### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON. D.C. 20460

MEMORANDUM
Date: November 

### 13,2014 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Zeta-Cypermethrin

- Human Health Risk Assessment to Support Increased Tolerances and Use Rate on Alfalfa Hay and Forage.
PC Code: 129064 Decision No.: 484398 Petition No.: 3F8214 Assessment Type: Single Chemical/ Aggregate TXRNo.: NA MRIDNos.: NA FROM: Elizabeth Holman, Physical ,Scienf William Drew, Chemist Zaida Figueroa, Industria ygierust Karlyn Middleton, Toxicologist Risk Assessment Branch II Health Effects Division (7509P) THROUGH: Christina Swartz, Branch Chief Risk Assessment Branch II Health Effects Division (7509P) DP Barcode: D416567 Registration No.: 279-3125,279-3126, 279-3426 Regulatory Action: Section 3 Registration Case No.: 2130 CAS No.: 52315-07-8 40 CFR: 180.418

TO: Richard Gebken and Olga Odiott Invertebrate and Vertebrate Branch 2 (IVB2) Registration Division (RD), 7505P

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### 1.0 Executive Summary In the current petition (3F8214), FMC is proposing to increase the currently established tolerances for zeta-cypermethrin residues in alfalfa forage and hay of 5.00 and 15.00 ppm, respectively. These higher tolerances are needed in conjunction with the proposed label amendments to double the use rates ofthree end-use products (EPs) on alfalfa grown for forage and hay. 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 ai/gal); Mustang Insecticide (EPA Registration #279- 3126), an emulsifiable water-based concentrate (EW) formulation containing 1. 5 lb ailgal; and F9114 EC Insecticide (EPA Registration #279- 3426) , an EC formulation containing 0.8lb ai/gal. Because F91 14 EC contains zeta
cypermethrin with a higher cis/trans ratio, it is applied at rates which are only half those of the Fury and Mustang formulations
. Zeta-cypermethrin is an enriched isomer of the pyrethroid insecticide cypermethrin, registered for both agricultural and residential uses . In addition, alpha

-cypermethrin is also an enriched isomer of cypermethrin. The tox icology database for the cypermethrins includes studies with cypermethrin and both of its enriched isomers, and i s considered complete for the purpose ofrisk assessment. The toxicological database for zeta-cypermethrin is complete (Holman, E., D378897, 10/12/2012). As stated above, although cypermethrin, alpha-cypermethrin and zetacypermethrin 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. Cypermethrin, zeta
-cypermethrin, and alpha

-cyperrnethrin are structurally similar Type II pyrethroids, and like other pyrethroids, cause neurotoxicity from interaction with sodium channels leading to clinical signs of neurotoxicity. Furt hermore, 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-cyperrnethrin, and alpha

-cyperrnethrin. Clinical signs related to neurotoxicity were noted in all ACN studies for all three chemica ls. For alpha

cypermethrin, clinical signs were most frequently noted in dosed rats between 3 to 8 hours post
dosing. In SCN studies with the three chemicals, neurotoxic effects were observed at comparable doses
. This is consistent with the toxicity profiles for all the pyrethroids, which are marked by rapid absorption, metabolism, and time

-to-peak effect. For purposes of endpoint select ion and exposure assessment, only single day risk assessments need to be conducted
. Cypermethrin, alpha-cypermethrin and zeta-cypermet hrin exposure to children <6 years old is expected and it must be considered in the context of the pyrethroids as a class. HED has determined that for all pyrethroids, there is uncertainty regarding susceptibility of infants and children for post-natal exposure, and t he required l OX Food Quality Protection Act (FQPA) Safety Factor (SF) has been reduced to 3X to account for thi s uncertainty, pending receipt of additional toxicity data. The 3X for all pyrethroids is considered adequately protective for children <6 years of age. The FQPA safety factor was reduced to 1 X for women of child bearing age (as well as for all adu lt populations and chi ldren**~6** years). Page 2 of9No systemic effects were observed in the 21

-day dermal rat study with zeta
-cypermethr in or cypermethrin up to the limit dose and there are no developmental or reproductive toxicity concerns.**Therefore~** a dermal endpoint was not selected, and risk associated with exposure via the dermal route is not of concern . A 21-day inhalation study in rats was selected to assess short

- and intermediate- term inhalation exposure . The NOAEL of0.01 mg/L was based on decreased body weight and increased salivation at the LOAEL of 0.05 mg/L. For occupationa l and residential inhalation exposure, a human equivalent concentration (HEC) and human equivalent dose (HED) were derived in accordance with st andard methodology that results in a reduction in the interspecies UF from 1

OX to 3X. The HED determined for the occupational inhalation risk assessment is 1. 1 0 mg/kg/day; the HED is 1
. 15 mg/kg/day for residential inhalation risk assessments. Since this hazard characterization was completed, HED's approach for calculating HEC's has evolved, which would result in slight changes in the points of departure (PODs) for inhalation risk assessment for the cypermethrins. However, these slight changes will not affect the risk assessment (i.e., the current estimated MOEs are protective). The benchmark dose (BMD) methodology was used to determine the POD for incidental oral exposure and risk assessment. The methods and assumptions used are described in detail in the aggregate risk assessment for zeta-cypermethrin. The dose used for risk assessment was determined using a BMD analysis using 1 standard deviation (BMDL1so) from the control group as the benchmark response (BMR), as suggested for continuous endpoints in the Agency's BMD guidance (USEPA 2012). The incidental oral benchmark dose level (BMDL1so) of7.16 mglkg was selected from an acute oral study in the rat, based on decreased locomotor activity at the BMD value of 11.20 mg/kg. The level of concern (LOC) for inhalation exposure and risk is 30 for adults and chi ldren 6 years ofage and over, which includes an interspecies factor of 3X (reduced from 1 OX for use ofthe HEC methodology for inhalation risk assessment) and intraspecies factor of 1 OX. For children younger than 6 years of age, the LOC is 100, which includes a 3X UF 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, an interspecies factor of 3X, and intraspecies factor of 1OX. The LOC for incidental oral exposure and risk is 300 for children under 6 years of age, which includes a 3X uncertainty factor retained to account for the increased quantitative susceptibility seen in the scientific literature related to pyrethroid pharmacokinetics, an interspecies factor of 1 OX and intraspecies factor of 1OX. The Agency has determined 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 cypermethrin. 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 linear or no-threshold approach to quantitation ofhuman cancer risk. No evidence ofcarcinogenicity was observed in carcinogenicity studies in rats with cypermethrin or in mice with alpha-cypermethrin. Carcinogenicity studies are not available for zeta
-cypermethrin; however, based on the structural Page 3 of9and toxicological similarities to alpha cypermethrin and cypermethrin the carcinogenic potential is expected to be similar. Therefore, HED considers conclusions regarding t he carcinogenic potential ofcypermethrin to be applicable to zeta-cypermethrin and alpha-cypermethrin. Due to the lack of a dermal endpoint, occupational handler assessments are based on inhalation exposures only. All occupational handler scenarios associated with the proposed (revised) use pattern resulted in MOEs greater than 3,300 (LOC=30) at baseline (i.e., single layer clothing and no respirator) and with the use ofengineering controls (enclosed cockpits) for aerial applications, and were not ofconcern (Figueroa, Z.; D423900; 11 / 13/2014). Based on the Agency's current practices , a quantitative non-cancer occupational post-applica tion inhalation exposure assessment was not performed for zeta-cypermethrin at this time. Ifnew policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational postapplication inhalation exposure assessment for zeta
-cypermethrin. Based on the proposed and existing use pattern, short

-term (1-30 days) exposures are expected for commercial and residential handlers who apply the proposed products, as well as for adults and children who may be exposed to previously treated areas (i.e. , post-application). Since no dermal endpoint of concern was identified, residential assessments for zetacypermethrin are based on inhalation and incidental oral (for children <6 years old) exposures only. There are no new residential uses associated with the proposed (revised) use pattern. Therefore, the previous residential exposure assessment accounts for the currently registered products containing zeta-cypermethrin that are used in residential settings (Collantes , M. ; D403601; 8/4/2012). The aggregate risk assessment for zeta-cypermethrin must consider potential exposure from all cypermethrins (i.e., cypermethrin and alpha

-cypermethrin) , since the 3 active ingredients are all considered to be essentially the same active from the mammalian toxicity perspective. The combined residential adult handler and children's scenarios previously assessed by HED still represent the worst case exposure for each life stage and thus are protective of all other residential uses (Collantes, M.; D403601; 8/4/2012); these existing uses result in risk estimates that are not of concern. The proposed tolerances associated with the increased use rate on alfalfa hay and forage has no impact on the dietary exposure assessment for the cypermethrins. These alfalfa commodities are livestock feed items that are not directly entered into the dietary exposure assessment. The existing tolerance for zeta-cypermethrin of40 ppm in non-grass animal feed (group 18) hay (clover was the representative crop for this tolerance) is protective of the increased tolerance in alfalfa hay to 30 ppm. Therefore, the proposed increased use rates on alfalfa grown for forage and hay will not result in the need to increase the tolerances in livestock commodities (Drew, W., D416982, 10/3112014). Consequently, the previously conducted dietary exposure assessment is protective of the increased use rate on alfalfa hay and forage. Furthermore, the drinking water estimates used in the existing dietary exposure assessment are protective (higher) than those recently estimated based on the proposed use pattern and using updated drinking water models (Abdel-Saheb, 

### I., D416746, 9 /3/2014; 

### I. Maher, D378901/D385246 , 22 February 2011). The results ofthis dietary exposure assessment are summarized below.
Page 4 of9Dietary 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 ri sk estimates resulting from the use of cypermethrin, alpha-cypermethrin, and zeta
-cypermethrin on the crops listed under 40 CFR 180.418 (Holman E, D403600, 7 September 2012). HED has used modeling to estimate dietary exposure to the cypermethrins. The modeling uses conservative assumptions regarding residues ofzeta-cypermethrin arid its breakdown products in drinking water. Since monitoring data were not available for all commodities, the modeling uses a combination ofhighly conservative assumptions (i.e., tolerance-level residues) and monitoring data with percent crop treated information for residues of zeta-cypermethrin and its breakdown products in food, as well as an extensive database offood consumption patterns for the U.S. population and population subgroups . For all registered and proposed uses, the acut e dietary exposure estimates are below HED's LOC (<100% ofthe acute population adjusted dose [aPAD] at the 99.9th percentile of exposure). Dietary exposure (food and drinking water) for the cypermethrins is 18% ofthe aPAD for the U.S. population and 87% ofthe aPAD for all infants and children 1

-2 years, the most highly exposed population subgroups. Cypermethrin and zeta-cypermethrin residential uses are included in the pyrethroidlpyrethrin cumulative risk assessment (CRA). The proposed changes in the zeta-cypermethrin exposure and risk assessment will have an insignificant impact on the cumula tive 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 tot al exposure. The residential uses for cypermethrin and zeta-cyperrnethrin, are not affected by the proposed change in the use pattern being proposed with this action Therefore, the proposed use will have no impact on the residential component of the cumulative risk estimates. 

### 2.0 HED Recommendations HED has no objection to the amended registration of zeta-cypermethrin and establishment of amended alfalfa forage and hay tolerances as summarized in Table 2.2.3. No risks of concern or data deficiencies were identified. For further details on the earlier risk assessment of zetacypermethrin, see Holman, E., D378897, 10/12/20 12. That assessment summarizes the toxicological database in detail, as well as the results from the dietary exposure, residential exposure, and aggrega te risk assessments associated with the existing use pattern. A new quantitative occupational exposure assessment was conducted for the revised use pattern on alfalfa, whereas the dietary , residential, and aggregate assessments are covered by the existing use pattern. For further details on this new quantitative occupationa l exposure assessment, see Figueroa, Z., D423900, 11/13/2014.


### 2 .1 Data Deficiencies None. Page 5 of9

### 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 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 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, zeta-cypermethrin, and alpha

- · cypermethrin are included in the same listing in the 40 CFR, but have separate sections and different crops listed; where there are tolerances established for both actives 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 zeta-cypermethrin, but all are in conjunction with MRLs for total cypermethrin isomers (no MRLs have been established solely for zeta
cypermethrin). However, although the definitions differ formally, they are effectively harmonized since the tolerance-enforcement methods are not stereospecific, and thus do not distinguish between residues ofcypermethrin, zeta
-cypermethrin and alpha-cypermethrin. For enforcement purposes, the same moiety is being regulated. There is a Codex MRL established in alfalfa fodder at 30 ppm, which would be harmonized with the proposed tolerance in alfalfa hay. Codex has not established an MRL in alfalfa forage. · Codex MRLs are established for cypermethrin, which includes both alpha

- and zeta
cypermethrin. Canada's PMRA does not establish MRLs in livestock feedstuffs, including alfalfa forage and hay. Therefore there are no international harmonization issues associated with this petition.

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### 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 zeta-cypermethrin is the parent compound. The tolerance enforcement methods for plant and animal commodities do not distinguish between cypermethrin, zeta-cypermethrin, and alphacypermethrin, even though they have separate tolerance listings in 40CFR 

### § 180.418.

TABLE2.2.3 Tolerance Summary for Zeta-Cypermethrin. Commodity Proposed Recommended Comments; Correct Commodity Tolerance (ppm) Tolerance (ppm) Dtifmition Alfalfa, hay 30.0 30 Alfalfa, forage 15 .0 15 

### 2.2.4 Revisions to Petitioned-For T olerances Instead ofthe proposed tolerance in alfalfa hay (30.0 ppm), HED recommends establishing the tolerance at 30 ppm. The Agency establishes tolerances using whole numbers for tolerances of 10 ppm or more, per the OECD's 

### User Guide ENV/JMIMON0(2011)2 for the OECD tolerance calculation procedure. For the same reason, HED recommends that the proposed tolerance of 15.0 ppm in alfalfa forage be revised to 15 ppm. 

### 2.3 · Label Recommendations None
. 

### 3.0 Chemical Identity

TABLE3.0 Zeta-Cyj)ermethrin Nomenclature. 

### -· . Compound 

### N Ill 

### 0 

# c Cl 

## .,p 

# 0'0 A**~I** Cl Common name**~eta cypermethrin**  Company experimental name FMC 56701 Molecular formula CnH19ChN03 'Molecu lar weight 416.3 IUPAC name (S)-a -cyano -3-phenoxybenzyl ( 1RS,3RS;1 RS,3SR)
- 3-(2,2

-dichlorovinyl)-2,2- dimethylcyclopropanecarboxylate CAS name (S)-cyano(3-phenoxyphenyl)methyl-3-(2,2-dichloroethenyl)-2,2- dimethylcyclopropanecarboxylate Page 7 of9TABLE3.0 Zeta-Cypermethrin Nomenclature. .,

. .. CAS registry number 52315-07-8 End-use products (EPs) Fury 1.5 EC Insecticide (EPA Registration #279-3125) Mustang Insecticide (EPA Registration #279-3126) F9114 EC Insecticide (EPA Registration #279

- 3426) , .


### 3.1 Physical/Chemical Characteristics Zeta-cypermethrin has a very low water solubility, and relatively high octanol /water partition coefficient (log 

### Kow > 6). These values account for the low surface and groundwater concentrations determined by the Environmental Fate and Effects Division (EFED's) drinking water models. The chemical has low vapor pressure (3 x 1

## o-9 rnm Hg at 20°C), which decreases its potential to volatilize. 

### 3.2 Pest icide Use Pattern FMC has requested that the single and seasonal use rates ofthe insecticide zeta-cypermethrin be increased on alfalfa grown for forage and hay, doubling the currently registered rates. The current use pattern states that a maximum of 0.05 pound ofzeta-cypermethrin
.may be applied ' per acre per cutting (2 applications, each at 0.025 lb ai/A), with a maximum of 0.15 pound zetacypermethrin applied per acre per season (0.05 lb ai/A per cutting with 3 cuttings). The proposed revised use pa ttern stipulates that a maximum of 0.1 pound of zeta-cypermethriri may be applied per acre per cutting (2 applications, each at 0.05 lb ai/ A) , with a maximum of 0.3 lbs ai applied per acre per season (0.1lb ai/A per cutting with 3 cuttings). FMC is requesting label amendments for the increased use rates of three EPs on alfalfa forage and hay. These EPs are Fury 1.5 EC Insecticide (EPA Registration #279

-3125), an EC formulation containing 1.5 lb ai/gal; Mustang Insecticide (EPA Registration #279-3126), anEW formulation containing 1.5 lb ai/gal; and F9114 EC Insecticide (EPA Registration #279-3426), an EC formulation containing 0.8 lb ai/gal. Because F9114 EC contains zeta
-cypermethrin with a higher cis/trans ratio, it is applied at rates which are only halfthose ofthe Fury and Mustang formulations. Examples of the proposed amended labels were provided, and the proposed use directions are suinmarized in Table 3.2. [Note that there are no changes in how zeta-cypermethrin products are used on alfalfa seed, for which the higher application rate is already registered. ]

Page 8 of9Table 3.2. Summary ofDirections for the Proposed Use ofZeta-cypermethrin . Applic. . Formula tion Applic. Max. No. Max. Timing, [EPA . Rate (lb Applic. per Seasonal PHI Type, and Applic. Rate (days) Use Directions and Limitations
. Reg. ail A) Season, Equip. No. ) (lb ail A) Alfalfa Forage and Hay F9114

EC Applications may be up to 3 days of Broadcast; Insect ici 0.014

- cutting or grazing, or up to 7 days of Aerial, de ; 0.050 lbs 3-6 0.15lb ail harvesting seed. Do not make Ground, 9.15%ai ; ail A per (depending Nseason 

## - applications more than 7 days apart. Chemigation EPA Reg cutting on rate) Spray volume for aerial applications No
. 279- = 2 gals
. Spray volume for ground 3426; 0.8 applications = 10 gals
. lbs ai/gal Mustang lnsectici Applications may be up to 3 days of Broadcast; de; 0.028- 3-6 cutting or grazing, or up to 7 days of

Aerial, 17.1%ai; 0
. 1 lbs 0.3 lb ail harvesting seed
. Do not make Ground, EPA Reg ail A per (depending Nseason 

## - applications more than 7 days apart. Chemigation No. 279- cutting on rate) Spray volume for aerial applications 3126; 1.5 = 2 gals
. Spray volume for ground lbs ai/gal applications = I0 gals.

.Fury 1.5 EC Applications may be up to 3 days of Broadcast; lnsectici 0.028- cutting or grazing, or up to 7 days of

Aerial, de; 0 .1 lbs 3-6 0.3 lb ail harvesting seed. Do not make Ground, 18.1% ai; ail A per (depending Nseason 

### - applications more than 7 days apart. Chemigation EPA Reg cutting on rate) Spray volume for aerial applications No. 279- = 2 gals. Spray volume for ground 3125; 1.5 applications = I0 gals. lbs ai/gal



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