Page 2 of 23 Table of Contents

1.0 Executive Summary ........................................................................................................... 3

2.0 HED Recommendations .................................................................................................... 4

2.1 Data Deficiencies ............................................................................................................ 4

2.2 Tolerance Considerations .............................................................................................. 4

2.3 Label Recommendations................................................................................................ 4

3.0 Introduction .................................................................................................................. ...... 5

3.1 Chemical Identity and Physica l/Chemical Characteristics ........................................ 5

3.2 Pesticide Use Pattern ...................................................................................................... 5

3.3 Anticipated Exposure Pathways ................................................................................... 6

3.4 Consideration of Environmental Justice ...................................................................... 6

4.0 Hazard Characterization and Dose-Response Assessment ............................................ 7

4.1 Toxicology Studies Available for Analysis ................................................................... 7

4.2 Absorption, Distribution, Metabolism, Excretion (ADME) ....................................... 7

4.3 Toxicological Effects ...................................................................................................... 8

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ................................. 9

4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 10

5.0 Dietary Exposure and Risk Assessment ......................................................................... 11

6.0 Residential (Non-Occupational) Expo sure/Risk Characterization ............................. 11

6.1 Spray Drift ................................................................................................................... . 11

7.0 Aggregate Exposure/Risk Characterization .................................................................. 11

8.0 Cumulative Exposure/Risk Characterization ............................................................... 12

9.0 Occupational Exposure/Risk Characterization ............................................................ 12

10.0 Public Health and Pesticide Epidemiology Data ........................................................... 12

11.0 Literature References ...................................................................................................... 12

12.0 References .................................................................................................................... ..... 13 Appendix A. Toxicology Profile ............................................................................................... . 14 Appendix B. Review of Human Research ................................................................................ 20 Appendix C. Endocrine Disruptor Screening Program ......................................................... 20 Appendix D. Picaridin Use Pattern .......................................................................................... 2 1Page 3 of 23 1.0 Executive Summary

Picaridin [hydroxyethyl isobutyl piperidine carboxylat e] is an insect repellent (non-food pesticide) approved for use on human skin. There are several registered formulations containing 5-20% picaridin as the active ingred ient. Formulations are applied di rectly to the skin of adults and children (e.g., spray, wipes, cream).

The Pesticide Re-evaluation Divi sion (PRD) requested that the Health Effects Division (HED)

conduct a review to iden tify any data gaps, and assessments needed to support the Registration Review of picaridin. Several sour ces of information were used for this evaluation, including the

most recent human health risk as sessments (D357835, D261567, D241258, D279005, and D323024). This memorandum contains HED’s re view and risk assessment for picaridin, reflecting updated hazard assessment, science policies and procedures.

HED identified data gaps for the required inha lation toxicity and imm unotoxicity studies. However, the Hazard and Science Policy Council (HASPOC), using a weight of the evidence (WOE) approach, concluded that these studies are not required for picaridin (TXR# 0056905). HED evaluated additional dermal absorption data and data submitted to address kidney effects

observed in dermal and oral t oxicity studies. The previous assessment of pi caridin, (2006) employed endpoints for dermal and incidental oral exposure based upon kidney and body weight effects. However, the new data indicate that th e kidney effects observed in the rat are a result of accumulation of alpha 2-u globulin, which is a speci es specific effect seen in rats and is not relevant for humans. Therefore, the kidney effects are not consider ed appropriate for use in risk assessment. Outside of the kidney effects, lim ited toxicity consisting of body weight changes, was observed in the picaridin toxi cological database. The body wei ght changes were seen at the limit dose (1000 mg/kg/day), and human exposure at this level is not anticipated. Due to the limited toxicity in the picaridin toxicological da tabase, HED has determin ed that a quantitative risk assessment is not needed for picaridin. Therefore, a qualitativ e human health risk assessment has been conducted to support registration re view for all registered uses of picaridin.

Exposure Profile

Since there are no registered food uses for picari din, dietary exposure is not expected. Further, there are no registered uses of picaridin that could result in occupational exposure, so only residential exposure scenario s have been considered.

Individuals (adults and/or childr en) are exposed to picaridin prim arily via the dermal route when applying it as an insect repellent directly to their skin. However, inhalation exposure is possible when sprays are used. Also, incidental oral expos ures are also expected fo r children if hands are not washed after application.

Hazard Profile

The toxicology database for picarid in is considered complete. The majority of the studies for picaridin were done via the dermal route; however , there are also a few oral studies available. Kidney effects were seen in the dermal and oral studies but were attribut ed to alpha 2-u globulin accumulation, which is species specific (i.e., seen onl y in the rat), and is not considered relevantPage 4 of 23 to humans. Body weight effects were seen in rats in oral studies, but only at the limit dose which is significantly higher than exposure expected from labeled use of products containing picaridin. There were some signs of skin irritation in a few dermal studies; however, no other effects were observed in the toxicological database. There was no evidence of neurotoxicity, developmental and/or reproductive toxicit y, or carcinogenicity.

In acute lethality oral, dermal, and inhalation st udies, exposure to picaridin resulted in low toxicity (Categories III a nd IV). It is moderately irritating to the eye and not irritating to the skin; it is not a dermal sensitizer.

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this preliminary human health risk assessment for pi caridin. However, there are no risks anticipated for picaridin due to the low toxicity observe d in the toxicological database. For more information, see Section 3.5: Consider ations of Environmental Justice.

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Those st udies are subject to ethics review, have received that review, and are complia nt with applicable ethics requirements.

A dermal absorption study with human volunteers is also available for picaridin. However, the study was not used in the current assessment. If EPA decides to use the study, EPA will ensure that all applicable regulatory requirements are met, including, but not limited to, the requirements for EPA ethics re view and Human Studies Review Board review of certain research involving intentional exposu re of human subjects (Appendix B).

2.0 HED Recommendations

HED has not identified any risk conc erns associated with the regist ered uses of picaridin as an insect repellent. There are no data gaps that would require submission of additional toxicity or exposure data.

2.1 Data Deficiencies

The currently available data are suffi cient to support risk conclusions.

2.2 Tolerance Considerations

Picaridin is not a food-use chemical, and there are no established US tolerances.

2.3 Label Recommendations

NonePage 5 of 23 3.0 Introduction

Picaridin is a widely used persona l insect repellent that can be applied directly to the skin of

adults and children. The structure and other id entifiers are found in the chemical identity table

below.

3.1 Chemical Identity and Phys ical/Chemical Characteristics

Chemical Structure:

Chemical Class: piperidine derivative Empirical Formula: C 12 H 23 NO 3 Molecular Weight: 229.3 g/Mol Vapor Pressure: 0.3 kPa (2.25 mm Hg) at 20  C

Odor: nearly odorless Solubility: in water: insoluble in 2-propanol: miscible

in ethanol: miscible

3.2 Pesticide Use Pattern

Picaridin [hydroxyethyl isobutyl piperidine carboxylate] is an insect repellent (non-food pesticide) approved for use on human skin. Th ere are 26 registered end-use products with formulations containing 5-20% pi caridin as the active ingredient . Formulations are applied directly to the skin of adults and children (e.g ., spray, aerosol, wipes, and lotion/cream) at a frequency of 1-3 applications per day depending on the product. There is also a registered product for use on all breeds of riding horses (h orses not intended for human consumption). Labels contain instructions which prohibit applic ation directly to the hands of children and limit the number of applications that can be made per day. Picaridin products can be used for several days or weeks or longer, depending on the activit y pattern and geographic area as well as pest

pressure.

Currently there are no registered uses of picaridin that could result in dietary or occupational exposures. There is no personal protective equipmen t (PPE) on the registered labels as these are

considered residential uses. Th e use directions for the picaridin products are summarized in Appendix D.

General use directions on the registered labels include the following:

 Avoid applying excessive amounts of this product. Excess amounts or frequent applications are unnecessary. Use just e nough repellent to cover exposed skin. AvoidPage 6 of 23 over-application of this product.

 Do not use under clothing.

 Do not apply over cuts, wounds, i rritated or sunburned skin.

 Do not allow children to handle this product. Do not apply on children’s hands. When using on children, apply to your own hands and then put it on the child.

 Do not apply directly onto face, near ey es and mouth. Apply sparingly around ears.

 After returning indoors, wash treated skin w ith soap and water. Wash treated clothing before wearing it again.

These use directions are consistent with the di rections on other insect repellent products and

should remain on the labels to decrease the likelih ood of any possible adverse health effects from misuse or overuse of these products.

3.4 Anticipated Exposure Pathways

Individuals (adults and/or childr en) are exposed to picaridin prim arily via the dermal route when applying insect repellent directly to their skin; however, inhala tion exposure is possible when sprays are used. Also, incidental oral exposures are also expected for children if hands are not washed after application. In the case of insect repellents, it is not appropriate to assess handler and post-application exposure sepa rately. Instead, self-applicati on and the subsequent exposure period are assessed as a single exposure event.

3.5 Consideration of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent po ssible, were considered in the preliminary human health risk assessment for pi caridin, in accordance with U.S. Executive Order 12898, "Federal Actions to Addre ss Environmental Justice in Minority Populations and LowIncome Populations,"http://www.epa.gov/compliance/res ources/policies/ej/exec_order_12898.pdf. As a part of every pesticide risk assessment, OPP c onsiders a large variety of consumer subgroups according to well-established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and ar ound the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns ar e compiled by the USDA under the Continuing Survey of Food Intake by Indi viduals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pest icide. These data are analyzed and categorized by subgroups based on age, season of the year , ethnic group, and region of the country. Additionally, OPP is able to assess dietary e xposure to smaller, specialized subgroups and exposure assessments are performed when condi tions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for t oddlers, youths, and adults enteri ng or playing on treated areas post-application are evaluated. Further considera tions are currently in development as OPP has committed resources and expertise to the developm ent of specialized software and models that consider exposure to bystanders and farm worker s as well as lifestyle and traditional dietary patterns among specific subgroups. However, there are no risks anticipated for picaridin due to the low toxicity observed in the toxicological database.Page 7 of 23 4.0 Hazard Characterization and Dose-Response Assessment

Picaridin is an insect repellent belonging to the piperidine chemical family. Since the chemical is dermally applied, the Agency recommended th at toxicological studies in support of this registration be conducted via the dermal route to reflect the use pattern and to provide route specific data for risk assessmen ts. With the excepti on of the acute neurotoxicity study (ACN) and developmental toxicity study in rats, the ma jority of the dermal toxicity studies were conducted at a maximum dose of 200 mg/kg/day. Th is was done to prevent excessive spreading of the dose beyond the application site at high dose s. The highest doses tested in the ACN and developmental toxicity study in rats were 2000 mg/kg and 400 mg/kg/day, respectively. It was in these studies that excessive sp reading of the dermally applied dose was identified. In addition to dermal studies, there are a few oral rat stud ies available for picaridin (14 day, 5 week, and 14 week subchronic studies). Since the la st risk assessments (D279005, 2001; D323024, 2006),

several in vitro dermal absorption studies with rat and human skin have been submitted and reviewed for picaridin. Additionally, more inform ation regarding the kidney effects observed in oral and dermal studies has also been submitted (see 4.3).

4.1 Toxicology Studies Available for Analysis

The toxicology database for picar idin is considered complete. Inhalation and immunotoxicity studies are not available; how ever, the Hazard and Science Policy Council (HASPOC), using a weight of the evidence (WOE) approach, conclu ded that these studies are not required for picaridin (TXR# 0056905). The available studies for picaridin include: 1) subchronic dermal and oral toxicity studies in rats , 2) dermal chronic studies in dogs and chronic/carcinogenicity studies in rats and mice, 3) dermal developmen tal studies in rats and rabbits, 4) a dermal reproduction study in rats 5) dermal acute and subchronic neurotoxicity studies, 6) dermal absorption ( in vivo and in vitro ) and dermal (and intravenous) me tabolism studies in rats, 7) a mutagenicity battery, and 8) acute lethality (LD5 0) studies. In addition, data characterizing the etiology of the kidney effects seen in rats are also available. Subchronic mouse and dog studies are not available for picaridin; how ever, new studies are not needed since potential toxicity can be adequately characterized by the available cancer mouse and chronic dog studies.

4.2 Absorption, Distribution, Metabolism, Excretion (ADME)

The absorption, distribution, metabolism, and e limination (ADME) of picaridin have been examined in rats following dermal and intr avenous (I.V.) administration with varying dose levels. Picaridin was rapidly ab sorbed, metabolized, and excreted in the urine. After dermal exposure, the onset of absorption was fast with half-lives of 0.8-3.4 hours and peak blood levels were reached within 6-8 hours of dosing; blood le vels were higher in females. Approximately,
60-66% of the administered dose was absorbed at the low dose and 40-55% at the high dose during the test duration of 7 days. The majority was absorbed (> 90%) within the first 24 hours after application. Following I.V. administration (within 48 hours of dosi ng), urinary elimination was 74-82% in males and 87-90% in females; f ecal elimination was 12-17% in males and 5-6% in females; and 0.4-0.5% remained in the body for both sexes. The metabolite profile and

relative distribution of metabolites was similar in urine and feces, and between dose groups and

sexes.Page 8 of 23 4.2.1 Dermal Absorption

Since the last risk assessment, several in vitro dermal absorption studies using rat and human

skin with different formulations have been s ubmitted for picaridin. The formulations with and

without ethanol indicate similar absorption values, which addresse s an uncertainty previously identified regarding the potential for ethanol to increase dermal absorption. Formulations with

and without sunscreen were also tested and the absence of sunscreen resu lted in a 2-fold higher absorption value. Additionally, the data demonstr ates that dermal absorption in rat skin is approximately 2X higher than dermal absorption in human skin after exposure to picaridin.

Technical/Formulations In vivo Rat (0.67 mg/cm 2 )

168 hours* In vitro Rat (0.63mg/cm 2 )

24 hours In vitro Human (0.63mg/cm 2 )

24 hours

KBR-3023 Technical 19.1% 25.2% 10.7%

KBR 3023 15% in ethanol N/A 22.3% 9.8%

Cutter Insect Repellant SS (

KBR3023 15% ethanol with sunscreen) N/A N/A 9.9%

Cutter Insect Repellant Formulation A- (KBR3023

15% ethanol without sunscreen) N/A N/A 18.9%

* The 168 hour time point was used for the in vivo rat since there was continued absorption after 8 and 24 hours.

4.3 Toxicological Effects

In the majority of the toxicity studies for picaridin, no treatment related effects were seen up to the highest doses tested. However, kidney effects were seen in or al and dermal toxicity studies

in rats at ≥ 500 mg/kg/day; body weight changes were seen in oral studies at the limit dose. The kidney effects observed included increased kidn ey weights, slight hyaline degeneration, an increased incidence of foci of tubular rege neration, chronic kidney inflammation, and protein droplet nephropathy.

The kidney effects observed in the picaridin database are consistent with nephrotoxicity resulting from alpha 2 u globulin (a 2u -g) accumulation. The first morphological manifestation of alpha 2 u globulin nephropathy is the rapid accumulation of hyaline droplets in proximal tubule cells, developing within 24 hours of dosing with some compounds (We bb, et al 1989); exposure to picaridin resulted in protein drople ts in oral subchronic rat studies at the limit dose. In order to confirm that the apparent nephrotoxicity seen with picaridin was related to a 2u -g accumulation, the registrant submitted pathology slides and drop let staining information. The protein droplets

observed in the oral studies with picaridin were stained with Mallory’s Heidenhain (MH) and Periodic Acid Schiff (PAS). The droplets were negative with PAS and positive with MH stains.

The observation is consistent with what is seen for a 2u -g hyaline droplets. The droplets stain positively with MH stain but are negative for PAS, indicating their protein composition (Alden et al., 1984).Page 9 of 23 Since a 2u -g is a male rat specific protein, acute and ch ronic renal effects induced in male rats are unlikely to occur in any species not producing a 2u -g, or a very closely related protein, in the large quantities typically seen in the male rat (Alden, 1989; Borg hoff et al., 1990; Green et al., 1990; Olson et al., 1990; Flamm and Lahman-McK eeman, 1991; Swanberg, 1991). Therefore, nephropathy induced by a 2u -g accumulation would not be expected to occur in female rats, mice (either sex) or other species, in cluding humans. As a result, the a 2u -g nephropathy in male rats is not an appropriate endpoint to determine noncan cer (systemic) effects potentially occurring in humans. Likewise, quantitative estimates of no ncancer risk (e.g., reference doses) and marginof-exposure determinations) should be based on other endpoints (USEPA , 1991). Therefore, the kidney effects were not considered appropriate for risk assessment.

In addition to kidney effects, a decrease in body weight was noted at the limit dose (1000 mg/kg/day) following oral exposures for 5 weeks or longer. It is noteworthy that no progression of toxicity was observed, since body weight de crements were lower after 14 weeks of oral exposure ( ↓ 11%) vs 5 weeks ( ↓ 16%).

There was no evidence of increased quantitati ve or qualitative susceptibility in dermal developmental toxicity studies in rats or rabbits or in a reproduc tion study in rats. No maternal or fetal/offspring effects were obs erved in the studies. There wa s no evidence of neurotoxicity in dermal acute and subchronic neurotoxicity studie s, or in any other st udies in the toxicology

database.

Although the tissue rece iving the highest dose in the dermal studies was the skin, no skin tumors or precursor lesions were observe d in the rat, mouse, or dog. Also, there is no evidence of carcinogenicity in dermal carcinogenicity studies in rats and/or mice and picar idin is classified as “not likely to be a carcinogenic to humans vi a the dermal route." Additionally, there is no mutagenicity concer n for picaridin.

In acute lethality oral, dermal, and inhalation st udies, exposure to picaridin resulted in low toxicity (Categories III a nd IV). It is moderately irritating to the eye and not irritating to the skin; it is not a dermal sensitizer.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

4.4.1 Food Quality Protection Ac t (FQPA) considerations

Food Quality Protection Act (FQPA) considerations do not apply to picaridin since the registered uses are non-food, and dietary expos ure is not anticipated. Howeve r, HED’s risk assessment has considered toxicity and exposure to sensit ive populations, includi ng infants and children.

4.4.2 Completeness of the Toxicology Database

The toxicology database for picar idin is adequate and considered complete for characterizing toxicity.Page 10 of 23 4.4.2 Evidence of Neurotoxicity

Dermal acute and subchronic neurotoxicity studie s are available for picaridin. No evidence of neurotoxicity was observed in the acute neurot oxicity study in rats up to 2000 mg/kg/day (limit dose) or in the subchronic neurotoxicity study up to 200 mg/kg/day. Additionally, no evidence of neurotoxicity was seen in the other availa ble toxicity studies for picaridin.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

No evidence of quantitative or qualitative susceptibility was observed in the dermal developmental and reproduction studies.

4.4.4 Residual Uncertainty in the Exposure Database

A quantitative risk assessment was not performed for picaridin. Therefore, there are no residual uncertainties regarding exposure.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Toxicity endpoints and points of departure were not selected for picaridin. A qualitative human

health risk assessment was conducted in lieu of a quantitative assessment, due to the limited toxicity seen in the database. Although kidney effects were seen in rats in dermal and oral toxicity studies, the effects are a result of accumulation of alpha 2-u globulin. Since a 2u -g is a male rat specific protein, kidney toxicity induced by its accumulation is not be expected to occur in female rats, mice, or in any other species, including humans. Therefore, the kidney effects

observed in male rats are not c onsidered appropriate for use in human health risk assessment. Outside of the kidney effects, toxicity was lim ited to body weight changes seen only at the limit dose (1000 mg/kg/day); human exposur e at this level is not anticip ated in conjunction with the use of products containing picaridin in accordance with registered labels.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

A quantitative risk assessment was not performed for picaridin. Therefor e, there are no exposure

routes to combine.

4.5.3 Classification of Carcinogenic Potential

Picaridin is classified as “not li kely to be a carcinogenic to huma ns”, via the dermal route. No

treatment-related increas e in tumors was observed in dermal carcinogenicity studies in rats and/or mice. Picaridin was negative in the majori ty of mutagenicity studie s. Clastogenicity was

observed in in vitro chromosomal aberration studies in Chinese Hamster Ovary (CHO K1) cells. However, the effect was not expressed in vivo . Therefore, there is no mutagenic concern for picaridin.Page 11 of 23 5.0 Dietary Exposure and Risk Assessment

Picaridin is a non-food active i ngredient; therefore, dietar y exposure is not expected.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

The residential exposure database is adequate to support the registra tion review process for picaridin. Picaridin is registered for use as an insect repellent applied directly to the skin of adults and children. There is also a registered picaridin product for use on horses (i.e., a readyto-use spray “Ride Together” to protect the rider and the horse). Picaridin products are available in multiple formulations, including aerosol sprays, creams, and lotions containing 5-20% picaridin. Labels contain instructions which prohibit application dire ctly to the hands of children, among other use directions , to decrease the likelihood of adverse health effects from possible misuse or overuse of insect repellent products. Picaridin products can be used for several days or weeks or longer, depending on the activity pattern and geographic area. Exposure is expected to be of short- and intermediate- termexposure duration; however, longterm exposures are possible for some individuals in some climates.

Insect repellents are used on pe ople of all ages. Adults are a ssumed to experience both dermal and inhalation handler exposures, as well as post-application derm al and, potentially, inhalation exposure. Adults are assumed to apply repellents to themselves or to others. Additionally, for aerosol and spray repellents, indi viduals to whom the products are being applied can experience indirect inhalation exposure dur ing the application. For chil dren, post-application exposure consists of dermal, (potentially) inhalation, and incidental oral (hand- to-mouth) exposure.

Several previous risk assessments have been co nducted to evaluate human exposure to picaridin in support of its proposed use as a repellent. However, based on current policies and an updated evaluation of the available toxicity data, no toxico logical endpoints and points of departure (for either the dermal, incidental or inhalation route of expos ure) have been selected for picaridin risk assessment. Therefore, an updated quantitative residential exposure and risk assessment is not required to support registration review.

6.1 Spray Drift

Registered picaridin uses were evalua ted as part of the Registration Review process to ensure that the potential for spray drift has been consid ered in the risk assessment. Based on the use pattern, HED determined that picaridin is not regi stered on use sites that would result in spray drift. Therefore, a qua ntitative spray drift assess ment was not conducted.

7.0 Aggregate Exposure/Risk Characterization

Based on the non-food use pattern, for picaridin, as well as a lack of toxi city associated with exposure to picaridin, HED concludes that aggregate risks are not of concern.Page 12 of 23 8.0 Cumulative Exposure/Risk Characterization

The Agency has not determined that picaridin shares a common mechanism of toxicity with other chemical substances; theref ore, a cumulative risk assessment to support registration review is not required.

9.0 Occupational Exposure/Risk Characterization

There is no occupational exposure associated with registered uses of picaridin.

10.0 Public Health and Pesticide Epidemiology Data

For this evaluation, the Agency consulted both the OPP Incident Data System (IDS) and the

Centers for Disease Control and Prevention/Na tional Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk-Pesticides (SENSOR) databases were consulte d for pesticide incident data on the active ingred ient picaridin (D417724, S. Recore, 2/11/2014). The purpose of the database search is to identify potential patterns in the frequency and severity of the heal th effects attributed to picaridin exposure. Picaridin is not included in the AHS, and theref ore this study does not provide information for

this document.

For the Main IDS, from January 1, 2009 to Ja nuary 15, 2014, there were 26 incidents reported for the single chemical only in the database. These incidents were classified as moderate severity, not life threatening and the person returned to his/her pr e-exposure state of health with no additional residual disability. There were no additional incidents reported involving more than one chemical. In the Aggregate IDS, fr om January 1, 2009 to January 15, 2014, there were 214 reported incidents involving picari din. These incidents were clas sified as minor severity and the symptoms resolved rapidly and usually invo lved skin, eye or resp iratory irritation.

A query of SENSOR-Pesticides 1998-2010 identifie s 22 cases involving pi caridin, 19 involving a single active ingredient and three involving mu ltiple active ingredients. Of the 19 cases involving the single active ingredie nt, eighteen cases were low in severity, largely involving dermal or eye irritation; one case was moderate in severity, and involved di rect application of a product containing picaridin to the face of an infant.

Based on the low frequency and low severity of in cident cases reported fo r picaridin in both IDS and SENSOR-Pesticides, there does not appear to be a concern at this time that would warrant further investigation.

11.0 Literature References

A literature search was performed for picaridin. The search did not reveal information that would impact the current risk assessment.Page 13 of 23 12.0 References

Alden, C.L., Kanerva, R.L., Ridder, G., and Stone, L.C. (1984) The pathogenesis of the nephrotoxicity of-volatile hydrocarbons in th e male rat: Mehlman, M.A., Hemstreet, G.P., Thorpe, J.J., and Weaver, N.K.(eds.), Advances in Modern Environmental Toxicology. Vol. VII. Renal Effects of Petroleum Hydrocarbons. Prince ton Scientific Publishers,Inc., Princeton, New Jersey, pp. 107-120.

Figueroa, Z., Vogel, D. (2006) Re-Evaluat ion of Exposure Assumptions for KBR 3023 (Picaridin). PC Code: 070705. DP 323024.

Figueroa, Z. (2008) Picardin: Evaluation of in vitro dermal penetration study using human and

rat skin for KBR 3023. PC Code: 070705. DP 357835.

Leshin, J. (2014) KBR 3023 (Picaridin): Summ ary of the Hazard and Science Policy Council (HASPOC): Recommendations on the Need for Additional Oral, Inhala tion and Immunotoxicity

Studies. TXR# 0056905.

Figueroa, Z. (2008) Picardin: Evaluation of in vitro dermal penetration study using human and

rat skin for KBR 3023. PC Code: 070705. DP 357835.

U.S. EPA. Alpha2u-Globulin: A ssociation with Chemically Induced Renal Toxicity and Neoplasia in the Male Rat. U.S. Environmen tal Protection Agency, Risk Assessment Forum, Washington, DC, EPA/625/ 3-91/019F (NTIS PB92143668), 1991.

Webb, D.R., Ridder, G.M., and Alden, C.L. (1989) Acute and subchronic nephrotoxicity of dlimonene in Fischer 344 rats. F d. Chern. Toxicol. 27: 639-649.

Weiss, S. (1999) Human Health Risk Assessmen t for KBR 3023 All Family Insect Repellent Spray & Cream. PC Code: 070705. DP 259708.

Whalan, J. (2000) Human Health Risk Assessm ent for KBR 3023 All Family Insect Repellent Spray & Cream. PC Code: 070705. DP 261567.

Whalan, J. (2001) Human Health Risk Assessm ent for KBR 3023 All Family Insect Repellent Spray & Cream. PC Code: 070705. DP 279005.Page 14 of 23 Appendix A. Toxicology Profile

Table A.1. Acute Toxicity Profile of KBR 3023 (Picaridin) Technical.
Guideline
Number Study Type

Classification MRID

Number Results Toxicity Category

870.1100 Acute Oral – Rat (w/ 2% Cremophor EL) 44408705

44408706 LD 50 = 4743 mg/kg (Males)

LD 50 = 2236 mg/kg (Females) III

870.1200 Acute Dermal - Rat 44408707 LD 50 >2000 mg/kg (limit test) NOEL = 2000 mg/kg NOAEL >2000 mg/kg III

870.1300 Acute Inhalation -

Rat 44408709 LC 50 >4.364 mg/L NOAEL = 4.364 mg/L (slight body weight anomalies) IV

870.2400 Primary Eye

Irritation - Rabbit 44408710 Moderate ocular irritant III

870.2500 Primary Skin

Irritation - Rabbit 44408712 Not a dermal irritant IV

870.2600 Dermal Sensitization - Guinea Pig 44408713

44408714

44408752

44408758 Not a dermal sensitizer* --

* There is no evidence of dermal sensitization in a Buehler test of KBR 3023; this stud y was classified unacceptable because there was no positive control group (MRID 44408713). Two of five trace components of KBR 3023 tested in a maximization test were significant dermal sensitizers (MRID 44408714). No dermal sensitization was observed in Buehler tests of the 20% alcoholic and cream formulations (MRID 44408752 and 44408758).Page 15 of 23 Table A.2. KBR 3023 (Picaridin) Subchronic, Chronic, and Other Toxicity.

GUIDELINE

NO. STUDY TYPE MRID NO. (YEAR)/

CLASSIFICATION /DOSES RESULTS

870.3100 14-Day Feeding - Rat [Range finding study] 45227601

0, 1000, 1500, 2000, 20,000 ppm

Males:0, 90, 141, 183, 731 mg/kg/day Females: 0, 109, 163, 202, 1826 mg/kg/day

Although this was a range-finding study, it was performed in compliance with the GLPs and was patterned after guideline OPPTS 870.3100 (90-day oral toxicity in rodents). NOAEL = 20,000 ppm (1731/1826 mg/kg/day, M/F) which exceeds the limit dose of 1000 mg/kg/day.
LOAEL - not determined

870.3100 5-Week Feeding -

Rat 45387901

0, 100, 150, 300, 1000 mg/kg/day

This study was a satellite to subchronic study MRID 45387902 (below). NOAEL = 308 mg/kg/day (actual daily intake) LOAEL = 1034 mg/kg/day based on decreased body weight and kidney effects (increased relative kidney weights and increased incidence of protein droplet nephropathy in males). The kidney effects observed are attributable to alpha 2-u globulin accumulation which is species specific (rat) and not appropriate for human risk

assessment.

870.3100 14-Week Feeding -

Rat 45387902
0, 100, 150, 300, 1000 mg/kg/day NOAEL = 301 mg/kg/day LOAEL =1033 mg/kg/day based on decreased body weight and kidney effects (increased relative kidney weights and increased incidence of protein droplet nephropathy in males). The kidney effects observed are attributable to alpha 2-u globulin accumulation which is species specific (rat) and not appropriate for human risk

assessment

870.3250 Dermal Subchronic -

Rat MRID 44408716
0, 80, 200, and 500 mg/kg/day NOAEL (systemic) = 200 mg/kg/day LOAEL (systemic) = 500 mg/kg/day based on kidney effects (hyaline degeneration in the kidneys, increased

incidence of foci of tubular regeneration, and chronic kidney inflammation). The kidney effects observed are attributable to alpha 2-u globulin accumulation which is speciesPage 16 of 23 Table A.2. KBR 3023 (Picaridin) Subchronic, Chronic, and Other Toxicity.

GUIDELINE

NO. STUDY TYPE MRID NO. (YEAR)/

CLASSIFICATION /DOSES RESULTS

specific (rat) and not appropriate for

human risk assessment. NOAEL (dermal irritation)=not

determined LOAEL (dermal irritation) = 80 mg/kg/day (scabs, red foci, and exfoliation at the dosing site).

870.3700 Dermal Developmental Toxicity - Rat MRID 44408725
0, 50, 200, and 400 mg/kg/day Maternal and Developmental NOAEL=400 mg/kg/day

LOAEL= not determined

870.3700 Dermal Developmental Toxicity - Rabbit MRID 44408721
0, 50, 100, and 200 mg/kg/day Maternal and Developmental NOAEL=200 mg/kg/day

LOAEL= not determined

870.3800 Dermal Reproductive Toxicity - Rat MRID 44408727
0, 50, 100, and 200 mg/kg/day Systemic, reproductive, and Offspring NOAEL=200 mg/kg/day
LOAEL= not determined

870.4100 Dermal Chronic Toxicity - Dog MRID 44408718 NOAEL=200 mg/kg/day

LOAEL= not determined

870.4200 Dermal Carcinogenicity - Mouse (18 months) MRID 44408719
0, 50, 100, and 200 mg/kg/day NOAEL=200 mg/kg/day
LOAEL= not determined

There is no evidence of carcinogenicity.

870.4300 Dermal Chronic Toxicity/Carcinogeni city-Rat MRID 44408728
0, 50, 100, and 200 mg/kg/day NOAEL=200 mg/kg/day

LOAEL= not determined

There is no evidence of carcinogenicity.

870.5265 Salmonella typhimurium

Mammalian

Activation Gene Mutation Assay MRID 44408729 Negative

870.5300 In Vitro Gene Mutation Assay in

Chinese Hamster

V79 Cells MRID 45231801 Negative

870.5375 In Vitro Mammalian
Chromosome MRID 44408732 Clastogenic in CHO cells in the

absence of metabolic activation.Page 17 of 23 Table A.2. KBR 3023 (Picaridin) Subchronic, Chronic, and Other Toxicity.

GUIDELINE

NO. STUDY TYPE MRID NO. (YEAR)/

CLASSIFICATION /DOSES RESULTS

Aberrations in CHO
Cells

870.5375 In Vitro Mammalian
Chromosome

Aberrations in CHO

Cells MRID 44408733 Clastogenic with metabolic activation for CHO cells; equivocal in the absence

of metabolic activation.

870.5395 In Vivo Mammalian Cytogenetics - Micronucleus Assay

in Mice MRID 44408734 Negative

870.5550 Unscheduled DNA Synthesis in Rat Hepatocytes MRID 44408730 Negative

870.6200 Acute Dermal Neurotoxicity - Rats MRID 44408715
0, 200, 600, and 2000 mg/kg/day NOAEL=2000 mg/kg/day

LOAEL= not determined

870.6200 Subchronic Dermal Neurotoxicity - Rats MRID 44408717
0, 50, 100, and 200 mg/kg/day NOAEL=200 mg/kg/day

LOAEL= not determined

870.6300 Dermal Developmental Neurotoxicity - Rat Not required

870.7485 Dermal and I.V.

Metabolism - Rat MRID 44408735 Dermal: Animals dosed dermally absorbed 60-66% of the low-dose (20 mg/kg, 0.5 mg/cm 2 ) and 40-55% of the high-dose (200 mg/kg, 5 mg/cm 2 ) which suggests saturation. Elimination was mostly in the urine. Approximately 19- 33% of the dose was not recovered, most likely due to evaporation. Radioactivity remaining in the carcass after 7 days was 0.4-0.5% in males and 0.2-0.4% in females. Absorption was rapid with half-lives of 0.8-3.4 hr. Plasma peak concentrations were

reached within 6-8 hou rs of dosing and were higher in females than males. Elimination of radioactivity from plasma of dermally dosed animals was dose- and sex-dependent.

I.V.: Within 48 hours of I.V. dosing, urinary elimination was 74-82% in males and 87-90% in females; fecal
elimination was 12-17% in males and 5- 6% in females; and 0.4-0.5% remained in the body for both sexes.Page 18 of 23 Table A.2. KBR 3023 (Picaridin) Subchronic, Chronic, and Other Toxicity.

GUIDELINE

NO. STUDY TYPE MRID NO. (YEAR)/

CLASSIFICATION /DOSES RESULTS

Metabolism: Nineteen metabolites

were identified in urine and feces of both I.V. and dermally dosed rats. The metabolite profile and relative

distribution of metabolites is similar in urine and feces, and between dose groups and sexes. The metabolism of KBR 3023 in rats primarily involves oxidation of the 2-hydroxyethyl group to an acid to form metabolite M16, coupled with hydroxylation of the 1- methylpropyl group to form metabolites M8, M9, and M10. The other minor phase I metabolites result from hydroxylation of the piperidine ring (M1-M4 and M7). Minor phase II metabolites result from conjugation of glucuronic acid with parent (M14 and M15) or phase I metabolites (M5, M6, and M11-M13).

870.7600 Dermal Absorption -

Rat MRID 44408737 Rats were dermally dosed at nominal levels of 8, 40, or 200 mg/kg (0.133, 0.67, or 3.33 mg/cm 2 ) for 8 hours. After 8 hours, absorption of the applied dose was 14.4, 9.8, and 6.9% in males, and 27.4, 12.6, and 8.9% in females, respectively; and skin retention of the applied dose was 5.5, 7.6, and 9.2% in males, and 4.8, 8.8, and 13.7% in females, respectively. After 168 hours (7 days) absorption of the applied dose was 18.5, 18.1, and 12.9% in males, and 24.9, 16.5, and 21.1% in females, respectively; and skin retention of the applied dose was 1.9, 1.0, and 0.8% in males, and 2.2, 1.0, and 1.0% in females, respectively. After 168 hours (7 days) total absorption and skin-retained of the applied dose was 20.4, 19.1, and 13.7% in males, and 27.1, 17.5, and 22.1% in females, respectively.

Note: A dermal absorption factor of 19.1% from the mid dose (40 mg/kg/day) after 168 hours (due to continued absorption) was used with the

in vitro dermal absorption data to

determine a refined dermal dose for risk

assessment.Page 19 of 23 Table A.2. KBR 3023 (Picaridin) Subchronic, Chronic, and Other Toxicity.

GUIDELINE

NO. STUDY TYPE MRID NO. (YEAR)/

CLASSIFICATION /DOSES RESULTS

870.7600 Comparative In Vitro
Dermal Penetration Study Using Rat and

Human Skin MRID 47342201 Mean total recoveries ranged from 100.1-115.1% of the applied dose. For the technical formulation, 7.3% of the applied dose was directly absorbed through human skin, while 21.8% of the applied dose was directly absorbed through rat skin (2.97-fold difference). For the 15% (w/v) ethanol formulation, 5.6% of the applied dose was directly absorbed through human skin, while 16.8% of the applied dose was directly absorbed through rat skin (3.01-fold difference). For the technical formulation, 10.7% of the applied dose was potentially absorbable through human skin, while 25.2% of the applied dose was potentially absorbable through rat skin (2.4-fold difference). For the 15% (w/v) ethanol formulation, 9.8% of the applied dose was potentially absorbable through human skin, while 22.3% of the applied dose was potentially absorbable through rat skin (2.3-fold difference).

870.7600 In Vitro Dermal Penetration Study Using Human Skin MRID 47340901 Higher mean dermal penetration in all skin layers was observed in Formula A compared to the SS formulation. The mean percentage of [ 14 C]-KBR 3023 that was directly absorbed was 2.1 fold higher in the Cutter Insect Repellent Formula A without sunscreen (12.44% dose) compared to the SS Formula with sunscreen (5.92% dose). Similarly, the mean percentage of [ 14 C]-KBR 3023 that was potentially absorbable was 1.6 fold higher in Formula A (6.47% dose) compared to the SS Formula (3.93% dose). Thus, the sum of the mean percentage of [ 14 C]-KBR 3023 that was directly absorbed and that which remained in the skin for potential absorption was 1.9 fold higher in Formula A (18.91% do se) compared to the SS Formula (9.85% dose).Page 20 of 23 Appendix B. Review of Human Research

A dermal absorption study with human volunteers [MRID 44408736 (1996) and 44408738 (1994)] involving intentional exposure to picaridin was used in earlier assessments to determine a dermal absorption factor. However, the study was not used in the cu rrent assessment and the dermal absorption factor was determined using in vivo dermal absorption data in the rat, along

with in vitro dermal absorption data in rat and human skin. If EPA decides to use any studies with human volunteers, EPA will ensure that a ll applicable regulatory requirements are met, including, but not limited to, the requirements fo r EPA ethics review a nd Human Studies Review

Board review of certain research involvi ng intentional exposure of human subjects.

Appendix C. Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews num erous studies to asse ss potential adverse outcomes from exposure to chemicals. Collectiv ely, these studies includ e acute, subchronic and chronic toxicity, including asse ssments of carcinogenicity, ne urotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influe nce, including effects on endocri ne target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess gr owth, developmental and reprod uctive effects in different taxonomic groups. As part of registration review for picaridin, EPA reviewed these data and selected the most sensitive endpoi nts for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), picaridin is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whet her certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or ot her such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making th e statutorily required

determinations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pest icide active ingredient s and 9 inert ingredients. A second list

of chemicals identified for EDSP sc reening was published on June 14, 2013 1 and includes some

1 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of

chemicals.Page 21 of 23 pesticides scheduled for registration review and chemicals found in water

. Neither of these lists

should be construed as a list of know n or likely endocrine disruptors.

For further information on the status of the ED SP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening batt ery, please visit our

website. 2

Appendix D. Picaridin Use Pattern

Appendix D. Summary of Directions for Use of Picaridin.

Formulation [EPA Reg. No.] Applic. Timing, Type, and

Equip. Single Applic.

Rate Max. No. Applic. per Day Specific Use Directions and

Limitations

KBR 3023 All-Family Insect Repellent Cream
20% ai [39967-50] 1 RTU Cream 1 appl. 2 appl./day Apply evenly. Avoid applying excessive amounts of this product. Do not apply on

children’s hands.

KBR 3023 All-Family Insect Repellent Spray
20% ai [39967-53] 1 RTU Spray 1 appl. 2 appl./day Do not apply in enclosed areas.

Cutter Insect Repellent 7K
7% ai [121-89] RTU Spray 1 appl. 3 appl./day Do not apply in enclosed areas.

Cutter Insect Repellent 5KT
5.75% ai [121-90] RTU
Towelettes 1 appl. (towelette) 3 appl./day Apply evenly.

Cutter Insect Repellent 15KP
15% ai [121-91] RTU Spray (6 oz container) 1 appl. 3 appl./day Do not apply in enclosed areas.

Cutter Insect Repellent 15KA
15% ai [121-92] RTU Spray (6 oz container) 1 appl. 3 appl./day Do not apply in enclosed areas.

Cutter Insect Repellent 12KT
12% ai [121-93] RTU
Towelettes 1 appl. (towelette) 3 appl./day Apply evenly.

Cutter Insect Repellent 10KP
10% ai [121-94] RTU Spray 1 appl. 3 appl./day Do not apply in enclosed areas.

Cutter Insect Repellent 10KA
10% ai [121-95] RTU Spray (6 oz container) 1 appl. 3 appl./day Do not apply in enclosed areas.

Cutter Insect Repellent SS

SPF 30
15% ai [121-97] RTU Spray (6 oz container) 1 appl. 3 appl./day Reapply every 3-4 hours. For sunscreen protection apply as needed after towel drying, swimming or sweating. Do not apply on children < 6 months old of age. Cutter Insect Repellent 20KP
20% ai [121-99] RTU Spray 1 appl. 2 appl./day Do not apply in enclosed areas.

2 http://www.epa.gov/endo/Page 22 of 23 Appendix D. Summary of Directions for Use of Picaridin.

Formulation [EPA Reg. No.] Applic. Timing, Type, and

Equip. Single Applic.

Rate Max. No. Applic. per Day Specific Use Directions and

Limitations

Cutter Insect Repellent 20KA
20% ai [121-100] RTU Spray (6 oz container) 1 appl. 1 appl./day Do not apply in enclosed areas.

Ecopel All-Family Insect Repellent Spray
20% ai [86374-1] RTU Spray (7 oz container) 1 appl. 2 appl./day Hold 4-6 inches from skin while spraying, keeping nozzle pointed away

from face.

KBR 3023 All-Family Insect Repellent Cream II
5% ai [3125-546 transferred to 4822- 535] RTU Cream 1 appl. 3 appl./day Apply evenly. Avoid applying excessive amounts of this product. Do not apply on

children’s hands.

KBR 3023 All-Family Insect Repellent Non-Aerosol Spray
5% ai [4822-536] RTU Spray 1 appl. 3 appl./day Reapply every 3-4 hours. Do not apply in

enclosed areas.

KBR 3023 All-Family Insect

Repellent Aerosol Spray
10% ai [4822-537] RTU Aerosol Spray (12 oz bottle) 1 appl. 3 appl./day (adult) 2 appl./day (children) Reapply every 6 hours. Do not apply in

enclosed areas.

Geneva-T

16% ai [4822-555] RTU
Towelettes 1 appl. (towelette) 2 appl./day Apply evenly.

OFF! Deep Woods Sportsmen Insect Repellent V
20% ai [4822-556] RTU Spray 1 appl. 2 appl./day Reapply every 8 hours.

OFF! Deep Woods Sportsmen Insect Repellent VI
20% ai [4822-564] RTU Spray 1 appl. 2 appl./day Reapply after 8 hours.

AVON Skin-So-Soft SSS IR3535 Bug Guard Plus Picaridin Insect Repellent Aerosol Spray
10% ai [806-29] RTU Aerosol Spray 1 appl. 2 appl./day Reapply every 7 hours for deer ticks, gnats, no-seeums, sand flies and biting midges; for mosquitos reapply after 6 hours; for black flies reapply after 3

hours.

AVON Skin-So-Soft SSS IR3535 Bug Guard Plus Picaridin Insect Repellent

Towelettes

10% ai [806-30] RTU
Towelettes 1 appl. (towelette) 2 appl./day Apply evenly. Reapply every 8 hours for mosquitos; reapply after 6 hours for gnats, no-seeums, sand flies and biting midges.

AVON Skin-So-Soft SSS IR3535 Bug Guard Plus Picaridin Insect Repellent Spray

10% [806-31] RTU Spray 1 appl. 2 appl./day Reapply every 12 hours for deer ticks; for gnats, no-seeums, sand flies and biting midges reapply after 6 hours; for mosquitos reapply after 8 hours.Page 23 of 23 Appendix D. Summary of Directions for Use of Picaridin.

Formulation [EPA Reg. No.] Applic. Timing, Type, and

Equip. Single Applic.

Rate Max. No. Applic. per Day Specific Use Directions and

Limitations

Natrapel 8-Hour Insect Repellent Wipes
20% ai [56575-14] RTU
Towelettes 1 appl. (towelette) 2 appl./day Apply evenly. Reapply every 8 hours.

Natrapel 8-Hour Insect Repellent Spray
20% ai [56575-15] RTU Spray 1 appl. 2 appl./day Slightly moisten skin or clothing with a slow sweeping motion. Use of this product may cause skin reactions in rare

cases. Insect Guard 3023 Insect Repellent

20% ai [54287-22] RTU Spray 1 appl. 2 appl./day Reapply every 8 hours.

Centaura Fly and Mosquito Spray Repellant
20% ai [85972-1] RTU Spray 1 appl. 2 appl./day A “Ride Together” spray to protect the rider and horse. For use on horse (all breeds) and riders. Do not apply on horses intended for human consumption

and under saddle. Insect Repellent Spray - Family

& Active-Use Protection

86459-1 RTU Spray 1 appl. 2 appl./day Apply evenly. Protection for 8 hours.

1 Major producer; product labels from companies with registered technical/manufacturing products.