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    ABAMECTIN: Addendum

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

         Explanation
         Evaluation for acceptable daily intake
              Biochemical aspects
                   Absorption, distribution and excretion
                   Biotransformation
              Toxicological studies
                   Acute toxicity
                   Short-term toxicity
                   Long-term toxicity and carcinogenicity
                   Reproductive toxicity
              Embryotoxicity and teratogenicity
                   Special studies
                        Sensitivity of CF-1 mice
              Comments
              Toxicological evaluation
         References

    Explanation

         Abamectin comprises at least 80% avermectin B1a and not more
    than 20% avermectin B1b. Abamectin was first evaluated by the
    Joint Meeting in 1992, when it was allocated an ADI of 0-0.0001
    mg/kg bw on the basis of the lowest NOAEL of 0.05 mg/kg bw per day
    for maternal toxicity observed in a study of teratogenicity in mice
    and a two-generation study of reproductive toxicity in rats. A
    safety factor of 500 was applied because of concern about the
    teratogenicity of the delta-8,9 isomer in CF-1 mice. The isomer is a
    photolytic degradation product which forms a variable part of the
    residue on crops. Abamectin was re-evaluated by the 1994 Joint
    Meeting in order to consider new information.

         This monograph addendum presents the data on abamectin
    submitted since 1992, comprising a study of the photo-oxidative
    stability of avermectin B1a, the main component of abamectin, and
    a study of the sensitivity of CD-1 mice to the toxicity of
    abamectin, and summarizes briefly the results of the studies
    described in the full monograph.

         Abamectin has a close structural relationship to ivermectin, a
    widely used therapeutic agent against onchocerciasis in humans, and
    the two compounds have similar toxic effects in various animal
    species. In 1992, the Joint FAO/WHO Expert Committee on Food

    Additives (JECFA) changed the ADI for ivermectin from 0-0.0002 to
    0-0.001 mg/kg bw (WHO, 1990, 1993a). The present Meeting therefore
    also considered additional data on ivermectin, comprising the
    results of two studies in primates and a published report of a study
    in humans, which were reviewed and summarized by JECFA (Dalgard  et
     al., 1986; Hendricks & Lankas, 1986 [summarized in WHO, 1991];
    Pacqui  et al., 1990 [summarized in WHO, 1993b]).

    Evaluation for acceptable daily intake

    1.  Biochemical aspects

         Under photolytic conditions in the laboratory and in the field,
    abamectin undergoes isomerization around the 8,9-double bond to
    produce small amounts of the delta-8,9 isomer. A study was conducted
    to investigate the stability of 0.15 EC formulations of avermectin
    B1a and the delta-8,9 isomer by exposing thin films of the
    compounds to simulated solar radiation for 1-23 h. Slightly higher
    degradation rates were seen for the delta-8,9 isomer than for
    avermectin B1a (Demchak & MacConnell, 1986).

    (a)  Absorption, distribution and excretion

         Rats were given oral doses of 0.14 or 1.4 mg/kg bw per day of
    abamectin or 1.4 mg/kg bw per day of the delta-8,9 isomer. Over
    seven days, the percentages excreted in urine were 0.3-1% of the
    administered dose of abamectin and 0.4% of the dose of the isomer.
    The animals eliminated 69-82% of the dose of abamectin and 94% of
    the dose of isomer in faeces (Annex I, reference 67; Chiu & Lu,
    1989).

    (b)  Biotransformation

         In rats, goats and cattle, unchanged parent compound accounted
    for up to 50% of the total radioactive residues in tissues. The
    24-hydroxymethyl derivative of abamectin was found in rats, goats
    and cattle treated with the compound and in rats treated with the
    delta-8,9 isomer, and the 3"-O-demethyl derivative was found in rats
    and cattle administered abamectin and in rats administered the
    isomer (Annex I, reference 67; Chiu & Lu, 1989). The metabolic
    pathways of abamectin are shown in Figure 1.

    Figure 1.  Main metabolic pathways of abamectin

    FIGURE 01

    2.  Toxicological studies

    (a)  Acute toxicity

         The acute toxicity of abamectin is summarized in Table 1.

         In monkeys given a single oral dose of abamectin, the NOAEL was
    1 mg/kg bw per day, with a plasma concentration of 38 ng/ml, and the
    LOAEL was 2 mg/kg bw per day, with a plasma concentration of 76
    ng/ml (Gordon  et al., 1985). The same NOAEL and LOAEL were
    observed with ivermectin in monkeys (WHO, 1991).

    Table 1.  Acute toxicity of abamacetin and its delta-8,9 isomer
                                                                    
    Species            Sex  Route    LD50        Component   Purity
                                     (mg/kg bw)              (%)
                                                                    

    Abamectin
    Mouse              F    Oral     13.6-23.8   B1a         NR
                                                 B1b         98.4
     Pregnantb                       11.8-19.0   B1a + B1b   94
     Non-pregnantb                   15.0-41.3   B1a + B1b   94
    Rat                M&F  Oral     approx. 11  B1a         NR
                       M&F  Oral     8.7-12.8    B1a + B1b   91
    Dog                M&F  Oral     approx. 8   B1a         NR
                                                 B1a + B1b
    Monkey             M&F  Oral     > 24        B1a + B1b
    Rat                     Dermal   > 330       B1a +B1b    87±9.4
    Rabbit                  Dermal   > 1600      B1a + B1b   91.4
                                                 B1a + B1b   94

    Delta-8,9 isomer
    Mouse              M&F  Oral     > 80
     (CF-1)
                                                                    

    NR, not reported
    a From Annex I, reference 67
    b Five-day mortality

    (b)  Short-term toxicity

         As shown in Table 2, abamectin induced acute effects on the
    central nervous system, manifested as tremors and mydriasis,
    particularly in dogs. CD-1 mice were less sensitive than rats and
    dogs.

    (c)  Long-term toxicity and carcinogenicity

         Long-term studies of toxicity in mice and rats are summarized
    in Table 3. The effects in the long-term study of abamectin in rats
    showed a steep dose-response relationship.

    (d)  Reproductive toxicity

         Studies of the reproductive toxicity of abamectin in rodents
    (Annex I, reference 67) reveal that pregnant CF-1 mice are
    particularly sensitive to effects on the central nervous system, as
    tremors were observed at a dose as low as 0.16 mg/kg bw per day in a
    study of maternal toxicity. No data on mice were available for the
    delta-8,9 isomer. In rats, the NOAELs and LOELs for maternal
    toxicity in most of the studies were higher than in CD-1 mice,
    ranging from > 0.4 to 1 mg/kg bw per day. In one study, however,
    an NOAEL of 0.12 mg/kg bw per day was found on the basis of reduced
    mating performance at a higher dose level.

         Studies of embryo- and fetotoxicity (Annex I, reference 67)
    have been performed only in rats. The NOAELs in the different
    studies were 0.1-0.3 mg/kg bw per day. The NOAELs and LOELs in most
    studies were lower for embryo- and fetotoxicity than for maternal
    toxicity, indicating that the developing organism is particularly
    sensitive. Increased pup mortality and reduced weight gain were
    consistent findings after postnatal exposure. The delta-8,9 isomer
    had no adverse effects in rats at the doses tested.

    (e)  Embryotoxicity and teratogenicity

         Studies on the embryotoxicity and teratogenicity of abamectin
    and the delta-8,9 isomer in rodents are summarized in Table 5.

    Mice

         In pregnant CF-1 mice treated with abamectin, the NOAEL for
    maternal toxicity, manifested as tremors, weight loss and death, was
    0.05 mg/kg bw per day, and the NOAEL for embryotoxicity and
    teratogenicity was 0.2 mg/kg bw per day. At higher doses (0.4 and
    0.8 mg/kg bw per day), at which pronounced maternal toxicity occurs,
    an increased incidence of cleft palates was seen in comparison with
    concurrent control. The increase was not related to dose, and the
    incidences are within the range of those of historical controls (up
    to 3%) (Annex I, reference 67).


    
    Table 2.  Short-term toxicity of abamectin
                                                                                                       
    Species    Treatment                           Effect level          Effects
                                                   (mg/kg bw per day)
                                                   NOAEL     LOAEL
                                                                                                       

    Mouse      12 weeks, 0, 2, 5, 10, 20 ppm and   8 (40)    12 (60)     Decreased body weight gain
    (CD-1)      3 weeks: 40, 60 ppm (diet)
    Rat        8 weeks: 0, 5, 10, 15, 20/25,       0.5 (10)  0.75 (15)   Tremors, reduced body
                40, 60 ppm (diet)                                         weight gain
    Dog        12 weeks: 0, 0.25, 0.5, 1,          0.5       1            Mydriasis
                4/2 mg/kg bw per day (diet)
                18 weeks: 0, 0.25, 0.5, 2,         0.25      0.5         Tremors, ataxia, mydriasis,
                8 mg/kg bw per day (gavage)                               hepatocellular vacuolation
                (avermectin B1a)                                          and lipid accumulation,
                                                                          single death
               53 weeks: 0, 0.25, 0.5,             0.25      0.5         Single instances of mydriasis,
                1 mg/kg bw per day (diet)                                 marginal effect
                                                                                                       

    From Annex 1, reference 67

    Table 3.  Long-term toxicity of abamectin
                                                                                                       
    Species    Treatment                           Effect level          Effects
                                                   (mg/kg bw per day)
                                                   NOAEL     LOAEL
                                                                                                       

    Mouse      94 weeks: 0, 2, 4, 8 mg/kg bw       4         8           Tremors, increased
    (CD-I)      per day (diet)                                            mortality, reduced body
                                                                          weight gain; no
                                                                          tumorigenicity
    Rat        104 weeks: 0, 0.75, 1.5, 2/2.5/2    1.5       2/2.5       Tremors (after increase in
                mg/kg bw per day (diet)                                   dose after 10 weeks),
                                                                          moribund condition; no
                                                                          tumorigenicity
                                                                                                       

    From Annex 1, reference 67

    

         In study 7 in Table 5, the delta-8,9 isomer was maternally
    toxic in CF-1 mice, inducing tremors, decreased weight gain and
    death, at doses above 0.1 mg/kg bw per day. The NOAEL for
    embryotoxicity and teratogenicity was > 0.03 mg/kg bw per day.
    The NOAEL for maternotoxicity was based on the finding of one
    moribund animal among 25 treated animals at 0.5 mg/kg bw per day. A
    marked increase in the incidence of cleft palates, which exceeded
    the range seen in historical controls, was observed at this
    maternally toxic dose. An increased incidence of cleft palates was
    seen at the NOAEL for maternal toxicity, but the value was clearly
    within the range of that of historical controls. An increased
    incidence of exencephaly was found at 0.03 mg/kg bw per day, which
    slightly exceeded the historical control range (up to 1.6%), so that
    the increase can be regarded as a borderline effect (Annex I,
    reference 67). The results of this study indicate that teratogenic
    effects occur at maternally toxic doses.

         In a second study of the delta-8,9 isomer in mice (study 8),
    the NOAEL for maternal toxicity was 0.1 mg/kg bw per day and that
    for embryotoxicity and teratogenicity was 0.05 mg/kg bw per day.
    Increased incidences of cleft palate and exencephaly were observed
    over those in concurrent controls at doses of 0.1 mg/kg bw per day
    and higher. Most of the anomalies were found at 0.1 mg/kg bw per day
    in one litter, but the range observed in historical controls was
    often exceeded (Annex I, reference 67). It is remarkable, therefore,
    that no dose-response relationship was seen with respect to these
    malformations. Its absence renders interpretation of these results
    difficult, and the conclusion that teratogenicity occurred in the
    absence of maternotoxicity in this study seems to be questionable.

         In a third study in mice (study 9), the NOAEL for maternal and
    embrotoxicity and teratogenicity was > 0.06 mg/kg bw per day
    (Annex I, reference 67). Although increased incidences of cleft
    palate and exencephaly were seen in comparison with concurrent
    controls, there was no dose-response relationship, and the
    incidences were within the historical control range.

         Assessment of the maternal toxicity of the delta-8,9 isomer in
    these three studies was difficult because of the very steep
    dose-response curve and the uncertainty of the end-points used
    (decreased body weight and slight tremors).



    
    Table 4.  Reproductive toxicity of abamectin and its delta-8,9 isomer
                                                                                                                   
    Species   Treatment                             Effect level                  Effects
                                                    (mg/kg bw per day)   

                                                    NOAEL           LOAEL
                                                                                                                   

    Abamectin
    Mouse     0, 0.06, 0.16, 0.33 mg/kg bw per day  0.06            0.16          Maternal toxicity: tremors
     (CF-1)    on days 6-15 of gestation (diet)

    Rat       14 weeks after exposure in utero:     > 0.4           > 0.4         No effects
               0, 0.1, 0.2, 0.4 mg/kg bw per day
               (gavage) (avermectin B1a)

              Two generations (F0, F1)  0, 0.5, 1,  < 0.5           0.5           Embryo- and fetotoxicity:
               2/1.5 mg/kg bw per day  (oral)                                       Reduced pup weight;
               (avermectin B1a)                                                     increased pup mortality;
                                                                                    developmental
                                                                                    retardation (eye opening)
                                                    1               2/1.5         Maternal toxicity: tremors,
                                                                                    deaths, decreased body
                                                                                    weight gain, weight loss

              Two generations (F0, F1):             0.1             0.2           Embryo- and fetotoxicity:
               0, 0.1, 0.2, 0.4 mg/kg bw per day                                    spastic movements, reduced
               (oral) (avermectin B1a)                                              weight gain, developmental
                                                                                    retardation (eye opening)
                                                    > 0.4           > 0.4         Maternal toxicity: no effects

              Two generations (F0, F1):                                           Embryo- and fetotoxicity in F1
               0, 0.15, 0.5, 1.5, 5 mg/l            0.3 (1.5 mg/l)  0.7 (5 mg/l)    pups: tremors, increased
              (drinking-water)                                                      mortality, decreased weight
                                                    > 0.7           > 0.7         Maternal toxicity

    Table 4 (contd)
                                                                                                                   
    Species   Treatment                             Effect level                  Effects
                                                    (mg/kg bw per day)   

                                                    NOAEL           LOAEL
                                                                                                                   

              Two generations (F0, F1)              0.12            0.4           Embryo- and fetotoxicity:
               0, 0.05, 0.12, 0.4 mg/kg bw                                          increased mortality, reduced
               per day (oral)                                                       weight
                                                    0.12 (?)        0.4           Maternal toxicity: reduced
                                                                                    body weight gain during
                                                                                    lactation in F0 and F1 not
                                                                                    related to dose
    Delta-8,9 isomer
    Rat       Two generations (F0, F1)              > 0.4           > 0.4         No treatment-related
               0, 0.06, 0.12, 0.4 mg/kg bw                                          effects
               per day (gavage)
                                                                                                                   

    From Annex I, reference 67

    Table 5.  Embryotoxicity and teratogenicity of abamectin and its delta-8,9 isomer
                                                                                                                                
    Study  Species  No.           Dose                Maternal toxicity                    Malformations
    no.                           (mg/kg bw           (no. of animals)                     (% fetuses)
                                  per day)
                                                                                                                                

    Abamectin
                                  Avermectin B1a
    1      Mouse    20            0                                                        Cleft palate (0.4)
           (CF-1)                 0.1                 Tremors, death (1)
                                  0.2
                                  0.4                 Tremors, death (3)                   Cleft palate (2.4)
                                  0.8                 Tremors, death (2)                   Cleft palate (2.5)

                                  Avermectin B1b
    2      Mouse    12            0
           (CF-1)                 0.025
                                  0.05                                                     Cleft palate, exencephaly (1)
                                  0.075               Tremors, weight loss, death (2)
                                  0.1

                                  Abamectin
    3      Rat      25            0                   None                                 Externala (0.3)
                                  0.4                 None
                                  0.8                 None                                 Externala (0.7)
                                  1.6                 None                                 Externala (0.6)

                                  Abamectin
    4      Rabbit   10            0
                                  0.5
                                  1
                                  2
                                  3                   All animals: stupor, loss of body    Not investigated
                                                      weight, reduced food and water
                                                      consumption; one moribund

    Table 5 (contd)
                                                                                                                                
    Study  Species  No.           Dose                Maternal toxicity                    Malformations
    no.                           (mg/kg bw           (no. of animals)                     (% fetuses)
                                  per day)
                                                                                                                                

                                  Abamectin
    5      Rabbit   18            0                                                        Externala (2.1)
                                  0.5                 One death
                                  1                   One death
                                  2                   Reduced food and water               Externala (7.4)
                                                      consumption, weight loss

    Delta-8,9 isomer
    6      Mouse    7-11          0
           (CF-1)                 1.5                 Deaths                               Only group with litters; cleft
                                  3                   Deaths                                palate (29)
                                  6.25                Deaths
                                  12.5                Deaths
                                  25                  Deaths
                                  50                  Deaths

    7      Mouse    12            0                                                        Exencephaly (0.7)
           (CF-1)                 0.05                Decreased body weight gain,
                                                      fewer implantsb
                                  0.1                 ?                                    Cleft palate (11), exencephaly (1.7)
                                  0.5                 Tremors, loss of body weight,        Cleft palate (1), exencephaly (4)
                                                      single deaths
                                  1                   Tremors, decrease or loss of body    Cleft palate (8), exencephaly (2)
                                                      weight; fewer implants, single
                                                      deaths

    8      Mouse    25            0
           (CF-1)                 0.015               None                                 Cleft palate (0.5)
                                  0.03                None                                 Exencephaly (1.3)
                                  0.06                None                                 Exencephaly (1.3)

    Table 5 (contd)
                                                                                                                                
    Study  Species  No.           Dose                Maternal toxicity                    Malformations
    no.                           (mg/kg bw           (no. of animals)                     (% fetuses)
                                  per day)
                                                                                                                                

    9      Mouse    25            0                                                        Exencephaly (0.4)
           (CF-1)                 0.015                                                    Cleft palate (0.4), exencephaly
                                                      (0.4)
                                  0.03                                                     Cleft palate (0.4), exencephaly
                                                      (2)
                                  0.1                                                      Cleft palate (2)
                                  0.5                 Moribund (1)                         Cleft palate (10), exencephaly
                                                      (0.4)

    10     Rat      25            0                   No effect                            No effect
                                  0.25                No effect                            No effect
                                  0.5                 No effect                            No effect
                                  1                   No effect                            No effect
                                                                                                                                

    From Annex I, reference 67. The historical control incidences of malformations in CF-1 mice (in % fetuses) were 0.3
    (max. 3) for cleft palate and 0.3 (max. 1.6) for exencephaly. In Charles River rats, the incidences in historical
    controls were 0.03 (max. 0.3) for cleft palate and 0.004 (max. 0.3) for gastroschisis.
    a Cleft palate, exencephaly, gastroschisis, omphaloceles, clubbed forefeet
    b Statistically nonsignificant and non-dose-related increases in the rates of resorptions and of dead fetuses in all
    treated groups; fewer implants per female at 0.05 and 1 mg/kg bw per day

    

    Rats

         In rats treated with abamectin, the NOAEL for both maternal
    toxicity, indicated by tremors and weight loss, and for
    embryotoxicity and teratogenicity was > 1.6 mg/kg bw per day. At
    0.8 and 1.6 mg/kg bw per day, the incidence of external
    malformations was greater than that in concurrent controls (Annex I,
    reference 67); the increase was not dose-related. The range of
    incidences of each malformation in historical controls indicates
    that the increases seen in animals treated with abamectin were not
    related to treatment.

         In rats treated with the delta-8,9 isomer, no maternal or
    embryotoxicity or teratogenicity was seen at doses ranging from 0 to
    1 mg/kg bw per day (Annex 1, reference 67).

    (g)  Special studies

    Sensitivity of CF-1 mice

         Multidrug resistance has been associated with over-expression
    of permeability glycoprotein (P-glycoprotein), which is a component
    of the plasma membrane in various cell types and species (Beck,
    1997; Gottesman & Pastan, 1993). Cells that express high levels of 
    P-glycoprotein have decreased rates of drug uptake, decreased
    steady-state levels of drugs and decreased drug retention (Beck  et
    al., 1983). Schinkel  et al. (1994) used mice that had been
    genetically engineered for disruption of the gene that encodes
    P-glycoprotein and showed that ivermectin is a substrate for this
    protein.

         In a short-term study of oral toxicity, comparisons were made
    of the sensitivity of  CF-1 and CD-1 mice to abamectin and their
    levels of P-glycoprotein, in order to determine whether low levels
    of the protein could explain the particularly high sensitivity of
    CD-1 mice to abamectin. Abamectin was administered orally in sesame
    oil to groups of 49 male and 50 female CF-1 mice and five male and
    five female CD-1 mice at 0.8 mg/kg bw per day for five days. A
    control group received only the vehicle. The LD50 for abamectin
    given orally is about 10 mg/kg bw for CF-1 mice and higher for CD-1
    mice. Signs of severe neurotoxicity appeared in 12 female and five
    male CF-1 mice 3-4 h after the first dose; no clinical signs of
    toxicity were seen in any of the other CF-1 mice or in any of the
    CD-1 or control mice. Immunohistochemical investigation of the
    cerebellum, cerebral cortex and jejunum showed that the
    abamectin-sensitive CF-1 mice had low levels of P-glycoprotein and
    the abamectin-insensitive CF-1 mice had higher levels, which were
    similar to those seen in CD-1 mice (Lankas  et al., 1994).

         These results indicate that about 17% of CF-1 mice are highly
    sensitive to abamectin and that there is a strong correlation
    between the P-glycoprotein level and sensitivity to abamectin.

    Comments

         In a study of photo-oxidative stability, the half-life of the
    delta-8,9 isomer was 4.5 and that of avermectin B1a was 6.5 h.

         Because of the close structural relationship between abamectin
    and ivermectin, a widely used therapeutic agent against human
    onchocerciasis and other parasitic diseases, and the very similar
    toxic effects of the two compounds in various animal species,
    additional data on ivermectin were considered, comprising the
    results of two studies in primates and a published report of a study
    in humans. A study in which expression of the P-glycoprotein (a
    permeability protein associated with multiple drug resistance) was
    correlated with sensitivity to avermectins in different mouse
    strains was also considered.

         A two-week study of the oral toxicity of ivermectin conducted
    in immature rhesus monkeys at doses of 0, 0.3, 0.6 and 1.2 mg/kg bw
    per day showed no adverse effects on body weight, clinical signs,
    ophthalmoscopic end-points, haematological, or clinical chemical
    parameters, or pathological manifestations. Thus, the NOAEL in this
    study was > 1.2 mg/kg bw per day. In a second two-week study with
    ivermectin, in which neonatal rhesus monkeys were administered doses
    of 0, 0.04 or 0.1 mg/kg bw per day by nasogastric intubation, the
    NOAEL was 0.1 mg/kg bw per day. The doses administered were 10-30
    times the dose that would be received by the nursing infant of a
    lactating mother who had been treated with ivermectin for
    onchocerciasis.

         New data were submitted which showed that the high sensitivity
    of the CF-1 mouse to the toxicity of avermectins on the nervous
    system is associated with a deficiency in the expression of
    P-glycoprotein in both the epithelium of the small intestine and the
    capillary endothelial cells of the blood-brain barrier. The
    deficiency is associated with a marked increase in the concentration
    of ivermectin in the brain and plasma after administration of the
    compound. CD-1 mice and those of the CF-1 strain that have higher
    levels of P-glycoprotein are less sensitive to the toxicity of
    abamectin on the central nervous system than the approximately 17%
    of CF-1 mice deficient in this protein. The oral LD50 for CF-1
    P-glycoprotein-deficient mice was about one order of magnitude lower
    than that of CD-1 mice and of CF-1 mice with higher levels of
    P-glycoprotein. This heterogeneity in the CF-1 mouse strain may
    explain the apparent absence of a dose-response relationship with
    respect to maternal toxicity in the studies of teratogenicity. These
    data cannot, however, be used to demonstrate a correlation between
    P-glycoprotein deficiency and teratogenicity, although, given the
    apparent absence of a dose-response relationship, such a correlation
    might be inferred.

         Extensive information available on the use of ivermectin in
    animal and human health was reviewed at the fortieth meeting of the
    Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1992.
    That Committee concluded that 'despite the extremely wide use of
    ivermectin, there is no evidence of significant incidences of
    adverse effects on reproductive performance in treated animals and
    the very limited data on reproductive toxicity in humans indicate
    that ivermectin does not increase the incidence of birth defects.'

         The Meeting confirmed that the lowest NOAEL was 0.05 mg/kg bw
    per day for maternal toxicity in the studies of teratogenicity in
    mice for abamectin and for the delta-8,9 isomer. The Joint Meeting
    in 1992 considered that slight decreases in body-weight gain early
    in the lactation period in one generation of rats in a study of
    reproductive toxicity provided supporting evidence. The present
    Meeting concluded that the NOAEL in the study on reproductive
    toxicity in rats was 0.12 mg/kg bw per day on the basis of toxicity
    to pups at the higher dose level.

         The Meeting concluded that the CF-1 mouse strain is
    heterogeneous with respect to sensitivity to abamectin and,
    therefore, may be an inappropriate model for studying the toxicity
    (including teratogenicity) of avermectins. The Meeting therefore
    decided to base the ADI on the NOAEL of 0.12 mg/kg bw per day for
    pup toxicity in the study of reproductive toxicity in rats. A safety
    factor of 500 was applied because the concern about the
    teratogenicity of the delta-8,9 isomer could not be assuaged by the
    additional data.

    Toxicological evaluation

    Levels that cause no toxic effect

         Rat:      0.12 mg/kg bw per day (two-generation study of
                   reproductive toxicity)

    Estimate of acceptable daily intake for humans

         0-0.0002 mg/kg bw

    Studies that would provide information useful for continued
    evaluation of the compound

    1.   Data on P-glycoprotein in other species, including humans

    2.   Establishment and validation of a more sensitive method to
         assess neurotoxic effects of avermectins in rodents

    3.   Acute toxicity of the delta-8,9 isomer in CF-1 and CD-1 mice,
         with measurements of P-glycoprotein and blood and brain levels
         of the compound

    4.   Study of the teratogenicity in CD-1 and CF-1 mice of abamectin
         and the delta-8,9 isomer with concurrent measurements of
         P-glycoprotein, in order to correlate its presence or  absence
         with maternal toxicity and teratogenicity

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    See Also:
       Toxicological Abbreviations