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    PESTICIDE RESIDUES IN FOOD - 1984


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    EVALUATIONS 1984




    The monographs



    Data and recommendations of the joint meeting
    of the FAO Panel of Experts on Pesticide Residues
    in Food and the Environment and the
    WHO Expert Group on Pesticide Residues
    Rome, 24 September - 3 October 1984

    Food and Agriculture Organization of the United Nations
    Rome 1985

    METHOPRENE

    Chemical name:           Isopropyl (E-E)-(RS)-11-methoxy-3,7,11-
                             trimethyldodeca-2,4-diednote

    Synonyms:                Altosid; Diacon; Dianea; Apex; Kabat

    Structural Formula:

               CH3                  CH3              CH3    o     CH3
               '                    '       H        /      "    /
        CH3 - C - CH2 - CH2 - CH2 - CH - CH2C = C - C = C - C = OCH
               '                                H       H         \
              OCH3                                                CH3

    Empirical Formula:       C19H34O3

    Other information on identity and properties:

    Molecular weight:        310

    State:                   A pale yellow liquid with faint fruity
                             odor

    Boiling pont:            100C at 0.05 mm Hg

    Vapour pressure:         2.37  10-5 mm Hg at 25C
                             1.60  10-4 mm Hg at 40C

    Solubility:              All organic solvents - infinite; water -
                             1.39 ppm

    Stability:               "good"

    Cis-trans ratio:         >8.92

    Flash point:             187C - open cup method

    Octanol/water
    partition coefficient:   >10,000

    Specification of technical material: No data

    EVALUATION OF ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Absorption, Distribution, Elimination and Bio-transformation

    Mouse

         Mice (eight males and two females) intubated with an alcoholic
    solution of tritiated methoprene at 7.7  cui/g b.w. eliminated 63.6
    percent of the administered radioactivity in urine (labeled at the
    C-10 position) and 12.3 percent in faeces within 24 hours of dosing.
    Total cumulative recovery of tritium radioactivity at the end of 96
    hours was 82 percent (68 percent in urine and 14 percent in faeces).
    Autoradiographic studies of single animals sacrificed at various
    intervals after the dose of tritiated methoprene showed a high
    concentration of radioactivity in the stomach and small amounts in the
    liver and kidneys at 0.5 hours post-treatment. At 6 hours,
    radioactivity occurred primarily in the small intestine, descending
    colon and rectum. By 12 hours, radioactivity had essentially been
    eliminated from the body and no residual radioactivity was found at 48
    hours. Placental transfer of radioactivity was not evident in two
    pregnant mice. (Cohen & Trudell, 1972).

    Rat

         In male and female rats (25 rats of each sex) given a single oral
    dose of 25 mg [5-14C]-methoprene/gk b.w., a total of 43.7% of the
    applied radioactive dose was excreted within 24 hours in urine (13%),
    faeces (5.2%) and expired air (25.5%). During the next 48 hours, an
    additional 5.6%, 9.6% and 10.1% (i.e. a total of 20.3%) was
    eliminated in the corresponding routes. By the end of a 5-day
    collection period, the cumulative 14C recovery from all 3 routes
    amounted to 76.4% of the administered dose (19.6% in urine, 18% in
    faeces and 38.8% in expired air). The maximum biological half-life for
    about 60% of the radioactivity was stated to be about ten hours and
    107 hours for a further 15%. Plasma concentration of 14C in these
    rats peaked at 6 hours post treatment and then declined slowly with a
    half-life of about 48 hours during the second to the fifth day after
    dosing. A sex difference in the rate of eliminiation of radioactive
    methoprene was not evident. Total amount of radioactivity in the
    plasma at 6 hours was 1.63% of the administered dose. Rats with
    cannulated bile duct excreted an average of about 27.4% of a single
    oral dose of 25 mg [5-14C]methoprene/kg b.w. in bile during the first
    48 hours with the rate of biliary elimination being most rapid during
    the first 24 hours after dosing. Analyses of tissues from male rats
    sacrificed at various intervals after a single oral dose of
    [5-14C]-methoprene at 25 mg/kg b.w. showed highest -14C levels in
    liver, plasma, kidney and lung during the first 6-12 hours post
    dosing. Significant levels of -14C residues were later found also in
    heart, adipose tissue and adrenal glands. At all time intervals
    studied, 14C levels were low in brain, eyes and testes. Whole-body
    autoradiography showed that much of the -14C was located in organs

    concerned with absorption, biotransformation and excretion. A
    relatively high concentration of radioactivity was found in the
    adrenal cortex, lacrimal glands and adipose tissue after 48 hours.

         A number of unidentified metabolites were excreted in urine,
    faeces and bile of rats treated with a single oral dose of 25 mg
    [5-14C]-methoprene/gk b.w. Unchanged methoprene was found only in the
    faeces and accounted for only a small proportion of the applied
    14C-dose. (Chasseaud, et al., 1974).

    Guinea-pig

         A guinea-pig given a single oral dose of approximately 49 mg
    [5-14C]-methoprene/gk b.w. eliminated a total of about 50% of the
    administered dose in urine (24%), faeces (9%) and expired air (17%)
    within 24 hours of dosing. In untreated urine, 95-99% of the
    radioactivity recovered was glucuronic acid conjugates and other polar
    compounds. In urine treated with H-1 glucuronidase, the major
    identifiable components were 11-hydroxy-3,7,11-trimethyl-dodeca-2,
    4-dienoic acid (ZR-724) and 11-methoxy-3,7,11-trimethyl-dodeca-2,
    4-dienoic acid (ZR-725). These two compounds together amounted to
    about 70% of the radioactivity in the urine. Other urinary metabolites
    identified included isopropyl 11-hydroxy-3,7,11-trimethyl-2,
    4-dodecadienoate (ZR-669), 7-methoxy citronellic acid (ZR-1945).
    Unchanged methoprene accounted for about 77-79% of the radioactivity
    recovered in the faeces. ZR-669, ZR-725 and ZR-724 were also found as
    faecal metabolites (Chamberlain, et al., undated a; Chamberlain,
    et al., undated b).

    TOXICOLOGICAL STUDIES

    Special Studies on Reproduction

    Rat

         Groups of 20 male and 20 female weanling rats (Long Evans) were
    fed technical methoprene (86.9-87.5% purity) at 0, 500 or 2500 ppm
    until at least 100 days of age prior to mating to initiate a three-
    generation (one litter/-generation) reproduction study. Pups (F1,
    F2) to become parents were selected at weaning and, following a
    70-day growth and feeding period, were mated to produce the successive
    generations. In the parental generations, no compound-related effects
    were observed on mortality, food consumption during the growth period,
    maternal growth rate during gestation and lactation periods, mating
    performance, pregnancy rate and duration of gestation period. Total
    weight gain during the growth period was slightly decreased at
    2500 ppm in Fo and F1 animals (both sexes). At the top dosage level,
    mean pup weight was reduced in F2 litters on day 21 and in F3
    litters on days 14 and 21. Additionally, the mean number of pups born
    dead per litter was elevated in F3 litters of this dosage group.
    There were no treatment-related effects on the other tested parameters
    including litter size (live pups) at birth, survival of pups over the

    lactation period, sex ratio of pups and necropsy findings of F3
    weanlings. The no-effect level on reproduction appeared to be at least
    500 ppm (Killeen & Rapp, 1974).

    Special Studies on Teratogenicity

    Mouse

         Groups of 30 mated mice of "ICR lineage" were intubated with
    technical methoprene (purity 95.7%) in olive oil at 0, 50, 200 or
    600 mg/kg b.w./day from days 7 to 14 of pregnancy. The pregnant dams
    (20-23 mice in each group) were sacrificed on day 18 of pregnancy and
    the foetuses were removed for external, internal and skeletal
    examination. There were no compound-related deaths. Pregnancy rate
    (66.7-76.7%) and food or water consumption during the gestation period
    were comparable in all groups. An increase in body weight (compared to
    controls) was noted in pregnant dams at both 200 and 600 mg/kg b.w. on
    day 18. The mean number of implantations and the mean number of live
    foetuses were both elevated at the top dosage level. Body weight of
    female foetuses of all treated groups was increased. No treatment-
    related effects were seen on the mean number of dead embryos or in the
    sex ratio of foetuses. No internal or external abnormalities were seen
    in foetuses of control and treated groups. (Specific information was
    not available on the number of foetuses per control or treated group
    examined for such abnormalities). Foetuses of all treated groups
    displayed a statistically significant increase in the number of caudal
    vertebrae, as compared to controls.

         These remaining pregnant mice were allowed to litter and rear
    their young until weaning prior to sacrifice. Pups from five litters
    per dosage group were sacrificed at weaning and those from the
    remaining litters were observed for seven additional weeks. No
    mortality or abnormal signs were noted in the dams. Maternal body
    weight change was stated to be unaffected during gestation or after
    parturition. Compound-related effects were not apparent on the mean
    number of implantations, duration of gestation period, mean litter
    size and survival rate of pups at birth or at weaning. No adverse
    effects were noted on the rate of physical development in pre-weaning
    pups as judged by auricle development, hair growth and opening of eye
    lids. In weaned pups, no dose-related effects were seen on the time
    when descent of testis or opening of vagina was observed. Behaviour of
    pups during the ten-week post partum period was normal. Pups
    necropsied at three or ten weeks of age showed no gross or skeletal
    abnormalities. A non-dose-related decrease in organ/body-weight ratio
    of testis was noted in pups of all treated groups sacrificed at 21
    days and in those of mid-and low dosage groups sacrificed at 70 days.
    Other variations from control values in the weight of a number of
    organs (such as the spleen and the kidney) were also observed but
    these were not dose-related, or only confined to the top dosage group.
    Histological examination of ovaries and testes of pups reportedly
    revealed a single case of atrophy of seminiferous tubules at
    50 mg/kg b.w. (Nakasawa, et al., 1975a).

    Rabbit

         Groups of 10 pregnant Japanese rabbits were treated orally with
    technical methoprene (purity 95.7%) in olive oil at 0, 50, 200 or
    2000 mg/kg b.c./day on days 7-18 of pregnancy. The does were
    sacrificed on day 28 of pregnancy and the foetuses were removed by
    caesarian section for examination for external, internal and skeletal
    abnormalities. There was no mortality or abnormal symptoms. In the top
    dosage group, two does aborted and maternal weight gain was depressed.
    An increase in the incidence of foetal deaths and in the proportion of
    female foetuses also occurred at the top dosage level. Foetuses at
    both 200 and 2000 mg/kg exhibited a non-dose-related decrease in tail
    length. No compound-related effects were observed with respect to the
    mean number of implantations, litter size (live foetuses), body weight
    or body length of foetuses or frequency of foetal abnormalities. The
    study demonstrated methoprene to be non-teratogenic under the
    conditions of the experiment (Nakasawa, Matsumia & Ishikawa, 1975).

    Special Studies on Mutagenicity

         See Table 1 for summary of mutagenicity tests.

    Special Studies on Carcinogenicity (Also see under "Long Term
    Studies")

    Mouse

         Groups of 50 male and 50 female mice (Charles River CD-1 strain)
    were fed dietary levels of technical methoprene (86.9-87.5% purity) at
    0, 250, 1000 or 2500 ppm for 78 weeks. All animals in the study were
    subjected to gross pathological examination. At termination,
    histopathological evaluation was conducted on a set of about 20
    tissues plus any grossly abnormal tissues from all terminal survivors
    of control and top-dosage groups, brain, heart, liver, lung, kidney,
    adrenal gland and urinary bladder from ten male and ten female
    terminal survivors of the two lower dosage groups and gross lesions
    from all animals dying during the study and from the other terminal
    survivors of the two lower dosage groups.

         Mortality was not increased by treatment. Survival in all groups
    was comparable except for females at 1000 ppm where survival rate was
    40% at 72 weeks when animals in that group were sacrificed for
    necropsy compared to 45-50% in the other groups. Clinical signs, food
    consumption and body weight were comparable between control and
    treated groups. No gross pathological findings attributable to the
    compound were observed. Histopathologically, a dose-related increase
    in incidence and severity of liver lesions characterized by pigment
    deposition in cytoplasm of liver parenchymal cells and focal
    accumulations of macrophages with brownish foamy cytoplasm was found
    in terminal survivors (both sexes) at 1000 ppm and above. An elevated
    frequency of amyloidosis of the small intestine in females was also
    seen at 2500 ppm. There was no compound-related increase in incidence

    of any particular type of tumour. Under the conditions of the
    experiment, there was no evidence suggestive of carcinogenic activity
    of the compound (Wazeter & Goldenthal, 1975a).

    Special Studies on Eye and Skin Irritation

         A primary eye irritation study in New Zealand White rabbits
    indicated that technical methoprene was not an irritant to eyes
    (Hallesy & Hill, 1973a).

         Technical methoprene was found to have a low irritant potential
    to skin in a primary dermal irritation study using New Zealand White
    rabbits (Hallesy & Hill, 1973b).

    Special Studies on Skin Sensitization

         Results of a skin sensitization study in guinea-pigs showed that
    technical methoprene was not a skin sensitizer. (Zoecon, 1975a).

    Special Studies on Endocrine Activity in Mammals

         Immature female mice (19-21 days of age) subcutaneously treated
    with methoprene at 0.015 or 0.15 mg/kg b.w./day for three days
    exhibited no increase in uterus/body weight ratio. When given
    subcutaneously to castrated male rats (21 days old) at 0.37 or
    3.7 mg/kg b.w./day for seven days methoprene did not induce an
    increase in organ/body weight ratio of seminal vesicles, ventral
    prostate or levator ani. In bilaterally adrenalectomized male rats
    (21 to 23 days old), daily subcutaneous doses of 0.9 or 9 mg/kg b.w.
    of methoprene for six days resulted in no decrease in thymus/body
    weight ratio.

         Results of the above studies suggest methoprene to be without
    estrogenic, androgenic, anabolic and glucocortical activity. (Rooks,
    undated).

    Special Studies on Toxicity of Metabolites of Methoprene

         See Table for metabolite toxicity studies.

    Eye and Skin Irritation

         In a primary eye irritation study with New Zealand rabbits,
    ZR-1564 (technical 97.7%) was found to be slightly irritating to the
    eyes (Wazeter & Goldenthal, 1973).

         Results of primary skin irritation study in New Zealand rabbits
    indicated that ZR-1564 (technical 97.7%) has a low potential for skin
    irritation (Wazeter & Goldenthal, 1973).

        Table 1.  Special Studies on Mutagenicity

                                                                                                                            

                                            Concentration of
    Test System         Test Object         Methoprene used               Purity         Results            Reference
                                                                                                                            

    Ames' Test          S. typhimurium      0.2 to                        Not            Negative in        Hsia,
    (with and           strains TA 98,      20 ug/plate                   specified      the presence       et al.
    without             TA 100, TA 1535,                                                 of metabolic       1979
    metabolic           TA 1537, TA 1538                                                 activation
    activation)

    Dominant            Rat                 a) single i.p. doses          Not            Negative           Johnston
    lethal                                  up to 2000 mg/kg bw           specified                         1973
                                            prior to mating
                                            weekly for 8 consecutive
                                            weeks
                                            b) daily i.p. doses up
                                            to 200 mg/kg bw for
                                            5 days prior to mating
                                            weekly for 7 consecutive
                                            weeks
                                                                                                                            
    
        Table 2.  Acute oral toxicity in rats: methoprene metabolites

                                                                                              
                                            LD50
    Metabolite               Sex            (mg/kg b.w.)       Reference
                                                                                              

    ZR-724 Tech.             M + F          > 6810             Knott & Johnston, 1972a

    ZR-725 Tech.             M              > 6810             Knott & Johnston, 1972b
                             F              4870

    ZR-669 Tech.             M              8910               Zirzow & Johnston, 1972
                             F              8260

    ZR-1945                  M              > 10,000           Olson, 1973
                             F              5763

    ZR-1602                  M + F          > 5000             Jorgenson, 1973a

    ZR-1564                  M + F          > 5000             Jorgenson, 1973b
                                                                                              

    ZR-724:  11-hydroxy-3,7,11-trimethyl-dodeca-2,4-dienoic acid
    ZR-725:  11-methoxy-3,7,11-trimethyl-dodeca-2,4-dienoic acid
    ZR-669:  isopropyl 11-hydroxy-3,7,11-trimethyl-2,4-dodecadienoate
    ZR-1945: 7-methoxy citronellic acid
    ZR-1602: 7-hydroxy citronellic acid
    ZR-1564: 7-methoxy citronellal
                                                                                              
    
    Acute Toxicity

         The acute toxicity of methoprene to several animal species is 
    given in Table 3.

        Table 3.  Acute toxicity of methoprene in animals

                                                                                              

                                            LD50
    Species        Sex       Route          (mg/kg b.w.)         Reference
                                                                                              

    Rat            M         oral           > 34,600             Jorgenson & Sasmore, 1972a

    Rat            ?         i.p.           4800                 Jorgenson & Sasmore, 1972a

    Rat            M         inhalation     > 210 mg/*l air      Hiddemen, 1972
                             (4-hour
                             exposure)

    Dog            M+F       oral           > 5000               Hallesy, Shott & Hill, 1972

    Dog            M+F       inhalation     **                   Zoecon, 1975b
                                                                                              

    *  LC50 in terms of nominal chamber concentration of the test material as an aerosol
    ** No mortality resulted when dogs were exposed over a 6-hour period to a mist (particle 
       size: 2 to 5 microns) of technical methoprene as a 2% aqueous ethanol solution at 
       estimated total amounts of up to 29.9 mg/kg b.w. (males or 19.4 mg/kg b.w. (females)
    
    Short-Term Studies

    Oral

    Rat

         In a range finding study, groups of Sprague-Dawley rats (five
    males and five females per group) were fed a diet containing technical
    methoprene (68.9%) at 0, 1000, 5000, 10,000, 20,000 or 40,000 ppm for
    two weeks and then maintained on a control diet for an additional
    week. No mortality occurred. Dose-related growth depression, noted at
    20,000 ppm and above on weeks 1 and 2, was still evident on week 3,
    although less marked. These effects were attributed to palatibility
    problems with the test material. Food consumption, decreased on weeks
    1 and 2 at both 20,000 and 40,000 ppm, was not significantly different
    from controls on week 3. Gross pathological examination of all animals
    in the top-dosage group reportedly revealed no abnormalities
    (Jorgenson & Sasmore, 1972a).

         Groups of 15 male and 15 female Sprague-Dawley rats (approx 28
    days old) were fed technical methoprene (68.9%) in their diet at 0,
    250, 500, 1000 or 5000 ppm for 90 days. There was no compound-related
    mortality. Behaviour was normal. Weekly body weight, food consumption
    and haematology at weeks 4, 8 and 13 were comparable to controls.
    Terminal blood chemistry values were not affected in any dose-related
    pattern. Urinalysis results at 13 weeks were normal. At termination,
    animals of the top-dosage group showed an increase in organ/body
    weight ratio of liver (both sexes) and of kidney (males only).
    Microscopic evaluation of kidney and liver from all animals of control
    and top-dosage groups and from animals at 1000 ppm and a number of
    selected tissue from ten males and ten females per control and top-
    dosage group revealed a slightly higher incidence in males at 5000 ppm
    than in controls of a kidney lesion characterized by vacuoles within
    swollen convoluted tubules. In addition, renal tubular regeneration,
    not seen in concurrent controls or in the females, was present in
    three males at 1000 ppm and seven males at 5000 ppm. A no-effect level
    could not be determined because no animals below 1000 ppm were
    subjected to histological evaluation of the kidney (Jorgenson &
    Sasmore, 1972b).

    Dog

         Groups of three young adult male beagles were fed dietary levels
    of technical methoprene (68.9% purity) at 0, 1000, 5000, or 20,000 ppm
    for two weeks and then placed on control diet for an additional week
    in a range-finding study. There was no mortality. Actual weight loss
    occurred at 10,000 ppm and above on weeks 1 and 2, and growth
    depression was seen at both 1000 and 5000 ppm on week 2. Food
    consumption was reduced at both 10,000 and 20,000 ppm during the
    first two weeks. Terminal sacrifice of all dogs at the end of three
    weeks showed a dose-related increase of liver/body weight ratio in all
    treated groups. Morphologic changes of the liver (swelling and
    vacuo-lation of hepatocytes) were found at both 10,000 and 50,000 ppm.
    No treatment-related histological lesions in adrenal glands, kidney or
    spleen were evident (Jorgenson & Sasmore, 1972a).

         Groups of four male and four female beagles (about 19 weeks old)
    were fed diets containing technical methoprene (68.9%) at 0, 250, 500
    or 5000 ppm for 90 days. No mortality occurred. Behaviour, body
    weight, food consumption and haemotology were not adversely affected.
    Urinalysis at weeks 4, 8 and 13 and eye examination at termination
    reportedly showed no abnormal findings. Serum alkaline phosphatase
    level was elevated at 5000 ppm in both sexes at weeks 4, 8 and 13. At
    terminal sacrifice, organ/body weight ratio of liver was increased in
    both sexes at 5000 ppm. Gross pathological examination of all animals
    in the study and microscopic evaluation of a number of selected
    tissues, including the liver, from all animals of control and top-
    dosage groups failed to show any treatment-related changes. The study
    demonstrated 500 ppm as a no-effect level (Jorgenson & Sasmore,
    1972b).

    Dermal

    Rabbit

         Groups of five male and five female Japanese Albino rabbits
    were exposed dermally to undiluted technical methoprene (purity
    not specified) at 0, 100, 300, 900 or 2700 mg/kg b.w./day for 30
    consecutive days. No mortality was observed. Food and water
    consumption during the study and terminal urinalysis and blood
    chemistry were not affected. Erythema at the application site was
    noted at and above 300 mg/kg b.w. Males at 300 mg/kg b.w. and above
    and females of all treated groups exhibited an increase in neutrophil
    counts at termination and actual weight loss or growth depression over
    the course of the experiment. Terminal leucocyte counts were elevated
    in all treated groups (both sexes). Variations from control values
    were seen in the weight of liver at the top dosage level and of kidney
    at the two high dosage levels. Gross and histopathological examination
    of the animals indicated the only compound-related findings being
    confined to the treated skin sites (Nakasawa, et al., 1975b).

    Inhalation

    Rat

         Groups of ten male and ten female rats were exposed by inhalation
    to an aerosol of technical methoprene (purity 68.9%) at nominal
    chamber concentrations of 0, 2 or 20 mg/l air, four hours/day, five
    days/week for three consecutive weeks. No animals died. Animals at
    20 mg/l air had a nasal discharge during each exposure. Weekly body
    weight and terminal haematological values were comparable to controls.
    Blood chemistry studies at the end of study showed variations from
    control values in a number of parameters such as serum alkaline
    phosphatase, total bilirubin, etc., in both dosage groups but did not
    indicate a consistent pattern of toxicity. Gross necropsies and
    histological evaluation of liver, lung, kidney and trachea showed no
    treatment-related changes (Olson & Willigan, 1972).

    Dog

         Groups of three male and three female beagles were exposed via
    inhalation to technical methoprene (in 2% ethanol solution) as an
    aerosol at 0.0125, 0.0250 or 0.0625 mg/kg b.w./day, six days/week for
    four weeks (particle size of aerosol = 0.5 - 2.5 microns). Vehicle
    control and untreated control groups had two males and two females
    each. There was no mortality. Salivation was noted in two animals of
    the top-dosage group during exposure the first day. No 
    compound-related effects were reported in any of the tested parameters
    measured: body weight, food and water consumption, haematology, blood
    chemistry, urinalysis and gross histopathological finds (Masao &
    Hiroyuki, 1975).

    Long-Term Studies

    Rat

         Groups of 50 male and 50 female rats (Charles River CD strain)
    were fed technical methoprene (86.9% purity) in their diet at 0, 250,
    1000 or 5000 ppm for two years. Survival rate, not influenced by
    treatment, was 38-54% in males and 48-68% in females of all groups
    including the control at the end of the study. (Fifty to 64% males and
    62-72% females in control and treated groups lived at least 96 weeks).
    General appearance and behaviour, body weight and food consumption
    were not adversely affected. No compound-related effects were noted on
    haematological, biochemical and urine parameters measured on five
    males and five females per group at five intervals over the course of
    the study. Ophthalmoscopic examination revealed no changes related to
    treatment. Absolute and relative weight of the liver was elevated at
    5000 ppm in females. Gross pathological examination indicated no
    findings attributable to inclusion of methoprene in the diet.
    Histopathological evaluation of a wide range of tissues revealed an
    increased incidence of hepatic lesions such as bile duct proliferation
    and portal lymphocyte infiltration in males at 5000 ppm. There was no
    significant difference between control and treated groups in incidence
    of any particular type of tumour. Based on the data, 1000 ppm was the
    no-effect level (Wazeter & Goldenthal, 1975b).

    Comments

         In mammals, a single oral dose of methoprene is eliminated via
    the urine, the faeces and the expired air. Limited data available on a
    guinea-pig, a cow and a steer showed degradation of the compound to
    primary metabolites and to natural body constituents.

         Methoprene and its known metabolites in animals and plants all
    appear to have a low order to acute oral toxicity with the LD50
    values being over 5000 mg/kg b.w. for the parent compound in both rats
    and dogs and for the metabolites in rats.

         A three-generation (one litter/generation) reproduction study in
    rats demonstrated a no-effect level on reproduction of at least
    500 ppm. Teratology studies in both mice and rabbits gave no evidence
    of teratogenicity under the conditions of the experiments. It should
    be noted, however, that pregnant mice and rabbits were treated with
    methoprene from days 7 to 14 and from the days 7 to 18 of gestation,
    respectively. The entire period of organogenesis, therefore, was not
    covered. The available mutagenicity studies were negative. A 78-week
    mouse and two-year rat oncogenicity study were negative.

         A minimum no-effect level of 500 ppm for rats was based on a
    three-generation study, and a no-effect level of 500 ppm for dogs was
    based on a 90-day feeding study. It was not possible to establish a
    no-effect level in the 90-day rat feeding study because of a kidney
    lesion, although a two-year rat study did not show this renal effect.

         Because no dog study longer than 3 months was available, both
    teratology studies presented were inadequate, and the three-generation
    reproduction study in rats covered only one litter per generation, the
    meeting allocated only a temporary ADI.

    Level Causing no Toxicological Effect

    Rat: 500 ppm in the diet, equivalent to 25 mg/kg b.w.

    Dog: 500 ppm in the diet, equivalent to 12.5 mg/kg b.w.

    Estimate of Temporary Acceptable Daily Intake for Humans

    0 - 0.06 mg/kg b.w.

    FURTHER WORK OR INFORMATION

    Required (by 1987)

    A six-month feeding study in dogs.

    A two-generation (two litters/generation) reproduction study in rats.

    Adequate teratology studies.

    Desirable:

    Observations in humans.

    REFERENCES

    Chamberlain, W.F., Hunt, L.M., Hopkins, D.E., Gingrich, A.R. &
    undated a      Gilbert, B.M. Absorption, excretion and metabolism of
                   Zoecon ZR-515 (ENT-70460) by a guinea-pig and by a
                   Hereford steer. U.S. Livestock Insects Laboratory.
                   Submitted by Zoecon Corp. USA to WHO. (Unpublished)

    Chamberlain, W.F., Hunt, L.M., Hopkins, D.E., Gingrich, A.R. & Miller,
    undated b      J.A. & Gilbert, B. Absorption, excretion and metabolism
                   of methoprene by a guinea-pig, a steer and a cow. U.S.
                   Livestock Insects Laboratory. Submitted by Zoecon Corp.
                   USA to WHO. (Unpublished)

    Chasseaud, L.F., Hawkins, D.R., Franklin, E.R. & Weston, K.T. The
    1974           metabolic fate of [5-14C]-isopropyl 11-methoxy-3,7,
                   11-trimethyl dodeca-2,4-dienoate (Altosid TM in the
                   rat. Huntingdon Research Centre, England. Submitted by
                   Zoecon Corp. USA to WHO. (Unpublished)

    Cohen, E.N. & Trudell, J. Untitled letter report to Zoecon Corp. on
    1972           metabolism of methoprene in mice. Standford University
                   Medical Center. Submitted by Zoecon Corp. USA to WHO.
                   (Unpublished)

    Hallesy, D.W., Shott, L.D. & Hill, R. Acute oral toxicity of ZR-515
    1972           for dogs. Syntex Research, USA. Submitted by Zoecon
                   Corp. USA to WHO. (Unpublished)

    Hallesy, D.W. & Hill, R. Primary eye irritation study with AltosidR
    1973a          using rabbits. Syntex Research, USA. Submitted by
                   Zoecon Corp. USA to WHO. (Unpublished)

    Hallesy, D.W. & Hill, R. Primary dermal irritation study of AltosidR
    1973b          in rabbits. Syntex Research, USA. Submitted by Zoecon
                   Corp. USA to WHO. (Unpublished)

    Hiddemen, J.W. Acute inhalation toxicity. AltosidTM (Technical
    1972           grade) in rats. Hazleton Laboratories, USA. Submitted
                   by Zoecon Corp. USA to WHO. (Unpublished)

    Hsia, M.T.S., Adamovics, J.A. & Kreamer, B.C. Microbial mutagenicity
    1979           studies of insect growth regulators and other potential
                   insecticidal compounds in Salmonella typhimurium.
                   Chemosphere 8:521-529. Submitted by Zoecon Corp. USA to
                   WHO

    Johnston, C.D. ZR-515-Dominant lethal test in rats. Woodard Research
    1973           Corp. Submitted by Zoecon Corp. USA to WHO.
                   (Unpublished)

    Jorgenson, T.A. & Sasmore, D.P. Toxicity studies of ZR-515 (AltosidTM
    1972a          technical) (1) Acute 1P in rats (2) Repeated 1P in rats
                   (3) Two-week, range-finding dietary studies in rats and
                   dogs. Stanford Research Institute, USA. Submitted by
                   Zoecon Corp. USA to WHO. (Unpublished)

    Jorgenson, T.A. & Sasmore, D.P. Toxicity studies of AltosidTM
    1972b          Technical (1) Ninety-day subacute in rats (2) Ninety-
                   day subacute in dogs. Stanford Research Institute, USA.
                   Submitted by Zoecon Corp. USA to WHO. (Unpublished)

    Jorgenson, T.A. Untitled letter report to Zoecon Corp. on acute oral
    1973a          toxicity study in rats of ZR-1602. Stanford Research
                   Institute, USA. Submitted by Zoecon Corp. USA to WHO.
                   (Unpublished)

    Jorgenson, T.A. Untitled letter report to Zoecon Corp. on acute oral
    1973b          toxicity study in rats of ZR-1564. Stanford Research
                   Institute, USA. Submitted by Zoecon Corp. USA to WHO.
                   (Unpublished)

    Killeen, J.C. & Rapp, W.R. A three-generation reporduction study of
    1974           the AltosidTM in rats. Bio/dynamics Inc., USA.
                   Submitted by Zoecon Corp. USA to WHO. (Unpublished)

    Knott, W.B. & Johnston, C.D. (1972). ZR-724 Technical. Acute oral
    1972a          toxicity to rats. Unpublished report from Woodard
                   Research Corp., USA. Submitted by Zoecon Corp. USA to
                   WHO. (Unpublished)

    Knott, W.B. & Johnston, C.D. (1972). ZR-725 Technical. Acute oral
    1972b          toxicity to rats. Unpublished report from Woodard
                   Research Corp., USA. Submitted by Zoecon Corp. USA to
                   WHO. (Unpublished) Investigation of the toxicity of
                   Altosid.

    Masao, N. & Hiroyuki, M. Determination of subacute toxicity to Beagle
    1975           dogs resulting from Altosid inhalation. Nomura Research
                   Laboratory, Japan. Submitted by Zoecon Corp. USA to
                   WHO. (Unpublished)

    Nakasawa, M., Matsumiya, H. & Ishikawa, I. Test of Altosid Toxicity,
    1975           III: determination of teratogenic potential of Altosid
                   administration orally to rabbits. Nomura Research
                   Institute, Japan. Submitted by Zoecon Corp. USA to WHO.
                   (Unpublished)

    Nakasawa, M., Nomura, A., Furuhashi, T., Mihori, J. & Ikeya, E.
    1975a          Determination of teratogenic potential of Altosid
                   administered orally to mice. Nomura Research Institute,
                   Japan. Submitted by Zoecon Corp. USA to WHO.
                   (Unpublished)

    Nakasawa, M., Shimizu, T., Miyoshi, K., Hasegawa, R., Furuhashi, T.,
    1975b          Ogawa, M. & Mihori, J. Test of Altosid toxicity, II:
                   rabbit subacute dermal toxicity of Altosid. Nomura
                   Research Laboratory, Japan. Submitted by Zoecon Corp.
                   USA to WHO. (Unpublished)

    Olson, W.A. & Willigan, D.A. Three-week inhalation exposure - rats.
    1972           Altosid (Technical grade). Hazleton Laboratories, Inc.,
                   USA. Submitted by Zoecon Corp. USA to WHO.
                   (Unpublished)

    Olson, W.A. Acute oral - Rats. ZR-1945 Final report. Hazleton
    1973           Laboratories, USA. Submitted by Zoecon Corp. USA to
                   WHO. (Unpublished)

    Rooks, W.H. II. Report on the mammalian endocrine testing
    undated        performed on ZR-515. Syntex Research Center, USA.
                   Submitted by Zoecon Corp. USA to WHO. (Unpublished)

    Wazeter, F.X. & Goldenthal, E.I. ZR-1564. Acute toxicity studies in
    1973           rabbits. International Research and Development Corp.,
                   USA. Submitted by Zoecon Corp. USA to WHO.
                   (Unpublished)

    Wazeter, F.X. & Goldenthal, E.I. Eighteen-month oral carcinogenic
    1975a          study in mice. International Research and Development
                   Corp., USA. Submitted by Zoecon Corp. USA to WHO.
                   (Unpublished)

    Wazeter, F.X. & Goldenthal, E.I. Two-year oral toxicity study in rats.
    1975b          International Research and Development Corp., USA.
                   Submitted by Zoecon Corp. USA to WHO. (Unpublished)

    Zirzow, G. & Johnston, C.D. Sample No.ZR-669 Tech.Acute oral toxicity
    1972           to Woodard Research Corp., USA. Submitted by Zoecon
                   Corp. USA to WHO. (Unpublished)

    Zoecon Corp. USA. Test of Altosid toxicity, V: skin sensitization
    1975a          of Altosid in guinea-pigs. Nomura Research Institute,
                   Japan. Submitted by Zoecon Corp. USA to WHO.
                   (Unpublished)

    Zoecon Corp. USA. Investigation of AltosidR toxicity, VII:
    1975b          determination of toxic consequences of acute inhalation
                   exposure of Beagle dogs to Altosid. Nomura Research
                   Institute, Japan. Submitted by Zoecon Corp. USA to WHO.
                   (Unpublished)


    See Also:
       Toxicological Abbreviations
       Methoprene (Pesticide residues in food: 1984 evaluations)