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 

Page 1 of9 
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 of three 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 ail gal; and F9114 EC Insecticide (EPA Registration #279-

3426), an EC formulation containing 0.8lb ai/gal. Because F91 14 EC contains zetacypermethrin 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 toxicology database for the cypermethrins includes studies with 

cypermethrin and both of its enriched isomers, and is considered complete for the purpose of risk 

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. 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-cyperrnethrin, and alpha-cyperrnethrin. Clinical signs 

related to neurotoxicity were noted in all ACN studies for all three chemicals. For alphacypermethrin, clinical signs were most frequently noted in dosed rats between 3 to 8 hours postdosing. 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 

selection and exposure assessment, only single day risk assessments need to be conducted. 

Cypermethrin, alpha-cypermethrin 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. HED has 

determined that for all pyrethroids, there is uncertainty regarding susceptibility of infants and 

children for post-natal exposure, and the required lOX Food Quality Protection Act (FQPA) 

Safety Factor (SF) has been reduced to 3X to account for this uncertainty, pending receipt of 

additional toxicity data. The 3X for all pyrethroids is considered adequately protective for 

children <6 years of age. The FQP A safety factor was reduced to 1 X for women of child bearing 

age (as well as for all adult populations and children ~6 years). 

Page 2 of9 
No systemic effects were observed in the 21-day dermal rat study with zeta-cypermethrin 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 occupational and residential inhalation exposure, a 

human equivalent concentration (HEC) and human equivalent dose (HED) were derived in 

accordance with standard 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 1.10 

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 children 6 years 

of age and over, which includes an interspecies factor of 3X (reduced from 1 OX for use of the 

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 1 OX. 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 1 OX. 

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 of human cancer risk. No evidence of carcinogenicity 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 of9 
and toxicological similarities to alpha cypermethrin and cypermethrin the carcinogenic potential 

is expected to be similar. Therefore, HED considers conclusions regarding the carcinogenic 

potential of cypermethrin 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 of engineering controls (enclosed cockpits) for aerial applications, 

and were not of concern (Figueroa, Z.; D423900; 11/13/2014). Based on the Agency's current 

practices, a quantitative non-cancer occupational post-application inhalation exposure 

assessment was not performed for zeta-cypermethrin at this time. If new 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 of 40 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 of this dietary exposure assessment are summarized below. 

Page 4 of9 
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 (Holman E, D403600, 7 September 2012). HED has used modeling to estimate dietary 

exposure to the cypermethrins. The modeling uses conservative assumptions regarding residues 

of zeta-cypermethrin arid its breakdown products in drinking water. Since monitoring data were 

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 zeta-cypermethrin and its breakdown products in food, as well as 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 LOC 

(<100% of the 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 aP AD 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 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. 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, 10/12/2012. That assessment summarizes the 

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

exposure, and aggregate 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 occupational 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 zetacypermethrin). However, although the definitions differ formally, they are effectively 

harmonized since the tolerance-enforcement methods are not stereospecific, and thus do not 

distinguish between residues of cypermethrin, zeta-cypermethrin and alpha-cypermethrin. For 

enforcement purposes, the same moiety is being regulated. 

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 zetacypermethrin. 

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. 

Page 6 of9 
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 Tolerances 

Instead of the 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 Cl ~I Common name ~eta cypermethrin 

Company experimental name FMC 56701 

Molecular formula CnH19ChN03 

'Molecular weight 416.3 

IUPAC name (S)-a-cyano-3-phenoxybenzyl ( 1 RS,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 of9 
TABLE3.0 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 Pesticide Use Pattern 

FMC has requested that the single and seasonal use rates of the 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 of zeta-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 pattern 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 half those of the 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 of9 
Table 3.2. Summary of Directions for the Proposed Use of Zeta-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; 

Insectici 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 = I 0 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 = I 0 gals. 

lbs ai/gal 

Page 9 of9