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5.4.2 Percent Crop Treated Used in Dietary Assessment.................................................... 42

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

5.4.4 Chronic Dietary Risk Assessment .............................................................................. 43

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

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

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 44

6.1 Registered Cypermethrin Residential Handler Exposure/Risk Estimates...................... 44

6.2 Cypermethrin Registered Residential Post-application Exposure/Risk Estimates ........ 45

6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios) ......................... 47

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

6.5 Spray Drift...................................................................................................................... 48

6.6 Residential Bystander Post-Application Inhalation Exposure ....................................... 49

7.1 Acute Aggregate Risk .................................................................................................... 50

7.2 Short- Term Aggregate Risk .......................................................................................... 50

7.3 Intermediate-Term/Chronic Aggregate Risk.................................................................. 50

8.0 Cumulative Exposure/Risk Characterization..................................................................... 51

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

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

9.2 Occupational Post-application Exposure/Risk Estimates .............................................. 55

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates.......................... 55

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates.............................. 55

Appendix A. Toxicology ............................................................................................................. 59

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

A.2 Toxicity Profiles................................................................................................................. 60

A.3 Toxicological Doses and Endpoints for Use in Human Risk Assessments....................... 68

A 4. HEC Inhalation Calculations ........................................................................................... 71

Appendix B. Physical/Chemical Properties.................................................................................. 75

Appendix C. International Harmonization................................................................................... 76

Appendix D. Review of Human Research................................................................................... 78
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1.0 Executive Summary

The pyrethroid insecticide zeta-cypermethrin is currently registered to FMC Corporation for use 

on a wide variety of food/feed crops, primarily as repeated broadcast foliar applications. In the 

current petitions, the Interregional Project Number 4 (IR-4) is proposing new uses on tropical 

fruits, barley, oat, buckwheat, rye, pistachio, and artichoke for two formulations of zetacypermethrin. Two agricultural products proposed for use on various crops are Fury®

1.5 EC 

Insecticide and Mustang®1.5 EW Insecticide. In addition, under a separate submission, Y-TEC 

Corp. has requested a new use for zeta-cypermethrin, as ZetaGard LBT Insecticide (File Symbol

39039-EN), for application to poultry litter in chicken broiler and turkey grow-out houses. 

The petitions for registration of these new uses of zeta-cypermethrin relies on zeta-cypermethrin 

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

the pending new active ingredient alpha-cypermethrin. Cypermethrin, zeta-cypermethrin and 

alpha-cypermethrin are isomer mixtures of the same chemical. Cypermethrin consists of a 

mixture of eight isomers (four diastereoisomeric pairs). Zeta-cypermethrin is composed of four 

of the eight isomers of cypermethrin, and also contains one of the isomers in alpha-cypermethrin. 

Alpha-cypermethrin consists of two of the four cis-isomers of cypermethrin. 

Zeta-cypermethrin is a type II synthetic pyrethroid chemical, and is a broad spectrum insecticide, 

effective against a variety of target pests through contact and ingestion. Pyrethroids disrupt the 

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

In developing this human health risk assessment, the Health Effects Division has examined the 

available hazard and exposure information regarding zeta-cypermethrin, as well as information 

for cypermethrin, alpha-cypermethrin, and pyrethroid chemicals as a 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 comparable toxicity profiles. For human health risk assessment purposes, the 

active ingredients are considered equally toxic and the most protective endpoints and points of 

departure (PODs) for each study type have been selected for risk assessment. In addition, this 

aggregate risk assessment considers not only the exposure associated with the proposed new uses 

for zeta-cypermethrin, but also the potential dietary and drinking water contribution and 

residential exposure from existing uses of the cypermethrins.

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 tremors, 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 female mice after chronic exposure. 

Given different levels of uncertainty for various risk assessment scenarios, USEPA is applying 

different FQPA safety factors for the protection of fetuses, infants, and children depending on the 

route of exposure, data gaps and the population exposed. For adults (including women of child-
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bearing age) and children ≥ 6 years of age, USEPA is reducing the Food Quality Protection Act 

(FQPA) safety factor to 1X. There was no evidence of increased qualitative or quantitative 

susceptibility in developmental toxicity studies in the rat and rabbit and in a rat two-generation 

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

did indicate some potential increased sensitivity in the offspring based on body weight changes 

in pups in the absence of treatment-related effects in maternal animals. However, based on the 

weight of the evidence, there is no residual concern for the effects observed in the study. There 

are no residual uncertainties with regard to neurotoxicity or dermal toxicity and there is no 

evidence of immunotoxicity. However, USEPA is retaining a 3X FQPA safety factor for 

children <6 years of age to account for juvenile sensitivity to pyrethroid toxicity observed in 

several literature studies. 

Cypermethrin is classified as a Group C “Possible human carcinogen”, based on an increased 

incidence of lung adenomas and adenomas plus carcinomas combined in females in a mouse 

carcinogenicity study. Based on the weight of evidence, the Agency has determined that 

quantification of risk using a non-linear approach (i.e., acute population adjusted dose (aPAD) or 

acute reference dose (aRfD)) will adequately account for all chronic toxicity, including 

carcinogenicity that could result from exposure to the cypermethrins. While the Agency would 

typically use a chronic Population Adjusted Dose (cPAD) to protect for cancer concerns, use of 

the aPAD is protective because increasing toxicity with increasing duration of exposure is not 

demonstrated for the cypermethrins, and because the exposure assessment associated with the 

acute dietary scenario reflects high-end consumption and residues.

The dose and endpoint for acute dietary risk assessment were selected from the Wolansky et al. 

(2006) acute oral study, in which decreased motor activity was observed. The dose used for risk 

assessment from the Wolansky study was determined using a benchmark dose (BMD) analysis 

conducted in accordance with standard Agency assumptions with respect to the benchmark 

response (BMR). There is no increase in toxicity from repeated exposures to the cypermethrins; 

therefore, the acute dietary exposure assessment is protective for chronic dietary exposures since 

acute exposure levels are higher than chronic exposure levels. Accordingly, a dietary exposure 

assessment for the purpose of assessing chronic dietary risk was not conducted. 

For inhalation risk assessments, an inhalation toxicity study in rats was chosen and human 

equivalent concentrations (HECs) were calculated and used for risk assessment. For inhalation 

risk assessments, the interspecies 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 the cypermethrins are adequately understood 

for the purpose of estimating residues in ground and surface water sources of drinking water that 

could result from the existing and proposed uses of zeta-cypermethrin. For all three 

cypermethrins, HED has concluded the residue of concern for risk assessment and tolerance 

enforcement is the parent compound, cypermethrin, zeta-cypermethrin and alpha-cypermethrin.
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Dietary exposure to zeta-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 estimates resulting from the existing use 

of cypermethrin and zeta-cypermethrin on the crops listed under 40 CFR 180.418, the proposed 

new uses of zeta-cypermethrin, and the pending registration of alpha-cypermethrin on various 

crops. Additional dietary exposure is not expected from the proposed uses of alphacypermethrin for the following reasons: (1) the lower application rate of alpha-cypermethrin 

relative to the other cypermethrins, (2) alpha-cypermethrin tolerances were bridged from 

cypermethrin, and (3) there are label prohibitions that limit the application rate of total 

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

modeling uses health-protective assumptions regarding residues of zeta-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 the cypermethrins is 18% of the aPAD for the U.S. population and 87% of 

the aPAD for all infants and children 1-2 years, the most highly exposed population 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 longerterm exposures. However, in order to assess short-term aggregate risk to cypermethrins, the 

average dietary (food and drinking water) exposure was calculated. The quantification of 

average dietary exposures required the use of average field trial residues, U.S. Department of 

Agriculture (USDA) Pesticide Data Program (PDP) monitoring data, and current tolerances as 

appropriate. The assessment also made use of PCT data where available. Drinking water 

information was incorporated using the mean concentration (1-in-10-year annual mean) for 

surface water generated by the FIRST (FQPA Index Reservoir Screening Tool) model.

In addition to the proposed uses on crops, HED has reviewed the new poultry house use request 

and has determined that the existing livestock tolerances are adequately protective of the 

potential residues from this new use and that this use has no impact on the zeta-cypermethrin 

dietary exposure assessment. ZetaGard LBT Insecticide is formulated as a dust and contains 

two active ingredients: zeta-cypermethrin and piperonyl butoxide. This assessment addresses 

only exposure and risk associated with the proposed end-use products for zeta-cypermethrin 

when used as directed. 

The only non-dietary exposure pathway relevant for adults and children greater than 6 years old 

is via inhalation, and the level of concern (LOC) is 30X, taking into account the 3X interspecies 

and 10X intraspecies factors. For children under 6 years old exposed via the inhalation route, the 

LOC is 100, which includes the 3X interspecies and 10X intraspecies factors, as well as the 3X 

FQPA factor. For children under 6 years old exposed via the incidental oral route, the LOC is 
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300, based on the standard 10X interspecies and 10X intraspecies factors, and the 3X FQPA 

factor. 

Although the incidental oral and inhalation routes of exposure have similar effects, the child 

inhalation and incidental oral routes have different LOCs. Therefore, combined exposure and 

risk from the various routes were evaluated using the aggregate risk index (ARI) approach. ARIs 

≥ 1 are not of concern.

There are no new requested uses for zeta-cypermethrin that involve a residential setting; 

however, residential exposure and risk were estimated for the currently registered residential 

uses of cypermethrin and zeta-cypermethrin in order to complete the aggregate risk assessment. 

The revised assessments included the updated endpoints for risk assessment as well as the most 

recent residential SOPs (2012). For the registered residential uses of the cypermethrins, there is 

a potential for residential handler exposure for adults only, as well as post-application exposure 

for adults and children (1 to < 2 years old) who re-enter treated areas. For the registered 

residential uses, exposure is expected to be short-term in duration. However, due to the 

pyrethroid toxicity profile, only single day risk assessments were conducted for residential 

exposure, which are protective of all durations of exposure. Residential intermediate-term 

exposures are not likely because of the intermittent nature of applications by homeowners. The 

scenarios chosen for the purpose of conducting residential and aggregate assessments were those 

that result in the highest exposures for adults and children, for both indoor and outdoor uses. 

Although 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. 

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 postapplication exposure and risk estimates (MOEs and ARIs) for adults and children were greater 

than their respective LOCs and are not of concern. Adult post-application exposure via the 

inhalation route resulted in an estimated MOE of 1,100,000, while children younger than 6 years 

of age exposed via the inhalation and incidental oral routes had MOEs ranging from 1000 to 

6,400,000, with an ARI of 13 for the combined routes of exposure. 

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

exposures and risks from three major sources: food, drinking water, and residential exposures. 

Therefore, the short-term aggregate exposure and risk assessment for the cypermethrins included

dietary (food and water) exposures anticipated from the registered and proposed uses, and nondietary exposures anticipated from the currently registered residential uses. An ARI approach 

was used to aggregate these exposures due to the different LOCs associated with oral and 

inhalation exposure pathways. No risks of concern were identified in this short-term aggregate 

assessment. An intermediate-term and/or chronic aggregate risk assessment was not conducted 

because the cypermethrins are acutely toxic and do not increase in potency with repeated dosing. 

Because acute toxicity studies can assess the risk for longer term studies, it is assumed that the 

acute and short-term aggregate assessments are protective for intermediate-term and chronic 

aggregate risks anticipated from cypermethrin exposure. 
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HED has also assessed exposure and risk associated with the proposed end-use products when 

used as directed by occupational workers. There is a potential for occupational exposure 

associated with handler activities (i.e., mixing, loading, and applying) as well as with postapplication 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 and poultry house use are expected to be short- term (1 to 30 days) and intermediate-term (1 

to 6 months). Long-term exposures (greater than 6 months) are not anticipated for either the new 

proposed uses or the existing uses. However, as with the residential exposure assessment, due to 

the pyrethroid toxicity profile, only single day risk assessments were conducted for occupational 

exposure, which are protective of all durations of exposure.

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

zeta-cypermethrin. All occupational handler inhalation exposure assessments resulted in MOEs 

greater than 3,500. As no dermal endpoint was identified, a quantitative post-application 

assessment was not performed. Post-application inhalation was not quantitatively assessed; 

however, an inhalation exposure assessment was performed for flaggers and it is considered 

protective of most outdoor agricultural and commercial post-application inhalation exposure 

scenarios. Occupational and residential exposure/risk assessment for the active ingredient 

piperonyl butoxide, which is included in the end-use product (EP) being proposed for use in 

poultry houses, has been addressed in a separate memo (Nieves, I. D402795). 

The cypermethrins were included in a recent cumulative risk assessment for pyrethrins and 

pyrethroids. The proposed new uses of zeta-cypermethrin will not have a significant impact on

cumulative exposure and risk because in the cumulative assessment, residential exposure was the 

greatest contributor to the total exposure. As there are no new residential uses for the 

cypermethrins, the proposed new uses will have no impact on the residential component of the 

cumulative risk estimates. Dietary exposures make a minor contribution to total pyrethroid 

exposure in the 2011 cumulative risk assessment. The dietary exposure assessment performed in 

support of the pyrethroid cumulative was much more highly refined than that performed for this 

single chemical assessment. The dietary exposure assessment for the single chemical included 

conservative assumptions, using field trial data for many commodities, including the proposed 

new uses, with the assumption of 100% crop treated. For the single chemical cypermethrins risk 

assessments, the most sensitive apical endpoint in the cypermethrins database was selected to 

derive the POD. Additionally, the POD selected for the cypermethrins is specific to the three 

actives, whereas the POD selected for the cumulative assessment was based on common 

mechanism of action data that are appropriate for all 20 pyrethroids included in the cumulative 

assessment.

This risk assessment is based, in part, on 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).
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2.0 HED Recommendations

HED is recommending in favor of registration of zeta-cypermethrin on the requested crops and 

establishment of tolerances as summarized in Table 2.2.3.

2.1 Data 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 chromatographic 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 livestock tissues. These methods are not 

stereospecific; thus no distinction is made between residues of cypermethrin (all 8 

stereoisomers), zeta-cypermethrin (enriched in 4 isomers) and alpha-cypermethrin (2 isomers). 

The January 1994 FDA PESTDATA database (PAM Volume I) indicates that residues of 

cypermethrin are completely recovered (>80%) using multi-residue method Sections 302 (Luke), 

303 (Mills, Onley and Gaither) and 304 (Mills fatty food). 

2.2.2 International Harmonization

There are no Canadian MRL’s for the proposed commodities. Mexico adopts US tolerances, 

and/or Codex maximum residue limits (MRLs), for its export purposes. The associated Codex 

MRLs for cypermethrin are listed in Appendix C. There are multiple Codex MRLs for zetacypermethrin, but all are in conjunction with MRLs for total cypermethrin isomers (no MRLs 

have been established solely for zeta-cypermethrin). However, although the definitions differ 

formally, they are effectively harmonized since the tolerance enforcement methods are not 

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

and alpha-cypermethrin. For enforcement purposes, the same moiety is being regulated. The 

recommended tolerances will result in harmonized MRLs between USEPA and Codex for mango 

(at 0.7 ppm) and papaya (at 0.5 ppm). The recommended tolerances for artichoke, barley, 

buckwheat, oats, and rye will not be harmonized with Codex for the following reasons. In the 

case of artichoke, Codex has set a lower MRL of 0.1 ppm based on field trials conducted with 

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

interval (PHI). The HED recommended tolerance for artichoke of 0.6 ppm is supported by the 

submitted residue data, with a higher use rate and shorter PHI. In addition, for grains (barley, 

oats, buckwheat, and rye), the Codex MRLs assume a post-harvest treatment whereas the 

proposed use pattern in the U.S. is for pre-harvest treatment. Given the proposed use pattern on 
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grains, HED recommends the tolerances as summarized below, further noting that the livestock 

feed items of hay and straw are unlikely to be exported. 

2.2.3 Recommended Tolerances

HED recommends that 40CFR §180.418(a)(2) be revised by establishing tolerances for the 

commodities listed in Table 2.2.3. Unless otherwise noted in Table 2.2.3, HED used OECD 

calculation procedures to develop these recommended tolerances. 

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

for zeta-cypermethrin is the parent compound. The tolerance enforcement methods for plant and 

animal commodities do not distinguish between cypermethrin and zeta-cypermethrin, even 

though they have separate tolerance listings in 40CFR §180.418. In addition, the existing 

tolerance expression for zeta-cypermethrin needs to be revised to reflect both coverage and 

compliance statements, in accordance with current policy. Therefore, the tolerance expression 

for zeta-cypermethrin in plant and livestock commodities, needs to be revised in 40CFR 

§180.418(a)(2), as follows:

Tolerances are established for residues of the insecticide, zetacypermethrin, (S-cyano(3-phenoxyphenyl) methyl (±))(cis-trans 3-(2,2-

dichloroethenyl)-2,2 dimethylcyclopropanecarboxylate), including its 

metabolites and degradates, in or on the commodities listed in table 2.23. 

Compliance with the tolerance levels specified below is to be determined 

by measuring only total cypermethrin, cyano(3-phenoxyphenyl)methyl 3-

(2,2-dichloroethenyl)-2,2-dimethylcyclopropane carboxylate, in or on the 

commodity. 

The proposed and recommended tolerances for zeta-cypermethrin are presented in Table 2.2.3.
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Table 2.2.3 Tolerance Summary for Zeta-Cypermethrin.

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; 

Correct Commodity Definition

Avocado 0.45 0.50

Papaya 0.45 0.50

Star apple 0.45 0.50

Black Sapote 0.45 0.50 Sapote, black

Mango 0.45 0.70

Adequate residue data are available on avocado. 

The recommended tolerance for other tropical 

fruit of 0.5 ppm was calculated using the OECD 

calculation procedures and the residue data from 

avocado. However, the value was raised from 

0.5 to 0.7 ppm for mango, in order to harmonize 

with the Codex MRL value of 0.7 ppm. 

Sapodilla 0.45 0.50

Canistel 0.45 0.50

Mamey Sapote 0.45 0.50 Sapote, mamey

Artichoke, globe 0.80 0.60

Barley, grain 1.7 3.0

Barley, hay 5.0 6.0

Barley, straw 19 20.0

Oat, grain 1.7 3.0

Oat, hay 5.0 6.0

Oat, straw 19 20.0

Buckwheat, grain 1.7 3.0

Buckwheat, hay 5.0 6.0

Buckwheat, straw 19 20.0

Rye, grain 1.7 3.0

Rye, hay 5.0 6.0

Rye, straw 19 20.0

Pistachio 0.05 0.05 Adequate existing residue data are available on 

tree nuts. 

2.2.4 Revisions to Petitioned-For Tolerances

As summarized above, several revisions to the proposed tolerances as proposed by IR4 were 

necessary. These revisions were primarily due to HED’s use of the OECD MRL calculation 

procedures compared to the use of the NAFTA calculator by IR4. In addition, the proposed 

commodity definitions for Mamey and Black sapote were revised to reflect the correct 

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

2.3 Label Recommendations
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1. For the poultry house use, HED recommends the following clarifications be made on the 

ZetaGard LBT Insecticide label: 

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

and turkey grow-out houses per flock of birds.

b) The application can be split into two 25 pound (lb) applications, or one single 50 lb 

application, per flock. These applications can occur as one application at the 50 lb rate prior to 

the flock being placed in the broiler house, or as one application at the 25 lb rate prior to the 

flock being placed in the broiler house and a second 25 lb application occurring not later than 

three weeks prior to shipping the birds for slaughter.

c) If one single application is made at the maximum rate of 50 lbs, slaughter cannot occur 

sooner than six weeks after application.

2. There are currently restrictions on the Fury and Mustang labels that limit the total seasonal 

application rate for registered uses associated with zeta-cypermethrin and cypermethrin, as well 

as the proposed new uses of zeta-cypermethrin. It is noted that when new active ingredient 

alpha-cypermethrin is registered, the Fury and Mustang labels will need to be updated to limit 

the total seasonal application rate associated with the use of all cypermethrins, including alphacypermethrin. 

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Zeta-Cypermethrin Nomenclature.

Compound

Cl

Cl O

O

O

H

N

Common name Zeta-cypermethrin

Company experimental name FMC 56701

IUPAC name (S)-α-cyano-3-phenoxybenzyl (1R)-cis-trans-3-(2,2-dichlorovinyl)-2,2-

dimethylcyclopropanecarboxylate

or

(S)-α-cyano-3-phenoxybenzyl (1RS, 3RS, 1SR, 3SR)-3-(2,2-dichlorovinyl)-2,2-

dimethylcyclopropanecarboxylate

CAS name (S)-cyano(3-phenoxyphenyl)methyl (±)-cis-trans-3-(2,2-dichloroethenyl)-2,2-

dimethylcyclopropanecarboxylate

CAS registry number 52315-07-8

End-use product (EP) 1.5 lb ai/gal EC (Fury®or Mustang® 1.5 EC Insecticide; USEPA Reg. No. 279-3125) 

1.5 lb ai/gal EW (Mustang®1.5 EW Insecticide; USEPA Reg. No. 279-3126)

0.4 lb ai/gal ZetaGard LBT Insecticide Dust; File Symbol 39039-EN
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3.2 Physical/Chemical Characteristics

Zeta-cypermethrin has a very low water solubility, and relatively high octanol/water partition 

coefficient (log KOW > 6). These values account for the low surface and groundwater 

concentrations determined by EFED’s drinking water models. The chemical has low vapor 

pressure (3 x 10-9 mm Hg at 20oC), which decreases its potential to volatilize. See Appendix B 

for a listing of the physical and chemical properties of zeta-cypermethrin. 

3.3 Pesticide Use Pattern

Zeta-cypermethrin products are intended to be used as insecticides for the control of a variety of 

pests before, during and after planting. Two agricultural products are proposed for use on 

various crops: Fury®1.5 EC Insecticide and Mustang®1.5 EW Insecticide. These end-use 

products may be applied through a variety of application methods including aerial, chemigation, 

and ground equipment. 

Fury®1.5 EC Insecticide (USEPA Reg. No. 279-3125) is formulated as an emulsifiable 

concentrate (EC) which contains 18.1% of the active ingredient (1.5 lb ai/gal), zetacypermethrin. Mustang® 1.5 EW Insecticide (USEPA Reg. No. 279-3126) is formulated as oilin-water (EW) emulsion which contains 17.1% of the active ingredient (1.5 lb ai/gal). Zetacypermethrin is proposed to be applied 4 to 6 times with a minimum 7 to 14 day spray interval, 

depending on crop and pest. The recommended maximum single application rate for both 

products is 0.05 lb ai/A. 

In accordance with the 2008 cypermethrin Reregistration Eligibility Decision (RED), agricultural 

products for cypermethrin and zeta-cypermethrin are restricted use due to ecotoxicity concerns. 

These products are only available for use by commercial and professional applicators. The 

proposed label specifies personal protective equipment (PPE) consisting of baseline clothing 

(i.e., long-sleeved shirt and long pants, shoes and socks), chemical-resistant gloves (e.g., nitrile, 

butyl, neoprene and/or barrier laminate) and protective eyewear. The restricted entry interval 

(REI) specified on the proposed labels is 12 hours. Non-agricultural products (residential, 

commercial, and industrial) containing cypermethrin and zeta-cypermethrin are for general use. 

The proposed agricultural use pattern for zeta-cypermethrin is anticipated to result in short- and 

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

exposures were assessed since increased duration of exposure does not result in increased 

toxicity. The short-term exposure assessment is protective of potential intermediate-term 

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

There are currently restrictions on the Fury and Mustang labels that limit the total seasonal 

application rate for registered uses associated with zeta-cypermethrin and cypermethrin, as well 

as the proposed new uses of zeta-cypermethrin. 

Poultry (Chicken Boiler and Turkey Grow-out) House Use
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ZetaGard LBT Insecticide (USEPA Reg. No. 39039-EN) is formulated as a dust and contains 

0.375% zeta-cypermethrin. It is to be applied using a drop type spreader in bands three feet wide 

under each feed line and along each wall for a total of four bands per house. The PPE statement 

on the proposed label requires handlers to wear baseline clothing (long-sleeved shirt, long pants, 

shoes and socks) and chemical-resistant gloves.

Table 3.3.1 Summary of Directions for Use of Zeta-cypermethrin.

Applic. 

Timing, 

Type, and 

Equip.

Formulation 

[USEPA Reg. 

No.] 

Max. 

Single 

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. 

Per 

Season

Max. 

Seasonal 

Applic. Rate 

(lb ai/A)

PHI (days) Use Directions and 

Limitations

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

Aerial; Ground 

(Groundboom, 

Airblast); 

Chemigation

Fury Insecticide, 

Emulsifiable 

Concentrate (EC),

18.1% ai

(1.5 lbs ai/gal)

Reg. No. 279-

3125

0.05 lbs 

ai/ A 6

0.30 lbs ai/ 

A/season 1

Application interval is 7-10 

days apart depending on crop.

Minimum Spray Volume = 10 

gal/A (aerial); 20-100 gal/A 

(ground) depending on crop.

Mustang 

Insecticide

Oil-in-Water 

(EW) 17.1% ai 

(1.5 lbs ai/gal)

Reg. No. 279-

3126

Artichoke

Aerial; 

Ground; 

Chemigation 

Fury Insecticide, 

Emulsifiable 

Concentrate (EC),

18.1% ai

(1.5 lbs ai/gal)

Reg. No. 279-

3125

0.05 lbs 

ai/ A 4

0.20 lbs ai/ 

A/season 5

Application intervals 14 days.

Minimum Spray Volume = 10 

gal/A (aerial); 20-100 gal/A 

(ground) depending on crop.

Mustang 

Insecticide

Oil-in-Water 

(EW) 17.1% ai 
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Table 3.3.1 Summary of Directions for Use of Zeta-cypermethrin.

Applic. 

Timing, 

Type, and 

Equip.

Formulation 

[USEPA Reg. 

No.] 

Max. 

Single 

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. 

Per 

Season

Max. 

Seasonal 

Applic. Rate 

(lb ai/A)

PHI (days) Use Directions and 

Limitations

(1.5 lbs ai/gal)

Reg. No. 279-

3126

Barley

Aerial; 

Ground; 

Chemigation 

Fury Insecticide, 

Emulsifiable 

Concentrate (EC),

18.1% ai

(1.5 lbs ai/gal)

Reg. No. 279-

3125

0.05 lbs 

ai/ A 5

0.25 lbs ai/ 

A/season 14

Application intervals 14 days.

Minimum Spray Volume = 10 

gal/A (aerial); 20-100 gal/A 

(ground) depending on crop.

Mustang 

Insecticide

Oil-in-Water 

(EW) 17.1% ai 

(1.5 lbs ai/gal)

Reg. No. 279-

3126

Pistachio

Aerial; Ground 

(Groundboom, 

Airblast);Che

migation 

Fury Insecticide, 

Emulsifiable 

Concentrate (EC),

18.1% ai

(1.5 lbs ai/gal)

Reg. No. 279-

3125

0.05 lbs 

ai/ A 5

0.25 lbs ai/ 

A/season 7

Application intervals 7 days.

Minimum Spray Volume = 10 

gal/A (aerial); 20-100 gal/A 

(ground) depending on crop.

Mustang 

Insecticide

Oil-in-Water 

(EW) 17.1% ai 

(1.5 lbs ai/gal)

Reg. No. 279-

3126
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Table 3.3.1 Summary of Directions for Use of Zeta-cypermethrin.

Applic. 

Timing, 

Type, and 

Equip.

Formulation 

[USEPA Reg. 

No.] 

Max. 

Single 

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. 

Per 

Season

Max. 

Seasonal 

Applic. Rate 

(lb ai/A)

PHI (days) Use Directions and 

Limitations

Poultry House

Rotary 

Spreader

ZetaGard LBT 

Insecticide Dust 

(0.375% ai)

Reg. No. 39039-

EN

0.4 lb 

ai/A

(505 

lbs/20,000 

ft2)

2

50 lbs/20,000 

ft2per six 

week period

NA

Do not exceed 50 lbs per 

20,000ft2per six week period. 

Do not treat less than six weeks 

prior to slaughter. Do not 

apply with power duster 

equipment. 

Do not enter or allow others to 

enter until dusts have settled.

There are currently no proposed new residential uses associated with zeta-cypermethrin. 

However, cypermethrin and zeta-cypermethrin are registered for use on a variety of indoor and 

outdoor residential environments including: lawns, gardens, pets, and 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 worst case use scenarios and 

thereby will be protective of all residential uses. Table 3.3.2 provides a summary of the 

representative use scenarios and respective application rates. Most of the information relative to 

use products and scenarios was obtained 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 document.

Table 3.3.2: Registered Residential Uses for Zeta-cypermethrin and Cypermethrin

Exposure Scenario Method of Application Application Rate

Turf (EC) Hose-end Sprayer 0.44 lb ai/A

Turf (WP) Back-pack Sprayer 0.6 lb ai/A

Garden (Liquid) 1.7 lb ai/A

Indoor Crack and Crevice (WP) Manually Pressurized Handwand 0.0169

Aerosol Can 0.0013 lb ai/16 oz 

can

Indoor Fogger (RTU) NA NA

Dog Tag (USEPA Reg. No. 39039-

14)

NA NA

3.4 Anticipated Exposure Pathways

As a result of the proposed uses of zeta-cypermethrin, humans may experience dietary exposure 

to zeta-cypermethrin residues via their food and drinking water. Exposures associated with the 

registered residential uses include dermal, inhalation, and, in the case of children, incidental oral 

(i.e., hand-to-mouth).
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In occupational settings, dermal and inhalation exposure may occur during mixing, loading or 

applying the pesticide. Furthermore, there is potential for post-application exposure to workers 

who enter treated fields after the pesticide has been applied. These exposures may occur via 

dermal and/or inhalation routes. 

For both occupational and non-occupational settings, this risk assessment considers all of the 

relevant exposure pathways, combining them as appropriate, to estimate overall exposure and 

risk.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas post-application are 

evaluated. Further considerations are currently in development as OPP has committed resources 

and expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Cypermethrin, zeta-cypermethrin, and alpha-cypermethrin are members of the pyrethroid class of

chemicals. Pyrethroids have historically been classified into two groups, Type I and Type II, 

based upon chemical structure and neurotoxicological effects. Type I pyrethroids lack an alphacyano moiety and induce a syndrome consisting of aggressive sparring, altered sensitivity to 

external stimuli, and fine tremor progressing to whole-body tremor and prostration in rats. These 

Type I pyrethroid-specific behaviors are collectively described as the T-syndrome. Type II 

pyrethroids contain an alpha-cyano moiety and produce a syndrome that includes pawing, 

burrowing, salivation, and coarse tremors leading to choreoathetosis in rats. These Type II 

pyrethroid-specific behaviors are collectively described as the CS-syndrome (Verschoyle and 

Aldridge 1980; Lawrence and Casida 1982). Cypermethrin, zeta-cypermethrin, and alphacypermethrin are structurally similar Type II pyrethroids. The adverse outcome pathway (AOP) 
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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, zeta-cypermethrin and alpha-cypermethrin are separate active 

ingredients with different end-use products, they are included together in the hazard evaluation 

based on the following considerations: 

Cypermethrin is a racemic mixture of eight isomers (each with percentages of 11-14%). 

Zeta- and alpha-cypermethrin are enrichments of the more insecticidally-potent isomers 

(i.e., alpha-S and cis-2-R isomers).

All three cypermethrins are structurally similar (type II-α-cyano pyrethroids) and share a 

common mode of action (interaction with voltage gated sodium channels). The main 

target tissue for all three chemicals is the central and peripheral nervous system.

The qualitative and quantitative nature of the toxicological effects (i.e., neurotoxicity) for 

the cypermethrins is similar following oral, dermal, and inhalation routes of exposure. 

Acute toxicity lethality studies resulted in similar PODs, and the overall evidence from 

repeated dose toxicology studies indicates 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 alphacypermethrin in foods.

There are a variety of factors that can influence the toxicity of pyrethroid chemicals 

(vehicle, method of administration, peak time); however, the available toxicology studies 

for the cypermethrins are relatively consistent across the database and the differences 

seen in the database are within expected variability. For risk assessment purposes, 

cypermethrin, zeta- and alpha-cypermethrin are considered equally toxic and the most 
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protective endpoints and PODs have been selected and used for risk assessment. 

The database of experimental toxicology studies available for cypermethrin, zetacypermethrin, and alpha-cypermethrin provides a robust characterization of the hazard 

potential for 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, 

developmental neurotoxicity, carcinogenicity, immunotoxicity, and dermal toxicity. In 

addition, there are on-going efforts to develop data to inform the potential sensitivity of 

infants and younger children to pyrethroids as a class, which is discussed further in 

Section 4.4. Despite these scientific efforts, HED is confident that 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 the 

cypermethrins:

-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 Inhalation Study (cypermethrin)

-90 Day Rat Studies (cypermethrin, alpha- and zeta-cypermethrin)

-90 Day Dog Studies (cypermethrin and alpha-cypermethrin)

-Chronic Dog Studies (cypermethrin and alpha-cypermethrin) 

-Chronic/Cancer Mouse Studies (cypermethrin and alpha-cypermethrin)

-Chronic/Cancer Rat Study (cypermethrin)

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

-Reproduction Studies in the Rat (cypermethrin and zeta-cypermethrin) 

-ACN Studies in the Rat (cypermethrin, alpha- and zeta-cypermethrin) 

-SCN Studies in the Rat (cypermethrin and zeta-cypermethrin) 

-DNT Study in the Rat (zeta-cypermethrin) 

The studies available for consideration of toxicity provide a comprehensive database. The 

Wolansky and WIL studies measure locomotor and functional observational battery (FOB) 

activity, respectively, and provide robust data to evaluate the hazard potential of cypermethrin, 

alpha- and zeta-cypermethrin.

In addition, numerous studies from the scientific literature conducted over several decades 

describe the pharmacodynamic and pharmacokinetic profile of the pyrethroids in general. This 

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

et. al. 2005; Wolansky and Harrill 2008). 

4.2 Toxicological Profile
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Cypermethrin, zeta-cypermethrin, and alpha-cypermethrin have been evaluated for a variety of 

toxic effects in experimental toxicity studies. Behavioral changes commonly seen with type II 

pyrethroids were consistently noted in the toxicology database. These included tremors, gait 

abnormalities, limb conditions, ataxia and 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 abnormalities, 

tremors, limb conditions, and hypersensitivity were observed at the mid and high doses. 

Additionally, slight nerve degeneration was seen in the acute neurotoxicity study with alphacypermethrin at the high dose. In the subchronic neurotoxicity 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 (rabbit), 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 toxicity study in rabbits with cypermethrin, 

systemic effects were observed (focal necrosis of the liver, decreased testicular weights and 

decreased body weight in females). However, these observations in the rabbit were not used for 

risk assessment because the testing method (i.e., abraded skin) does not simulate actual exposure 

and results in compromised test conditions. Additionally, there would be physiological 

differences between abraded and non-abraded animals, further undermining the relevance of 

these results for risk assessment.

 

Developmental toxicity and reproduction studies are available for the cypermethrins. In the 

developmental toxicity studies in rats with cypermethrin and zeta-cypermethrin, there was no 

evidence of developmental toxicity up to the highest doses tested. 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 developmental 

toxicity study in rats with alpha-cypermethrin, offspring effects were limited to decreased fetal 

body weight. Maternal effects observed in the study were unsteady gait, piloerection, limb splay, 

and hypersensitivity to sound and touch at the same dose. In the developmental toxicity studies 

in rabbits with cypermethrin, zeta-cypermethrin, and alpha-cypermethrin, there was no evidence 

of developmental toxicity up to the highest dose tested. Maternal effects seen with cypermethrin 

included decreased body weight gain, anorexia, abdomino-genital staining, decreased feces, and 

red or pink material in the pan. With alpha-cypermethrin, maternal effects were body weight 

loss and decreased food consumption. Multi-generation reproduction studies in rats are available 

for cypermethrin and zeta-cypermethrin. In the reproduction study with cypermethrin, decreased 

body weight gain was observed in adult animals and decreased body weight was seen in 

offspring animals at the highest dose tested. In the reproduction study with zeta-cypermethrin, 

decreased body weight gain and mortality were observed in offspring animals in the presence of 

mortality, increased brain weights, decreased body weights, and neurotoxicity in maternal 

animals. 
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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 females (CPRC, 1988) 

in a mouse carcinogenicity study. The presence of common benign tumors (lung adenomas), in 

one species (mice) and one sex (female), with no increase in the proportion of malignant tumors 

or decrease in the time-to-tumor occurrence, together with the lack of mutagenic activity, was 

not considered strong enough to warrant a quantitative estimation of human risk. Quantification 

of risk using a non-linear approach (i.e., aPAD, aRfD) will adequately account for all chronic 

toxicity, including carcinogenicity, that could result from exposure to cypermethrin (see 4.5.3). 

Acute lethality studies conducted with cypermethrin, zeta-cypermethrin, and alpha-cypermethrin 

indicate moderate acute toxicity via the oral 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 the cypermethrins are similar to those 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 repeated 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 cypermethrin, radiolabel in the feces is largely 

unmetabolized parent (>90% parent).
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4.3 Pyrethroid Pharmacokinetic and Pharmacodynamic Profile

The extensive body of scientific literature on the pyrethroids provides insight into the 

contributions of pharmacokinetics (PK) and pharmacodynamics (PD) to the general toxicity 

profile of this class of chemicals. This information also provides valuable insight into the 

potential age-related differences in toxicity for the pyrethroids. The following sections discuss 

the specific issues related to pyrethroid pharmacokinetics, pyrethroid pharmacodynamics, and 

age-related differences in pyrethroid toxicity.

4.3.1 Pharmacokinetics

Pharmacokinetics 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 important determination of their 

toxicity because the concentration of pyrethroid at the sodium channel relates to the extent of 

toxicity; greater pyrethroid concentration translates as increased neurotoxicity. Physiological 

processes that significantly contribute to the PK include metabolism, protein binding, and 

partitioning. Carboxylesterases and cytochrome P450 enzymes are the two major enzyme 

families responsible for the metabolism of pyrethroids. It is the ontogeny of these enzymes that 

accounts for the age-related sensitivity observed after pyrethroid exposures. However, 

pyrethroid residues in fatty tissue are not available to interact with the voltage-gated sodium 

channels (VGSCs) in vital tissues and, therefore, do not contribute to overall toxicity. 

Physiologically-based pharmacokinetic (PBPK) models, designed to predict pyrethroid 

concentration in tissues following in vivo exposure, have recently been developed by the 

Agency. The Agency has determined that the important PK properties relevant for the 

metabolism and distribution of pyrethroids in the body are sufficiently similar for members of 

this class such that using a ‘generic’ or family model structure for this class is scientifically 

appropriate. In other words, due to the similarities in the PK profiles of pyrethroids, a single 

model structure is able to predict the tissue dose based on the pharmacokinetics of 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 profile 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 enzymes which metabolize and detoxify the pyrethroids are present in rats and 

humans at birth (Koukouritaki et. al. 2004; Yang et. al. 2009). As a result, both juveniles and 

adults are able to tolerate low doses of pyrethroids when the internal dose, or the amount of 

pyrethroid at the sodium channel, is low. However, the activity of these enzymes increases with 

age, conveying in adults a greater capacity to detoxify pyrethroids compared to juveniles (Anand 

et. al. 2006; de Zwart et. al. 2008; Yang et. al. 2009). For example, the rate of in vitro

metabolism of deltamethrin by plasma carboxyesterases, plus hepatic carboxyesterases and 

cytochrome P450s (microsomes) is at least 6 times higher for PND 90 rats compared to PND 10 
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rats (Anand et. al. 2006). As a consequence, higher internal doses (i.e., those associated with 

high doses in experimental toxicology studies) overwhelm the clearance mechanisms in juveniles 

but because adults have greater enzyme activity, they are able to tolerate higher doses prior to the 

onset of toxicity. As a matter of perspective, the anticipated exposures from typical dietary or 

residential activities are not expected to overwhelm the premature metabolic systems in 

juveniles. 

Predictive PBPK models have recently been developed to describe the PK of a few pyrethroids 

(Mirfazaelian et. al. 2006; Godin et. al. 2010). Among these is an age-dependent model 

developed by the Agency which is capable of predicting the concentration of deltamethrin in the 

brains of rats at multiple ages (Tornero-Velez et. al. 2010). The brain is considered the primary 

target organ for pyrethroids, and increased pyrethroid concentrations are correlated with 

increasing systemic toxicity. This model predicts that, compared to adult rats (i.e., 90-days old), 

equivalent brain concentrations of deltamethrin would be achieved with a 3.8X fold lower oral 

dose in 10-day old rats and 2.5X lower dose in 21-day old rats (Tornero-Velez et. al. 2010). For 

example, a 1 mg/kg dose in the adult is equivalent to a 0.26 mg/kg dose (≈1 mg/kg÷3.8mg/kg) in 

the 10-day old rats and to a 0.4 mg/kg (≈1 mg/kg÷2.5mg/kg) dose in a 21-day old rat. The 

difference between a 3.8- and a 2.5-fold dose is within 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 Pharmacodynamics

Pharmacodynamics can be defined as the changes that chemicals cause to the body, in this case, 

how pyrethroids interact with the sodium channels. Substantial evidence from in vitro and in 

vivo studies support the AOP illustrated in Figure 4.1 and the disruption of sodium channels by 

pyrethroids as an early key event (Lund and Narahashi 1982; Salgado et. al. 1989; Song and 

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

altered neuronal excitability, Type I pyrethroids cause slight prolongations of the sodium current 

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

pyrethroids significantly prolong sodium current tails (e.g. 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 pyrethroids, 

including cypermethrin, with mammalian VGSCs expressed in Xenopus oocytes. Cypermethrin 

behaved in a manner consistent with type II pyrethroids by producing prolonged tail currents that 

activated more slowly and did not detectably inactivate during a 40-ms depolarization. 

Additionally, Cao et. al. (2011a) measured Na influx in primary cultures of mammalian (mouse) 

neurons and demonstrated that cypermethrin caused increases in Na influx in this model; this 

confirms the ability of cypermethrin 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.
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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 extracted from Figure 3 in Choi and Soderlund (2006). 

HED would prefer to use an early key event in the AOP for pyrethroids in selection of PODs. 

However, in vivo measures of VGSC alteration and altered neuronal excitability are not readily 

available for use in risk assessment at this time, and approaches for extrapolating in vitro

findings like those discussed here to in vivo measures are not yet developed. Therefore, the 

Agency is focusing its efforts in hazard characterization and identification on the apical endpoint 

(i.e., changes in neurobehavior in laboratory animals). Neurotoxicity resulting from pyrethroids 

is generally characterized by tremors, hyper- or hypothermia, heightened response to stimuli, 

salivation, tremors and convulsions (Soderlund et. al. 2002; Wolansky and Harrill 2008; Weiner 

et. al. 2009). 

In contrast to the age-related PK differences identified in the 2011 analysis, PD contributions to 

pyrethroid toxicity are not age-dependent even though 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 dynamic 

information in vivo. To date, a readily useable biomarker of in vivo pyrethroid interaction with 

sodium channels has not been identified, making it impractical to determine the isoform 

combinations that are present and being acted upon by pyrethroids. Therefore, much of the 

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 compared to isoforms expressed in adults and that, pharmacodynamically, the rat is 

a conservative model for humans. For example, Meacham et al. (2008), compared the sensitivity 

of an adult isoform and a juvenile isoform expressed in frog oocytes to deltamethrin. The 

isoforms had comparable responses at environmentally relevant concentrations (<500 nM) of 

deltamethrin, suggesting a lack of PD difference between juveniles and adults at low exposure 

levels. In addition, in a direct comparison of a homologous rat and human VGSC isoform, 

NaV1.3, revealed that the rat isoform was 4-fold more sensitive than the equivalent human 

sodium channel to the pyrethroid tefluthrin (Tan and Soderlund 2009). These data suggest that 

the rat is a highly-sensitive model and extrapolations from the rat would be protective of human

health. The occurrence and ontogeny of voltage-gated sodium channels in humans is not well 
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characterized compared to the rat. However, based on the comparable function and distribution 

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

human PD (Goldin et. al. 2000; Goldin 2002). As a result, the Agency concludes that juvenile 

rats are not more sensitive than adults with respect to pyrethroid pharmacodynamics.

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 rapid, with a time to peak effect for neurobehavioral effects ranging from 4 to 8 hours 

(Wolansky and Harrill 2008; Weiner et. al. 2009; Scollon et. al. 2011). Furthermore, rapid 

metabolism and elimination preclude accumulation and increased potency following repeated 

dosing. Several neurotoxic effects were seen in acute neurotoxicity (ACN) and subchronic 

neurotoxicity (SCN) studies in rats with cypermethrin, zeta-cypermethrin, and alphacypermethrin. 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). 
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1BMD1SD 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. BMDL1SD is the 95% lower confidence limit of the central estimate. Data located in Wolansky (2006), MRID 47885701. ≠ No 

neurotoxicity observed in the study.

Table 4.3.3. Points of Departure with neurological effects for toxicology studies with Cypermethrin, Zeta-cypermethrin, and Alphacypermethrin.

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)

BMDL1SD

1 Acute, 

single 

exposure

BMDL1SD =

7.16

BMD = 

11.20

BMDL1SD =

N/A

BMD = 

N/A

BMDL1SD =

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/A
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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 BMDL1SD 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 study is protective of all effects observed in the toxicology database.

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

Cypermethrin, zeta- and alpha-cypermethrin exposure to children <6 years old is expected and it 

must be considered in the context of the pyrethroids as a class. For infants and children less than 

six years of age, USEPA is reducing the FQPA safety factor to 3X based on the increased 

quantitative susceptibility seen in the scientific literature related to pyrethroid pharmacokinetics. 

 

High-dose LD50 studies (studies assessing what dose results in lethality to 50 percent of the 

tested population) in the scientific literature indicate that pyrethroids can result in increased 

quantitative sensitivity in the young. Examination of pharmacokinetic and pharmacodynamic 

data indicates that the sensitivity observed at high doses is related to pyrethroid age-dependent 

pharmacokinetics - the 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 juveniles compared to adults. No evidence of increased quantitative 

or qualitative susceptibility was seen in the pyrethroid scientific literature related to 

pharmacodynamics (the effect of pyrethroids at the target tissue) both with regard to interspecies differences between rats and humans and to differences between juveniles and adults. 

Specifically, there are in vitro pharmacodynamic data and in vivo data indicating similar 

responses between adult and juvenile rats at low doses and 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 

absence of the requested data on juvenile sensitivity to pyrethroids, USEPA is retaining a 3X 

additional safety factor as estimated by pharmacokinetic modeling. For several reasons, USEPA 

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 expected 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 

studies for pyrethroids, despite the relatively high doses used in those studies. Second, the 

portions of the uncertainty factors that account for potential pharmacodynamic differences are 

likely to overstate the risk of inter- and intraspecies pharmacodynamic differences, given the data 

showing similarities in pharmacodynamics between juveniles and adults and between humans
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and rats. For both the inter-species and intra-species uncertainty factors, the pharmacodynamic 

portions are generally considered to be 3X, however for pyrethroids it is reduced to 1X since no 

differences among the various groups are observed. Finally, as indicated, pharmacokinetic

modeling only predicts a 3X difference between juveniles and adults.

This information described above is summarized in Re-Evaluation of the FQPA Safety Factor for 

pyrethroid pesticides (USEPA 2011c). 

In guideline developmental and reproduction studies with the cypermethrins, there was no 

evidence of increased qualitative or quantitative susceptibility in rats or rabbits. 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 observed in the reproduction studies where body weight changes (decreased BW gain) 

were seen in maternal and offspring animals at doses similar to the DNT study, with no 

indication of increased susceptibility. Therefore, there is no residual concern for effects 

observed in the study (see 4.4.3).

4.4.1 Completeness of the Toxicology Database

The toxicology database for the cypermethrins is not complete, because the Agency lacks 

sufficient information to fully characterize the potential for juvenile sensitivity. However, when 

evaluated together, the toxicity database for cypermethrin, zeta-cypermethrin, and alphacypermethrin 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 rats, 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 Neurotoxicity

There are no residual uncertainties with regard to neurotoxicity for cypermethrin, zetacypermethrin, 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 Animal
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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, there was a 5-8% decrease in maternal body weight in this study, a body 

weight decrease of <10% is generally not 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 body weight 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 zetacypermethrin, the decrease in body weight of the young is comparable to adults; however, it was 

considered adverse in the young but not in the adults. This disparity in interpretation leads to an 

apparent increase in sensitivity in the young; however, concern is reduced since the magnitude of 

body weight decrements was similar in adult and young animals. The results from the DNT 

study are 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 

DNT 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 to the cypermethrins, including zeta- and alphacypermethrin.

Additionally, after reviewing the extensive body of peer-reviewed literature on pyrethroids, the 

Agency has also reached a number of conclusions regarding juvenile sensitivity for pyrethroids 

including the following:

The Agency has no residual uncertainties regarding age related sensitivities for women of 

child bearing age as well as for all adult populations and children ≥ 6 years of age, based 

on the absence of pre-natal sensitivity observed in 76 guideline studies 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 scientific literature related to pharmacodynamics. 

The Agency will retain a 3X uncertainty factor to protect for exposures to children < 6 

years of age based on the increased quantitative susceptibility seen in the scientific 

literature related to pyrethroid pharmacokinetics. 

Additional in vitro and in vivo studies are currently being conducted that could potentially inform 

a number of issues related to pyrethroid toxicity as a class. In 2010, the Agency requested 

proposals for study protocols which could identify and quantify potential juvenile sensitivity and 

received a single, coordinated response from the Pyrethrin and Pyrethroids Working Group 

(PPTWG), a conglomerate of pyrethroid registrants. The PPTWG protocol was reviewed during 

a July 2010 FIFRA SAP meeting. Based on comments from the SAP, the initial study proposal 

was refined. At the present time, pesticide registrants and product formulators have come 

together as the Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA)

and plan on doing the following: 1) conducting in vitro studies demonstrating the interaction of 
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pyrethroids exogenously expressed rat and human VGSCs in Xenopus oocytes; 2) conducting in 

vitro studies demonstrating interaction of pyrethroids in rat neurolemma cells; 3) developing rat 

and human PBPK models, including additional pharmacokinetic data; and 4) conducting in vivo

behavioral testing using auditory startle testing in rats. As these data become available, the 

Agency will determine whether re-evaluation of the age-related sensitivity of pyrethroids is 

appropriate. 

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to dietary and residential exposure. The dietary 

exposure assessments are based on high-end health protective residue levels (that account for 

parent and metabolites of concern), processing factors, and percent crop treated assumptions. 

Furthermore, conservative, upper-bound assumptions were used to determine exposure through 

drinking water and residential 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 zeta-cypermethrin and the existing residential uses for both zetacypermethrin and cypermethrin, the expected exposure profile will be for dietary, dermal, 

inhalation and incidental oral exposures. 

As previously indicated, the toxicity endpoints for cypermethrin, zeta-cypermethrin, and alphacypermethrin are consistently based on clinical signs of neurotoxicity consistent with type II 

pyrethroids. The available studies include multiple species, study designs, and durations. 

Moreover, the acute exposure or bolus dosing studies generally result in lower NOAELs 

compared to longer term dietary administration studies, consistent with other pyrethroids in this 

class. Because uncertainty associated with the POD is propagated 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 benchmark dose (BMD) estimates determined from this study. Moreover, 

each pyrethroid was evaluated by the same scientist thus decreasing some of the variability 

associated with neurobehavioral measures. In the WIL study, 17 pyrethroids have been 

evaluated using a specially designed (FOB) study focused on the outcomes associated with 

pyrethroid toxicity syndromes. The cypermethrin data from the WIL study were not used as part 
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of the POD selection since the Wolansky study was considered more appropriate based on study 

design. 

Observations of tremors, gait abnormalities, limb conditions, and hypersensitivity were 

prominent findings in the guideline experimental toxicology studies and were considered in the 

point of departure (POD) determination. However, guideline studies typically have only three 

treatment groups and often do not evaluate clinical signs at the time of peak effect. Moreover, 

scoring metrics for behavioral parameters vary widely among guideline studies. Given the 

multiple strengths associated with the design of the Wolansky et. al. (2006) study and the 

resulting well-defined dose-response curve, it was determined that the study provided the most 

robust data set for extrapolating risk from cypermethrin, zeta-cypermethrin, and alphacypermethrin. 

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 performing BMD analysis, 

a benchmark response (BMR) must be selected. As a general approach, it is preferred to use a 

combination of biological and statistical factors in the BMR selection. In the case of motor 

activity data, there is no specific level of change established by the scientific 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 

determination, HED has estimated both the BMD1SD and the BMDL1SD (where the BMDL1SD is 

the lower 95% confidence limit of the BMD1SD). The BMD1SD and the BMDL1SD for 

cypermethrin are 11.20 mg/kg and 7.16 mg/kg, respectively. As a matter of science policy, 

USEPA uses the BMDL, not the BMD, for deriving PODs. Thus the BMDL1SD 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 

BMDL1SD value of 7.16 mg/kg based on decreased locomotor activity at the BMD1SD value of 

11.20 mg/kg. There is no increase in hazard from repeated exposures to the cypermethrins; 

therefore, the acute dietary exposure assessment is protective of chronic dietary exposures since 

acute exposure levels are higher than chronic exposure levels. Accordingly, a dietary exposure 

assessment for the purpose of assessing chronic dietary risk was not conducted. 

Incidental Oral (Short-term) 

For the purpose of assessing potential risk associated with incidental oral exposure to children reentering 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 BMDL1SD value of 7.16 

mg/kg, based on decreased locomotor activity and the BMD1SD of 11.20 mg/kg. 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 study is a very robust study 

with 6 doses, uses a sensitive vehicle and volume to determine a BMDL and therefore provides a 
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more accurate point of departure than other studies considered for incidental oral endpoint and 

dose selection. 

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 have a low absorption value of ≤ 5%. Combined with the high rate of 

metabolism, the amount of parent available to interact with sodium channel is minimal and 

therefore neurotoxic effects are not routinely observed in dermal studies. The absorption rate in 

the alpha-cypermethrin study is slightly higher, at 13%. However, systemic effects were not 

observed in the rat at 1000 mg/kg/day. Since rat skin is typically more porous to xenobiotics 

compared to human skin, it’s highly unlikely sufficient cypermethrin will penetrate human skin 

in sufficient quantities to cause neurotoxicity. Furthermore, pyrethroids are lipophilic and 

therefore much of the measured radioactivity measured in the skin was captured in the upper 

dermal layers and not available for absorption. Based on these factors just discussed, HED does 

not anticipate systemic toxicity via the dermal route of exposure.

Inhalation (Short- and intermediate-term)

A route-specific 21-day rat inhalation study with cypermethrin was used to assess short- and 

intermediate- term 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 

effects were seen following exposure via the route (inhalation) and duration (short- and 

intermediate-term) of concern. Additionally, the effects seen in the inhalation study are 

consistent with the pyrethroid profile and are protective of neurotoxicity. 

For cypermethrin, human equivalent concentrations (HECs) for the inhalation NOAEL were 

calculated for use in MOE calculations, based on the methods and dosimetry equations described 

in USEPA’s reference concentration (RfC) guidance (1994). The regional deposited-dose ratio 

(RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter 

[MMAD] and geometric standard deviation [g] of aerosols), can be used to estimate the different 

dose fractions deposited along the respiratory tract. The RDDR is also based on interspecies 

differences in ventilation and respiratory-tract surface areas. 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 respiratorytract 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 exposures. The resulting HEC 

is 0.023 mg/L. For human residential exposure, 24 hrs/day was assumed and the HEC is 0.008. 
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For the current risk assessment, the use of 24 hours of exposure to calculate an HEC is 

considered protective and very conservative since handler exposure via the inhalation route is 

expected to be less than 24 hours. Human equivalent doses (HEDs) of 1.10 mg/kg/day for 

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

assessment.

Based on the exposure profile, HED does not anticipate long-term inhalation exposure for adults 

or children.

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

HED’s level of concern for occupational and residential risk estimates is based on the various 

uncertainty and safety factors retained or applied for specific routes of exposure. The LOCs 

relevant for risk assessment for the cypermethrins are described in the table below. For 

inhalation risk assessments, the 10X interspecies factor was reduced to 3X to account for 

interspecies differences, in accordance with the RfC guidance. The only exposure pathway for 

adults and children greater than 6 years old is via inhalation, for which a 30X uncertainty factor 

has been retained. The intra-species variability factor of 10X is combined with an interspecies 

extrapolation factor of 3X, based on the use of a human equivalent dose for inhalation risk 

assessment. For children under 6 years old, exposed via the 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 old: 300X

Residential Dermal Exposure (Adults/Children) NA

Residential Inhalation Exposure ≥ 6 years old: 30X

< 6 years old: 100X

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk 

assessment must address exposures from three major sources, oral, dermal and inhalation, and 

determine whether the individual exposures can be combined if they have the same toxicological 

effects. For the cypermethrins, short-term oral and inhalation exposures can be combined for 

children, since endpoints are based on the same toxicological effects (clinical signs related to 

neurotoxicity). Although dermal exposure occurs during and following use of zetacypermethrin, there is no toxicity via the dermal route, and, therefore, the exposure does not need 

to be combined with any other routes.
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4.5.3 Cancer Classification and Risk Assessment Recommendation

Cypermethrin is classified as a Group C “Possible human carcinogen”, based on an increased 

incidence of lung adenomas and adenomas plus carcinomas combined in females in a mouse 

carcinogenicity study. The presence of common benign tumors (lung adenomas), in one species 

(mice) and one sex (female), with no increase in the proportion of malignant tumors or decrease 

in the time-to-tumor occurrence, together with the lack of mutagenic activity, was not considered 

strong enough to warrant a quantitative 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., aPAD or 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 

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 tumors 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 evidence 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 endpoints/PODs follow, and the full toxicological profile is 

presented in Appendix A.

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Zeta-cypermethrin, Cypermethrin, and 

Alpha-cypermethrin for Use in Dietary and Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, Level of Concern 

for Risk Assessment

Study and Toxicological 

Effects

Acute Dietary 

(children ≥ 6 

years old and 

adults)

Wolansky 

BMDL1SD = 

7.16 mg/kg

UFA= 10x

UFH=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 

BMDL1SD = 

7.16 mg/kg

UFA= 10x

UFH=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 

BMDL1SD = 

7.16 mg/kg

UFA= 10x

UFH=10x

FQPA SF= 3x

Residential LOC for MOE = 

300

Wolansky BMD = 11.20 

mg/kg

based on motor activity

Dermal (All 

exposures) No systemic toxicity seen in dermal toxicity studies & no developmental concern. 
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Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Zeta-cypermethrin, Cypermethrin, and 

Alpha-cypermethrin for Use in Dietary and Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, Level of Concern 

for Risk Assessment

Study and Toxicological 

Effects

Short-term 

Inhalation

(1 to 30 days)

(children <6 

years old)

NOAEL = 

0.01 mg/L 

HEC= 

0.008 mg/L

HED = 

1.15

mg/kg/day

UFA= 3x

UFH=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 days)

(children ≥ 6 

years old and 

adults)

NOAEL = 

0.01 mg/L 

HEC= 

0.008 mg/L

HED = 

1.15

mg/kg/day

UFA= 3x

UFH=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 Q1* 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. BMD = benchmark dose. BMDL = 

benchmark dose (lower limit of a 95% confidence interval). UF = uncertainty factor. UFA = extrapolation from animal to human 

(interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = 

FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of 

exposure. LOC = level of concern. N/A = not applicable. HEC = human equivalent concentration; HED = human equivalent 

dose.

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Zeta-cypermethrin, Cypermethrin, and 

Alpha-cypermethrin 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) No systemic toxicity seen in dermal toxicity studies & no developmental concern. 
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Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Zeta-cypermethrin, Cypermethrin, and 

Alpha-cypermethrin for Use in Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Short- and 

Intermediateterm Inhalation 

(1 day to 6 

months)

NOAEL = 

0.01 mg/L 

HEC= 0.023 

mg/L

HED = 1.10 

mg/kg/day

UFA= 3x

UFH=10x

Occupational LOC 

for MOE = 30

21-day inhalation study in the rat.

LOAEL = 0.05 mg/L based on increased 

salivation.

Cancer (oral, 

dermal, 

inhalation)

Classification: Group C “Possible human carcinogen based on lung adenomas in female mice. 

No Q1* 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. UFA = 

extrapolation from animal to human (interspecies). UFH = 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

HED MARC Determination of Residues of Concern (D269584, Y. Donovan, 11/3/2000)

The nature of zeta-cypermethrin residues is adequately understood in plants, rotational crops, 

livestock commodities, surface water, and groundwater based on information previously 

provided on cypermethrin and zeta-cypermethrin. All studies were conducted in a manner 

appropriate for the proposed uses. In addition, metabolism studies for alpha-cypermethrin in 

cabbage, wheat, lactating cow, and laying hen have been recently submitted and provide further 

confirmation of the conclusions drawn from cypermethrin and zeta-cypermethrin data (W. Drew, 

D378683, 7 September 2012). 

An acceptable confined rotational study was previously submitted. A limited field rotational 

crop study was submitted, and is considered acceptable. Residues of 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 Degradation
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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. 

Zeta-cypermethrin is expected to have little mobility in soil surfaces (Koc ≥ 20,800 L/kg) and 

leaching into groundwater is not expected to be an important transport process. Volatilization is 

not expected to be an important transport process either, since zeta-cypermethrin has a relatively 

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

moderately persistent in the environment and degrades through a combination of biotic and 

abiotic mechanisms. Zeta-cypermethrin is relatively stable to hydrolysis at acidic and neutral pH 

levels, but degrades in a few days under alkaline conditions (pH 9, half-life of ~2 days). Zetacypermethrin is relatively light stable, but still undergoes photolysis in water, with half-lives of 

about a month or more in distilled water. The rate of photolysis appears to be enhanced in 

natural waters (which contain photosensitizing agents 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 conditions, the 

degradation rate is enhanced, with half-lives of around 9 to 17 days. If released to water, zetacypermethrin partitions to sediment and may degrade slowly. Major degradates observed in 

laboratory studies result from cleavage at the ester moiety 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 zeta-cypermethrin is similar to that of cypermethrin, based on a comparison 

of the metabolic profiles from studies with zeta-cypermethrin and cypermethrin. A wide range 

of studies in mice, rats, dogs, sheep, cows and humans has shown that cypermethrin is 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 absorption, distribution, retention 

or excretion between the species. Differences, where they do occur, are related to the rate rather 

than the nature of the metabolites formed, and the conjugation reactions. 

Cypermethrin, both the cis and trans isomers, and zeta-cypermethrin are primarily metabolized 

by cleavage of the ester bond. The 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 cypermethrin, but humans and rats have the same pathway. Minor quantities of 

hydroxylated PBA (conjugated) may also be found. 
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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 plant studies, nor are there any unique metabolic pathways in 

the plant, that are not represented in the rat metabolism study.

5.1.4 Residues of Concern Summary and Rationale

The toxicological and residue chemistry databases for zeta-cypermethrin have been examined to 

determine residue definitions for tolerance-setting and risk-assessment purposes. The nature of 

zeta-cypermethrin residues is adequately understood in plants, rotational crops, livestock 

commodities, surface water, and groundwater based on information provided on cypermethrin 

and zeta-cypermethrin. In addition, metabolism studies for alpha-cypermethrin in cabbage, 

wheat, lactating cow, and laying hen have been recently submitted and provide further 

confirmation of the conclusions drawn from cypermethrin and zeta-cypermethrin data (W. Drew, 

D378683, 7 September 2012). 

In previous risk assessments, HED had included the metabolite and degradate DCVA in its 

residues of concern for risk assessment, but subsequently concluded (D269584; Y. Donovan; 3 

November 2000) that for cypermethrin and zeta-cypermethrin, the parent compound is the only 

residue of concern that needs to be included in the dietary risk assessment, including drinking 

water. This conclusion was based on the following considerations: 

1) Reduced 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) The residue data indicated that in the majority of crops, parent compound accounts 

for at least 90% of the total residue. In those crops where DCVA was found at 

greater than 10%, the detected DCVA levels were below the limit of quantitation 

(LOQ), or the maximum livestock dietary burden contributions from DCVA for these 

commodities are equal to or less than the LOQ.

3) Although DCVA levels in liver and kidney are greater than those of the parent, the 

contribution of these foods to the total dietary exposure is not considered to be 

significant, and the overall exposure to DCVA would be negligible.

4) EFED provided information which indicates that at neutral pH (i.e., environmental 

pH relevant for human health risk assessment), the parent compound is stable, and the 

formation of the degradate is less likely to occur than at higher pHs, as demonstrated 

by the environmental fates studies.

Based on the available data, HED has 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 zeta-cypermethrin, alphacypermethrin, and cypermethrin. These conclusions are summarized in Table 5.1.4.
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Table 5.1.4 Residue Definitions for Zeta-cypermethrin

Matrix Risk Assessment Tolerance Expression

Plants Primary Crop Zeta-cypermethrin Zeta-cypermethrin

Rotational Crop Zeta-cypermethrin Zeta-cypermethrin

Livestock Ruminant Zeta-cypermethrin Zeta-cypermethrin

Poultry Zeta-cypermethrin Zeta-cypermethrin

Drinking Water Zeta-cypermethrin Not Applicable

5.2 Food Residue Profile

E. Holman, D379486, 20 September 2012

D. McNeilly, D399692, 20 September 2012

Adequate residue chemistry data have been provided for the new proposed uses of zetacypermethrin. IR-4 has submitted field trial data for avocado, globe artichoke, and barley. The 

results from these studies are summarized in Table 5.2.1. In addition, IR-4 is requesting that the 

existing field trial data on tree nuts be used to support setting a tolerance for pistachio. 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 the fate of zeta-cypermethrin in processed commodities. Therefore, 

the submitted and existing data support the setting of tolerances for all proposed new agricultural 

uses (E. Holman, D379486, 20 September 2012). Review of the field trial data and associated 

processing study on barley indicates that the existing livestock tolerances do not need to be 

revised, as they are adequately protective of the anticipated dietary exposure from livestock 

commodities associated with the proposed new uses. 

Previously reviewed confined rotational crop studies with cypermethrin show that the 

metabolism in rotated crops is similar to that in primary crops. Limited field rotational crop 

studies generated with validated analytical methods, and supported by adequate storage stability 

data, demonstrated that residues were not likely in any commodity 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.

Table 5.2.1. Summary of Residue Data from Crop Field Trials with Zeta-Cypermethrin (EC or EW).

Crop matrix Total Applic. 

Rate (lb ai/A)

PHI 

(days)

Residue Levels (ppm)

n Min. Max. HAFT1 Median Mean Std. Dev.

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

Avocado 0.294-0.306 1 14 0.05 0.28 0.27 0.075 0.12 0.08

Artichoke (Proposed use = 0.2 lb ai/A total application rate, 5-day PHI)

Artichoke 0.204-0.212 5 6 0.066 0.29 0.26 0.21 0.18 0.09

Barley (Proposed use = 0.25 lb ai/A total application rate, 14-day PHI)
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Table 5.2.1. Summary of Residue Data from Crop Field Trials with Zeta-Cypermethrin (EC or EW).

Crop matrix Total Applic. 

Rate (lb ai/A)

PHI 

(days)

Residue Levels (ppm)

n Min. Max. HAFT1 Median Mean Std. Dev.

Barley, grain 0.236-0.291 13-17 32 0.3 2.0 1.85 0.65 0.72 0.35

Barley, straw 0.236-0.291 13-17 32 0.76 14.4 14 2.7 4.5 3.7

Barley, hay 0.236-0.260 7-14 32 0.6 4.6 4.05 1.5 1.72 0.97

1HAFT = highest average field trial.

In addition, HED has reviewed the submitted data and determined there is no need to revise the 

existing poultry commodity tolerance levels as a result of the proposed new use on poultry litter 

in chicken broiler and turkey grow-out houses (D. McNeilly, D399692, 20 September 2012). 

The existing tolerances for poultry are based on residues in or on poultry feed items and are 

adequate to cover the very low residues resulting from the proposed use on poultry litter in 

chicken broiler and turkey grow-out houses. The residue levels expected from this use are 

expected to be non-detectable (ND) provided that the label is revised to restrict the treatment to 

occur at least three weeks prior to slaughter. Therefore, HED concludes that this new poultry 

house use will have no impact on the dietary exposure assessment as described in Section 5.4. 

HED notes that data for eggs were not submitted, and that the use should not be expanded to 

include treatment of laying hen facilities. Further, as discussed previously in Section 2.3, HED 

recommends a label restriction indicating that if one single application is made at the maximum 

rate of 50 lbs, slaughter cannot occur sooner than six weeks after application.

5.3 Water Residue Profile

I. Maher, D378901/D385246, 22 February 2011

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). 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 Environmental Fate and Effects Division (EFED) provided estimated residues of zetacypermethrin in drinking water from the use of zeta-cypermethrin and cypermethrin on cotton. 

The cotton use results in the highest estimated drinking water concentrations (EDWCs) for all 

assessed use scenarios, including those associated with the petitions currently under review. The 

EDWCs used in this dietary assessment are summarized in Table 5.3. The surface water 

EDWCs were generated using the FQPA Index Reservoir Screening Tool (FIRST) Model and 

the ground water estimates are from the Screening Concentration In GROund Water (SCI-GroW) 

Model. The models and their descriptions are available at the USEPA 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 
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changes, HED incorporated the 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 0.066 ppb 

was used.

The use of the surface water values in the dietary assessment is therefore protective of potential 

exposure through ground water sources of drinking water.

Table 5.3. Tier I Analysis - EDWCs in surface water and ground water for cypermethrin and zetacypermethrin.

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 Continuing 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 alphacypermethrin and zeta-cypermethrin. Adequate field trial data are available to support the new 

uses of zeta-cypermethrin. The proposed new uses of the pending new active ingredient alphacypermethrin are being reviewed under a separate petition (Petition No. 0F7690).

5.4.1 Description of Residue Data Used in Dietary Assessment

Partially refined (probabilistic) dietary exposure assessments were performed in order to 

determine the exposure and risk estimates which result from the use of cypermethrin, alphacypermethrin, and zeta-cypermethrin on the crops listed under 40 CFR 180.418 and the proposed 

new uses. Anticipated residues from USDA Pesticide Data Program (PDP) monitoring data, 

field trial data, empirical processing factors, and percent crop treated estimates were used where 

appropriate. For the acute assessment, residue distributions were generally used when PDP and 

field trial data were included. In order to assess short-term aggregate risk to the cypermethrins, 

average dietary exposure estimates (i.e., food and drinking water) were calculated. Because the 

endpoint from the acute study is protective of endpoints from repeat dosing studies, a chronic 

dietary risk assessment was not conducted. 

The previous dietary analysis for cypermethrin/zeta-cypermethrin was conducted using version 

2.03 of the DEEM software together with USDA’s Continuing Surveys of Food Intakes by 

Individuals (CSFII) from 1994-1996 and 1998 consumption data (D335224, D. McNeilly, 5-

Nov-2007). The current assessment updates the prior assessment by 1) taking into account 

revised toxicological endpoints, requiring a refined acute dietary exposure assessment 2) adding 
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the new proposed uses of zeta-cypermethrin, and 3) incorporation of updated anticipated residue 

levels and percent crop treated estimates where appropriate. 

HED considers the dietary assessments to be partially refined, but at the same time, very healthprotective. 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 were one to two

orders of magnitude lower than the field trial data for the same commodities. Therefore, field 

trial data represent conservative estimates of exposure. The assessment is also conservative in 

that tolerance level residues were used for many commodities in the acute assessment. 

Due to the many conservative assumptions made in this assessment, in particular, the use of field 

trial data (as opposed to monitoring data) for many commodities, HED is confident that the acute 

and average dietary assessments overestimate exposures to the general U.S. population and all 

population subgroups.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The following maximum percent crop treated estimates (BEAD Screening Level Usage Analysis 

(SLUA), 10/31/2011) were used in the acute dietary risk assessment for the following crops that 

are currently registered for zeta-cypermethrin/cypermethrin: almonds: 2.5%; apples: 2.5%; 

broccoli: 30%; cabbage: 30%; carrot: 10%; cauliflower: 25%; celery: 60%; 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 

watermelon: 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/zetacypermethrin: almonds: 1%; apples: 1%; broccoli: 20%; cabbage: 15%; carrot: 2.5%; 

cauliflower: 15%; celery: 35%; cherries: 5%; grapefruit: 35%; green beans: 15%; green peas: 

10%; lemon: 1%; lettuce: 55%; orange: 35%; peach: 2.5%; peppers: 15%; potato: 1%; sweet 

corn: 15%; spinach: 30%; tomato: 5%; and watermelon: 2.5%. 

5.4.3 Acute Dietary Risk Assessment

Acute dietary risk estimates are below HED’s level of concern for all population subgroups 

(Table 5.4.6a). For acute exposures, the dietary risk for the U.S. population is estimated to be 

18% of the acute population-adjusted dose (aPAD) at the 99.9th percentile. Acute risk for all 

infants (<1 year old) and children 1-2 years old, the highest-exposed population subgroup, are 

both estimated to be 87% of the aPAD at the 99.9th percentile. This was a partially refined with 
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PDP monitoring data and field trial data residue distributions used for some commodities. This 

assessment is considered to be conservative, because tolerance level residues and distributions of 

field trial data (as opposed to monitoring data) were used for many commodities. Additionally, 

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 subgroups is presented in 

Table 5.4.6b. 

5.4.6 Summary Tables

Table 5.4.6a. Summary of the Acute Exposure and Risk Estimates for Cypermethrins

Population 

Subgroup

Acute Assessment (99.9th Percentile)

aPAD, mg/kg/day Exposure Estimate, mg/kg/day % aPAD

U.S. Population 0.07 0.012516 18

All infants (< 1 yr) 0.023 0.020100 87 

Children 1-2 yrs 0.023 0.019915 87 

Children 3-5 yrs 0.023 0.016233 71 

Children 6-12 yrs 0.07 0.009550 14 

Youth 13-19 yrs 0.07 0.009147 13 

Adults 20-49 yrs 0.07 0.010018 14 

Adults 50+ yrs 0.07 0.008213 12 

Females 13-49 yrs 0.07 0.008979 13 

Populations with the highest exposure estimates are bolded. Although the exposure estimate for all infants is slightly higher than 

for children 1-2 years old, with rounding the %aPAD is essentially equivalent. 

Table 5.4.6b. Summary of the Average Exposure Estimates for Cypermethrins

Population Subgroup Exposure Estimate, mg/kg/day

U.S. Population 0.000920

All infants (< 1 yr) 0.001602

Children 1-2 yrs 0.003441

Children 3-5 yrs 0.002458

Children 6-12 yrs 0.001475

Youth 13-19 yrs 0.000746

Adults 20-49 yrs 0.000662

Adults 50+ yrs 0.000582

Females 13-49 yrs 0.000575
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed new residential uses for zeta-cypermethrin; however, there are registered 

residential uses for cypermethrin and zeta-cypermethrin that have been reassessed in this 

document to reflect updates to HED’s 2012 Residential SOPs along with policy changes for body 

weight assumptions and inhalation rates. Revisions of the residential exposures will impact the 

human health aggregate risk assessment for zeta-cypermethrin. HED has determined that shortterm exposures are likely to occur in a residential setting; however, the cypermethrins do not

increase in potency with repeated dosing. Therefore, only single day residential exposures were 

assessed.

6.1 Registered Cypermethrins Residential Handler Exposure/Risk Estimates

Cypermethrin and zeta-cypermethrin are registered for use on a variety of indoor and outdoor 

residential environments including: lawns, gardens, pets, and indoor surfaces and spaces. The 

registered products are formulated as liquids, wettable powders, granules, ready to use aerosols 

and foggers. Numerous non-occupational/residential 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, handler scenarios and application rates for the cypermethrins 

in the Revised Occupational and Residential Exposure Assessment for the Reregistration

Eligibility Decision Document (RED), the 2011 Pyrethroid Cumulative Risk Assessment 

(PCRA, D394576) and various registered labels were used to capture and summarize handler 

scenarios which resulted in the most conservative and worst-case exposure scenarios. The PCRA 

provided exposure scenarios for cypermethrin as the representative active ingredient. The 

quantitative exposure/risk assessment developed for residential handlers is based on the 

following scenarios: 

Mixer/loader/applicator using hose-end sprayer on turf

Mixer/loader/applicator using backpack on turf and gardens

Mixer/loader/applicator using manually pressurized handwand for indoor surfaces

Application via aerosol can for indoor surfaces and space

Registered Residential Handler Non-Cancer Exposure and Risk Estimates

Since a dermal endpoint was not selected, only a quantitative inhalation handler exposure 

assessment was performed. Residential handler inhalation exposure estimates were calculated 

based on a HEC and human equivalent dose which reflect 24 hours of exposure. Since handler 

exposure is expected to be significantly less than 24 hours, the inhalation exposure estimates are 

sufficiently protective of all scenarios. Table 6.1 provides estimates of residential handler 

inhalation exposure and risk resulting from use of cypermethrin on turf, gardens, and indoor 

surface space. Although there is potential inhalation exposure resulting from the application of 

dog tags and spot-on products for pets, inhalation exposure is considered negligible for these 

scenarios and therefore, a quantitative assessment was not performed for these uses. All 
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inhalation risk estimates resulted in MOEs ranging from 6,100 to 48,000, are greater than the 

LOC of 30 and are not of concern.

Table 6.1. Short-Term Residential Handler Inhalation Exposure and Risk Estimates for Cypermethrins.

Exposure 

Scenario 

Target 

MOE

Inhalation Unit 

Exposure (mg/lb 

ai)

Maximum 

Application 

Ratea

(lb ai/A)

Amount handled 

or Area Treated 

/ Dayb

Inhalation

Dose (mg/kg/day)c MOEd

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 Cypermethrins Registered Residential Post-application Exposure/Risk Estimates

There is the potential for post-application exposure for individuals as a result of being in an 

environment that has been previously treated with cypermethrin or zeta-cypermethrin. Postapplication inhalation 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 conducted. 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 pathways 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 exposures 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, 
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Incidental oral (hand-to-mouth and object-to-mouth) exposure from pets for children, 

Inhalation exposure for adults and children resulting from crack and crevice application 

to an indoor surface, and

Incidental oral (hand-to-mouth and object-to-mouth) exposure for children from indoor 

surface applications.

Combining Exposure and Risk 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 across 

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 since post-application inhalation 

exposure is considered negligible. However, inhalation and incidental oral exposures were 

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

Inhalation and incidental oral routes have different LOCs. Therefore, in order to combine 

exposure from the various routes the aggregate risk index (ARI) approach is used to estimate 

exposure and risk. ARIs ≥ 1 are not of concern.

The incidental oral scenarios from indoor exposure following crack and crevice applications and 

outdoor exposure from turf were not combined, not only because they are not likely to co-occur, 

but also because combining these scenarios would be overly-conservative due to the conservative 

nature of each of the individual assessments. 

Summary of Residential Post-application Exposure and Risk Estimates

There is potential for residential post-application incidental oral risk estimates resulting from use 

of the cypermethrins on turf and pets, or as a crack and crevice treatment using a manually 

pressurized handwand or fogger. Table 6.2 provides estimates of residential post-application 

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

scenarios for children resulted in MOEs ranging from 1000 to 6,400,000 and ARIs ranging from 

3 to 13. All post-application exposure estimates resulted in MOEs and ARIs greater than their 

respective LOCs and are not of concern.

Table 6.2. Residential Post-application Exposure and Risk Estimates for Cypermethrin and Zetacypermethrin.

Lifestage Post-application Exposure Scenario Dosea MOEb Combined 

Routes

ARIc

Adult

Indoor Crack & 

Crevice 

(Manuallypressurized 

handwand)

Inhalation 0.0000011 1,100,000 NA

NA

Child Turf (WP)

TTRd

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
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Table 6.2. Residential Post-application Exposure and Risk Estimates for Cypermethrin and Zetacypermethrin.

Lifestage Post-application Exposure Scenario Dosea MOEb Combined 

Routes

ARIc

Object-to-Mouth 0.001 7,600 N/A

Indoor Crack & 

Crevice 

(Manuallypressurized 

handwand)

Inhalation 0.0000046 250,000 X

Hand to Mouth 13 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/ARIinhalation) + (1/ARIoral)] where, ARIi = MOEinhalation/100 and ARIoral = MOEoral/300. ARIs greater than 1 

are not of concern.

d. TTR = Transferable Turf Residue; TTR data from MRID 45111501

6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

HED combines exposure and risk values resulting from separate residential exposure scenarios 

when it is likely that they can occur simultaneously based on the use-pattern and the behavior 

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 garden within the same treatment period. Similarly, in the case of indoor treatment of pests, 

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. 

6.4 Residential Risk Estimates for Use in Aggregate Assessment

Residential handler and post-application scenarios should generally not be combined. Although 

there is potential for the same individual (i.e., adult) to apply a pesticide in and around the home 

and be exposed by reentering a treated area in the same day, this is an unlikely exposure 

scenario, especially on a daily basis for up to 30 days. Combining both of these exposure 

scenarios would also be inappropriate because of the conservative nature of each individual 

assessment. Therefore, HED selected only the most conservative or worst case residential 

scenarios to be included in the aggregate risk estimates, based on the lower overall MOEs (i.e., 

higher risk estimates). 
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The recommended residential exposure 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 6,100 (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 previously 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 exposures and risk estimates recommended for the zetacypermethrin aggregate assessment is provided in Table 6.4.

Table 6.4. Recommendations for the Residential Exposures and Risk Estimates for the Zeta-cypermethrin Aggregate 

Assessment.

Lifestage

Handler 

Exposure 

(mg/kg/day)a

Residential 

Handler Total 

Exposure 

(mg/kg/day)c

Residential 

Handler 

MOEa

(ARI)

Post-application 

Exposure

(mg/kg/day)b

Residential Postapplication MOEb

Residential 

Postapplication 

ARIc

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 1000b3.3

Child –

Pressurized 

hand wand

0.0000046 0.0017 250,000 4,000 13

a. Table 6.1. Short-Term Residential Handler Exposure and Risk Estimates for Cypermethrin.

b. Table 6.2 Residential Post-application Exposure and Risk Estimates for Cypermethrin

c. Table 6.2 Residential Post-application Exposure and Risk Estimates for Cypermethrin

6.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for zetacypermethrin. The Agency has been working with the Spray Drift Task Force, USEPA 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/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 
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developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios. 

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

estimate post-application residential exposure of 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 zeta-cypermethrin applications.

6.6 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for zeta-cypermethrin at this time primarily because of the low 

acute inhalation toxicity (Toxicity Category III), low vapor pressure (3 x 10-9 mm Hg (20 C), 

and the low proposed use rate (0.025 lb ai/A). However, volatilization of pesticides may be a 

source of post-application inhalation exposure to individuals nearby pesticide applications. The 

Agency sought expert advice and input on issues related to volatilization of pesticides from its 

Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in 

December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.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, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for zeta-cypermethrin.

7.0 Aggregate Exposure/Risk Characterization

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

exposures and risks from three major sources: food, drinking water, and residential exposures. 

In an aggregate assessment, exposures from relevant sources are added together and compared to 

quantitative estimates of hazard (e.g., a BMDL, HED or PAD), or the risks themselves can be 

aggregated. When aggregating exposures and risks from various sources, HED considers both 

the route and duration of exposure.

Residential exposure to the cypermethrins is anticipated from existing registered use for 

cypermethrin and zeta-cypermethrin on lawns, gardens, pets, and indoor surfaces and spaces. 
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Therefore, the short-term aggregate exposure and risk assessment for the cypermethrins includes 

dietary (food and water) exposures anticipated from the registered and proposed uses, and nondietary exposures anticipated from the currently registered residential uses. 

 

7.1 Acute Aggregate Risk

HED typically includes only food and water in the acute aggregate assessment, as one day 

residential exposures are not routinely assessed. Therefore, the acute aggregate risk is equal to 

the acute dietary exposure and risk. Please refer to Section 5.4.3 for a detailed discussion of the 

acute dietary risk assessment. 

7.2 Short- Term Aggregate Risk

For assessing short-term aggregate risk, the average dietary exposure estimate was used since it 

represents a background exposure level from food and drinking water that may co-occur with 

residential exposures. Dietary and oral (hand to mouth) risks for children, and dietary and 

inhalation risks for adults were combined in this assessment, since the toxicological endpoints 

were the same. However, the level of concern (LOC) values were different (oral adults and 

children ≥6= 100; children<6=300), while inhalation LOC = 30); therefore, the respective risk 

estimates are combined using the aggregate risk index (ARI) approach. When this approach is 

used, aggregate risks are not of concern provided the calculated ARI is greater than 1. As shown 

in the table below, all ARIs are greater than 1, and therefore the risk estimates are not of concern. 

The adult residential scenario used to estimate aggregate exposure was handler applications to 

turf via backpack sprayer, while the children’s residential exposure scenario was hand-to-mouth 

exposure following use of an indoor fogger. The results of these calculations are presented in 

Table 7.2.

Table 7.2 Short-Term Aggregate Risk Calculations for Zeta-cypermethrin1

Population

Short-Term Scenario

Dietary

Exposure2

Oral Residential 

Exposure3

Dermal 

Residential 

Exposure

Inhalation 

Residential 

Exposure

Aggregate ARI 

(food, water, 

and 

residential)4,5

MOE ARI MOE ARI MOE ARI MOE ARI

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

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

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

2 MOE dietary = [BMD of 7.16 mg/kg-day)/(average dietary exposure)]. ARI dietary = [(MOE dietary)/(MOE 

target)]. MOE target = 100 for children ≥6 and adults; MOE target = 300 for children <6.

From Table 5.4.3, Child Average Dietary Exposure = children 1-2 yrs (maximum exposure) = 0.003441 mg/kg/day; 

and Adult Average Dietary Exposure = US Population (maximum exposure) = 0.000920 mg/kg/day

3 MOE oral = [(7.16 mg/kg-day)/(hand-to-mouth-residential /fogger)]. ARI oral = [(MOE oral)/(MOE target)]. 

Child Hand-to-mouth residential exposure = 0.007 mg/kg-day (Table 6.3) MOE target = 300. Residential handlerInhalation (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
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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-2008-0489-0006). 

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-HQOPP-2011-0746. No cumulative risks of concern were identified allowing the Agency to 

consider new uses for pyrethroids. For information regarding USEPA’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 were included in a recent cumulative risk assessment for pyrethrins and 

pyrethroids. The proposed new uses of zeta-cypermethrin will not significantly impact the 

cumulative assessment because, in the cumulative assessment, residential exposure was the 

greatest contributor to the total exposure. As there are no new residential uses for the 

cypermethrins, the proposed new uses will have no impact on the residential component of the 

cumulative risk estimates. Dietary exposures make a minor contribution to total pyrethroid 

exposure in the 2011 cumulative risk assessment. The dietary exposure assessment performed in 

support of the pyrethroid cumulative was much more highly refined than that performed for the 

single chemical. The dietary exposure assessment for the single chemical included conservative 

assumptions, using field trial data for a many commodities, including the proposed new uses 

with the assumption of 100% crop treated, and 3) for the cypermethrin risk assessment, the most 

sensitive apical endpoint in the cypermethrin hazard database was selected to derive the POD. 

Additionally, the POD selected for cypermethrin is specific to cypermethrin, whereas the POD 

selected for the cumulative assessment was based on common mechanism of action data that are 

appropriate for all 20 pyrethroids included in the cumulative assessment. 

9.0 Occupational Exposure/Risk Characterization

M. Collantes, D385662, 20 September 2012

9.1 Occupational Handler Exposure/Risk Estimates

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, short- and intermediate-term occupational handler exposure is 
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expected from the proposed uses; however, zeta-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 for agricultural crops,

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

• Mixing/Loading Liquids for Chemigation for agricultural crops,

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

• Applying Sprays with Groundboom Equipment for agricultural crops,

• Applying Sprays with Aerial Equipment for agricultural crops, 

• Applying Sprays with Airblast Equipment for agricultural crops,

• Flagging for Aerial Applications for agricultural crops, and

• Loader/Applicator with Push-Type Rotary Spreader for poultry house.

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

In completing the occupational assessment for zeta-cypermethrin, HED used standard 

assumptions with respect to the application rate (i.e., maximum proposed rate), area treated, adult 

body weight, and unit exposures derived from surrogate data generated by the various task 

forces. These assumptions were incorporated into the assessment using standard methodology 

used by HED for occupational exposure assessments.

Occupational Handler Non-Cancer Exposure and Risk Estimates

Table 9.1 presents the estimated short- and intermediate-term inhalation risk estimates 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 MOEs ranging 

from 9,300 to 200,000. 

The estimated handler MOE resulting from loading and applying the dust formulation for rotary 

spreaders was based on granular surrogate data. HED believes this is protective of the proposed 

dust formulation because of the magnitude of the estimated MOE and because of the 

conservative assumption regarding the application rate assumed to be done as a broadcast 

application rather than in 36 inch bands as proposed on the label.
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Table 9.1. Occupational Exposure and Risk Estimates for Zeta-cypermethrin. 

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure 

(mg/lb ai)a

Maximum Single

Application Rate 

(lb ai/A)b

Area Treated 

Daily (A)c

Inhalation

Mitigation Level Dose (mg/kg/day)d MOEe

Mixer/Loader

Liquids for Groundboom 

Applications

(AHETF)

Avocado, Black Sapote, 

Canistel, Maney Sapote, 

Mango, Papaya, Sapodilla, Star 

Apple, Artichoke, Pistachio

0.000219

(No respirator)

0.05 80 0.000011 100,000

Barley 0.000219

(No respirator)

0.05 200 0.000027 40,000

Liquids for Aerial 

Application

(AHETF)

Avocado, Black Sapote, 

Canistel, Maney Sapote, 

Mango, Papaya, Sapodilla, Star 

Apple, Artichoke, Pistachio

0.000219

(No respirator)

0.05 350 0.000048 23,000

Barley 0.000219

(No respirator)

0.05 1,200 0.00016 67,000

Liquids for Chemigation

(AHETF)

Avocado, Black Sapote, 

Canistel, Maney Sapote, 

Mango, Papaya, Sapodilla, Star 

Apple, Artichoke, Pistachio, 

Barley

0.000219

(No respirator)

0.05 350 0.000048 23,000

Liquids for Airblast

(AHETF)

Avocado, Black Sapote, 

Canistel, Maney Sapote, 

Mango, Papaya, Sapodilla, Star 

Apple, Pistachio

0.000219

(No respirator) 0.05 40 0.0000055 200,000

Applicator

Sprays for Groundboom 

Applications

(AHETF)

Artichoke 0.00034

(No respirator)

0.05 80 0.000017 65,000

Barley 0.00034

(No respirator) 0.05 200 0.0000425 26,000
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Table 9.1. Occupational Exposure and Risk Estimates for Zeta-cypermethrin. 

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure 

(mg/lb ai)a

Maximum Single

Application Rate 

(lb ai/A)b

Area Treated 

Daily (A)c

Inhalation

Mitigation Level Dose (mg/kg/day)d MOEe

Sprays for Aerial 

Application

(AHETF)

Avocado, Black Sapote, 

Canistel, Maney Sapote, 

Mango, Papaya, Sapodilla, Star 

Apple, Artichoke, Pistachio

0.000068

(No respirator) 0.05 350 0.000015 75,000

Barley 0.000068

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

Sprays for Airblast 

Application

(AHETF)

Avocado, Black Sapote, 

Canistel, Maney Sapote, 

Mango, Papaya, Sapodilla, Star 

Apple, Pistachio

0.00471

(No respirator) 0.05 40 0.00018 9,300

Flagger

Flagging for Aerial 

Applications 

(PHED)

Avocado, Black Sapote, 

Canistel, Maney Sapote, 

Mango, Papaya, Sapodilla, Star 

Apple, Artichoke, Pistachio, 

Barley

0.00035

(No respirator) 0.05 350 0.000076 14,000

Loader/Applicator

Rotary Spreader - granule Chicken Broiler and Turkey 

Growout Houses 0.01 0.4 1 0.00005 22,000

a. Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (OPHED; March, 2012). Level of mitigation: Baseline, PPE, Eng. Controls).

b. Based on proposed labels (USEPA Reg. Nos. # 279-3125; 279-3126; and 39039-EN).

c. Exposure Science Advisory Council Policy #9.1.

d. Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/A) x Area Treated (A/day) /BW (80 kg).

e. Inhalation MOE = Inhalation HED (1.1 mg/kg/day)/ Inhalation Dose (mg/kg/day).
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9.2 Occupational Post-application Exposure/Risk Estimates

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for zeta-cypermethrin at this time primarily because of the low 

acute inhalation toxicity (Toxicity Category III), low vapor pressure (3 x 10-9 mm Hg at 20*C), 

and the low proposed use rate (0.4 lb ai/A for poultry house use; 0.05 lb ai/A for agricultural 

crop uses). However, there are multiple potential sources of post-application inhalation exposure 

to individuals performing post-application activities in previously treated fields. These potential 

sources include volatilization of pesticides and resuspension of dusts and/or particulates that 

contain pesticides. The Agency sought expert advice and input on issues related to volatilization 

of pesticides from 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-application inhalation exposure assessment for zeta-cypermethrin.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application 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 reenter treated fields, there is no toxicity associated with dermal exposure to the cypermethrins, 

and therefore a quantitative dermal post-application exposure assessment was not performed. 

Given the proposed use pattern associated with the poultry house use, there is no anticipated 

dermal post-application exposure for workers re-entering poultry houses, and thus a postapplication exposure assessment is not required. HED does not anticipate post-application 

dermal risks after exposure to zeta-cypermethrin.

Restricted Entry Interval (REI)

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

technical material which is classified as Category III for acute dermal and eye irritation, and 

Category IV for skin irritation. Based on the acute toxicity profile of zeta-cypermethrin, the 12-
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hour REI appearing on the proposed label is appropriate to protect agricultural workers from 

post-application exposures to zeta-cypermethrin.

10.0 References 

OPP Memoranda

M. Collantes, 9/20/2012, D385662, Zeta-cypermethrin. Occupational and Residential 

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

W. Drew, 9/7/2012, D378683, Alpha-Cypermethrin. Petition to 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-Cypermethrin

Uses on Various Raw and Processed Agricultural Commodities.

E. Holman, 9/20/2012, D379486, Zeta-Cypermethrin. Petitions for Use on Tropical Fruit, 

Artichoke, Barley, Oat, Rye, Buckwheat, and Pistachio. Summary of Analytical Chemistry and 

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I. Maher, 2/22/2011, D378901, Drinking Water Assessment for Zeta-Cypermethrin 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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Application to Litter in Chicken Broiler and Turkey Grow-Out Houses. 

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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.

Table A1. Toxicology Requirements for Cypermethin, Zeta-cypermethrin, and Alphacypermethrin

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

yes
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A.2 Toxicity Profiles

Table A.2a Acute Toxicity of Zeta-cypermethrin and Cypermethrin Technical 

Guideline 

No. Study Type MRIDs # Results

Toxicity 

Category

870.1000 Acute Oral – rat

Zeta-cypermethrin

41776115 LD50 (M): 134.4 mg/kg

(F): 86.0 mg/kg

Clinical signs of neurotoxicity observed.

II

870.1000 Acute Oral -

Cypermethrin

00056800 LD50 (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-cypermethrin

47944061 LD50 Females > 2000 kg/kg bw III

870.1100 Acute Dermal

Rats - Cypermethrin

Rabbits - Cypermethrin

00056800

00056800

LD50 > 4920 mg/kg/day. Clinical signs of 

neurotoxicity.

Abraded skin: LD50 > 2460 mg/kg. 

Lacrimation, discharge from the eye and 

"nervous and shaking". 

III

III

870.1100 Acute Dermal

Rats –

Alpha-cypermethrin

47944062 LD50 > 2000 mg/kg bw 

Males, females combined 

III

870.1200 Acute Inhalation - rat 

Cypermethrin

42395702 LC50: (not calculated but higher than)

LC50: 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-cypermethrin

47944063 LC50 Males > 2.47 mg/L

LC50 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-cypermethrin

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-cypermethrin

47944065 Moderately irritating III
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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-cypermethrin

47944066 Not a sensitizer N/A

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

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

870.3100 90-Day oral toxicity – rat

cypermethrin

MRID 00056802 & 92027034 

(1980)/Unacceptable

ppm = 0, 75, 150 or 1500

mg/kg/day = 0, 3.75, 7.5 or 75

NOAEL = 7.5 mg/kg/day

LOAEL = 75 mg/kg/day based on 

decreased body weight in both sexes.

870.3100 90-Day oral toxicity - rat: 

zeta-cypermethrin

MRID 41776101 (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 

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

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

mg/kg/day= 0, 0.75, 2.25, 6.75 abnormalities, ataxia, agitation, head 

nodding, and lip licking).

870.3200 21-Day dermal toxicity -

rat 

zeta- cypermethrin

MRID 45010401 (1999)/Acceptable

mg/kg/day = 0, 100, 500 or 1000

NOAEL = systemic: 1000 

mg/kg/day. Dermal: <100 

mg/kg/day

LOAEL = systemic: >1000 

mg/kg/day (LIMIT DOSE). Dermal: 

100 mg/kg/day, based on erythema 

&/or eschar 1/10 M & 6/10 F; 

desquamation 0/10 M & 2/10 F (no 

effects in any M or F controls).

870.3200 21-Day dermal toxicity –

rabbit

cypermethrin

MRID 00090035 (1981)/Acceptable 

mg/kg/day = 0, 2, 20, 200

NOAEL = Systemic non-abraded 

animals: 200 mg/kg/day (HDT)

Dermal NOAEL: 20 mg/kg/day

LOAEL = Systemic non-abraded 

animals: >200 mg/kg/day (HDT).

Dermal: 200 mg/kg/day based on 

signs of dermal irritation.

870.3465 21-Day inhalation toxicity 

– rat

cypermethrin

MRID 43507101 (1994)/Acceptable

mg/L = 0, 0.01, 0.05 or 0.25 (nose 

only)

NOAEL = 0.01 mg/L

LOAEL = 0.05 mg/L based on 

increased salivation.

870.3700a Prenatal developmental in 

rats

cypermethrin

MRID 00056804, 92027039 & 92027601

(1978)/Acceptable

mg/kg/day = 0, 17.5, 35 or 70

Maternal NOAEL = 17.5 mg/kg/day

LOAEL = 35 mg/kg/day based on 

decreased body wt gain; at 

70mg/kg/day, splayed limbs, spasms 

& hypersensitivity to noise & 

convulsions.

Developmental NOAEL = 70 

mg/kg/day (HDT).

LOAEL = not established.

870.3700a Prenatal developmental in 

rats zeta- cypermethrin

MRID 41776102 (1990)/Acceptable

mg/kg/day = 0, 5, 12.5, 25 or 35

Maternal NOAEL = 12.5 mg/kg/day

LOAEL = 25 mg/kg/day, based on 

ataxia, urine-stained abdominal fur, 

fecal-stained perineal fur, decreased 

food consumption & decreased body 

wt gain.

Developmental NOAEL 35 

mg/kg/day

LOAEL = not established

870.3700a Prenatal developmental in 

rats alpha- cypermethrin

MRID 47944073

(1994)/Acceptable mg/kg/day = 0, 3, 9, or 

18/15

Maternal NOAEL = 9 mg/kg/day

LOAEL = 15 mg/kg/day based on 

decreased body wt gain and food 

consumption, and increased incidence 

of clinical signs (unsteady gait, 

piloerection, limb splay, and 

hypersensitivity to sound and touch).

Developmental NOAEL = 9 

mg/kg/day 

LOAEL = 15 mg/kg/day based on 

decreased fetal weights (4%).

870.3700b Prenatal developmental in 

rabbits

MRID 43776301 & 43776302 

(1994)/Acceptable

Maternal NOAEL = 100 mg/kg/day

LOAEL = 450 mg/kg/day based on 
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Page 63 of 78

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

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

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

abdomino-genital staining, decreased 

feces & red or pink material in the 

pan (few does). At 700, anorexia, 

abdomino-genital staining, decreased 

feces & red or pink material in the 

pan were observed.

Developmental 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

Maternal NOAEL = 30 mg/kg/day

LOAEL > 30 mg/kg/day (HDT)

Developmental NOAEL = 30 

mg/kg/day

LOAEL = > 30 mg/kg/day (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 animals (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/day
Zeta-Cypermethrin Human Health Risk Assessment DP No. D378897, D385242, D397298

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

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

cypermethrin (1982)/Acceptable

ppm = control 1, control 2, 20, 150 or 

1500

mg/kg/day = 0, 1, 7.5 or 75

LOAEL = 75 mg/kg/day based on 

decreases in body wt gain (both 

sexes)

870.4100b

cypermethrin

Chronic toxicity dogs 

(capsule)

MRID 00112909, 42068503 & 92027037 

(1982)/Acceptable

mg/kg/day = 0, 1, 5 or 15

NOAEL = 5 mg/kg/day

LOAEL = 15 mg/kg/day based on 

body tremors, gait abnormalities, 

uncoordination, disorientation & 

hypersensitivity to noise plus 

decrease in body weight.

870.4100b Chronic toxicity dogs 

(feeding)

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 clinical signs (tremors, 

excessive salivation, irregular gait); at 

33.9 mg/kg/day, mortality. 18.1 

mg/kg/day (F) based on decreased 

body wt & wt gains.

870.4100b Chronic toxicity dogs 

(feeding)

alpha-cypermethrin

MRID 47944070

1995)/Acceptable

ppm = 0, 60, 120, or 240 

mg/kg/day = M: 0, 2.02, 4.11, or 7.90

F: 0, 2.18, 4.29, or 8.45 

NOAEL = 4.11 mg/kg/day (M); 4.29 

mg/kg/day (F)

LOAEL = 7.9 mg/kg/day (M); 8.45 

mg/kg/day (F)

based on clinical signs (skin 

reddening, hair loss, and tail 

irritation)

870.4200a Carcinogenicity rats

cypermethrin

MRID 00112910 & 9202741 

(1982)/Acceptable

ppm = 0 #1, 0 #2, 20, 150 or 1500

mg/kg/day = 0, 0, 1, 7.5 or 75

NOAEL = 7.5 mg/kg/day

LOAEL = 75 mg/kg/day based on 

decreases in body wt gain (both 

sexes).

No evidence of carcinogenicity

870.4200b Carcinogenicity mice

cypermethrin

MRID 00112911 & 92027038 

(1982)/Acceptable

ppm = 0 #1, 0 #2, 100, 400 or 1600

mg/kg/day = 0, 0, 14, 57 or 229

[M = 97 weeks; F = 101 weeks]

NOAEL = 14 mg/kg/day

LOAEL = 57 mg/kg/day (M) based 

on increased absolute (20%) liver wts

Females, there was a 15% increase in 

relative liver wts only at 229 

mg/kg/day.

Benign alveologenic neoplasms were 

observed at 229 mg/kg/day.

870.4200b Carcinogenicity mice

alpha-cypermethrin

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

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

870.5100 Salmonella typhimurium 

& S. cerevisiae reverse 

mutation assay

zeta-cypermethrin

MRID 41968205

(1992)/Acceptable

0, 100, 333, 1000, 3333, 5000, 10000 

μg/plate

Weak mutagen effects noted at 10, 

000, 5000 and 3333 ug/plate in 

absence of metabolic activation in 

Salmonella strain TA100 in two 

studies. Strains TA98, TA1S3S, 

TA1537 and TA 1538 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 

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

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

posture, splayed hindlimbs, soiled fur 

& unable to walk); at 250, more 

severe findings.

870.6200a Acute neurotoxicity 

screening battery rats 

alpha-cypermethrin

MRID 47944067

(1993)

mg/kg/day = 0, 4, 20, or 40

NOAEL = 4 mg/kg/day

LOAEL = 20 mg/kg/day based on 

clinical signs (gait abnormalities, 

prostration, thrashing, vocalization, 

piloerection, unkempt appearance), 

FOB findings (limb abnormalities 

and increased reactivity), and 

mortality. At 40 mg/kg/day, clinical 

neurotoxic signs, 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. Developmental 

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

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

been demonstrated from these 

studies: cypermethrin is readily 

absorbed from the 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 site.

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/cm2) 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) BMDL1SD = 7.16

BMD = 11.20

Non-Guideline WIL Study 

Acute Oral Toxicity in 

Rats - FOB

MRID 47050505 (2006) 

Acceptable

BMDL20 =55.9 

BMD20 = 76.3

*alpha-cypermethirn and zeta-cypermethrin are bridged to the database with cypermethrin. Therefore, selected studies for 

all are included. 
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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: BMDL1SD = 7.16 mg/kg, based on decreased motor 

activity 

Uncertainty Factor:

Adults and Children ≥ 6 years old: 100X (1X FQPA, 10X interspecies extrapolation, 10X 

intraspecies variability)

Acute RfD = 

100 ( )

7.16 /

UF

mg kg = 0.07 mg/kg

Children < 6 years old: 300X (3X FQPA, 10X interspecies extrapolation, 10X intraspecies 

variability)
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Comments about Study/Endpoint: The selected NOAEL (BMDL1SD ) 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. (2006) 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. There is no increase in hazard from repeated exposures to the cypermethrins; therefore, 

the acute dietary exposure assessment is protective of chronic dietary exposures since acute 

exposure levels are higher than chronic exposure levels. Accordingly, a dietary exposure 

assessment for the purpose of assessing chronic dietary risk was not conducted. 

Human equivalent Doses for Wolansky Study and Relevant Long-term Studies 

Study Point of Departure Human Equiv. Dose * Uncertainty

Rat (Wolansky) BMD BMDL Factors 1SD BMD BMDL1SD

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; NOAELH=NOAELD (BWD/BWH)^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: BMDL1SD = 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 = 

300 ( )

7.16 /

UF

mg kg = 0.023 mg/kg
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Comments about Study/Endpoint: The selected NOAEL (BMDL1SD) 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. 

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/day). The observations 

in the abraded rabbits were not used for risk assessment since the method (abraded skin) does not 

simulate actual exposure and results in compromised test conditions. Additionally, there would 

be physiological differences between the abraded and non-abraded animals. Based on the 

exposure profile, HED does not anticipate long-term dermal exposure for adults or children.

Inhalation Exposure (Short-, and Intermediate-Term)

Study Selected: Inhalation Toxicity Study in Rats (Cypermethrin)

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/UFs: In a 21 day inhalation toxicity study in rats, increased 

salivation was 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 USEPA’s RfC guidance (1994). The HECs were used to calculate human 

equivalent doses (HED) that were used in inhalation risk assessments (see A.4). The 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 = 

300 ( )

7.16 /

UF

mg kg = 0.023 mg/kg
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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 the RDDR value of 3.1 based on 

extrarespiratory effects (body weight changes, salivation) as shown below. The inputs for the 

program are: MMAD=2.63; σ=1.87; BW for Wistar Rats from study report=271g; Standard 

human BW information (i.e., 70 kg). 

 Figure 1. Regional Deposited Dose Ratios (RDDR) for Cypermethrin
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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: intraspecies 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: 
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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 factor 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 

Development (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 pharmacodynamic (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 10X1. Thus, the UF when using 

the RfC methodology is customarily 30X.

For the cypermethrins, 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-ofentry effect. For cypermethrin, systemic (extrarespiratory) effects were observed 

and therefore, only systemic HECs were derived. 

2. Time adjustments are traditionally needed for non-occupational (bystander) 

versus occupational exposure scenarios. Traditionally, HECs for nonoccupational 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 adjustment 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. 
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The RfC methodology applies a dosimetric adjustment that takes into consideration not only the 

differences in ventilation rate (MV) but also the 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 

USEPA’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 

exposure 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 incorporates 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 derivation of a HEC for inhaled gases is described by the following 

equation:

Where:

PODstudy: Point of departure identified in the critical toxicology study

Danimal exposure: Duration of daily animal exposure (hrs/day)

Danticipated exposure: Anticipated daily human duration of exposure (hrs/day)

Wanimal exposure: Duration of weekly animal exposure (days/week)

Wanticipated exposure: Anticipated weekly human duration of exposure (days/week)

RGDR: Regional Gas Dose Ratio

Calculations used to estimate the inhalation 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 aerodynamic diameter [MMAD]) and the geometric standard deviation (σg), 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 

inhalation particulate exposure concentration for a human (H) that would be associated with the 

same dose delivered to the region or target tissue.

RDDRr = (RDDr/Normalizing Factor)A

 (RDDr/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 σg defined from an aerosol 

inhalation study. The values for the species-specific parameters used to calculate the RDDR are 

provided in the USEPA document “Methods for Derivation of Inhalation Reference 

Concentrations and Application of Inhalation Dosimetry.”

HEC = POD * D 

D 

* W

W

study * RGDR animal exposure (hrs/ day)

human exposure (hrs/ day)

animal exposure (days / wk)

human exposure (days/ wk)
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Appendix B. Physical/Chemical Properties

Table B.1. Physicochemical Properties of the Technical Grade Test Compound: Zeta-Cypermethrin.

Parameter Value Reference

Melting point -22.4°C MRID 46971402 1, 

unless otherwise noted. pH 4.5 (1% suspension)

Density 1.219 g/mL at 25°C

Water solubility (25°C) 45 ppb

Solvent solubility miscible in acetone, acetonitrile, methylene 

chloride, and toluene

Vapor pressure 3 x 10-9 mm Hg at 20°C2

Dissociation constant, pKa Not available

Octanol/water partition coefficient, Log(KOW) >6

UV/visible absorption spectrum Not available

1 Values as reported by the petitioner.

2 

 Cypermethrin: Phase 4 HED Risk Assessment for the Reregistration Eligibility Decision (RED). PC Code 109702; DP 

Barcode D293416. April 6, 2006. 
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Appendix C. International Harmonization

Zeta-Cypermethrin (PC Code 129064; May 26, 2011)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: Cypermethrin. There are no separate MRLs for zeta-cypermethrin per se

US Canada Mexico2 Codex3

40 CFR 180. 418(a)(1)

Plant/Livestock: cypermethrin (±)alpha 

cyano-(3-phenoxyphenyl)methyl(±)cis,trans3(2,2-dichloroethenyl-2,2-

dimethylcyclopropanecarboxylate

180. 418 (a)(2)

Z-cypermethrin (S-cyano(3-phenoxyphenyl) 

methyl (±))(cis-trans 3-(2,2-dichloroethenyl)-

2,2 dimethylcyclopropanecarboxylate and its 

inactive R-isomers

(RS)-α-cyano-3-

phenoxybenzyl 

(1RS, 3RS)-(1RS, 

3SR)-

3-(2,2-

dichlorovinyl)-2,2-

dimethylcycloprop

anecarboxylate

cypermethrin (sum of 

isomers). The residue 

is fat-soluble.

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Artichoke, globe 0.6 0.1

Avocado 0.5

Barley, grain 3 2 Po

Barley, hay 6

10 straw and fodder 

(dry) of cereal grains

Barley, straw 20 10 straw and fodder 

(dry) of cereal grains

Black Sapote 0.5

Buckwheat, grain 3

0.3 cereal grains, 

except rice barley, 

oats, rye, and wheat

Buckwheat, hay 6

10 straw and fodder 

(dry) of cereal grains

Buckwheat, straw 20 10 straw and fodder 

(dry) of cereal grains

Canistel 0.5

Mamey Sapote 0.5

Mango 0.7 0.7

Oat, grain 3 2 Po

Oat, hay 6

10 straw and fodder 

(dry) of cereal grains

Oat, straw 20 10 straw and fodder 

(dry) of cereal grains

Papaya 0.5 0.5

Pistachio 0.05

Rye, grain 3 2 Po

Rye, hay 6

10 straw and fodder 

(dry) of cereal grains
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Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: Cypermethrin. There are no separate MRLs for zeta-cypermethrin per se

US Canada Mexico2 Codex3

Rye, straw 20 10 straw and fodder 

(dry) of cereal grains

Sapodilla 0.5

Star Apple 0.5

Completed: M. Negussie; May 26, 2011

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.
Zeta-Cypermethrin Human Health Risk Assessment DP No. D378897, D385242, D397298

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Appendix D. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These 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 included review by the Human Studies Review Board. Descriptions of 

data sources as well as guidance on their use can be found at: 

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

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