Absorption, Distribution and Excretion
Poor skin absorption. Permethrin is rapidly metabolized into inactive metabolites via ester hydrolysis, primarily excreted in urine. Lactating dairy cows (three cows per group) were fed permethrin at doses of 0, 0.2, 1.0, 10, and 50 mg/kg for 28 days without mortality; growth and milk production were normal. In the two highest dose groups, permethrin residues were detectable in milk within 3 days; its levels appeared to plateau rapidly and no longer increase over time. Analysis of the cis and trans isomers indicated that the proportion of permethrin isomers in milk appeared to change during the study, with the cis isomer being dominant. Permethrin residues were not detected in animal tissues at doses of 1 mg/kg or lower. Residues were detected in tissues at doses of 10 or 50 mg/kg, primarily in adipose tissue. Low concentrations of residues were also detected in muscle and kidneys at the highest dose levels. Permethrin did not appear to accumulate in adipose tissue, but rather rapidly reached a plateau. (14)C-cis-permethrin was dissolved in 0.1 mL of acetone at a dose of 1 mg/kg body weight and applied to the shaved skin of mice. Mice were fixed until the solvent evaporated and then placed in metabolic cages. Mice were sacrificed at 1, 5, 15, 50, 480, and 2880 minutes after administration, and the absorption, distribution, and excretion of the insecticide were assessed. Approximately 40% of permethrin was transferred from the application site within 5 minutes after administration and rapidly spread to other parts of the body. When (14)C-trans or (14)C-cis-permethrin (labeled on the acid or alcohol fraction, respectively) was administered orally 0.2-0.3 mg/kg body weight/day for 10 consecutive times, 72-79% of the trans isomer dose and 25-36% of the cis isomer dose were excreted in the urine of lactating goats, and 12-15% of the trans and cis isomer doses were excreted in the feces, respectively. The radiocarbon content detected in the milk of any of the four (14)C-labeled preparations was less than 0.7%. In the tissue residues 24 hours after the last administration, radiocarbon was detected in most tissues, but the trans isomer content did not exceed 0.04 mg/kg and the cis isomer content did not exceed 0.25 mg/kg.
Two volunteers who received approximately 2 mg and 4 mg of permethrin (25:75), respectively, excreted 18-37% and 32-39% of the administered dose, respectively, after urine collection and acid hydrolysis within 24 hours. These doses were detected as the metabolite Cl2CA.
For more complete data on the absorption, distribution, and excretion of permethrin (37 in total), please visit the HSDB record page.
Metabolism/Metabolites

Rapidly metabolized to inactive metabolites via ester hydrolysis, primarily excreted in the urine.
When four (14)C-preparations of (IRS)-trans, (IR)-trans, (IRS)-cis, and (IR)-cis permethrin, labeled with the alcohol and acid moieties, respectively, were orally administered to male rats at doses of 1.6-4.8 mg/kg, these compounds were rapidly metabolized, with the ¹⁴C-labeled acid and alcohol moieties being almost completely cleared from the body within a few days. The main metabolic reactions of the two isomers of permethrin (trans and cis) are: oxidation of the trans and cis portions of the dimethyl group in the acid moiety and the 2'- and 4'- positions of the alcohol moiety; ester bond cleavage; and the combination of the resulting carboxylic acid, alcohol, and phenol with glucuronic acid, glycine, and sulfuric acid. The cis isomer is more stable than the trans isomer. The cis isomer produces four fecal ester metabolites, which are generated by hydroxylation reactions at the 2' and 4' positions of the phenoxy group, the trans methyl group, and the latter two positions, respectively. Metabolites with ester bond cleavage are excreted in large quantities in the urine, while metabolites with ester bond retention are only present in the feces. There is no significant difference in metabolism between the (IRS)-isomer and the (IR)-isomer. When white Leghorn chickens were orally administered one of the four (14)C-trans and cis-permethrin isomers (soluble in alcohol or acid, at a dose of 10 mg/kg body weight) for three consecutive days, no symptoms of poisoning were observed. Nine days after the first dose, over 87% of the radiocarbon from the four labeled formulations was present in excrement, with 0.7% to 4.7% of the dose exhaled as CO2, and 0.12% to 0.47% and 0.06% to 0.66% of the radiocarbon recovered in egg yolk and fat (subcutaneous and visceral fat), respectively. The recovery rates of the cis isomers labeled in the alcohol and acid fractions in fat and egg yolk were 3 to 10 times higher than those of the corresponding trans isomers. The content of cis-permethrin in excrement (0–72 hours) was 1.7 times that of trans-permethrin. Hydroxylated ester metabolites of trans-permethrin were not excreted, but four monohydroxy and dihydroxy esters of cis-permethrin (i.e., trans-hydroxypermethrin, 4'-hydroxypermethrin, 4'-hydroxy, trans-hydroxypermethrin, and trans-hydroxypermethrin sulfate) were detected. The metabolites of the acidic moieties of both isomers are Cl₂CA isomers, including free, glucuronide-bound, and taurine-bound forms, specifically trans-hydroxy-Cl₂CA, cis-hydroxy-Cl₂CA, cis-hydroxy-Cl₂CA lactone, and cis-hydroxy-Cl₂CA sulfate. The cis isomer produces a higher content of trans-hydroxy-Cl₂CA than the trans isomer, while the trans isomer produces a higher content of cis-hydroxy-Cl₂CA than the cis isomer. Alcohol metabolites include PBacid, PBacid, and their 4'-hydroxy derivatives and corresponding sulfates (glucuronides of PBacid), as well as several unidentified 4'-OH-PBalc and 4'-OH-PBacid conjugates. Taurine conjugates of PBacid were not detected. The most abundant metabolites were unidentified conjugates of 4'-OH-PBalc (6-13% of dose) and 4'-OH-PBacid (2-11% of dose). Five and six days after the first administration, the content of cis-permethrin in egg yolk was 4.4 times that of trans-permethrin (in unmetabolized form), and it contained the same cis-permethrin ester metabolites as in feces. Other metabolites in egg yolk were essentially the same as those in feces. Overall, the content of cis-permethrin in egg yolk, adipose tissue, and excrement was higher than that of trans-permethrin. The radiocarbon residue time in blood from cis-permethrin formulations was also longer than that from trans-permethrin formulations. Based on the relative content of the two isomer hydrolysis products in chicken feces, this may be due to the faster ester bond breakage rate of the trans isomer compared to the cis isomer. Two volunteers ingested approximately 2 mg and 4 mg of permethrin, respectively (25:75). After collecting urine samples within 24 hours and performing acid hydrolysis, the levels of the metabolite Cl2CA in their urine were detected to be 18-37% and 32-39% of the ingested dose, respectively. In goats, the metabolites of permethrin are formed through ester bond cleavage, hydroxylation of gem-dimethyl cis- or trans-methyl groups, and hydroxylation at the 4' position of phenoxybenzyl. Some metabolites are further oxidized and/or conjugated with glycine, glutamic acid, and glucuronic acid. The main compounds found in feces after administration of cis-permethrin were the unmetabolized parent compound 4'-OH-permethrin, trans-OH-permethrin, PBalc, cis-OH-cis-Cl2CA-lactone, and eight unidentified ester metabolites. Goat feces treated with the trans isomer contained high levels of the parent compound (41-79% of fecal 14C), PBalc (8-25%), and cis-OH-trans-Cl2CA-lactone. Additionally, three unidentified ester metabolites were found (8-23%). On the other hand, the major urinary metabolites of the alcohol moiety of both isomers were PBacid-glycine (7-9% of urinary 14C) and r'-OH-PBacid-glycine (4-12%). PBalc, PBacid, 4'-OH-PBalc, 4'-OH-PBacid, PBacid-glutamic acid, and 4'-OH-PBacid-glutamic acid were also identified as minor metabolites. The major component of goat urine treated with both isomers was the free form of Cl2CA (2-4% of urinary 14C). Metabolites detected in urine included C-14 and glucuronide (27-71%). The trans isomer produced a higher concentration of Cl2CA-glucuronide than the cis isomer. Other major metabolites of the cis isomer were cis-OH-Cl2CA (33%) (9-11%) and cis-OH-cis-Cl2CA-lactone (11-16%). Trans-OH-Cl2CA was a minor metabolite for both isomers. Goat milk contained the parent compounds PBacid-glycine and 4'-OH-PBacid-glycine. More of the parent compounds were excreted in milk after administration of the cis isomer compared to the trans isomer. Conversely, the PBacid-glycine content detected in milk was higher after administration of the trans isomer than after administration of the cis isomer. Most of the radioactivity in the fat was attributed to parent compounds or ester metabolites, such as trans-hydroxy-permethrin and trans-hydroxy-permethrin conjugates. For more complete data on the metabolism/metabolites of permethrin (25 in total), please visit the HSDB record page. The proposed metabolic pathways for cis and trans-permethrin are as follows. The five major metabolic sites of the two permethrin isomers are ester bond cleavage, cis and trans-methyl oxidation of the acid moiety (gem-dimethyl group), and oxidation at the 2' and 4' positions of the phenoxy group. The resulting carboxylic acids, alcohols, and phenols are associated with varying degrees of glucuronic acid, glycine, and sulfuric acid. Cis-permethrin is more stable than trans-permethrin. The cis isomer produces four fecal ester metabolites resulting from hydroxylation. Ester bond cleavage occurs at the 2' or 4' position of the phenoxy group, or at the trans or cis methyl group on the cyclopropane ring. Metabolites with ester bond cleavage are primarily excreted in urine, while metabolites with retained ester bonds are found only in feces. The major metabolites of the two isomer acid moieties are chlorobenzoic acid (Cl2CA) in its free (1-8%) and glucuronide (14-42%) forms. Other important metabolites include trans-hydroxychlorobenzoic acid (trans-OH-Cl2CA, 1-5%) and cis-hydroxychlorobenzoic acid (cis-OH-Cl2CA) in their free (3-5%), lactone (0-4%), and glucuronide (1-2%) forms. On the other hand, the alcohol moieties released after the ester bonds of the two isomers are mainly converted to sulfate of 3-(4'-hydroxyphenoxy)benzoic acid (4'-OH-PBacid) (29-43% by dose) and benzoic acid (PBacid). The free (1-10%) and glucuronide (7-15%) forms are its metabolites. Other important metabolites of the alcohol moiety include PBalic, PBacid-glycine, and sulfate of 3-(2'-hydroxyphenoxy)benzoic acid (2'-OH-PBacid). Studies by Nakamura et al. have shown that after hydrolysis by carboxylesterase (CES), the resulting PBalic is oxidized to PBalic, which is further oxidized to PBalic by the P450 system in rat liver microsomes. (A559, A256)
Elimination pathway: Permethrin is rapidly metabolized into inactive metabolites via ester hydrolysis, primarily excreted in the urine.

---

Biological half-life
The toxicokinetics after a single oral dose of 460 mg/kg and an intravenous injection of 46 mg/kg permethrin are as follows: This study used male Sprague-Dawley rats. A series of blood samples were collected after oral and intravenous administration, and brain, medulla oblongata, sciatic nerve, and liver samples were collected after oral administration. The concentrations of permethrin and its metabolites m-phenoxybenzyl alcohol and m-phenoxybenzoic acid in plasma, hypothalamus, cerebellum, frontal cortex, caudate nucleus-putamen, hippocampus, medulla oblongata, sciatic nerve, and liver were determined by high-performance liquid chromatography (HPLC). The plasma concentration curves of permethrin were adequately described using a two-compartment open model. After intravenous administration, the elimination half-life (t_1/2β) and mean plasma residence time of permethrin were 8.67 h and 11.19 h, respectively; after oral administration, they were 12.37 h and 17.77 h, respectively. Total plasma clearance was not affected by dose concentration or route of administration and reached a certain value. After a single oral administration, permethrin absorption was slow, with a peak time (Tmax) of 3.52 h. The peak plasma concentration was 49.46 μg/mL. The oral bioavailability of permethrin was 60.69%. Following oral administration of permethrin, the plasma concentration-time data for its metabolites, as well as the tissue concentration-time data for permethrin and its metabolites, conformed to a one-compartment open model. The elimination half-life (t1/2el) of permethrin in the hippocampus, medulla oblongata, frontal cortex, and sciatic nerve were 23.10, 22.36, 13.86, and 16.27 hours, respectively, all longer than that in plasma (t1/2β, 12.37 hours). The maximum concentration of permethrin in the cerebellum, hippocampus, and caudate nucleus was 0.058 L/h, ... The concentrations of pyrethroids in the putamen, frontal cortex, hypothalamus, and sciatic nerve were approximately 1.5 times, 2 times, 2 times, 2.7 times, 4.8 times, and 7.5 times higher than in plasma, respectively, indicating the accumulation of pyrethroids in neural tissues. The area under the curve (AUC) for tissue/plasma concentrations (1.16, 3.71, 1.57, 4.27, 3.48, and 8.77, respectively) also reflected the accumulation of permethrin in nerve tissue. Within 48 hours of administration, the metabolites m-phenoxybenzyl alcohol and m-phenoxybenzoic acid of permethrin were detected in plasma and all selected tissues, indicating that both tissue metabolism and hematogenous diffusion into tissues are possible pathways. Studies have shown that the half-lives of (+)-trans- and (+)-cis-permethrin applied to the leaf surface of legumes are 7 hours and 7 hours, respectively, lasting for 9 days.

Toxicity Summary
Pyrethroid insecticides work 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 overactivity, which may result in paralysis and/or death. Other mechanisms of action of pyrethroid insecticides include antagonizing GABA-mediated inhibition, modulating nicotinic cholinergic transmission, enhancing norepinephrine release, and acting on calcium ions. (T18, L857)

---

Effects during pregnancy and lactation
◉ Overview of use during lactation
Because the absorption rate after topical application is less than 2%, and it is rapidly metabolized into inactive metabolites, it can be safely applied directly to the infant's skin. Therefore, breastfeeding women can safely use topical permethrin products. However, if there is extensive exposure due to agricultural use or malaria prevention, there may be long-term health risks, as residues may be present in breast milk. Only water-soluble creams, gels, or liquid products should be applied to the breasts, as ointments may expose the infant to high concentrations of mineral paraffin through licking.
◉ Effects on breastfed infants
In a telephone follow-up study, five mothers who used permethrin while breastfeeding reported no adverse reactions in their breastfed infants.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

---

Toxicity Data
LC50 (Rat) = 485 mg/m3
Oral, Rat LD50: 430 - 4000 mg/kg
Dermal, Rabbit LD50: 2000 mg/kg
LD50: 3801 mg/kg (Oral, Rat) (L857)

---

Interactions
This study investigated the effects of pyrethroids on the breakdown of phosphatidylinositol in the synaptosome of guinea pigs. Similar to other drugs that activate voltage-dependent sodium channels, both type I and type II pyrethroids stimulate the breakdown of phosphatidylinositol. Type II pyrethroids (such as deltamethrin and cypermethrin) are more potent, and at least deltamethrin is more effective than type I pyrethroids (such as allethrin, permethrin, and cypermethrin). The sodium channel blocker tetrodotoxin partially inhibits the effects of type II pyrethroids.
5 μM tetrodotoxin had no effect on the effects of allethrin and permethrin. The stimulatory effect of cypermethrin on phosphatidylinositol degradation showed an additive effect with the stimulatory effects of the receptor agonists carbachol and norepinephrine, but no additive effect with the stimulatory effects of sodium channel blockers (drug poison frog toxin, scorpion venom, and pumilatoxin B). The stimulatory effect of allethrin showed no additive effect with the stimulatory effects of either receptor agonists or sodium channel blockers. Submaximal concentrations of allethrin (a type I pyrethroid) had little effect on the dose-dependent stimulatory effect of type II pyrethroids (deltamethrin), while higher concentrations of allethrin inhibited the further stimulatory effect of type II pyrethroids. The local anesthetic debucaine inhibited sodium channel activation and thus inhibited type II pyrethroid-induced phosphatidylinositol degradation, but had no inhibitory effect on type I pyrethroid-induced phosphatidylinositol degradation unless the concentration was high. Therefore, type II pyrethroids appear to stimulate the breakdown of phosphatidylinositol in the synaptosome in a manner similar to other sodium channel inhibitors, while type I pyrethroids induce phosphatidylinositol breakdown through a different mechanism that may not involve sodium channels. The detoxification effect of pyrethroids…is important in fruit flies, but the addition of synergists (such as organophosphates or carbamates) may delay this process to ensure lethality. … Synergist ethers enhance the insecticidal activity of pyrethroids by inhibiting the hydrolytic enzymes responsible for pyrethroid metabolism in arthropods. When piperine butyl ether is used in combination with pyrethroids, the latter's insecticidal activity can be increased by 2–12 times. /Pyrethroids/
When 1000 ppm pyrethroids and 10000 ppm piperine butyl ether are added to the feed…/enlargement, marginalization, and cytoplasmic inclusions in rat hepatocytes/are noticeable within just 8 days, but…they do not reach their maximum extent. These changes are dose-proportional and similar to the effects of DDT. The effects of the two drugs have an additive effect. /Pyrethroids/
/Nuclear Magnetic Resonance/ (NMR) combined with pattern recognition technology has recently been introduced as a new technique for rapidly assessing the toxicity of exogenous substances. This study investigated the metabolic changes in body fluids in rats 90 days after oral administration of propoxyurea, permethrin, and their mixtures. Propoxyurea administration led to increased urinary taurine, creatinine, and glucose levels, while the highest dose of permethrin resulted in increased urinary lactate and acetic acid levels. The mixed-dose group showed increased urinary acetic acid, alanine, lactate, and trimethylamine levels, while urinary tricarboxylic acid cycle intermediate levels decreased. Furthermore, the highest dose of the mixed-dose group showed increased serum levels of 3-D-hydroxybutyrate, acetic acid, and lactate. Long-term combined exposure to propoxyurea and permethrin may induce hepatotoxicity and nephrotoxicity. Increased urinary acetate, alanine, and formate levels may be potential sensitive biomarkers of the chronic combined effects of permethrin and propoxyurea.

---

Non-human toxicity values
Oral LD50 in rats: 1,500 mg/kg
Oral LD50 in rats: 600 mg/kg
Oral LD50 in rats: 1,300 mg/kg
Oral LD50 in rats: 430-4000 mg/kg /cis-trans isomer ratio: 40:60/
For more complete non-human toxicity data on permethrin (30 items in total), please visit the HSDB record page.

Therapeutic Uses

Medication (Veterinary Use)
Scabty (Norwegian) scabies is a rare variant of common scabies, a highly contagious infection in which thousands of scabies mites infest the skin. Due to its atypical clinical presentation, this infection is often overlooked. Patients with cognitive impairment or immunodeficiency diseases (including those receiving immunosuppressive therapy) are more susceptible to crusty scabies. The infection typically presents as systemic dermatitis with crusted hyperkeratosis on the palms and soles. Diagnosis is made by examining skin scrapings from the crusted lesions. Lindane is the most commonly used scabicide for treating crusty scabies. Eradication usually requires repeated applications, and care must be taken to avoid lindane poisoning. Permethrin cream is as effective as lindane in treating common scabies. Due to its greater safety profile, permethrin may become the first-line treatment for crusty scabies.
Permethrin is a synthetic pyrethroid with low mammalian toxicity and superior insecticidal efficacy compared to natural pyrethroids. Due to its highly effective ovicidal activity and persistence on hair, a single application of 1% permethrin cream rinse can eliminate head lice. Less than 1% of patients require repeat treatment after seven days. Permethrin has an ovicidal effect on lice; some of its activity may stem from the drug remaining on the hair for up to two weeks or longer, which kills nymphs hatching from eggs. An in vitro study using live lice and live lice eggs collected from healthy children infested with lice in Panama showed that exposure to 1% permethrin cream rinse killed 30% of lice within 5 minutes, 53% within 10 minutes, and 100% within 1 hour. Within 10 minutes, 89% of lice eggs were killed. However, when 1% permethrin was diluted with water at a ratio of 10:1 to simulate the dilution when applied to wet hair, 11% of lice were killed within 5 minutes, 44% within 10 minutes, and 94% within 1 hour; after treatment with the diluted solution, 81% of lice eggs were killed within 10 minutes. For more complete data on the therapeutic uses of permethrin (19 in total), please visit the HSDB record page. Drug Warnings The safety and efficacy of permethrin in children under 2 years of age have not been established. Patients intolerant to chrysanthemum, pyrethroids, and other synthetic pyrethroids may not tolerate permethrin. Pharmacodynamics Permethrin is a pyrethroid insecticide effective against a variety of pests, including lice, ticks, fleas, mites, and other arthropods.

C21H20CL2O3

391.29

390.078

52645-53-1

Permethrin-d5;1794760-19-2;Permethrin-d9;trans-Permethrin;61949-77-7

40326

Colorless crystals to a viscous liquid; Color, white to pale yellow
Pure permethrin cis-isomer forms colorless crystals at room temperature but a mixture of cis and trans isomers normally occurs as a liquid, with its appearance depending on the ratio of isomers. Pure permethrin (40:60) is a colorless, viscous liquid, whereas the technical compound is a yellow to yellow-brown viscous liquid.

1.3±0.1 g/cm3

465.9±45.0 °C at 760 mmHg

34-35°C

159.4±27.7 °C

0.0±1.2 mmHg at 25°C

1.616

7.15

0

3

7

26

521

0

Cl/C(=C(/[H])\C1([H])C([H])(C(=O)OC([H])([H])C2C([H])=C([H])C([H])=C(C=2[H])OC2C([H])=C([H])C([H])=C([H])C=2[H])C1(C([H])([H])[H])C([H])([H])[H])/Cl

RLLPVAHGXHCWKJ-UHFFFAOYSA-N

InChI=1S/C21H20Cl2O3/c1-21(2)17(12-18(22)23)19(21)20(24)25-13-14-7-6-10-16(11-14)26-15-8-4-3-5-9-15/h3-12,17,19H,13H2,1-2H3

(3-phenoxyphenyl)methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate

1RS,cis-Permethrin; Transpermethrin; Permethrin

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 : ~50 mg/mL (~127.78 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.39 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.

---

Solubility in Formulation 2: 2.5 mg/mL (6.39 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (6.39 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.

---

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