UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: May 18, 2015 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Zeta-Cypermethrin- Human Health Risk Assessment for a Petition to 

Amend (Increase) the Established Tolerances for the Insecticide in Field 

Corn and Popcorn Stover, and in Field Corn Forage. 

PC Code: 129064 

Decision No.: 492384 

DP Barcode: D422259 

Petition No.: 4F8290 

Assessment Type: Single 

Chemical/ Aggregate 

TXRNo.: NA 

Registration No.: 279-3 125, 279-3126, 

279-3426 

Regulatory Action: Section 3 

Registration Case No.: 2130 

MRID Nos.: NA 

CAS No.: 52315-07-8 

40 CFR: §180.41 8 

FROM: 

William 

Elizabeth 

T. 

Holman

Drew, 

, 

Chemist 

Physical 

1AJ 

~c~Risk 

f ~ 

Assessor ~ 

Risk Assessment Branch II 

Health Effects Division (7509P) ;\ ..-

THROUGH: Christina Swartz, Branch Chie ~/ ~ Risk Assessment Branch II 

Health Effects Division (7509P) 

TO: Julie Chao/Kable Davis, RM Team 3 

Invertebrate and Vertebrate Branch 1 (JVB 1) 

Registration Division (7505P) 

Page 1 of 10 

1+.-L--
1.0 Executive Summary 

Zeta-cypermethrin is a broad-spectrum, pyrethroid insecticide containing the same eight 

stereoisomers that are present in cyperrnethrin. However, zeta-cyperrnethrin is enriched in the 

four insecticidally activeS isomers, and contains % each of the inactive R isomers. It is 

registered for both agricultural and residential uses. In addition, alpha-cypermethrin is 

comprised of the two most insecticidally active cis-2 isomers of cyperrnethrin, also with both 

agricultural and residenti al uses. Although cypermethrin, alpha- and zeta-cypermethrin are 

separate active ingredients with different end-use products, they are included together in the 

hazard evaluation for the purpose of human health risk assessment. The toxicology database for 

the cypermethrins includes studies with cyperrnethrin and both of its enriched isomers, for 

evaluating potential hazard, and is adequate for risk assessment. 

In the current petition (4F8290), FMC is proposing label amendments specifying decreased preharvest intervals (PHis) for field com and popcorn, from the current 30 days for grain and stover, 

and 60 days for forage, to 7 days for all of these commodities. FMC is also proposing to amend 

(by increasing) the currently established tolerances for zeta-cyperrnethrin residues in field corn 

forage of 0.20 ppm, and in field com and popcorn stover of3.00 ppm. The label amendments 

would apply to three end-use products (EPs). These EPs are Fury 1.5 EC Insecticide (EPA 

Registration #279-3125), an emulsifiable concentrate (EC) formulation containing 1.5 pounds of 

active ingredient per gallon (lb ailgal); Fury 1.5 EW (formerly Mustang) Insecticide (EPA 

Registration #279-3 126), an emulsifiable water-based concentrate (EW) fom1Ulation containing 

1.5 lb ai/gal; and F911 4 EC Insecticide (EPA Registration #279-3426), an EC formulation 

containing 0.8 lb ai/gal. 

Cypermethrin, zeta-cypermethrin, and alpha-cypermethrin are Type II pyrethroids that share the 

same mode of action. Like other pyrethroids, the cypermethrins cause neurotoxicity from 

interaction with sodium channels leading to clinical signs of neurotoxicity. Clinical signs of 

neurotoxicity were noted throughout the toxicology database. 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., 20 II ). 

Furthermore, rapid metabolism and elimination preclude accumulation and increased potency 

following repeated dosing. Therefore, for endpoint selection and risk assessment, only single 

day exposure assessments need to be conducted. 

No evidence of carcinogenicity was observed in carcinogenicity studies in rats with 

cypermethrin, or in mice with alpha-cypermethrin. However, lung tumors were seen in females 

in a carcinogenicity study with cypermethrin. Cypermethrin is classified as a Group C .. Possible 

human carcinogen." However, the Agency has detem1ined that the quantification of cancer risk 

using a non-linear approach (i.e., RID) will adequately account for all chronic toxicity, including 

carcinogenicity, which could result from exposure to cyperrnethrin. While the Agency would 

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

the acute Population Adjusted Dose (aPAD) is protective because increasing toxicity with 

increasing duration of exposure is not demonstrated for the cyperrnethrins. 

Page 2 of 10 
There was no systemic toxicity observed via the dermal route, and therefore no appropriate 

endpoint for dermal risk assessments. Therefore, only acute dietary, incidental oral and 

inhalation endpoints were selected for risk assessment, all based on neurotoxicity. 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). 

As mentioned previously, 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 hjgher than chronic exposure levels. Accordingly, a 

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

The Wolansky study was also used to assess incidental oral exposure. 

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 I OX to 3X because the 

HEC calculation accounts for pharrnacokinetic (not pharmacodynamic) interspecies differences 

between animals and humans. Since the last risk hazard characterization was completed 

(0378897; E. Holman; 12 October 2012), HEO's approach for calculating HECs has evolved. A 

new inhalation assessment based on current procedures would result in slight changes in the 

points of departure for inhalation risk assessment for the cypermethrins. However, these slight 

changes will not change HEO's conclusions with respect to the risk assessment (i.e. the current 

estimated margins of exposure (MOEs) are protective). 

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 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. For adults 

(including women of child-bearing age) and children > 6 years of age, EPA is reducing the 

FQPA safety factor to lX. 

The level of concern (LOC) for inhalation exposure and risk is 30 for adults and children 6 years 

of age and over, which includes an interspecies factor of 3X and intraspecies factor of lOX. For 

children younger than 6 years of age, the LOC is 100 based on the FQPA safety factor of3X, an 

interspecies factor of 3X and the intraspecies factor of I OX. The LOC for incidental oral 

exposure and risk is 300 for children under 6 years of age, which includes a FQPA safety factor 

of 3X, interspecies factor of I OX and intraspecies factor of 1 OX. 

Based on the proposed and existing use pattern, short-term (1 -30 days) and intermediate-term (1-

6 months) exposures are expected for occupational handlers (i.e., mixing, loading, and applying 

the EP) and during post-application activities (i.e., re-entering treated areas). ln addition, shortterm exposures are expected for commercial and residential handlers who apply the proposed 

products in residential settings, as well as for adults and children who may be exposed to 

previously treated areas (i.e., post-application). Long-term exposures are not expected. Since no 

dermal endpoint was identified, residential assessments for zeta-cypermethrin are based on 

Page 3 of 10 
inhalation and incidental oral (for children) exposures, and occupational assessments are based 

on inhalation exposures only. 

Due to the fact that the proposed amended use on corn had no impact on the existing use rate for 

the registered products, HED did not conduct a new quantitative occupational exposure 

assessment for this action. Therefore, occupational risk estimates for the amended use on corn 

would be the same as those previously assessed for the existing registered products, which were 

not of concern (M. Collantes; 0385662; 09/20/20 12). 

The crop field trial data submitted in support of the current action, along with previously 

reviewed data, are adequate for purposes of risk assessment and tolerance assessment for the 

proposed amended uses under review. These field trial data are supported by adequate storage 

stability data and adequate analytical methods. Maximum residues of zeta-cypermethrin are 

expected to occur at moderate levels (up to 9.0 ppm in field corn forage, and up to 30 ppm in 

field corn and popcorn stover) from the shorter PHis on field com and popcorn proposed in the 

current petition (W. Drew; D42280 l; 02/20/20 15). It is noted that zeta-cypermethrin residues in 

corn grain were below the limit of quantitation (LOQ) in all field trials; therefore, the existing 

zeta-cypermethrin corn grain tolerances do not need to be revised. For further details on the 

residues observed in corn, please see Appendix A. 

All of the tolerances that are being increased are for livestock feed items (corn forage and corn 

stover) and have the potential to impact the livestock dietary burden. However, based on a 

review of the residue data, the livestock commodity tolerances that are currently set are adequate 

and do not need to be revised (W. Drew; D422801 ; 02/20/2015). The existing zeta-cypermethrin 

use on com was previously included in the dietary exposure assessment (E. Holman; D403600; 

9/7/2012). Therefore, decreasing the PHI and increasing the zeta-cypermethrin tolerances for 

popcorn stover, field corn stover, and field corn forage, will have no impact on the dietary risk 

estimates, as they are already covered in the existing dietary assessment. The results of the 

dietary exposure assessment are summarized below. 

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

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

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

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

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

modeling uses conservative assumptions regarding residues of zeta-cypermethrin and its 

breakdown products in drinking water. Since monitoring data was not available for all 

commodities, the modeling uses a combination of highly conservative assumptions (i.e. tolerance 

level residues) and monitoring data with percent crop treated information for residues of zetacypermethrin and its breakdown products in food, as well as an extensive database of food 

consumption patterns for the entire U.S. population and various population subgroups. 

For all registered and proposed uses, the acute dietary exposure estimates are below HED's LOC 

{<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 subgroup. 

Page 4 of 10 
The aggregate risk assessment for zeta-cypermethrin considers potential exposure from all 

cypennethrins (i.e., cypermethrin and alpha-cypermethrin). The combined residential adult 

handler and children's scenarios previously assessed by HED for the cypermethrins still 

represent the worst case exposure for each life stage and thus are protective of all other 

residential uses (M. Collantes; 0385662; 09/20/20 12); proposed and existing uses result in risk 

estimates that are not of concern. 

Cypermetbrin, alpha-cypermethrin and zeta-cypermethrin residential uses are included in the 

pyrethroid/pyrethrin cumulative risk assessment (CRA). Given that this petition did not make 

any changes to the existing use rates for all registered products, these proposed revisions to the 

zeta-cypermethrin field com and popcorn PHis will have no impact on the cumulative risk 

assessment. No dietary, residential, or aggregate risk estimates of concern have been identified 

in the single chemical assessment. In the cumulative assessment, residential exposure was the 

greatest contributor to the total exposure. Although there are residential uses for cypermethrin. 

alpha-cypermethrin and zeta-cypermethrin, the products involved in this petition are not for 

residential use. Therefore, the proposed revisions will have no impact on the residential 

component of the cumulative risk estimates. 

2.0 HED Recommendations 

HED has no objection to the proposed PHI revisions for the use of zeta-cypermethrin on field 

corn and popcorn. Pending submission of a revised Section F (to propose tolerances in 

accordance with those recommended by HED), there are no residue chemistry issues that would 

preclude increasing the currently established tolerances for zeta-cypermethrin residues of0.20 

and 3.00 ppm in field corn forage, and field corn and popcorn stover, respectively, to 9.0 and 30 

ppm. The recommended tolerances are listed in Table 2.2.3, below. No risks of concern or data 

deficiencies were identified. For further details on the earlier risk assessment of zetacypermethrin, see D378897, E. Holman, 10/ 12/2012. This assessment summarizes the 

toxicological database in detail, as well as the results from the dietary exposure, occupational and 

residential exposure, and aggregate risk assessments associated with the existing use pattern. No 

new quantitative exposure assessments were conducted for the proposed amended uses, since the 

proposed use pattern and exposure scenarios have been assessed in conjunction with the existing 

use pattern for the chemical. 

2.1 Data Deficiencies 

None. 

2.2 Tolerance Considerations 

2.2.1 Enforcement Analytical Method 

Adequate tolerance enforcement methods are available in PAM Volume If for determining 

residues of cypern1ethrin, zeta-cypermethrin and alpha-cypermethrin in plant (Method I) and 

livestock (Method II) commodities. Both methods are gas chromatographic methods with 

Page 5 of 10 
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 of0.005 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 (enriched in 2 

isomers). 

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

cypennethrin 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, zeta-cypermethrin, and alphacypermethrin are included in the same listing in the 40 CFR (§ 180.418), 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. 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 zetacypermethrin. 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 and alpha-cypennethrin. For 

enforcement purposes, the same moiety is being regulated. 

There are no Codex MRLs for cypermethrin, which includes both alpha- and zeta-cypermethrin, 

established in com forage or stover. Canada's PMRA does not establish MRLs in livestock 

feedstuffs, including corn forage or stover. 

2.2.3 Recommended Tolerances 

The current tolerance expression for zeta-cypermethrin (40CFR § l80.418[a][3]) is adequate, and 

includes both coverage and compliance statements for enforcement purposes. 

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

commodities listed in Table 2.2.3. 

TABLE 2.2.3 Tolerance Summary for Zeta-Cypermetbrin. 

Commodity Proposed Recommended Comments; Correct Commodity 

Tolerance (ppm) Tolerance (ppm) Definition 

Com, field, forage 9.0 9.0 

Corn, field, stover 30.0 30 

Com, pop, stover 30.0 30 

Page 6 of 10 
2.2.4 Revisions to Petitioned-For Tolerances 

Instead of the proposed tolerances in field corn and popcorn stover (30.0 ppm), HED 

recommends establishing the tolerances at 30 ppm. The Agency establishes tolerances using 

whole numbers for tolerances of 10 ppm or more, per the OECD's User Guide 

ENV/JM/MON0(2011)2 for the OECD tolerance calculation procedure. 

2.3 Label Recommendations 

None. 

3.0 Chemical Identity 

~LE3 0 zeta-CypermethiJn Nomenclature. -· .. ~: 

Compound N 

Ill 

0 c 

Cl ~ ~ 0'0 A 0 

Cl I 

# I Common name Zeta-cypermethrin 

Company experimental name FMC 56701 

Molecular formula C22H19ChN03 

Molecular weight 4 16.3 

IUPAC name (S)-a-cyano-3-phenoxybenzyl ( I RS,3RS; I RS,3SR)-3-(2,2-dichlorovinyl)-2,2-

dimethylcyclopropanecarboxylate 

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

dimethylcyclopropanecarboxylate 

CAS registry number 52315-07-8 

End-use products (EPs) Fury 1.5 EC Insecticide (EPA Registration #279-3125) 

Mustang Insecticide (EPA Registration #279-3 126) 

F9 1 14 EC Insecticide (EPA Registration #279-3426) 

3.1 PhysicaVChemica l Characteristics 

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

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

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

pressure (3 X 1 o-9 mm Hg at 20°C), which decreases its potential to volatilize. 

3.2 Pesticide Use Pattern 

FMC is proposing label amendments specifying decreased PHfs for field corn and popcorn, from 

the current 30 days for grain and stover, and 60 days for forage, to 7 days for all of these 

commodities. FMC is also proposing to amend (by increasing) the currently established 

tolerances for zeta-cypermethrin residues in field corn forage of 0.20 ppm, and in field corn and 

Page 7 of 10 
popcorn stover of 3.00 ppm. The label amendments would apply to three EPs. These EPs are 

Fury 1.5 EC Insecticide (EPA Registration #279-3 125), an EC formulation containing 1.5 

pounds of active ingredient per gallon (lb ai/gal); Fury 1.5 EW Insecti cide (EPA Registration 

#279-3126), an EW formulation containing 1.5 lb ai/gal; and F9l14 EC Insecticide (EPA 

Registration #279-3426), an EC formulation containing 0.8 lb ai/gal. 

Because F9114 EC contains zeta-cypermethrin with a hjgher cis/trans ratio, it is applied at rates 

which are only half those of the Fury 1.5 EC and Fury 1.5 EW formulations. The proposed 

revised use directions are summarized in Table 3.2, below. 

TABLE 3.2 Summar) of Proposed Use Directions for Zeta-Cypermethrin on Field Corn and Popcorn. 

Application Type; Single Use Max. Max. PIIP Use Directions, Application 

Equipment• Rate (lb Uses Per Seasonal Use (Days) Timing, and Limitations3 

ail A) Season Rate (lb ail A) 

Fury 1.5 EC and Fun 1.5 EW End-use Products 

Foliar; ground, aerial or 0.016-0.05 NS4 0.2 7 Minimum RTI

5 of3 days. May 

chemig_ation equipment. be applied via chemigation. 

F911 4 EC End-use Product 

Foliar; ground, aerial or 0.008-0.025 NS 0.1 7 Minimum RTI of3 days. May 

chemigation equipment. be applied via chemigation. . . I. For ground apphcat10n, apply m a mmtmum of 10 gallons of water per acre (GPA). Do not apply through any 

ultra-low volume (ULV) spray system. For aerial application, apply in a minimum of2 GPA. For 

chernigation, use only through sprinkler systems, includ ing center pivot, lateral move, end tow, side 

(wheel) roll, traveler, big gun, solid set, or hand move irrigation systems. Do not apply through any other 

rype of irrigation system. 

2. PHI = Pre-Harvest Interval. 

3. Begin applications when insect pest populations reach economic threshold levels. 

4. NS = Not Specified. 

5. RTI = Re-Treatment Interval. 

Conclusions: The proposed use directions for application on field com and popcorn are 

sufficient to allow for evaluation of the submitted residue data relative to the proposed use 

patterns. 

References 

W. Drew, 02/20/2015, D422801, Zeta-Cypermethrin. Petition to Amend (Increase) the 

Established Tolerances for the Insecticide in Field Corn and Popcorn Stover. and in Field Corn 

Forage. Summary of Analytical Chemistry and Residue Data. 

E. Holman, 10/12/2012, D378897, Zeta-Cypermethrin- Human Health Risk Assessment for 

New Poultry House Use and Agricultural Uses on Tropical Fruit, Artichoke, Barley, Oat, Rye, 

Buckwheat, and Pistachio. 

E. Holman, 9/7/2012, D403600, Cypermethrin, Alpha-Cypermethrin, and Zeta-Cypem1ethrin. 

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. 

Page 8 of 10 
M. Coil antes, 09/20/2012, D3 85662, Zeta-cyperrnethrin. Occupational and Residential 

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

Page 9 of 10 
Appendix A. Summary of Zcta-Cypermetbrin Field T rial Data on Corn 

Please see 0422801; W. Drew; 02/20/2015 for further details. 

TABLE Al Summary of Residue Data from Field Corn Field Trials with Zeta-Cypermetbrin (MRIDs 

#47440501 and 49412201 . 

Commodity Total Use Rate Pm Residue Levels (ppm) 

(lb ai/A)1 (Days) nl Min. Max. RAFr3 Median Mean Std. Dev. 

Field com grain 0.20 6-8 15 <0.05 <0.05 <0.05 0.05 0.05 0 

Field com forage 0.20 6-8 13 0.683 7.09 6.30 2.54 2.59 1.61 

Field corn stover 0.20 6-8 15 0.215 17.6 15.9 3.61 4.76 4.39 

- I. Target apphcat1on rate (4 x 0.0) lb ail A). 

2. Except for sample minimax, values reflect per trial averages; n = number of field trials. For calculation of 

median, mean and standard deviation, the LOQ (0.05 ppm) was used for any results reported as <LOQ. 

3. HAFT = Highest Average Field Trial. 

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