Absorption, Distribution and Excretion
In a rat skin metabolism study, 61-66% of the dose was absorbed through the skin after transdermal application of 20 mg/kg radiolabeled icagridin. Peak plasma concentrations in male rats after topical application of 20 mg/kg icagridin were 0.5 μg/mL, and in female rats, they were 0.8-1.6 μg/mL. In a human volunteer study, less than 6% of the dose was absorbed after topical application of 14.7 or 15.0 mg of industrial-grade icagridin followed by 8 hours of protective dressing coverage. Following topical application of 20 mg/kg icagridin in rats, urinary excretion was the primary elimination route, with 73-88% of the parent compound recovered in the urine. At a dose of 200 mg/kg, 33-40% of the administered dose was excreted in the urine or feces. Data on the composition of the parent compound and its metabolites in animal or human urine are currently unavailable. In a rat study, picaridin was applied to the skin at doses of 20 mg/kg and 200 mg/kg. In the 20 mg/kg group, plasma concentrations in male rats were 0.5 μg/ml and in female rats were 0.8–1.6 μg/ml; in the 200 mg/kg group, plasma concentrations in male rats were 4.48 μg/ml and in female rats were 1.70 μg/ml. Picaridin applied to the arms of human volunteers was not detected in plasma. Information regarding picaridin clearance is currently unavailable. Picaridin and oxybenzone are two active ingredients in mosquito repellents and sunscreens, respectively. We conducted a series of in vitro diffusion studies to evaluate the transmembrane permeability of picaridin and oxybenzone on human epidermis and polydimethylsiloxane (PDMS) membranes. When both active ingredients are used simultaneously, the penetration of picaridin (PCR) and oxybenzone (OBZ) into the human epidermis is inhibited; increasing the concentration of the tested compounds further reduces the penetration rates of picaridin and oxybenzone. Although the permeability properties of the human epidermis and PDMS membranes are correlated, the permeability of the PDMS membrane is significantly higher than that of the human epidermis. These results differ from the case of simultaneous use of the mosquito repellent DEET and the sunscreen oxybenzone, where a synergistic effect enhancing penetration was observed. Therefore, further comparative studies are needed to understand the penetration mechanisms and interactions between picaridin and oxybenzone. Increased awareness of skin cancer and mosquito-borne diseases has led to increased use of mosquito repellents and sunscreens. The challenge in developing recommendations for sunscreen use and reapplication lies, especially when using multiple sunscreens simultaneously, in finding a balance between ensuring product durability and effective protection against natural and physical factors such as water, sweat, temperature, and friction, while limiting transdermal absorption and reducing potential skin and systemic toxicity risks. Compared to organic sunscreens, inorganic sunscreens have little or no transdermal absorption or toxicity, while organic sunscreens vary in their skin penetration and the degree of adverse skin reactions. Picaridin, an alternative to N,N-diethyl-m-toluamide (DEET), the gold standard ingredient in traditional mosquito repellents, appears to be equally effective with a lower risk of toxicity and may reduce the transdermal absorption of both compounds when used concurrently with sunscreen. Conversely, concurrent use of DEET with sunscreen leads to a significant increase in the absorption of both compounds. It is crucial to raise consumer awareness of the increased toxicity risks associated with the "wash-in" of various compounds and the varying needs for reapplication due to "wash-out" caused by water, sweat, and abrasion. While many questions remain to be answered, modern research tools, including those related to skin pharmacokinetics, should contribute to these anticipated advances in order to maximize efficacy and minimize toxicity. Six male volunteers in each group had their skin exposed to either 15.0 or 14.7 mg/person (37 μCi/person) of undiluted 14C-KBR 3023 or an ethanol formulation (15% (w/w)). Subjects were exposed to the test substance for 8 hours under a non-occlusive protective membrane. After treatment, the treated area was wiped with isopropanol and rinsed with alcohol. Swabs and alcohol were preserved for further analysis. Adhesive tape was removed from the area near the application site at 1, 23, and 45 hours post-exposure. Blood samples were collected at 0, 2, 4, 6, 8, 10, 12, 16, 24, and 36 hours post-exposure. Urine samples were collected from the ipsilateral and contralateral arms at 48, 72, and 120 hours post-exposure. Urine samples were collected before administration and at the following time points after administration: 0–4 hours, 4–8 hours, 8–12 hours, 12–24 hours, 24–36 hours, 36–48 hours, 48–60 hours, 60–72 hours, 72–84 hours, 84–96 hours, 96–108 hours, 108–120 hours, and 120–128 hours. Stool samples were collected throughout the 128-hour collection period. At the end of the exposure period, most of the administered dose was recovered in flushing fluid, swabs, protective films, and duodenal patches. 94.16% of the test substance was recovered in the ethanol solution, and 95.23% in the undiluted test substance. Radiolabeled substances were recovered in the urine. The mean percentages of the administered dose were 3.76% (range: 2.20%–7.00%) in the solution and 1.66% (range: 0.70%–2.29%) in the undiluted solution and 1.66% (range: 0.70%–2.29%), respectively. 93% to 94% of the labeled substance was recovered within the first 24 hours. The recovery of radiolabeled compounds from plasma was negligible. Under the conditions of this study, absorption of the radiolabeled compound through the skin was very limited. The use of a solvent (ethanol) appeared to enhance its absorption.
…The skin of five male and female rats was treated daily for two weeks with 20 mg/kg of unlabeled KBR 3023 technical grade (purity: 99.1%), followed by exposure to a single dose of 20 mg/kg of the radiolabeled test substance for seven days. /In the second test/The skin of five male and female rats was exposed to…a single dose of 200 mg/kg of the radiolabeled test substance for seven consecutive days. …The primary route of excretion was urine (73% to 88% of the absorbed dose). Pretreatment did not appear to affect excretion. For a 200 mg/kg skin administration, the mean percentage of the administered dose recovered in urine and feces was 33% to 40% in males and females, respectively. The radioactivity recovered in urine accounted for 78% and 91% of the total radioactivity in males and females, respectively.

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Metabolism/Metabolites
Data on the metabolism of this drug and its metabolites are limited; however, it is estimated that icocalidine undergoes phase I metabolism involving hydroxylation of the 2-methylpropyl side chain or the piperidine ring. Additionally, oxidation of the hydroxyethyl side chain to carbonyl groups has been noted. Phase II metabolism is very rare. Isoirin.
Metabolite analysis indicates that the major modifications to the parent compound are phase I reactions, where the piperidine ring or 2-methylpropyl side chain is hydroxylated, or the hydroxyethyl side chain is oxidized to carbonyl groups. Phase II binding reactions with glucuronide, linoleic acid, or oleic acid account for only a small fraction of the recovered metabolites.

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Biological Half-Life
In one study, researchers investigated the first elimination half-life of isoirin in five male and female rats that received a single transdermal administration of 20 mg/kg. The half-life was 35.7 hours in male rats and 23.9 hours in female rats. In another study, researchers treated rats with 20 mg/kg of unlabeled isocheridin daily for two weeks, followed by a single dose of 20 mg/kg of radiolabeled isocheridin. After seven consecutive days of administration of isocheridin to male and female rats, the first elimination half-life was 10.9 hours and 9.1 hours, respectively, and the second half-life was 144 hours and 105 hours, respectively. Five rats of each sex received a single intravenous injection of 20 mg/kg of the test substance via the femoral vein. The test substance was prepared with physiological saline. …The first, second, and third elimination half-lives for male rats were 0.9 hours, 5.2 hours, and 45.5 hours, respectively, and for female rats, they were 0.7 hours, 2.8 hours, and 73.0 hours, respectively. …The skin of five rats of each sex was exposed to a single dose of 20 mg/kg of the radiolabeled test substance for seven consecutive days. …In the low-dose skin study, only the first elimination half-life was determined. The half-lives were 35.7 hours… 23.9 hours for male rats and 23.9 hours for female rats. Five rats of each sex were treated daily for two weeks with 20 mg/kg of unlabeled KBR 3023 technical grade (purity: 99.1%) skin treatment, followed by a single 20 mg/kg treatment with radiolabeled test material for 7 days. For the high-dose skin treatment, the first elimination half-lives for male and female rats were 10.9 hours and 9.1 hours, respectively. The second half-lives were 144 hours and 105 hours, respectively.

Toxicity Summary
Identification and Uses: Picaridin is a colorless liquid. Picaridin is an insect repellent that can be applied to the skin of humans or animals. It is particularly effective against mosquitoes. Human Exposure and Toxicity: One patient has been reported to have developed allergic contact dermatitis, presenting with erythema and itching, following routine use of picaridin. It is currently unclear whether the solvent methylglucose dioleate has a pathogenic or additive effect. However, for patients allergic to DEET-containing products, picaridin-containing insect repellents may be an acceptable alternative. The main symptoms of all insect repellent exposures include eye irritation/pain, vomiting, red eyes/conjunctivitis, and oral irritation. Accidental ingestion of picaridin-containing insect repellents and other insect repellents has been associated with only mild toxicity. Animal Studies: 50 rats per group (per sex per group) received skin treatment with 0, 50, 100, or 200 mg/kg/day of the test substance, 5 days a week, for 2 years (two-year group). In addition, 20 rats per group (per sex per group) received either 0 or 200 mg/kg/day of the test substance, and 10 rats per group (per sex per group) received either 50 or 100 mg/kg/day of the test substance. These animals received treatment for one year (one-year group). Treatment did not result in a significant increase in mortality. Treatment had no effect on mean body weight, food consumption, clinical symptoms, ophthalmological examination, hematological examination, clinical chemistry, urinalysis, absolute or relative organ weight, or histopathology. Skin of 30 rats per group (per sex per group) was treated with 0, 50, 100, or 200 mg/kg/day of the test substance, 5 days a week, for two generations. The treatment period included 10 weeks before mating, during mating, 3 weeks of gestation, and 3 weeks of lactation. At this time, 30 F1 generation animals (per sex per group) were selected as parents and received an additional 10 weeks of treatment, followed by mating, and 3 weeks of gestation and 3 weeks of lactation for the F2 generation. Neither generation of parent animals exhibited significant treatment-related clinical symptoms, nor were systemic toxicities or effects on average body weight and food consumption observed. At the administration site, some control animals also showed hyperkeratosis and acanthosis, with severity increasing with dose. Reproductive parameters and development in both generations of offspring were unaffected. Picaridin was tested in Salmonella strains TA98, TA100, TA1535, and TA1537 at concentrations ranging from 8 to 5000 μg/plate (two tests), incubated at 37°C for 48 hours with or without metabolic activation. No treatment-related increase in reversion mutation rate was observed. No treatment-related increase in micronucleus number was also observed in mouse micronucleus assays.

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Currently, there is no clinical information regarding the use of icaridin during lactation. However, the Centers for Disease Control and Prevention (CDC) and the Environmental Protection Agency (EPA) consider picaridin to be safe and effective when used as directed during breastfeeding. Breastfeeding women should use picaridin to avoid exposure to mosquito-borne viruses. [1] Avoid direct application to the nipples and other areas where the infant may ingest the virus.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
No information is available on the protein binding of picaridin.

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Toxicity data
LC50 (rat)>4,364 mg/m3

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Interactions
Picaridin and oxybenzone are two active ingredients in mosquito repellents and sunscreens, respectively. We conducted a series of in vitro diffusion studies to evaluate the transmembrane permeability of picaridin and oxybenzone across human epidermis and polydimethylsiloxane (PDMS) membranes. When both active ingredients are used simultaneously, the penetration of picaridin (PCR) and oxybenzone (OBZ) through the human epidermis is inhibited; increasing the concentration of the tested compounds further reduces the penetration rates of picaridin and oxybenzone. Although the permeability properties of the human epidermis and polydimethylsiloxane (PDMS) membranes are correlated, the permeability of PDMS membranes is significantly higher than that of the human epidermis. This finding differs from the case of simultaneous use of the mosquito repellent DEET and the sunscreen oxybenzone, where a synergistic effect enhancing penetration was observed. Therefore, further comparative studies are needed to understand the penetration mechanisms and interactions between picaridin and oxybenzone. Increased awareness of skin cancer and mosquito-borne diseases has led to increased use of mosquito repellents and sunscreens. The challenge in developing recommendations for sunscreen use and reapplication lies, especially when using multiple sunscreens simultaneously, in finding a balance between ensuring product durability and effective protection against natural and physical factors such as water, sweat, temperature, and friction, while limiting transdermal absorption and reducing potential skin and systemic toxicity risks. Compared to organic sunscreens, inorganic sunscreens have little or no transdermal absorption or toxicity, while organic sunscreens vary in their skin penetration and the degree of adverse skin reactions. Picaridin, an alternative to N,N-diethyl-m-toluamide (DEET), the gold standard ingredient in traditional mosquito repellents, appears to be equally effective with a lower risk of toxicity and may reduce the transdermal absorption of both compounds when used concurrently with sunscreen. Conversely, concurrent use of DEET with sunscreen leads to a significant increase in the absorption of both compounds. Raising consumer awareness of the potential increased toxicity risks associated with various compounds “washing into” the skin, while also recognizing that “wash-off” due to water, sweat, and friction can alter the need for reapplication, is crucial. Although many questions remain to be answered, modern research tools, including those related to skin pharmacokinetics, should contribute to these potential advances in order to maximize efficacy and minimize toxicity.

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Non-human toxicity values
Oral LD50 in rats: 4743 mg/kg
Dermal LD50 in rats: >2000 mg/kg
Inhalation LC50 in male rats: >4364 mg/m³ (4 hours)

Butyl-2-yl-2-(2-hydroxyethyl)piperidine-1-carboxylic acid ester is a carboxylic acid belonging to the piperidine class of compounds. Picaridin, also known as hydroxyethyl isobutylpiperidine carboxylic acid ester, is a cyclic amine, also belonging to the piperidine class of compounds. Piperidine is a structural component of piperine, which is extracted from the Piper plant (also known as pepper). Picaridin is widely used as a topical insect repellent in many countries and received official approval in the United States in 2001 and in Canada in 2012. Picaridin was synthesized by Bayer in the 1980s based on molecular modeling. The Tropical Medicine and Travel Advisory Committee of the Public Health Agency of Canada considers picaridin to be the preferred insect repellent for travelers aged 6 months to 12 years. Picaridin has been reported to be less irritating than another common insect repellent, diethyltoluamide, and products containing up to 20% picaridin are considered safe for long-term use in adults.
Picaridin, also known as picaridin or KBR 3023, INCI name hydroxyethyl isobutylpiperidine carboxylic acid ester, and trade names Bayrepel and Saltidin, is an insect repellent. It has broad-spectrum insecticidal activity against a variety of insects and is virtually colorless and odorless.
Drug Indications

Picaridin is suitable for repelling insects such as mosquitoes, biting flies, ticks, chiggers, and fleas. It can be applied topically or sprayed onto clothing.
Mechanism of Action

The exact mechanism by which picaridin repels insects and the target molecules are not fully understood; it is speculated that piperine interacts with the olfactory system, which consists of odorant receptors (OR) and ionotropic receptors (IR) requiring a common co-receptor (ORCO), preventing insects from recognizing signals from their host. Other studies have shown that picaridin may bind to different binding sites on odor-binding protein 1 (AgamOBP1). A study has shown that picaridin inhibits the odor-induced response of AaOR2 and AaOR8 expressed in Xenopus laevis oocytes, thereby altering olfactory input to olfactory sensory neurons (OSNs). DEET, 2-undecanoate (2-U), IR3535, and picaridin are widely used as insect repellents to prevent human contact with a variety of arthropods, including mosquitoes. In recent years, the molecular mechanisms of action of these repellents have been investigated, leading to some seemingly contradictory theories, including their inhibitory (odor molecule-dependent) and excitatory (odor molecule-independent) effects on insect olfactory sensory neurons (OSNs) and odorant receptor proteins (ORs). This study investigated the effects of these repellents on two olfactory receptors, AaOR2 and AaOR8, in Aedes aegypti mosquitoes. These two receptors are co-expressed with the common co-receptor AaOR7 in Xenopus laevis oocytes. They are activated by indole (AaOR2) and (R)-(-)-1-octen-3-ol (AaOR8), respectively. These two olfactory molecules are used to locate oviposition sites and host animals. In the absence of olfactory molecules, DEET activates AaOR2 but not AaOR8, while 2-U activates AaOR8 but not AaOR2; IR3535 and picaridin do not activate these receptors. In the presence of odor, DEET strongly inhibits AaOR8 but not AaOR2; while 2-U strongly inhibits AaOR2 but not AaOR8; IR3535 and picaridin strongly inhibit both olfactory receptors. These data suggest that repellents can act as olfactory agonists or antagonists, thereby modulating the activity of olfactory receptors and converging conflicting models.

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Pharmacodynamics
Picaridin is a cyclic amine and piperidine compound expected to stimulate sensory hairs on insect antennae.

C12H23NO3

229.32

229.167

119515-38-7

125098

Colorless liquid

1.0±0.1 g/cm3

330.9±15.0 °C at 760 mmHg

below -170ºC

153.9±20.4 °C

0.0±1.6 mmHg at 25°C

1.478

1.56

1

3

5

16

220

0

O(C([H])(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])C([H])([H])C([H])([H])O[H])=O

QLHULAHOXSSASE-UHFFFAOYSA-N

InChI=1S/C12H23NO3/c1-3-10(2)16-12(15)13-8-5-4-6-11(13)7-9-14/h10-11,14H,3-9H2,1-2H3

butan-2-yl 2-(2-hydroxyethyl)piperidine-1-carboxylate

HSDB 7374; EC 423-210-8; Icaridin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

DMSO : ~250 mg/mL (~1090.18 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (9.07 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 20.8 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: ≥ 2.08 mg/mL (9.07 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 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.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (9.07 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 20.8 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.)