Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 3 of 78 5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .................... 42
5.4.3 Acute Dietary Risk Assessment

................................ ................................ ................. 42
5.4.4 Chronic Dietary Risk Assessment

................................ ................................ .............. 43
5.4.5 Average Dietary Exposure Assessment

................................ ................................ ...... 43
5.4.6 Summary Tables

................................ ................................ ................................ ......... 43
6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .... 44
6.1 Registered Cypermethrin Residential Handler Exposure/Risk Esti mates

...................... 44
6.2 Cypermethrin Registered Residential Post

- application Exposure/Risk Estimates

........ 45
6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

......................... 47
6.4 Residential Risk Estimates for Use in Aggregate Assessment

................................ ...... 47
6.5 Spray Drift

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

6.6 Residential Bystander Post

- Application Inhalation Exposure

................................ ....... 49
7.1 Acute Aggregate Risk

................................ ................................ ................................ .... 50
7.2 Short

- Term Aggregate Risk

................................ ................................ .......................... 50
7.3 Intermediate

- Term/Chronic Aggregate Risk

................................ ................................ .. 50
8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 51
9.0 Occupational Exposure/Risk Characterization

................................ ................................ .. 51
9.1 Occupational Handler Exposure/Risk Estimates

................................ ............................ 51
9.2 Occupational Post

- application Exposure/Risk Estimates

................................ .............. 55
9.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

.......................... 55
9.2.2 Occupational Post

- application Dermal Exposure/Risk Estimates

.............................. 55 Appendix A. Toxicology

................................ ................................ ................................ ............. 59
A.1 Toxicology Data Requirements

................................ ................................ ...................... 59 A.2 Toxicity Profiles

................................ ................................ ................................ ................. 60
A.3 Toxico logical Doses and Endpoints for Use in Human Risk Assessments

....................... 68
A 4. HEC Inhalation Calculations

................................ ................................ ........................... 71 Appendix B. Physical/Chemical Properties

................................ ................................ .................. 75 Appendix C. International Harmonization

................................ ................................ ................... 76 Appendix D. Review of Human Research

................................ ................................ ................... 78Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 4 of 78 1.0 Executive Summary

The pyrethroid insecticide z eta

- cypermethrin is currently registered to FMC Corporation for use on a wide variety of food/feed crops, primarily as repeated broadcast foliar applica tions. In the current petition s , the Interregional Proje ct Number 4 (IR

- 4) is proposing new uses on tropical fruits, barley, oat, buckwheat, rye, pistachio, and artichoke for two formulations of zeta

cypermethrin. Two agricultural products proposed for use on various crops are Fury ® 1.5 EC
Insecticide and Must ang ® 1.5 EW Insecticide. In addition, under a separate submission , Y

- TEC Corp. has requested a new use for zeta

- cypermethrin, as ZetaGard LBT Insecticide ( File Symbol
39039

- EN) , for application to poultry litter in chicken broiler and turkey grow

- out houses.

The petition s for registration of these new uses of zeta

- cypermethrin relies on zeta

- cypermethrin
data

, as well as previously submitted data for the r elated registered in secticide cypermethrin , and
the pending new active ingredient alpha

- cypermethrin. Cypermethrin, zeta

- cypermethrin and alpha

- cypermethrin are isomer mixtures of the same chemical. Cypermethrin consists of a mixture of eight isomers (four diastereoisomeric pairs). Zeta

- cypermethrin is composed of four of the eight isomers of cypermethrin, and also contains one of the isomers in alpha

- cypermethrin. Alpha

- cypermethrin consists of two of the four cis

- isomers of cypermethrin.

Zeta

- cypermethrin is a type II synthetic pyrethroid chemical, and is a broad spectrum insecticide, effective against a variety of target pests through contact and ingestion. Pyrethroids disrupt the voltage

- gated sodium channels in the nervous system, resulting in neurotoxicity.

In d eveloping this human health risk assessment, the Health Effects Division has examined the available hazard and exposure information regarding zeta

- cypermethrin, as well as information for cypermethrin, alpha

- cypermethrin, and pyrethroid chemicals as a clas s. Although cypermethrin, alpha

- and zeta

- cypermethrin are separate active ingredients with different end

- use products, they were included together in the hazard evaluation due to structural and toxicological similarities and comparable toxicity profiles. For human health risk assessment purposes, the active ingredients are considered equally toxic and the most protective endpoints and points of departure ( PODs ) for each study type have been selected for risk assessment. In addition, this aggregate risk a ssessment considers not only the exposure associated with the proposed new uses for zeta

- cypermethrin, but also the potential dietary and drinking water contribution and residential exposure from existing uses of the cypermethrin s

.

Behavioral changes comm only seen with pyrethroids were consistently noted in the toxicology database for the cypermethrins, which is considered to be complete for the purpose of human health risk assessment. These behavioral changes included tremors, gait abnormalities, limb

co nditions, ataxia and hypersensitivity. Additional toxic effects observed with the cypermethrins were changes in body weight, mortality in a few studies with rats and dogs, and an increased incidence of lung tumors in female mice after chronic exposure.

Given different levels of uncertainty for various risk assessment scenarios, US EPA is applying different FQPA safety factors for the protection of fetuses, infants, and children depending on the route of exposure, data gaps and the population exposed. Fo r adults (including women of child

-Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 5 of 78 bearing age) and children ≥ 6 years of age, US EPA is reducing the Food Quality Protection Act ( FQPA ) safety factor to 1X. There was no evidence of increased qualitative or quantitative susceptibility in developmental tox icity studies in the rat and rabbit and in a rat two

- generation reproductive toxicity study. A developmental neurotoxicity (DNT) study with zeta

- cypermethrin did indicate some potential increased sensitivity in the offspring based on body weight changes
i n pups in the absence of treatment

- related effects in maternal animals. However, b ased on the weight of the evidence, there is no residual concern for the effects observed in the study. There are no residual uncertainties with regard to neurotoxicity or dermal toxicity and there is no evidence of immunotoxicity. However, US EPA is retaining a 3X FQPA safety factor for children <6 years of age to account for juvenile sensitivity to pyrethroid toxicity observed in
several literature studies.

Cypermethrin is classified as a Group C “Possible human carcinogen”, based on an increased incidence of lung adenomas and adenomas plus carcinomas combined in females in a mouse carcinogenicity study. Based on the weight of evidence, the Agency has determined that

qu antification of risk using a non

- linear approach (i.e., acute population adjusted dose ( aPAD ) or acute reference dose ( aRfD) ) will adequately account for all chronic toxicity, including carcinogenicity that could result from exposure to the cypermethrins. While the Agency would typically use a chronic Population Adjusted Dose (cPAD) to protect for cancer concerns, use of the aPAD is protective because increasing toxicity with increasing duration of exposure is not demonstrated for the cypermethrins , and be cause the exposure assessment associated with the acute dietary scenario reflects high

- end consumption and residues

.

The dose and endpoint for acute dietary risk assessment were selected from the Wolansky et al. (2006) acute oral study, in which decreased motor activity was observed. The dose used for risk assessment from the Wolansky study was determined using a benchmark dose (BMD) analysis conducted in accordance with standard Agency assumptions with respect to the benchmark response (BMR). There is no increase in toxicity from repeated exposures to the cypermethrins; therefore, the acute dietary exposure assessment is protective for chronic dietary exposures since acute exposure levels are higher than chronic exposure levels. Accordingly, a dietary exposure assessment for the purpose of assessing chronic dietary risk was not conducted.

For inhalation risk assessments, an inhalation toxicity study in rats was chosen and human equivalent concentrations (HECs) were calculated and used for r isk assessment. For inhalation risk assessments, the interspe cies uncertainty factor was reduced from 10X to 3X because the
HEC calculation accounts for pharmacokinetic (not pharmacodynamic) interspecies differences
between animals and humans. A quantitati ve dermal risk assessment was not conducted based on
the lack of treatment

- related effects in dermal toxicity studies.

The residue chemistry data submitted or cited in support of the proposed uses are considered adequate, and the environmental fate param eters for the cypermethrin s are adequately understood for the purpose of estimating residues in ground and surface water sources of drinking water that could result from the existing and proposed uses of zeta

- cypermethrin . For all three cypermethrins, HED has concluded the residue of concern for risk assessment and tolerance enforcement is the parent compound, cypermethrin, zeta

- cypermethrin and alpha

- cypermethrin.Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 6 of 78 Dietary e xposure to zeta

- cypermethrin may occur from consuming treated crops or their

proce ssed commodities. Partially refined (probabilistic) dietary exposure assessments were performed in order to determine the exposure and risk estimates resulting from the existing use of cypermethrin and zeta

- cypermethrin on the cr ops listed under 40 CFR 180.418, the proposed

new uses of zeta

- cypermethrin, and the pending registration of alpha

- cypermethrin on various

crops

. Additional dietary exposure is not expected from the proposed uses of alpha

cypermethrin for the following re asons: (1) the lower application rate of alpha

- cypermethrin relative to the other cypermethrins, (2) alpha

- cypermethrin tolerances were bridged from cypermethrin , and (3) there are label prohibitions that limit the application rate of total cypermethrins

. HED has used modeling to estimate dietary exposure to the cypermethrins. The modeling uses health

- protective assump tions regarding residues of zet a

- cypermethrin and its breakdown products in food and drinking water and incorporation of percent crop trea ted (PCT) information, in combination with an extensive database of food consumption patterns for the U.S. population and population subgroups.

For all registered and proposed uses, the acute dietary exposure estimates are below HED’s level of concern ( <100% aPAD at the 99.9th percentile of exposure ) . Dietary exposure (food and drinking water) for the cypermethrins is 18% of the aPAD for the U.S. population and 87% of
the aPAD for all infants and children 1

- 2 years, the most highly exposed population su bgroups.

As mentioned previously, a chronic risk assessment was not conducted since the endpoint from the acute study is protective of the endpoints from repeat dosing studies, which represent longer

term exposures. However, in order to assess short

- te rm aggregate risk to cypermethrins, the average dietary (food and drinking water) exposure was calculated. The quantification of average dietary exposures required the use of average field trial residues, U.S. Department of Agriculture (USDA) Pesticide Da ta Program ( PDP ) monitoring data, and current tolerances as appropriate. The assessment also made use of PCT data where available. Drinking water information was incorporated using the mean concentration (1

- in

- 10

- year annual mean) for surface water gener ated by the FIRST (FQPA Index Reservoir Screening Tool) model.

In addition to the proposed uses on crops , HED has reviewed the new poultry house use request and has determined that the existing livestock tolerances are adequately protective of the potential residues from this new use and that this use has no impact on the zeta

- cypermethrin dietary exposure assessment. ZetaGard LBT Insecticide is formulated as a dust and contains two active ingredients: zeta

- cypermethrin and piperonyl butoxide. Th is assessment addresses only exposure and risk associated with the proposed end

- use products for zeta

- cypermethrin
when used as directed.

The only non

- dietary exposure pathway relevant for adults and children greater than 6 years old
is via inhalation , and the level of concern (LOC) is 30X, taking into account the 3X interspecies and 10X intraspecies factors. For children under 6 years old exposed via the inhalation route, the LOC is 100, which includes the 3X interspecies and 10X intraspecies factors , as well as the 3X FQPA factor. For children under 6 years old exposed via the incidental oral route, the LOC isZeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 7 of 78 300, based on the standard 10X interspecies and 10X intraspecies factors, and the 3X FQPA
factor.

Although the incidental oral and inhalation routes of exposure have similar effects, the child inhalation and incidental oral routes have different LOCs. Therefore, combined exposure and risk from the various routes were evaluated using the aggregate risk index (ARI) approach

. ARIs ≥ 1 are not of concern.

T here are no new requested uses for zeta

- cypermethrin that involve a residential setting; however, residential exposure and risk were estimated for the currently registered residential

uses of cypermethrin and zeta

- cypermethrin in orde r to complete the aggregate risk assessment

. The revised assessments included the updated endpoints for risk assessment as well as the most recent residential SOPs (2012). For the registered residential uses of the cypermethrins, there is a potential for residential handler exposure for adults only, as well as post

- application exposure for adults and children (1 to < 2 years old) who re

- enter treated areas. For the registered residential uses, exposure is expected to be short

- term in duration. However, due to the pyrethroid toxicity profile, only single day risk assessments were conducted for residential exposure, which are protective of all durations of exposure. Residential intermediate

- term exposures are not likely because of the intermittent nature of applications by homeowners. The scenarios chosen for the purpose of conducting residential and aggregate assessments were those that result in the highest exposures for adults and children, for both indoor and outdoor uses

. A lthough not all residenti al products were re

- assessed with the updated endpoints and SOPs, the representative scenarios are considered to be worst

- case and are protective.

Residential handler inhalation risk estimates for cypermethrin and zeta

- cypermethrin uses are not
of conce rn, with inhalation MOEs ranging from 6,100 to 48,000. Likewise, residential post

application exposure and risk estimates (MOEs and ARIs) for adults and children were greater than their respective LOC s and are not of concern. Adult post

- application exposure via the
inhalation route resulted in an estimated MOE of 1,100,000, while children younger than 6 years of age exposed via the inhalation and incidental oral routes had MOEs ranging from 1000 to 6,400,000 , with a n ARI of 13 for the combined routes of exposure

.

In accordance with the FQPA, HED must consider and aggregate cypermethrin pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.
The refore, the short

- term aggregate exposure and risk asses sment for the cypermethrins include d dietary (food and water) exposures anticipated from the registered and proposed uses, and non

dietary exposures anticipated from the currently registered residential uses. An ARI approach was used to aggregate these ex posures due to the different LOCs associated with oral and inhalation exposure pathways. No risks of con c ern were identified in this short

- term aggregate

assessment. An intermediate

- term and/or chronic aggregate risk assessment was not conducted
because the cypermethrins are acutely toxic and do not increase in potency with repeated dosing. Because acute toxicity studies can assess the risk for longer term studies, it is assumed that the
acute and short

- term aggregate assessments are protective for inter mediate

- term and chronic aggregate risks anticipated from cypermethrin exposure.Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 8 of 78 HED has also assessed exposure and risk associated with the proposed end

- use products when used as directed by occupational workers. There is a potential for occupational exposure associated with handler activities (i.e., mixing, loading, and applying) as well as with post

application activities (i.e., re

- entering treated areas). Based on the proposed use pattern (i.e., 1

- 3 applications per season), the duration of exposur e for occupational workers for the proposed food uses and poultry house use are expected to be short

- term (1 to 30 days) and intermediate

- term (1 to 6 months). Long

- term exposures (greater than 6 months) are not anticipated for either the new proposed us es or the existing uses. However, as with the residential exposure assessment, due to the pyrethroid toxicity profile, only single day risk assessments were conducted for occupational exposure, which are protective of all durations of exposure.

There are no risk estimate s of concern for occupational handlers mixing, loading, and applying

zeta

- cypermethrin. All occupational handler inhalation exposure assessments resulted in MOEs greater than 3,500 . As no dermal endpoint was identified, a quantitative po st

- application assessment was not performed. Post

- application inhalation was not quantitatively assessed; however, an inhalation exposure assessment was performed for flaggers and it is considered protective of most outdoor agricultural and commercial pos t

- application inhalation exposure
scenarios

. Occupational and residential exposure/risk assessment for the active ingredient piperonyl butoxide, which is included in the end

- use product ( EP ) being proposed for use in poultry houses, has been addressed in a separate memo ( Nieves, I. D402795)

.

The cypermethrins were included in a recent cumulative risk assessment for pyrethrins and pyrethroids. T he proposed new uses of zeta

- cypermethrin will not have a significant impact on cumulative exposure and risk because in the cumulative assessment, residential exposure was the greatest contributor to the total exposure. As there are no new residential uses for the cypermethrins, the proposed new uses will have no impact on the residential component of the
cumul ative risk estimates. Dietary exposures make a minor contribution to total pyrethroid exposure in the 2011 cumulative risk assessment. The dietary exposure assessment performed in support of the pyrethroid cumulative was much more highly refined than tha t performed for th is single chemical assessment

. The dietary exposure assessment for the single chemical included conservative assumptions, using field trial data for many commodities, including the proposed

new uses , with the assumption of 100% crop trea ted. F or the single chemical cypermethrin s risk

assessment s , the most sensitive apical endpoint in the cypermethrin s database was selected to derive the POD. Additionally, the POD selected for the cypermet hrin s is specific to the three
actives , whereas t he 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.

This risk assessment is based, in part, o n data from studies in which adult huma n subjects were intentionally exposed to a pesticide or other chemical. These studies are compliant with applicable ethics requirements. Although no special quantitative assessments have been conducted, HED has, to the extent possible, taken environmental justice consideration into account (see Section 3.5).Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 9 of 78 2.0 HED Recommendations

HED is recommending in favor of registration of zeta

- cypermethrin on the requested crops and
establishment of tolerances as summarized in Table 2.2.3.

2.1 Data Def

iciencies

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate tolerance

- enforcement methods are available in PAM Volume II for determining residues of cypermethrin, zeta

- cypermethrin and alpha

- cypermethrin in plant (Method I) and livestock (Method II) commodities. Both methods are gas chromatographic methods with
electron

- capture detection (GC/ECD), and have undergone succes sful Agency petition method validations (PMVs). Method I has a limit of detection (LOD) of 0.01 ppm, and Method II has LODs of 0.005 ppm in milk, and 0.01 ppm in livestock tissues. These methods are not stereospecific; thus no distinction is made between residues of cypermethrin (all 8 stereoisomers), zeta

- cypermethrin (enriched in 4 isomers) and alpha

- cypermethrin (2 isomers).

The January 1994 FDA PESTDATA database ( PAM Volume I ) indicates that residues of cypermethrin are completely recovered (>80%) using multi

- residue method Sections 302 (Luke), 303 (Mills, Onley and Gaither) and 304 (Mills fatty food).

2.2.2 International Harmonization

There are no Canadian MRL’s for the proposed commodities. Mexico adopts US tolerances,
and/or Codex maximum res idue limits (MRLs), for its export purposes. The associated Codex MRLs for cypermethrin are listed in Appendix C

. There are multiple Codex MRLs for zeta

cypermethrin, but all are in conjunction with MRLs for total cypermethrin isomers (no MRLs have been established solely for zeta

- cypermethrin). However, although the definitions differ formally, they are effectively harmonized since the tolerance enforc ement methods are not stereospecific, and thus do not distinguish between residues of cypermethrin, zeta

- cypermethrin and alpha

- cypermethrin. For enforcement purposes, the same moiety is being regulated. The
recommended tolerances will result in harmoniz ed MRLs between USEPA and Codex for mango (at 0.7 ppm) and papaya (at 0.5 ppm). The recommended tolerances for artichoke, barley, buckwheat, oats, and rye will not be harmonized with Codex for the following reasons. In the case of artichoke, Codex has se t a lower MRL of 0.1 ppm based on field trials conducted with alpha

- cypermethrin with a different use pattern, including a lower use rate and longer pre

- harvest interval ( PHI ) . The HED recommended tolerance for artichoke of 0.6 ppm is supported by the
sub mitted residue data, with a higher use rate and shorter PHI. In addition, for grains (barley, oats, buckwheat, and rye), the Codex MRLs assume a post

- harvest treatment whereas the proposed use pattern in the U.S. is for pre

- harvest treatment. Given the p roposed use pattern onZeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 10 of 78 grains, HED recommends the tolerances as summarized below, further noting that the livestock feed items of hay and straw are unlikely to be exported.

2.2.3 Recommended Tolerances

HED recommends that 40CFR §180.418 (a)(2) be revis ed by establishing tolerances for the
commodities listed in Table 2.2.3. Unless otherwise noted in Table 2.2.3, HED used OECD calculation procedures to develop these recommended tolerances.

HED has determined that the residue of concern for tolerance e nforcement and risk assessment
for zeta

- cypermethrin is the parent compound. The tolerance enforcement methods for plant and animal commodities do not distinguish between cypermethrin and zeta

- cypermethrin, even though they have separate tolerance listing s in 40CFR §180.418

. In addition, the existing tolerance expression for zeta

- cypermethrin need s to be revised to reflect both coverage and compliance statements, in accordance with current policy. Therefore, the tolerance expression
for zeta

- cypermethrin in plant and livestock commodities, needs to be revised in 40CFR §180.418(a)(2), as follows:

Tolerances are established for residues of the insecticide, zeta

cypermethrin, ( S

- cyano(3

- phenoxyphenyl) methyl (±))(cis

- trans 3

- (2,2

- dichloroethenyl)

- 2,2 dimeth ylcyclopropanecarboxylate ) , including its metabolites and degradates, in or on the commodities listed in table 2.23. Compliance with the tolerance levels specified below is to be determined by measuring only total cypermethrin, cyano(3

- phenoxyphenyl)methyl 3

- (2,2

- dichloroethenyl)

- 2,2

- dimethylcyclopropane carboxylate, in or on the commodity.

The proposed and recommended tolerances for zeta

- cypermethrin are presented in Table 2.2.3.Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 11 of 78 Table 2.2.3 Tolerance Summary for Zeta

- Cypermethrin.
Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments;

Correct Commodity Definition

Avocado 0.45 0.50

Papaya 0.45 0.50

Star apple 0.45 0.50
Black Sapote 0.45 0.50 Sapote, black

Mango 0.45 0.70 Adequate residue data are available on avocado. The recommended tolerance for other tropical fruit of 0.5 ppm was calculated using the OECD calculation procedures and the residue data from avocado. However, the value was raised from 0.5 to 0.7 ppm for ma ngo, in order to harmonize with the Codex MRL value of 0.7 ppm.
Sapodilla 0.45 0.50

Canistel 0.45 0.50
Mamey Sapote 0.45 0.50 Sapote, mamey
Artichoke, globe 0.80 0.60
Barley, grain 1.7 3.0
Barley, hay 5.0 6.0
Barley, straw 19 20.0

Oat, grain 1.7 3.0
Oat, hay 5.0 6.0

Oat, straw 19 20.0
Buckwheat, grain 1.7 3.0
Buckwheat, hay 5.0 6.0

Buckwheat, straw 19 20.0
Rye, grain 1.7 3.0
Rye, hay 5.0 6.0
Rye, straw 19 20.0

Pistachio 0.05 0.05 Adequate existing residue data are available on

tree nuts.

2.2.4 Revisions to Petitioned

- For Tolerances

As summarized above

, several revisions to the proposed tolerances as proposed by IR4 were
necessary. These revisions were primarily due to HED’s use of the OECD MRL calculation procedures compared to the use of the NAFTA calculator by IR4. In addition , the proposed commodity definitions for Mamey and Black sapote were revised to reflect the correct

commo dity definitions, per the Agency’s current commodity vocabulary.

2.3 Label RecommendationsZeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 12 of 78 1. For the poultry house use, HED recommends the following clarifications be made on the
ZetaGard LBT Insecticide label:

a ) There is a maximum use rate of 50 pounds (lbs) of product that can be applied in "broiler" and turkey grow

- out houses per flock of birds.
b ) The application can be split into two 25 pound (lb) applications, or one single 50 lb application, per flock. These applications can occur as one application at the 50 lb rate prior to the flock being placed in the broiler house, or as one application at the 25 lb rate prior to the flock being placed in the broiler house and a second 25 lb application occurring not later than three weeks prior to sh ipping the birds for slaughter.

c ) If one single application is made at the maximum rate of 50 lbs, slaughter cannot occur sooner than six weeks after application.

2. There are currently restrictions on the Fury and Mustang labels that limit the total se asonal application rate for registered uses associated with zeta

- cypermethrin and cypermethrin, as well as the proposed new uses of zeta

- cypermethrin. It is noted that when new active ingredient alpha

- cypermethrin is registered, the Fury and Mustang label s will need to be updated to limit the total seasonal application rate associated with the use of all cypermethrins

, including alpha

cypermethrin.

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Zeta

- Cypermethrin Nomenclature.

Compound

Common name Zeta

- cypermethrin

Company experimental name FMC 56701

IUPAC name (S)

- α

- cyano

- 3

- phenoxybenzyl (1R)

- cis

- trans

- 3

- (2,2

- dichlorovinyl)

- 2,2

- dimethylcyclopropanecarboxylate

or (S)

- α

- cyano

- 3

- phenoxybenzyl (1RS, 3RS, 1SR, 3SR)

- 3

- (2,2

- dichlorovinyl)

- 2,2

- dimethylcyclopropanecarboxylate

CAS name (S)

- cyano(3

- phenoxyphenyl)methyl (±)

- cis

- trans

- 3

- (2,2

- dichloroethenyl)

- 2,2

- dimethylcyclopropanecarboxylate

CAS registry number 52315

- 07

- 8

End

- use product (EP) 1.5 lb ai /gal EC (Fury ® or Mustang ® 1.5 EC Insecticide; US EPA Reg. No. 279

- 3125)
1.5 lb ai /gal EW (Mustang ® 1.5 EW Insecticide; US EPA Reg. No. 279

- 3126) 0.4 lb ai/gal ZetaGard LBT Insecticide Dust; File Symbol 39039

- ENZeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 13 of 78 3.2 Physical/Chemical Characteristics

Zeta

- cypermethrin has a very low water solubility, and relatively high octanol/water partition coefficient (log K OW > 6 ). These values account for the low surface and groundwater concentrations determined by EFED’s drinking water models. The chemical has low vapor

pressu re ( 3 x 10 - 9 mm Hg at 20oC ), which decreases its potential to volatilize

. See Appendix B for a listing of the physical and chemical properties of zeta

- cypermethrin.

3.3 Pesticide Use Pattern

Zeta

- cypermethrin products are intended to be used as insecti cides for the control of a variety of pests before, during and after planting. Two agricultural products are proposed for use on various crops: Fury ® 1.5 EC Insecticide and Mustang ® 1.5 EW Insecticide. These end

- use products may be applied through a variety of application methods including aerial, chemigation, and ground equipment.

Fury ® 1.5 EC Insecticide ( US EPA Reg. No. 279

- 3125) is formulated as an emulsifiable concentrate (EC ) which contains 18.1% of the active ingredient (1.5 lb ai/gal), zeta

cypermethrin. Mustang® 1.5 EW Insecticide ( US EPA Reg. No. 279

- 3126) is formulated as oil

in

- water (EW) emulsion which contains 17.1% of the active ingredient (1.5 lb ai/gal). Zeta

cype rmethrin is proposed to be applied 4 to 6 times with a minimum 7 to 14 day spray interval, depending on crop and pest. The recommended maximum single application rate for both products is 0.05 lb ai/A.

In accordance with the 2008 cypermethrin Reregistration Eligibility Decision ( RED ) , agricultural products for cypermethrin and zeta

- cypermethrin are restricted use due to ecotoxicity concerns. These products are only available for use by commercial and professional applicators. The proposed lab el specifies personal protective equipment (PPE) consisting of baseline clothing (i.e., long

- sleeved shirt and long pants, shoes and socks), chemical

- resistant gloves (e.g., nitrile, butyl, neoprene and/or barrier laminate) and protective eyewear. The res tricted entry interval (REI) specified on the proposed label s is 12 hours. Non

- agricultural products (residential, commercial, and industrial) containing cypermethrin and zeta

- cypermethrin are for general use. The proposed agricultural use pattern for ze ta

- cypermethrin is anticipated to result in short

- and
intermediate

- term exposure durations for occupational handlers. However, only short

- term exposures were assessed since increased duration of exposure does not result in increased toxicity. The short

- term exposure assessment is protective of potential intermediate

- term

exposures. Table 3.3.1 provides a summary of the proposed uses.

There are currently restrictions on the Fury and Mustang labels that limit the total seasonal application rate for regi stered uses associated with zeta

- cypermethrin and cypermethrin, as well as the proposed new uses of zeta

- cypermethrin.

Poultry (Chicken Boiler and Turkey Grow

- out) House UseZeta

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Page 14 of 78 ZetaGard LBT Insecticide ( US EPA Reg. No. 39039

- EN) is formulated as a dust and contains
0.375% zeta

- cypermethrin. It is to be applied using a drop type spreader in bands three feet wide under each feed line and along each wall for a total of four bands per house. The PPE statement on the proposed label requires handlers to wear ba seline clothing (long

- sleeved shirt, long pants, shoes and socks) and chemical

- resistant gloves.

Table 3.3.1 Summary of Directions for Use of Zeta

- cypermethrin.

Applic. Timing, Type, and Equip. Formulation

[ US EPA Reg. No.] Max.

Single Applic.
Rate (lb ai/A) Max. No.

Applic.
Per
Season Max.

Seasonal Applic. Rate (lb ai/A) PHI (days) Use Directions and
Limitations

Avocado, Black Sapote, Canistel, Maney Sapote, Mango, Papaya, Sapodilla, Star Apple

Aerial; Ground (Groundboom, Airblast); Chemigation Fury Insecticide,

Emulsifiable Concentrate (EC),

18.1% ai

(1.5 lbs ai/gal)

Reg. No. 279

- 3125 0.05 lbs

ai/ A 6 0.30 lbs ai/

A/season 1 Application interval is 7

- 10 days apart depending on crop. Minimum Spray Volume = 10 gal/A (aerial); 20

- 100 gal/A (ground) depending on crop. Mustang
Insecticide

Oil

- in

- Water (EW) 17.1% ai (1.5 lbs ai/gal)

Reg. No. 279

- 3126

Artichoke

Aerial; Ground; Chemigation Fury Insecticide,

Emulsifiable Concentrate (EC),

18.1% ai

(1.5 lbs ai/gal)

Reg. No. 279

- 3125 0.05 lbs

ai/ A 4 0.20 lbs ai/

A/season 5 Application intervals 14 days. Minimum Spray Volume = 10 gal/A (aerial); 20

- 100 gal/A (ground) depending on crop.

Mustang
Insecticide

Oil

- in

- Water (EW) 17.1% aiZeta

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Page 15 of 78 Table 3.3.1 Summary of Directions for Use of Zeta

- cypermethrin.

Applic. Timing, Type, and Equip. Formulation

[ US EPA Reg. No.] Max.

Single Applic.
Rate (lb ai/A) Max. No.

Applic.
Per
Season Max.

Seasonal Applic. Rate (lb ai/A) PHI (days) Use Directions and
Limitations

(1.5 lbs ai/gal)

Reg. No. 279

- 3126

Barley

Aerial; Ground; Chemigation Fury Insecticide,

Emulsifiable Concentrate (EC),

18.1% ai

(1.5 lbs ai/gal)

Reg. No. 279

- 3125 0.05 lbs

ai/ A 5 0.25 lbs ai/

A/season 14 Application intervals 14 days. Minimum Spray Volume = 10 gal/A (aerial); 20

- 100 gal/A (ground) depending on crop.
Mustang
Insecticide

Oil

- in

- Water (EW) 17.1% ai (1.5 lbs ai/gal)

Reg. No. 279

- 3126

Pistachio

Aerial; Ground (Groundboom, Airblast);Che migation Fury Insecticide,

Emulsifiable Concentrate (EC),

18.1% ai
(1.5 lbs ai/gal)
Reg. No. 279

- 3125

0.05 lbs

ai/ A 5 0.25 lbs ai/

A/season 7 Application intervals 7 days.

Minimum Spray Volume = 10 gal/A (aerial); 20

- 100 gal/A (ground) depending on crop. Mustang
Insecticide
Oil

- in

- Water (EW) 17.1% ai (1.5 lbs ai/gal) Reg. No. 279

- 3126Zeta

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Page 16 of 78 Table 3.3.1 Summary of Directions for Use of Zeta

- cypermethrin.

Applic. Timing, Type, and Equip. Formulation

[ US EPA Reg. No.] Max.

Single Applic.
Rate (lb ai/A) Max. No.

Applic.
Per
Season Max.

Seasonal Applic. Rate (lb ai/A) PHI (days) Use Directions and
Limitations

Poultry House

Rotary Spreader ZetaGard LBT

Insecticide Dust (0.375% ai) Reg. No. 39039

- EN 0.4 lb

ai/A

(505 lbs/20,000
ft 2 ) 2 50 lbs/20,000

ft 2 per six week period NA Do not exceed 50 lbs per 20,000ft 2 per six week period.
Do not treat less than six weeks prior to slaughter. Do not apply with power duster equipment.
Do not enter or allow others to
enter until dusts have settled.

There are currently no proposed new residential uses associated with zeta

- cypermethrin. However, cypermethrin and zeta

- cypermethrin are registered for use on a variety of indoor and outdoor residential environments including: lawns, gardens, pets, and ind oor surfaces and spaces. The registered products are formulated as liquids, wettable powders, granules, ready to use aerosols and foggers. For purposes of performing the aggregate assessment, various residential use scenarios were selected to represent t he most conservative and worst case use scenarios and thereby will be protective of all residential uses. Table 3.3. 2 provides a summary of the representative use scenarios and respective application rates. Most of the information relative to use products and scenarios w as obtained from the 2006 Revised Occupational and Residential Exposure Assessment for the Reregistra tion Eligibility Decision Document and the 2011 Pyrethroid Cumulative Risk Assessment. Registration numbers for individual products were not provided in either document.

Table 3.3. 2 : Registered Residential Uses for Zeta

- cypermethrin and Cypermethrin Exposure Scenario Method of Application Application Rate Turf (EC) Hose

- end Sprayer 0.44 lb ai/A Turf (WP) Back

- pack Sprayer 0.6 lb ai/A
Garden (Liquid) 1.7 lb ai/A Indoor Crack and Crevice (WP) Manually Pressurized Handwand 0.0169

Aerosol Can 0.0013 lb ai/16 oz

can Indoor Fogger (RTU) NA NA Dog Tag ( US EPA Reg. No. 39039

- 14) NA NA

3.4 Anticipated Exposure Pathways

As a result of the proposed uses of zeta

- cypermethrin, humans may experience dietary exposure

to zeta

- cypermethrin residues via their food and drinking water. Exposures associated with the registered residential uses include dermal, inhalation, and, in the case of children, incidental oral (i.e., hand

- to

- mouth).Zeta

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Page 17 of 78 In occupational settings, dermal and inhalation exposure may occur during mixing, loading or applying the pesticide. Furthermore, there is potential for post

- application exposure to workers who enter treated fields after the pesticide has been applied. T hese exposures may occur via
dermal and/or inhalation routes.

For both occupational and non

- occupational settings, this risk assessment considers all of the relevant exposure pathways, combining them as appropriate, to estimate overall exposure and
risk

.

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 Enviro nmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every pesticide risk assessment, OPP consider s a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption,
and a ctivities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk ass essments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, special ized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and ad ults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to byst anders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Cypermethrin, zeta

- cypermethrin, and alpha

- cypermethrin are members of the pyrethroid class of chemicals. Pyrethroids have historically been classified into two groups, Type I and Type II, based upon chemical structure and neurotoxicological effect s . Type I pyrethroids lack an alpha

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

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

- specific behaviors are collectively described as the T

- syndrome. Type II pyrethroids contain an alpha

- cyano m oiety and produce a syndrome that includes pawing, burrowing, salivation, and coarse tremors leading to choreoathetosis in rats. These Type II pyrethroid

- specific behaviors are collectively described as the CS

- syndrome ( Verschoyle and Aldridge 1980 ; Lawrence and Casida 1982 ) . Cypermethrin, zeta

- cypermethrin, and alpha

cypermethrin are structurally similar Type II pyrethroids. The adverse outcome pathway (AOP)Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 18 of 78 shared by pyrethroids involves the ability to interact with voltage

- gated sod ium channels (VGSCs) in the central and peripheral nervous system, 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

Although cypermethrin, zeta

- cypermethrin and alpha

- cypermethrin are separate active ingredients with different end

- use products, they are included together in the hazard evaluation based on the following considerations:

Cypermethrin is a racemic mixture of eight isomers (each with percentages of 11

- 14%).

Z eta

- and alpha

- cypermethrin are enrichments of the more insecticidally

- potent isomers (i.e., alpha

- S and cis

- 2

- R isomers)

.

All three cypermethrins are structurally similar (type II

- α

- cyano pyrethroids) and share a common mode of action (interaction with voltage gated sodium channels). The main target tissue for all three chemicals is the central and peripheral nervous system

.

The qualitative and quantitative nature of the toxicological effects (i.e., neurotoxicity) for the cypermethrins is similar following oral, dermal, and inhalation routes of exposure.

Acute toxicity lethality studies resulted in similar PODs

, and the overall evidence from repeated dose toxicology studies indicate s that the thre e chemicals have comparable qualitative toxic effects.

Current analytical methods for tolerance enforcement are not stereospecific; thus no distinction is made between residues of cypermethrin, zeta

- cypermethrin, and alpha

cypermethrin in foods.

There are a variety of factors that can influence the toxicity of pyrethroid chemicals (vehicle, method of administration, peak time); however, the available toxicology studies for the cypermethrins are relatively consistent across the database and the differenc es seen in the database are within expected variability. For risk assessment purposes,

cyper methrin, zeta

- and alpha

- cypermethrin are considered equally toxic and the mostZeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 19 of 78 protective endpoints and PODs have been selected and used for risk assessment

.

The database of experimental toxicology studies available for cypermethrin, zeta

cypermethrin, and alpha

- cypermethrin provides a robust characterization of the hazard potential for children 6 years old and older, and for adults. Guideline toxicology studi es are available that examine a variety of species, durations, routes, and lifestages and evaluate potential for neurotoxicity, developmental toxicity, reproductive toxicity, developmental neurotoxicity, carcinogenicity, immunotoxicity, and dermal toxicity . In addition, there are on

- going efforts to develop data to inform the potential sensitivity of infants and younger children to pyrethroids as a class, which is discussed further in Section 4.4. Despite these scientific efforts, HED is confident that th e PODs and uncertainty factors selected in this risk assessment are health protective and have a strong
scientific foundation.

The data from the following studies were used to evaluate the hazard potential of the cypermethrin s :

- Wolansky Acute Oral Rat S tudy (cypermethrin)

- WIL Acute Oral Rat Study (cypermethrin)

- 21 Day Dermal Studies in the Rat and Rabbit (cypermethrin and zeta

- cypermethrin)

21

- Day Inhalation Study (cypermethrin)

- 90 Day Rat Studies (cypermethrin, alpha

- and zeta

- cypermethrin)

- 90 Day Dog Studies (cypermethrin and alpha

- cypermethrin)

- Chronic Dog Studies (cypermethrin and alpha

- cypermethrin)

- Chronic/Cancer Mouse Studies (cypermethrin and alpha

- cypermethrin)

- Chronic/Cancer Rat Study (cypermethrin)

- Developmental Studies in the Rat and Rabbit (cypermethrin, alpha

- and zeta

- cypermethrin)

- Reproduction Studies in the Rat (cypermethrin and zeta

- cypermethrin)

- ACN Studies in the Rat (cypermethrin, alpha

- and zeta

- cypermethrin)

- SCN Studies in the Rat (cypermethrin and zeta

- cypermethrin)

- DNT Study in the Rat (zeta

- cypermethrin)

The studies available for consideration of toxicity provide a comprehensive database. The Wolansky and WIL studies measure locomotor and functional observational battery (FOB) activity, respectively, and provide robust data to evaluate the hazard potential of cypermethrin, alpha

- and zeta

- cypermethrin.

In addition, numerous studies from the scientific literature conducted over several decades describe the pharmacodynamic and pharmacokinetic profile of the pyreth roids in 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 ProfileZeta

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Page 20 of 78 Cypermethrin, zeta

- cypermethrin, and alpha

- cypermethrin have been evaluated for a variety of toxic effects in experimental toxicity studies. Behavioral changes commonly seen with type II pyrethroids were consistently noted in the toxicology database. These included tremors, gait abnormalities, limb conditions, ataxia and hypersensiti vity. Additionally, body weight changes were routinely observed and mortality was seen in a few studies in rats and dogs. Clinical signs were also noted in all acute neurotoxicity studies. Decreased activity, gait abnormalities, tremors, limb conditions , and hypersensitivity were observed at the mid and high doses. Additionally, slight nerve degeneration was seen in the acute neurotoxicity study with alpha

cypermethrin at the high dose. In the subchronic neurotoxicity studies with cypermethrin and

zet a

- cypermethrin, similar behavioral effects were seen along with decreased food consumption, body weight, and body weight gain.

Dermal toxicity studies are available for zeta

- cypermethrin (rat) and cypermethrin (rabbit), in
which local irritation was o bserved in rats and rabbits at the highest doses tested. No systemic
effects were observed in the 21

- day dermal study in the rat conducted with zeta

- cypermethrin at dose levels up to 1000 mg/kg/day. In the dermal toxicity study in rabbits with cypermethr in, systemic effects were observed (focal necrosis of the liver, decreased testicular weights and decreased body weight in females). However, the se observations in the rabbit were not used for
risk assessment because the testing method ( i.e., abraded skin ) does not simulate actual exposure and results in compromised test conditions. Additionally, there would be physiological
differences between abraded and non

- abraded animals , further undermining the relevance of
these results for risk assessment

.

Developmental toxicity and reproduction studies are available for the cypermethrins. In the developmental toxicity studies in rats with cypermethrin and zeta

- cypermethrin, there was no evidence of developmental toxicity up to the highest doses tested. Ma ternal toxicity included decreased body weight gain and food consumption in both chemicals. Splayed limbs, spasms & hypersensitivity to noise and convulsions were seen with cypermethrin, and ataxia, urine

- stained abdominal fur, and fecal

- stained fur were seen with zeta

- cypermethrin. In the developmental toxicity study in rats with alpha

- cypermethrin, offspring effects were limited to decreased fetal body weight. Maternal effects observed in the study were unsteady gait, piloerection, limb splay, and hype rsensitivity to sound and touch at the same dose. In the developmental toxicity studies in rabbits with cypermethrin, zeta

- cypermethrin, and alpha

- cypermethrin, there was no evidence of developmental toxicity up to the highest dose tested. Maternal effect s seen with cypermethrin included decreased body weight gain, anorexia, abdomino

- genital staining, decreased feces, and red or pink material in the pan. With alpha

- cypermethrin, maternal effects were body weight loss and decreased food consumption. Multi

- generation reproduction studies in rats are available for cypermethrin and zeta

- cypermethrin. In the reproduction study with cypermethrin, decreased body weight gain was observed in adult animals and decreased body weight was seen in offspring animals at the highest dose tested. In the reproduction study with zeta

- cypermethrin, decreased body weight gain and mortality were observed in offspring animals in the presence of mortality, increased brain weights, decreased body weights, and neurotoxicity in mat ernal
animals.Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 21 of 78 No effects were observed in an immunotoxicity study in rats with alpha

- cypermethrin up to the
limit dose.

Cypermethrin is classified as a Group C “Possible human carcinogen”, based on an increased incidence of lung adenomas and adenomas p lus carcinomas combined in females (CPRC, 1988) in a mouse carcinogenicity study. The presence of common benign tumors (lung adenomas), in one species (mice) and one sex (female), with no increase in the proportion of malignant tumors
or decrease in the t ime

- to

- tumor occurrence, together with the lack of mutagenic activity, was not considered strong enough to warrant a quantitative estimation of human risk. Quantification of risk using a non

- linear approach (i.e., aPAD, a RfD) will adequately account for a ll chronic toxicity, including carcinogenicity, that could result from exposure to cypermethrin (see 4.5.3)

.

Acute lethality studies conducted with cypermethrin, zeta

- cypermethrin, and alpha

- cypermethrin indicate moderate acute toxicity via the oral rou te (Category II) and low toxicity via the acute dermal or inhalation routes (Categories III). Additionally, mild irritation was seen in primary eye and skin irritation studies but no dermal sensitization was observed.

Metabolism data are available for cy permethrin and alpha

- cypermethrin. The pharmacokinetics
for the cypermethrins are similar to th ose of other pyrethroids, i.e., rapid absorption and
clearance. Metabolism studies are available for the cis

- and trans

- isomers of cypermethrin separately, and cypermethrin (i.e., equimolar mixture of the cis and trans isomers). In single dose studies in rats with either 0.6 mg/kg cis or trans, > 70% of the radiolabel was excreted within 24 hours, with >53% in the urine and <20% in the feces in males. However, in females, cis was excreted equally in urine and feces, approximately 35% of the administered dose (AD)
via each route. Pharmacokinetics were not different for the molecules labeled with C14 in either the benzyl or the cyclopropyl portion of the molecul e. Less than 1% of the AD was expired in the air. Radiolabel was retained in fatty tissues after dosing with the cis and trans isomers, with little reduction from day 1 to day 8. Liver was also a target organ, however, concentrations rapidly decreased a fter dosing on day 1.

A single dose metabolism study of alpha

- cypermethrin indicates that the pharmacokinetics are very similar to cis, trans, and cypermethrin , as previously discussed. However, the amount absorbed from the gastrointestinal tract was slightly lower, at 53

- 55%. Additional toxicokinetic parameters were characterized for alpha

- cypermethrin including fatty tissue elimination half

- life
of 1.6

- 2.7 days within the first 8 days of exposure increasing to 12

- 40 days determined 40 days after exposure. Removal from non

- fatty tissues was considerably faster, with levels below the detection limit 2 days after dosing.

Pyrethroids are susceptible to ester hydrol ysis in the plasma and oxidative metabolism by cytochrome P450 enzymes. Major biotransformation products from single and repeated dose rat metabolism studies included oxidation of the methyl group on the acid moiety, hydroxylation at
the 4’

- position of t he alcohol moiety, cleavage of the ester linkage, and conjugation with sulfuric and glucuronic acid. However, in the case of cypermethrin, radiolabel in the feces is largely unmetabolized parent (>90% parent).Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 22 of 78 4.3 Pyrethroid Pharmacokinetic and Pharmacod ynamic Profile

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

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

age

- related differences in pyret hroid toxicity.

4.3.1 Pharmacokinetics

Pharmacokinetics 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) which de termine the concentration of the pyrethroids reaching sodium channels. The underlying pharmacokinetics of pyrethroids is an important determination of their toxicity because the concentration of pyrethroid at the sodium channel relates to the extent of

to xicity; greater pyrethroid concentration translates as increased neurotoxicity. Physiological processes that significantly contribute to the PK include metabolism, protein binding, and partitioning. Carboxylesterases and cytochrome P450 enzymes are the t wo 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.

Physiologically

- based pharmacokinetic (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 usin g a ‘generic’ or family model structure for this class is scientifically appropriate. In other words, due to the similarities in the PK profiles of pyrethroids, a single model structure is able to predict the tissue dose based on the pharmacokinetics of e very member of the class. The family modeling approach was presented to and supported by the FIFRA SAP ( USEPA 2007 )

.

In 2011 the Agency conducted an analysis of the toxicokinetic profile of pyrethroids as a class. Several studies in this analysis indicate that there are age

- dependent pharmacokinetic differ ences for the pyrethroids (i.e., there are differences in the ability of adults and juveniles to metabolize pyrethroids). The enzymes which metabolize and detoxify the pyrethroids are present in rats and
humans at birth ( Koukouritaki et. al. 2004 ; Yang et. al. 2009 )

. As a result, both juveniles and adults are able to tolerate low doses of pyrethroid s when the internal dose, or the amount of pyrethroid at the sodium channel, is low. However, the activity of these enzymes increases with age, conveying in adults a greater capacity to detoxify pyrethroids compared to juveniles ( Anand
et. al. 2006 ; de Zwart et. al. 2008 ; Yang et. al. 2009 ) . For example, the rate of in vitro metabolism of deltamethrin by plasma carboxyesterases, plus hepatic carboxyesterases and cytochrome P450s (microsomes) is at least 6 times higher for PND 90 rats compared to PND 10Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 23 of 78 rats ( Anand et. al. 2006 ) . As a consequence, higher internal doses (i.e., those associated with high doses in experimental toxicology studies) overwhelm the clea rance mechanisms in juveniles but because adults have greater enzyme activity, they are able to tolerate higher doses prior to the onset of toxicity. As a matter of perspective, the anticipated exposures from typical dietary or
residential activities are not expected to overwhelm the premature metabolic systems in juveniles.

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

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

- Velez et. al. 2010 ) . The brain is considered the primary target organ for pyrethroids, and increased pyrethroid concentrations are correlated with increasing systemic toxicity. This model predicts that, compared to adult rats (i.e., 90

- days old), equivalent brain concentrations of deltamethrin would be achieved with a 3.8X fold lower oral
dose in 10

- day old rats and 2.5X lower dose in 21

- day old rats ( Tornero

- Velez et. al. 2010 ) . For example, a 1 mg/kg dose in the adult is equivalent to a 0.26 mg/kg dose (≈1 mg/kg÷3.8mg/kg) in
the 10

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

- day old rat. The
difference between a 3.8

- and a 2.5

- fold dose is within back ground variability of the model. As a result, the Agency concludes that juvenile rats are 3X more sensitive than adults with respect to pyrethroid pharmacokinetics.

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 4.1 and the disr uption of sodium channels by pyrethroids as an early key event ( Lund and Narahashi 1982 ; Salgado et. al. 198 9 ; Song and
Narahashi 1996 ; Tabarean and Narahashi 1998 ; Soderlund et. al. 2002 (review) ) With respect to altered neuronal excitability, Type I pyrethroids cause slight prolongations of the sodium current tails (e.g. ~20 ms), often resulting in long trains of action potentials. In contrast, Type II pyrethroids significantly prolon g sodium current tails (e.g. 200ms to minutes) typically resulting in increased resting membrane potential and ultimately causing depolarization dependent action potential block. Choi and Soderlund ( 2006 ) examined interactions of several pyrethr oids, including cypermethrin, with mammalian VGSCs expressed in Xenopus oocytes. Cypermethrin behaved in a manner consistent with type II pyrethroids by producing prolonged tail currents that activated more slowly and did not detectably inactivate during a 40

- ms depolarization. Additionally, Cao et. al. ( 2011a ) measured Na influx in primary cultures of mammalian (mouse) neurons and demonstrated that cypermethrin caused increases in Na influx in this model; this confirms the ability of cyperme thrin to interact with VGSC in intact mammalian neurons. An additional study by Cao et. al. ( 201 1b ) demonstrated that the interaction of cypermethrin with VGSC caused changes in neuronal excitability that resulted in calcium influx into intact mouse neurons. As this effect of cypermethrin 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.Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 24 of 78 Figure 4.3 Resting modification of rat Nav1.8 sodium channels by cypermethrin expressed in Xenopus oocytes. Channel c urrent vs time traces from individual representative oocytes in the absence or presence (*) of 100 μM cypermethrin 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 . Data 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 like those discussed here to in vivo measures are not yet developed. There fore, the Agency is focusing its efforts in hazard characterization and identification on the apical endpoint (i.e., changes in neurobehavior in laboratory animals). Neurotoxicity resulting from pyrethroids is generally characterized by tremors, hyper

- or hypothermia, heightened response to stimuli, salivation, tremors and convulsions ( Soderlund et. al. 2002 ; Wolansky and Harrill 2008 ; Weiner
et. al. 2009 )

.

In contrast to the age

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

- dependent even though th ere are several variations of sodium channels, called isoforms, which are differentially expressed by tissue and age. Due to the nature of the interaction of pyrethroids with sodium channels, it is difficult 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 acted upon by pyrethroids. Therefore, much of the
informat ion 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 direc t quantitative measure
of in vivo pyrethroid activity. However, these techniques consistently and qualitatively demonstrate that channel isoforms expressed in juveniles are not more sensitive to pyrethroid perturbation compared to isoforms expressed in ad ults 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, in a direct comparison of 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 wellZeta

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Page 25 of 78 characterized compared to the rat. However, based on the comparable function and distribution of sodium channels between the species, the rat is an appropriate su rrogate for the evaluation of
human PD ( Goldin et. al. 2000 ; Goldin 2002 ) . As a result, the Agency concludes that juvenile rats are not more sensitive than adults with respect to pyrethroid pharmacodynamics.

4.3.3 Critical Dur ation of Exposure

One of the key elements in risk assessment is the appropriate integration of temporality between the exposure and hazard assessments. The onset of neurotoxicity following an acute pyrethroid dose is rapid, with a time to peak effect for neurobehavioral effects ranging from 4 to 8 hours ( Wolansky and Har rill 2008 ; Weiner et. al. 2009 ; Scollon et. al. 2011 ) . Furthermore, rapid metabolism and elimination preclude accumulation and increased potency following repeated dosing. Several neurotoxic effects were seen in acute neurotoxicity (ACN) and subchronic neurotoxicity (SCN) studies in rats with cypermethri n, zeta

- cypermethrin, and alpha

cypermethrin. Clinical signs related to neurotoxicity were noted in the ACN studies for all three
chemicals. For alpha

- cypermethrin, clinical signs were most frequently noted in rats dosed between 3 to 8 hours post

- dosing. In SCN studies with the three chemicals, neurotoxic effects were observed at comparable doses. No neurotoxic effects were seen in chronic toxicity studies in rats (Table 4.3.3).Zeta

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Page 26 of 78 1 BMD 1SD is the central estimate of the dose that results in decreased motor activity compared to control animals based upon a 1 stand ard deviation using Benchmark Dose Analysis. BMDL 1SD is the 95% lower confidence limit of the central estimate. Data located in Wolansky (2006), MRID 47885701. ≠ No neurotoxicity observed in the study. Table 4.3.3. Points of Departure with neurological effects for toxicology studies with Cypermethrin, Zeta

- cypermethrin, and Alpha

cypermethrin

. Study Duration Study findings Cypermethrin Zeta

- cypermethrin Alpha

- cypermethrin

NOAEL (mg/kg/day) LOAEL

(mg/kg/day) NOAEL

(mg/kg/day) LOAEL

(mg/kg/day) NOAEL

(mg/kg/day) LOAEL

(mg/kg/day)

BMDL 1SD 1 Acute,

single

exposure BMDL 1SD =

7.16 BMD =

11.20 BMDL 1SD =

N/A BMD =

N/A BMDL 1SD =

N/A BMD =

N/A

Acute neurotoxicity Acute,

single

exposure 30 100 10 50 4 20

Subchronic neurotoxicity 90 days 31 77 5/31 (M/F) 26.3/55.6 N/A N/A

Subchronic Rat 90 days ≠ ≠ ≠ ≠ 9.3 29.6 Developmental

Rat 10 days 17.5 35 12.5 25 9 15

Developmental
Rabbit 10 days 100 450 N/A N/A ≠ ≠

Sub

- chronic dog 90 days 24.6 37.0 N/A N/A 2.25 6.75 Reproductive toxicity 120 days ≠ ≠ 7 27 N/A N/A

Chronic dog (feeding) 1 year 6/5.7 (M/F) 20.4/18.1 N/A N/A ≠ ≠

Chronic dog (capsule) 1 year 5 15 N/A N/A N/A N/AZeta

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Page 27 of 78 Comparing NOAELs and LOAELs from single dose and repeated dose studies, neurotoxicity
does n ot seem to progress with increased exposure, which is consistent with the kinetic profile for pyrethroids

. The BMDL 1SD selected (7.16 mg/kg) for risk assessment from the acute Wolansky study is lower than the majority of PODs in the database. Lower PODs were determined for the subchronic dog, chronic dog and carcinogenicity studies in mice. However,
when HECs were compared for the studies and the appropriate safety factors were applied, the use of the Wolansky study was still the more conservative appro ach ( See A.3) . Therefore, the Wolansky study is protective of all effects observed in the toxicology database

.

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

Cypermethrin, zeta

- and alpha

- cypermethrin exposure to children <6 years old is expected and it must be considered in the context of the pyrethroids as a class. For infants and children less than six years of age, US EPA is reducing the FQPA safety factor to 3X based on the increased quantitative susceptibility seen in the scientific literature related to pyrethroid pharmacokinetics.

H igh

- dose LD 50 studies (studies assessing what dose results in lethality to 50 percent of the tested population) in the scientific literature indicat e that pyrethroids can result in increased quantitative sensitivity in the young. Examination of pharmacokinetic and pharmacodynamic data indicates that the sensitivity observed at high doses is related to pyrethroid age

- dependent pharmacokinetics

- the ac tivity of enzymes associated with the metabolism of pyrethroids. With otherwise equivalent administered doses for adults and juveniles, predictive pharmacokinetic
models indicate that the differential adult

- juvenile pharmacokinetics will result in a 3X g reater dose at the target organ in juveniles compared to adults. No evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics (the effect of pyrethroids at the target tiss ue) both with regard to inter

species differences between rats and humans and to differences between juveniles and adults. Specifically, there are in vitro pharmacodynamic data and in vivo data indicating similar responses between adult and juvenile rats at low doses and data indicating that the rat is a conservative model compared to the human based on species

- specific pharmacodynamics of homologous sodium channel isoforms in rats and huma ns.

In light of the high

- dose literature studies showing juvenile sensitivity to pyrethroids and the absence of the requested data on juvenile sensitivity to pyrethroids, US EPA is retaining a 3X additional safety factor as estimated by pharmacokinetic mod eling. For several reasons, US EPA concludes there are reliable data showing that a 3X factor is protective of the safety of infants and children. First, the high doses that produced juvenile sensitivity in the literature studies are
well above normal die tary or residential exposure levels of pyrethroids to juveniles and these lower levels of exposure are not expected to overwhelm the ability metabolize pyrethroids as occurred with the high doses used in the literature studies. This conclusion is confirme d by the lack of a finding of increased sensitivity in the majority of the pre

- and post

- natal guideline
studies for pyrethroid s , despite the relatively high doses used in those studies. Second, the portions of the uncertainty factors that account for po tential pharmacodynamic differences are likely to overstate the risk of inter

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

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Page 2 8 of 78 and rats. For both the int er

- species and intra

- species uncertainty factors, the pharmacodynamic portions are generally considered to be 3X, however for pyrethroids it is reduced to 1X since no differences among the various groups are observed. Finally, as indicated, pharmacokinetic modeling only predicts a 3X difference between juveniles and adults.

This information described above is summarized in Re

- Evaluation of the FQPA Safety Factor for pyrethroid pesticides (USEPA 2011c).

In guideline developmental and reproduction studies with the cypermethrins, t here was no evidence of increased qualitative or quantitative susceptibility in rat s or rabbit s

. In a guideline DNT study with zeta

- cypermethrin, there was increased sensitivity in the offspring based on body weight changes in pup s in the absence of treatment

- related effects in maternal animals. However, concern is reduced since the magnitude of body weight decrements was similar in adult (5

- 8%) and young animals (5

- 10%). The results from the DNT study are very similar to
results obser ved in the reproduction studies where body weight changes (decreased BW gain) were seen in maternal and offspring animals at doses similar to the DNT study, with no
indication of increased susceptibility. Therefore, there is no residual concern for effects observed in the study (see 4.4.3)

.

4.4.1 Completeness of the Toxicology Database

The toxicology database for the cypermethrins is not complete, because the Agency lacks sufficient information to fully characterize the potential for juvenile sensitivity. However, w hen evaluated together, the toxicity database for cypermethrin, zeta

- cypermethrin, and alpha

cypermethrin can be used to characterize most effects, including potential developmental and reproductive toxicity, immunotoxicity, and neu rotoxicity. Acceptable developmental toxicity studies in rats and rabbits, reproduction studies in rats, neurotoxicity studies (ACN, SCN, and DNT) in rats, and immunotoxicity studies in rats are available. In addition, route

- specific dermal
and inhalatio n studies are available.

For the reasons discussed in Section 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 additio nal 3X for risk assessments for infants and children < 6 years of age.

4.4.2 Evidence of Neurotoxicity

There are no residual uncertainties with regard to neurotoxicity for cypermethrin, zeta

cypermethrin, and alpha

- cypermethrin. Like other pyrethroids, t he chemicals cause neurotoxicity by interacting with sodium channels leading to clinical signs of neurotoxicity. Neurotoxicity was observed in several of the toxicity studies for the three active ingredients. These effects are adequately assessed by the available guideline and non

- guideline studies.

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

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Page 29 of 78 In the DNT study with zeta

- cypermethrin, there was increased sensitivity in the offspring based on body weight changes in pups (5

- 10%) in the absence of treatment

- related effects in maternal
animals. Although, t here was a 5

- 8% decrease in mat ernal body weight in this study, a body weight decrease of <10% is generally no t considered adverse in adults

, as this is considered to be
wit hin the range of variability because the magnitude of body weight per se is typically small (as an example , a 3 gram decrease in b ody w eight from a 338 g rat), and adults are no longer in the growth/development phase. In contrast, the offspring are at a stage of growth and development and are therefore expected to be gaining rather than losing weight. Thus, a smaller % decrease in body weigh t is considered adverse in the young relative to adults. In the case of zeta

cypermethrin, the decrease in b ody w eight of the young is comparable to adults; however, it was considered adverse in the young but not in the adult s . This disparity in interpret ation leads to an apparent increase in sensitivity in the young; however, concern is reduced since the magnitude of
b ody w eight decrements was similar in adult and young animals. The results from the DNT study are very similar to results observed in the r eproduction studies where body weight changes (decreased BW gain) were seen in maternal and offspring animals at doses similar to those in the

D NT study

, with no indication of increased susceptibility. Therefore, there is no residual
concern for effects o bserved in the study. The FQPA factor of 3X which is being retained by the Agency for all pyrethroids is considered adequately protective of potential effects of body weight for children <6 years of age exposed to the cypermethrins, includi ng zeta

- and al pha

cypermethrin.

Additionally, a fter reviewing the extensive body of peer

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

The Agency has no residual uncertainties regarding age related sensitivities 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 f or 24 pyrethroids, the scientific literature, and the cypermethrin, alpha

- and zeta

- cypermethrin guideline toxicological studies. No evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics.

The Agency will retain a 3X uncertainty factor to protect for exposures to children < 6 years of age based on the increased quantitative susceptibility seen in the scientific literature related to pyrethroid pharmacokinetics.

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

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Page 30 of 78 pyrethroids exogenously expressed rat and human VGSCs in Xenopus oocytes; 2) conducting in

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

- evaluation of the age

- related sensitivity of pyrethroids is appropriate.

4.4.4 Residual Uncertainty in the Exposure Database

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

- end health protective residue levels (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 source s, such that these exposures have not been underestimated.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response and Hazard Assessment

The details for selecting toxicity endpoints and PODs are presented in Appendix A (A.3). Based

o n the proposed use patterns for zeta

- cypermethrin and the existing residential uses for both zeta

cypermethrin and cypermethrin, the expected exposure profile will be for dietary, dermal, inhalation and incidental oral exposures.

As previously indicated, the toxicity endpoints for cypermethrin, zeta

- cypermethrin, and alpha

cypermethrin are consistently based on clinical signs of neurotoxicity consistent with type II pyrethroids. The available studies include multiple species, study designs, and durations

. Moreover, the acute exposure or bolus dosing studies generally result in lower NOAELs compared to longer term dietary administration studies, consistent with other pyrethroids in this class. Because uncertainty associated with the POD is propagated thr oughout the risk assessment, one of the key factors in POD selection is the robustness of the dose

- response data. The guideline experimental toxicology studies available for cypermethrin, zeta

- cypermethrin, and alpha

- cypermethrin are generally high qualit y and were considered in the POD selection process (A.2) and in the weight of the evidence evaluation. In addition to the typical guideline studies, data from two special studies (Wolansky study on motor activity and the WIL FOB study evaluating neurobeha vioral outcomes ) are available for cypermethrin ( Nemec 2006 ; Wolansky et. al. 2006 ) . Wolansky et al. ( 2006 ) measured motor activity at the time of peak effect after exposure to 11 pyrethroids, including cypermethrin. Dose

- response relationships
were determined us ing 6

- 11 doses per pyrethroid (6 doses used for cypermethrin) and 3

- 18 rats per dose group ( 8 animals/group used for cypermethrin) , minimizing variability and increasing
the confidence in the benchmark dose ( BMD ) estimates determined from this study. More over, each pyrethroid was evaluated by the same scientist thus decreasing some of the variability associated with neurobehavioral measures. In the WIL study, 17 pyrethroids have been evaluated using a specially designed (FOB) study focused on the outcomes associated with pyrethroid toxicity syndromes. The cypermethrin data from the WIL study were not used as partZeta

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Page 31 of 78 of the POD selection since the Wolansky study was considered more appropriate based on study design.

Observations of tremors, gait abnormaliti es, limb conditions, and hypersensitivity were prominent findings in the guideline experimental toxicology studies and were considered in the point of departure (POD) determination. However, guideline studies typically have only three treatment groups and often do not evaluate clinical signs at the time of peak effect. Moreover, scoring metrics for behavioral parameters vary widely among guideline studies. Given the multiple strengths associated with the design of the Wolansky et. al. ( 2006 ) study and the resulting well

- defined dose

- response curve, it was determined that the study provided the most robust data set for extrapolating risk from cypermethrin, zeta

- cypermethrin, and alpha

cypermeth r in.

A BMD analysis has been cond ucted by the Agency for all the pyrethroids included in the Wolansky study (MRID 47885701) . Overall, due to 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 general approach, it is preferred to use a combination of biological and statistical factors in the BMR selection. In the case of motor activity data, there is no specific level of change established by the scientif ic community as being considered adverse. Therefore, OPP has elected to use one standard deviation (1SD) from the control group as suggested for continuous endpoints in the Agency’s draft BMD guidance ( USEPA 2000 ) as the BMR. For the cypermethrins hazard assessment and point of departure
determinat ion, HED 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 cypermethrin are 11.20 mg/kg and 7.16 mg/kg, respectively. As a matter of science policy,
US EPA uses the BMDL, not the BMD, for deriving PODs. Thus the BMDL 1SD of 7.16 mg/kg is being used as the POD for acute dietary risk assessment for the cypermethrins.

Acute Dietary (all populations) As mentioned above, HED selected the POD and endpoint from the acute oral ( Wolansky ) study
in rats for acute dietary exposure

. Acute dietary risk assessment was performed using the

BMDL 1SD value of 7.16 mg/kg based on decreased locomotor activity at the BMD 1SD value of 11.20 mg/kg. There is no increase in hazard from repeated exposures to the cypermethrins; therefore, the acute dietary exposure assessment is protective of chronic dietary exposures since acute exposure levels are higher than chronic exposure levels. Accordingly, a dietary exposure
assessment for the purpose of assessing chronic dietary risk was not conducted.

Incidental Oral (Short

- term) For the purpose of assessing potential risk associated with incidental oral exposure to children re

entering treated areas, HED selected the dose (POD) and endpoint from the acute oral Wolansky study in rats. Incidental oral risk assessment was performed using the BMDL 1SD value of 7.16 mg/kg, based on decreased locomotor activity and the BMD 1SD of 11.20 mg/kg. The decreases in motor and locomotor activity are considered potential single

- dose e ffects because they were
observed within the first hours follow ing dosing. The Wolan sky study is a very robust study with 6 doses, uses a sensitive vehicle and volume to determine a BMDL and therefore provides aZeta

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Page 32 of 78 more accurate point of departure than other studies considered for incidental oral endpoint and
dose selec tion.

Dermal (Short

- and intermediate

- term) A dermal assessment was not conducted for children or adults. No systemic effects were
observed in the 21

- day rat study with zeta

- cypermethrin up to the limit dose. No systemic
effects were observed with cy permethrin in animals with non

- abraded skin up to the highest dose tested (1000 mg/kg/day in the rat and 200 mg/kg/day in the rabbit). Additionally, there are no developmental concerns . Based on the exposure profile, HED does not anticipate long

- term dermal exposure for adults or children.

A dermal absorption study for alpha

- cypermethrin in the rat is available for consideration. Typically pyrethroids have a low absorption value of ≤ 5%. Combined with the high rate of metabolism, the amount of parent available to interact with sodium channel is minimal and therefore neurotoxic effects are not routinely observed in dermal studies. The absorption rate in the alpha

- cypermethrin study is slightly higher

, at 13%. However, systemic effects were not observed in the rat at 1000 mg/kg/day. Since rat skin is typically more porous to xenobiotics compared to human skin, it’s highly unlikely sufficient cypermethrin will penetrate human skin

in sufficient quantities to cause neurotoxicity. Furthermore, pyrethroids are lipophilic and therefore much of the measured radioactivity measured in the skin was captured in the upper dermal layers and not available for absorption. Based on these factors just discussed, HED does not anticipate systemic toxicity via the dermal route of exposure.

Inhalation (Short

- and intermediate

- term)

A route

- specific 21

- day rat inhalation study with cypermethrin was used to assess short

- and
intermediate

- term inhalatio n exposure. The NOAEL of 0.01 mg/L and the LOAEL of 0.05 mg/L were based on increased salivation. This dose and endpoint are appropriate since the
effect s w ere seen following exposure via the route (inhalation) and duration (short

- and
intermediate

- term) of concern. Additionally, the effects seen in the inhalation study are consistent with the pyrethroid profile and are protective of neurotoxicity.

For cypermethrin, human equivalent concentrations ( HECs ) for the inhalation NOAEL were
calculated for use in MOE calculations, based on the methods and dosimetry equations described
in US EPA’s reference concentration ( RfC ) guidance (1994). The regional deposited

- dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter [ MMAD] and geometric standard deviation [ g ] of aerosols), can be used to estimate the different dose fractions deposited along the respiratory tract. The RDDR is also based on interspecies differences in ventilation and respiratory

- tract surface areas. Th us, the RDDR can be used to adjust an observed inhalation particulate exposure of an animal to the predicted inhalation exposure for a human. For the 21

- day inhalation study, a RDDR was estimated at 3.1 based on the reported MMAD of 2.63 μm and geometric s tandard deviation ( g ) of 1.87 and the respiratory

tract surface area of the rat relative to the human (see A.4 for detailed calculations). Since the rat inhalation study was carried out for 6 hr/day for 5 days/week, the only exposure adjustment
made was in the assumption of 8 hrs/day for human occupational ex posures. The resulting HEC is 0.023 mg/L. For human residential exposure, 24 hrs/day was assumed and the HEC is 0. 008.Zeta

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Page 33 of 78 For the current risk assessment, the use of 24 h ours of exposure to calculate an HEC is
considered protective and very conservative since handler exposure via the inhalation route is expected to be less than 24 hours

. Human equivalent doses (HEDs) of 1.10 mg/ kg/day for occupational and 1.15 mg/kg/day for residential were also calcu lated and used for risk

assessment.

Based on the exposure profile, HED does not anticipate long

- term inhalation exposure for adults
or children.

HED’s Level of Concern (LOC) for Margin of Exposure (MOE)

HED’s level of concern for occupational and reside ntial risk estimate s is based on the various uncertainty and safety factors retained or applied for specific routes of exposure. The LOCs relevant for risk assessment for the cypermethrins are described in the table below. For
inhalation risk assessments , the 10X interspecies factor was reduced to 3X to account for interspecies differences, in accordance with the RfC guidance. The only exposure pathway for adults and children greater than 6 years old is via inhalation, for which a 30X uncertainty factor
has been retained. The intra

- species variability factor of 10X is combined with an interspecies extrapolation factor of 3X, based on the use of a human equivalent dose for inhalation risk assessment. For children under 6 years old, exposed via the inhala tion route, the LOC is 100, based on a 10X factor for intraspecies variability, 3X for interspecies extrapolation, and 3X for juvenile sensitivity. For children exposed via the oral route, the LOC is 300, based on the
traditional 10X factors for intra

- spe cies variability and interspecies extrapolation, and the additional 3X FQPA factor.

Route LOC

Occupational Dermal Exposure NA Occupational Inhalation Exposure 30X

Residential Incidental Oral Exposure < 6 years old: 300X

Residential Dermal Exposure (Adults/Children) NA

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

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources

, oral, dermal and inhalation

, and determine whether the individual exposures can be combined if they have the same toxicological
effects. For th e cypermethrins , short

- term oral and inhala tion exposures can be combined for children, since endpoints are based on the same toxicological effects (clinical signs related to neurotoxicity)

. Although dermal exposure occurs during and following use of zeta

cypermethrin, there is no toxicity via the dermal route , and

, therefore

, the exposure does not need
to be combined with any other routes

.Zeta

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Page 34 of 78 4.5.3 Cancer Classification and Risk Assessment Recommendation

Cypermethrin is classified as a Group C “Possible human carcinogen”, based on an increased incidence of lung adenomas and adenomas plus carcinomas combined in females in a mouse carcinogenicity study. The presence of common benign tumors (lung adenomas), in one species (mice) and one sex (female), with no increase in the proportion of malignant tumors or decrease
in the time

- to

- tumor occurrence, together with the lack of mutagenic activity, was not considered strong enough to warrant a quantitative estimat ion of human risk. Taking into account all of this information, t he Agency has determined that quantification of risk using a non

- linear approach (i.e., aPAD or aRfD ) will adequately account for all chronic toxicity, including carcinogenicity
that could r esult from exposure to the cypermeth r ins. While the Agency would typically use a cPAD to protect for cancer concerns, use of the aPAD is protective because increasing toxicity with increasing duration of exposure is not demonstrated for the cypermethrins. The NOAEL observed in the mouse cancer study in which tumors were observed is 14 mg/kg/day, 2

- fold higher than the POD used for acute risk assessment. The LOAEL in the mouse cancer study is 57 mg/kg/day based on liver effects, not tumor formation. The t umors were seen at 229 mg/kg/day. The acute point of departure (POD) of 7.16 mg/kg/day selected for risk assessment is 32 fold lower than the dose that induced lung tumors in mice. Only the mouse study with cypermethrin resulted in tumor formation , no evi dence of carcinogenicity was observed in cancer studies in rats with cypermethrin or mice with alpha

- cypermethrin.

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

Details for selecting toxicity endpo ints/ PODs follow, and t he full toxicological profile is presented in Appendix A

.

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Zeta

- c ypermethrin, Cypermethrin, and Alpha

- c ypermethrin for Use in Dietary and Non

- Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety
Factors RfD, PAD, Level of Concern

for Risk Assessment Study and Toxicological
Effects

Acute Dietary (children ≥ 6 years old and adults) Wolansky

BMDL 1SD = 7.16 mg/kg UF A = 10x

UF H =10x FQPA SF= 1x Acute RfD = 0.07 mg/kg/day

aPAD = 0.07 mg/kg/day Wolansky BMD = 11.20 mg/kg
based on motor activity

Acute Dietary (children<6 years old) Wolansky

BMDL 1SD = 7.16 mg/kg UF A = 10x

UF H =10x FQPA SF= 3x Acute RfD = 0.07 mg/kg/day

aPAD = 0.023 mg/kg/day Wolansky BMD = 11.20 mg/kg
based on motor activity

Incidental Oral
Short

- Term (1

- 30 days) Wolansky

BMDL 1SD = 7.16 mg/kg UF A = 10x

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

300 Wolansky BMD = 11.20 mg/kg
based on motor activity

Dermal (All exposures) N o systemic toxicity seen in dermal toxicity studies & no developmental concern.Zeta

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Page 35 of 78 Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Zeta

- c ypermethrin, Cypermethrin, and Alpha

- c ypermethrin for Use in Dietary and Non

- Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD, Level of Concern

for Risk Assessment Study and Toxicological
Effects

Short

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

0.01 mg/L
HEC= 0.008 mg/L

HED =
1.15 mg/kg/day UF A = 3x

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

100 21

- day inhalation study in the

rat. LOAEL = 0.05 mg/L based
on increased salivation.

Short

- term Inhalation ( 1 to 30 day s) (children ≥ 6 years old and adults) NOAEL =

0.01 mg/L
HEC= 0.008 mg/L

HED =
1.15 mg/kg/day UF A = 3x

UF H =10x FQPA SF= 1x Residential LOC for MOE = 30 21

- day inhalation study in the

rat. LOAEL = 0.05 mg/L based
on increased salivation.

Cancer (oral, dermal, inhalation) Classification: Group C “Possible human carcinogen based on lung adenomas in female mice.

No Q 1 * has been derived. A non

- linear approach is recommended for cancer assessment.

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 l evel. BMD = benchmark dose. BMDL = benchmark dose (lower limit of a 95% confidence interval ). UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human populati on (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. HEC = human equivalent concentration; HED = human equivalent
dose.

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Zeta

- c ypermethrin, Cypermethrin, and Alpha

- c ypermethrin for Use in Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Dermal (All exposures) N o systemic toxicity seen in dermal toxicity studies & no developmental concern.Zeta

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Page 36 of 78 Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Zeta

- c ypermethrin, Cypermethrin, and Alpha

- c ypermethrin for Use in Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Short

- and
Intermediate

term Inhalation ( 1 day to 6
month s) NOAEL =

0.01 mg/L
HEC= 0.023 mg/L

HED = 1.10 mg/kg/day UF A = 3x

UF H =10x Occupational LOC

for MOE = 30 21

- day inhalation study in the rat.

LOAEL = 0.05 mg/L based on increased
salivation.

Cancer (oral, dermal, inhalation) Classification: Group C “Possible human carcinogen based on lung adenomas in female mice.

No Q 1 * has been derived. A non

- linear approach is recommended for cancer assessment.

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). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. HEC = human equiv alent concentration; HED = human equivalent dose.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

HED MARC Determination of Residues of Concern (D269584, Y. Donovan, 1 1/3/2000)

The nature of zeta

- cypermethrin residues is adequately understood in plants, rotational crops, livestock commodities, surface water, and groundwater based on information previously provided on cypermethrin and zeta

- cypermethrin. All studies wer e conducted in a manner appropriate for the proposed uses. In addition, metabolism studies for alpha

- cypermethrin in cabbage, wheat, lactating cow, and laying hen have been recently submitted and provide further
confirmation of the conclusions drawn from cypermethrin and zeta

- cypermethrin data (W. Drew, D378683, 7 September 2012).

An acceptable confined rotational study was previously submitted. A limited field rotational crop study was submitted, and is considered acceptable. Residues of cypermethri n and its
metabolites were non

- detectable (<0.01 ppm) in the rotational crop commodities of leafy vegetables, root and tuber vegetables, and cereal grain crops that were planted 30 days after the soil plots were treated at an exaggerated rate. Since neith er cypermethrin nor its metabolites were detected in any of the rotational crop commodities, a comparison between the metabolism in rotational crops and the metabolism in primary crops is not possible.

5.1.2 Summary of Environmental DegradationZeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 37 of 78 I. Maher, D378901/D385246, 22 February 2011

Based on similarities in the chemical properties and toxicological endpoints, environmental fate and ecotoxicity data are bridged between racemic cypermethrin and the enriched isomeric mixtures (i.e., alpha

- cyperme thrin and zeta

- cypermethrin). There is a complete environmental
fate database for zeta

- cypermethrin.

Zeta

- cypermethrin is expected to have little mobility in soil surfaces (Koc ≥ 20,800 L/kg) and leaching into groundwater is not expected to be an impo rtant transport process. Volatilization is not expected to be an important transport process either, since zeta

- cypermethrin has a relatively low vapor pressure and Henry's Law constant (refer to Appendix B). Zeta

- cypermethrin is moderately persistent in the environment and degrades through a combination of biotic and
abiotic mechanisms. Zeta

- cypermethrin is relatively stable to hydrolysis at acidic and neutral pH levels, but degrades in a few days under alkaline conditions (pH 9, half

- life of

~ 2 days). Zeta

cypermethrin is relatively light stable, but still undergoes photolysis in water, with half

- lives of about a month or more in distilled water. The rate of photolysis appears to be enhanced in natural waters (which contain photosensitizing agents li ke humic and fulvic acids), where the accelerated degradation results in half

- lives of a few days. Zeta

- cypermethrin photo

- degrades on
soil with dark control corrected half

- lives of ~128 days. Under both aerobic and anaerobic soil conditions, zeta

- cyperm ethrin biodegrades relatively slowly in soils, with half

- lives on the order of about 2 months. In contrast, under aerobic and anaerobic aquatic metabolism conditions, the degradation rate is enhanced, with half

- lives of around 9 to 17 days. If released t o water, zeta

cypermethrin partitions to sediment and may degrade slowly. Major d egradates observed in laboratory studies result from cleavage at the ester moiety of zeta

- cypermethrin, which formed 3

- (2,2

- dichloro

- ethenyl)

- 2,2

- dimethylcyclopropanecarboxyl ic acid (DCVA) and 3

- phenoxybenzaldehyde. The latter is further oxidized to 3

- phenoxybenzoic acid (3

- PBA). Another product observed in the soil photolysis study only was cyperamide

.

5.1.3 Comparison of Metabolic Pathways

The metabolism of zeta

- cypermethrin is similar to that of cypermethrin, based on a comparison of the metabolic profiles from studies with zeta

- cypermethrin and cypermethrin. A wide range of studies in mice, rats, dogs, sheep, cows and humans has shown that cypermethrin is rapi dly absorbed, distributed to a variety of organs and tissues, metabolized, and rapidly excreted from the body (WHO; 1989). There are no major differences in the absorption, distribution, retention or excretion between the species. Differences, where they do occur, are related to the rate rather than the nature of the metabolites formed, and the conjugation reactions.

Cypermethrin, both the cis and trans isomers, and zeta

- cypermethrin are primarily metabolized by cleavage of the ester bond. The metabol ites PBA and cyclopropane carboxylic acid ( CPA ) are mainly excreted as conjugates. The type of conjugate differs in a number of animal species dosed with cypermethrin, but humans and rats have the same pathway. Minor quantities of hydroxylated PBA (conju gated) may also be found.Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 38 of 78 The metabolites identified in the plant metabolism studies are either found as metabolites in the animal studies, or are intermediaries in the metabolic pathways elucidated in animals; therefore,
there are no residues of concer n in plant studies, nor are there any unique metabolic pathways in the plant, that are not represented in the rat metabolism study.

5.1.4 Residues of Concern Summary and Rationale

The toxicological and residue chemistry databases for zeta

- cypermethrin hav e been examined to
determine residue definitions for tolerance

- setting and risk

- assessment purposes. The nature of

zeta

- cypermethrin residues is adequately understood in plants, rotational crops, livestock commodities, surface water, and groundwater based on information provided on cypermethrin
and zeta

- cypermethrin . In addition, metabolism studies for alpha

- cypermethrin in cabbage, wheat, lactating cow, and laying hen have been recently submitted and provide further
confirmation of the conclusions drawn from cypermethrin and zeta

- cypermethrin data (W. Drew, D378683, 7 September 2012)

.

In previous risk assessments, HED had included the metabolite and degradate DCVA in its residues of concern for risk assessment, but subsequently concluded (D269584; Y. Donovan ; 3 November 2000) that for cypermethrin and zeta

- cypermethrin, the parent compound is the only residue of concern that needs to be included in the dietary risk assessment, including drinking

water

. This conclusion was based on the following consid erations :

1) R educed concern for the toxicity of DCVA was supported by negative mutagenicity

tests , and acute toxicity testing that demonstrated lower acute toxicity than the parent compound

. 2) T he residue data indicated that in the majority of crops, parent compound accounts
for at least 90% of the total residue. In those crops where DCVA was found at greater than 10%, the detected DCVA levels were below the limit of quantitation (LOQ), or the maximum livestock dietary burden contributions from DCVA for the se commodities are equal to or less than the LOQ

. 3) A lthough DCVA levels in liver and kidney are greater than those of the parent

, the
contribution of these foods to the total dietary exposure is not considered to be significant, and the overall exposure to DCVA would be negligible

. 4) EFED provided information which indicates that at neutral pH (i.e., environmental pH relevant for human health risk assessment)

, the parent compound is stabl e, and the formation of the degradate is less likely to occur than at higher pHs, as demonstrated by the environmental fates studies.

Based on the available data, HED ha s concluded that for all three active ingredients, the parent compound is the only residue of concern for both tolerance enforcement and risk assessment in plants, and livestock commodities, and in drinking water. The tolerance enforcement methods for plant and animal commodities do not dist inguish between zeta

- cypermethrin, alpha

cypermethrin, and cypermethrin. These conclusions are summarized in Table 5.1.4.Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 39 of 78 Table 5.1.4 Residue Definitions for Zeta

- c ypermethrin

Matrix Risk Assessment Tolerance Expression

Plants Primary Crop Zeta

- cypermethrin Zeta

- cypermethrin

Rotational Crop Zeta

- cypermethrin Zeta

- cypermethrin

Livestock Ruminant Zeta

- cypermethrin Zeta

- cypermethrin

Poultry Zeta

- cypermethrin Zeta

- cypermethrin Drinking Water Zeta

- cypermethrin Not Applicable

5.2 Food Residue Profile E. Holman, D379486, 20 September 2012 D. McNeilly, D399692, 20 September 2012

Adequate residue chemistry data have been provided for the new proposed uses of zeta

cypermethrin

. IR

- 4 has submitted field trial data for avocado, globe artichoke, and barley. The results from these studies are summarized in Table 5.2.1. In addition, IR

- 4 is requesting that the existing field trial data on tree nuts be use d to support setting a tolerance for pistachio. Field trials were of adequate number and geograp hic representation, were generated using adequate analytical methods, and were supported by adequate storage stability data. Adequate studies
were submitted to elucidate the fate of zeta

- cypermethrin in processed commodities. Therefore,
the submitted and existing data support the setting of tolerances for all proposed new agricultural

uses (E. Holman, D379486, 20 September 2012). Review of the field trial data and associated processing study on barley indicates that the existing livestock tolerances do n ot need to be
revised , as they are adequately protective of the anticipated dietary exposure from livestock
commodities associated with the proposed new uses.

Previously reviewed c onfined rotational crop studies with cypermethrin show that the
metabolis m in rotated crops is similar to that in primary crops. Limited field rotational crop studies generated with validated analytical methods, and supported by adequate storage stability data, demonstrated that residues were not likely in any commodity plante d 30 days after the soil plots were treated with cypermethrin

.

In general, USDA’s pesticide data program (PDP) monitoring results show no, or very low,
residues of the cypermethrins in tested food commodities.

Table 5.2.1

. Summary of Residue Data from Crop Field Trials with Zeta

- Cypermethrin (EC or EW).
Crop matrix Total Applic.

Rate (lb ai/A) PHI

(days) Residue Levels (ppm)

n Min. Max. HAFT 1 Median Mean Std. Dev.

Tropical Fruits (Proposed use = 0.3 lb ai/A total application rate, 1

- day PHI)

Avocado 0.294

- 0.306 1 14 0.05 0.28 0.27 0.075 0.12 0.08

Artichoke (Proposed use = 0.2 lb ai/A total application rate, 5

- day PHI)

Artichoke 0.204

- 0.212 5 6 0.066 0.29 0.26 0.21 0.18 0.09
Barley (Proposed use = 0.25 lb ai/A total application rate, 14

- day PHI)Zeta

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Page 40 of 78 Table 5.2.1

. Summary of Residue Data from Crop Field Trials with Zeta

- Cypermethrin (EC or EW).
Crop matrix Total Applic.

Rate (lb ai/A) PHI

(days) Residue Levels (ppm)

n Min. Max. HAFT 1 Median Mean Std. Dev.

Barley, grain 0.236

- 0.291 13

- 17 32 0.3 2.0 1.85 0.65 0.72 0.35
Barley, straw 0.236

- 0.291 13

- 17 32 0.76 14.4 14 2.7 4.5 3.7
Barley, hay 0.236

- 0.260 7

- 14 32 0.6 4.6 4.05 1.5 1.72 0.97

1 HAFT = highest average field trial.

In addition, HED has reviewed the submitted data and determined there is no need to revise the existing poultry commodity tolerance levels as a result of the proposed new use on poultry litter in chicken broiler and turkey grow

- out houses (D. McNei lly, D399692, 20 September 2012). The existing tolerances for poultry are based on residues in or on poultry feed items and are adequate to cover the very low residues resulting from the proposed use on poultry litter in chicken broiler and turkey grow

- ou t houses. The residue levels expected from this use are expected to be non

- detectable (ND) provided that the label is revised to restrict the treatment to occur at least three weeks prior to slaughter. Th erefore, HED concludes that this new poultry
house use will have no impact on the dietary exposure assessment as described in Section 5.4. HED notes that data for eggs were not submitted, and that the use should not be expanded to include treatment of laying hen facilities. Further, as discussed previously in Section 2.3, HED recommends a label restriction indicating that if one single application is made at the maximum rate of 50 lbs, slaughter cannot occur sooner than six weeks after application.

5.3 Water Residue Profile

I. Maher, D378901/D385246, 22 February 2011

I n general

, cypermethrin is applied at a maximum seasonal use rate (0.6 lb ai/A for most uses)
4X that of zeta

- cypermethrin (0.15 lb ai/A for most uses)

. As a class of chemicals, the pyrethroids have l ow solubility in water and a high affinity to bind to soils. Given these physical/chemical properties, it is unlikely that oral exposure from drinking water will be a major pathway of exposure.

T he Environmental Fate and Effects Division (EFED) provide d estimated residues of zeta

cypermethrin in drinking water from the use of zeta

- cypermethrin and cypermethrin on cotton. The cotton use results in the highest estimated drinking water concentrations (EDWCs) for all assessed use scenarios, including those associated with the petitions currently under review. The EDWCs used in this dietary assessment are summarized in Table 5.3. The surface water EDWCs were generated using the FQPA Index Reservoir Screening Tool (FIRST) Model and the ground water estimate s are from the Screening Concentration In GROund Water (SCI

- GroW) Model. The models and their descriptions are available at the US EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

No moni toring data are currently available to further characterize potential drinking water exposure. In the dietary risk assessment conducted to support the proposed uses and labelZeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 41 of 78 changes, HED incorporated the surface water EDWCs directly into the dietary mode l, since surface water estimates were higher than those provided for ground water. In the acute assessment, an EDWC of 3.77 ppb was used. In the chronic assessment, an EDWC of 0. 0 66 ppb
was used.

The use of the surface water values in the dietary assessment is therefore protective of potential exposure through ground water sources of drinking water.

Table 5.3. Tier I Analysis

- EDWCs in surface water and ground water for cypermethrin and zeta

cypermethrin

. Drinking Water Source Maximum Use Pattern Exposure EDWC (ppb)

Surface water Cotton Peak (acute) 3.77 Annual average (chronic) 0.066

Ground water Cotton Peak & annual average 0.0036

5.4 Dietary Risk Assessment

E . Holman, D403600, 7 September 2012

Acute and average dietary (food+drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM

- FCIDTM, Version 2.03 which uses food consumption data from the U.S. Department of Agriculture’s C ontinuing Surveys of Food Intakes by Individuals (CSFII) from 1994

- 1996 and 1998. The dietary assessment included all existing uses of cypermethrin and zeta

- cypermethrin, as well as proposed new uses of alpha

cypermethrin and zeta

- cypermethrin. Adequate field trial data are available to support the new
uses of zeta

- cypermethrin. The proposed new uses of the pending new active ingredient alpha

cypermethrin are being reviewe d under a separate petition (P etition No

. 0F7690 ).

5.4.1 Description of Residue Data Used in Dietary Assessment

Partially refined (probabilistic) dietary exposure assessments were performed in order to determine the exposure and risk estimates which result from the use of cypermethrin, alpha

cypermethrin, and zeta

- cypermethrin on the crops listed under 40 CFR 180.418 and the proposed new uses. Anticipated residues from USDA Pesticide Data Program (PDP) monitoring data, field trial data, empirical processing factors, and percent crop treated estimates were used where appropriate. For the acute assessment, residue distributions were generally used when PDP and
field trial data were included. In order to assess short

- term aggregate risk to the cypermethrins, average dietary exposure estimates (i.e., food and drinking water) were calcul ated. Because the endpoint from the acute study is protective of endpoints from repeat dosing studies, a chronic dietary risk assessment was not conducted.

The previous dietary analysis for cypermethrin/zeta

- cypermethrin was conducted using version

2 .03 of the DEEM software together with USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994

- 1996 and 1998 consumption data (D335224, D. McNeilly, 5

- Nov

- 2007). The current assessment updates the prior assessment by 1) taking into acco unt revised toxicological endpoints, requiring a refined acute dietary exposure assessment 2) addingZeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 42 of 78 the new proposed uses of zeta

- cypermethrin, and 3) incorporation of updated anticipated residue levels and percent crop treated estimates where appropriate

.

HED considers the dietary assessments to be partially refined, but at the same time, very health

protective. Refinements were made to most of the risk drivers in the assessment; however, in many cases, including the proposed new uses of zeta

- cypermet hrin, these refinements consisted of the incorporation of field trial data. HED has learned from past experience that monitoring data are often significantly lower than field trial data. Monitoring data more accurately represent
the residue levels to whi ch people will actually be exposed to pesticide residues in their diets. In 2004, HED compared field trial and monitoring data for the pyrethroids permethrin, lambda cyhalothrin, and esfenvalerate. For those compounds, the monitoring data were one to two orders of magnitude lower than the field trial data for the same commodities. Therefore, field trial data represent conservative estimates of exposure. The assessment is also conservative in that tolerance level residues were used for many commodities i n the acute assessment.

Due to the many conservative assumptions made in this assessment, in particular, the use of field trial data (as opposed to monitoring data) for many commodities, HED is confident that the acute
and average dietary assessments ov erestimate exposures to the general U.S. population and all population subgroups.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The following maximum percent crop treated estimates (BEAD Screening Level Usage Analysis ( SLUA ) , 10/31/2011) were used in the acute dietary risk assessment for the following crops that are currently registered for zeta

- cypermethrin/cypermethrin: almonds: 2.5%; apples: 2.5%; broccoli: 30%; cabbage: 30%; carrot: 10%; cauliflower: 25%; celery: 60%; ch erries: 5%; grapefruit: 50%; green beans: 20%; green peas: 15%; lemon: 2.5%; lettuce: 65%; orange: 45%; peach: 5%; peppers: 30%; potato: 5%; sweet corn: 20%; spinach: 45%; tomato: 10%; and
watermelon: 10%.

The following average percent crop treated esti mates were used to calculate average dietary

exposures for the following crops that are currently registered for cypermethrin/zeta

cypermethrin: almonds: 1%; apples: 1%; broccoli: 20%; cabbage: 15%; carrot: 2.5%; cauliflower: 15%; celery: 35%; cherries: 5 %; grapefruit: 35%; green beans: 15%; green peas: 10%; lemon: 1%; lettuce: 55%; orange: 35%; peach: 2.5%; peppers: 15%; potato: 1%; sweet corn: 15%; spinach: 30%; tomato: 5%; and watermelon: 2.5%.

5.4.3 Acute Dietary Risk Assessment

Acute dietary risk estimates are below HED’s level of concern for all population subgroups (Table 5.4.6 a ). For acute exposures, the dietary risk for the U.S. population is estimated to be

1 8 % of the acute population

- adjusted dose ( a PAD) at the 99.9 th percentile . Acute risk for all infants (<1 year old) and children 1

- 2 years old, the highest

- exposed population subgroup, are both estimated to be 87% of the a PAD at the 99.9 th percentile . This was a partially refined withZeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 43 of 78 PDP monitoring data and field trial data residue distributions used for some commodities. This assessment is considered to be conservative, because tolerance level residues and distributions of field trial data (as opposed to monitoring data) were used for many commodities . Additionally,
altho ugh upper

- bound estimates were used for drinking water , drinking water is not considered to be a major source of dietary exposure for the cypermethrins

.

5.4.4 Chronic Dietary Risk Assessment

Chronic and cancer dietary risk assessments were not conducted for the cypermethrins. Because of the rapid reversibility of the most sensitive neurotoxicity endpoint used for quantifying risks, there is no increase in hazard with increasing dosing duration, and therefore the acute dietary endpoint is protective for chronic and cancer dietary exposures.

5.4. 5 Average Dietary Exposure Assessment

Average dietary exposures were quantified for the purpose of assessing short

- term aggregate risk (i.e., food, drinking water, and residential exposures) of the proposed and established uses. A summary of average dietary exposures estimated for all population subgr oups is presented in
Table 5.4. 6b

.

5.4. 6 Summary Table s

Table 5.4. 6a. Summary of the Acute Exposure and Risk Estimates for Cypermethrins Population Subgroup Acute Assessment (99.9 th Percentile)

aPAD, mg/kg/day Exposure Estimate, mg/kg/day % aPAD U.S. Population 0.07 0.012516 18 All infants (< 1 yr) 0.023 0.020100 87
Children 1

- 2 yrs 0.023 0.019915 87

Children 3

- 5 yrs 0.023 0.016233 71

Children 6

- 12 yrs 0.07 0.009550 14

Youth 13

- 19 yrs 0.07 0.009147 13

Adults 20

- 49 yrs 0.07 0.010018 14 Adults 50+ yrs 0.07 0.008213 12

Females 13

- 49 yrs 0.07 0.008979 13 Populations with the highest exposure estimates are bolded. Although the exposure estimate for all infants is slightly higher than
for children 1

- 2 years old, with rounding the %aPAD is essentially equivalent.

Table 5.4. 6b. Summary of the Average Exposure Estimates for Cypermethrins Population Subgroup Exposure Estimate, mg/kg/day U.S. Population 0.000920 All infants (< 1 yr) 0.001602

Children 1

- 2 yrs 0.003441

Children 3

- 5 yrs 0.002458

Children 6

- 12 yrs 0.001475

Youth 13

- 19 yrs 0.000746

Adults 20

- 49 yrs 0.000662 Adults 50+ yrs 0.000582

Females 13

- 49 yrs 0.000575Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 44 of 78 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed new residential uses for zeta

- cypermethrin; however, there are registered residential uses for cypermethrin and zeta

- cypermethrin that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs along with policy changes for body weight assumptions and inha lation rates. R evis ions of the residential exposures will impact the human health aggregate risk assessment for zeta

- cypermethrin

. HED has determined that short

term exposure s are likely to occur in a residential setting ; however, the cypermethrins do not increase in potency with repeated dosing. Therefore, only single day residential exposures were
assessed.

6.1 Registered Cypermethrin s Residential Handler Exposure/Risk Estimates

Cypermethrin and zeta

- cypermethrin are registered for use on a variety of indoor and outdoor residential environments including: lawns, gardens, pets, and indoor surfaces and spaces. The registered products are formulated as liquids, wettable powders, granules, ready to use aerosols and foggers. Numerous non

- occupational/resid ential handler exposure assessments for the use of

zeta

- cypermethrin and cypermethrin have been previously assessed (M. Collantes; December 4, 2001; D279002

, S. Wang, July 16, 2006, D312472 and March 30, 2007

, D337823; S Tadayon, D293417 and D293417, April 5, 2006). In order to conduct a health protective aggregate risk assessment for the cypermethrins, h andler scenarios and application rates for the cypermethrins
in the Revised Occupational and Residential Exposure Assessment for the Reregist ration Eligibility Decision Document (RED), the 2011 Pyrethroid Cumulative Risk Assessment (PCRA, D394576) and various registered labels were used to capture and summarize handler
scenarios which resulted in the most conservative and worst

- case exposure scenarios

. The PC RA provided exposure scenarios for cypermethrin as the representative active ingredient. The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:

Mixer/loader/applicator using hose

- end s prayer on turf Mixer/loader/applicator using backpack on turf and gardens Mixer/loader/applicator using manually pressurized handwand for indoor surfaces Application via aerosol can for indoor surfaces and space

Registered Residential Handler Non

- Cancer E xposure and Risk Estimates

Since a dermal endpoint was not selected, only a quantitative inhalation handler exposure assessment was performed. Residential handler inhalation exposure estimates were calculated
based on a HEC and human equivalent dose which reflect 24 hours of exposure. Since handler exposure is expected to be significantly less than 24 hours, the inhalation exposure estimates are sufficiently protective of all scenarios. Table 6 .1 provides estimates of residential handler
inhalation exp osure and risk resulting from use o f cypermethrin on turf, gardens, and indoor surface space. Although there is potential inhalation exposure resulting from the application of dog tags and spot

- on products for pets, inhalation exposure is considered negli gible for these

scen a rios and therefore

, a quantitative assessment was not performed for these uses

. AllZeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 45 of 78 inhalation risk estimates resulted in MOEs ranging from 6,100 to 48,000, are greater than the
LOC of 30 and are not of concern.

Table 6 .1. Short

- Term Residential Handler Inhalation Exposure and Risk Estimates for Cypermethrin s

.

Exposure
Scenario Target

MOE Inhalation Unit

Exposure (mg/lb ai) Maximum

Application
Rate a
(lb ai/A) Amount handled

or Area Treated / Day b Inhalation

Dose (mg/kg/day) c MOE d

Mixer/Loader/Applicator Using Hose

- End Sprayer

Turf (EC) 30 0.024 0.44 0.5 A 0.000066 17,000

Mixer/Loader/Applicator Using Backpack

Turf (WP) 30 1.1 0.6 0.023 A 0.00019 6,100

Garden (liquid) 0.12 1.7 0.000058 20,000

Mixer/Loader/Applicator Using Low Pressure Handwand (Manually Pressurized Handwand)

Indoor Crack & Crevice (WP) 30 1.1 0.0169 lb ai/gal 0.5 gals 0.00012 9,600

Applicator Using Aerosol Can

Indoor Crack &
Crevice 30 3 0.0013 lb ai/16

oz. can 0.5/16 oz can 0.000024 48,000

a. Based on registered labels and scenarios identified in the 2011 Pyrethroid Cumulative Risk Assessment.
b. Revised Residential SOP 2012

c. Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gal/day)/BW (80kg).
d. Inhalation MOE = Human Equivalent Dose, HED (1.15 mg /kg/day) / Inhalation Dose (mg/kg/day).

6.2 Cypermethrin s Registered Residential Post

- application Exposure/Risk Estimates

There is the potential for post

- application exposure for individuals as a result of being in an environment that has been previously treated with cypermethrin or zeta

- cypermethrin

. Post

application inhalation exposure resulting from activities on or around previously treated turf i s generally not assessed ; the combination of low vapor pressure for chemicals typically used as active ingredients in outdoor residential pesticide products and dilution in outdoor air is likely to result in minimal inhalation exposure. Therefore, a quan titative post

- application inhalation exposure assessment for cypermethrin turf uses was not c onducted

. Since a dermal endpoint was not selected, and indoor post

- application inhalation exposure resulting from aerosol space sprays, foggers, and pet (i.e., d og tag, spot

- on) uses is negligible, the only potential post

- application exposure pathway s of concern are incidental oral for children

, and post

- application inhalation exposure for adults and children resulting from indoor crack and crevice applications ma de with

a manually pressurized handwand. The quantitative exposure/risk assessment for residential
post

- application exposure s is based on the following scenarios :

Incidental oral (hand

- to

- mouth, object

- to

- mouth, and soil ingestion) exposure from turf
f or children,

Incidental oral (hand

- to

- mouth and object

- to

- mouth) exposure from indoor foggers for children,Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 46 of 78 Incidental oral (hand

- to

- mouth and object

- to

- mouth) exposure from pets for children, Inhalation exposure for adults and children resulting from crack and crevice application

to an indoor surface, and Incidental oral (hand

- to

- mouth and object

- to

- mouth) exposure for children from indoor surface applications.

Combining Exposure and Risk Esti mates Risk estimates resulting from different exposure routes may be combined when it is likely that they can occur simultaneously based on the use pattern and when the toxicological effects across different routes of exposure are the same. Although, in t he case of children, inhalation and incidental oral exposure routes share a common toxicological endpoint, risk estimates were not
combined for those routes for turf, indoor fogger, and pet since post

- application inhalation

expo sure is considered negligibl e. However, inhalation and incidental oral exposure s were combined for post

- application risk assessment associated with the indoor crack and crevice use.

I nhalation and incidental oral routes have different LOCs. Therefore, in order to combine exposure f

rom the various routes the aggregate risk index (ARI) approach is used to estimate exposure and risk. ARIs ≥ 1 are not of concern.

The incidental oral scenarios from indoor exposure following crack and cr e vice applications and outdoor exposure from turf were not combined, not only because they are not likely to co

- occur, but also because c ombining these scenarios would be overly

- conservative due to the conservative

nature of each of the individual assessment s

.

Summary of Residential Post

- application Ex posure and Risk Estimates There is potential for residential post

- application incidental oral risk estimates resulting from use
of the cypermethrin s on turf and pets, or as a crack and crevice treatment using a manually pressurized handwand or fogger. Table 6.2 provides estimates of residential post

- application exposure and risk resulting from application of cypermethrin. The post

- application exposu re scenarios for children resulted in MOEs ranging from 1000 to 6,400,000 and ARIs ranging from
3 to 13. All post

- application exposure estimates resulted in MOEs and ARIs greater than their respective LOCs and are not of concern.

Table 6.2. Residential Post

- application Exposure and Risk Estimates for Cypermethrin and Zeta

c ypermethrin.

Lifestage Post

- application Exposure Scenario Dose a MOE b Combined

Routes ARI c

Adult Indoor Crack &

Crevice (Manually

pressurized handwand) Inhalation 0.0000011 1,100,000 NA

NA

Child Turf (WP)

TTR d Hand to Mouth 0.0000365 200,000

NA

Object to Mouth 0.0000011 6,400,000 Incidental Soil Ingestion 0.00002 350,000 Indoor Fogger Hand to Mouth 0.007 1,000 NA 3.3Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 47 of 78 Table 6.2. Residential Post

- application Exposure and Risk Estimates for Cypermethrin and Zeta

c ypermethrin.

Lifestage Post

- application Exposure Scenario Dose a MOE b Combined

Routes ARI c

Object

- to

- Mouth 0.001 7,600 N/A

Indoor Crack &
Crevice (Manually

pressurized handwand) Inhalation 0.0000046 250,000 X 13

Hand to Mouth 0.0017 4,000 X

Object to Mouth 0.00024 30,000 NA NA

Dog

- tag Hand

- to

- Mouth 0.0068 1100 NA

a. Dose = attached residential SOP spread sheets
b. MOE = POD (mg/kg/day/Dose (mg/kg/day)

c. ARI = 1/[(1/ARI inhalation ) + (1/ARI oral )] where, ARI i = MOE inhalation /100 and ARI oral = MOE oral /300. ARIs greater than 1
are not of concern.
d. TTR = Transferable Turf Residue ; TTR data from M R I D 45111501

6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

HED combines exposure and risk values resulting from separate residential exposure scenarios when it is likely that they can occur simultaneously based on the use

- pattern and the behavior

a ssociated with the exposed lifestage. Combinations for residential exposure scenarios should have a reasonable probability of occurring on a single day and being applied to the same pest that an individual is attempting to control. Two major residential use scenarios were considered in this assessment: 1) outdoor treatment of turf, and 2) indoor crack and crevice treatment. HED does not expect outdoor turf treatments to co

- occur with indoor treatment for insect pests. Therefore, indoor and outdoor expos ure estimates were not combined.

Furthermore, although cypermethrin is available for use on turf and gardens, the registered products are formulated as a wettable powder (WP) and liquid. Although it is likely that a homeowner would apply the same produ ct to their turf and garden simultaneously , it is not practical that a homeowner would use two different products and formulations to treat their lawn and garden within the same treatment period. Similarly, in the case of indoor treatment of pest s , it ’ s n ot likely that a homeowner would use two different methods of application (i.e.

, fogger and manually pressurized handwand) within the same treatment period.

6.4 Residential Risk Estimates for Use in Aggregate Assessment

Residential handler and post

- application scenarios should generally not be combined. Although there is potential for the same individual (i.e., adult) to apply a pesticide in and around the home and be exposed by reentering a treated area in the same day, this is an unlikely exposure scenario, especially on a daily basis for up to 30 days. Combining both of these exposure scenarios would also be inappropriate because of the conservative nature of each individual assessment. Therefore, HED selected only t he most conservative or worst case residential
scenario s to be included in the aggregate risk estimates , based on the lower overall MOEs (i.e., higher risk estimates).Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 48 of 78 The recommended residential exposure for use in the adult aggregate assessment refle cts handler inhalation exposure from application to turf using a backpack sprayer which
resulted in an estimated MOE of 6,1 00 ( ARI of 200 ) and is not of concern.

The recommended residential exposure for use in the child (1 to <2 year olds) aggregate

ass essment reflects hand

- to

- mouth exposure resulting from indoor fogger use. The
estimated hand

- to

- mouth MOE of 1,000 and an ARI of 3.3 is not of concern.

As previous ly indicated, indoor and outdoor exposure estimates are not combined as they are not

expe cted to co

- occur. Furthermore, treatment of indoor crack and crevices is not anticipated to be performed using different methods of application; therefore crack crevice exposure estimates were not combined. Finally, only hand

- to

- mouth exposure is estimat ed for incidental oral exposure as inclusion of object

- to

- mouth and soil ingestion is considered an over estimate of exposure. A summary of the residential exposures and risk estimates recommended for the zeta

cypermethrin aggregate assessment is provided in Table 6. 4

.

Table 6

. 4 . Recommendations for the Residential Exposures and Risk Estimates for the Zeta

- c ypermethrin Aggregate
Assessment.

Lifestage Handler

Exposure (mg/kg/day) a Residential

Handler Total Exposure (mg/kg/day) c Residential

Handler
MOE a (ARI) Post

- application

Exposure (mg/kg/day) b Residential Post

application MOE b Residential
Post

application
ARI c Inhalation Inhalation Oral Inhalation Oral

Adult 0.00019

NA 6,100 (200) 0.0000011 N/A 1,100,000 NA 37,000

Child

- fogger

N/A N/A NA 0.007 NA 1000 b 3 .3

Child

– Pressurized
hand wand 0.0000046 0.0017 250,000 4,000 13

a. Table 6.1. Short

- Term Residential Handler Exposure and Risk Estimates for Cypermethrin.

b. Table 6.2 Residential Post

- application Exposure and Risk Estimates for Cypermethrin

c. Table 6.2 Residential Post

- application Exposure and Risk Estimates for Cypermethrin

6. 5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aeria l application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for zeta

cypermethrin. The Agency has been working with the Spray Drift Task Force, US EPA Regional Offices and State Lead Agen cies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticid e registrants, and isZeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 49 of 78 developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks
associated with drift.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure scenarios

.

It is noted that the 0.6 lb ai/acre application rate for cypermethrin on turf was modeled to estimate post

- application residential exposure of child ren. As this rate is equal to or higher than many of agricultural application rates, this scenario is protective of any exposure of farm children via spray drift from agricultural zeta

- cypermethrin applications.

6

. 6 Residential Bystander Post

- Application Inhalation Exposure

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

- application inhalation exposure assessment was not performed for zeta

- cypermethrin at this time primarily because of the low acute inhalation toxicity (Toxicity Category III), low vapor pressure ( 3 x 10 - 9 mm Hg ( 20 C ),
and the low proposed use rate (0.025 lb ai/A). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilizat ion 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/2009/120109meeting.html ). The Ag ency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

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

- application inhalation exposure assessment
for zeta

- cypermethrin.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate cypermethrin pesticide exposures and risks 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 ha zard (e.g., a BMDL, HED or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

Residential exposure to the cypermethrins is anticipated from ex isting registered use for cypermethrin and zeta

- cypermethrin on lawns, gardens, pets, and indoor surfaces and spaces.Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 50 of 78 Therefore, the short

- term aggregate exposure and risk assessment for the cypermethrins includes dietary (food and water) exposures antici pated from the registered and proposed uses, and non

dietary exposures anticipated from the currently registered residential uses.

7.1 Acute Aggregate Risk

HED typically includes only food and water in the acute aggregate assessment, as one day residential exposur es are not routinely assessed. Therefore, the acute aggregate risk is equal to the acute dietary exposure and risk. Please refer to Section 5.4.3 for a detailed discussion of the acute dietary risk assessment.

7. 2 Short

- Term Aggregat e Risk

For assessing short

- term aggregate risk, the average dietary exposure estimate was used since it represents a background exposure level from food and drinking water that may co

- occur with residential exposures. Dietary and oral (hand to mouth) ris ks for children

, and dietary and
inhalation risks f

o r adults were combined in this assessment, since the toxicological endpoints were the same. However, the level of concern (LOC) values were different ( oral adults and
children ≥ 6= 100; children<6=300) , while inhalation LOC = 30 ); therefore, the respective risk estimates are combined using the aggregate risk index ( ARI ) approach. When this approach is used, aggregate risks are not of concern provided the calculated ARI is greater than 1. As shown
in t he table below, a ll ARIs are greater than 1, and therefore the risk estimates are not of concern. The adult residential scenario used to estimate aggregate exposure was handler applications to turf via backpack sprayer, while the child ren’s residential ex posure scenario was hand

- to

- mouth exposure f

ollowing use of an indoor fogger. The results of these calculations are presented in
Table 7.2

.

Table 7.2 Short

- Term Aggregate Risk Calculations for Zeta

- cypermethrin 1

Population Short

- Term Scenario

Dietary Exposure 2 Oral Residential

Exposure 3 Dermal

Residential Exposure Inhalation

Residential Exposure Aggregate ARI

(food, water,
and residential) 4 ,5 MOE ARI MOE ARI MOE ARI MOE ARI

Adult 7800 78 NA NA N/A N/A 6,100 200 56

Child 2100 7 1,000 3.3 N/A N/A N/A N/A 2.3

1 HED is concerned if the ARI is less than 1. (ARI = Aggregate Risk Index.)

2 MOE dietary = [BMD of 7.16 mg/kg

- day)/( average dietary exposure)]. ARI dietary = [(MOE dietary)/(MOE target)]. MOE target = 100 for children ≥ 6 and adults; MOE target = 300 for children <6.
From Table 5.4.3 , Child Average Dietary Exposure = children 1

- 2 yrs (maximum exposure) = 0.003441 mg/kg / day ; and Adult Average Dietary Exposure = US Population (maximum exposure) = 0.000920 mg/kg / day

3 MOE oral = [(7.16 mg /kg

- day)/(hand

- to

- mouth

- residential /fogger )]. ARI oral = [(MOE oral)/(MOE target)].
Child Hand

- to

- mouth residential exposure = 0.0 07 mg/kg

- day ( Table 6. 3 ) MOE target = 300. Residential handler

Inhalation (from Table 6.3) = 0.00019 mg/kg/day.

4 Children’s ARI = 1/[(1/ARI dietary) + (1/ARI oral)]

5 Adult ARI Aggregate = 1/[(1/ARI dietary) + (1/ARI inhalation)]

7.3 Intermediate

- Term/Chronic Aggregate RiskZeta

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Page 51 of 78 An intermediate

- term and/or chronic aggregate risk assessment was not conducted because the cypermethrins are acutely toxic and do not increase in potency with repeated dosing. Because acute toxicity studies can assess the risk for longer term studies, it is assumed that the acute and
short

- term aggregate assessments are protective for intermediate

- term and chronic aggregate risks anticipated from cypermethrin exposure.

8.0 Cumulative Exposure/Risk Characterization

The Agency is required to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. The Agency has determined that the pyrethroids and pyrethrins share a common mechanism of toxicity ( http://www.regulations.gov ; EPA

- HQ

- OPP

- 200 8

- 0489

- 0006). The members of this group share the ability to interact with 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 pyrethroids. For information regarding US EPA’s efforts to evaluate the

ri sk of exposure to this class of chemicals, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids

- pyrethrins.html

.

The cypermethrins were included in a recent cumula tive risk assessment for pyrethrins and pyrethroids. T he proposed new uses of zeta

- cypermethrin will not significantly impact the
cumulative assessment because

, in the cumulative assessment, residential exposure was the greatest contributor to the total e xposure. As there are no new residential uses for the cypermethrins, the proposed new uses will have no impact on the residential component of the cumulative risk estimates. Dietary exposures make a minor contribution to total pyrethroid exposure in the 2011 cumulative risk assessment. The dietary exposure assessment performed in support of the pyrethroid cumulative was much more highly refined than that performed for the single chemical. The dietary exposure assessment for the single chemical included conservative assumptions, using field trial data for a many commodities, including the proposed new uses with the assumption of 100% crop treated, and 3) for the cypermethrin risk assessment, the most sensitive apical endpoint in the cypermethrin hazard da tabase was selected to derive the POD. Additionally, the POD selected for cypermethrin is specific to cypermethrin, whereas the POD
selected for the cumulative assessment was based on common mechanism of action data that are appropriate for all 20 pyrethr oids included in the cumulative assessment.

9.0 Occupational Exposure/Risk Characterization

M. Collantes, D385662, 20 September 2012

9.1 Occupational Handler Exposure/Risk Estimates

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, short

- and intermediate

- term occupational handler exposure isZeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 52 of 78 expected from the proposed uses; however, zeta

- cypermethrin does not i ncrease in potency with repeated doses. Therefore, only single day exposures are assessed. The quantitative exposure/risk assessment developed for occupational handlers is based on the following
scenarios:

• Mixing/Loading Liquids for Groundboom Application for agricultural crops,

• Mixing/Loading Liquids for Aerial Application for agricultural crops,

• Mixing/Loading Liquids for Chemigation for agricultural crops,

• Mixing/Loading Liquids for Airblast Application for agricultural crops,

• Applying Sprays with Groundboom Equipment for agricultural crops,

• Applying Sprays with Aerial Equipment for agricultural crops,

• Applying Sprays with Airblast Equipment for agricultural crops,

• Flagging for Aerial Applications for agricultural crops, and

• Loader/Applicator with Push

- Type Rotary Spreader for poultry house

.

Handler exposures are not expected from applying sprays via chemigation systems.

In completing the occupational assessment for zeta

- cypermethrin, HED used standard assumptions with respect to the applica tion rate (i.e., maximum proposed rate), area treated, adult body weight, and unit exposures derived from surrogate data generated by the various task forces. These assumptions were incorporated into the assessment using standard methodology used by HED f

or occupational exposure assessments.

Occupational Handler Non

- Cancer Exposure and Risk Estimates

Table 9.1 presents the estimated short

- and intermediate

- term inhalation risk estimate s for workers. All occupational handler scenarios for the proposed and existing uses resulted in MOEs greater than the level of concern at the baseline PPE level of protection (i.e. single layer clothing and no respirator), and engineering controls for ae rial applications. The MOEs shown in the table are all higher than HED’s level of concern of an MOE of 30, with MOEs ranging from 9,300 to 200,000.

The estimated handler MOE resulting from loading and applying the dust formulation for rotary spreaders was based on granular surrogate data. HED believes this is protective of the proposed dust formulation because of the magnitude of the estimated MOE and because of the conservative assumption regarding the application rate assumed to be done as a broadcas t application rather than in 36 inch bands as proposed on the label.Zeta

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Page 53 of 78 Table 9 .1. Occupational Exposure and Risk Estimates for Zeta

- cypermethrin

.

Exposure Scenario Crop or Target Inhalation Unit Exposure (mg/lb ai) a Maximum Single

Application Rate
(lb ai/A) b Area Treated

Daily (A) c Inhalation

Mitigation Level Dose (mg/kg/day) d MOE e

Mixer/Loader

Liquids for Groundboom Applications
(AHETF) Avocado, Black Sapote,

Canistel, Maney Sapote, Mango, Papaya, Sapodilla, Star Apple, Artichoke, Pistachio 0.000219 (No respirator) 0.05 80 0.000011 100,000

Barley 0.000219

(No respirator) 0.05 200 0.000027 40,000

Liquids for Aerial Application
(AHETF) Avocado, Black Sapote,

Canistel, Maney Sapote, Mango, Papaya, Sapodilla, Star Apple, Artichoke, Pistachio 0.000219 (No respirator) 0.05 350 0.000048 23,000

Barley 0.000219

(No respirator) 0.05 1,200 0.00016 67,000

Liquids for Chemigation
(AHETF) Avocado, Black Sapote,

Canistel, Maney Sapote, Mango, Papaya, Sapodilla, Star Apple, Artichoke, Pistachio,

Barley 0.000219

(No respirator) 0.05 350 0.000048 23,000

Liquids for Airblast
(AHETF) Avocado, Black Sapote,

Canistel, Maney Sapote, Mango, Papaya, Sapodilla, Star Apple, Pistachio 0.000219 (No respirator) 0.05 40 0.0000055 200,000

Applicator

Sprays for Groundboom Applications
(AHETF) Artichoke 0.00034 (No respirator) 0.05 80 0.000017 65,000

Barley 0.00034

(No respirator) 0.05 200 0.0000425 26,000Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 54 of 78 Table 9 .1. Occupational Exposure and Risk Estimates for Zeta

- cypermethrin

.

Exposure Scenario Crop or Target Inhalation Unit Exposure (mg/lb ai) a Maximum Single

Application Rate
(lb ai/A) b Area Treated

Daily (A) c Inhalation

Mitigation Level Dose (mg/kg/day) d MOE e

Sprays for Aerial Application
(AHETF) Avocado, Black Sapote,

Canistel, Maney Sapote, Mango, Papaya, Sapodilla, Star Apple, Artichoke, Pistachio 0.000068 (No respirator) 0.05 350 0.000015 75,000

Barley 0.000068

(No respirator) 0.05 1,200 0.000051 22,000

Sprays for Airblast Application
(AHETF) Avocado, Black Sapote,

Canistel, Maney Sapote, Mango, Papaya, Sapodilla, Star Apple, Pistachio 0.00471 (No respirator) 0.05 40 0.00018 9,300

Flagger

Flagging for Aerial Applications
(PHED) Avocado, Black Sapote,

Canistel, Maney Sapote, Mango, Papaya, Sapodilla, Star Apple, Artichoke, Pistachio,

Barley 0.00035

(No respirator) 0.05 350 0.000076 14,000

Loader/Applicator

Rotary Spreader

- granule Chicken Broiler and Turkey
Growout Houses 0.01 0.4 1 0.00005 22,000

a. Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (OPHED; March, 2012). Level of mitigation: Baseline, PPE, Eng. Controls).
b. Based on proposed labels ( US EPA Reg. Nos. # 279

- 3125; 279

- 3126; and 39039

- EN ).

c. Exposure Science Advisory Council Policy #9.1.
d. Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/A) x Area Treated (A/day) /BW (80 kg).

e. Inhalation MOE = Inhalation HED (1.1 mg/kg/day)/ Inhalation Dose (mg/kg/day).Zeta

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Page 55 of 78 9.2 Occupational Post

- application Exposure/Risk Estimates

9.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

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

- application inhalation exposure

assessment was not performed for zeta

- cypermethrin at this time primarily because of the low acute inhalation toxicity (Toxicity Category III), low vapor pressure (3 x 10 - 9 mm Hg at 20*C), and the low proposed use rate (0.4 lb ai/A for poultry house use; 0.05 lb ai/A for agricultural

crop uses ). However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticid es and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (S AP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposu re data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational
post

- application inhalation exposure into the Agency's risk a ssessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational
post

- application inhalation exposure assessment for zeta

- cypermethrin.

Although a quantitative occupational post

- application inh alation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

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

- application inhalation exposure scenarios.

9.2.2 Occupational Post

- application Dermal Exposure/Risk Estimates

Based o n the proposed use pattern and directions, short

- and intermediate

- term dermal exposures are expected for workers conducting post

- application activities on agricultural crops. Although
short

- and intermediate

- term dermal post

- application exposures are exp ected for workers who re

enter treated fields, there is no toxicity associated with dermal exposure to the cypermethrins, and therefore a quantitative dermal post

- application exposure assessment was not performed. Given the proposed use pattern associated with the poultry house use, there is no anticipated dermal post

- application exposure for workers re

- entering poultry houses , and thus a post

application exposure assessment is not required. HED does not anticipate post

- application dermal risks after exp osure to zeta

- cypermethrin.

Restricted Entry Interval (REI)

The REI specified on the proposed labels is based on the acute toxicity of zeta

- cypermethrin technical material which is classified as Category III for acute dermal and eye irritation, and
Cate gory IV for skin irritation. Based on the acute toxicity profile of zeta

- cypermethrin, the 12

-Zeta

- Cypermethrin Human Health Risk Assessment DP No. D37 8897, D385242, D397298

Page 56 of 78 hour REI appearing on the proposed label is appropriate to protect agricultural workers from
post

- application exposures to zeta

- cypermethrin.

10.0 References

OPP Memoranda

M. Collantes, 9/20/2012

, D 385662

, Zeta

- cypermethrin

. Occupational and Residential Exposure and Risk Assessment to Support Proposed Uses on Crops and in Poultry Houses.

W. Drew, 9 / 7/2012, D378683, Alpha

- Cypermethrin . Petition to Establis h Permanent Tolerances
for Residues of the New Insecticide Resulting from Food/Feed Use on Various Raw and Processed Agricultural Commodities

. Summary of Analytical Chemistry and Residue Data.

E. Holman, 9/ 7/2012, D403600 , Cypermethrin, Alpha

- Cypermethrin, and Zeta

- Cypermethrin. Acute and Chronic Dietary Exposure and Risk Assessment

– Zeta

- Cypermethrin Uses on Tropical Fruit, Artichoke, Barley, Oat, Rye, Buckwheat, and Pistachio, and Alpha

- Cypermethrin Uses on Various Raw and Processed Ag ricultural Commodities

.

E. Holman, 9/20/2012, D379486, Zeta

- Cypermethrin. Petitions for Use on Tropical Fruit, Artichoke, Barley, Oat, Rye, Buckwheat, and Pistachio. Summary of Analytical Chemistry and
Residue Data. Petition Numbers OE7717.

I. Maher, 2/22/2011, D378901

, Drinking Wa ter Assessment for Zeta

- Cypermet hrin for New Food Use on Globe Artichoke, Barley. Buckwheat, Oats, Rye, Pistachio. Avocado, Papaya, Star Apple, Black Sapote, Mango, Sapodilla, Canistel, and Marney Sapote

D. McNeilly, 9/20/20 12, D399692, Zeta

- Cypermethrin. Residues in Poultry Following Application to Litter in Chicken Broiler and Turkey Grow

- Out Houses.

Toxicology References

Anand, S. S., J. V. Bruckner, W. T. Haines, S. Muralidhara, J. W. Fisher and S. Padilla (2006). "Characterization of deltamethrin metabolism by rat plasma and liver microsomes." Toxicology and Applied Pharmacology 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 Insectic ide

- Induced
Stimulation of Calcium Influx in Neocortical Neurons." J Pharmacology and Experimental Therapy 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. de Zwart, L., M. Scholten, J. G. Monbaliu, P. P. Annaert, J. M. Van Houdt, I. Van den Wyngaert, L. M. De Schaepdrijver, G. P. Bailey, T. P. Coogan, W. C. C oussement and G. S.Zeta

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Page 57 of 78 Mannens (2008). "The ontogeny of drug metabolizing enzymes and transporters in the
rat." Reproductive Toxicology 26 (3

- 4): 220

- 230. Godin, S. J., M. J. DeVito, M. F. Hughes, D. G. Ross, E. J. Scollon, J. M. Starr, R. W. Setzer, R.
B. Con olly 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., R. Barchi, J. Caldwell, F. Hofmann, J. Howe, J. Hunter, R. Kallen, G. Mandel, M. Meisler, YBNetter, M. Noda, M. Tamkun, S. Waxman, J. Wood and W. Catterall (2000). "Nomenclature of voltage

- gated sodium channels." neuron 28 (2): 365

- 368. Goldin, A. L. (2002). "Evolution of voltage

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

- 584. 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
CY P2C19." Journal of Pharmacology and Experimental Therapeutics 308 (3): 965

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

toxicity relationships." Pesticide Biochemistry and Physiology 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 [alpha]

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

- 281. Mirfazaelian, A., K. Kim, S. Anand, H. Kim, R. Tornero

- Velez, J. Bruckner and J. Fisher (2006). "Development of a phy siologically based pharmacokinetic model for deltamethrin in the adult male Sprague

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

- 442. Nemec, M. (2006). An Acute Functional Observational Battery Comparison Study in Rats. WIL Research Laboratories, LLC, 1407 George Road, Ashland, OH 44805

- 9281. Laboratory report numbers: 02

- PWG

- 001 and WIL

- 409002, April 28, 2006. MRID 47050505. Unpublished. Salgado, V., M. Herman and T. Narahashi (1989). "Interactions of the pyrethroid fenvalerate
with nerve membrane sodium channels : Temperature dependence and mechanism of depolarization." Neurotoxicology 10 (1): 1

- 14. 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 wit h neurotoxicity in the rat." Toxicology 290 (1): 1

- 6. Shafer, T. J., D. Meyer and K. M. Crofton (2005). "Developmental neurotoxicity of pyrethroid
insecticides: critical review and future needs." Environmental Health Perspectives
113 (2): 123

- 136. Soderlund, D., J. Clark, L. Sheets, L. Mullin, V. Piccirillo, D. Sargent, J. Stevens and M. Weiner (2002). "Mechanisms of pyrethroid neurotoxicity: implications for cumulative 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

- 453. Tabarean, I. V. and T. Narahashi (1998). "Potent Modulation of Tetrodotoxin

- Sensitive a nd
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 channelsZeta

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Page 58 of 78 differ in inactivation properties and sensitivi ty 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

m aturing rat using a PBPK model." Toxicol Appl Pharmacol 244 : 208

- 217. USEPA (2000). "Benchmark Dose Technical Guidance Document, Draft Report. Risk Assessment Forum, Office of Research and Development, U.S. Environmental Protection Agency. Washington, DC . EPA/630/R

- 00/001.". USEPA (2007). "Meeting Minutes: FIFRA SAP Meeting on Assessing Approaches for the Development of PBPK Models of Pyrethroid Pesticides. Document ID: EPA

- HQ

- OPP

2007

- 0388

- 0049. www.regulatio ns.gov. " USEPA (2010). "Pyrethroids: Evaluation of Data from Developmental Neurotoxicity Studies and Consideration of Comparative Sensitivity, D31723 Jan 20, 2010. Document ID: EPA

HQ

- OPP

- 2008

- 0331

- 0028; USEPA (2011). Reevaluation of the FQPA Safety Fac tor for Pyrethroid Pesticides, D381210,
6/27/11. 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.
Wola nsky, 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." Neurotoxicology and Teratology 30 (2): 55

- 78. Yang, D., R. E. Pearce, X. Wang, R. Gaedigk, Y.

- J. Y. Wan and B. Yan (2009). "Human carboxylesterases HCE1 and HCE2: Ontogenic expression, inter

- individual variability
and diff erential hydrolysis of oseltamivir, aspirin, deltamethrin and permethrin." Biochemical Pharmacology 77 (2): 238

- 247.Zeta

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Page 59 of 78 Appendix A. Toxicology

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for the cypermethrins are in Table A1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Tabl e A1 . Toxicology Requirements for Cypermethin, Zeta

- c ypermethrin, and Alpha

c ypermethrin

Guideline Number and Toxicity Study Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

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

870.3100 Oral Sub

- chronic (Rodent)

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

- chronic (Non

- Rodent)

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

- Day Dermal

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

- Day Dermal

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

- Day Inhalation

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

no yes yes yes yes

- yes

870.3700 Developmental Toxicity (Rodent)

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

- rodent)

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

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

870.4100 Chronic Toxicity (Rodent)

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

- rodent)

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

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

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

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

870.5265 Mutagenicity: Gene Mutation

- bacterial

............................... 870.5380 Mutagenicity: Cytogenetics

................................ ................... 870.5450 Mutagenicity: Dominant Lethal Assay

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

................................ . 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

yesZeta

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Page 6 0 of 78 A.2 Toxicity Profiles

Table A.2a Acute Toxicity of Zeta

- c ypermethrin and Cypermethrin Technical

Guideline
No. Study Type MRIDs # Results Toxicity Category

870.1000 Acute Oral

– rat

Zeta

- c ypermethrin 41776115 LD 50 (M): 134.4 mg/kg (F): 86.0 mg/kg Clinical signs of neurotoxicity observed. II

870.1000 Acute Oral

-

Cypermethrin 00056800 LD 50 (M): 247 mg/kg (F): 309 mg/kg
females

Deaths: 150 mg/kg, usually in first day. Clinical signs of neurotoxicity, gait abnormalities; some persisting to 14 days. II

870.1000 Acute Oral

–

Alpha

- c ypermethrin 47944061 LD 50 Females > 2000 kg/kg bw III

870.1100 Acute Dermal

Rats

- Cypermethrin

Rabbits

- Cypermethrin 00056800

00056800 LD 50 > 4920 mg/kg/day. Clinical signs of

neurotoxicity.

Abraded skin: LD 50 > 2460 mg/kg. Lacrimation, discharge from the eye and "nervous and shaking". III

III

870.1100 Acute Dermal

Rats

– Alpha

- c ypermethrin 47944062 LD 50 > 2000 mg/kg bw Males, females combined III

870.1200 Acute Inhalation

- rat

Cypermethrin 42395702 LC 50 : (not calculated but higher than)
LC 50 : 2.5 (1.6

- 3.4) mg/L. Clinical signs of neurotoxicity. MMAD ranged from 2.22 to 2.62 μm IV

870.1200 Acute Inhalation

- rat

Alpha

- c ypermethrin 47944063 LC 50 Males > 2.47 mg/L
LC 50 Females > 1.07 mg/L III

870.2400 Primary Eye Irritation

-

rabbit Cypermethrin 00056800 Slight redness of conjunctivae, chemosis & discharge. Persisted to day 7. III

870.2400 Primary Eye Irritation

-

rabbit Alpha

- c ypermethrin 47944064 No positive effects at 48 hours III

870.2500 Primary Skin Irritation

–

rabbit Cypermethrin 00056800 Slight to mild erythema on intact & abraded skin. Reversed by 48 hours. Primary Irritation Index: 0.71 IV

870.2500 Primary Skin Irritation

–

rabbit Alpha

- c ypermethrin 47944065 Moderately irritating IIIZeta

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Page 61 of 78 870.2600 Dermal Sensitization

-

Cypermethrin 00056800
40377701 Not a sensitizer in Buehler assay.

Moderate sensitizer in Magnusson Kligman Maximization method. N/A

870.2600 Dermal Sensitization

–

Alpha

- c ypermethrin 47944066 Not a sensitizer N/A

Table A.2.b Subchronic, Chronic, and Other Toxicity

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

870.3100 90

- Day oral toxicity

– rat

cypermethrin MRID 00056802 & 92027034 (1980)/Unacceptable ppm = 0, 75, 150 or 1500 mg/kg/day = 0, 3.75, 7.5 or 75 NOAEL = 7.5 mg/kg/day LOAEL = 75 mg/kg/day based on decreased body weight in both sexes.

870.3100 90

- Day oral toxicity

- rat:

zeta

- cypermethrin MRID 417761 01 (1990)/Acceptable ppm = 0, 10, 50, 150, 250, 500 or 900 mg/kg/day = M: 0, 0.6, 2.7, 8.4, 13.8, 28.2 or 55.7;F: 0, 0.6, 3.3, 9.6, 16.3, 32.2 or
65.2 NOAEL = M = 13.8 (M), 16.3 (F) mg/kg/day LOAEL = 28.2 mg/kg/day (M) based on decreased body wt, body wt gain and food consumption; at 55.7 mg/kg/day, mortality as well as decreased RBC, WBC, HGB & HCT plus increase in BUN. 32.2 mg/kg/day (F) based on decreased body wt, body wt gain and food consumption as well as interference with estrous cycle and
decrea sed glucose; mortality at 65.2 mg/kg/day.

870.3100 90

- Day oral toxicity

- rat:

alpha

- cypermethrin MRID 47944068 (1982)/Acceptable ppm = 0, 20, 60, 180, or 540 mg/kg /day = M/F: 0/0, 1.02/1.2, 1.74/3.8, 9.3/11.3, or 29.6/35 NOAEL = 9.3 mg/kg/day LOAEL = 29.6 mg/kg/day based on decreased body weight, body weight gain, food consumption, and gait changes.

870.3150 90

- Day oral toxicity in

dogs (feeding) cypermethrin MRID 44527002 (1994)/Acceptable ppm = 0, 300, 600, 800 or 1100 mg/kg /day = M : 0, 10.4, 20.7, 24.6 or 37.0 F: 0, 12.2, 25.4, 34.3 or 45.2 NOAEL = 24.6 (M), 34.3 (F) mg/kg/day LOAEL = 37.0 (M), 45.2 (F) mg/kg/day based on tremors as well as decreased body wt and body wt gains in both sexes.

870.3150 90

- Day oral toxicity in

dogs (feeding) cypermethrin MRID 00112929 (1977)/Unacceptable ppm = 0, 5, 50, 500 or 1500 mg/kg/day = 0, 0.125, 1.25, 12.5 or 37.5 NOAEL = 12.5 mg/kg/day LOAEL = 37.5 mg/kg/day based on clinical signs (whole body tremors, exaggerated gait, ataxia, incoordination, hyperaesthesia, licking & chewing of paws; diarrhea, anorexia) & decreased body wt).

870.3150 90

- Day oral toxicity in

dogs (feeding) alpha

- cypermethrin MRID 47944069 (1984)/Acceptable ppm = 0, 30, 90, or 270 NOAEL = 2.25 mg/kg/day LOAEL = 6.75 mg/kg/day based on clinical signs (tremors, gaitZeta

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Page 62 of 78 Table A.2.b Subchronic, Chronic, and Other Toxicity

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results
mg/kg/day= 0, 0.75, 2.25, 6.75 abnormalities, ataxia, agitation, head nodding, and lip licking).

870.3200 21

- Day dermal toxicity

-

rat

zeta

- cypermethrin MRID 45010401 (1999)/Acceptable mg/kg/day = 0, 100, 500 or 1000 NOAEL = systemic : 1000 mg/kg/day. Dermal : <100 mg/kg/day
LOAEL = systemic : >1000 mg/kg/day (LIMIT DOSE). Dermal : 100 mg/kg/day, based on erythema &/or eschar 1/10 M & 6/10 F; desquamation 0/10 M & 2/10 F (no
effects in any M or F controls).

870.3200 21

- Day dermal toxicity

–

rabbit cypermethrin MRID 00090035 (1981)/Acceptable mg/kg/day = 0, 2, 20, 200 NOAEL = Systemic non

- abraded animals: 200 mg/kg/day (HDT) Dermal NOAEL: 20 mg/kg/day LOAEL = Systemic non

- abraded animals: >200 mg/kg/day (HDT). Dermal: 200 mg/kg/day based on signs of dermal irritation.

870.3465 21

- Day inhalation toxicity

– rat cypermethrin MRID 43507101 (1994)/Acceptable mg/L = 0, 0.01, 0.05 or 0.25 (nose only) NOAEL = 0.01 mg/L
LOAEL = 0.05 mg/L based on
increased salivation.

870.3700a Prenatal developmental in

rats cypermethrin MRID 00056804, 92027039 & 92027601 (1978)/Acceptable mg/kg/day = 0, 17.5, 35 or 70 Maternal NOAEL = 17.5 mg/kg/day LOAEL = 35 mg/kg/day based on decreased body wt gain; at 70mg/kg/day, splayed limbs, spasms & hypersensitivity to noise &
convulsions. Developmental NOAEL = 70 mg/kg/day (HDT).
LOAEL = not established.

870.3700a Prenatal developmental in

rats zeta

- cypermethrin MRID 41776102 (1990)/Acceptable mg/kg/day = 0, 5, 12.5, 25 or 35 Maternal NOAEL = 12.5 mg/kg/day LOAEL = 25 mg/kg/day, based on ataxia, urine

- stained abdominal fur,
fecal

- stained perineal fur, decreased food consumption & decreased body wt gain. Developmental NOAEL 35 mg/kg/day
LOAEL = not established

870.3700a Prenatal developmental in

rats alpha

- cypermethrin MRID 47944073 (1994)/Acceptable mg/kg/day = 0, 3, 9, or
18/15 Maternal NOAEL = 9 mg/kg/day LOAEL = 15 mg/kg/day based on decreased body wt gain and food consumption, and increased incidence of clinical signs (unsteady gait, piloerection, limb splay, and hypersensitivity to sound and touch). Developmental NOAEL = 9 mg/kg/day LOAEL = 15 mg/kg/day based on decreased fetal weights (4%).

870.3700b Prenatal developmental in

r abbits MRID 43776301 & 43776302 (1994)/Acceptable Materna l NOAEL = 100 mg/kg/day LOAEL = 450 mg/kg/day based onZeta

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Page 63 of 78 Table A.2.b Subchronic, Chronic, and Other Toxicity

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

cypermethrin mg/kg/day = 0, 100, 450 or 700 decreased body wt gain; anorexia,
abdomino

- genital staining, decreased feces & red or pink material in the pan (few does). At 700, anorexia,
abdomino

- genital staining, decreased feces & red or pink material in the pan were observed. Developmenta l NOAEL = 700 mg/kgday LOAEL = >700 mg/kg/day (highest dose tested)

870.3700b Prenatal developmental in

rab bits cypermethrin MRID 00056805 (1978)/Unacceptable [dosed by capsule] mg/kg/day = 0 (empty), 0 (corn oil), 3, 10
or 30 Materna l NOAEL = 30 mg/kg/day LOAEL > 30 mg/kg/day (HDT) Developmenta l NOAEL = 30 mg/kg/day LOAEL = > 30 mg/kg/day (highest
dose test ed)

870.3700b Prenatal developmental in

rabbits alpha

- cypermethrin MRID 47944072 (1994)/Acceptable mg/kg/day = 0, 3, 15,
or 30 Maternal NOAEL = 15 mg/kg/day LOAEL = 30 mg/kg/day based on a slight body weight loss and decreased food consumption. Developmental NOAEL = 30 mg/kg/day (HDT).
LOAEL = not established

870.3800 Reproduction and fertility

effects cypermethrin MRID 00112912, 42068504 & 92027040 (1982)/Acceptable ppm = 0, 50, 150 or 1000/750 (to 750 after wk 12 due to

severe neurological signs) mg/kg/day = 0, 2.5, 7.5 or 50/37.5 [2 litters/ generation] Parental/Offspring NOAEL = 7.5 mg/kg/day LOAEL = 50/37.5 mg/kg/day based on decreased body wt gain in both
sexes and decreased mean litter weight gain during lactation.

870.38 00 Reproduction and fertility

effects cypermethrin MRID 00090040 (1979)/Unacceptable ppm = 0, 10, 100 or 500 mg/kg/day = 0, 0.5, 5 or 25 [2 litters/generation] Parental/Systemic NOAEL = 5 mg/kg/day
LOAEL = 25: based on decreased body wt gain. Offspring NOAEL = 5 mg/kg/day
LOAEL = 25: based on decreased body wt gain (lactation day 21).

870.3800 Reproduction and fertility

effects

zeta

- cypermethrin MRID 41968204 (1991)/Acceptable ppm = 0, 7.5, 25, 100, 375 or 750 mg/kg/day = 0, 0.5, 1.8, 7, 27 or 45 [1 litter/generation] Parental/Systemic NOAEL = 7 mg/kg/day LOAEL = 27 mg/kg/day based on decreased body wt gain (most noticeable during lactation) and increased relative brain wts M & F; at 45 mg/kg/day, some neurotoxic clinical signs in a few animals (s ome mortality) . Offspring NOAEL = 7 mg/kg/day LOAEL = 27 mg/kg/day, based on decreased body wt gain during lactation; at 45 mg/kg/day, pup mortality.

870.4100a Chronic toxicity rats MRID 00112910 & 9202741 NOAEL = 7.5 mg/kg/dayZeta

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Page 64 of 78 Table A.2.b Subchronic, Chronic, and Other Toxicity

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

cypermethrin (1982)/Acceptable ppm = control 1, control 2, 20, 150 or
1500 mg/kg/day = 0, 1, 7.5 or 75 LOAEL = 75 mg/kg/day based on decreases in body wt gain (both sexes)

870.4100b cypermethrin Chronic toxicity dogs

(capsule) MRID 00112909, 42068503 & 92027037 (1982)/Acceptable mg/kg/day = 0, 1, 5 or 15 NOAEL = 5 mg/kg/day LOAEL = 15 mg/kg/day based on body tremors, gait abnormalities, uncoordination, disorientation & hypersensitivity to noise plus decrease in body weight.

870.4100b Chronic toxicity dogs

(feed ing) cypermethrin MRID 44536801 (1995)/Acceptable ppm = 0, 100, 200, 600 or 1100 mg/kg/day = M: 0, 2.9, 6.0, 20.4, 33.9 F: 0, 3.3, 5.7, 18.1, 38.1 NOAEL = 6 mg/kg/day (M), 5.7 mg/kg/day (F) LOAEL = 20.4 mg/kg/day (M) based
on abnormal cl inical signs (tremors, excessive salivation, irregular gait); at 33.9 mg/kg/day, mortality. 18.1 mg/kg/day (F) based on decreased body wt & wt gains.

870.4100b Chronic toxicity dogs

(feeding) alpha

- cypermethrin MRID 47944070 1995)/Acceptable ppm = 0, 60, 120, or 240 mg/kg/day = M: 0, 2.02, 4.11, or 7.90 F: 0, 2.18, 4.29, or 8.45 NOAEL = 4.11 mg/kg/day (M); 4.29 mg/kg/day (F) LOAEL = 7.9 mg/kg/day (M); 8.45 mg/kg/day (F) based on clinical signs (skin reddening, hair loss, and tail irritation)

870.4200a Carcinogenicity rats

cypermethrin MRID 00112910 & 9202741 (1982)/Acceptable ppm = 0 #1, 0 #2, 20, 150 or 1500 mg/kg/day = 0, 0, 1, 7.5 or 75 NOAEL = 7.5 mg/kg/day LOAEL = 75 mg/kg/day based on decreases in body wt gain (both sexes). No evidence of carcinogenicity

870.4200b Carcinogenicity mice

cypermethrin MRID 00112911 & 92027038 (1982)/Acceptable ppm = 0 #1, 0 #2, 100, 400 or 1600 mg/kg/day = 0, 0, 14, 57 or 229 [M = 97 weeks; F = 101 weeks] NOAEL = 14 mg/kg/day
LOAEL = 57 mg/kg/day (M) based on increased absolute (20%) liver wts Females, there was a 15% increase in relative liver wts only at 229 mg/kg/day.

Benign alveologenic neoplasms were observed at 229 mg/kg/day.

870.4200b Carcinogenicity mice

alpha

- cypermethrin MRI D 47944071 1999)/Acceptable ppm = 0, 30, 100, 0r 300 mg/kg/day (M/F) = 0/0, 3.0/3.5, 10.6/11.5, or 35.2/37.7 Male NOAEL = 3 mg/kg/day LOAEL = 11 mg/kg/day (M) based on decreased body weight, body weight gains, and food efficiency and clinical signs indicative of poor
health

Female NOAEL=12 mg/kg/day LOAEL = 38 mg/kg/day based on decreased body weight and body weight gains

No evidence of carcinogenicityZeta

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Page 65 of 78 Table A.2.b Subchronic, Chronic, and Other Toxicity

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

870.5100 Salmonella typhimurium

& S. cerevisiae reverse mutation assay

zeta

- cypermethrin MRID 41968205 (1992)/Acceptable 0, 100, 333, 1000, 3333, 5000, 10000 μg/plate Weak mutagen effects noted at 10, 000, 5000 and 3333 ug/plate in
absence of metabolic activation in
Salmonella strain TA100 in two studies. Strains TA98, TA1S3S,
TA1537 and TA 1538 di d not indicate mutagenic effect in presence
or absence of S

- 9 activation.

870.5100 Salmonella typhimurium

& S. cerevisiae reverse mutation assay cypermethrin MRIDs 00090037, 92027042, 92027062, 00090036, 00126834 (1981)/Acceptable 4, 20, 100, 500, 2500 · g/plate Negative up to doses of 2500 ·g/plate.

870.5300 In vitro cell gene mutation

test

zeta

- cypermethrin MRID 41968206 (1990)/Acceptable 0, 14, 45, 140, 450 1400 and 4500 ug/ml. Negative up to doses of 4500 ug/mL.

870.5380 in vivo cytogenetics

cypermethrin MRIDs 0090038, 92027043 (1980)/Acceptable 0, 20, 40 mg/kg No evidence of structural
chromosomal aberrations in rat bone marrow at 20 or 40 mg/kg.

870.5450 Dominant lethal assay in

the rodent cypermethrin MRID 00090039 1980/Acceptable 0, 2.5, 5, 7.5, 10 mg/kg/day for 5 days No evidence of dominant lethal activity in CD

- 1 strain mice up to 10 mg/kg/day for five consecutive days.

870.5550 Unscheduled DNA

synthesis in mammalian
cells in culture cypermethrin MRID 41599801 (1990)/Acceptable 100, 200 mg/kg No unscheduled DNA synthesis was observed at any dose level up to 200mg/kg in corn oil in Alpk:APfSD strain rats (males) assessed 4 and 12 hours post dosing. 200 mg/kg dose
was considered near the MTD.

870.5550 Unscheduled DNA

synthesis in ma mmalian
cells in culture

zeta

- cypermethrin MRID 41968207 (1989)/Acceptable 0, 1, 10, 25, 50, 100 (estimated limit of solubility), 400, 700 and 1000 ug/ml Negative

870.6200a Acute neurotoxicity

screening battery rats cypermethrin MRID 43152001 (1994)/Acceptable mg/kg = 0, 30, 100 or 200 NOAEL = 30 mg/kg/day LOAEL = 100 mg/kg based primarily on ataxia and related conditions (staggered or impaired gait, decreased activity, splayed hindlimbs and limp conditions in
addition to decreased motor ac tivity in males and females on days 0, 1 or 2).

870.6200a Acute neurotoxicity

screening battery rats cypermethrin MRID N/A 1993/Acceptable mg/kg = 0, 20, 60, 120
LITERATURE STUDY NOAEL = < 20 mg/kg/day LOAEL = 20 mg/kg based on
decreased motor acti vity and gait abnormalities. (Conducted at RTP).

870.6200a Acute neurotoxicity

screening battery rats

zeta

- cypermethrin MRID 44962201 (1998)/Acceptable mg/kg/day = 0, 10, 50 or 250 NOAEL = 10 mg/kg/day LOAEL = 50 mg/kg/day based on clinical signs (abdominogenital staining, oral discharge, splayed hindlimbs, staggered gait & tremors); FOB findings (abnormal mobileZeta

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Page 66 of 78 Table A.2.b Subchronic, Chronic, and Other Toxicity

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results
posture, splayed hindlimbs, soiled fur & unable to walk); at 250, more severe findings.

870 .6200a Acute neurotoxicity

screening battery rats alpha

- cypermethrin MRID 47944067 (1993) mg/kg/day = 0, 4, 20, or 40 NOAEL = 4 mg/kg/day LOAEL = 20 mg/kg/day based on clinical signs (gait abnormalities, prostration, thrashing, vocalization, piloerection, unkempt appearance), FOB findings (limb abnormalities and increased reactivity), and mortality. At 40 mg/kg/day, clinical neurotoxic sign s, FOB effects, mortality, and slight nerve degeneration.

870.6200b Subchronic neurotoxicity

screening battery rats cypermethrin MRID 43152002 1993/Acceptable ppm = 0, 500, 1300 or 1700 mg/kg/day = M: 0, 31, 77 or 102; F: 0, 37, 95 or 121 NOAEL = 31 mg/kg/day LOAEL = 77 mg/kg/day based on the following: males: decreased body weight gain and increased landing foot splay; females:ataxia, splayed hindlimbs, impaired gait and
decreased feces as well as decreased body weight gain.

870.6200b Subchronic neurotoxicity

screening battery rats

zeta

- cypermethrin MRID 44962202 (1999)/Acceptable ppm = 0, 75, 400 or 750 mg/kg/day = M: 0, 5.0, 26.3 or 47.2; F: 0, 5.9, 31.5 or 55.6 NOAEL = 5.0 mg/kg/day (M); 31.5 mg/kg/day (F) LOAEL = 26.3 mg/kg /day (M) based on decreased motor activity, increased landing foot splay, and decreased body weights, body weight gains, and food consumption; 55.6 mg/kg/day (F) based on decreased body weights, body weight gains, and food consumption.

870.6300. Develo pmental

neurotoxicity rats

zeta

- cypermethrin MRID 46670402 (2005). Acceptable/

Non

- guideline. ppm= 0, 50, 125 or 300 mg/kg/day = 0, 2.9, 7.4 or 17.3. Maternal: NOAEL= 17.3 mg/kg/day Decreased body weight of 5

- 8%
observed in maternal animals but not
considered adverse.
LOAEL= not established Offspring: NOAEL = 7.4 mg/kg/day LOAEL = 17.3 mg/kg/day based on decreased body weight (5

- 10%)

870.7485 Metabolism and

pharmacokinetics rats cypermethrin MRID 41551102

- 04 (1977

- 78)/Acceptable 0.61 mg/animal; 1 .3mg/kg; 1 mg/kg or
less Several studies with both rats, dogs and mice are available to support the requirement for metabolism in
mammals. Some of these studies
assess individual cis and trans radiolabelled isomers and other
studies assess the metabolism of cypermethrin with the label in either the cyclopropyl of the phenoxybenzyl ring. In general the following hasZeta

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Page 67 of 78 Table A.2.b Subchronic, Chronic, and Other Toxicity

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

been demonstrated from these studies: cypermethrin is readily
absorbed from th e gastrointestinal tract and extensively metabolized. It mostly excreted in the urine that
contains several characterized metabolites derived from conjugation of the hydrolysis products of the parent compound following cleavage of the esteratic linkage si te.
870.7800 Immunotoxicity rats

alpha

- cypermethrin MRID 48273201; 48273202 Acceptable ppm = 0, 50, 150 or 450 mg/kg/day = 0, 4, 12, or 34 NOAEL = 34 mg/kg/day
LOAEL = not determined

870.7600 Dermal penetration rat

alpha

- cypermethrin MRID 47944084 Acceptable The low dose (1.5 μg/cm 2 ) provided
the most conservative estimate of total absorption at 13% AD, and
should be considered for a dermal penetration factor in risk assessment

Non

- Guideline Wolansky et. al.

Acute Oral Toxicity in

Rats

- Motor Activity MRID 47885701 (2006) BMDL 1SD = 7.16
BMD = 11.20

Non

- Guideline WIL Study

Acute Oral Toxicity in

Rats

- FOB MRID 47050505 (2006) Acceptable BMDL 20 =55.9

BMD 20 = 76.3

*alpha

- cypermethirn and zeta

- cypermethrin are bridged to the database with cypermethrin. Therefore, selected studies for
all are included.Zeta

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Page 68 of 78 A. 3 Toxicological Doses and Endpoints for Use in Human Risk Assessments

Hazard Identification and Endpoint Selection

Acute Reference Dose (aRfD)

– All Populations Including Infants and Children and Females Age 13

- 49 Study Selected : Wolansky et. al. (2006)
MRID # : 47885701 Dose and Endpoint for Risk Assessment : BMDL 1SD = 7.16 mg/kg, based on decr eased motor activity Uncertainty Factor :

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

Acute RfD = = 0.07 mg/kg

Children < 6 years old: 300X (3X FQPA, 10X interspecies extrapolation, 10X intraspecies variability)Zeta

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Page 69 of 78 Comments about Study/Endpoint: The selected NOAEL (BMDL 1SD ) of 7.16 mg/kg is from a study of the appropriate route and duration. The decreases in motor and locomotor activity are considered potential single

- dose effects because they were observed within the first hours following dosing. The Wolansky et. al. (20 06) study is a very robust study with 6 doses, using a sensitive vehicle and volume to determine a BMDL and therefore provides a more accurate point of departure. Additionally, the study is protective of the effects observed in the toxicology
database. Th ere is no increase in hazard from repeated exposures to the cypermethrins; therefore, the acute dietary exposure assessment is protective of chronic dietary exposures since acute exposure levels are higher than chronic exposure levels. Accordingly, a diet ary exposure assessment for the purpose of assessing chronic dietary risk was not conducted.

Human equivalent Doses for Wolansky Study and Relevant Long

- term Studies

Study Point of Departure Human Equiv. Dose * Uncertainty

Factors Rat (Wolansky ) BMD BMDL 1SD BMD BMDL 1SD 11.19 7.16 3.25 2.08 300X

NOAEL LOAEL NOAEL LOAEL 100X Chronic Dog

- feeding (cypermethrin) 5.7 20.4 3.50 12.50 100X

Subchronic Dog 2.25 6.75 1.38 4.15 100X Chronic Dog

- capsule (cypermethrin) 5 15 3.07 9.22 100X

Chronic Dog (alpha

- cypermethrin) 4.11 7.9 2.53 4.86 100X

Carcinogenicity Mouse (alpha

- cypermethrin) 3 11 0.41 1.51 100X

*Human Equivalent based on allometric scaling: Scaling Factor 0.75; Default weights: rat = 0.5 kg, mouse=0.25 kg, dog = 10 kg, Human = 70 kg; NOAEL H =NOAEL D (BW D /BW H )^1

- 0.75; Sample and Arenal, Bull Environ Contam Toxicol (1999) 62:653

- 63

Incidental Oral Exposure (Short

- Term) Study Selected : Wolansky et. al. (2006)
MRID # : 47885701 Dose and Endpoint for Risk Assessment : BMDL 1SD = 7.16 mg/kg, based on decreased motor activity Uncertainty Factor :

Children < 6 years old: 300X (3X FQPA, 10X interspecies extrapolation, 10X intraspecies variability) Acute RfD = = 0.023 mg/kgZeta

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Page 70 of 78 Comments about Study/Endpoint: The selected NOAEL (BMDL 1SD ) of 7.16 mg/kg is from a study of the appropriate route and duration. The decreases in motor and locomotor activity are considered potential single

- dose effects because they were observed within the first hour s following dosing.

Dermal Exposure (Short

- and Intermediate

- Term)

A dermal assessment was not conducted. No systemic effects were observed in the 21

- day rat study with zeta

- cypermethrin up to the limit dose. In a 21 day dermal study in rabbits with

c ypermethrin, focal necrosis of the liver, decrease in testicular weights and body weight loss (females) were noted in animals with abraded skin. No systemic effects were observed in
animals with non

- abraded skin up to the highest dose tested (200 mg/kg/da y). The observations in the abraded rabbits were not used for risk assessment since the method (abraded skin) does not simulate actual exposure and results in compromised test conditions. Additionally, there would be physiological differences between the abraded and non

- abraded animals. Based on the exposure profile, HED does not anticipate long

- term dermal exposure for adults or children.

Inhalation Exposure (Short

- , and Intermediate

- Term)

Study Selected: Inhalation Toxicity Study in Rats (Cypermethr in)

MRID No.: 43507101

Dose and Endpoint for Risk Assessment: The LOAEL=0.05mg/L, based on increased salivation. The NOAEL is 0.01mg/L. Human equivalent concentrations and doses (HEC/HED) for occupational and residential inhalation exposure were calcu lated for cypermethrin and used
for risk assessment.

UF(s): Adults and Children ≥ 6 years old

- 100X : 30X (1X FQPA, 3X interspecies extrapolation, 10X intraspecies variability) . Children < 6 years old

- 100X (3X FQPA, 3X interspecies extrapolation, 10X intraspecies variability)

Comments on Study/Endpoint/ UF s : In a 21 day inhalation toxicity study in rats, increased
salivation w as seen at 0.05 mg/L. The NOAEL is 0.01 mg/L. Human equivalent concentrations (HE Cs) were calculated for the inhalation NOAEL using the methods and dosimetry equations
described in US EPA’s RfC guidance (1994). The HECs were used to calculate human equivalent doses (HED) that were used in inhalation risk assessments (see A.4 ). The dos e and endpoint are appropriate since effects were seen following exposure via the route (inhalation) and duration (short

- and intermediate

- term) of concern. Based on the exposure profile, HED does not anticipate long

- term inhalation exposure for adults or children. Acute RfD = = 0.023 mg/kgZeta

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Page 71 of 78 Residential HED: (0.008 mg/L) x 1 x 6 x 24 x 1 = 1.15 mg/kg/day Occupational HED: (0.023 mg/L) x 1 x 6 x 8 x 1 = 1.10 mg/kg/day

A 4 . HEC Inhalation Calculations

A 21

- day rat inhalation study was conducted to assess the toxic effects of the pyrethroid cypermethrin via the inhalation route. Cypermethrin was administered to 5/sex Wistar rats (nose only) 6 hours/day, 5 days/week, as an aerosol with an average mass medium aerodynamic diameter (MMAD) of 2.63 and a geometric standard deviation (σ) of 1.87. The LOAEL of 0.05 mg/L is based on increased salivation. The NOAEL is 0.01 mg/L.

RDDR for Cypermethrin

Because the respired material used in the inhalation study is an aerosol, the RDDR ratio, which incorporates MMAD and σ, is appropria te to use for HEC calculation (table below). The “RDDR.exe” software program was used to obtain the RDDR value of 3.1 based on extrarespiratory effects (body weight changes, salivation) as shown below. The inputs for the program are: MMAD=2.63; σ=1.87; BW for Wistar Rats from study report=271g; Standard human BW information (i.e., 70 kg).

Figure 1. Regional Deposited Dose Ratios (RDDR) for CypermethrinZeta

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Page 72 of 78 Table A.4 : HEC Array for Non

- Occupational and Occupational Risk Assessment §

Relevant Study LOAEL (mg/L) NOAEL

(mg/L) Da Dh Wa Wh RDDR HEC (mg/L) inter intra UF

Short

- & Intermediate

- Term Occupational Exposure

Inhalation

– Rat ( MRID 48723301 )
28

- day Systemic 0.05 0.01 6 8 * 1 * 1 3.112 0.023 3 10 NA

Short

- & Intermediate

- Term Non

- Occupational (Residential) Exposure

Inhalation

– Rat ( MRID 48723301 )
28

- day Systemic 0.05 0.01 6 24 * 1 * 1 3.112 0.008 3 10 3x for
kids < 6years

Long Term Exposure: Not appropriate

Key for Array Tables

LOAEL : Lowest observed adverse effect level

Da : Daily animal exposure (hrs/day)

Wa : Weekly animal exposure (days/week)

RRDR : Regional Deposited Dose Ratio

inter : interspecies extrapolation uncertainty factor Dh : Anticipated daily human exposure (hrs/day)
Wh : Anticipated weekly human exposure (days/week)

HC: Human Concentration
HEC : Human Equivalent Concentration

intra : intrasp ecies variation uncertainty factor

UF : Other uncertainty factor(s)

Calculation of the Human Equivalent Concentration (HEC) and Human Equivalent Dose Human Equivalent Concentrations

Human Equivalent Doses Using the HECs calculated a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows:Zeta

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Page 73 of 78 dose (systemic HEC value) mg/L x A x CF (L/hr/kg) x D (hours) x AF = mg/kg; Occupational: (0.023 mg/L) x 1 x 6 x 8 x 1 = 1.10 mg /kg/day
Residential: (0.008 mg/L) x 1 x 6 x 24 x 1 = 1.15 mg/kg/day

Where:
A absorption: ratio of deposition and absorption in respiratory tract compared to absorption by the oral route.
CF Conversion Factor: A L/hr/kg fac tor which accounts for respiratory volume and body weight for a given species and strain (Table 1 of guidance document).

D Duration: Duration of daily animal or human exposure (hours).

AF Activity Factor: Animal default is 1.

When conducting inhalation risk assessments, the magnitude of the UFs applied is dependent on the methodology used to calculate risk. For studies in this risk assessment with inhalation animal data, UFs are based on the RfC methodology developed by the Office of Research and
Develo pment (ORD) for the derivation of inhalation reference concentration s (RfCs) and human equivalent concentrations (HECs) for use MOE calculations. Since the RfC methodology takes into consideration the pharmacokinetic (PK) differences but not pharmacodyna mic (PD)
differences , the UF for interspecies extrapolation may be reduced to 3X (to account for the PD differences) while the UF for intraspecies variation is retained at 10X 1 . Thus, the UF when using the RfC methodology is customarily 30X.

For the cype rmethrins , HED believes exposures can be short

- (1

- 30 days) or intermediate

- (1 to 6 months) term in duration. Long

- term exposures are not anticipated based on proposed labeled
uses. For short

- and intermediate

- term scenarios, inhalation data from the 4 week inhalation rodent study was most appropriate for determining HECs. In the RfC methodology, different HECs may be calculated for the same experimental NOAEL due to:

1. Different algorithms are used to derive HECs for systemic versus port

- of

- entry effects. Typically, HECs are calculated separately for systemic versus port

- of

entry effect. For cypermethrin, systemic (extrarespiratory) effects were observed and therefore, only systemic HECs were derived.

2. 

### Ti me adjustments are traditionally needed for non

- occupational (bystander) versus occupational exposure scenarios. Traditionally, HECs for non

occupational exposure are based on the number of hours an individual may be at home. Therefore, the most conservative estimate of hours spent at home would be 24 hours/day and 7 days/week. In comparison, the average work week for an occupational worker is 8 hours/day and 5 days/week. The HEC array table reflects the time adjus tment in the calculations (Table A.3.5B).

Methodologies for Human

- Equivalent Concentration (HEC) Calculations.

1 A 3X UF for interspecies extrapolation is retained to account for the PD differences between animals and humans which are not accounted for in the RfC methodology.Zeta

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Page 74 of 78 The RfC methodology applies a dosimetric adjustment that takes into consideration not only the differences in ventilation rate (MV) but also th e physicochemical properties of the inhaled compound, the type of toxicity observed ( e.g. systemic vs. port of entry) and the pharmacokinetic (PK) but not pharmacodynamic (PD) differences between animals and humans. Based on the
US EPA’s RfC guidance (1994 ), the methodology for RfCs derivation is an estimate of the quantitative dose

- response assessment of chronic non

- cancer toxicity for individual inhaled chemicals and includes dosimetric adjustment to account for the species

- specific relationships of

expos ure concentration to deposited/delivered dose. This adjustment is influenced by the physicochemical properties of the inhaled compound as well as the type of toxicity observed ( e.g. systemic vs. port of entry), and takes into consideration the PK differenc es between animals
and humans. Though the RfC methodology was developed to estimate toxicity of inhaled chemicals over a lifetime, it can be used for other inhalation exposures ( e.g. acute and short

- term exposures) since the dosimetric adjustment incorpor ates mechanistic determinants of disposition that can be applied to shorter duration of exposures provided the assumptions underlying the methodology are still valid. These assumptions, in turn, vary depending on the type of toxicity
observed. Thus the d erivation of a HEC for inhaled gases is described by the following equation:

Where:
POD study : Point of departure identified in the critical toxicology study

D animal exposure : Duration of daily animal exposure (hrs/day)

D anticipated exposure : Anticipated daily human duration of exposure (hrs/day)

W animal exposure : Duration of weekly animal exposure (days/week)

W anticipated exposure : Anticipated weekly human duration of exposure (days/week) RGDR: Regional Gas Dose Ratio

Calculations used to estimate the in halation risk to humans from aerosols are dependent not on the RGDR as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies using aerosols characterize particulate exposure by defining the particulate diameter (mass median aerody namic diameter [MMAD]) and the geometric standard deviation (σ g ), which is then used to determine the RDDR. The RDDR is a multiplicative factor used to adjust an observed inhalation particulate exposure concentration of an animal (A) to the predicted
inha lation particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the region or target tissue.

RDDR
r = (RDD
r

/Normalizing Factor) A (RDD
r /Normalizing Factor) H

As with calculations for gases, the regions and potential target tissues are the three respiratory regions (ET, TB, PU). The RDDR is easily calculated by using a software program designed specifically for computing the RDDR from the MMAD and σ g defined from an aerosol inhalation study. The values for the species

- specific parameters used to calculate the RDDR are provided in the US EPA document “Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry.”Zeta

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Page 75 of 78 Appendix B. Physical/Chemical Properties

Table B.1. Physicochemical Properties of the Technical Grade Test Compound: Zeta

- Cypermethrin

.
Parameter Value Reference

Melting point

- 22.4°C MRID 46971402 1

, unless otherwise noted. pH 4.5 (1% suspension)

Density 1.219 g/mL at 25°C

Water solubility (25°C) 45 ppb

Solvent solubility miscible in acetone, acetonitrile, methylene chloride, and toluene

Vapor pressure 3 x 10
- 9 mm Hg at 20 °C 2

Dissociation constant, pK

a Not available

Octanol/water partition coefficient, Log(K OW ) >6

UV/visible absorption spectrum Not available

1 Values as reported by the petitioner.

2 Cypermethrin: Phase 4 HED Risk Assessment for the Reregistration Eligibility Decision (RED). PC Code 109702; DP Barcode D293416. April 6, 2006.Zeta

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Page 76 of 78 Appendix C. International Harmonization



### Zeta

- Cypermethrin (PC Code 129064 ; May 26, 2011)
Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : Cypermethrin. There are no separate MRLs for zeta

- cypermethrin per se US Canada Mexico 2 Codex 3

40 CFR 180. 418(a)(1)

Plant/Livestock: cypermethrin (±)alpha

cyano

- (3

- phenoxyphenyl)methyl(±)cis,trans

3(2,2

- dichloroethenyl

- 2,2

- dimethylcyclopropanecarboxylate

180. 418 (a)(2)

Z

- cypermethrin (S

- cyano(3

- phenoxyphenyl) methyl (±))(cis

- trans 3

- (2,2

- dichloroethenyl)

- 2,2 dimethylcyclopropanecarboxylate and its
inactive R

- isomers ( RS )

- α

- cyano

- 3

- phenoxybenzyl
(1 RS , 3 RS )

- (1 RS

, 3 SR )

- 3

- (2,2

- dichlorovinyl)

- 2,2

- dimethylcycloprop anecarboxylate cypermethrin (sum of isomers). The residue
is fat

- soluble.

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex
Artichoke, globe 0.6 0.1

Avocado 0.5 Barley, grain 3 2 Po

Barley, hay 6 10 straw and fodder (dry) of cereal grains

Barley, straw 20 10 straw and fodder (dry) of cereal grains Black Sapote 0.5

Buckwheat, grain 3 0.3 cereal grains, except rice barley, oats, rye, and wheat

Buckwheat, hay 6 10 straw and fodder (dry) of cereal grains

Buckwheat, straw 20 10 straw and fodder (dry) of cereal grains

Canistel 0.5 Mamey Sapote 0.5 Mango 0.7 0.7 Oat, grain 3 2 Po

Oat, hay 6 10 straw and fodder (dry) of cereal grains

Oat, straw 20 10 straw and fodder (dry) of cereal grains Papaya 0.5 0.5

Pistachio 0.05 Rye, grain 3 2 Po

Rye, hay 6 10 straw and fodder (dry) of cereal grainsZeta

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Page 77 of 78 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : Cypermethrin. There are no separate MRLs for zeta

- cypermethrin per se US Canada Mexico 2 Codex 3

Rye, straw 20 10 straw and fodder (dry) of cereal grains Sapodilla 0.5 Star Apple 0.5

Completed: M. Negussie; May 26, 2011

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed ha ve not been finalized by the CCPR and the CAC.Zeta

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Page 78 of 78 Appendix D. 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 dat a, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1) and the Agricultural Handler Exposure Task Force (AHETF) database, and the 2012 Revised Residential SOP for Turf and Lawn, Indoor Environments and Pets are subjec t to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies that review may have included review by the Human Studies Review Board. Descriptions of
data sources as well a s guidance on their use can be found at: http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.