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    WORLD HEALTH ORGANIZATION             FOOD AND AGRICULTURE
                                          ORGANIZATION
    ORGANISATION MONDIALE DE LA SANTE     ORGANISATION POUR L'ALIMENTATION
                                          ET L'AGRICULTURE

                                                      VBC/DS/84.47

                                                      ORIGINAL: ENGLISH






    DATA SHEETS ON PESTICIDES No. 47

    METHOPRENE






         It must be noted that the issue of a Data Sheet for a
    particular pesticide does not imply endorsement of the pesticide by
    WHO or FAO for any particular use, or exclude its use for other
    purposes not stated. While the information provided is believed to
    be accurate according to data available at the time when the sheet
    was compiled, neither WHO nor FAO are responsible for any errors or
    omissions, or any consequences therefrom.

    The issue of this document does    Ce document ne constitue pas une
    not constitute formal              publication. Il ne doit faire
    publication. It should not be      l'objet d'aucun compte rendu ou
    reviewed, abstracted or quoted     résumé ni d'aucune citation sans
    without the agreement of the       l'autorisation de l'Organisation
    Food and Agriculture               des Nations Unies pour
    Organization of the United         l'Alimentation et l'Agriculture
    Nations or of the World Health     ou de l'Organisation Mondiale de
    Organization.                      la Santé.

                             CLASSIFICATION:

                             Primary use: Insect growth regulator

                             Secondary use:

                             Chemical group: Juvenile hormone analogue

    1.  GENERAL INFORMATION

    1.1  COMMON NAME:

    Methoprene (ISO, BSI, ANSI)

    1.1.1  Identity:

    IUPAC and CAS No. 1:  Isopropyl (2E, 4E)-11-methoxy-3,7,11
                            trimethyl-2-1,4-dodecadienoate

    CAS Reg. No.:  40596-69-8
    Molecular formula:  C19H34O3
    Molecular weight:  310.0
    Structural formula:

    CHEMICAL STRUCTURE

    1.1.2  Synonyms:

    Altosid(R); Kabat(R); Apex(R); Diacon(R); Minex(R);
    Pharorid(R); Precor(R); Manta(R); Altosand(R); ZR-515

    1.2  SYNOPSIS:

    Methoprene is a selective, stable and potent larvicide; an ether and
    diunsaturated fatty acid ester; a juvenile hormone analogue, its
    toxicity to insects is manifest through interference with
    metamorphosis, a process without parallel in mammals. Methoprene is
    non-persistent and non-toxic to mammals and presents no long-term
    hazard to other species at recommended application rates.

    1.3  SELECTED PROPERTIES

    1.3.1  Physical characteristics

    Methoprene technical material is an amber liquid boiling at 100°C
    (0.05 mmHg) and having a specific gravity of 0.261 at 20°C.

    1.3.2  Solubility

    In water, 1.39 mg/l; soluble in organic solvents.

    1.3.3  Stability

    It is described as a stable compound though non-persistent due to
    rapid biodegradation mainly to CO2. The soil half-life is 10 days;
    in water, less than one day in sunlight and over four weeks in dark
    and, on plants, 1-2 days.

    1.3.4  Vapour pressure

    3.15 x 10-6 kPa (2.37 x 10-5 mmHg) at 20°C.

    1.4  AGRICULTURE, HORTICULTURE AND FORESTRY

    1.4.1  Common formulations

    Methoprene is available as an emulsifiable concentrate; in granules
    and briquettes; and, premixed in ant baits and cattle feed
    supplements at concentrations up to 10% a.i.

    1.4.2  Pests controlled

    These include fleas., flies, moths, pharaoh's ants, bollweevil,
    lice, mosquitos, leaf hoppers, plant hoppers, cucumber beetles,
    cigarette beetle, tobacco moth and others.

    1.4.3  Use pattern

    Methoprene may be sprayed on flooded pasture and crops at a rate of
    40-100 g/ha for control of mosquitos, etc. It may also be fed to
    livestock in a premix food supplement for control of hornfly. When
    used in structures (e.g. tobacco curing sheds), use as directed. It
    should not be mixed with oil or other pesticides.

    1.4.4  Unintended effects

    Methoprene is not phytotoxic, it may be toxic to some beneficial
    aquatic invertebrates when used at excessive rates. Used in Japan to
    treat silkworms making them extend the time period in which they
    produce silk.

    1.5  PUBLIC HEALTH USE

    As in 1.4, for control of nuisance and disease vector pests, the
    most important being the control of flood water mosquitos.

    1.6  HOUSEHOLD USE

    For control of fleas at approximately 0.15 µg/1000 cm2. Also used
    in houseplant sprays.

    2.  TOXICOLOGY AND RISKS

    2.1  TOXICOLOGY - MAMMALS

    2.1.1  Absorption route

    Methoprene may be absorbed from the gastrointestinal tract; through
    the intact skin; and, by inhalation of spray mist.

    2.1.2  Mode of action

    Methoprene is an invertebrate metabolic inhibitor which does not
    seem to cause direct toxic effects in mammals. In in vitro studies
    of mouse L929 cells, methoprene inhibited macromolecular synthesis
    including DNA and RNA, at concentrations exceeding its maximum water
    solubility level. Degeneration of cells and uncoupling of oxidative
    phosphorylation has also been reported in mouse hepatocyte cultures
    at very high dose levels.

    2.1.3  Excretion products

    Methoprene metabolism and excretion have been studied in several
    vertebrate organisms - cattle, rodents and hens. Methoprene is
    metabolized primarily by hepatocyte microsomal esterases, mainly to
    methoprene acid, which after alpha oxidation is susceptible to beta
    oxidation to acetate then, via the Krebs' cycle to carbon dioxide or
    intermediary metabolites. In 14C-labelled methoprene studies at
    low doses, most of the radioactivity was respired from the body as
    CO2. The remainder, was found to be associated with complex and
    simple secondary metabolites in body tissues and fluids and also as
    primary breakdown products in urine and faeces. A significant amount
    of radioactivity was also found in the milk of lactating cows and in
    eggs of laying hens. Less than 1% of this excreted radioactivity was
    found as methoprene and the rest was associated with natural
    products; no primary metabolites were found. The finding of large
    quantities of unmetabolized methropene in faeces but not in urine or
    blood suggests poor intestinal absorption at higher doses and rapid
    metabolism of the absorbed material. The primary products of urinary
    excretion are the hydroxyepter (isopropyl
    11-hydroxy-3,7,11-trimethyl - 2,4-dodecadienoate), the hydroxyacid
    (11-methoxy-3,7,11-trimethyl-2,4-dodecadienoic acid), and several
    lesser metabolites including 7-methoxycitronellic acid,
    7-hydroxycitronellic acid and 7-methoxycitronellal. These are
    excreted as free compounds and as conjugates.

    2.1.4  Toxicity, single dose

    Oral LD50:

    Rat: + 34 600 mg/kg b.w. Technical material

    Dog: 5000-10 000 mg/kg b.w. Technical material

    Dermal LD50:

    Rabbit: 3000-10 000 mg/kg b.w. Technical material

    Rat: + 5000 mg/kg b.w. Technical material

    Inhalation LC50:

    Rat and guinea pig: + 210 mg/l (highest dose tested) Technical
    material

    2.1.5  Toxicity, repeated doses

    Oral: See 2.1.6, Dietary studies and 2.1.7, Teratogenicity.

    Dermal: No signs of toxicity were observed in a 21-day dermal
    toxicity test in rabbits given 400 (mg/kg b.w.)/day.

    Inhalation: No toxic effects were observed in a 21-day inhalation
    test in rats at a 20 mg/l dose level.

    Cumulation of compound: There was no evidence of the accumulation
    of methoprene or its primary metabolites in body tissues and fluid
    in 14C-labelled methoprene tracer studies.

    2.1.6  Dietary studies

    Short-term: In 90-day studies, dogs and rats showed no toxic
    effects at the 500 mg/kg diet level and there were no irreversible
    ill-effects at the 5000 mg/kg diet level. No deaths occurred in any
    of the diet groups. In a 6-month study, male and female rats were
    fed 0, 80, 400, 2000 or 10 000 mg/kg of diet. One female on the
    2000 mg/kg diet died. At 10 000 mg/kg, mild degenerative changes,
    which would be expected to be reversible, were observed in hepatic
    parenchyma cells. The maximum no-effect-level for rats was estimated
    to be 20 (mg/kg b.w.)/day in a 90-day study.

    Long-term: In two-year studies rats were fed diets containing 250,
    1000 or 5000 mg/kg of methoprene. The no observed adverse effect
    level was determined to be 5000 mg/kg (diet), equivalent to 250
    (mg/kg b.w.)/day.

    Mice were fed dietary levels of 250, 1000 or 2500 mg/kg for 18
    months. There was no treatment related mortality. Amyloidosis was
    more prevalent in the high dose group than others and hepatic
    pigmentation was also observed at this dose level and to a lesser
    extent at 1000 mg/kg (diet). The no observed effect level was
    determined to be 250 mg/kg (diet), equivalent to 37.5 (mg/kg
    b.w.)/day.

    2.1.7  Supplementary studies of toxicity

    Carcinogenicity: No evidence of carcinogenic potential was
    obtained in the long-term dietary studies with mice and rats nor in
    the several studies of mutagenicity described below.

    Mutagenicity: Methoprene was not mutagenically active in a
    microbial assay with S. typhimurium strains sensitive to base pair
    substitutions and frame shift mutations. It was also not active in a
    mouse cell culture assay or in a (rat) dominant lethal mutagenicity
    study at 2000 mg/kg b.w. (single dose).

    Teratogenicity: No evidence of teratogenic activity was observed
    in sheep (dose unknown), in rabbits at 500 (mg/kg b.w.)/day, in rats
    at 1000 (mg/kg b.w.)/day or in mice at 600 (mg/kg b.w.)/day.

    Reproduction: In a three-generation study, rats continuously fed
    2500 mg/kg diets showed no toxic or reproductive adverse effects.
    Mortality, pregnancy and fertility rates, food consumption, duration
    of gestation, foetal viability, neonatal survival, litter size and
    sex ratios were normal. No reproductive or embryotoxic effects were
    seen in quail or ducks at 30 ppm continuous feeding.

    Neurotoxicity: No adverse clinical or pathological findings were
    noted in the acute, subchronic or chronic studies.

    Endocrine effects: Methoprene was found to have no estrogenic,
    androgenic, anabolic or glucocorticoid activity in mice and rats.

    Primary irritation and skin sensitization: No eye irritation was
    observed in rabbits up to 72 hours after applications of 0.1 ml of
    69.8% solution. No dermal irritation was observed in rabbits exposed
    to 0.5 ml of a 69.8% solution for 24 hours on either intact or
    abraded skin under occlusive wraps. Methoprene showed no
    sensitization potential in two standard guinea-pig sensitization
    tests.

    2.1.8  Modification of toxicity

    No information available.

    2.2  TOXICOLOGY - MAN

    2.2.1  Absorption routes

    Methoprene may be absorbed from the gastrointestinal tract; through
    the intact skin; or by inhalation of spray mist.

    2.2.2  Dangerous doses

    Not known.

    2.2.3  Observations on occupationally exposed workers

    No reports of adverse effects.

    2.2.4  Observations on exposure of the general population

    No information available.

    2.2.5  Observations on volunteers

    Following a standard Draize method skin sensitization study on 231
    volunteers it was concluded that the test substance, a domestic use
    formulation, was not a human skin sensitizer.

    2.2.6  Reported mishaps

    No information available.

    2.3  TOXICITY TO NON-MAMMALIAN SPECIES

    2.3.1  Fish

    Methoprene is only slightly toxic to fish, 10 weekly treatments of
    wild populations of mosquito fish in ponds at 56-560 g/ha caused no
    mortalities or long-lasting ill effects.

    LD50 static tests:

    Bluefill               4.62 ppm    Technical material
    Channel catfish     + 100.0 ppm    Technical material
    Coho salmon            32.0 ppm    Technical material
    Trout                  4.39 ppm    Technical material
    Trout                 106.0 ppm    Technical material

    2.3.2  Birds

    Methoprene is relatively non-toxic to birds. No adverse effects were
    found in adult birds in reproductive studies of Bobwhite quail and
    Mallard ducks at a dose level of 30 ppm (continuous feeding), no
    reproductive nor embryotoxic adverse effects were observed in these
    studies.

    Dietary studies LC50:

    Mallard duck       10 000 ppm    Technical material
    Bobwhite quail     10 000 ppm    Technical material
    Chicken             4 640 ppm    Technical material

    2.3.3  Other species

    Methoprene has shown no clear adverse effects in most aquatic
    invertebrate organisms. Mayfly naiads and diving beetle populations
    declined temporarily at an application rate of 80 g/ha but rapidly
    recovered after treatment stopped. Crustaceans have shown the
    greatest sensitivity.

    LC50 (5-day exposures):

    Crayfish                100 ppm    Technical material
    Fresh water shrimp      100 ppm    Technical material
    White and pink shrimp   100 ppm    Technical material

    Methoprene was well tolerated by juvenile Bufo boreas

    3.  FOR REGULATORY AUTHORITIES - RECOMMENDATIONS ON REGULATION
        OF COMPOUND

    3.1  RECOMMENDED RESTRICTIONS ON AVAILABILITY

    (For definition of categories see Introduction to data sheets).

    All formulations, Category 5

    3.2  TRANSPORTATION AND STORAGE

    Formulations in Category 5 - Should be transported and stored in
    clearly labelled, leakproof containers out of reach of children,
    away from food and drink. Avoid contact with metals other than
    aluminium and tin.

    3.3  HANDLING

    Formulations in Category 5 - No facilities other than those needed
    for the handling of any chemical are required.

    3.4  AND/OR DECONTAMINATION OF CONTAINERS

    All formulations - Containers need not be decontaminated.
    Containers should not be used for other purposes, they should be
    burned or should be crushed and buried below topsoil. Care must be
    taken to avoid subsequent contamination of water sources.

    3.5  SELECTION, TRAINING AND MEDICAL SUPERVISION OF WORKERS

    Formulations in Category 5 - Warning of workers to minimize
    contact is essential. No pre-employment or periodic medical
    examinations are required.

    3.6  ADDITIONAL REGULATIONS RECOMMENDED IF DISTRIBUTED BY AIRCRAFT

    All formulations - Pilots and loaders should have special training
    in application methods and recognition of early warning symptoms of
    poisoning, when using solvent containing formulations. Flagmen
    should wear overalls and a broad brimmed hat and be well away from
    the dropping zone when using solvent containing formulations.

    3.7  LABELLING

    Formulations in Category 5 - Minimum cautionary statement

                                   CAUTION

    This formulation contains methoprene. Keep the material out of reach
    of children and well away from foodstuffs, animal feed and food
    containers.

    3.8  RESIDUES IN FOOD

    Maximum residue limits for methoprene have not yet been recommended
    by the joint FAO/WHO Meeting on Pesticide Residues.

    4.  PREVENTION OF POISONING IN MAN AND EMERGENCY AID

    4.1  PRECAUTIONS IN USE

    4.1.1  General

    Methoprene is a fatty-acid derivative of no known health hazard to
    man. It may be absorbed from the gastrointestinal tract; through the
    intact skin and by inhalation of spray mist.

    4.1.2  Manufacture and formulation - TLV

    No information. Closed systems and forced ventilation may be
    required to reduce, as much as possible, the exposure of workers to
    the chemical.

    4.1.3  Mixers and applicators

    When opening a container and when mixing, protective impermeable
    boots, clean overalls, impermeable gloves and a respirator should be
    worn. Mixing, if not mechanical, should always be carried out with a
    paddle of appropriate length. Avoid contact to mouth and eyes.
    Before eating, drinking or smoking, hands and other exposed skin
    should be thoroughly washed with alkaline soap.

    4.1.4  Other associated workers (including flagmen in aerial
           operations)

    Persons exposed to methoprene and associated with this application
    should wear protective clothing and observe precautions as described
    in 4.1.3.

    4.1.5  Other populations likely to be affected

    With good application practice other populations are not likely to
    be exposed to significant amounts of methoprene which is essentially
    non-toxic.

    4.2  ENTRY OF PERSONS INTO TREATED AREAS

    Unprotected persons may enter treated areas immediately after
    spraying without being exposed to a health hazard.

    4.3  SAFE DISPOSAL OF CONTAINERS AND SPILLAGES

    Residues in containers Should be emptied in a diluted form into a
    deep pit taking care to avoid ground waters. The empty containers
    need not be decontaminated, they should be burned or crushed and
    buried below topsoil. Containers should not be used for any other
    purposes.

    4.4  EMERGENCY AID

    4.4.1  Early symptoms of poisoning

    No clinical or laboratory signs of toxicity to man or other animals
    are known. Methoprene is only slightly toxic to mammals other than
    man.

    4.4.2  Treatment before a person is seen by a
    physician

    If a person shows signs of illness from exposure to formulations of
    methoprene, supportive therapy should be given.

    5.  FOR MEDICAL AND LABORATORY PERSONNEL

    5.1   MEDICAL DIAGNOSTICS AND TREATMENT OF POISONING

    5.1.1  General information

    Methoprene is an organic acid derivative; a sesquiterpenoid compound
    of no known health hazard to man. It may be absorbed from the
    gastro-intestinal tract; through the intact skin; and by inhalation
    of spray mist. It is readily metabolized via intermediatry metabolic
    pathways.

    5.1.2  Signs and symptoms

    Methoprene is not sufficiently toxic to produce clearly recognizable
    clinical and laboratory signs of toxicity in man or other mammals.

    5.1.3  Laboratory

    No information available.

    5.1.4  Treatment

    If a person shows signs of illness due to exposure to methoprene
    formulations these are most likely due to the solvent, treat
    accordingly.

    5.1.5  Prognosis

    Not applicable since acute poisoning is not expected even with large
    ingested doses.

    5.1.6  References to previously reported cases

    None.

    5.2  SURVEILLANCE TEST

    None.

    5.3  LABORATORY METHODS

    References only are given.

    5.3.1  Detection and assay of compound and residues -

    L. L. Dunahm et al. (1975) J. Chromatogr. Sci.: 13(7), 334-336

    L. M. Hunt & B. N. Gilbert (1976) J. Agric. Food Chem.: 24(3),
    669-670

    W. W. Miller (1975) Environ. Qual. Saf., Suppl.: Vol. 3, ISS
    Pesticides, pp. 105-109

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