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    ABAMECTIN

    First draft prepared by E. Bosshard
    Federal Office of Public Health,
    Schwerzenbach, Switzerland

    EXPLANATION

         Abamectin is a macrocyclic lactone product derived from the
    soil microorganism  Streptomyces avermitilis. Abamectin contains at
    least 80% avermectin B1a and not more than 20% avermectin B1b
    (see Figure 1). It is used as an insecticide and acaricide. The
    compound was considered for the first time by the present Meeting.

         Because of the very similar biological and toxicological
    properties of the individual B1a and B1b components, they can be
    considered to be equivalent. Abamectin is degraded photolytically to
    the delta-8,9-isomer which therefore forms a part of the residue.

         In addition to data on abamectin, human data on ivermectin,
    which is structurally similar, were considered.
    
    FIGURE 1


    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, and excretion

    Rats

         A study was carried out to evaluate the tissue distribution and
    elimination of 3H- and 14C-labelled avermectin B1a in a sesame
    oil vehicle after oral administration to male and female rats.
    Sixty-two CRCD strain rats/sex were divided into groups and dosed as
    follows: a single high dose (1.4 mg/kg bw); a single low dose (0.14
    mg/kg bw); fourteen daily low doses (0.14 mg/kg bw/day) of
    unlabelled avermectin B1a, followed by a single low dose of
    tritium-labelled avermectin B1a; a single high dose (1.4 mg/kg bw)
    of a mixture of tritium - and 14C-labelled avermectin B1a; a
    single dose of vehicle only to serve as controls for groups with
    single dosing regimen or fifteen daily doses of vehicle only to
    serve as controls for the multiple dosing experiment. The control
    groups were sacrificed seven days after the last (or single) dose,
    while rats from the treated groups were sacrificed on days 1, 2, 4
    and 7 after dosing. Urine and faeces were collected each day after
    dosing while the organs were collected from all rats at time of
    sacrifice. All samples were assayed for total radioactivity.
    Elimination in the urine was 0.3-0.6% of the applied dose in females
    and 0.8-1.1% in males over the 7 days collection period. Elimination
    in faeces ranged from 69-77% and 70-82% in females and males,
    respectively. Residue levels in liver ranged from about 0.001-0.02
    ppm, in kidney from 0.003-0.06 ppm, in muscle from 0.001-0.02 ppm
    and in fat from 0.008-0.01 ppm in the different dosing groups, 7
    days post-dose. The total residue level in the organs of the females
    were generally higher than in males. The residue levels were dose
    dependent, the residues in the high dose groups being roughly ten-
    fold greater than in the low dose groups, whereas the depletion
    rates were similar among the different tissues. The total
    radioactive residues depleted from the tissues with half-lives of
    approximately 1.2 days indicating that the residues did not persist.
    Repeated dosing did not influence elimination rates or residue
    levels. The tritiated avermectin B1a residue levels and depletion
    rates were comparable to the 14C residue levels. Thus the tritium
    label at the 5-position of avermectin B1a was not labile during
    the course of the study. The stability of the label was also
    demonstrated in an experiment for volatile/exchangeable tritium,
    demonstrating that less than 2% of the tritiated avermectin B1a
    sample was volatile (Alvaro  et al., 1984).

         Selected tissue samples (liver, kidney, muscle, fat) were
    analyzed for unchanged avermectin B1a and metabolites. Two

    metabolites that were also formed  in vitro after rat liver
    microsomal incubation, in addition to unchanged avermectin B1a,
    accounted for most of the residues: The metabolites were identified
    as 24-hydroxymethyl-avermectin B1a (24-OHMe-B1a) and 3"-desmethyl
    avermectin B1a (3"-DM-B1a) (Maynard 1986b). A minor metabolite
    was identified as -alpha-hydroxy-avermectin B1a (Gruber, 1988).

    Toxicological studies

    Acute toxicity studies

         The main clinical signs were ataxia and tremors found in all
    species investigated and irrespective of the route of
    administration. The data are summarized in Tables 1 and 2.
    
    Table 1: Acute toxicity of abamectin

                                                                                                 
    Species  Sex               Route   LD50        Component           Reference
                                       (mg/kg bw)  (purity)
                                                                                                 

    Mouse    F                 oral    13.6-23.8   B1a                 Mandel (1977)
                                       19.8        B1b (98.4%)         Gordon  et al. (1984a)
             5-day mortality:
             pregnant:                 11.8-19.0   B1a+B1b (94%)       Gordon  et al. (1984b)
             non pregnant:             15.0-41.3   B1a+B1b (94%)       Gordon  et al. (1985a)

    Rat      F,M               oral    ca. 11      B1a                 Mandel, 1977
             F,M               oral    8.7-12.8    B1a+B1b (91%)       Robertson  et al. (1981a)

    Dog      M,F               oral    ca. 8       B1a                 Robertson and Allen (1976)
                                                   B1a+B1b             Gordon  et al. (1984f)

    Monkey   M,F               oral    > 24        B1a+B1b             Gordon  et al. (1985b)
    Rat                        dermal  >330        B1a/B1b (87%/9.4%)  Gordon & Mandel (1978)
    Rabbit                     dermal  >1600       B1a+B1b (91.4%)     Robertson  et al. (1981b)
                                                   B1a + B1b (94%)     Gordon  et al. (1983d)

    Delta-8,9-isomer (photolytic degradation product)
    Mouse    M,F               oral    > 80                            (Gordon  et al. 1984c
                                                                       & 1984e)
                                                                                                 

    Table 2: Dermal and ocular irritation studies with abamectin,
             technical material
                                                                                    
    Species  Sex          Target  Findings              Reference
                          Organ
                                                                                    

    Rabbit   M,F          eye     very slight           Robertson et al. (1981c)
                                  irritation

    Rabbit   M,F          skin    non irritating on     Robertson et al. (1981d)
                                  intact or abraded
                                  skin

    Guinea-  M,F          skin:   negative              Gordon et al. (1983a)
    pig                           sensitization
                                                                                    
    
    Short-term toxicity studies

    Mice

         In a twelve-week dietary range-finding study groups of mice
    (CD-1 strain;15/sex/group) were fed dietary concentrations of 0,
    2/40 (increase in week 9), 5, 10 or 20 ppm abamectin over 12 weeks
    and 40 or 60 ppm over 3 weeks. There were no physical signs or
    mortality. Decrease in body-weight gain at 60 ppm was the only
    change observed. The NOAEL in this study was 40 ppm, equal to 8
    mg/kg bw/day (Gordon  et al., 1982f).

    Rats

         In an eight-week oral range-finding study in rats abamectin
    (purity 94%) was administered to groups of rats (Charles River CD
    albino rats, 10/sex/group) at dietary concentrations of 0, 5, 10,
    15, 20/25 (increase in week 7), 40 or 60 ppm. Due to mortality and
    the appearance of severe clinical signs of toxicity (tremors,
    decreased activity) in the first study week, remaining animals at 40
    and 60 ppm were sacrificed on days 15 and 5, respectively. These
    groups were replaced by groups at 10 and 15 ppm in study week 5.
    Decreases in mean body-weight gain were seen at 15, 20/25 (3 and 5%
    decrease in males and females, respectively) and 40 ppm. Tremors
    occurring at 15 and 20/25 ppm were no longer evident after study
    week 1. One animal at 5 ppm showed slight tremors on day 2 only. No
    gross or microscopic examination was performed. Based on clinical
    signs and body-weight effects it appears that there is a steep dose-
    response curve. Therefore the doses recommended for the
    carcinogenicity study were 0.75, 1.5 and 2.0 mg/kg bw/day (Gordon
     et al., 1982g).

    Dogs

         In a twelve-week oral range-finding study abamectin (purity
    94%) was fed to groups of beagle dogs (2/sex/dose) at doses of 0,
    0.25, 0.5, 1 or 4/2 mg/kg bw/day. Because of signs of toxicity
    (tremors, weakness, incoordination, disorientation) and markedly
    decreased food consumption at 4 mg/kg bw/day in one dog, this dose
    was decreased to 2 mg/kg bw in study week 4. Inability to constrict
    pupils after light stimulus was observed in some dogs at 1 mg/kg
    bw/day or higher doses. Depression of body-weight gain or weight
    loss occurred in dogs at 2 mg/kg bw/day and higher. No gross or
    microscopic examination was performed. Based on the clinical signs
    and body-weight effects recommended doses for the one-year oral dog
    study were 0.25, 0.5 and 1 mg/kg/ bw/day. The NOAEL in this study
    was 0.5 mg/kg bw/day (Gordon  et al., 1982e).

         Avermectin B1a (purity not specified) was orally administered
    by gavage to beagle dogs (15/sex/dose) at dose levels of 0, 0.25,
    0.5, 2 or 8 mg/kg bw/day over a period of 18 weeks. The treatment
    did not affect parameters of urinalyses, ophthalmologic examination
    or organ weights. Deaths occurred at incidences of 1/30, 3/30 and
    3/30 at 0.5, 2 and 8 mg/kg bw/day, respectively. Signs of toxicity
    at levels of > 0.5 mg/kg bw/day consisted of whole body muscular
    tremors, ataxia, mydriasis and ptyalism (hypersalivation); in
    addition, tonic convulsions and emesis occurred at 2 and 8 mg/kg
    bw/day. Reduced body-weight gain was only observed at dose levels of
    0.5 and 2 mg/kg bw/day, but not in surviving dogs at 8 mg/kg bw/day.
    At 8 mg/kg bw/day changes in haematologic and serum biochemical
    parameters included slightly increased values of haemoglobin,
    haematocrit, erythrocytes, nonsegmented neutrophils and glucose
    level. Electrocardiographic changes (elongation of the QT interval
    and bradycardia) were noted at 8 mg/kg bw/day only at the beginning
    of the study. Histopathologic changes were seen only in animals that
    died or were killed moribund and consisted of diffuse hepato-
    cellular vacuolation (without lipid accumulation) at dose levels of
    0.5, 2 and 8 mg/kg bw/day and edema of the gallbladder at 2 and 8
    mg/kg bw/day. The NOAEL in this study was 0.25 mg/kg bw/day
    (Robertson & Allen 1976).

         Groups of beagle dogs (6/sex/dose) were fed abamectin (purity
    > 89%) for 53 weeks at concentrations resulting in doses of 0,
    0.25, 0.5 or 1 mg/kg bw/day. The doses were selected on the basis of
    the results of a previous range-finding study (Gordon  et al.,
    1982e). The compound administration had no effect on
    ophthalmological examination, urinalyses or organ weights. Decreased
    or even absence of constriction of pupils to light was evident at
    0.5 mg/kg bw/day (occurrence rate 3%) and 1 mg/kg bw/day (15%) and
    as single instances and in single animals also at 0.25 mg/kg bw/day.
    At 1 mg/kg bw/day one dog was found dead (week 38), two others were
    killed moribund (weeks 33 and 38). Reduced body-weight gain most
    probably due to food unpalatability and therefore reduced food

    consumption was observed at the highest dose level. A slight
    decrease in serum urea nitrogen at 1 mg/kg bw/day was most probable
    a consequence of decreased protein intake at this dose level. Slight
    leukocytosis and increased packed cell volume was noted in one dog
    killed in poor condition. There were no gross or microscopic changes
    that could be attributed to treatment. The NOAEL in this study was
    < 0.25 mg/kg bw/day, the single instance of mydriasis at this
    dose being considered a borderline effect (Gordon  et al., 1982i).

    Long-term toxicity carcinogenicity studies

    Mice

         Abamectin (purity 90%) was administered in the diet to groups
    of mice (Crl:CD-1(ICR)BR;74/sex/group; 24/sex/group for interim
    sacrifice) at concen-trations resulting in doses of 0, 2, 4 or 8
    mg/kg bw/day over a period of 94 weeks. In females, treatment-
    related tremors were observed in all dose groups and deaths occurred
    at 4 and 8 mg/kg bw/day. These effects were not observed in the 12-
    week range-finding study at dosage levels up to 11 mg/kg bw/day (60
    ppm). No explanation could be found for the sensitivity of these
    female mice. Plasma samples taken from affected and unaffected
    animals revealed no significant differences. A subsequent batch of
    females did not show this unexpected sensitivity and following
    restart of the study with a new group of female mice, tremors
    occurred only in single animals at 8 mg/kg bw/day. In males, tremors
    occurred in single moribund animals of the control and 8 mg/kg
    bw/day group. In this group the mortality rate was increased:
    towards the end of the study the mortality reached 60% compared to
    45% in controls. Body-weight gain was reduced about 21% in females
    and 7% in males at 8 mg/kg bw/day. There was a dose-related increase
    in food consumption in treated females but a decrease in food
    efficiency at 8 mg/kg bw/day. The treatment had no effect on
    ophthalmic examinations, haematologic or biochemical parameters,
    organ weights, gross pathology, histopathologic changes (with the
    exception of a higher incidence of dermatitis at 2 and 8 mg/kg
    bw/day in males). The tumour incidence was not increased by the
    treatment. The NOAEL in this study was 4 mg/kg bw/day (Gordon  et
     al., 1983b).

    Rats

         Abamectin (purity 91%) was fed to groups of rats (Crl:CD(SD)Br;
    65/sex/group) at dietary concentrations resulting in doses of 0,
    0.75, 1.5 or 2/2.5/2 mg/kg bw/day over two years. Since no effects
    attributable to abamectin were observed through study week 10, the
    high dose level was increased to 2.5 mg/kg/ bw/day in week 11.
    Because of the appearance of severe signs of CNS toxicity, the dose
    was decreased again to 2 mg/kg bw/day in study week 13 for the
    remainder of the study. No treatment-related changes with respect to
    ophthalmoscopic, haematologic or serum biochemical parameters,

    urinalyses and organ weights were observed. Increases in body-weight
    gain were seen in all dosage groups during the first year on study.
    By the end of the study comparable mean body-weight gains for all
    groups of females were found, but an increased gain was noticed in
    males. The increases in body-weight gain are considered treatment-
    related, but the effect is not considered as an adverse effect.
    Clinical signs consisting of tremors appeared in study week 12
    correlated with the increase in dosage from 2 to 2.5 mg/kg bw/day in
    week 11. The tremors in all the affected animals persisted
    intermittently until sacrifice despite reduction in the high-dose
    level back to 2 mg/kg bw/day in week 13. Several high-dose group
    animals, which exhibited tremors, were sacrificed in a moribund
    condition. The increase in mortality reflects the induction of
    tremors during the early stage of the study and subsequent sacrifice
    of the affected animals. Following the reduction in dose to 2
    mg/kg/bw/day no new cases of tremors occurred and mortality in all
    treated and control groups was comparable. No increase in tumour
    incidence or treatment-related non-neoplastic histopathologic
    changes were observed. The NOAEL in this study was 1.5 mg/kg bw/day
    (Gordon  et al., 1982h).

    Reproduction studies

    Mice

         In a ten-day dietary maternotoxicity study abamectin (purity >
    88%) was fed at dietary concentrations resulting in target dose
    levels of 0, 0.1, 0.3 or 0.6 mg/kg bw/day (actual doses = 0.06,
    0.16, or 0.33 mg/kg bw/day) to groups of pregnant mice (albino CF1;
    20 females/group) on days 6 through 15 of gestation. Marked tremors
    at 0.33 and at 0.16 mg/kg bw/day were observed. Reproductive
    parameters (numbers of implants, resorptions and live and dead
    fetuses) were not influenced. The NOAEL in this study was 0.06 mg/kg
    bw/day (Gordon  et al., 1983c).

    Rats

         One hundred-and-fifty F1 offspring, from five groups of F0
    female rats (Charles River CD), that had been exposed  in utero to
    avermectin B1a at dosage levels of 0 (two groups), 0.1, 0.2 or 0.4
    mg/kg bw/day were selected for a fourteen-week study of oral
    toxicity. Groups of weanling rats (15/sex/group) received avermectin
    B1a at doses of 0, 0.1, 0.2 or 0.4 mg/kg bw/day by gavage. The
    treatment did not have any effects on mortality, ocular changes,
    haematology, serum biochemistry, organ weights or gross and
    microscopic tissue alterations. The increased body-weight gain of
    male rats at 0.4 mg/kg bw/day was considered as treatment-related
    but not as an adverse effect. The NOAEL in this study was 0.4 mg/kg
    bw/day (Norbury and Wolf, 1977).

         Avermectin (B1a) was administered orally to three groups of
    female rats (12 females/dose group) at dose levels of 0, 0.5, 1, or
    2/1.5 mg/kg bw/day from 14 days before mating throughout gestation
    and lactation until day 21 postpartum. The high dose was reduced
    after five doses to 1.5 mg/kg bw/day due to whole body muscular
    tremors at 2 mg/kg bw/day. Two deaths occurred at the high dose, one
    animal at this dose level became moribund. The significant decrease
    in body-weight gain in the 1.5 mg/kg bw/day group was a result of
    weight loss of the 3 moribund or dead animals. Weight gain increases
    were observed during some periods at 1 and 1.5 mg/kg bw/day. A
    treatment-related decrease in the number of live pups per litter on
    day 1 postpartum at 1.5 mg/kg bw was observed. The pup weights were
    decreased at this dose level on day 1. Pups at all dosage levels
    showed decreases in average weight per litter throughout the study.
    Dose-related increase in mortality among pups at all dose levels
    were observed resulting in survival rates of 0, 14% and 76%, in the
    1.5, 1 and 0.5 mg/kg bw/day groups  respectively, compared to 98% in
    the control group. There was a developmental retardation (eye
    opening) at 0.5 and 1 mg/kg bw/day in surviving pups. The NOAELs in
    this study were < 0.5 mg/kg bw/day for embryo-fetotoxicity and 1
    mg/kg bw/day for maternotoxicity (MSDRL, 1977a).

         Avermectin (B1a) was administered orally to three groups of
    15 female rats at dose levels of 0, 0.1, 0.2 or 0.4 mg/kg bw/day
    from 14 days before mating, throughout mating, gestation and
    lactation until day 21 postpartum. No maternotoxic effects were
    observed and the reproduction status was not adversely affected.
    Among pups at 0.2 and 0.4 mg/kg bw/day a dose-related incidence of
    spastic movements was noted increasing in severity with increasing
    dose. At 0.2 and 0.4 mg/kg bw/day reduction in average pup weight
    was observed (dose-related). Developmental retardation (eye opening,
    ear opening, hear growth), occurred at 0.2 and 0.4 mg/kg bw/day
    (dose-related). The NOAEL in this study was 0.1 mg/kg bw/day for
    embryo-fetotoxicity (MSDRL, 1977b).

         In an oral range-finding study (multigeneration) abamectin was
    administered to groups of rats (Crl: CD (SD) BR Sprague-Dawley; 12
    females/group) in the drinking water at concentrations of 0, 0.15,
    0.5, 1.5 or 5 mg/l. Treatment was conducted from 14 days prior to
    cohabitation with untreated males through day 21 postpartum and
    subsequently through the F1 generation. Water consumption in
    groups 0.15-1.5 mg/l increased during the lactation period and
    decreased slightly in the 5 mg/l group. No accurate measurement of
    water consumption could be performed prior to transfer to delivery
    boxes on day 17 of gestation. Thereafter mean levels of water
    consumption were comparable in all groups resulting in dose ranges
    of 0.017-0.037, 0.066-0.127, 0.192-0.396, or 0.556-0.685 mg/kg
    bw/day for the 0.15, 0.5, 1.5 mg/l or 5 mg/l group, respectively. In
    the F0 generation the only effect observed was an increase in
    body-weight gain in the 5 mg/l group in the first study week. In the
    F1 generation an increase in postnatal mortality at 5 mg/l (53%

    compared to 1% in control) was observed, physical signs observed in
    pups at the highest dose level consisted of tremors; pup weights in
    the 5 mg/l group were decreased. 3/116 Fetuses (2.6%) (from 2
    litters) in the 5 mg/l group showed single malformations (1 cleft
    palate, 1 sternebral malformation, 1 sternebral variation). One
    fetus in the 0.5 mg/l group had lumbar ribs. Because of the single
    incidences in the study groups and because of the occurrence of
    these alterations in historical control groups it is questionable if
    these effects are treatment-related (Gordon  et al., 1981).

         In a two-generation study, groups of rats
    (Crl:COBSTMCDTM(SD) BR/30/sex/group) were orally treated
    (gavage) with dosages of 0, 0.05, 0.12 or 0.4 mg abamectin/kg bw/day
    . F0 and F1b rats were mated to produce F1a and F1b litters,
    F2a and F2b litters. At 0.12 and 0.4 mg/kg bw/day both sexes of
    the F0 rats during the first gestation period (F0-F1a) showed
    increased body-weight gains, whereas during the subsequent lactation
    period (F0-F1a) a reduction in body-weight gain compared to
    control was observed at these two dose levels particularly on the
    first days of lactation. Similar changes were also observed in the
    next generation. During the second mating period of F0 rats (to
    produce the F1b litters) mating performance was reduced (reduction
    of incidence of mating) at 0.4 mg/kg bw/day as compared to control
    animals. The reduction in mating performance was presumed to be
    associated with irregular estrous cycles observed during the second
    mating period of F0 female rats. This effect was not observed in
    matings resulting in the F1a litters or the F2a and F2b
    litters. During the lactation periods of both generations effects in
    the 0.4 mg/kg bw/day group consisted of increased pup mortality,
    reduced viability and lactation indices and lower average pup body-
    weights. The incidence of pups which appeared thin and weak was
    increased. These effects were less severe in the F2 litters than
    in the F1 litters. No skeletal anomalies associated with the test
    agent were revealed. Histopathological examination showed retinal
    anomalies in 3/4 males and 1/5 females in the high-dose group
    compared wich 1/10 in the control group (F1b weanlings). The
    anomalies consisted of single or multiple retinal folds of many
    layers that included pigment epithelium. The same lesion was seen in
    one control female and in one male in the 0.05 and 0.12 mg/kg bw/day
    groups of the F1b weanlings. In the F1b parental animals (both
    sexes) only 1/35 showed this retinal anomaly. In the F2b weanlings
    histopathology was performed on a greater number of animals. There
    was a significant increase in retinal anomalies in the high-dose
    group with the following incidences (M + F): 4.6% and 22% in the
    control and 0.4 mg/kg bw/day, respectively. As will become evident
    from the results of a reproduction study in rats conducted with
    comparable doses of the delta-8,9-isomer of abamectin the control
    incidence of retinal anomalies (4.6%) in the present study is much
    smaller than in the other study, where a control incidence of 20%
    was found. Therefore the difference observed may be incidental

    following an unusually low incidence of this lesion in the
    concurrent control group of the present study.

         Among both the F1b and F2b weanlings the high-dose group
    pups were the smallest. One hypothesis to explain the presence of
    retinal folds in the high-dose group weanlings and the disappearance
    with maturity proposed by the study authors is that the ocular globe
    size is relatively smaller in the small pups (where there was
    pronounced pup toxicity) relative to the size of the retina which
    perhaps carried on at its normal growth rate. Therefore it may be
    assumed that the retinal effects observed are a secondary effect.
    Reversibility of the retinal anomalies is evidenced by its absence
    in the high dose adults. The NOAELs in this study were 0.12 mg/kg
    bw/day for pup toxicity and retinal anomalies and 0.05 mg/kg bw/day
    for maternotoxicity (Gordon  et al., 1982n).

    Special studies on embryotoxicity/teratogenicity

    Mice

         Avermectin B1a was administered orally (gavage) to groups of
    mice (albino CF1 strain/20 females/dose) from days 6 through 15 of
    gestation at dose levels of 0, 0.1, 0.2, 0.4 or 0.8 mg/kg bw/day.
    The doses of the B1a component were calculated as the parent
    compound.

         Deaths occurred in the 0.1, 0.4 and 0.8 mg/kg bw/day groups (1,
    3 and 2 animals respectively), in most cases preceded by tremors.
    Body-weight gain was not influenced by the treatment; neither was
    the reproductive status (number of implants, resorptions, live and
    dead fetuses per litter). An increased incidence of cleft palate at
    0.4 (4/165; 2.4%) and 0.8 mg/kg bw/day (5/199; 2.5%) was observed
    compared to a control incidence of 0.4%. The NOAELs in this study
    were < 0.1 mg/kg bw/day for maternotoxicity and 0.2 mg/kg bw/day
    for embryo-fetotoxicity and teratogenicity (Robertson 1977a).

         Groups of mice (albino CF1 strain/20 female/group) were
    administered avermectin B1a by gavage from day 6 through 15 of
    gestation at dose levels of 0, 0.025, 0.05, 0.075 or 0.1 mg/kg
    bw/day. One animal died at 0.1 mg/kg bw/day and tremors were
    observed in several additional mice at this dose. One animal at
    0.075 mg/kg bw/day exhibited muscular tremors and became moribund.
    Maternal body-weight gains were unaffected at any dosage level. The
    NOAEL in this study was 0.05 mg/kg bw/day for maternotoxicity
    (Robertson, 1977b).

         In an oral maternotoxicity study the minor component of
    abamectin, avermectin B1b was administered by gavage to groups of
    mice (Crl:CF1 BR; 12 females/dose) at dose levels of 0, 0.025, 0.05,
    0.075 or 0.1 mg/kg bw/day on days 6 through 15 of gestation. At the
    0.075 mg/kg bw/day dose level two deaths occurred preceded by weight

    loss and tremors. Single fetuses at all dose levels showed
    malformations consisting of exencephaly and cleft palates resulting
    in incidences of about 1% in all dose groups. The highest incidences
    for historical control groups are 1.6% for exencephaly and 1.3 % for
    cleft palates (overall incidence 0.3% for exencephaly and cleft
    palate each). There was no evidence of fetotoxicity. The NOAEL in
    this study was 0.05 mg/kg bw/day for maternotoxicity (Gordon  et
     al., 1985e).

    Rats

         In a range-finding study groups of mated female rats (Charles
    River; 10/group) were administered abamectin by gavage at dose
    levels of 0, 0.25, 0.5, 1 or 2 mg/kg bw/day on gestation days 6
    through 17. One female at 2 mg/kg bw/day exhibited weight loss and
    tremors and was sacrificed after receiving 12 doses. There was no
    other evidence of maternal toxicity. At 0.25 and 2 mg/kg bw/day
    there was a slightly increased body-weight gain that is considered
    to be treatment-related but not an adverse effect. The NOAEL in this
    study was 1 mg/kg bw/day (Gordon  et al., 1982j).

         In a rat teratology study groups of mated rats (Charles River;
    25 females/group) were orally treated (gavage) with abamectin
    (purity 94%) at dosage levels of 0, 0.4, 0.8 or 1.6 mg/kg bw/day on
    days 6 through 19 of gestation. There was no evidence of maternal
    toxicity. Slightly increased maternal body-weight gain was seen at
    all dosage levels between days 6 and 14 of gestation. An increased
    incidence of fetuses with external fetal malformations was observed
    (exencephaly, cleft palate, gastroschisis) at 0.8 and 1.6 mg/kg
    bw/day. The incidences were: 2/279 (0.7%) and 2/326 (0.6%),
    respectively, compared to 1/319 (0.3%) in the control group.
    Historical control incidence of cleft palate in this rat strain is
    0.03% (overall) or 0.3% (single study with highest incidence).
    Gastroschisis alone has an overall incidence of 0.004% or the
    highest incidence in a single study of 0.3%. Based on the fact, that
    in historical controls one single malformation (cleft palate) may
    occur in up to 0.3% of control animals and no dose-response-
    relationship is evident, it may be assumed that the increase
    observed may either not be treatment-related or may be a borderline
    effect. Visceral examination indicated a higher incidence of
    distended ureters in the treated groups up to 3% compared to 0% in
    controls), but without any dose-effect relationship. This effect is
    observed at incidences of up to 7% in historical control groups.
    Skeletal examination revealed a higher incidence of fetuses with
    lumbar ribs and count variations at 1.6 mg/kg bw/day: at 1.6 mg/kg
    bw/day an incidence of 72/326 (22%) was found, compared to 41/320
    (13%) at 0.4, and 45/279 (16%) at 0.8 mg/kg bw/day compared to
    44/319 (14%) in the control group. The increase at 1.6 mg/kg bw/day
    may not be treatment-related because higher incidences are observed
    in historical controls. For example, in historical controls lumbar
    ribs occurred at an incidence of 14% (overall) or 27.8% (single

    study with highest incidence). The NOAELs in this study were 1.6
    mg/kg bw/day for maternotoxicity and < 1.6 mg/kg bw/day for
    fetotoxicity and teratogenicity (Gordon  et al., 1982k).

    Rabbit

         In a range-finding study groups of New Zeeland albino rabbits
    (10 females/dose) were given abamectin at oral dosage levels of 0,
    0.5, 1, 2 or 3 mg/kg bw/day on gestational days 6 through 18.
    Maternotoxicity was observed at 3 mg/kg bw/day. One female at 3
    mg/kg bw/day was sacrificed moribund on day 16 of gestation after 11
    doses. All females at 3 mg/kg bw/day were in a stupor after the
    fourth and subsequent doses and showed yellow or green discharge
    from nose or mouth. Moreover animals at 3 mg/kg bw/day had a
    decreased food and water consumption, and showed body-weight loss.
    The NOAEL in this study was 2 mg/kg bw/day (Gordon  et al., 1982).

         In a teratogenicity study groups of female New Zeeland albino
    rabbits (18/dose) were given abamectin (purity 94%) at oral dosage
    levels of 0, 0.5, 1 or 2 mg/kg bw/day on day 6 through 27 of
    gestation. There were single deaths in all the treatment groups. At
    2 mg/kg bw/day the animals showed decreased food and water
    consumption and weight loss. Fetuses of the 2 mg/kg bw/day showed
    cleft palates, omphaloceles and clubbed forefeet at higher
    incidences than in the concurrent control group: 7.4% versus 2.1% in
    concurrent control. The incidence of clubbed fore foot alone in
    historical control groups is 0.2% (overall) and 3.9%, respectively,
    in a single study with highest incidence. No data are available
    concerning historical control incidences of cleft palates and
    omphaloceles in rabbits. The clearly higher incidence of these
    malformations at 2 mg/kg bw/day is therefore considered to be
    treatment-related. With respect to skeletal fetal examination higher
    incidences of skeletal terata (vertebral malformations, branched and
    fused ribs) were observed at 0.5, 1 and 2 mg/kg bw/day with
    incidences of 4%, 2% and 4% of the fetuses showing these
    malformations respectively, compared to 0% in the concurrent control
    group. In historical controls single vertebral malformations may
    occur at incidences of up to 0.5% (overall) (e.g., caudal vertebral
    malformations) with the highest value of 9% in a single study (e.g.,
    fused ribs). At 0.5 and 2 mg/kg bw/day there were increased
    incidences of incompletely ossified sites particularly in sternebrae
    and metacarpals. These effects were more pronounced in the highest
    dose group. Because the incidences observed at 1 mg/kg bw/day were
    comparable to the incidences in the control group the absence of a
    dose-relationship in the lower dose levels of 0.5 and 1 mg/kg bw/day
    indicates that the increased incidence at 0.5 mg/kg bw/day is
    possibly not treatment-related. The NOAEL in this study was 1 mg/kg
    bw/day for maternotoxicity, embryo-fetotoxicity, and teratogenicity
    (Gordon  et al., 1982m).

    Special studies on genotoxicity

         A number of genotoxicity studies have been conducted with
    abamectin. The results are summarized in Table 3.

    Special studies on the delta-8,9-isomer of avermectin B

    Biochemical aspects

    Rat

         Male rats were orally (gavage) dosed with 1.4 mg3H-labelled
    delta-8,9-isomer avermectin B1a/kg bw. The delta-8,9-isomer of
    abamectin is a photolytic degradation product of abamectin. The
    stability of the tritium label at the 5th carbon position was
    previously demonstrated with avermectin B1a in rats. Within 7 days
    after dosing 94% of the administered dose was eliminated with the
    faeces, and 0.4% in the urine. The levels of residues in liver,
    kidney, fat and muscle ranged from 0.28 ppm (muscle) to 1.4 ppm
    (fat) on day 1 after dose and decreased to a range of 0.017 to 0.1,
    respectively, on day 7 after dosing. The half-lives for the tissue
    residues in muscle, kidney, liver and fat varied between 1.45 and
    1.64 days. As major metabolite the 3"-desmethyl-delta-8,9 isomer was
    isolated. The 3"-DM-delta-8,9 isomer was also isolated and
    identified after rat liver microsomal incubation of the delta-8,9-
    isomer. The minor metabolite 24-hydroxymethyl-Delta-8,9-isomer,
    (also formed  in vitro), was identified.

         By comparison, the elimination by rats of both the delta-8,9-
    isomer avermectin B1a in this study and the avermectin B1a in a
    previous study was very similar. In both studies 94-96% of the
    administered dose were recovered within 7 days after dosing in the
    excreta. The tissue residue levels were also demonstrated to be
    similar for both compounds. The average half-life for the residue in
    the edible tissues was 1.1 and 1.5 days for avermectin B1a and
    delta-8,9-isomer, respectively. The metabolites generated were very
    similar with rats metabolizing both compounds to the 3"-desmethyl
    and the 24-hydroxymethyl metabolites. Similarly, both avermectin
    B1a and ivermectin B1 (22,23-dihydro-avermectin B1) have been
    shown to be primarily metabolized to the 3"-desmethyl and/or 24-
    hydroxymethyl metabolite(s) by many other animal species (Maynard
     et al., 1986a).


    
    Table 3. Results of genotoxicity assays on abamectin
                                                                                                            
    Test System          Test Object         Concentration            Results         Reference
                                             (purity)
                                                                                                            

    Ames test            Salmonella          100-10 000 g/plate      negative        Gordon  et al. (1982a)
                         typhimurium         (precipitate at conc.
                                             > 3000 g/plate)
                                              activation
                                             (94%)

    Ames test            Salmonella          1-2000 g/plate *        negative        Skeggs (1976)
                         typhimurium

    Ames test            Salmonella          100-10 000 g/plate      negative        Gordon  et al. (1985f)
                         typhimurium         without activation
                                             (89%)
                                             3-1000 g/plate
                                              activation
                                             (94%)

    V-79 mammalian       V-79 Chinese        0.03 - 0.05 mM           negative        Gordon  et al. (1982b)
    cell assay           hamster lung cells  (+ activation)
    (HGPRT Locus)                            0.003-0.006 mM
                                             (- activation)

    Alkaline elution     Rat hepatocytes     0.01-0.6 mM              positive in     Gordon  et al. (1982c)
    assay in vitro                                                    concentrations
    (DNA single                                                       (> 0.2 mM)
    strand breaks)

    Test System          Test Object         Concentration            Results         Reference
                                             (purity)

    Table 3 (contd)
                                                                                                            
    Test System          Test Object         Concentration            Results         Reference
                                             (purity)
                                                                                                            

    In vitro             Chinese hamster     0.005 - 0.025 mM         negative        Gordon  et al. (1985g)
    chromosomal          ovary cells         with activation
    aberration
                                             0.01 - 0.035 mM
                                             without activation

    Alkaline elution     Rat oral            up to 10.6 mg/kg bw      negative        Gordon  et al. (1982d)
    assay in vivo                            (approx. LD50)
    (DNA single 
    strand breaks)

    In vivo cytogenetic  Mouse oral          1, 2, 4,                 negative        Blazak  et al. (1983)
    assay                                    12 mg/kg bw
    (mouse bone marrow)  (94%)

    Delta-8,9-isomer:    Salmonella          10-3000 g/plate         negative        Gordon  et al. (1987a)
    reverse mutation     typhimurium          activation
    test                 and E. coli         (precipitation at conc.
                                             > 1000 g/plate)
                                             (91,6%)

    Polar degradates:    Salmonella          100-10 000 g/plate      negative        Gordon  et al. (1987a)
    reverse mutation     typhimurium          activation
    test                 and E. coli         (precipitation at
                                             10 000 g/plate)
                                                                                                            

    * avermectin B1a

    


    Embryotoxicity/teratogenicity and reproduction

    Mice

         The delta-8,9-isomer of abamectin was given by gavage in sesame
    oil to groups of 7-11 mated female mice (Crl:CF1 BR) at doses of 0,
    1.5, 3, 6.25, 12.5, 25, or 50 mg/kg bw/day on day 6 through 15 of
    gestation. Treatment-related deaths occurred at all dosage levels.
    The groups at 3 mg/kg bw/day and higher doses were terminated on
    days 6-8 of gestation. There was a slight decrease in body-weight
    gain on single days at 1.5 mg/kg bw/day compared to control. Because
    of early termination, no body-weights were measured after the
    beginning of dosing in the other dose groups. Fetal effects became
    apparent at 1.5 mg/kg bw/day (the only group with litters) as an
    increased incidence of fetuses with cleft palate (24/83 (29%)
    compared to 0% in the concurrent control. The NOAEL in this study
    was <1.5 mg/kg bw/day for maternotoxicity and teratogenicity
    (Gordon  et al., 1984d).

         A subsequent study with the delta-8,9-isomer was performed to
    establish a no-effect level. Oral doses were administered to groups
    of mice (Crl: CF1 BR; 12 mated females/dose) at levels of 0, 0.05,
    0.1, 0.5 or 1 mg/kg bw/day on days 6 through 15 of gestation. Single
    females at 0.5 and 1 mg/kg bw/day showed clinical signs including
    tremors and loss of body-weight. Decreases in body-weight gain were
    observed at 0.05 and 1 mg/kg bw/day, but not at 0.1 mg/kg bw/day. No
    dose-related increase in the incidence of resorptions and dead
    fetuses occurred in any treatment groups. In addition there were
    fewer implants per female in the 0.05 (10.4 per female) and 1 mg/kg
    bw/day (9.8 per female) groups compared to 12.5 per female in the
    control group resulting in decreases in live fetuses per female at
    0.05 (8.7) and 1 mg/kg bw/day (8.3) compared to control (11.3).
    These differences from control and particularly those at the low
    dose level were probably not treatment-related since the changes
    were slight and were not observed at the intermediate dose levels.

         An increased incidence of cleft palates were observed at dose
    levels of 0.1 mg/kg bw/day and above with incidences of 13/115
    (11%), 1/90 (1%) and 7/91 (8%) at dose levels of 0.1, 0.5, and 1
    mg/kg bw/day, respectively, compared to 0% in the concurrent control
    group. The highest historical control incidence of cleft palates was
    reported to be 3% in one study (overall 0.3%). There were also
    slightly increased incidences of exencephaly at dose levels of 0.1
    mg/kg bw/day and above: of 1/115 (1.7%), 4/90 (4%), and 2/91 (2%) at
    the dosage levels of 0.1, 0.5 and 1.0 mg/kg bw/day, respectively,
    compared to 1/136 (0.7%) in the concurrent control. The highest
    incidence of historical control incidence was reported to be 1.6% in
    a single study (overall 0.3%). As with the incidence of cleft
    palates no dose-response-relationship was evident but the observed
    incidences were clearly higher than the range of historical controls

    reported. The NOAELs in this study were 0.1 mg/kg bw/day for
    maternotoxicity and 0.05 mg/kg bw/day for fetotoxicity and
    teratogenicity (Gordon  et al., 1984d).

         The delta-8,9-isomer of avermectin B1 was orally administered
    to groups of mice (Crl:CF1 BR; 25 females/dose group) at dosage
    levels of 0, 0.015, 0.03 or 0.06 mg/kg bw/day on days 6 through 15
    of gestation (original intent was to have dosage levels of 0.025,
    0.05 and 0.1 mg/kg bw/day; but an error in preparation resulted in
    different dose levels). No signs of maternotoxicity were observed.
    Increased incidences of exencephaly in the 0.03 and 0.06 mg/kg
    bw/day groups were found, but without any dose-response
    relationship. The incidence in both groups was about 1.3% compared
    to 0% in the concurrent control and the 0.015 mg/kg bw/day group.
    Compared to the incidences of historical controls the present
    incidence of 1.3% is slightly smaller than the highest incidence of
    1.6% of a single study in historical control animals. A single fetus
    (1/210) in the 0.015 mg/kg bw/day group had a cleft palate resulting
    in an incidence of about 0.5%. The NOAELs in this study were 0.06
    mg/kg bw/day for maternotoxicity and < 0.06 mg/kg bw/day for
    teratogenicity (Gordon  et al., 1985c).

         The delta-8,9-isomer of avermectin B1 was orally administered
    to groups of mice (Crl:CF1 BR;25 females/group) on days 6 through 15
    of gestation at dosage levels of 0, 0.015, 0.03, 0.1 or 0.5 mg/kg
    bw/day. One animal at 0.5 mg/kg bw/day was sacrificed in a moribund
    condition. Incidence of cleft palate was 24/233 (10%), 6/279 (2%),
    and single fetuses (0.4%) at 0.5, 0.1, and at both 0.03 and 0.015
    mg/kg bw/day, respectively. The overall incidence of cleft palate in
    historical controls is reported to be 0.3%. The incidences of
    exencephaly of about 0.4% that occurred in single fetuses in the
    control, 0.015 and 0.5 mg/kg bw/day groups and in 5/238 (2%) in the
    0.03 mg/kg bw/day group did not show any dose-response-relationship.
    This compares with, but is greater than, the overall incidence of
    0.3% and is less than 1.6% (highest incidence) of historical control
    animals except at 0.03 mg/kg bw/day. The NOAELs in this study were
    0.1 mg/kg bw/day for maternotoxicity and 0.03 mg/kg bw/day for
    embryo-fetotoxicity and terato-genicity (Gordon  et al., 1985d).

    Rats

         In an oral study groups of rats (Sprague-Dawley Crl:CD(SD)BR;
    25 females/group) were treated with dosage levels of 0, 0.25, 0.5 or
    1.0 mg/kg bw/day of the delta 8,9-isomers of abamectin on days 6
    through 17 of gestation. The body-weight gain in treatment groups
    was slightly greater than in the control group. This effect on body-
    weight gain was seen in previous teratology and reproductive studies
    with the parent compound at comparable doses (Gordon  et al.,
    1982k,n). As in the previous studies, this increased body-weight
    gain is considered treatment-related but not an adverse effect. No
    evidence of embryo- or fetotoxicity or teratogenicity at any dose

    level was given. The NOAEL in this study was > 1 mg/kg bw/day
    (Gordon  et al., 1987b)

         In a single generation study groups of rats (Sprague-Dawley
    [Crl: CD(SD)BR]; 20 females/dose) were orally treated (gavage) at
    dosage levels of 0, 0.06, 0.12 or 0.4 mg of the delta-8,9-isomer of
    abamectin/kg bw/day. The period of dosing was fifteen days prior to
    cohabitation through day 20 of lactation. There were no treatment-
    related effects on F0 female reproductive performance (mating
    index, fertility, length of gestation). Histopathological
    examination of the F1 weanlings revealed retinal anomalies in all
    groups including controls, consisting particularly of intra-retinal
    folds. The incidences were 20, 16, 16 and 22% in control, 0.06, 0.12
    and 0.4 mg/kg bw/day groups, respectively. More severe retinal
    anomalies were identified in animals of the low- and mid-dose groups
    compared to control animals. These changes were compared with the
    severity of retinal anomalies observed in control weanling rats of a
    previous two-generation study conducted with abamectin (Gordon  et
     al., 1982n). According to the statement of the study authors the
    retinal anomalies observed in the present study have comparable
    severity as those in the previous control animals, but no original
    data were presented. The study authors conclude that no ocular
    lesions were produced as a result of the administration of the
    compound. The fact that no clear dose-response with regard to the
    incidence and severity of these retinal effects is observed supports
    the suggestion that in fact they are not caused by the treatment
    (Gordon  et al., 1987d).

         Polar degradates (unidentified mixture of residues generated
     in vitro and in a field study on oranges).

         In two oral developmental toxicity studies groups of female
    mice (Crl:CF1 BR; 25/group) were orally treated (gavage) at dosage
    levels of 0, 0.25, 0.5 and 1 mg/kg bw/day on days 6 through 15 of
    gestation. The treatment did not have maternotoxic effects and did
    not influence the reproductive performance. On fetal examination
    there was no evidence of embryotoxic/fetotoxic or teratogenic
    effects of the compounds (Gordon  et al., 1987c, 1988).

    Genotoxicity studies with metabolites

         See Table 3.

    Antidote study of abamectin intoxication in dogs

         Ipecac given at a rate of 30 ml/dog by stomach tube 15 min
    after a lethal oral dose of abamectin of 8 mg/kg bw induced vomiting
    within 15-45 min after ipecac was given. This treatment was adequate
    to prevent coma and death in dogs given a lethal dose of abamectin.
    Ipecac treatment only after 30 min or longer after the dose of

    abamectin did not prevent coma and death of the dogs (Gordon  et
     al., 1984f).

    Observations in humans and non-human primates

         The comparison of the toxicological data of the two members of
    the avermectin family of compounds, abamectin and ivermectin,
    reveals a lot of similarities. Ivermectin has been used extensively
    in humans at an oral therapeutic dose of 0.2 mg/kg bw for the
    treatment of onchocerciasis without serious drug-related adverse
    effects (Greene  et al., 1989). Therefore the human experience with
    a closely related compound offers useful information to be
    considered in the evaluation of abamectin.

    Comparative studies with ivermectin in monkeys

         Safety assessment studies with abamectin and ivermectin have
    shown that the susceptibility of different animal species to these
    compounds varies considerably. The pregnant mouse is the most
    sensitive mammal examined so far. In view of the similarity in
    structure and toxicity of abamectin and ivermectin and the diversity
    of responses among the different species it was suggested that an
    acute oral toxicity study in rhesus monkeys might serve as a
    valuable source of information about the potential toxicity of the
    compounds in primates. Such a study might provide a more rational
    basis for predicting the toxicity of abamectin in humans.

         The purpose of the study was to determine the minimum toxic
    dose (mTD) of abamectin and ivermectin in monkeys and to determine
    the plasma levels of drug at that dose.

         Single oral doses of abamectin or ivermectin were given to four
    rhesus monkeys (2/sex) each at intervals of 2-3 weeks, in the
    following chronological dose levels: 0.2, 0.5, 1, 2, 4, 6, 8, 12 or
    24 mg/kg bw. The most sensitive indicator of toxicity was emesis
    occurring at dose levels of 2 mg/kg bw and higher. The incidence of
    emesis was dose-related and the time after dosing when emesis
    occurred tended to decrease with increasing dose. Marked mydriasis
    (lack of pupillary constriction) was noted only at 24 mg
    abamectin/kg bw. Less pronounced mydriasis was observed after doses
    of 24 mg ivermectin/kg bw. At 24 mg/kg bw both compounds induced
    slight to moderate sedation.

         Since no emesis occurred with doses below 2 mg/kg bw and since
    no other drug-related physical signs of toxicity were observed at
    lower doses, it was concluded that emesis was the most appropriate
    physical sign for characterizing minimum toxic doses of the
    compounds in monkeys and that the mTD was 2 mg/ kg bw for both
    compounds. This dose is tenfold higher than the human dose for
    onchocerciasis therapy of 200 g/kg bw.

         Plasma concentrations of ivermectin were similar to the levels
    of abamectin for up to 4 h following the 2 mg/kg bw doses, but
    thereafter ivermectin levels were higher on the average than those
    of abamectin. Peak levels occurred between 8-24 h post-dose with
    maximum values of 110 ng/ml for ivermectin and 76 ng/ml for
    abamectin after a 2 mg/kg bw dose. The average maximum plasma level
    following the 24 mg/kg bw dose of ivermectin was 680 ng/ml, after
    the same dose of abamectin it was 390 ng/ml. Despite roughly
    proportional increases in plasma levels with increased doses, the
    severity of clinical signs did not worsen appreciably and no
    tremors, convulsions or deaths occurred even at a dose of 24 mg/kg
    bw. The dose-response curve for acute toxicity of abamectin and
    ivermectin in monkeys seems to be much flatter than for mice,
    indicating that in primates, clinical evidence of intoxication
    (emesis) may occur well in advance of serious or life-threatening
    toxicity. Mean peak plasma level measured in humans given the 200
    g/kg bw therapeutic dose of ivermectin was 20 ng/ml (Gordon  et
     al., 1985b).

    Observations in humans

         Whereas for abamectin no observations in humans are reported,
    information is available concerning the therapeutic use and the
    safety of ivermectin, extensively tested in human onchcerciasis. In
    a single yearly dose it suppresses microfilaria in the skin and eyes
    and prevents disease progression in most infected persons. A single
    oral dose of 30 g/kg bw or 50 g/kg bw exhibited microfilaricidal
    activity. Transient pruritus was observed soon after treatment, but
    no abnormal laboratory results were produced (Aziz  et al., 1982).
    In a 12-month follow-up study investigating the efficacy of
    different dosages of the drug it was shown that doses of 100 g/kg
    bw did not produce different reactions from the placebo group,
    whereas dose levels of 150 and 200 g/kg bw only produced mild
    reversible clinical reactions (Mazzotti-like reactions). It is
    suggested therefore that 150 g/kg bw is probably the optimal dose
    in terms of its antiparasitic activity and side effects. A single
    oral dose of 150 g/kg bw annually induces a minimal reaction in 5-
    15% of infected adults and a more significant reaction in about 1%.
    Its use was associated with hypotension, usually occurring within 24
    h of administration in 1 out of 1000 persons (Greene  et al.,
    1989).

    COMMENTS

         Following oral administration of abamectin to rats, 69-82% of
    the administered dose was eliminated in the faeces and only 1% in
    the urine. Biliary excretion was the major cause of the high level
    of faecal excretion. Biotrans-formation proceeds mainly by
    demethylation and hydroxylation.

         Orally administered abamectin elicited dose-dependent CNS
    effects, including tremors and ataxia.

         In a one-year dietary study in dogs at doses of 0, 0.25, 0.5 or
    1 mg/kg bw/day, a borderline NOAEL of 0.25 mg/kg bw/day was
    determined, despite single instances of mydriasis at this lowest-
    dose level.

         In a two-year long-term/carcinogenicity study in mice,
    abamectin was administered in the diet at concentrations resulting
    in doses of 0, 2, 4 or 8 mg/kg bw/day. The NOAEL was 4 mg/kg bw/day,
    based on the occurrence of tremors, a higher mortality rate and
    reduced body-weight gain at 8 mg/kg bw/day. Abamectin was not
    carcinogenic in the mouse.

         In a two-year long-term/carcinogenicity study in rats,
    abamectin was administered in the diet at concentrations resulting
    in doses of 0, 0.75, 1.5 or 2 mg/kg bw/day. The NOAEL was 1.5 mg/kg
    bw/day. Higher doses caused CNS toxicity. Abamectin was not
    carcinogenic in rats.

         In two one-generation reproduction studies in rats avermectin
    B1a was administered in the diet at concentration resulting in
    dosage levels ranging from 0.1 to 2 mg/kg bw/day in rats.
    Maternotoxicity was observed at dose levels above 1 mg/kg bw/day.
    Fetotoxicity, consisting of reduced pup survival rates, reduced pup
    weight growth and retardation became evident at dose levels of 0.5
    mg/kg bw/day and higher. The NOAEL for fetotoxicity was 0.1 mg/kg
    bw/day.

         In a two-generation reproduction study in rats at dose levels
    of 0.05, 0.12 or 0.4 mg abamectin/kg bw/day, the NOAEL for
    maternotoxicity was 0.05 mg/kg bw/day, based on reduced maternal
    body-weight gain during lactation at 0.12 mg/kg bw/day and above. 
    The NOAEL for pup toxicity was 0.12 mg/kg bw/day, based on increased
    mortality and lowered pup weights at 0.4 mg/kg bw/day.

         The teratogenic potential of abamectin administered by gavage
    was investigated in mice, rats and rabbits. Teratogenic effects,
    including cleft palates, omphaloceles and clubbed fore feet, were
    observed at maternotoxic doses in mice and rabbits. The NOAEL for
    teratogenicity in the most sensitive species, the mouse (CF1 strain)
    was 0.2 mg/kg bw/day, while for maternotoxicity the NOAEL was 0.05

    mg/kg bw/day, based on the occurrence of tremors and deaths at
    higher doses.

         Various studies to investigate the teratogenic potential of the
    delta-8,9-isomer have been conducted in mice and rats. Similar
    teratogenic effects to those seen with abamectin were observed in
    the most sensitive species, the mouse. The NOAELs for
    maternotoxicity in the mouse were 0.1 mg/kg bw/day, and for
    fetotoxicity/teratogenicity, 0.05 mg/kg bw/day.

         After reviewing the available genotoxicity data, the Meeting
    concluded that abamectin was not genotoxic.

         Although no human data were available on abamectin, extensive
    data on field and community-based trials with ivermectin in humans
    infected with  Onchocera spp. were available (WHO, 1993). The main
    effects noted were those arising from the death of parasites, the
    so-called Mazzotti reaction, which is characterized by arthralgia,
    pruritus, fever, hypertension, tachycardia, headache, and ocular
    changes. Very limited data in humans indicate that ivermectin does
    not increase the incidence of birth defects, although it is
    teratogenic in mice, rats and rabbits (WHO, 1990).

         The available data provided adequate toxicological information
    to permit the allocation of an ADI for abamectin and its delta-8,9-
    isomer, based on the NOAELs for abamectin of 0.05 mg/kg bw/day in
    the teratogenicity study in mice and in the two-generation
    reproduction study in rats. The NOAEL for the delta-8,9-isomer was
    0.05 mg/kg bw/day in the teratogenicity study in mice. A safety
    factor of 500 was used because of concern over the teratogenicity of
    the delta-8,9-isomer which forms part of the residue in food.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

    Abamectin (and components avermectin B1a and B1b):

         Mouse:    4 mg/kg bw/day (2 year feeding study)
                   0.05 mg/kg bw/day (teratology study, maternotoxicity)
                   0.2 mg/kg bw/day (teratology study, teratogenicity)

         Rat:      1.5 mg/kg bw/day (2-year study)
                   0.1 mg/kg bw/day (1-generation reproduction study)
                   0.05 mg/kg bw/day (2-generation reproduction study,
                              maternotoxicity)
                   0.12 (2-generation reproduction study, pup toxicity)

         Dog       0.25 mg/kg (borderline) (1-year study)

    Delta-8,9-isomer

         Mouse     0.1 mg/kg bw/day (teratology study, maternotoxicity)
                   0.05 mg/kg bw/day (teratology study, teratogenicity)

    Estimate of acceptable daily intake for humans (abamectin and 
    delta-8,9-isomer)

         0-0.0001 mg/kg bw.

    Studies which will provide information valuable in the continued 
    evaluation of the compound

         1.   Ongoing studies on the mechanism of central nervous system
              toxicity.
         2.   Observations in humans.

    REFERENCES

    Alvaro, R.F., Green, M.L., Halley, B.A., Maynard, M.S., &
    Meriwether, H.T. (1984) Distribution and clearance of avermectin
    B1a in rats. Unpublished report ARM-1 prepared by Merck Sharp &
    Dohme Research Laboratories, West Point, Pennsylvania, USA.
    Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Aziz, M.A., Biallo, S., Diopp, I. and Lariviere, M. (1982) Efficacy
    and tolerance of ivermectin in human onchocerciasis. Lancet, 24
    July, p. 171-173. Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Blazak, W.F., Mitchell, A.D., & Skinner, W.A. (1983) An assessment
    of the mutagenic potential of abamectin (mk 0936) utilizing the  in
     vivo mouse bone marrow cytogenetics assay. Study Number TT 83-900-
    6. Unpublished report prepared by SRI International, Menlo Park, CA,
    USA. Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R. & Mandel, J. (1978) Acute dermal toxicity study in rats
    with abamectin (avermectin B1; C-076). Study Number TT 78-3607.
    Unpublished report prepared by Merck Sharp & Dohme Research
    Laboratories, West Point, Pennsylvania, USA. Submitted to WHO by
    MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., Nickell, B.E., Collevechio, K., Mutchler, M., & Clark,
    R.L. (1981) Oral-range-finding study (multigeneration) in rats with
    abamectin (MK 0936). Study No. 82-707-0. Unpublished report prepared
    by Merck Sharp & Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Gordon, L.R., Bradley, M.O., Cook, M.M., Berglund, R.M., & Prato, M.
    (1982a) Microbial mutagen test on abamectin (MK 0936) with and
    without rat liver enzyme activation. Study No. TT 82-8013.
    Unpublished report prepared by Merck Sharp & Dohme Research
    Laboratories, West Point, Pennsylvania, USA. Submitted to WHO by
    MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., Bradley, M.O., & Patterson, S.K. (1982b) V-79
    mammalian cell mutagenesis assay with abamectin (MK 0936). Study No.
    TT 82-8506, 82-8510, 82-8512, 82-8519. Unpublished report prepared
    by Merck Sharp & Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Gordon, L.R., Bradley, M.O., Patterson, S.K., Taylor, V.E., &
    Dysart, G.R. (1982c)  In vitro alkaline elution/rat hepatocyte
    assay with abamectin (MK 0936). Study No. TT 82-8520, 82-8523, 82-
    8525, 82-8526. Unpublished report prepared by Merck Sharp & Dohme
    Research Laboratories, West Point, Pennsylvania, USA. Submitted to
    WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., Bradley, M.O., Patterson, S.K., Taylor, V.E., &
    Dysart, G.R. (1982d)  In vivo alkaline elution/rat hepatocyte assay
    with abamectin (MK 0936). Study No. TT 82-8302. Unpublished report
    prepared by Merck Sharp & Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Gordon, L.R., Bokelman, D.L., & Stone, C.A. (1982e) Twelve-week oral
    range-finding study in dogs given abamectin (MK 0936). Study No. TT
    82-073-0. Unpublished report prepared by Merck Sharp & Dohme
    Research Laboratories, West Point, Pennsylvania, USA. Submitted to
    WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., Peter, Ch.P., Nickell, B.E., Buck, J.F., & Schultz,
    A.K. (1982f) Twelve-week oral dietary range-finding study in mice
    given abamectin (MK 0936). Study No. TT82-082-0,-2,-2. Unpublished
    report prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Gordon, L.R., Lankas, G.R., Nickell, B.E., Buck, J.F., & Jackson, L.
    (1982g) Eight-week dietary range-finding study in rats given
    abamectin (MK 0936). Study No. TT 82-075-0, -1. Unpublished report
    prepared by Merck Sharp & Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Gordon, L.R., Bokelman, D.L., & Skolnick, E.M. (1982h) One-hundred-
    five week dietary carcinogenicity and toxicity study of abamectin
    (MK 0936) in rats with a 53-week interim necropsy. Study No. TT 82-
    099-0. Unpublished report prepared by Merck Sharp & Dohme Research
    Laboratories, West Point, Pennsylvania, USA. Submitted to WHO by
    MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R. Allen, H.L., Nickell, B.E., Satiritz, S.M., Powzaniuk,
    W., Roux, L., & McKeon, J. (1982i) Fifty-three week dietary study in
    dogs given abamectin (MK 0936). Study No. TT 82-104-0. Unpublished
    report prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Gordon, L.R., Clark, R.L., Nickell, B.E., Collevechio, K., & Weller,
    J.V. (1982j) Oral range-finding study in pregnant rats given
    abamectin (MK 0936). Study Number TT 82-705-1. Unpublished report
    prepared by Merck Sharp & Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Gordon, L.R., Clark, R.L., Nickell, B.E., Collevechio, K., &
    Siriani, L.B. (1982k) Oral teratology study in rats given abamectin
    (MK 0936). Study No. TT 82-705-0. Unpublished report prepared by

    Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania,
    USA. Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., Clark, R.L., Nickell, B.E., Collevechio, K., &
    Siriani, L.B. (1982l) Oral range finding study in pregnant rabbits
    given abamectin (MK 0936). Study No. TT 82-706-1. Unpublished report
    prepared by Merck Sharp & Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Gordon, L.R., Clark, R.L., Nickell, B.E., Collevechio, K., & Vetter,
    C.M. (1982m) Oral teratology study in rabbits given abamectin (MK
    0936). Study No. TT 82-706-0. Unpublished report prepared by Merck
    Sharp & Dohme Research Laboratories, West Point, Pennsylvania, USA.
    Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., Mildred, S.C., & Hoberman, H.M. (1982n) Reproductive
    effects of abamectin (MK 0936) administered orally by gavage to Crl:
    COBS CD(SD)BR rats for two Generations. Study No. TT 82-9010.
    Unpublished report prepared by Argus Research Laboratories, Horsham,
    Pennsylvania, USA and by Merck Sharp & Dohme Research Laboratories,
    West Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three
    Bridges, NJ, USA.

    Gordon, L.R., Mandel, J., McDonald, J.S., Nickell, B.E., Powzaniuk,
    W., & Bielinski, T.C. (1983a) Guinea pig skin maximization test with
    abamectin (MK 0936). Study No. TT 83-2506. Unpublished report
    prepared by Merck Sharp & Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Gordon, L.R., Lankas, G.R., Fabry, A., Nickell, B.E., Powzaniuk, W.,
    Buck, J.F., Satiritz, S.M., & Schultz, A. (1983b) Ninety-four week
    dietary carcinogenicity and toxicity study in mice given abamectin
    (MK 0936). Study No. TT 83-002-0,-1,-2,-3. Unpublished report
    prepared by Merck Sharp & Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Gordon L.R., Minsker, D.H., Nickell, B.E., Collevechio, K., &
    Battisti, G.A. (1983c) Ten-day dietary maternotoxicity study in mice
    given abamectin (MK 0936). Study No. TT 83-705-1. Unpublished report
    prepared by Merck Sharp & Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Gordon, L.R., McDonald, J.S., Nickell, B.E., Mandel, J., Powzaniuk,
    W., & Stolz, W.W. (1983d) Acute dermal toxicity study in rabbits
    given abamectin (MK 0936). Study No. TT 83-064-0. Unpublished report
    prepared by Merck Sharp & Dohme Research Laboratories, West Point,

    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Gordon, L.R., McDonald, J.S., Allen, H.L., Nickell, B.E., Mandel,
    J., Powzaniuk, W., & McAfee, J.L. (1984a) Acute oral toxicity study
    in mice given Avermectin B1b. Study No. TT 84-107-0. Unpublished
    report prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Gordon, L.R., McDonald, J.S., Mandel, J., & McAfee, J.L. (1984b)
    Five-day acute oral toxicity study in pregnant and non-pregnant cf1
    mice with abamectin (MK 0936). Study No. TT 84-2842-0. Unpublished
    report prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Gordon, L.R., Mandel, J., Majka, J.A., & McAfee, J.L. (1984c) Acute
    oral toxicity study in mice given the Delta-8,9-isomer of abamectin
    (MK 0936). Study No. 84-112-0. Unpublished report prepared by Merck
    Sharp & Dohme Research Laboratories, West Point, Pennsylvania, USA.
    Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., Clark, R.L., Allen, H.L., Nickell, B.E., Collevechio,
    K., & Landis, D.K. (1984d) Oral maternotoxicity study in mice with
    the Delta-8,9 isomer of abamectin (avermectin B1). Study No. 84-
    722-0,-1. Unpublished report prepared by Merck Sharp & Dohme
    Research Laboratories, West Point, Pennsylvania, USA. Submitted to
    WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R. (1984e) Acute oral toxicity study in mice with Delta-
    8,9-isomer of abamectin (MK 0936). Study No. TT 84-2820. Unpublished
    report prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Gordon, L.R., Bokelman, D.L., & Stone, C.A. (1984f) Exploratory non-
    specific antidote study of abamectin (MK 0936) intoxication in dogs.
    Study No. 84-085-0. Unpublished report prepared by Merck Sharp &
    Dohme Research Laboratories, West Point, Pennsylvania, USA.
    Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., McDonald, J.S., Mandel, J., & McAfee, J.L. (1985a)
    Five-day acute oral toxicity study in pregnant and nonpregnant CF1
    mice with abamectin (MK 0936). Study No. TT 85-2593. Unpublished
    report prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Gordon, L.R., Kornbrust, D.J., Douwning, G.V., Nickell, B.E., Buck,
    J., & Rafferty, C.E. (1985b) Oral toxicity and plasma level study in

    monkeys with Ivermectin (MK 0933) and abamectin (MK 0936). Study No.
    T 85-013-0. Unpublished report prepared by Merck Sharp & Dohme
    Research Laboratories, West Point, Pennsylvania, USA. Submitted to
    WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., Clark, R.L., Nickell, B.E., Collevechio, K., & Landis,
    D.K. (1985c) Oral teratology study in mice with the Delta-8,9-Isomer
    of abamectin (avermectin B1). Study No. TT 85-710-0. Unpublished
    report prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Gordon, L.R., Clark, R.L., Nickell, B.E., Collevechio, K., & Geiger,
    J.E. (1985d) Oral teratology study in mice with the Delta-8,9-Isomer
    of abamectin (avermectin B1). Study No. 85-710-1. Unpublished
    report prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Gordon, L.R., Clark, R.L., Allen, H.L., Nickell, B.E., Collevechio,
    K., Powzaniuk, W., & Landis, D.K. (1985e) Oral maternotoxicity study
    in mice with Avermectin B1b. Study No. 84-721-0. Unpublished report
    prepared by Merck Sharp & Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Gordon, L.R., Sina, J., Patterson, S.K., Berglind, R.M., Prato, M.,
    & Quillin, F. (1985f) Microbial mutagenesis assays with abamectin
    (avermectin B1; MK 0936). Study No. TT 85-8005 and 85-8051
    Unpublished reports prepared by Merck Sharp & Dohme Research
    Laboratories, West Point, Pennsylvania, USA. Submitted to WHO by
    MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., Galloway, S., Patterson, S.K., Armstrong, M., Bean,
    Ch.L., & Deasy, D. (1985g) Abamectin (MK 0936) assay for chromosomal
    aberrations  in vitro, in chinese hamster ovary cells Study No. TT
    85-8631, 85-8632, 85-8635. Unpublished report prepared by Merck
    Sharp & Dohme Research Laboratories, West Point, Pennsylvania, USA.
    Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., Sina, J.F., Wright, S.P., Prato, M., & Quillin, F.
    (1987a) Microbial mutagenesis assays of the Delta-8,9-isomer and
    polar degradates of abamectin (Avermectin B1; MK 0936). Study Nos.
    TT 87-8046, 87-8047, 87-8058. Unpublished reports prepared by Merck
    Sharp & Dohme Research Laboratories, West Point, Pennsylvania, USA.
    Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., Wise,L.D., Jensen, R.D., Nickell, B.E., Collevechio,
    K., & Vetter, C.H. (1987b) Oral developmental toxicity study in rat
    given the Delta-8,9-Isomer of abamectin (avermectin B1). Study No.
    TT 87-715-0. Unpublished report prepared by Merck Sharp & Dohme

    Research Laboratories, West Point, Pennsylvania, USA. Submitted to
    WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon, L.R., Minsker, D.H., Anderson, C.A., Nickell, B.E.,
    Collevechio, K. & Deyerle-Brooks, K.A. (1987c) Oral developmental
    toxicity study in mice given the polar degradates of abamectin (MK
    0936). Study No. TT 87-717-0. Unpublished report prepared by Merck
    Sharp & Dohme Research Laboratories, West Point, Pennsylvania, USA.
    Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Gordon L.R., Wise, L.D., Vonderfecht, St.L., Nickell, B.E.,
    Collevechio, K., Powzaniuk, W., & McMahon, M.G. (1987d) Single
    generation study in rats with the Delta-8,9-isomer of abamectin
    (avermectin B1). Study No. 87-716-0. Unpublished report prepared
    by Merck Sharp & Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Gordon, L.R., Wise, L.E., Allen, M.L., Nickell, B.E.,
    Collovechio,K., Powzaniuk, W., & Sina, J.L. (1988) Oral
    developmental toxicity study in mice with L-930,463 (polar
    degradate). Study No. TT 88-713-0. Unpublished report prepared by
    Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania,
    USA. Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Greene, B.M., Brown, K.R., & Taylor, H.R. (1989) Use of Ivermectin
    in humans, In: Ivermectin and Abamectin, ed. by Campbell, W.C.,
    Springerverlag, Chapter 21, p. 311-323. Submitted to WHO by MSDRL,
    Three Bridges, NJ, USA.

    Gruber, V.I. (1988) Identification of -alpha-hydroxy-avermectin
    B1a as a metabolite of avermectin B1a in rats. Unpublished
    report of Merck sharp and Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    Mandel, J. (1977) Acute oral toxicity studies in mice and rats with
    avermectin B1a (C-076(B1a)). Study Nos. TT 77-3248, 77-3250, 77-
    3264, 77-3787, 77-3789, 77-3788, 77-3337 and 77-3346. Unpublished
    reports prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Maynard, M.S., Wislocki, P.G., & Lu, A.Y.H. (1986a) The metabolism
    of Delta-8,9-Z-isomer avermectin B1a in rats. Unpublished report
    ARM-2, prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Maynard, M.S., Wislocki, P.G., & Lu, A.Y.H. (1986b) The metabolism
    of avermectin B1a in rats. Unpublished report prepared by Merck

    Sharp & Dohme Research Laboratories, West Point, Pennsylvania, USA.
    Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    MSDRL (1977a) Oral reproduction study in rats with avermectin B1a
    (C-076(B1a)). Study Number 77-706-0. Unpublished report prepared
    by Merck Sharp & Dohme Research Laboratories, West Point,
    Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges, NJ,
    USA.

    MSDRL (1977b) Oral reproduction study in rats. Study Number 77-712-0
    with avermectin B1a (C-076(B1a)). Unpublished report prepared by
    Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania,
    USA. Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Norbury K.C. & Wolf, G.L. (1977) Fourteen-week oral toxicity study
    in rats following  in utero exposure to avermectin B1a (C-
    076(B1a)). Study number TT 77-043-0. Unpublished report prepared by
    Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania,
    USA. Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    Robertson, R.T. & Allen, H.L. (1976) Eighteen-week oral toxicity
    study in dogs with avermectin B1a (C-076(B1a)). Study No. TT 76-
    073-0. Unpublished report prepared by Merck Sharp & Dohme Research
    Laboratories, West Point, Pennsylvania, USA. Submitted to WHO by
    MSDRL, Three Bridges, NJ, USA.

    Robertson, R.T. (1977a) Oral teratology study in mice with
    avermectin B1a (C-076(B1a)). Study No. TT 77-705-0. Unpublished
    report prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Robertson, R.T. (1977b) Ten-day oral toxicity study in pregnant mice
    with avermectin B1a (C-076(B1a)). Study No. TT 77-717-1.
    Unpublished report prepared by Merck Sharp & Dohme Research
    Laboratories, West Point, Pennsylvania, USA. Submitted to WHO by
    MSDRL, Three Bridges, NJ, USA.

    Robertson, R.T., McDonald, J.S., Mandel., J., Everett, M.A., Wolf,
    G.L., & Powzaniuk, W., (1981a) Acute oral toxicity study in rats
    with abamectin (avermectin B1). Study No. TT 81-2937. Unpublished
    report prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Robertson, R.T., McDonald, J.S., Mandel, J., Wolf, G.L., Stolz,
    W.W., & Bielinski, T.C. (1981b) Acute dermal toxicity study in
    rabbits with abamectin (avermectin B1). Study No. TT 81-3021.
    Unpublished report prepared by Merck Sharp & Dohme Research
    Laboratories, West Point, Pennsylvania, USA. Submitted to WHO by
    MSDRL, Three Bridges, NJ, USA.

    Robertson, R.T., McDonald, J.S., Mandel, J., Stolz, W.W., &
    Bielinski, T.C. (1981c) Acute ocular irritation study in rabbits
    with abamectin (avermectin B1). Study No. TT 81-2940. Unpublished
    report prepared by Merck Sharp & Dohme Research Laboratories, West
    Point, Pennsylvania, USA. Submitted to WHO by MSDRL, Three Bridges,
    NJ, USA.

    Robertson, R.T., McDonald, J.S., Mandel, J., Stolz, W.W., &
    Bielinski, T.C. (1981d) Primary dermal irritation study in rabbits
    with abamectin (avermectin B1). Study No. TT 81-2941, 81-2943, 81-
    2945. Unpublished report prepared by Merck Sharp & Dohme Research
    Laboratories, West Point, Pennsylvania, USA. Submitted to WHO by
    MSDRL, Three Bridges, NJ, USA.

    Skeggs, H. (1976) Microbial mutagenesis assay with avermectin B1a
    (C-076(B1a)). Study No. TT 76-8052. Unpublished report prepared by
    Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania,
    USA. Submitted to WHO by MSDRL, Three Bridges, NJ, USA.

    WHO (1990) Evaluation of certain veterinary drug residues in food
    (Thirty-sixth report of the Joint FAO/WHO Expert Committee on Food
    Additives). WHO Technical Report Series, No. 799, Geneva.

    WHO (1993) Toxicological evaluation of certain veterinary drug
    residues in food. WHO Food Additive Series No. 31, Geneva.


    See Also:
       Toxicological Abbreviations
       Abamectin (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)