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Activity: Acaricide, Insecticide (pyrethroid)
Structure:

Adverse Effects:
Ataxia
Body Weight Decrease
Bone
Clastogenic / Genotoxicity
Dermal
Liver
Spleen
Environmental

Ataxia (click on for all fluorinated pesticides)

-- Groups of 28 mated female rats received doses of 0, 0.5, 1.0 r 2.0 mg/kg bw per day orally by gavage from days 6 to 15 of gestation. The test substance was administered in a vehicle of 2% aqueous Emulphor. Signs of toxicity (hypoactivity, ptosis, ataxia and salivation) were observed in the dams given 1.0 and 2.0 mg/bw day. Body weight and food consumption were significantllly reduced in the 2.0 mg/kg bw group. The incidence of foetal delayed ossification was significantly increased in the 2.0 mg/kg bw group... The NOELs were 0.5 mg/kg bw per day for maternal toxicity and 1.0 mg/kg bw per day for foetotoxicity.
-- Neurotoxicity was evaluated in the inclined plane test with flumethrin administered as a single dose in Cremophor:water (2%) or corn oil/milk emulsions. The NOELs were 0.3 mg/kg bw and 1.0 mg/kg bw for the Cremophor and milk formulations respectively. Statisticlaly significant effects were found following dosing with 5 mg/kg bw in either vehicle. No positive control group was included and the sensitivity of the study is uncertain.
Ref: Committee for Veterinary Medicinal Products. Flumethrin. Summary Report (1). June 1998. EMEA/MRL/469/98-FINAL. The European Agency for the Evaluation of Medicinal Products.
http://www.fluorideaction.org/pesticides/flumethrin.eu.june.1998.pdf

Body Weight Decrease (click on for all fluorinated pesticides)

Groups of 15/sex/dose Wistar rats were fed diets containing 0, 10, 50 or 250/150 mg/kg feed for 13 weeks. The test substance was a 50% premix with colloidal SiO2 carrier. Due to severe weight loss the dose level of 250 mg/kg feed was reduced to 150 mg/kg feed during week 3. Body weight gain was significantly reduced in the rats given 150 mg/kg feed compared with the controls. Skin lesions, described as ulcerative dermatitis, were observed in the 50 and 150 mg/kg feed groups and were dose-related in severity. The NOEL was 10 mg/kg feed, equivalent to 0.7/0.8 mg/kg bw per day...
-- IN GLP repeated-dose toxicity study, groups of 20/sex/dose Wistar rats were fed diets containing 0, 10, 40 or 160 mg/kg feed flumethrin for up to 15 weeks. During mixing of the diets, 1% peanut oil was added to minimise dust formation. At 160 mg/kg feed, body weight gain was significantly reduced...
-- Groups of 4/sex/dose Beagle dogs were fed diets containing 0, 50, 100 or 200 mg/kg feed flumethrin for 13 weeks. The test substance was a 45.3% premix with colloidal SiO2 carrier. Skin lesions and emesis were observed in the groups receiving 50 mg/kg feed and above and were dose-related in incidence and severity. Over the 13 weeks, the mean body weight of males given 200 mg/kg feed was decreased and females in this group gained less weight than the controls...
-- In a 2-generation reproduction study in rats with 2 litters per generation, flumethrin was administered in the diet at concentrations of 0, 1, 5 or 50 mg/kg feed. The test substance was a 45.6% premix with colloidal SiO2 carrier. Food consumption and body weight gain were reduced in parental animals of the P and F1 generations... In the 50 mg/kg feed group, pup viability on days 1 to 4 post-partum and pup body weights were depressed and signs of pyrethroid-poisoning were observed in the pubs of the F1a and F 1b litters. The NOEL was 5 mg/kg feed, equivalent to 0.36 and 0.40 mg/kg bw per day, in males and females respectively...
-- Groups of 28 mated female rats received doses of 0, 0.5, 1.0 r 2.0 mg/kg bw per day orally by gavage from days 6 to 15 of gestation. The test substance was administered in a vehicle of 2% aqueous Emulphor. Signs of toxicity (hypoactivity, ptosis, ataxia and salivation) were observed in the dams given 1.0 and 2.0 mg/bw day. Body weight and food consumption were significantllly reduced in the 2.0 mg/kg bw group. The incidence of foetal delayed ossification was significantly increased in the 2.0 mg/kg bw group... The NOELs were 0.5 mg/kg bw per day for maternal toxicity and 1.0 mg/kg bw per day for foetotoxicity.
Ref: Committee for Veterinary Medicinal Products. Flumethrin. Summary Report (1). June 1998. EMEA/MRL/469/98-FINAL. The European Agency for the Evaluation of Medicinal Products.
http://www.fluorideaction.org/pesticides/flumethrin.eu.june.1998.pdf

Bone (click on for all fluorinated pesticides)

Studies conducted with flumethrin in mice showed induction of chromosomal aberrations in bone marrow cells after a single dermal application of 5,325 mg/kg to a shaved area or a single intraperitoneal injection of 2,083 mg/kg, but not after repeated intraperitoneal injections of 128 mg/kg (Nakano et al. 1996). In contrast, micronuclei frequency was not significantly elevated after a single dermal dose of 5,325 mg/kg, but was increased after repeated intraperitoneal doses of 128 mg/kg (Nakano et al. 1996). (P 61)
Ref: September 2001. Draft Toxicological Profile for Pyrethrins and Pyrethroids. US Department of Health and Human Services. Public Health Service Agency for Toxic Substances and Disease Registry.

-- Groups of 28 mated female rats received doses of 0, 0.5, 1.0 r 2.0 mg/kg bw per day orally by gavage from days 6 to 15 of gestation. The test substance was administered in a vehicle of 2% aqueous Emulphor. Signs of toxicity (hypoactivity, ptosis, ataxia and salivation) were observed in the dams given 1.0 and 2.0 mg/bw day. Body weight and food consumption were significantllly reduced in the 2.0 mg/kg bw group. The incidence of foetal delayed ossification was significantly increased in the 2.0 mg/kg bw group... The NOELs were 0.5 mg/kg bw per day for maternal toxicity and 1.0 mg/kg bw per day for foetotoxicity.
Ref: Committee for Veterinary Medicinal Products. Flumethrin. Summary Report (1). June 1998. EMEA/MRL/469/98-FINAL. The European Agency for the Evaluation of Medicinal Products.
http://www.fluorideaction.org/pesticides/flumethrin.eu.june.1998.pdf

Abstract: The genotoxic potential of the pyrethroid flumethrin was evaluated by using the combined protocol of metaphase analysis and micronucleus test in vivo in mouse bone marrow. The dermal route was tested in a single treatment and the intraperitoneal (i.p.) route in a single and a multiple treatment. Flumethrin showed a cytotoxic effect on both myelopoiesis and erythropoiesis, as evidenced by a reduction in the mitotic index and in polychromatic erythrocyte values. An increase in the frequency of gaps after the dermal exposure and of breaks only at the highest dose tested in the i.p. treatment indicates a weak clastogenic potential of the compound. A significant increase in the frequency of micronucleated polychromatic erythrocytes was observed after single and multiple i.p. treatments. In the latter, the induction of micronuclei was highly significant but not accompanied by an increase in breaks. This may indicate that the clastogenic effect might not account by itself for the induction of micronuclei, which could also have arisen from an aneugenic potential of flumethrin.
Ref: Nakano E et al. (1996). Evaluation of the Genotoxic Potential of Flumethrin in Mouse Bone Marrow by Chromosomal Analysis and Micronucleus Test. Teratogenesis, Carcinogenesis, and Mutagenesis, Vol. 16, No. 1, pages 37-48.

Clastogenic / Genotoxicity (click on for all fluorinated pesticides)

Abstract: The genotoxic potential of the pyrethroid flumethrin was evaluated by using the combined protocol of metaphase analysis and micronucleus test in vivo in mouse bone marrow. The dermal route was tested in a single treatment and the intraperitoneal (i.p.) route in a single and a multiple treatment. Flumethrin showed a cytotoxic effect on both myelopoiesis and erythropoiesis, as evidenced by a reduction in the mitotic index and in polychromatic erythrocyte values. An increase in the frequency of gaps after the dermal exposure and of breaks only at the highest dose tested in the i.p. treatment indicates a weak clastogenic potential of the compound. A significant increase in the frequency of micronucleated polychromatic erythrocytes was observed after single and multiple i.p. treatments. In the latter, the induction of micronuclei was highly significant but not accompanied by an increase in breaks. This may indicate that the clastogenic effect might not account by itself for the induction of micronuclei, which could also have arisen from an aneugenic potential of flumethrin.
Ref: Nakano E et al. (1996). Evaluation of the Genotoxic Potential of Flumethrin in Mouse Bone Marrow by Chromosomal Analysis and Micronucleus Test. Teratogenesis, Carcinogenesis, and Mutagenesis, Vol. 16, No. 1, pages 37-48.

The above paper was abstracted in Food and Chemical Toxicology, Volume 34, Issue 10, October 1996, Page 1021 : Flumethrin genotoxicity. Flumethrin, a synthetic pyrethroid insecticide, tested as the technical product Bayticol 60%, induced chromosomal damage in the bone marrow cells when administered to mice by intraperitoneal injection (Nakano et al., Teratogenesis, Carcinogenesis and Mutagenesis 1996, 16, 37).

Dermal (click on for all fluorinated pesticides)

A single case report was located in which a 47-year-old farmer developed a hypersensitive response that included a widespread dermal rash after dipping sheep in a solution, the active component of which was flumethrin (Box and Lee 1996). The relative contributions of dermal and inhalation exposure were not indicated in the report.
Ref: DRAFT TOXICOLOGICAL PROFILE FOR PYRETHRINS AND PYRETHROIDS. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Public Health Service Agency for Toxic Substances and Disease Registry. September 2001.
http://www.atsdr.cdc.gov/toxprofiles/tp155.pdf

-- Groups of 15/sex/dose Wistar rats were fed diets containing 0, 10, 50 or 250/150 mg/kg feed for 13 weeks. The test substance was a 50% premix with colloidal SiO2 carrier... Skin lesions, described as ulcerative dermatitis, were observed in the 50 and 150 mg/kg feed groups and were dose-related in severity. The NOEL was 10 mg/kg feed, equivalent to 0.7/0.8 mg/kg bw per day...
-- IN GLP repeated-dose toxicity study, groups of 20/sex/dose Wistar rats were fed diets containing 0, 10, 40 or 160 mg/kg feed flumethrin for up to 15 weeks. During mixing of the diets, 1% peanut oil was added to minimise dust formation. At 160 mg/kg feed, body weight gain was significantly reduced. Sever skin lesions were observed in the 160 mg/kg feed group. Some mild skin lesions were also observed in the 40 mg/kg feed group. Decreased red cell values and increased leucocyte counts in the 160 mg/kg feed group were probably associated with the skin lesions. At termination, histopathological examination revealed ulcerative skin lesions in all rats given 160 mg/kg feed and some rats from the 40 mg/kg feed group. Increased extramedullary haematopoiesis and reduced haemosiderin storage in the spleen were also observed in the 160 mg/kg feed group. The NOEL was 10 mg/kg feed, equivalent to 0.7/0.8 mg/kg bw per day in males/females respectively.
-- Groups of 4/sex/dose Beagle dogs were fed diets containing 0, 50, 100 or 200 mg/kg feed flumethrin for 13 weeks. The test substance was a 45.3% premix with colloidal SiO2 carrier. Skin lesions and emesis were observed in the groups receiving 50 mg/kg feed and above and were dose-related in incidence and severity. Over the 13 weeks, the mean body weight of males given 200 mg/kg feed was decreased and females in this group gained less weight than the controls... Blood urea nitrogen (BUN) concentrations were significantly increased in dogs given 200 mg/kg feed and slightly increased in dogs given 100 mg/kg feed. At termination, treatment-related skin lesions were observed in all treated groups; the epithelial layer of the epidermis was thickened and covered with hyperkeratotic material in places. In 2 dogs given 200 mg/kg feed, the epidermis was ulcerated. No NOEL was established in this study.
Ref: Committee for Veterinary Medicinal Products. Flumethrin. Summary Report (1). June 1998. EMEA/MRL/469/98-FINAL. The European Agency for the Evaluation of Medicinal Products.
http://www.fluorideaction.org/pesticides/flumethrin.eu.june.1998.pdf

Liver (click on for all fluorinated pesticides)

Abstract: The effects of repeated exposure to the pyrethroid insecticide flumethrin (40 mg/kg intraperitoneally once a day for 6 days) on the activity of cytochrome P450-dependent monooxygenases and UDP-glucuronosyltransferase as well as on antipyrine disposition were investigated in male Wistar rats. Pretreatment with flumethrin decreased the activities of NADPH-cytochrome c reductase (38%), aniline hydroxylase (53%), aminopyrine N-demethylase (54%), and UDP-glucuronosyltransferase (34%), and the content of cytochrome P450 (36%) in hepatic microsomes. Total plasma clearance of antipyrine was decreased by flumethrin pretreatment (54%), while the elimination half-life at beta phase and the mean residence time of antipyrine were increased (96 and 88%, respectively). Urinary excretion of norantipyrine, 4-hydroxyantipyrine, and 3-hydroxymethylantipyrine was decreased by 60, 38, and 33%, respectively, in the 96 hr after flumethrin treatment. In addition, the rate constants for formation of each of these metabolites were decreased by an average of approximately 74%. These findings provide evidence that flumethrin exposure diminishes hepatic enzyme levels and catalytic activities of monooxygenase systems as well as oxidative metabolism of antipyrine.
Ref: Effects of flumethrin on hepatic drug-metabolizing enzymes and antipyrine disposition in rats; by A Anadon et al. Toxicol Appl Pharmacol 1995 May;132(1):14-8.

Spleen (click on for all fluorinated pesticides)

-- IN GLP repeated-dose toxicity study, groups of 20/sex/dose Wistar rats were fed diets containing 0, 10, 40 or 160 mg/kg feed flumethrin for up to 15 weeks. During mixing of the diets, 1% peanut oil was added to minimise dust formation. At 160 mg/kg feed, body weight gain was significantly reduced. Sever skin lesions were observed in the 160 mg/kg feed group. Some mild skin lesions were also observed in the 40 mg/kg feed group. Decreased red cell values and increased leucocyte counts in the 160 mg/kg feed group were probably associated with the skin lesions. At termination, histopathological examination revealed ulcerative skin lesions in all rats given 160 mg/kg feed and some rats from the 40 mg/kg feed group. Increased extramedullary haematopoiesis and reduced haemosiderin storage in the spleen were also observed in the 160 mg/kg feed group. The NOEL was 10 mg/kg feed, equivalent to 0.7/0.8 mg/kg bw per day in males/females respectively..
Ref: Committee for Veterinary Medicinal Products. Flumethrin. Summary Report (1). June 1998. EMEA/MRL/469/98-FINAL. The European Agency for the Evaluation of Medicinal Products.
http://www.fluorideaction.org/pesticides/flumethrin.eu.june.1998.pdf