CHAPTER 16 Diazinon 16.1 INTRODUCTION Diazinon, an organophosphorus compound with an anticholinesterase mode of action, was released for experimental evaluation in the early 1950s Diazinon is now used extensively by commercial and home applicators in a variety of formulations to control flies, cockroaches, lice on sheep, insect pests on ornamental plants and food crops (especially corn, rice, onions, and sweet potatoes), forage crops such as alfalfa, and nematodes and soil insects in turf, lawns, and croplands (Anonymous 1972; Meier et al 1976; Allison and Hermanutz 1977; Berg 1984; Stone and Gradoni 1985; Eisler 1986; Wan 1989; Menconi and Cox 1994; Moore and Waring 1996) Diazinon is the most widely used organophosphorus pesticide in Pakistan to control cabbage root fly and carrot fly (Alam and Maughan 1992) In 1992, more than 612,000 kg diazinon were used in California on alfalfa, nuts, stone fruits, vegetables, and other crops (Menconi and Cox 1994) Avian and terrestrial wildlife can acquire diazinon by drinking contaminated water, by absorbing it through legs and feet, by consuming treated grass or grain, or by ingesting pesticide-impregnated carrier particles (Stone and Knoch 1982; Stone and Gradoni 1985) Diazinon was detected at low concentrations (14 days 1000 14 0.2 0.5 2, 14 14 1.2 1.3 2.0 13.0 1.4b 25 800b 29,200 1 1 2 14 80 (60–100) 90–400 11, 12, 15–17 2, a FRESHWATER Aquatic Plants Invertebrates Amphipod, Gammarus fasciatus Cladoceran, Ceriodaphnia dubia Daphnid, Daphnia magna Dust (27%) Emulsifiable concentrate (47.5%) Technical grade (91.9%) Oil solution (0.5%) Cladoceran, Simocephalus serrulatus Stonefly, Pteronarcys californica Daphnid, Daphnia pulex Rotifer, Brachionus calyciformes Fish European eel, Anguilla anguilla Rainbow trout, Oncorhynchus mykiss © 2000 by CRC Press LLC Table 16.2 (continued) Acute Toxicity of Diazinon to Aquatic Organisms (All values shown are in micrograms of diazinon [active ingredients] per liter of medium fatal to 50% in 96 h.) Ecosystem, Taxonomic Group, Organism, and Other Variables LC50 (96 h) ( g/L) Reference Technical grade Emulsifiable concentrate Dust Oil solution Bluegill, Lepomis macrochirus Technical grade Emulsifiable concentrate Dust Oil solution Lake trout, Salvelinus namaycush Brook trout, Salvelinus fontinalis Guppy, Poecilia reticulata Flagfish, Jordanella floridae Cutthroat trout, Oncorhynchus clarki Freshwater fish, Barilus vagra Murrel, Channa punctatus Common carp, Cyprinus carpio Fathead minnow, Pimephales promelas Goldfish, Carassius auratus Zebrafish, Brachydanio rerio Tilapia, Tilapia nilotica 110 3000 3200 19,000 90–670 120 530 170 160 602 770 800 1600 1700 1900–2900 3100 3400–5000 5100–15,000 9000 8000 20,000 1 1 2–4, 14 1 1 14, 20 18 18, 19 4, 20 13 >2,000,000c 4.8 28b 8 1470 3200d 5500d 25.1d 27.8d 10 10 10 10 a Amphibians Bullfrog, Rana catesbeiana MARINE Invertebrates Mysid shrimp, Mysidopsis bahia Penaeid shrimp, Penaeus aztecus Fish Sheepshead minnow, Cyprinodon variegatus Striped knifejaw, Opelgnathus fasciatus Egg Prelarvae Postlarvae Juvenile a b c d 1, Meier et al 1976; 2, Johnson and Finley 1980; 3, Anonymous 1972; 4, Allison and Hermanutz 1977; 5, Sastry and Malik 1982; 6, Jarvinen and Tanner 1982; 7, Hudson et al 1984; 8, Nimmo et al 1981; 9, Goodman et al 1979; 10, Seikai 1982; 11, Sancho et al 1993a; 12, Sancho et al 1992b; 13, Sakr and Gabr 1992; 14, Menconi and Cox 1994; 15, Ferrando et al 1991; 16, Sancho et al 1992a; 17, Sancho et al 1993b; 18, Adam and Maugham 1993; 19, Adam and Maugham 1992; 20, Keizer et al 1991 48 h value Single oral dose, in mg/kg body weight 24 h value 16.3.3 Birds Diazinon adversely affects survival of developing mallard embryos when the eggshell surface is subjected for 30 seconds to concentrations 25 to 34 times higher than recommended field application rates Mortality patterns were similar for solutions applied in water or in oil (Table 16.3) © 2000 by CRC Press LLC Table 16.3 Mortality of Mallard Embryos after Immersion for 30 seconds in Graded Strength Diazinon Solutions Age of Eggs (days) Solution Vehicle (water or oil) Diazinon Conc (mg/L) Percen t Dead Approximate Field Application Rate 3 3 Water Water Water Water Oil Oil Oil Oil 11 110 542 597 13 133 648 741 None 50 50 None 50 50 0.5 25 27 0.6 29 34 Modified from Hoffman, D.J and W.C Eastin, Jr 1981 Effects of malathion, diazinon, and parathion on mallard embryo development and cholinesterase activity Environ Res 26:472-485 This laboratory finding suggests that eggs of mallards, and probably other birds, are protected when diazinon is applied according to label directions Chickens dipped in solutions containing 1000 mg of diazinon/L, an accidentally high formulation, experienced 60% mortality within days; no other deaths occurred during the next months (Sokkar et al 1975) Results of 5-day feeding trials with 2-week-old Japanese quail (Coturnix japonica), followed by days on untreated feed, showed an LD50 of 167 mg diazinon/kg diet — a concentration considered “very toxic.” No deaths were observed at dietary levels of 85 mg diazinon/kg, but 53% died at 170 mg/kg, and 87% at 240 mg/kg (Hill and Camardese 1986) Diazinon has a potential for causing acute avian poisoning episodes (Schafer et al 1983) Ingestion of granules of Diazinon 14G (14.3% diazinon) killed 80% of house sparrows (Passer domesticus), and all red-winged blackbirds to which they were administered (Balcomb et al 1984) Ingestion of fewer than granules of Diazinon 14G, each containing about 215 µg diazinon, could be lethal to sparrow-sized birds (i.e., 15 to 35 g body weight), especially juveniles of seed-eaters (Hill and Camardese 1984) Acute oral LD50 values indicate that 15 mg diazinon/kg body weight is fatal to virtually all species tested, and that to mg/kg is lethal to the more sensitive species (Table 16.4) Signs of diazinon poisoning in birds included muscular incoordination, wing spasms, wing-drop, hunched back, labored breathing, spasmodic contractions of the anal sphincter, diarrhea, salivation, lacrimation (tear production), eyelid drooping, prostration, and arching of the neck over the back (Hudson et al 1984) Most of these signs have been observed in birds poisoned by compounds other than diazinon; these compounds also act via an anticholinesterase mode of action (Hudson et al 1984) 16.3.4 Mammals Signs of diazinon poisoning in mammals included a reduction in blood and brain cholinesterase activity, diarrhea, sweating, vomiting, salivation, cyanosis, muscle twitches, convulsions, loss of reflexes, loss of sphincter control, and coma (Anonymous 1972) Other compounds that produce their toxic effects by inhibiting AChE, such as organophosphorus pesticides and many carbamates, show similar effects (Murphy 1975) Two species of marmoset accidentally poisoned by diazinon exhibited — prior to death — high-pitched voices, trembling, frog-like jumping, a stiff gait, and pale oral mucous membranes Internally, bone marrow necrosis and hemorrhages in several organs were evident (Brack and Rothe 1982) Internal damage was also observed in swine and dogs that died following controlled administration of diazinon Swine showed histopathology of liver and intestinal tract, and duodenal ulcers; dogs showed occasional rupture of the intestinal wall and testicular atrophy (Earl et al 1971) © 2000 by CRC Press LLC Results of acute oral toxicity tests indicated that the rat was the most sensitive mammalian species tested, with an acute oral LD50 of 224 mg diazinon/kg body weight (Table 16.4) It is clear that mammals are significantly more resistant to acute oral poisoning by diazinon than birds (Table 16.4) Diazinon was also toxic to mammals when administered dermally, through inhalation, and in the diet (Table 16.5) The lowest dermal LD50 recorded was 600 mg diazinon/kg body weight for rabbits (Lepus sp.) using an emulsifiable (4E) formulation The single datum for inhalation toxicity indicated that 27.2 mg of diazinon/L of air killed 50% of test rabbits after exposure for h (Table 16.5) Pregnant mice fed diets containing mg of diazinon/kg during gestation all survived, but some pups died prior to weaning (Table 16.5) Results of chronic oral toxicity tests of diazinon indicated that death was probable if daily doses exceeded mg/mg body weight for swine, or 10 mg/kg for dogs (Table 16.5) Table 16.4 Acute Oral Toxicity of Diazinon to Birds and Mammals (All values shown are in milligrams of diazinon/kg body weight fatal to 50% after a single oral dose.) Taxonomic Group, Organism, and Other Variables LD50 (range) (mg/kg body weight) Referencea BIRDS Turkey, Meleagris gallopavo Red-winged blackbird, Agelaius phoeniceus Age 0–3 days Age unspecified Age 4–7 days Age 8–11 days Adults Goslings, Anser spp Turkey Ducks, Anas spp Mallard, Anas platyrhynchos European quail, Coturnix coturnix Ring-necked pheasant, Phasianus colchicus Northern bobwhite, Colinus virginianus Chicks, Gallus gallus Chicken, Gallus gallus Turkey European starling, Sturnus vulgaris Age 0–3 days Age 8–11 days Age unspecified Adults Ducklings Northern bobwhite Northern bobwhite 2.5 2.4 (1.3–6.1) 2.6 3.4 8.3 (6.6–10.0) 9.1 (3.9–15.9) 2.7 3.5 3.5 3.5 (2.4–5.3) 4.2 4.3 (3.0–6.2) 5.0b 5.0c 9.0 10.0c 9 9 3 4, 4, 12.7 (10.9–15.1) 93.2 213 602 14.0 14.7 25.0c 9 6 425 350 327 542 735 3, 7 7 521 224 400 450 7 3 MAMMALS Rat, Rattus rattus Technical grade AG 500 (granule) E (emulsion) S (spray) 50 W (wettable) Males Females Pig, Sus scrofa Guinea pig, Cavia cobaya © 2000 by CRC Press LLC Table 16.4 (continued) Acute Oral Toxicity of Diazinon to Birds and Mammals (All values shown are in milligrams of diazinon/kg body weight fatal to 50% after a single oral dose.) Taxonomic Group, Organism, and Other Variables LD50 (range) (mg/kg body weight) Dog, Canis familiaris Sheep, Ovis aries a b c >500 >1000 Referencea 1, Egyed et al 1974; 2, Schaefer et al 1983; 3, Machin et al 1975; 4, Hudson et al 1984; 5, Zinkl et al 1978; 6, Hill et al 1984; 7, Anonymous 1972; 8, Earl et al 1971; 9, Wolf and Kendall 1998 No mortality seen All animals tested died Table 16.5 Toxicity of Diazinon to Laboratory Animals via Dermal, Inhalation, Dietary, and Chronic Oral Routes of Administration Mode of Administration, Units, Organism, Formulations, and Other Variables Effect Referencea 900 600 735 >15,400 >2000 LD50 LD50 LD50 LD50 LD50 1 1 2750 LD50 LC50 No pup deaths at weaning 12% of pups dead prior to weaning 3 None dead in months All dead in 30 days None dead in 15 days None dead in days None dead in months 75% dead in 30 days 4 4 4 Dose DERMAL, mg/kg body weight Rabbit, Lepus sp AG-500 (granule E (emulsion) S (spray) 14 G (granule) 50 W (wettable) Mice, Mus musculus Technical diazinon INHALATION, mg/L air Rabbitb 27.2 DIETARY, mg/kg diet, during gestation only Mice Mice 0.18 CHRONIC ORAL, mg/kg body weight daily Dog, Canis familiaris Dog Dog Dog Swine, Sus scrofa Swine a b 10 20 25 50 10 1, Anon., 1972; 2, Skinner and Kilgore 1982; 3, Barnett et al 1980; 4, Earl et al 1971 Exposure for h to 4% aqueous suspension 16.3.5 Terrestrial Invertebrates Accidental spraying of beehives in Connecticut with diazinon resulted in a complete kill of resident honeybees Dead bees contained up to mg diazinon/kg (Anderson and Glowa 1984) Diazinon is an effective insecticide LD50 values for diazinon and adult houseflies (Musca domestica), applied topically, were 0.4 µg/insect, or 4.6 mg/kg body weight (Negherbon 1959) LD50 values for larvae of the large white butterfly, applied topically, were 8.8 mg/kg body weight for diazinon, and 11.0 mg/kg body weight for diazoxon (Wahla et al 1976) Pretreatment of larvae © 2000 by CRC Press LLC with methylene dioxyphenyl compounds antagonized the action of diazinon by a factor of about 2, but synergized the action of diazoxon by an order of magnitude (Wahla et al 1976) 16.4 SUBLETHAL EFFECTS 16.4.1 General Among sensitive species of aquatic organisms, diazinon was associated with reduced growth and reproduction in marine and freshwater invertebrates and teleosts, spinal deformities in fish, reduced emergence in stream insects, measurable accumulations in tissues, increased numbers of stream macroinvertebrates carried downstream by currents (drift), possible mutagenicity in fish, and interference with algal–invertebrate interactions In birds, diazinon is a known teratogen It is also associated with reduced egg production, decreased food intake, and loss in body weight Diazinon fed to pregnant mice resulted in offspring with brain pathology, delayed sexual maturity, and adverse behavioral modifications that became apparent late in life For all groups tested, diazinon directly or indirectly inhibited cholinesterase activity 16.4.2 Aquatic Organisms Atlantic salmon (Salmo salar) exposed to 0.3 to 45.0 µg diazinon/L for 120 h had reduced levels of reproductive steroids in blood plasma at all concentrations Exposure to µg/L for only 30 produced a significant reduction in olfactory response to prostaglandin F2a (Moore and Waring 1996) Carp and other species of freshwater teleosts that survived high sublethal concentrations of diazinon had impaired swimming and abnormal pigmentation (Alam and Maughan 1992) Spinal deformities, mostly lordosis and scoliosis, were among the more insidious effects documented for diazinon Malformations were observed in fathead minnows (Pimephales promelas) after 19 weeks in water containing 3.2 µg diazinon/L (Allison and Hermanutz 1977), in yearling brook trout (Salvelinus fontinalis) within a few weeks at 4.8 µg/L (Allison and Hermanutz 1977), and in various species of freshwater teleosts after exposure for days to 50 µg diazinon/L (Kanazawa 1978) Exposure of bluegills (Lepomis macrochirus) to 15 µg diazinon/L for only 24 h resulted in mild hyperplasia of the gills that increased in severity with increasing concentration (30 to 75 µg/L) and may lead to death (Dutta et al 1993) Diazinon is a noncarcinogen and reportedly has no significant mutagenic activity in microbial systems, yeast, and mammals, including humans (as quoted in Vigfusson et al 1983) However, Vigfusson et al (1983) have measured a significant increase in the frequency of sister chromatid exchange in central mud minnows (Umbra limi) that were exposed in vivo for 11 days to solutions containing 0.16 to 1.6 µg diazinon/L This finding requires verification In general, diazinon does not bioconcentrate to a significant degree and is rapidly excreted after exposure (Menconi and Cox 1994; Tsuda et al 1995) Diazinon in water is bioconcentrated by brook trout at levels as low as 0.55 µg/L, but tissue residues for all aquatic organisms seldom exceeds 213 times that of ambient water, even after months of continuous exposure (Table 16.6) Common carp (Cyprinus carpio) exposed to 1.5 to 2.4 µg/L for 168 h had bioconcentration factors of 12 in muscle, 12 in gallbladder, 50 in kidney, and 51 in liver; almost all was excreted in 72 h on transfer to clean water, except for kidney, which is the major organ for excretion (Tsuda et al 1990) High bioconcentration factors of 800 in liver, 1600 in muscle, 2300 in gill, and 2730 in blood are reported for juvenile European eels (Anguilla anguilla) after exposure to 42 to 56 µg/L for 96 h However, diazinon residues in tissues were usually not detected in tissues after 24 h in clean water (Sancho et al 1992b, 1993a) The half-time persistence of diazinon in tissues of European eels was estimated at 17 to 31 h in liver, 32 to 33 h in muscle, and 27 to 38 h in gill © 2000 by CRC Press LLC on cattle hair, and no stereoselective degradation occurred Hair contained 14.8 mg/kg FW fenvalerate after 30 days with two ear tags (Yeung et al 1989) Cows fed fenvalerate in grain at 10 mg/kg diet for days excreted most of the fenvalerate, essentially unchanged, in urine (Wszolek et al 1981b) A secondary excretion route is feces, accounting for about 25% of the ingested dose Milk accounted for 0.44 to 0.64% of the total excreted (Wszolek et al 1980) Half-time persistence of fenvalerate in milk of treated cows is about 6.4 days (Frank et al 1984) Effects of low concentrations (1.14 to 6.8 µg/L) of fenvalerate in milk of treated cows on newborn suckling calves are unknown and merit additional research (Frank et al 1984) Fenvalerate toxicity is antagonized by atropine sulfate or methocarbamol, which may be effective in treating severe cases of poisoning (Hiromori et al 1986) Conversely, some compounds exacerbate the toxicity of fenvalerate and interfere with a desired use Domestic cats (Felis domesticus) treated with Fendeet (an aerosol mixture of fenvalerate and N-N-diethyl-m-toluamide) to control fleas and ticks sometimes show signs of toxicosis, such as tremors, hypersalivation, ataxia, vomiting, depression, and seizures Signs usually appeared within hours of topical application, and females and juveniles seem to be the most sensitive groups The demonstrated ability of N-Ndiethyl-m-toluamide to enhance the dermal absorption of fenvalerate is the probable cause of toxicosis (Dorman et al 1990) In occupational settings, fenvalerate produces temporary irritation and itching (Bradbury and Coats 1989a) Among human fenvalerate applicators, sensitive individuals complain of a burning and tingling skin sensation after using the insecticide, and sometimes they substitute a more toxic insecticide to nontarget species in order to avoid this uncomfortable sensation (Flannigan et al 1985) This practice, if widespread, may compromise existing or proposed natural resource management practices Table 20.7 Lethal and Sublethal Effects of Fenvalerate on Mammals Organism, Route of Administration, Dose, and Other Variables Effect Referencea Residues ranged up to 0.002 mg/L in milk, 0.022 mg/L in cream, 0.014 mg/kg fresh weight (FW) in fat, 0.006 mg/kg FW in liver, and 5000 mg/kg BW Dermal mg/kg BW, single application 60, 600, or 1800 mg/kg BW, single application Intraperitoneal injection 3.9 mg/kg BW 62 mg/kg BW 89 mg/kg BW Diet Fed 5, 15, or 50 mg/kg on days 6–15 of gestation Fed 10, 50, 250, or 1250 mg/kg feed for years Fed 50, 250, or 1250 mg/kg feed for years Fed 100, 300, 1000, or 3000 mg/kg feed for 78 weeks 125 mg/kg diet, weeks, 2R,αS isomer Fed 500 mg/kg diet of three isomers (2S,αS; 2R,αS; 2R,αR) for weeks © 2000 by CRC Press LLC Effect Referencea Residues of the 2R,αS-isomer were 9–16 times higher in adrenal than the other isomers (2S,αS; 2S,αR; 2R,αR), at least 20 times higher in heart, 6–14 times higher in kidney, 17–28 times higher in liver, at least 15 times higher in lung, 3–6 times higher in mesenteric lymph node, and >30 times higher in spleen Maximum concentrations, in mg/kg FW, were 7.3 in hair, 0.9 in fat, 0.5 in skin, 0.3 in blood, and 0.08 in liver Maximum concentrations, in mg/kg FW, were 2.3 in hair, 0.8 in fat, 0.3 in stomach contents, 0.1 in skin, and 0.05 in blood LD50; 2S,αS-isomer LD50 11 Slight increase in frequency of chromosome aberrations in bone marrow cells LD50; 2S,αR isomer LD50; 2R,αR isomer 17 12 12 13 1, 13–16 13 13 Penetration through skin was 1.9% at 60 min, 2.2% at h, and 9.1% at 24 h Of penetrated dose, maximum percent distribution was 83% in carcass at 60 min, 1.3% in blood at h, 11.5% in liver at h, 2.2% in kidney at h, 0.7% in fat at h, and 73% in feces at 24 h At 1800 mg/kg BW, 20% died in 96 h; no deaths in other groups Survivors in 600 and 1800 mg/kg groups were hyperactive All survivors preferred 0.3% saccharin solution to water 18, 19 LD50; 2S,αS-isomer LD50 LD99 14 14 Maternal toxicity at 50 mg/kg BW, but no effect on embryonic development Increased mortality, reduced growth, disrupted enzyme activity at 1250 mg/kg Nonneoplastic microgranulomas in lymph, liver, and spleen of 250 and 1250 mg/kg male mice; less severe microgranulatomous changes in mesenteric lymph node of 50 and 250 mg/kg groups; no observable effect at 10 mg/kg diet Nonneoplastic pathological changes diagnosed as multifocal microganulomas in lymph nodes, liver, and spleen of males at all dose levels, and in females at the 250 and 1250 mg/kg diet level No evidence of carcinogenicity at any dose tested Noobservable-effect-level (NOEL) was 100 mg/kg diet (equivalent to 15 mg/kg BW); dose-related effects noted in liver at 300 mg/kg diet and higher No deaths; 70% incidence of microgranulomas in liver Residues, in µg/kg FW, of the 2R,αS isomer were significantly higher than that of other isomers tested in adrenal (173 vs 10–21), heart (15 vs 2), kidney (22 vs 9–10), liver (105 vs 13); lung (31 vs 2–5), mesenteric lymph nodes (86 vs 8–12), and spleen (21 vs 1) 10 34 20 20 11 Table 20.7 (continued) Lethal and Sublethal Effects of Fenvalerate on Mammals Organism, Route of Administration, Dose, and Other Variables 500 mg/kg diet, 13 weeks 500 mg/kg diet, 52 weeks, 2S,αS-isomer 500 or 1000 mg/kg diet, 52 weeks, 2S,αR isomer 1000 mg/kg diet, weeks, 2S,αS isomer 1000 mg/kg diet, weeks, 2R,αS isomer 1000 mg/kg diet, 13 weeks, 2R,αR isomer 2000 mg/kg diet, weeks, 2S,αR isomer Intraperitoneal (ip) injection 40 mg/kg BW, daily doses (total of 100 mg/kg BW) Subcutaneous injection Given daily doses totaling 100, 150, or 200 mg/kg BW Effect Referencea No deaths; 100% incidence of microgranulomas or giant cell infiltration No microgranulomas or giant cell infiltration in liver, spleen, or lymph nodes No deaths; no microgranulomas 20 20 20 Severe hyperexcitability and tremors and 100% kill No microgranulomas present No deaths; 100% incidence of microgranulomas 20 20 No deaths; no microgranulomas or giant cell infiltration 20 All dead; no microgranulomas 20 Significant increase in frequency of chromosome aberrations induced in bone marrow cells — but frequency lower than single-dose ip injection of 200 mg/kg BW 17 After 35 days, incidence of sperm abnormalities was significantly increased over controls: 3.3% abnormal sperm in 100-mg/kg-group, 5.9% in 150-mg/kg-group, and 6.3% in 200-mg/kg-group vs 2.3% in controls 17 Minor increases in cutaneous blood flow, skin reddening, and skin thickening 22 Synthesis of protein and RNA inhibited in muscle in a dosedependent manner; maximum inhibition was 0.2 mg/L for RNA synthesis and 10 mg/L for protein The reverse was observed in liver; maximum stimulation was at mg/L 23 Tissue residues, in mg/kg DW, were 3.6–4.4 in renal fat, 0.2 in leg muscle, and 0.1 in liver 24 RABBIT, Oryctolagus sp Dermal 0.13 mg/cm2 skin, applied days weekly for 16 weeks In vitro 0.2–10 mg/L, liver and muscle tissues DOMESTIC SHEEP, Ovis aries Diet 3-month-old lambs fed 45 mg/kg feed for 10 days, equivalent to 20 mg daily LABORATORY WHITE RAT, Rattus spp Diet Fed 1, 5, 25, or 250 mg/kg ration for up to years Fed diets containing 1, 5, 25, or 250 mg/kg feed for generations Fed 1, 5, 25, 250, or 500 mg/kg ration for years Fed 50, 150, 500, or 1500 mg/kg feed for 15 months Fed 1000 mg/kg ration for years © 2000 by CRC Press LLC No measurable effect on body weight, food consumption, hematology, clinical chemistry, or organ weights of any diet No teratogenic or fetotoxic effects Females in third generation fed highest dose had reduced growth NOEL at 250 mg/kg, equivalent to 12.5 mg/kg BW; growth suppression at 500 mg/kg diet NOEL at 50 mg/kg, equivalent to 2.5 mg/kg BW Higher doses had adverse effects on growth, food consumption, and behavior Growth inhibited; organ/BW ratios increased in brain, liver, spleen, kidney, heart (females), and testes Mammary and pituitary tumors commonly observed in treated and in control groups No statistically significant difference in number or type of neoplasms, except for mammary tumors 25 1 25 Table 20.7 (continued) Lethal and Sublethal Effects of Fenvalerate on Mammals Organism, Route of Administration, Dose, and Other Variables Oral 1.7 mg/kg BW daily for consecutive days, or single dose of 8.4 mg/kg BW Technical fenvalerate and 2S,αS-isomer tested separately Single dose, 2.5 mg/kg BW; residues, in µg/kg FW, in tissues measured days after exposure 2R,αS isomer 2S,αS isomer 2S,αR isomer 2R,αR isomer Single dose of mg/kg BW, individual isomers tested, fat analyzed periodically during 21-day observation period Decarboxyfenvalerate, single dose, mg/kg BW Single dose, mg/kg BW, residues measured days later Single doses between 15–200 mg/kg BW Adults given 25 or 75 mg/kg BW, days a week for 10 weeks 450–3000 mg/kg BW 451 mg/kg BW Single dose of 850 mg/kg BW, observed for days Dermal 31, 155, or 310 mg/kg BW, days weekly for weeks; observed for weeks after last treatment Intravenous injection 50–100 mg/kg BW a Effect Referencea No apparent differences in the nature and amount of metabolites and in the pattern of excretion and tissue residues between the racemic mixture and the 2S,αS isomer 26 Residues in tissues were usually much higher than those of other isomers tested: adrenal, 371; fat, 304; heart, 40; kidney, 25; liver, 72; lung, 25; mesenteric node, 318; and spleen, 62 Residues were 511 in fat, 45 in mesenteric lymph node, and