UN ITED STATES ENVIRONMENTAL PR OTECTION A GE NCY

WASHINGTON, D

. C. 20460

MEMORANDUM

Date: 9/15/2014 OFFICE OF CHEMICAL SAFETY

AND POLLU TION PREVENTION

SUBJECT : Prallethrin. Human Health Risk Assessment for the Tolerance Petition to

Amend the Section 3 Mosquito Adulticide Registration to Include Use of the

In sect icide Over All Crops

PC Code: 128722

Decision No.: 470627

Petition No.: 2F8090

Risk Assessment Type: Single Chemical Aggregate

TXRNo.: NA

MRIDNo.: NA

FROM:

Ray Kent

, Ph.D., Toxicologist

Wade Britton

, Industrial Hygie DP Barcode: 0420116 Registration Nos.: I 021-1795, 1021-2562 Regulatory Action: Section 3 Re g is t ration

CaseNo

. : 7418

CAS No.: 23031-36-9

40 CFR: § 180.545

HED Risk Assessment Re view Comm ttee

TO: Kevin Sweeney/R ichard Gebken, RM Team 10 ln$ecticide Branch (IB) Regis tration Division (7505P)Prallethrin Human Health Risk Assessment DP No. D420116

The Registration Division (RD) requested that the Health Effects Division (HED) conduct a 

### human health risk assessment for the proposed label amendment for the use of th e insecticide prallethrin as a mosquito adulticide.

This document contains the human health risk assessment associated with this action and incorporates updated endpoints for risk assessment, updated percent food handling establishment

treated assumptions, as well as the most rece n t data and assumpt i ons for conducting residential

and occupational exposure assessments

. No risks of concern were iden t i fied for the proposed

l abel amendment.

Page 2 of70Prallethrin Human Health Risk Assessment DP No. D420116

Page 3 of 70 1.0 Executive Summary

................................ ................................ ................................ ............ 5

2.0 HED Recommendations

................................ ................................ ................................ ...... 8

2.1 Data Deficiencies/Conditions of Registration

................................ ................................ 8

2.2 Tolerance Considerations

................................ ................................ ................................ 9

2.2.1 Enforcement Analytical Method

................................ ................................ ................. 9

2.2.2 International Harmonization

................................ ................................ ....................... 9

2.2.3 Recommended Tolerances

................................ ................................ .......................... 9

2.2.4 Revisions to Petitioned

- For Tolerances

................................ ................................ .... 10

2.3 Label Recommendations

................................ ................................ ........................... 10

3.0 Introduction

................................ ................................ ................................ ....................... 10

3.1 Chemical Identity

................................ ................................ ................................ .......... 10

3.2 Ph ysical/Chemical Characteristics

................................ ................................ ................ 11

3.3 Pesticide Use Pattern

................................ ................................ ................................ ..... 11

3.4 Anticipated Exposure Pathways

................................ ................................ ................... 1 3

3.5 Consideration of Environmental Justice

................................ ................................ ....... 13

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ............... 1 4

4.1 Toxicology Studies Available for Analysis

................................ ................................ .. 1 5

4.2 Toxicological Profile

................................ ................................ ................................ .... 1 5

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

................................ ........ 1 6

4. 3 .1 Pharmacokinetics

................................ ................................ ................................ ...... 1 6

4.3.2 Pharmacodynamics

................................ ................................ ................................ ... 1 8

4.3.3 Critical Duration of Exposure

................................ ................................ ................... 1 9

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

................................ ..... 2 1

4.4.1 Completeness of the Toxic ology Database

................................ ............................... 2 2

4.4.2 Evidence of Neurotoxicity

................................ ................................ ........................ 2 3

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

........... 2 3

4.4.4 Residual Uncertainty in the Exposure Database

................................ ....................... 2 4

4.5 Toxicity Endpoint and Point of Departure Selections

................................ .................. 2 5

4.5.1 Dose

- Response Assessment

................................ ................................ ...................... 2 5

4.5.2 Recommendation for Combining Rout es of Exposure for Risk Assessment

........... 2 8

4.5.3 Cancer Classification and Risk Assessment Recommendation

................................ 2 8

4.5.4 Summary of Points of Departure and Toxicity Endpoints

................................ ....... 2 8

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ........... 31

5.1 Metabolite/Degradate Residue Profile

................................ ................................ .......... 31

5.1.1 Summary of Plant and Animal Metabolism Studies

................................ ................. 31

5.1.2 Summary of Environmental Degradation

................................ ................................ . 31

5.1.3 Comparison of Metabolic Pathways

................................ ................................ ......... 32

5.1.4 Residues of Concern Summary and Rationale

................................ .......................... 3 2

5.2 Food Residue Profile

................................ ................................ ................................ ..... 32

5.3 Water Residue Profile

................................ ................................ ................................ ... 33

5.4 Dietary Risk Assessment

................................ ................................ .............................. 33

5.4.1 Description of Residue Data Used in Dietary Assessment

................................ ....... 34

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .................. 35

5.4.3 Acute Dietary Risk Assessment

................................ ................................ ................ 35

5.4.4 Chronic Dietary Exposure Assessment

................................ ................................ ..... 3 6Prallethrin Human Health Risk Assessment DP No. D420116

Page 4 of 70 5.4.5 Summary Table

................................ ................................ ................................ ......... 36

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ ... 3 6

6.1 Residential Handler and Post

- Application Exposure and Risk Estimates

.................... 3 7

6.2 Post

- Application Exposure

................................ ................................ ........................... 3 9

6.3 Residential Risk Estimates for Use in Aggregat e Assessment

................................ ..... 43

6.4 Residential Bystander Post

- Application Inhalation Exposure

................................ ...... 45

6. 5 Spray Drift

................................ ................................ ................................ .................... 4 5

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ...... 45

7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 45

7.2 Short

- Term Aggregate Risk Estimates

................................ ................................ ......... 46

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ .... 47

9.0 Occupational Exposure/Risk Characterization

................................ ................................ . 47

9.1 Occupational Handler Exposure/Risk Estimates

................................ .......................... 4 8

9.2 Post

- A pplication Risk

................................ ................................ ................................ ... 50

9. 2.1 Derm al Post

- Application Risk

................................ ................................ .................. 50

9. 2.2 Inhalation Post

- Application Risk

................................ ................................ .............. 50

10.0 References

................................ ................................ ................................ ......................... 51 Appendix A. Toxicology Profile

................................ ................................ ................................ .. 52

A.1 Toxicology Data Requirements

................................ ................................ .................... 52

A.2 Toxicity Profile Table s

................................ ................................ ................................ . 53

A.3 Hazard Identification and Endpoint Selection

................................ .............................. 56

A.4 Human Equivalent Analysis

................................ ................................ ......................... 60

A.5 Pyrethroid Cumulative Screen

................................ ................................ ...................... 63 Appendix B . Physical/Chemical Properties

................................ ................................ ................. 6 7 Appendix C . Review of Human Research

................................ ................................ ................... 6 8 Appendix D. Aggregate Risk Calculations

................................ ................................ .................. 69Prallethrin Human Health Risk Assessment DP No. D420116

Page 5 of 70 1.0 Executive Summary

Prallethrin (CAS name 2

- methyl

- 4

- oxo

- 3

- (2

- propyn

- 1

- yl)

- 2

- cyclopenten

- 1

- yl

- 2,2

- dimethyl

- 3

- (2

- methyl

- 1

- propen

- 1

- yl)cyclopropanecarboxylate, CAS number 23031

- 36

- 9) is a pyrethroid insecticide able to effect the quick knockdown of target pests. Prallethrin is currently registered for use as a mosquito adulticide in outdoor resident ial and recreational area s . The registrant

, McL au ghlin Gormley King Company (MGK), petitioned the Agency for a label amendment that allows the end use products to be “applied over agricultural areas for the control of adult mosquitoes within or adjacent t o these areas

. ” P rallethrin is also registered for a variety of

residential use s for control of pests on pets, turf, and in homes and commercial settings, including food handling establishments (FHEs)

. There are no other food uses for prallethrin. A

to lerance is established at 1.0 ppm in/on all food items to cover the food handling use (40 CFR §180.545). The registrant has proposed that this tolerance also cover residues that might result from the amended use pattern for the mosquito adulticide

.

Prallethrin i s classified as a type I pyrethroid. Type I pyrethroids lack an alpha

- cyano moiety and induce a syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, and fine tremor progressing to whole

- body tremor and prostrat ion in rats. These Type I pyrethroid

- specific behaviors are collectively described as the T

- syndrome. The adverse outcome pathway (AOP) shared by pyrethroids involves the ability to interact with voltage

- gated sodium channels (VGSCs) in the central and p eripheral nervous system, leading to changes in neuron firing, and ultimately neurotoxicity

.

The toxicology database for prallethrin is considered complete with respect to guideline toxicity studies. However, the Agency lacks additional information to fully characterize the potential for juvenile sensitivity to the neurotoxic effects of pyrethroids

. T he toxicity database for prallethrin

does include studies that can be used to characterize most effects, including potential developmental

, reproductive

, and neurotoxic effects . The prallethrin database lacks acceptable immunotoxicity and developmental neurotoxicity (DNT) studies. However, HED’s Hazard and Science Policy Council (HASPOC) concluded that the immunotoxicity study is not required. An

immuno toxicity study is not anticipated to provide a lower point of departure ( POD ) or result in a more sensitive endpoint than those already used . Additionally, EPA has determined that DNTs for pyrethroid insecticides do not adequately characterize potential s usceptibility of the young. Therefore, registrants who have not fulfilled requirements for the DNT study may instead cite six previously

- submitted pyrethroid DNT studies, rather than conduct a new study.

Prallethrin has been evaluated for a variety of to xic effects in experimental toxicity studies. Neurotoxicity was observed throughout the database, and effects were seen across species, sexes,

and routes of administration. Effects were also observed in the liver (rats, mice, and dogs), heart (dogs), thy roid gland (rats), and kidney (mice and rats). However, neurotoxicity was the most sensitive endpoint in the toxicology database, and other effects were generally seen in the presence of neurotoxicity and/or at higher doses. The endpoints and PODs select ed for risk assessment are based on neurotoxicity in a number of species and are protective of the toxic

effects observed in the database. Literature studies indicate a possibility of increased sensitivity in juvenile rats to the neurotoxic effects of pyr ethroid insecticides. In light of the literature studies, and pending receipt of additional information to better characterize potential sensitivityPrallethrin Human Health Risk Assessment DP No. D420116

Page 6 of 70 of the young, an additional 3x Food Quality Protection Act (FQPA) Safety Factor (as estimated by pharmacok inetic modeling) has been applied to risk assessments for infants and children < 6 years old

. Prallethrin is classified as “not likely to be carcinogenic to humans,” and there is no concern for mutagenicity.

For oral exposures (acute dietary and incidental oral), the endpoint and POD were selected from a chronic dog study in which neurotoxicity was observed within 4 weeks of dosing and was considered to have potentially resulted from a single dose, based on a weight of the evidence. For dermal assessment, the endpoint was selected from the route

- specific 21

- day dermal study in the rat, in which clinical signs were observed within 1 to 3 days of dosing. The endpoints being

used to assess oral and dermal expos ures are the same (neurotoxicity); therefore, risks from those routes of exposure were combined. Although the LOAEL for inhalation is also based on neurotoxicity, derivation of the human equivalent concentrations (HECs) used for inhalation risk

assessment shows that assessing inhalation exposure based on the portal

- of

- entry effects is protective of the systemic endpoints, including neurotoxicity. As a result, inhalation exposure

was not combined with either the dermal or the oral routes of exposure.

Acut e lethality studies conducted with prallethrin indicate moderate acute toxicity via the oral and inhalation routes of administration (Category II) and low acute toxicity via the dermal route (Categor y IV). It is not irritating to the skin (Category IV)

, b ut is minimally irritating to the eye (Category IV). It is not a dermal sensitizer.

T he toxicological profile of pyrethroids characterizes pyrethroids , including prallethrin, as being rapid in onset and associated with acute, peak exposures. Although th e single day, acute studies for prallethrin do not provide the most sensitive PODs, neurotoxicity was observed in most of the

repeat

- dose toxicology studies within a few days of dosing. As such, the totality of the information suggests that only single da y risk assessments need to be conducted for prallethrin. Based on the toxicity profile, HED will not conduct an intermediate or long

- term exposure
assessment for adults or children. A short

- term exposure assessment is protective of exposures with longer durations.

Adequate residue data are available for the purpose of evaluating the proposed use of prallethrin as a mosquito adulticide over agricultural areas

. Following application at a 10x exaggerated rate, the highest observed residue (0.045 ppm) was w ell below the 1.0 ppm tolerance associated with

the FHE use.

The toxicological kinetic data for prallethrin demonstrate that it is not appropriate to assess chronic dietary risk for this insecticide due to a lack of increased toxicity with increased durat ion of exposure . However, the residential use sites for prallethrin and the patterns for exposure require estimates of chronic dietary (i.e. background from food and water) exposure in order to estimate aggregate risk.

A cute and chronic dietary exposure estimates were derived using the Dietary Exposure

Evaluation Model (DEEM) with consumption data from the 2003

- 2008 National Health and Nutrition Examination Surveys (NHANES) . The assessment s w ere refined by incorporating anticipated residues from simulate d warehouse residue trials and through the use of a percentPrallethrin Human Health Risk Assessment DP No. D420116

Page 7 of 70 FHE treated value provided by the Biological and Economic Analysis Division (BEAD)

. Potential residues from the mosquito adulticide use were accounted for through the use of the maximum residue (acute exposure assessment) or average residue (chronic exposure assessment)

from the adulticide residue trials. For the adulticide use, 100% cro p treated was us ed for both

the acute and chronic assessments . This value is considered to be an overestimate of the potential for the mosquitocide to drift onto growing crops

. For drinking water, conservative

modeled surface water concentration s generat ed with the FIRST Model w ere used. The acute dietary risk estimates for prallethrin are below HED’s level of concern (LOC) for all population subgroups, including those comprised of infants and children. The acute risk estimate for the general U.S. popul ation is 1 0 % of the acute population adjusted dose (aPAD). The population subgroup with the highest acute dietary risk estimate is Children 1

- 2, which uses 76 % of the

aPAD.

Re sidential handler scenario s
, which represent the worst case of exposure for registered

residential uses of prallethrin

, were reevaluated with the most updated endpoints and PODs

, as well as the most recent version of the Residential SOPs for risk assessment resulting in dermal and inhalation risk estimates greater than their r espective LOCs (dermal MOE ≥ 100 and inhalation MOE ≥ 30) and are not of concern. Furthermore, all adult and child post

- application exposure scenarios for mosquito adulticide vector control and other registered residential use s resulted in risk estimates greater than their respective LOCs (adult dermal LOC = dermal MOE ≥100; and child dermal and incidental oral LOC = MOE ≥300) and are not of concern.

The acute aggregate risk estimate s are equivalent to the corresponding dietary (food plus water)

risk estimate s, which are not of concern. The s hort

- term aggregate risk assessment is based on residues in background dietary (food + drinking water) and residential uses for adults and

children. The recommended residential exposure s for use in the adult and child aggregate

assessment s re sult from post

- application dermal and incidental oral (hand

- to

- mouth for children only) exposure resulting from use of prallethrin on turf. For adults, dermal post

- application exposure was combined with background exposure f rom food and water. For children, dermal

post

- application exposure was combined with incidental oral (i.e., hand to mouth ) and background exposure from food and water. The short

- term aggregate risk estimates for adults

and children are not of concern.

O ccupational handler scenarios for aerial and truck

- mounted fogger mosquito adulticide applications r esulted in dermal and inhalation MOEs greater than their respective LOCs (dermal

MOE ≥ 100 and inhalation MOE ≥ 30) at the baseline level of personal prote cti ve equipment (PPE) ( i.e., single layer clothing, socks, shoes, no gloves or respirator) and are not of concern. The Multicide product labels indicate that portable, motorized backpack equipment can be used to apply ultra

- low volume (ULV) particle spray s. Currently, HED does not have unit exposure

data to assess this handler scenario. Therefore, chemical

- specific data to support this scenario are needed, and constitute a data gap. These data need to be submitted under the Part 158 data requirements (G uideline 875.1400). D ermal post

- application exposure r esulted in MOEs significantly greater than the LOC (MOE ≥ 100) and are not of concern. Based on the Agency ’ s current practices, a quantitative post

- application inhalation exposure assessment i s not be ing performed for prallethrin at this time . If new policies or procedures are put into place, thePrallethrin Human Health Risk Assessment DP No. D420116

Page 8 of 70 Agency m ight revisit the need for a quantitative occupational post

- application inhalation exposure assessment for prallethrin.

Pralle thrin was included in a cumulative risk assessment for pyrethrins and pyrethroids ( D394576, K. Whitby, 10/4/2011 )

. In the cumulative assessment, residential exposure was the greatest contributor to the total exposure. The proposed new uses will contribute minimal additional exposure and risk to the overall cumulative assessment. Furthermore, HED evaluated an existing turf use of prallethrin to determine its contribution to the overall cumulative

assessment. Ne i ther the proposed new uses n or the currently register ed turf use will have an impact on the residential component of the cumulative risk estimates

. D ietary exposures ma d e a minor contribution to total pyrethroid exposure in the 2011 cumulative risk assessment. The dietary exposure assessment performed in s upport of the pyrethroid cumulative was much more highly refined than that performed for the single chemical. In addition, f or the pralle thrin risk assessment, the most sensitive apical endpoint in the pralle thrin database was selected to derive

the POD

. Additionally, the POD selected for pralle thrin is specific to pralle thrin , whereas the

POD selected for the cumulative assessment was based on common mechanism of action data that are appropriate for all 20 pyrethroids included in the cumulative assessment.

There are no human health risk concerns associated with the proposed label amendment. The established tolerance of 1.0 ppm for the use of prallethrin in FHEs is adequate to cover residues that might occur as a result of the mosquito adulticid e use.

Potential areas of environmental justice concerns were considered in this human health risk assessment to the extent possible. An assessment was performed to estimate residues resulting from mosquito adulticide vector control for individuals in tr eated areas and addresses community

exposures . The assessment resulted in no risks of concern. For more information, see Section

3.5 : Considerations of Environmental Justice

.

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

2.0 HED Recommendations

HED does not object to the propo sed label amendment expanding the use of prallethrin to the airspace above agricultural areas to control mosquitoes above and adjacent to these areas.

2.1 Data Deficiencies/Conditions of Registration

Since t he estimated residential turf post

- application exposure for residential turf using default turf transferable residue ( TTR ) values for prallethrin is not minimal in comparison to the LOC (i.e., the calculated MOE is not greater than 10 times higher than the LOC

, MOE = 90 0 compared to the LOC of 300 0

, future refinements of this post

- application exposure for prallethrin m ight be necessary due to increased use of prallethrin or advances in E PA risk

assessment s . Therefore, EPA is requiring the 40 CFR TTR data requirement to facilitate anyPrallethrin Human Health Risk Assessment DP No. D420116

Page 9 of 70 necessary exposure assessment refinement and to further EPA’s general understanding of the availability of turf transferable pesticide residues.

The Multic ide product labels indicate that portable, motorized backpack equipment can be used to apply ULV particle sprays. Currently, HED does not have unit exposure data to assess this

handler scenario. Therefore, chemical

- specific data to support this scenario are needed, and constitute a data gap. These data need to be submitted under the Part 158 data requirements (Guideline 875.1400).

2. 2 Tolerance Considerations

2. 2 .1 Enforcement Analytical Method

A method based on gas chromatography with electron capture detection ( G C/ ECD)

, ID #262 , is adequate for the enforcement of tolerances for residues of prallethrin in or on crop commodities.

The repor ted l imits of qua n ti ta tion ( LOQ s ) a re 0.01 to 0.10 ppm , depending on the commodity

. The l imits of detection ( LODs ) were reported to be 0.004 to 0.06 ppm, depending on the commodity

.

Multiresidue methods testing for prallethrin has not been conducted , and is not required, based on previous Agency discussions with the petitioner on 11/3/2010

.

2. 2 .2 International Harmonization

There are no Codex or Canadian maximum residue limits ( MRLs ) for prallethrin. As a result, there are no harmonization issues for the chemical with respect to either the residue definition or

M RLs.

2. 2 .3 Recommended Tolerance s

Currently, a t olerance of 1.0 ppm is established for residues of the insecticide in or on food commodities in food handling establishments where food and food products are held, processed, prepared, and/or served. The tolerance does not need to be increased for the proposed label amendment expanding the mosquito adulti cide use; however, the tolerance expression needs to

be modified as discussed below.

Note to RD: HED recommends that the title/header for 40CFR §180 .545 be amended from

“ Prallethrin (

RS )

- 2

- methyl

- 4

- oxo

- 3

- (2

- propynyl)cyclopent

- 2

- enyl (1 RS )

- cis, trans

- chrysanthemate; tolerances for residues. ” to “ Prallethrin; tolerances for residues. ” to reflect the format in which essentially all other title/headers for citations 40CFR §180.101 t hrough 40CFR §180.671 are stated.

HED recommends that the petitioner submit a revised Section F for the proposed amended paragraph to be cited under 40CFR §180.545[a][1], referring to prallethrin by the CAS name, 2

- methyl

- 4

- oxo

- 3

- (2

- propyn

- 1

- yl)

- 2

- cyclopenten

- 1

- yl

- 2,2

- dimethyl

- 3

- (2

- methyl

- 1

- propen

- 1

-Prallethrin Human Health Risk Assessment DP No. D420116

Page 10 of 70 yl)cyclopropanecarboxylate, instead of the currently used name, ( RS )

- 2

- methyl

- 4

- oxo

- 3

- (2

- propynyl)cyclopent

- 2

- enyl(1 RS )

- cis,trans

- chrysanthemate.

HED recommends that the tolerance expression for prallethrin, cited under 40CFR §180.545[a][1], be amended to read as follows:

A tolerance of 1.0 ppm is established for residues of the insecticide prallethrin,

includi ng its metabolites and degradates, in or on all raw agricultural commodities and processed food from use of prallethrin in food handling establishments where food and food products are held, processed, prepared and/or served, or as a wide

area mosquito adu lticide. Compliance with the tolerance level specified is to be determined by measuring only prallethrin, 2

- methyl

- 4

- oxo

- 3

- (2

- propyn

- 1

- yl)

- 2

- cyclopenten

- 1

- yl

- 2,2

- dimethyl

- 3

- (2

- methyl

- 1

- propen

- 1

- yl)cyclopropanecarboxylate.

Additiona l ly, HED recommends t hat RD delete 40CFR §180.545[a][2], 40CFR §180.545[a][3]

, and 40CFR §180.545[a][4]

. 40CFR §180.545[a][2] should be deleted because it is being replaced by 40CFR §180.545[a][1], above. Parts [3] and [4] can be deleted because t hese part s are use directio ns that are not necessary or needed in the 40CFR listing for prallethrin.

2. 2 .4 Revision s to Petitioned

- For Tolerance s

The re is no revision to the petitioned

- for tolerance

.

2. 3 Label Recommendations

Multicide Flying Insect Killer 27471 (EPA Reg. No. 1021

- 1710) ha s a separate occupational and residential use section on the registered label. HED’s update d assessment of the residential exposure scenarios using the revised Residential SOPs resulted in risks of concern. In an effort to mitigate the se res idential risks of concern, the registrant agreed to remove the r esidential use

section from the label. The Registration Division (RD) should ensure that the residential use

section of the label for Multicide Flying Insect Killer 27471 ( EPA Reg. No. 1021

- 1 710) is

removed and that all references for use in kitchens are removed.

3.0 In troduction

3.1 Chemical IdentityPrallethrin Human Health Risk Assessment DP No. D420116

Page 11 of 70 TABLE 3 .1

. Prallethrin Nomenclature

Chemical S tructure

Common N ame Prallethrin Company E xperimental N ame Not A vailable

Molecular F ormula C 19 H 24 O 3 Molecular W eight 300.4 amu

IUPAC N ame ( RS )

- 2

- methyl

- 4

- oxo

- 3

- prop

- 2

- ynylcyclopent

- 2

- enyl (1 RS ,3 RS ;1 RS ,3 SR )

- 2,2

- dimethyl

- 3

- (2

- methylprop

- 1

- enyl)cyclopropanecarboxylate

CAS N ame 2

- methyl

- 4

- oxo

- 3

- (2

- propyn

- 1

- yl)

- 2

- cyclopenten

- 1

- yl 2,2

- dimethyl

- 3

- (2

- methyl

1

- propen

- 1

- yl)cyclopropanecarboxylate

CAS R egistry N umber 23031

- 36

- 9

End

- use P roduct s (EP) M ulticide Fogging Concentrate 2798 , 0.075 lb ai/gal liquid formulation

M ulticide Fogging Concentrate 2 922, 0.084 lb ai/gal liquid formulation

3.2 Physical/Chemical Characteristics

Pralle thrin has very low water solubility ( 8.03 mg/L at 25oC) and a relatively high octanol/water partition coefficient ( l og K OW = 4.49 )

. These values account for the low surface and groundwater concentrations determined by the Environmental Fate and Effects Division’s (EFED’s) drinking water models , and indicate that the compound has potential to partition into fatty tissues

. The chemical has a vap or pressure of 3.2 x 10

- 5 mm Hg at 2 5 oC

. See Appendix B for a listing of additional p hysical and c hemical properties.

3.3 Pesticide Use Pattern

Multicide Fogging Concentrate 2798 (EPA Registration #1021

- 1795), and Multicide Fogging

Concentrate 2922 (EPA Registration #1021

- 2562) are currently registered for controlling public health pests in outdoor residential and recreational areas and in vegetation surrounding parks, woodlands, swamps, marshes, overgrown areas

, and golf courses . The labels co ntain statements

that prohibit use in areas that would potentially allow drift onto growing crops. MGK submitted a request to amend the labels by adding a statement that the products “may be applied over agricultural areas for the control of adult mosquit oes within or adjacent to these areas.” Both Multicide products are formulated as liquid concentrates and contain 1% prallethrin, 5%

sumithrin

, and 5% piperonyl butoxide. This assessment only addresses the potential exposure associated with the proposed u ses of prallethrin. Multicide 2798 contains 0.075 lbs per gallon of the active ingredient (ai) prallethrin

, and Multicide 2922 contains 0.084 lbs ai per gallon

. ThePrallethrin Human Health Risk Assessment DP No. D420116

Page 12 of 70 use directions on the labels are not changing as a result of the label amendment. The pr oducts

a re applied by aerial, ground, and handheld motorized equipment at a maximum application rate of 0.00072 lb ai per acre in a 24

- hour period. Application rates are not to exceed 0.02 lbs ai per acre per year. These products are only to be applied by federal, state

, tribal

, or local government officials responsible for public health or adult mosquito control.

The PPE statements on the proposed labels require applicators and other handlers to wear long

sleeved shirt and long pants, socks, and shoes. The proposed use directions are summarized in

Table 3.3

. a. T he use rate specified on the proposed labels has not changed ; therefore

, the proposed labels reflect the existing rate, timing

, and frequency of application.

Prallethrin is also registered for use in a variety of residential sites including homes, commercial settings, and FHEs. In addition, there are pet uses as well as outdoor uses for control of pests on
turf . A residential assessm ent was performed in 1999. Since that time, the majority of the representative products have been cancelled (i.e., Evercide Carpet and Surface Spray 2655

– Reg. No. 1021

- 1696; Flea Stop Linatoc Dip

– Reg. No. 4758

- 163; and Permethrin Pet Plus Spray

, EPA Reg. No. 4758

- 181) or the residential use has been removed from the product label (Multicide Flying Insect Killer 27471 Reg. No. 1021

- 1710). A summary of the remaining representative registered residential products and use sites with the highest applicati on rates or percent ai is provided in Table 3.3.b . This table also includes a residential turf use (MGK Formula 2964 Microencapsul at ed Suspension Concentrate Insecticide

- Reg. No. 1021

- 2574)

, which is registered but was never previously assessed. Table 3.3

. a. Summary of Direction s for Mosquito Adulticide U se of Prallethrin

Method of Application Product and

Formulation (Reg. No.) Application

Rate (lb ai/A) Maximum

No. Applications per Season Maximum

Seasonal Application

Rate (lb ai/A) PHI Use Directions, Application Timing, Type and Limitations

Aerial, Ground

and Hand Held Equipment Multicide 2798

Reg. No 1021

- 1795

(0.075 lb ai/gal)

Multicide 2922

Reg. No. 1021

- 2562

(0.084 lbs ai/gal) 0.00024

-

0.00072

lb ai/acre

(0.41

– 1.23 fl oz/acre) 28 0.02 lb ai/acre in one year NA More frequent applications may be made to prevent or

control a threat to public/animal health determined by a state,

tribal

, or local health or vector control agency.

Not for use in outdoor residential misting

systems or meter released systems.Prallethrin Human Health Risk Assessment DP No. D420116

Page 13 of 70 3.4 Anticipated Exposure Pathways

Humans could be exposed to prallethrin residues from the following use scenarios: from consuming food treated in FHEs, fr om residential turf and indoor/outdoor spray uses

, and from mosquito adulticide applications

. The mosquito adulticide applications can result in prallethrin reaching surface and groundwater, both of which can serve as sources of drinking water. However, because of the low water solubility of the chemical and its affinity to bind to soil organic matter

, drinking water concentrations will be very low

. Occupational appl icators can be exposed while handling the pesticide prior to application, mixing/loading the pesticide, and during application. Homeowners can be exposed dermally and via inhalation during mixing, loading, and applying non

- restricted end

- use products in r esidential settings. There is also potential for residential post

- application exposure via inhalation, dermal, and incidental oral (children only) routes of exposure.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice c oncerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations, ” ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a resid ential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture under the National Health and Nutrition Examination Survey, What We E at in Table 3.3.b . Revised Registered Residential Handler Use of Prallethrin

Product and

Formulation Use Site Method of Application Application

Rate (lb ai/A) Use Directions,

Application Timing, Type

and Limitations

EVERCIDE®

NY L AR Total

Release Aerosol

2644

(0.04% ai)

Reg. No. 1021

- 1656

(assessed in 1999) Indoor Use (carpets, upholstery,

floor cracks and cabinets) Fogger 1 fogger/room Do not use in room smaller

than 5 ft x 5 ft. Vacate treated house immediately after application. Wait 2

hours after application and then open window, vents

, and doors for 2 hours.

MGK Formula 2964 Microencapsulated Suspension

Concentrate

Insecticide
(1.6% a.i.)
Reg. No. 1021

- 2574 Lawns, landscapes, ornamentals,

and recreational parks and fields Spray 0.045 lb ai/A or

0.00011 lb ai/ gal All outdoor applications

are limited to crack and crevice treatment only

, except for applications to

lawns

, which may be

treated as broadcast.Prallethrin Human Health Risk Assessment DP No. D420116

Page 14 of 70 America, (NHANES/WWEIA). These food consumption patterns are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups

, and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for chil dren , youths, and adults entering or playing on treated areas

post

- application are evaluated. A residential post

- application exposure assessment was performed to estimate potential exposure to residues resulting from mosquito adulticide applications to in dividuals in treated areas. Exposure risk estimates were not of concern. Further considerations are currently in development

, as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Prallethrin is a member of the pyrethroid class of insecticide s. Pyrethroids have histori cally been classified into two groups, Type I and Type II, based upon chemical structure and neurotoxicological effect. Type I pyrethroids lack an alpha

- cyano moiety and induce a syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, and fine tremor progressing to whole

- body tremor and prostration in rats. These Type I pyrethroid

- specific behaviors are collectively described as the T

- syndrome. Type II pyrethroids contain an alpha

cyano moiety and produce a syndrome that incl udes pawing, burrowing, salivation, and coarse tremors leading to choreoathetosis in rats. These Type II pyrethroid

- specific behaviors are collectively described as the CS

- syndrome ( Verschoyle and Aldridge 1980 ; Lawrence and

Casida 1982 ) . Prallethrin is structurally similar to Type I pyrethroids. The adverse outcome pathway (AOP) shared by pyrethroids involves the ability to interact with voltage

- gated sodium channels (VGSCs) in the central and peripheral nervous system, leading to chan ges in neuron firing, and ultimately neurotoxicity (Figure 4.0).

Figure 4.0. Adverse outcome pathway for pyrethroids Target
Tissue

Dose VGSC

Alterations In Vivo

Clinical Signs Altered

Neuronal ExcitabilityPrallethrin Human Health Risk Assessment DP No. D420116

Page 15 of 70 4.1 Toxicology Studies Available for Analysis

The database of experimental toxicology studies available for prallethrin provides a robust characterization of the hazard potential for children 6 years old and older as well as for adults. The data from the following studies were used to evaluate the hazard potential of prallethrin:

- WIL Laboratory Acute Oral Study in the Rat

- 21 Day Dermal Study in the Rat

- 90 Day Oral Studies in the Rat, Mouse, and Dog

- Chronic/Carcinogenicity Studies in the Rat, Mouse, and Dog

- Developmenta l Studies in the Rat and Rabbit

- Reproduction Study in the Rat

- Acute and Subchronic Neurotoxicity Studies in the Rat

- Mutagenicity Battery of Studies

- 28 Day Subchronic Inhalation Study

An immunotoxicity study is not available for consideration as required under the Part 158 toxicology data requirements. However, HED’s Hazard and Science Policy Council (HASPOC) concluded that the study is not required for prallethrin. An immunotoxicity study is not anticipated to provide a lower POD or result in a more sensitive endpoint than those already used (TXR No. 0056830). A developmental neurotoxicity study ( DNT ) study is not available for prallethrin. However, EPA has determined that DNTs for pyrethroid insecticides do not adequately characterize potential susceptibility of the young. Therefore, registrants who have not fulfilled requirements for the DNT may instead cite six previously

- submitted pyrethroid DNT studies, rather than conduct a fu ll new study.

The studies available for consideration of toxicity provide a comprehensive database for prallethrin. The WIL study is an acute oral non

- guideline study that measures functional observational battery (FOB) activity in rats that were trea ted acutely with various pyrethroids. In addition, numerous studies from the scientific literature conducted over several decades describe the pharmacodynamic and pharmacokinetic profile of the pyrethroids in general. This scientific

literature has been recently reviewed by several groups ( Soderlund et al. 2002 ; Shafer et al.,

2005 ; Wolansky and Harrill 2008 )

. A literature study is also available that measures motor activity after pyrethroid exposure for a number of pyrethroid chemicals (Wolansky et al. 2006). However, pralle thrin was not included in the study.

In addition, there are ongoing efforts to develop data to inform the potential sensitivity of infants and younger children to pyrethroids as a class (see Section 4.4). Despite these scientific efforts,

HED is confid ent that it has chosen points of departure and uncertainty factors in this risk assessment that are health protective and have a strong scientific foundation.

4.2 Toxicological Profile

Prallethrin has been evaluated for a variety of toxic effects in experimental toxicity studies. Neurotoxicity was observed throughout the database and is the most sensitive endpoint . E ffects were seen across species, sexes, and routes of administration. In the acute rat neurotoxicityPrallethrin Human Health Risk Assessment DP No. D420116

Page 16 of 70 study, decreased exploratory behav ior was seen at the time of peak effect (2 hrs). Reduced motor activity and transient tremors were also observed in the study. In the subchronic rat neurotoxicity study, a higher arousal rate was observed in animals at the highest dose tested.

Clinical signs of neurotoxicity were also observed in other toxicity studies (subchronic and chronic oral studies in dogs, developmental toxicity studies in the rat and rabbit, 21

- day dermal

and 28

- day inhalation studies in rats)

. No neurotoxic effects were observ ed in rats in the chronic toxicity study.

Effects were also observed in the liver (rats, mice, and dogs), heart (dogs), and thyroid gland (rats). Some effects were also seen in the kidney (mice and rats). However, neurotoxicity was

the most sensitive endpoint in the toxicology database

, and other effects were generally seen in the presence of neurotoxicity and/or at higher doses. Liver effects observed included increased weight, elevated serum cholesterol and alkaline phosphatase activity, centrilobul ar hepatocyte vacuolation, histiocytic infiltration, enlarged liver, and perilobular hepatocellular hypertrophy. In dogs, myocardial fiber degeneration was seen in females in the subchronic study at the highest

dose tested. Heart effects were also seen i n one mid

- dose female in the chronic study (hemorrhage and red discoloration). However, there was no dose response for the observed heart lesions in the study. Thyroid effects were observed in rats and consisted of increases in the

number of small follic les and follicular cell hypertrophy and hyperplasia. The thyroid effects

were seen in short

- term studies in the presence o f liver effects. Kidney effects observed were increased weights and histopathology.

Developmental and reproduction studies are a vailable for prallethrin. There was no evidence of increased quantitative or qualitative susceptibility in any of the studies. In the developmental studies, no toxic effects were noted in fetuses up to the highest doses tested. Maternal effects in

the s tudies included tremors, salivation, exaggerated reflexes, and chromorhinorrhea. In the reproduction study, decreased pup body weights were seen during the lactation period. Effects seen in parental animals were decreased body weights and body weight gai ns, increased liver weights and microscopic findings in the liver, kidney, thyroid

, and pituitary.

Prallethrin is classified as “not likely to be carcinogenic to humans.” No tumors were observed in rat and mouse carcinogenicity studies up to the highest doses tested. In both the rat and mouse studies, the animals could have tolerated higher dose levels; however, HED determined that dose levels were adequate to assess potential carcinogenicity.

Prallethrin tested negative in the majority of the genotoxic ity studies. It also tested negative in

an in vitro chromosomal aberration study in Chinese Hamster Ovary (CHO K1) cells without metabolic activation, but tested positive at all doses with metabolic activation. However, clastogenicity was not clearly dos e

- related, was seen at nontoxic and slightly toxic doses, was not expressed in in vivo studies

, and structure

- activity comparisons with the other pyrethroids

revealed no correlations with clastogenicity . Other gene mutation, chromosomal aberration

, and unscheduled DNA synthesis ( UDS ) studies were negative. Therefore, there is no concern for genotoxicity.

Acute lethality studies conducted with prallethrin indicate moderate acute toxicity via the oral and inhalation routes of administration (Category II) and low acute toxicity via the dermal routePrallethrin Human Health Risk Assessment DP No. D420116

Page 17 of 70 (Categories IV). It is not irritating to the skin (Category IV) but is minimally irritating to the eye (Category IV). It is not a dermal sensitizer.

Metabolism data are available for prallethrin. The pharmac okinetics for prallet h rin are similar to

those for other pyrethroids, i.e., rapid absorption and clearance. Metabolism studies in rats with

the cis

- and trans

- isomers indicate that

, with an oral dose of 2 or 100 mg/kg/day or with repeated

oral doses of 2 mg/kg day, the cis

- and trans

- isomers are rapidly absorbed, distributed, metabolized, and excreted under all dosing regimens. Most of the radioactivity is recovered in

the urine and feces within 48 hours for both males and females for both isomers. A mu ch greater proportion of the administered dose of the trans

- isomer was eliminated in the urine (45.2

- 58.1% administered dose [AD] for males, 52.1

- 62.1% AD for females) than was the cis

- isomer (13.3

- 15.8% AD for males, 21

- 23.3% AD for females). This occurr ed as a result of easier cleavage of the ester linkage of the trans

- isomer by esterase. For the rats administered the cis

- isomer, urinary excretion was a minor route compared to fecal excretion. Females excreted a greater proportion of the radioactivity in the urine than did males for both isomers. Bioaccumulation and retention

of the cis

- and trans

- isomers are low. Based on the metabolites identified, the major

biotransformation reactions of the cis

- and trans

- isomers include: (1) oxidation at the meth yls of the isobutenyl group in the acid moiety and at the C

- 1 or C

- 2 positions of the propynyl group in the alcohol moiety; (2) cleavage of the ester linkage; (3) conjugation of hydroxy derivatives with glucuronic acid and sulfuric acid.

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

The extensive body of scientific literature on the pyrethroids provides insight into the contributions of pharmacokinetics (PK) and pharmacodynamics (PD) to the general toxicity profile of this class of chemical s. This information also provides valuable insight into the potential age

- related differences in toxicity for the pyrethroids. The following sections discuss the specific issues related to pyrethroid pharmacokinetics, pyrethroid pharmacodynamics, and

age

- related differences in pyrethroid toxicity.

4.3.1 Pharmacokinetics

Pharmacokinetics (PK) can be defined as what the body does to the chemical; in this case, how pyrethroids are distributed and eliminated following exposure. Specific to pyrethroids, PK refers to the process(es) that determine the concentration of the pyrethroids reaching sodi um channels. The underlying pharmacokinetics of pyrethroids is an important determination of their toxicity because the concentration of pyrethroid at the sodium channel relates to the extent of toxicity; greater pyrethroid concentration translates as inc reased neurotoxicity. Physiological processes that significantly contribute to the PK include metabolism, protein binding, and partitioning. Carboxylesterases and cytochrome P450 enzymes are the two major enzyme families responsible

for the metabolism of pyrethroids. It is the ontogeny of these enzymes that accounts for the age

related sensitivity observed after pyrethroid exposures. However, pyrethroid residues in fatty tissue are not available to interact with the VGSCs in vital tissues and, therefore , do not contribute to overall toxicity.Prallethrin Human Health Risk Assessment DP No. D420116

Page 18 of 70 In 2011 the Agency conducted an analysis of the toxicokinetic profile of pyrethroids. Several studies in this analysis indicate that there are age

- dependent pharmacokinetic differences for the pyrethroids (i.e., there are differences in the ability of adults and juveniles to metabolize pyrethroids). The enzymes that metabolize and detoxify the pyrethroids are present in rats and

humans at birth ( Koukouritaki et al. 2004 ; Yang et al. 2009 )

. As a result, both juveniles and adults are able to tolerate low doses of pyrethroids when the internal dose, or t he amount of pyrethroid at the sodium channel, is low. However, the activity of these enzymes increases with age, conveying in adults a greater capacity to detoxify pyrethroids compared to juveniles ( Anand

et al. 2006 ; de Zwart et al. 2008 ; Yang et al. 2009 ) . For example, the rate of in vitro metabolism of deltamethrin by plasma carboxyesterases, plus hepatic carboxyesterases and cytochrome P450s (microsomes) is at least 6 times as high for PND 90 rats as for PND 10 rats ( Anand et al.

2006 ) . As a consequence, higher internal doses (i.e., those associated with high doses in

expe rimental toxicology studies) overwhelm the clearance mechanisms in juveniles

, but because adults have greater enzyme activity, they are able to tolerate higher doses prior to the onset of toxicity. As a matter of perspective, the anticipated exposures fro m typical dietary or residential activities are not expected to overwhelm the premature metabolic systems in juveniles.

Predictive PBPK models have recently been developed to describe the PK of a few pyrethroids ( Mirfazaelian et al. 2006 ; Godin et al. 2010 ) . Among these is an age

- dependent model developed by the Agency that is capable of predicting the conc entration of deltamethrin in the brains of rats at multiple ages ( Tornero

- Velez et al. 2010 ) . The brain is considered the primary target organ for pyrethroids, and increased pyrethroid concentrations are correla ted with increasing systemic toxicity. This model predicts that, compared to adult rats (i.e., 90 days old), equivalent brain concentrations of deltamethrin would be achieved with a 3.8 x fold lower oral

dose in 10

- day old rats and 2.5 x lower dose in 21

- da y old rats ( Tornero

- Velez et al. 2010 ) . For example, a 1 mg/kg dose in the adult is equivalent to a 0.26 mg/kg dose (≈1 mg/kg ÷ 3.8mg/kg)

in the 10

- day old rats and to a 0.4 mg/kg (≈1 mg/kg ÷ 2.5mg/kg) dose in a 21

- day old rat. The

difference between a 3.8

- and a 2.5

- fold dose is within background variability of the model. As a result, the Agency concludes that juvenile rats are three times as sensitive as adults with respect to pyrethroid pharmacokinetics. Th erefore, the pharmaco kinetic contribut ion to the FQPA factor

will be 3 x.

4.3.2 Pharmacodynamics

Pharmacodynamics (PD) can be defined as the changes that chemicals cause to the body, in this case, how pyrethroids interact with the sodium channels. Substa ntial evidence from in vitro and

in vivo studies support the AOP illustrated in Figure 4.1 and the disruption of sodium channels by pyrethroids as an early key event ( Lund and Narahashi 1982 ; Salgado et al. 1989 ; Song and

Narahashi 1996 ; Tabarean and Narahashi 1998 ; Soderlund et al. 2002 (review) )

. With respect to altered neuronal excitability, Type I pyrethroids cause slight prolongations of the sodium current tails (e.g.

, ~20 ms) , often resulting in long trains of action potentials. In contrast, Type II pyrethroids significantly prolong sodium current tails (e.g.

, 200 ms to minutes) typically resulting in increased resting membrane potential and ultimately causing depolarization dependent action potential block. Choi and Soderlund ( 2006 ) examined interactions of several pyrethroids with mammalian VGSCs expressed in Xenopus oocytes.Prallethrin Human Health Risk Assessment DP No. D420116

Page 19 of 70 HED would prefer to use an early key event in the AOP for pyrethroids in selection o f PODs.
However, in vivo measures of VGSC alteration and altered neuronal excitability are not readily available for use in risk assessment at this time, and approaches for extrapolating in vitro findings such as those discussed here to in vivo measures a re not yet developed. Therefore, the Agency is focusing its efforts in hazard characterization and identification on the apical endpoint (i.e., changes in neurobehavior in laboratory animals). Neurotoxicity resulting from pyrethroids is generally charact erized by tremors, hyper

- or hypothermia, heightened response to stimuli, salivation, tremors and convulsions ( Soderlund et al. 2002 ; Wolansky and Harrill 2008 ; Weiner

et al. 2009 )

.

In contrast to the age

- related PK differences identified in the 2011 analysis, PD contributions to pyrethroid toxicity are not age

- dependent even though there are several variations of sodium channels, called isoforms, that are differentially expressed by tissue and age. Because of the nature of the interaction of pyrethroids with sodium channels, it is difficult to obtain dy namic

information in vivo. To date, a readily useable biomarker of in vivo pyrethroid interaction with sodium channels has not been identified, making it impractical to determine the isoform combinations that are present and being acted upon by pyrethroid s. Therefore, much of the information available to the Agency to characterize the PD relationship between pyrethroids and

sodium channels has been derived from in vitro studies using frog oocytes or neuronal cells

cultured in defined media. These in vitr o techniques do not provide a direct quantitative measure

of in vivo pyrethroid activity. However, these techniques consistently and qualitatively demonstrate that channel isoforms expressed in juveniles are not more sensitive to pyrethroid perturbation c ompared to isoforms expressed in adults and that, pharmacodynamically, the rat is a conservative model for humans. For example, Meacham et al. ( 2008 ) , compared the sensitivity

to deltamethrin of an adult isoform and a juvenile isoform expressed in frog oocytes. The isoforms had comparable responses at environmentally relevant concentrations (<500 nM) of deltamethrin, suggesting a lack of PD difference between juveniles and adults at low exposure levels. In addition, a study directly comparing a homolog ous rat and human VGSC isoform,

NaV 1.3 , revealed that the rat isoform was 4

- fold more sensitive than the equivalent human sodium channel to the pyrethroid tefluthrin ( Tan and Soderlund 2009 ) . These data suggest that the rat is a highly sensitive model

, and extrapolations from the rat would be protective of human health. The occurrence and ontogeny of voltage

- gated sodium channels in humans is not well characterized compared to the rat. However, based on the comparable function and distribution

of sodium channels between the species, the rat is an appropriate surrogate for the evaluation of

human PD ( Goldin et. al. 2000 ; Goldin 2002 ) . As a result, the Agency concludes that juvenile rats are not more sensitive than adults with respect to pyre throid pharmacodynamics. Therefore, the pharmacodynamic contribution to the FQPA factor will be 1x.

4.3.3 Critical Duration of Exposure

One of the key elements in risk assessment is the appropriate integration of temporality between the exposure and ha zard assessments. For prallethrin, neurotoxicity is the most sensitive endpoint

, with effects being observed within the first few days of dosing. Effects were also observed in the liver (rats, mice, and dogs), heart (dogs), and thyroid gland (rats). Some effects were also seen in the kidney (mice and rats). H owever, the effects were generally seen in thePrallethrin Human Health Risk Assessment DP No. D420116

Page 20 of 70 presence of neurotoxicity or at higher doses. Thus, endpoints selected for neurotoxicity are protective for effects observed in the toxicity datab ase.

Consistent with the mode of action, in general, onset of neurotoxicity following an acute pyrethroid dose is rapid, with a time to peak effect for neurobehavioral effects ranging from 4 to

8 hours ( Wolansky and Harrill 2008 ; Weiner et al. 2009 ; Scollon et al. 2011 ) . Furthermore, rapid metabolism and elimination preclude accumulation and increased potency fol lowing repeated dosing. Therefore, for most pyrethroids, the acute toxicity studies typically demonstrate neurotoxicity at doses lower than doses in other studies

. However, the available single dose, acute studies (i.e., the WIL FOB study ) and the acute neurotoxicity (ACN) study) for prallethrin did not provide the PODs. In fact, the PODs from the WIL FOB and ACN studies are approximately 10

- fold higher than PODs from other studies where neurotoxicity was observed. It is notable that both acute gavage s tudies used relatively high vehicle volumes of 5 and 10

m L /kg, respectively. For some pyrethroids, the gavage volume can play an important role in

potency becaus e the volume impacts the absorption characteristics (e.g., timing, amount) (Crofton et al, 199 5). In the prallethrin studies, it is plausible that the relatively high corn oil volume causes a reduction in the peak level of prallethrin in the brain; thereby increasing the

POD.

As noted in Table 4.3.3, when comparing the Human Equivalent Doses (HEDs) for the developmental rat study, subchronic neurotoxicity study (SCN), and two dog studies, there is striking consistency across species and duration. In the studies, neurotoxicity was generally observed during the first few days or first week of t he study , hours after dosing

.

T he weight of evidence from the available guideline, non

- guideline

, mechanism of action, and pharmacokinetics studies support s characterizing the toxicological profile of pyrethroids, including prallethrin, as being rapid in onset and associated with acute, peak exposures. Although the single day, acute studies for prallethrin do not provide the most sensitive PODs, neurotoxicity was observed in most of the repeat

- dose toxicology studies within a few days of dosing. As su ch, the totality of the information suggests that only single day risk assessments

need to be conducted for prallethrin.Prallethrin Human Health Risk Assessment DP No. D420116

Page 21 of 70 * day neurotoxicity initially observed

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

The prallethrin toxicity database includes developmental toxicity studies in the rat and rabbit, and a reproduction study in the rat. N o evidence of increased qualitative or quantitative susceptibility was noted in any of these studies. This lack of susc eptibility is consistent with the results of guideline developmental and reproduction studies with other pyrethroid pesticides.

High

- dose LD 50 studies (studies assessing what dose results in lethality to 50 percent of the tested population) in the scienti fic literature indicate that pyrethroid exposure can result in increased quantitative sensitivity in the young , specifically in the form of neurotoxicity

. Examination of pharmacokinetic and pharmacodynamic data indicates that the sensitivity

observed at h igh doses is related to pyrethroid age

- dependent pharmacokinetics

- the activity of enzymes associated with the metabolism of pyrethroids. With otherwise equivalent administered doses for adults and juveniles, predictive pharmacokinetic models indicate th at the differential

adult

- juvenile pharmacokinetics will result in a 3 x greater dose at the target organ in juveniles compared to adults. No evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics (the effect of pyrethroids at the target tissue) both with regard to interspecies differences between rats and humans and to differences between juveniles and adults. Specifically, there are in vitro pharmacodynamic data

and in vivo data indicating similar responses between adult and juvenile rats at low doses and Table 4.3.3. Points of Departure with N eurological E ffects for T oxicology S tudies with P rallethrin

Study MRID Duration Study finding s

NOAEL (mg/kg/day) LOAEL

(mg/kg/day) 3⁄4 Body Weight

Adjustment for HED Comparison

NOAEL LOAEL

WIL Laboratories FOB study Rat(Gavage

- 5m L /kg corn oil) 48333801 Acute, single

exposure 150 250

--- ---

Acute N eurotoxicity Rat (Gavage

- 10m L

/kg corn oil) 43343301 Acute, single

exposure 100 300

--- ---

Developmental Rat (Gavage

- 0.5% methylcellulose) 42030905 10 days

*GD9&10 10 30 2.91 8.72

Subchronic N eurotoxicity

Rat (Dietary) 43694501 90 days *wk12 9.3 74 2.70 21.51

Subchronic Dog (Capsule) 41321817 90 days

*wk1 3 10 1.84 6.15

Chronic Dog (Capsule) 42077002 1 year

*wk 4 2.5 5 1.54 3.07Prallethrin Human Health Risk Assessment DP No. D420116

Page 22 of 70 data indicating that the rat is a conservative model compared to the human based on species

specific pharmacodynamics of homologous sodium channel isoforms in rats and humans.

In light of the literature studies indicating a possibility of increased sensitivity in juvenile rats at high doses

, EPA is retaining a 3 x additional safety factor as estimated by pharmacokinetic modeling for infants and children less than 6 years old . For several reasons, EPA concludes there are reliable data showing that a 3 x factor is protective of the safety of infants and children. First, the high doses that produced juvenile sensitivity in the lite rature studies are well above normal dietary or residential exposure levels of pyrethroids to juveniles

, and these lower levels of exposure are not expected to overwhelm the ability to metabolize pyrethroids

, as occurred with the high doses used in the lit erature studies. This conclusion is confirmed by the lack of a finding of increased sensitivity in the majority of the pre

- and post

- natal guideline studies for pyrethroids, despite the relatively high doses used in those studies. Second, the portions of the uncertainty factors that account for potential pharmacodynamic differences are likely to

over estim ate the risk of inter

- and intraspecies pharmacodynamic differences, given the data showing similarities in pharmacodynamics between juveniles and adults and between humans

and rats. For the FQPA S afety F actors, the pharmacodynamic portions are generally considered

to be 3 x; however

, for pyrethroids

, it is reduced to 1 x becau se no differences among the various groups are observed. Finally, as indicated, pharmacokinetic modeling only predicts a 3 x difference between juveniles and adults.

The information described above is summarized in Re

- Evaluation of the FQPA Safety Factor for Pyrethroid Pesticides ( D381210, E. Scollon, A. Lowit, 6/27/2011 ).

4.4.1 Completeness of the Toxicology Database

The toxicology database for prallethrin is considered complete with respect to guideline toxicity studies for prallethrin. However, the Agency lacks additional information to fully characterize the potential for ju venile sensitivity to the neurotoxic effects of pyrethroids

. T he toxicity database for prallethrin does include studies that can be used to characterize most effects, including potential developmental and reproductive toxicity and neurotoxicity. Acceptab le developmental toxicity studies in rats and rabbits, a reproduction study in rats, and neurotoxicity studies (ACN, and SCN) in rats are available. In addition, route

- specific dermal and inhalation studies are available. The prallethrin database lacks a cceptable immunotoxicity and developmental neurotoxicity (DNT) studies. However, HED’s Hazard and Science Policy Council (HASPOC) concluded that the immunotoxicity study is not required. An immunotoxicity study is not anticipated to provide a lower POD o r result in a more sensitive endpoint than those already used (TXR No. 0056830). Additionally, EPA has determined that DNTs for pyrethroid insecticides do not adequately characterize potential susceptibility of the young. In 2009, EPA stated that registr ants who have not fulfilled requirements for the DNT may instead cite six previously

- submitted pyrethroid DNT studies, rather than conduct a full new study.Prallethrin Human Health Risk Assessment DP No. D420116

Page 23 of 70 4.4.2 Evidence of Neurotoxicity

Like other pyrethroids, prallethrin causes neurotoxicity by interacting with sodium channels leading to clinical signs of neurotoxicity. Neurotoxicity typical of pyrethroids was observed in several of the toxicity studies for the active ingredient. These effects are assessed by the available guideline and non

- gui deline studies.

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

Based on the prallethrin

- specific data, there is no indication of increased juvenile sensitivity. However, after reviewing the extensive body of data and peer

- reviewed literature on pyrethroids, the Agency has reached a number of conclusions regarding fetal and juvenile sensitivity for pyrethroids, including the following:

Based on an evaluation of over 70 guideline toxicity studies for 24 pyrethroids submitted to the Agency, including prenatal developmental toxicity studies in rats and rabbits, and pre

- and postnatal multi

- generation reproduction toxicity studies and DNTs i n rats in support of pyrethroid registrations, there is no evidence that pyrethroids directly impact developing fetuses. None of the studies show any indications of fetal toxicity at doses that do not cause maternal toxicity.

 The developmental and repro duction studies for prallethrin did not demonstrate susceptibility of the young or developing animal , which is consistent with the majority of the pyrethroid database. However, increased susceptibility was seen in offspring

animals in DNT studies with ano ther pyrethroid, zeta

- cypermethrin (decreased pup body weights) and in DNT and reproduction studies with beta

- cyfluthrin (decreased body weights and tremors). T he reductions in body weight and the other non

- specific effects observed occurred at higher dos es than neurotoxicity, the effect of concern for pyrethroids. Overall, findings of increased sensitivity in juvenile animals in pyrethroid

studies are rare. Therefore, the residual concern for the postnatal effects seen in the

studies is reduced.

 Increa sed susceptibility was seen in offspring animals in the DNT study with the pyrethroid zeta

- cypermethrin (decreased pup body weights) and DNT and reproduction

studies with another pyrethroid beta

- cyfluthrin (decreased body weights and tremors).
However, the reductions in body weight and the other non

- specific effects occur at higher doses than neurotoxicity, the effect of concern for pyrethroids. The available developmental and reproduction guideline studies in rats with zeta

- cypermethrin did not

show incre ased sensitivity in the young to neurotoxic effects. Overall, findings of increased sensitivity in juvenile animals in pyrethroid studies are rare. Therefore, the residual concern for the postnatal effects is reduced.

 High

- dose LD 50 studies in the scie ntific literature indicate that pyrethroids can result in increased quantitative sensitivity to juvenile animals. Examination of pharmacokinetic and pharmacodynamic data indicates that the sensitivity observed at high doses is related to age

- dependent pyr ethroid pharmacokinetics

. Furthermore, a rat PBPK modelPrallethrin Human Health Risk Assessment DP No. D420116

Page 24 of 70 predicts a 3

- fold increase of pyrethroid concentration in juvenile brain s compared to

adult brains at high doses.

 In vitro pharmacodynamic data and in vivo data indicate that adult and juvenile rats have similar responses to pyrethroids at low doses and

, therefore

, juvenile sensitivity is not expected at relevant environmental exposures. Further, data also show that the rat is a conservative model compared to the human based on species

- specific pharmacodynamics of homologous sodium channel isoforms.

Additional in vitro and in vivo studies are currently being conducted that could potentially inform a number of issues related to pyrethroid toxicity as a c lass. In 2010, the Agency requested proposals for study protocols t h at could identify and quantify potential juvenile sensitivity . The Agency received a single, coordinated response from the Pyrethrin and Pyrethroids Working Group (PPTWG), a conglomerate of pyrethroid registrants. The PPTWG protocol was reviewed during a July 2010 FIFRA SAP meeting. Based on comments from the SAP, the initial study proposal was refined. At the present time, pesticide registrants and product formulators have come togeth er as the Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA) and plan on doing the following: 1) conducting in vitro studies demonstrating the interaction of pyrethroids with exogenously expressed rat and human VGSCs; 2) conducting in

vitro studies demonstrating interaction of pyrethroids in rat neurolemma cells; 3) developing rat and human PBPK models, including additional pharmacokinetic data; and 4) conducting in vivo behavioral testing using auditory startle testing in rats. As th ese data become available, the Agency will determine whether re

- evaluation of the age

- related sensitivity of pyrethroids is appropriate.

Although EPA is seeking additional data to further characterize the potential neurotoxicity for pyrethroids, EPA has r eliable data that show that reducing the FQPA SF to 3X will protect the safety of infants and children less than 6 years old.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to dietary exposure. The di etary exposure
assessments are based on highly conservative residue levels for the mosquito adulticide use and

for the FHE uses . Furthermore, conservative, upper

- bound assumptions were used to determine exposure through drinking water and residential sources, such that these exposures have not been

underestimated.

Although EPA has required additional data on transferable residues from treated turf for prallethrin, EPA is confident that it has not underestimated turf exposure due to the

conservativenes s of the default turf transfer value and conservative assumptions in the short

- term turf assessment procedures (e.g., assuming residues do not degrade over the thirty day assessment period and assuming high

- end activities on turf for every day of the asses sment period). The additional data on turf transferable residues have been required in case refinement of exposure assessments is needed in the future and to further EPA’s general understanding of the availability of pesticide residues on turf.Prallethrin Human Health Risk Assessment DP No. D420116

Page 25 of 70 4.5 Toxic ity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response and Hazard Assessment

The details for selecting toxicity endpoints and PODs are presented in Appendix A.3. Based on the proposed use patterns for prallethrin, the expected exposure prof ile will be for dietary, dermal, inhalation

, and incidental oral exposures. Based on the toxicity profile, HED will not be conducting intermediate

- or long

- term exposure risk assessments for adults or children because

the data do not demonstrate an increa se in the severity of neurotoxic effects with increasing duration of exposure

.

As previously indicated, the toxicity endpoints for prallethrin are consistently based on clinical signs of neurotoxicity consistent with pyrethroid neurotoxicity. The availab le studies include multiple species, study designs, and durations. Because uncertainty associated with the POD is propagated throughout the risk assessment, one of the key factors in POD selection is the

robustness of the dose

- response data. There is a s pecial study available for a number of pyrethroids that measures motor activity (Wolansky et al, 2006) that is being used to derive

PODs for some chemicals in this class. However, prallethrin was not one of the chemicals evaluated in the study. There are guideline experimental toxicology studies available for prallethrin that are of high quality. Additionally, data from another special study are available for prallethrin ( MRID 48333801 ) . WIL Laboratories performed this study to evaluate neurobehavioral outcomes. However, as discussed in Section 4.3.3

, the WIL FOB study and the ACN study both used high vehicle volumes that likely impacted absorption characteristics of prallethrin

, thereby increasing the POD. When using 3⁄4 body weight scaling to compare human equivalent doses for rat and dog studies showing neurotoxicity, they are generally very similar (within 2 x). However , the chronic dog study still provided a slightly lower POD. Therefore, the dog study was used for acute dietary and incidental oral risk assessments.

Acute Dietary : The chronic dog study was selected based on neurotoxic effects observed at the

LOAEL of 5 mg/kg/day (NOAEL=2.5 mg/kg/day) . For acute dietary risk assessment, the endpoint used is commonly based on adverse effects attributed to a single

- dose exposure. However, for prallethrin, it is based on neurotoxic effects initially observed at 4 weeks. For pyrethroid chemicals, the pharmacokinetics indicate that the onset of neurotoxicity is rapid, with the time to peak effect for neurobehavioral effects occurring within hours. This is followed by rapid metabolism and elimination that does not result in accumulation. Therefore, repeated dosing is essentially a series of acute exposures

, and the effects seen in the dog study after 4 weeks are still appropriate for setting the a cute reference dose (a RfD )

.

In the dog study, animals were given a bolus dose (capsule) of prallethrin once daily for 52 weeks. The dogs were observed daily for clinical signs and mortality. At 4 weeks, trembling

was observed in one dog at the LOAEL of 5 mg/kg/day. A lthough trembling was observed in only one dog on one occasion at the 5 mg/kg/day dose , there was a clear dose response for the

effect. In the same dog, convulsions and tremors were seen at week 19. C onvulsions, panting, salivation, rapid eye blinking, and muscl e twitching were seen 5 hours after dosing prior to the

death of the dog during week 44. Based on the toxicity profile for pyrethroids

, clinical signs would be expected sooner than 4 weeks ; however, it could have been easily missed due to thePrallethrin Human Health Risk Assessment DP No. D420116

Page 26 of 70 timing of th e post

- dosing clinical examination

, since prallethrin has a rapid time to peak effect

. At the next highest dose of 10 mg/kg/day, the incidence and frequency of trembling substantially increased

, with 5 dogs being affected on numerous occasions (over 40). Additionally, effects were seen much earlier ( during 1 week). At 20 mg/kg/day, all dogs (8)

were affected with increased frequency

. At 10 and 20 mg/kg/day, t he trembling was also accompanied by dose

- related rapid eye blinking , hunched posture, salivat ion , and panting

. Although the use of 5 mg/kg/day as a POD is a conservative approach, it is only 2 fold lower than where numerous clinical signs were observed (during week 1) . The use of 5 mg /kg / day as

the POD is supportable when all of the information is considered together (time to peak effect for prallethrin, dose response relationship at 5mg/kg/day, earlier onset of effects at 10 mg/kg/day)

. Therefore, the chronic dog study was selected to protect for potential neurotoxicity.

It is noteworth y to mention that t he one dog in the 5 mg/kg/day group with clinical signs of neurotoxicity also had heart effects (red discoloration of the left ventricle and hemorrhage) that

were not considered treatment

- related as there was no dose response. Based on the available data, it is unclear whether the clinical signs observed in the dog are indicative of neurotoxicity

or related to the heart effects also observed in the animal. It should be noted that the neurotoxic effects seen in the dog were also observed at higher doses in the absence of heart effects.

The developmental rat and rabbit, acute neurotoxicity, and WIL studies were all considered for

risk assessment. H igher NOAELs were determined in the acute rat (ACN and WIL) and developmental rat and rab bit studies, so they were not selected for risk assessment. The WIL FOB study and the ACN study both used high vehicle volumes which likely impacted absorption characteristics of prallethrin thereby increasing the POD. Given what is known about pyrethroi d toxicokinetics/dynamics, in general, and as there is no apparent increase in hazard from repeated/chronic exposures to prallethrin, the acute dietary exposure assessment is protective of chronic dietary exposures.

Incidental O ral Short

- Term: For incidental oral exposure and assessment, the chronic dog study was also selected

, based on neurotoxic effects observed beginning at week 4. Signs of neurotoxicity (trembling, convulsions, heavy panting, salivation, rapid eye blinking, and muscle

twi tching) were observed in one dog at the LOAEL of 5 mg/kg/day. Additionally, neurotoxicity was seen within hours of dosing prior to the death of the animal during week 44 (see acute dietary). The NOAEL of 2.5 mg/kg/day is protective of potential offspring /developmental effects, as well as systemic effects, including neurotoxicity, observed in the toxicology database ( s ee Section 5.4.3: A cute D ietary R isk A ssessment).

Dermal Short

- Term: For dermal exposure and risk assessment, the 21

- day dermal toxicity study in rats was selected. The NOAEL is 30 mg/kg/day and the LOAEL is 150 mg/kg/day, based on clinical signs (fixation, abnormal gait, tremors, sensitivity to external stimuli, vocalization, twitching, and writhing spasms). The POD and endpoint are cons idered appropriate for short

- term risk assessment because it is a route

- specific study, the endpoint is based on the effect of concern (neurotoxicity), and there is no evidence of developmental toxicity or increased susceptibility.Prallethrin Human Health Risk Assessment DP No. D420116

Page 27 of 70 Inhalation Short

- Term: For inhalation exposure and risk assessment, the 28

- day inhalation toxicity study in rats was selected. The NOAEL is 0.001 mg/L and the LOAEL is 0.0044 mg/L,

based on nasal discharge, irregular respiration, decreased spontaneous activity, sal ivation, and incontinence. The dose and endpoint are appropriate becaus e the effects were seen following exposure via the route (inhalation) and duration (short

- and intermediate

- term) of concern. Additionally, the endpoint is based on portal of entry ef fects (nasal discharge, irregular respiration), as well as the effect of concern (neurotoxicity), and there is no evidence of developmental toxicity or increased susceptibility. Human equivalent concentrations (HECs) for portal of entry and systemic effec ts were calculated for prallethrin. The portal of entry HECs were used for risk assessment and are considered protective of systemic effects since they were

15 x lower than the systemic HECs.

The methods and dosimetry equations described in EPA’s refere nce concentration (RfC) guidance (1994) and OPP’s guidance on the application of the RfC methodology (2014) are suited for calculating HECs based on the inhalation toxicity N OAEL for use in MOE

calculations

. The regional

- deposited

- dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter ( MMAD ) and geometric standard deviation (  g ) of aerosols), can be used to estimate the different dose fractions deposited along the respiratory

tract

. The RDDR is also based on inter species differences in ventilation and respiratory

- tract
surface areas

. Thus, the RDDR can be used to adjust an observed inhalation particulate exposure of an animal to the predicted inhalation exposure for a human (see toxicity endpoint summary table in Section 4.5.4 for values and Appendix A.4 for calculations).

. HED’s Levels of Concern for Margin of Exposure

HED’s LOC for occupational and residential risks is based on the various uncertainty and safety factors retained or applied for specific routes of exposure. For inhalation risk assessments, the

10 x interspecies factor was reduced to 3 x to account for interspecies differences, in accordance

with the reference concentration ( RfC ) guidance. The intraspecies variability factor of 10 x is combined with an interspecies extrapolation factor of 3 x , based on the use of a human equivalent

dose for inhalation risk assessment. Therefore, for inhalation risk assessments for adults and

children 6 years of age or older, a 30 x uncertainty factor has been retained. For children under 6 years old, exposed via the inhalation route, the LOC is 100, based on a 10 x factor for intraspec ies variability, 3 x for interspecies extrapolation, and 3 x for juvenile sensitivity. For assessing dermal and oral exposures, the LOC for children under 6 years old is 300, based on the

traditional 10 x factors for intraspecies variability and interspecies extrapolation, and the

additional 3 x FQPA Safety F actor

. For adults and children 6 years and older, the traditional factors apply (10 x intraspecies and 10 x interspecies) for dermal and oral exposures (Table 4.5.1)

.Prallethrin Human Health Risk Assessment DP No. D420116

Page 28 of 70 Table 4.5.1. HED’s LOCs for MOEs

Route LOC
Occupational Dermal Exposure 100 x Occupational Inhalation Exposure 30 x Residential Incidental Oral Exposure < 6 years old: 300 x

Residential Dermal Exposure ≥ 6 years old: 100 x < 6 years old: 300 x

Residential Inhalation Exposure ≥ 6 years old: 30 x < 6 years old: 100x

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources, oral, dermal and inhalation, and determine whether the individual exposures can be combined if they have th e same toxicological

effects. For prallethrin, dermal and oral exposures are both based on clinical signs related to neurotoxicity and should be combined for risk assessment

. Although the LOAEL for inhalation is also based on neurotoxicity, derivation of the HEC s used for inhalation risk assessment (Appendix A.4) show that assessing inhalation exposure based on the portal

- of

- entry effects is protective of the systemic endpoints ( including neurotoxicity ) since the portal of entry HEC is

15 x lower than the systemic HEC . As a result, inhalation exposure should not be combined with either the dermal or the oral routes of exposure.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Prallethrin is classified as “not likely to be carcinogenic t o humans.” No tumors were observed in rat and mouse carcinogenicity studies up to the highest doses tested. For both the rat and mouse studies, the animals could have tolerated higher dose levels; however, HED determined that dose levels were adequate to assess potential carcinogenicity.

Prallethrin tested negative in the majority of the genotoxicity studies. It also tested negative in

an in vitro chromosomal aberration study in Chinese Hamster Ovary (CHO K1) cells without metabolic activation, but tested positive at all doses with metabolic activation. However, clastogenicity was not clearly dose

- related, was seen at nontoxic and slightly toxic d oses, was not expressed in in vivo studies

, and structure

- activity comparisons with the other pyrethroids

revealed no correlations with clastogenicity . Other gene mutation, chromosomal aberration

, and unscheduled DNA synthesis ( UDS ) studies were negative. Therefore, there is no concern for genotoxicity.

4.5.4 Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

T oxicity endpoints/PODs are given in the table below , and the full toxicological profile is presented in Appendix A.Prallethrin Human Health Risk Assessment DP No. D420116

Page 29 of 70 Table 4.5.4. a. Summary of Toxicological Doses and Endpoints for Prallethrin for Use in Dietary and

Non

- Occupational Human Health Risk Assessments

Exposure/ Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD, Level

of Concern for

Risk Assessment Study and Toxicological

Effects

Acute Dietary (children ≥ 6 years old and adults)

NOAEL = 2.5 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Acute RfD =

0.025 mg/kg/day

aPAD = 0.025 mg/kg/day Chronic dog study

(capsule) LOAEL = 5 mg/kg/day

based on clinical signs of neurotoxicity

. Acute Dietary (children<6 years old) UF A = 10x

UF H =10x FQPA SF= 3x Acute RfD =

0.025mg/kg/day

aPAD = 0.008 mg/kg/day

Incidental Oral Short

Term (1

- 30 days) UF A = 10x

UF H =10x FQPA SF= 3x Residential LOC

for MOE = 300

Short

- term Dermal (1 to 30 days) (children <6 years old)

Dermal NOAEL= 30 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 3x Residential LOC

for MOE = 300

21

- day Dermal Rat

LOAEL = 150 mg/kg/day

based on observed clinical signs of toxicity (fixation, abnormal gait, tremors, sensitivity to external stimuli, vocalization, twitching and writhing spasms), all beginning between days 1 and 3 of a 21 day dermal study in

rats. Shor t

- term Dermal (1 to 30 days) (children ≥ 6 years old and adults) UF A = 10x

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

for MOE = 100

Short

- term Inhalation (1 to 30 days) (children <6 years old) Inhalation NOAEL = 0.001 mg/L

HEC/HED

calculations used for risk assessment (see below) UF A = 3x

UF H =10x FQPA SF= 3x Residential LOC

for MOE = 100

28

- Day Inhalation Rat

LOAEL = 0.0044 mg/L based on irregular respiration, decreased spontaneous activity, salivation, incontinence,

and nasal discharge. Short

- term Inhalation (1 to 30 days) (children ≥ 6 years old and adults) UF A = 3x

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

for MOE = 30Prallethrin Human Health Risk Assessment DP No. D420116

Page 30 of 70 Table 4.5.4.a. Continued. Summary of Toxicological Doses and Endpoints for Prallethrin for Use in Dietary and Non

- Occupational Human Health Risk Assessments

Residential HECs and

HEDs

Residential LOC for

MOE = 100 ( children <6 years old)

Residential LOC for

MOE = 30 (children ≥ 6 years old and adults) Residential HECs HEDs

Handler/Outdoor Postapplication 0.00020 mg/L 0.006 mg/kg/day

Indoor Postapplication

without air

ventilation 0.00014 mg/L N/A*

Indoor Postapplication

with air ventilation Adults: 0.00004 mg/L

Children: 0.00003 mg/L N/A*

Bystander 0.00002 mg/L N/A*

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. UF A = extrapolation from animal to human (interspecies). UF H = potent ial variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level

of concern. HEC = hu man equivalent concentration; HEC = POD x RDDR x daily duration x weekly duration. HED = human equivalent dose. HED = dose (systemic HEC value) mg/L x A (absorption) x CF (conversion factor) L/hr/kg) x D (duration

- hours) x AF (activity factor)

. *MOEs ca lculated directly from HECs.

Table 4.5.4. b. Summary of Toxicological Doses and Endpoints for Prallethrin for Use in

Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertain

ty Factors Level of Concern for

Risk Assessment Study and Toxicological Effects

Short

- term
Dermal (1 to 30 days) Dermal

NOAEL= 30 mg/kg/day UF A = 10x

UF H =10x Occupational LOC for

MOE = 100 21

- day Dermal Rat LOAEL = 150 mg/kg/day based on observed clinical signs of toxicity (fixation, abnormal gait, tremors, sensitivity to external stimuli, vocalization, twitching and writhing spasms), all beginning between days 1 and 3 of a 21 day dermal study in ratsPrallethrin Human Health Risk Assessment DP No. D420116

Page 31 of 70 Table 4.5.4. b. Summary of Toxicological Doses and Endpoints for Prallethrin for Use in

Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertain

ty Factors Level of Concern for

Risk Assessment Study and Toxicological Effects

Short

- term
Inhalation (1 to 30 days) Inhalation

NOAEL = 0.001 mg/L

HEC/HED

calculations used

for risk assessment (see below) UF A = 3x

UF H =10x Occupational LOC for

MOE = 30 28

- Day Inhalation Rat

LOAEL = 0.0044 mg/L based on irregular respiration, decreased spontaneous activity, salivation, incontinence, and nasal discharge

Occupational

HECs and

HEDs O c cupational HECs HEDs

Ventilation rate=8.3 L/min

0.00010 mg/L 0.006 mg/kg/day

Ventilation rate= 16.7 L/min 0.0 12 mg/kg/day

Ventilation rate= 29 L/min 0.0 20 mg/kg/day

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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in

sens itivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of

concern. HEC = human equivalent concentration; HEC = POD x RDDR x daily duration x weekly duration. HED = human equivalent dose. HED = dose (system ic HEC value) mg/L x A (absorption) x CF (conversion factor) L/hr/kg) x D (duration

- hours) x AF (activity factor)

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

N o metabolism studies in plants or animals have been conducted

, and none are required, based on previous Agency discussions with the petitioner on 11/ 3 / 2010

. For the use in food handling

establishments and the proposed use over or near agricultural crops, EPA assume s that the

residue of concern is the parent compound only.Prallethrin Human Health Risk Assessment DP No. D420116

Page 32 of 70 5.1.2 Summary of Environmental Degradation

Prallethrin has a relatively low solubility in water, and adheres moderately to soil containing organic material ( organic sorption K OC = 2,533 mL/g). The potential for prallethrin to move off the site of application with rain or irrigation water (mobility) is moderate. Prallethrin degrades rapidly via photolysis ( sunlight ) when it is in the air

, but more slow ly when it is in/ on vegetation,

soil

, or water. Prallethrin is moderate ly persistent . I t is likely to take between 1 week and 2 months (t 1/2 = 3 to 3 7 days) for prallethrin to degrade to half of the applied concentration ( in/ on soil, water

, or vegetation).

5.1.3 Comparis on of Metabolic Pathways

As metabolism studies were not performed on plant or livestock commodities, comparison of the

relevant metaboli c pathways is not possible. For a discussion of metabolism in rats, see Section

4.2.

5.1.4 Residues of Concern Summar y and Rationale

For the use in food handling establishments and the proposed use over or near agricultural crops,

EPA assume s that the residue of concern is the parent compound only. Given that residues resulting from the mosquitocide use are expected to be very low or non

- detectable, there are no residues expected in rotational crops.

T able 5 .1. 4. Summary of Metabolites and Degradates to be inc luded in Risk Assessment and

Tolerance Expression

Matrix Residues I ncluded in Risk

Assessment Residues I ncluded in Tolerance Expression for Compliance Monitoring

Plants Primary Crops Prallethrin Prallethrin

Rotational Crops Not Applicable Not Applicable

Livestock Ruminants Prallethrin Prallethrin

Poultry Prallethrin Prallethrin

Drinking Water Prallethrin Not Applicable

5 .2 Food Residue Profile

In support of the proposed adulticide use, t he registrant submitted residue trial s for prallethrin on alfalfa, grass

, and leaf lettuce

. Three trials (1 for each crop ) were conducted in the US in typi cal growing areas for these crops and in accordance with study protocol s agreed to in discussions with the Agency

. The protocol specified that applications would be made at the 1x and 10x application rates from an elevation of 50 feet above ground. The prallethrin residue data are summarized in Table 5. 2 .1.Prallethrin Human Health Risk Assessment DP No. D420116

Page 33 of 70 In the residue trials, applications were made in the airspace above leaf lettuce, alfalfa, and Sudan grass at a 10x label application rate (0.0072 lb a.i./Acre) . In addition, a trial was performed on alfalfa at a 1x application rate (0.00072 lb a.i./Acre) . Thirty

- six samples were analyzed from each trial. None of the samples of alfalfa treated at the 1x application rate or leaf lettuce treated at the 10x application rate contained residues above the LOQ of 0.01 ppm. Only one sample of alfalfa treated at the 10x application rate contained quantifiable residues (0.0107 ppm). However, 11 of the 36 samples of Sudan grass forage contained quantifiable residues. The highest residue was 0.045 ppm.

The s ubmitted alfalfa, grass

, and leaf lettuce field trial data are adequate , and demonstrate that the use of the mosquitocide in accordance with the registered label would result in very low residues, in the range of the LOQ. The existing established toleranc e for prallethrin residues of 1.0 ppm in/on all food commodities, resulting from use of the insecticide in FHE s, is adequate to

cover residues resulting from the proposed use in the vicinity of, or the airspace above, agricultural field crops.

T able 5. 2 .1

. Summary of Residue Data from Crop Field Trials with Prallethrin

Crop n Use

Rate 1 Number

of NDs 2 Number of

Peak s at RT 3 Number

<LOD 4 Number >LOD

and <LOQ 5 Number

>LOQ Highest

Residue (ppm)

Leaf Lettuce 36 10 x 31 5 2 3 0 0.00994

Alfalfa 36 1 x 36 0 0 0 0 0

Alfalfa 36 10 x 24 12 3 7 1 0.0107

Sudan Grass 36 10 x 5 31 4 16 11 0.0450

1. 1 x use rate = 0.00072 lb ai/A, 1 0 x use rate = 0.0072 lb ai/A

. 2. ND = Not Detected. N o visible peak was seen in the chromatogram at the r etention t ime ( R T) of prallethrin

. 3. In these samples, there was a visible peak present at the RT of prallethrin ; some were below the LOD. 4. LOD = 0.003 ppm. 5. LOQ = 0.010 ppm.

There are no Codex or Canadian MRLs for prallethrin. As a result, there are no harmonization issues for the chemical with respect to either the residue definition or to MRLs.

The registrant has not submitted processing stud ies or livestock feeding studies for prallethrin,

and none are needed.

As agricultural crops are not being di rectly treated, and water concentrations are expected to be extremely low, bioconcentration in fish is not an issue for prallethrin

.

5.3 Water Residue Profile

EFED p rovided the results of a drinking water assessment that was performed for pralle thrin (D 40 8885

, H. Zhong

, 2/4 /201 3 ) . In this memo, EFED stated that the results of a previous assessment (D 274758 , J. Melendez, 6 /3 0 /200 3 ) should be used in the current dietary exposure

and risk assessment

. In the 2003 assessment, the acute (peak) and annual average surface water concentrations were generated using the FIRST Model, and the groundwater concentrations were generated using the SCIGROW Model. T he estimated drinking water concentration ( EDWC ) for

the acute assessment was 0.591 pp b and that for the chronic assessment was 0.0375 pp b . ThePrallethrin Human Health Risk Assessment DP No. D420116

Page 34 of 70 groundwater value wa s 0.001 μg/L. The surface water EDWCs of 0.591 pp b and 0.0375 pp b were used instead of the groundwater value because they were higher and, therefore, more

conservative. The drinking water model s EFED uses and their d escription s are available at the

EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

5.4 Dietary Risk Assessment

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16 . This software uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We E at in America, (NHANES/WWEIA). The chronic assessment was conducted solely for the purpose of obtaining estimates of backgr ound levels of dietary exposure for estimating aggregate risk.

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute Assessment

The acute assessment is partially refined. It is based on the assumption that most commodities

will have residues at one

- half the LOQ of the analytical method used in the FHE residue trials (0.05 ppm). It was also based on the assumptions that all flour food forms will contain residues at the highest level found in the FHE residue trials on flour, and that tree nuts and peanuts will contain residues at the highest level found in the FHE residue trials on peanuts. The 4.65% of

FHE facilities treated estim ate from BEAD was used to calculate the number of zeros used in the RDFs for nonblended and partially blended commodities. The zeros were replaced with the highest residue from the mosquito adulticide trials (0.0045 ppm). In addition, 0.0045 ppm was

adde d to the residue values in the RDFs. F or blended commodities , the residue value was multiplied directly by the percent FHE value (0.0465) and 0.0045 ppm was added

. By treating the data in this manner, the percent FHE value was applied to the FHE residue values

, and the adulticide residues were incorporated at a level of 100%. A modeled EDWC of 0.000591 ppm from EFED was used for drinking water , as discussed in the Water Residue Profile section above (Section 5.3). Processing factors were not used because the assumption was made that foods in an FHE could be treated after processing.

Chronic Assessment

The chronic dietary exposure assessment is partially refined. The exposure estimates are based on the highest residue value from the FHE residue t rials for tree nuts, peanuts, and all flour food forms; and on the LOQ of the method used in the FHE trials (0.10 ppm). The data were treated in the same manner as the data for the blended commodities in the acute assessment, with the exception that the a verage residue value from the adulticide trials (0.0007 ppm) was used instead of the highest residue value (0.0045 ppm). As a result, the residue value was multiplied by 0.0465 and 0.0007 ppm was added. As with the acute assessment, by treating the data in this manner, the percent FHE value was applied to the FHE residue values

, and the adulticide residues were incorporated at a level of 100%. Finally, a modeled EDWC of 0.0000375 ppmPrallethrin Human Health Risk Assessment DP No. D420116

Page 35 of 70 from EFED was used for drinking water , as discussed in the Water Residu e Profile section above (Section 5.3). Processing factors were not used because the assumption was made that foods in an FHE could be treated after processing.

C a nc er Assessment

C ancer risk is not of concern for pralle thrin because the compound is cla ssified as “not likely to be carcinogenic to humans. ”

5.4.2 Percent Crop Treated Used in Dietary Assessment

BEAD provided an estimate of a 4.65% probability that a food a person consumes contains

residues as a result of treatment in an FHE at some point with any pesticide (i.e., i t is not specific to prallethrin )

. For both the acute and chronic assessments, t his value was used for all commodities with the exception of drinking water. With respect to the mosquito adulticide application , the assumpt ion was made that 100% of all commodities would contain residues as a

result of this use.

5.4.3 Acute Dietary Risk Assessment

The acute risk estimates are below HED’s LOC for all population subgroups, including those comprised of infants and children. Generally, HED is concerned when risk estimates exceed 100% of the population

- adjusted dose (PAD). The acute risk estimate for the general U.S. population is 1 0 % of the aPAD. The population subgroup with the highest acute dietary risk

estimate is Childr en 1

- 2, which uses 76 % of the aPAD. As a %FHE treated estimate was used for all commodities, the risk estimates are being reported at the 99.9 th percentile of exposure. The acute dietary exposure and risk es timates are given in Table 5.4. 5

.

As stated above, the acute as sessment is partially refined; however, there is still a significant degree of conservatism in the assessment. The residue levels are from trials designed to produce maximum residues. Typically, residues in foods at the time of consump tion are lower than those

obtained from such trials.

The percent FHE treatment estimate provided by BEAD is a conservative estimate of FHE treatment with prallethrin. It represents the probability that a food a person consumes contains

residues as a res ult of treatment in an FHE at some point with any pesticide , and is not specific to prallethrin. S ales and production data for prallethrin indicate that the percent of facilities treated

with that chemical are lower than the all

- pesticide estimate. In ad dition, the conservative assumption was made for the mosquito adulticide use that all commodities would be treated to a

level of 100%

, (i.e., all crops contain inadvertent residues resulting from mosquito control use), and residues would be present at the maximum level found in the adulticide trials.Prallethrin Human Health Risk Assessment DP No. D420116

Page 36 of 70 5.4. 4 Chronic Dietary Exposure Assessment

The chronic dietary exposure estimates range from 0.00 0 102 to 0.00 0581 mg/kg/day. The chronic assessment is partially refined. As with the acute assessment, the inputs to the chronic assessment convey significant conservatism in both the residue values used and the application of the percent

- of

- treatment estimates. The chronic dietary exposure estimates are given in Table

5.4. 5

.

5.4. 5 Summary Table

Table 5.4.5 . Summary of the Acute Exposure and Risk Estimates for Pralle thrin

Population Subgroup Acute Assessment (99.9 th Percentile) Chronic Assessment
aPAD,

m g /k g /d ay Exposure Estimate,

mg /kg /day % aPAD cPAD,

m g /k g /d ay Exposure Estimate,

mg /kg /day %

cPAD
U.S. Population 0.025 0.002536 10 NA 0.000155

NA All infants 0.0083 0.004464 54 NA 0.000263

Children 1

- 2 yrs* 0.0083 0.006275 76 NA 0.000581

Children 3

- 5 yrs 0.0083 0.003609 43 NA 0.000421

Children 6

- 12 yrs 0.025 0.002335 9.3 NA 0.000253

Youth 13

- 19 yrs 0.025 0.001343 5.4 NA 0.000137

Adults 20

- 49 yrs 0.025 0.000959 3.8 NA 0.000116

Adults 50

- 99 yrs 0.025 0.000855 3.4 NA 0.000102

Females 13

- 49 yrs 0.025 0.000998 4.0 NA 0.000110 *Most highly exposed population subgroup

6 .0 Residential Exposure and Risk Estimates
(M. Collantes, D407642, 8/9/2013 and D417631, 5/8/2014)

There are no new proposed residential uses at this time; however, there are existing residential uses as well as products registered for controlling public hea lth pests (mosquito control) in outdoor residential and recreational areas and in vegetation surrounding parks, woodlands, swamps, marshes, overgrown areas

, and golf courses

. Several of t hese registered residential uses

w ere evaluated in the 1999 occupati onal and residential exposure (ORE) assessment and have

since been cancelled or removed from the label . The remaining registered residential u se scenarios have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs, along with policy changes for body weight assumptions and updated inhalation toxicological endpoints and points of departure

.

T he toxicological profile of pyrethroid s characterizes pyrethroids , including prallethrin, as being rapid in onset and associated with acute, peak exposures. Although the single day, acute studies for prallethrin do not provide the most sensitive PODs, neurotoxicity was observed in most of the

repeat

- dose toxicology studies within a few days of dosing. As such, the totality of the information suggests that only single day risk assessments need to be conducted for prallethrin. Based on the toxicity profile, HED did not conduct an intermediate or long

- term exposure
assessment for adults or children. A short

- term exposure assessment is protective of exposures with longer durations.Prallethrin Human Health Risk Assessment DP No. D420116

Page 37 of 70 6 .1 Residential Handler Exposure/Risk Estimates

T he prallethrin labels do not identify the residential use products as restricted use ; therefore , a revised residential handler exposure assessment was performed to be protective of potential homeowners who apply prallethrin products

. The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:

 Applying a fogger to indoor use sites , and

 Mixing/Loading/Applying spray to lawns

Combining Exposures/Risk Estimates:

Residential exposure pathways for adults include dermal and inhalation routes for application

related scenarios. For prallethrin, dermal and inhalation exposures are both based on clinical signs related to neurotoxicity. However, the H EC for inhalation exposure was based on portal of entry effects that resulted in lower HECs than the HEC for systemic (neurotoxicity)

effects. Therefore, the portal of entry HEC is protective of the neurotoxic systemic effects

, and inhalation and dermal routes of exposure should not be combined.

Summary of Residential Handler Exposure and Risk Estimates

Registered residential uses were reassessed using the revised 2012 Residential SOPs and a new inhalation endpoint and point of departure . All residential handler scenarios resulted in dermal and inhalation risk estimates greater than their respective LO Cs (dermal MOE ≥ 100 and inhalation MOE ≥ 30) and are not of concern. A quantitative assessment was not required for handling of the total release fogger product since the labels state that room/house must be vacated immediately by the user once fogger is initiated. The residential h andler exposure risk

estimates are summarized in Table 6.1

.Prallethrin Human Health Risk Assessment DP No. D420116

Page 38 of 70 Table 6.1. Registered Residential Handler Exposure and Risk Estimates for Prallethrin

Exposure Scenario Level of

Concern Dermal Unit

Exposure (mg/lb ai) Inhalation Unit

Exposure
(mg/lb ai) Maximum

Application

Rate 1 Area Treated

Daily 2 Dermal Inhalation

Dose (mg/kg/day) 3 MOE 4 Dose (mg/kg/day) 5 MOE 6

MGK Formula 2964 Microencapsulated Suspension

Concentrate Insecticide
(1.6% a.i.)
Reg. No. 1021

- 2574 Dermal

LOC = 100

Inhalation

LOC = 30 13.4

hose

- end

sprayer 0.022

hose

- end

sprayer 0.045 lb ai/A 0.5 A 0.0038 8000 0.0000062 970

130
backpack 0.14 backpack 0.00011
lb ai/ gal 1

, 200 ft 2 0.0021 14,000 0.0000023 2,600

EVERCIDE® NYlAR Total Release Aerosol Fogger 2644

Reg. No. 1021

- 1656 Quantitative assessment not required because the label s state that room/house must be vacated immediately once fogger is initiated. Do not remain in area during treatment.

1 Based on registered labels.

2 Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ).

3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated × Dermal Absorption Factor (%) ÷ Body Weight (80 kg).

4 Dermal MOE = Dermal NOAEL (30 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

5 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated (A/day or gallons /day) ÷ Body Weight (80 kg).

6 Inhalation MOE = Inhalation HED (0.00 6 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).Prallethrin Human Health Risk Assessment DP No. D420116

Page 39 of 70 6.2 Post

- Application Exposure

There is the potential for residential post

- application exposure for individuals exposed as a result

of b eing in an environment that has been previously treated with prallethrin. A residential post

application exposure assessment was previously performed for the mosquito control (G. Bangs, D293820, 9/30/2003) as well as for indoor and pet uses (M. Collantes, D260355, 11/17/1999). Several of the previously assessed residential products have been cancelled or removed from

current labels. Risk estimates for the mosquito control and remaining registered residential post

application exposure scenarios are revise d in this assessment to incorporate the use of new toxicological inhalation endpoints and points of departure , the revised 2012 Residential SOPs and appropriate body weights and life stages. The quantitative exposure/risk assessment for residential post

- a pplication exposures is based on the following short

- term duration scenarios:

 Dermal exposure from contact with residues deposited on turf resulting from mosquito control;

 Incidental oral (hand

- to

- mouth) contact with residues deposited on turf resulting from mosquito control;

 Inhalation exposure of residues resulting from mosquito vector control;

 Dermal exposure from contact with residues deposited on indoor surfaces from fogger ;

 Incidental oral (hand

- to

- mouth) contact with residues deposited on indoor s urfaces from fogger;

 Inhalation exposure of residues resulting from exposure to indoor pesticide vapors from fogger ;

 Dermal exposure from contact with residues deposited on turf/lawns ; and

 Incidental oral (hand

- to

- mouth) contact with residues deposited on turf/lawns

Combining Exposures and Risk Estimates:

The child dermal and incidental oral routes of exposure are generally combined as it is likely that they can occur simultaneously based on the use pattern, and the toxicological effects across these

rou tes of exposure are the same. Therefore, exposure from the incidental oral route should be combined with dermal exposure and background exposure from food and water in order to complete an undated aggregate risk assessment for prallethrin.

Mosquito Adul ticide Use

No chemical

- specific exposure data have been submitted to support the mosquito adulticide use. Therefore, to calculate airborne concentrations from aerial ULV applications, HED used

AGDISP modeling software, version 8.26

. AGDISP predicts the motion of spray material released from aircraft, and determine s the amount of application volume that remained aloft and the amount of the resulting droplets deposited on the surfaces in the treatment area as well as

downwind from the treatme nt area. The model also allows for the estimation of air concentrations in the breathing zones of adults and children for use in calculating the post

application inhalation risks to individuals residing in areas being treated by aerial application of pral lethrin. P ost

- application inhalation estimates resulting from aerial applications have beenPrallethrin Human Health Risk Assessment DP No. D420116

Page 4 0 of 70 revised to incorporate the new HEC which is based on a 4

- hour exposure duration

. Furthermore, to calculate refined airborne concentrations from ULV truck fogger a pplications, HED used the 2012 Residential SOPs for Outdoor Fogging/Misting Systems, with minimal modification to the

W ell

- M ixed B ox (WMB) M odel. For both adults and children, the exposure duration was adjusted to 4 hours as opposed to a default of 1.5 hour s to mimic an exposure duration consistent

with the 4

- hour animal inhalation toxicity study used to define the endpoint and POD used as the

basis of this assessment . The WMB M odel allows for the estimation of air concentrations in the breathing zones of adults and children for use in calculating the post

- application inhalation

exposure to individuals residing in areas being treated by ground application of prallethrin. T his methodology is a modification of the previous method used in assessing post

- ap plication inhalation exposure resulting from truck mounted mosquito fogger . The revised methodology more accurately accounts for dilution using the WMB M odel as discussed above.

All post

- application mosquito control exposure scenarios resulted in MOEs g reater than their respective LOCs and are not of concern

. Table 6.2.1 provides a summary of the calculated air concentrations and respective inhalation MOEs resulting from aerial and ground (fogger truck) applications of prallethrin.

Table 6.2.1

. Inhalation Exposure & Risk Estimates from Mosquito Adulticide Using the

AgDISP and WMB Model s

.

Population Air Concentration

Estimate (mg/m 3 ) HEC d (mg/m 3 ) Inhalation MOE e

Aerial ULV (100 ft release height)

– AGDISP Model

Adults 0.00014 a 0.2 1400

Children 1 to <2 years old 0.00015 b 1300

ULV Truck Fogger

– WMB Model

Adults 0.000014 c 0.2 1400

Children 1 to <2 years old
a Air concentration estimate produced from AGDISP Model at approximately 6 feet from ground.

b Air concentration estimate produced from AGDISP Model at approximately 3 feet from ground. c Air concentration estimate produced from WMB Model

d H uman equivalent concentration (HEC) = 0. 2 mg/m 3
e Inhalation MOE = HEC (0

. 2 mg/m 3 ) /Air Concentration (mg/m 3 )

The AGDISP M odel is also capable of estimating the amount of residues depositing on turf for use in calculating the dermal post

- application risk estimates to individuals residing in areas being treated by aerial application of prallethrin. For ground

- based ULV applications

, a 5% deposition

is used based on a study conducted by Teitze et al., ( Mass Recovery of Malathion in Simulated Open Field Mosquito Adulticide Tests ; Archives of Environmental Contamination and Toxicology; 26: 473

- 477; 1994). The 2012 Lawn an d Turf Residential SOP for dermal post

application exposure was used to estimate resulting TTRs for dermal and incidental oral (hand

to

- mouth) exposure estimates resulting from aerial and ground applications . The TTRs werePrallethrin Human Health Risk Assessment DP No. D420116

Page 41 of 70 adjusted for air (0.79) depositi on provided by AGDISP and ground (0.05) deposition provided by

data in the Teitze et al., study . The hand

- to

- mouth scenario represents the worst case incidental oral exposure scenario and is thus protective of all other incidental oral scenarios. Tables 6.2.2

and 6.2.3 provide a summary of the post

- application dermal and incidental oral exposure

estimates. Table 6.2. 4 provides a summary of the combined dermal and incidental oral risk

estimates.

Table 6.2.2. Dermal Post

- application Exposure Estimates Resulting from Multicide 2798 Reg.

No. 1021

- 1795 and Multicide 2922 Reg. No. 1021

- 2562.

Use Application

Rate (lb ai/A) TTR a

(ug/cm 2 ) AGDISP

Deposition

Fraction Adjusted

TTR b (ug/cm 2 ) Transfer

Coefficient c (cm 2 /hr) Dermal Dose d

(mg/kg/day) Dermal

MOE e

Adult

air

0.00072 0.0008 0.79 0.000063 180,000 0.0002 140,000
ground 0.05 0.000004 49,000 0.00001 2,200,000

Child (1

- 2 yrs)

air

0.00072 0.0008 0.79 0.000063 180,000 0.0004 71,000
ground 0.05 0.000004 49,000 0.00003 1,100,000

a. TTR t = AR (0.00072 lb ai/A) * F (0.01) * (1

- F D ) t * CF2 (4.54 x 10 8 μg/lb) * CF3 (2.47 x 10

- 8 A/cm 2 ).

b. Adjusted TTR(ug/cm 2 ) = TTR (0.0008 ug/cm 2 ) x AgDISP Deposition Fraction (0.79 aerial or 0.05 dermal )

c. Transfer Coefficient (cm 2 /hr) = See Turf SOP In Appendix B in D407643 or Appendix A in D417631

d. Dermal Dose (mg/kg/day) = TTR t * CF1 ( 0.001 mg/μg) * TC * ET (1.5 hrs)

e. Dermal MOE = NOAEL (30 mg/kg/day)/Dermal Dose (mg/kg/day) ; Adult LOC = MOE ≥ 100; Child (1

- 2 yrs) LOC =
MOE ≥ 300

Table 6.2.3

. Incidental Oral Exposure Estimates Resulting from Multicide 2798 Reg. No. 1021

-

1795 and Multicide 2922 Reg. No. 1021

- 2562.

Use Application Rate

(lb ai/A) Hand Residue a

(mg/ c m 2 ) Incidental Oral Dose b (mg/kg/day) Incidental Oral MOE c

air 0.00072 0.0000008 0.00001 290,000

ground 0.0000001 0.000001 4,600,000

a. Hand Residue =

b. Incidental Oral Dose (mg/kg/day) = [HR * ( F M * SA H ) * (ET * N_Replen) * (1

- (1

- SE ) (Freq_HtM/N

- Replen) )]

c. Incidental Oral MOE = NOAEL (2.5 mg/kg/day)/Incidental Oral Dose (mg/kg/day) ; LOC = MOE ≥ 300

Table 6.2. 4. Combined Dermal and Incidental Oral Post

- application E xposure and Risk Estimates

Lifestage Use Site Route of Exposure Application

Rate 1 Air

Concentration Estimate (mg/m 3 ) Dose

(mg/kg/day) 2
or (mg/m 3 ) MOEs 4 Combined

MOE

Adult Truck Mounted Fogger

Multicide 2798 Reg. No 1021

- 1795 (0.075 lb ai/gal)

and Dermal

0.00024

- 0.00072 NA 0.0001 2,200,000

NA Inhalation 0.00014 NA 1,400

Child Dermal

NA 0.00003 1,100,000
900,000 Hand to Mouth 0.000001 4,600,000

Inhalation NA 1,400Prallethrin Human Health Risk Assessment DP No. D420116

Page 42 of 70 Table 6.2. 4. Combined Dermal and Incidental Oral Post

- application E xposure and Risk Estimates

Lifestage Use Site Route of Exposure Application

Rate 1 Air

Concentration Estimate (mg/m 3 ) Dose

(mg/kg/day) 2
or (mg/m 3 ) MOEs 4 Combined

MOE

Multicide 2922 Reg. No. 1021

- 2562 (0.084 lb ai/gal) lb ai/acre

(0.41

– 1.23 fl oz/acre) 0.00014 NA

Adult Aerial Application

Multicide 2798 Reg. No 1021

- 1795 (0.075 lb ai/gal)

and

Multicide 2922 Reg. No. 1021

- 2562 (0.084 lb ai/gal) Dermal NA 0.0002 140,000

NA

Inhalation 0.00014 NA 1,400

Dermal NA 0.0004 71,000
57,000 Hand to Mouth NA 0.00001 290,000

Inhalation 0.00015 NA 1,300 NA

1 Based on registered or proposed labels.

2 Dose (mg/kg/day) ( see equations in Appendix A and B of D417631 ORE assessment)

3 MOE = POD (mg/kg/day or mg/m 3 ) ÷ Dose or air concentration (mg/kg/day or mg/m 3 ).

4. Combined MOE = 1 ÷[(1 ÷ Dermal MOE) + (1 ÷ Inhalation MOE)]

.

Registered Residential Uses

For the purpose of conducting an aggregate (dietary and residential exposure) a revised residential post

- application exposure assessment was also performed for turf and indoor fogger

uses. All post

- application residential expo sure scenarios resulted in MOEs greater than their respective LOCs and are not of concern

. Furthermore, a ll combined post

- application exposure scenarios (i.e., child dermal + hand

- to mouth) resulted in MOEs greater than their respective

LOCs and are not o f concern. Table 6.2. 5 provides a summary of the residential post

- application exposure risk estimates.

Table 6.2.5

. Residential Post

- application Exposure and Risk Estimates

Lifestage Use Site Route of Exposure Application

Rate 1 Air

Concentration Estimate (mg/m 3 ) Dose

(mg/kg/day) 2
or (mg/m 3 ) MOEs 4 Combined

MOE

Adult MGK Formula 2964

Microencapsulated Suspension Concentrate

Insecticide for use on

Lawns
(1.6% a.i.)
Reg. No. 1021

- 2574 Dermal

0.045 lb ai/A

or
0.00011 lb ai/ gal NA 0.017 1

, 800

NA Inhalation NA

Child Dermal 0.033 900

730 Hand to Mouth 0.0007 3

, 600

Inhalation NA NA

Adult EVERCIDE NYLAR

Total Release Aerosol Fogger (Indoor Use) Reg. No. 1021

- 1656 Dermal 1 fogger can deposited

residues

– 0.1 ug/cm 2 NA 0.0041 7

, 400

NA Inhalation NA

Child Dermal 0.0039 7

, 600
2,700 Hand to Mouth 0.00058 4, 200

Inhalation NA NA

1 Based on registered or proposed labels.

2 Dose (mg/kg/day) ( see equations in Appendix A and B of D417631 ORE assessment)

3 MOE = POD (mg/kg/day or mg/m 3 ) ÷ Dose or air concentration (mg/kg/day or mg/m 3 ).

4. Combined MOE = 1 ÷[(1 ÷ Dermal MOE) + (1 ÷ Inhalation MOE)]

.Prallethrin Human Health Risk Assessment DP No. D420116

Page 43 of 70 Since the estimated residential turf post

- application exposure for residential turf/mower/golf course using def

ault TTR values for prallethrin is not minimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 10 times higher than the level of concern,

MOE = 900 compared to the LOC of 3000 ), future refinements of this post

- application exposure

for prallethrin may be necessary due to increased use of prallethrin or advances in EPA risk

assessments. Therefore, EPA is requiring the 40CFR TTR data requirement to facilitate any necessary exposure assessment refinement and to fur ther EPA’s general understanding of the availability of turf transferable pesticide residues.

6 .3 Residential Risk Estimates for Use in Aggregate Assessment

For the purpose of performing an aggregate assessment , HED selected only the most

conservative

, or worst case

, residential adult scenario to be included in the aggregate d estimates

, based on the lowest overall MOE (i.e., highest risk estimates). Although post

- application inhalation exposure from mosquito adulti cide applications via aer ial application for adults and children resulted in the most conservative exposure risk estimates, the inhalation POD was based on portal of entry effects. For the purpose of performing an aggregate assessment, exposure based on portal of entry effects sh ould not be combined with exposure from background dietary (food and water) exposure. Therefore, worst case post

- application dermal and incidental oral (children only) exposures resulting from use of prallethrin on turf were used to estimate

aggregate exp osure (i.e., these exposure estimates were added to background exposure from food

and water , Section 7 ). All scenarios resulted in MOEs greater than their respective LOC s and are

not of concern. The dermal risk estimates resulted in an MOE of 1,800 for a dults and 900 for

children. The incidental oral risk estimate for children resulted in an MOE of 3

, 600. Combined dermal and incidental oral risk estimates resulted in MOEs equal to or greater than 730. A summary of the residential exposures and risk est imates recommended for the aggregate assessment is provided in Table 6 .3.Prallethrin Human Health Risk Assessment DP No. D420116

Page 44 of 70 Table 6.3

. Residential Risk Estimates for Use in Aggregate Assessment

Residential Handler Residential Post

- application

Scenario Dose (mg/kg/day) 2 MOE 3 Dose (mg/kg/day) 4 or Air Concentration (mg/m 3 ) MOEs 5 Combined

MOE

Dermal Inhalation Total Dermal Inhalation Total Dermal Inhalation Oral Total Dermal Inhalation Oral

Adult T urf 0.00 38 0.00000 62 NA 8 ,000 97 0 NA 0.017 NA NA NA 1,800 NA NA NA

Child Turf NA 0.033 NA 0.0007 900 3,600 730

1 Shaded risk estimates should contribute to the residential exposure portion of the aggregate assessment.

2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed from Table 6 .1.

3 Residential Handler MOE = the MOEs associated with the highest doses identified in Table 6 .1.

4 Residential Post

- application Dose = the highest dose for each applicable lifestage of all scenarios assessed from Table 6.2.5.

5 Residential Post

- application MOE = th e MOEs associated with the highest doses identified in Table 6.2.5Prallethrin Human Health Risk Assessment DP No. D420116

Page 45 of 70 6.4 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency ’ s current practices, a quantitative post

- application inhalation exposure

assessment i s not being performed for prallethrin at this time primarily because of the low proposed us e rate (0.00072 lb ai/A). However, volatilization of pesticides can be a source of

post

- application inhalation exposure to individuals in close proximity to pesticide applications. The Agency sought expert advice and input on issues related to volatiliza tion of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010. The Agency is in the process of evaluating the SAP report and m ight , as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency ’ s risk assessments. If new policies or procedures are developed, the Agency m ight revisit the need for a quantitative post

- application inhalation exposure assessment for prallethrin

.

6.5 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, bu t, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom

, airblast ; and truck mounted ULV fogger for mosquito adulticide vector control ) employed for prallethrin. The Agency has be en working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop th e best spray drift management practices (see the Agency’s Spray Drift website for more information). The Agency is also taking means to qualitatively and qua nti tatively address spray drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift and chemical specific properties of pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures

that all uses for that pesticide will be considered concurrently.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and

risk estimate s from three major sources: food, drinking water, and re sidential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risk estimate s themselves can be aggregated. When aggregating exposures an d risks from various sources, HED considers both the route and duration of exposure.

7.1 Acute Aggregate Risk

A cute aggregate risk of exposure to prallethrin r esult s from exposure to residues in food and drinking water alone. The acute dietary exposure analysis included both food and drinking

water ; t herefore, acute aggregate risk estimates are equivalent to the acute dietary risk estimates

,Prallethrin Human Health Risk Assessment DP No. D420116

Page 46 of 70 as discussed in Section 5.4.3, above. Acute aggregate risk is not of concern for the general U.S. population or a ny population subgroup

.

7.2 Short

- Term Aggregate Risk Estimates

Short

- term aggregate risk assessments are needed for adults and children , and include exposure through the oral and dermal routes. The oral endpoint is based on neurotoxic effects seen in the chronic dog study in which the NOAEL was 2.5 mg/kg/day. The dermal endpoint i s based on

neurotoxic effects seen in the 21

- day rat dermal study in which the NOAEL was 30 mg/kg/day.

As the dietary, derma l

, and incidental oral PODs are all based on neurotoxic effects, the exposures from the se pathways are aggregated. For adults, post

- application dermal exposure estimates resulting from use on turf w ere combined with background exposure from food and

water

. For children, post

- application incidental oral (i.e., hand to mouth ) exposures were

combined with background exposure from food and water and then aggregated with dermal

exposure

.

As indicated previously, the HEC s used for inhalation risk assessment w ere based on portal of entry effects

, and should not be combined with dermal or oral exposures, which result in systemic effects.

The chronic dietary exposure estimates are the background exposure levels that were added directly to the residential derma l and incidental oral post

- application exposure estimates. Of the population subgroups that include adults, the U.S. population had the highest dietary exposure estimate. Risk to adult females was assessed by determining risk to Females 13

- 49 years old

. For the population subgroups comprised of child ren
, the most highly exposed subgroup was

C hildren 1

- 2 years old

.

As the levels of concern are identical, the 1/MOE approach is used for calculating the short

- term aggregate MOEs. The short

- term aggregate risk assessment s resulted in a n MOE of 62 0 for

children and an MOE of 1, 6 00 for adult females and the general U.S. population

. The adult and

child MOEs a re greater than their respective LOC s of 100 and 300

. As a result, the short

- term

ag gregate risk estimates are not of concern for the general U.S. population or any population subgroup. The short

- term aggregate risk estimates are given in Table 7.2 and t he equations used to determine the aggregate MOEs are given in Appendix D

.Prallethrin Human Health Risk Assessment DP No. D420116

Page 47 of 70 Table 7.2

. Short

- Term A ggregate Risk Calculations

1/MOE Approach

– All Levels of Concern are Identical

Population Short

- Term Scenario

LOC for Aggregate

Risk 1 Dietary

MOE MOE Oral

Residential Exposure MOE Dermal

Residential Exposure 2 MOE

Inhalation

Residential Exposure Aggregate

MOE (food, water, and residential)
U.S. Population 100 16,129 NA 1,7 77 NA 1, 6 00

Females 13

- 49 100 22,727 NA 1,7 77 NA 1, 6 00

Children 1

- 2 300 4,303 3, 648 8 9 8 NA 620

1. An UF of 100x was applied to adults to account for interspecies extrapolation (10x) and intraspecies variation (10x). No additional uncertainty factors/safety factors are required for adults.

An F QPA Safety Factor of 3 x was applied to children <6 years of age 2. Residential Exposure = Dermal exposure from treated turf (see table 6. 3 ).

8.0 Cumulative Exposure/Risk Characterization

The Agency is required to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. The Agency has determined that the pyrethroids and pyrethrins share a

comm on mechanism of toxicity ( http://www.regulations.gov ; EPA

- HQ

- OPP

- 2008

- 0489

- 0006). The members of this group share the ability to interact with voltage

- gated sodium channels ultimately leading to neurotoxicity. T he cumulative risk assessment for the pyrethroids/ pyrethrins was published on 11/9/2011 and is available at http://www.regulations.gov ; EPA

- HQ

OPP

- 2011

- 0746. No cumulative risks of concern were identified

, allo wing the Agency to consider new uses for pyrethroid s . For information regarding EPA’s efforts to evaluate the risk of exposure to this class of chemicals , refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids

- pyrethrins.html

.

Prallethrin is included in the pyrethroids/pyrethrins cumulative risk assessment. No dietary,

residential

, or aggregate risk estimates of concern have been identified in the single che mical assessment. In the cumulative assessment, residential exposure was the greatest contributor to the total exposure. An existing residential turf use for prallethrin was evaluated to determine the potential contribution it would have on the cumulativ e risk assessment. Although the turf use was considered the main contributor for residential exposure, the turf assessment indicated that exposure from turf would not impact the residential component of the cumulative risk estimate for pyrethroids. There fore, a s the proposed mosquito adulticide use contributes far less exposure than the registered turf uses

, there will be no impact on the residential component of the

cumulative risk estimates.

Dietary exposures make a minor contribution to the total pyre throid exposure. The dietary exposure assessment performed in support of the pyrethroid cumulative was much more highly refined than that performed for prallethrin. In addition, for the prallethrin risk assessment, the most sensitive apical endpoint in t he prallethrin database was selected to derive the POD. Further, the POD selected for prallethrin is specific to prallethrin, whereas the POD selected for the cumulative assessment was based on common mechanism of action data that are appropriatePrallethrin Human Health Risk Assessment DP No. D420116

Page 48 of 70 for all 20 pyrethroids included in the cumulative assessment. Dietary exposure to prallethrin residues resulting from the proposed mosquito adulticide use over all crops will contribute very little to the dietary exposure to prallethrin alone; therefore, the prop osed use will make an insignificant contribution to dietary risk to the pyrethroids as a whole.

9.0 Occupational Exposure/Risk Characterization

(M. Collantes, D407642, 8/9/2013 and D417631, 5/8/2014)

9.1 Occupational Handler Exposure/ Risk Estimates

No chemical

- specific data were submitted in support of this action. It HED ’s policy 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, i nclude studies from Pesticide Handler Exposure Database ( PHED ) 1.1

, the Agricultural Handler Exposure Task Force ( AHETF ) database or other registrant

- submitted occupational exposure studies

. Some of these data are proprietary (e.g., AHETF data), and subje ct 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.

Refer to Table 3.3 .a. for a complete use pattern description. The inputs for area treated were based on information in ExpoSAC Policy 9.1.

T his document provides the revised occupational HEDs for the proposed mosquito adulticide use of prallethrin. Only short

- term exposures are expected for occupational handlers from this use. As mentioned before, f

or prallethrin the selected endpoints and PODs for dermal and inhalation risk assessment are based on clinical signs related to neurotoxicity. However, the HECs used for inhalation risk assessment were calculated based on porta l of entry effects, which resulted in lower HEC values than those calculated for systemic effects. Therefore, the portal of entry HECs are protective of the systemic effects (including neurotoxicity) observed in the toxicology database. As a result, hand ler inhalation and dermal routes of exposure are not combined.

O ccupational handler scenarios for aerial and truck

- mounted fogger applications r esulted in dermal and inhalation MOEs greater than their respective LOCs, (dermal MOE ≥ 100 and

inhalation MOE ≥ 30) at baseline ( i.e., single layer clothing, no gloves or respirator) and are not

of concern. No additional PPE recommendations are needed on the labels. A summary of the occupational handler risk estimates is provided in Table 9.1.

The Multicide 2798 and 2922 labels specify the use of portable, motorized backpack equipment adjusted to deliver ULV particles of less than 100 microns. HED does not have unit exposure handler data for hand held fogging equipme nt. Therefore, chemical

- specific data are needed to support this scenario, and constitute a data gap for prallethrin. These data need to be submitted

under the Part 158 data requirements (Guideline 875.1400).Prallethrin Human Health Risk Assessment DP No. D420116

Page 49 of 70 Table 9 .1

. Occupational Handler Exposure Ris k Estimates for Prallethrin

Exposure Scenario Crop or Target Dermal Unit Exposure
(μg/lb ai) 1 Inhalation Unit

Exposure
(μg/lb ai) 1 Maximum

Application

Rate 2

(lb ai/A) Area

Treated Daily 3 Dermal Inhalation

Mitigation Level Mitigation Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7

Mixer/Loader

Liquid for Aerial Applications

Mosquito

C ontrol 220

(Baseline) 0.219

(Baseline) 0.00072 7

, 500 A 0.015 2

, 000 0.000015 810

Liquids for

Groundboom Applications (surrogate for Truck

Mounted Ground fogger) 3

, 000 A 0.006 5

, 100 0.000006 2

, 000

Applicator

Aerial Sprays

(ULV Wide Area)
Mosquito

C ontrol 2.08

( E ngineering C ontrols) 0.0049

( E ngineering

C ontrols)

0.00072 7

, 500 A .0.00014 210

, 000 0.0000003.3 60,000

Airblast Sprays
(surrogate for Truck

Mounted Ground

F ogger) 1770

(Baseline) 4.71

(Baseline) 3

, 000 A 0.048 630 0.000128 47

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline, PPE, En g. Controls.

2 Based on registered or proposed label

3 Exposure Science Advisory Council best professional judg e ment

. 4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handle d (A or gal/day) ÷ BW (80 kg).

5 Dermal MOE = Dermal NOAEL (30 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposures (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or ga l) × Area Treated or Amount Handled (A or gal/day) ÷ BW (80 kg). 7 Inhalation MOE = Inhalation HED (ventilation rate 8.3 L/m = 0.006 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).Prallethrin Human Health Risk Assessment DP No. D420116

Page 50 of 70 9 .2 Post

- application Risk

9.2.1 Dermal Post

- application Risk

There is potential for dermal post

- application exposure to workers entering fields under the airspace receiving treatment with prallethrin. For purposes of estimating post

- application dermal exposure, small vine climbing fruit was selected as the surrogat e crop because its respective highest transfer coefficients represent the worst case exposure scenarios to account for the mosquito control practices. This dermal post

- application exposure scenario resulted in MOEs significantly greater than the LOC (MOE ≥ 100) and are not of concern.

Table 9 .2. Occupational Post

- application Non

- Cancer Dermal Exposure and Risk Estimates for

Prallethrin.

Crop/Site Activities Transfer Coefficient (cm 2 /hr) DFR 1 Dermal Dose (mg/kg/day) 2 MOE 3

Small vine climbing

fruit girdling 19

, 300 0 .002 0 .004 7,700

1 DFR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.25 and D = 0.10 per day

2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hr/day ×]  BW (80 kg).

3 MOE = POD (30 mg/kg/day) / Daily Dermal Dose.

9.2.2 Inhalation Post

- application Risk

Based on the Agency ’ s current practices, a quantitative post

- application inhalation exposure

assessment i s not being performed for prallethrin at this time

. If new policies or procedures are put into place, the Agency m ight revisit the need for a quantitative occupational post

- application inhalation exposure assessment for prallethrin.

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 outdoors is likely to result in higher exposure than post

- application ex posure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.Prallethrin Human Health Risk Assessment DP No. D420116

Page 51 of 70 10.0 References

D289335, Prallethrin: Human Health Risk Assessment for the Pub lic Health Use of Mosquito

Adul ticides Containing Prallethrin, M. Collantes, G. Bangs, 11/21/2003

Uma Habiba , TXR# 005 6729 , Summary of Hazard and Science Policy Council (HASPOC) Meeting o n Ju l y 25 , 201 3 : Recommendations on Data Requirement for Immunotoxicity Studies for Synthetic Pyrethroid Pesticides , 8/12/2013

M. Perron, Prallethrin

- Summary of Toxicology Science Advisory Council (ToxSAC) Meeting of April 25, 2013, 7/30/2013

E. Scollon, A. Lowit, D381210, Re

- Evaluation of the FQPA Safety F actor for Pyrethroid

Pesticides , 6/27/2011

D411615, Prallethrin. Petition to Amend the Section 3 Registration to Include Food Use of the

Insect icide as a Mosquito Adulticide for the Fogging of Airspace Over and/or Near Agricultural Crop Fields. Summary of Analytical Chemistry and Residue Data , W. Drew, 7/24/2013

D 413314, Prallethrin Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action to Include Use of the

Insecticide as a Mosquito Adulticide for the Fogging Application Near Agricultural Crop Fields

, D. Dotson, 6 / 18 /201 4

M. Collantes

, D407642

, Prallethrin. Occupational and Residential Exposure Assessment for Proposed Label Amendments For Mosquito Adulticide Vector Control

, 8/9/2013

M. Collantes, D417631, Prallethrin. Addendum to the Occupational and Residential Exposure

Assessment for Proposed Label Amendments for Mosquito Adulticide Vector Control Use

, 5/8/2014

He Zhong , D407324, Prallethrin Drinking Water Assessment fo r the New U se of Two

Multicide ® Fogging Concentrates 2798 and 2922 as Adult Mosquitocides in All Agriculture Crop Areas, 2/4/2013

K. Whitby, D394576, Pyrethroid Cumulative Risk Assessment , 10/4/2011Prallethrin Human Health Risk Assessment DP No. D420116

Page 52 of 70 Appendices

Appendix A: Toxicology Profile

Appendix A.1. Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for prallethrin are in Table A

. 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A

. 1. Toxicology Requirements for Prallethrin

Guideline Number and Toxicity Study Required Satisfied

870.1100 Acute Oral Toxicity

................................ ............................... 870.1200 Acute Dermal Toxicity

................................ .......................... 870.1300 Acute Inhalation Toxicity

................................ ...................... 870.2400 Primary Eye Irritation

................................ ............................ 870.2500 Primary Dermal Irritation

................................ ...................... 870.2600 Dermal Sensitization

................................ .............................. yes
yes
yes
yes
yes
yes yes
yes
yes
yes
yes
yes

870.3100 Oral Sub

- chronic (Rodent)

................................ ..................... 870.3150 Oral Sub

- chronic (Non

- Rodent)

................................ ............. 870.3200 21

- Day Dermal

................................ ................................ ...... 870.3250 90

- Day Dermal

................................ ................................ ...... 870.3465 90/28

- Day Inhalation

................................ ............................. yes
yes
yes

no
yes yes
yes
yes

- yes

870.3700 Developmental Toxicity (Rodent)

................................ ........ 870.3700 Developmental Toxicity (Non

- rodent)

................................ ... 870.3800 Reproduction

................................ ................................ ......... yes
yes
yes yes
yes
yes

870.4100 Chronic Toxicity (Rodent)

................................ ..................... 870.4100 Chronic Toxicity (Non

- rodent)

................................ .............. 870.4200 Oncogenicity (Rat)

................................ ................................ . 870.4200 Oncogenicity (Mouse)

................................ ........................... 870.4300 Chronic/Oncogenicity

................................ ............................ yes
yes
yes
yes
yes yes
yes
yes
yes
yes

870.5100 Mutagenicity: Bacterial reverse mutation assay

..................... 870.5265 Mutagenicity: Reverse mutation assay

................................ ... 870.5300 Mutagenicity: In vitro Mammalian Cell Assay

...................... 870.5375 Mutagenicity: In vitro Mammalian Cell Assay

...................... 870.5395 Mutagenicity: In vivo Cytogenetics

................................ ....... 870.5550 Mutagenicity: Unscheduled DNA Synthesis

.......................... yes

no
yes
yes
yes

no
yes yes
yes
yes
yes
yes
yes
yes

870.6100 Acute Delayed Neurotoxicity (Hen)

................................ ...... 870.6100 90

- Day Neurotoxicity (Hen)

................................ .................. 870.6200 Acute Neurotoxicity Screening Battery (Rat)

........................ 870.6200 90 Day Neuro. Screening Battery (Rat)

................................ . 870.6300 Developmental Neurotoxicity

................................ ................ no

no
yes
yes
yes -

- yes
yes no*

870.7485 General Metabolism

................................ ............................... 870.7600 Dermal Penetration

................................ ................................ 870.7800 Immunotoxicity....................................................................... yes

no

yes yes

-

no a

*A developmental neurotoxicity (DNT) is not available for prallethrin. However, EPA has determined that DNTs for pyrethroid insecticides do not adequately characterize potential susceptibility of the young. In 2009, EPA stated that registrants who have not fulfilled requirements for the DNT may instead cite 6 previously submitted pyrethroid DNT studies, rather than conducting a full new study.

a The requirement for the immunotoxicity study was waived by HED’s Hazard and Science Policy Council (HASPOC).Prallethrin Human Health Risk Assessment DP No. D420116

Page 53 of 70 Appendix A.2 Toxicity Profile Table s

Table A.2

. a

. Acute Toxicity of Prallethrin Technical

GDLN Study Type MRID Results Tox Category

870.1100 Acute Oral 42030903 LD 50 : 640 mg/kg ( ♂ ) 460 mg/kg ( ♀ ) II

870.1200 Acute Dermal 41321812 LD 50 > 5000 mg/kg ( ♂ + ♀ ) IV

870.1300 Acute Inhalation 42030904

41321813 LC 50 : 288 mg/m 3 ( ♂ ) 333 mg/m 3 ( ♀ ) II

870.2400 Acute Eye Irritation 42030905

41321814 Minimally irritating III

870.2500 Acute Skin Irritation 42030905

41321814 Non

- irritating IV

870.2600 Skin Sensitization 41321815 Not a sensitizer N/A

Table A.2.b

. Subchronic, Chronic, and Other Toxicity

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 Subchronic

Feeding

- Rat MRID 41321816

42030906 0, 7.93, 24.0, 79.1, 230 mg/kg/day (♂); 0, 8.96, 26.1, 82.3, 244 mg/kg/day ( ♀ ) NOAEL: 79.1 (♂), 82.3 ( ♀ ); LOAEL: 230 (♂), 244
( ♀ ), based on alopecia (days 1

- 2), decreased body weights, hematological & clinical chemistry changes, hepatocellular hypertrophy, increas ed # small follicles in thyroid.

870.3100 Subchronic Feeding

- Mouse MRID 42077004

0, 39, 374, 808, 1839 mg/kg/day (♂); 0, 47, 444, 890, 1884 mg/kg/day ( ♀ ) NOAEL: 374 (♂), 444 ( ♀ ); LOAEL: 808 (♂), 890 ( ♀ ),

based on increases in liver weights, enlargement of hepatocytes, increases in cholesterol & creatinine

levels

.

870.3150 Subchronic Oral

(Capsules)

- Dog. MRID 41321817

42077001 0, 3, 10, 30 mg/kg/day NOAEL: 3; LOAEL: 10, based on tremors (9th week), decreased A/G ratio, increased cholesterol & phospholipids, enlarged livers

. 870.3200 21

- Day Dermal

Toxicity

- Rat MRID 42999101

0, 30, 150, 750 mg/kg/day NOAEL: 30; LOAEL: 150, based on clinical signs of toxicity (day 1) a nd decreases in body weight gain

.

870. 3465 28

- Day Inhalation

-

Rat MRID 42030907

41321818 0, 0.0010, 0.0044, 0.019 mg/L; 4 hr/day NOAEL: 0.0010 mg/L ; LOAEL: 0.0044 mg/L, based

on irregular respiration, decreased spontaneous activity, salivation

, incontinence, and nasal discharge.

870.3700 Oral Developmental

Toxicity

- Rat MRID 42030905

42077005 0, 10, 30, 100, 300 mg/kg/day Maternal NOAEL: 10; Maternal LOAEL: 30 , based on

tremors (GD 9), salivation (GD 10), and chromorrhinorrhea (GD 10 ) Developmental NOAEL: 300 (HDT).Prallethrin Human Health Risk Assessment DP No. D420116

Page 54 of 70 Table A.2.b

. Subchronic, Chronic, and Other Toxicity

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3700 Subcutaneous

Developmental Toxicity & Reproductive

Parameters

- Rat MRID 41321820

0, 12.5, 25.0, 50.0 mg/kg/day Maternal NOAEL: 25; Maternal LOAEL: 50 ,ba sed on tremors (GD 9) and exaggerated reflexes (GD 9). Developmental NOAEL: 50 (HDT). Offspring NOAEL: 50 (HDT).

870.3700 Oral

Developmental Toxicity

- Rabbit MRID 42030908

42899501 0, 10, 30, 100, 200 mg/kg/day Maternal NOAEL: 30; Maternal LOAEL: 100 , based

on tremors from range

- finding study: (GD 11). Developmental NOAEL: 200 (HDT).

870.3700 Subcutaneous

Developmental Toxicity

- Rabbit MRID 41321821

0, 1, 3, 10 mg/kg/day Maternal NOAEL: 10 (HDT); LOAEL: 30

, from

range

- finding study (mortality in nonpregnant animals). Developmental NOAEL: 10 (HDT).

870.3800 Reproductive

Toxicity

- rat MRID 42077006

42178501 0, 6, 31, 156, 329 mg/kg/day (♂); 0, 7, 37, 185, 375 mg/kg/day ( ♀ ) Parental/Offspring systemic NOAEL: 31 (♂), 37 ( ♀ ). LOAEL: 156 (♂), 185 ( ♀ ),based on decreased bodyweights, bodyweight gains, increased liver weights, microscopic findings in liver, kidney, thyroid, pituitary in parents; decreased p up bodyweights during

lactation

. Reproductive NOAEL: 329 (♂), 375 ( ♀ ) (HDT).

870.4100 Chronic Oral

(Capsule )

- Dog MRID 42077002

0, 2.5, 5, 10, 20 mg/kg/day NOAEL: 2.5

. LOAEL: 5 , based on clinical signs of neurotoxicity

- tremors (wk4), convulsions (wk19),

convulsion s , saliva tion, and rapid eye blinking (wk44)

. At 10: (trembling (wk 1), rapid eye blinking (wk 8), hunched posture (wk 12), panting (wk 11), and increased cholesterol, phospholipids, and AP were

seen

. 870.4300 Chronic

toxicity/Carcino

genicity

- Rat MRID 41321819

42061401 0, 3.3, 16.3, 83.5 mg/kg/day (♂); 0, 4.0, 19.1, 103.4 mg/kg/day ( ♀) NOAEL: 83.5 (♂) (HDT), 19.1 ( ♀ ); LOAEL: 103.4 ( ♀ ),based on decreases in bodyweight gains and histiocytic infiltration in liver

. No evidence of carcinogenicity

870.4200 Carcinogenicity

Mouse MRID 42077003

0, 13, 68, 347, 708 mg/kg/day (♂); 0, 16, 78, 384, 778 mg/kg/day ( ♀ ) NOAEL: 68 (♂), 778 ( ♀ ) (HDT); LOAEL: 347 (♂)

, based on kidney effects (increased weights, basophilic tubules, and amyloidosis)

.

870.5100 &

870.5265 Gene Mutation

-

Salmonella & E.

Coli MRID 41321822

Up to 5000 μg/plate with &

without metabolic activation Prallethrin did not induce any increases in reverse mutations in any of the bacterial strains tested.

870.5300 Forward Mutation

Assay in Chinese Hamster Lung

Fibroblasts MRID 41321823

Up to cytotoxic levels (5 x 10

-

5 M concentration without metabolic activation (S9), 3 x

10

- 4 M concentration with metabolic activation). Prallethrin did not induce a significant increase in forward mutations at the hypoxanthine

- guanine phosphoribos yl transferase (HGPRT) locus in Chinese hamster lung (V79) cells.

870.5375 In vitro

chromosomal aberration study in

Chinese Hamster Ovary (CHO K1)

cells MRID 42030910; 41321824

Up to cytotoxic levels (8 x 10

- 5

M without metabolic activation

and 3 x 10

- 4 M with metabolic

activation Prallethrin tested negatively at all doses without metabolic activation and tested positively at all doses with metabolic activation. It was not clearly dose

related but clastogenicity was seen at nontoxic and slightly toxic dos es.Prallethrin Human Health Risk Assessment DP No. D420116

Page 55 of 70 Table A.2.b

. Subchronic, Chronic, and Other Toxicity

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.5395 Micronucleus Assay MRID 42999901 48, 95 or 190 mg/kg Prallethrin had no effect on micronucleus formation in bone marrow cells up to a lethal dose. There was no bone marrow cytotoxicity.

870.5550 DNA Repair Assay MRID 42030912; 41321826 Single dose of 400 mg/kg Prallethrin tested negatively for inducing unscheduled DNA synthesis in rat hepatocytes.

870.6200 Acute neurotoxicity

- Rat MRID 43343301

0, 30, 100, 300 mg/kg bw NOAEL: 100; LOAEL: 300 , based on reduced motor activity in both sexes a nd tremors and death in

females

. 870.6200 Subchronic

neurotoxicity

– Rat MRID 43694501

0, 9.3, 74, 363 mg/kg/day (♂) 0, 11.1, 88, 420 mg/kg/day ( ♀ ) NOAEL: 74 (♂), 88 ( ♀ ); LOAEL: 363 (♂), 420 ( ♀ )

, based on decreases in bodyweight and food

consump tion. No indications of neuropathology, however, indications of higher arou sal rate in females

. Non

Guideline WIL Laboratories

Acute neurotoxicity comparison study

Rat MRID 48333801

0, 150, 250 or 400 mg/kg/day NOAEL: 150; LOAEL: 250 , based on clonic convulsions, flattened posture, splayed hind legs and/or slight to coarse tremors. Slightly to moderately impaired mobility, coarse tr emors, ataxia

, and impaired gait

. 870.7485 Metabolism

- Rat MRID 42030913; 41321827 Single labeled low or high dose or 14

- day repeated low dose followed by a labeled low dose. Cis and trans

isomers rapidly absorbed, distributed, metabolized and excreted under all dosing regimens. Most of radioactivity recovered in urine and feces within 48 hours for both sexes and isomers. Much greater proportion of trans isomer eliminated in urine than cis isomer because of easier cleavage of ester linkage of

trans

- isomer by esterase. Cis isomer: urinary excretion minor compared to fecal. Females exc reted greater proportion of radioactivity in urine than males for both isomers. Repeated dosing appears to induce metabolism (only 2% of parent found in feces). Low

bioaccumulation. No sex differentiation in tissue distribution. Higher residue levels in k idneys and liver (both isomers) and blood ( trans

- isomer). Major metabolic pathway: ester cleavage.

Single low oral or subcutaneous dose. No differences in absorption, distribution, metabolism or excretion in rats dosed orally or subcutaneously. Major

b iotransformation reactions of cis and trans

- isomers

include: o xidation at the methyls of the isobutenyl group in the acid moiety and at the C

- 1 or C

- 2 positions of the propynyl group in the alcohol moiety; cleavage of ester linkage; conjugation of hydroxy derivatives with glucuronic acid and sulfuric acid.

870.7800 Immunotoxicity

- Rat Study not required.Prallethrin Human Health Risk Assessment DP No. D420116

Page 56 of 70 Appendix A.3

. Toxicological Doses and Endpoints for Use in Human Risk Assessment

Hazard Identification and Endpoint Selection

Acute Reference Dose (aRfD)

– All Populations Including Infants and Children and Females Age 13

- 49

Study Selected : Chronic Dog

MRID # : 4 2077002 Dose and Endpoint for Risk Assessment : NOAEL is 2.5 mg/kg/day, based on neurotoxicity at

the LOAEL of 5 mg/kg/day

.

Uncertainty Factor : Adults and Children ≥ 6 years old: 100 x (1 x FQPA, 10 x interspecies extrapolation, 10 x intraspecies variability)

Acute RfD = = 0. 025 mg/kg /day

Children < 6 years old: 300 x (3 x FQPA, 10 x interspecies extrapolation, 10 x intraspecies variability)Prallethrin Human Health Risk Assessment DP No. D420116

Page 57 of 70 Comments about Study/Endpoint : The chronic dog study was selected based on neurotoxic effects observed at the LOAEL of 5 mg/kg/day. For acute dietary risk assessment, the endpoint used is commonly based on adverse effects attributed to a single dose exposure. However, for prallethrin, it is based on neurotoxic effects initially observed at 4 weeks. For pyrethroid chemicals, the pharmacokinetics indicate that the onset of neurotoxicity is rapid, with the time to peak effect for neurobehavioral effects occurring within hours. This is f ollowed by rapid

metabolism and elimination that does not result in accumulation. Therefore, repeated dosing is essentially a series of acute exposures

, and the effects seen in the dog study after 4 weeks are still appropriate for setting the aRfD.

In t he dog study, animals were given a bolus dose (capsule) of prallethrin once daily for 52 weeks. The dogs were observed daily for clinical signs and mortality. At 4 weeks, trembling

was observed in one dog at the LOAEL of 5 mg/kg/day. A lthough trembling was observed in only one dog on one occasion at the 5 mg/kg/day dose , there was a clear dose response for the

effect. In the same dog, convulsions and tremors were seen at week 19. C onvulsions, panting, salivation, rapid eye blinking, and muscle twitchin g were seen 5 hours after dosing prior to the

death of the dog during week 44. Based on the toxicity profile for pyrethroids

, clinical signs would be expected sooner than 4 weeks ; however, it could have been easily missed due to the timing of the post

- dos ing clinical examination, since prallethrin has a rapid time to peak effect

. At the next highest dose of 10 mg/kg/day, the incidence and frequency of trembling substantially increased

, with 5 dogs being affected on numerous occasions (over 40).

Additio nally, effects were seen much earlier (during 1 week). At 20 mg/kg/day, all dogs (8)

were affected with increased frequency

. At 10 and 20 mg/kg/day, t he trembling was also accompanied by dose

- related rapid eye blinking , hunched posture, salivation , and p anting

. Although the use of 5 mg/kg/day as a POD is a conservative approach, it is only 2 fold lower than where numerous clinical signs were observed (during week 1). The use of 5 mg /kg / day as

the POD is supportable when all of the information is conside red together (time to peak effect for prallethrin, dose response relationship at 5mg/kg/day, earlier onset of effects at 10 mg/kg/day)

. Therefore, the chronic dog study was selected to protect for potential neurotoxicity.

The developmental rat and ra bbit, acute neurotoxicity, and WIL studies were all considered for

risk assessment. However, higher NOAELs were determined in the acute rat (ACN and WIL) and developmental rat and rabbit studies, so they were not selected for risk assessment. The

WIL FOB study and the ACN study both used high vehicle volumes which likely impacted absorption characteristics of prallethrin

, thereby increasing the POD. Given what is known about pyrethroids ’ toxicokinetics/dynamics in general, and since there is no apparent increase in hazard from repeated/chronic exposures to prallethrin, the acute dietary exposure assessment is protective of chronic dietary exposures.

Incidental Oral Exposure (Short

- Term)

Study Selected : Chronic Dog Acute RfD = = 0.008 mg/kg /dayPrallethrin Human Health Risk Assessment DP No. D420116

Page 58 of 70 MRID # : 4 2077002 Dose and Endpoint for Risk Assessment : NOAEL is 2.5 mg/kg/day, based on neurotoxicity at

the LOAEL of 5 mg/kg/day Uncertainty Factor : Adults and Children < 6 years old: 300X (3 x FQPA, 10 x interspecies extrapolation, 10 x intraspecies variability)

Comments about Study/Endpoint: T he chronic dog study was selected based on neurotoxic

effects initially observed at week 4. Signs of neurotoxicity (trembling, convulsions, heavy panting, salivation, rapid eye blinking, and muscle twitching) were observed in 1 dog at the

LOAEL of 5 mg/kg/day. Additionally, neurotoxicity was seen within hours of dosing prior to

the death of th e animal during week 44 (see acute dietary). The NOAEL of 2.5 mg/kg/day is protective of potential offspring/developmental effects, as well as systemic effects, including neurotoxicity, observed in the toxicology database ( S ee acute dietary risk assessmen t ).

Dermal Exposure (Short

- Term)

Study Selected: 21

- Day Dermal Toxicity Study in Rats

MRID No.: 42030907

Dose and Endpoint for Risk Assessment: The LOAEL=150 mg/kg/day, based on clinical signs (trembling, fixation, abnormal gait, sensitivity to stimu li, twitching, and writhing spasms) and body weight changes. The NOAEL is 30 mg/kg/day.

Uncertainty Factor : Adults and Children ≥ 6 years old: 100X (1 x FQPA, 10 x interspecies extrapolation, 10 x intraspecies variability) Children < 6 years old: 300X (3 x FQPA, 10 x interspecies extrapolation, 10 x intraspecies variability)

Comments on Study/Endpoint/ UF s : The dermal rat study was selected based on neurotoxic

effects (trembling, fixation, abnormal gait, sensitivity to stimuli, twitching, and writhing spasms) and body weight changes observed at the LOAEL of 150 mg/kg/day. The NOAEL is 30 mg/kg/day. The POD and endpoint are considered appropriate for short

- term risk assessment since it is a route specific study, the endpoint is based on the effect of c oncern, and there is no evidence of developmental toxicity or increased susceptibility.

Inhalation Exposure (Short

- Term)

Study Selected: Inhalation Toxicity Study in Rats

MRID No.: 42030907

Dose and Endpoint for Risk Assessment: The LOAEL=0.0044mg/L, based on irregular respiration, decreased spontaneous activity, salivation, incontinence, and nasal discharge. The NOAEL is 0.001mg/L.Prallethrin Human Health Risk Assessment DP No. D420116

Page 59 of 70 Uncertainty Factor : Adults and Children ≥ 6 years old: 100X (1 x FQPA, 3 x interspecies extrapol ation, 10 x intraspecies variability) Children < 6 years old: 300 x (3 x FQPA, 3 x interspecies extrapolation, 10 x intraspecies variability)

.

Comments on Study/Endpoint/ UF s : In a 28

- day inhalation toxicity study in rats, nasal discharge, irregular respiratio n, decreased spontaneous activity, salivation, and incontinence

were seen at the LOA EL of 0.004 mg/L. The NOAEL is 0.001 mg/L. Human equivalent

concentrations (HECs) and doses were calculated and used for risk assessment (see values below and section A.4 for calculations). For inhalation risk assessment, both portal of entry and systemic HECs were calculated for prallethrin, based on the effects observed in the inhal ation study. The portal of entry HEC was significantly lower (15 x ) than the systemic HEC; therefore, the portal of entry HEC was used for risk assessment, and it is considered protective of the systemic effects observed in the inhalation study.

Human Equivalent concentrations (HECs) and Human Equivalent Doses (HEDs) for

Prallethrin HECs HEDs

Occupational ventilation rate= 8.3 L/min 0.00010 mg/L 0.006 mg/kg/day

ventilation rate= 16.7 L/min 0.012 mg/kg/day

ventilation rate= 29 L/min 0.020 mg/kg/day

Residential Handler/Outdoor Post

- application 0.00020 mg/L 0.006 mg/kg/day

Indoor Post

- application without

air ventilation 0.00014 mg/L N/A*

Indoor Post

- application with air

ventilation Adults: 0.00004 mg/L Children: 0.00003 mg/L N/A*

Bystander 0.00002 mg/L N/A* *MOEs calculated directly from HECs.

Based on the exposure profile, HED does not anticipate long

- term inhalation exposure for adults

or children.Prallethrin Human Health Risk Assessment DP No. D420116

Page 60 of 70 Appendix A

. 4. H uman E quivalent Analysis

The methods and dosimetry equations described in EPA’s reference concentration (RfC) guidance (1994) and OPP’s guidance on the application of the RfC methodology (2014) are suited for calculating HECs based on the inhalation toxicity N OAEL for use in MOE calculations. The regional

- deposited

- dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter [MMAD] and geometric standard deviation [  g ] of aerosols), can be used to estimate the different dose fractions deposited along the respiratory

trac t. The RDDR is also based on interspecies differences in ventilation and respiratory

- tract surface areas. Thus, the RDDR can be used to adjust an observed inhalation particulate exposure of an animal to the predicted inhalation exposure for a human.

RD DR for Prallethrin

In the 28

- day rat inhalation study, p rallethrin was administered to 10/sex Sprague Dawley rats, 4 hours/day, 5 days/week, as an aerosol with an average mass medium aerodynamic diameter (MMAD) of 3.77 and a geometric standard deviation (σ) of 1.30. The LOAEL of 0.004 4 mg/L

is based on nasal discharge, irregular respiration, decreased spontaneous activity, salivation , and

i ncontinence . The NOAEL is 0.001 mg/L.

Because the respired material used in the inhalation study is an aerosol, the RDDR ratio, which incorporates MMAD and σ, is appropriate to use for HEC calculation (table below). The “RDDR.exe” software program was used to obtain the RDDR value of 0.201 based on

extrathoracic portal of entry effects (POE) (Figure A.4. 1). The RDDR selected and the resulting HEC was significantly lower than the systemic RDDR and resulting HEC. Therefore, the POE HEC is protective of systemic effects. The inputs for the program are: MMAD=3.77; σ=1.30; body weight for Sprague Dawley Rats : 236g; Standard human body weight information : 70 kg.Prallethrin Human Health Risk Assessment DP No. D420116

Page 61 of 70 Figure A.4. 1. Regional Deposited Dose Ratios (RDDR) for Prallethrin

Calculation of the Human Equivalent Concentration (HEC) and Human Equivalent Dose

Human Equivalent Concentrations

Occupational HEC (Handler ) = 0.00010 mg/L POD (0.001mg/L) x RDDR (0.201) x daily duration (4hr/8hr) x weekly duration (5 days/5days) Residential HEC (Handler) = 0.0002 mg/L POD (0.001mg/L) x RDDR (0.201) x daily duration (4hr/4hr) x weekly duration (5 days/5days) Adult Residential HEC (Indoor post

- application with ventilation) = 0.00004 mg/L POD (0.001mg/L) x RDDR (0.201) x daily duration (4hr/16hr) x weekly duration (5days/7days) Children Residential HEC (Indoor post

- application with ventilation) = 0.0 0003 mg/L POD (0.001mg/L) x RDDR (0.201) x daily duration (4hr/18hr) x weekly duration (5days/7days) Residential HEC (Indoor

- without ventilation) = 0.00014 mg/L POD (0.001mg/L) x RDDR (0.201) x daily duration ( not applicable ) x weekly duration (5hr/7hr)

Re sidential HEC ( Bystander ) = 0.00002 mg/L POD (0.001mg/L) x RDDR (0.201) x daily duration ( 4hr/24hr ) x weekly duration (5days/7days)

Human Equivalent Doses

Using the calculated HECs

, a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows: dose (systemic HEC value) mg/L x A (absorption) x CF (conversion factor) L/hr/kg) x D (duration

- hours) x AF (activity factor) = mg/kg/day.Prallethrin Human Health Risk Assessment DP No. D420116

Page 62 of 70 Human Equiva lent Doses (HEDs)

Occupational

Scenarios with ventilation rates of 8.3 L/min: HED= 0.00010mg/L x 1 x 11.8 x 8 x 0.6 = 0.006 mg/kg/day

Scenarios with ventilation rates of 16.7 L/min HED=0.00010mg/L x 1 x 11.8 x 8 x 1.2 = 0.012 mg/kg/day

Scenarios with ventilation rates of 29 L/min HED= 0.00010mg/L x 1 x 11.8 x 8 x 2.1 = 0.020 mg/kg/day Residential (Handler and Outdoor Post

- application) HED =0.00020 mg/L x 1 x 11.8 x 2 x 1.2 = 0.006 mg/kg/day

For residential indoor post

- application and b ystander exposure, margins of exposure were calculated directly from the HECs

.Prallethrin Human Health Risk Assessment DP No. D420116

Page 63 of 70 Appendix A

. 5. Pyrethroid Cumulative Screen

The Agency is required to consider the cumulative risks of chemicals sharing a common
mechanism of toxicity. The Agency has determined that the pyrethroids and pyrethrins share a
common mechanism group (http://www.regulations.gov; EPA

- HQ

- OPP

- 2008

- 0489

- 0006). The
members of this group share the ability to interact with voltage

- gated sodium channels ultimately
leading to neuroto xicity. The cumulative risk assessment (CRA) for the pyrethroids/pyrethrins
was published on Nov. 9, 2011 (USEPA, 2011a) and is available at http://www.regulations.gov;

EPA

- HQ

- OPP

- 2011

- 0746. No cumulative risk estimates of concern were identified

, allowi ng the Agency to consider new uses for pyrethroid actives. For information regarding EPA’s efforts
to evaluate the risk of exposure to pyrethroids, refer to
http://www.ep a.gov/oppsrrd1/reevaluation/pyrethroids

- pyrethrins.html

.

A lthough the active ingredient, prallethrin

, was included in the initial common mechanism grouping (CMG) science policy document from 2008 , the registered use on turf was not assessed

in the Novembe r 2011 pyrethroid cumulative risk assessment. However, the Agency has

determined

, based on its chemical structure and based on the observation of neurobehavioral effects consistent with Type II pyrethroids, that prallethrin should be included in the CMG f or this class of pesticides. As such, the Agency must consider the potential contribution of prallethrin to the cumulative risk assessment. As part of the assessment for the registered prallethrin turf uses, the Agency has performed an analysis to determ ine if the use will significantly contribute to or change the overall findings in the pyrethroid CRA.

Cumulative Hazard Assessment: Relative Potency Estimation for Prallethrin

The 2011 pyrethroid CRA relies on the relative potency factor (RPF) approach using administered dose as the metric for quantifying chemical potency. In the RPF approach, the toxic potency of each chemical in the common assessment group (CAG) is determined. One

member of the CAG is selected as the index chemical that is used as t he point of reference for standardizing neurobehavioral potency of the other members of the CAG. In order to develop such potency estimates, EPA prefers to use a uniform measure of toxicity. In other words, the Agency prefers to use data that are from the same endpoint and same duration and to the extent possible any other factors that a ffect potency (e.g., time to peak effect, sex, etc). In the pyrethroid CRA, the Agency used the two special WIL Functional Observational Battery (FOB) studies for estimating relative potency. T hese studies were selected because they examined many behaviors, including key ones for evaluating neurotoxicity specific to pyrethroids. Specifically, the studies looked at a number of key parameters that are directly

r elevant to the Type I (e.g., hyperthermia tremors and clonus) and Type II (e.g., hypothermia, salivation, and mobility) syndromes. In addition to the WIL FOB studies, there is another study (Wolansky et al, 2006) that provides a high quality data set for estimating relative potency. Whereas the WIL FOB studies focus on endpoints specific to pyrethroid toxicity syndromes, the Wolansky study measured motor activity. Motor activity is considered an apical endpoint

because it measures alterations in the acti vity level of an intact rat. Although the Wolansky study provides a potential data source for a uniform measure of potency, it was not utilized in thePrallethrin Human Health Risk Assessment DP No. D420116

Page 64 of 70 CRA because of the lack of specific relevance to the common mechanism of action for the pyrethroids.

I n the CRA, deltamethrin was used as the index chemical. The RPFs used for the CAG in the pyrethroid screening level cumulative were determined by dividing the chemical

- specific BMD20 by the BMD20 of the index chemical, deltamethrin. A RPF of 0.10 was use d to quantify comparative exposures from the registered prallethrin turf use.

Cumulative Exposure and Risk Issues

In order to determine if the registered pr allethrin turf use will significantly contribute to or change the overall findings in the pyrethroid CRA the Agency performed a quantitative exposure

and risk assessment. This assessment used the prallethrin RPF as well as the same exposure algorithms and inputs that were used in the 2011 pyrethroid CRA.

MOEs calculated and presented in Appendix Table A

. 5.a were compared with the MOEs currently driving turf exposures and risks in Table 6.4.7a from the 2011 pyrethroid CRA

. The routes of exposure include handler and post

- ap plication dermal for adults, and post

- application dermal and incidental oral for children. Quantitative post

- application inhalation exposures from

the turf use are not included in the CRA because this is not a significant route of exposure.

Handler derma l exposures and risks resulting from use of a pyrethroid on turf are currently driven by the cy fluthrin turf use pattern (i.e., mixing/loading/applying emulsifiable concentrate using hose

- end sprayer) with an MOE of 9

, 2 00, which is lower than the MOE of 54 0,000 estimated for adult dermal exposure from the registered prallethrin turf (i.e., mixing/loading/ applying microencapsulated using hose

- end sprayer)

. D ermal post

- application exposure and risk

estimates for adult s and children < 6 year s old are currently driven by the cy fluthrin turf use pattern with adult and children < 6 year s old dermal MOEs of 4,5 00 and 3,0 00, respectively, both

of which are lower than the estimated MOEs for prallethrin ( 220 ,000 and 1 50 ,000, respectively).

For children < 6 y ear s old, hand

- to

- mouth post

- application exposure and risk estimates are currently driven by the cy fluthrin turf pattern with an MOE of 2 1 ,000, which is less than the

estimated MOE for prallethrin ( 1,100,000 ). A summary of these MOEs is presented in Appen dix

Table A

. 5.a while the detailed calculations are presented in Appendix Table A

. 5.b . In all cases,

the estimated prallethrin MOEs using the RPF method were higher (i.e., less of a risk concern) than those used in the 2011 pyrethroid CRA. Thus

, the Agen cy has determined that the proposed prallethrin turf use will not significantly contribute to or change the overall findings in the 2011 pyrethroid CRA.Prallethrin Human Health Risk Assessment DP No. D420116

Page 65 of 70 Table A.5.a. Prallethrin Screening Level “Cumulative” Combined Exposure and Risk from the

Registered Turf Use

Chemical Exposure

Scenario Route of

Exposure Population MOE Combined

MOE

Registered

Use Prallethrin Turf/Lawn Handler Dermal

– Hose

- end Sprayer Adult 520,000 NA

Post

- Application

Dermal 220,000 NA

Post

- Application

Dermal Children

(< 6 years old) 150,000
130,000 Post

- Application

Incidental Oral 1,100,000

CRA Cyfluthrin Turf/Lawn Handler Dermal

– Hose

- end Sprayer Adult 9,200 NA

Post

- Application

Dermal 4,500 NA

Post

- Application

Dermal Children

(< 6 years old) 3,000
2,700 Post

- Application

Incidental Oral 21,000Prallethrin Human Health Risk Assessment DP No. D420116

Page 66 of 70 Table A.5.b. Prallethrin Screening Level “Cumulative” MOEs

Turf Handler Exposure

Exposure

Scenario Application

Rate ( lb ai/A ) Amount

Treated Daily (A) Baseline

Dermal

Unit Exposure (mg/lb ai) Baseline

Inhalation

Unit Exposure (mg/lb ai) Baseline Dermal

Exposure Baseline

Inhalation Exposure Baseline

Dermal Dose Adjusted

Baseline

Dermal Dose (mg/kg/day) a Adjusted

Baseline

Dermal

MOE b Baseline

Inhalation

Dose Adjusted

Baseline

Inhalation

Dose (mg/kg/day) Baseline

Inhalation MOE Combined

MOE

Turf Dermal (adults) 0.045 0.5 13.4 0.022 0.30 0.0005 0.0002 0.00002 520,000 7.07E

- 6 6.84E

- 7 15,000,000 500,000

Turf Post

- application Hand

- to

- Mouth Exposure

Exposure

Scenario Fai hands 1

- 2 yr old

Dermal Exposure SA H

(cm 2 ) HR t

(mg/cm 2 ) F M

Exposure

Time (hours/day) N_Replen SE Freq_HtM

BW Average Daily Dose (mg/kg/day) Adjusted Dose

(mg/kg/day) a Adjusted

MOE b Fraction of Hand

Surface Area

Mouthed / Event Number of replenishment intervals per hr (intervals/hr) Extraction by

Saliva H

- t

- M

events per
hour

Hand to

Mouth (1 < 2 year olds) 0.03 4 0. 168 150 1.834 E

- 0 5 0.13 0.9 4 0.5 13.9 11.4 1.0E

- 4 9.99E

- 6 1,100,00 0

Turf Post

- application Dermal Exposure

Exposure

Scenario Application Rate

( lb ai/ A ) Body Weight (kg) Exposure Time

(hours ) Conversion

Factor (mg/ug) TTR (ug/cm 2 ) c Transfer Coefficient (cm 2 /hr) Absorbed Dermal Dose

(mg/kg/day) Adjusted Dose

(mg/kg/da y) a Adjusted

MOE b

Turf Dermal (< 6 year olds) 0.045 11.4 0.9

0.001 0.0108 37,000 0.00071 6.86E

- 5 150,000

Turf Dermal (adults) 71.8 1.1 130,000 0.00048 4.67E

- 5 220,000

a

. Doses were adjusted based on an estimated prallethrin RPF of 0.1 0

. b

. MOEs were calculated by comparing the adjusted dose to the oral BMD 20 from the WIL FOB data for the index chemical, deltamethrin (14.5 mg/kg/day)

. c. Cyfluthrin TTR was used for all chemicals that did not have TTR data since cyfluthrin had the highest v alue.Prallethrin Human Health Risk Assessment DP No. D420116

Page 67 of 70 Appendix B

. Physical/Chemical Properties

Table B. 1. Physicochemical Properties of Prallethrin

Parameter Value Reference
Melting point/range

- 25 oC (Liquid at room temperature)

. Sumitomo Chemical MSDS (23 May 2010) Boiling point (at 760 mm Hg) 313.5 oC WHO Specification 743/TC (November 2004) pH ( at 20°C) 3.22 Sumitomo Chemical MSDS (23 May 2010) Density ( at 20oC ) 1.03 g/mL Water solubility (mg/L at 25oC, pH

5.5

- 5.6) 8.03 WHO Specification 743/TC (November 2004) Solvent solubility (20

- 25°C) Miscible with most organic solvents. Sumitomo Chemical MSDS (23 May 2010) Vapor pressure (at 2 5 oC) 4.2 x 10

- 3 Pa ( 3.2 x 10

- 5 mm Hg) Petition # 2F8090 Dissociation constant, pK

a Not applicable (does not dissociate). WHO Specification 743/TC (November 2004) Octanol/water partition coefficient, Log K OW (at 25°C, pH 5.6

- 5.9) 4.49

UV/visible absorption spectrum Not available.Prallethrin Human Health Risk Assessment DP No. D420116

Page 68 of 70 Appendix C

. Review of Human Research

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 are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies

, that 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 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/ science/post

- app

- exposure

- data.html

.Prallethrin Human Health Risk Assessment DP No. D420116

Page 69 of 70 Appendix D. Aggregate Risk Calculations

The following equations were used to calculate the risk estimates provided in Table 7.2 of the

Short

- Term Aggregate Risk Estimates Section

MOE = NOAEL/Exposure

MOE = 1 ÷ [1/MOE oral + 1/MOE dermal ]

Short

- term Aggregate Risk for Children <6

F or the population subgroups comprised of children, the most highly exposed subgroup was

Children 1

- 2.

The incidental oral (hand

- to

- mouth) exposure for Children 1

- 2 is added to the background dietary exposure to arrive at the total oral exposure estimate.

Dietary Exposure + Incidental Oral Exposure = 0.000581 + 0.000685 = 0.001266 mg/kg/day

MOE oral = Oral NOAEL/Oral Exposure = 2.5/0.001266 = 1975

MOE dermal = 897.65

Total Aggreg ate MOE = 1 ÷ [1/MOE oral + 1/MOE dermal ]

Total Aggregate MOE = 1 ÷ [1/1,975 + 1/897.65]

Total Aggregate MOE for Children 1

- 2 = 620

For adults, the only oral exposure is the background dietary exposure from food and drinking water. This exposure is combined with post

- application dermal exposure. The same equations

used above are used to determine the adult total MOE.

MOE = 1 ÷ [1/MOE dietary + 1/MOE dermal ]

MOE dietary = NOAEL/Dietary ExposurePrallethrin Human Health Risk Assessment DP No. D420116

Page 70 of 70 Short

- term Aggregate Risk for t he general U.S. population :

MOE dietary = NOAEL/Dietary Exposure = 2.5/0.000155 = 16,129

MOE dermal = 1,777

Total Aggregate MOE = 1 ÷ [1/MOE dietary + 1/MOE dermal ]

Total Aggregate MOE = 1 ÷ [1/1,629 + 1/1,777]

Total Aggregate MOE for the General U.S. Population = 1, 6 0 0

Short

- term Aggregate Risk f or Females 13

- 49 :

MOE dietary = NOAEL/Dietary Exposure = 2.5/0.000110 = 22,727

MOE dermal = 1,777

Total Aggregate MOE = 1 ÷ [1/MOE dietary + 1/MOE dermal ]

Total Aggregate MOE = 1 ÷ [1/22,727 + 1/1777]

Total Aggregate MOE for Females 13

- 49 = 1, 600