UNITED STATES ENVIRONME N TAL PROTECT I ON AGENCY

WASHINGTON

, D

. C

. 2 0460

MEMORANDUM

DATE: 10 / 10/2014 OFF I CE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

SUBJECT: Deltamethrin. Human H ealth Risk Assessment for the Proposed Use of

Del tamethr in Without U.S

. Registration on Finfish

PC Code: 097805

Decision No.: 478936

Petition No.: 3£8178 DP Barcode: 0413048 Registration No.: NA Regulatory Action: Tolerance Without U.S

.

Risk Assessment Type: Sing l e Chem i cal Aggregate Case No.: 7414 Registration

TXRNo.: NA

MRJDNo.:NA CAS No.: 52918-63-5

40 CFR: §180.435

FROM: Doug l as A. Dotson

, Ph

. D

. , Chemist 

## j}.**/)~** Jaime D'Agostino, Ph

. D.

,

### To**xico ogist** **}t~ d**  

## t

- . Margari ta Collantes, M.S., .J?iolog ist 

## '7/l**{~** William Drew

, Chemist

### ~~~**:~** .... ., Risk Assessment Branch 

## ff" v r; V"'C? V"'V

Health Effec ts Division (7509P)**~**

THROUGH: Karl y n Middleton, Toxicologist

,

### ~ Michael Dohert y, Ph.D.

, Sen i or Che ist**~"" }**  Zai da Figueroa, M.S., Industrial Hygienist · Christina Swartz, Branch Chie

Risk Assessment Branch II

Health Effects Division (7509P)

P.V. Shah, Ph.D., Toxico lo ist

Je ff Daw son, Chem i st

HED Risk Assessment Revi

TO : O l ga Odiott!Mark Suarez, PM Team 13

Insecticide Branch (IB) Registration Division (7505P)Deltamethrin Human He a lth Ri s k Assessment DP No. D413048



### The Registration Division (RD) 

### requested that the Heal th Effec ts Division (HED) conduct a

h uman health risk assessment for th e proposed tol erance, without U.S. registration, for res idues

of the in secticide deltamethrin on finfish.

This document contains the human health ri s k assessment associated with thi s action and incorporates updated en dpoints for risk assessment as well as t he most recent data and assumptions for conducting residential and occupational exposure assessments. No risks of

concern were identified.

Page 2 of64Deltamethrin Human Health Risk Assessment DP No. D413048

Page 3 of 64 Table of Contents

1.0 Executive Summary

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

2.0 HED Recommendations

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

2. 1 Data Deficiencies/Conditions of Registration

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

2.2 Tolerance Considerations

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

2.2.1 Enforcement Analytical Method

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

2.2.2 International Harmonization

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

2.2.3 Recommended Tolerances

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

2.2.4 Revisions to Petitioned

- For Tolerances

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

2.3 Label Recommendations

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

3.0 Introduction

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

3.1 Chemical Identity

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

3.2 Physical/Chemical Characteristics

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

3.3 Pesticide Use Pattern

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

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 4

4.2 Toxicological Profile

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

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

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

4. 3 .1 Pharmacokinetics

................................ ................................ ................................ ...... 1 7

4.3.2 Pharmacodynamics

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

4.3.3 Critical Duration of Exposure

................................ ................................ ................... 20

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 2

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

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

4.4.4 Residual Uncertainty in the Exposure Database

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

4.5 Toxicity Endpoint and Point of Departure Selections

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

4.5.1 Dose

- Response and Hazard Assessment

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

4.5.2 Recommendation for Combining Rout es of Exposure for Risk Assessment

........... 2 6

4.5.3 Cancer Classification and Risk Assessment Recommendation

................................ 2 6

4.5.4 Summary of Points of Departure and Toxicity Endpoints

................................ ....... 2 7

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ........... 27

5.1 Metabolite/Degradate Residue Profile

................................ ................................ .......... 27

5.1.1 Summary of Plant and Animal Metabolism Studies

................................ ................. 28

5.1.2 Summary of Environmental Degradation

................................ ................................ . 28

5.1.3 Comparison of Metabolic Pathways

................................ ................................ ......... 29

5.1.4 Residues of Concern Summary and Rationale

................................ .......................... 29

5.2 Food Residue Profile

................................ ................................ ................................ ..... 29

5.3 Water Residue Profile

................................ ................................ ................................ ... 30

5.4 Dietary Risk Assessment

................................ ................................ .............................. 30

5.4.1 Description of Residue Data Used in Dietary Assessment

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

5.4.2 Percent Crop Treated Used in Dietary Assessment

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

5.4.3 Acute Dietary Risk Assessment

................................ ................................ ................ 32Deltamethrin Human Health Risk Assessment DP No. D413048

Page 4 of 64 5.4.4 Chronic Dietary Exposure Assessment

................................ ................................ ..... 3 3

5.4.5 Summary Table

................................ ................................ ................................ ......... 3 3

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ ... 3 3

6.1 Residential Handler Exposure / Risk Estimates for Registered Uses

............................. 3 3

6.2 Residential Post

- Application Exposure /Risk Estimates for Registered Uses

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

6.3 Residential Risk Estimates for Use in Aggregate Assessment

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

6.4 Residential Bystander Post

- Application Inhalation Exposure

................................ ...... 40

6. 5 Spray Drift

................................ ................................ ................................ .................... 4 0

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ...... 40

7.1 Acute Aggregate Risk

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

7.2 Short

- Term Aggregate Risk Estimates

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

8.0 Cumulative Exposu re/Risk Characterization

................................ ................................ .... 41

9.0 Occupational Exposure/Risk Characterization

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

10.0 References

................................ ................................ ................................ ......................... 43 Appendix A. Toxicology Profile

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

A.1 Toxicology Data Requirements

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

A.2 Toxicity Profile Table s

................................ ................................ ................................ . 48

A.3 Toxicological Doses and Endpoint s for Use in Human Risk Assessments

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

A.4 Pyrethroid Cumulative Screen

................................ ................................ ...................... 58 Appendix B . Physical/Chemical Properties

................................ ................................ ................. 6 3 Appendix C . Review of Human Research

................................ ................................ ................... 6 4Deltamethrin Human Health Risk Assessment DP No. D413048

Page 5 of 64 1.0 Executive Summary

Deltamethrin (1R,3R)

- R

- cyano(3

- phenoxyphenyl)methyl 3

- (2,2

- dibromoethenyl)

- 2,2

- dimethylcyclopropanecarboxylate) is a broad

- spectrum pyrethroid insecticide that is registered in

the U

. S

. for direct application to a wide variety of food/feed crops, for use on stored grains, and for use in food/feed handling e stablishments (FHEs)

. Numerous formulations of deltamethrin are also registered for use in commercial and residential outdoor and indoor sites, as well as in paint additive and pet products. Pharmaq AS proposed a tolerance without U.S. registration for

r esidues of deltamethrin in finfish , resulting from its use to control fish lice in farmed fish

. T here are no new residential uses associated with this regulatory action ; however, a revised assessment of the registered residential uses is provided for the purpose of updating the aggregate risk assessment.

Pyrethroids have historically been classified into two groups, Type I and Type II, based on chemical structure and toxicological effects. Pyrethroids disrupt the voltage

- gated sodium

channels in the nerv ous system, resulting in neurotoxicity. Deltamethrin is a Type II pyrethroid

. Neurotoxicity was observed throughout the database and c linical signs characteristic of Type II pyrethroids, such as increased salivation, altered mobility /gait , and tremors

, we re the most

common effects observed. Other observed neurotoxic effects included increased sensitivity to external stimuli, abnormal vocalization, and decreased fore

- and hind

- limb grip strength.

T he database of deltamethrin experimental toxicology studies is largely complete and provides a

robust characterization profile for children 6 years old and older

, as well as for adults. In addition to the standard guideline studies, numerous studies from the scientific literature that describe the pharmacodynamic and pharmacokinetic profile of the pyrethroids in general have

been considered in this assessment. Many of these studies were conducted with deltamethrin. A

28

- or 90

- day inhalation study was not available

, but the requi rement for this study was waived by HED’s Hazard and Science Policy Council (HASPOC)

. In addition, there are ongoing efforts to develop data in juvenile rats to gain more i nform ation concerning the potential sensitivity of infants and young children to py rethroids as a class. Despite the missing studies and the ongoing scientific efforts, HED is confident that it has chosen endpoints, points of departure

, and uncertainty factors that are protective for all populations, including infants and children

.

Del tamethrin is rapidly absorbed following an oral dose , and effects are typically observed within two to five hours after dosing

. For pyrethroids, as a class, the combination of rapid absorption, metabolism, and elimination precludes accumulation and increa sed potency following repeated dosing. This is also true of deltamethrin. No observed adverse effect levels ( NOAELs ) for the acute and chronic studies are similar , and the acute endpoint is protective of the endpoints from repeat dosing studies. Thus, f or purposes of endpoint selection and exposure assessment, only single

- day risk assessments need to be conducted.

There were no indications of fetal toxicity in any of the guideline studies. Evidence of increased juvenile qualitative sensitivity was obse rved in the developmental neurotoxicity and 2

- generation reproduction studies. The se observations are consistent with the findings of juvenile sensitivity

in the literature for deltamethrin

. However, the observations of increased sensitivity were at

dose s that were considered to be relatively high (i.e., near lethal doses)

, whereas at doses near theDeltamethrin Human Health Risk Assessment DP No. D413048

Page 6 of 64 point of departure

, no effects on parental animals or offspring were observed in either the developmental neurotoxicity ( DNT ) or 2

- generation reproduction study and

, therefore

, there is no susceptibility at these doses. T he Agency has retain ed a 3 X uncertainty factor to protect for

exposures o f child ren <6 years of age based on increased quantitative susceptibility seen in

stud ies on pyrethroid pharmacokinetics (primarily conducted with deltamethrin) and the increased quantitative juvenile susce ptibility observed in high dose guideline and literature

studies with deltamethrin and other pyrethroids.

The Wolansky et al

. acute ora l study (2006), in which decrease d motor activity was observed, provides the most robust data set for extrapolating risk from exposure to deltamethrin . The dose used for risk assessment was determined using a benchmark dose (BMD) analysis using 1

standard deviation from the control group as the benchmark response (BMR) as suggested for continuous endpoints in the Agency’s BMD guidance (USEPA 2012). The Wolansky acute study, endpoint, and dose were used for all dietary (acute), non

- occupational (incidental oral and inhalation), and occupational exposure (inhalation) scenarios because it was the most robust data set for extrapolating risk from deltamethrin

, and the re is a lack of increased hazard from repeated/chronic exposure to deltamethrin . A dermal risk assessment was not conducted based

on the lack of effects in a 21

- day dermal study and low potential for dermal absorption for deltamethrin. These findings are consistent with the toxicology profile of many pyrethroids.

HED has characterized deltameth rin as “not likely to be carcinogenic to humans” in accordance with the EPA Final Guidance for Carcinogen Risk Assessment (3/29/ 20 05).

Adequate residue data are available for the purpose of evaluating risk from the u se of

deltam ethrin on finfish. Following treatment of finfish to deltamethrin at the maximum

allowable concentration, residues were below the level of quantification ( LOQ ) of 0.01 ppm in all samples of finfish muscle with skin and finfish liver.

The toxicological kinetic data for delta methrin demonstrate that it is not appropriate to assess chronic dietary risk for this insecticide because of a lack of increased toxicity with increased duration of exposure . However, the residential use sites for deltam ethrin and the patterns for

exposu re require estimates of chronic dietary exposure (i.e. background from food and water) 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 acute risk estimates are below HED’s level of concern for all population subgroups, including those comprised of infants and children. As percent crop treated estimates we re used for some commodities, the risk estimates are being reported at the 99.9 th percentile of exposure. A lthough a chronic dietary endpoint wa s not required for deltamethrin

, a chronic dietary exposure assessment was performed to provide background expo sure for aggregation with residential exposure.

There are no new proposed residential uses associated with this action. However, this document includes a revised handler and post

- application exposure assessment for existing residential use scenarios (i .e., indoor, outdoor, pet collar , and paint additive) to reflect updates to HED’s 2012Deltamethrin Human Health Risk Assessment DP No. D413048

Page 7 of 64 Residential SOPs

, policy changes for body weight assumptions

, updated inhalation and incidental oral toxicological endpoints and uncertainty factors (UFs)

. These use sc enarios are representative of all residential scenarios associated with deltamethrin products.

All the residential handler scenarios resulted in inhalation risk estimates that are not of concern

, i.e., the margins of exposure ( MOEs ) are greater than or equal to the level of concern (LOC) of

100 (in this case ). Post

- application inhalation exposure for adults and children is anticipated to be negligible for the representative residential registered uses; therefore, a quantitative post

application inhalation exposure assessment was not performed.

All the representative indoor/outdoor and pet collar residential use scenarios resulted in incidental oral (hand

- to

- mouth) post

- application risk estimates for children ranging from an

MOE of 6 30 to an MOE of 400,000 and are not of concern

, as all MOEs were greater than the

incidental oral LOC of 300

.

The acute aggregate risk estimates are equivalent to the corresponding dietary (food plus water) risk estimates, which are not of concern. The short

- term aggregate risk assessment is based on residues in background dietary exposure (food + drinking water) a nd residues resulting from residential exposure. For adults, residential exposure consist s of post

- application inhalation exposure and for children, residential exposure consist s of incidental oral ( hand

- to

- mouth )

transfer. The short

- term aggregate ris k estimates are not of concern for adults or children

.

Deltamethrin was included in a cumulative risk assessment for pyrethrins and pyrethroids (CRA, D394576, K. Whitby, 10/4/2011). Typically, proposed new residential uses of pyrethroid

chemicals are eva luated to determine whether they would contribute significantly to or change the overall findings of the CRA.

Since the 2011 CRA, no new residential uses have been proposed for deltamethrin. Therefore,

the current tolerance evaluation and the currently registered residential uses for deltamethrin will have no impact on the residential component of the cumulative risk estimates. T he revised point of departures ( POD s ) selected for deltamethrin are specific to deltamethrin , whereas the PO D s selected for the cumulative assessment w ere based on common mechanism of action data that are appropriate for all 20 pyrethroids included in the cumulative assessment.

There are no occupational scenarios associated with the proposed tolerance on import ed fish; therefore, an occupational exposure assessment is not required for this action.

There are no human health risk concerns associated with the proposed use. HED does not object

to the establish ment of a tolerance of 0.0 1 ppm for residues of deltame thrin in or on finfish

.

Potential areas of environmental justice concerns were considered in this human health risk assessment to the extent possible. The assessment resulted in no risks of concern

.

This risk assessment relies in part on data from studi es in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from

the Residential Standard Operating Procedures ( SOPs )( Turf/Lawn, Indoor Environments, andDeltamethrin Human Health Risk Assessment DP No. D413048

Page 8 of 64 Pets, Impregnated Materials and T reated Paints and Preservative ), are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the

Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website.

2.0 HED Recommendations

HED does not object to the establishment of tolerance s for imported freshwater and saltwater

finfish as specified in Table 2.2.3

.

2.1 Data Deficiencies/Conditions of Registration

There are no data deficiencies associated with the proposed tolerance for use of deltamethrin on imported fin fish. However, HED has identified the need for a turf transferable residue (TTR) study to support the existing uses of deltamethrin. This deficiency was not identified in the 2010 human health assessment scoping document in support of r egistration r eview and

, therefore

, the

Data Call

- In for deltamethrin did not include the required TTR study.

Since the estimated residential turf post

- application exposure for residential turf using default TTR values for deltamethrin is not minimal in comparison to the le vel of concern (i.e., the calculated MOE is not greater than 10 times higher than the level of concern, MOE = 750 compared to the LOC of 3000), future refinements of this post

- application exposure for deltamethrin may be necessary due to increased use of d eltamethrin or advances in EPA risk assessments. Therefore, EPA is requiring the 40 CFR TTR data requirement to facilitate any necessary exposure assessments refinements and to further EPA’s general understanding of the availability of turf transferable p esticide residues.

2. 2 Tolerance Considerations

2. 2 .1 Enforcement Analytical Method

Adequate methods, utilizing gas chromatograph y with electron capture detection (GC/ECD), are available for enforcing tolerances for residues of deltamethrin in plant commodities, as described

in Pesticide Analytical Manual ( PAM ) Volume II, Section 180.422. Another GC/ECD method (Method HRAV

- 22) is av ailable for enforcing tolerances in livestock commodities. Adequate confirmatory method validation data have been submitted for these methods, along with adequate independent laboratory validation (ILV) trials.

Multiresidue method s data for cis

- deltamethrin and trans

- deltamethrin were pre viously sent to
FDA. Cis

- deltamethrin is completely recovered through Methods 302 and 303, and partially recovered through Method 304. Trans

- Deltamethrin is partially recovered through Method 303

, but not recovered through Method 304.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 9 of 64 2. 2 .2 International Harmonization

There are currently no established Codex or Canadian maximum r esidue l imit s ( MRLs ) for

deltamethrin in finfish . There is an MRL in salmon set at 0.03 ppm by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), as a veterinary drug (not a pesticide) in 2003. As such, harmonization of HED’s recommended tolerance for residues of deltamethrin in import ed finfish is un necessary.

2. 2 .3 Recommended Tolerances

HED has exami ned the residue chemistry database for deltamethrin. Pending submission of a revised Section F (to correct the commodity definitions), there are no human health risk issues that would preclude establishing tolerances in freshwater and saltwater finfish. HED recommends in favor of establishing tolerances for residues of deltamethrin in finfish, as specified in the table below.

Table 2.2. 3 Tolerance Summary for Deltamethrin

. Commodity as Proposed by Registrant Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition

Fin fish 0.01 0.01 Fish

- freshwater finfish

0.01 Fish

- freshwater finfish, farm raised

0.01 Fish

- saltwater finfish, other

0.01 Fish

- saltwater finfish, tuna

Note to RD: According to HED’s Interim Guidance on Tolerance Expressions (S. Knizner; 27 May 2009), the tolerance expression for deltamethrin cited in 40 CFR §180.435[a] should be

revised to state:

Tolerances are established for residues of deltamethrin, including its metabolites and degradates, in or on the commodities listed in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only deltamethrin [(1 R ,3 R )

- 3

- (2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylic

ac id ( S )

- alpha

- cyano

- 3

- phenoxybenzyl ester ], and its major metabolites, trans deltamethrin [( S )

- alpha

- cyano

- m

- phenoxybenzyl(1R,3S)

- 3

- (2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylate] and alpha

- R

- deltamethrin [( R )

- alpha

cyano

- m

- phenoxybenzyl

- (1 R ,3 R )

- 3

- ( 2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylate] in or on the commodity.

2. 2 .4 Revisions to Petitioned

- For Tolerances

Pharmaq AS requested the establishment of a permanent tolerance

, without Section 3 (U

. S

. ) registration

, for residues of the insecticide deltamethrin in all imported commercially farmed

finfish at 0.01 ppm. There is, however, no commodity definition covering all finfish. Therefore, HED is recommending in favor of establishing tolerances for residues of del tamethrin at 0.01 ppm in the following four commodities: f ish

- freshwater finfish ; f

ish

- freshwater finfish, farm

raised ; f ish

- saltwater finfish, other ; and fish

- saltwater finfish, t una

.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 10 of 64 2. 3 Label Recommendations

None

.

3.0 In troduction

3.1 Chemical Identity

T able 3.1 Test Compound Nomenclature.

Compound Chemical Structure

Common Name Cis

- d eltamethrin

Molecular Formula C 22 H 19 Br 2 NO 3 Molecular Weight 505.24 Company Experimental Name AEF108569

IUPAC Name (S)

- α

- cyano

- 3

- phenoxybenzyl (1R,3R)

- 3

- (2,2

- dibromovinyl)

- 2,2

- dimethylcyclopropanecarboxylate

CAS Name (1R,3R)

- R

- cyano(3

- phenoxyphenyl)methyl 3

- (2,2

- dibromoethenyl)

- 2,2

- dimethylcyclopropanecarboxylate

CAS Number 52918

- 63

- 5

End

- use Products (EPs) AlphaMax (No current EPA r egistration); AMX (No current EPA registration)

.

3.2 Physical/Chemical Characteristics

Deltamethrin is a solid under ambient conditions. The compound has a ve r y low solubility in water, and low to high solubility in organic solvents. Its octanol/water partition coefficient suggests that accumulation of deltamethrin in fatty tissues is possible. See Appendix B for a listing of additional p hysical and c hemical properties.

3.3 Pesticide Use Patt ern

Pharmaq AS listed the use directions for the AlphaMax/AMX 1% ME formulation of deltamethrin in the administrative volume of petition 3E8178 . A summary of the proposed use pattern is presented in Table 3.3 .a , below

.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 11 of 64 T able 3.3

. a. Summary of Proposed Directions for Use of Deltamethrin on Finfish.

Application Timing; Type; Equipment 1 Use

Rate (ppb) Maximum

Uses Per

Season Max. Seasonal

Use Rate (lb ai/A) PHI 2

(Degree Days) Use Directions,

Application Timing,

and Limitations Upon sea lice infestation; bath

treatment in seawater ; closed treatment unit (well

- boat or sea

cage enclosed by a tarpaulin). 2 [3] 2 NA 3 5 Treatment period of 30 [40] minutes. Minimum

RTI 4 of 14 days.

1. In Chile, t reatment s may also be made in a semi

- closed system (skirt) ; parameters for this treatment method are in

brackets (i.e., 3 ppb for 40 minutes)

. 2 . PHI = Pre

- Harvest Interval; divide the PHI (5 degree days) by the water temperature (oC) to obtain the number of days after treatment that fish must be held before harvest. 3. NA = Not Applicable.

4. RT I = R e

- Treatment Interval.

There are no occupational or new proposed residential uses associated with this action for establishing a tolerance on imported fin fish. However, deltamethrin is registered to control a variety of indoor and outdoor pests found on turf, in homes, and in commercial settings, including food handling establishments; as well as in pet and paint additive products. For the purpose of upda ting the aggregate human health risk assessment, only previously assessed representative residential uses have been re

- evaluated using the revised 2012 Residential SOPs

. A more comprehensive assessment m ight be completed during r egistration r eview. A summary of the registered uses is provided in Table 3.3.b

.

Table 3.3.b . Summary of Registered Residential Uses for Deltamethrin.

Method of Application Product and

Formulation ( EPA Reg. No.) Application

Rate Maximum

No. Application s

per Season Maximum

Seasonal Application

Rate (lb ai/A) Use Directions,

Application Timing, Type and Limitations

Aerosol Spray D

- Force

Insecticide

0.06% ai

(279

- 9554) 0.00075

lb ai/can NA Continues killing insects up to

8 weeks For indoor and outdoor

use as a spot or crack and crevice use. Also apply to

mattress es , especially tufts, folds

, and edges for control of bed bugs. Spray surface until slightly wet.

Low pressure

hand held equipment for

indoor uses and hand pressurized

or power operated

sprayers for

outdoor use sites K

- Othrine® SC

Insecticide

4.75% ai

(432

- 763)

(contains 0.42 lb ai/gal) Indoor use

–

0.005 lb ai/gal

Outdoor perimeter

- 0.214 lb ai/A or

0.005 lb ai/gal

Turf

–

0.13 lb ai/A

Ornamentals

0.00026

lb ai/gal NA NA Indoor applications are to be made as spot or crack and crevice applications. Do not apply as a space

spray
, and do not treat entire floor, carpet or coverings.

Outdoor applications are to be made as building perimeter treatments or broadcast to lawns, recreational grounds and

ornamentals.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 12 of 64 Table 3.3.b . Summary of Registered Residential Uses for Deltamethrin.

Method of Application Product and

Formulation ( EPA Reg. No.) Application

Rate Maximum

No. Application s

per Season Maximum

Seasonal Application

Rate (lb ai/A) Use Directions,

Application Timing, Type and Limitations

Delta Wettable

Powder 5% ai

(432

- 832) 0.005 lb ai/gal NA NA Indoor applications are to be made as spot or crack and crevice applications. Do not apply as a space

spray
, and do not treat entire floor, carpet or coverings.

Outdoor applications are

to be made as broadcast to lawns, recreational grounds

, and ornamentals as a general surface spray.

Hose

- end Sprayer or hand held pressurized

sprayer RUC

- 415

Insecticide

4.75% ai

(432

- 805) Lawn

–

0.005 lb ai/gal

Perimeter

– 0.0023 lb ai/gal Repeat as

needed for

lawns and every 7 to 10 days for

ornamentals

if needed. NA For use by homeowners on lawns, ornamentals, decks, foundations, patios

, and other outdoor areas.

Ready

- to

- Use Container, hand duster, or

bulbous duster Green Light

Many Purpose

Dust

0.05% ai

(73327

- 14) Crack and

crevice

0.00000025

lb ai/ft 2

Home vegetable garden

– 0.00000066

lb ai/ft 2 Repeat at 7

-

day intervals

as necessary. NA Apply indoors to crack

and crevices. Do not apply as a broadcast application or to

mattresses. For

ornamental and home garden use

, apply thin layer of dust on upper and lower sides of leaves,

stems

, and flowers

Granular Spreader Delta Granules

0.1% ai

(4

- 422) 0.000003

lb ai/ft 2 or

0.13 lb ai/A Repeat as

needed NA Apply to home lawns, under shrubbery

, and

other ornamental recreational turf grass

areas.

Ready

- to

- Use Deltamethrin 4%

Pet Collar for Dogs

4 % ai

(68451

- 1) 0.0024 lb ai/pet Reapply new collar every

six months NA Use only on dogs to

control fleas and ticks.

Do not use on puppies

under 12 weeks old.

Brush, roller or

conventional

airless equipment Bug Juice

Insecticide

Additive

4.75% ai

(47332

- 11)

0.42 lb ai/gal 0.005

lb ai/gal/can NA NA Add 1 2⁄3 or 8 1⁄3 fluid

ounces to either 1 or 5 gallons of latex coating, oil base coating, stains

, or sealers

, then mix well to proper dilution. Apply product in and on

residential and non

-Deltamethrin Human Health Risk Assessment DP No. D413048

Page 13 of 64 Table 3.3.b . Summary of Registered Residential Uses for Deltamethrin.

Method of Application Product and

Formulation ( EPA Reg. No.) Application

Rate Maximum

No. Application s

per Season Maximum

Seasonal Application

Rate (lb ai/A) Use Directions,

Application Timing, Type and Limitations

residential buildings and structures including

residential kitchens and all

types of food handling

establishments. Do not apply as a broadcast interior application.

3.4 Anticipated Exposure Pathways

Humans could be exposed to deltame thrin from consuming food with residues resulting from agricultural applications (both pre

- harvest and stored grains), and from consuming food treated

in FHEs

. Furthermore, agricultural applications c ould result in deltame thrin reaching surface and groundwater, both of which can serve as sources of drinking water. However, because of the

low water solubi lity of the chemical and its affinity to bind to soil organic matter

, drinking water concentrations will be very low

. Typically there would be potential for exposure to o ccupational applicators while handling the pesticide prior to application as well as during application

. However, there is no occupational or residential exposure associated with this tolerance action

. T he potential exposure and risk for h omeowners exposed via inhalation during mixing, loading, and applying non

- restricted end

- use product s in residential settings , as well as residential post

application incidental oral exposure for children have been reassessed only for the purpose of completing an aggregate risk assessment.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, 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 Lo w

- 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 acco rding 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 involv e pesticide use in a residential 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 America, (NHANES/WWEIA). These food consum ption 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 t o 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 risksDeltamethrin Human Health Risk Assessment DP No. D413048

Page 14 of 64 for adul t applicators and for children , youths, and adults entering or playing on treated areas

post

- application are evaluated. Exposure risk estimates were not of concern. Further considerations are currently in development

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

4.0 Hazard Characterization and Dose

- Response Assessment

Deltamethrin is a member of the pyrethroid class of insecticides. Pyrethroids have historically been classified into two groups, Type I and Type II, based on chemical structure and toxicological effects. Type I pyrethroids, which lack an alpha

- cyano moi ety, induce in rats a syndrome consisting of aggressive sparring, altered sensitivity to external stimuli, hyperthermia, and fine tremor progressing to whole

- body tremor and prostration (T

- syndrome). Type II pyrethroids, which contain an alpha

- cyano moiet y, produce in rats a syndrome that includes pawing, burrowing, salivation, hypothermia, and coarse tremors leading to choreoathetosis (CS

syndrome) ( Verschoyle and Aldridge 1980 ; Lawrence and Casida 1982 ) . Deltam ethrin is a T ype II pyrethroid. The adverse outcome pathway (AOP, identified using a weight

- of

- evidence approach based on the Bradford

- Hill criteria) shared by pyrethroids involves the ability to interact with voltage

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

Figure 4.0. Adverse outcome pathway for pyrethroids

4.1 Toxicology Studies Available for Analysis

The database of experimental toxicology studies available for deltamethrin provides a robust characterization of the hazard profile for children 6 years old and older

, as well as for adults. A

28

- or 90

- day inhalation study is not available for consideration as required under the Part 158 toxicology data requirements ; however, HED’s HASPOC determined that a subchronic inhalation study in the rat is not required for del tamethrin ( TXR# 0056944 , K. Rury, 4/29/2014 ). In addition, there are ongoing efforts to develop data in juvenile rats (see Section 4.4) to inform the potential sensitivity of infants and young children to pyrethroids as a class. Despite the missing studi es and the ongoing scientific efforts, HED is confident that it has chosen points of departure and uncertainty factors in this risk assessment that are health protective and have a strong scientific foundation. The data from the following studies were use d to evaluate the hazard potential of deltamethrin:

- Wolansky Acute Oral Study in the Rat

- WIL Laboratory Acute Oral Study in the Rat Target
Tissue

Dose VGSC

Alterations In Vivo

Clinical Signs Altered

Neuronal ExcitabilityDeltamethrin Human Health Risk Assessment DP No. D413048

Page 15 of 64 - 21

- Day Dermal Study in the Rat

- 90

- Day Oral Stud ies in the Rat and Dog

- Chronic/Carcinogenicity Studies in the Rat, Mo use, and Dog

- Developmental Studies in the Rat and Rabbit

- Reproduction Study in the Rat

- Acute (ACN) , Subchronic (SCN) , and Developmental Neurotoxicity (DNT) Studies in

the Rat

- Immunotoxicity Study in the Rat

- Mutagenicity Battery of Studies

The stud ies available for consideration of deltamethrin toxicity provide a comprehensive database. The Wolansky and WIL studies are acute oral non

- guideline studies that measure locomotor and functional observational battery (FOB) activity, respectively, and prov ide robust data to evaluate the hazard potential of deltamethrin. In addition, numerous studies from the

scientific literature conducted over several decades describe the pharmacodynamic and pharmacokinetic profile of deltamethrin and of the pyrethroids i n general. This scientific literature has been recently reviewed by several groups ( Soderlund et al. 2002 ; Shafer et al.,

2005 ; Wolansky and Harrill 2008 )

.

4.2 Toxicological Profile

Deltamethrin has been evaluated for a variety of toxic effects in experimental t oxicity studies. Deltamethrin targets the nervous system. Neurotoxicity was observed throughout the database

, and effects were seen across species, sexes, exposure duration

, and routes of administration. Clinical signs characteristic of Type II pyrethro ids, such as increased salivation, altered mobility /gait , and tremors were seen in experimental toxicology studies including neurotoxicity

studies (acute and subchronic) in rats , subchronic and chronic studies in dogs and rats, and developmental and reprod uction studies in rats. In addition to the clinical signs noted above, increased sensitivity to external stimuli, abnormal vocalization, and decreased fore

- and hind

limb grip strength were commonly observed in the database

.

Deltamethrin did not result i n any systemic toxicity following dermal exposure for 21 days up to

the limit dose. There was also no toxicity observed following acute dermal exposure to deltamethrin up to a dose of 2000 mg/kg /day

. This finding is consistent with the toxicology profile of many pyrethroids, including fenpropathrin, zeta

- cypermethrin, and allethrin. Typically

, pyrethroids have a low absorption value of ≤ 5% and a high rate of metabolism.

D eltamethrin had a slightly higher absorption value of 11.3%

, although the majority of the radioactivity measured was at the skin site (10.6%). This is typical of the p yrethroids

, as they are lipophilic

, and much of the radioactivity measured in the skin of dermal penetra tion studies with pyrethroids is captured in the upper dermal layers an d not available for absorption or systemic

circulation.

Deltamethrin did not have any adverse effects on fetuses or offspring in the prenatal developmental studies in rats and rabbits. However, potential qualitative susceptibility was observed at high doses in the DNT and 2

- generation reproduction study

. In the DNT study, an increased incidence of vocalization when handled was observed during FOB observations onDeltamethrin Human Health Risk Assessment DP No. D413048

Page 16 of 64 PND 4 for male pups

, and decreased pre

- and post

- weanin g body weight was observed in pups of

both sex es at 16.1 mg/kg/day. In maternal animals, only decreased body weight and body weight gain were observed despite undergoing the same neurological measurements as the pups, including FOB analysis.

In the 2

- ge neration reproduction study, t reatment

- related effects in the parental animals at the high dose (21.2/23.5 mg/kg/day, M/F) were limited to lesions on head, neck

, or forelimbs

, and alopecia in the males and ataxia and hypersensitivity in the females during gestation. In the F 1 generation, there were increased pup mortalities (PND 8

- 14) and clinical findings that were observed early in the post

- weaning period (i.e.

, impaired righting reflexes, hyperactivity, splayed limbs, vocalization, and excessive salivat ion) at the high dose (24.9/27.2 mg/kg/day, M/F)

. There was no increase in mortality or clinical signs in the F 2 generation. Decreased body weight

was observed in the adult P and F 1 generations

, and decreased pup weight was observed in both

the F 1 and F 2 pups. It is notable that the dose (24.9/27.2 mg/kg/day) and age of pups (PND 8

- 14) where mortality was observed i s consistent with the LD 50 in PND 11 pups for deltamethrin (11 mg/kg; Sheets et al. 1994) observed in the literature

.

The increased qualitative susceptibility in the DNT and 2

- generation reproduction study were observed at doses 10

- to 20

- fold higher than the current points of departure (PODs) selected for risk assessment. Therefore, t he current PODs are protecti ve of th e observed sensitivity.

There w as no evidence of immunotoxicity after deltamethrin exposure in the toxicology database

or in an immunotoxicity study in rats. Deltamethrin is classified as “ n ot like ly to be carcinogenic

to humans. ” There was no evidence of carcinogenicity in the combined chronic/carcinogenicity study in rats or the carcinogenicity study in mice. In a battery of mutagenicity studies there was no evidence of a mutagenic effect.

Deltamethrin has either moderate (Toxicity Category II, MRID 00070734) or minimal (Toxicity Category IV, MRID 41651019) toxicity via the oral route of exposure in acute lethality studies (LD 50 ) in rats

. The acute oral study

, which co ncluded that deltamethrin was of Toxicity Category IV

, used aqueous methyl cellulos e as the vehicle, while an other study used both PEG 200 and sesame oil as the vehicles. It has been reported that deltamethrin is less toxic when dissolved in aqueous vehicles such as methyl cellulose

, and this m ight explain the considerable

difference in results between the two studies (Crofton et al., 1995)

. Deltamethrin has moderate acute toxicity via the inhalation (Toxicity Category II/III) route of exposure and minimal toxicity via the dermal (Toxicity Category III) route of exposure. It is minimal ly irritating to the eye (Toxicity Category III) and non

- irritating to the skin (Toxicity Category IV). It is not a skin

sensitizer.

4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

OPP is making best use of the extensive scientific knowled ge about the mode of action/adverse outcome pathway ( MOA/AOP ) on pyrethroids in the risk assessments for this class of pesticides. In this way, information on a subset of pyrethroids can be used to help interpret and understand the toxicological profile for other members of the class. It is notable that a signific ant portion of the scientific literature on pyrethroids utilizes deltamethrin as the test chemical. In the on

- goingDeltamethrin Human Health Risk Assessment DP No. D413048

Page 17 of 64 work by the Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA), deltamethrin is one of two sentinel pyrethroids being used to develop the initial, extensive

database of in vitro and in vivo toxicology studies and highly refined p hysiologically

- based pharmacokinetic (PBPK) models. As such, in the near future, extensive new data will become

available to further refine the deltamethrin hazard assessment.

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 sodium c hannels. The underlying PK 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 increased neurotoxici ty. 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 voltage

- gated sodium channels (VGSCs) in vital

tissues and, therefore, do not contribute to overall toxicity.

A ge

- dependent pharmacokinetic differences have been identified for several pyrethroids (i.e., there are differences in the ability of adults and juveniles to metabolize pyrethroids). The

enzymes that metabolize and detoxify 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 the amount of pyrethroid at the sodium channel, is low. However, the activity of these enzymes increases with ag e, 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 carboxy l esterases

, plus hepatic carboxy l esterases and cytochrome P450s (microsomes) is at least 6 times higher for PND 90 rats compared to PND 10 rats ( Anand et al.

2006 ) . As a consequence, higher internal doses (i.e., those associated with high doses in experimental toxicology studies) overwhelm the clearance mechanisms in juveniles

, but because

adults hav e greater enzyme activity, they are able to tolerate higher doses prior to the onset of toxicity. As a matter of perspective, the anticipated exposures from typical dietary or residential activities are not expected to overwhelm the premature metabolic sy stems in juveniles. To better understand the role of pharmacokinetics and reduce uncertainty associated with extrapolating across species (i.e., rat to human) and life stages, PBPK models, designed to predict pyrethroid concentration in tissues following in vivo exposure, have recently been developed by the Agency. The Agency has determined that the important PK properties relevant for the metabolism and distribution of pyrethroids in the body are sufficiently similar for

members of this class such that using a ‘generic’ or family model structure for this class is scientifically appropriate. In other words, because of the similarities in the PK profiles ofDeltamethrin Human Health Risk Assessment DP No. D413048

Page 18 of 64 pyrethroids, a single model structure is able to predict the tissue dose based on the pharmacokinet ics of every member of the class. The family modeling approach was primarily developed based on PBPK modeling performed with deltamethrin and was presented to and supported by the F ederal Insecticide, Fungicide, and Rodenticide Scientific Advisory Panel ( FIFRA SAP ), ( USEPA 2007 )

.

The initial deltamethrin PBPK model presented to the SAP was developed in the adult male SD rat (Mirfazaelian et al. 2006). The deltamethrin PBPK model was further refined based on oral bioavailability and disposition studies in rats and included estimate s for target tissue concentrations in humans (Godin et al. 2010). The initial PBPK model was also extended by accounting for age

- dependent changes in physiological and biochemical parameters (Tornero

Velez et al. 2010) to address juvenile sensitivity in r ats. Currently, the CAPHRA, a group of pesticide registrants and product formulators, is collecting metabolism and tissue dosimetry data from rats and human tissues across different life stages. Th ese data will be used to inform the development of PBPK m odels for additional pyrethroids. The code for the models for the initial

model is expected to be submitted to the Agency in late 2014 to early 2015. Because of the evolving nature of the PBPK model for deltamethrin, the A gency has decided not to use the existing model for conducting animal to human extrapolation. However, the A gency expects
that in future risk assessments PBPK modeling will be used to perform interspecies extrapolation.

4.3.2 Pharmacodynamics

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

vivo studies support the AOP illustrated in Figure 4. 0 and the disr uption 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 )

. Choi and Soderlund ( 2006 ) examined interactions of several pyrethroids , including deltamethrin, with mammalian VGSCs expressed in Xenopus (frog) oocytes. Deltamethrin produced modifications of sodium

channel kinetics consistent with other T ype II compounds (Figure 4.3 .2 ). With respect to altered neuronal excitability, Type II pyrethroids significantly prolong sodium current tails (e.g. 200 ms to minutes) typically resulting in increased resting membrane potential and ultimately causing depo larization dependent action potential block. Cao et al. (2011a) measured sodium influx in primary cultures of mammalian (mouse) neurons and demonstrated that deltamethrin caused

increases in sodium influx in this model . T his observation confirms the abil ity of deltamethrin to

interact with VGSC in intact mammalian neurons. An additional study by Cao et al

. (2011b) demonstrated that the interaction of deltamethrin with VGSC caused changes in neuronal excitability that resulted in calcium influx into intac t mouse neurons. As this effect of deltamethrin was entirely blocked by the VGSC blocker tetrodotoxin, it provides evidence that the changes in sodium channel function lead to changes in neuronal excitability, as illustrated in Figure 4.3. 2.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 19 of 64 Figure 4.3 .2

. Resting modification of rat Nav1.8 sodium channels by deltamethrin expressed in Xenopus oocytes.
Channel current vs

. time traces from individual representative oocytes in th e absence or presence (*) of 10 μM

deltamethrin were obtained during and after 40

- ms depolarizations from 100 mV to 10 mV. Calibration bars: 20 ms

for the x

- axis and 500 nAmp on the y

- axis. Figure e xtracted from Figure 3 in Choi and Soderlund ( 2006 )

.

HED would prefer to use an early key event in the AOP for pyrethroids in selection of 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 lik e those discussed here to in vivo measures are 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 res ulting from pyrethroids is generally characterized by tremors, hyper

- or hypothermia, heightened response to stimuli, salivation, 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, pharmacodynamic ( PD ) contributions to pyre throid 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 d ifficult to obtain dynamic 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 act ed upon by pyrethroids. 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 vitro 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 pyre throid perturbation compared 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 of an adult isoform and a juvenile isoform expressed in frog oocytes to deltamethrin. 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 directl y comparing a homologous 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 those in the rat. However, based on the comparable function and

distributi on of sodium channels between the species, the rat is an appropriate surrogate for theDeltamethrin Human Health Risk Assessment DP No. D413048

Page 20 of 64 evaluation of human PD ( Goldin et al. 2000 ; Goldin 2002 ) . As a result, the Agency concludes that juvenile rats are not more sensitive tha n adults with respect to pyrethroid pharmaco

dynamics. Therefore, the pharmacodynamic contribution to the FQPA factor will be 1 X

.

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 hazard assessments. Following a single oral gavage dose, deltamethrin is absorbed quickly in rats. Effects such as tremors, salivation, and impaired mobility were observed within 3 hours following oral gavage dosing in the deltamethrin acute neurotoxicity study. In addition, effects on motor activity in the W olansky acute study, FOB observations in the WIL acute study , and abnormalities in ga it in the chronic dog toxicity study were observed

within 2

, 4 , and 5 hours, respectively, following administration of deltamethrin. These observations are consistent with the toxicity profiles for other pyrethroids t h at are marked by rapid absorption, me tabolism, and elimination, 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 )

.

The combination of rapid absorption, metabolism, and elimination precludes accumulation and increased potency following repeated dosing. Therefore, for most pyrethroids, the acute toxici ty studies typically result in neurotoxicity at lower doses. In the case of deltamethrin, the chronic dog study (NOAEL =1 mg/kg/day) and Wolansky study (BMDL 1SD = 1.49 mg/kg) have very similar PODs and are the lowest amongst the available studies. The h u man e quivalent d oses (HED) based on allometric scaling (Table 4.3.3) indicate that the BMDL 1SD from the Wolansky study is lower than the NOAEL from the chronic dog study. T he other two acute studies (WIL acute study and the acute neurotoxicity study) have PODs that are approximately 2 0

- 30 fold higher than the Wolansky acute study (Table 4.3.3). It is notable that both the WIL acute study and the acute neurotoxicity study us ed relatively high vehicle volumes of 5 m L /kg, compared to

a vehicle volume of 1 m L /kg in the Wolansky acute study , which may account for the differences observed. For deltamethrin, the gavage volume can play an important role in potency

since the volume impacts the absorption characteristics (e.g., timing and amount ; Crofton et al, 1995). In the WIL and acute neurotoxicity studies, it is likely that the relatively high corn oil volume caused a reduction in the peak level of deltamethrin in the brain , res ulting in lower toxicity, thereby increasing the POD.

In general, rat dietary studies tend to have higher NOAELs/LOAELs for pyrethroids becaus e
, as rats feed continuously

, pyrethroids are metabolized and excreted from the system relatively quickly

, and th e overall systemic concentration in the rat remains low. In contrast, bolus/gavage dosing results in greater maximal plasma concentrations immediately after dosing. The results from the deltamethrin studies are similar in this respect

, with the dietary s tudies having higher NOAELs than the bolus/gavage studies. Comparing the POD s established from the Wolansky acute study and repeat dosing studies, it is apparent that repeat exposures do not result in lower

POD s (Table 4.3.3)

. This observation is consist ent with the general kinetic profile for pyrethroids. Therefore, the endpoint from the Wolansky acute study is protective of the endpoints from the repeat dosing studies and

, for the purposes of endpoint selection and exposure assessment, only single

- day risk assessments need to be conducted.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 21 of 64 Table 4.3.3. Deltamethrin Point of Departure Values versus Treatment Time for Signs of Neurotoxi city

Study Duration Study findings

NOAEL (mg/kg/day) or
BMDL LOAEL

(mg/kg/day)

or BMD 3⁄4 Body

Weight Adjustment

for HED Comparison C
Wolansky acute rat (Gavage

- 1 m L /kg corn oil) Acute, single

exposure A BMDL 1SD = 1.49 BMD 1SD = 2.48 0.43

WIL acute rat (Gavage

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

exposure B BMDL 20 = 10.5 BMD 20 = 14.5 3.05

Acute neurotoxicity rat (Gavage

- 5

m L /kg corn oil) Acute, single

exposure 15 50 4.36

Developmental Rat ( Gavage

- 1 m L /kg corn oil) 10 days 3.3 7 0.96

Subchronic neurotoxicity rat (Dietary) 90 days 14 54 4.07

Sub

- chronic rat (Gavage

- 2.5 m L /kg corn oil) 90 days 2.5 10 0.73

Reproductive toxicity (Dietary) 120 days 5.4 21.2 1.57 Chronic dog (Capsule) 1

- year 1 10 0.61 Chronic/carcinogenicity rat (Dietary) 2

- years 22.2 35.9 6.40

A BMD 1SD is the central estimate of the dose that results in decreased motor activity compared to control animals based upon 1 standard deviation using Benchmark Dose Analysis. BMDL 1SD is the 95% lower confidence limit of the central estimate. Data and analysis can be found in MRID 47885701.

B BMD 20 is the central estimate of the dose that results in a 20% d ifference in FOB scores compared to control animals using Benchmark Dose Analysis. BMDL is the 95% lower confidence limit of the central estimate. Data and analysis can be found in

MRID 48714301

. C Human Equivalent Doses based on allometric scaling: Scaling Factor 0.75; Default weights: rat = 0.5 kg, dog = 10 kg, Human = 70 kg; NOAEL H =NOAEL D (BW D /BW H )^1

- 0.75; Sample and Arenal, 1999.

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

There were no indicatio ns of fetal toxicity in any of the guideline studies, including developmental studies in the rat and rabbit, a developmental neurotoxicity study in rats, and a 2

- generation reproduction study in rats. There was evidence of increased juvenile qualitative

s usceptibility at high doses observed in both the DNT and 2

- generation reproduction studies. However, these high

- dose effects are only at doses 10

- to 20

- fold higher than the deltamethrin

POD. The observations of increased qualitative juvenile sensitivity in the guideline studies are consistent with the findings of juvenile sensitivity in the literature for deltamethrin

, which are also high

- dose effects.

After reviewing the extensive body of peer

- reviewed literature on pyrethroids, the Agency has no

resid ual uncertainties regarding age

- related sensitivity for women of child bearing age as well as for all adult populations and children >6 years of age, based on the absence of pre

- natal sensitivity observed in 76 guideline studies for 24 pyrethroids and the scientific literature. Additionally, no evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics. The Agency is retaining a 3X uncertainty factor to protect for exposure s of children <6 years of age based on the increased quantitative susceptibility seen in studies on pyrethroid pharmacokinetics and the increased quantitative juvenile susceptibility observed in high dose studies, such as the deltamethrin guideline DNT and 2

- generation reproduction studies.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 22 of 64 4.4.1 Completeness of the Toxicology Database

The toxicology database for deltamethrin is largely complete including developmental toxicity studies in rats and rabbits, a reproduction study in rats, and acute neurotoxic ity ( A CN)

, subchronic neurotoxicity ( SCN ) , and developmental neurotoxicity (DNT) studies. HED’s

HAS POC determined that a subchronic inhalation study in the rat is not required for deltamethrin ( TXR# 0056944 ). At this time, EPA lacks additional data to address the potential for juvenile sensitivity to many pyrethroids, including deltamethrin.

The Agency is expecting additional in vitro and in vivo data . In 2010, the Agency requested proposals for study protocols that could identify and quantify potential juvenile sensitivity and received a single response from the Pyrethrin and Pyrethroids Technical 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, the CAPHRA is 1 ) conducting in vitro studies demonstrating the interaction of pyrethroids with exogenously expressed rat and human VGSCs in Xenopus
oocytes; 2 ) conducting in vitro studies demonstrating interaction of pyrethroids with VG S Cs in rat neurolemma cells; 3 ) developing rat and human PBPK models, including additional pharmacokinetic data; and 4 ) conducting in vivo behavioral testing using aud itory startle testing

in rats. As more data for deltamethrin and other individual pyrethroids become available, the Agency will determine whether re

- evaluation of the age

- related sensitivity of pyrethroids is appropriate.

For the reasons discussed in Se ction 4.4, the uncertainty regarding the protectiveness of the intraspecies uncertainty factor raised by the literature studies and the absence of the requested data warrant application of an additional 3X for risk assessment for infants and children <6 ye ars of age.

4.4.2 Evidence of Neurotoxicity

As with other pyrethroids, deltamethrin causes neurotoxicity from interaction with sodium channels leading to clinical signs of neurotoxicity. These effects are well characterized and adequately assessed by the available guideline and non

- guideline studies.

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

H igh

- dose studies in the scientific literature indicate that younger animals are more susceptible to the toxicity of pyrethr oids. For example, Sheets et al

. (1994) found increased brain deltamethrin levels in young rats (PND 11 and 21) relative to adult rats (PND 72). These age

related differences in toxicity are principally due to age

- dependent pharmacokinetics . T he

activit y of enzymes associated with the metabolism of pyrethroids increase with age (Anand et

al

. , 2006). However, in context, normal dietary or residential exposures of juveniles are not expected to overwhelm their ability to metabolize pyrethroids. In support , at a dose of 4.0 mg/kg deltamethrin (near the Wolansky study LOAEL value of 3.0 mg/kg for deltamethrin), the change in the acoustic startle response was similar between adult and young rats (Sheets et al, 1994). In addition, EPA’s Office of Research and Development ( ORD ) recently developed anDeltamethrin Human Health Risk Assessment DP No. D413048

Page 23 of 64 age

- dependent PBPK model for deltamethrin (Tornero

- Velez et al, 2010) that predicts a 3

– fold increase of pyrethroid in neuronal tissue in younger animals compared to adults. There are several studies ( in vitro and in vivo ) that indicate that PD contributions to pyrethroid toxicity are

not age

- dependent. Examination of specific VGSCs has demonstrated that there is a lack of increased sensitivity in either juvenile specific isoforms (Meacham et al

. , 2008) or in human isoforms compared to rat variants (Tan and Soderlund, 2009).

There were no indications of fetal toxicity in any of the guideline studies, including developmental studies in the rat and rabbit, a developmental neurotoxicity study in rats, and a 2

- generation reproduction study in rats. There was evidence of increased juvenile qualitative susceptibility at high doses observed in both the DNT and 2

- generation reproduction studies. In the DNT study, increased vocalization was observed during FOB handling of pups on PND 4 at the same dose where decreased body weight and body weight gain were observed in maternal animals (16.1 mg/kg/day)

. No findings were observed in the maternal animals during FOB handling in the DNT. In the 2

- generation reproduction study, the P generation showed limited clinical signs of neurotoxicity and decreased body weights at the highest dose tested (21.2/23.5 mg/kg/day, M/F). Effects observed in the F 1 generation at the same dose included decreased pup weight, increased pup mortality between PND 8

- 14, increased pup mortality within the first 8

d ays post

- weaning, and additional clinical signs of neurotoxicity not observed in the parental generation. The increased mortality and additional clinical signs were considered to be evidence of qualitative sensitivity in juveniles.

The observations of i ncreased qualitative juvenile sensitivity in the guideline studies are consistent with the findings of juvenile sensitivity in the literature for deltamethrin

. The increased sensitivity in the DNT and 2

- generation reproduction study were observed in anima ls of a similar life stage (PND 4 and PND 8

- 14, respectively) as those in the Sheets study (Sheets et al., 1994). Furthermore, the dose at which increased pup death was observed in the 2

- generation reproduction study (~25 mg/kg/day) is similar to the LD 50 value in the Sheets study for pups on PND 11 and 21 (11 mg/kg/day). T he qualitative sensitivity observed in the DNT and 2

- generation reproduction studies w as seen at the highest doses tested . These doses are considered to be relatively high (i.e., near the lethal doses) and are ~30

- to 50

- fold greater than the point of departure selected for the acute and chronic dietary reference dose ( 1.49 mg/kg ) ; therefore, the current risk assessment is protective of the observed sensitivity

. At doses near the Wolan sky POD, no effects on parental animals or offspring were observed in either the DNT or

2

- generation reproduction study and

, therefore

, there is no susceptibility at these doses.

After reviewing the extensive body of peer

- reviewed literature on pyrethroi ds, the Agency has no residual uncertainties regarding age

- related sensitivity for women of child bearing age as well as for all adult populations and children >6 years of age, based on the absence of pre

- natal sensitivity observed in 76 guideline studies for 24 pyrethroids and the scientific literature. Additionally, no evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics. The Agency is retaining a 3X uncertainty fac tor to protect for exposures of children <6 years of age based on the increased quantitative susceptibility seen in studies on pyrethroid PK and the increased quantitative juvenile susceptibility observed in high doses studies, such as the deltamethrin gui deline DNT

and 2

- generation reproduction studies.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 24 of 64 4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to dietary exposure . The dietary exposure assessments are based on high

- end health protective residue le vels that account for parent and metabolites of concern, processing factors, and percent crop treated assumptions. 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

deltam ethrin, EPA is confident that it has not underestimated turf exposure due to the

conservativeness 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 assessment period). T he 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.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response and Hazard Assessment

Endpoint selection is discussed in Appendix A.3. Based on the existing and proposed use patterns for deltamethrin, the expected exposure profile will be for acute dietary, short

- term incidental oral, dermal

, and inhalation exposures. Based on the toxicity profile, HED is not conducting dermal (all durations) or intermediate

- and long

- term inhalation exposure

assessments for adults or children. A chronic dietary risk assess ment is not being conducted because there is no apparent increase in hazard from repeated/chronic exposures to deltamethrin. Therefore, the acute endpoint is protective of the endpoints from repeat dosing studies. A chronic dietary exposure assessment is being performed in order to generate background exposure estimates to aggregate with residential exposure estimates for the short

- term aggregate
risk assessment.

As previously indicated, the toxicity endpoints in the deltamethrin database are consistentl y based on clinical signs of neurotoxicity. The studies include multiple species, study designs, and durations (Table 4.3.3). Because uncertainty associated with the POD is propagated throughout the risk assessment, one of the key factors in POD selectio n is the robustness of the dose

response data. In addition to the typical guideline studies, data from two special studies (Wolansky study on motor activity and WIL FOB study) evaluating neurobehavioral outcomes

are available for deltamethrin ( Wolansky et. al. 2006 ; Weiner et. al. 2009 ) . Wolansky et al.

m easured motor activity at the time of peak effect after exposure to 11 pyrethroids, including deltamethrin, although other neurobehavioral parameters were not assessed. Dose

- response relationships were determined using 6

- 11 doses per pyrethroid (6 doses used for deltamethrin)

and 8

- 18 rats per dose group, minimizing variability and increasing the confidence in the BMD estimates determined from this study. Moreover, each pyrethroid was evaluated by the same scientist, thus decreasing some of the variabil ity associated with neurobehavioral measures. In the WIL study, 17 pyrethroids including deltamethrin were evaluated using a specially designedDeltamethrin Human Health Risk Assessment DP No. D413048

Page 25 of 64 FOB study focused on the outcomes associated with pyrethroid toxicity syndromes at the time to peak effect. Do se

- response relationships were determined using 2

- 3 doses per pyrethroid (3 doses used for deltamethrin) and 10 male rats per dose group. However, as discussed in Section

4.3.3

, the WIL FOB study and the ACN study both used high vehicle volumes that likel y impacted absorption characteristics of deltamethrin

, thereby increasing the POD.

Observations of salivation, effects on mobility /gait , and tremors were the most prominent findings in the guideline experimental toxicology studies and were considered in t he POD determination. Given the multiple strengths associated with the study design of Wolansky, et al. ( 2006 ) and the resulting well

- defined dose

- response curve, the Wolansky study provides the most robust data set for extrapolating risk from deltamethrin. Although the guideline studies typically have only three treatment groups

, they often do not evaluate clinical signs at the time of peak effect, and the scoring metrics for neuro toxicity parameters vary widely among guideline studies, the NOAELs/LOAELs from the guideline studies, in general, are consistent with

, and

support

, the findings of the Wolansky study.

A BMD analysis was conducted by the Agency for all the pyrethroids i ncluded in the Wolansky study (MRID 4 7885701 ) . Overall, because of the large number of doses and high quality measurements, the BMD analysis yielded high

- confidence results. In performing BMD analysis, a benchmark response (BMR) must be selected. As a g eneral approach, it is prefer able to use a combination of biological and statistical factors in the BMR selection. In the case of motor activity data, the scientific community has not established a specific level of change that would

be considered to be a dverse. Therefore, OPP has elected to use one standard deviation (1SD) from the control group, as suggested, for continuous endpoints in the Agency’s BMD guidance ( USEPA 20 12 ) as the BMR. OPP has estimated both the BMD 1SD and the BMDL 1SD (where the

BMDL 1SD is the lower 95% confidence limit of the BMD 1SD ). The BMD 1SD and the BMDL 1SD for deltamethrin are 2.48 mg/kg and 1.49 mg/kg, respectively. As a matter of science policy, EPA uses the BMDL, not the BMD, for deriving PODs. Therefore, the BMDL 1SD of 1.49 mg/kg is being used as the dose for risk assessment.

As described in section 4.3.1, there are PBPK models currently available for species extrapolation from rats to humans. For the current action, the use of PBPK models to predict human equivalent concentrations is not necessary to establish a tolerance on finfish.

Acute Dietary (All Age Groups) : Quantitation of the dietary risks was performed using the acute oral Wolansky study, with a BMDL 1SD value of 1.49 mg/kg and a BMD 1SD value of 2.48 mg/kg based on decreased locomotor activity. The acute neurotoxicity, chronic dog, and WIL acute

studies were all considered for risk assessment because they all had effects that were o bserved within hours of dosing. However, the Wolansky study had the lowest POD among all studies and is considered the most robust study in the database. The chronic dog study had a slightly lower NOAEL (1 mg/kg/day); however, the human equivalent dose b ased on allometric scaling was actually higher for the chronic dog study (0.61 mg/kg/day) compared to the Wolansky study (0.43 mg/kg) (Table 4.3.3). As there is no apparent increase in hazard from repeated/chronic exposures to deltamethrin, the acute diet ary exposure assessment is protective of chronic dietary

exposures. Accordingly, a chronic dietary assessment was no t conducted.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 26 of 64 Incidental oral short

- term : Quantitation of the incidental oral risks was performed using the acute oral Wolansky study, wit h a BMDL 1SD value of 1.49 mg/kg and a BMD 1SD value of 2

. 48 mg/kg based on decreased locomotor activity. The BMDL 1SD value of 1

. 49 mg/kg is pr otective of potential offspring effects observed in the DNT and 2

- generation reproduction study.

Short

- term Derma l : A 21

- day dermal study in rat for deltamethrin is available for consideration.
However, no treatment

- related findings were observed at the limit dose . There was also no toxicity observed following acute dermal exposure to deltamethrin up to a dose of 2000 mg/kg

. T herefore, a dermal hazard was not identified for deltamethrin

, and no dermal risk assessment

will be conducted

. This finding is consistent with the toxicology profile of many pyrethroids. No dermal hazard has been identified for fenpropathr in, zeta

- cypermethrin, or allethrin. Typically

, pyrethroids have a low dermal absorption value of ≤ 5% and a high rate of

metabolism

. D eltamethrin had a slightly higher dermal absorption value of 11.3%

, although the majority of the radioactivity measured was at the skin site (10.6%). This is typical of the pyrethroids

, as they are lipophilic

, and much of the radioactivity measured in the skin of dermal penetration studies with pyrethroids is captured in the upper dermal layers an d not available for absorption or systemic circulation.

Short

- term Inhalation : A route

- specific inhalation study is not available for deltamethrin ; however, H ASPOC waived the requirement for this study (TXR# 0056944 ) . As a re sult, the oral

BMDL 1SD of 1

. 49 mg/kg from the Wolansky acute rat study is being used for this endpoint to extrapolate inhalation risk because of the overall robust nature of the study and the lack of increased hazard from repeated/chronic exposures to delt amethrin

. Absorption and t oxicity via

the inhalation route are assumed to be equal to toxicity via the oral route.

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major ro u t es : oral, dermal

, and inhalation, and determine whether the individual exposures can be combined if they have t he same toxicological effects. For deltamethrin, there are no routes to combine despite all exposure scenarios being based on the same endpoint : decreased motor activity. No dermal hazard was identified for

deltamethrin

, and the inhalation route of expo sure only applies to occupational and residential

handlers

. Furthermore, i nhalation post

- application exposure is expected to be minimal

. T herefore

, incidental oral is the only potential route of exposure for children.

4.5.3 Cancer Classification and R isk Assessment Recommendation

There was no evidence of carcinogenicity in either the rat or mouse long

- term dietary studies up to the highest dose tested

, nor was there any mutagenic activity in bacteria or cultured

mammalian cells. Deltamethrin is class ified as “not likely to be carcinogenic to humans” in accordance with the EPA Final Guidance for Carcinogen Risk Assessment (3/29/2005).Deltamethrin Human Health Risk Assessment DP No. D413048

Page 27 of 64 4.5.4 Summary of Points of Departure and Toxicity Endpoints

Table 4.5.4.1 Summary of Deltamethrin Toxicological Doses and Endpoints for Use in Dietary and Non

Occupational Human Health Risk Assessment

Exposure

Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD, Level of

Concern for Risk

Assessment Study and

Toxicological Effects

Acute Dietary

- (≥ 6 years old) Wolansky

BMDL 1SD = 1.49 mg/kg UF A = 10X

UF H = 10X FQPA SF = 1 X Acute RfD = 0.0 15 mg/kg

aPAD =0.0 1 5 mg/kg/day Wolansky BMD 1SD = 2.48 mg/kg

based on decreased motor activity

Acute Dietary

- (< 6 years old) Wolansky

BMDL 1SD = 1.49 mg/kg UF A = 10X

UF H = 10X FQPA SF = 3X Acute RfD = 0.0 1 5 mg/kg

aPAD =0.00 5 mg/kg/day Wolansky BMD 1SD = 2.48 mg/kg

based on decreased motor activity

Incidental Oral (Short

term) Wolansky

BMDL 1SD = 1.49 mg/kg UF A = 10X

UF H = 10X FQPA SF = 3X Residential LOC for

MOE = 300 Wolansky BMD 1SD = 2.48 mg/kg

based on decreased motor activity

Dermal (short

- term;
all populations) A dermal assessment was not conducted based on the lack of effects in a 21

- day dermal study

and low potential for dermal absorption for delta methrin.

* Inhalation (Short

- term; ≥ 6 years old) Wolansky

BMDL 1SD = 1.49 mg/kg UF A = 10X

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

MOE = 100 Wolansky BMD 1SD = 2.48 mg/kg

based on decreased motor activity

* Inhalation (Short

- term; < 6 years old) Wolansky

BMDL 1SD = 1.49 mg/kg UF A = 10X

UF H = 10X FQPA SF = 3X Residential LOC for

MOE = 300 Wolansky BMD 1SD = 2.48 mg/kg

based on decreased motor activity
Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of treatment

related tumor s in two adequate rodent carcinogenicity studies.

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertaint y factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). R fD = reference dose. MOE = margin of exposure. LOC = level of concern. * Inhalation absorption is assumed to be equivalent to oral absorption.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue ProfileDeltamethrin Human Health Risk Assessment DP No. D413048

Page 28 of 64 5.1.1 Summary of Plant and Animal Metabolism Studies

Based on acceptable metabolism data in plants and animals, HED has concluded that the nature of the residue in plants and animals is adequately understood. In both plants and animals, the

residues of concern for both t olerance enforcement and risk assessment are the cis

- , trans

- and alpha

- R

- isomers of deltamethrin.

In acceptable tomato, cotton, apple

, and corn metabolism studies

, the three deltamethrin isomers ( cis

- , trans

- , and alpha

- R

- ) were the major [ 14 C]

- residues . All other metabolites were present at

<10% of the total radioactive residue ( TRR ) , or accounted for <0.01 ppm. In plants, the main component of the active ingredient, cis

- deltamethrin, undergoes isomerization to form trans

- and alpha

- R

- deltamethrin. E ach of these isomers can also undergo cleavage at the ester linkage to yield 3

- phenoxybenzaldehyde, and cis

- or trans

- Br 2 CA metabolites that can be further oxidized,

reduced

, and/or conjugated. Deltamethrin is also directly hydroxylated to 4’

- hydroxydeltamethrin, or the nitrile group can be hydrolyzed to form an amide metabolite.

Acceptable cattle and poultry metabolism studies were conducted using [ 14 C]

- tralomethrin , a closely related pyrethroid that breaks down into deltamethrin via debromination. In these studies, d eltamethrin was the major residue in cattle fat, muscle

, and milk (48

- 96% TRR), and was detected in kidneys at 1

- 2% of the TRR. In t he poultry metabolism studies, deltamethrin was also the major residue identified in fat, muscle

, and egg yolks (32

- 85% TRR), and was detected in liver at 14% of the TRR. In both the cattle and poultry studies, deltamethrin was further metabolized by clea vage at the ester linkage to yield 3

- phenoxybenzaldehyde and Br 2 CA metabolites, which were further oxidized, reduced

, and/or conjugated. Free and conjugated

residues of Br 2 CA and 3

- phenoxybenzaldehyde were major components detected in liver, kidney

, and m uscle of both cattle and poultry. In poultry, minor amounts of 4’

- hydroxydeltamethrin were also detected in liver.

5.1.2 Summary of Environmental Degradation

When applied to the field, deltamethrin is likely to partition in to the soil and organic matter in the

crops . It appears to bind strongly to soil and organic matter, though binding is not instantaneous (K OC >>100,000, immobile). It is not expected to leach into sub

- surfaces. It m ight reach aquatic environments via spray drift or in runoff events accompanied by erosion. Deltamethrin appears to be moderately to highly persistent in terrestrial environments. It has the potential to persist in

aq uatic environments, where it might partition with the sediment. Because of its low Henry’s Law

Constant , deltamethrin is unlikely to volatilize substantially.

Deltamethrin is relatively stable at pH 5 and 7. However, it rapidly degrade s (half

- life of 2.5 days) at an alkaline pH of 9 to form Br 2 CA and 3

- phenoxybenzaldehyde. It does not appear to photode grade substantially in aqueous solutions.

Based on acceptable aerobic soil metabolism data, deltamethrin d egrade s rapidly (half

- life 11

- 19 days) to form DBVA or Br 2 CA (<10%) and CO 2 . The proposed routes of degradation are ester hydrolysis and microbial

- mediated mineralization to CO 2

. In an anaerobic soil metabolism study, deltamethrin degraded in an Arizona sandy loam (pH 8.1) with a half

- life of 32

- 36 days for theDeltamethrin Human Health Risk Assessment DP No. D413048

Page 29 of 64 benzyl and gem inal labels, respectively. For the gem inal label experiment, only 1 meta bolite,

Br 2 CA or decamethrinic acid, was found at 49% of the applied radioactivity by D ay 30, and

remained at about this level on D ays 59 (52%) and 90 (48%). For the benzyl label, the only

metabolite identified was 3

- phenoxybenzoic acid, which was only de tected in a D ay

- 30 sample, accounting for only 3% of the applied radioactivity. In an aerobic aquatic metabolism study, consisting of loam or sandy loam test systems from the Netherlands, the half

- lives for the whole systems were 26 and 120 days

, respecti vely. The major transformation product was the alpha

- R

isomer of deltamethrin, at up to 24% in the sandy loam.

In a fish bioconcentration study, deltamethrin had bio

- concentration factors of 1 89 x and 3630 x in edible and visceral fish tissues, respectiv ely. The whole body BCF of 698 x was calculated from edible and visceral fish tissue results. The majority of the radioactive residue found in fish was parent, accounting for 78 and 83% of the TRR in edible and viscer al fish tissues, respectively.

5.1.3 Comparison of Metabolic Pathways

In the rat metabolism studies, deltamethrin was relatively well absorbed after oral dosing, with rapid excretion via the urine and feces. Fecal extracts contained mostly unabsorbed, unchanged deltamethrin. Absorbed deltamethrin was cleaved at the ester site, a nd the cleaved products were rapidly conjugated into 4’SO 4

- m

- phenoxybenzoic acid and dibromocyclopropanecarboxylic

acid

- glucuronide, and then excreted in the urine

.

In plants and animals, parent cis

- deltamethrin can form the trans and alpha

- R isomers, whi ch can then undergo hydrolysis at the ester linkage.

5.1.4 Residues of Concern Summary and Rationale

The residues of concern in plants and livestock for both risk assessment and tolerance

enforcement are cis

- , trans

- , and alpha

- R deltamethrin. These s ame three isomers are the residues of concern for risk assessment in drinking water.

T ABLE 4.1.1 Summary of Deltamethrin Metabolites and Degradates to be Included in Risk Assessment

and the Tolerance Expression.

Matrix Residues in Risk Assessment Residues in the Tolerance Expression

Plants Primary crops Cis

- , trans

- and alpha

- R

- deltamethrin Cis

- , trans

- and alpha

- R

- deltamethrin

Rotational crops Not Applicable Not A pplicable

Livestock Ruminants Cis

- , trans

- and alpha

- R

- deltamethrin Cis

- , trans

- and alpha

- R

- deltamethrin

Poultry Drinking water Cis

- , trans

- and alpha

- R

- deltamethrin Not A pplicable

5 .2 Food Residue Profile

Pharmaq AS submitted the results o f a total of six deltamethrin magnitude of the residue studies

on finfish

. The studies examined the magnitude of residue in Atlantic salmon and rainbow trout following bath treatment in seawater

. R esidues were below the LOQ in all samples in all six

studies

.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 30 of 64 In the first set of residue studies, the fish were treated one time in tanks containing 3 ppb

deltamethrin for 40 minutes at either 5°C or 10 °C . Residues of deltamethrin were below the limit of quantitation (LOQ) of 0.01 ppm in all samples of salmon muscle with skin, and salmon

liver.

In the second set of studies, deltame thrin residues were measured in large Atlantic salmon and

rainbow trout after bath treatment in seawater . The fish were treated one time in tanks containing deltamethrin at 3 ppb in seawater for 40 minutes at 5°C. Residues of deltamethrin

were below the LO D (<0.005 ppm) in all samples of salmon muscle with skin collected 1, 2

, and 6 hours after exposure, and in all samples of rainbow trout muscle with skin collected 2 and 6 hours after exposure. In samples of rainbow trout muscle with skin collected 1 ho ur after exposure, quantifiable residues were observed in one sample at 0.0056 ppm . R esidues were

below the LO D of 0.005 ppm in all remaining samples.

Th e third set of studies investigat ed the magnitude of deltamethrin residues in large commercial

Atla ntic salmon and rainbow trout following bath treatment in seawater . In both studies, the fish were treated one time in tanks containing 2 ppb deltamethrin for 30 minutes at ≤12°C. Residues of deltamethrin were below the LOQ (<0.005 ppm) in all samples of salmon muscle with skin, and in all samples of rainbow trout muscle with skin.

T he residue data are presented in Table 5. 2 .1.

T able 5.2.1

. Summary of Residue Data from Fish Treatment Study with Deltamethrin

Matrix Exposure

Level Time Point

(Hours) 1 Residue Levels (ppm) 2

n Min. Max. Median Mean Std. Dev.

Muscle with

skin 3 ppb 2 10 <0.01 <0.01 0.01 0.01 NA

6 20 <0.01 <0.01 0.01 0.01 NA

24 20 <0.01 <0.01 0.01 0.01 NA

Liver 2 10 <0.01 <0.01 0.01 0.01 NA

6 20 <0.01 <0.01 0.01 0.01 NA

24 20 <0.01 <0.01 0.01 0.01 NA

1. Time after termination of bath exposure to deltamethrin in seawater for 40 minutes at 10 or 5°C.

2. For calculation of median, mean

, and standard deviation, the LOQ (0.01 ppm) was used for any results reported as <LOQ ( n = number of samples; NA = Not A pplicable )

.

There are currently no established Codex or Canadian maximum r esidue l imit s ( MRLs ) for

deltamethrin in finfish . There is an MRL in salmon set at 0.03 ppm by the Joint FAO/WHO Expert Committee on Food Additi ves (JECFA), as a veterinary drug (not a pesticide) in 2003. As such, harmonization of HED’s recommended tolerance for residues of deltamethrin in import ed finfish is un necessary.

The registrant has not submitted processing stud ies for finfish , and non e are needed.

5.3 Water Residue Profile

EFED p rovided the results of a drinking water assessment that was performed for deltame thrin (D 335136

, J. Melendez

, 4/24 /20 07 )

. EFED calculated t he e stimated drinking waterDeltamethrin Human Health Risk Assessment DP No. D413048

Page 31 of 64 concentrations ( EDWCs ) for deltamethrin ba sed on a maximum application rate of 0.45 lb

a.i./A/season

. The acute drinking water concentration in surface water is 0. 20 pp b

, based on application to sweet corn. The cancer/chronic EDWC is 0.07 71 pp b (based on application to sweet corn with the high est application rate). The S creening C oncentration in G roundwater (SCIGROW) Model for groundwater generated an EDWC of 0. 200 pp b. This value is the same

as the surface water value and was recommended for use both for acute and chronic exposures.

Both the acute surface drinking water concentration and the ground drinking water concentration were limited by the solubility of deltamethrin.

5.4 Dietary Risk Assessment

Acute and chronic dietary (food and drinking water) exposure 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 Exa mination Survey,

What We E at in America, (NHANES/WWEIA). The chronic assessment was conducted solely for the purpose of obtaining estimates of background levels of dietary exposure for estimating aggregate risk.

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute Assessment

The acute dietary exposure assessment is partially refined. It is based on tolerance level residues for most commodities and Pesticide Data Program (PDP) monitoring data for cereal grains, apples, apple juice, apple s auce, cantaloupe, carrots, pears, tomatoes, watermelons, cucumbers, soybeans, and milk. Modeled EDWCs from EFED were used for drinking water. The assessment is also based on the maximum percent crop treated estimates provided by the Biological and Econom ic Analysis Division (BEAD). DEEM

- FCID Version 7.81 default processing factors were used for some processed commodities and empirical factors were used

for others.

Chronic Assessment

Deltamethrin is registered for use in food handling establishments (FHE s ) . As a result, residue

values were entered for all commodities in DEEM

- FCID. For most commodities with established and proposed tolerances, the tolerance was used as the residue value. For cereal grain commodities, average monitoring data values were used. For milk, PDP monitoring data were used. For the commodities for which the only established tolerance is the FHE tolerance, a residue value of 0.025 ppm (1⁄2 the FHE tolerance) was used. For commodities with tolerances for agricultural uses, BE AD’s average percent crop treated estimates were generally used. BEAD provided an estimate of the probability that a food a person consumes contains residues as a result of treatment in an FHE at some point with any pesticide. It is not specific to

delta methrin. This estimate is 4.65%. In the chronic assessment, this value was used for the same commodities as the ones with the FHE residue value (0.025 ppm). As with the acute assessment, modeled EDWCs were used for drinking water.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 32 of 64 C a nc er Assessment

C an cer risk is not of concern for deltam e thrin because the compound is classified as “not likely to be carcinogenic to humans. ”

5.4.2 Percent Crop Treated Used in Dietary Assessment

Acute Assessment

The following maximum percent crop treated estimates ( SLUA, 5/5/2014, BEAD Usage and Label Use Team) were used in the acute dietary risk assessment for the following crops that are currently registered for deltamethrin:

Crops with an assumption of 2.5% CT: apples

, cantaloupes

, carrots

, soybeans

, tomatoes

, and

watermelons

.

Crops with an assumption of 5% CT: cucumbers and pears.

Chronic Assessment

The following average percent crop treated estimates were used in the chronic dietary risk assessment for the following crops that are currently registered for deltamethrin:

Crops with an assumption of 1% CT: apples

, cantaloupes

, carrots

, cotton

, potatoes (some food forms), pumpkins

, radishes

, squash

, tomatoes

, turnips

, and watermelon s

.

Crops with an assumption of 2.5% CT: cucumbers

, leeks

, onions

, pears
, and sunflowers

.

Crops with an assumption of 4.65% CT: almonds, pistachios, potatoes (some food forms), soybeans, sweet corn, and walnuts.

Crops with an assumption of 5% CT: canola and peppers.

Finally, BEAD estimated 40% CT for globe artichokes

.

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 deltam ethrin )

. In the chronic assessment, for the commodities for which 1⁄2 the FHE tolerance was used, the assumption was made that there was a 4.65% chance that a food item consumed by a person contained deltamethrin residues as a result of treatment at some point in an FHE.

5.4.3 Acute Dietary Risk Assessment

The acute dietary 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 dietary risk e stimate for theDeltamethrin Human Health Risk Assessment DP No. D413048

Page 33 of 64 general U.S. population is 17% of the aPAD. The population subgroup with the highest acute dietary risk estimate is Children 3

- 5 years old , which uses 80% of the aPAD. As percent crop treated estimates were used for some commodities, the risk estimates are being reported at the

99.9 th percentile of exposure.

5.4. 4 Chronic Dietary Exposure Assessment

The chronic dietary exposure estimate for the general U.S. population is 0.000 25 4 mg/kg/day. The population subgroup with the highest chronic dietary exposure estimate is Children 1

- 2 years old , which has a dietary exposure estimate of 0.000 822 mg/kg/day.

5.4. 5 Summary Table

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

Population Subgroup Acute Assessment (99.9 th Percentile) Chronic Assessment
aPAD, mg/kg/day Exposure Estimate,

mg/kg/day % aPAD

cPAD Exposure Estimate, mg/kg/day % cPAD

U.S. Population 0.0149 0.00 2588 17 NA 0.000254

NA All infants 0.005 0. 003359 67 NA 0.000298

Children 1

- 2 yrs* 0.005 0. 003797 7 6 NA 0.000822

Children 3

- 5 yrs * 0.005 0. 003989 80 NA 0.000601

Children 6

- 12 yrs 0.0149 0.00 2346 16 NA 0.000378

Youth 13

- 19 yrs 0.0149 0.00 1682 11 NA 0.000207

Adults 20

- 49 yrs 0.0149 0.0 02211 15 NA 0.000194

Adults 50

- 99 yrs 0.0149 0.00 1709 11 NA 0.000210

Females 13

- 49 yrs 0.0149 0.00 2672 18 NA 0.000192 *Most highly exposed population subgroup s

6.0 Residential (Non

- Occupational) Exposure /R isk Characterization

(M.Collantes, D4 18867

, 6/11 /2014)

This document provides a revised residential handler and post

- application exposure assessment

for existing residential indoor, outdoor, pet, and paint preservative uses that were evaluated in

the 2004 ORE assessment (M. C ollantes, D307927, Oct. 14, 2004). The revised assessments reflect updates to HED’s 2012 Residential SOPs

, along with policy changes for body weight assumptions , updated inhalation and incidental oral toxicological endpoints and doses, and reduced FQPA Sa fety Factors for adult and children’s populations . The revis ed residential

exposure estimates have been provided for the purpose of updating the aggregate human health

risk assessment.

6 .1 Residential Handler Exposure/Risk Estimates for Registered Uses

As the deltamethrin label s do not identify th ese residential use product s as a restricted use, a

revised residential handler exposure assessment was performed to be protective of potential

homeowner s who apply deltamethrin as indoor, outdoor, turf, paint, and pet collar use/ treatment.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 34 of 64 The quantitative exposure/risk assessment developed for the previously assessed residential handlers is based on the following (wors t case) scenarios:

 M ix/Load/Apply liquid s prays u sing manually pressurized h andwand for indoor spot and crack & crevice treatment,

 M ix/Load/Apply liquid s uspension concentrate (SC) s prays u sing hose

- end sprayer for turf/lawn,

 M ix/Load/Apply liquid (SC) s prays u sing backpack sprayer for turf/lawn,

 Mix/Load/Apply wettable powder using man ually pressurized handwand for turf/lawn,

 M ix/Load/Apply wettable powder u sing backpack sprayer for turf/lawn,

 M ix/Load/Apply paint additive using airless sprayer,

 Load/Apply granules using belly grinder to lawn/turf,

 Load/Apply granules using shaker can t o outdoor sites,

 Apply aerosol spray to outdoor and indoor areas as a spot and crack & crevice treatment,

 Apply insecticidal dust to outdoor crack and crevice sites using shaker can, and

 Apply pet collar to dogs.

Summary of Residential Handler Exposure a nd Risk Estimates

Representative registered residential uses were reassessed using the revised 2012 Residential SOPs and revised inhalation endpoints and doses. All residential handler scenarios resulted in inhalation risk estimates greater than the LOC (MOEs ≥ 100) and are not of concern. The exposure estimates are summarized for the worst

- case residential handler exposure scenario for each registered product in Table 6.1

.

Table 6.1. Residential Handler Exposure and Risk Estimates for Deltamethrin Re gistered Uses.

Exposure Scenario Level of

Concern Inhalation

Unit Exposure (mg/lb ai) Maximum

Application

Rate 1 Area Treated or

Amount

Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

Mix/Load/Appl y
Manually Pressurized

Handwand for Indoor

Crack & Crevice and

Mattress Treatment

K

- Othrine SC Insecticide (4.75% ai)
Reg. No.432

- 763

100 1.1 0.005 lb ai/gal 0.5 gals 0.000034 43,000

Hose

- end Sprayer

– Turf

K

- Othrine SC Insecticide (4.75% ai)
Reg. No.432

- 763 0.022 0 .13 lb ai /A 0.5 A 0.000018 83,000

Back Pack

- Garden and

Trees

K

- Othrine SC Insecticide (4.75% ai)
Reg. No.432

- 763 0.14 0.005 lb ai/gal 5 gals 0.000044 3 4 ,000Deltamethrin Human Health Risk Assessment DP No. D413048

Page 35 of 64 Table 6.1. Residential Handler Exposure and Risk Estimates for Deltamethrin Re gistered Uses.

Exposure Scenario Level of

Concern Inhalation

Unit Exposure (mg/lb ai) Maximum

Application

Rate 1 Area Treated or

Amount

Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

Manually Pressurized

Handwand and Backpack

– Lawn/Turf

and Gardens/Trees

Delta Wettable Powder

(5% ai)
Reg. No. 432

- 832 1.1 0.005 lb ai/gal 5 gals 0.00034 4,3 00

Airless Sprayer
Bug Juice Insecticidal Additive (4.75% ai)
Reg. No. 47332

- 11 0.56 0.005
lb ai/gal/can 5 gals 0.00018 8

, 5 00

Load/Appl y Belly Grinder

Delta Granules (0.1% ai )
Reg. No. 4

- 422 100 0.039 0.000003

lb ai/ft 2 1200 ft 2 0.0000018 85 0,000

Appl y

Shaker Can

– Garden/Trees
Many Purpose Dust
RTU (0.05% ai)
Reg. No. 73327

- 14

100 18 0.00000066

lb ai/ft 2 1200 ft 2 0.00018 8,4 00

Aerosol Spray

– Garden/Trees

D

- Force Insecticide

(0.06% ai)
Reg. No. 279

- 9554

3 0.00075

lb ai/can 2 cans 0.000056 26 ,000

Aerosol Spray

– Indoor Crack & Crevice

and Mattress

D

- Force Insecticide

(0.06% ai)
Reg. No. 279

- 9554 0.5 can 0.000014 110,000

Ready

- to

- Use Pet Collar

(4% ai)
Reg. No. 4

- 422 negligible 0.0024 lb ai/pet 2 pet NA

1 Based on registered or proposed label s

. 2 Based on HED’s 2012 Residential SOPs

3 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate × Area Treated or Amount Handled ÷ B ody W eight ( 80 kg).

4 Inhalation MOE = Inhalation NOAEL ( 1.49 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).Deltamethrin Human Health Risk Assessment DP No. D413048

Page 36 of 64 6

. 2 Residential Post

- application Exposure/Risk Estimates for Registered Uses

There is the potential for post

- application exposure for individuals resulting from being in an environment that has been previo usly treated with deltamethrin. A residential post

- application exposure assessment and amendment were previously performed for existing residential indoor, outdoor, lawn, pet collar

, and paint uses in 2003 and 2004 (D287835, M. Collantes, 7/18/2003;

and D 307927, M. Collantes, 10/14/2004). Risk estimates for these registered residential

scenarios have been revised to reflect updates to HED’s 2012 Residential SOPs along with policy changes for body weight assumptions and updated toxicological endpoints. T he quantitative exposure assessment for residential post

- application exposures is based on the following scenarios:

 Incidental oral (hand

- to

- mouth and object

- to

- mouth ) contact with residues deposited on

lawn/ turf resulting from liquid and granular formu lations

,

 Incidental oral ( soil ingestion ) contact with residues deposited on lawn/ turf resulting from liquid and granular formulations

,

 Episodic g ranular i ngestion resulting from granular formulations

,

 Incidental oral (hand

- to

- mouth and object

- to

- mouth ) contact with residues deposited on

indoor surfaces from spot and crack & crevice treatment s resulting from liquid formulations

,

 Inhalation exposure of residues resulting from exposure to indoor pesticide vapors from liquid formulations

, and

 Incidental or al (hand

- to

- mouth) contact with residues from dogs wearing treated pet collars.

Residential Post

- application Exposure Data and Assumptions :

A series of assumptions and exposure factors served as the basis for completing the residential

post

- application risk assessment and are briefly described below. Each assumption and factor is detailed in the 2012 Residential SOPs and a chemical specific d islodgeable residue study performed on dogs wear ing impregnated pet collars ( Deltamethrin: Two month dislodgeable residue study of deltamethrin in beagle dogs treated with Scalibor ® Protector Band; MRID# 49350101; D420043; March 2014; A. Prohaczik, D.M.V. Ph.D.; MSD Animal Health Innovation SAS, Beaucouze France )

. This residue transfer study was recently submitted in support of the registered pet collar use. It was determined to be acceptable for risk quantitation. A summary of this study is provided in the 2014 occupational and residential exposure assessment for deltamethrin (D41 8867 , M. Collantes, 6 / 11 /2014).

Episodic Granular Ingestion

The product, Delta Granules (Reg. No. 4

- 422) may be applied by a spreader to home lawns, under shrubbery

, and to other ornamental recreational turf grass areas. The Residential SOP for Turf and Lawns was used to estimate post

- application doses from incidental ingestion of pesticide granules applied to lawns and gardens. Ingestion of granules is considered an episod ic (or acute) event and not a routine behavior for children. Since HED does not believe that this would occur on a regular basis, the scenario is considered to be an acute poisoning rather than a

short

- term exposure typically assessed in HED’s human healt h risk assessments. Furthermore,Deltamethrin Human Health Risk Assessment DP No. D413048

Page 37 of 64 the registered label instructs the user to thoroughly water treated areas after application so that both granules and lawns are moistened to ensure granules dissolve properly.

In an effort to refine the post

- application dose and respective MOE for incidental ingestion of granules, the default granular ingestion rate of 0.3 g/day was adjusted to 0.14 g/day to reflect the amount of product applied on a per area basis (3 lb/1000 ft 2 ). This adjustment resulted in a dose

of 0.14 mg/kg/day and a n MOE of 120. In order to achieve an MOE greater than the LOC (MOE ≥ 300), the application rate would need to be reduced from 0.000003 lb ai/ft 2 to 0.000001

lb ai/ft 2 , which would result in a post

- application dose of 0.005 and a n MOE o f 300.

Summary of Residential Post

- application Non

- Cancer Exposure and Risk Estimates

In the absence of toxicity via the dermal route, no qua n titative dermal post

- application exposure assessment was required. All the representative indoor/outdoor and pe t incidental oral (hand

- to

mouth , object

- to

- mouth, soil ingestion, and episodic granule ingestion ) post

- application scenarios resulted in risk estimates ranging from an MOE of 630 to 24,000 and are not of

concern. A summary of the registered residential p ost

- application exposure and risk estimates for deltamethrin is provided in Table 6.2

.

Table 6.2. Registered Residential Post

- application Non

- cancer Exposure and

Risk Estimates for Deltamethrin.

Lifestage Post

- application Exposure

Scenario Application

Rate 1 Dose

(mg/kg/day) 2 MOEs 3 Combined MOEs

Use Site Route of

Exposure

Adult Indoor C&C

K

- Othrine SC

Insecticide Reg. No.432

- 763 (0.06% ai) Dermal

0.005 lb ai/gal NA NA

NA Inhalation

Child Dermal NA NA Inhalation

HTM 0.0000614 24,000

OTM 0.000039 38,000

Adult Indoor C&C

and Mattress

D

- Force Ready

- to

- Use Aerosol Spray Reg. No. 279

- 9554 Dermal

0.00075 lb

ai/can NA NA Dermal Mattress

Inhalation

Child Dermal

NA NA

Dermal Mattress

Inhalation

HTM 0.0023 630

OTM 0.00031 4700

Adult

Lawn/Turf

Delta

Granules Reg.

No. 4

- 422 Dermal

0.13 lb ai/A

or
0.000003 lb

ai/ft 2 NA NA

NA Inhalation

Child Dermal NA NA Inhalation

HTM 0.0002 7,600

OTM 0.00001 120,000

Soil Ingestion 0.000044 340,000
Episodic Ingestion 0.0127 120

Adult Lawn/Turf Dermal 0.13 lb ai/A NA NA InhalationDeltamethrin Human Health Risk Assessment DP No. D413048

Page 38 of 64 Table 6.2. Registered Residential Post

- application Non

- cancer Exposure and

Risk Estimates for Deltamethrin.

Lifestage Post

- application Exposure

Scenario Application

Rate 1 Dose

(mg/kg/day) 2 MOEs 3 Combined MOEs

Use Site Route of

Exposure

Child K

- Othrine SC

Insecticide Reg. No.432

- 763 (0.06% ai) Dermal NA NA

Inhalation

HTM 0.002 750

OTM 0.00006 25,000
Soil Ingestion 0.000034 340,000

Adult

4%

Deltamethrin

Pet Collar (Reg. No.

68451

- 1) Dermal

0.0024 lb ai/pet NA NA Inhalation

Child Dermal NA NA Inhalation

HTM (small dog) 0.000014 11,000

HTM (medium size dog) 0.0000058 26,000

HTM (large dog) 0.0000037 400,000

1 Based o n registered or proposed label

. 2 Dose (mg/kg/day) equations: see Appendixes B

- D for specific equations used by exposure scenario.

3 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day).

Turf Transferable Residue (TTR) Data

In accordance with 40CFR § 158, TTR data are required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses that could result in post

- application exposure to turf. In the absence of chemical

- specific TTR data, EPA uses default values. The 2012 SOPs for Residential Pesticide Exposure Assessment includes an analysis of all TTR data, available at the time, which resulted in the selection of revised liquid and granular def ault values for the fraction of the application rate (FAR) available for transfer after a turf application. These values are based on an analysis of 59 TTR studies performed with the Modified California Roller Method (36 studies using liquids, 11 studies using wettable powders/water dispersible granules, and 12 studies using granules). The liquid results (N=131) indicate a range of FAR values from

0.0005% to 6.1%

, and the granular results (N=37) indicate a range of 0.00064% to 0.69%. In both the liquid a nd granular data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient

, formulation

, field

conditions in the studies

, weather conditions (e.g., humidity)

, or many other factors that are difficult to quantify. Although witnessed across multiple chemicals, this range in FAR values is not expected when considering TTR data for a single chemical. HED selected 1% and 0.2% as high

- end default values for liquid and granular pr oducts, respectively. Because TTR data are not available for deltamethrin, EPA is using the default value of 1%. Although there may be a small degree of uncertainty in the use of the default TTR value for deltamethrin (i.e., there is a smallDeltamethrin Human Health Risk Assessment DP No. D413048

Page 39 of 64 chance that the FAR value may exceed the applicable default value), it is likely that the health

protective aspects of EPA’s residential post

- application turf assessment methodology will more than compensate for this potential uncertainty (i.e., the methodology is lik ely to overestimate exposure by a factor greater than the factor by which the highest measured FAR values exceed the defaults). For example, when assessing residential post

- application turf exposure, EPA assumes the following: exposures occur to zero

- day (i.e., day of application) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs,

e.g., it doesn’t rain, the grass is not mowed, etc); individuals perform the same post

- application activities perf

ormed in the turf transfer coefficient study day after day (e.g., tumbling, playing on turf with toys, etc.); and individuals engage in these post application activities for a high

- end amount of time every day that is represented by data reflecting time ch ildren spend outdoors and not specifically engaged in activities on turf, when in actuality

, children do not spend all of their

outdoor time on turf

, and high

- end levels of activity will not occur every day.

Given the conservatisms discussed above and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being underestimated.

Since the estimated residential turf incidental oral post

- applic ation exposu re for residential

turf using default TTR values for deltamethr in 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 = 750 compared to the LOC of 3000), future refinements of this post

- application incidental

oral exposure for deltamethrin may be necessary due to i ncreased use of deltamethrin or

advances in EPA risk assessments. Therefore, EPA i s requiring the 40 CFR § 158 TTR requirement to facilitate any necessary exposure assessment r efinements and to further EPA’s general understanding of the availability of turf transferable pesticide residues.

6

. 3 Residential Risk Estimates for Use in Aggregate Assessment

The recommended residential exposure for use in the adult aggregate assessment reflects the inhalation handler exposure resulting from the flea control scenario (i.e., treatment of lawns/turf and gardens/trees by manually pressurized handgun and backpack). T his scenario resulted in a n MOE of 4,300 and is not of concern.

The incidental oral (hand

- to

- mouth) post

- application exposure scenario for the c ontrol of bed bugs was selected to estimate the child aggregate assessment. This scenario resulted in a n MOE

of 630 and is not a risk of concern. A summary of the residential risk estimates for use in the

aggregate assessment is provided in Table 6.3

.

Table 6.3. Recommendation for Residential Exposures to be Included in the Deltamethrin Aggregate Assessment

Lifestage Residential Handler Residential Post

- application

Dose (mg/kg/day) MOE Dose (mg/kg/day) MOE

Dermal Inhalation Total Dermal Inhala

tion Total Dermal Inhala

tion Oral Total Dermal Inhal

ation Oral Total

Back Pack

– Garden and Trees Bed Bug Scenario (Indoor)

Adult Male NA 0.00034 NA NA 4,300 NA NA N/A N/A NA NA N/A N/A NA Adult Female

Child N/A 0.002 63 0Deltamethrin Human Health Risk Assessment DP No. D413048

Page 40 of 64 6.4 Residential Bystander Post

- application Inhalation Exposure

V olatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby outdoor pesticide applications. The agency sought expert advice and input on issues related to volatilization 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 ( http://www .epa.gov/scipoly/SAP/meetings/2009/120109 meeting.html )

. The A gency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). During Registration Review, the A gency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for deltamethrin

.

6.5 Spray Drift

There is no potential for spray drift associated with the proposed use on finfish. However, s pray drift is a potential source of exposure to those nearby pesticide applications of deltamethrin to agricultural field crops . This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for deltamethrin

. The A gency has been 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 the best spray drift management practices (see the agency’s Spray Drift website for more information). 1 The

A gency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides.

The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Rev iew process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Standard Oper ating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification

of indirect non

- occupational exposure to drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risk

estimate s from three major sources: food, drinking water, and residential 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 and risks from various sources, HED considers both the route and duration of exposure.

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmDeltamethrin Human Health Risk Assessment DP No. D413048

Page 41 of 64 7.1 Acute Aggregate Risk

A cute aggregate risk of exposure to de ltam ethrin 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

, as discussed in Section 5.4.3, above. Acute aggregate risk is not of concern for the general U.S. population or any population subgroup

.

7.2 Short

- Term Aggregate Risk Estimates

S hort

- term aggregate risk assessments are needed for adults and children

. F or the short

- term aggregate assessment for adults, residential handler inhalation exposure needs to be combined with background exposure from food and water. For the short

- term aggregate assessment for

children

, post

- application incidental oral exposure ( i.e., hand to mouth transfer ) need s to be combined with background exposure from food and water. The chronic dietary exposure estimates serve as the background dietary exposure. Of the population subgroups comprised of adults, the U.S. population has the highest dietary exposure estimate. Of the population subgroups comprised of infants and children, the subgroup with the highest dietary exposure

estimate is Children 1

- 2 years old. As the oral and inhalation endpoints and points of departure

are the sam e, the exposures for both adults and children can be added to determine the total

exposure. The LOC for adult populations is 100. The MOE s for the general U.S. population and

Females 13

- 49 are 2, 5 00 and 2, 8 00

, respectively . These MOEs are not of concern. The LOC for

children < 6 years old is 300. The MOE for Children 1

- 2 years old is 5 3 0 and is not of concern. A summary of the aggregate risk estimates is provided in Table 7.2.

Table 7.2 Short

- Term Aggregate Risk Calculations

Oral and Inhalation Endpoints and Points of Departure A re the S ame

Population Short

- Term Scenario

BMDL 1SD mg/kg/day LOC 1 Max

Allowable Exposure 2 mg/kg/day Average Food

and Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Tota l

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5
U.S. Population 1.49 100 0.0149 0.000 25 4 0.00034 0.000 59 4 2, 5 00

Females 13

- 49 1.49 100 0.0149 0.000 192 0.00034 0.000 532 2, 8 00

Child ren 1

- 2 1.49 300 0.005 0.000 822 0.002 0.002 822 5 3 0

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 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = Oral exposure (children) or Inhalation Exposure (adults)

. See Table 6.3 for residential exposure estimates.

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure

5 Aggregate MOE = BMDL 1SD (1.49 mg/kg/day) ÷ (Avg Food & Water Exposure + Residential Exposure)

8.0 Cumulative Exposure/Risk Characterization

The Agency is required to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. Th e Agency has determined that the pyrethroids and pyrethrins share aDeltamethrin Human Health Risk Assessment DP No. D413048

Page 42 of 64 common mechanism of toxicity ( http://www.regulations.gov ; EPA

- HQ

- OPP

- 2008

- 0489

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

- gated sodium channels ultimately leading to neurotoxicity. The 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

, allowing 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

.

Deltam e thrin is included in the pyrethroid/pyrethrin cumulative risk assessment (CRA) . The proposed i mport tolerance on finfish ha s an insignificant impact on the cumulative risk assessment. No dietary, residential, or aggregate risk estimates of concern have been identified in the single chemical assessment. In the cumulative assessment, residential ex posure was the greatest contributor to the total exposure . A lthough there are residential uses for deltam ethrin

, the proposed import tolerance for finfish will have no impact on the residential component of the

cumulative risk estimates

. In order to dete rmine if the registered deltamethrin indoor and turf

uses 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

deltamethrin relati ve potency factor ( 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 .2 of the 2011 pyrethroid CRA were compared with the MOEs currently driving turf and indoor crack and crevice exposures and risks

in Table 6.4.7a from the pyrethroid CRA

. Adult handler exposures and risks estimates are currently driven by cyfluthrin turf use (i.e. mixing/loading/applying via hose

- end sprayer) with a

dermal MOE of 9,200 and combined (dermal + inhalation) MOE of 8,900, which are lower than the estimated deltamethrin dermal MOE of 15,000 and combined MOE of 500,000. Adult and child dermal post

- application exposure and risk are also currently driven by cyfluthrin tur f use with an MOE of 4,500 and 3,000 respectively. For children < 6 year s old, hand

- to

- mouth post

application exposure and risk estimates are currently driven by the cy halothrin indoor crack and

crevice use with an MOE of 9,7 00, which is lower than the est imated deltamethrin MOE o f 16,0 00. A summary of these MOEs is presented in Appendix Table A .2

, while the detailed

calculations for deltamethrin are presented in Appendix Table A .3. In all cases, the estimated

deltamethrin MOEs using the RPF method were h igher (i.e., less of a risk concern) than those used in the 2011 pyrethroid CRA. Thus

, the Agency continues to support the previous

assessment

, and concludes that the registered deltamethrin use will not significantly contribute to the overall findings in the 2011 pyrethroid CRA.

D ietary exposures make a minor contribution to the total pyrethroid exposure. The dietary exposure assessment performed in support of the pyrethroid cumulative was much more highly refined than that performed for the single chem ical. In addition, f or the deltam e thrin risk assessment, the most sensitive apical endpoint in the deltam e thrin database was selected to derive the POD. Additionally, the POD selected for deltam e thrin is specific to deltame 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. Dietary exposure to deltame thrin residues resulting from the proposed import tolerance on finfishDeltamethrin Human Health Risk Assessment DP No. D413048

Page 43 of 64 will contribute very little to the dietary exposure to deltame thrin alone. As a result, the proposed

tolerance will make an insignificant contribution to dietary risk to the pyrethroids as a whole.

9.0 Occupational Exposure/Risk Characterization

There is no occupational exposure associated with this action to establish tolerance s on imported finfish; t herefore, an occupational exposure assessment was not completed.

10.0 References

D41 313 5, Deltamethrin. Petition to Establish Permanent Tolerances (without US Section 3 Registration) for Residues Resulting from Use of the Insecticide on Imported Finfish . Summary of Analytical Chemistry and Residue Data.

, 6 / 17 /201 4

D420895, Deltamethrin. Acut e and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Proposed Use of Deltamethrin Without U.S. Registration

on Finfish

, D. Dotson, 8/4 /201 4

M. Collantes, D41 8867

, Revised Residential Exposure Assessment to Support A Tolerance without a U.S. Registration on Imported Fish, June 11, 2014.

D335136, J. Melendez

, Tier I Estimated Drinking Water Concentrations of Deltamethrin for the

Use in the Human Health Risk Assessm ent: IR

- 4 Tolerance Petition for the Use of Deltamethrin

on Flax

, 4/ 2 4 /20 07

K. Whitby, D394576, Pyrethroid Cumulative Risk Assessment , 10/4/2011

TXR# 0056944, Deltamethrin: Summary of Hazard and Science Policy Council (HASPOC) Meeting of February13, 20 14: Recommendation on the Requirements for a Subchronic Inhalation Study

, K. Rury, 4/29/2014

Anand, S. S., J. V. Bruckner, W. T. Haines, S. Muralidhara, J. W. Fisher and S. Padilla (2006).
“Ch aracterization of deltamethrin metabolism by rat plasma and liver microsomes.” Toxicol Appl Pharmacol 212(2): 156

- 166.

Cao, Z., T. J. Shafer, K. M. Crofton, C. Gennings and T. F. Murray (2011a). “ Additivity of Pyrethroid actions on sodium influx in cerebrocortical neurons in primary culture” Environ Health Perspect

.

Cao, Z., T. J. Shafer and T. F. Murry (2011b). “ Mechanisms of pyrethroid insecticide

- induced

stimulation of calcium influx in neocortical neurons. ” J Pharmacol Exper Ther 336(1): 197

- 205.

Choi, J.

- S. and D. M . Soderlund (2006). “ Structure

- activity relationships for the action of 11 pyrethroid insecticides on rat Nav1.8 sodium channels expressed in Xenopus oocytes. ” Toxicology and Applied Pharmacology 211(3): 233

- 244.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 44 of 64 Crofton, K. M., L. S. Kehn and M. E. Gilber t (1995). “ Vehicle and route dependent effects of a pyrethroid insecticide, deltamethrin, on motor function in the rat. ” Neurotoxicol Teratol 17(4)

489

- 495.

Godin, S. J., M. J. DeVito, M. F. Hughes, D. G. Ross, E. J. Scollon, J. M. Starr, R. W. Setzer, R

. B. Conolly and R. Tornero

- Velez (2010). “ Physiologically based pharmacokinetic modeling of deltamethrin: Development of a rat and human diffusion

- limited model. ” Toxicol Sci 115(2):

330

- 343. Goldin, A. L., R. L. Barchi, J. H. Caldwell, F. Hofmann, J. R. Howe, J. C. Hunter, R. G. Kallen, G. Mandel, M. H. Meisler, Y. B. Netter, M. Noda, M. M. Tamkun, S. G. Waxman, J. N. Wood, and W. A. Catterall (2000). “ Nomenclature of voltage

- gated sodium channels. ” Neuron 28(2): p.

365

- 368.

Goldin, A. L. (2002). “ Evolution of voltage

- gated Na+ channels. ” J Exp Biol 205(5): p. 575

Koukouritaki, S. B., J. R. manro, S. A. Marsh, J. C. Stevens, A. E. Rettie, D. G. McCarver, and R. N. Hines (2004). “ Developmental expression of human hepatic CYP2C9 and CYP2C19. ” J

Pha rmacol Exp Ther 308(3): p. 965

- 974.

Lawrence, L. and J. Casida (1982). “ Pyrethroid toxicology: Mouse intracerebral sturcture

toxicity relationships. ” Pestic Biochem Physiol 18: 9

- 14.

Lund, A. and T. Narahashi (1982). “ Dose

- dependent interaction of the pyrethroid isomers with sodium channels of squid axon membranes. ” Neurotoxicology 3(1): 11

- 24.

Meacham, C. A., P. D. Brodfuehrer, J. A. Watkins and T. J. Shafer (2008). “ Developmentally

regulated sodium channel subunits are differentially sensitive to [a lpha]

- cyano containing pyrethroids. ” Toxicology and Applied Pharmacology 231: 273

- 81.

Mirfazaelian, A., K. B. Kim, S. S. Anand, H. J. Kim, R. Tornero

- Velez, J. V. Bruckner, and J. W. Fisher (2006). “ Development of a physiologically based pharmacokinetic model for deltamethrin in the adult male Sprague

- Dawley rat. ” Toxicol Sci 93(2): p. 432

- 442.

Salgado, V., M. Herman and T. Narahashi (1989). “ Interactions of the pyrethroid fenvalerate with nerve membrane sodium channels: Temperature dependence and me chanism of depolarization. ” Neurotoxicology 10(1): 1

- 14.

Sample, B. E. and C. A. Arenal (1999). “ Allometric Models for Interspecies Extrapolation of Wildlife Toxicity Data. ” Bull Environ Contam Toxicol 62: 653

- 663.

Scollon, E. J., J. M. Starr, K. M. Crofton, M. J. Wolansky, M. J. DeVito, and M. F. Hughes (2011). “ Correlation of tissue concentrations of the pyrethroid bifenthrin with neurotoxicity in

the rat. ” Toxicology 290: 1

- 6.

Shafer, T. J., D. Meyer and K. M. C rofton (2005). “ Developmental neurotoxicity of pyrethroid

insecticides: critical review and future needs. ” Environ Health Persp 113(2): 123

- 136.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 45 of 64 Sheets, L. P., J. D. Doherty, M. W. Law, L. W. Reiter and K. M. Crofton (1994). “ Age

dependent differences in the susceptibility of rats to deltamethrin. ” Toxicol Appl Pharmacol 126(1): 186

- 190.

Soderlund, D., J. Clark, L. Sheets, L. Mullin, V. Piccirillo, D. Sargent, J. Stevens and M. Weiner (2002). “ Mechanisms of pyrethroid neurotoxicity: implications for cum ulative risk assessment. ” Toxicology 171(1): 3

- 59. Song, J. H. and T. Narahashi (1996). “ Modulation of sodium channels of rat cerebellar purkinje neurons by the pyrethroid tetramethrin. ” Journal of Pharmacology and Experimental Therapeutics 277: 445

- 53

.

Tabarean, I. V. and T. Narahashi (1998). “ Potent modulation of tetrodotoxin

- sensitive and

tetrodotoxin

- resistant sodium channels by the Type II pyrethroid deltamethrin. ” J Pharmacol Exp Ther 284(3): 958

- 965.

Tan, J. and D. M. Soderlund (2009). “ Human and rat Nav1.3 voltage

- gated sodium channels differ in inactivation properties and sensitivity to the pyrethroid insecticide tefluthrin. ” Neurotoxicology 30(1): 81

- 89.

Tornero

- Velez, R., A. Mirfazaelian, K.

- B. Kim, S. S. Anand, H. J. Kim, W. T. Haines, B . James V and J. W. Fisher (2010). “ Evaluation of deltamethrin kinetics and dosimetry in the maturing rat using a PBPK model. ” Toxicol Appl Pharmacol 244: 208

- 217.

USEPA, 2007, Meeting Minutes: FIFRA SAP Meeting on assessing approaches for the developme nt of PBPK models of pyrethroid pesticides. Document ID: EPA

- HQ

- OPP

- 2007

- 0388

- 0049.

USEPA, 2012, Benchmark Dose Technical Guidance EPA/100/R

- 12/001.

Verschoyle, R. D. and W. N. Aldridge (1980). “ Structure

- activity relationships of some pyrethroids in rats. ” Arch Toxicol 45(4): 325

- 329.

Weiner, M. L., M. Nemec, L. Sheets, D. Sargent and C. Breckenridge (2009). “ Comparative functional observational battery study of twelve commercial pyrethroid insecticides in male rats following acute oral exposure. ” Neurotoxicology 30 Suppl 1: S1

- 16.

Wolansky, M., C. Gennings and K. Crofton (2006). “ Relative potencies for acute effects of pyrethroids on motor function in rats. ” Toxicol Sci 89(1): 271

- 277.

Wolansky, M. J. and J. A. Harrill (2008). “ Neurobehavioral toxicology of pyrethroid insecticides

in adult animals: A critical review. ” Neurotoxicol Teratol 30(2): 55

- 78.

Yang, D., R. E. Pearce, X. Wang, R. Gaedigk, Y. J. Wan, and B. Yan (2009). “ Human carboxylesterases HCE1 and HCE2: Ontogenic expression, inter

- individual variability andDeltamethrin Human Health Risk Assessment DP No. D413048

Page 46 of 64 differential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin. ” Biochem

Pharmacol 77 (2): p. 238

- 247.

de Zwart, L., M. Scholten, J. G. Monbaliu, P. P. Annaert, J. M. Van Houdt, I. Van den Wyngaert,

L. M. De Scha epdrijver, G. P. Bailey, T. P. Coogan, W. C. Coussement, and G. S. Mannens (2008). “ The ontogeny of drug metabolizing enzymes and transporters in the rat. ” Reprod

Toxicol 26(3

- 4): p. 220

- 230.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 47 of 64 Appendices

Appendix A: Toxicology Profile

Appendix A.1. Toxicology Data Requirements

Toxicology Requirements for Deltamethrin

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

no 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 (Rat)

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

yes
yes
yes
yes

870.5100 Mutagenicity: Gene Mutation

- bacterial

............................... 870.5300 Mutagenicity: Gene Mutation

- mammalian

.......................... 870.5375 Mutagenicity: Structural Chromosomal Aberrations

............. 870.5385 Mutagenicity: Structural Chromosomal Aberrations

............. 870.5500 Mutagenicity: Other Genotoxic Effects

................................ . 870.5550 Mutagenicity: Other Genotoxic Effects

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

870.7485 General Metabolism

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

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

yes yes

yes

yesDeltamethrin Human Health Risk Assessment DP No. D413048

Page 48 of 64 Appendix A2. Toxicity Profile Tables

Table A2.1 Acute Toxicity of Deltamethrin

Guideline No./Study Type MRID Results Toxicity Category

870.1100 Acute oral toxicity (rat) 41651019

00070734 LD 50 = > 5000 mk/kg (1% aqueous

methyl cellulose)

LD 50 = 66.7 mg/kg (M), 86 mg/kg (F) (polyethylene glycol)

LD 50 = 128.5 mg/kg (M), 138.7 mg/kg (F) (sesame oil) IV

II

870.1200 Acute dermal toxicity (rat) 41651020 LD 50 = >2000 mg/kg III

870.1300 Acute inhalation toxicity (rat) 41651021

00070734 LC 50 = 2.2 mg/L

LC 50 = 0.6 mg/L III

II

870.2400 Acute eye irritation (rabbit) 41651022 Mild/moderate eye irritant III

870.2500 Acute dermal irritation (rabbit) 41651023 Not a dermal irritant IV

870.2600 Skin sensitization (guinea pig) 41651024 Not a dermal sensitizer NA

Table A2.2 Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification

/Doses Results

870.3100

90

- Day oral toxicity

rat 00098103 (1977) Acceptable /non

- guideline (stability and purity data absent)

M / F: 0, 0.1, 1.0, 2.5, 10.0 mg/kg/day NOAEL = 2.5 mg/kg/day LOAEL = 10 mg/kg/day based on increased hypersensitivity to sound in males and

females at week 6.

870.3150

90

- Day oral toxicity

dog 00098104 (1977) Acceptable /non

- guideline (agent purity not listed, too few animals (n=3 per sex/group), number of required observations were absent)

M/ F: 0, 0. 1, 1.0, 2.5, 10 mg/kg/day NOAEL = 1 mg/kg/day LOAEL = 2.5 mg/kg/day based on pupil dilation, depressed patellar reflex, and an increased incidence of diarrhea and vomiting.

870.3200

21

- Day dermal toxicity

- rat 42773901 (1993) Acceptable/guideline

M/ F: 0, 100, 300, 1000 mg/kg/day Systemic NOAEL = > 1000 mg/kg/day (limit dose)

The dermal NOAEL was not established: signs of local irritation (paresthesia) seen at

all doses.

LOAEL = not identified.

870.3250

90

- Day dermal toxicity NA NADeltamethrin Human Health Risk Assessment DP No. D413048

Page 49 of 64 Table A2.2 Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification

/Doses Results

21

- Day inhalation toxicity

- rat 00098089 (1978) Unacceptable/non

- guideline (Concerns over the distribution of deltamethrin inside the exposure chamber, particle size (no MMAD or GSD reported), and lack of incidence data reported for clinical findings).

M/ F: 0, 0 .003, 0.0096, 0.0563 mg/L for 6 h/day for 5 days/week NOAEL = 0.003 mg/L (0.783 mg/kg/day) LOAEL = 0.0096 mg/L (2.5 mg/kg/day) based on excessive salivation, hunched posture, peripheral vasodilation, aggressive behavior, hypersensitivity to noise, and

sc arring of the ears.

870.3700a

Prenatal developmental

- rat 41651025 (1990) Acceptable/guideline F: 1.0, 3.3, 7, 11 mg/kg/day Maternal NOAEL = 3.3 mg/kg/day LOAEL = 7 mg/kg/day based on increased

salivation in 11/25 animals and convulsions in

one animal (9 animals had convulsions at the next highest dose). Developmental NOAEL >11 mg/kg/day

LOAEL was not observed

.

00098092 (1976) Unacceptable/ guideline (not noted if increased in delayed ossification

were noted in fetal and/or litter incidences; neither route of administration or vehicle noted) F: 0, 0.1, 1.0, 10 mg/kg/day Maternal NOAEL = 1.0 mg/kg/day LOAEL = 10 mg/kg/day based on slightly

reduced body weight. Developmental NOAEL = 1.0 mg/kg/day LOAEL = 10 mg/kg/day based on delayed ossification of the sternebrae; fetal losses increased from controls (2.2, 2.6, 2.7, and 4%), though not statistically different.

870.3700b

Prenatal developmental

- mou se 00098092 (1976) Unacceptable/ guideline (not noted if increased in delayed ossification

were noted in fetal and/or litter incidences) F: 0, 0.1, 1.0, 10 mg/kg/day Maternal NOAEL =  10 mg/kg/day

LOAEL was not observed. Developmental NOAEL = 0.1 mg/kg/day LOAEL = 1.0 mg/kg/day based on decreased fetal weight, and delayed ossification of the sternebrae and paws

.

870.3700b

Prenatal developmental

- rabbit 45881901 (2001) Acceptable/ non

- guideline F: 0, 3, 10, 32 mg/kg/day in corn oil Maternal NOAEL = 32 mg/kg/day

LOAEL = not established. Developmental NOAEL  32 mg/kg/day

LOAEL = not established.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 50 of 64 Table A2.2 Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification

/Doses Results

00098092 (1976) Unacceptable /guideline (neither

route of administration or vehicle noted; details of teratogenic parameters examined not given) F: 0, 1, 4, 16 mg/kg/day Maternal NOAEL =  16 mg/kg/day

LOAEL was not observed Developmental NOAEL = 4 mg/kg/day LOAEL = 16 mg/kg/day based on decreased fetal weights and increased fetal loss (6.6, 18.5, 15.5, 10.2, 27.4%)

41651026 (1990) Unacceptable /guideline F: 0, 10, 25, 100 mg/kg/day in carboxymethylcellulose (deltametrhin dissolved in aqueous vehicles is reported to be less toxic) Maternal NOAEL = 100 mg/kg/day

LOAEL = was not established. Developmental NOAEL = 25 mg/kg/day

LOAEL = 100 mg/kg/day based on increases in delayed ossification and skeletal variations

.

870.3800 Reproduction and fertility effects

- rats 44398101 (1992) Acceptable/guideline M&F: 0, 5, 20, 80, 320 ppm

Parental animals M: 0, 0.3, 1.3, 5.4, 21.2 mg/kg/day F: 0, 0.4, 1.5, 6.1, 23.5 mg/kg/day

F 1 animals M: 0, 0.4, 1.4, 5.8, 24.9 mg/kg/day F: 0, 0.4, 1.7, 6.7, 27.2 mg/kg/day Parental/Systemic NOAEL = M: 5.4; F: 6.1 mg/kg/day LOAEL = M: 21.2; F: 23.5 mg/kg/day based on clinical signs in P generation (lesio ns on head, neck, and forearms in males and ataxia and hypersensitivity in females), decreased body weights in both the P and F 1 generation, and gross pathological findings in the F 1 generation. Offspring NOAEL = M: 5.8; F: 6.7 mg/kg/day LOAEL = M: 24.9; F: 27.2 mg/kg/day based on increased pup mortality (PND 8

- 14) in the

F 1 generation, increased mortality during the first 8 days post weaning in the F 1 generation, clinical signs that were observed early in the post weaning period in the F 1 generation (impa ired righting reflex, urine stained fur, hyperactivity, splayed limbs, vocalization, and salivation) and decreased pup weights in

the F 1 (PND 4

- 21) and F 2 generation (PND 7

- 21). Reproductive NOAEL = M:  24.9; F: 27.2 mg/kg/day

LOAEL = M:  21.2; F: 2 3.5 mg/kg/day

.

870.4100a Chronic toxicity

- rat Same as Chronic Toxicity/Carcinogenicity

- rat see below (870.4300) See below (870.4300)Deltamethrin Human Health Risk Assessment DP No. D413048

Page 51 of 64 Table A2.2 Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification

/Doses Results

870.4100b Chronic toxicity

- dog 44372601 (1993) Acceptable/guideline

M/ F: 0, 1, 10, 50 mg/kg/day (gelatin capsule)

- 52 weeks NOAEL = 1 mg/kg/day LOAEL = 10 mg/kg/day based on chewing and scratching of extremities, abnormal gait with body tremors, and liquid feces.

870.4200b Carcinogenicity

- mouse 44372602 (1995) Acceptable/guideline

M/ F: 0, 10, 100, 1 000, 2000 ppm M: 0, 1.5, 15.7, 155.4, 314.8 mg/kg/day F: 0, 2.0, 19.6, 189.3, 395.1 mg/kg/day NOAEL = 314.8/395.1 mg/kg/day ( M/F,HDT)

LOAEL = 603.4/738.8 mg/kg/day (M/F) based on decreased body weight observed in

the 12

- week range finding study.

No evidence of carcinogenicity, HDT assumed to be adequate to characterize the carcinogenic potential based on a 12

- week

range finding study in mice showing decreased body weight at 603.4/738.8 mg/kg/day (M/F).

870.4300

Chronic/ Carcinogenicity

- rat 44398102 (1995) Acceptable/guideline

M/ F: 0, 25, 125, 500, 800 ppm M: 0, 1.1 5.4, 22.2, 35.9 mg/kg/day F: 0, 1.5, 7.3, 29.5, 47.1 mg/kg/day NOAEL = 22.2/29.5 mg/kg/day (M/F) LOAEL = 35.9/47.1 based on unsteady gait and splayed hindlimbs observed in t he first few weeks of the study in male rats. No evidence of carcinogenicity, HDT assumed to be adequate to characterize the carcinogenic potential based on a 13

- week toxicity study in rats showing death, reduced body weight gains and marked neurological d isturbances at  1000 ppm

.

00098105 (1980) Unacceptable /guideline (inadequate dosing) M&F: 0, 2, 20, 50 ppm M&F: 0, 0.1, 1.0, 2.5 mg/kg/day NOAEL = >50 ppm (HDT)

LOAEL was not determined

No evidence of carcinogenicity

.

870.5100

Bacterial reverse mutation test

S. typhimurium 42475902 (1980) Acceptable/guideline 0, 2, 10, 50, 200, 1000, 5000 μg/plate +/

- S9 There was no evidence of an induced mutagenic effect at concentrations up to the limit dose (5000 μg/plate +/

- S9). Compound precipitation seen at  200 μg/plate.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 52 of 64 Table A2.2 Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification

/Doses Results

870.5375

In vitro mammalian

chromosome

aberration test

Chinese hamster ovary (CHO) cells 4 1651027 (1989) Acceptable/guideline 0, 19, 38, 75, 150 μg/mL +/

- S9 There was no evidence of an induced mutagenic effect up to cytotoxic
concentrations (  38 μg/mL

- S9; 150 μg/mL +S9). Levels  75 μg/mL were insoluble.

Other Genotoxicity

870.5550

Bacterial DNA damage/repair

E. coli 42475902 (1980) Acceptable/guideline 0, 1250, 2500, 5000 μg/well +/

- S9 There was no evidence of DNA repair/damage up to the limit dose (5000 μg/well +/

- S9). Compound precipitation seen

at  200 μg/well.

Other Genotoxicity

870.5550 Unscheduled DNA synthesis in primary rat hepatocytes 41651028 (1989) Acceptable/guideline 0, 0.13, 4.2, 13, 42, 130, 420, 1300, 4200 μg/mL There was no evidence that unscheduled DNA synthesis was induced up to insoluble

conce ntrations (  130 μg/mL).

870.6200a Acute neurotoxicity screening battery

- rats 44557901 (1998) Acceptable/guideline M&F: 0, 5, 15, 50 mg/kg Neurotoxic NOAEL= 15 mg/kg/day LOAEL = 50 mg/kg/day based on clinical signs during handling, open field, and sensory observations including, convulsions and tremors, increased salivation, soiled fur, impaired mobility, low arousal, decreased rearing, decreased fore

- and hind

- limb grip strength, and decreased body temperature.

870.6200b

Subchronic neurotoxicity screening battery 44557902 (1998) Acceptable/guideline M&F: 0, 50, 200, 800 ppm M: 0, 4, 14, 54 mg/kg/day F: 0, 4, 16, 58 mg/kg/day Neurotoxic NOAEL= M: 14; F: 16 mg/kg/day LOAEL = M: 54; F: 58 mg/kg/day based on mortality, clinical signs, FOB findings, and decreased body weights, body weight gains, and food consumption

.

870.6300 Developmental neurotoxicity 46814301 (2006) Acceptable/Non

- Guideline (pending review of positive

- control data) 0, 20, 80, 200 ppm 0, 1.6, 6.8, 16.1 mg/kg/day (gesta tion and lactation) Maternal NOAEL = 6.8 mg/kg/day.

Maternal LOAEL = 16.1 mg/kg/day based on decreased body weight (6

- 7% on GD 13 and GD 20). Offspring NOAEL = 6.8 mg/kg/day Offspring LOAEL = 16.1 mg/kg/day based on decreased pre

- and post

- weaning body weight and increased incidence of vocalizations (males) during FOB.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 53 of 64 Table A2.2 Subchronic, Chronic, and Other Toxicity Studies

Guideline No./ Study Type MRID No. (year)/Classification

/Doses Results

870.7485

Metabolism and pharmacokinetics

- rats 41677401 (1990) Acceptable/guideline

M/ F: 0.55, 5.5 mg/kg The test material was relatively well absorbed. Excretion was almost complete within 48 hours. Approximately 36

- 59% of

the dose was found in feces and an approximately equal amount in urine. Absorbed deltamethrin was cleaved by hydrolysis at the ester site follo wed by rapid sulfate and glucuronide conjugation.

870.7600 Dermal penetration NA NA

870.7800 Immunotoxicity 48988205 (2012) Acceptable/guideline F: 0, 8.3, 23.5, 48.3 mg/kg/day NOAEL = 48.3 mg/kg/day

LOAEL = not established. No evidence of systemic toxicity or immunotoxicity was observed in the study up to the highest dose tested.

Literature studies

Wolansky et al.

- Acute Oral Toxicity in Rats

Motor Activity 47885701 (2006) Acceptable/non

- guideline 0, 0.03, 0.1, 0.3, 1, 3, and 10 mg/kg

Vehicle: Corn oil Volume: 1 ml/kg BMDL 1SD = 1.49 mg/kg

BMD 1SD = 2.48 mg/kg based on decreased motor activity.

WIL Study

- Acute Oral Toxicity in Rats

FOB 47050504 (2006) Acceptable/Non

- Guideline 0, 12.5, 25, and 35 mg/kg via gavage in corn oil (5 mL/kg) BMDL 20 = 10.5 mg/kg

BMD 20 = 14.5 mg/kg based on multiple FOB changes.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 54 of 64 A.3 Toxicological Doses and Endpoints for Use in Human Risk Assessments

Figure A3. 1 Decision tree for evaluating potential toxicity studies for endpoint selection

Hazard

Identification and Endpoint Selection A.3.1 Acute Reference Dose (aRfD)

– All Populations Including Infants and Children and Females Age 13

- 49

Study Selected : Acute Motor Activity (Wolansky et al., 2006)

MRID # : 47885701

Dose and Endpoint for Risk Assessment : BMDL 1SD = 1.49 mg/kg, based on decreased motor activity seen at 3 mg/kg.

Uncertainty Factor : Adults and Children ≥ 6 years old: 100X (1X FQPA, 10X interspecies extrapolation, 10X intraspecies variability)

Acute RfD = = 0.0 15 mg/kg

Children < 6 years old: 300X (3X FQPA, 10X interspecies extrapolation, 10X intraspecies variability)Deltamethrin Human Health Risk Assessment DP No. D413048

Page 55 of 64 Comments about Study/Endpoint : The Wolansky study was selected based on decreased motor activity observed within 3 hours following an acute exposure. BMD analysis was

conducted and a BMDL 1SD value of 1.49 mg/kg was determined. Endpoints for risk assessment are not typically selected from literature studies. However, the Wolansky et al. (2006) study is uniquely appropriate based on: 1) the large number of dose levels (6); 2) the large number of animals (8

- 18 per group); 3) neurotoxicity was determined at the time to peak effect (2 hours post dosing); and 4) motor activity is recognized as one of the most common techniques for determining pyrethroid neurotoxicity in laboratory animal studies (Wolansky and Harrill 2008)

. Furthermore, the selection of the BMDL 1SD from the Wolansky study is supported by multiple guideline and literature studies. The ACN, chronic dog, and WIL studies were all considered for risk assessment since they all had effects that were observed within hours following dosing. However, these studies all had higher NOAELs and were not selected for risk assessment. The chronic dog study had a slightly lower NOAEL (1 mg/kg/d ay); however, the human equivalent dose based on allometric scaling was actually higher for the chronic dog study (0.61 mg/kg/day) compared to the Wolansky study (0.43 mg/kg). The WIL study and the ACN study both used relatively high vehicle volumes (5 ml /kg vs. 1 ml/kg in Wolansky) which likely impacted the absorption characteristics of deltamethrin, thereby increasing the POD. Since there is no apparent increase in hazard from repeated/chronic exposures to deltamethrin , the acute dietary exposure

assessm ent is protective of chronic dietary exposures since acute exposure levels are higher than chronic exposure levels. Accordingly, a chronic dietary risk assessment was not conducted.

A.3.2 Incidental Oral Exposure (Short

- Term)

Study Selected : Acute Mot or Activity (Wolansky et al., 2006)

MRID # : 47885701

Dose and Endpoint for Risk Assessment : BMDL 1SD = 1.49 mg/kg, based on decreased motor activity seen at 3 mg/kg.

Uncertainty Factor : Adults and Children < 6 years old: 300X (3X FQPA, 10X interspecies extrapolation, 10X intraspecies variability)

Comments about Study/Endpoint : The Wolansky study was selected based on decreased motor activity observed within 3 hours following an acute exposure. BMD analysis was

conducted and a BMDL 1SD value of 0 1.49 mg/kg was determined. Endpoints for risk assessment are not typically selected from literature studies. However, the Wolansky et al. (2006) study is uniquely appropriate based on: 1) the large number of dose levels (6); 2) the large number of animals (8

- 18 per group); 3) neurotoxicity was determin ed at the time to peak effect (2 hours post dosing); and 4) motor activity is recognized as one of the most common Acute RfD = = 0.00 5 m g/kgDeltamethrin Human Health Risk Assessment DP No. D413048

Page 56 of 64 techniques for determining pyrethroid neurotoxicity in laboratory animal studies (Wolansky and Harrill 2008) . Furthermore, the selection of the BMDL 1SD from the Wolansky study is supported by multiple guideline and literature studies. The short

- term oral stu dies, developmental and reproduction studies, and the chronic oral studies were all considered for risk assessment. However, the Wolansky study provided the most appropriate NOAEL that is protective of potential developmental/offspring effects, as well as other systemic effects observed in the toxicology database.

A.3.3 Dermal Exposure (Short

- Term)

A 21

- day dermal study in rat for deltamethrin is available for consideration. However, no

treatment

- related findings were observed at the limit dose . There was also no toxicity observed following acute dermal exposure to deltamethrin up to a dose of 2000 mg/kg . T herefore, a

dermal hazard was not identified for deltamethrin and no dermal risk assessment will be

conducted

. This finding is consistent with the toxicology profile of many pyrethroids. No dermal hazard has been identified for fenpropathrin, zeta

- cypermethrin, allethrin, and prallethrin. Typically pyrethroids have a low absorption value of ≤ 5% and a high rate of metabolism

. D eltamethrin had a slightly higher absorption value of 11.3%

, although the majority of the radioactivity measured was at the skin site (10.6%). This is typical of the pyrethroids

, as they are lipophilic and much of the radioactivity measured in the skin of dermal penet ration studies with pyrethroids is captured in the upper dermal layers an d not available for absorption or systemic

circulation.

A.3.4 Inhalation Exposure (Short

- Term)

Study Selected : Acute Motor Activity (Wolansky et al., 2006)

MRID # : 47885701

Do se and Endpoint for Risk Assessment : BMDL 1SD = 1.49 mg/kg, based on decreased motor activity seen at 3 mg/kg.

Uncertainty Factor :

Adults and Children ≥ 6 years old: 100X (1X FQPA, 3X interspecies extrapolation, 10X intraspecies variability)

Children < 6 years old: 300X (3X FQPA, 10X interspecies extrapolation, 10X intraspecies variability)

Comments about Study/Endpoint : An acceptable inhalation study was not available for

deltamethrin. The HASPOC waived the requirement for a subchronic inhalation st udy (TXR# 0056944)

. In the absence of an inhalation study an oral study is being used. T he Wolansky study was selected based on decreased motor activity observed within 3 hours following an

acute exposure. BMD analysis was conducted and a BMDL 1SD value o f 1.49 mg/kg was

determined. Endpoints for risk assessment are not typically selected from literature studies.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 57 of 64 However, the Wolansky et al. (2006) study is uniquely appropriate based on: 1) the large number of dose levels (6); 2) the large number of animals (8

- 18 per group); 3) neurotoxicity

was d etermined at the time to peak effect (2 hours post dosing); and 4) motor activity is recognized as one of the most common techniques for determining pyrethroid neurotoxicity in laboratory animal studies (Wolansky and Harrill 2008) . Furthermore, the selection of the

BMDL 1SD from the Wolansky study is supported by multiple guideline and literature studies.

The short

- term o ral studies, developmental and reproduction studies, and the chronic oral studies were all considered for risk assessment. However, the Wolansky study provided the most appropriate NOAEL that is protective of potential developmental/offspring effects, as well as other systemic effects observed in the toxicology database. Absorption and toxicity via the inhalation route are assumed to be equal to toxicity via the oral route.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 58 of 64 Appendix A

. 4

. 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

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

- gated sodium channels ultimately leading to neurotoxicity. The cumulative risk assessment (CRA) for the pyrethroids/pyrethrins was published on Nov. 9, 2011 (USEPA, 2011a) and is ava ilable at http://www.regulations.gov;

EPA

- HQ

- OPP

- 2011

- 0746. No cumulative risk estimates of concern were identified allowing the Agency to consider new uses for pyrethroid actives. For information regarding EPA’s efforts to evaluate the risk of exposure t o pyrethroids, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids

- pyrethrins.html

.

The active ingredient, deltamethrin

, was assessed in the November 2011 pyret hroid cumulative

risk assessment. T he Agency has determined based on its chemical structure and based on the observation of neurobehavioral effects consistent with Type II pyrethroids, that deltamethrin should be included in the CMG for this class of pest icides. As such, the Agency must consider the potential contribution of deltamethrin to the cumulative risk assessment. No new residential use scenarios have been proposed or registered since the 2011 pyrethroid CRA. Therefore, there has been no change to the overall findings in the pyrethroid CRA due to contribution of

deltamethrin uses.

A

. 4

. 1. Cumulative Hazard Assessment: Relative Potency Estimation for Deltamethrin

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 which is used as the poi nt 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 which are from the sam e endpoint and same duration and to the extent possible any other factors which effect 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. Th ese studies were was selected because the y 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

relevant 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 activity 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 the CRA because of the lack of specific relevance to the common mechanism of action for the pyrethroids.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 59 of 64 In the CRA, deltamethrin was used as the index chemical. Deltamethrin stands out as having one of the most robust databases of guideline and literature studies. For example, multiple studies on deltamethrin have been identified examining in vivo neurotoxicity, in vi tro sodium channel interaction, metabolism, pharmacokinetics following multiple routes of administration (oral, dermal, intravenous, intercerebral, etc.) and PBPK modeling. Furthermore, t he deltamethrin PoD derived from the FOB data is of sufficiently hig h quality to minimize error or uncertainty in

the cumulative risk estimates. The RPFs used for the CAG in the pyrethroid screening level cumulative were determined by dividing the chemical

- specific BMD 20 by the BMD 20 of the index chemical (deltamethrin). Therefore, for deltamethrin the RPF is 1.00.

T able A. 4 .1: Pyrethroid RPF Comparison FOB vs. Motor Activity

Pyrethroid FOB Motor Activity

lambda

- cyhalothrin 1.63 1.90 a

tefluthrin 1.36 1.11 a

cyfluthrin 1.15 1.14 a

bifenthrin 1.01 1.96 a

deltamethrin 1.00 1.00 a

fenpropathrin 0.50 0.33 a

metofluthrin 0.48

--

esfenvalerate 0.36 2.09 a

cypermethrin 0.19 0.23 a

tau

- fluvalinate 1.00

-- cyphenothrin 0.15

--

d

- allethrin 0.11

--

allethrin 0.11 0.03 a

prallethrin 0.10

-- permethrin 0.09 0.15 a

resmethrin 0.05 0.02 a

pyrethrins 0.02

--
imiprothrin 0.02

--

flumethrin

-- 5.02 b

a Represents motor activity data from the Wolansky study b Represents motor activity data from the flumethrin A CN studyDeltamethrin Human Health Risk Assessment DP No. D413048

Page 60 of 64 A

. 4

. 2. Cumulative Exposure and Risk Issues

In order to determine if the registered deltamethrin indoor and turf uses 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 deltamethrin 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

. 4

. 2 .a were compared with the MOEs currently driving turf and indoor crack and crevice exposures and risks in Table 6.4.7a from the 2011 pyrethroid CRA

. Adult handler exposures and risks estimates are currently driven by cyfluthrin turf use (i.e. mixing/loa ding/applying via hose

- end sprayer) with a dermal MOE of 9,200 and combined (dermal + inhalation) MOE of 8,900, which are lower than the estimated deltamethrin dermal MOE of 15,000 and combined MOE of 500,000. Adult and child dermal

post

- application expos ure and risk are also currently driven by cyfluthrin turf use with an MOE of 4,500 and 3,000 respectively. For children < 6 year s old, hand

- to

- mouth post

- application exposure and risk estimates are currently driven by the cy halothrin indoor crack and crev ice use

with an MOE of 9,7 00, which is lower than the estimated deltamethrin MOE o f 16,0 00. A summary of these MOEs is presented in Appendix Table A

. 4. 2 .a while the detailed calculations

for deltamethrin are presented in Appendix Table A

. 4.2.b . In all cases, the estimated

deltamethrin MOEs using the RPF method were higher (i.e., less of a risk concern) than those used in the 2011 pyrethroid CRA. Thus the Agency continues to support the previous

assessment and concludes that the registered deltamethrin use will not significantly contribute to the overall findings in the 2011 pyrethroid CRA.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 61 of 64 Table A. 4

. 2. a. Comparison of Deltamethrin MOEs with Pyrethroid Cumulative MOEs

Chemical Exposure

Scenario Route of Exposure Population MOE Combined

MOE

Registered Use Deltamethrin

Turf (EC)

– M/L/A

Hose

- end Sprayer Handler Dermal

Adult 15,000 500,000

Handler Inhalation 420,000

Post

- application Dermal 7,700 NA

Post

- application Dermal Child 5,300 4,600 Post

- application HTM 36,000

CRA C yfluthrin Handler Dermal

Adult 9,200 8,900 Handler Inhalation 280,000

Post

- application D ermal 4,500 NA

Post

- application Dermal Child 3,000 2,700 Post

- application HTM 21,000

Registered Use Deltamethrin

Indoor

– M/L/A

crack & crevice Handler Dermal

Adult 87,000 66,000

Handler Inhalation 270,000

Post

- application Dermal 70,000 NA

Post

- application Dermal

Child 58,000
12,000 Post

- application HTM 16,000

CRA C yfluthrin Handler Dermal 43,000 33,000 Handler Inhalation 140,00

Cyhalothrin Post

- application Dermal 43,000 NA

Post

- application Dermal 36,000 7,600 Post

- application HTM 9,700Deltamethrin Human Health Risk Assessment DP No. D413048

Page 62 of 64 Table A. 4 .2.b. Deltamethrin Screening Level “Cumulative” MOEs

Handler Exposure

Exposure

Scenario Application

Rate Amount

Treated Daily (animals) Baseline

Dermal

Unit Exposure (mg/lb ai) Baseline

Inhalation

Unit Exposure (mg/lb ai) Baseline Dermal

Unit Exposure (mg/lb ai) Baseline

Inhalation

Unit Exposure (mg/lb ai) 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) Bas eline Inhalation MOE

Adult

- Turf 0.13

lb ai/A 0.5 15 0.024 0.98 0.3 0.0007 0.00068 15,000 2.23E

- 5 2.2E

- 5 470,000

A dult

– Indoor

C&C 0.0005

lb ai/gal 0.5 69 1.1 0.17 0.00275 0.0001 0.00012 87,000 3.8E

- 5 3.8E

- 5 270,000

Post

- app lication 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

Child

- Turf ( 6 > year s old) 0.03 4 0. 45 150 5.15 E

- 5 0.13 0.9 4 0.5 13.9 11.4 0.0002 8 0.000 28 36 ,000

Chil d

– C&C ( 6 > year s old) 0.15 0.04 150 2E

- 5 0.13 5 4 0.5 20 11.4 0.00066 0.00066 16,000

Post

- application Dermal Exposure

Exposure

Scenario Application Rate Body Weight (kg) Hours of

Exposure Conversion

Factor (mg/ug) DFR/TTR

(ug/cm 2
DAT 0) Transfer

Coefficient (cm 2 /hr) Absorbed Dermal Dose

(mg/kg/day) Adjusted Dose (mg/kg/day) a Adjusted

MOE b

Child

- Turf ( 6> year s old) 0.13 lb ai/A 11.4 0.9 0.001 0.0 105 37, 500 0.00 2 0.00 19 35 ,000

Adult

- Turf 0.13 lb ai/A 71.8 1

. 1 0.001 0.0 1 0 5 130

, 0 00 0.0014 0.00 1 35 77 ,000

Exposure

Scenario Surrogate Deposition

(ug/cm 2 ) Conversion Factor 1 (ug/lb) Conversion

Factor 2 (ft 2 to cm2) Surface

Residue (ug/cm 2 ) Fraction

Transferred Transfer

Coefficient (cm 2 /hr) Exposure

Time (hr/day) CF3

(mg/ug) Adjusted Dose

(mg/kg/day) Adjusted

MOE

Child

– C&C 0.2 4.5E+8 1.08E

- 3 0.2 0.02 2,000 5 1E

- 3 0.00018 58,000

Adult

– C&C 0.2 4.5E+8 1.08E

- 3 0.2 0.02 6,800 8 1E

- 3 0.00015 70,000
a Doses were adjusted based on an estimated deltam ethrin RPF of 5.02 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 Handler inhalation exposure is expected to be negligible from deltam ethrin pet collars and

, thus

, a quantitative assessment was not performed.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 63 of 64 Appendix B

. Physical/Chemical Properties

T able B.1. Physicochemical Properties of Technical Grade Deltamethrin.*

Parameter Value Melting Point/Range (°C) 100

- 102 pH Not available. Density (g/cm 3 at 25°C) 0.550 Water Solubility (ug/L at 25°C) <0.2 Solvent Solubility (% by w eight at 20oC) Acetone 33

Alcohol 0.6 Isopropanol 0.2 Ethyl acetate 25

n

- Hexane 0.2

Toluene 23

DMF 38

Dioxane 39 Vapor Pressure (mm Hg at 25oC) [mPa at 25°C] 1.5 x 10

- 8 [1.24 x 10

- 5 ]

Dissociation C onstant, pK
a Does not dissociate

. Octanol/ Water Partition C oefficient, K OW ( at 25oC ) 2.7 x 10 5

UV/ V isible A bsorption S pectrum Not available

. * Reference: MARC Briefing Memorandum; D284320; D. Dotson; 5 November 2002.Deltamethrin Human Health Risk Assessment DP No. D413048

Page 64 of 64 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 C FR 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 fou nd at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.