Page 1 of 18 

### UNITED STATES ENVIRONMEN TAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION

MEMORANDUM

Date: February, 2013

SUBJECT: KBR 3023 (Picaridin): Summary of the Hazard and Science Policy Council (HASPOC): Recommendations on the Need for Oral Developmental, Reproduction, and Cancer Studies and Inhalation and Immunotoxicity Studies.

PC Code: 070705 DP Barcode: N/A
Decision No.: N/A Registration No.: N/A
Petition No.: N/A Regulatory Action: N/A Risk Assessment Type: N/A Case No.: N/A

TXR No.: CAS No.: N/A

MRID No.: N/A 40 CFR: N/A



### FROM: Kristin Rury, MPH Executive Secretary Hazard and Science Policy Council (HASPOC) Health Effects Division (HED 7509P

THROUGH: Jess Rowland, Co-Chair Anna Lowit, Ph.D, Co-Chair

HASPOC Health Effects Division (7509P)

TO: Karlyn Middleton, Toxicologist Christina Swartz, Branch Chief Risk Assessment Branch II (RAB II) Health Effects Division (HED; 7509P)

MEETING ATTENDEES

HASPOC Members: Anna Lowit, Elizabeth Mendez, Elissa Reaves, Jonathan Chen

Presenters: Karlyn Middleton, Zaida FigueroaPage 2 of 18 

### I. PURPOSE OF MEETING:

Risk Assessment Branch II (RABII) is cu rrently preparing a human health risk assessment for the insect repellant KBR 3023 which contains 5- 20% picaridin (1- methylpropyl 2-(2-hydroxyethyl)-1 -piperidine carboxylate) as the active ingredient. The active ingredient is referred to as "K BR 3023" throughout this document. During the data development for the repellent the Health Effects Division (HED) recommended that animal studies be performed by the dermal rout e to reflect the use pattern and to allow for accurate route-specific assessments. Because there was a problem with the neat test article spreading beyond the dosing sites, most repeated dosing studies had maximum doses of 200 mg/kg/day. As a result, there were a number of toxicity studies that did not elicit toxic effects. At the time, all guid eline studies with the exception of the acute studies were conducted by the dermal route; or al toxicity studies we re not available with the exception of the acute oral study. While preparing a hum an health risk assessment,
HED identified risk concerns for infants/ch ildren after a single a pplication. KBR 3023 was presented to the Hazard Identification Assessment Review committee (HIARC) who
raised concern over the lack of an oral st udy to assess hazard from incidental oral exposure for children. Also there was concern th at the dosing levels in the dermal studies were not high enough to fully evaluate pot ential carcinogenicity and developmental toxicity. Therefore, additiona l oral toxicity studies were identified as data gaps by HIARC, including: oral subchronic studies, de velopmental toxicity study in rabbits (only one species required at the time per guideline), oral carcinogenicity studies, and dermal pharmacokinetic studies in rats and humans. Subsequently, oral subchronic toxicity studies and eventually dermal penetration studies (rat and human skin) were submitted to the Agency. The other studies identified by HIARC as data gaps were ultimately not required by HED. The team (RAB II) requ ested input from the Hazard and Science Policy Council (HASPOC) regarding the ade quacy of the existing toxicology database for KBR 3023 (which consists of mostly derm al toxicity studies) and the need for the previously required oral studies , as well as the need for an oral developmental toxicity study in rats and a reproduction toxicity st udy in rats, now required for all non-food use chemicals. Additionally, RAB II wanted to discuss the need for inhalation and immunotoxicity studies required in accord ance with the current 40 CFR Part 158 Toxicology Data Requirements. The Hazar d and Science Policy Council (HASPOC) met on February 13, 2013 to discuss the need for addi tional oral toxicity studies, as well as inhalation and immunotoxicity studies.

II. SUMMARY OF USE PROFILE, EXPOSURE, AND HAZARD
CONSIDERATIONS

Use Profile: There are several formulations for KBR 3023 containing 5-20% picaridin as the active ingredient. Formulations are ap plied directly to the skin of adults and
children. Labels contain instru ctions which prohibit applicati on directly to the hands of children and limit the number of applicat ions per day (e.g., “Do not exceed two applications per day.”). However, KBR 3023 pr oducts can be used for several days or weeks or longer, depending on the activity pattern and geographic area. Although an incidental oral endpoint was selected and the FQPA factor was reduced to 1X, the KBRPage 3 of 18 

### 3023 use is non-food and any inci dental dietary exposure woul d not appear to trigger FQPA considerations. The Office of Genera l Counsel determined that KBR 3023 is not legally subject to the FQPA provisions.

Toxicity Profile: The majority of studies for KBR 3023 were done dermally and dermal
irritation was observed in seve ral studies; however, the derm al irritant effects were generally not dose-related. Dermal absorption studies show that absorption in males is 11.5-times greater in rats than in human s over 7 days. Even though the short, intermediate, and long-term ra t dermal NOAELs are all 200 mg /kg/day, there is evidence of modest systemic accumulation in rats. Sk in retention is very low in humans (0.02% one hour after dosing site washi ng), excretion is rapid (94% w ithin 24 hours), and there is little likelihood of systemic accumulation.

Although the skin received the highest dose, th e target organs are the liver and possibly the kidneys. In the dermal subchronic rat study, lesions seen at 500 mg/kg/day included slight to moderate diffuse liver hypertr ophy, necrotic liver cells, slight hyaline degeneration in the kidneys, increased inci dence of foci of tu bular regeneration, and chronic kidney inflammation. There was full reve rsibility after a 4-w eek recovery period. The NOAEL in the study is 200 mg/kg/day. In the dermal chronic toxicity/carcinogenicity study in rats, no treatment re lated effects were observed at doses up to the highest dose tested of 200 mg/kg/day.

There was no evidence of neurotoxicity in dermal acute and subchronic neurotoxicity studies, or in any other studi es. No treatment related e ffects were seen in dermal developmental and reproductive toxicity studi es. Ossification variations observed in
treated and control rat fetuses were attributed to maternal stress due to the dermal dosing regimen. There was no evidence of increased quan titative or qualitative susceptibility in the developmental or reproductive toxicity studies.

Dermal absorption studies are available for KBR 3023 that demonstrate absorption ranging from 7-27% after 8 hours in rats. In humans, dermal absorption after 8 hours ranged from 1-4%.

KBR 3023 is classified as not likely to be a car cinogen by the dermal route. There is no evidence of carcinogenicity in dermal cancer studi es in the rat or mouse, the mutagenicity studies are negative, and the structure of the molecule doe s not suggest a carcinogenic concern (SAR).

Risk Assessment: Acute and chronic dietary exposure is not anticipated for KBR 3023; therefore, assessments were not conducted. Currently, the inci dental oral risk assessment is based on body weight changes and kidney effects observed in the 5 week oral toxicity study at the LOAEL of 1034 mg/kg/day; NOAEL= 308 mg/g/day (Table 3a). For short-term dermal exposure, the dermal developmental rabbit was used with a NOAEL of 200 mg/kg/day; no treatment relate d effects were seen in the study. For intermediate-term dermal, the 90 day dermal study was used based on liver and kidney effects seen at the LOAEL of 500 mg/kg/da y (NOAEL= 200 mg/kg/da y). For long-termPage 4 of 18 

### dermal, the dermal rat carcinogenicity st udy was used with a NOAE L of 200 mg/kg/day;
no treatment related effects were seen in the study (Table 3b). Alt hough there is potential for short-term inhalation exposure, inhalati on risk assessments were not selected in previous risk assessments, the decision was based on the low toxicity noted in acute inhalation lethality studies.

III. STUDY WAIVER REQUESTS

a. Oral Developmental, Reproduction, a nd Carcinogenicity Toxicity Studies

Dermal developmental, reproduction, and carci nogenicity studies ar e available for KBR 3023. In the dermal rat developmental study, the rat maternal and developmental NOAELs were 400 mg/kg/day, the highest dose test ed. At this dose, the dams had slight increases in liver weight (9% absolute, 5% relative) which was considered an adaptive response. The fetuses at this dose had delayed ossification that the re viewer attributed to maternal stress due to the dermal dosing regime n. In the dermal rabbit study, no systemic toxicity was seen in the rabbit does or fetuses at doses up to the highest dose tested of 200 mg/kg/day. Dermal lesions were observed in the studies. In th e dermal reproductive study in rats, no treatment rela ted systemic (dams or offspr ing animals) or reproductive toxicity was observed at doses up to 200 mg/kg/day. No trea tment related toxicity or tumors were observed in the dermal carcinogenic ity studies in mice or rats at doses up to 200 mg/kg/day. KBR 3023 is cla ssified as not likely to be a carcinogen by the dermal

route.

Since there were minimal effects noted in the studies due to problems with the neat test article spreading beyond the dosi ng sites, there was concern that the dosing levels in the dermal studies were not high enough to fully evaluate potential carcinogenicity and developmental effects. Therefore, the following additional oral toxicity studies were identified by HIARC as data gaps but ul timately were not required by HED.

 Oral Developmental Toxicity in Rabbits The HIARC felt that although no developmen tal toxicity occurred in dermally dosed rats or rabbits, there is potential for developmental toxicity in pregnant women exposed by the oral route (hand- to-mouth transfer). Since an oral developmental toxicity study would not be restrained by dosing limitations, it would demonstrate any potential for devel opmental effects by the oral route. A study in only one species was required (due to guideline requirements at the time).

 Oral Carcinogenicity Studies The requirement for these studies was rese rved pending the results of the oral subchronic toxicity study. Subchronic oral studies ( 14 day, 5 week, and 14 week) were submitted and reviewed by the Agency. No toxic effects were seen in the 14 day study up to the limit dose of 1000 mg/ kg/day. In the 5 and 14 week study, body weight changes and kidney effects were seen at the limit dose.

Note: since developmental studies in two species and reproduction studies are nowPage 5 of 18 

### required for all non-food use chemicals. The de velopmental toxicity study in rats and the reproduction study in rats are also considered possible data gaps.

b. Inhalation Toxicity Study

Previously, the Office of Pesticide Programs (OPP) used a set of criteria to determine whether or not an inhalation study could be waived. These criteria considered the scientific information available for the chemical, including its: (1) degree of irritation and corrosivity; 2) volatility; 3) aerosol particle size; and 4) Acute Toxicity Category and extrapolated MOEs (e.g., MOEs 10 times hi gher than the target). In 2009, OPP developed an issue paper on risk assessment a pproaches for semi-volatile pesticides. As part of that issue paper, an analytical comparison was conducted of oral and inhalation experimental toxicology studies. In general, this analysis showed that the degree to which oral PoDs were protective of potential inhalation toxicity va ried. In many cases the oral PoD was protective, but in some cases the inhalation PoDs were significantly more sensitive. Currently, OPP uses a wei ght of the evidence (WOE) approach that builds upon OPP’s experience using the criteria listed above and conclusions from the 2009 SAP. As approaches for route-to-rout e extrapolation conti nue to evolve and improve, OPP may incorporate additional cons iderations into the WOE analysis.

Inhalation exposure can be to vapors, droplet s, and/or particles/dusts. The form of inhalation exposure is determined by a numbe r of factors includi ng physical-chemical properties, use pattern, and exposure scenarios. OPP’s interim WOE approach considers:

1. Physical Chemical Properties: Vapor pressure and Henry’s law constant are key considerations with respect to the volatilization after sprays have settled. Picaridin (229.3 g/Mol) has a high vapor pressure of 4.4x10 -4 

### mm Hg at 25 ° C and Henry’s 

### Law constant of 3.0 x 10 -11 

### atm·m 3 

### /mol at 25 °C

2. Use pattern & exposure scenarios: Any application scen ario that leads to inhalation exposure to droplets needs to be considered in the WOE analysis for an inhalation toxicology study waiv er request. In the case of insect repellents, unlike other pesticide applications, “handler” a nd “post-application” exposures resulting from insect repellent applications ar e not truly separate events since many applications are self-appli cations. Adults are assumed to apply repellents to
themselves or to others. For aerosol and pump-sprayer re pellent products, the individual applying insect repellents is the “handler .” Therefore, inhalation exposure for adults and children during the application process is possible and can
be evaluated under the standard “handler ” assessment. For insect repellents, inhalation exposure is only assessed as part of the handler scenario. Handler exposure for repellent applications is gene rally considered shor t-term in duration. The amount of active ingredient handled per day varies base d on the type of product being applied and is estimate d based on the percentage of active ingredient specified on the product la bel and the amount of product being sprayed. For KBR 3023, the percentage of active ingredient ranges from 5% to 20%. As a default, 1 can or pump spray bottle per day for handlers is assumed for
exposure assessment.Page 6 of 18 

### 3. Margins of Exposure (MOEs): An inhalation risk assessment was not previously done for KBR 3023. Howe ver, MOE estimates for inhalation scenarios were calculated using an oral t oxicity study and should be considered in the WOE analysis for an i nhalation toxicology study waiver request. In the past, OPP has used MOEs of approximately 10 times higher than the level of concern as a benchmark for granting waiver reque sts. The 2009 analysis suggests this approach is appropriate for most pesticid es but not all. Using this interim WOE approach, MOEs from 10-100 times greater than the level of concern will be
considered in combination with other factors discussed here. All handler
inhalation MOEs are ≥ 7,500 for handlers using in sect repellent products containing picaridin (Table 2).

c. Immunotoxicity

1. Evidence for potential immunotoxici ty in the KBR3023 database of toxicology studies: There are no signs of immunot oxicity following subchronic or chronic dosing in multiple species in the toxicology database for KBR 3023 (Table 1.)

Table 1. Parameter Findings

Hematology Indicators (WBC changes) None

Clinical Chemistry Indicators (A/G Ratio) None

Organ Weight Indicators (Spleen, Thymus) None

Histopathology Indicators (Spleen, Thymus, Lymph nodes) None

Toxicity Profile (Target Organs) None



### 2. Evidence for potential immunotoxicity for structure activity relationship (SAR) chemicals -retrospective analysis: Picaridin belongs to the piperidine class of chemicals. Picaridin has a carbamate substructure; however, when compared to other pesticides belonging to the carbamate class (e.g. the neurotoxic N-methyl carbamates), picaridin is not si milar in structure. Furthermore, there was no indication of immunotoxicity in th e carbamate database. A DEREK run
was done for KBR 3023 and there was no evidence for potential immunotoxicity for SAR chemicals. The DEREK report di d highlight a concern for chromosome damage based on an analogy to urethane (ethyl carbamate). Urethane is positive
in an in vivo mouse micronucleus study. Howeve r, KBR 3023 is negative in the

in vivo mouse micronucleus study, so the concern for chromosome damage is not supported.

IV. HASPOC CONCLUSIONS

Subchronic Inhalation Toxicity Study: In determining the need for a subchronic inhalation study, EPA’ weight of evidence decision process included both hazard andPage 7 of 18 

### exposure considerations as well as incorporation of a presumed 10X Database Uncertainty Factor (UF DB 

### ) for the lack of this study. Thus, the Agency’s Level of Concern in the HASPOC’s weight of the evidence evaluation for inhalation exposure risk assessment is a Margin of Exposure (MOE) of 1000 which includes the 10X Inter-species extrapolation, 10X intra-species variation, and the 10X UF DB 

### . For residential exposure
the use of an oral POD resulted in MOEs significantly higher than the LOC of 1000.

The HASPOC, based on a WOE approach, co ncludes that a subchronic inhalation toxicity study is not required for picaridin at this time. This approach considered all
of the available hazard and exposure information for picarid in, including: (1) its low acute inhalation toxicity; 2) th e potential for repeated inhala tion exposure; and (2) the use of an oral POD resulting in MOEs that are well above (> 7500) the Agency’s level of concern (< 1000).

Oral Developmental/Reproduction and Carconogenicity studies: The HASPOC concluded, based on a weight of evidence (WOE) approach, that the oral developmental/reproduction and carcinogenicity studies can be waived at this time. This approach included th e following considerations:

 Dermal developmental, reproduction, and car cinogenicity studies are available for

KBR 3023 with no/limited effects observ ed in the studies up to 200/400 mg/kg/day. Additionally, the de rmal route is the most re levant route of exposure and reflects the use pattern for KBR 3023.

 Although oral developmental/reproduction a nd cancer studies ar e not available for picaridin, there are oral s hort-term studies that dem onstrate NOAELs comparable to or higher than the derm al studies. Furthermore, treatment-related effects (when observed) in the available oral studies we re only seen at doses exceeding the limit

dose.

 Based on the results from the available stud ies, the target orga ns for picaridin are the liver and kidneys.

Immunotoxicity Study: The HASPOC concl uded, based on a weight of evidence (WOE) approach, that the immunotoxicity study can be waived at this time . The conclusion was based on the following:

 There was no evidence of adverse effects on the immune system in mice, rats, or dogs in the KBR 3023 data base and SAR anal ysis did not reveal any evidence of

treatment-related effects on the immune system, suggesting that immune system is not the primary target organ.

 The liver and kidney , not the immune sy stem, are target organs for KBR 3023Page 8 of 18 

###  PODs are based on the most sensitive endpoints obtained via the appropriate routes of exposure.

All these factors indica te that an immunotoxicity study w ould most likely not result in an

adverse effect that could be us ed as an endpoint for KBR 3023.Page 9 of 18Table 2. Residential Inhalation Non-Cancer Exposure and Risk Estimates for PicaridinExposure ScenarioCrop or TargetInhalation Unit Exposure(mg/lb ai)1MaximumApplicationRate2Amount or AreaTreated3InhalationDose (mg/kg/day)4MOE5Ready-to-Use Aerosol CanInsect RepellentAdult3.0 0.15 lb ai/day 1 can/day0.0056 55,000Children (1< 2 yrs)0.0410 7,500Ready-to-Use Trigger-sprayBottle Insect RepellentAdult0.061 0.15 lb ai/day 1 bottle/day0.00011 2,700,000Children (1< 2 yrs)0.00083 370,0001. Based on the “Standard Operating Procedures for Residential Pesticide Exposure Assessment” (October, 2012).2. Based on registered labels (EPA Reg. No. 39967-53).3. Exposure Science Advisory Council Policy #9.1.4. Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/A) × Area Treated (A/day) ÷ BW (80 kg for Adults; 11 kg for Children).5. Inhalation MOE = Inhalation NOAEL (308 mg/kg/day)÷ Inhalation Dose (mg/kPage 10 of 18 Summary of Toxicological Doses and Endpoints for KB R 3023 (Picaridin) for Use in Human Health Risk
Assessments

Table 3a. Toxicological Doses and Endpoints for KBR 3023 (Picaridin) Selected for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/ Scenario Point of Departure Uncertainty/FQP A Safety Factors RfD, PAD, Level of
Concern for Risk
Assessment Study and Toxicological
Effects

Acute Dietary Non-food use. Acute dietary exposure is not anticipated
Chronic Dietary Non-food use. Chronic dietar y exposure is not anticipated

Incidental Oral, ShortTerm (1-30 days) and
Intermediate-Term (1-6 months) NOAEL =

308 UF A = 10x

UF H =10x FQPA SF=1x Residential LOC for

MOE = 100 5-Week feeding toxicity – Rats (MRID 45387902) LOAEL= 1034 mg/kg/day, based on decreased body weight/weight gain in males, increased relative kidney weights (males), and increased incidence of protein droplet nephropathy in males (possibly
due to α 2 μ -globulin accumulation).

Dermal, Short-Term (1-30 days) NOAEL =

200 UF A = 10x

UF H =10x FQPA SF=1x Residential LOC for

MOE = 100 Dermal Developmental toxicity –Rabbits (MRID 44408721)

LOAEL= not determined. No maternal or developmental toxicity at the highest dose
tested.

Dermal IntermediateTerm (1-6 months) NOAEL =

200 UF A = 10x

UF H =10x FQPA SF=1x Residential LOC for

MOE = 100 Dermal 90-Day – Rats (MRID 44408716) LOAEL= 500 mg/kg/day,
based on diffuse liver hypertrophy and individual
necrotic liver cells in both sexes; and slight hyaline degeneration in the kidneys, an
increased incidence of foci of tubular regeneration, and chronic kidney inflammation in
males at the

Dermal Long-Term (>6 months) NOAEL =

200 UF A = 10x

UF H =10x FQPA SF=1x Residential LOC for

MOE = 100 Dermal Chronic/ Carcinogenicity – Rats (MRID 44408728)
LOAEL=not determined

Inhalation Inhalation endpoints were not selected in previous risk a ssessments due to low toxicity via acute inhalation toxicity. Ho wever, there is potential for short-term inhalation exposure based on the use pattern.Page 11 of 18Table 3a. Toxicological Doses and Endpoints for KBR 3023 (Picaridin) Selected for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/ Scenario Point of Departure Uncertainty/FQP A Safety Factors RfD, PAD, Level of
Concern for Risk
Assessment Study and Toxicological
Effects

ENDPOINT
SELECTED FOR
HASPOC MEETING

Inhalation Potential endpoint
selected for HASPOC meeting NOAEL =

308 UF A = 10x

UF H =10x FQPA SF=1x Residential LOC for

MOE = 100 5-Week feeding toxicity – Rats (MRID 45387902) LOAEL= 1034 mg/kg/day, based on decreased body weight/weight gain in males, increased relative kidney weights (males), and increased incidence of protein droplet nephropathy in males (possibly
due to α 2 μ -globulin accumulation).

Cancer (oral, dermal, inhalation) Classification: “Not likely to be carcinogenic to humans.”

Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). PAD = population adjusted dose (a = acute, c = chronic). RfD = reference do se. LOC = level of concern.

Table 3b. Summary of Toxicological Doses and Endpoints for KBR 3023 (Picaridin) for Use in Occupational Human
Health Risk Assessments

Exposure/ Scenario Point of Departure Uncertainty/FQP A Safety Factors RfD, PAD, Level of
Concern for Risk
Assessment Study and Toxicological
Effects

Dermal, Short-Term (1-30 days) NOAEL =

200 UF A = 10x

UF H =10x FQPA SF=1x Occupational LOC for

MOE = 100 Dermal Developmental toxicity –Rabbits (MRID 44408721)

LOAEL= not determined. No maternal or developmental toxicity at the highest dose
tested.

Dermal IntermediateTerm (1-6 months) NOAEL =

200 UF A = 10x

UF H =10x FQPA SF=1x Occupational LOC for

MOE = 100 Dermal 90-Day – Rats (MRID 44408716) LOAEL= 500 mg/kg/day,
based on diffuse liver hypertrophy and individual
necrotic liver cells in both sexes; and slight hyaline degeneration in the kidneys, an
increased incidence of foci of tubular regeneration, and chronic kidney inflammation in
males at the

Dermal Long-Term (>6 months) NOAEL =

200 UF A = 10x

UF H =10x FQPA SF=1x Occupational l LOC for

MOE = 100 Dermal Chronic/ Carcinogenicity – Rats (MRID 44408728)
LOAEL=not determined.Page 12 of 18 Table 3b. Summary of Toxicological Doses and Endpoints for KBR 3023 (Picaridin) for Use in Occupational Human
Health Risk Assessments

Exposure/ Scenario Point of Departure Uncertainty/FQP A Safety Factors RfD, PAD, Level of
Concern for Risk
Assessment Study and Toxicological
Effects

Inhalation Inhalation endpoints were not selected in previous risk a ssessments due to low toxicity via acute inhalation toxicity. Ho wever, there is potential for short-term inhalation exposure based on the use pattern.

ENDPOINT
SELECTED FOR
HASPOC MEETING

Inhalation Potential endpoint
selected for HASPOC meeting NOAEL =

308 UF A = 10x

UF H =10x FQPA SF=1x Residential LOC for

MOE = 100 5-Week feeding toxicity – Rats (MRID 45387902) LOAEL= 1034 mg/kg/day, based on decreased body weight/weight gain in males, increased relative kidney weights (males), and increased incidence of protein droplet nephropathy in males (possibly
due to α 2 μ -globulin accumulation).

Cancer (oral, dermal, inhalation) Classification: “Not likely to be carcinogenic to humans.”

Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intrasp ecies). MOE = margin of exposure. LOC = level of

concern.Page 13 of 18 TOXICITY PROFILE TABLES FOR KBR 3023 (PICARIDIN)

Table 4. 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 14 of 18 Table A. 2 KBR 3023 (Picaridin) Subc hronic, 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 weig ht/weight gain (both sexes; not statistically significant in females), increased relative kidney weights (males), and increased incidence of protein droplet nephropathy in males (possibly due to α 2 μ -globulin accumulation).

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 weig ht/weight gain in both sexes, and effects on the male kidneys including increased relative kidney weights and increased incidence of protein droplet degenerative nephropathy (possibly
due to α 2 μ -globulin accumulation).

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 (slight to minimal diffuse liver hypertrophy, individual necrotic liver cells, slight hyaline degeneration in the kidneys, increased incidence of foci of tubular regeneration, and chronic kidney inflammation) NOAEL (dermal irritation)=not
determined LOAEL (dermal irritation) = 80 mg/kg/day (scabs, red foci, and exfoliation at the dosing site) Note: Complete reversal was seen after a 4-week recovery period.Page 15 of 18 Table A. 2 KBR 3023 (Picaridin) Subc hronic, Chronic, and Other Toxicity

GUIDELINE
NO. STUDY TYPE MRID NO. (YEAR)/ CLASSIFICATION
/DOSES RESULTS

870.3700 Dermal Developmental Toxicity - Rat MRID 44408725
0, 50, 200, and 400 mg/kg/day NOAEL (maternal) = 400 mg/kg/day (HDT; slight increases in absolute and relative liver weights; 9% and 5%, respectively) LOAEL (maternal) >400 mg/kg/day NOAEL (developmental) = 400 mg/kg/day (delayed ossification
attributed to maternal stress due to the dermal dosing regimen) LOAEL (developmental) > 400 mg/kg/day

870.3700 Dermal Developmental Toxicity - Rabbit MRID 44408721
0, 50, 100, and 200 mg/kg/day NOAEL (systemic) >200 mg/kg/day (HDT) NOAEL (developmental) >200 mg/kg/day NOAEL (dermal irritation) <50 mg/kg/day LOAEL (dermal irritation) = 50 mg/kg/day (LDT)

870.3800 Dermal Reproductive Toxicity - Rat MRID 44408727
0, 50, 100, and 200 mg/kg/day NOEL (systemic) = 200 mg/kg/day (HDT) NOAEL (systemic) >200 mg/kg/day NOEL (reproductive) = 200 mg/kg/day NOAEL (reproductive) >200 mg/kg/day

870.4100 Dermal Chronic Toxicity - Dog MRID 44408718
0, 50, 100, and 200 mg/kg/day NOAEL (systemic) = 200 mg/kg/day (HDT) NOAEL (dermal irritation) = 200 mg/kg/day

870.4200 Dermal Carcinogenicity - Mouse (18 months) MRID 44408719
0, 50, 100, and 200 mg/kg/day NOEL = 200 mg/kg/day (HDT) NOAEL >200 mg/kg/day
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 (HDT; liver cystic degeneration with no corroborating liver weight or clinical pathology anomalies)
There is no evidence of carcinogenicity.

870.5265 Salmonella typhimurium
Mammalian
Activation Gene Mutation Assay MRID 44408729 NegativePage 16 of 18 Table A. 2 KBR 3023 (Picaridin) Subc hronic, Chronic, and Other Toxicity

GUIDELINE
NO. STUDY TYPE MRID NO. (YEAR)/ CLASSIFICATION
/DOSES RESULTS

870.5300 In Vitro Gene Mutation Assay in
Chinese Hamster
V79 Cells MRID 45231801 Negative

870.5375 In Vitro Mammalian
Chromosome
Aberrations in CHO
Cells MRID 44408732 Clastogenic in CHO cells in the
absence of metabolic activation.

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 NOEL = 2000 mg/kg (HDT) NOAEL > 2000 mg/kg

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

870.6300 Dermal Developmental Neurotoxicity - Rat Not required because there is no evidence of increased neurologic or developmental susceptibility.

870.7485 Dermal and I.V.
Metabolism - Rat MRID 44408735 Dermal: Animals dosed dermally for 7 consecutive days absorbed 58-63% 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 absorption saturation. Elimination was mostly in the urine. Approximately 19- 33% of the dose was not recovered, most likely due to evaporation during the 7 day exposure. 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. Maximum plasma concentrations were reached within 6-8 hours of dosing and werePage 17 of 18 Table A. 2 KBR 3023 (Picaridin) Subc hronic, Chronic, and Other Toxicity

GUIDELINE
NO. STUDY TYPE MRID NO. (YEAR)/ CLASSIFICATION
/DOSES RESULTS

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.
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).

870.7485
Dermal
Metabolism -

Human [OPPTS guidelines do not require human data.] MRID 44408736 Biotransformation of [ 14 C]KBR 3023 in humans primarily involves conjugation of KBR 3023 with glucuronic acid through the 2-hydroxyethyl moiety to form Metabolites M14 and M15, which together accounted for 43.1% of the radioactivity in urine. Other major
metabolites in urine included: M5 (17.4%) another glucuronic acid conjugate which is hydroxylated in the 1-methyl-propyl moiety; M16 (8.5%) in which the 2-hydroxyethyl group is oxidized to an acid; M8 (6.2%) in which the 2-hydroxyethyl group is oxidized and the 1-methyl-propyl group is hydroxylated; and M11-M13 (6.9%)
which are isomers in which the 2- hydroxyethyl group has been oxidized to an acid and conjugated with glucuronic acid. The remaining metabolites, M1-M4, M6, M7, M9, andPage 18 of 18 Table A. 2 KBR 3023 (Picaridin) Subc hronic, Chronic, and Other Toxicity

GUIDELINE
NO. STUDY TYPE MRID NO. (YEAR)/ CLASSIFICATION
/DOSES RESULTS

M10 each accounted for  3.1% of the radioactivity in urine.

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. Urinary excretion was the principle route of elimination. After 3-7 days, 1.5-3.0% of radioactivity remained in the body.

870.7600 Dermal Absorption -

Human

[OPPTS guidelines do not require human data.] MRID 44408738 Humans were dermally dosed on the
forearm with either neat KBR 3023 or
15% KBR 3023 in ethanol at a nominal dose of 15 mg/person (0.625 mg/cm 2 ). The dosing sites were washed after 8 hours. Absorption after 8 hours was <4% of the applied dose. After 128 hours (5 days), total absorbed dose was 1.66% for neat KBR 3023, and 3.77%
for 15% KBR 3023 in ethanol. Within 24 hours, 94% of the absorbed radioactivity was excreted, mostly in theurine. After 60 hours (52 posttreatment), radioactivity in urine had returned to background levels for both dose groups.