PESTICIDE RESIDUES IN FOOD - 1984 Sponsored jointly by FAO and WHO 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: 100°C at 0.05 mm Hg Vapour pressure: 2.37 × 10-5 mm Hg at 25°C 1.60 × 10-4 mm Hg at 40°C Solubility: All organic solvents - infinite; water - 1.39 ppm Stability: "good" Cis-trans ratio: >8.92 Flash point: 187°C - 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 µ 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)