Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 3 of 87 5.4.5 Average Dietary Risk Assessment

................................ ................................ ............. 40
5.4.6 Summary Table

................................ ................................ ................................ ........... 40
6.0 Resident ial (Non

- Occupational) Exposure/Risk Characterization

................................ .... 41
6.1 Registered Cypermethrin Residential Handler Exposure/Risk Estimates

...................... 41
6.2 Cypermethrin Registered Residential Post

- application Exposure/Risk Estimates

........ 42
6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

......................... 44
6.4 Resid ential Risk Estimates for Use in Aggregate Assessment ................................4 5
6.5 Spray Drift

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

6.6 Residential Bystander Post

- Application Inhalation Exposure

................................ ....... 46
7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ....... 47
7.1 Acute Aggregate Risk

................................ ................................ ................................ .... 47
7.2 Shor t

- Term Aggregate Risk

................................ ................................ .......................... 47
7.3 Intermediate

- Term/ Chronic Aggregate Risk

................................ ................................ .. 4 8
8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 48
9.0 Occupational Exposure/Risk Characterization

................................ ................................ .. 48
9.1 Occupational Handler Exposure/Risk Estimates

................................ ............................ 49
9.2 Occupational Post

- application Exposure/Risk Estimates

................................ .............. 54
9.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

.......................... 54
9.2.2 Occupational Post

- application Dermal Exposure/Risk Estimates

.............................. 54
10.0 References

................................ ................................ ................................ .......................... 55 Appendix A. Toxicology Profile and Executive Summaries

................................ ....................... 58
A.1 Toxicology Data Requirements

................................ ................................ ...................... 58
A.2 Toxicity Profiles

................................ ................................ ................................ ............. 59
A.3 Toxicological Doses and Endpoints for Use in Human Risk Assessments

................... 67
A 4. HEC Inhalation Calculations

................................ ................................ ........................... 70 Appendix B. Physical/Chemical Properties

................................ ................................ ................. 73 Appendix C. International Harmonization

................................ ................................ ................... 7 5 Appendix D

. Review of Human Research

................................ ................................ ................... 77 Appendix E . Executive Summaries for Submitted Studies for Alpha

- cypermethrin

.................. 77Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 4 of 87 1.0 Executive Summary

BASF Corporation has petitioned the Agency for Section 3 registration of end

- use products containing the new pesticide active ingredient alpha

- cypermethrin for use on a variety of crops. Additionally, BASF has requested the establishment of permanent tolerances for resi dues of alpha

- cypermethrin, in or on various commodities, at the same levels as tolerances established
for zeta

- cypermethrin in those commodities. The petition for registration of alpha

- cypermethrin relies on alpha

- cypermethrin data

, as well as previously submitted data for the related registered insecticides, cypermethrin and zeta

- cypermethrin. Cypermethrin, zeta

- cypermethrin and alpha

cypermethrin are isomer mixtures of the same chemical. Cypermethrin consists of a mixture of eight isomers (four diaste reoisomeric pairs). Alpha

- cypermethrin consists of two of the four cis

isomers of cypermethrin. Zeta

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

- cypermethrin. Therefore, studies

co nducted to support the registrations of cypermethrin and zeta

- cypermethrin are applicable to the registration of alpha

- cypermethrin.

Alpha

- cypermethrin is a broad spectrum insecticide, effective against target pests through contact and ingestion. Alpha

- cypermethrin is a type II synthetic pyrethroid chemical. Pyrethroids disrupt the voltage

- gated sodium channels in the nervous system, result ing in neurotoxicity.

In developing this human health risk assessment, the Health Effects Division has examined the available hazard and exposure information regarding alpha

- cypermethrin, as well as information for cypermethrin, zeta

- cypermethrin, and py rethroid chemicals as a class. 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 co mparable toxicity profiles. For 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 assessment considers not only the exposure associated with the proposed food uses for alpha

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

- cyp ermethrin.

Behavioral changes commonly 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 t remors, gait abnormalities, limb conditions, 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 fem ale mice after chronic exposure.

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

bearing age) and children > 6 years of age, EPA is reducing the FQPA safety factor to 1X.Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 5 of 87 There was no evidence of increased qualitative or quantitative susceptibility in developmental

tox icity studies in the rat and rabbit and 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 in p ups 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 der mal toxicity and there is no evidence of immunotoxicity.

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 st udy. 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 no t considered strong enough to warrant a quantitative estimation of human risk. Taking into account all of this information, the Agency has determined that quantification of risk using a non

- linear approach (i.e., acute population adjusted dose ( aPAD ) or a cute 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 canc er concerns, use of the aPAD is protective because increasing toxicity with increasing duration of exposure is not demonstrated for the cypermethrins , and because the exposure assessment associated with the acute dietary scenario reflects high

- end consumpt ion
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 determ ined 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 inh alation risk assessments, an inhalation toxicity study in rats was chosen and human equivalent concentrations (HECs) were calculated and used for risk 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 quantitative 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 parameters for alpha

- cypermethrin, zeta

- cypermethrin and cypermethrin are adequately understood for the purpose of estimating residues in ground and surface water sources of drinking water. For all three cypermethrins, HED has concluded theAlpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 6 of 87 residue of concern for risk assessment and tolerance enforcement is the parent compound, cypermethrin, zeta

- cypermethrin and alp ha

- cypermethrin.

Dietary e xposure to alpha

- cypermethrin may occur from consuming treated crops or their processed commodities. Partially refined (probabilistic) dietary exposure assessments were performed in order to determine the exposure and risk estim ates resulting from the use of cypermethrin, alpha

- cypermethrin, and zeta

- cypermethrin on the crops listed under 40 CFR 180.418 and the proposed new uses. HED has used modeling to estimate dietary exposure to the cypermethrins. The modeling uses health

- p rotective assumptions regarding residues of alpha

cypermethrin and its breakdown products in food and drinking water and incorporation of percent crop treated (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 th e 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 subgroups.

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

- term aggregate risk to cypermethrins, the average dietary (food and drinking water) exposure was calcu lated. The quantification of average dietary exposures required the use of average field trial residues, PDP data, and current tolerances as appropriate. The assessment also made use of PCT data where available. Drinking water information was incorporat ed using the mean concentration (1

- in

- 10

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

This assessment addresses 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 exposure for occupational workers for the proposed food uses is expected to be short

- t erm (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 uses or the existing uses. However, due to the pyrethroid toxicity profile, only single day risk

assessm ents were conducted for occupational and residential exposure

, which are protective of all durations of exposure.

At this time, there are no registered or requested uses for alpha

- cypermethrin that involve a residential setting; however, residential exposure and risk were estimated for registered
residential uses of cypermethrin and zeta

- cypermethrin . For the registe red residential uses of the cypermethrins, there is a potential for residential exposure associated with handler activities for adults only, as well as with post

- application activities 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, since the cypermethrins do not increase in potency with repeatedAlpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 7 of 87 dosing, only single day residential exposures were assessed. Residential intermediate

- te rm exposures are not likely because of the intermittent nature of applications by homeowners. An inhalation handler exposure assessment was performed for residential turf, indoor surface sprays, foggers, and pet uses. 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 residential products were re

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

- case and are protective.

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 t he 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 exposed via the incidental oral route, the LOC is 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, in order to combine exposure from the various routes the aggregate risk index (ARI) is used to estimate exposure and
risk. ARIs ≥ 1 are not of concern.

Residential handler inhalation risk estimates for cypermethrin and zeta

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

application ex posure and risk estimates (MOEs and ARIs) for adults and children were greater than their respective LOC and 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
and an ARI for the combined routes of 13.

Exposure has also been assessed for occupational handlers mixing, loading, and applying alpha

cypermethr in. All occupational handler inhalation exposure assessments resulted in MOEs ranging from 14, 000 to 410,000 and are not of concern. As no dermal endpoint was identified, a quantitative post

- application assessment was not performed. Post

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

- application inhalation exposure scenarios

.

This risk assessm ent is based, in part, o n data from studies in which adult human 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).

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

- c ypermethrin will not impact the cumulativeAlpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 8 of 87 assessment because: 1) the alpha

- cypermethrin application rates are lower than the zeta

cypermethrin rates and are expected to result in lower residue levels; and 2) zeta

- cypermethrin has already been registered f or use on the crops proposed in the current alpha

- cypermethrin petition and those uses were incorporated into the cumulative assessment. Additionally, no new residential uses are proposed, so the residential cumulative assessment will not be impacted.

2.0 HED Recommendations

HED is recommending in favor of registration of alpha

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

2.1 Data Deficiencies

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 chr omatographic methods with
electron

- capture detection (GC/ECD), and have undergone successful 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 lives tock 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

Currently established US tolerances for cypermethrin and zeta

- cypermethrin are included in the same listing in the 40 CFR, but have separate sections and different crops listed ; where there are tolerances for both actives set on the same crop, the levels are the same. Tolerances for residues of alpha

- cypermethrin will be established in another separate section

. Mexico adopts US tolerances, and/or Codex maximum residue limits (MRLs), for its export purposes. Canada has established MRLs for cypermethrin only. There are currently no Canadian MRLs established for residues of alpha

- cypermethrin or zeta

- cypermethrin. There are multiple Codex MRLs for alpha

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

- cypermethrin). However, although the definitions differ formally, they are effectively harmonized since the tolerance

- enforcement methods are not stereospecific, and thus do not distinguish between residues of cypermethrin, zeta

- cypermethrinAlpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 9 of 87 and alpha

- cypermethrin. For enforcement purposes, the same moiety is being regulated. The current petition proposes alpha

- cypermethrin tolerances at the same levels as existing zeta

cypermethrin tolerances in the corresponding commodities. Several of the proposed tolerances are harmonized with the Codex MRLs (those in tree nuts, tomatoes , and cattle meat byproducts). Many of the proposed US use patterns differ from those upon which the Codex MRLs are based ;

t herefore, harmonization of the recommended tolerances (o ther than those mentioned above) with existing Codex MRLs is not feasible (Appendix C)

.

2.2.3 Recommended Tolerances

HED recommends that 40CFR §180.418 be revised by establishing tolerances for the
commodities listed in Table 2.2.3.

HED has determined that the residue of concern for tolerance enforcement and risk assessment for alpha

- 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 listings in 40CFR §180.418

. The same holds true for alpha

cypermethrin. In addition, the existing tolerance expression for cypermethrin and zeta

cypermethrin, as well as the proposed tolerance expre ssion for alpha

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

- cypermethrin in plant and livestock commodities, to be cited in a new par agraph under 40CFR §180.418(a)(3), is as follows:

Tolerances are established for residues of the insecticide, alpha

cypermethrin, ( R )

- cyano(3

- phenoxyphenyl)methyl (1 S ,3 S )

- rel

- 3

- (2,2

- dichloroethenyl)

- 2,2

- dimethylcyclopropane carboxylate, including its

meta bolites 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

- dimethylcyclopro pane carboxylate, in or on the commodity.

The alpha

- cype r methrin tolerances should be listed separately in 40CFR §180.418 (a)(3).

The tolerance expressions for cypermethrin, cited in 40CFR §180.418(a)(1), and zeta

cypermethrin in 40CFR §180.418(a)(2), should be revised when possible, to reflect coverage and compliance statements.

The proposed and recommended tolerances for alpha

- cypermethrin are presented in Table 2.2.3.Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 10 of 87 TABLE 2.2.3 Tolerance Summary for Alpha

- c ypermethrin

.

Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition

Cottonseed 0.50 0.50 Cotton, undelinted seed Root and tuber vegetables, except sugar beet (Group 1) 0.10 0.10 Vegetable, root and tuber, group 1, except sugar beet

Tree nuts (Group 14) 0.05 0.05 Nut, tree, group 14 Edible podded legume vegetable (Subgroup 6A) 0.50 0.50 Vegetable, legume, edible podded, subgroup 6A Succulent shelled pea and bean (Subgroup 6B) 0.10 0.10 Pea and bean, succulent shelled, subgroup 6B

Dried shelled pea and bean, except soybean (Subgroup 6C) 0.05 0.05 Pea and bean, dried shelled, except soybean, subgroup 6C Leafy vegetable, except brassica (Group 4) 10.00 10 Vegetable, leafy, group 4

Head and stem brassica (Subgroup 5A) 2.00 2.0 Brassica, head and stem, subgroup

5A Corn grain 0.05 0.05 Corn, field, grain Pop corn 0.05 0.05 Corn, pop, grain

Sweet corn 0.05 0.05 Corn, sweet, kernel plus cob with
husks removed Soybean, seed 0.05 0.05 Sugar beet roots 0.05 0.05 Beet, sugar, roots Sorghum grain 0.50 0.50 Sorghum, grain, grain Rice grain 1.50 1.5 Rice, grain Cucurbit vegetables (Group 9) 0.20 0.20 Vegetables, cucurbit, group 9 Fruiting vegetables (Group 8) 0.20 0.20 Vegetables, fruiting, group 8

- 10 Sugar beet tops 0.20 0.20 Beet, sugar, tops Wheat grain 0.20 0.20 Wheat, grain Citrus fruit (Group 10) 0.35 0.35 Fruit, citrus, group 10

- 10

Citrus oil 4.00 4.0 Citrus, oil Citrus dried pulp 1.80 1.8 Citrus, dried pulp Alfalfa hay 15.00 15 Alfalfa, hay Cattle, fat None 1.0 Cattle, meat None 0.20 Cattle, meat byproducts None 0.05 Egg None 0.05 Goat, fat None 1.0 Goat, meat None 0.20 Goat, meat byproducts None 0.05 Hog, fat None 0.10 Hog, meat None 0.05 Horse, fat None 1.0
Horse, meat None 0.20 Horse, meat byproducts None 0.05 Milk, fat, reflecting 0.10 ppm in
whole milk None 2.5

Poultry, fat None 0.05 Poultry, meat None 0.05 Sheep, fat None 1.0 Sheep, meat None 0.20Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 11 of 87 TABLE 2.2.3 Tolerance Summary for Alpha

- c ypermethrin

.

Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition Sheep, meat byproducts None 0.05

2.2.4 Revisions to Petitioned

- For Tolerances

No revisions to the tolerance levels in the petition, as proposed by BASF, were necessary. However, all the proposed commodity definitions (except for soybean, seed) were revised to reflect the correct commodity definitions, per the Agency’s current commodit y vocabulary. Additionally, appropriate tolerances for alpha

- cypermethrin in livestock commodities (which were not proposed by BASF) are recommended by HED (reflecting those established for zeta

cypermethrin), based on the potential for residues in livest ock feed items associated with the proposed uses.

2.3 Label Recommendations

None.

3.0 Introduction

3.1 Chemical Identity

TABLE 3.1 Test Compound Nomenclature. Compound chemical

structure

Common name Alpha

- cypermethrin Company experimental name BAS 310 I or AC 900049 Empirical formula C 22 H 19 Cl 2 NO 3 Molecular weight 416.3 g/molAlpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 12 of 87 TABLE 3.1 Test Compound Nomenclature.

IUPAC name A racemic mixture comprised of: ( R )

- α

- cyano

- 3

- phenoxybenzyl (1 S ,3 S )

- 3

- (2,2

- dichlorovinyl)

- 2,2

- dimethylcyclopropanecarboxylate
and ( S )

- α

- c yano

- 3

- phenoxybenzyl (1 R ,3 R )

- 3

- (2,2

- dichlorovinyl)

- 2,2

- dimethylcyclopropanecarboxylate or (synonymously) ( R )

- α

- cyano

- 3

- phenoxybenzyl (1 S )

- cis

- 3

- (2,2

- dichlorovinyl)

- 2,2

- dimethylcyclopropanecarboxylate
and ( S )

- α

- cyano

- 3

- phenoxybenzyl (1 R )

- cis

- 3

- (2,2

- dichlorovinyl)

- 2,2

- dimethylcyclopropanecarboxylate

CAS name ( R )

- cyano(3

- phenoxyphenyl)methyl (1 S ,3 S )

- rel

- 3

- (2,2

- dichloroethenyl)

- 2,2

- dimethylcyclopropanecarboxylate CAS registry number 67375

- 30

- 8

End

- use product (EP) BAS 310 40 I EC insecticide (EPA File Symbol 7969

- EOI), 10.9% ai (w/w), 0.83 lb ai/gal.

3.2 Physical/Chemical Characteristics

Alpha

- cypermethrin has a very low water solubility, and relatively high octanol/water partition coefficient (log K OW = 5.5). These values account for the low surface and groundwater concentrations determined by EFED’s drinking water models. The chemical has low vapor pressure (2.55 x 10 - 9 mm Hg at 25oC), which decreases its potential to volatilize

. See Appendix B for a listing of the physical and chemica l properties of alpha

- cypermethrin.

3.3 Pesticide Use Pattern

Alpha

- cypermethrin is proposed for control of a variety of pests on agricultural crops before, during, or after planting. Alpha

- cypermethrin is formulated as a 10.9 % liquid (0.83 lbs ai/gal ). Broadcast applications are to be made by aerial, ground and chemigation methods. In addition, the proposed product is to be applied through sprinkler irrigation systems, including center pivot, lateral move, end tow, side (wheel) roll, traveler, big g un, solid set, or hand move irrigation
systems.

C ypermethrin is generally 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), which is 2X the proposed maximum seasonal rate for alpha

- cypermethrin (0.075 lb ai/A).

Note: The following statement is included on the proposed label for alpha

- cypermethrin : “DO NOT apply more than the maximum seasonal total for cypermethrin (including alpha

cypermethrin, zeta

- cypermethrin, and any other products containing cypermethrin) product when used alone. DO NOT apply more than the combined maximum seasonal total for cypermethrin (including alpha

- cypermethrin, zeta

- cypermethrin, and any other products containing

cyperme thrin) products.”Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 13 of 87 In accordance with the 2008 cypermethrin RED, agricultural products for cypermethrin and zeta

cypermeth r in are restricted use due to ecotoxicity concerns. The proposed label for alpha

cypermethrin also reflects the restricted use design ation. These products are only available for use by commercial and professional applicators. The proposed label specifies personal protective equipment (PPE) consisting of baseline clothing (i.e., long

- sleeved shirt and long pants, shoes and socks), chem ical

- resistant gloves (e.g., nitrile, butyl, neoprene and/or barrier
lam inate) and protective eye wear. The restricted entry interval (REI) specified on the proposed
label is 12 hours. Non

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

- cypermethrin are for general use. The proposed agricultural use pattern for alpha

- 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.

Table 3.3 .1 Summary of Directions for Use of Alpha

- cypermethrin.

Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.
7969

- EOI] 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

Brassica, citrus fruits, cucurbit vegetables group, fruiting vegetables group, leafy vegetables group, legume vegetables (suc culent or dried except soybeans), root and tuber vegetables (except sugar beet), sugar beets, tree nuts, sorghum ( grain) and millet, soybeans, wheat and

tricale

Foliar; Broadcast Aerial; Ground (Groundboom, Airblast); Chemigation BAS 310 40 I EC

Insecticide, Liquid,
10.9% ai (0.83 lbs ai/gal) 0.025 lbs

ai/ A 3 0.075 lbs ai/

A/season

(11.4 fl ozs product/A/
season) 1

- 50

(depending on crop) Application interval is 4

- 14 days

apart depending on crop. Minimum Spray Volume = 2

- 10 gal/A (aerial); 10

- 100 gal/A (ground) depending on crop.
Leaves of root and tuber vegetables cannot be used for
food or feed. Do not graze or h arvest treated soybean forage, straw or hay
for livestock feed.

Alfalfa, rice, wild rice

Foliar; Broadcast Aerial; Ground (Groundboom ); Chemigation BAS 310 40 I EC

Insecticide, Liquid,
10.9% ai (0.83 lbs ai/gal) 0.025 lbs

ai/ A 3 0.075 lbs ai/

A/season

(11.4 fl ozs product/A/
season) 3

- 14 Application intervals from 3

- 7 days, but may vary depending on application rate and crop. Minimum Spray Volume = 2

- 5 gal/A (aerial); 5

- 10 gal/A (ground) depending on crop.
Ultra

- low Volume (ULV) spray application is prohibited.
Corn (Field), Field Corn Grown for Seed, Popcorn, Sweet Corn

At

- planting; Foliar;
Broadcast ; Aerial; Ground (Groundboom ); Chemigation BAS 310 40 I EC

Insecticide, Liquid,
10.9% ai (0.83 lbs ai/gal) 0.025 lbs

ai/ A 3 0.075 lbs ai/

A/season

(11.4 fl ozs product/A/
season) 3

- 60 Application interval is 3

- 5 days apart depending on crop. Do not apply within 30 days of harvest for grain and 60 for forage. Do not apply within 3 days ofAlpha

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Page 14 of 87 Table 3.3 .1 Summary of Directions for Use of Alpha

- cypermethrin.

Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.
7969

- EOI] 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

harvest of ears or forage or livestock grazing. Minimum Spray Volume = 2 gal/A (aerial); 10

- 20 gal/A (ground).

Cotton

Pre

- and Post

emergence; Foliar;
Broadcast Aerial; Ground (Groundboom ); Chemigation BAS 310 40 I EC

Insecticide, Liquid,
10.9% ai (0.83 lbs ai/gal) 0.025 lbs

ai/ A 3 0.075 lbs ai/

A/season

(11.4 fl ozs product/A/
season) 14 Application interval is 3

- 5 days depending on pests. Do not graze or feed cotton for forage. Minimum Spray Volume = 1 gal/A (aerial); 5 gal/A (ground).

There are currently no registered or proposed residential uses associated with alpha

cypermethrin. However, cypermethrin and zeta

- cypermethrin are registered for use on a variety of indoor and outdoor residential environments including: lawns, gardens, pe ts, and indoor 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 the most conservative
and w orst 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 were obtai ned from the 2006 Revised Occupational and Residential Exposure Assessment for the Reregistration Eligibility Decision Document and the 2011 Pyrethroid Cumulative Risk Assessment. Registration numbers for individual products were not provided in either do cument.

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 (EPA Reg. No. 39039

- 14) NA NA

3.4 Anticipated Exposure Pathways

As a result of the proposed uses of alpha

- cypermethrin, humans may experience dietary exposure to alpha

- cypermethrin residues via their food and drinking water. At this time, there are no proposed or registered uses of alpha

- cypermethrin that are likely to result in exposures in a non

occup ational (residential) setting. However, there are registered residential uses forAlpha

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Page 15 of 87 cypermethrin and zeta

- cypermethrin that will impact the human health aggregate risk assessment for alpha

- cypermethrin. Exposures associated with residential uses include dermal, inhalation, and, in the case of children, incidental oral (i.e., hand

- to

- mouth).

In occu pational 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. These ex posures may occur via dermal and/or inhalation routes. However, a quantitative dermal exposure and risk assessment
was not conducted since there i s no toxicity via the dermal route of exposure.

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, we re considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

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

- established procedures. In line with OPP policy, HED estimates r isks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption p atterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based

on age, s eason of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

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

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

4.0 Hazard Characte rization 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 structu re and neurotoxicological effect. Type I pyrethroids lack an alpha

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

- body tremor and prostration in rats. Th ese Type I pyrethroid

- specific behaviors are collectively described as the T

- syndrome. Type IIAlpha

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Page 16 of 87 pyrethroids contain an alpha

- cyano moiety and produce a syndrome that includes pawing, burrowing, salivation, and coarse tremors leading to choreoathetosis in r ats. 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 to Type II pyrethroids. The adverse outcome pathwa y (AOP) shared by pyrethroids involves the ability to interact with voltage

- gated sodium 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, alpha

- and zeta

- cypermethrin are separate active ingredients with
different end

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

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

- 14%). Alpha

- and zeta

- 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 that the three 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 chemicalsAlpha

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Page 17 of 87 (vehicle, method of administration, peak time); however, the available toxicology studies
for the cypermethrins are relatively consistent across the database and the differences
seen in the database are within expected variability. For risk assessment purposes,

cyper methrin, alpha

- and zeta

- cypermethrin are considered equally toxic and the most
protec tive 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 fo r children 6 years old and older, and for adults. Guideline toxicology studies are available that examine a variety of species, durations, routes, and lifestages and evaluate potential for neurotoxicity, developmental toxicity, reproductive toxicity,
deve lopmental 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 furthe r in Section 4.4. Despite these scientific efforts, HED is confident that the 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 cypermethrin, alpha

- and zeta

- cypermethrin:

- Wolansky Acute Oral Rat Study (cypermethrin)

- WIL Acute Oral Rat Study (cypermethrin)

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

- cypermethrin)

21

- Day I nhalation 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 (cypermethri n 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 (cyp ermethrin, 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 literatu re conducted over several decades describe the pharmacodynamic and pharmacokinetic profile of the pyrethroids in general. This scientific literature has been recently reviewed by several groups ( Soderlund et. al. 2002 ; Shafer

e t. al. 2005 ; Wolansky and Harrill 2008 )

.Alpha

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Page 18 of 87 4.2 Toxicologi cal Profile

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, li mb conditions, ataxia and hypersensitivity. 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 a bnormalities, 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 neurotoxi city studies with cypermethrin and

zeta

- 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 (ra bbit), in which local irritation was observed 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 tox icity study in rabbits with cypermethrin, systemic effects were observed (focal necrosis of the liver, decreased testicular weights and decreased body weight in females). However, the observations in the abraded rabbits were not
used for risk assessment b ecause 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.

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. Maternal 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 dev elopmental 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 hypersensitivity to sound and touch at the s ame 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 effects seen with cypermethrin
included decrea sed 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 reprod uction 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 maternal
animals.Alpha

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Page 19 of 87 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 plus carcinomas combined in female s (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 time

- to

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

- linear approach (i.e., aPAD, a RfD) will adequately account for all chronic toxicity, including ca rcinogenicity, 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 route (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 cypermethrin and alpha

- cypermethrin . The pharmacokinetics for cypermethrins are similar to that 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 molecule. 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 after 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 hydrolysis in the plasma and oxidative metabolism by cytochrome P450 enzymes. Major biotransformation products from single and repea ted dose rat metabolism studies included oxidation of the methyl group on the acid moiety, hydroxylation at
the 4’

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

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Page 20 of 87 4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

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

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

age

- related differences in pyrethroid 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 determine the concentration of the pyrethroids reaching sodium channels. The underlying pharmacokinetics of pyrethroids is an imp ortant determination of their toxicity because the concentration of pyrethroid at the sodium channel relates to the extent of toxicity; greater pyrethroid concentration translates as increased neurotoxicity. Physiological processes that significantly cont ribute to the PK include metabolism, protein binding, and partitioning. Carboxylesterases and cytochrome P450 enzymes are the two major enzyme families responsible for the metabolism of pyrethroids. It is the ontogeny of these enzymes that
accounts for t he 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 toxicit y.

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 using a ‘generic’ or family model structure for this class is scientifically appropriate. In other words, due to the similarities i n the PK profiles of pyrethroids, a single model structure is able to predict the tissue dose based on the pharmacokinetics of every 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 p rofile of pyrethroids as a class. Several studies in this analysis indicate that there are age

- dependent pharmacokinetic differences for the pyrethroids (i.e., there are differences in the ability of adults and juveniles to metabolize pyrethroids). The e nzymes 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 pyrethroids when the internal dose, or the a mount 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 10Alpha

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Page 21 of 87 rats ( Anand et. al. 2006 ) . As a consequence, higher internal doses (i.e., those associated with high doses in experimen tal toxicology studies) overwhelm the clearance mechanisms in juveniles but because adults have greater enzyme activity, they are able to tolerate higher doses prior to the onset of toxicity. As a matter of perspective, the anticipated exposures from typi cal 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
b rains 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 toxici ty. 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 background 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 Pha rmacodynamics

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 disruption of sodium channels by pyrethroids as an early key event ( Lund and Narahashi 1982 ; Sal gado et. al. 1989 ; Song and
Narahashi 1996 ; Tabarean and Narahashi 1998 ; Soderlund et. al. 2002 (review) ) With respect to altered neuronal excitability, Type I pyrethroids cause slight prolongations of the sodium current tails (e.g. ~20 ms), often resulting in long trains of action potentials. In contrast, Type II pyrethroids significantly pr olong 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 pyr ethroids, 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 dur ing 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 cyp ermethrin to interact with VGSC in intact mammalian neurons. An additional study by Cao et. al. ( 2011b ) 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.Alpha

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Page 22 of 87 Figure 4.3 Resting modification of rat Nav1.8 sodium channels by cypermethrin expressed in Xenopus oocytes. Channel current 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 exc itability 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. Therefore, the Agency is focusing its efforts in hazard ch aracterization 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,
salivat ion, tremors and convulsions ( Soderlu nd 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 ar e not age

- dependent even though there 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 dyn amic
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 information available to the Agency to characterize the PD relationship between pyrethroids and
sodium channels has been derived from in vitro studies using frog oocytes or neuronal cells
cultured in defined media. These in vitro techniques do not provide a direct quantitative measure
of in vivo pyrethroid activity. However, these techniques consistently and qualitatively demonstrate that channel isoforms expressed in juveniles are not more sensitive to pyrethroid perturbation co mpared to isoforms expressed in adults and that, pharmacodynamically, the rat is a conservative model for humans. For example, Meacham et al. ( 2008 ) , compared the sensitivity of an adult isoform and a juvenile isoform expressed in frog oocytes to deltamet hrin. 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 th e rat would be protective of human health. The occurrence and ontogeny of voltage

- gated sodium channels in humans is not wellAlpha

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Page 23 of 87 characterized compared to the rat. However, based on the comparable function and distribution of sodium channels between the spe cies, the rat is an appropriate surrogate for the evaluation of
human PD ( Goldin et. al. 2000 ; Goldin 2002 ) . As a result, the Agency concludes that juvenile rats are not more sensitive than adults with respect to pyrethroid phar macodynamics.

4.3.3 Critical Duration of Exposure

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

1 BMD 1SD is the central estimate of the dose that results in decreased motor activity compared to control animals based upon a 1 standard deviation using Benchmark Dose Analysis. BMDL 1SD is the 95% lower confidence limit of
the central estimate. Data located in Wol ansky (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/AAlpha

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Page 24 of 87 Comparing NOAELs and LOAELs from single dose and repeated dose studies, neurotoxicity does not 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 approach ( See A.3) . Therefore, the Wolansky s tudy is protective of all effects observed in the toxicology database

.

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

Cypermethrin, alpha

- and zeta

- 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, EPA is reducing the FQPA safety factor to 3X based on the increased quantitative susceptibility seen in th e 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 incre ased 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 activity 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 greater dose at the target organ in ju veniles compared to adults. No evidence of increased quantitative or qualitative susceptibility was seen in the pyrethroid scientific literature related to pharmacodynamics (the effect of pyrethroids at the target tissue) both with regard to 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 humans.

In light of the high

- dose literature studies showing juvenile sensitivity to pyrethroids and the
ab sence of the requested data on juvenile sensitivity to pyrethroids, EPA is retaining a 3X additional safety factor as estimated by pharmacokinetic modeling. For several reasons, 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 dietary or residential exposure levels of pyrethroids to juveniles and these lower levels of exposure are not e xpected to overwhelm the ability metabolize pyrethroids as occurred with the high doses used in the literature studies. This conclusion is confirmed by the lack of a finding of increased sensitivity in the majority of the pre

- and post

- natal guideline

stu dies for pyrethroid s , despite the relatively high doses used in those studies. Second, the portions of the uncertainty factors that account for potential pharmacodynamic differences are likely to overstate the risk of inter

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

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Page 25 of 87 and rats. For both the inter

- species and intra

- species uncertainty factors, the pharmacodynamic portions are generally con sidered 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 describe d above is summarized in Re

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

In guideline developmental and reproduction studies with the cypermethrins, t here was no evidence of increased qualitative or quantitative suscept ibility 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 pups 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 i n 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 t oxicology 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

- cypermet hrin, and alpha

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

- specific dermal
and inhalation 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 additional 3X for risk assessments for infants and children < 6 years of age.

4.4.2 Evidence of Neurotoxi city

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

cypermethrin, and alpha

- cypermethrin. Like other pyrethroids, the 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 AnimalAlpha

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Page 26 of 87 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 within 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 weight 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 interpretation 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 ar e very similar to results observed in the reproduction 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 observed 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 t o the cypermethrins, includi ng zeta

- and alpha

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
in cluding 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 i n 76 guideline studies for 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 scient ific 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 S AP 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 following: 1) conducting in vitro studies demonstrating the interaction ofAlpha

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Page 27 of 87 pyrethroids exogenously expressed rat and human VGSCs in Xenopus oocytes; 2) conducting in

vitro studies demonstrating interaction of pyrethroids in rat neuro lemma 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

- eval uation 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 h igh

- 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 wa ter and residential sources, 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 on the proposed use patterns for the cypermethrins, the expected exposure profile will be for dietary, dermal, inhalation and incidental oral exposures.

As previously indicated, the toxicity endpoints for cypermethrin, zeta

- cyper methrin, 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 stud ies 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 throughout 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 quality 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 neurobehavioral 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 using 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 BMD estimates determined from this study. Moreover, each pyrethroid was evaluated by the same scientist thus d ecreasing 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 cypermethri n data from the WIL study w ere not used as part of the POD selection since the Wolansky study was considered more appropriate based on study design.Alpha

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Page 28 of 87 Observations of tremors, gait abnormalities, limb conditions, and hypersensitivity were prominent finding s 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

- respons e 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 conducted 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 performi ng BMD analysis, a 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 s cientific 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 det ermination, 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, E PA 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 haz ard 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 f

or 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 following 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 a

more accurate point of departure than other studies considered for incidental oral endpoint and
dose selection.Alpha

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Page 29 of 87 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 cypermethrin 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 h ave 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 absorpt ion. 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 inhalation 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 rout e (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, HECs for the inhalation NOAEL were calculated for use in MOE calculations, based on the methods and dosimetry equations described in 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

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

- day inhalation study, a RDDR was estimated at 3.1 based on the reported MMAD of 2 .63 μm and geometric standard 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. For the current risk assessment, the use of 24 h ours of e xposure 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
of 1.10 mg/

kg/day for occupational and 1.15 mg/kg/day for residential were also calculated andAlpha

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Page 30 of 87 used for risk assessment. The level of concern for inhalation risk assessment is 30X for adults and children 6 years of age and over, which includes an interspecies factor of 3X and intraspecies factor of 10X.

Based on the expo sure profile, HED does not anticipate long

- term inhalation exposure for adults
or children.

FQPA Factor

The FQPA safety factor was reduced to 1X for women of child bearing age (as well as for all adult populations and children > 6 years). For exposures from birth to <6 years of age, a 3X FQPA safety factor was retained (section 4.4)

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

HED’s level of concern for occupational and residential risks 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 tabl e 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 inhala tion, 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 inhalation 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

- species 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 o ld: 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 cyp ermethrins , short

- term oral and inhalation exposures can be combined for children, since endpoints are based on the same toxicological effects (clinical signs related toAlpha

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Page 31 of 87 neurotoxicity)

.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Cype rmethrin 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 o ne 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 estimation 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 resul t 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 tumor s 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 evidenc e 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 the f ull toxicological profile is presented in Appendix A

.

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Alpha

- c ypermethrin, Cypermethrin, and
Zeta

- c ypermethrin for Use in Dietary and Non

- Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/F

QPA 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.Alpha

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Page 32 of 87 Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Alpha

- c ypermethrin, Cypermethrin, and
Zeta

- c ypermethrin for Use in Dietary and Non

- Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/F

QPA 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 confidence limit). UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies).

UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). 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 Alpha

- c ypermethrin, Cypermethrin, and
Zeta

- 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.

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.Alpha

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Page 33 of 87 Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Alpha

- c ypermethrin, Cypermethrin, and
Zeta

- 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

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 = uncertainty factor. UF A = extrapo lation 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 equivalent 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

W. Drew , D378683, 7 September 2012

Acceptable studies depicting the metabolic fate of alpha

- cypermethrin in target crops, rotational crops, and livestock are available. All studies were conducted in a manner appropriate for the proposed uses. For alpha

- cypermethrin, the target crop studies were conducted with cabbage and wheat; and the livestoc k studies with laying hens and lactating cows. An acceptable rotational crop study in leafy, root, and tuber vegetables, and cereal grains was previously submitted for cypermethrin which supports tolerances for alpha

- cypermethrin.

In the cabbage study, radiolabelled with alpha

- cypermethrin or racemic cypermethrin, residue levels showed very good agreement between the samples treated with alpha

- cypermethrin and cypermethrin. At harvest, the highest radioactive residues were present in the older, outer l eaves of the plants, which would be expected since these leaves would be the most developed, and present the most exposed surfaces, during the treatment period. The lower levels of radioactivity in the heart, stalk and roots most likely reflect the lack o f translocation of pyrethroid insecticides, a fact which has been previously established. The patterns of metabolism in inner leaves, and old and new outer leaves, were similar in each case. Co

- chromatography with known products of cypermethrin metabolis m in other crops suggested that similar products were formed, and that the principal residue at harvest was the parent insecticide which had undergone cis/trans

isomerization. This isomerization is presumably photochemical, and has been shown to occur
with other pyrethroids. Because of their similarity, it was expected that the metabolism of alpha

cypermethrin would be similar to that of cypermethrin, and this was confirmed by the cabbage
metabolism data.

The only major, identified residue from the wheat study with alpha

- cypermethrin (radiolabelled at the benzyl or cyclopropane moieties) was cypermethrin, which occurred almost exclusively as alpha

- cypermethrin. Seven minor metabolites were also identified. The identified metabolitesAlpha

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Page 34 of 87 indicate that, following foliar application to wheat, alpha

- cypermethrin underwent oxidative ring hydroxylation of the phenyl ring, and hydrolysis at the ester linkage. Subsequent oxidative
catabolism occurred. Inter

- conversi on between the cis and trans configurations of the parent
molecule occurred in raw agricultural commodities ( RACs ) (forage, hay and straw) which were exposed to natural sunlight, but not in grain. The results are consistent with findings of photo

isomeriz ation for alpha

- cypermethrin and cypermethrin in cabbage. The metabolic fate of alpha

cy per methrin in wheat is similar to that reported in the cabbage study.

In laying hens, with alpha

- cypermethrin radiolabelled in the cyclopropyl or benzyl ring, parent alpha

- cypermethrin was the major residue in eggs, fat and skin. In liver, numerous components were characterized, but only a few were identified, including parent compound at approximately 15% of the total radioactive residue (TRR). Residues in muscle w ere too low to characterize. In studies with the cyclopropyl label, dichlorovinyl acid (DCVA) was identified in eggs, fat, skin and liver. The identified metabolites indicate that alpha

- cypermethrin underwent oxidative ring hydroxylation at the phenyl ri ng, and hydrolysis of the ester linkage.

In lactating cows, with alpha

- cypermethrin radiolabelled in the benzyl ring, levels of radioactivity were low in milk, most of which was in cream. Muscle, fat and milk samples each contained mainly alpha

- cyperme thrin. Liver and kidney contained a range of components. The liver extract contained at least eight metabolites with a broad range of polarities. The kidney extract contained at least nine metabolites with a broad range of polarities.

An acceptable c onfined rotational study was previously submitted. A limited field rotational crop study was submitted, and is considered acceptable. Residues of cypermethrin 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 neither 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 Degradat ion

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

- cypermethrin and zeta

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

- cypermethrin , which is being used to support the alpha

- cypermethrin risk
assessment as described below

.

Zeta

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

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

- cypermethrin is moderately persistent in the environment and degrades through a combination of biotic andAlpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 35 of 87 abiotic mechanisms. Zeta

- cypermethrin is relatively stable to hydrolysis at acidic and neut ral 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 rat e of photolysis appears to be enhanced in natural waters (which contain photosensitizing agents like 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

- cypermethrin biodegrades relatively slowly in soils, with half

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

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

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

- cypermethrin, which formed 3

- (2,2

- dichloro

- ethenyl)

- 2,2

- dimethylcyclopropanecarboxylic 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 alpha

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

- cypermethrin and cypermethrin. A wide rang e of studies in mice, rats, dogs, sheep, cows and humans has shown that cypermethrin is rapidly 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 ab sorption, 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 alpha

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

- life for elimination of alpha

- cypermethrin from the fat of rats is 17

- 26 days, compared to 18.9 days for cis

cypermeth rin (WHO; 1992).

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 concern in plan t 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 alpha

- cypermethrin have been examined
to determine residue definitions for tolerance

- setting and risk

- assessment purposes. The nature of alpha

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

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 36 of 87 on cypermethrin and zeta

- cypermethrin , but also on the s tudies reflecting the metabolism of alpha

- cypermethrin in cabbage, wheat, lactating cow, and laying hen. The cabbage study was
conducted as a side

- by

- side compar ison of the metabolism of alpha

- cypermethrin and cypermethrin. In addition to these studies , BASF submitted a rationale for using metabolism data from cypermethrin to support the registration of alpha

- cypermethrin.

In previous risk assessments, HED had i ncluded 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 considerations :

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 least90% of the total residue. In those crops where DCVA was found at greater than 10%, the detecte d DCVA levels were below the limit of quantitation (LOQ), or the maximum livestock dietary burden contributions from DCVA for these 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 hum an 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, and the bridging rationale, 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 distinguish between alpha

- cypermethrin, cypermethrin, and zeta

- cypermethrin. These conclusions are
summarized in Table 5.1.4.

Table 5.1.4 Residue Definitions for Alpha

- c ypermethrin

Matrix Risk Assessment Tolerance Expression

Plants Primary Crop Alpha

- cypermethrin Alpha

- cypermethrin

Rotational Crop

-- 1

-- Livestock Ruminant Alpha

- cypermethrin Alpha

- cypermethrin

Poultry Alpha

- cypermethrin Alpha

- cypermethrin Drinking Water Alpha

- cypermethrin Not Applicable

1 Residues of concern in rotational crops are not expected as a result of the proposed use patterns.Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 37 of 87 5.2 Food Residue Profile

The submitted data on the metabolism of alpha

- cypermethrin indicate that residues were generally low, and do not translocate thro ughout the plants. The highest residues were generally found in the foliage or forage portions of plants, with lower residues in the tubers, seeds or grains
of these commodities.

Adequate residue chemistry data have been provided for zeta

- cypermethrin in support of alpha

cypermethrin . Field trials were of adequate number and geographic representation, were generated using adequate analytical methods, and were supported by adequate storage stability data. Adequate studies were submitted to elucidate th e fate of zeta

- cypermethrin in processed commodities. Aside from citrus oil and dried pulp, residues did not concentrate in processed fractions. Confined rotational crop studies with cypermethrin show that the metabolism in rotated crops is similar to th at 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 planted 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.

5.3 Water Residue Profile

I. Maher, D378901/D385246, 22 February 2011

As stated previously, in 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), which is 2X the
maximum proposed seasonal rate for alpha

- cypermethrin (0.075 lb a i/A). As a class of chemicals, the pyrethroids have low 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.

The water solubility of alpha

- cypermethrin (technical active ingredient, 98.0%), at 20°C in 0.01M buffers (at pH values of approximately 4 to 9), ranges from 4.59 to 7.87 μg/L. In distilled
water alone

, the solubility is slightly less (2.06 μg/L). The solubi lity is not strongly dependent on pH values within the range of 4 to 9. It is likely that differing ionic strengths account for the differences between the solubility of alpha

- cypermethrin in pure water, and the solubility in the
buffer solutions.

T he Environmental Fate and Effects Division (EFED) provided 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 allAlpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 38 of 87 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 Scre ening Tool (FIRST) Model and the ground water estimates are from the Screening Concentration In GROund Water (SCI

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

.

No monitoring data are currently available to further characterize potential drinking water exposure. In the dietary risk assessment conducted to support the proposed uses and label changes, HED incorporated th e surface water EDWCs directly into the dietary model, 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 0.66 ppb
was used.

The u se 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 zeta

- cypermethrin are being reviewe d under separate petitions (P etition Nos. 0 E7804 and 0 E7717).

5.4.1 Description of Residue Data Used in Dietary Assess ment

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, resi due 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 calculated. Because theAlpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 39 of 87 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 to gether 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 account revised toxicological endpoints, requiring a refined acute dietary exposure assessment 2) adding the new proposed uses of ze ta

- cypermethrin, and 3) incorporation of updated anticipated residue levels and percent crop treated estimates where appropriate. Note that no new residue data were needed to support alpha

- cypermethrin, since the proposed tolerances are being bridged from existing uses.

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

- cypermethrin, 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 which 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 we re 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 in the acute assessment.

Percent crop treated estimates and monitoring data were not available for two of the risk drivers for children less than 6 years of age, oats and milk. As a result, 100% CT was used for these commodities. If usage estimates were available and had been used, including the use of heavy cream monitoring data in place of anticipated residues for milk, the risk estimates for these population subgroups would have been lower. 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
overestimate exposures to the general U.S. population and all population su bgroups.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The following maximum percent crop treated estimates (BEAD 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%; cherries: 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 wate rmelon: 10%.

The following average percent crop treated estimates were used to calculate average dietary

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

-Alpha

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Page 40 of 87 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%.

Based on personal electronic communication with OPP BEAD (David Brassard

, 4/11/2012) the

zeta

- cypermethrin % CT data can be used as a surrogate for future % CT of alpha

- cypermethrin

.

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). 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. This was a partially refined (probabilistic assessment), with PDP monitoring data and
field trial data residue distributions used for some commoditi es. 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, although 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 14Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 41 of 87 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 0.000575

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed or registered residential uses associated with alph a

- 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 inhalation rates. The se revis ed residential

exposures have been incorporated into the human health aggregate risk assessment for alpha

cypermethrin , which must consider all potential exposures to the cypermethrins

. HED has
determined that short

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

6.1 Registered Cypermethrin Residential Handler Exposure/Risk Estimates

Cypermethrin and zeta

- cypermethrin are registered for use on a variety of indo or 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/residenti al 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, HED identified the residential scenarios with the highest exposure estimates, and used these to quantitativel y evaluate residential exposure and risk.
These scenarios were identified from the Revised Occupational and Residential Exposure Assessment for the Reregistered Eligibility Decision Document (RED), the 2011 Pyrethroid Cumulative Risk Assessment (PCRA, D39 4576) and various registered labels . The risk estimates
associated with the identified worst

- case exposure scenarios are protective for all other
residential handler scenarios. The PC RA provided exposure scenarios for cypermethrin as the representative act ive ingredient. The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 42 of 87 Mixer/loader/applicator using hose

- end sprayer on turf Mixer/loader/applicator using backpack on turf and gardens

Mixer/l oader/applicator using manually pressurized handwand for indoor surfaces Application via aerosol can for indoor surfaces and space

Registered Residential Handler Non

- Cancer Exposure and Risk Estimates

Since a dermal endpoint was not selected, only a quan titative 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 signific antly less than 24 hours, the inhalation exposure estimates are sufficiently protective of all scenarios. Table 6 .1 provides estimates of residential handler
inhalation exposure and risk resulting from use o f cypermethrin on turf, gardens, and indoor

su rface space. Although there is potential inhalation exposure resulting from the application of dog tags and spot

- on products for pets, inhalation exposure is considered negligible for these

scen a rios and therefore a quantitative assessment was not perform ed for these uses

. All inhalation risk estimates resulted in MOEs 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.

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 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. Post

- application inhalationAlpha

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Page 43 of 87 exposure resulting from activities on or around previously treated turf is 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 quantitative 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., dog 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 made 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 for children,

Incidental oral (hand

- to

- mouth and object

- to

- mouth) exposure from indoor foggers for children, Incidental oral (hand

- to

- m outh 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 Estimates 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 acr oss different routes of exposure are the same. Although, in the 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 sinc e post

- application inhalation

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

- application risk assessment associated with the indoor crack and crevice use.
The incidental oral scenarios from indo or 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 Exposure and Risk Estimates There is potential for residential post

- application incidental oral risk estimates resulting from use of cypermethrin 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. All individual and combined post

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

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 44 of 87 Table 6.2. Residential Post

- application Exposure and Risk Estimates for Cypermethrin and Zeta Cypermethrin.

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 3.3

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 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 likel y that they can occur simultaneously based on the use

- pattern and the behavior associated 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 exposure 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 product 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 gardens within the same treatment period. Similarly, in the case of indoor treatment of pest s , it ’ s not likely that a homeowner would use two different methods of application (i.e.

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

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 45 of 87 6.4 Residen tial 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 i ndividual assessment. Therefore, HED selected only the 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).

The recommended residential exp osure for use in the adult aggregate assessment reflects
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
assessment 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 indicated, indoor and outdoor exposure estimates are not combined as they are not expected 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 estimated 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 expos ures and risk estimates recommended for the aggregate assessment is provided in Table 6. 4

.

Table 6

. 4 . Recommendations for the Residential Exposures and Risk Estimates for the Cypermethrin Aggregate
Assessment.

Lifestage Handler

Exposure (mg/kg/day) a Re sidential

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 CypermethrinAlpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 46 of 87 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 aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for alpha

cypermethrin. The Agency has been working wi th the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp 00001/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. pesticide registrants, and is 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 a nd 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 quantitati ve 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 represent ative 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 children. 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 alph a

- 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 alpha

- cypermethrin at this time primarily because of the low acute inhalation toxicity (Toxicity Category III), low vapor pressure ( 2.55 x 10 - 9 mm Hg (25 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 inp ut on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meeting s/2009/120109meeting.html ). The Agency 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, theAlpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 47 of 87 Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for alpha

- 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 hazard (e.g., a NOAEL 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 existing registered use for cypermethrin and zeta

- cypermethrin on lawns, gardens, pets, and indoor surfaces and spaces. Therefore, the short

- term aggregate exposure and risk assessment for the cypermethrins includes
d ietary (food and water) exposures anticipated 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 acut e aggregate assessment, as one day residential exposur es are not routinely assessed. Please refer to Section 5.4.3 for a detailed discussion of the acute dietary risk assessment.

7. 2 Short

- Term Aggregate Risk

For assessing short

- term aggregate risk, the average dietary exposure estimate wa s 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) risks 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 ); theref ore, the respective risk estimates are combined using the aggregate risk index ( ARI ) approach. When this approach is used, HED risks are not of concern provided the calculated ARI is greater than 1. All ARIs are greater than 1, and therefore the risk est imates 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 exposure scenario was hand

- to

- mouth exposure f ollowing use of an
indoor f ogger. The results of these calculations are presented in Table 7.2

.

Table 7.2 Short

- Term Aggregate Risk Calculations 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 56Alpha

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Page 48 of 87 Table 7.2 Short

- Term Aggregate Risk Calculations 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

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)/(chronic 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 Chronic Dietary Exposure = children 1

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

3 MOE oral = [(7.16mg/kg

- day)/(hand

- to

- mou th

- 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 Risk

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 EPA’s efforts to evaluate the risk of exposure to this class of chemicals, refer to http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids

- pyrethrins.html

.

The cypermethrins are included in the common assessment group of the pyrethroid/pyrethrin
cumulative risk assessment. However, t he proposed new uses of alpha

- cypermethrin will not impact the cumulative assessment because: 1) the alpha

- cypermethrin application rates are lower
than the zeta

- cypermethr in rates and are expected to result in lower residue levels; and 2) zeta

cypermethrin has already been registered for use on the crops proposed in the current alpha

cypermethrin petition and those uses were incorporated into the cumulative assessment.Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 49 of 87 Add itionally, no new residential uses are proposed, so the residential cumulative assessment will not be impacted.

9.0 Occupational Exposure/Risk Characterization

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 is expected from the proposed uses; however, alpha

- cypermethrin does not increase 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,

• Mixing/Loading Liquids for Aeria l Application,

• Mixing/Loading Liquids for Chemigation,

• Mixing/Loading Liquids for Airblast Application,

• Applying Sprays with Groundboom Equipment,

• Applying Sprays with Aerial Equipment,

• Applying Sprays with Airblast Equipment, and

• Flagging for Aerial Applications.

No handler exposures are expected from applying sprays via chemigation systems.

Occupational Handler Exposure Data and Assumptions

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

Application Rate : The maximum single application rate on the proposed labels was used to assess all handler exposure scenarios. The maximum single application r ate for all proposed uses is 0.025 lb ai/A. The maximum application rate per acre per year is 0.075 lb ai/A/yr. The number of applications per year at the maximum single application rate range s from 1

- 3

, depending on the use.

Unit Exposures:
It is HED policy to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultu ral Handler Exposure Task Force (AHETF) database. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf), which,Alpha

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Page 50 of 87 along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

data.html

.

Area Treated or Amount Handled: Based on HED’s Exposure Science Advisory Council Policy Number 9.1, the following assumptions were used for acres treated or amount handled per day:

• 80

- 200 acres/day for groundboom application,
• 350

- 1,200 acres/day for aerial application, • 350 acres/day for chemigation, • 40 acres/day for airblast application, and
• 350 acres/day for flagging during application.

Occupational Handler Non

- Cancer Exposure and Risk Estimates Table 9.1 presents the estimated short

- and intermediate

- term inhalation risks 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 aerial applications. The MOEs shown in the table are all higher than HED’s level of concern of an MOE of 30, with the lowest MOE of 14,000 identified
for a mixer/loader preparing s prays for aerial application to high acreage crops

.Alpha

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Page 51 of 87 Table 9.1. Short

- and Intermediate

- Term Occupational Exposure and Risk Estimates for Alpha

- 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

(Assumes no Respirator is Used) Dose (mg/kg/day) d MOE e

Mixer/Loader

Liquids for
Groundboom Applications
(AHETF) B rassica, cucurbit

vegetables, fruiting vegetables, leafy vegetables, legume vegetables (succulent or dried except soybeans), root and tuber vegetables (except sugar beet), sugar beets, sorghum (grain) and millet 0.000219 0.025 80 0.0000054 200,000

soybeans, wheat, tricale,

cotton, corn 0.000219 0.025 200 0.0000135 81,000

Liquids for Aerial Application
(AHETF) B rassica, cucurbit

vegetables, fruiting vegetables, leafy vegetables, legume vegetables (succulent or dried except soybeans), root and tuber vegetables (except sugar beet), sugar beets, sorghum (grain) and millet, citrus,

tree nuts 0.000219 0.025 350 0.0000236 47,000

soybeans, wheat, tricale,

cotton, corn 0.000219 0.025 1,200 0.000081 14,000

Liquids for Chemigation
(AHETF) All crops

0.000219 0.025 350 0.0000236 47,000Alpha

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Page 52 of 87 Table 9.1. Short

- and Intermediate

- Term Occupational Exposure and Risk Estimates for Alpha

- 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

(Assumes no Respirator is Used) Dose (mg/kg/day) d MOE e

Liquids for Airblast
(AHETF) citrus, tree nuts 0.000219 0.025 40 0.0000027 410,000

Applicator

Sprays for Groundboom Applications
(AHETF) B rassica, cucurbit

vegetables, fruiting vegetables, leafy vegetables, legume vegetables (succulent or dried except soybeans), root and tuber vegetables (except sugar beet), sugar beets, sorghum (grain) and millet 0.00034 0.025 80 0.0000085 130,000

soybeans, wheat, tricale,

cotton, corn 0.00034 0.025 200 0.0000212 52,000

Sprays for Aerial Application
(AHETF) B rassica, cucurbit

vegetables, fruiting vegetables, leafy vegetables, legume vegetables (succulent or dried except soybeans), root and tuber vegetables (except sugar beet), sugar beets, sorghum (grain) and millet, citrus,

tree nuts 0.000068 0.025 350 0.0000074 150,000

soybeans, wheat, tricale,

cotton, corn 0.000068 0.025 1,200 0.0000255 43,000

Sprays for Airblast citrus, tree nuts 0.00471 0.025 40 0.0000588 19,000Alpha

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Page 53 of 87 Table 9.1. Short

- and Intermediate

- Term Occupational Exposure and Risk Estimates for Alpha

- 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

(Assumes no Respirator is Used) Dose (mg/kg/day) d MOE e

Application
(AHETF)

Flagger

Flagging for Aerial Applications
(PHED) All Low Acreage Crops

0.00035 0.025 350 0.000038 29,000

a. Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (OPHED; March, 2012). Level of mitigation is b aseline, i.e., no respirator; for aerial applicators, a closed cockpit was assumed, i.e.

, Eng. Controls).
b. Based on proposed label (EPA Reg. No. #7969

- EOI ).

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).Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 54 of 87 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 alpha

- cypermethrin at this time primarily because of the low

acu te inhalation toxicity (Toxicity Category III), low vapor pressure ( 2.55 x 10 - 9 mm Hg at
25 *C), and the low proposed use rate (0.025 lb ai/A). 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 pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to v olatilization 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 Agency is in the process of evaluating the SAP report as well as available post

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

- applica tion inhalation exposure assessment for alpha

- cypermethrin.

Although a quantitative occupational post

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

- application 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 on 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 expected for workers who re

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

- application exposure assessment was not performed. HED does not anticipate post

- appli cation dermal risks after exposure to alpha

- cypermethrin.

Restricted Entry Interval (REI)

The REI specified on the proposed label is based on the acute toxicity of alpha

- cypermethrin technical material which is classified as Category III for acute derma l and eye irritation, and Category IV for skin irritation. Based on the acute toxicity profile of alpha

- cypermethrin, the

12

- hour REI appearing on the proposed label is appropriate to protect agricultural workers from
post

- application exposures to alpha

- c ypermethrin.Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 55 of 87 10.0 References

OPP Memoranda

M. Collantes, 9 / 4/ 2012, D403601 , Alpha

- Cypermethrin. Occupational and Residential Exposure
and Risk Assessment to Support the Registration of the New Active Ingredient on a Variety of Food Crops.

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

- Cypermethrin . Petition to Establish 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

- Cyper methrin Uses on Various Raw and Processed Agricultural Commodities

.

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

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- 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."
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assessment." Toxicology 171 (1): 3

- 59. Song, J. H. and T. Narahas hi (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

- Se nsitive and
Tetrodotoxin

- Resistant Sodium Channels by the Type II Pyrethroid Deltamethrin." J Pharmacol Exp Ther 284 (3): 958

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

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

- 89.

Tornero

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

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

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

- 00/001.". USEPA (2007). "Meeting Minutes: FIFRA SAP Meeting on Assessing Approaches for theAlpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 57 of 87 Development of PBPK Models of Pyrethroid Pesticides. Document ID: EPA

- HQ

- OPP

2007

- 0388

- 0049. www. regulations.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 S afety Factor 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.Alpha

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Page 58 of 87 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

yesAlpha

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Page 59 of 87 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 IIIAlpha

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Page 60 of 87 870.2600 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 Subchron ic, 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, gaitAlpha

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Page 61 of 87 Table A.2.b Subchron ic, 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 a ny 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 onAlpha

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Page 62 of 87 Table A.2.b Subchron ic, 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

rabbits 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/d ay (highest dose tested)

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.

870.3800 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 a nimals (some 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/dayAlpha

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Page 63 of 87 Table A.2.b Subchron ic, 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

- cyperm ethrin MRID 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 carcinogenicityAlpha

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Page 64 of 87 Table A.2.b Subchron ic, 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 did 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 mammalian
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

a ddition to decreased motor activity 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 activity 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 mobileAlpha

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Page 65 of 87 Table A.2.b Subchron ic, 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 Acu te 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 hasAlpha

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Page 66 of 87 Table A.2.b Subchron ic, 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.Alpha

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Page 67 of 87 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 decreased motor

a ctivity 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)Alpha

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Page 68 of 87 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/kgAlpha

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Page 69 of 87 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 cypermethrin, 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/d ay). 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 th e 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 (Cypermeth rin)

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 calculated 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 (HECs) were calculated for the inhalation NOAEL using the methods and dosimetry equations described in EPA’s RfC gui dance (1994). The HECs were used to calculate human equivalent doses (HED) that were used in inhalation risk assessments (see A.4 ). The dose 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/kgAlpha

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Page 70 of 87 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 appropriate to use for HEC calculation (table below). The “RDDR.exe” software program was used to obtain th e 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 CypermethrinAlpha

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Page 71 of 87 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:Alpha

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Page 72 of 87 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.Alpha

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Page 73 of 87 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 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

exposur e 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 differences 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 incorporat es 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 der ivation 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 da ily 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 inha lation 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 aerodyna mic 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
inhala tion 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 EPA document “Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry.”Alpha

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Page 74 of 87 Appendix B . Physical/Chemical Properties

Table B.1 Physicochemical Properties of Technical Grade (95.4

- 99.0%) Alpha

- c ypermethrin.

Parameter Value Reference Melting point/range 81.4

- 83.7 C FAO/WHO Evaluation Report
454/2005 pH Not available. Density 1.33 g/cm 3 47 th Joint FAO/WHO Expert
Committee on Food Additives (JECFA 47) 1997 Water solubility 2.06 μg/L (20°C) * Solvent solubility (21°C) Solvent
Acetone
Dichloromethane Ethyl acetate

n

- Hexane
Methanol
Toluene

2

- Propanol Solubility (g/L)

Miscible
Miscible
584
6.5
21.3
596
9.6 Vapor pressure 2.55 x 10 - 9 mm Hg (25 C) Dissociation constant, pK

a Not available. Octanol/water partition coefficient, Log(K OW ) 5.5 FAO/WHO Evaluation Report
454/2005 UV/visible absorption spectrum Not available.

* The water solubility of alpha

- cypermethrin (98.0%), at 20°C in 0.01M buffers at pH values of approximately 4 to 9, ranges from 4.59 to 7.87 μg/L, as measured by the OECD and EEC microcolumn techniques. In distilled water
alone

, the solubility is less (2.06 μg/L). The solubility is not strongly dependent on pH values within the range of 4 to 9. It is likely that ionic strength differences account for differences in solubility between values in pure water and
in the buffer solutions.Alpha

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Page 75 of 87 Appendix C. International Harm onization

TABLE C.1 International Harmonization of Recommended Tolerances for Alpha

- cypermethrin.

Correct Commodity Definition Recommended
Tolerance (ppm) Corresponding Codex MRL (mg/kg) US Use Rate (lb ai/A) Codex Use

Rate (lb ai/A) 1

Cotton, undelinted seed 0.50 * 0.075 * Vegetable, root and tuber, group 1, except sugar beet 0.10 0.01 0.075 0.009

- 0.050 Nut, tree, group 14 0.05 0.05 2 0.075 No data 3
Vegetable, legume, edible podded, subgroup 6A 0.50 * 0.075 * Pea and bean, succulent shelled, subgroup 6B 0.10 * 0.075 * Pea and bean, dried shelled, except soybean, subgroup 6C 0.05 * 0.075 * Vegetable, leafy, group 4 10 0.7 0.075 0.008

- 0.050 Brassica, head and stem, subgroup 5A 2.0 1 0.075 0.009

- 0.050 Corn, field, grain 0.05 0.3 (cereal grain 4 ) 0.075 0.018

- 0.050 Corn, pop, grain 0.05 0.3 (cereal grain 4 ) 0.075 0.018

- 0.050 Corn, sweet, kernel plus cob with husks removed (K+CWHR) 0.05 0.05 0.075 0.050 Soybean, seed 0.05 * 0.075 * Beet, sugar, roots 0.05 0.1 0.075 0.009

- 0.050 Sorghum, grain, grain 0.50 0.3 (cereal grain 4 ) 0.075 No data 3
Rice, grain 1.5 2 0.075 0.050 Vegetables, cucurbit, group 9 0.20 * 0.075 * Vegetables, fruiting, group 8

- 10 0.20 0.2 (tomato), 0.1 (pepper), 0.03(eggplant) 0.075 0.010

- 0.050

Beet, sugar, tops 0.20 * 0.075 * Wheat, grain 0.20 2 5 0.075 0.013

- 0.050 Fruit, citrus, group 10

- 10 0.35 2 0.075 No data 3

Citrus, oil 4.0 * 0.075 * Citrus, dried pulp 1.8 * 0.075 * Alfalfa, hay 15 30 (fodder) 0.075 0.050 Cattle, fat 1.0 * NA 6 NA Cattle, meat 0.20 2 (fat) NA NA Cattle, meat byproducts 0.05 0.05 NA NA Egg 0.05 0.01 NA NA Goat, fat 1.0 * NA NA Goat, meat 0.20 2 (fat) NA NA Goat, meat byproducts 0.05 0.05 NA NAAlpha

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Page 76 of 87 TABLE C.1 International Harmonization of Recommended Tolerances for Alpha

- cypermethrin.

Correct Commodity Definition Recommended
Tolerance (ppm) Corresponding Codex MRL (mg/kg) US Use Rate (lb ai/A) Codex Use

Rate (lb ai/A) 1
Hog, fat 0.10 * NA NA Hog, meat 0.05 2 (fat) NA NA Horse, fat 1.0 * NA NA
Horse, meat 0.20 2 (fat) NA NA Horse, meat byproducts 0.05 0.05 NA NA Milk, fat, reflecting 0.10 ppm in whole milk 2.5 0.5 NA NA Poultry, fat 0.05 0.1 2 NA NA Poultry, meat 0.05 0.1 (fat) NA NA Sheep, fat 1.0 * NA NA Sheep, meat 0.20 2 (fat) NA NA Sheep, meat byproducts 0.05 0.05 NA NA

* No Codex MRL established.
Bold type indicates that the US tolerance and the Codex MRL are harmonized. 1. Some of the field trials were conducted with cypermethrin and/or zeta

- cypermethrin. 2. Proposed MRL is at Step 3 (has not been finalized). 3. No field trial use pattern data were available for tree nuts, sorghum, or citrus fruits. 4. Except for barley, oats, rice, rye and wheat.
5. Post

- harvest treatment. 6. NA = Not Applicable. US tolerances in livestock commodities are based on MRBDs; Codex MRLs reflect direct applications in addition to dietary sour ces.Alpha

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Page 77 of 87 Appendix D. Review of Human Research

This risk assessment relies in part on data from studies in which adul t human subjects were intentionally exposed to a pesticide or other chemical. These data, 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 subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies that review may have in cluded review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at: http://www.epa.gov/pesticides/science/handler

- ex posure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.

Appendix E . Executive Summaries for Alpha

- cypermethrin studies

90

- Day Oral Toxicity [feeding]

- [rat] ; OPPTS 870.3100 [§82

- 1a]; OECD 408.

EXECUTIVE SUMMARY : In a subchronic oral toxicity study (MRID 47944068), WL 85871, 98.2% a.i.; batch number OCD/7, was administered in the diet to Wistar rats. In addition to 40/sex in controls, 20/sex/ dose at doses of 0, 20, 60, 180, or 540 ppm (approximately equivalent to 0/0, 1.01/1.2, 1.74/3.8, 9.3/11.3, or 29.6/35 mg/kg/day) for males/females respectively were dosed for 13 weeks (values calculated by reviewer).

Additionally, 25 rats/sex were contro l treated for 2 weeks, and then sacrificed for screening of potential diseases and potential health problems in the main study animals: 3 of 5 animals tested positive for Sendai virus antibodies. The study animals did not exhibit signs or symptoms of a

c urrent disease.

At 540 ppm there were 3 males which displayed a gait problem. Gait abnormalities were observed
on the 3 rd and 4 th week of treatment and persisted throughout the remainder of the study. This abnormal gait sign is considered treatment rela ted, particularly since it did not occur in any other animals on the study. Otherwise, no adverse, treatment related clinical effects were noted. Examinations included hematology, urinalysis, gross or histological pathology. Several statistically signif icant spurious findings including a decrease in gamma and alpha globulins of 3.01% and 11.42% at 60 ppm compared to 3.35% and 12.72% at 540 ppm compared to control values for dosed females were noted. Other changes which are considered spurious are a slig ht increase in serum sodium values and a slight increase in blood urea values in the highest dosed females. There was a statistically significant reduction in alkaline phosphatase values at both 180 and 540 ppm
doses which are not considered as a toxicolo gical significant event. Hematological changes occurred in both male and female animals but only at the 540 ppm dose level. These included increased platelet counts, slightly reduced hemoglobin values, slightly increased lymphocyte counts, and a reduced e osinophil count in males. These findings were not considered adverse.

Statistically significant (p≤0.05) reductions in body weights were seen in males at 60 and 180 ppm; however, decreases were less than 5% with no dose response relationship observed andAlpha

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Page 78 of 87 therefore, not considered treatment

- related. Females receiving 180 ppm in the diet displayed only a slight reduction in mean body weights compared to controls and decreases were not statistically significant.

At 540 ppm, statistically significant reductions (p≤0.01) in body weight were observed in males. Decreases of 13.5% were seen at week 1 and body weights remained lower than controls (8.7%

- 12%) throughout the entire study. Decreased weekly body weight gains were also noted in 540 ppm males dur ing all Weeks except 7, 8, 9 and 13. The largest losses in gains occurred in the first 2 weeks. The first and second weeks show a 49% and 22%, respectively lower gain than controls. In females, statistically significant reductions (p≤0.01) in body weigh t (up to 8%) were also seen at 540 ppm.

Decreased food consumption was noted in the 540 ppm females on weeks 1

- 13 (decr 7.1%), and was significant (p ≤ 0.01) when compared to the control group. Reduced food consumption in
males started in weeks 1

- 6 as ext remely reduced (

- 26.5%) and became less to

- 9.3% at week 6 improved to

- 3.9% at week 12.

Significant increases in organ were noted in males and females when adjusted for terminal body weights. Reported findings at180 ppm and 540 ppm of the weight incre ases in the liver (p≤0.01) in both sexes and possibly the increased kidney weight changes at 540 ppm in both sexes, suggest that they could be related to the animal exposure to the test material. However, the effects of just weight increases alone without other tissue changes to support the effects should
not in themselves be considered adverse.

The LOAEL is 540 ppm (equivalent to approximately 29.6/35 mg/kg/day ), based on reduced body weights, body weight gains (males), decreased food consumption in bo th sexes, and gait changes (males). The NOAEL is 180 ppm (approximately equivalent to 9.3/11.3 mg/kg/day).

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3100; OECD 408) for a subchronic oral toxicity study in the rat. This study was initiated in 1982 and followed the concurrent guideline requirements.

Subchronic Oral Toxicity in Dogs (dietary); OPPTS 870.3150 [§82

- 1b];

EXECUTIVE SUMMARY : In a subchronic oral toxicity study in dogs (MRID 47944069), WL 85871, Alpha

- Cypermethrin.; 95.8% a.i.; Batch Nos.F830047B, Shell Code No. ST 84/0051
was adminis tered daily in a dose volume of 400 grams of diet formulation to four beagle dogs/sex/dose group at doses of 0, 30, 90, and to 6 dogs/sex/dose at 270 ppm for 90 days

At 270 ppm, treatment

- related neurological signs were observed in the males and females. On Day5 of week 5, dosing was halted in a 270 ppm group female and euthanasia was completed for humane reasons. No adverse, treatment

- related effects were observed on food consumption, ophthalmoscopic examinations, hematology, clinical chemistry, urinaly sis, organ weights, or gross pathology in either males or females. The treatment

- related clinical findings observed in these dogs included the following: head nodding, lip licking, abnormal gait, body tremors,Alpha

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Page 79 of 87 agitation, slight ataxia and poor limb co

- ord ination. These signs became stronger and became a 24 hour duration by study end.

There were no histopathological findings reported in the study. No other clinical signs of toxicity were observed.

At 90 ppm, three dogs on 1 day and 1 time presented with neurological signs which included lip licking, excitability, or body tremors. While these are classical signs of pyrethroids, the incidence is low with one finding per dog. No other signs or adverse clinical findings were reported. At 30 ppm, There were no adverse signs or clinical parameters recorded.

From day 2 or 3 of dosing, all the animals receiving 270 ppm WL 85871 displayed clinical signs
within 3

- 6 hours after feeding. These characteristically comprised body tremors together with variable degrees of head nodding, “lip licking”, subduedness, ata xia, or agitation. In week 3 all these dogs also developed a high stepping gait and this observation together with the instances of body tremors, head nodding, lip “licking “and ataxia increased gradually as the study progressed. Initially the signs rarel y persisted overnight to the next working day. However, as the study progressed, the signs gradually persisted until around week 7 all the high dose level animals continually exhibited the described effects to varying degrees.”

The LOAEL is 270 ppm, (6.7 5 mg/kg/day, based 40 ppm = 1 mg/kg) based on significant neurological signs in both sexes. The NOAEL is 90 ppm (2.25 mg/kg/day).

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3150; OECD 409) for a subc hronic oral toxicity study in dogs.

Prenatal Developmental Toxicity Study in Rats (gavage); 870.3700a [§83

- 3a]; OECD 414.

EXECUTIVE SUMMARY : In an oral developmental toxicity study (MRID 47944073 ), alpha

cypermethrin (technical grade, 95.6% a.i., Batch # ST 91/243; analytical laboratory Batch # 02156, drum 1085) in corn oil vehicle was administered via daily oral gavage in a dose volume of 4 mL/kg to 24 time

- mated female Sprague

- Dawley rats/dose group at doses of 0, 3, 9, or 18/15 mg/kg/day from gestatio n days (GD) 6

- 15 inclusive . Due to the severity of clinical signs noted after 2 to 4 doses at 18 mg/kg/day, the dose level was decreased to 15 mg/kg/day from GD
10

- 15. Subsequently, another group of 24 females was added and dosed at 15 mg/kg/day from
GD 6

- 15 inclusive. On GD 20, all dams were euthanized; each dam’s uterus was removed via cesarean section and its contents examined. Fetuses were examined for external, visceral, and
skeletal malformations and variations.

No treatment

- related effects on mo rtality, gross pathology, or cesarean section data were observed in the dams at any dose.

At 18/15 mg/kg/day, i ncreased incidence (# affected/24 vs. 0/24 controls) of the following clinical signs were noted generally from GD 7

- 9: (i) unsteady gait (14) ; (ii) piloerection (11); (iii) limb splay (12); (iv) hypersensitivity to sound (10); (v) excess salivation (7); and (vi)Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 80 of 87 hunched posture (8). Six females exhibited hypersensitivity to touch, and four of these females (nos. 75, 78, 86, and 90) were partic ularly affected and showed intermittent rolling; 3 of these animals (nos. 75, 78, and 86) were later observed to be prostrate. Consequently, the dose level was decreased to 15 mg/kg/day from GD 10

- 15. Treatment

- related effects persisted for the 3
severel y affected females on GD 10 and also for animal # 86 on GD 11 and 12, but all other females in this group recovered after the dose level reduction. Body weight gains were decreased (p<0.001) by 21% compared to controls during the entire dosing period (GD 6

- 15) and by 12% (no statistical analysis) for the overall (GD 0

- 20, calculated by reviewers) study. Also at this dose, body weights were decreased (p<0.05) by 4

- 5% on GD 12 and 20 and maternal food consumption values were decreased (p<0.05) throughout th e dosing period by 7

- 17%.

At 15 mg/kg/day (Group 5), increased incidence of the following clinical signs were noted generally from GD 9

- 15: (i) unsteady gait (11); (ii) piloerection (6); (iii) limb splay (11); (iv) hypersensitivity to sound (11); and (v) hypersensitivity to touch (11). These findings were generally less severe than those observed at 18 mg/kg/day. Mean body weights were increased (p<0.001) compared to controls on GD 0 and 6; however, as these animals were allocated to the study 10 days la ter than the control group animals, body weight gains were not directly comparable. Nevertheless, there was a significant decrease (p<0.001) in body weight gain (decr. 44%) compared to controls during the dosing period (GD 6

- 15). Additionally at this dos e, overall (GD 0

- 20) body weight gain was decreased by 11% (no statistical analysis) and maternal food consumption values were decreased (p<0.01) throughout the dosing period by 10

- 23%. Although significantly decreased body weight gain (20%) was seen at 9 mg/kg/day between GD
9

- 12, it was not considered an adverse effect because no decreases were seen at other intervals, including cumulative gain during the GD 6

- 15 dosing interval. This level may be a threshold NOAEL for weight changes, based on the magnit ude of change seen at 15 and 18 mg/kg/day.

The maternal LOAEL is 15 mg/kg/day based on decreased body weight gain, food consumption, and increased incidence of clinical signs of toxicity. The maternal NOAEL is 9 mg/kg/day.

Mean fetal weight (combined sexes) was decreased by 4% (not significant) in the 18/15 and 5% (p<0.05) in the 15 mg/kg/day groups. These findings were considered to be a consequence of the
observed maternal effects. No other evidence of treatment

- related developmental toxicity was

o bserved at any dose. There were no abortions, premature deliveries, complete litter resorptions, or dead fetuses and no effects of treatment on the numbers of litters, live fetuses, early resorptions, or late resorptions. Similarly, sex ratio and pre

- an d post

- implantation losses of the treated groups were comparable to controls. There were no effects of treatment on development of the fetuses, and there were no treatment

- related effects on ossification of the skeleton.
There were no adverse treatment

- related external, visceral, or skeletal variations or
malformations.

The developmental LOAEL is 15 mg/kg/day based on decreased fetal weights. The developmental NOAEL is 9 mg/kg/day.

This study is classified acceptable/guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rats

.Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 81 of 87 Prenatal Developmental Toxicity Study in Rabbits (gavage); 870.3700a [§83

- 3b];
OECD 414.

EXECUTIVE SUMMARY : In an oral developmental toxicity study (MRID 47944 072 ), alpha

cypermethrin (technical, 95.6% a.i.; Batch # 02156; ST 91/243) in corn oil was administered via daily oral gavage in a dose volume of 2 mL/kg to 16 time

- mated New Zealand White rabbits/dose group at doses of 0, 3, 15 or 30 mg/kg/day from gestat ion days (GD) 7

- 19 inclusive

. On GD 28, all dams were euthanized; each dam’s uterus was removed, weighed and its contents examined via cesarean section. Fetuses were examined for external, visceral, and skeletal
malformations and variations.

Due to the severity of weight loss and low food consumption, two control females (nos. 2 and 8), three females treated at 15 mg/kg/day (nos. 33, 38, and 43), and two females treated at 30 mg/kg/day (nos. 60 and 62) were sacrificed in extremis between GD 15 and 22. T he only abnormalities observed at necropsy were related to dehydration of the gastro

- intestinal contents or body fat. These findings were not considered treatment

- related because they were observed among controls at similar incidence.

In all dose groups, including controls, there was mean body weight loss after the start of dosing (GD 7

- 8), as well as marked reductions in food consumption compared to pre

- treatment during all intervals of the dosing period (GD 7

- 11, 11

- 15, and 15

- 19). It was stated that t his was a marked, although not unexpected, effect of dosing with corn oil as a vehicle. The relative amount of body weight loss was similar in all dose groups. Following the dosing period, food consumption values returned to levels similar to those durin g pre

- dosing. Food consumption at 30 mg/kg/day was decreased by 13

- 15% (not significant) compared to controls from GD 11

- 15
and 15

- 19. A small body weight loss was observed for the overall treatment period (GD 7

- 19) at 30 mg/kg/day (

- 0.03 kg) compared to controls (0.7 kg), although body weight at the end of treatment (GD 19) in this dose group were comparable to controls. These decreases in weight gain and food consumption at 30 mg/kg/day were considered treatment

- related, based on rebound of weight gain postdosing (52% above controls, p<0.01) and toxicity observed in the preliminary dose range

- finding study at doses of 25

- 35 mg/kg/day. No treatment

- related effects were noted at 3 or 15 mg/kg/day. The maternal LOAEL is 30 mg/kg/day, based on slight body weight loss and decreased food consumption during dosing. The maternal NOAEL is 15 mg/kg/day.

At 15 mg/kg/day, one female aborted on the day of scheduled necropsy. One dead fetus was noted in the control and 3 mg/kg/day groups each. There were no prem ature deliveries or complete litter resorptions, and no effects of treatment on the numbers of litters, live fetuses, or resorptions. Similarly, sex ratio and pre

- and post

- implantation losses of the treated groups were unaffected by treatment. There wer e no effects of treatment on development of the fetuses, and
there were no treatment

- related effects on ossification of the skeleton. There were no adverse

treatment

- related external, visceral, or skeletal variations or malformations. The developmental NOAEL is 30 mg/kg/day (HDT). The developmental LOAEL was not observed (>30 mg/kg/day).Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 82 of 87 This study is classified Acceptable/guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414 ) in rabbits . Although marginal body weight and food consumption effects were observed at the high dose of 30 mg/kg/day, selection of the LOAEL is supported by the results of a preliminary dose range

- finding study (Toxicol. Report Ref. No. SLN/3/92; Marc h, 1994).

Dietary carcinogenicity study in mice; OPPTS 870.4200b [§83

- 2b]; OECD 451.

EXECUTIVE SUMMARY : In an oral carcinogenicity study (MRID 47944071), α

cypermethrin (technical grade, 95.4% a.i.; Batch No. 02156) was administered in the diet to CD

1 mice (52/sex/dose) for up to 78 weeks at doses of 0, 30, 100, or 300 ppm (equivalent to 0/0, 3.0/3.5, 10.6/ 11.5, or 35.2/37.7 mg/kg bw/day in males/females). Groups of 20 mice/sex/dose were treated similarly for 52 weeks for interim sacrifice.

No treatment

- related effects were observed on mortality, food consumption, leukocyte differential count, organ weight s, or microscopic pathology.

Body weights were decreased (statistical analysis not performed) compared to controls at Weeks 13, 52, and 78 in the 100 ppm males by 7

- 8%, in the 300 ppm males by 14%, and in the 300 ppm females by 9

- 13%. In the 300 ppm gr oup, terminal weights were decreased (p<0.05) by 16

- 17%. Body weight gains were analyzed statistically at specific time intervals. Decreases (p<0.05) in body weight gains were observed in the 100 ppm males at Weeks 0

- 13, 0

- 52, and 0

- 78 by 13

- 17% (not stat istically significant at Weeks 0

- 78); in the 300 ppm males at Weeks 0

- 13, 0

- 25, 0

- 52, and 0

- 78 by 24

- 30%; and in the 300 ppm females at Weeks 0

- 13, 0

- 25, 0

- 52, and 0

- 78 by

24

- 27%. During the interval of Weeks 1

- 14, food conversion efficiency was decreased in the 100 (3.7%) and 300 (3.2%) ppm males compared to controls (4.6%), as well as in the 300 ppm females (2.2%) compared to controls (2.7%). As food consumption was similar in the treated groups to controls, the effects observed on food conversion effic iency correlated with those observed on body weight gain.

In the 300 ppm males, the incidences of the following findings were increased: thin build, penis mutilation, swollen area, piloerection, ungroomed , pallor of skin, reddening of skin, hunched posture, skin encrustation, skin scab, urine staining, and yellow staining. In the 100 ppm males, the incidences of the following findings were increased: ungroomed, skin encrustration, and urine staining. Th e increase in incidence became clear by Months 2 (ungroomed) and 5 (thin; skin encrustation); however, the incidence was not summarized on a monthly basis for all findings. Increases were noted in the number of males with palpable swellings and total numb er of swellings; mean time of onset was similar to controls. However, microscopic pathology could not determine the etiology of these swellings. These findings were considered general indications of poor health rather than indicative of a particular toxi cological syndrome. These observations were supported by similar observations made during gross pathology. At the interim and terminal sacrifices, gross observations included the following: pale skin, thickened skin, skin encrustation, skin abrasions, a nd thin appearance. As percentage affected, these gross findings were less prevalent at the terminal sacrifice than at the interim sacrifice.Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 83 of 87 The LOAEL in males is 100 ppm (11 mg/kg/day), based on decreased body weight, body weight gains, and food conv ersion efficiency and clinical signs indicative of poor health. The LOAEL in females is 300 ppm (38 mg/kg/day), based on decreased body weight and weight gain. The NOAEL in males is 30 ppm (3 mg/kg/day) and the NOAEL in females is 100 mg/kg/day (12 mg/kg /day).

At the doses tested, there was no treatment

- related increase in tumor incidence when compared to controls. Dosing was considered adequate in both sexes based on decreases in body weight, body weight gain, and food conversion in both sexes and clini cal signs indicative of poor health
in the males.

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.4200b; OECD 451) for a carcinogenicity study in mice.

A cute Neurotoxicity

- Rats OPPTS 870.6200a [§81

- 8 a]; OECD 424

EXECUTIVE SUMMARY : In an acute neurotoxicity study (MRID 47944067 ), WL85871 (alpha

- cypermethrin ; 95.6% a.i., Batch # 02156) as a constant concentration of 0.6% (w/v) in corn oil was administered once via gavage (0.67 to 6.67 mL/kg) to 10 CD rats/sex/gr oup to achieve dose levels of 0, 4, 20, or 40 mg/kg. The animals were fasted overnight prior to dosing.
In an additional stud y, 5 rats/sex/dose were similarly treated at the some dose levels and subsequently used for neuropathological examinations. Neurobehavioral assessment (functional observational battery [FOB] and motor activity testing) was performed on all main study rats at

pre

- dosing and Days 1 (approximately 5 hours post

- dosing), 7, and 14. At the main study termination, 5 rats /sex/group were anesthetized and perfused in situ for neuropathological examination. The tissues from the perfused animals in the control and 40 mg/kg groups from the main and additional studies were subjected to histopathological evaluation of brain and peripheral nervous system tissues. The sciatic n erve was examined microscopically in all dose groups. Positive control data were not provided.

No adverse, compound

- related effects were observed in body weights, body weight gains, motor activity or gross pathology.

At 20 and 40 mg/kg, in the additiona l study, one male each was found dead on the day following dosing, after having shown clinical signs of neurotoxicity. These rats were replaced in order to maintain 5 males in these dose groups. In both the main and additional studies, treatment

- related clinical signs of toxicity (abnormal/splayed gait, prostration, thrashing, vocalization, piloerection, unkempt appearance, soiled/stained body areas, and diarrhea) were most frequently noted in male rats dosed at 20 and 40 mg/kg and usually developed betwe en 3 to 8 hours post

dosing. Similar signs were sometimes noted in the females at these doses, but occurred at much lower frequencies and were not considered adverse. These signs usually resolved within 3 days after dosing. The frequency and time of ons et for these signs were similar in the main and additional study animals. During the FOB evaluations a t 5 hours post

- dosing (main study only), gait abnormalities (laterally deviated limb position, splaying or dragging hind limbs, and altered
fore and hind limb extension) and increased reactivity (posture in home cage, removal from cage,Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 84 of 87 and during handling) were noted in the 20 and 40 mg/kg males, but not in females. Additional findings at 40 mg/kg included decreased righting reflex and altered fur appear ance in the males.

The only histopathological finding which appeared to show any relationship to treatment was very slight to slight nerve fiber degeneration in the sciatic nerve. The changes were observed more frequently in the proximal than the dista l part of the nerve. This finding was noted at all dose levels including controls, but the incidence was significantly increased (p<0.05) in the 20 and 40 mg/kg males in the additional study. This finding is a well established effect of pyrethroids and i s generally regarded to be a secondary consequence of the primary biochemical action of pyrethroids on the axon and is entirely reversible (Aldrich, 1990). Additionally, spontaneous occurrence of axonal degeneration is commonly observed in rats of this ag e and strain. Therefore, this finding is of equivocal toxicological significance.

The LOAEL was 20 mg/kg based on mortality, clinical signs of toxicity, and FOB findings
in males

. The NOAEL is 4 mg/kg.

T his study is classified as acceptable/guideline and does not satisfy the guideline requirement (OPPTS 870.6200a) for an acute neurotoxicity study in rats.

Metabolism in Rats; OPPTS 870.7485 (§85

- 1); OECD 417

EXECUTIVE SUMMARY : In a series of rat oral metabolism studies (MRIDs 47944080, 47944081, and 47944083), Wistar rats were treated with a single gavage dose of [ 14 C

- benzyl] or [ 14 C

- cyclopropyl] cypermethrin (radiochemical purity >99%) at 2 or 200 mg/kg in Mazola corn oil (2 mL/kg dosing volume). The following studies were performed. (1) Metabolism (MRID 47944080) : An experiment was performed in 5 rats/sex receiving 2 mg/kg [ 14 C

- benzyl] cypermethrin that evaluated the excretion and tissue distribution of radioactivity at up to 4 days
post

- dose. Additionally, metabolite isolation from excreta and metabolite identification were performed by TLC separation and comigration with standards. (2) Tissue depletion in females (MRID 47944081) : Tissue distribution was assayed in 8 su bgroups of 3 female rats/time point sacrificed at 8 intervals up to 42 days after the administration of 2 mg/kg [ 14 C

- benzyl] cypermethrin. (3) Blood kinetics and plasma metabolism (MRID 47944083): In a whole blood kinetics experiment, both doses and radi olabeled compounds were evaluated in 6 rats/sex/dose/radiolabel, and blood samples were collected up to 1 day after administration of the low dose or 3 days after administration of the high dose. Radioactive residues were measured in all collected samples . In a plasma metabolite experiment, both doses and radiolabeled compounds were evaluated in 5

- 7 rats/sex/radiolabel, and blood samples were collected up to 9 hours after administration of the low dose or 72 hours after administration of the high dose. T he proportion of radioactivity in the plasma attributable to cypermethrin was measured, as well as the plasma concentrations of cypermethrin. Animals in the [ 14 C

- benzyl] cypermethrin

- treated groups were evaluated for clinical signs after dosing.

At 200 m g/kg, signs of toxicity were observed. These signs ranged from mild (such as slight high rear gait) to death. Treatment with [ 14 C

- benzyl] cypermethrin at 200 mg/kg resulted in
death at 4 hours post

- dose in one male (M4; found dead) and one female (F1; eu thanizedAlpha

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Page 85 of 87 moribund). Other reported findings included subdued or very active behavior, panting, tremor, wide rear gate, ataxia, salivating, tail thrashing, wild thrashing, very slow respiration, and convulsions. No signs of toxicity were reported at 2 mg /kg. Excessive toxicity at 200 mg/kg may have confounded the results of these groups. Considerable animal

- specific variation was reported. The clinical signs were consistent with neurotoxic effects expected from exposure to pyrethroids.

Total recovery was 94

- 95% of the administered dose (AD) in the excretion and tissue distribution groups administered 2 mg/kg [ 14 C

- benzyl] cypermethrin. At least half of the dose was absorbed (53

- 55% AD), and radioactivity was quickly eliminated (>76% AD within 24 hours) . After 4 days, slightly more of the dose was excreted in the urine (50

- 53% AD) than in the feces (38

- 43% AD). Biliary excretion was not evaluated. Radioactive residues in the cage wash, tissues, and the residual carcass accounted for <2% AD each. Ther e were no significant

sex

- related differences in absorption and excretion.

In the 2 mg/kg groups evaluated for blood kinetics, absorption and excretion were rapid;
maximum concentrations were observed in the blood within 3

- 4 hours (≤1.75 μg equiv./mL) and negligible amounts were observed at 16 hours post

- dose. No sex differences were noted in maximum concentrations or times to maximum concentration. The concentrations in the [ 14 C

benzyl] cypermethrin groups were approximately 3

- fold higher than observed in the [ 14 C

- cyclopropyl] cypermethrin groups, but the radiolabel position did not affect the times at
which the maximum concentrations were observed.

In the 200 mg/kg groups evaluated for blood kinetics, maximum concentrations of radioactivity
in the bl ood were as follows: in the [ 14 C

- benzyl] cypermethrin groups (males

– 39.7 μg equiv./mL at 23 hours; females

– 41.9 μg equiv./mL at 16 hours) and in the [ 14 C

- cyclopropyl] cypermethrin groups (males

– 10.3 μg equiv./mL at 24 hours; females

– 6.65 μg equiv./ mL at 8 hours). No significant sex differences were noted in maximum concentrations, but concentrations reached maximum sooner in the plasma of females than in males, regardless of the radiolabel position. The concentrations in the [ 14 C

- benzyl] cypermeth rin groups were higher by approximately 4

- fold in males and 6

- fold in females compared to the [ 14 C

- cyclopropyl] cypermethrin groups, but the radiolabel position did not have an appreciable effect on the times at which the highest concentrations were observ ed. The concentrations were <5 μg equiv./mL in all high dose groups by 48 hours post dose. An increase in dose of 100

- fold led to an increase in
blood of 12

- to 28

- fold, suggesting absorption may have been saturated at the high dose.

Radioactive residue s in the tissues and residual carcass at 96 hours post

- dose accounted for <1% AD each in rats administered 2 mg/kg [ 14 C

- benzyl] cypermethrin . The maximum concentrations of radioactivity (μg equiv./g ) were reported on Day 1 in fat (0.335

- 0.561), skin (0.1 19), liver (0.232), and kidney (0.122). By Day 14 post

- dose, average concentrations of radioactivity were
<0.1 μg equiv./g in fat, 0.012 μg equiv./g in skin, and ≤0.003 μg equiv./g in liver and kidney. Tissue retention occurred only in the adipose tissue , but only negligible amounts were noted in any tissue (including fat) at 42 days after dosing.

Bi

- phasic elimination of the radioactivity occurred in fatty tissues and skin, with an initial rapid depletion from the body followed by a slower clearance. T he half

- lives based on data obtainedAlpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 86 of 87 from Days 1 to 8 were 1.6

- 2.7 days in skin and fat. The half

- lives based on data obtained from Days 14 to 42 were 40 days in skin, 26 days in perovarian fat, 19 days in peri

- renal fat, and 17 days in subcutaneous fat. In contrast, elimination of radioactivity in other tissues was rapid: in the liver and kidney the half

- lives were 2.3 and 2.0 days, respectively, and levels of radioactivity at two weeks’ post

- dosing were below the limit of detection.

A total of 6 compounds were tentatively identified in the excreta (identified using TLC separation with standards for identification: further analytical methods were not employed). There was only one major metabolite that was isolated: 3

- (4

- hydroxypheno xybenzoic acid O

sulfate ester was isolated from the urine (34

- 40% AD). In the feces of the combined sexes, the parent was the predominant compound (22% AD). Metabolism of cypermethrin occurs by ester

cleavage followed by hydroxylation and sulfation of t he 3

- phenoxybenzoic acid portion of the compound. The cyclopropanecarboxylic acid portion of the insecticide is rapidly eliminated as the glucuronide conjugate. Hydroxylation of the intact ester also occurs to a small degree.

The proportion of the rad ioactive residues isolated in the hexane extract of peri

- renal and parovarian fat (as opposed to the acetonitrile phase) increased steadily with time from 28% of the TRR at Day 3 to 48% at Day 22. As cypermethrin partitions almost exclusively into the

ace tonitrile fraction, this suggests that lipophilic metabolites are present in the fat at increasing levels over time. The lipophilic metabolites were not further analyzed in this study.

In the [ 14 C

- benzyl] cypermethrin treated animals, a steady increase with time in the %TRR in the plasma attributable to cypermethrin was observed at both doses; however, no obvious effect on this percentage was noted in animals treated with [ 14 C

- cyclopropyl] cypermethrin. Concentrations of cypermethrin in the plasma were an order of magnitude higher in the [ 14 C

- benzyl] cypermethrin groups compared to the [ 14 C

- cyclopropyl] cypermethrin groups.

These metabolism studies in the rat are classified Acceptable/nonguideline and satisfy the guideline requirement for a Tier 1 meta bolism study [OPPTS 870.7485, OECD 417] in rats when considered together. Although these studies were conducted prior to publication of GLP and current metabolism study guidelines, and some study deficiencies were identified, the data provide sufficien t metabolism data on cypermethrin to characterize its metabolism in the rat. The proposed pathway is similar to the metabolic pathway of other pyrethroids, such as permethrin. Additional metabolism data are not required at this time.

In Vivo Dermal Pen etration Study in Rats; OPPTS 870.7600 [§85

- 2]; OECD 427.

EXECUTIVE SUMMARY : In an in vivo dermal penetration study (MRID 47944084), [ 14 C] alpha

- cypermethrin (BAS 310 I technical; 99.8% radiochemical purity; Batch No. 775

- 0203) was applied to the shaved skin (10 cm 2 ) of male Crl:WI (Han) rats. Actual doses of 1.5 or 333 μg/cm 2 skin were applied to the skin of each rat in volumes of 10 μl/cm 2 skin in a vehicle consisting of the blank formulation BAS 308 4 I or a 1/200 aqueous dilution of the blank
formula tion plus test material, respectively. Four rats/dose/time point were tested using an exposure duration of 6 hours and termination times of 6, 24, or 120 hours post

- application. Urine and feces samples were collected at 6 hr (end of dosing), 24 hr and th en at 24 hour intervals until study termination.Alpha

- Cypermethrin Human Health Risk Assessment DP No. D 376098

Page 87 of 87 Analytical recoveries were 96

- 114% of the administered dose (AD) . The amount absorbed included radioactivity found in the cage wash, blood cells, plasma, urine, feces, and carcass. The
amount absorbed was only 0.12

- 1.13% AD at the high dose, but was 4

- 13.4% AD at the low dose. Approximately 27 to 34

- fold greater absorption (as % AD) was observed in the lower dose groups at the 6 and 24 hour sacrifices compared to the higher dose groups. Absorption at the 120
hour sacrifice was 12

- fold higher in the low dose group, suggesting that absorption mechanisms were saturated at the higher dose. The amount absorbed increased with time at both doses, indicating that further absorption occurs from the skin after was hing. Most of the non

- excreted absorbed dose was found in the carcass at all times evaluated (0.09

- 3.52% AD). In the blood, most of the radioactivity was found in the blood cells rather than in the plasma. The urine was the primary route of excretion (0 .61 and 6.19% of AD at 120 hours for the high and low dose, respectively). The majority of the dose was removed with the first skin wash (83

- 96% AD).

Based on the likely worker exposure time frame, it is considered most appropriate to adopt the
dermal absorption value calculated for the group of animals for which the skin site was washed after 6 hours and terminated 120 hours after application. Because absorption continued to occur throughout the study, the absorbable dose should also be considered in a conservative estimate of absorption. However, only 0.76

- 0.78% AD remained in the skin at the application site and surrounding skin at 120 hours post

- application, indicating absorption was essentially complete at that time. The low dose (1.5 μg/cm 2 ) at 120 hours post

- dosing provided the most conservative
estimate of total absorbed at 13.4% AD.

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 870.7600; OECD none) for a dermal penetration study in rats.