses of 0, 0.1 or
    0.3 mg/kg bw/day doramectin (purity 92.5%) in sesame oil for 92 days.
    The only treatment-related finding was mild to moderate mydriasis
    which was diagnosed in 1 female given 0.3 mg/kg bw/day. Plasma drug
    levels were dose-related, with approximate mean concentrations of 0.1
    and 0.28 g/ml, respectively. The NOEL in this study was 0.1 mg/kg
    bw/day (Pfizer, 1990b).

    2.2.3  Reproductive toxicity studies

    2.2.3.1  Rats

         In a 2-generation reproductive toxicity study, groups of
    Long-Evans rats (45/sex/group) were given gavage doses of 0, 1.5, 3 or
    6 mg/kg bw/day doramectin (purity 92.5%) in sesame oil. Males were
    dosed from 10 weeks before pairing and to the end of the mating
    period. Females were dosed from 2 weeks prior to pairing until the end
    of the study.

         There were no effects on food consumption or body weight of F0
    adults, and copulation, pregnancy rate and gestation length were
    unaffected. Size and weight of F1 litters at birth were similar
    between groups. During lactation, pup weights decreased in the 3 and
    6 mg/kg bw/day groups and most of these pups died by day 7
    post-partum. Survival was unaffected in the 1.5 mg/kg bw/day group but
    body-weight gain was lower in these offspring and the study was
    discontinued on lactation day 7.

         Subsequently, a number of F0 dams with litters (culled to 8
    pups/litter), were assigned to 6 groups consisting of 3 females each.
    Gavage doses of 0, 0.25, 0.5, 1, 3 or 6 mg/kg bw/day were administered
    on lactation days 12 to 21 to determine potential effects on older
    pups. Pup survival was not affected but body-weight gain was reduced
    at 6 mg/kg bw/day (Pfizer, 1990c).

         In a 2-generation reproductive toxicity study, groups of
    Long-Evans rats (45/sex/group) were given gavage doses of 0, 0.1, 0.3
    or 1 mg/kg bw/day doramectin (purity 92.5%) in sesame oil. Treatment
    of F0 males commenced 10 weeks prior to pairing, continuing until
    the end of the mating period. F0 females were treated from 2 weeks
    before pairing, through gestation until the end of lactation. Food
    intake, body-weight gain, copulation, pregnancy rate and duration of
    gestation were unaffected in F0 rats and gross examination of these
    animals did not reveal any abnormalities.

         F1 litter size, weight at birth, and post-natal survival were
    similar in all groups. There was slight depression of body-weight gain
    of the 1 mg/kg bw/day pups during lactation and the weight of these
    animals remained below other groups for the remainder of the study.
    Where necessary, F1 litters were reduced to 8 pups each on lactation
    day 4. At weaning, 25 male and 25 female pups/group were randomly
    selected to produce the F2 generation and were dosed until the end
    of the study. On pairing of F1 rats, copulation incidences were
    adversely affected leading to low pregnancy rates in all groups, most
    notably in the control.

         F2 litter sizes at birth were lower than normal in all groups
    but subsequent survival was not affected. Body weights of the 1 mg/kg
    bw/day offspring were lower throughout the lactation period. In
    limited tests for post-natal development in 1 male and 1 female/litter,
    there were no significant treatment-related deficits. Gross examination
    of treated F1 rats and F2 pups showed no abnormalities.

         Due to the adverse effects on conception described above, the
    study was terminated, except for rats in the F1 control group which
    were paired for a second mating. Again, pregnancy rates were very low,
    and vaginal smears indicated irregular estrous cycling in many of the
    females with some not cycling at all (Pfizer, 1992c).

         In a 2-generation reproductive toxicity study, groups of
    Long-Evans rats (45/sex/group) were administered gavage doses of
    0, 0.1, 0.3 or 1 mg/kg bw/day doramectin (purity 92.5%) in sesame oil.
    F0 males were treated from 10 weeks prior to pairing until the end
    of mating, and females were dosed from 2 weeks prior to pairing,
    during mating, gestation, and lactation periods. There were no effects
    on food consumption or body weight of F0 rats and copulation,
    pregnancy rate and gestation length were unaffected. Gross examination
    of these animals was unremarkable.

         F1 litter size and weight at birth and subsequent survival and
    growth were similar in all groups. Each F1 litter was culled to 8
    pups, where necessary, on lactation day 4. At weaning, 30 male and 30
    female pups/group were randomly selected to produce the F2
    generation and were dosed directly until study termination. These F1
    rats were paired on two occasions, at age 11 to 12 weeks and 22 to
    23 weeks. On both occasions, copulation and duration of gestation were
    unaffected. However, conception was impaired in all groups, the
    pregnancy rate being approximately 70% for the F2a and 50% for the
    2bF matings, respectively. Gross examinations of F1 rats showed no
    internal or external abnormalities.

         In both the F2a and F2b litters, the number and weight of
    offspring at birth, and survival to the end of lactation were not
    affected by treatment. Pup body-weight gain was depressed in the
    1 mg/kg bw/day group. On lactation day 21, 1 male and 1 female
    pup/F2a litter were tested for locomotor activity and auditory
    function and were given an ophthalmoscopic examination. No
    treatment-related effects were observed in these developmental tests
    or on gross examination of all F2a and F2b pups. The NOEL in this
    study was 0.3 mg/kg bw/day (Pfizer, 1991b).

    2.2.4  Special studies on neonatal toxicity

    2.2.4.1  Rats

         Groups of 7 (2 in control group) presumed pregnant Long-Evans
    rats were given gavage doses of 0, 1.5, 3 or 6 mg/kg bw/day doramectin
    (purity 92.5%) in sesame oil from gestation day 2 to day 3 post-partum.
    There was no effect on body weight of dams but 1 female given 6 mg/kg
    bw/day was sacrificed moribund. Milk, blood and brain of dams were
    collected 3-4 h after the last dose. Blood and brain from the pups
    were collected 24 h after dosing of the dams.

         Analysis of drug levels in plasma samples revealed higher levels
    in dams than in pups. However, drug levels in the brain of dams were
    generally lower than in pup brains. The plasma to brain ratio was
    approximately 16 in dams and 2 in pups indicating that doramectin was
    more accessible to the CNS of neonates. Milk to plasma ratios in dams
    were about 2-3, indicating that the drug was readily excreted in milk
    (Pfizer, 1990d).

         Groups of 10 presumed pregnant Long-Evans rats were given gavage
    doses of 0, 0.1, 0.2, 0.5 or 1 mg/kg bw/day doramectin (purity 92.5%)
    in sesame oil during gestation days 4 to lactation day 21. Litters
    were culled to 8 pups each on lactation day 4, surviving pups and dams
    were killed on lactation day 21. There was no effect on body weight of
    dams. One dam given 1 mg/kg bw/day showed piloerection and lethargy
    and died on day 13 of treatment. Litter size and weight at birth were
    unaffected. At a dose of 1 mg/kg bw/day, pups body-weight gain was
    reduced during lactation and 6 of 8 pups in a single litter died
    (Pfizer, 1992d).

    2.2.5  Special studies on embryotoxicity and teratogenicity

    2.2.5.1  Mice

         Groups of 9 presumed pregnant CD-1 mice were given gavage doses
    of 0, 0.1, 0.2, 0.4, 0.8 or 1.6 mg/kg bw/day doramectin (purity 93.6%)
    in sesame oil on gestation days 6 to 13. There were no effects on body
    weight of dams, one female given 1.6 mg/kg bw/day had blood in the
    urogenital area and was found dead on gestation day 12. The remaining
    dams were killed on gestation day 18. Embryomortality and number of
    live fetuses were similar between groups. Fetal weights were lower at
    1.6 mg/kg bw/day. Fetuses were not examined (Pfizer, 1988d).

         Groups of 7 presumed pregnant CD-1 mice were given gavage doses
    of 0, 1.5, 3 or 6 mg/kg bw/day doramectin (purity 92.3%) in sesame oil
    on gestation days 6 to 13. One 6 mg/kg bw/day female showed
    hypothermia, piloerection and blood on the vagina, but there were no
    treatment-related deaths and no effects on body weight. Dams were
    killed on gestation day 18. There were no effects on embryomortality,
    number of live fetuses or fetal body weight. Fetuses were not examined
    (Pfizer, 1988e).

         Groups of 20 presumed pregnant CD-1 mice were given gavage doses
    of 0, 1.5, 3 or 6 mg/kg bw/day doramectin (purity 92.1%) in sesame oil
    on gestation days 6 to 13. There were no drug-related deaths or
    clinical signs in dams and body weight was unaffected. Dams were
    killed on gestation day 18. Embryomortality was increased at 6 mg/kg
    bw/day but did not attain statistical significance. Fetal body weight
    and the incidence of fetal abnormalities were unchanged.

         An additional group of 10 mice were similarly treated with
    6 mg/kg bw/day for analysis of drug levels on gestation day 13. Plasma
    drug levels in dams, 1 h after the last dose varied from 0.088 to
    0.28 g/ml. Six hours after dosing, plasma levels in dams were between
    0.37 and 0.58 g/ml, amniotic fluid levels varied from non-detectable
    to 0.019 g/ml and fetal levels varied from non-detectable to
    0.12 g/g. The NOEL in this study was 3 mg/kg bw/day (Pfizer, 1988f).

    2.2.5.2  Rats

         Groups of 6 or 7 presumed pregnant Sprague-Dawley rats were given
    gavage doses of 0, 0.1, 0.2, 0.4, 0.8 or 1.6 mg/kg bw/day doramectin
    (purity 92.3%) in sesame oil on gestation days 6 to 15. Dams showed no
    signs of toxicity or effects on body weight. Females were killed on
    gestation day 20. Embryomortality, number of live fetuses and fetal
    body weight were similar between groups. Fetuses were not examined
    (Pfizer, 1988g).

         Groups of 7 presumed pregnant Sprague-Dawley rats were given
    gavage doses of 0, 1.5, 3 or 6 mg/kg bw/day doramectin (purity 92.3%)
    in sesame oil on gestation days 6 to 15. Dams were killed on gestation
    day 20. No toxic signs or adverse effects on body weight were noted in
    dams. Embryotoxicity and numbers of live fetuses and fetal body weight
    were unaffected. Fetuses were not examined (Pfizer, 1988h).

         Groups of 20 presumed pregnant Sprague-Dawley rats were given
    gavage doses of 0, 1.5, 3 or 6 mg/kg bw/day doramectin (purity 92.1%)
    in sesame oil on gestation days 6 to 15. Dams were killed on gestation
    day 20. There were no effects on body weight of dams. Embryomortality
    was increased at 6 mg/kg bw/day but was not statistically significant

    and was within the historical control range. Fetal examination
    revealed slightly increased incidences of rudimentary ribs, wavy ribs,
    unossified hyoid and 5th metacarpals, and dilatation of ureters and
    kidney pelves, but the incidences were not dose-related and were
    within the historical control range.

         A satellite group of 10 rats were administered 6 mg/kg bw/day and
    used for drug analysis on gestation day 15. Plasma drug levels in
    dams, 1-5 h after dosing, varied from 0.41 to 1.27 g/ml. Five hours
    after the dose, amniotic fluid showed a mean level of 0.014 g/ml and
    fetal levels were between 0.27 and 1.1 g/g. The NOEL in this study
    was 6 mg/kg bw/day, the highest dose tested (Pfizer, 1988i).

    2.2.5.3  Rabbits

         Groups of 7 presumed pregnant New Zealand white rabbits were
    given gavage doses of 0, 0.2, 0.8 or 1.6 mg/kg bw/day doramectin
    (purity 92.3%) in sesame oil on gestation days 7 to 18. Body-weight
    gain was reduced in the 1.6 mg/kg bw/day group during gestation days 1
    to 19. Does were killed on gestation day 28. Embryomortality was
    slightly increased at 1.6 mg/kg bw/day but with no effect on fetal
    weight. Fetuses were not examined. Plasma drug levels in dams given
    1.6 mg/kg bw/day, 2 h after dosing on gestation day 17, ranged between
    0.037 and 0.42 g/ml (Pfizer, 1988j).

         Groups of 7 presumed pregnant New Zealand white rabbits were
    given gavage doses of 0, 1.5, 3 or 6 mg/kg bw/day doramectin (purity
    92.1%) in sesame oil on gestation days 7 to 18. Body-weight gain was
    significantly depressed at 6 mg/kg bw/day, in association with reduced
    food consumption, on gestation days 7 to 28. Dams were killed on
    gestation day 28. Embryonic death was increased and foetal weight was
    slightly depressed in the 6 mg/kg bw/day group. Fetuses were not
    examined (Pfizer, 1988k).

         Groups of 20 presumed pregnant New Zealand white rabbits were
    given gavage doses of 0, 0.75, 1.5 or 3 mg/kg bw/day doramectin
    (purity 92.1%) in sesame oil on gestation days 7 to 18. There was no
    drug-related mortality but during the treatment period, food intake
    was reduced at 1.5 and 3 mg/kg bw/day with reduced body-weight gain at
    3 mg/kg bw/day. Embryomortality and fetal weight were similar between
    groups. Major malformations, occurring in the 3 mg/kg bw/day group
    only, were cleft palate in 3 fetuses from 1 litter and 1 fetus which
    exhibited phocomelia, syndactyly and coelosomia. The incidence of
    cleft palate was within the historical control range whereas the other
    fetal abnormalities had never been observed in the testing laboratory.
    Ossification of pubic bones was delayed at 1.5 and 3 mg/kg bw/day.

         A satellite group of 4 rabbits were dosed with 3 mg/kg bw/day and
    sacrificed on gestation day 18 for analysis of drug levels. Maternal
    plasma levels, measured 1, 3 and 5 h after dosing, ranged from 0.126
    to 0.838 g/ml. Doramectin was not detected in amniotic fluid or fetal
    tissue, 5 h after the last dose, but detection limits were relatively
    high due to interfering peaks. The NOEL in this study was 0.75 mg/kg
    bw/day (Pfizer, 1988l).

    2.2.6  Special studies on genotoxicity

         The results of genotoxicity studies with doramectin are given in
    Table 4.

    2.2.7  Special study on permeability of blood-brain barrier

    2.2.7.1  Mice

         Groups of 3 adult female CD-1 and CF-1 mice were given a single
    gavage dose of 0.4 mg/kg bw ivermectin in sesame oil. Additional
    groups received an i.p. injection of 50 mg/kg bw CP-100,356, an
    inhibitor of p-glycoprotein activity, 1 h prior to ivermectin
    administration. Animals were killed 24 h after drug dosing for removal
    of blood and brain samples.

         In CD-1 mice, ivermectin B1a could not be detected in plasma
    (limit of quantitation 10 ng/ml), while brain levels were
    1.38-1.98 ng/g. Pretreatment with CP-100,356 resulted in plasma levels
    of 17.2-18.7 ng/ml and brain levels of 1.95-2.13 ng/g.

         In CF-1 mice, ivermectin B1a levels in plasma were
    14.9-21.0 ng/ml and brain levels were 109, 3.69 and 2.59 ng/g.
    Pretreatment with CP-100,356 resulted in plasma levels of 30.1, 33.1
    and 17.4 ng/ml and brain levels of 6.06, 8.97 and 1.98 ng/g.
    Pretreatment with the p-glycoprotein inhibitor did not markedly affect
    plasma or brain drug levels in either strain. Since the study used
    very few animals and the treatment schedule and tissue sampling times
    were not justified, no conclusion can be drawn from this study
    (Pfizer, 1995).

    2.2.8  Special studies on pharmacology

         Table 5 summarizes the results of pharmacological studies with
    doramectin.

        Table 4.  Results of genotoxicity assays on doramectin
                                                                                                             

    Test system1          Test object              Concentration             Results         Reference
                                                                                                             

    Reverse mutation2     S. typhimurium           0.02 to 10 mg/plate       negative        Pfizer, 1991c
                          TA98, TA100              (-S9)3
                          TA1535,                  0.005 to 2 mg/plate       negative
                          TA 1537                  (+S9)3
                                                   Urine from mice           negative
                                                   dosed with 0.2 to
                                                   4 mg/kg ip (-S9)3

    Reverse mutation2     S. typhimurium           9.8 to 5000 g/plate      negative        Pfizer, 1991d
                          TA98, TA100,             (S9)3
                          TA1535, TA1537
                          E. coli WP2 uvrA.

    Forward mutation2     L5178Y mouse             8 to 35 g/ml             negative        Pfizer, 1991c
                          lymphoma cells.          (-S9)3
                                                   13 to 62 g/ml            negative
                                                   (+S9)3

    UDS assay             Primary culture          1.7 to 10 g/ml3          negative        Pfizer, 1991c
                          of rat hepatocytes.

    Micronucleus          Mouse bone               500 to 2000 mg/kg         negative        Pfizer, 1991e
    test                  marrow                   bw/day for 3 days,
                                                   po.4
                                                                                                             

    1.   Positive controls used
    2.   Both with and without liver microsomal activation
    3.   Vehicle was dimethylsulfoxide
    4.   Vehicle was 0.5% methylcellulose

    Table 5.  Results of pharmacological assays with doramectin
                                                                                                             

    Assay type            Species             Dose              Result                 Reference
                                              (mg/kg bw)
                                                                                                             

    Safety study1         Collie dogs         0.062             negative               Cruthers, 1991
                          (n = 2)             0.125             negative
                                              0.25              negative
                                              0.5               vomiting, moist
                                                                muzzle, enlarged
                                                                pupils, unsteady
                                                                legs

    Diuretic assay        SD rats(n= 10)      0.1 to 1.0        negative               Gromelski et al, 1991a

    Gastrointestinal      CD-1 mice           0.1 to 1.0        negative               Varner et al, 1991
    motility assay        (n = 10)

    Arterial              SD rats             0.1 to 1.0        negative               Gromelski et al, 1991b
    blood gas             (n = 10)
                                                                                                             

    1.   Ivermectin was tested in this same experiment and elicited clinical effects
         at doses as low as 0.125 mg/kg bw.
    
    3.  COMMENTS

         The Committee considered data from a range of studies on
    doramectin, including the results of studies on its metabolism, acute
    and short-term toxicity, reproductive and developmental toxicity, and
    genotoxicity.

         The oral bioavailability of doramectin in rats, as measured by
    the plasma concentration of the drug and the area under the plasma
    concentration-time curve, was approximately six times greater when
    doramectin was administered in sesame oil as compared to an aqueous
    vehicle or in the diet. Metabolism studies in rats, dogs and cattle
    revealed a similar spectrum of metabolites in the liver and faeces of
    each species, suggesting that laboratory animals are suitable models
    for testing the toxicity of doramectin.

         Acute toxicity studies were carried out in rodents. When
    doramectin was administered orally in an aqueous vehicle, the LD50
    values were in the range 500-2000 mg/kg bw in rats and greater than
    2000 mg/kg bw in mice. When the drug was given in a sesame oil
    vehicle, the oral LD50s were 50-200 mg/kg bw in rats and
    75-500 mg/kg bw in mice. These marked differences in acute toxicity
    reflect the enhanced absorption of doramectin when administered as an
    oil preparation. A further investigation in mice showed that the acute
    toxicities of orally administered doramectin and ivermectin were
    similar and that both compounds were less acutely toxic than abamectin
    or moxidectin. Toxic signs were indicative of effects on the CNS,
    since doramectin, like abamectin and other drugs in this class,
    affects gamma-aminobutyric acid (GABA)-sensitive neurons, which can
    lead to neurotoxicity, as shown by tremors, ataxia and gait
    abnormalities.

         Short-term administration of doramectin in the diet to mice was
    associated with clinical signs of neurotoxicity, and there was
    evidence of minor toxic effects on the liver and kidney at and above
    doses of 100 mg/kg bw/day. Plasma drug levels were dose-related,
    although the relationship was non-linear, up to 100 mg/kg bw/day and
    reached a plateau at doses greater than 100 mg/kg bw/day, which
    suggests that the absorption of doramectin from the feed reached
    saturation. The highest plasma concentration was 3.9 g/ml.

         A number of short-term toxicity studies were carried out in rats
    for periods of up to 3 months. Administration of doramectin in the
    diet at doses of 30 mg/kg bw/day and above resulted in markedly
    reduced food intake and body-weight gain, as well as severe
    neurotoxicity, which necessitated the early sacrifice of some of the
    animals. Other findings at the same doses were atrophic changes in

    hepatocytes and lymphoid organs and nephrosis. Minor increases in
    liver weight were seen at 20 mg/kg bw/day in the diet, but hepatic
    morphology was unaffected at this dose. The maximum plasma drug level
    attained in these studies was 5.8 g/ml. In a 1-month study in which
    doramectin was given in the diet, the NOEL in rats was
    10 mg/kg bw/day.

         In two studies, rats were given doses of doramectin by gavage for
    up to 3 months. Signs of CNS toxicity were observed at the highest
    dose of 10 mg/kg bw/day. At doses of 5 mg/kg bw/day and above, there
    were increases in liver weight, while kidney weight was increased at
    8 mg/kg bw/day. However, there were no concomitant pathological
    changes and all other parameters were unaffected. Plasma drug levels
    reached a peak of 3.2 g/ml. The NOEL in gavage studies in rats was
    2 mg per kg of body weight per day.

         When dogs were fed doramectin in the diet for periods of up to 36
    days, the only treatment-related findings were mydriasis and reduced
    body weight at a dose of 4 mg/kg bw/day. The highest plasma drug level
    was 0.88 g/ml. The NOEL in this study was 2 mg/kg bw/day.

         In three studies in dogs, which received doramectin by gavage in
    a sesame oil vehicle for up to 92 days, body weights were depressed at
    4 mg/kg bw/day and clinical signs of CNS toxicity were noted at
    2 mg/kg bw/day and above. The most sensitive indication of a
    drug-related effect was mydriasis, which was seen at doses as low as
    0.3 mg/kg bw/day. No other toxic effects were observed. The maximum
    plasma drug level in these studies was 3 g/ml. The NOEL was 0.1 mg/kg
    bw/day.

         Reproductive toxicity studies in rats revealed treatment-related
    deaths among pups during the early postnatal period and a reduction in
    body-weight gain of pups throughout the lactation period. These
    effects were observed at doses as low as 3 and 1 mg/kg bw/day,
    respectively. Doramectin was shown to be readily excreted in the milk
    of lactating rats following administration by gavage and, as compared
    with adult animals, higher drug levels were attained in the brain of
    neonates, suggesting greater penetration through the incompletely
    formed blood-brain barrier in newborn rats. The NOEL was 0.3 mg/kg
    bw/day, based on toxicity in neonatal animals.

         The administration of doramectin by gavage to pregnant mice and
    rats did not result in fetal abnormalities. The only drug-related
    finding was a slight increase in embryo mortality in mice given
    6 mg/kg bw/day. The NOEL in mice was 3 mg/kg bw/day, while in rats
    there were no adverse effects at the highest dose of 6 mg/kg bw/day.
    In rabbits given 3 mg/kg bw/day during pregnancy, there was
    significant maternal toxicity, and cleft palate was observed in three

    fetuses from one litter; one fetus also exhibited phocomelia,
    syndactyly and coelosomia. Ossification of pubic bones was delayed at
    doses of 1.5 and 3 mg/kg bw/day. In a dose-ranging study, a dose of
    6 mg/kg bw/day caused severe maternal toxicity and embryotoxicity. The
    NOEL for maternal toxicity in rabbits was 0.75 mg/kg bw/day.

         In view of the negative results in a range of  in vitro
    genotoxicity assays and a micronucleus test in mouse bone marrow, the
    Committee concluded that doramectin was not genotoxic.

         The Committee noted the close structural similarities between
    doramectin and abamectin, the only difference being the presence of a
    cyclohexyl group at the C-25 position in the doramectin molecule
    rather than an isopropyl or isobutyl group in the case of abamectin
    B1a and abamectin B1b, respectively. The available metabolic data
    suggest that the biotransformation of doramectin and abamectin follows
    a similar pathway. Extensive toxicological tests have been conducted
    on both compounds, and the Committee reviewed several aspects of their
    comparative toxicology. Both compounds exert a pharmacological effect
    on the CNS through effects on gamma-aminobutyric acid-sensitive
    neurons, which results in a range of neurotoxic signs such as
    mydriasis, tremors, ataxia and gait abnormalities. In multiple-dose
    studies, the compounds have been associated with few adverse
    toxicological effects, reduced body-weight gain and minor toxic
    effects on the liver being the most common. Toxicity in neonates is
    the most sensitive indicator in reproductive toxicity studies with
    both compounds. Neither compound is considered to have any genotoxic
    activity. Carcinogenicity studies with abamectin were negative at
    maximum tolerated doses in mice and rats. In view of the chemical,
    biochemical and toxicological similarities, the Committee concluded
    that it was unnecessary to request data from long-term toxicity and
    carcinogenicity studies on doramectin.

    4.  EVALUATION

         The Committee considered that the most relevant effect for the
    safety evaluation of residues of doramectin was the effect on the
    mammalian nervous system. An ADI of 0-0.5 g/kg bw was established,
    based on a NOEL of 0.1 mg/kg bw/day for mydriasis in the 3-month
    gavage study in dogs. A safety factor of 200 was applied because the
    test systems used to assess the neurotoxicity of doramectin were of
    uncertain sensitivity (see section 2.2 of the Report, Annex 1,
    reference 119). The ADI provides an adequate margin of safety for
    neonatal toxicity in rats and developmental toxicity in rabbits.

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    Groton, CT. Submitted to WHO by Pfizer, USA.

    Pfizer (1994a). Single Dose Oral Toxicity Study in Albino (CD-1) Mice.
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    Groton, CT. Submitted to WHO by Pfizer, USA.

    Pfizer (1994b). A Range Finding Feed Study in CD-1 Mice. Unpublished
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    Submitted to WHO by Pfizer, USA.

    Pfizer (1994c). Three Month Range Finding Feeding Study in CD-1 Mice.
    Unpublished study No. 92-657-27 from Pfizer Central Research,
    Groton, CT. Submitted to WHO by Pfizer, USA.

    Pfizer (1994d). Three Month in Feed Study in Long-Evans Rats.
    Unpublished study No. 92-657-26 from Pfizer Central Research,
    Groton, CT. Submitted to WHO by Pfizer, USA.

    Pfizer (1995). Comparison of Plasma/Brain Ivermectin (B1a) Ratios in
    CD-1 and CF-1 Mice. Unpublished study No. AHDM-94-08 from Pfizer
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    Varner, L.L., Panasevich, R.E. & Ciofalo, V.B. (1991).  Gastro-
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    Pfizer, USA.

    Zufall, F., Franke, Ch. & Hatt, H. (1989). The insecticide avermectin
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    See Also:
       Toxicological Abbreviations
       Doramectin (JECFA Food Additives Series 49)
       DORAMECTIN (JECFA Evaluation)