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5.4.5 Average Dietary Risk Assessment ............................................................................. 40

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

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 41

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

6.2 Cypermethrin Registered Residential Post-application Exposure/Risk Estimates ........ 42

6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios) ......................... 44

6.4 Residential Risk Estimates for Use in Aggregate Assessment................................45

6.5 Spray Drift...................................................................................................................... 45

6.6 Residential Bystander Post-Application Inhalation Exposure ....................................... 46

7.0 Aggregate Exposure/Risk Characterization....................................................................... 47

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

7.2 Short- Term Aggregate Risk .......................................................................................... 47

7.3 Intermediate-Term/Chronic Aggregate Risk.................................................................. 48

8.0 Cumulative Exposure/Risk Characterization..................................................................... 48

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

9.1 Occupational Handler Exposure/Risk Estimates............................................................ 49

9.2 Occupational Post-application Exposure/Risk Estimates .............................................. 54

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates.......................... 54

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates.............................. 54

10.0 References.......................................................................................................................... 55

Appendix A. Toxicology Profile and Executive Summaries....................................................... 58

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

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

A.3 Toxicological Doses and Endpoints for Use in Human Risk Assessments ................... 67

A 4. HEC Inhalation Calculations ........................................................................................... 70

Appendix B. Physical/Chemical Properties................................................................................. 73

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

Appendix D. Review of Human Research................................................................................... 77

Appendix E. Executive Summaries for Submitted Studies for Alpha-cypermethrin .................. 77
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1.0 Executive Summary

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

containing the new pesticide active ingredient alpha-cypermethrin for use on a variety of crops. 

Additionally, BASF has requested the establishment of permanent tolerances for residues of 

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

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

relies on alpha-cypermethrin data, as well as previously submitted data for the related registered 

insecticides, cypermethrin and zeta-cypermethrin. Cypermethrin, zeta-cypermethrin and alphacypermethrin are isomer mixtures of the same chemical. Cypermethrin consists of a mixture of 

eight isomers (four diastereoisomeric pairs). Alpha-cypermethrin consists of two of the four cisisomers of cypermethrin. Zeta-cypermethrin is composed of four of the eight isomers of 

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

conducted to support the registrations of cypermethrin and zeta-cypermethrin are applicable to 

the registration of alpha-cypermethrin. 

Alpha-cypermethrin is a broad spectrum insecticide, effective against target pests through 

contact and ingestion. Alpha-cypermethrin is a type II synthetic pyrethroid chemical. 

Pyrethroids disrupt the voltage-gated sodium channels in the nervous system, resulting in 

neurotoxicity. 

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

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

for cypermethrin, zeta-cypermethrin, and 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 risk assessment purposes, the active 

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

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

aggregate risk assessment considers not only the exposure associated with the proposed food 

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

residential exposure from existing uses of cypermethrin and zeta-cypermethrin.

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, EPA is applying 

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

route of exposure, data gaps and the population exposed. For adults (including women of childbearing age) and children > 6 years of age, EPA is reducing the FQPA safety factor to 1X.
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There was no evidence of increased qualitative or quantitative susceptibility in developmental 

toxicity studies in the rat and rabbit and a rat two-generation reproductive toxicity study. A 

developmental neurotoxicity (DNT) study with zeta-cypermethrin did indicate some potential 

increased sensitivity in the offspring based on body weight changes in 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. 

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., 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 alpha-cypermethrin, zeta-cypermethrin and 

cypermethrin are adequately understood for the purpose of estimating residues in ground and 

surface water sources of drinking water. For all three cypermethrins, HED has concluded the 
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residue of concern for risk assessment and tolerance enforcement is the parent compound, 

cypermethrin, zeta-cypermethrin and alpha-cypermethrin.

Dietary exposure to alpha-cypermethrin may occur from consuming treated crops or their 

processed commodities. Partially refined (probabilistic) dietary exposure assessments were 

performed in order to determine the exposure and risk estimates resulting from the use of 

cypermethrin, alpha-cypermethrin, and zeta-cypermethrin on the crops listed under 40 CFR 

180.418 and the proposed new uses. HED has used modeling to estimate dietary exposure to the 

cypermethrins. The modeling uses health-protective assumptions regarding residues of alphacypermethrin 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, PDP 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.

This assessment addresses exposure and risk associated with the proposed end-use products 

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

associated with handler activities (i.e., mixing, loading, and applying) as well as with 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 is expected to be short- term (1 to 30 days) and intermediate-term (1 to 6 months). Longterm exposures (greater than 6 months) are not anticipated for either the new proposed uses or 

the existing uses. However, due to the pyrethroid toxicity profile, only single day risk 

assessments were conducted for occupational and residential exposure, which are protective of 

all durations of exposure.

At this time, there are no registered or requested uses for alpha-cypermethrin that involve a 

residential setting; however, residential exposure and risk were estimated for registered 

residential uses of cypermethrin and zeta-cypermethrin. For the registered residential uses of the 

cypermethrins, there is a potential for residential exposure associated with handler activities for 

adults only, as well as with post-application activities for adults and children (1 to < 2 years old) 

who re-enter treated areas. For the registered residential uses, exposure is expected to be shortterm in duration. However, since the cypermethrins do not increase in potency with repeated 
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dosing, only single day residential exposures were assessed. Residential intermediate-term 

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

inhalation handler exposure assessment was performed for residential turf, indoor surface sprays, 

foggers, and pet uses. The scenarios chosen for the purpose of conducting residential and 

aggregate assessments were those that result in the highest exposures for adults and children, for 

both indoor and outdoor uses. 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. 

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 exposed via the incidental oral route, the LOC is 300, based on the 

standard 10X interspecies and10X intraspecies factors, and the 3X FQPA factor. 

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

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

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

risk. ARIs ≥ 1 are not of concern.

Residential handler inhalation risk estimates for cypermethrin and zeta-cypermethrin uses are not 

of concern, with inhalation MOEs ranging from 6,100 to 48,000. Likewise, residential postapplication exposure and risk estimates (MOEs and ARIs) for adults and children were greater 

than their respective LOC and not of concern. Adult post-application exposure via the inhalation 

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

exposed via the inhalation and incidental oral routes had MOEs ranging from 1000 to 6,400,000 

and an ARI for the combined routes of 13. 

Exposure has also been assessed for occupational handlers mixing, loading, and applying alphacypermethrin. All occupational handler inhalation exposure assessments resulted in MOEs 

ranging from 14,000 to 410,000 and are not of concern. As no dermal endpoint was identified, a 

quantitative post-application assessment was not performed. Post-application 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. 

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).

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

pyrethroids. The proposed new uses of alpha-cypermethrin will not impact the cumulative
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assessment because: 1) the alpha-cypermethrin application rates are lower than the zetacypermethrin rates and are expected to result in lower residue levels; and 2) zeta-cypermethrin 

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

petition and those uses were incorporated into the cumulative assessment. Additionally, no new 

residential uses are proposed, so the residential cumulative assessment will not be impacted.

2.0 HED Recommendations

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

establishment of tolerances as summarized in Table 2.2.3.

2.1 Data Deficiencies

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate tolerance-enforcement methods are available in PAM Volume II for determining 

residues of cypermethrin, zeta-cypermethrin and alpha-cypermethrin in plant (Method I) and 

livestock (Method II) commodities. Both methods are gas 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

Currently established US tolerances for cypermethrin and zeta-cypermethrin are included in the 

same listing in the 40 CFR, but have separate sections and different crops listed; where there are 

tolerances for both actives set on the same crop, the levels are the same. Tolerances for residues 

of alpha-cypermethrin will be established in another separate section. Mexico adopts US 

tolerances, and/or Codex maximum residue limits (MRLs), for its export purposes. Canada has 

established MRLs for cypermethrin only. There are currently no Canadian MRLs established for 

residues of alpha-cypermethrin or zeta-cypermethrin. There are multiple Codex MRLs for 

alpha-cypermethrin, but all are in conjunction with MRLs for total cypermethrin isomers (no 

MRLs have been established solely for alpha-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 
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and alpha-cypermethrin. For enforcement purposes, the same moiety is being regulated. The 

current petition proposes alpha-cypermethrin tolerances at the same levels as existing zetacypermethrin tolerances in the corresponding commodities. Several of the proposed tolerances 

are harmonized with the Codex MRLs (those in tree nuts, tomatoes, and cattle meat byproducts). 

Many of the proposed US use patterns differ from those upon which the Codex MRLs are based; 

therefore, harmonization of the recommended tolerances (other than those mentioned above) 

with existing Codex MRLs is not feasible (Appendix C). 

2.2.3 Recommended Tolerances

HED recommends that 40CFR §180.418 be revised by establishing tolerances for the 

commodities listed in Table 2.2.3.

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

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

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

though they have separate tolerance listings in 40CFR §180.418. The same holds true for alphacypermethrin. In addition, the existing tolerance expression for cypermethrin and zetacypermethrin, as well as the proposed tolerance expression for alpha-cypermethrin, need to be 

revised to reflect both coverage and compliance statements, in accordance with current policy. 

Therefore, the tolerance expression for alpha-cypermethrin in plant and livestock commodities, 

to be cited in a new paragraph under 40CFR §180.418(a)(3), is as follows:

Tolerances are established for residues of the insecticide, alphacypermethrin, (R)-cyano(3-phenoxyphenyl)methyl (1S,3S)-rel-3-(2,2-

dichloroethenyl)-2,2-dimethylcyclopropane carboxylate, 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 alpha-cypermethrin tolerances should be listed separately in 40CFR 

§180.418 (a)(3). 

The tolerance expressions for cypermethrin, cited in 40CFR §180.418(a)(1), and zetacypermethrin in 40CFR §180.418(a)(2), should be revised when possible, to reflect coverage and 

compliance statements. 

The proposed and recommended tolerances for alpha-cypermethrin are presented in Table 2.2.3.
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TABLE 2.2.3 Tolerance Summary for Alpha-cypermethrin. 

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Cottonseed 0.50 0.50 Cotton, undelinted seed

Root and tuber vegetables, except 

sugar beet (Group 1)

0.10 0.10 Vegetable, root and tuber, group 

1, except sugar beet

Tree nuts (Group 14) 0.05 0.05 Nut, tree, group 14

Edible podded legume vegetable 

(Subgroup 6A)

0.50 0.50 Vegetable, legume, edible podded, 

subgroup 6A

Succulent shelled pea and bean 

(Subgroup 6B)

0.10 0.10 Pea and bean, succulent shelled, 

subgroup 6B

Dried shelled pea and bean, except 

soybean (Subgroup 6C)

0.05 0.05 Pea and bean, dried shelled, 

except soybean, subgroup 6C

Leafy vegetable, except brassica 

(Group 4)

10.00 10 Vegetable, leafy, group 4

Head and stem brassica (Subgroup 

5A)

2.00 2.0 Brassica, head and stem, subgroup 

5A

Corn grain 0.05 0.05 Corn, field, grain

Pop corn 0.05 0.05 Corn, pop, grain

Sweet corn 0.05 0.05 Corn, sweet, kernel plus cob with 

husks removed

Soybean, seed 0.05 0.05

Sugar beet roots 0.05 0.05 Beet, sugar, roots

Sorghum grain 0.50 0.50 Sorghum, grain, grain

Rice grain 1.50 1.5 Rice, grain

Cucurbit vegetables (Group 9) 0.20 0.20 Vegetables, cucurbit, group 9

Fruiting vegetables (Group 8) 0.20 0.20 Vegetables, fruiting, group 8-10

Sugar beet tops 0.20 0.20 Beet, sugar, tops

Wheat grain 0.20 0.20 Wheat, grain

Citrus fruit (Group 10) 0.35 0.35 Fruit, citrus, group 10-10

Citrus oil 4.00 4.0 Citrus, oil

Citrus dried pulp 1.80 1.8 Citrus, dried pulp

Alfalfa hay 15.00 15 Alfalfa, hay

Cattle, fat None 1.0

Cattle, meat None 0.20

Cattle, meat byproducts None 0.05

Egg None 0.05

Goat, fat None 1.0

Goat, meat None 0.20

Goat, meat byproducts None 0.05

Hog, fat None 0.10

Hog, meat None 0.05

Horse, fat None 1.0

Horse, meat None 0.20

Horse, meat byproducts None 0.05

Milk, fat, reflecting 0.10 ppm in 

whole milk

None 2.5

Poultry, fat None 0.05

Poultry, meat None 0.05

Sheep, fat None 1.0

Sheep, meat None 0.20
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TABLE 2.2.3 Tolerance Summary for Alpha-cypermethrin. 

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Sheep, meat byproducts None 0.05

2.2.4 Revisions to Petitioned-For Tolerances

No revisions to the tolerance levels in the petition, as proposed by BASF, were necessary. 

However, all the proposed commodity definitions (except for soybean, seed) were revised to 

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

Additionally, appropriate tolerances for alpha-cypermethrin in livestock commodities (which 

were not proposed by BASF) are recommended by HED (reflecting those established for zetacypermethrin), based on the potential for residues in livestock feed items associated with the 

proposed uses.

2.3 Label Recommendations

None.

3.0 Introduction

3.1 Chemical Identity

TABLE 3.1 Test Compound Nomenclature. 

Compound chemical 

structure

Common name Alpha-cypermethrin

Company experimental name BAS 310 I or AC 900049

Empirical formula C22H19Cl2NO3

Molecular weight 416.3 g/mol
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TABLE 3.1 Test Compound Nomenclature. 

IUPAC name A racemic mixture comprised of: 

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

dimethylcyclopropanecarboxylate 

and 

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

dimethylcyclopropanecarboxylate

or (synonymously)

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

dimethylcyclopropanecarboxylate 

and 

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

dimethylcyclopropanecarboxylate

CAS name (R)-cyano(3-phenoxyphenyl)methyl (1S,3S)-rel-3-(2,2-dichloroethenyl)-2,2-

dimethylcyclopropanecarboxylate

CAS registry number 67375-30-8

End-use product (EP) BAS 310 40 I EC insecticide (EPA File Symbol 7969-EOI), 10.9% ai (w/w), 0.83 

lb ai/gal. 

3.2 Physical/Chemical Characteristics

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

coefficient (log KOW = 5.5). These values account for the low surface and groundwater 

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

pressure (2.55 x 10-9 mm Hg at 25oC), which decreases its potential to volatilize. See Appendix 

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

3.3 Pesticide Use Pattern

Alpha-cypermethrin is proposed for control of a variety of pests on agricultural crops before, 

during, or after planting. Alpha-cypermethrin is formulated as a 10.9 % liquid (0.83 lbs ai/gal). 

Broadcast applications are to be made by aerial, ground and chemigation methods. In addition, 

the proposed product is to be applied through sprinkler irrigation systems, including center pivot, 

lateral move, end tow, side (wheel) roll, traveler, big gun, solid set, or hand move irrigation 

systems. 

Cypermethrin is generally applied at a maximum seasonal use rate (0.6 lb ai/A for most uses) 4X 

that of zeta-cypermethrin (0.15 lb ai/A for most uses), which is 2X the proposed maximum 

seasonal rate for alpha-cypermethrin (0.075 lb ai/A). 

Note: The following statement is included on the proposed label for alpha-cypermethrin: “DO 

NOT apply more than the maximum seasonal total for cypermethrin (including alphacypermethrin, zeta-cypermethrin, and any other products containing cypermethrin) product when 

used alone. DO NOT apply more than the combined maximum seasonal total for cypermethrin 

(including alpha-cypermethrin, zeta-cypermethrin, and any other products containing 

cypermethrin) products.”
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In accordance with the 2008 cypermethrin RED, agricultural products for cypermethrin and zetacypermethrin are restricted use due to ecotoxicity concerns. The proposed label for alphacypermethrin also reflects the restricted use designation. 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 

label 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 alpha-cypermethrin is anticipated to result in short- and intermediate-term exposure durations

for occupational handlers. However, only short-term exposures were assessed since increased 

duration of exposure does not result in increased toxicity. The short-term exposure assessment is 

protective of potential intermediate-term exposures. Table 3.3.1 provides a summary of the 

proposed uses. 

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

Applic. Timing, 

Type, and Equip.

Formulation 

[EPA Reg. No. 

7969-EOI]

Max. 

Single 

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate 

(lb ai/A)

PHI (days) Use Directions and 

Limitations

Brassica, citrus fruits, cucurbit vegetables group, fruiting vegetables group, leafy vegetables group, legume vegetables (succulent or dried 

except soybeans), root and tuber vegetables (except sugar beet), sugar beets, tree nuts, sorghum (grain) and millet, soybeans, wheat and 

tricale

Foliar; Broadcast

Aerial; Ground 

(Groundboom, Airblast); 

Chemigation

BAS 310 40 I EC 

Insecticide, 

Liquid,

10.9% ai

(0.83 lbs ai/gal)

0.025 lbs 

ai/ A 3

0.075 lbs ai/ 

A/season

(11.4 fl ozs 

product/A/

season)

1-50 

(depending 

on crop)

Application interval is 4-14 days 

apart depending on crop. 

Minimum Spray Volume = 2-10 

gal/A (aerial); 10-100 gal/A 

(ground) depending on crop.

Leaves of root and tuber 

vegetables cannot be used for 

food or feed.

Do not graze or harvest treated 

soybean forage, straw or hay

for livestock feed.

Alfalfa, rice, wild rice

Foliar; Broadcast

Aerial; Ground 

(Groundboom); 

Chemigation

BAS 310 40 I EC 

Insecticide, 

Liquid,

10.9% ai

(0.83 lbs ai/gal)

0.025 lbs 

ai/ A 3

0.075 lbs ai/ 

A/season

(11.4 fl ozs 

product/A/

season)

3-14

Application intervals from 3-7 

days, but may vary depending on 

application rate and crop.

Minimum Spray Volume = 2-5 gal/A 

(aerial); 5-10 gal/A (ground) 

depending on crop.

Ultra-low Volume (ULV) spray 

application is prohibited.

Corn (Field), Field Corn Grown for Seed, Popcorn, Sweet Corn

At-planting; Foliar; 

Broadcast;

Aerial; Ground 

(Groundboom); 

Chemigation

BAS 310 40 I EC 

Insecticide, 

Liquid,

10.9% ai

(0.83 lbs ai/gal)

0.025 lbs 

ai/ A 3

0.075 lbs ai/ 

A/season

(11.4 fl ozs 

product/A/

season)

3-60

Application interval is 3-5 days 

apart depending on crop. 

Do not apply within 30 days of 

harvest for grain and 60 for 

forage.

Do not apply within 3 days of 
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Table 3.3.1 Summary of Directions for Use of Alpha-cypermethrin.

Applic. Timing, 

Type, and Equip.

Formulation 

[EPA Reg. No. 

7969-EOI]

Max. 

Single 

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate 

(lb ai/A)

PHI (days) Use Directions and 

Limitations

harvest of ears or forage or 

livestock grazing.

Minimum Spray Volume = 2 

gal/A (aerial); 10-20 gal/A 

(ground).

Cotton 

Pre- and Postemergence; Foliar; 

Broadcast

Aerial; Ground 

(Groundboom); 

Chemigation

BAS 310 40 I EC 

Insecticide, 

Liquid,

10.9% ai

(0.83 lbs ai/gal)

0.025 lbs 

ai/ A 3

0.075 lbs ai/ 

A/season

(11.4 fl ozs 

product/A/

season)

14

Application interval is 3-5 days 

depending on pests. 

Do not graze or feed cotton for 

forage.

Minimum Spray Volume = 1 

gal/A (aerial); 5 gal/A (ground).

There are currently no registered or proposed residential uses associated with alphacypermethrin. 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 were 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 (EPA Reg. No. 39039-14) NA NA

3.4 Anticipated Exposure Pathways

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

to alpha-cypermethrin residues via their food and drinking water. At this time, there are no 

proposed or registered uses of alpha-cypermethrin that are likely to result in exposures in a nonoccupational (residential) setting. However, there are registered residential uses for
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cypermethrin and zeta-cypermethrin that will impact the human health aggregate risk assessment 

for alpha-cypermethrin. Exposures associated with residential uses include dermal, inhalation, 

and, in the case of children, incidental oral (i.e., hand-to-mouth).

In 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. However, a quantitative dermal exposure and risk assessment 

was not conducted since there is no toxicity via the dermal route of exposure. 

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

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

risk.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, 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 effect. 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 
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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 to Type II pyrethroids. The adverse outcome pathway 

(AOP) shared by pyrethroids involves the ability to interact with voltage-gated sodium channels 

(VGSCs) in the central and peripheral nervous system, leading to changes in neuron firing, and 

ultimately neurotoxicity (Figure 4.0). 

Figure 4.0. Adverse outcome pathway for pyrethroids

4.1 Toxicology Studies Available for Analysis

Although cypermethrin, alpha- and zeta-cypermethrin are separate active ingredients with 

different end-use products, they are included together in the hazard evaluation based on the 

following considerations: 

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

Alpha- and zeta-cypermethrin are enrichments of the more insecticidally-potent isomers 

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

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

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

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

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

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

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

repeated dose toxicology studies indicate that the three chemicals have comparable 

qualitative toxic effects. 

Current analytical methods for tolerance enforcement are not stereospecific; thus no 

distinction is made between residues of cypermethrin, zeta-cypermethrin, and alphacypermethrin in foods.

There are a variety of factors that can influence the toxicity of pyrethroid chemicals 
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(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, alpha- and zeta-cypermethrin are considered equally toxic and the most 

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 cypermethrin, 

alpha- and zeta-cypermethrin:

-Wolansky Acute Oral Rat Study (cypermethrin)

-WIL Acute Oral Rat Study (cypermethrin) 

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

21-Day 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). 
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4.2 Toxicological Profile

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

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

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

abnormalities, 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, the observations in the abraded rabbits were not 

used for risk assessment because the method (abraded skin) does not simulate actual exposure 

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

differences between the abraded and non-abraded animals.

 

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

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

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

decreased body weight gain and food consumption in both chemicals. Splayed limbs, spasms & 

hypersensitivity to noise and convulsions were seen with cypermethrin, and ataxia, urine-stained 

abdominal fur, and fecal-stained fur were seen with zeta-cypermethrin. In the 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 cypermethrins are similar to that of other pyrethroids, i.e., rapid absorption and clearance. 

Metabolism studies are available for the cis- and trans-isomers of cypermethrin separately, and 

cypermethrin (i.e., equimolar mixture of the cis and trans isomers). In single dose studies in rats 

with either 0.6 mg/kg cis or trans, > 70% of the radiolabel was excreted within 24 hours, with 

>53% in the urine and <20% in the feces in males. However, in females, cis was excreted 

equally in urine and feces, approximately 35% of the administered dose (AD) via each route. 

Pharmacokinetics were not different for the molecules labeled with C14 in either the benzyl or 

the cyclopropyl portion of the molecule. Less than 1% of the AD was expired in the air. 

Radiolabel was retained in fatty tissues after dosing with the cis and trans isomers, with little 

reduction from day 1 to day 8. Liver was also a target organ, however, concentrations rapidly 

decreased after dosing on day 1. 

A single dose metabolism study of alpha-cypermethrin indicates that the pharmacokinetics are 

very similar to cis, trans, and cypermethrin, as previously discussed. However, the amount 

absorbed from the gastrointestinal tract was slightly lower, at 53-55%. Additional toxicokinetic 

parameters were characterized for alpha-cypermethrin including fatty tissue elimination half-life 

of 1.6-2.7 days within the first 8 days of exposure increasing to 12-40 days determined 40 days 

after exposure. Removal from non-fatty tissues was considerably faster, with levels below the 

detection limit 2 days after dosing.

Pyrethroids are susceptible to ester hydrolysis in the plasma and oxidative metabolism by 

cytochrome P450 enzymes. Major biotransformation products from single and 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). 

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

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

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

quantitative susceptibility seen in 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, EPA is retaining a 3X 

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

concludes there are reliable data showing that a 3X factor is protective of the safety of infants 

and children. First, the high doses that produced juvenile sensitivity in the literature studies are 

well above normal dietary or residential exposure levels of pyrethroids to juveniles and these 

lower levels of exposure are not 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 (US EPA 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 the cypermethrins, the expected exposure profile will be for 

dietary, dermal, inhalation and incidental oral exposures. 

As previously indicated, the toxicity endpoints for cypermethrin, zeta-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 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 of the POD 

selection since the Wolansky study was considered more appropriate based on study design. 
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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 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, EPA 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 

more accurate point of departure than other studies considered for incidental oral endpoint and 

dose selection. 
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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, HECs for the inhalation NOAEL were calculated for use in MOE calculations, 

based on the methods and dosimetry equations described in EPA’s reference concentration (RfC)

guidance (1994). The regional deposited-dose ratio (RDDR), which accounts for the particulate 

diameter (mass median aerodynamic diameter [MMAD] and geometric standard deviation [g] of 

aerosols), can be used to estimate the different dose fractions deposited along the respiratory 

tract. The RDDR is also based on interspecies differences in ventilation and respiratory-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 respiratory-tract surface area of the rat relative to the human (see 

A.4 for detailed calculations). Since the rat inhalation study was carried out for 6 hr/day for 5 

days/week, the only exposure adjustment made was in the assumption of 8 hrs/day for human 

occupational exposures. The resulting HEC is 0.023 mg/L. For human residential exposure, 24

hrs/day was assumed and the HEC is 0.008. For the current risk assessment, the use of 24 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 

of 1.10 mg/kg/day for occupational and 1.15 mg/kg/day for residential were also calculated and 
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used for risk assessment. The level of concern for inhalation risk assessment is 30X for adults 

and children 6 years of age and over, which includes an interspecies factor of 3X and 

intraspecies factor of 10X. 

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

or children.

FQPA Factor

The FQPA safety factor was reduced to 1X for women of child bearing age (as well as for all 

adult populations and children > 6 years). For exposures from birth to <6 years of age, a 3X 

FQPA safety factor was retained (section 4.4).

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

HED’s level of concern for occupational and residential risks is based on the various uncertainty 

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

assessment for the cypermethrins are described in the 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 
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neurotoxicity). 

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 Alpha-cypermethrin, Cypermethrin, and 

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

Exposure/

Scenario

Point of 

Departure

Uncertainty/F

QPA Safety 

Factors

RfD, PAD, Level of Concern 

for Risk Assessment

Study and Toxicological 

Effects

Acute Dietary 

(children ≥ 6 

years old and 

adults)

Wolansky 

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 Alpha-cypermethrin, Cypermethrin, and 

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

Exposure/

Scenario

Point of 

Departure

Uncertainty/F

QPA Safety 

Factors

RfD, PAD, Level of Concern 

for Risk Assessment

Study and Toxicological 

Effects

Short-term 

Inhalation

(1 to 30 days)

(children <6 

years old)

NOAEL = 

0.01 mg/L 

HEC= 

0.008 mg/L

HED = 

1.15

mg/kg/day

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 confidence limit). 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 Alpha-cypermethrin, Cypermethrin, and 

Zeta-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. 

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

Zeta-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

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

W. Drew, D378683, 7 September 2012

Acceptable studies depicting the metabolic fate of alpha-cypermethrin in target crops, rotational 

crops, and livestock are available. All studies were conducted in a manner appropriate for the 

proposed uses. For alpha-cypermethrin, the target crop studies were conducted with cabbage and 

wheat; and the livestock studies with laying hens and lactating cows. An acceptable rotational 

crop study in leafy, root, and tuber vegetables, and cereal grains was previously submitted for 

cypermethrin which supports tolerances for alpha-cypermethrin. 

In the cabbage study, radiolabelled with alpha-cypermethrin or racemic cypermethrin, residue 

levels showed very good agreement between the samples treated with alpha-cypermethrin and 

cypermethrin. At harvest, the highest radioactive residues were present in the older, outer leaves 

of the plants, which would be expected since these leaves would be the most developed, and 

present the most exposed surfaces, during the treatment period. The lower levels of radioactivity 

in the heart, stalk and roots most likely reflect the lack of translocation of pyrethroid insecticides, 

a fact which has been previously established. The patterns of metabolism in inner leaves, and 

old and new outer leaves, were similar in each case. Co-chromatography with known products 

of cypermethrin metabolism in other crops suggested that similar products were formed, and that 

the principal residue at harvest was the parent insecticide which had undergone cis/transisomerization. This isomerization is presumably photochemical, and has been shown to occur 

with other pyrethroids. Because of their similarity, it was expected that the metabolism of alphacypermethrin would be similar to that of cypermethrin, and this was confirmed by the cabbage 

metabolism data. 

The only major, identified residue from the wheat study with alpha-cypermethrin (radiolabelled 

at the benzyl or cyclopropane moieties) was cypermethrin, which occurred almost exclusively as 

alpha-cypermethrin. Seven minor metabolites were also identified. The identified metabolites 
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indicate that, following foliar application to wheat, alpha-cypermethrin underwent oxidative ring 

hydroxylation of the phenyl ring, and hydrolysis at the ester linkage. Subsequent oxidative 

catabolism occurred. Inter-conversion between the cis and trans configurations of the parent 

molecule occurred in raw agricultural commodities (RACs) (forage, hay and straw) which were 

exposed to natural sunlight, but not in grain. The results are consistent with findings of photoisomerization for alpha-cypermethrin and cypermethrin in cabbage. The metabolic fate of alphacypermethrin in wheat is similar to that reported in the cabbage study. 

In laying hens, with alpha-cypermethrin radiolabelled in the cyclopropyl or benzyl ring, parent

alpha-cypermethrin was the major residue in eggs, fat and skin. In liver, numerous components 

were characterized, but only a few were identified, including parent compound at approximately 

15% of the total radioactive residue (TRR). Residues in muscle were too low to characterize. In 

studies with the cyclopropyl label, dichlorovinyl acid (DCVA) was identified in eggs, fat, skin 

and liver. The identified metabolites indicate that alpha-cypermethrin underwent oxidative ring 

hydroxylation at the phenyl ring, and hydrolysis of the ester linkage. 

In lactating cows, with alpha-cypermethrin radiolabelled in the benzyl ring, levels of 

radioactivity were low in milk, most of which was in cream. Muscle, fat and milk samples each 

contained mainly alpha-cypermethrin. Liver and kidney contained a range of components. The 

liver extract contained at least eight metabolites with a broad range of polarities. The kidney 

extract contained at least nine metabolites with a broad range of polarities. 

An acceptable 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

I. Maher, D378901/D385246, 22 February 2011

Based on similarities in the chemical properties and toxicological endpoints, environmental fate 

and ecotoxicity data are bridged between racemic cypermethrin and the enriched isomeric 

mixtures (i.e., alpha-cypermethrin and zeta-cypermethrin). There is a complete environmental 

fate database for zeta-cypermethrin, which is being used to support the alpha-cypermethrin risk 

assessment as described below. 

Zeta-cypermethrin is expected to have little 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 
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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 alpha-cypermethrin is similar to that of cypermethrin, based on a comparison 

of the metabolic profiles from studies with alpha-cypermethrin and cypermethrin. A wide 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 alpha-cypermethrin are primarily metabolized 

by cleavage of the ester bond. The metabolites PBA and cyclopropane carboxylic acid (CPA)

are mainly excreted as conjugates. The type of conjugate differs in a number of animal species 

dosed with cypermethrin, but humans and rats have the same pathway. Minor quantities of 

hydroxylated PBA (conjugated) may also be found. The terminal half-life for elimination of 

alpha-cypermethrin from the fat of rats is 17-26 days, compared to 18.9 days for ciscypermethrin (WHO; 1992). 

The metabolites identified in the plant metabolism studies are either found as metabolites in the 

animal studies, or are intermediaries in the metabolic pathways elucidated in animals; therefore, 

there are no residues of concern in 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 alpha-cypermethrin have been examined 

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

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

commodities, surface water, and groundwater based in part on information previously provided 
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on cypermethrin and zeta-cypermethrin, but also on the studies reflecting the metabolism of 

alpha-cypermethrin in cabbage, wheat, lactating cow, and laying hen. The cabbage study was 

conducted as a side-by-side comparison of the metabolism of alpha-cypermethrin and 

cypermethrin. In addition to these studies, BASF submitted a rationale for using metabolism 

data from cypermethrin to support the registration of alpha-cypermethrin.

In previous risk assessments, HED had 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 least90% 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, and the bridging rationale, 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 alpha-cypermethrin, cypermethrin, and zeta-cypermethrin. These conclusions are 

summarized in Table 5.1.4.

Table 5.1.4 Residue Definitions for Alpha-cypermethrin

Matrix Risk Assessment Tolerance Expression

Plants Primary Crop Alpha-cypermethrin Alpha-cypermethrin

Rotational Crop --

1

--

Livestock Ruminant Alpha-cypermethrin Alpha-cypermethrin

Poultry Alpha-cypermethrin Alpha-cypermethrin

Drinking Water Alpha-cypermethrin Not Applicable

1 Residues of concern in rotational crops are not expected as a result of the proposed use patterns.
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5.2 Food Residue Profile

The submitted data on the metabolism of alpha-cypermethrin indicate that residues were 

generally low, and do not translocate throughout the plants. The highest residues were generally 

found in the foliage or forage portions of plants, with lower residues in the tubers, seeds or grains 

of these commodities. 

Adequate residue chemistry data have been provided for zeta-cypermethrin in support of alphacypermethrin. 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. Aside from citrus oil and dried pulp, residues did not concentrate in processed 

fractions. Confined rotational crop studies with cypermethrin show that the metabolism in 

rotated crops is similar to 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.

5.3 Water Residue Profile

I. Maher, D378901/D385246, 22 February 2011

As stated previously, in general cypermethrin is applied at a maximum seasonal use rate (0.6 lb 

ai/A for most uses) 4X that of zeta-cypermethrin (0.15 lb ai/A for most uses), which is 2X the 

maximum proposed seasonal rate for alpha-cypermethrin (0.075 lb ai/A). As a class of 

chemicals, the pyrethroids have low solubility in water and a high affinity to bind to soils. Given 

these physical/chemical properties, it is unlikely that oral exposure from drinking water will be a 

major pathway of exposure. 

The water solubility of alpha-cypermethrin (technical active ingredient, 98.0%), at 20°C in 

0.01M buffers (at pH values of approximately 4 to 9), ranges from 4.59 to 7.87 μg/L. In distilled 

water alone, the solubility is slightly less (2.06 μg/L). The solubility is not strongly dependent 

on pH values within the range of 4 to 9. It is likely that differing ionic strengths account for the 

differences between the solubility of alpha-cypermethrin in pure water, and the solubility in the 

buffer solutions. 

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 
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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 EPA internet site: 

http://www.epa.gov/oppefed1/models/water/.

No monitoring data are currently available to further characterize potential drinking water 

exposure. In the dietary risk assessment conducted to support the proposed uses and label 

changes, HED incorporated 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 0.66 ppb 

was used.

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

exposure through ground water sources of drinking water.

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

Drinking Water Source Maximum Use Pattern Exposure EDWC (ppb)

Surface water Cotton Peak (acute) 3.77

Annual average (chronic) 0.066

Ground water Cotton Peak & annual average 0.0036

5.4 Dietary Risk Assessment

E. Holman, D403600, 7 September 2012

Acute and average dietary (food+drinking water) exposure and risk assessments were conducted 

using the Dietary Exposure Evaluation Model DEEM-FCIDTM, Version 2.03 which uses food 

consumption data from the U.S. Department of Agriculture’s 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 zeta-cypermethrin are being reviewed 

under separate petitions (Petition Nos. 0E7804 and 0E7717).

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 
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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 

the new proposed uses of zeta-cypermethrin, and 3) incorporation of updated anticipated residue 

levels and percent crop treated estimates where appropriate. Note that no new residue data were 

needed to support alpha-cypermethrin, since the proposed tolerances are being bridged from

existing uses.

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

Percent crop treated estimates and monitoring data were not available for two of the risk drivers 

for children less than 6 years of age, oats and milk. As a result, 100% CT was used for these 

commodities. If usage estimates were available and had been used, including the use of heavy 

cream monitoring data in place of anticipated residues for milk, the risk estimates for these 

population subgroups would have been lower. Due to the many conservative assumptions made 

in this assessment, in particular, the use of field trial data (as opposed to monitoring data) for 

many commodities, HED is confident that the acute and average dietary assessments 

overestimate exposures to the general U.S. population and all population subgroups.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The following maximum percent crop treated estimates (BEAD SLUA, 10/31/2011) were used 

in the acute dietary risk assessment for the following crops that are currently registered for zetacypermethrin/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/zeta-
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cypermethrin: almonds: 1%; apples: 1%; broccoli: 20%; cabbage: 15%; carrot: 2.5%; 

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

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

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

Based on personal electronic communication with OPP BEAD (David Brassard, 4/11/2012) the 

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

5.4.3 Acute Dietary Risk Assessment

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

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

18% of the acute population-adjusted dose (aPAD). 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. This was a partially refined (probabilistic assessment), with 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 upperbound 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 
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Adults 50+ yrs 0.07 0.008213 12 

Females 13-49 yrs 0.07 0.008979 13 

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

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

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

Population Subgroup Exposure Estimate, mg/kg/day

U.S. Population 0.000920

All infants (< 1 yr) 0.001602

Children 1-2 yrs 0.003441

Children 3-5 yrs 0.002458

Children 6-12 yrs 0.001475

Youth 13-19 yrs 0.000746

Adults 20-49 yrs 0.000662

Adults 50+ yrs 0.000582

Females 13-49 yrs 0.000575

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed or registered residential uses associated with alpha-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. These revised residential 

exposures have been incorporated into the human health aggregate risk assessment for alphacypermethrin, which must consider all potential exposures to the cypermethrins. HED has 

determined that short-term 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 Cypermethrin 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, HED identified the residential scenarios with the highest 

exposure estimates, and used these to quantitatively evaluate residential exposure and risk. 

These scenarios were identified from the Revised Occupational and Residential Exposure 

Assessment for the Reregistered Eligibility Decision Document (RED), the 2011 Pyrethroid 

Cumulative Risk Assessment (PCRA, D394576) and various registered labels. The risk estimates 

associated with the identified worst-case exposure scenarios are protective for all other 

residential handler 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: 
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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 

inhalation risk estimates resulted in MOEs greater than the LOC of 30 and are not of concern.

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

Exposure 

Scenario 

Target 

MOE

Inhalation Unit 

Exposure (mg/lb 

ai)

Maximum 

Application 

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 Cypermethrin Registered Residential Post-application Exposure/Risk Estimates

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

environment that has been previously treated with cypermethrin. Post-application inhalation 
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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 postapplication 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, 

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. 

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 cypermethrin on turf and pets, or as a crack and crevice treatment using a manually 

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

exposure and risk resulting from application of cypermethrin. All individual and combined postapplication exposure estimates resulted in MOEs and ARIs greater than their respective LOCs 

and are not of concern.
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Table 6.2. Residential Post-application Exposure and Risk Estimates for Cypermethrin and Zeta 

Cypermethrin.

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

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 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 gardens 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. 
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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). 

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

expected to co-occur. Furthermore, treatment of indoor crack and crevices is not anticipated to 

be performed using different methods of application; therefore crack crevice exposure estimates 

were not combined. Finally, only hand-to-mouth exposure is estimated for incidental oral 

exposure as inclusion of object-to-mouth and soil ingestion is considered an over estimate of 

exposure. A summary of the residential exposures and risk estimates recommended for the 

aggregate assessment is provided in Table 6.4.

Table 6.4. Recommendations for the Residential Exposures and Risk Estimates for the Cypermethrin Aggregate 

Assessment.

Lifestage

Handler 

Exposure 

(mg/kg/day)a

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
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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 alphacypermethrin. The Agency has been working with the Spray Drift Task Force, EPA Regional 

Offices and State Lead Agencies for pesticide regulation and other parties to develop the best 

spray drift management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/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 

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 alpha-cypermethrin applications.

6.6 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for alpha-cypermethrin at this time primarily because of the low 

acute inhalation toxicity (Toxicity Category III), low vapor pressure (2.55 x 10-9 mm Hg (25 C), 

and the low proposed use rate (0.025 lb ai/A). However, volatilization of pesticides may be a 

source of post-application inhalation exposure to individuals nearby pesticide applications. The 

Agency sought expert advice and 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 
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Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for alpha-cypermethrin.

7.0 Aggregate Exposure/Risk Characterization

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

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

In an aggregate assessment, exposures from relevant sources are added together and compared to 

quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be 

aggregated. When aggregating exposures and risks from various sources, HED considers both 

the route and duration of exposure.

Residential exposure to the cypermethrins is anticipated from existing registered use for 

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

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

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. 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, HED risks are not of concern provided the calculated ARI is greater than 1. 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 Calculations1

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
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Table 7.2 Short-Term Aggregate Risk Calculations1

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

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

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

2 MOE dietary = [BMD of 7.16 mg/kg-day)/(chronic dietary exposure)]. ARI dietary = [(MOE dietary)/(MOE 

target)]. MOE target = 100 for children >6 and adults; MOE target = 300 for children <6.

From Table 5.4.3, Child Chronic Dietary Exposure = children 1-2 yrs (maximum exposure) = 0.003441 mg/kg/day; 

and Adult Chronic Dietary Exposure = US Population (maximum exposure) = 0.000920 mg/kg/day

3 MOE oral = [(7.16mg/kg-day)/(hand-to-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

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 EPA’s efforts to evaluate the risk

of exposure to this class of chemicals, refer to

http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html.

The cypermethrins are included in the common assessment group of the pyrethroid/pyrethrin 

cumulative risk assessment. However, the proposed new uses of alpha-cypermethrin will not 

impact the cumulative assessment because: 1) the alpha-cypermethrin application rates are lower 

than the zeta-cypermethrin rates and are expected to result in lower residue levels; and 2) zetacypermethrin has already been registered for use on the crops proposed in the current alphacypermethrin petition and those uses were incorporated into the cumulative assessment. 
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Additionally, no new residential uses are proposed, so the residential cumulative assessment will 

not be impacted. 

9.0 Occupational Exposure/Risk Characterization

9.1 Occupational Handler Exposure/Risk Estimates

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, short- and intermediate-term occupational handler exposure is 

expected from the proposed uses; however, alpha-cypermethrin does not increase in potency 

with repeated doses. Therefore, only single day exposures are assessed. The quantitative 

exposure/risk assessment developed for occupational handlers is based on the following 

scenarios:

• Mixing/Loading Liquids for Groundboom Application,

• Mixing/Loading Liquids for Aerial Application,

• Mixing/Loading Liquids for Chemigation,

• Mixing/Loading Liquids for Airblast Application,

• Applying Sprays with Groundboom Equipment,

• Applying Sprays with Aerial Equipment, 

• Applying Sprays with Airblast Equipment, and

• Flagging for Aerial Applications.

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

Occupational Handler Exposure Data and Assumptions

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

handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate: 

The maximum single application rate on the proposed labels was used to assess all handler 

exposure scenarios. The maximum single application rate for all proposed uses is 0.025 lb ai/A. 

The maximum application rate per acre per year is 0.075 lb ai/A/yr. The number of applications 

per year at the maximum single application rate ranges from 1-3, depending on the use.

Unit Exposures: 

It is HED policy to use the best available data to assess handler exposure. Sources of generic 

handler data, used as surrogate data in the absence of chemical-specific data, include the 

Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler 

Exposure Task Force (AHETF) database. Some of these data are proprietary (e.g., AHETF 

data), and subject to the data protection provisions of FIFRA. The standard values recommended 

for use in predicting handler exposure that are used in this assessment, known as “unit 

exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate 

Reference Table” (http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, 
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along with additional information on HED policy on use of surrogate data, including descriptions 

of the various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html.

Area Treated or Amount Handled: 

Based on HED’s Exposure Science Advisory Council Policy Number 9.1, the following 

assumptions were used for acres treated or amount handled per day:

• 80-200 acres/day for groundboom application, 

• 350-1,200 acres/day for aerial application, 

• 350 acres/day for chemigation, 

• 40 acres/day for airblast application, and

• 350 acres/day for flagging during application.

Occupational Handler Non-Cancer Exposure and Risk Estimates

Table 9.1 presents the estimated short- and intermediate-term inhalation risks for workers. All 

occupational handler scenarios for the proposed and existing uses resulted in MOEs greater than 

the level of concern at the baseline PPE level of protection (i.e. single layer clothing and no 

respirator), and engineering controls for aerial applications. The MOEs shown in the table are all 

higher than HED’s level of concern of an MOE of 30, with the lowest MOE of 14,000 identified 

for a mixer/loader preparing sprays for aerial application to high acreage crops.
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Table 9.1. Short- and Intermediate-Term Occupational Exposure and Risk Estimates for Alpha-cypermethrin. 

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure 

(mg/lb ai)a

Maximum Single

Application Rate

(lb ai/A)b

Area Treated 

Daily (A)c

Inhalation

(Assumes no 

Respirator is Used) Dose (mg/kg/day)d MOEe

Mixer/Loader

Liquids for 

Groundboom 

Applications

(AHETF)

Brassica, cucurbit 

vegetables, fruiting 

vegetables, leafy vegetables, 

legume vegetables 

(succulent or dried except 

soybeans), root and tuber 

vegetables (except sugar 

beet), sugar beets, sorghum 

(grain) and millet 

0.000219 0.025 80 0.0000054 200,000

soybeans, wheat, tricale, 

cotton, corn

0.000219 0.025 200 0.0000135 81,000

Liquids for Aerial 

Application

(AHETF)

Brassica, cucurbit 

vegetables, fruiting 

vegetables, leafy vegetables, 

legume vegetables 

(succulent or dried except 

soybeans), root and tuber

vegetables (except sugar 

beet), sugar beets, sorghum 

(grain) and millet, citrus, 

tree nuts

0.000219 0.025 350 0.0000236 47,000

soybeans, wheat, tricale, 

cotton, corn

0.000219 0.025 1,200 0.000081 14,000

Liquids for 

Chemigation

(AHETF)

All crops

0.000219 0.025 350 0.0000236 47,000
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Table 9.1. Short- and Intermediate-Term Occupational Exposure and Risk Estimates for Alpha-cypermethrin. 

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure 

(mg/lb ai)a

Maximum Single

Application Rate

(lb ai/A)b

Area Treated 

Daily (A)c

Inhalation

(Assumes no 

Respirator is Used) Dose (mg/kg/day)d MOEe

Liquids for Airblast

(AHETF)

citrus, tree nuts 0.000219 0.025 40 0.0000027 410,000

Applicator

Sprays for Groundboom 

Applications

(AHETF)

Brassica, cucurbit 

vegetables, fruiting 

vegetables, leafy vegetables, 

legume vegetables 

(succulent or dried except 

soybeans), root and tuber 

vegetables (except sugar 

beet), sugar beets, sorghum 

(grain) and millet 

0.00034 0.025 80 0.0000085 130,000

soybeans, wheat, tricale, 

cotton, corn 0.00034 0.025 200 0.0000212 52,000

Sprays for Aerial 

Application

(AHETF)

Brassica, cucurbit 

vegetables, fruiting 

vegetables, leafy vegetables, 

legume vegetables 

(succulent or dried except 

soybeans), root and tuber 

vegetables (except sugar 

beet), sugar beets, sorghum 

(grain) and millet, citrus, 

tree nuts

0.000068 0.025 350 0.0000074 150,000

soybeans, wheat, tricale, 

cotton, corn

0.000068 0.025 1,200 0.0000255 43,000

Sprays for Airblast citrus, tree nuts 0.00471 0.025 40 0.0000588 19,000
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Table 9.1. Short- and Intermediate-Term Occupational Exposure and Risk Estimates for Alpha-cypermethrin. 

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure 

(mg/lb ai)a

Maximum Single

Application Rate

(lb ai/A)b

Area Treated 

Daily (A)c

Inhalation

(Assumes no 

Respirator is Used) Dose (mg/kg/day)d MOEe

Application

(AHETF)

Flagger

Flagging for Aerial 

Applications 

(PHED)

All Low Acreage Crops

0.00035 0.025 350 0.000038 29,000

a. Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (OPHED; March, 2012). Level of mitigation is baseline, i.e., no respirator; 

for aerial applicators, a closed cockpit was assumed, i.e., Eng. Controls).

b. Based on proposed label (EPA Reg. No. #7969-EOI).

c. Exposure Science Advisory Council Policy #9.1.

d. Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/A) x Area Treated (A/day) /BW (80 kg).

e. Inhalation MOE = Inhalation HED (1.1 mg/kg/day)/ Inhalation Dose (mg/kg/day).
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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 alpha-cypermethrin at this time primarily because of the low 

acute inhalation toxicity (Toxicity Category III), low vapor pressure (2.55 x 10-9 mm Hg at 

25*C), and the low proposed use rate (0.025 lb ai/A). However, there are multiple potential 

sources of post-application inhalation exposure to individuals performing post-application 

activities in previously treated fields. These potential sources include volatilization of pesticides 

and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert 

advice and input on issues related to 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 alpha-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. 

HED does not anticipate post-application dermal risks after exposure to alpha-cypermethrin.

Restricted Entry Interval (REI)

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

technical material which is classified as Category III for acute dermal and eye irritation, and 

Category IV for skin irritation. Based on the acute toxicity profile of alpha-cypermethrin, the 

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

post-application exposures to alpha-cypermethrin.
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10.0 References 

OPP Memoranda

M. Collantes, 9/4/2012, D403601, Alpha-Cypermethrin. Occupational and Residential Exposure 

and Risk Assessment to Support the Registration of the New Active Ingredient on a Variety of 

Food Crops.

W. Drew, 9/7/2012, D378683, Alpha-Cypermethrin. Petition to Establish Permanent Tolerances 

for Residues of the New Insecticide Resulting from Food/Feed Use on Various Raw and 

Processed Agricultural Commodities. Summary of Analytical Chemistry and Residue Data. 

E. Holman, 9/7/2012, D403600, Cypermethrin, Alpha-Cypermethrin, and Zeta-Cypermethrin.

Acute and Chronic Dietary Exposure and Risk Assessment – Zeta-Cypermethrin Uses on 

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

Uses on Various Raw and Processed Agricultural Commodities.

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

Toxicology References

Anand, S. S., J. V. Bruckner, W. T. Haines, S. Muralidhara, J. W. Fisher and S. Padilla (2006). 

"Characterization of deltamethrin metabolism by rat plasma and liver microsomes." 

Toxicology and Applied Pharmacology 212(2): 156-166.

Cao, Z., T. J. Shafer, K. M. Crofton, C. Gennings and T. F. Murray (2011a). "Additivity of 

Pyrethroid Actions on Sodium Influx in Cerebrocortical Neurons in Primary Culture." 

Environ Health Perspect.

Cao, Z., T. J. Shafer and T. F. Murry (2011b). "Mechanisms of Pyrethroid Insecticide-Induced 

Stimulation of Calcium Influx in Neocortical Neurons." J Pharmacology and 

Experimental Therapy 336(1): 197-205.

Choi, J.-S. and D. M. Soderlund (2006). "Structure-activity relationships for the action of 11 

pyrethroid insecticides on rat Nav1.8 sodium channels expressed in Xenopus oocytes." 

Toxicology and Applied Pharmacology 211(3): 233-244.

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

L. M. De Schaepdrijver, G. P. Bailey, T. P. Coogan, W. C. Coussement and G. S. 

Mannens (2008). "The ontogeny of drug metabolizing enzymes and transporters in the 

rat." Reproductive Toxicology 26(3-4): 220-230.

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

B. Conolly and R. Tornero-Velez (2010). "Physiologically Based Pharmacokinetic 

Modeling of Deltamethrin: Development of a Rat and Human Diffusion-Limited Model." 

Toxicol. Sci. 115(2): 330-343.

Goldin, A., R. Barchi, J. Caldwell, F. Hofmann, J. Howe, J. Hunter, R. Kallen, G. Mandel, M. 

Meisler, YBNetter, M. Noda, M. Tamkun, S. Waxman, J. Wood and W. Catterall (2000). 

"Nomenclature of voltage-gated sodium channels." neuron 28(2): 365-368.
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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
Alpha-Cypermethrin Human Health Risk Assessment DP No. D376098

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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
Alpha-Cypermethrin Human Health Risk Assessment DP No. D376098

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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 
Alpha-Cypermethrin Human Health Risk Assessment DP No. D376098

Page 61 of 87

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 
Alpha-Cypermethrin Human Health Risk Assessment DP No. D376098

Page 62 of 87

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
Alpha-Cypermethrin Human Health Risk Assessment DP No. D376098

Page 63 of 87

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
Alpha-Cypermethrin Human Health Risk Assessment DP No. D376098

Page 64 of 87

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 EPA’s RfC guidance (1994). The HECs were used to calculate human equivalent 

doses (HED) that were used in inhalation risk assessments (see A.4). The 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 

EPA’s RfC guidance (1994), the methodology for RfCs derivation is an estimate of the 

quantitative dose-response assessment of chronic non-cancer toxicity for individual inhaled 

chemicals and includes dosimetric adjustment to account for the species-specific relationships of 

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 EPA 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 Technical Grade (95.4-99.0%) Alpha-cypermethrin. 

Parameter Value Reference

Melting point/range 81.4-83.7 C FAO/WHO Evaluation Report 

454/2005

pH Not available.

Density 1.33 g/cm347th Joint FAO/WHO Expert 

Committee on Food Additives 

(JECFA 47) 1997

Water solubility 2.06 μg/L (20°C)*

Solvent solubility (21°C) Solvent

Acetone

Dichloromethane

Ethyl acetate

n-Hexane

Methanol

Toluene

2-Propanol

Solubility (g/L)

Miscible

Miscible

584

6.5

21.3

596

9.6

Vapor pressure 2.55 x 10-9 mm Hg (25 C)

Dissociation constant, pKa Not available.

Octanol/water partition coefficient, 

Log(KOW)

5.5 FAO/WHO Evaluation Report 

454/2005

UV/visible absorption spectrum Not available.

* The water solubility of alpha-cypermethrin (98.0%), at 20°C in 0.01M buffers at pH values of approximately 4 to 

9, ranges from 4.59 to 7.87 μg/L, as measured by the OECD and EEC microcolumn techniques. In distilled water 

alone, the solubility is less (2.06 μg/L). The solubility is not strongly dependent on pH values within the range of 4 

to 9. It is likely that ionic strength differences account for differences in solubility between values in pure water and 

in the buffer solutions. 
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Appendix C. International Harmonization

TABLE C.1 International Harmonization of Recommended Tolerances for Alpha-cypermethrin. 

Correct Commodity Definition Recommended 

Tolerance (ppm)

Corresponding Codex MRL (mg/kg) US Use Rate 

(lb ai/A)

Codex Use 

Rate (lb ai/A)1

Cotton, undelinted seed 0.50 * 0.075 *

Vegetable, root and tuber, group 1, except sugar beet 0.10 0.01 0.075 0.009-0.050

Nut, tree, group 14 0.05 0.0520.075 No data3

Vegetable, legume, edible podded, subgroup 6A 0.50 * 0.075 *

Pea and bean, succulent shelled, subgroup 6B 0.10 * 0.075 *

Pea and bean, dried shelled, except soybean, subgroup 6C 0.05 * 0.075 *

Vegetable, leafy, group 4 10 0.7 0.075 0.008-0.050

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

Corn, field, grain 0.05 0.3 (cereal grain4) 0.075 0.018-0.050

Corn, pop, grain 0.05 0.3 (cereal grain4) 0.075 0.018-0.050

Corn, sweet, kernel plus cob with husks removed (K+CWHR) 0.05 0.05 0.075 0.050

Soybean, seed 0.05 * 0.075 *

Beet, sugar, roots 0.05 0.1 0.075 0.009-0.050

Sorghum, grain, grain 0.50 0.3 (cereal grain4) 0.075 No data3

Rice, grain 1.5 2 0.075 0.050

Vegetables, cucurbit, group 9 0.20 * 0.075 *

Vegetables, fruiting, group 8-10 0.20 0.2 (tomato), 0.1 (pepper), 

0.03(eggplant)

0.075 0.010-0.050

Beet, sugar, tops 0.20 * 0.075 *

Wheat, grain 0.20 2

5

0.075 0.013-0.050

Fruit, citrus, group 10-10 0.35 2 0.075 No data3

Citrus, oil 4.0 * 0.075 *

Citrus, dried pulp 1.8 * 0.075 *

Alfalfa, hay 15 30 (fodder) 0.075 0.050

Cattle, fat 1.0 * NA6 NA

Cattle, meat 0.20 2 (fat) NA NA

Cattle, meat byproducts 0.05 0.05 NA NA

Egg 0.05 0.01 NA NA

Goat, fat 1.0 * NA NA

Goat, meat 0.20 2 (fat) NA NA

Goat, meat byproducts 0.05 0.05 NA NA
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TABLE C.1 International Harmonization of Recommended Tolerances for Alpha-cypermethrin. 

Correct Commodity Definition Recommended 

Tolerance (ppm)

Corresponding Codex MRL (mg/kg) US Use Rate 

(lb ai/A)

Codex Use 

Rate (lb ai/A)1

Hog, fat 0.10 * NA NA

Hog, meat 0.05 2 (fat) NA NA

Horse, fat 1.0 * NA NA

Horse, meat 0.20 2 (fat) NA NA

Horse, meat byproducts 0.05 0.05 NA NA

Milk, fat, reflecting 0.10 ppm in whole milk 2.5 0.5 NA NA

Poultry, fat 0.05 0.12 NA NA

Poultry, meat 0.05 0.1 (fat) NA NA

Sheep, fat 1.0 * NA NA

Sheep, meat 0.20 2 (fat) NA NA

Sheep, meat byproducts 0.05 0.05 NA NA

* No Codex MRL established. 

Bold type indicates that the US tolerance and the Codex MRL are harmonized. 

1. Some of the field trials were conducted with cypermethrin and/or zeta-cypermethrin. 

2. Proposed MRL is at Step 3 (has not been finalized). 

3. No field trial use pattern data were available for tree nuts, sorghum, or citrus fruits. 

4. Except for barley, oats, rice, rye and wheat. 

5. Post-harvest treatment. 

6. NA = Not Applicable. US tolerances in livestock commodities are based on MRBDs; Codex MRLs reflect direct applications in addition to dietary sources. 
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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.

Appendix E. Executive Summaries for Alpha-cypermethrin studies

90-Day Oral Toxicity [feeding]-[rat]; OPPTS 870.3100 [§82-1a]; OECD 408.

EXECUTIVE SUMMARY: In a subchronic oral toxicity study (MRID 47944068), WL 85871, 

98.2% a.i.; batch number OCD/7, was administered in the diet to Wistar rats. In addition to 

40/sex in controls, 20/sex/dose at doses of 0, 20, 60, 180, or 540 ppm (approximately equivalent 

to 0/0, 1.01/1.2, 1.74/3.8, 9.3/11.3, or 29.6/35 mg/kg/day) for males/females respectively were 

dosed for 13 weeks (values calculated by reviewer).

Additionally, 25 rats/sex were control treated for 2 weeks, and then sacrificed for screening of 

potential diseases and potential health problems in the main study animals: 3 of 5 animals tested 

positive for Sendai virus antibodies. The study animals did not exhibit signs or symptoms of a 

current disease.

At 540 ppm there were 3 males which displayed a gait problem. Gait abnormalities were observed 

on the 3rd and 4th week of treatment and persisted throughout the remainder of the study. This 

abnormal gait sign is considered treatment related, particularly since it did not occur in any other 

animals on the study. Otherwise, no adverse, treatment related clinical effects were noted. 

Examinations included hematology, urinalysis, gross or histological pathology. Several statistically 

significant spurious findings including a decrease in gamma and alpha globulins of 3.01% and 

11.42% at 60 ppm compared to 3.35% and 12.72% at 540 ppm compared to control values for 

dosed females were noted. Other changes which are considered spurious are a slight increase in 

serum sodium values and a slight increase in blood urea values in the highest dosed females. There 

was a statistically significant reduction in alkaline phosphatase values at both 180 and 540 ppm 

doses which are not considered as a toxicological significant event. Hematological changes 

occurred in both male and female animals but only at the 540 ppm dose level. These included 

increased platelet counts, slightly reduced hemoglobin values, slightly increased lymphocyte 

counts, and a reduced eosinophil count in males. These findings were not considered adverse.

Statistically significant (p≤0.05) reductions in body weights were seen in males at 60 and 180 

ppm; however, decreases were less than 5% with no dose response relationship observed and
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therefore, not considered treatment- related. Females receiving 180 ppm in the diet displayed 

only a slight reduction in mean body weights compared to controls and decreases were not 

statistically significant.

At 540 ppm, statistically significant reductions (p≤0.01) in body weight were observed in males. 

Decreases of 13.5% were seen at week 1 and body weights remained lower than controls (8.7%-

12%) throughout the entire study. Decreased weekly body weight gains were also noted in 540 

ppm males during all Weeks except 7, 8, 9 and 13. The largest losses in gains occurred in the first 

2 weeks. The first and second weeks show a 49% and 22%, respectively lower gain than controls. 

In females, statistically significant reductions (p≤0.01) in body weight (up to 8%) were also seen at 

540 ppm.

Decreased food consumption was noted in the 540 ppm females on weeks 1-13 (decr 7.1%), and 

was significant (p ≤ 0.01) when compared to the control group. Reduced food consumption in 

males started in weeks 1-6 as extremely reduced (-26.5%) and became less to -9.3% at week 6 

improved to -3.9% at week 12. 

Significant increases in organ were noted in males and females when adjusted for terminal body 

weights. Reported findings at180 ppm and 540 ppm of the weight increases in the liver (p≤0.01) 

in both sexes and possibly the increased kidney weight changes at 540 ppm in both sexes, 

suggest that they could be related to the animal exposure to the test material. However, the 

effects of just weight increases alone without other tissue changes to support the effects should 

not in themselves be considered adverse. 

The LOAEL is 540 ppm (equivalent to approximately 29.6/35 mg/kg/day), based on reduced 

body weights, body weight gains (males), decreased food consumption in both sexes, and gait 

changes (males). The NOAEL is 180 ppm (approximately equivalent to 9.3/11.3 mg/kg/day). 

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3100; OECD 408) for a subchronic oral toxicity study in the rat. This study was initiated in 

1982 and followed the concurrent guideline requirements.

Subchronic Oral Toxicity in Dogs (dietary); OPPTS 870.3150 [§82-1b]; 

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

WL 85871, Alpha-Cypermethrin.; 95.8% a.i.; Batch Nos.F830047B, Shell Code No. ST 84/0051 

was administered daily in a dose volume of 400 grams of diet formulation to four beagle 

dogs/sex/dose group at doses of 0, 30, 90, and to 6 dogs/sex/dose at 270 ppm for 90 days

At 270 ppm, treatment-related neurological signs were observed in the males and females. On 

Day5 of week 5, dosing was halted in a 270 ppm group female and euthanasia was completed for 

humane reasons. No adverse, treatment-related effects were observed on food consumption, 

ophthalmoscopic examinations, hematology, clinical chemistry, urinalysis, organ weights, or 

gross pathology in either males or females. The treatment-related clinical findings observed in 

these dogs included the following: head nodding, lip licking, abnormal gait, body tremors, 
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agitation, slight ataxia and poor limb co-ordination. These signs became stronger and became a 

24 hour duration by study end.

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

toxicity were observed.

At 90 ppm, three dogs on 1 day and 1 time presented with neurological signs which included lip 

licking, excitability, or body tremors. While these are classical signs of pyrethroids, the 

incidence is low with one finding per dog. No other signs or adverse clinical findings were 

reported. At 30 ppm, There were no adverse signs or clinical parameters recorded. 

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

within 3- 6 hours after feeding. These characteristically comprised body tremors together with 

variable degrees of head nodding, “lip licking”, subduedness, ataxia, or agitation. In week 3 all 

these dogs also developed a high stepping gait and this observation together with the instances of 

body tremors, head nodding, lip “licking “and ataxia increased gradually as the study progressed.

Initially the signs rarely persisted overnight to the next working day. However, as the study 

progressed, the signs gradually persisted until around week 7 all the high dose level animals 

continually exhibited the described effects to varying degrees.”

The LOAEL is 270 ppm, (6.75 mg/kg/day, based 40 ppm = 1 mg/kg) based on significant 

neurological signs in both sexes. The NOAEL is 90 ppm (2.25 mg/kg/day).

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3150; OECD 409) for a subchronic oral toxicity study in dogs.

Prenatal Developmental Toxicity Study in Rats (gavage); 870.3700a [§83-3a]; OECD 414.

EXECUTIVE SUMMARY: In an oral developmental toxicity study (MRID 47944073), alphacypermethrin (technical grade, 95.6% a.i., Batch # ST 91/243; analytical laboratory Batch # 

02156, drum 1085) in corn oil vehicle was administered via daily oral gavage in a dose volume 

of 4 mL/kg to 24 time-mated female Sprague-Dawley rats/dose group at doses of 0, 3, 9, or 

18/15 mg/kg/day from gestation days (GD) 6-15 inclusive. Due to the severity of clinical signs 

noted after 2 to 4 doses at 18 mg/kg/day, the dose level was decreased to 15 mg/kg/day from GD 

10-15. Subsequently, another group of 24 females was added and dosed at 15 mg/kg/day from 

GD 6-15 inclusive. On GD 20, all dams were euthanized; each dam’s uterus was removed via 

cesarean section and its contents examined. Fetuses were examined for external, visceral, and 

skeletal malformations and variations.

No treatment-related effects on mortality, gross pathology, or cesarean section data were 

observed in the dams at any dose. 

At 18/15 mg/kg/day, increased incidence (# affected/24 vs. 0/24 controls) of the following 

clinical signs were noted generally from GD 7-9: (i) unsteady gait (14); (ii) piloerection (11); 

(iii) limb splay (12); (iv) hypersensitivity to sound (10); (v) excess salivation (7); and (vi) 
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hunched posture (8). Six females exhibited hypersensitivity to touch, and four of these females 

(nos. 75, 78, 86, and 90) were particularly affected and showed intermittent rolling; 3 of these 

animals (nos. 75, 78, and 86) were later observed to be prostrate. Consequently, the dose level 

was decreased to 15 mg/kg/day from GD 10-15. Treatment-related effects persisted for the 3 

severely affected females on GD 10 and also for animal # 86 on GD 11 and 12, but all other 

females in this group recovered after the dose level reduction. Body weight gains were 

decreased (p<0.001) by 21% compared to controls during the entire dosing period (GD 6-15) and 

by 12% (no statistical analysis) for the overall (GD 0-20, calculated by reviewers) study. Also at 

this dose, body weights were decreased (p<0.05) by 4-5% on GD 12 and 20 and maternal food 

consumption values were decreased (p<0.05) throughout the dosing period by 7-17%.

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

generally from GD 9-15: (i) unsteady gait (11); (ii) piloerection (6); (iii) limb splay (11); (iv) 

hypersensitivity to sound (11); and (v) hypersensitivity to touch (11). These findings were 

generally less severe than those observed at 18 mg/kg/day. Mean body weights were increased 

(p<0.001) compared to controls on GD 0 and 6; however, as these animals were allocated to the 

study 10 days later than the control group animals, body weight gains were not directly 

comparable. Nevertheless, there was a significant decrease (p<0.001) in body weight gain (decr. 

44%) compared to controls during the dosing period (GD 6-15). Additionally at this dose, 

overall (GD 0-20) body weight gain was decreased by 11% (no statistical analysis) and maternal 

food consumption values were decreased (p<0.01) throughout the dosing period by 10-23%. 

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

9-12, it was not considered an adverse effect because no decreases were seen at other intervals, 

including cumulative gain during the GD 6-15 dosing interval. This level may be a threshold 

NOAEL for weight changes, based on the magnitude of change seen at 15 and 18 mg/kg/day.

The maternal LOAEL is 15 mg/kg/day based on decreased body weight gain, food 

consumption, and increased incidence of clinical signs of toxicity. The maternal NOAEL is 

9 mg/kg/day.

Mean fetal weight (combined sexes) was decreased by 4% (not significant) in the 18/15 and 5% 

(p<0.05) in the 15 mg/kg/day groups. These findings were considered to be a consequence of the 

observed maternal effects. No other evidence of treatment-related developmental toxicity was 

observed at any dose. There were no abortions, premature deliveries, complete litter resorptions, 

or dead fetuses and no effects of treatment on the numbers of litters, live fetuses, early 

resorptions, or late resorptions. Similarly, sex ratio and pre- and post-implantation losses of the 

treated groups were comparable to controls. There were no effects of treatment on development 

of the fetuses, and there were no treatment-related effects on ossification of the skeleton. 

There were no adverse treatment-related external, visceral, or skeletal variations or 

malformations.

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

developmental NOAEL is 9 mg/kg/day.

This study is classified acceptable/guideline and satisfies the guideline requirement for a 

developmental toxicity study (OPPTS 870.3700; OECD 414) in rats.
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Prenatal Developmental Toxicity Study in Rabbits (gavage); 870.3700a [§83-3b]; 

OECD 414.

EXECUTIVE SUMMARY: In an oral developmental toxicity study (MRID 47944072), alphacypermethrin (technical, 95.6% a.i.; Batch # 02156; ST 91/243) in corn oil was administered via 

daily oral gavage in a dose volume of 2 mL/kg to 16 time-mated New Zealand White 

rabbits/dose group at doses of 0, 3, 15 or 30 mg/kg/day from gestation days (GD) 7-19 inclusive. 

On GD 28, all dams were euthanized; each dam’s uterus was removed, weighed and its contents 

examined via cesarean section. Fetuses were examined for external, visceral, and skeletal 

malformations and variations.

Due to the severity of weight loss and low food consumption, two control females (nos. 2 and 8), 

three females treated at 15 mg/kg/day (nos. 33, 38, and 43), and two females treated at 30 

mg/kg/day (nos. 60 and 62) were sacrificed in extremis between GD 15 and 22. The only 

abnormalities observed at necropsy were related to dehydration of the gastro-intestinal contents 

or body fat. These findings were not considered treatment-related because they were observed 

among controls at similar incidence.

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

(GD 7-8), as well as marked reductions in food consumption compared to pre-treatment during 

all intervals of the dosing period (GD 7-11, 11-15, and 15-19). It was stated that this was a 

marked, although not unexpected, effect of dosing with corn oil as a vehicle. The relative 

amount of body weight loss was similar in all dose groups. Following the dosing period, food 

consumption values returned to levels similar to those during pre-dosing. Food consumption at 

30 mg/kg/day was decreased by 13-15% (not significant) compared to controls from GD 11-15 

and 15-19. A small body weight loss was observed for the overall treatment period (GD 7-19) at 

30 mg/kg/day (-0.03 kg) compared to controls (0.7 kg), although body weight at the end of 

treatment (GD 19) in this dose group were comparable to controls. These decreases in weight 

gain and food consumption at 30 mg/kg/day were considered treatment-related, based on 

rebound of weight gain postdosing (52% above controls, p<0.01) and toxicity observed in the 

preliminary dose range-finding study at doses of 25-35 mg/kg/day. No treatment-related effects 

were noted at 3 or 15 mg/kg/day. The maternal LOAEL is 30 mg/kg/day, based on slight 

body weight loss and decreased food consumption during dosing. The maternal NOAEL is 

15 mg/kg/day.

At 15 mg/kg/day, one female aborted on the day of scheduled necropsy. One dead fetus was 

noted in the control and 3 mg/kg/day groups each. There were no premature deliveries or 

complete litter resorptions, and no effects of treatment on the numbers of litters, live fetuses, or 

resorptions. Similarly, sex ratio and pre- and post-implantation losses of the treated groups were 

unaffected by treatment. There were no effects of treatment on development of the fetuses, and 

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

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

developmental NOAEL is 30 mg/kg/day (HDT). The developmental LOAEL was not 

observed (>30 mg/kg/day). 
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This study is classified Acceptable/guideline and satisfies the guideline requirement for a 

developmental toxicity study (OPPTS 870.3700; OECD 414) in rabbits. Although marginal 

body weight and food consumption effects were observed at the high dose of 30 mg/kg/day, 

selection of the LOAEL is supported by the results of a preliminary dose range-finding study 

(Toxicol. Report Ref. No. SLN/3/92; March, 1994).

Dietary carcinogenicity study in mice; OPPTS 870.4200b [§83-2b]; OECD 451.

EXECUTIVE SUMMARY: In an oral carcinogenicity study (MRID 47944071), αcypermethrin (technical grade, 95.4% a.i.; Batch No. 02156) was administered in the diet to CD1 mice (52/sex/dose) for up to 78 weeks at doses of 0, 30, 100, or 300 ppm (equivalent to 0/0, 

3.0/3.5, 10.6/11.5, or 35.2/37.7 mg/kg bw/day in males/females). Groups of 20 mice/sex/dose 

were treated similarly for 52 weeks for interim sacrifice.

No treatment-related effects were observed on mortality, food consumption, leukocyte 

differential count, organ weights, or microscopic pathology. 

Body weights were decreased (statistical analysis not performed) compared to controls at Weeks 

13, 52, and 78 in the 100 ppm males by 7-8%, in the 300 ppm males by 14%, and in the 300 ppm 

females by 9-13%. In the 300 ppm group, terminal weights were decreased (p<0.05) by 16-17%. 

Body weight gains were analyzed statistically at specific time intervals. Decreases (p<0.05) in 

body weight gains were observed in the 100 ppm males at Weeks 0-13, 0-52, and 0-78 by 13-

17% (not statistically significant at Weeks 0-78); in the 300 ppm males at Weeks 0-13, 0-25, 0-

52, and 0-78 by 24-30%; and in the 300 ppm females at Weeks 0-13, 0-25, 0-52, and 0-78 by 

24-27%. During the interval of Weeks 1-14, food conversion efficiency was decreased in the 

100 (3.7%) and 300 (3.2%) ppm males compared to controls (4.6%), as well as in the 300 ppm 

females (2.2%) compared to controls (2.7%). As food consumption was similar in the treated 

groups to controls, the effects observed on food conversion efficiency correlated with those 

observed on body weight gain. 

In the 300 ppm males, the incidences of the following findings were increased: thin build, penis 

mutilation, swollen area, piloerection, ungroomed, pallor of skin, reddening of skin, hunched 

posture, skin encrustation, skin scab, urine staining, and yellow staining. In the 100 ppm males, 

the incidences of the following findings were increased: ungroomed, skin encrustration, and 

urine staining. The increase in incidence became clear by Months 2 (ungroomed) and 5 (thin; 

skin encrustation); however, the incidence was not summarized on a monthly basis for all 

findings. Increases were noted in the number of males with palpable swellings and total number 

of swellings; mean time of onset was similar to controls. However, microscopic pathology could 

not determine the etiology of these swellings. These findings were considered general 

indications of poor health rather than indicative of a particular toxicological syndrome. These 

observations were supported by similar observations made during gross pathology. At the 

interim and terminal sacrifices, gross observations included the following: pale skin, thickened 

skin, skin encrustation, skin abrasions, and thin appearance. As percentage affected, these gross 

findings were less prevalent at the terminal sacrifice than at the interim sacrifice. 
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The LOAEL in males is 100 ppm (11 mg/kg/day), based on decreased body weight, body 

weight gains, and food conversion efficiency and clinical signs indicative of poor health. 

The LOAEL in females is 300 ppm (38 mg/kg/day), based on decreased body weight and 

weight gain. The NOAEL in males is 30 ppm (3 mg/kg/day) and the NOAEL in females is 

100 mg/kg/day (12 mg/kg/day).

At the doses tested, there was no treatment-related increase in tumor incidence when compared 

to controls. Dosing was considered adequate in both sexes based on decreases in body weight, 

body weight gain, and food conversion in both sexes and clinical signs indicative of poor health 

in the males.

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.4200b; OECD 451) for a carcinogenicity study in mice.

Acute Neurotoxicity - Rats OPPTS 870.6200a [§81-8a]; OECD 424

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

(alpha-cypermethrin; 95.6% a.i., Batch # 02156) as a constant concentration of 0.6% (w/v) in 

corn oil was administered once via gavage (0.67 to 6.67 mL/kg) to 10 CD rats/sex/group to 

achieve dose levels of 0, 4, 20, or 40 mg/kg. The animals were fasted overnight prior to dosing. 

In an additional study, 5 rats/sex/dose were similarly treated at the some dose levels and 

subsequently used for neuropathological examinations. Neurobehavioral assessment (functional 

observational battery [FOB] and motor activity testing) was performed on all main study rats at 

pre-dosing and Days 1 (approximately 5 hours post-dosing), 7, and 14. At the main study 

termination, 5 rats/sex/group were anesthetized and perfused in situ for neuropathological 

examination. The tissues from the perfused animals in the control and 40 mg/kg groups from the 

main and additional studies were subjected to histopathological evaluation of brain and 

peripheral nervous system tissues. The sciatic nerve was examined microscopically in all dose 

groups. Positive control data were not provided.

No adverse, compound-related effects were observed in body weights, body weight gains, motor 

activity or gross pathology.

At 20 and 40 mg/kg, in the additional study, one male each was found dead on the day following 

dosing, after having shown clinical signs of neurotoxicity. These rats were replaced in order to 

maintain 5 males in these dose groups. In both the main and additional studies, treatment-related 

clinical signs of toxicity (abnormal/splayed gait, prostration, thrashing, vocalization, 

piloerection, unkempt appearance, soiled/stained body areas, and diarrhea) were most frequently 

noted in male rats dosed at 20 and 40 mg/kg and usually developed between 3 to 8 hours postdosing. Similar signs were sometimes noted in the females at these doses, but occurred at much 

lower frequencies and were not considered adverse. These signs usually resolved within 3 days 

after dosing. The frequency and time of onset for these signs were similar in the main and 

additional study animals. During the FOB evaluations at 5 hours post-dosing (main study only), 

gait abnormalities (laterally deviated limb position, splaying or dragging hind limbs, and altered 

fore and hind limb extension) and increased reactivity (posture in home cage, removal from cage, 
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and during handling) were noted in the 20 and 40 mg/kg males, but not in females. Additional 

findings at 40 mg/kg included decreased righting reflex and altered fur appearance in the males. 

The only histopathological finding which appeared to show any relationship to treatment was 

very slight to slight nerve fiber degeneration in the sciatic nerve. The changes were observed 

more frequently in the proximal than the distal part of the nerve. This finding was noted at all 

dose levels including controls, but the incidence was significantly increased (p<0.05) in the 20 

and 40 mg/kg males in the additional study. This finding is a well established effect of 

pyrethroids and is generally regarded to be a secondary consequence of the primary biochemical 

action of pyrethroids on the axon and is entirely reversible (Aldrich, 1990). Additionally, 

spontaneous occurrence of axonal degeneration is commonly observed in rats of this age and 

strain. Therefore, this finding is of equivocal toxicological significance. 

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

in males. The NOAEL is 4 mg/kg.

This study is classified as acceptable/guideline and does not satisfy the guideline requirement 

(OPPTS 870.6200a) for an acute neurotoxicity study in rats. 

Metabolism in Rats; OPPTS 870.7485 (§85-1); OECD 417

EXECUTIVE SUMMARY: In a series of rat oral metabolism studies (MRIDs 47944080, 

47944081, and 47944083), Wistar rats were treated with a single gavage dose of [14C-benzyl] or 

[

14C-cyclopropyl] cypermethrin (radiochemical purity >99%) at 2 or 200 mg/kg in Mazola corn 

oil (2 mL/kg dosing volume). The following studies were performed. (1) Metabolism (MRID 

47944080): An experiment was performed in 5 rats/sex receiving 2 mg/kg [14C-benzyl] 

cypermethrin that evaluated the excretion and tissue distribution of radioactivity at up to 4 days 

post-dose. Additionally, metabolite isolation from excreta and metabolite identification were 

performed by TLC separation and comigration with standards. (2) Tissue depletion in females 

(MRID 47944081): Tissue distribution was assayed in 8 subgroups of 3 female rats/time point 

sacrificed at 8 intervals up to 42 days after the administration of 2 mg/kg [14C-benzyl] 

cypermethrin. (3) Blood kinetics and plasma metabolism (MRID 47944083): In a whole blood 

kinetics experiment, both doses and radiolabeled compounds were evaluated in 6 

rats/sex/dose/radiolabel, and blood samples were collected up to 1 day after administration of the 

low dose or 3 days after administration of the high dose. Radioactive residues were measured in 

all collected samples. In a plasma metabolite experiment, both doses and radiolabeled 

compounds were evaluated in 5-7 rats/sex/radiolabel, and blood samples were collected up to 9 

hours after administration of the low dose or 72 hours after administration of the high dose. The 

proportion of radioactivity in the plasma attributable to cypermethrin was measured, as well as 

the plasma concentrations of cypermethrin. Animals in the [14C-benzyl] cypermethrin-treated 

groups were evaluated for clinical signs after dosing.

At 200 mg/kg, signs of toxicity were observed. These signs ranged from mild (such as slight 

high rear gait) to death. Treatment with [

14C-benzyl] cypermethrin at 200 mg/kg resulted in 

death at 4 hours post-dose in one male (M4; found dead) and one female (F1; euthanized 
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moribund). Other reported findings included subdued or very active behavior, panting, tremor, 

wide rear gate, ataxia, salivating, tail thrashing, wild thrashing, very slow respiration, and 

convulsions. No signs of toxicity were reported at 2 mg/kg. Excessive toxicity at 200 mg/kg 

may have confounded the results of these groups. Considerable animal-specific variation was 

reported. The clinical signs were consistent with neurotoxic effects expected from exposure to 

pyrethroids.

Total recovery was 94-95% of the administered dose (AD) in the excretion and tissue 

distribution groups administered 2 mg/kg [14C-benzyl] cypermethrin. At least half of the dose 

was absorbed (53-55% AD), and radioactivity was quickly eliminated (>76% AD within 24 

hours). After 4 days, slightly more of the dose was excreted in the urine (50-53% AD) than in 

the feces (38-43% AD). Biliary excretion was not evaluated. Radioactive residues in the cage 

wash, tissues, and the residual carcass accounted for <2% AD each. There were no significant 

sex-related differences in absorption and excretion.

In the 2 mg/kg groups evaluated for blood kinetics, absorption and excretion were rapid; 

maximum concentrations were observed in the blood within 3-4 hours (≤1.75 μg equiv./mL) and

negligible amounts were observed at 16 hours post-dose. No sex differences were noted in 

maximum concentrations or times to maximum concentration. The concentrations in the [14Cbenzyl] cypermethrin groups were approximately 3-fold higher than observed in the 

[

14C-cyclopropyl] cypermethrin groups, but the radiolabel position did not affect the times at 

which the maximum concentrations were observed. 

In the 200 mg/kg groups evaluated for blood kinetics, maximum concentrations of radioactivity 

in the blood were as follows: in the [14C-benzyl] cypermethrin groups (males – 39.7 μg 

equiv./mL at 23 hours; females – 41.9 μg equiv./mL at 16 hours) and in the [14C-cyclopropyl] 

cypermethrin groups (males – 10.3 μg equiv./mL at 24 hours; females – 6.65 μg equiv./mL at 8 

hours). No significant sex differences were noted in maximum concentrations, but 

concentrations reached maximum sooner in the plasma of females than in males, regardless of 

the radiolabel position. The concentrations in the [14C-benzyl] cypermethrin groups were higher 

by approximately 4-fold in males and 6-fold in females compared to the [14C-cyclopropyl] 

cypermethrin groups, but the radiolabel position did not have an appreciable effect on the times 

at which the highest concentrations were observed. The concentrations were <5 μg equiv./mL in 

all high dose groups by 48 hours post dose. An increase in dose of 100-fold led to an increase in 

blood of 12- to 28-fold, suggesting absorption may have been saturated at the high dose.

Radioactive residues in the tissues and residual carcass at 96 hours post-dose accounted for <1% 

AD each in rats administered 2 mg/kg [

14C-benzyl] cypermethrin. The maximum concentrations 

of radioactivity (μg equiv./g ) were reported on Day 1 in fat (0.335-0.561), skin (0.119), liver 

(0.232), and kidney (0.122). By Day 14 post-dose, average concentrations of radioactivity were 

<0.1 μg equiv./g in fat, 0.012 μg equiv./g in skin, and ≤0.003 μg equiv./g in liver and kidney. 

Tissue retention occurred only in the adipose tissue, but only negligible amounts were noted in 

any tissue (including fat) at 42 days after dosing.

Bi-phasic elimination of the radioactivity occurred in fatty tissues and skin, with an initial rapid 

depletion from the body followed by a slower clearance. The half-lives based on data obtained 
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from Days 1 to 8 were 1.6-2.7 days in skin and fat. The half-lives based on data obtained from 

Days 14 to 42 were 40 days in skin, 26 days in perovarian fat, 19 days in peri-renal fat, and 17 

days in subcutaneous fat. In contrast, elimination of radioactivity in other tissues was rapid: in 

the liver and kidney the half-lives were 2.3 and 2.0 days, respectively, and levels of radioactivity 

at two weeks’ post-dosing were below the limit of detection.

A total of 6 compounds were tentatively identified in the excreta (identified using TLC 

separation with standards for identification: further analytical methods were not employed). 

There was only one major metabolite that was isolated: 3-(4-hydroxyphenoxybenzoic acid Osulfate ester was isolated from the urine (34-40% AD). In the feces of the combined sexes, the 

parent was the predominant compound (22% AD). Metabolism of cypermethrin occurs by estercleavage followed by hydroxylation and sulfation of the 3-phenoxybenzoic acid portion of the 

compound. The cyclopropanecarboxylic acid portion of the insecticide is rapidly eliminated as 

the glucuronide conjugate. Hydroxylation of the intact ester also occurs to a small degree. 

The proportion of the radioactive residues isolated in the hexane extract of peri-renal and 

parovarian fat (as opposed to the acetonitrile phase) increased steadily with time from 28% of the 

TRR at Day 3 to 48% at Day 22. As cypermethrin partitions almost exclusively into the 

acetonitrile fraction, this suggests that lipophilic metabolites are present in the fat at increasing 

levels over time. The lipophilic metabolites were not further analyzed in this study.

In the [14C-benzyl] cypermethrin treated animals, a steady increase with time in the %TRR in the 

plasma attributable to cypermethrin was observed at both doses; however, no obvious effect on 

this percentage was noted in animals treated with [14C-cyclopropyl] cypermethrin. 

Concentrations of cypermethrin in the plasma were an order of magnitude higher in the 

[

14C-benzyl] cypermethrin groups compared to the [14C-cyclopropyl] cypermethrin groups.

These metabolism studies in the rat are classified Acceptable/nonguideline and satisfy the 

guideline requirement for a Tier 1 metabolism study [OPPTS 870.7485, OECD 417] in rats when 

considered together. Although these studies were conducted prior to publication of GLP and 

current metabolism study guidelines, and some study deficiencies were identified, the data 

provide sufficient metabolism data on cypermethrin to characterize its metabolism in the rat. 

The proposed pathway is similar to the metabolic pathway of other pyrethroids, such as 

permethrin. Additional metabolism data are not required at this time.

In Vivo Dermal Penetration Study in Rats; OPPTS 870.7600 [§85-2]; OECD 427.

EXECUTIVE SUMMARY: In an in vivo dermal penetration study (MRID 47944084), 

[

14C] alpha-cypermethrin (BAS 310 I technical; 99.8% radiochemical purity; Batch No. 775-

0203) was applied to the shaved skin (10 cm2) of male Crl:WI (Han) rats. Actual doses of 1.5 or 

333 μg/cm2skin were applied to the skin of each rat in volumes of 10 μl/cm2skin in a vehicle 

consisting of the blank formulation BAS 308 4 I or a 1/200 aqueous dilution of the blank 

formulation plus test material, respectively. Four rats/dose/time point were tested using an 

exposure duration of 6 hours and termination times of 6, 24, or 120 hours post-application. 

Urine and feces samples were collected at 6 hr (end of dosing), 24 hr and then at 24 hour 

intervals until study termination.
Alpha-Cypermethrin Human Health Risk Assessment DP No. D376098

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Analytical recoveries were 96-114% of the administered dose (AD). The amount absorbed 

included radioactivity found in the cage wash, blood cells, plasma, urine, feces, and carcass. The 

amount absorbed was only 0.12-1.13% AD at the high dose, but was 4-13.4% AD at the low 

dose. Approximately 27 to 34-fold greater absorption (as % AD) was observed in the lower dose 

groups at the 6 and 24 hour sacrifices compared to the higher dose groups. Absorption at the 120 

hour sacrifice was 12-fold higher in the low dose group, suggesting that absorption mechanisms 

were saturated at the higher dose. The amount absorbed increased with time at both doses, 

indicating that further absorption occurs from the skin after washing. Most of the non-excreted 

absorbed dose was found in the carcass at all times evaluated (0.09-3.52% AD). In the blood, 

most of the radioactivity was found in the blood cells rather than in the plasma. The urine was 

the primary route of excretion (0.61 and 6.19% of AD at 120 hours for the high and low dose, 

respectively). The majority of the dose was removed with the first skin wash (83-96% AD). 

Based on the likely worker exposure time frame, it is considered most appropriate to adopt the 

dermal absorption value calculated for the group of animals for which the skin site was washed 

after 6 hours and terminated 120 hours after application. Because absorption continued to occur 

throughout the study, the absorbable dose should also be considered in a conservative estimate of 

absorption. However, only 0.76-0.78% AD remained in the skin at the application site and 

surrounding skin at 120 hours post-application, indicating absorption was essentially complete at 

that time. The low dose (1.5 μg/cm2) at 120 hours post-dosing provided the most conservative 

estimate of total absorbed at 13.4% AD. 

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.7600; OECD none) for a dermal penetration study in rats.