FLUMETHRIN First draft prepared by D.B. McGregor, International Agency for Research on Cancer, Lyon, France Explanation Evaluation for acceptable daily intake Biochemical aspects Absorption, distribution, and excretion Biotransformation Effects on enzymes Toxicological studies Acute toxicity Short-term toxicity Long-term toxicity and carcinogenicity Reproductive toxicity Developmental toxicity Genotoxicity Special studies Dermal and ocular irritation and dermal sensitization Neurotoxicity Anti-allergic and pseudi-allergic activity Bronchial activity Effect on concentration of glucose and triglycerides in blood Effects on gastrointestinal tract of rats Haematological and cardiovascular effects Diuretic effects Toxicity of metabolites: Flumethrin acid Observations in humans Comments Toxicological evaluation References Explanation Flumethrin is an alpha-cyano-3-phenoxyphenyl pyrethroid insecticide used in the control of ectoparasites on cattle, sheep, goats, horses, and dogs. It is formulated as a 6% solution for use as a spray or dip and as a 1% solution for the pour-on treatment of cattle. In addition, flumethrin is marketed as strips for the diagnosis and control of varroatosis in bee hives. Flumethrin as currently produced and used is the result of optimization of the manufacturing process and consists of > 90% trans-Z-1 and trans-Z-2 isomers (with < 2% cis-Z and < 1% trans-E isomers as by-products). The development of flumethrin first led to a substance that was a mixture of 30-45% trans Z-1 and trans Z-2 isomers and 45-63% trans E-1 and trans E-2 isomers, the corresponding cis isomers occurring as by-products at < 6%. This material was used in a long-term study of toxicity and carcinogenicity in rats and is referred to as flumethrin with a low trans-Z content. Flumethrin was evaluated for the first time by the present Meeting. Evaluation for acceptable daily intake 1. Biochemical aspects (a) Absorption, distribution, and excretion After a single oral dose of [F-phenyl-U-14C]-flumethrin was given to rats, about 30% of the dose was absorbed (Steinke et al., 1983). The kinetics and metabolism of flumethrin were investigated in Wistar BOR: WISW rats with [Cl-phenyl-U-14C]-labelled compound administered in physiological saline solution containing 5% Cremophor EL (Klein, 1993a). The dosing regimes were as follows: 1 mg/kg bw administered orally as a single dose to male and female rats, 5 mg/kg bw administered orally as a single dose to male rats, 1 mg/kg bw administered orally to male rats on seven consecutive days, or 1 mg/kg bw administered intraduodenally to bile-fistulated male rats. Absorption was rapid but incomplete. In rats with a fistulated bile duct, about 75% of the dose was absorbed and 77-88% was eliminated in the faeces, mostly after absorption and excretion in the bile; only about 2% was excreted in the urine. The difference in absorption found in these studies appears to be dependent upon the position of the label and may be due to ester hydrolysis in the stomach. The highest concentrations were found in the plasma. The time for a rise in the plasma concentration from 25 to 75% of the maximal value varied between 2 and 3.5 h, the maximum being achieved in about 8 h. The elimination half-lives were 130-160 h, demonstrating the slow release of radiolabel from the plasma, also reflected in the low clearance values (< 12 ml/kg bw per h) and very low renal clearance (< 1.2 ml/kg bw per h). The concentrations of radiolabel found in the organs examined 48 h after dosing were 3- to 50-fold lower than in plasma. Particularly low concentrations were found in spleen, fat, brain, and bone. The distribution volume under steady-state conditions was 25-44% of the body volume, indicating either slow or limited distribution to peripheral compartments from plasma (considered as the central compartment). Redistribution into plasma before biliary excretion was also slow, as indicated by the relatively large mean residence times (190-235 h). Radiolabel accumulated in plasma after multiple dosing, so that the relative plasma concentration had increased almost 10-fold after seven days. Once dosing had stopped, the plasma concentration of radiolabel fell very slowly, the elimination half-life being about 155 h; seven days after administration, 9-20% of the dose was still present in the body (excluding the gastrointestinal tract). The distribution of [Cl-phenyl-U-14C]-flumethrin and its metabolites were investigated by whole-body autoradiography in rats for 1-48 h after a single oral dose of 5 mg/kg bw. The distribution pattern was established within 1 h after dosing, the concentrations decreasing only slowly thereafter. The highest concentration was found in the liver, but high concentrations were also found in the spleen, kidney, lung, adrenal cortex, cartilage, bone marrow, pineal gland, pituitary, and subcutaneous adipose tissue; the lowest concentrations were found in the central nervous system (Klein, 1993b). (b) Biotransformation In the experiment of Klein (1993a), the main radioactive compounds found in the faeces were unchanged flumethrin (which accounted for about 50% of the radiolabel recovered from male rats and about 25% of that from female rats) and the metabolite, 3-[2-chloro- 2-(4-chlorophenyl)ethenyl]-2,2-dimethylcyclopropanecarboxylic acid, flumethrin acid (BNF 5533A), which accounted for 15-18% of the radiolabel recovered from male rats and about 30% of that from female rats. No other biotransformation products were found in the faeces. With [fluorophenyl-U-14C]-flumethrin (low trans Z) given orally to rats, two primary metabolites were identified in the urine (Ecker, 1983). These were 3-(4'-hydroxy-phenoxy)-4-fluorobenzoic acid and 3-phenoxy-4-fluorobenzoic acid, which accounted for 50 and 35%, respectively, of the urinary radiolabel over 0-24 h and 80 and 10% of the urinary activity over 24-48 h. Glycine conjugates of the primary metabolites were also identified, but each accounted for no more than 4 and 7.4%, respectively, of the urinary radiolabel. In the metabolism of other compounds containing the alpha-cyano-3-phenoxybenzyl moiety (e.g. fenvalerate, Kaneko et al., 1981), the phenyl ring may be hydroxylated and, following ester bond hydrolysis, the cyano group is converted to SCN- and carbon dioxide and 3-phenoxybenzaldehyde is oxidized to the carboxylic acid. The resultant acids and phenols can then conjugate with glucuronic acid, sulfate, and/or amino acids. The metabolic pathway of flumethrin is shown in Figure 1. Kinetics and tissue residues were investigated in a 530-kg lactating cow after application of [F-phenyl-U-14C]-flumethrin at 1.77 mg/kg bw to the skin of the back. The plasma concentration of total radiolabel rose to a maximum of 6.3 ng/ml 23 h after application. The highest concentration in the milk (3 ng/ml) was found 31 h after application. By 48 h after dosing, when the cow was slaughtered, the flumethrin-equivalent concentrations of radiolabel were 70 ng/ml in bile in the gall-bladder and 281 ng/ml in urine in the urinary bladder. Of the tissues examined, the liver (9 ng/g tissue) and kidneys (10 ng/g tissue) contained the highest concentrations of residues; 71.7% of the applied dose remained at the application site (Cameron, 1986).In a study with [Cl-phenyl-U-14C]-flumethrin, a dose of 1 mg/kg bw was administered intravenously to one 545-kg dairy cow and one 340-kg steer. Both animals were slaughtered 8 h after administration, and the quantities of radiolabel present in all excreta and in liver, kidneys, muscle, fat, and milk were measured. The highest concentrations were found in the liver (cow, 13 µg/g; steer, 3.5 µg/g), followed by the kidney (cow, 0.88 µg/g; steer, 1.4 µg/g). The metabolite flumethrin acid was also found in all the materials examined, except the milk, and was present as the glucuronide in the liver and kidneys. In milk, an additional degradation product was found but not identified, which constituted 11.5% of the total residues in milk (Klein, 1995). (c) Effects on enzymes Pyrethroids can interact with liver drug-metabolizing enzymes, but there appears to be a difference between some Type II pyrethroids that contain an alpha-cyano function and inhibit such enzymes, e.g. deltamethrin (Anadón et al., 1990), and the Type I pyrethroids that do not contain this function and may induce drug-metabolizing enzymes, e.g. permethrin (Carlson & Shoening, 1980; Anadón et al., 1988). In experiments in which groups of 12 male Wistar rats received flumethrin by intraperitoneal injection for six days, the Type II pyrethroid response was demonstrated, in that there were reductions in cytochrome P450 protein content (36%), NADPH-cytochrome c reductase activity (38%), aniline hydroxylase activity (52%), aminopyrine N-demethylase activity (54%), and UDP-glucuronosyl transferase activity (34%) (Anadón et al., 1995). 2. Toxicological studies (a) Acute toxicity The results of studies of the acute toxicity of flumethrin are listed in Table 1. The acute toxicity is slightly greater in female than male rats and depends on the vehicle used. The sex difference may reflect the greater metabolic conversion in female rats, and differences between the solvents in respect of polarity, which determines the proportion of the dose adsorbed from the gastrointestinal tract, may explain the differences in oral toxicity. The formulation containing Cremophor EL, which is known to enhance absorption, was markedly more toxic; however, this formulation is used only for administration in toxicological studies. The acute toxicity of flumethrin in the other vehicles was moderate to low. Table 1. Acute toxicity of flumethrin and products Formulation Route Species Sex LD50 Reference (mg/kg bw) Flumethrin in Oral Rat Male > 100 Bomann (1994a) water/Cremophor EL Female > 100 Oral Rat Male 56 Bomann (1992a) Female 41 Flumethrin in arachis oil Oral Rat Male 911 Renhof (1983a) Female 662 Flumethrin in miglyol Oral Rat Male 3849 Renhof (1983a) Female 2248 Flumethrin in 1:10 Oral Rat Male 302 Renhof (1983b) acetone:arachis oil Female 138 Flumethrin in corn oil Dermal Rat Male > 2000 Bomann (1994b) Female > 2000 1% pour-on formulation Oral Rat Male > 20 Schmidt (1984a) Female > 20 Oral Mouse Male > 20 Schmidt (1984a) Female > 20 Dermal Rat Male > 5 Schmidt (1984a) Female > 5 Dermala Rat Male > 5 Schmidt (1984a) Female > 5 Intraperitoneal Mouse Male approx. .1 Schmidt (1984b) Female approx. 5 Bayticol EC 6% in Oral Rat Male > 500-< 2000 Bomann (1992b) Solvesso 200 Female > 500-< 2000 Dermal Rat Male > 5000 Bomann (1992c) Female > 5000 Table 1. (Cont'd) Formulation Route Species Sex LD50 Reference (mg/kg bw) Bayvarol strips Oral Rat Male > 2000 Bomann (1992d) (0.55 g Bayticol/100g) Female > 2000 Dermal Rat Male > 5000 Bomann (1992e) Female > 5000 Bayticol EC 7.5% Inhalation Rat Male approx. 3000 Thyssen (1982) (4 h) Female > 2934 a On scarified skin After acute administration of flumethrin, the most prominent clinical signs were manifestations of central nervous system toxicity, such as reduced motor activity, respiratory disorders, altered gait, and salivation. The onset of action occurred 1-15 min after administration, and the effects were comparatively long-lasting. The reported manifestations of toxicity are largely consistent with those known collectively as the choreoathetosis (sinuous writhing) with salivation syndrome, which is produced by other insecticidal pyrethroids, classified on this basis as Type II pyrethroids, which contain an alpha-cyano-2-phenoxybenzyl alcohol group (Vijversberg & van den Bercken, 1982). In the studies of acute toxicity, particular attention was paid to effects on the central nervous system. In animals investigated for behaviour on an inclined plane, flumethrin was administered orally in a vehicle which enhances toxicity, i.e. as an emulsion in water/Cremophor EL, and, for comparison, in milk, a vehicle of relevance as regards the consumer. Doses of 5 mg/kg bw in both formulations had a slight effect, i.e. the inclination of the plane at which the dosed animals slipped off was lower than that at which the control animals slipped off. A dose of 1 mg/kg bw, administered as an emulsion in water/Cremophor, also had a very slight effect, but no effect was seen with 0.3 mg/kg bw or with 1 mg/kg bw administered as an emulsion in milk (Bomann, 1994c). After dermal application, the LD50 was > 2000 mg/kg bw. The clinical signs were comparable to those observed after oral administration. Evidence of skin reactions, such as scaling and incrustation and sometimes scratches, were found at the application site (Bomann, 1994b). Studies of flumethrin products (Table 1) did not indicate potentiation by the other constituents of commercially available formulations. The results obtained were within the respective ranges calculated on the basis of the toxicity of the active ingredient. Dermal application of a dose of 5 ml/kg bw of a pour-on formulation had no systemic or local effects (Schmidt, 1984a), and intraperitoneal administration of the 1% pour-on formulation to mice also showed little toxicity (Schmidt, 1984b). Deaths occurred after inhalation of the product Flumethrin EC 7.5% at a nominal concentration > 10 000 mg/m3 (Table 1). At 500 mg/m3, inhalation was tolerated with no adverse effects (Thyssen, 1982). (b) Short-term toxicity Rats Groups of 15 male and 15 female Wistar BOR: WISW rats received diets containing flumethrin (purity, 98.7%) to provide concentrations of 0, 10, 50, or 250/150 ppm (150 ppm from the third week onwards) for 13 weeks. An additional 10 rats of each sex per group were killed after four weeks. At concentrations > 50 ppm, skin lesions were seen on the head, neck, shoulder girdle, and front extremities. Although treatment was continued, these changes had cleared up in about half of the animals by the end of the study. During the first two weeks of the study, both food intake and water consumption of the group at 250 ppm were depressed by about 40%; these effects were accompanied by body-weight losses in animals of each sex. With the change to a dose of 150 ppm, food and water consumption became indistinguishable from the control values and there were no further weight losses. Body weights remained slightly reduced throughout the study in this group (terminal differences in comparison with controls being about 9% in males and 8% in females). Unscheduled deaths occurred only in animals at 250/150 ppm, four females and one male dying during the first two weeks of treatment and another male during week 5. The NOAEL was 10 ppm, equal to 0.7 mg/kg bw per day in males and 0.8 mg/kg bw per day in females (Hahnemann & Rühl, 1985). Groups of 20 male and 20 female Wistar BOR: WISW rats received flumethrin (purity, 94.6%) in the diet at levels providing concentrations of 0, 10, 40, or 160 ppm for 15 weeks. Dosing at 160 ppm resulted in a reduction in food intake, retardation of body-weight development, and clinical signs, but none of the animals died. The body weights of animals at 160 ppm were 24% lower than those of controls for males and 8% for females, but there were no significant differences in the other groups. The principal clinical signs in animals at 160 ppm were piloerection, increases or decreases in motor activity, and spastic or staggering gait. Immediately after the start of dosing, the animals at this dose were also seen to groom their fur intensively and in particular to make frequent scratching movements. This produced skin lesions, some of which were several centimeters in diameter and bled after being scratched repeatedly. A small proportion of these skin lesions, and similar ones found on a few animals at 40 ppm, healed as the study progressed. Alpha-cyano pyrethroids are known to have a paraesthetic effect, which is regarded as the most probable cause of the skin lesions. Correlated with the presence of skin lesions on particular rats at this dose at the end of the study were reductions in erythrocyte count (approx. 16%), haematocrit (approx. 12%), and haemoglobin concentration (approx. 14%) and an increase in the leukocyte count (approx. 50%). The differential blood count showed a reduction in the proportion of lymphocytes (approx. 11%), with a corresponding increase in neutrophils (approx. 145%), a usual reaction during inflammation. The compound did not appear to affect blood chemistry, and the changes seen, such as a reduction in protein (approx. 10%) and albumin (approx. 18%) concentrations in animals at the highest dose, are regarded as consequences of the poor condition and of the skin lesions. Male animals at 160 ppm also had a reduced cholesterol concentration (24%) and a reduction in the protein content of the urine, but females had an increased protein content accompanied by a reduction in the volume of urine with a corresponding increase in the density of the urine. At necropsy, only skin lesions were found. In animals at the highest dose, the marked differences in body weight resulted in reductions in the weights of some organs and increases in the relative weights. Animals at 160 ppm showed evidence of stimulation of extramedullary haematopoiesis in the spleen and a reduction in stored haemosiderin, which were considered to have been the result of the blood losses described above. The reduction in the neutral fat content of the liver and in the size of the seminal vesicles of animals at the highest dose were considered to have been due to the poor condition of the animals and not to be related directly to flumethrin. The NOAEL was thus 10 ppm, equal to 0.7 mg/kg bw per day (Bomann & Sander, 1995). Dogs Groups of four male and four female beagle dogs, about eight months old, received diets containing flumethrin (purity, 98.7%) to provide concentrations of 0, 50, 100, or 200 ppm for 13 weeks. Animals at doses > 50 ppm showed thinned hair or hairlessness, and in some instances weeping, ulcerative, scabbed patches were seen on the neck, back, tall, ears, and limbs. These lesions had partially healed by the end of the study. The group at 200 ppm had reduced food intake and body-weight gains. Those at 100 and 200 ppm had slightly raised blood urea values, which were statistically significant in week 13 in animals at the highest dose (6.4 versus 7.9 mmol/litre); however, there was no evidence of gross pathological changes in the kidneys (Hoffmann & Kaliner, 1984). There was no NOAEL in this study. In a study to achieve a no-effect level that was not found in the earlier study because of the presence of skin lesions, groups of four male and four female beagle dogs about six months old received diets containing flumethrin (same batch as used in the previous study) providing concentrations of 0 or 25 ppm for 13 weeks. No differences were observed between the two groups of dogs, although histopathological examination was not performed since no histological differences were observed in the previous study. In particular, no skin lesions were detected. The NOAEL was 25 ppm, equal to 0.88 mg/kg bw per day in males and 0.94 mg/kg bw per day in females (Hoffmann, 1985). Cattle A single dose of 50 ml of a 1% flumethrin formulation was administered by gavage to two six-week-old calves, and one calf received a placebo formulation. All three animals were observed for five days. The two animals given the flumethrin formulation voided watery faeces for a short time within the first 24 h, and their food intake was lower in the first 48 h after administration. There were no changes in body-weight development or in haematological, clinicochemical, or urinary parameters, and no changes were seen in the calf give the placebo. Thus, if an animal were to lick the product off treated skin, the only effects likely to occur are mild and reversible (Iida et al., 1988). A dose of 4 mg/kg bw, i.e. twice the therapeutic dose, was applied to the backs of 18 calves, which were then observed for the next 2 h and daily for three weeks. The treatment was well tolerated, and there were no clinical signs or local effects on the skin (Dorn, 1989a). In a similar study in which 4 mg/kg bw was applied to the dorsal midline of 15 young bovines, there was no evidence of local or systemic effects during daily observation for three weeks (Dorn, 1989b). When the same dose was applied to the backs of 13 pregnant cows, the treatment had no effect on the animals' behaviour or general health. There was also no evidence of an effect on labour or on the calves, which were given a clinical examination at delivery and thereafter at weekly intervals (Dorn, 1989c). (c) Long-term toxicity and carcinogenicity No studies of the long-term toxicity or carcinogenicity of flumethrin have been conducted, but a two-year study was carried out with flumethrin with a low trans-Z isomer content (purity, 91.3%) in which groups of 50 male and 50 female Wistar BOR:WISW (SPF Cpb) rats received diets containing providing concentrations of 0, 2, 10, 50, or 250 ppm. An additional 10 rats of each sex per group were killed after 12 months of treatment. No significant effects were seen on growth, mortality, food or water consumption, or behaviour at doses < 50 ppm. At 250 ppm, both male and female rats showed retarded growth development, and their mean body weights were > 10% lower than those of the controls at 50 weeks. At 103 weeks, the numbers of deaths in the groups given 0, 2, 10, 50, and 250 ppm were 7, 5, 8, 7 and 3 males and 10, 11, 7, 9, and 19 females. Much of the increased mortality among the female rats at 250 ppm was due to the fact that several were killed in a moribund state or died from severe skin lesions and the related poor general condition. These lesions consisted of ulcerative dermatitis occurring at a dose-dependent incidence and severity, which first appeared in the second week of treatment. The maximal incidences were seen after four weeks. These lesions later healed in females at 50 ppm and in males at 50 or 250 ppm. Some inconsistent, statistically significant changes were observed on periodic haematological examination: the number of polymorphonuclear neutrophils increased, mainly in males at 250 ppm, and inconsistent increases were also seen in other groups. Slight decreases in lymphocyte counts were observed almost exclusively in males at 50 and 250 ppm after 26, 52, and 78 weeks, but the decreases were not significant after 104 weeks. These may be nonspecific reactions to the inflammatory changes in the skin and were similar to those reported in the 15-week dietary study described above (Bomann & Sander, 1995). Sporadic differences were observed in erythrocyte and haemoglobin parameters, but these were inconsistent with respect to dose and time and are not considered to be treatment-related. While statistically significant differences between groups did occur, studies of blood chemistry did not indicate any consistent, dose-related changes in albumin, bilirubin, urea, creatinine, cholesterol, glucose, or the activities of the plasma enzymes alkaline phosphatase, alanine transaminase, aspartate transaminase, creatine kinase, and lactate dehydrogenase. No biologically important changes were seen in chloride (deviation from control, < 4%), and the larger changes in phosphate ion concentrations did not show a dose-response relationship. The sodium ion concentration was unaltered and that of potassium showed dose-related increases in males only at 52 and 104 weeks, but not at 26 or 78 weeks. Similarly, decreases in calcium ion in both males and females occurred at 52 and 104 weeks, but not at 26 or 78 weeks. This erratic pattern of changes does not indicate that they were the result of treatment. Urine analysis showed no variations attributable to treatment in either male or female rats at 26, 52, 78, or 104 weeks. At autopsy, no treatment-related changes were observed, but one female at 250 ppm killed at 52 weeks had the skin lesions described above. The relative weights of the lungs and kidneys were increased in both male and female rats at 250 ppm at the end of the study: lung, 368 mg/100 g bw in controls vs 407 in males at 250 ppm and 426 mg/ 100 g bw vs 482 in females; kidney, 605 mg/100 g bw vs 658 at 250 ppm in males and 665 mg/100 g bw vs 717 in females. The absolute weights of these organs were not changed; the weights relative to brain weight were not available because the brain was not weighed. Most of the effects appeared to be due to reductions in total body weight in animals at 250 ppm. Histological examinations were restricted to the groups at 0 and 250 ppm groups. Few non-neoplastic histopathological findings were considered to be treatment-related. Two male and five female rats had skin ulcerations, the etiology of which was not established. Male rats, but not females, also had slight proliferation of the bile duct, the incidences after 104 weeks being 12/50 in controls, 17/50 animals at 2 ppm, 12/50 of those at 10 ppm, 16/50 of those at 50 ppm, and 23/50 of those at 250 ppm. The incidences of neoplastic lesions were not affected by treatment, the numbers of tumour-bearing rats per group of 50 being 25 male controls and 11 at 2 ppm, five at 10 ppm, eight at 50 ppm, and 15 at 250 ppm, and 31 female controls, 18 at 2 ppm, 19 at 10 ppm, 23 at 50 ppm, and 23 at 250 ppm. The incidences of specific, more frequent tumours were similar in the controls and animals at 250 ppm, with mammary carcinomas in 6/44 control females, 2/49 at 2 ppm, 0/47 at 10 ppm, 5/47 at 50 ppm, and 0/45 at 250 ppm; mammary fibroadenomas were found in 2/44 controls, 5/49 at 2 ppm, 3/47 at 10 ppm, 4/47 at 50 ppm, and 4/45 at 250 ppm. Pituitary adenomas were found in 14/39 controls, in 4/39 animals at 2 ppm (in 4/4 masses subjected to histological examination), in 12/43 animals at 10 ppm (12/12 masses), in 11/41 animals at 50 ppm (11/11 masses), and 6/30 animals at 250 ppm. The NOAEL was 10 ppm, equal to 0.5 mg/kg bw per day in males and 0.6 mg/kg bw per day in females (Bomhard et al., 1987, 1991). (d) Reproductive toxicity Rats A two-generation study was conducted on groups of 30 male and 30 female Wistar/HAN rats [strain: Kfm: WIST (SPF)] fed diets containing flumethrin (45.6% in Aerosil 200) at concentrations providing concentrations of 0, 1, 5, or 50 ppm. The F0 generation received the test diet for 84 days before mating and during the mating period, gestation, and lactation until day 21 after littering. The F1 parental generation received the test diet from the age of four to seven weeks for 105 days before mating and thereafter over the same periods as the F0 generation. No effects of treatment with 1 or 5 ppm were discernible in any generation. After treatment with 50 ppm, skin lesions developed on male and female animals of the F0 generation and on females of the F1 generation. Male rats at this dose showed a reduction in food consumption before mating in the F0 generation and in all phases of the study in the F1 generation; females had a reduced food consumption in the F0 generation in all phases and in the F1 generation during the two lactation phases. The body-weight development of males of the F0 generation and of males and females of the F1 generation was retarded in all phases. The reductions in food consumption and body-weight gain were seen as early as the first week of dosing before mating. Survival in all F1 and F2 generations was lower during the first four days after delivery, but the losses up to day 21 after delivery were greatest in the F1b, F2a, and F2b generations. In addition, the weight gain of the pups of the F1 and F2 generations was retarded. A higher incidence of pups with a cramped or bent posture, stiff limbs in caudal posture, and/or pectus carinatum was seen, with hypothermia, and vocalization was more frequent. These observations are probably secondary to the toxic effects on the parents. No malformations were found. Investigations of the haematological status of the F1 parental animals gave no indication of treatment-related changes. The NOAEL was 5 ppm, equal to 0.36 mg/kg bw per day for males and 0.40 mg/kg bw per day for females (Dotti et al., 1992). (e) Developmental toxicity Rats Groups of 28 female Charles River Crl:CD Br rats, 11 weeks old when mated, were given flumethrin (purity, 93.5%) formulated as a 0.4 mg/ml solution in distilled water containing 5% Emulphor EL-719 and 5% ethanol, orally at doses of 0, 0.5, 1, or 2 mg/kg bw per day on days 6-15 of gestation. Day 0 of gestation was defined as the day on which spermatozoa were found in the vagina. The rats tolerated the dose of 0.5 mg/kg bw per day, but doses > 1 mg/kg bw per day were toxic to the dams, the effects including increased salivation and lacrimation, reduced activity, ataxia, and ptosis. At 2 mg/kg bw per day, there was a reduction in food intake during treatment and a reduction in body-weight gain. There was no evidence of teratogenicity at any dose and no embryotoxic or fetotoxic effects in animals at 0.5 or 1 mg/kg bw per day. Animals at 2 mg/kg bw per day had significant reductions in placental weights (0.53 g vs 0.48 g in controls) and fetal weights (3.8 g vs 3.4 g, sexes combined); they also had an increased number of fetuses with reduced ossification of the skull bones (42% vs 67%) and cervical vertebral arches (1% vs 16%). The NOAEL was 0.5 mg/kg bw per day for maternal toxicity and 1 mg/kg bw per day for developmental toxicity (Kowalski et al., 1987). Rabbits Groups of 17 American-Dutch rabbits, at least 4.5 months old when they were artificially inseminated with semen from proven males, received flumethrin (purity, 93.5%) formulated as a 0.4 mg/ml solution in distilled water containing 5% Emulphor EL-719 and 5% ethanol orally at doses of 0, 0.5, 1.7, or 6 mg/kg bw per day on days 7-19 of gestation. The high dose was selected on the basis of a range-finding study in pregnant rabbits (source not identified). Dosing at 0.5 or 1.7 mg/kg bw per day was tolerated with no adverse effects. Animals at 6 mg/kg bw per day had reduced food intake during treatment and reduced body weights; reproductive function was not affected. At 6 mg/kg bw per day, a slight trend for a reduction in the weights of the fetuses, particularly the females, was seen, but this was not significant. There was no indication of teratogenic potential. The NOAEL was 1.7 mg/kg bw per day (Clemens & Hartnagel, 1987). (f) Genotoxicity Flumethrin has been adequately tested for its ability to induce point mutations, DNA damage, and clastogenicity (Table 2). An early bacterial mutagenesis assay using four strains of Salmonella typhimurium gave equivocal results in several strains and weakly positive results in strain TA98, but the latter were not confirmed in later experiments. Tests with the isolated trans-Z-1 and trans-Z-2 isomers in S. typhimurium also gave negative results. A small increase in the frequency of chromosomal aberrations was observed in Chinese hamster V79 cells 18 h after treatment with flumethrin in the presence of an exogenous metabolic system. This effect was not observed in an earlier experiment with human lymphocytes, and there was no indication of chromosomal aberration induction in vivo, as might be indicated by the results of tests for micronucleus formation in bone-marrow cells of mice. In these and all other tests with flumethrin, the results were clearly negative. The Meeting concluded that flumethrin is not genotoxic. (g) Special studies (i) Dermal and ocular irritation and dermal sensitization In tests for ocular and dermal (occluded patch) irritation in New Zealand white rabbits, a 1% pour-on formulation of flumethrin produced slight erythema of the conjunctivae for up to 48 h after treatment and slight oedema of the conjunctivae for up to 24 h after treatment. Dermal application induced pronounced reddening and some oedema after 24 h. These effects had largely resolved by 72 h (Schmidt, 1984a). Two pour-on formulations of flumethrin were tested in New Zealand white rabbits exposed for 4 h. One formulation was not irritating, while the other was slightly irritating to the skin. Exposure for 24 h resulted in irritation with both formulations (Pauluhn, 1985a). In a test for irritation on the skin and the mucous membrane of the eyes of New Zealand white rabbits, flumethrin was applied as a 10% formulation in olive oil. No irritation of either skin (4-h exposure) or eyes (24-h exposure) was observed (Krötlinger, 1994). Flumethrin (purity, 88.3%) was tested for dermal sensitizing activity in the Magnusson and Kligman maximization test on male Bor:DHPW guinea-pigs. For intradermal induction, flumethrin was administered as a 5% solution in PEG 400; for topical induction and for challenge, it was administered as a 50% solution in PEG 400. There were no post-challenge skin reactions (Diesing, 1991). Table 2. Results of tests for the genotoxicity of flumethrin End-point Test system Concentration Purity Results Reference (%) Without S9 With S9 Flumethrin Reverse mutation S. typhimurium TA100 15 625 µg/plate 97.6 Inconclusive Negative Herbold (1984) Reverse mutation S. typhimurium TA1535 15 625 µg/plate 97.6 Negative Inconclusive Herbold (1984) Reverse mutation S. typhimurium TA1537 15 625 µg/plate 97.6 Inconclusive Negative Herbold (1984) Reverse mutation S. typhimurium TA98 15 625 µg/plate 97.6 Inconclusive Weakly Herbold (1984) positive Reverse mutation S. typhimurium TA100 5000 µg/plate 94.6 Negative Negativea Gahlmann (1993a) Reverse mutation S. typhimurium TA1535 5000 µg/plate 94.6 Negative Negativea Gahlmann (1993a) Reverse mutation S. typhimurium TA1537 5000 µg/plate 94.6 Negative Negativea Gahlmann (1993a) Reverse mutation S. typhimurium TA98 5000 µg/plate 94.6 Negative Negativea Gahlmann (1993a) Reverse mutation S. typhimurium TA100 15 000 µg/plate 94.6 Negative Negative Gahlmann (1993a) Reverse mutation S. typhimurium TA1535 15 000 µg/plate 94.6 Negative Negative Gahlmann (1993a) Reverse mutation S. typhimurium TA1537 15 000 µg/plate 94.6 Negative Negative Gahlmann (1993a) Reverse mutation S. typhimurium TA98 15 000 µg/plate 94.6 Negative Negative Gahlmann (1993a) Reverse mutation S. cerevisiae D7 10 000 µg/ml 92.7 Negative Negative Herbold (1985a) Cell mutation, tk Mouse lymphoma 1000 µg/ml 92.7 Negative Negative Cifone & Myhr locus L5178Y cells (1985) Cell mutation, hprt Chinese hamster lung 100 µg/ml 95.1 Inconclusive Negative Brendler-Schwaab locus V79 cells (1995) Unscheduled DNA Rat hepatocyte 300 µg/ml 94.6 Negative Not tested Brendler-Schwaab synthesis primary culture (1994) Chromosomal Chinese hamster lung 125 µg/ml 95.1 Negative Negative Herbold (1995a) aberration V79 cells (18- and 30-h sampling) Table 2. (Cont'd) End-point Test system Concentration Purity Results Reference (%) Without S9 With S9 Chromosomal Human lymphocyte 1000 µg/ml 92.7 Negative Negative Herbold (1985b) aberration primary culture (24-h sampling) Micronucleus Mouse bone marrow 50 mg/kg bw × 1 93.5 Negative Herbold (1986) induction in vivo (24-, 48-, and orally 72-h sampling) Micronucleus Mouse bone marrow 1000 mg/kg × 1 95.1 Negative Herbold (1995b) induction in vivo (16-, 24-, and intraperitoneally 48-h sampling) Flumethrin-trans-Z-1 isomer Reverse mutation S. typhimurium TA98 15 000 µg/plate 98.3 Negative Negative Herbold (1990a) Flumethrin-trans-Z-2-isomer Reverse mutation S. typhimurium TA98 15 000 µg/plate 95.4 Negative Negative Herbold (1990b) S9, 9000 × g supernatant of liver microsomes used as exogenous metabolic activation system a An additional test in the presence of 30% S9; all bacterial studies include duplicate experiments with 10% S9 Repetition of this maximization test with another batch of flumethrin (purity, 94.6), formulated in the same manner and at the same concentrations as above but with an additional 25% concentration for challenge, also gave no evidence of any potential for inducing skin sensitization (Vohr, 1994). (ii) Neurotoxicity Male and female Wistar Bor: WISW rats received flumethrin by gavage for 14 days at doses of 20 mg/kg bw for males and 10 mg/kg bw for females for the first four days, but due to signs of severe toxicity and one death, the doses for the remainder of the study were reduced to 10 mg/kg bw for males and 5 mg/kg bw for females. The treatment was followed by 31 days of observation. This study was conducted because other pyrethroids such as cypermethrin, fenvalerate, and permethrin cause slight axonal degeneration, mainly in peripheral nerves, at highly toxic doses in rats (WHO, 1989, 1990a,b). Two to three hours after the first administration, the rats showed apathy, reduced motility, accelerated breathing, salivation, and head twitching. Later in the study, spastic gait was also seen, and digging and shaking movements replaced the head twitch. The intensity of these symptoms had declined only marginally by 24 h. When the doses were reduced, the symptoms moderated in some rats. Some symptoms persisted for up to two days after the 14-day dosing period, but the surviving rats had completely recovered by the end of the observation period. Thus, the high doses used caused dysfunction of the nervous system, the observable effects of which were fully reversible. Histopathological examination of the central and peripheral nervous system gave no evidence of neurotoxicity-related morphological damage (Flucke & Schilde, 1988). Single doses of 0, 10, 31.5, or 100 mg/kg bw flumethrin were administered orally to male Bor: WISW rats and Bor: CF1 mice. No muscle-relaxant, analgesic, anticonvulsant, or cataleptic effects were seen in animals at any dose, using standard pharmacological tests. There was no evidence of impairment of central coordination, function, reflexes, or neuromuscular transmission in the rats. Flumethrin caused moderate stimulation of spontaneous motor activity in mice at all doses, and the degree of stimulation was statistically significant among animals of 31.5 and 100 mg/kg bw. Orientational activity was also inhibited in these animals. Those at 100 mg/kg bw showed slight potentiation of the duration and depth of hexobarbital-induced anaesthesia (Starke, 1985). (iii) Anti-allergic and pseudo-allergic activity Histamine release in rat peritoneal mast cells sensitized passively by exposure to immunoglobulin E from mouse serum was not affected by concentrations of 0, 10-7, 10-6, or 10-5 g/ml flumethrin (Gardiner et al., 1985). (iv) Bronchial activity Flumethrin at concentrations of 10-9 to 10-5 g/ml had no effect on leukotrine D4- or histamine-induced contraction in isolated guinea-pig tracheas (Gardiner et al., 1985). (v) Effect on concentration of glucose and triglycerides in blood Single doses of 0, 10, 32, or 100 mg/kg bw flumethrin were administered orally to fasting and fed rats. The concentrations of glucose in the blood of fed animals at all doses and of fasted animals at the lowest and highest dose were slightly (24-64%) but significantly increased for dose-related times of 60-240 min. There was no effect on the triglyceride concentration. As marked variations in the blood glucose concentration are seen even under physiological conditions, these increases are not considered to be of particular relevance (Puls & Bischoff, 1985). (vi) Effects on gastrointestinal tract of rats Single doses of 0, 10, 30, or 100 mg/kg bw flumethrin were administered orally to rats. At the highest dose, a statistically significant increase in intestinal transit time was seen in the charcoal propulsion test. No gastric lesions were observed at autopsy. Intraduodenal administration of 10, 30, or 100 mg/kg bw caused a slight, non-significant, not dose-related reduction in acid secretion in the perfused stomach (to 79, 58, and 75%, respectively, of the control level) (Bonabello et al., 1987). (vii) Haematological and cardiovascular effects Single doses of 0, 10, 32, or 100 mg/kg bw flumethrin were administered orally to rats, and blood samples were taken 90 min later. Neither coagulation, platelet aggregation, nor fibrinolysis was affected (Seuter et al., 1985). Flumethrin at doses of 10, 32, or 100 mg/kg bw administered orally to anaesthetized dogs induced slight increases in heart rate, unrelated to dose, in one of three animals at 10 and 100 mg/kg bw. These increases were not considered to be related to treatment (Knorr, 1986). (viii) Diuretic activity Flumethrin at doses of 0, 10, 32, or 100 mg/kg bw was administered orally to rats, and urine was collected over 6 h to determine sodium and potassium concentrations. Clinical signs including increased salivation and reduced motor activity were seen in a few treated animals. None of the doses changed urine output or sodium excretion. Potassium excretion was significantly increased by the 10 and 100 mg/kg bw doses but not by 32 mg/kg bw. The variations were not considered to be treatment-related (Hirth, 1985). (ix) Toxicity of metabolites: Flumethrin acid Flumethrin acid is the major metabolite of flumethrin in rats and cattle. The oral LD50 of flumethrin acid in fasted rats was 935 mg/kg bw (95% confidence interval [CI], 549-1594) in males and 620 mg/kg bw (95% CI, 500-771) in females. The principal clinical signs were piloerection, lethargy, reduced motor activity, staggering gait, animals lying prone or on their side, atonia, and slow and laboured breathing. After dermal application of 5000 mg/kg bw, none of the animals died. The only clinical signs were lethargy and reduced motor activity. Small lesions and slight hyperaemia were observed at the application site. Exposure of male and female rats to 338 mg/m3 by inhalation, the highest concentration of flumethrin acid that it was technically feasible to generate, for 4 h was well tolerated, and no clinical signs of toxicity were observed (Pauluhn, 1985b). When rats were observed for possible effects on the central nervous system, by measuring the angle at which they slip from a plane before and at various times from 1 to 24 h after treatment with 0, 1, 3, or 10 mg/kg bw flumethrin, no treatment-related reduction in the angle was observed (Bomann, 1995a). In tests for dermal and ocular irritancy in rabbits, flumethrin acid had no effect (Pauluhn, 1985b). In a test for reverse mutation in S. typhimurium TA98, flumethrin acid showed no activity (Herbold, 1984a). In a four-week study in which Wistar rats were given dietary concentrations of 0, 30, 100, or 300 ppm flumethrin acid, no clinical signs of toxicity or effects on food consumption or body-weight development were seen. There was no evidence of treatment-related changes in haematological, clinicochemical, or necroscopic findings. No treatment-related histological changes were observed. The NOAEL was thus 300 ppm, equivalent to 27 mg/kg bw, the highest dose tested (Bomann, 1995b). 3. Observations in humans No reported cases of systemic poisoning with flumethrin in humans were available to the Meeting. There are, however, published reports of cases of poisoning with other pyrethroids. In a review of 573 cases of poisoning with other alpha-cyano pyrethroids (delamethrin, fenvalerate, and cypermethrin), poisoning was due to either incorrect occupational use of the product, attempted suicide, or accidents. In cases in which the product had come into contact with the skin, the presentation comprised a burning sensation on the face, tingling, papules, and dermatitis. In cases of mild poisoning, there was also dizziness, headache, nausea, anorexia, and weakness. In cases of moderate poisoning, the signs and symptoms were more intense, and there were states of reduced consciousness and muscle twitching in the extremities. Seven deaths are listed; two are attributable to misdiagnosis and inappropriate treatment. Most patients recovered within six days. In the more severe cases, recovery took up to 55 days. Treatment consisted of symptomatic and supportive measures. There were no delayed complications (He et al., 1989). There is no basis for considering that flumethrin would act differently from the compounds studied. Comments Flumethrin was absorbed rapidly, but not completely, after oral administration in all species investigated. The concentrations in the tissues of rats two days after dosing were three- to 50-fold lower than those in the blood; the lung contained higher concentrations than other tissues, and the central nervous system had the lowest concentrations. Excretion occurred primarily in the faeces. The main metabolite was flumethrin acid, which was distinctly less toxic than the parent substance in acute and four-week dietary studies in rats and did not induce reverse mutation in bacteria. The acute oral toxicity of flumethrin in laboratory animals is moderate to low. The reported manifestations of its toxicity are largely consistent with those known collectively as the choreoathetosis with salivation (CS) syndrome, which is produced by other insecticidal pyrethroids containing an alpha-cyano-3-phenoxybenzyl alcohol group. After acute dermal application, the toxicity of flumethrin was low; the clinical signs were the same as those seen after oral administration. There was no evidence of acute toxicity after dermal application of 5 ml/kg bw of a 1% pour-on formulation. In tests for dermal and ocular irritancy, the active substance proved not to be irritating. In tests for local irritancy with the 1% pour-on formulation, slight, transient skin changes (mainly barely perceptible erythema and/or swelling) were seen, but no changes in the mucous membrane of the eye, were observed. WHO has not classified flumethrin for acute toxicity. After oral administration of flumethrin for three months to rats at dietary concentrations of 0, 10, 40, or 160 ppm and to dogs at dietary concentrations of 0, 25, 50, 100, or 200 ppm, the NOAELs were 10 ppm (equal to 0.7 mg/kg bw per day) for rats and 25 ppm (equal to 0.88 mg/kg bw per day) for dogs. In both species, the most obvious findings were skin alterations, but these were not due to primary dermatitis caused by flumethrin but to frequent scratching, with attendant bleeding and, in some instances, inflammation. Alpha-cyano pyrethroids are known to produce paraesthesia, which is considered to be the most probable cause of the observed skin lesions. The toxicological studies provided no evidence of immunotoxicity, e.g. effects on leukocyte counts or on other relevant organs (thymus and spleen). The results of studies of developmental toxicity in rats at doses of 0, 0.5, 1, or 2 mg/kg bw per day on days 6-15 of gestation and rabbits at doses of 0, 0.5, 1.7, or 6 mg/kg bw per day on days 7-19 of gestation provided no evidence that flumethrin is teratogenic at doses extending into the range that is toxic to the dams. Some fetotoxicity was observed at doses that also induced maternal toxicity in both species. The NOAELs were 0.5 mg/kg bw per day for rats and 1.7 mg/kg bw per day for rabbits. A two-generation study of reproductive toxicity in rats exposed to flumethrin at dietary concentrations of 0, 1, 5, or 50 ppm did not indicate primary reproductive toxicity; the reduced pup survival and body-weight gain and certain postural and behavioural changes in the pups at the highest dose may have been secondary to maternal toxicity. The NOAEL was 5 ppm, equal to 0.36 mg/kg bw per day. No studies of long-term toxicity or carcinogenicity have been conducted with the currently used isomeric mixture of flumethrin. A two-year study was available, however, in which rats were fed diets providing flumethrin with a low trans-Z content at dietary concentrations of 0, 2, 10, 50, or 250 ppm. Skin lesions developed in rats at 50 and 250 ppm, and there was slight proliferation of the bile ducts in male rats at 250 ppm. Neither the number of tumour-bearing rats nor the incidence of any specific neoplasm was increased. The Meeting considered the following toxicological findings: (i) Flumethrin with a low trans-Z content has no carcinogenic potential. (ii) Other pyrethroids, such as cyhalothrin (WHO, 1990a), cypermethrin (WHO, 1989a), fenvalerate (WHO, 1990d), and the related resmethrins (WHO, 1989b) also have no carcinogenic potential. (iii) Treatment with permethrin (WHO, 1990b) resulted in small increases in the incidence of lung tumours in female mice in three studies, but no increases were found in either rats or male mice. (iv) Treatment with deltamethrin was associated with unspecified thyroid adenomas in rats in one study, but no tumours were induced in mice or in either species in other studies (WHO, 1990c). (v) Flumethrin had no genotoxic potential in a number of well-conducted tests covering a variety of end-points. (vi) Flumethrin showed no sensitizing potential. (vii) No preneoplastic responses were seen in studies of up to 13 weeks in duration. The Meeting considered that the carcinogenic potential of the trans-Z isomers that are present in the currently used isomeric mixture of flumethrin had been assessed in the study in rats in which the low trans-Z product was tested. Oral administration of highly toxic doses of flumethrin to rats can cause dysfunction of the nervous system, but the effect is rapidly reversible and is not accompanied by morphological damage to the central or peripheral nervous system. Pharmacological tests in experimental animals gave no evidence of impairment of vital functions. Studies to establish the tolerance of calves and cattle to flumethrin showed no significant effects, even when animals licked the application site. An ADI of 0-0.004 mg/kg bw was allocated, on the basis of the NOAEL of 0.36 mg/kg bw per day in the two-generation study of reproductive toxicity in rats, using a 100-fold safety factor. Toxicological evaluation Levels that cause no toxic effect Rat: 10 ppm, equal to 0.7 mg/kg bw per day (13- and 15-week studies of toxicity) 5 ppm, equal to 0.36 mg/kg bw per day (two-generation study of reproductive toxicity) 0.5 mg/kg bw per day (maternal toxicity in a study of developmental toxicity) Rabbit: 1.7 mg/kg bw per day (maternal and fetal toxicity in a study of developmental toxicity) Dog: 25 ppm, equal to 0.88 mg/kg bw per day (13-week study of toxicity) Estimate of acceptable daily intake for humans 0-0.004 mg/kg bw Studies that would provide information useful for continued evaluation of the compound Results of any studies that are planned or in progress in rodents, dogs, or exposed human subjects Toxicological criteria for estimating guidance values for dietary and non-dietary exposure to flumethrin Exposure Relevant route, study type, species Results, remarks Short-term (1-7 days) Oral, toxicity, rat LD50 = 41-3849 mg/kg bw, depending on the vehicle Dermal, toxicity, rat LD50 > 2000 mg/kg bw Inhalation, toxicity, rat LC50 = 225 mg/m3 Dermal, irritation, rabbit Not irritating Ocular, irritation, rabbit Not irritating Dermal, sensitization, guinea-pig Not sensitizing Medium-term (1-26 weeks) Repeated oral, 15 weeks, toxicity, rat NOAEL = 0.7 mg/kg bw per day Repeated oral, 13 weeks, toxicity, dog NOAEL = 0.88 mg/kg bw per day Repeated oral, reproductive toxicity, rat NOAEL = 0.36 mg/kg bw per day, reduced body-weight gain of adults Repeated oral, developmental toxicity, rat NOAEL = 1 mg/kg bw per day, developmental toxicity Repeated oral, developmental toxicity, rabbit NOAEL = 1.7 mg/kg bw per day, maternal and developmental toxicity Long-term (> 1 year) Repeated oral, 2 years, toxicity and NOAEL = 0.5 mg/kg bw per day, skin lesions; carcinogenicity, rat no carcinogenicity References Anadón, A., Diez, M.J., Sierra, M., Sanchez, J.A. & Teran, M.T. (1988) Microsomal enzyme induction by permethrin in rats. Vet. Hum. Toxicol., 30, 309-312. Anadón, A., Martinez-Larrañaga, M.R., Fernandez, M.C., Díaz, M.J. & Bringas, P. (1990) Effect of ciprofloxacin on antipyrine pharmacokinetics and metabolism in rats. Antimicrob. Agents Chemother. 34, 2148-2151. Anadón, A., Martinez-Larrañaga, M.R., Díaz, M.J., Bringas, P., Fernandez, M.C., Martinez, M.A. & Fernandez-Cruz, M.L. (1995) Effects of flumethrin on hepatic drug-metabolizing enzymes and antipyrine disposition in rats. Toxicol. Appl. Pharmacol., 132, 14-18. Bomann, W. (1992a) Bay Vq 1950 (Flumethrin). Investigations of acute oral toxicity in rats. Report No. 20924, 7.1.1992. Submitted to WHO by Bayer AG, Leverkusen, Germany. Bomann, W. (1992b) Bayticol EC 6% (c.n.: Flumethrin). Investigations of acute oral toxicity in rats. Report No. 20922, 7.1.1992. Submitted to WHO by Bayer AG, Leverkusen, Germany. Bomann, W. (1992c) Bayticol EC 6% Bayticol EC6% (c.n.: Flumethrin). Investigations of acute oral toxicity in rats. Report No. 20923, 7.1.1992. Submitted to WHO by Bayer AG, Leverkusen, Germany. Bomann, W. (1992d) Bayvarol-Strips (c.n.: Flumethrin). Untersuchungen zur akuten oralen Toxizität an Ratten. Ber. No. 21093, 17.2.1992. Submitted to WHO by Bayer AG, Leverkusen, Germany. Bomann, W. (1992e) Bayvarol-Strips (c.n.: Flumethrin). Untersuch- ungenzur akuten dermalen Toxizität an Ratten. Ber. No. 21094, 17.2.1992. Submitted to WHO by Bayer AG, Leverkusen, Germany. Bomann, W. (1994a) Bayticol P (c.n.: Flumethrin). Study for acute oral toxicity in rats. Report No. 23422, 19.10.1994. Submitted to WHO by Bayer AG, Leverkusen, Germany. Bomann, W. (1994b) Bayticol P (c.n.: Flumethrin). Study for acute dermal toxicity in rats. Report No. 23421, 19.10.1994. Submitted to WHO by Bayer AG, Leverkusen, Germany. Bomann, W. (1994c) Bayticol P (c.n.: Flumethrin). Study for acute oral toxicity of Bayticol P formulated in water/Cremophor EL and in milk in female rats. Report No. 23493, 23.11.1994. Submitted to WHO by Bayer AG, Leverkusen, Germany. Bomann, W. (1995a) Bayticol acid (Bayticolsäure). Study for acute oral toxicity in Wistar rats. Report No. 23863, 22.3.1995. Submitted to WHO by Bayer AG, Leverkusen, Germany. Bomann, W. (1995b) Bayticol acid (Bayticolsäure). Investigations of subacute toxicity in Wistar rats (feeding study over 4 weeks). Report No. 24057, 7.6.1995. Submitted to WHO by Bayer AG, Leverkusen, Germany. Bomann, W. & Sander, E. (1995) Bayticol P (c.n.: Flumethrin). Investigations or subchronic toxicity in Wistar rats (feeding study over 15 weeks). Report No. 23925, 11.4.1995. Submitted to WHO by Bayer AG, Leverkusen, Germany. Bomhard, E., Ramm, W. & Rühl-Fehlert, C. (1987) Flumethrin (BAY V1 6045) Studies on the chronic toxicity and carcinogenicity in Wistar rats. Report No. 16245, 25.11.1987. Submitted to WHO by Bayer, AG, Leverkusen, Germany. Bomhard, E., Ramm, W. & Rühl-Fehlert, C. (1991) Flumethrin (BAY V1 6045) Studies on the chronic toxicity and carcinogenicity in Wistar rats. Amendment. Report No. 16245a, 24.5.1991. Submitted to WHO by Bayer, AG, Leverkusen, Germany. Bonabello, A. & Grassi, A. (1987) Safety pharmacology of Bay Vq 1950 in the gastrointestinal tract: Its effect on intestinal charcoal transit, on gastric tolerability and on basal gastric acid secretion in rats. Berich No. 4137 (P), 23.7.1987. Submitted to WHO by Bayer, AG, Leverkusen, Germany. Brendler-Schwaab, S. (1994) Evaluation of Bayticol P in the rat primary hepatocyte unscheduled DNA synthesis assay. Report No. 23461, 8.11.1994. Submitted to WHO by Bayer AG, Leverkusen, Germany. Brendler-Schwaab, S. (1995) Flumethrin. Mutagenicity study for the detection of induced forward mutation in the V79-HPRT assay in vitro. Report No. 24162, 14.7.1995. Submitted to WHO by Bayer AG, Leverkusen, Germany. Cabral, J.R.P., Galendo, D., Laval, M. & Lyandrat, N. 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Cytogenetic investigations in human lymphocyte cultures in vitro to check for chromosome damaging activity (in vitro). Report No. 13167 (F). Submitted to WHO by Bayer AG, Leverkusen, Germany. Herbold, B. (1986) Bayticol P. Micronucleus test in mice to evaluate for clastogenic activity. Report No. 14501. Submitted to WHO by Bayer AG, Leverkusen, Germany. Herbold, B. (1990a) Flumethrin- trans-Z-1-isomer. Salmonella/microsome test using Salmonella TA98. Report No. 19573. Submitted to WHO by Bayer AG, Leverkusen, Germany. Herbold, B. (1990b) Flumethrin- trans-Z-2-isomer. Salmonella/microsome test using Salmonella TA 98. Report No. 19572. Submitted to WHO by Bayer AG, Leverkusen, Germany. Herbold, B. (1995a) Flumethrin. In vitro mammalian chromosome aberration test with Chinese hamster V79 cells. Report No. 24524. Submitted to WHO by Bayer AG, Leverkusen, Germany. Herbold, B. (1995b) Flumethrin. Micronucleus test on the mouse. Report No. 23869. Submitted to WHO by Bayer AG, Leverkusen, Germany. Hirth, C. (1985) Bay Vq 1950. Study of diuretic activity in rats. Report No. 14092. Submitted to WHO by Bayer AG, Leverkusen, Germany. Hoffmann, K. & Kaliner, G. (1984) Bay Vq 1950. Subchronic toxicity study in dogs with oral administration (13 weeks feeding study). Report No. 13155. Submitted to WHO by Bayer AG, Leverkusen, Germany. Hoffmann, K. (1985) Bay Vq 1950. Subchronic toxicity study in dogs with oral administration/supplementary study (13 weeks feeding study). Report No. 13169. Submitted to WHO by Bayer AG, Leverkusen, Germany. Iida, M., Akagi, H. & Hashizume, M. (1988) Study on safety of Bayticol pour-on in calves. Rep. No. 89/13245. Submitted to WHO by Bayer AG, Leverkusen, Germany. Kaneko, H., Ohkawa, H. & Miyamoto, J. (1981) Comparative metabolism of fenvalerate and the [2S, alpha S]-isomer in rats and mice. J. Pestic. Sci., 6, 317-326. Klein, O. (1993a) [Cl-Phenyl-U-14C] Flumethrin: Investigation of the biokinetic behaviour and the metabolism in the rat. Bericht No., PF-3823, ME-16/93, KNO 58. Submitted to WHO by Bayer AG, Leverkusen, Germany. Klein, O. (1993b) [Cl-Phenyl-U-14C] Flumethrin: Investigations on the distribution of the total radioactivity in the rat. Projekt-No. M1840667. Report in preparation, 1995. Submitted to WHO by Bayer AG, Leverkusen, Germany. Klein, O. (1995) Metabolism of [14C]-Bayticol in the dairy cow and male beef cattle. Project No. M1840667-2. Report No. MR 323/95 KNO68. Submitted to WHO by Bayer AG, Leverkusen, Germany. Knorr, A. (1986) Influence on hemodynamics and cardiac contractility of anesthesized dogs after oral administration. Pharma-Bericht No. Submitted to WHO by Bayer AG, Leverkusen, Germany. Kowalski, R.L., Clemens, G.R. & Hartnagel, R.E. (1987) A teratology study with Bayticol-P (Flumethrin = Bay Vq 1950) in the rat. R-Bericht No. 3960. Unpublished report from Miles Laboratories, Inc., Elkhart, IN, USA. Submitted to WHO by Bayer, AG, Leverkusen, Germany. Krötlinger, F. (1994) Bayticol P. Study for skin and eye irritation/ corrosion in rabbits. Ber-No. 23559. Submitted to WHO by Bayer AG, Leverkusen, Germany. Pauluhn, J. (1985a) Bayticol P pour on 1%. Study on the irritancy/ corrosion potential on rabbit skin. Report No. 14033. Submitted to WHO by Bayer AG, Leverkusen, Germany. Pauluhn, J. (1985b) Bayticol-P-Säure. Untersuchungen zur Gewer- betoxikologie. Ber-No. 13643. Submitted to WHO by Bayer AG, Leverkusen, Germany. Puls, W. & Bischoff, H. (1985) Bay Vq 1950. Influence of orally administered Bay Vq 1950 on the blood glucose and serum triglyceride concentrations in fed rats and fasted rats. Report No. 14366. Submitted to WHO by Bayer AG, Leverkusen, Germany. Renhof, M. (1983a) Bay Vq 1950 in peanut oil and miglyol. Acute oral toxicity in the rat. Report No. 12047 (P). Submitted to WHO by Bayer AG, Leverkusen, Germany. Renhof, M. (1983b) Bay Vq 1950 in acetone/peanut oil 1:10. Acute oral toxicity in the rat. Report No. 12048 (P). Submitted to WHO by Bayer AG, Leverkusen, Germany. Schmidt, M. (1984a) Bay Vq 1950 pour on 1%. Acute toxicity in the rat and the mouse. Study of primary irritant/corrosive activity on rabbit skin and eye. Report No. 12761 (P). Submitted to WHO by Bayer AG, Leverkusen, Germany. Schmidt, M. (1984b) Bay Vq 1950 pour on 1%. Acute toxicity in the rat and mouse after intraperitoneal application. Report No. 12760 (P). Submitted to WHO by Bayer AG, Leverkusen, Germany. Seuter, F. & Perzborn, E. (1985) Blood-pharmacological investigations. Report No. 14213. Submitted to WHO by Bayer AG, Leverkusen, Germany. Starke, B. (1985) CNS safety pharmacology study with Bay Vq 1950 (Bayticol P) on oral administration. Pharma-Bericht No. 3541. Submitted to WHO by Bayer AG, Leverkusen, Germany. Steinke, W., Weber, H. & Suwelack, D. (1983) [14C] BAY V1 6045: Pharmakokinetik in Ratten. PH-Report No. 11941. Submitted to WHO by Bayer AG, Leverkusen, Germany. Thyssen, J. (1982) Bayticol EC 7.5%. Investigation into the acute toxicity on inhalation. Report No. 10946. Submitted to WHO by Bayer AG, Leverkusen, Germany. Vijversberg, H.P.M. & Van den Bercken, J. (1982) Action of pyrethroid insecticides on the vertebrae nervous system. Neuropathol. Appl. Neurobiol., 8, 421-440 Vohr, H.-W. (1994) Bayticol P. Investigations of skin sensitization in guinea pigs (Magnusson & Kligman test). Report No. 23026. Submitted to WHO by Bayer AG, Leverkusen, Germany. WHO (1989a) Cypermethrin (Environmental Health Criteria 82), International Programme on Chemical Safety, Geneva, 154 pp. WHO (1989b) Resmethrins (Environmental Health Criteria 92), International Programme on Chemical Safety, Geneva, 79 pp. WHO (1990a) Cyhalothrin (Environmental Health Criteria 99), International Programme on Chemical Safety, Geneva, 106 pp. WHO (1990b) Deltamethrin (Environmental Health Criteria 97), International Programme on Chemical Safety, Geneva, 133 pp. WHO (1990c) Fenvalerate (Environmental Health Criteria 95), International Programme on Chemical Safety, Geneva, 121 pp. WHO (1990d) Permethrin (Environmental Health Criteria 94), International Programme on Chemical Safety, Geneva, 125 pp.
See Also: Toxicological Abbreviations Flumethrin (UKPID)