* New compounda-cyano-4-fluoro-3-phenoxybenzyl 3-(b,4-dichlorostyryl)-2,2-dimethylcyclopropanecarboxylate
Flumethrin is a fat-soluble pyrethroid insecticide used in the control of ectoparasites on cattle, sheep, goats, horses, and dogs. It is also marketed 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). Flumethrin was evaluated for the first time by the present Meeting.
TOXICOLOGY
The development of flumethrin first led to a substance which 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 (low trans-Z content).
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. Elimination was mainly 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 mutations 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 a-cyano-3-phenoxybenzyl group. After dermal application, the acute 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), but no changes in the mucous membrane of the eye, were observed. WHO has not classified flumethrin for acute toxicity.
After the 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) in rats and 25 ppm (equal to 0.88 mg/kg bw per day) in 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. a-Cyano pyrethroids are known to produce paraesthesia, which is considered to be the most likely cause of the observed skin lesions. The toxicological studies provided no evidence of immunotoxicity, e.g. effects on leucocyte 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 in 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 in rats and 1.7 mg/kg bw per day in 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 24-month study was available, however, in which rats were fed diets containing flumethrin with a low trans-Z content at 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, cypermethrin, fenvalerate and the resmethrins also have no carcinogenic potential. (iii) Treatment with permethrin 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. (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 observed in studies 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.
A toxicological monograph was prepared, summarizing the data that were reviewed at the present Meeting.
TOXICOLOGICAL EVALUATION
Levels that cause no toxic effect
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Rat: |
10 ppm, equal to 0.7 mg/kg bw per day (13-week and 15-week studies of toxicity) |
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5 ppm, equal to 0.36 mg/kg bw per day (two-generation study of reproductive toxicity) |
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0.5 mg/kg bw per day (maternal toxicity in a study of developmental toxicity) |
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Rabbit: |
1.7 mg/kg bw per day (maternal and fetal toxicity in a study of developmental toxicity) |
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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 the 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 setting guidance values for dietary and non-dietary exposure to flumethrin.
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EXPOSURE |
RELEVANT ROUTE, STUDY, TYPE, SPECIES |
RESULT, REMARKS |
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Short-term (1-7 days)
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Oral, toxicity, rat |
LD50 = 41-3800 mg/kg bw, depending on the vehicle |
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Dermal toxicity, rat |
LD50 > 2000 mg/kg bw |
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Inhalation toxicity, rat |
LC50 = 225 mg/m3 |
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Dermal irritation, rabbit |
Not irritating |
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Ocular irritation, rabbit |
Not irritating |
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Dermal sensitization, guinea pig |
Not sensitizing |
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Medium-term (1-26 weeks)
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Repeated oral, 15-week, toxicity, rat |
NOAEL = 0.7 mg/kg bw per day |
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Repeated oral, 13-week, toxicity, dog |
NOAEL = 0.88 mg/kg bw per day |
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Repeated oral, reproductive toxicity, rat |
NOAEL = 0.36 mg/kg bw per day, reduced body-weight gain of adults |
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Repeated oral, developmental toxicity, rat |
NOAEL = 1 mg/kg bw per day, developmental toxicity |
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Repeated oral, developmental toxicity, rabbit |
NOAEL = 1.7 mg/kg bw per day, maternal and developmental toxicity |
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Long-term (> one year) |
Repeated oral, two-year, toxicity and carcinogenicity, rat |
NOAEL = 0.5 mg/kg bw per day, skin lesions; no carcinogenicity |
RESIDUE AND ANALYTICAL ASPECTS
The Meeting reviewed extensive studies of metabolism in rats and cattle, information on GAP, methods of analysis, and the results of national monitoring. Data from supervised trials of ectoparasite control on cattle, sheep and goats and of the use of flumethrin in honey-bee colonies were evaluated.
Analysis for residues is usually by HPLC which can determine flumethrin per se and in some cases also the predominant metabolite flumethrin acid (BFN 5533A). The residue is defined as the parent compound for regulatory purposes and recommended MRLs for meat apply to the carcase fat.
Although no residues (<0.002 mg/kg) were detected in honey, low residues were found in beeswax. Recommended MRLs for the meat and milk of cattle and, at the limit of determination, for honey are recorded in Annex I, where STMR levels are also recorded for the estimation of dietary intake.
FURTHER WORK OR INFORMATION
Desirable
1. Information on the stability of flumethrin residues in stored analytical samples of liver and kidney in relation to the periods and conditions of storage of the samples from supervised trials.
2. Submission of data from new supervised trials on animals expected to be available in June 1996 (Webster et al., 1996).
3. Results of analyses of tissues and milk from additional supervised trials on cattle in which multiple, especially pour-on, applications have been made in accordance with approved uses.
4. Studies on the fate of flumethrin in the environment, especially its persistence and mobility in soil.
