Document ID: EPA-HQ-OPP-2022-0444-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2023-08-14T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                           WASHINGTON, D.C. 20460   

                                                     	OFFICE OF CHEMICAL SAFETY
                                                      	AND POLLUTION PREVENTION
	

Date:	04/04/2023							
					
Subject:	Flupyradifurone. Occupational and Residential Exposure Assessment for Proposed Indoor and Outdoor Non-Food Uses.

PC Code: 122304
DP Barcode: D466307
Decision No.: 577702
Registration No.: 432-RAEE
Petition No.: NA
Regulatory Action: Section 3
Risk Assessment Type: Occupational/Residential Exposure Assessment
Case No.: NA
TXR No.: NA
CAS No.: 951659-40-8
MRID No.: NA
40 CFR: NA

From:	Briana Lee, M.S., Biologist 
	Risk Assessment Branch 3
	Health Effects Division (7509T)

Through:	Thomas Moriarty, Branch Chief  for 
	Risk Assessment Branch 3
	Health Effects Division (7509T)
	
	and

	Wade Britton, ExpoSAC Reviewer 
	Jesse Hale, ExpoSAC Reviewer
	Exposure Science Advisory Committee (ExpoSAC) / HED
	
To:	Marianne Lewis, Risk Manager Reviewer
	Melissa Bridges, Acting Product Manager 7
	Deanna Colby, Branch Chief
	Invertebrates Branch 3
	Registration Division (7505T)

Introduction		
The Registration Division (RD) of the Office of Pesticide Programs (OPP) has requested that the Health Effects Division (HED) conduct an exposure and risk assessment for proposed new uses of flupyradifurone for use in and around residential sites (including mattresses), commercial facilities, and other man-made structures. Flupyradifurone was first assessed in 2014 and therefore, has not undergone registration review. The most recent Section 3 quantitative human health risk assessment (HHRA) for flupyradifurone was completed in 2020 (R. McGovern, et al., D453708 and D454504, 06/30/2020). 

It is HED policy to use the best available data to assess exposure. Several sources of generic data were used in this assessment as surrogate data in the absence of chemical-specific data, including the Outdoor Residential Exposure Task Force (ORETF) database and the 2012 Residential Standard Operating Procedure (Indoor Environments; Gardens and Trees). Some of these data are proprietary, and subject to the data protection provisions of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). 

The conclusions conveyed in this assessment were developed in full compliance with EPA Scientific Integrity Policy for Transparent and Objective Science, and EPA Scientific Integrity Program's Approaches for Expressing and Resolving Differing Scientific Opinions. The full text of EPA Scientific Integrity Policy for Transparent and Objective Science, as updated and approved by the Scientific Integrity Committee and EPA Science Advisor can be found here: 
EPA's Scientific Integrity Policy. The full text of the EPA Scientific Integrity Program's Approaches for Expressing and Resolving Differing Scientific Opinions can be found here: Approaches for Expressing and Resolving Differing Scientific Opinions | US EPA

Note: This memorandum was reviewed by the Exposure Science Advisory Committee (ExpoSAC) on August 18, 2022.
                               Table of Contents

1.0 Executive Summary	4
2.0 Risk Assessment Conclusions and Recommendations	6
2.1 Summary of Risk Estimates	6
2.2 Label Recommendations	6
2.3 Data Deficiencies and Requirements	7
3.0 Hazard Characterization	7
4.0 Use Profile	9
5.0 Residential Exposure and Risk Estimates	11
5.1 Residential Handler Exposure/Risk Estimates	11
5.2 Residential Post-application Exposure/Risk Estimates	14
5.3 Residential Risk Estimates for Use in Aggregate Assessment	16
6.0 Non-Occupational Spray Drift Exposure and Risk Estimates	17
7.0 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk Estimates	17
8.0 Occupational Exposure and Risk Estimates	18
8.1 Occupational Handler Exposure/Risk Estimates	18
8.2 Occupational Post-application Exposure/Risk Estimates	22
8.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates	22
8.2.2 Occupational Post-application Dermal Exposure/Risk Estimates	23
Appendix A. Summary of Occupational and Residential Non-cancer Algorithms	24

1.0 Executive Summary

Flupyradifurone, [4-[[(6-chloro-3-pyridinyl)methyl](2,2-difluoroethyl)amino]-2(5H)-furanone], is a butanolide class of insecticide that can be used to control a broad range of sucking insects. As a Group 4D insecticide, flupyradifurone's mode of action (MOA) is thought to be via binding and stimulation of insect nicotinic acetylcholine receptors, which leads to paralysis and death. Flupyradifurone is currently registered for foliar, soil drench, and seed treatment for a variety of agricultural crops, as well as residential garden uses. 

Proposed Use Profile
The registrant, Bayer Crop Sciences, has submitted a request for a Section 3 registration for proposed new uses of flupyradifurone in and around residential sites (including mattresses), commercial facilities, and other man-made structures for the new end-use product (EP), ESP005 Insecticide (alternate brand name, Temprid Dust Insecticide) (EPA File Symbol No. 432-RAEE). Temprid Dust is formulated as a dust with 1% active ingredient (ai), flupyradifurone, per pound of product (lb product). This product also contains the ai, beta-cyfluthrin, which will be assessed separately. Applications are made by handheld duster, brush, bulb duster, electric duster, or other suitable equipment at single maximum application rates ranging from 0.25 to 0.50 lb product per 1,000 square feet. The retreatment interval (RTI) is 7 to 10 days. There are no label-stated attire nor personal protective equipment (PPE) requirements. The proposed use pattern does not fall under the Worker Protection Standards (WPS) and, therefore, does not have a restricted entry interval (REI) requirement. 

Exposure Profile
Based on the proposed uses of flupyradifurone, it is expected that short- (1 to 30 days) and intermediate-term (1 to 6 months) dermal and inhalation occupational handler. Occupational post-application exposures are not anticipated for the proposed uses as commercial applicators do not typically return to previously treated areas after an indoor/outdoor application (i.e., warehouses, food handling establishments, hotels, etc.). Chronic exposure is not expected for the proposed use patterns. 

Short-term residential handler dermal and inhalation exposures are expected to occur from the proposed uses of the product in residential sites. There is a potential for post-application dermal exposure to adults and children 1 to <2 years old and incidental oral exposures to children (1 to <2 years old) from hand-to-mouth activities while contacting treated surfaces. 

Hazard Characterization
The toxicological database for flupyradifurone is complete. With repeated dosing, reductions in body weight and food consumption were commonly seen in various studies and in all species of test animals (rats, mice, dogs, and rabbits). Flupyradifurone also produced skeletal muscle atrophy/degeneration in dogs at a lower dose level (28 mg/kg/day) relative to other effects. Consequently, the skeletal muscle atrophy/degeneration seen in the 90-day and one-year dog studies formed the basis for the short- and intermediate-term occupational toxicity endpoints. No effects were observed in the dermal study in rabbits up to 500 mg/kg/day, the highest dose tested. In addition, the Hazard and Science Policy Council (HASPOC) based on a weight-of-evidence (WOE) approach, recommended that the subchronic inhalation study is not required at this time (M. Perron, TXR 0056903, 03/08/2014). The point of departure (POD) is 12 mg/kg/day for short- and intermediate-term dermal, inhalation, and incidental oral non-occupational and occupational exposures.

Flupyradifurone also produced clinical signs (piloerection and pupillary dilatation) indicative of neurotoxicity in the acute neurotoxicity study. The exposure databases are complete or are estimated based on data that reasonably account for potential exposures. Flupyradifurone is classified as "not likely to be carcinogenic to humans." There was no evidence of quantitative or qualitative pre-natal susceptibility in the rat developmental study. However, evidence of quantitative susceptibility was observed in the rabbit developmental toxicity study and in the two-generation reproduction toxicity study, but the PODs used for risk assessment were protective of the increased quantitative susceptibilities in the pups and fetuses. The exposure databases are complete or are estimated based on data that reasonably account for potential exposures. Therefore, the Food Quality Protection Act (FQPA) safety factor (SF) has been reduced to 1X.

Flupyradifurone was categorized as having low acute toxicity via the oral (Toxicity Category III), dermal (Toxicity Category III), and inhalation (Toxicity Category IV). Flupyradifurone was not irritating to rabbit skin and caused only slight ocular irritation (redness of the conjunctivae) which was reversed within 48 hours.

Residential Exposure and Risk
Flupyradifurone is currently being proposed for use in residential indoor environments. Short-term residential handler combined inhalation and dermal risk estimates are not of concern (i.e., Margins of Exposure (MOEs) >= the level of concern (LOC) of 100); combined MOEs range from 470 to 19,000. 

Residential post-application dermal exposures for adults and children 1 to <2 years old are also not of concern. Post-application dermal MOEs for adults range from 3,200 to 96,000. Post-application MOEs for children 1 to <2 years old (combined dermal and incidental oral) range from 1,100 to 42,000. Residential post-application outdoor exposures were not assessed as they are expected to be negligible.

Occupational Exposure and Risk
Short- and intermediate-term occupational handler combined dermal and inhalation risk estimates are not of concern (i.e., MOEs >= the LOC of 100) with baseline attire, defined as a single layer of clothing consisting of a long sleeved shirt, long pants, and shoes plus socks. No PPE such as protective gloves and a respirator are proposed. Combined MOEs were 14,000. 

Commercial applicators do not typically return to the treated areas after an indoor/exterior commercial pesticide application (sites such as warehouses, food handling establishments, and hotels, etc.). Thus, a quantitative occupational post-application dermal exposure assessment was not performed for commercial applicators.

In addition, based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment was not performed for flupyradifurone at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for flupyradifurone.

Human Studies Review
This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the ORETF database and the 2012 Residential Standard Operating Procedure (Indoor Environments; Gardens and Trees), are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website.

2.0 Risk Assessment Conclusions and Recommendations

2.1 Summary of Risk Estimates

All residential handler scenarios for the proposed uses resulted in combined dermal and inhalation risk estimates that are not of concern. MOEs range from 470 to 19,000 (LOC = 100). 

All residential post-application scenarios for the proposed uses resulted in combined dermal (adults and children 1 to <2 years old) and incidental oral (for children 1 to <2 years old) risk estimates that are not of concern. MOEs range from 3,200 to 96,000 (LOC = 100) for adults and from 1,100 to 42,000 (LOC = 100) for children 1 to <2 years old. 

All occupational handler scenarios for the proposed uses resulted in combined dermal and inhalation risk estimates that are not of concern with baseline attire (i.e., single layer, no gloves/no respirator). MOEs are 14,000 (LOC = 100). 

An occupational post-application assessment was not conducted since commercial applicators do not typically return to the treated areas after an indoor/external commercial pesticide application (sites such as residential living spaces, warehouses, food handling establishments, and hotels, etc.). 

2.2 Label Recommendations 

HED recommends that the label include language clarifying if the use pattern is intended for shaker cans as potential application equipment and to clarify use directions for brush applications (e.g., whether it is meant to be dipped into the dust and applied or used with a special type of brush equipment and include example).

2.3 Data Deficiencies and Requirements

None.

3.0 Hazard Characterization

The toxicity database for flupyradifurone is complete and remains unchanged since the previous assessment. A full description of the flupyradifurone toxicological profile can be found in a previous risk assessment (K. Rury et al., D407063, 08/05/2014).

Acute Toxicity
Flupyradifurone exhibits low acute mammalian toxicity via oral, dermal, and inhalation routes of exposure (Category III or IV for acute lethality and irritation studies) and is not a dermal irritant or sensitizer. 

Table 3.1. Acute Toxicity Profile: Flupyradifurone
                                   Guideline
                                      No.
                                  Study Type
                                    MRID(s)
                                    Results
                               Toxicity Category
                                   870.1100
Acute Oral (rat)
                                   48844101
LD50 > 300 mg/kg and > 2,000 mg/kg (F)
At 2,000 mg/kg, 1/3 animals died. 
In ACN 2/12 test animals died at 800 mg/kg.
                                      III
                                   870.1200
Acute Dermal (rat)
                                   48844104
LD50 > 2,000 mg/kg (M & F)
                                      III
                                   870.1300
Acute Inhalation (rat) 
                                   48844105
LC50 > 5.0 mg/L (M & F)
                                      IV
                                   870.2400
Primary Eye Irritation (rabbit)
                                   48844106
Redness of the conjunctivae, reversed within 48 hours (score 2).
                                      III
                                   870.2500
Primary Skin Irritation (rabbit)
                                   48844107
Non-irritating.
                                      IV
                                   870.2600
Dermal Sensitization (mouse)
                                   48844108
Skin sensitizer[1] (LLNA)
                                      N/A
LLNA = Local lymph node assay.
[1] MRID 48844108 was classified as Unacceptable. The subject product, EPA Reg. No. 264-1143, will be classified as a skin sensitizer. (TXR 5015231, D423578, M. Lewis, 10/29/2014).

Toxicological Points of Departure (PODs) Used for Risk Assessment
With repeated dosing, reductions in body weight with associated decreases in body weight gains and food consumption were commonly seen in various studies and in all species of the test animals (rats, mice, dogs, and rabbits). The liver and thyroid were also common targets of flupyradifurone toxicity. With adjusting for body weight (body weight (3/4) scaling factor), the dog appears to be the most sensitive species to flupyradifurone. In dogs, flupyradifurone produced skeletal muscle atrophy/degeneration at doses substantially lower than those producing liver, thyroid, and body weight effects. Flupyradifurone is classified as "not likely to be carcinogenic to humans." 

The 90-day dog and the two-generation reproduction toxicity studies were selected as co-critical to evaluate short- and intermediate-term incidental oral, dermal, and inhalation exposures with a POD of 12 mg/kg/day. The POD is based on skeletal muscle atrophy/degeneration observed in the subchronic dog and decreased pup (LD7) body weight observed in the two-generation reproduction toxicity study. The co-critical studies are protective of: (1) any effects seen in the developmental studies in rats and rabbits, and (2) pup body weight decrease seen at the LOAEL of 38.7 mg/kg/day in the two-generation rat reproduction toxicity study (no observed adverse effect level; NOAEL = 12 mg/kg/day). No dermal effects were observed in the dermal toxicity study; however, since increased susceptibility was observed in the database, an oral point of departure was selected for dermal risk assessment because the dermal toxicity study did not evaluate developmental or reproductive endpoints. The subchronic inhalation study is not recommended at this time (M. Perron, TXR 0056903, 03/08/2014), so an oral point of departure was selected for inhalation risk assessment. Inhalation toxicity is assumed to be equivalent to oral toxicity. Oral, dermal and inhalation exposure risk estimates should be combined because they are based on the same toxicological endpoints. The FQPA safety factor has been reduced (i.e., from 10X to 1X). The LOC for incidental oral, dermal and inhalation risk assessment is an MOE of 100 (i.e., an MOE < 100 is of concern). 

Table 3.2. Summary of Toxicological Doses and Endpoints for use in Non-Occupational and Occupational Exposure and Risk Assessments for Flupyradifurone.
                               Exposure Scenario
                              Point of Departure 
                                       
                       Uncertainty / FQPA Safety Factors
                     Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Oral Short- 
(1-30 days) and Intermediate-term (1-6 months)
NOAEL = 12 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF = 1X

                                   LOC = 100
Oral toxicity study-dog (90-day)
LOAEL= 33 mg/kg/day based on skeletal muscle atrophy/degeneration. 

2-Generation reproduction study- rat (co-critical study)
NOAEL= 7.7 mg/kg/day.
Offspring LOAEL=38.7 mg/kg/day based on pup body weight decrease.
Dermal 
Short-(1-30 days) and Intermediate-terms (1-6 months)
NOAEL = 12 mg/kg/day

DAF = 7.42%[a]
UFA = 10X
UFH =10X
FQPA SF = 1X (when applicable)
                                   LOC = 100
Oral toxicity study-dog (90-day)
LOAEL= 33 mg/kg/day based skeletal muscle atrophy/degeneration. 

2-Generation reproduction study- rat (co-critical study)
NOAEL= 7.7 mg/kg/day.
Offspring LOAEL=38.7 mg/kg/day based on pup body weight decrease.
Inhalation Short-(1-30 days) and Intermediate-terms (1-6 months)
NOAEL = 12 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SFa = 1X (when applicable)

                                   LOC = 100
Oral toxicity study-dog (90-day)
LOAEL= 33 mg/kg/day based on skeletal muscle atrophy/degeneration. 

2-Generation reproduction study- rat (co-critical study)
NOAEL= 7.7 mg/kg/day.
Offspring LOAEL=38.7 mg/kg/day based on pup body weight decrease.
Cancer (oral, dermal, inhalation)
Classification: not likely to be carcinogenic to humans- based on data showing no treatment-related increase in tumors incidence in rat and mouse carcinogenicity studies. No mutagenic concern was reported in the genotoxicity studies. 
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). FQPA SF = FQPA Safety Factor. LOC = level of concern.
[a] This DAF was calculated based on the dermal absorption values from the 24 hours measurements of the most dilute test formulation used in the in vivo rat and in vitro human and rat skin dermal penetration studies. To estimate the human dermal absorption factor (DAF), the following equation is used: Human DAF = (in vitro human % absorption) x [(in vivo rat % absorption/ (in vitro rat % absorption)].

Cancer Classification
Flupyradifurone is classified as "not likely to be carcinogenic to humans" based on data showing no treatment-related increase in tumour incidence in rat and mouse carcinogenicity studies. No mutagenic concern was reported in the genotoxicity studies.

Absorption
A dermal absorption factor of 7.42% was used for the exposure assessment and is based on 24-hour measurements of dermal absorption in in vivo and in vitro dermal absorption studies. Since no inhalation absorption data are available, toxicity by the inhalation route is considered equivalent to the estimated toxicity by the oral route of exposure. 

Body Weight
The standard body weight for the general population (80 kg) was used for the adult exposure scenarios covered in this risk assessment since the endpoints selected were not female-specific, developmental, and/or fetal effects. For the assessment of residential uses, the body weight(s) used for children was 11 kg (1 to <2 years old).

4.0 Use Profile 

The registrant, Bayer Crop Sciences, has submitted a request for a Section 3 registration for proposed new uses of flupyradifurone in and around residential sites (including mattresses), commercial facilities, and other man-made structures for the new EP, ESP005 Insecticide (alternate brand name, Temprid Dust Insecticide) (EPA File Symbol No. 432-RAEE). Temprid Dust is formulated as a dust with 1% ai, flupyradifurone, per pound of product (lb product). This product also contains the ai beta-cyfluthrin, which will be assessed separately. Applications are made by handheld duster, brush, bulb duster, electric duster, or other suitable equipment at single maximum application rates ranging from 0.25 to 0.50 lb product per 1,000 square feet. The RTI is 7 to 10 days. There are no label-stated attire nor PPE requirements. The proposed use pattern does not fall under the WPS and therefore does not have a REI requirement. 

Table 4.0.1. Summary of Directions for Non-Occupational Uses of Flupyradifurone.
                              Formulation, %ai, 
                              EPA File Symbol No.
                             Applic. Timing, Type,
                                   and Equip.
                                     Max. 
                               Single. Applic. 
                                     Rate 
                           Max. No. Applic. / Season
                                     Max. 
                               Seasonal Applic. 
                                     Rate 
                       Use Directions and Limitations[1]
In/around residential and commercial facilities, manmade structures, and mattresses
                                     Dust
                                       
                               1% ai/lb product
                                       
                                   432-RAEE
                                 Post-Emergent
                                       
                      C&C, perimeter, spot, broadcast
                                       
           Plunger, Bulb, Electric/Power, and/or Hand Crank Dusters
                               0.50 lb product/
                                 1,000 sq ft 
                                       
                             (0.01 lb ai/lb dust)
                                      NS
                                      NS
        RTI = 7 to 10 days, as needed, until infestation is eliminated.
                                       
                   Spot treatments must not exceed 2 sq ft.
                                       
In living areas, avoid deposits on exposed surfaces and avoid introducing the dust into the air.
                                       
All outdoor applications must be limited to spot or C&C treatments only except for specific permitted uses.[2]
                                       
       For infested mattresses, apply to tufts, seams, folds, and edges.
[1] RTI = re-treatment interval. NS = not specified. C&C = crack and crevice.
[2] Specific permitted uses include: Applications to underside of eaves, soffits, doors, or windows permanently protected from rainfall by a covering, overhang, awning, or other structure.

Table 4.0.2. Summary of Directions for Occupatioanl Uses of Flupyradifurone.
                              Formulation, %ai, 
                              EPA File Symbol No.
                             Applic. Timing, Type,
                                   and Equip.
                                     Max. 
                                Single Applic. 
                                     Rate
                           Max. No. Applic. / Season
                                     Max. 
                               Seasonal Applic. 
                                     Rate 
                       Use Directions and Limitations[1]
Food handling establishments, warehouses, residential living spaces (homes/apartments), childcare centers/schools/institutions, and exterior building components (e.g., foundations, perimeters, door/window frames, etc.) 
                                     Dust
                                       
                               1% ai/lb product
                                       
                                   432-RAEE
                                 Post-Emergent
                                       
                      C&C, perimeter, spot, broadcast
                                       
           Plunger, Bulb, Electric/Power, and/or Hand Crank Dusters
                               0.50 lb product/
                                 1,000 sq ft 
                                       
                            (0.000005 lb ai/sq ft)
                                      NS
                                      NS
        RTI = 7 to 10 days, as needed, until infestation is eliminated.
                                       
                   Spot treatments must not exceed 2 sq ft.
                                       
Living areas: avoid deposits on exposed surfaces and avoid introducing the dust into the air.
                                       
All outdoor applications must be limited to spot or C&C treatments only except for specific permitted uses.[2]
                                       
   Poultry houses: do not apply more than 2 whole house treatments per year.

Do not apply to food/feed areas of commercial food/feed handling establishments, restaurants, or other commercial establishments where food/feed is commercially prepared, processed, or served.
[1] RTI = re-treatment interval. NS = not specified. C&C = crack and crevice.
[2] Specific permitted uses include: Applications to underside of eaves, soffits, doors, or windows permanently protected from rainfall by a covering, overhang, awning, or other structure.

5.0 Residential Exposure and Risk Estimates

Based on the proposed uses, residential exposures are anticipated for both residential handlers and to adults and children 1 to <2 years old following application to indoor environments.

5.1 Residential Handler Exposure/Risk Estimates

HED uses the term "handlers" to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handlers are addressed somewhat differently by HED as homeowners are assumed to complete all elements of an application without use of any protective equipment.

There is a proposed flupyradifurone product label with residential use sites (e.g., indoor environments) that do not require specific clothing (e.g., long sleeve shirt/long pants) and/or PPE, and these labels have been considered in the residential handler assessment for flupyradifurone. 

Label-permitted outdoor spot and crack and crevice (C&C) applications were evaluated via the garden and trees scenarios since exposure data is available for the specified application equipment and formulation.

Residential Handler Exposure Data and Assumptions
A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. Each assumption and factor is detailed below.

Application Rate: The flupyradifurone quantitative exposure/risk assessment developed for residential handlers is based on the proposed application rates listed in Table 4.0.1. 

Unit Exposures and Area Treated or Amount Handled: Unit exposure values and estimates for area treated or amount handled were taken from HED's 2012 Residential SOPs. 

Exposure Duration: For flupyradifurone, based on the proposed uses and their use patterns, short- and intermediate-term exposures are expected. Repeated treatments for less than 1 month may be considered a series of short-term exposures, while those > 30 days would be considered intermediate-term exposures. However, since the short- and intermediate-term inhalation POD is the same for both durations, the short-term assessment is protective of both durations. Long-term exposures are not likely because of the nature of applications by homeowners.

Residential Handler Non-Cancer Exposure and Risk Estimate Equations
The algorithms used to estimate exposure and dose for residential handlers can be found in the 2012 Residential SOPs.

Combining Exposures/Risk Estimates:
Dermal and inhalation risk estimates were combined in this assessment, since the toxicological effects for these exposure routes were similar. Dermal and inhalation risk estimates were combined using the following formula:

 Total MOE = Point of Departure (mg/kg/day) / Combined Dermal + Inhalation dose (mg/kg/day)

Summary of Residential Handler Non-Cancer Exposure and Risk Estimates
All residential handler risk estimates are not of concern with combined MOEs ranging from 470 to 19,000 (LOC = 100). A full summary of risk estimate is provided in Table 5.1.1 below.

Table 5.1.1. Residential Handler Non-cancer Exposure and Risk Estimates for Flupyradifurone.
                               Exposure Scenario
                                       
                        Dermal Unit Exposure (mg/lb ai)
                               Inhalation Unit 
                              Exposure (mg/lb ai)
                             Max. Applic. Rate[1]
                    Area Treated or Amount Handled Daily[2]
                                    Dermal
                                  Inhalation
                                     Total
                                       
                                       
                                       
                                       
                                       
                              Dose (mg/kg/day)[3]
                                    MOE[4]
                                  (LOC = 100)
                              Dose (mg/kg/day)[5]
                                    MOE[6]
                                  (LOC = 100)
                                    MOE[7]
                                  (LOC = 100)
                              Indoor Environments
                Dust, Plunger Duster, Broadcast, Perimeter/Spot/
                          Bedbug (course application)
                                      250
                                      1.7
                                     0.01 
                                 lb ai/lb dust
                                     0.5 
                                    lb dust
                                    0.0012
                                    10,000
                                    0.00011
                                    110,000
                                     9,500
                       Dust, Bulb Duster, Perimeter/Spot/
                                Bedbug; C&C
                                      250
                                      1.7
                                     0.01 
                                 lb ai/lb dust
                                     0.25 
                                    lb dust
                                    0.00058
                                    21,000
                                   0.000053
                                    230,000
                                    19,000
 Dust, Electric/Power Duster, Electric/Hand Crank Duster, and Shaker Can, Broadcast, Perimeter/Spot/
                          Bedbug (course application)
                                     4,300
                                      18
                                     0.01 
                                 lb ai/lb dust
                                     0.5 
                                    lb dust
                                     0.02
                                      600
                                    0.0011
                                    11,000
                                      570
Gardens/Trees (representative of outdoor spot and C&C application scenarios)
                             Dust, Plunger Duster
                                      250
                                      1.7
                             0.000005 lb ai/ft[2]
                                  1,200 ft[2]
                                    0.0014
                                     8,600
                                    0.00013
                                    94,000
                                     7,900
                               Dust, Bulb Duster
                                      250
                                      1.7
                             0.000005 lb ai/ft[2]
                                  1,200 ft[2]
                                    0.0014
                                     8,600
                                    0.00013
                                    94,000
                                     7,900
    Dust, Electric/Power Duster, Electric/Hand Crank Duster, and Shaker Can
                                     4,300
                                      18
                             0.000005 lb ai/ft[2]
                                  1,200 ft[2]
                                     0.024
                                      500
                                    0.0014
                                     8,900
                                      470
1	Based on proposed label (EPA File Symbol No. 432-RAEE) as detailed in Table 4.0.1.
2	Based on HED's 2012 Residential SOPs (https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/standard-operating-procedures-residential-pesticide).
3	Dermal Dose = Dermal Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A/day or gallons/day) x Dermal Absorption Factor (7.42%) / Body Weight (80 kg).
4	Dermal MOE = Dermal POD (12 mg/kg/day) / Dermal Dose (mg/kg/day).
5	Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A/day or gallons/day) / Body Weight (80 kg).
6	Inhalation MOE = Inhalation POD (12 mg/kg/day) / Inhalation Dose (mg/kg/day).
7	Total MOE = 1 / [(1 / Dermal MOE) + (1 /Inhalation MOE)].

5.2 Residential Post-application Exposure/Risk Estimates

There is the potential for post-application exposure for individuals exposed as a result of being in an environment that has been previously treated with flupyradifurone. The quantitative exposure/risk assessment for residential post-application exposures is based on the scenarios summarized in Table 5.2.1. Residential post-application outdoor dermal exposures (e.g., bedbug treatments to patio furniture) are also represented by the indoor dermal post-application assessment for mattresses. All other outdoor spot and C&C uses are expected to result in negligible dermal and inhalation exposures and were not assessed.

The lifestages selected for each post-application scenario are based on an analysis provided in Appendix A of the 2012 Residential SOPs. While not the only lifestage potentially exposed for these post-application scenarios, the lifestage that is included in the quantitative assessment is health protective for the exposures and risk estimates for any other potentially exposed lifestage.

Residential Post-application Exposure Data and Assumptions
A series of assumptions and exposure factors served as the basis for completing the residential post-application risk assessment. Each assumption and factor is detailed in the 2012 Residential SOPs[5].

Application Rate: The flupyradifurone quantitative exposure/risk assessment developed for the residential post-application is based on the proposed application rates listed in Table 4.0.1. 

Fraction of Residue Available for Transfer (Fai): Chemical-specific data for the fraction of residue available for transfer on indoor surfaces has not been submitted for flupyradifurone. Therefore, this assessment uses HED's 2012 Residential SOPs recommended point estimates of 0.06 (for carpets), 0.08 (for hard surfaces), and 0.06 (for mattresses) for dermal exposures and 0.15 (for mattresses) for incidental oral exposures. Submission of dust-specific data may further refine risk estimates.

Exposure Duration: For flupyradifurone, based on the proposed uses and their use patterns, short- and intermediate-term exposures are expected. Repeated treatments for less than 1 month may be considered a series of short-term exposures, while those > 30 days would be considered intermediate-term exposures. However, since the short- and intermediate-term inhalation POD is the same for both durations, the short-term assessment is protective of both durations. Long-term exposures are not likely because of the nature of applications by homeowners.

Residential Post-application Non-Cancer Exposure and Risk Equations
The algorithms used to estimate residential post-application exposure and dose can be found in the 2012 Residential SOPs.

Combining Exposure and Risk Estimates
Since the dermal and incidental oral exposure routes share a common toxicological endpoint, risk estimates have been combined for those routes. The incidental oral scenarios (i.e., hand-to-mouth and object-to-mouth) should be considered inter-related and it is likely that they occur interspersed amongst each other across time. Combining these scenarios with the dermal exposure scenario would be overly-conservative because of the conservative nature of each individual assessment. Therefore, the post-application exposure scenarios that were combined for children 1 to <2 years old are the dermal and hand-to-mouth scenarios. This combination should be considered a protective estimate of children's exposure.

Summary of Residential Post-application Non-Cancer Exposure and Risk Estimates
Residential post-application risks estimated are not of concern with combined MOEs ranging from 1,100 to 96,000 (LOC = 100). Residential post-application risk estimates have been summarized in Table 5.2.1 below.

Table 5.2.1. Residential Post-application Non-cancer Exposure and Risk Estimates for Flupyradifurone.
                                   Lifestage
                      Post-application Exposure Scenario
                              Application Rate[1]
                              Dose (mg/kg/day)[2]
                                     MOEs
                                (LOC = 100)[3]
                                   Combined 
                                   Routes[4]
                                   Combined 
                                    MOEs[5]
                                       
                                   Use Site
                               Route of Exposure
                                       
                                       
                                       
                                       
                                       
                                     Adult
                                    Carpet
                               (Perimeter/Spot/
                                    Bedbug)
                                    Dermal
                                   0.000005
                                  lb ai/sq ft
                                    0.0037
                                     3,200
                                      NA
                                     3,200
                                   Children 
                            (1 to <2 years old)
                                       
                                    Dermal
                                       
                                    0.0036
                                     3,400
                                       X
                                     1,100
                                       
                                       
                                      HTM
                                       
                                    0.0072
                                     1,700
                                       X
                                       
                                       
                                       
                                      OTM
                                       
                                    0.0010
                                    12,000
                                      --
                                       
                                     Adult
                        Hard Surfaces (Perimeter/Spot/
                                    Bedbug)
                                    Dermal
                                       
                                    0.0012
                                     9,700
                                      NA
                                     9,700
                                   Children 
                            (1 to <2 years old)
                                       
                                    Dermal
                                       
                                    0.0024
                                     5,000
                                       X
                                     2,500
                                       
                                       
                                      HTM
                                       
                                    0.0024
                                     5,000
                                       X
                                       
                                       
                                       
                                      OTM
                                       
                                    0.00064
                                    19,000
                                      --
                                       
                                     Adult
                                    Carpet
                                   (C&C)
                                    Dermal
                                       
                                    0.00074
                                    16,000
                                      NA
                                    16,000
                                   Children 
                            (1 to <2 years old)
                                       
                                    Dermal
                                       
                                    0.00071
                                    17,000
                                       X
                                     5,600
                                       
                                       
                                      HTM
                                       
                                    0.0014
                                     8,300
                                       X
                                       
                                       
                                       
                                      OTM
                                       
                                    0.00019
                                    62,000
                                      --
                                       
                                     Adult
                            Hard Surfaces (C&C)
                                    Dermal
                                       
                                    0.00025
                                    49,000
                                      NA
                                    49,000
                                   Children 
                            (1 to <2 years old)
                                       
                                    Dermal
                                       
                                    0.00048
                                    25,000
                                       X
                                    13,000
                                       
                                       
                                      HTM
                                       
                                    0.00048
                                    25,000
                                       X
                                       
                                       
                                       
                                      OTM
                                       
                                    0.00013
                                    94,000
                                      --
                                       
                                     Adult
                                  Mattresses
                                    Dermal
                                       
                                    0.00012
                                    96,000
                                      NA
                                    96,000
                                   Children 
                            (1 to <2 years old)
                                       
                                    Dermal
                                       
                                    0.00028
                                    42,000
                                       X
                                    42,000
1	Based on proposed label (EPA File Symbol No. 423-RAEE) as summarized in Table 4.1.
2	Dose (mg/kg/day) algorithms provided in 2012 Residential SOPs (https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/standard-operating-procedures-residential-pesticide).
3	MOE = POD (12 mg/kg/day) / Dose (mg/kg/day).
4	X indicates scenarios included in Combined MOE.
5	Combined MOE = 1 / [(1/dermal MOE) + (1/inhalation MOE) + (1/incidental oral MOE)], where applicable.

5.3 Residential Risk Estimates for Use in Aggregate Assessment

In addition to the residential uses assessed in this memorandum. there are additional uses that have been previously registered. Table 5.3.1 reflects all relevant residential risk estimates that are recommended for use in the aggregate assessment for flupyradifurone.

 The recommended residential exposure for use in the adult aggregate assessment is combined dermal and inhalation handler exposure to outdoor spot/C&C applications (surrogate: gardens and trees) via electric/power, and electric/hand crank dusters applications with dust formulation.
 The recommended residential exposure for use in the children 1 to <2 years old aggregate assessment is combined dermal and hand-to-mouth from applications to carpet (perimeter/spot/bedbug) in indoor environments combined with dermal from applications to mattresses.
 The recommended residential exposure for use in the children 6 to <11 years old aggregate assessment is dermal exposures from post-application exposures to gardens from ready-to-use applications (R. McGovern, et al., D453708 and D454504, 06/30/2020).

Table 5.3.1. Recommendations for the Residential Exposures for the Flupyradifurone Aggregate Assessment.
                                   Lifestage
                               Exposure Scenario
                              Dose (mg/kg/day)[1]
                                    MOE[2]
                                       
                                       
                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
                                    Dermal
                                   (LOC=100)
                                  Inhalation
                                   (LOC=100)
                                     Oral
                                   (LOC=100)
                                     Total
                                   (LOC=100)
                                     Adult
Handler  -  electric/power, and electric/hand crank dusters, and shaker cans to gardens and trees
                                     0.024
                                    0.0014
                                      N/A
                                     0.025
                                      500
                                     8,900
                                      N/A
                                      470
                                   Children
                                 (1 to <2)
      Post-Application  -  dust applications to carpet (perimeter/ spot/
                           bedbug) and to mattresses
                                    0.0039
                                      N/A
                                    0.0072
                                     0.011
                                     3,100
                                      N/A
                                     1,700
                                     1,100
                                   Children
                                 (6 to <11)
        Post-Application  -  Ready to Use (RTU) applications to gardens
                                     0.028
                                      N/A
                                      N/A
                                     0.028
                                      430
                                      N/A
                                      N/A
                                      430
1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + incidental oral (where applicable).
2 MOE = the MOEs associated with the highest residential doses. Total = 1 / [(1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental Oral MOE)], where applicable.

6.0 Non-Occupational Spray Drift Exposure and Risk Estimates

Spray drift is a potential source of exposure to individuals who are located in close proximity to pesticide applications. This is particularly the case with aerial application, which tends to have the highest amount of drift as evaluated, but spray drift can also be a potential source of exposure from the ground application methods. The Agency has developed best spray drift management practices with input from the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation as well as other parties (see the Agency's Spray Drift website for more information). The Agency has also prepared a draft document on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The approach is outlined in the revised 2013 Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift, which can be found at https://www.regulations.gov in docket identification number EPA-HQ-OPP-2013-0676. The potential for spray drift from flupyradifurone uses will be evaluated during the ongoing Registration Review process to ensure that all uses for that pesticide will be considered concurrently. Based on the proposed uses and equipment, non-occupational spray drift exposure is not anticipated.

7.0 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk Estimates

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from FIFRA Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010. The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (Human Health Bystander Screening Level Analysis: Volatilization of Conventional Pesticides). During Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for flupyradifurone.

A quantitative residential post-application inhalation exposure assessment was not performed; based on the proposed use patterns, exposures are anticipated to be negligible. 

8.0 Occupational Exposure and Risk Estimates

8.1 Occupational Handler Exposure/Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the scenarios presented below in 8.1.1. 

Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate: The flupyradifurone quantitative exposure/risk assessment developed for occupational handlers is based on the proposed application rates listed in Table 4.0.2 

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include Pesticide Handler Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task Force (AHETF) database, the ORETF database, or other registrant-submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures", are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table", which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website. 

Area Treated or Amount Handled: The inputs for area treated/amount handled were based on information in ExpoSAC Policy 9.2. 

Exposure Duration: HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months as intermediate-term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one-month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region). 

For flupyradifurone, based on the proposed uses and their use patterns, short- and intermediate-term exposures are expected. However, since the short- and intermediate-term inhalation POD is the same for both durations, the short-term assessment is protective of both durations.

Personal Protective Equipment: Estimates of dermal and inhalation exposure were calculated considering the personal protective equipment (PPE) listed on product labels, and any additional PPE necessary to identify risk estimates not of concern. The flupyradifurone proposed product labels direct mixers, loaders, applicators and other handlers to wear baseline attire and no additional PPE. The attire that was considered and assessed includes baseline, defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator. 

Occupational Handler Non-Cancer Exposure and Risk Estimate Equations
The algorithms used to estimate non-cancer exposure and dose for occupational handlers can be found in Appendix A.

Combining Exposures/Risk Estimates
Dermal and inhalation risk estimates were combined in this assessment, since the toxicological effects for these exposure routes were similar. Dermal and inhalation risk estimates were combined using the following formula:

 Total MOE = Point of Departure (mg/kg/day) / Combined dermal + inhalation dose (mg/kg/day)

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates
There are no risks of concern (i.e., all MOEs >= the LOC) for occupational handlers at baseline (e.g., single layer of clothing, no gloves and no respirator). At baseline (e.g., single layer of clothing, no gloves and no respirator) combined MOEs range from 600 to 14,000 (LOC = 100). 
Table 8.1.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Flupyradifurone.
                                   Exposure 
                                   Scenario
                                   Crop or 
                                    Target
                                    Dermal 
                                     Unit 
                           Exposure 
(μg/lb ai)[1]
                                       
                                [Level of PPE] 
                    Inhalation
Unit
Exposure
(μg/lb ai)[1]
                                       
                                [Level of PPE]
                                 Max.
Applic. 
                                    Rate[2]
                                       
                                     Area 
                                   Treated 
                          or
Amount Handled Daily[3]
                                       
                                    Dermal
                                  Inhalation
                                     Total

                                     Dose 
                                (mg/kg/day)[4]
                                      MOE
                                (LOC = 100)[5]
                              Dose (mg/kg/day)[6]
                                     MOE 
                                (LOC = 100)[7]
                                     MOE 
                                (LOC = 100)[8]
                                  Applicator
                                    Dust, 
                                  Shake Can, 
                                   Broadcast
                                   Warehouse
                                   4,042,000
                                   [SL/No G]
                                    17,500
                                    [No-R]
                                   0.000005
                                  lb ai/ft[2]
                                     1,000
                                     Ft[2]
                                    0.0187
                                      640
                                    0.00109
                                    11,000
                                      600
                                       
     Poultry House (feedline/perimeter, treatment of litter, walls, etc.)
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
Exterior Building Components (e.g., foundations, perimeters, door/window frames, etc.)
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                               Loader/Applicator
                                    Dust, 
                                 Bulb duster, 
                                    C&C
                                       
                          Food handling establishment
                                    166,000
                                     [SL/
                                     No G]
                                     1,690
                                    [No-R]
                                   0.000005
                                  lb ai/sqft
                                     1,000
                                     sqft
                                    0.00077
                                    16,000
                                   0.000106
                                    110,000
                                    14,000
                                       
                                   Warehouse
                                    166,000
                                     [SL/
                                     No G]
                                     1,690
                                    [No-R]
                                   0.000005
                                  lb ai/sqft
                                     1,000
                                     sqft
                                    0.00077
                                    16,000
                                   0.000106
                                    110,000
                                    14,000
                                       
                 Residential Living Spaces (homes, apartments)
                                    166,000
                                     [SL/
                                     No G]
                                     1,690
                                    [No-R]
                                   0.000005
                                  lb ai/sqft
                                     1,000
                                     sqft
                                    0.00077
                                    16,000
                                   0.000106
                                    110,000
                                    14,000
                                       
                               Childcare center/
                                   schools/
                                 institutions
                                    166,000
                                     [SL/
                                     No G]
                                     1,690
                                    [No-R]
                                   0.000005
                                  lb ai/sqft
                                     1,000
                                     sqft
                                    0.00077
                                    16,000
                                   0.000106
                                    110,000
                                    14,000
                                    Dust, 
                               Plunger duster, 
                                   Broadcast
   Exterior Building Components (e.g., foundations, perimeters, door/window 
                                 frames, etc.)
                                    166,000
                                     [SL/
                                     No G]
                                     1,690
                                    [No-R]
                                   0.000005
                                  lb ai/sqft
                                     1,000
                                     sqft
                                    0.00077
                                    16,000
                                   0.000106
                                    110,000
                                    14,000
[1] Unit Exposures: Based on the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handler-exposure-data). Level of PPE: SL/No G = single layer, no gloves; No-R = no respirator.
[2] Maximum Application Rate: Based on proposed label (see Table 4.1).
[3] Area Treated or Amount Handled: Exposure Science Advisory Council Policy #9.2.
[4] Dermal Dose: Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled Daily (A or gal/day) x DAF (7.42 %) / BW (80 kg).
[5] Dermal MOE: Dermal MOE = Dermal POD (12 mg/kg/day) / Dermal Dose (mg/kg/day). LOC = 100.
[6] Inhalation Dose: Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled Daily (A or gal/day) / BW (80 kg).
[7] Inhalation MOE: Inhalation MOE = Inhalation POD (12 mg/kg/day) / Inhalation Dose (mg/kg/day). LOC = 100.
[8] Total MOE: Total MOE = 1 / (1/Dermal MOE + 1/Inhalation MOE).

8.2 Occupational Post-application Exposure/Risk Estimates

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

8.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates

There are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from FIFRA Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010. The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (Human Health Bystander Screening Level Analysis: Volatilization of Conventional Pesticides). During Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for flupyradifurone.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides indoor and outdoors is likely to result in higher exposure than post-application exposure, and all of the occupational handler scenarios resulted in inhalation risk estimates that were not of concern at baseline (i.e., all inhalation MOEs without a respirator >= the LOC). Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

Further, commercial applicators do not typically return to the treated areas after an indoor/exterior commercial pesticide application (sites such as residential living spaces, warehouses, food handling establishments, and hotels, etc.) and thus an occupational post-application inhalation exposure assessment was not performed for commercial applicators.

8.2.2 Occupational Post-application Dermal Exposure/Risk Estimates

Commercial applicators do not typically return to the treated areas after an indoor/exterior commercial pesticide application (sites such as residential living spaces, warehouses, food handling establishments, and hotels, etc.). Thus, a quantitative occupational post-application dermal exposure assessment was not performed for commercial applicators. The proposed use pattern does not fall under the Worker Protection Standards and therefore does not have a proposed restricted entry interval (REI) requirement. 

Appendix A. Summary of Occupational and Residential Non-cancer Algorithms

Residential Non-cancer Handler Algorithms

Indoor Environments
Daily dermal and inhalation exposure (mg/day) for residential pesticide handlers, for a given formulation-application method combination, is estimated by multiplying the formulation-application method-specific unit exposure by an estimate of the amount of active ingredient handled in a day, using the equation below:

                                E = UE * AR * A

where:
E = exposure (mg/day);
UE = unit exposure (mg/lb ai);
AR = application rate (e.g., lb ai/ft[2], lb ai/gal); and
A = area treated or amount handled (e.g., ft[2]/day, gal/day).

Residential Non-cancer Post-application Algorithms

Indoor Environments - Post-Application Dermal Exposure Algorithm (hard surfaces and carpets)
The algorithm to calculate exposure is as follows:

E=TR*TC*ET*CF1

where:	
      E	= exposure (mg/day);
      TR	= indoor surface transferable residue (ug/cm[2]);
      TC	= transfer coefficient (cm[2]/hr); 
      ET	= exposure time (hr/day); and
      CF1	= conversion factor (0.001 mg/ug).

If chemical-specific TR data are available, this is preferred and should be used to calculate exposure. However, if chemical-specific TR data are not available, then TR can be calculated using the following formula:

TR=DepR* Fai 

	
where:
      TR	= indoor surface transferable residue (ug/cm[2]);
      DepR	= deposited residue (mg/cm[2]), based on (in order of preference):
      		(1) Chemical-specific residue deposition data (mg/cm[2]),
      		(2) Application rate (lb ai/area), or
      		(3) Default residue based on type of application (mg/cm[2]); and
      Fai	= fraction of ai available for transfer from carpet or hard surface (unitless).

Absorbed dermal dose, normalized to body weight, are calculated as:

D= E*AFBW

	
where:
      D	= dose (mg/kg-day);
      E	= exposure (mg/day);
      AF	= absorption factor; and
      BW	= body weight (kg).

Table A-1: Indoor Environments (Hard Surfaces and Carpets)  -  Inputs for Residential Post-application Dermal Exposure 
                              Algorithm Notation
                                Exposure Factor
                                    (units)
                               Point Estimate(s)
                                      TR
                             Transferable residue
                                  (mg/cm[2])
(1) Chemical-specific transferable residue data OR
(2) Estimated: DepR * Fai
                                     DepR
                               Deposited residue
                                  (mg/cm[2])
(1) Chemical-specific residue deposition data,
(2) Estimated based on application rate, or 
(3) Estimated based on default residue related to type of application
                                      Fai
                 Fraction of DepR as TR following application
                                    Carpets
                                    0.06[a]
                                       
                                       
                                 Hard surfaces
                                    0.08[a]
                                      TC
                             Transfer Coefficient
                                  (cm[2]/hr)
                                     Adult
                                     6,800
                                       
                                       
                          Children 1 < 2 years old
                                     1,800
                                      ET
                            Exposure Time (hrs/day)
                                    Adults
                                    Carpets
                                       8
                                       
                                       
                                       
                                 Hard Surfaces
                                       2
                                       
                                       
                          Children 1 < 2 years old
                                    Carpets
                                       4
                                       
                                       
                                       
                                 Hard Surfaces
                                       2
                                      BW
                               Body weight (kg)
                                     Adult
                                      80
                                       
                                       
                          Children 1 < 2 years old
                                      11

Post-Application Dermal Exposure Algorithm (mattresses)
The algorithm to calculate absorbed dose is as follows:

D=DR* SABW*F*Fai*PF*AF*CF1

where:

	D		=	Dermal dose (mg/kg-day);
	DR		=	Deposited residue (mg/cm2);
	SA/BW 	=	Surface area / Body Weight Ratio (cm[2]/kg);
	F		=	Fraction of body that contacts residue;
	CF1		=	Conversion factor (mg/mg);
	AF		=	Absorption factor;
	Fai		=	fraction of ai available for transfer from treated mattress; and
	PF		=	Protection factor to account for the presence of a single layer of 
				fabric (e.g. bed sheet) 	between the treated material and individual.

Table A-2: Indoor Environments (mattresses)  -  Inputs for Residential Post-application Dermal Exposure
                              Algorithm Notation
                                Exposure Factor
                                    (units)
                               Point Estimate(s)
                                      DR
                               Deposited residue
                                  (mg/cm[2])
             (1) Calculated based on information provided on label
                                      OR
                      (2) based on default residue values
                                     SA/BW
                       Surface area / Body Weight Ratio
                                  (cm[2]/kg)
                                     Adult
                                      280
                                       
                                       
                          Children 1 < 2 years old
                                      640
                                       F
                    Fraction of body that contacts residue
                                      0.5
                                      Fai
                     Fraction of DR available for transfer
                                     0.06
                                      PF
                               Protection Factor
                                      0.5

Post-application Hand-to-Mouth Exposure Algorithm
Exposure from hand-to-mouth activity is calculated as follows (based on algorithm utilized in SHEDS-Multimedia):

E=HR* FM* SAH* ET*N_Replen* 1-1-SE Freq_HtMN_Replen

	
where:
      E		= exposure (mg/day);
      HR		= hand residue loading (mg/cm[2]);
      FM		= fraction hand surface area mouthed / event (fraction/event);
      ET		= exposure time (hr/day);
      SAH		= surface area of one hand (cm[2]);
      N_Replen 	= number of replenishment intervals per hour (intervals/hour);
      SE 		= saliva extraction factor (i.e., mouthing removal efficiency); and
      Freq_HtM	= number of hand-to-mouth contacts events per hour (events/hour).

and
                                       

HR= Faihands*DESAH*2

where:
	HR	=	hand residue loading (mg/cm[2]);
  	Faihands	=	fraction ai on hands compared to total surface residue from jazzercise study (unitless);
	DE	=	dermal exposure (mg); and
      SAH	= typical surface area of one hand (cm[2]).

and

Dose, normalized to body weight, is calculated as:

D= EBW

	
where:
      D	= dose (mg/kg-day);
      E	= exposure (mg/day); and
      BW	= body weight (kg).

Table A-3: Indoor Environments  -  Inputs for Residential Post-application Hand-to-Mouth Exposure 
                              Algorithm Notation
                                Exposure Factor
                                    (units)
                               Point Estimate(s)
                                   Faihands
                 Fraction of ai on hands from jazzercise study
                                  (unitless)
                                     0.15
                                      DE
                                Dermal exposure
                                     (mg)
                                  Calculated
                                      HR
                        Residue available on the hands 
                                  (mg/cm[2])
                                  Calculated
                                      SAH
                       Surface area of one hand (cm[2])
                          Children 1 < 2 years old
                                      150
                                      AR
                               Application rate
                    (mass active ingredient per unit area)
                                See Table 4.0.1
                                      FM
                      Fraction of hand mouthed per event 
                               (fraction/event)
                                     0.13
                                   N_Replen
                       Replenishment intervals per hour
                                (intervals/hr)
                                       4
                                      ET
                                 Exposure time
                                (hours per day)
                          Children 1 < 2 years old
                                    Carpets
                                       4
                                       
                                       
                                       
                                 Hard Surfaces
                                       2
                                      SE
                           Saliva extraction factor
                                  (fraction)
                                     0.48
                                   Freq_HtM
                             Hand-to-mouth events 
                                   per hour
                                  (events/hr)
                          Children 1 < 2 years old
                                      20
                                      BW
                                  Body Weight
                                     (kg)
                          Children 1 < 2 years old
                                      11

Post-application Object-to-Mouth Exposure Algorithm
Exposure from object-to-mouth activity is calculated as follows (based on algorithm utilized in SHEDS-Multimedia):

E=OR*CF1* SAMO* ET*N_Replen* 1-1-SE Freq_OtMN_Replen

where:
      
      E		=	exposure (mg/day);
      OR		=	chemical residue loading on an object (mg/cm[2]);
      CF1		=	weight unit conversion factor (0.001 mg/mg);
      SAMO		=	area of the object surface that is mouthed (cm[2]/event);
      ET		=	exposure time (hr/day);
      N_Replen	= 	number of replenishment intervals per hour (intervals/hour);
      SE 		= 	saliva extraction factor (i.e., mouthing removal efficiency); and
      Freq_OtM 	= 	number of object-to-mouth contact events per hour (events/hour).

and

OR=DepR* FO

	
where:
	
      OR	=	chemical residue loading on the object (μg/cm[2]);
	DepR	=	deposited residue (μg/cm[2]); and
	FO	=	fraction of residue transferred to an object (unitless).

and

Oral dose, normalized to body weight, is calculated as:

D= EBW

	
where:
	
      D	=	dose (mg/kg-day);
	E	=	exposure (mg/day); and
	BW	=	body weight (kg).

Table A-4: Indoor Environments  -  Inputs for Residential Post-application Object-to-Mouth Exposure
                              Algorithm Notation
                                Exposure Factor
                                    (units)
                               Point Estimate(s)
                                      AR
                               Application rate
                    (mass active ingredient per unit area)
                                See Table 4.0.1
                                      FO
                 Fraction of residue transferred to an object
                                    Carpets
                                    0.06[a]
                                       
                                       
                                 Hard surfaces
                                    0.08[a]
                                     SAMO
                        Surface area of object mouthed
                                 (cm[2]/event)
                                      10
                                   N_Replen
                       Replenishment intervals per hour
                               (intervals/hour)
                                       4
                                      SEO
                           Saliva extraction factor
                                     0.48
                                      ET
                                 Exposure Time
                                (hours per day)
                          Children 1 < 2 years old
                                    Carpets
                                       4
                                       
                                       
                                       
                                 Hard Surfaces
                                       2
                                   Freq_OtM
                        Object-to-mouth events per hour
                                 (events/hour)
                          Children 1 < 2 years old
                                      14
                                      BW
                                  Body Weight
                                     (kg)
                          Children 1 < 2 years old
                                      11

Occupational Non-cancer Handler Algorithms

Potential daily exposures for occupational handlers are calculated using the following formulas:

E=UE * AR * A * 0.001 mg/ug

where:

E	=	exposure (mg ai/day),
UE	=	unit exposure (ug ai/lb ai),
AR	=	maximum application rate according to proposed label (lb ai A or lb ai/gal), and
A	=	area treated or amount handled (e.g., A/day, gal/day).
 
The daily doses are calculated using the following formula:

ADD=  E * AFBW

where:

ADD	= 	average daily dose absorbed in a given scenario (mg ai/kg/day),
E	=	exposure (mg ai/day),
AF	=	absorption factor (dermal and/or inhalation), and
BW 	= 	body weight (kg).

Margin of Exposure: Non-cancer risk estimates for each application handler scenario are calculated using a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint to the daily dose of concern. The daily dermal and inhalation dose received by occupational handlers are compared to the appropriate POD (i.e., NOAEL) to assess the risk to occupational handlers for each exposure route. All MOE values are calculated using the following formula:

MOE= PODADD

where:

MOE	=	margin of exposure: value used by HED to represent risk estimates (unitless),
POD	=	point of departure (mg/kg/day), and
ADD	=	average daily dose absorbed in a given scenario (mg ai/kg/day).