Fenvalerate exhibits no effect on PP2B-Bβ [1].

Absorption, Distribution and Excretion
This study used high-performance liquid chromatography (HPLC) to determine the metabolism and bioaccumulation of the insecticide cypermethrin and its metabolites in the liver, kidney, and brain tissues of rats after oral administration of a sublethal dose (15 mg/kg) for 7, 15, and 30 days, respectively. The results showed that the cleavage of the ester bond of cypermethrin to generate two metabolites is the primary step in its biodegradation in rat organs. These metabolites were purified to homogeneity by HPLC and identified by infrared spectroscopy as 4-chloro-α-(1-methylethyl)phenylacetic acid and 3-phenoxybenzoic acid. The in vivo distribution kinetics of cypermethrin were investigated after applying 100 mL of 0.25% (w/v) cypermethrin solution to the skin of goats. The insecticide persisted in the blood for 72 hours. The mean (± standard error) volume of distribution (Vd) and apparent half-life (t1/2) were 9.92 ± 1.44 L/kg and 17.51 ± 2.65 h, respectively, while the area under the curve (AUC) and plasma concentration (ClB) were 82.15 ± 7.40 μg·h/mL and 0.56 ± 0.05 L/(kg·h), respectively. Four days after transdermal administration, the highest residual concentration of cypermethrin was observed in the adrenal glands, followed by the biceps brachii, greater omentum fat, liver, kidneys, lungs, and brain. Cypermethrin caused hyperglycemia but had no effect on serum protein and cholesterol levels. Serum acetylcholinesterase activity increased after 24 hours but fell below initial values after 48 to 120 hours. Absorption was poor in rabbit skin. Clearance from adipose tissue was slow, with a half-life of 7–10 days. Fenvalerate is rapidly cleared from the brain, with a half-life of 2 days, likely due to more efficient brain perfusion and the presence of esterases in brain tissue. For more complete data on the absorption, distribution, and excretion of fenvalerate (21 in total), please visit the HSDB record page. Metabolites/Metabolites: Fenvalerate is hydroxylated to 2'- or 4'-hydroxyphenoxy esters, and hydrolyzed to 3-phenoxybenzoic acid and its hydroxy derivatives (free and conjugated), 3-(4-chlorophenyl)-isovalerate and its hydroxy derivatives (free, lactone, and conjugated), thiocyanate, and carbon dioxide. The metabolism of fenvalerate in rats and mice has been studied using fenvalerates radiolabeled with the acidic moiety or benzyl or cyano groups. Except for cyano-labeled compounds, the administered radioactive material is readily eliminated (up to 99% within 6 days). The main metabolic reactions are ester bond cleavage and 4'-hydroxylation. Studies have shown that various oxidation and conjugation reactions also occur, generating complex mixtures of products. When cyano-labeled cypervalerate was used in studies, the clearance of the radioactive dose was slow (up to 81% within 6 days). The remaining radioactive material was primarily retained in the skin, hair, and stomach as thiocyanate. A minor but very important metabolic pathway is the formation of a lipophilic conjugate of (2R)-2-(4-chlorophenyl)isovalerate. This conjugate, associated with granuloma formation, has been detected in the adrenal glands, liver, and mesenteric lymph nodes of rats, mice, and several other species. Despite lacking a cyclopropane ring in its acid group, cypermethrin is rapidly metabolized in rats, similar to conventional pyrethroids, through ester bond cleavage and hydroxylation. Oral administration of (14)C-isfenvalerate or partially labeled (14)C-cypermethrin at doses of 2.5 and 10 mg/kg/day, respectively, resulted in generally higher levels of (14)C in maternal blood and placenta compared to fetal and amniotic fluid levels. These two compounds and their metabolites do not readily transfer from maternal blood to the fetus, with less than 0.07% of the dose transferred (14)C. There were no substantial differences in fetal (14)C levels and transfer rates ((14)C tissue level/(14)C maternal blood level) between the two labeled formulations. The major 14C compounds in fetal, maternal blood, and placenta were the maternal compound CPIA (2-(4-chlorophenyl)isovaleric acid) and its hydroxylated derivatives. The metabolic pathways of the two compounds showed no qualitative differences, but trace amounts of CPIA cholesterol ester (cholesterol(2R)-2-(4-chlorophenyl)isovalerate) were detected only in maternal blood and placenta after administration of cypermethrin. CPIA cholesterol ester does not appear to transfer from maternal blood to the fetus. Overall, efflorescentic acid and cypermethrin appear to behave similarly in terms of placental transport. For more complete data on the metabolism/metabolites of cypermethrin (23 in total), please visit the HSDB records page.
The known human metabolites of phellandrene include 4'-hydroxy-phellandrene ester and 2'-hydroxy-phellandrene ester.
After ingestion, pyrethroid insecticides are hydrolyzed in the gastrointestinal tract by various digestive enzymes. However, small amounts of insecticidal compounds or their derivatives are absorbed, as can be seen from their toxicity and effects on the liver. Pyrethroid insecticides can also be absorbed through inhalation or skin contact. They are rapidly distributed to most tissues, particularly those with high lipid content, and accumulate in central and peripheral nerve tissues. It is currently unclear whether pyrethroid insecticides or their metabolites are stored in the body or excreted in breast milk, but no studies have explored this using modern methods. The main metabolic pathways of pyrethroid insecticides involve the hydrolysis of the central ester bond, oxidative attack at multiple sites, and conjugation reactions, resulting in a complex series of water-soluble primary and secondary metabolites that are excreted in the urine. Metabolism is thought to involve nonspecific microsomal carboxylesterases and microsomal mixed-function oxidases, which are present in almost all tissue types, with particularly high activity in the liver. Metabolites are excreted in urine and feces. (L857, L889)

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Biological half-life
When carp (Cyprinus carpio) were exposed to ((14)C-CN)-(2S, αRS)-cypermethrin (0.8 μg/L) under semi-static conditions for 7 days, the radioactivity in the fish increased to 922 μg/kg. Once the fish were transferred to freshwater, the radioactivity level in the fish decreased, with an initial half-life of 5 days…. /(2S, αRS)-cypermethrin/
Elimination from body fat is slow, with a half-life of 7–10 days; elimination from the brain is less. The drug is metabolized slowly, with a half-life of 2 days (Marei et al., 1982), which may be due to more efficient brain perfusion and the presence of esterases in brain tissue. This study investigated the metabolism of ((14)C-chlorophenyl)- or ((14)C-phenoxybenzyl)-cyanopentate in dogs at a single oral dose of 1.7 mg/kg body weight, dissolved in corn oil and encapsulated in gelatin. Excrement and blood were collected daily for three consecutive days, and radioactivity was analyzed using liquid scintillation counting. …Compared to animals administered ((14)C-phenoxybenzyl)-cyanopentate, animals administered ((14)C-chlorophenyl)-cyanopentate showed higher total radioactivity recovery, with half-lives of 1 day and 0.7 days, respectively. …

Toxicity Summary
Both type I and type II pyrethroids exert their effects by prolonging the opening time of sodium ion channels during nerve cell excitation. They appear to bind to membrane lipids near sodium ion channels, thereby altering channel dynamics. This blocks the closing of sodium ion channels in the nerve, thus prolonging the time it takes for the membrane potential to return to its resting state. Repetitive (sensory, motor) neuronal firing and prolonged negative afterpotentials produce effects very similar to DDT, leading to nervous system hyperactivity, which may result in paralysis and/or death. Other mechanisms of action of pyrethroids include antagonism of γ-aminobutyric acid (GABA)-mediated inhibition, regulation of nicotinic cholinergic transmission, enhancement of norepinephrine release, and action on calcium ions. They also inhibit calcium ion channels and Ca2+,Mg2+-ATPase. (T10, T18, L857)

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Toxicity Data
LD50: 70.2 mg/kg (oral, rat) (T13)
LD50: 2500 mg/kg (dermal, rabbit) (T13)
LD50: 340 mg/kg (intraperitoneal, rat) (T92)
LD50: 65 mg/kg (intravenous, mouse) (T92)
LC50: >101 g/m3 (4 hours) (inhalation, rat) (T93)

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Interactions
The widely used insecticide cypermethrin was administered orally to goats at a dose of 15 mg/kg body weight daily for 270 days. Ninety days after administration, all animals (including the corresponding control group) were vaccinated with Brucella 19 strain vaccine. Fluorovalerate reduced humoral and cellular immune responses, as assessed by standard tube agglutination and delayed-type hypersensitivity tests. This study investigated whether daily diazepam at 3 mg/kg could alter neurobehavioral and neurochemical changes induced by perinatal exposure to Ambush and Pydrin. Seventy-two pregnant female rats were used as subjects. Starting from day 1 of gestation, half of the subjects received diazepam via subcutaneous osmotic pump, and the other half received excipients, for 33 days. Each group was further divided into six gavage treatment groups: corn oil, corn oil + 96% xylene, 1.25 or 0.125 mg/kg Pydrin, and 4.0 or 0.4 mg/kg Ambush. Half of the pups from each litter were used for behavioral assessment, and the other half for neurochemical analysis. Behavioral assessment included motor activity, screening tests, and passive avoidance learning. Brain tissue used for neurochemical analysis was extracted and sectioned, divided into the frontal cortex, caudate nucleus, hippocampus, and cerebellum. Neurochemical analysis examined levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), serotonin (5-HT), homovanillic acid (HVA), aspartic acid, glutamate, glutamine, glycine, γ-aminobutyric acid (GABA), and taurine. Diazepam treatment did produce some neurotoxicity in control pups, but diazepam exposure reversed the cerebellar amino acid elevations induced by pyrethroid pesticides. Furthermore, diazepam reversed the effects of pyrethroid pesticides on activity and muscle coordination in pups. These diazepam effects were not specific to type I or type II pyrethroids. This study investigated the behavioral and neurochemical toxicity of perinatal oral exposure to two pyrethroid formulations—ambush (type I) and pyridine (type II). Thirty-six female rats were exposed to various pyrethroid insecticides via gavage from the first day of gestation until 12 days of age (8 pups per litter). Six female rats received one of the following treatments daily: corn oil control group, corn oil + 96% xylene group, 1.25 mg/kg pyridine (insecticide: cypermethrin), 0.125 mg/kg pyridine, 4.0 mg/kg ambush (insecticide: permethrin), or 0.4 mg/kg ambush. Half of the pups in each litter (24 pups per group) were subjected to behavioral assessments of motor activity, muscle coordination, and passive avoidance learning. The remaining pups were euthanized, and brain tissue was extracted and sectioned, divided into frontal cortex, hippocampus, caudate nucleus, and cerebellum for neurochemical analysis. The levels of monoamine neurotransmitters DA, DOPAC, 5-HIAA, 5-HT, and HVA, as well as the levels of amino acids aspartate, glutamate, glutamine, glycine, GABA, and taurine, were measured in various brain regions. High-dose Pydrin and Ambush treatment shortened gestation time, but only the 4.0 mg/kg Ambush group showed a significant reduction in pups' body weight. No physical deformities were observed in pups across all treatment groups, but the mortality rate in the high-dose Pydrin treatment group was 4%. Behavioral changes were observed in both motor activity and muscle coordination. The cross-stage motor habituation curves differed among the xylene, corn oil, and high-dose Ambush groups. Compared to other pups, these two groups had lower activity levels on day 1 and higher activity levels on days 2 and 3. High-dose Ambush and Pydrin resulted in a slower rate of habituation within each group. Muscle coordination was slightly improved after low-dose exposure to both pesticides, but decreased after high-dose exposure. Brain regions of the cortex, cerebellum, and caudate nucleus had normal weights, but hippocampal weight increased by 64% in juvenile rats treated with 4.0 mg/kg Ambush. Amino acid assays showed that the cerebellum was most affected; exposure to xylene or pyrethroids decreased the levels of glutamate, glutamine, aspartate, and taurine in the cerebellum. Pyrethroid exposure also decreased the levels of the biogenic amine neurotransmitter serotonin (5-HT) in multiple brain regions. These data suggest that even concentrations as low as LD50/10,000 of Ambush and Pydrin can alter behavior and neurotransmitter function.
In male Wistar rats, the activities of tryptophan-2,3-dioxygenase, indoleamine-2,3-dioxygenase, kynurenine, kynurenase, kynurenine transaminase, and pyridoxal phosphokinase were measured in the liver, kidneys, and lungs after single or multiple oral administrations of dimethyl sulfide, carbaryl, and cypermethrin. In single-dose trials, the dose of each insecticide was 10% of the median lethal dose (LD50); in repeated-dose trials, the dose administered orally for 5 consecutive days was 5% of the LD50. Weight and organ loss was observed only after repeated oral administration of dimethyl sulfide. Repeated administration of dimethyl sulfide significantly reduced the activities of kynurenine-3-hydroxylase, kynurenine-2-ketoglutarate transaminase, kynurenine-pyruvate transaminase, and pyridoxal phosphokinase. Repeated administration of carbaryl resulted in a significant reduction in the activities of apotryptophan-2,3-dioxygenase, kynurenine-2-ketoglutarate transaminase, kynurenine-pyruvate transaminase, and serine-glyoxylate transaminase. Adding different concentrations of insecticide to the incubation mixture inhibited tryptophan-2,3-dioxygenase activity. The activities of other enzymes remained unchanged after this treatment.
For more complete data on interactions of fenvalerate (14 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 451 mg/kg
Dermal LD50 in rats: > 5000 mg/kg
Oral LD50 in rats: 3200 mg/kg (industrial grade pyridine suspension)
Oral LD50 in rats: 1-3 g/kg (industrial grade)
For more complete non-human toxicity data on fenvalerate esters (29 in total), please visit the HSDB record page.

[1]. Specific Inhibition of Calcineurin by Type II Synthetic Pyrethroid Insecticides. Biochem Pharmacol. 1992 Apr 15;43(8):1777-84.

[2]. Regulation of Organelle Movement in Melanophores by Protein Kinase A (PKA), Protein Kinase C (PKC), and Protein Phosphatase 2A (PP2A). J Cell Biol. 1998 Aug 10;142(3):803-13.

Therapeutic Uses

Medication (Veterinary): External Parasite Killer
/Veterinary Use:/ Lice control requires the use of effective insecticides or drugs… Some compounds can be used as systemic sprays for lice control. Some formulations are effective with only a small amount of spray, while others may require saturation through the hair to the skin. …Cypermethrin can be sprayed on pigs and sheep. Low-volume cypermethrin sprays are approved for use in sheep and non-lactating goats. …Cypermethrin drops are approved for lice control in pigs, sheep, and non-lactating goats.

C25H22CLNO3

419.905

419.128

51630-58-1

Fenvalerate-d5;1246815-00-8;Fenvalerate-d6;82523-66-8

3347

Off-white to light yellow solid powder

1.2±0.1 g/cm3

538.9±50.0 °C at 760 mmHg

39.5 - 53.7 °C

279.7±30.1 °C

0.0±1.4 mmHg at 25°C

1.586

6.68

0

4

8

30

586

0

NYPJDWWKZLNGGM-UHFFFAOYSA-N

InChI=1S/C25H22ClNO3/c1-17(2)24(18-11-13-20(26)14-12-18)25(28)30-23(16-27)19-7-6-10-22(15-19)29-21-8-4-3-5-9-21/h3-15,17,23-24H,1-2H3

[cyano-(3-phenoxyphenyl)methyl] 2-(4-chlorophenyl)-3-methylbutanoate

Evercide 2362; Fenvalerate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~238.15 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)