イカリジン

Pesticides -> Insect Repellents

Pesticide

Insoluble

In water, 8.2 g/L (pH 4-9); 8.6 g/L (unbuffered), at 20 °C

In water, 8.2X10+3 mg/L at 20 °C, pH 4-9

In acetone, 7520 g/L at 20 °C

296 °C

BP: 208 °C at 1013 hPa

< -170

< -170 °C

0.00044 [mmHg]

VP: 3.4X10-4 hPa at 20 °C; 5.9X10-4 hPa at 25 °C; 7.1X10-3 hPa at 50 °C

4.43X10-4 mm Hg at 25 °C

Warning

H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

P264+P265, P280, P305+P351+P338, and P337+P317 (click each P-code to see the statement)

Aggregated GHS information provided per 50 reports by companies from 1 notifications to the ECHA C&L Inventory.

Warning

H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

REACH registered substance: (RS)-sec-butyl (RS)-2-(2-hydroxyethyl)piperidine-1-carboxylate (EC: 423-210-8)

Picaridin: HSNO Approval: HSR007997 Approved with controls

USEPA; Office of Prevention, Pesticides and Toxic Substances, New Pesticide Fact Sheet for Picaridin (May 20, 2005).[Available from, as of June 24, 2016: https://www3.epa.gov/pesticides/chem_search/reg_actions/registration/fs_PC-070705_01-May-05.pdf]

Eye Irrit. 2 (100%)

Eye Irrit. 2 (100%)

Safe Storage of Pesticides. Always store pesticides in their original containers, complete with labels that list ingredients, directions for use, and first aid steps in case of accidental poisoning. Never store pesticides in cabinets with or near food, animal feed, or medical supplies. Do not store pesticides in places where flooding is possible or in places where they might spill or leak into wells, drains, ground water, or surface water.

If a spill occurs, clean it up promptly. Don't wash it away. Instead, sprinkle the spill with sawdust, vermiculite, or kitty litter. Sweep it into a plastic garbage bag, and dispose of it as directed on the pesticide product label.

After Applying a Pesticide, Indoors or Outdoors. To remove pesticide residues, use a bucket to rinse tools or equipment three times, including any containers or utensils that you used when mixing the pesticide. Then pour the rinsewater into the pesticide sprayer and reuse the solution by applying it according to the pesticide product label directions. After applying any pesticide wash your hands and any other parts of your body that may have come in contact with the pesticide..To prevent tracking pesticides inside, remove or rinse your boots or shoes before entering your home. Wash any clothes that have been exposed to a lot of pesticide separately from your regular wash.

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

Safe Disposal of Pesticides. The best way to dispose of small amounts of excess pesticides is to use them - apply them - according to the directions on the label. If you cannot use them, ask your neighbors whether they have a similar pest control problem and can use them. If all of the remaining pesticide cannot be properly used, check with your local solid waste management authority, environmental agency, or health department to find out whether your community has a household hazardous waste collection program or a similar program for getting rid of unwanted, leftover pesticides. These authorities can also inform you of any local requirements for pesticide waste disposal.

Safe Disposal of Pesticides. An empty pesticide container can be as hazardous as a full one because of residues left inside. Never reuse such a container. When empty, a pesticide container should be rinsed carefully three times and the rinsewater thoroughly drained back onto the sprayer or the container previously used to mix the pesticide. Use the rinsewater as a pesticide, following label directions. Replace the cap or closure securely. Dispose of the container according to label instructions. Do not puncture or burn a pressurized container like an aerosol - it could explode. Do cut or puncture other empty pesticide containers made of metal or plastic to prevent someone from reusing them. Wrap the empty container and put it in the trash after you have rinsed it.

Picaridin and oxybenzone are two active ingredients found in repellent and sunscreen preparations, respectively. We performed a series of in vitro diffusion studies to evaluate the transmembrane permeation of picaridin and oxybenzone across human epidermis and poly(dimethylsiloxane) (PDMS) membrane. Permeation of picaridin (PCR) and oxybenzone (OBZ) across human epidermis was suppressed when both active ingredients were used concurrently; increasing concentration of the test compounds further reduced the permeation percentage of picaridin and oxybenzone. While permeation characteristics were correlative between human epidermis and PDMS membrane, permeability of PDMS membrane was significantly larger than that of human epidermis. The findings were different from concurrent use of repellent DEET and sunscreen oxybenzone in which a synergistic permeation enhancement was observed. Further comparative studies are therefore needed to understand permeation mechanisms and interactions between picaridin and oxybenzone.

Increased awareness of skin cancer and mosquito-transmitted diseases has increased use of insect repellents and sunscreens. The challenge in setting recommendations for use and reapplication, especially when used concomitantly, lies in finding the balance between applying a durable product effective in withstanding natural and physical factors such as water, sweat, temperature and abrasion, while limiting percutaneous absorption and decreasing risk of potential dermal and systemic toxicity. Inorganic sunscreens show no or little percutaneous absorption or toxic effects in comparison to organic sunscreens, which show varying levels of dermal penetration and cutaneous adverse effects. An alternative to N,N-diethyl-m-toluamide (DEET), the traditional gold standard compound in insect repellents, picaridin appears as efficacious, has lower risk of toxicity, and when used simultaneously with sunscreen may decrease percutaneous absorption of both compounds. Conversely, combined use of DEET and sunscreen results in significantly higher absorption of both compounds. It is important to increase consumer awareness of "washing in" of various compounds leading to increased risk of toxicity, as well as differences in reapplication need due to "washing off" caused by water, sweat and abrasion. Although much remains to be studied, to maximize efficacy and decrease toxicity, contemporary research tools, including dermatopharmokinetics, should aid these prospective advances.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 80(SRC), determined from a structure estimation method(2), indicates that picaridin is expected to have high mobility in soil(SRC). Volatilization of picaridin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.6X10-8 atm-cu m/mole(SRC), based upon its vapor pressure, 4.43X10-4 mm Hg(3), and water solubility, 8200 mg/L(3). Picaridin is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(3). Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 80(SRC), determined from a structure estimation method(2), indicates that picaridin is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.6X10-8 atm-cu m/mole(SRC), derived from its vapor pressure, 4.43X10-4 mm Hg(4), and water solubility, 8200 mg/L(4). Picaridin did not undergo hydrolysis at pH 5, 7 and 9, 25 °C over 30 days(4). According to a classification scheme(5), an estimated BCF of 14(SRC), from its log Kow of 2.23(4) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), picaridin, which has a vapor pressure of 4.43X10-4 mm Hg at 25 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase picaridin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 7 hours(SRC), calculated from its rate constant of 5.6X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Picaridin does not contain chromophores that absorb at wavelengths >290 nm(2) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Picaridin is a colorless liquid. Picaridin is an insect repellent, for application to human or animal skin. In particular, it is used as mosquito repellent. HUMAN EXPOSURE AND TOXICITY: Allergic contact dermatitis has been reported in a human following routine application of picaridin and produced erythema and pruritis. It is not clear whether the solvent methyl glucose-dioleate had a causative or additive effect. However, insect repellents containing picaridin may be acceptable alternatives in patients who demonstrate sensitivity to products containing DEET. Primary symptoms across all insect repellent exposures included ocular irritation/pain, vomiting, red eye/conjunctivitis, and oral irritation. Unintentional ingestion of picaridin-containing and other insect repellents was associated only with minor toxicity. ANIMAL STUDIES: The skin of 50 rats/sex/group was treated with 0, 50, 100 or 200 mg/kg/day 5 days per week for 2 years (the two year cohort). Additionally, 20 animals/sex/group were treated with 0 or 200 mg/kg/kg and 10 animals/sex/group were treated with 50 or 100 mg/kg/day of the test material. These animals received the treatment for one year (one year cohort). There was no apparent effect of an increased mortality due to the treatment. There was no treatment-related effect upon mean body weight, food consumption, clinical signs, ophthalmology, hematology, clinical chemistry, urinalysis, absolute or relative organ weights, or histopathology. The skin of 30 rats/sex/group was treated with 0, 50, 100, or 200 mg/kg/day 5 days/week for two generations. The treatment periods included 10 weeks prior to mating, mating, 3 weeks gestation and 3 weeks of lactation. At that time, 30 F1 animals/sex/group were selected as parents and treated for an additional 10 weeks, followed by mating and 3 weeks each for gestation and lactation of the F2 generation. There were no apparent treatment-related clinical signs related to systemic toxicity or effects upon the mean body weights and food consumption of the parental animals in either generation. At the application site, hyperkeratosis and acanthosis, apparent for even some of the control animals, increased in severity in a dose-related manner. There was no effect upon the reproductive parameters or development of the offspring in either generation. Picaridin was tested in S. typhimurium TA98, TA100, TA1535 and TA1537 strains at levels ranging from 8 to 5000 ug/plate (both trials) with or without metabolic activation and incubated for 48 hours at 37 °C. There was no apparent treatment-related increase in the incidence of reverse mutation. There was no treatment-related increase in the number of micronuclei in mouse micronucleus test.

/OTHER TOXICITY INFORMATION/ ... Mosquitoes use their sense of smell to detect DEET, but there are currently two hypotheses regarding its mode of action: activation of ionotropic receptor IR40a vs. odorant receptor(s). Here, we demonstrate that DEET, picaridin, insect repellent 3535, and p-menthan-3,8-diol activate the odorant receptor CquiOR136 of the southern house mosquito, Culex quinquefasciatus. Electrophysiological and behavioral assays showed that CquiIR40a knockdown had no significant effect on DEET detection and repellency. By contrast, reduction of CquiOR136 transcript levels led to a significant decrease in electroantennographic responses to DEET and a complete lack of repellency. Thus, direct activation of an odorant receptor, not an ionotropic receptor, is necessary for DEET reception and repellency in Culex mosquitoes. Interestingly, methyl jasmonate, a repellent derived from the nonvolatile jasmonic acid in the signaling pathway of plant defenses, elicited robust responses in CquiOR136-CquiOrco-expressing Xenopus oocytes, thus suggesting a possible link between natural products with long insect-plant evolutionary history and synthetic repellents.

/OTHER TOXICITY INFORMATION/ Acts on certain olfactory receptor cell types to reduce the activating or attracting effect of odor sources.

/OTHER TOXICITY INFORMATION/ The interactions between insect repellents and the olfactory system have been widely studied, however relatively little is known about the effects of repellents on the gustatory system of insects. In this study, we show that the gustatory receptor neuron (GRN) located in the medial styloconic sensilla on the maxillary palps of gypsy moth larvae, and known to be sensitive to feeding deterrents, also responds to the insect repellents DEET, IR3535, and picaridin. These repellents did not elicit responses in the lateral styloconic sensilla. Moreover, behavioral studies demonstrated that each repellent deterred feeding. This is the first study to show perception of insect repellents by the gustatory system of a lepidopteran larva and suggests that detection of a range of bitter or aversive compounds may be a broadly conserved feature among insects.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of July 7, 2016: http://actor.epa.gov/dashboard/]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of picaridin can be estimated to be 80(SRC). According to a classification scheme(2), this estimated Koc value suggests that picaridin is expected to have high mobility in soil.

/HUMAN EXPOSURE STUDIES/ For the use of topical insect repellents, DEET and picaridin, human health risk assessments were conducted for various population subgroups. Acute, subchronic, and chronic dermal exposures were examined. No-observed-effect-levels (NOELs) of 200, 300, and 100 mg/kg body weight (BW) were used as endpoints for DEET for acute, subchronic, and chronic exposures, respectively. For picaridin, a NOEL of 2000 mg/kg BW/day for acute exposure and a NOEL of 200 mg/kg BW/day for subchronic and chronic exposures were used. Daily exposures to several population subgroups were estimated. Risks were characterized using the Margin of Exposure (MOE) method (NOEL divided by the estimated exposure), whereby estimated MOEs were compared to an MOE of 100. Estimates of daily exposures ranged from 2 to 59 mg/kg BW/day for DEET and 2 to 22 mg/kg BW/day for picaridin. Children had the lowest MOEs. However, none of the estimated exposures exceeded NOELs for either repellent. At 40% DEET for acute exposure, children < or = 12 years had MOEs below 100. For subchronic and chronic exposures children at > or = 25% DEET and at 15% picaridin had MOEs below 100. Therefore, we found no significant toxicological risks from typical usage of these topical insect repellents.

/SIGNS AND SYMPTOMS/ Allergic contact dermatitis has been reported in a human following routine application /of picaridin/ and produced erythema and pruritis. It is not clear whether the solvent methyl glucose-dioleate had a causative or additive effect.

/CASE REPORTS/ Topical insect repellent is commonly used throughout the world. Active ingredients typically include N,N-diethyl-meta-toluamide (DEET) or picaridin. Reactions to topical repellents have ranged from contact dermatitis to urticaria. Exposure to DEET can produce contact urticaria; however, it is unknown if patients with a sensitivity to DEET can tolerate picaridin. We report the case of a 22-year-old man who presented for evaluation of contact urticaria that had developed immediately after the application of insect repellent and contact with individuals who had used DEET-containing repellents. No systemic manifestations were noted. Commercially available products containing DEET or picaridin were used for open patch testing. The patient showed immediate urticarial responses to 7% DEET and 7% DEET in ethanol, but patch tests for 5% picaridin and 5% picaridin in ethanol were negative. Based on these results, we conclude that insect repellents containing picaridin may be acceptable alternatives in patients who demonstrate sensitivity to products containing DEET.

/SURVEILLANCE/ ... The purpose of this study was to review National Poison Data System (NPDS) data regarding ingestion of insect repellents containing picaridin and compare those to insect repellents containing DEET and other insect repellents not containing DEET. NPDS was queried for single agent human insect repellent ingestions reported between 1 January 2000 and 31 May 2015 using the American Association of Poison Control Center generic categories 201048 (Insect Repellents with DEET) and 201049 (Insect Repellents without DEET). Picaridin-containing product exposures were assessed using Poisindex product ID 6744589. Insect repellents of unknown type were not included. 68,429 exposures occurred; 24% were non-DEET-containing products, of which 2% were picaridin-containing products. Among picaridin exposures, 92.9% were managed outside of a health-care facility; there were no reported cases of major effect or death, and only one case of moderate effect. Primary symptoms across all insect repellent exposures included ocular irritation/pain, vomiting, red eye/conjunctivitis, and oral irritation. Treatment primarily included dilution/irrigation/wash. Unintentional ingestion of picaridin-containing and other insect repellents was associated only with minor toxicity and was generally managed outside of a health-care facility.

The exact mechanism and target molecules of icaridin repelling insects are not fully understood; it is presumed that piperine interacts with the olfactory system consisting of odorant receptors (ORs) that need a common co-receptor (ORCO), and of ionotropic receptors (IR), leading to the insect's inability to recognize its host's cues. It is also suggested that icaridin may bind to odorant binding protein 1 (AgamOBP1) at different binding sites. A study demonstrated that icaridin inhibited the odorant-induced responses of AaOR2 and AaOR8 expressed in Xenopus oocytes, leading to altered olfactory inputs by olfactory sensory neurons (OSN).

DEET, 2-undecanone (2-U), IR3535 and Picaridin are widely used as insect repellents to prevent interactions between humans and many arthropods including mosquitoes. Their molecular action has only recently been studied, yielding seemingly contradictory theories including odorant-dependent inhibitory and odorant-independent excitatory activities on insect olfactory sensory neurons (OSNs) and odorant receptor proteins (ORs). Here we characterize the action of these repellents on two Aedes aegypti ORs, AaOR2 and AaOR8, individually co-expressed with the common co-receptor AaOR7 in Xenopus oocytes; these ORs are respectively activated by the odors indole (AaOR2) and (R)-(-)-1-octen3-ol (AaOR8), odorants used to locate oviposition sites and host animals. In the absence of odorants, DEET activates AaOR2 but not AaOR8, while 2-U activates AaOR8 but not AaOR2; IR3535 and Picaridin do not activate these ORs. In the presence of odors, DEET strongly inhibits AaOR8 but not AaOR2, while 2-U strongly inhibits AaOR2 but not AaOR8; IR3535 and Picaridin strongly inhibit both ORs. These data demonstrate that repellents can act as olfactory agonists or antagonists, thus modulating OR activity, bringing concordance to conflicting models.

The first elimination half-lives of icaridin were determined in a study of five male and female rats treated with a single dose of 20 mg/kg icaridin dermally. The half-lives were 35.7 hours for male and 23.9 hours in female rats. In another study of rats treated daily for 2 weeks with 20 mg/kg of unlabeled icaridin, followed by exposure to a single dose of 20 mg/kg of the radiolabeled icaridin for 7 days, the 1st elimination half-lives were 10.9 and 9.1 hours for the males and females, respectively. The 2nd half-lives were 144 and 105 hours, respectively.

Five rats/sex were dosed iv in the femoral vein with a single dose of 20 mg/kg of the test material. The test material was prepared in physiological saline. ... The 1st , 2nd and 3rd elimination half-lives were 0.9, 5.2 and 45.5 hours for the males and 0.7, 2.8 and 73.0 hours for the females.

... The skin of a total of 5 rats/sex was exposed to a single dose of 20 mg/kg of the radiolabeled test material for 7 days. ... Only 1st elimination half-lives were determined for the low dose dermal studies. These half-lives were 35.7 ... hours for the males and 23.9 ... hours for the females.

... The skin of a total of 5 rats/sex was treated daily for 2 weeks with 20 mg/kg of unlabeled KBR 3023 technical (purity: 99.1%), followed by exposure to a single dose of 20 mg/kg of the radiolabeled test material for 7 days. ... For the high dose dermal treatments, the 1st elimination half-lives were 10.9 and 9.1 hours for the males and females, respectively. The 2nd half-lives were 144 and 105 hours, respectively.

There is limited data on the metabolism and resulting metabolites of the drug; however, it is estimated that icaridin undergoes phase I metabolic reactions involving 2-methylpropyl side chain or the piperidine ring being hydroxylated. It is also noted that the hydroxyethyl sidechain was oxidized to produce a carbonyl group. There was very little Phase 2 metabolism of the icaridin.

Analysis of the metabolites revealed that the predominant modifications of the parent compound were phase 1 reactions in which the piperidine ring or the 2-methylpropyl sidechain was hydroxylated or the hydroxyethyl sidechain was oxidized to the carbonyl moiety. Phase 2 conjugation reactions with glucuronide, linoleic or oleic acid constituted a very minor fraction of the recovered metabolites.

In a dermal metabolism rat study, dermal application of 20 mg/kg of radio-labeled icaridin resulted in 61-66% of the dose absorbed through the skin. Following topical application of 20 mg/kg on rats, the peak plasma concentrations were measured to be 0.5 μg/mL in male rats and 0.8-1.6 μg/mL in female rats. In a study of human volunteers, less than 6% of the applied doses were absorbed after topical application of 14.7 or 15.0 mg of technical grade icaridin and covering the application site with a protective wrap for eight hours.

Following topical administration on rats at doses of 20 mg/kg, urinary excretion was reported to be the primary route of elimination where 73-88% of the parent compound was recovered in the urine. At doses of 200 mg/kg, 33-40% of the administered dose was excreted in the urine or feces. No data were available on the composition of parent compound and metabolites in the urine of either animals or humans.

In a rat study, dermal application of icaridin at doses of either 20 mg/kg or 200 mg/kg resulted in plasma concentrations ranging from 0.5 μg/ml for males and 0.8-1.6 μg/ml for females in the 20 mg/kg test group, and 4.48 μg/ml in male rats and 1.70 μg/ml and female rats in the 200 mg/kg test group. Icaridin applied to the arms of human volunteers was not found in blood plasma.

There is no available information on the clearance of icaridin.

Picaridin and oxybenzone are two active ingredients found in repellent and sunscreen preparations, respectively. We performed a series of in vitro diffusion studies to evaluate the transmembrane permeation of picaridin and oxybenzone across human epidermis and poly(dimethylsiloxane) (PDMS) membrane. Permeation of picaridin (PCR) and oxybenzone (OBZ) across human epidermis was suppressed when both active ingredients were used concurrently; increasing concentration of the test compounds further reduced the permeation percentage of picaridin and oxybenzone. While permeation characteristics were correlative between human epidermis and PDMS membrane, permeability of PDMS membrane was significantly larger than that of human epidermis. The findings were different from concurrent use of repellent DEET and sunscreen oxybenzone in which a synergistic permeation enhancement was observed. Further comparative studies are therefore needed to understand permeation mechanisms and interactions between picaridin and oxybenzone.

Increased awareness of skin cancer and mosquito-transmitted diseases has increased use of insect repellents and sunscreens. The challenge in setting recommendations for use and reapplication, especially when used concomitantly, lies in finding the balance between applying a durable product effective in withstanding natural and physical factors such as water, sweat, temperature and abrasion, while limiting percutaneous absorption and decreasing risk of potential dermal and systemic toxicity. Inorganic sunscreens show no or little percutaneous absorption or toxic effects in comparison to organic sunscreens, which show varying levels of dermal penetration and cutaneous adverse effects. An alternative to N,N-diethyl-m-toluamide (DEET), the traditional gold standard compound in insect repellents, picaridin appears as efficacious, has lower risk of toxicity, and when used simultaneously with sunscreen may decrease percutaneous absorption of both compounds. Conversely, combined use of DEET and sunscreen results in significantly higher absorption of both compounds. It is important to increase consumer awareness of "washing in" of various compounds leading to increased risk of toxicity, as well as differences in reapplication need due to "washing off" caused by water, sweat and abrasion. Although much remains to be studied, to maximize efficacy and decrease toxicity, contemporary research tools, including dermatopharmokinetics, should aid these prospective advances.

Used as insect repellent applied to skin against biting flies, mosquitoes, chiggers, ticks, and fleas; [Reference #1]

For picaridin (USEPA/OPP Pesticide Code: 070705) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./

Mosquito repellent

Icaridin is an insect repellent, for application to human or animal skin.

Cutter Insect Repellent 7K (Spectrum, A Division of United Industries Corporation): Active ingredient: Picaridin 7.0%.

Cutter Insect Repellent 5KT (Spectrum, A Division of United Industries Corporation): Active ingredient: Picaridin 5.75%.

Cutter Insect Repellent 15KP (Spectrum, A Division of United Industries Corporation): Active ingredient: Picaridin 15.0%.

Cutter Insect Repellent 15KA (Spectrum, A Division of United Industries Corporation): Active ingredient: Picaridin 15.0%.

For more Formulations/Preparations (Complete) data for PICARIDIN (28 total), please visit the HSDB record page.