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UNITED STATES ENVIRONMENTAL 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 Figueroa 

 
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I. PURPOSE OF MEETING: 

Risk Assessment Branch II (RABII) is currently 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 "KBR 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 route 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 guideline studies with the exception of the acute 

studies were conducted by the dermal route; oral toxicity studies were not available with 

the exception of the acute oral study. While preparing a human health risk assessment, 

HED identified risk concerns for infants/children after a single application. KBR 3023 

was presented to the Hazard Identification Assessment Review committee (HIARC) who 

raised concern over the lack of an oral study to assess hazard from incidental oral 

exposure for children. Also there was concern that the dosing levels in the dermal studies 

were not high enough to fully evaluate potential carcinogenicity and developmental 

toxicity. Therefore, additional oral toxicity studies were identified as data gaps by 

HIARC, including: oral subchronic studies, developmental 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) requested input from the Hazard and Science 

Policy Council (HASPOC) regarding the adequacy of the existing toxicology database 

for KBR 3023 (which consists of mostly dermal 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 study 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 accordance with the current 40 CFR Part 158 

Toxicology Data Requirements. The Hazard and Science Policy Council (HASPOC) met 

on February 13, 2013 to discuss the need for additional 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 applied directly to the skin of adults and 

children. Labels contain instructions which prohibit application directly to the hands of 

children and limit the number of applications per day (e.g., “Do not exceed two 

applications per day.”). However, KBR 3023 products 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 KBR 
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3023 use is non-food and any incidental dietary exposure would not appear to trigger 

FQPA considerations. The Office of General 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 several studies; however, the dermal irritant effects were 

generally not dose-related. Dermal absorption studies show that absorption in males is 

11.5-times greater in rats than in humans over 7 days. Even though the short, 

intermediate, and long-term rat dermal NOAELs are all 200 mg/kg/day, there is evidence 

of modest systemic accumulation in rats. Skin retention is very low in humans (0.02% 

one hour after dosing site washing), excretion is rapid (94% within 24 hours), and there is 

little likelihood of systemic accumulation. 

Although the skin received the highest dose, the 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 hypertrophy, necrotic liver cells, slight hyaline 

degeneration in the kidneys, increased incidence of foci of tubular regeneration, and 

chronic kidney inflammation. There was full reversibility after a 4-week recovery period. 

The NOAEL in the study is 200 mg/kg/day. In the dermal chronic 

toxicity/carcinogenicity study in rats, no treatment related 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 studies. No treatment related effects were seen in dermal 

developmental and reproductive toxicity studies. 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 quantitative 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 carcinogen by the dermal route. There is no 

evidence of carcinogenicity in dermal cancer studies in the rat or mouse, the mutagenicity 

studies are negative, and the structure of the molecule does 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 incidental 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 related 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/day (NOAEL= 200 mg/kg/day). For long-term 
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dermal, the dermal rat carcinogenicity study was used with a NOAEL of 200 mg/kg/day; 

no treatment related effects were seen in the study (Table 3b). Although there is potential 

for short-term inhalation exposure, inhalation 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, and Carcinogenicity Toxicity Studies 

Dermal developmental, reproduction, and carcinogenicity studies are available for KBR 

3023. In the dermal rat developmental study, the rat maternal and developmental 

NOAELs were 400 mg/kg/day, the highest dose tested. 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 reviewer attributed to 

maternal stress due to the dermal dosing regimen. 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 the dermal reproductive 

study in rats, no treatment related systemic (dams or offspring animals) or reproductive 

toxicity was observed at doses up to 200 mg/kg/day. No treatment related toxicity or 

tumors were observed in the dermal carcinogenicity studies in mice or rats at doses up to 

200 mg/kg/day. KBR 3023 is classified 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 dosing 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 ultimately were not required by HED. 

 Oral Developmental Toxicity in Rabbits 

The HIARC felt that although no developmental 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 developmental 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 reserved 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 now 
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required for all non-food use chemicals. The developmental 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 higher than the target). In 2009, OPP 

developed an issue paper on risk assessment approaches 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 varied. In many cases 

the oral PoD was protective, but in some cases the inhalation PoDs were significantly 

more sensitive. Currently, OPP uses a weight 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-route extrapolation continue to evolve and 

improve, OPP may incorporate additional considerations into the WOE analysis. 

Inhalation exposure can be to vapors, droplets, and/or particles/dusts. The form of 

inhalation exposure is determined by a number of factors including 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·m3

/mol at 25 °C 

 

2. Use pattern & exposure scenarios: Any application scenario that leads to 

inhalation exposure to droplets needs to be considered in the WOE analysis for an 

inhalation toxicology study waiver request. In the case of insect repellents, unlike 

other pesticide applications, “handler” and “post-application” exposures resulting 

from insect repellent applications are not truly separate events since many 

applications are self-applications. Adults are assumed to apply repellents to 

themselves or to others. For aerosol and pump-sprayer repellent 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 generally considered short-term in duration. 

The amount of active ingredient handled per day varies based on the type of 

product being applied and is estimated based on the percentage of active 

ingredient specified on the product label 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. 
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 3. Margins of Exposure (MOEs): An inhalation risk assessment was not 

previously done for KBR 3023. However, MOE estimates for inhalation 

scenarios were calculated using an oral toxicity study and should be considered in 

the WOE analysis for an inhalation 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 requests. The 2009 analysis suggests this 

approach is appropriate for most pesticides 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 insect repellent products 

containing picaridin (Table 2). 

c. Immunotoxicity 

1. Evidence for potential immunotoxicity in the KBR3023 database of 

toxicology studies: There are no signs of immunotoxicity 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 similar in structure. Furthermore, there 

was no indication of immunotoxicity in the carbamate database. A DEREK run 

was done for KBR 3023 and there was no evidence for potential immunotoxicity 

for SAR chemicals. The DEREK report did highlight a concern for chromosome 

damage based on an analogy to urethane (ethyl carbamate). Urethane is positive 

in an in vivo mouse micronucleus study. However, 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 and 
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exposure considerations as well as incorporation of a presumed 10X Database 

Uncertainty Factor (UFDB) 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, concludes 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 picaridin, including: (1) its low 

acute inhalation toxicity; 2) the potential for repeated inhalation 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 the following considerations: 

 Dermal developmental, reproduction, and carcinogenicity studies are available for 

KBR 3023 with no/limited effects observed in the studies up to 200/400 

mg/kg/day. Additionally, the dermal route is the most relevant route of exposure 

and reflects the use pattern for KBR 3023. 

 Although oral developmental/reproduction and cancer studies are not available for 

picaridin, there are oral short-term studies that demonstrate NOAELs comparable 

to or higher than the dermal studies. Furthermore, treatment-related effects (when 

observed) in the available oral studies were only seen at doses exceeding the limit 

dose. 

 Based on the results from the available studies, the target organs for picaridin are 

the liver and kidneys. 

Immunotoxicity Study: The HASPOC concluded, 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 analysis 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 system, are target organs for KBR 3023 
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 PODs are based on the most sensitive endpoints obtained via the appropriate 

routes of exposure. 

All these factors indicate that an immunotoxicity study would most likely not result in an 

adverse effect that could be used as an endpoint for KBR 3023. 
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Table 2. Residential Inhalation Non-Cancer Exposure and Risk Estimates for Picaridin 

Exposure Scenario Crop or Target Inhalation Unit Exposure (mg/lb ai)1 Maximum Application Rate2 Amount or Area Treated3 Inh

Dose (mg/kg/day)4 

Ready-to-Use Aerosol Can 

Insect Repellent 

Adult 

3.0 0.15 lb ai/day 1 can/day 0.0056 

Children (1< 2 yrs) 0.0410 

Ready-to-Use Trigger-spray 

Bottle Insect Repellent 

Adult 

0.061 0.15 lb ai/day 1 bottle/day 0.00011 

Children (1< 2 yrs) 0.00083 

1. 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 Adult

5. Inhalation MOE = Inhalation NOAEL (308 mg/kg/day) ÷ Inhalation Dose (mg/k
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Summary of Toxicological Doses and Endpoints for KBR 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 dietary exposure is not anticipated 

Incidental Oral, ShortTerm 

(1-30 days) and 

Intermediate-Term 

(1-6 months) 

NOAEL = 

308 

UFA= 10x 

UFH=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 α2μ-globulin 

accumulation). 

Dermal, Short-Term 

(1-30 days) NOAEL = 

200 

UFA= 10x 

UFH=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 

UFA= 10x 

UFH=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 

UFA= 10x 

UFH=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 assessments due to low toxicity via 

acute inhalation toxicity. However, there is potential for short-term inhalation exposure 

based on the use pattern. 
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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 

ENDPOINT 

SELECTED FOR 

HASPOC MEETING 

Inhalation 

Potential endpoint 

selected for HASPOC 

meeting 

NOAEL = 

308 

UFA= 10x 

UFH=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 α2μ-globulin 

accumulation). 

Cancer (oral, dermal, 

inhalation) Classification: “Not likely to be carcinogenic to humans.” 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). PAD = population adjusted dose (a = acute, c = 

chronic). RfD = reference dose. 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 

UFA= 10x 

UFH=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 

UFA= 10x 

UFH=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 

UFA= 10x 

UFH=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 assessments due to low toxicity via 

acute inhalation toxicity. However, 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 

UFA= 10x 

UFH=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 α2μ-globulin 

accumulation). 

Cancer (oral, dermal, 

inhalation) Classification: “Not likely to be carcinogenic to humans.” 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). 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

LD50 = 4743 mg/kg 

(Males) 

LD50 = 2236 mg/kg 

(Females) 

III

870.1200 Acute Dermal - Rat 44408707 LD50 >2000 mg/kg (limit 

test) 

NOEL = 2000 mg/kg 

NOAEL >2000 mg/kg 

III 

870.1300 Acute Inhalation - 

Rat 

44408709 LC50 >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 study 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) 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/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 α2μ-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 weight/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 α2μ-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) Subchronic, 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 Negative 
Page 16 of 18 

Table A. 2 KBR 3023 (Picaridin) Subchronic, 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/cm2

) 

and 40-55% of the high-dose (200 

mg/kg, 5 mg/cm2

) 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 were 
Page 17 of 18 

Table A. 2 KBR 3023 (Picaridin) Subchronic, 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 [14C]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, and 
Page 18 of 18 

Table A. 2 KBR 3023 (Picaridin) Subchronic, 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/cm2

) 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/cm2

). 

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 the 

urine. After 60 hours (52 posttreatment), radioactivity in urine had 

returned to background levels for both 

dose groups.