Toxicologic Information About Insecticides
Used for Eradicating Mosquitoes
(West Nile Virus Control)
April 2005
Methoprene is an insect growth regulator used as a larvicide. It is a synthetic analogue of the insect juvenile hormone. Unlike conventional insecticides that act as direct poisons, methoprene disrupts the morphologic development of insects. It interferes with an insect’s life cycle (metamorphosis) and prevents it from reaching maturity or reproducing. Methoprene is used in the production of foods, including meat, milk, eggs, mushrooms, peanuts, rice, and cereals. It is used as a feed additive for cattle to prevent breeding of hornflies in manure. It also is used in aquatic areas to control mosquitoes and several types of flies, moths, beetles, and fleas (EPA 1991).
Section 1. Environmental Factors
Methoprene rapidly biodegrades in soil, with a soil half-life of 10 days. Its half-life in water is <1 day in sunlight and >4 weeks in darkness. Methoprene rapidly degrades in plants, with a half-life of 1–2 days. If released to air, a vapor pressure of 2.36x10–5 mm Hg at 25oC indicates methoprene will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase methoprene degrades in the atmosphere by reaction with photochemically produced hydroxyl radicals and ozone; the estimated half-lives for these reactions in air are 1.5 hours and 48 minutes, respectively. Particulate-phase methoprene is removed from the atmosphere by wet and dry deposition. If released to soil, methoprene is expected to be immobile at an estimated Koc of 23,000. If released into water, methoprene is expected to adsorb to suspended solids and sediment at the estimated Koc. An estimated bioconcentration factor of 3,400 suggests that the potential for bioconcentration in aquatic organisms is very high (HSDB 2002). Methoprene is slightly toxic to fish but highly toxic to freshwater and estuarine invertebrates (EPA 1991).
Section 2. Potential for Exposure
People can be exposed to small amounts of methoprene through the food supply. However, the amount of methoprene in the U.S. consumer’s diet is well below the level at which any adverse health effects could occur. People also can be exposed to methoprene while mixing, loading, or applying the pesticide and while working among treated crops (EPA 1991). Occupational exposure to methoprene can occur through inhalation and dermal contact with this compound where methoprene is produced or used. Methoprene's insecticidal applications suggest that the most probable exposure pathway for the general population is dermal contact with treated products (HSDB 2002).
Section 3. Health Effects/Toxicity
Studies in laboratory animals exposed to methoprene dermally, orally, or by inhalation are summarized in Table 1, with no-observed-adverse-effect levels (NOAELs) and lowest-observedadverse- effect levels (LOAELs) indicated.
Methoprene has a very low acute oral and inhalation toxicity potential and is not an eye or skin irritant (EPA 1991). Technical-grade methoprene has a low irritant potential to skin in a primary dermal irritation study using New Zealand white rabbits (Hallesy and Hill 1973). Results of a skin sensitization study in guinea pigs showed that technical-grade methoprene was not a skin sensitizer (Zoecon 1975), and a primary eye irritation study in New Zealand white rabbits indicated that technical-grade methoprene was not an irritant to eyes (Hallesy and Hill 1973). In a 30-day study of rabbits exposed dermally (Nakasawa et al. 1975b), erythema at the application site was noted at >300 mg/kg.
Table 1. Health Effect Levels of Methoprene in Laboratory Animals
(PDF Version 98k)
Methoprene has an inhalation LC50 for rats of >210,000 mg/m3 air. No-effect inhalation values were 20,000 mg/m3 in a 3-week rat study and 0.0625 mg/kg/day in a 4-week dog study. Methoprene oral LD50 values range from 2,323 to >34,600 mg/kg in rats, 2,285 mg/kg in mice, and 5,000 mg/kg in dogs. Mortality reached 20% in 4 months in rats receiving 232 mg/kg/day, but a dose of 116 mg/kg/day was without effect (HSDB 2002). A three-generation (one litter/generation) reproduction study in rats demonstrated a NOAEL on reproduction of at least 500 ppm in the diet (Killeen and Rapp 1974). A NOAEL of 500 ppm for dogs was seen in a 90-day feeding study (Jorgenson and Sasmore 1972b). Teratology studies in both mice and rabbits showed no evidence of teratogenicity under the conditions of the experiments. However, pregnant mice and rabbits were treated with methoprene from days 7 to 14 and from days 7 to 18 of gestation, respectively. The entire period of organogenesis, therefore, was not covered. Mutagenicity studies were negative, and a mouse and a rat oncogenicity study were negative (WHO 1984).
Methoprene is rapidly metabolized and eliminated by mammals. Mice (eight males and two females) intubated with an alcoholic solution of tritiated methoprene eliminated 63.6% of the administered radioactivity in urine and 12.3% in feces within 24 hours of dosing. Total cumulative recovery of tritium radioactivity at the end of 96 hours was 82% (68% in urine and 14% in feces). Autoradiographic studies 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 and Trudell 1972).
When 14C methoprene was administered orally to rats, slightly <20% was excreted within 5 days in the urine and a similar amount in feces, and almost 40% was excreted as 14CO2. About 17% was retained in the body. Highest concentrations were in liver (84.5 ppm), kidneys (29 ppm), lungs (26 ppm), fat (36.5 ppm), and the adrenal cortex (12–13 ppm). About 12 labeled compounds were detected in the urine, but no unchanged methoprene was observed (Hawkins 1977).
In male and female rats (25 rats of each sex) given one oral radioactive dose of 25 mg methoprene/kg body weight, a total of 43.7% of the applied radioactive dose was excreted within 24 hours in urine (13%), feces (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 three routes amounted to 76.4% of the administered dose (19.6% in urine, 18% in feces, and 38.8% in expired air). The maximum biologic half-life reported for about 60% of the radioactivity was about 10 hours and 107 hours for a further 15%. Plasma concentration of 14C in these rats peaked at 6 hours post-treatment, then declined slowly, with a half-life of about 48 hours during the 2nd–5th day after dosing. A sex difference in the rate of elimination of radioactive methoprene was not evident. Total amount of radioactivity in the plasma at 6 hours was 1.63% of the administered dose. Analyses of tissues from male rats sacrificed at various intervals 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 in heart, adipose tissue, and adrenal glands. At all time intervals studied, 14C levels were low in the brain, eyes, and testes. Whole-body autoradiography showed that much of the 14C was located in organs concerned with absorption, biotransformation, and excretion (Chasseaud et al. 1974).
The metabolism of methoprene was studied in a guinea pig, a steer, and a cow (Chamberlain et al. 1975). In the guinea pig, 24% of the dose was excreted in the urine over 24 hours, 9.1% in the feces, and 17.2% in expired air. Highest tissue concentrations occurred in blood, muscle, and fat. In the steer, 21.6% of the dose was excreted in the urine after 2 weeks, 38.8% in the feces after 2 weeks, and 2.7% in the expired air after 96 hours. Highest tissue concentrations of radiolabel were found in the bile, gall bladder, liver, and kidney. In the cow, 15.1% of the dose was excreted in the expired air, 7.6% in the milk, 19.8% in the urine, and 30.2% in the feces. The highest levels of radioactivity were found in the bile, liver, skin, fetus, and udder. In all species, approximately 40% of the radioactivity in the feces was attributable to unchanged methoprene. No methoprene was found in the urine. Major metabolites identified in the steer and the guinea pig included 7-methoxycitronellic acid, 11- methoxy-3,7,11-trimethyl-2,4-dodecadienoic acid, and 11-hydroxy-3,7,11-trimethyl-2,4- dodecadienoic acid.
The toxicity of methoprene could be altered by interactions with other chemicals that have the same mechanism of action, or with chemicals that affect its metabolism.
Section 5. Standards and Guidelines for Protecting Human Health
Methoprene can be used safely as a feed additive in accordance with the following prescribed conditions: (1) it is used as a feed additive in the form of mineral and/or protein blocks or other feed supplements in the feed of cattle at 22.7–45.4 mg per 100 pounds of body weight per month; (2) it is used to prevent the breeding of hornflies in the manure of treated cattle; (3) it is used to ensure safe use of the additive, the label and labeling of the pesticide formulation containing this additive shall conform to the label and labeling registered by EPA; (4) tolerances are established for residues of methoprene in or on the following feed additive commodities: cereal grain milled fractions (except flour and rice hulls)—10 ppm and rice hulls—25 ppm (HSDB 2002).
Tolerances have been established for residues of methoprene in or on the following raw agricultural commodities: barley—5 ppm; buckwheat—5 ppm; cattle fat—1 ppm; cattle meat—0.1 ppm; cattle meat by-products—0.1 ppm; corn (except popcorn and sweetcorn)—5 pm; eggs—0.1 ppm; goat fat—1 ppm; goat meat—0.1 ppm; goat meat by-products—0.1 ppm; hog fat 1 ppm; hog meat—0.1 ppm; hog meat by-products—0.1 ppm; horse fat—1 ppm; horse meat 0.1 ppm; horse meat byproducts —0.1 ppm; milk—0.1 ppm; millet—5 ppm; mushrooms—1 ppm; oats—5 ppm; peanuts—2 ppm; poultry fat—1 ppm; poultry meat—0.1 ppm; poultry meat by-products—0.1 ppm; rice—5 ppm; rye— 5 ppm; sheep fat—1 ppm; sheep meat—0.1 ppm; sheep meat by-products—0.1 ppm; sorghum (milo) —5 ppm; and wheat—5 ppm (HSDB 2002).
Methoprene also is allowed for oral use in dogs aged >9 weeks and >4 pounds of body weight to prevent and control fleas (HSDB 2002).
No other regulatory standards or guidance values were located.
Chamberlain WF, Hunt LM, Hopkins DE, et al. 1975. Absorption, excretion, and metabolism of methoprene by a guinea pig, a steer and a cow. J Agric Food Chem 23:736–42.
Chasseaud LF, Hawkins DR, Franklin ER, Weston KT. The metabolic fate of [5-14C]-isopropyl 11-methoxy-3,7,11- trimethyl dodeca-2,4-dienoate (Altosid) in the rat. Huntingdon Research Centre, England. Submitted by Zoecon Corp. USA to WHO. (Unpublished study cited in WHO 1984)
Cohen EN, Trudell J. 1972. Untitled letter report to Zoecon Corp. on metabolism of methoprene in mice. Stanford University Medical Center. Submitted by Zoecon Corp. USA to WHO. (Unpublished study cited in WHO 1984)
EPA. 1991. Methoprene Reregistration Eligibility Document Facts.Washington, DC: US Environmental Protection Agency.
Hallesy DW, Hill R. 1973. Primary dermal irritation study of Altosid in rabbits. Syntex Research, USA. Submitted by Zoecon Corp. USA to WHO. (Unpublished study cited in WHO 1984)
Hawkins DR, Weston KT, Chasseaud LF, Franklin ER. 1977. Fate of methoprene (Isopropyl (2E,4E)-11-Methoxy-3,7,11- trimethyl-2,4-dodecadienoate) in rats. J Argric Food Chem 25:398–403. (Cited in HSDB 2002)
HSDB. 2002. Hazardous Substance Data Bank: Methoprene. National Library of Medicine, National Toxicology Program. Available at http://www.toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB Accessed December 17, 2002.
Jorgenson TA, Sasmore DP. 1972a. Toxicity studies of ZR-515 (Altosid 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 study cited in WHO 1984)
Jorgenson TA, Sasmore DP. 1972b. Toxicity studies of Altosid 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 study cited in WHO 1984)
Killeen JC, Rapp WR. 1974. A three-generation reproduction study of Altosid in rats. Bio/dynamics Inc., USA. Submitted by Zoecon Corp. USA to WHO. (Unpublished study cited in WHO 1984)
Masao N, Hiroyuki M. 1975. Determination of subacute toxicity to Beagle dogs resulting from Altosid inhalation. Nomura Research Laboratory, Japan. Submitted by Zoecon Corp. USA toWHO. (Unpublished study cited in WHO 1984)
Nagano IK, et al. 1977. Botyu Kagaku 42(2):63–74. (Cited in HSDB 2002)
Nakasawa M, Matsumiya H, Ishikawa I. 1975a. Test of Altosid toxicity, III: determination of teratogenic potential of Altosid administration orally to rabbits. Nomura Research Institute, Japan. Submitted by Zoecon Corp. USA to WHO. (Unpublished study cited in WHO 1984)
Nakasawa M, Nomura A, Furuhashi T, Mihori J, Ikeya E. 1975b. Determination of teratogenic potential of Altosid administered orally to mice. Nomura Research Institute, Japan. Submitted by Zoecon Corp. USA to WHO. (Unpublished study cited in WHO 1984)
Nakasawa M, Shimizu T, Miyoshi K, Hasegawa R, Furuhashi T, Ogawa M, Mihori J. 1975c. Test of Altosid toxicity, II: rabbit subacute dermal toxicity of Altosid. Nomura Research Laboratory, Japan. Submitted by Zoecon Corp.USA to WHO. (Unpublished study cited in WHO 1984)
Olson WA, Willigan DA. 1972. Three-week inhalation exposure—rats. Altosid (Technical grade). Hazleton Laboratories, Inc., USA. Submitted by Zoecon Corp. USA to WHO. (Unpublished study cited in WHO 1984)
Wazeter FX, Goldenthal EI. 1975a. Eighteen month oral carcinogenic study in mice. Report No. 322-003. International Research and Development Corporation, dated 14 March. Submitted to WHO by Novartis Animal Health Australasia, Ltd, Pendle Hill, NSW, Australia. (Unpublished study cited in WHO 1984)
Wazeter FX, Goldenthal EI. 1975b. Chronic oral toxicity studies with Altosid technical. Report No. 322-001. International Research and Development Corporation, dated 14 March. Submitted to WHO by Novartis Animal Health Australasia, Ltd, Pendle Hill, NSW, Australia. (Unpublished study cited in WHO 1984)
WHO. 1984. Methoprene—Pesticide residues in food: 1984 evaluations. International Program on Chemical Safety. Geneva: World Health Organization.
Zoecon Corp. USA. 1975. Test of Altosid toxicity, V: skin sensitization of Altosid in guinea-pigs. Nomura Research Institute, Japan. Submitted by Zoecon Corp. USA to WHO. (Unpublished study cited in WHO 1984)
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