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



### MEMORANDUM

Date: October28, 2014 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Alpha-Cypermethrin -HumanHealth RiskAssessment for Two New Proposed Products for Use in Commercial/Residential Settings.

PC Code: 209600 DecisionNo.: 481579 Petition No.: 3F88189 Assessment Type: Single Chemical/ Aggregate TXRNo.: NA MRID Nos.: See Bibliography DP Barcode: D414726 RegistrationNo.: 499-LTN, 499-LAO Regulatory Action: Section 3 Registration Case No.: NA CAS No.: 67375-30-8 40 CFR: 180.418 

### FROM: Elizabeth Holman, Physical**Scientist/Ri~sk** s ssor**~ l~**  Zaida Figueroa, Industrial HygienisL Karlyn Middleton, Toxicologist 

# 1..... Risk Assessment Branch II Health Effects Division (7509P) 

### THROUGH: Christina Swartz, Branch Chief Risk Assessment Branch II Health Effects Division (7509P) 

### TO: Elizabeth Fertich/Kable Davis IVB 1 Branch Registration Division (7505P)

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### 1.0 Executive Summary
A Section 3 registration was requested byBASF Corporation onbehalfofWhitmire Micro-Gen Research Laboratories, Inc., for the use oftwo alpha-cypermethrinproducts to control insects outdoors/indoors incommercial, residential, food handling establishments and institutional settings. Alpha-cypermethrinis an enriched isomer ofthe pyrethroidinsecticide cypermethrin, registered for both agricultural and residential uses. In addition, zeta-cypermethrinis also an enriched isomer ofcypermethrin. The toxicology database for the cypermethrins includes studies with cypermethrin and both ofits enriched isomers, and is considered complete for the purpose ofrisk assessment. The first product, TC-327 (EPA File Symbol499-LAO), is a ready-to-use (RTU) pressurized insecticide containing 0.05% alpha-cypermethrin as the sole active ingredient, and maybe applied indoors/outdoors into crack and crevices and as a spot (localized) and perimeter treatment. This producthas the following additional brand names: PT® FendonaPressurized Insecticide and PT® Cy-KickAC Pressurized Insecticide. The secondproduct, TC-305 (EPA File Symbol499-LTN), is a microencapsulated liquid concentrate to be diluted in water and contains 3.0% alpha-cypermethrin as the sole active ingredient; the productmay be applied indoors/outdoors into crack and crevices and as a spot (localized) andperimeter treatment. Thisproducthas the following additional brand names: FendonaTM CS Insecticide and Cy-Kick® AC Insecticide. The toxicological database for alpha-cypermethrin is complete (Middleton, K., D376098, 8/1112012). As stated above, although cypermethrin, alpha- and zeta-cypermethrin are separate active ingredients with different end-use products, they are includedtogether inthe hazard evaluationfor the purpose ofhuman health risk assessment. Cypermethrin, zeta-cypermethrin, and alpha-cypermethrin are structurally similar Type II pyrethroids, and like otherpyrethroids, cause neurotoxicity from interaction with sodium channels leading to clinical signs ofneurotoxicity. Furthermore, rapid metabolism and eliminationpreclude 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 alpha-cypermethrin. Clinical signs related to neurotoxicity were noted in all ACN studies for all three chemicals.
For alpha-cypermethrin, clinical signs were most frequently noted inrats dosed between 3 to 8 hours post-dosing. In SCN studies withthe three chemicals, neurotoxic effects were observed at comparable doses. This is consistentwiththe toxicity profiles for all the pyrethroids which are marked byrapid absorption, metabolism, and time-to-peak effect. Forpurposes ofendpoint selection and exposure assessment, only single day risk assessments need to be conducted. Cypermethrin, alpha- and zeta-cypermethrinexposure to children <6 years old is expected and it mustbe considered inthe context ofthe pyrethroids as a class. The FQPA UF of3Xfor all pyrethroids is considered adequately protective for children <6 years ofage. The FQPA safety

Page 

### 2 of8factor was reduced to 1 X for women ofchild bearing age (as well as for all adult populations and children> 6 years). The level ofconcern (LOC) for inhalation exposure and risk is 30 for adults and children 6 years ofage and over, which includes aninterspecies factor of3Xand intraspecies factor oflOX. For childrenyounger than 6 years ofage, the LOC is 100 based on a 3X uncertainty factor to protect for exposures to children <6 years ofage based onthe increased quantitative susceptibility seen inthe scientific literature related to pyrethroid pharmacokinetic, an interspecies factor of3X and intraspecies factor of 1 OX. The LOC for incidental oral exposure and risk is 300 for children under 6 years ofage, which includes a 3Xuncertainty factor retained to account for the increased quantitative susceptibility seeninthe scientific literature related to pyrethroid pharmacokinetics, an interspecies factor of 1 OX and intraspecies factor of 1 OX.
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 there is no risk associated with exposure viathe dermal route. A 21-day inhalation study in rats was selected to assess short- and intermediate- term inhalation exposure. The NOAEL ofO.Ol mg/L was based ondecreased body weight and increased salivation at the LOAEL of0.05 mg!L. For occupational and residential inhalationexposure, a human equivalent concentration (HEC) and human equivalent dose (HED) were derived in accordance with standard methodology thatresults in a reduction in the interspecies uncertainty factor (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 inhalationrisk assessments. For adults and children 6 years and older, the level ofconcern (LOC) for inhalation exposure and risk is a margin ofexposure (MOE) of30. For children youngerthan 6 years of age, the LOC is anMOE of 100. Since this hazard characterization was completed, RED's approach for calculating HEC's has evolved whichwould result in slight changes inthe points of departure for inhalationrisk 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 point ofdeparture (POD) for incidental oral exposure and risk assessment. The methods and assumptions used are described indetail inthe aggregate risk assessment for alpha-cypermethrin. The dose used for risk assessment was determined using a benchmark dose (BMD) analysis using 1 standard deviation (BMDLtso) from the control group as the benchmarkresponse (BMR) as suggested for continuous endpoints inthe Agency's BMD guidance (USEPA 2012). The incidental oral benchmark dose level (BMDL1so) of7.16 mg/kg was selected from an acute oral study in the rat, based on decreased locomotor activity at the BMD value of 11.20 mg/kg. For children under 6 years old, the LOC for incidental oral exposure andrisk is an MOE of300. The Agency has determined thatthe quantification ofcancerrisk using a non-linear approach (i.e., RID) will adequately account for all chronic toxicity, including carcinogenicity, which could result from exposure to cypermethrin. No evidence ofcarcinogenicity was observed in carcinogenicity studies in rats with cypermethrin or inmice with alpha-cypermethrin. Page 3 of8Based onthe proposed use pattern, short-term (1-30 days) exposures are expected for commercial and residential handlers who apply the proposedproducts, as well as for adults and children who may be exposedto previously treated areas (i.e., post-application). Since no dermal endpoint ofconcern was identified, residential assessments for alpha-cypermethrin are based oninhalation and incidental oral (for children) exposures only. These proposed newuses were compared againstthe existing use pattern in a recent occupational andresidential exposure assessment (D414733, Z. Figueroa, 9/10/2014). Based on application rates and treatment directions (e.g., cracks and crevices, spot or perimeter applications near infested egg laying sites, harborages orforage/feeding areas 1; outdoor spot, perimeter and spray treatments), the exposures for the proposed products are expected to be lowerthan those ofother currently registered products containing alpha-cypermethrin that are used in residential settings for outdoor (e.g., lawns) and indoor (e.g., fogger) broadcasttreatments. The aggregate risk assessment for alpha-cypermethrin must considerpotential exposure from all cypermethrins (i.e., cypermethrin and zeta-cypermethrin), since the 3 active ingredients are consideredto be essentiallythe same active from the mammaliantoxicity 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 ofall other residential uses (Collantes, M.; D403601; 8/4/2012); proposed and existing uses result inrisk esatimates that are not ofconcern. The proposed tolerances associated withthe food handling establishment (FHE) use ofalphacypermethrin are identical to those currently established for zeta-cypermethrin. Based onthe available alpha-cypermethrinresidue data submitted for this new use petition, this FHE use will not result in alpha-cypermethrin residues above the recommended tolerances (0414740, E. Holman, October 2014). The FHE use ofzeta-cypermethrin was previously includedinthe dietary exposure assessment, withthe assumption of 100% crop treated for all commodities without an existing tolerance to account for this FHE use (D403600, E. Holman, 7 September 2012). It is also not anticipated that the zeta-cypermethrin and alpha-cypermethrin FHE products would be used at the same time in a single FHE. Therefore, the addition ofthese FHE uses for alpha-cypermethrin will have no impact on the dietary risk estimates, as they are already covered in the existing assessment. The results ofthis dietary exposure assessment are summarized below. Dietary exposure to alpha-cypermethrin may occurfrom consuming treated crops ortheir processed commodities. Partially refined (probabilistic) dietary exposure assessments were performed in orderto determine the exposure and risk estimates resulting from the use of cypermethrin, alpha-cypermethrin, and zeta-cypermethrin onthe crops listed under 40 CFR 180.418. HED has used modeling to estimate dietary exposureto the cypermethrins. The modeling uses conservative assumptions regarding residues ofalpha-cypermethrin and its breakdownproducts in drinking water. Since monitoring datawas not available for all commodities, the modeling uses a combination ofhighly conservative assumptions (i.e. tolerance

1Examples oflocations include hollow spaces in floors, walls, ceilings; cracks and crevices around pipes, doors, windows, refrigerators, stoves; behind orunderbaseboards, cupboards, cabinets, etc. Page 4 of8level residues) and monitoring data withpercent crop treated information for residues ofalphacypermethrin and its breakdown products in food, as well as an extensive database offood consumption patterns for the U.S. population andpopulation subgroups.
For all registered and proposed uses, the acute dietary exposure estimates are belowRED's level ofconcern (<100% aPAD at the 99.9thpercentile ofexposure). Dietary exposure (food and drinking water) for the cypermethrins is 18% ofthe aPAD for the U.S. population and 87% of the aPAD for all infants and children 1-2 years, the mosthighly exposed population subgroups. Cypermethrin and zeta-cypermethrinresidential uses are included inthe pyrethroidlpyrethrin cumulative risk assessment (CRA). The proposed products containing alpha-cypermethrin have an insignificant impact on the cumulative risk assessment. No dietary, residential, or aggregate risk estimates ofconcern have been identified inthe single chemical assessment. Inthe cumulative assessment, residential exposure wasthe greatest contributorto the total exposure. Although there are residential uses for cypermethrin and zeta-cypermethrin, the exposures for the proposedproducts are expectedto be lowerthanthose ofother currently registered products containing alpha-cypermethrinthat are used inresidential settings for outdoor (e.g., lawns) and indoor (e.g., fogger) broadcasttreatments. Therefore, the proposeduse will have no impact on the residential component ofthe cumulative risk estimates. 

### 2.0 HED Recommendations
HED has no objectionto registration ofalpha-cypermethrin for the proposed products and establishment oftolerances as summarized in Table 2.2.3. No risks ofconcern or data deficiencies were identified. For further details onthe earlierrisk assessment ofalphacypermethrin, see Middleton, K., D376098, 8/1112012. 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 associated with these newproducts, as they were covered in all cases by the previously assessed existing use pattern.



### 2.1 Data Deficiencies
None. 

### 2.2 Tolerance Considerations
2.2.1 Enforcement Analytical Method Adequate tolerance enforcementmethods are available in PAM Volume IIfor determining residues ofcypermethrin, zeta-cypermethrin and alpha-cypermethrin inplant (Method I) and livestock (Method II) commodities. Bothmethods are gas chromatographic methods with electron-capture detection (GC/ECD), and have undergone successful Agency petition method validations (PMVs). Method I has a limit ofdetection (LOD) of0.01 ppm, and Method II has LODs of0.005 ppm in milk, and 0.01 ppm in livestocktissues. These methods are not Page 5 of8stereospecific; thus no distinction is made betweenresidues ofcypermethrin (all 8 stereoisomers), zeta-cypermethrin (enriched in4 isomers) and alpha-cypermethrin (2 isomers). The January 1994 FDAPESTDATA database (PAM Volume I) indicates thatresidues 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 alphacypermethrin are included in the same listing in the 40 CFR, buthave separate sections and different crops listed; where there are tolerances for both actives set onthe same crop, the levels are the same. Mexico adopts US tolerances, and/or Codex maximum residue limits (MRLs), for its exportpurposes. Canadahas established MRLs for cypermethrin only. There are currently no Canadian MRLs established for residues ofalpha-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 alphacypermethrin). 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 enforcementpurposes, the same moiety is being regulated. The currentpetitionproposes alphacypermethrintolerances atthe same levels as existing zeta-cypermethrin tolerances in the corresponding commodities.
Forthe proposed tolerances associated with this new use petition, there are no equivalentFHE use tolerances established by either Canada or Codex. Therefore there are no international harmonization issues associated withthis petition.


### 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 ofconcernfor 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, zeta-cypermethrin, and alphacypermethrin, eventhough they have separate tolerance listings in40CFR §180.418.

TABLE2.2.3 Tolerance Summaryfor Alpba-cypermetbrin. Commodity Proposed Recommended Comments; Co"ect Commodity Tolerance (ppm) Tolerance (ppm) Definition Food commodities/feed 0.05 0.05 commodities (otherthan those covered by a higher tolerance as a result ofuse on growing crops) in food/feed handling establishments
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### 2.2.4 Revisions to Petitioned-For Tolerances
No revisions to the tolerance levels in the petition, as proposed by BASF, were necessary. 

### 2.3 Label Recommendations
None.


### 3.0 Chemical Identity

TABL:t!!3.0 Test Coinpc:und**Nomen~•ature. "~** **~** ..;_ '"•,, •' " Compound chemical structure 01 

# (f< (R)-oloohol (IS)-oO-ooid \ N**p~c** c-o, ;c# 

# p
Cl \ CH II c.-' 

# "' o w"

# 0--o

Cl H 0

\ t' \. N 

# c)f:c-o, c-' 

# 0 I CH3 -" 

# C\ H H H/0--

CH3 

### rf (S)-alcohol (1R)-cis-acid
Common name Alpha-cypermethrin Company experimental name BAS 310 I orAC 900049 Empirical formula C22H19CbN03 Molecular weight 416.3 glmol IUPAC name A racemic mixture comQrised of: (R)-a-cyano-3-phenoxybenzyl (1S,3S)-3-(2,2-dichlorovinyl)-2,2- dimethylcyclopropanecarboxylate and (S)-a-cyano-3-phenoxybenzyl (1R,3R)-3-(2,2-dichlorovinyl)-2,2- dimethylcyclopropanecarboxylate or**(s:monymousl~}** (R)-a-cyano-3-phenoxybenzyl (1S)-cis-3-(2,2-dichlorovinyl)-2,2- dimethylcyclopropanecarboxylate and (S)-a-cyano-3-phenoxybenzyl ( 1 R)-cis-3-(2,2-dichlorovinyl)-2,2- dimethylcyclopropanecarboxylate CAS name (R)-cyano(3-phenoxyphenyl)methyl (1S,3S)-re/-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.


### 3.1 Physical/Chemical Characteristics Alpha-cypermethrin has a very lowwater solubility, and relatively high octanol!waterpartition Page 7 of8coefficient (log 

### Kow = 5.5). These values account for the low surface and groundwater concentrations determined by EFED's drinking water models. The chemical has lowvapor pressure (2.55 X 10"9 mmHg at 25°C), which decreases its potentialto volatilize.


### 3.2 Pesticide Use Pattern Two newproducts are proposed to controls a variety ofpests (e.g., cockroaches, house flies, fire/carpenter ants, ticks, crawling insects, bees, hornet, wasps, and other insects): TC-327 (EPA File Symbol499-LAO) and TC-305 (EPA File Symbol499-LTN). The proposed use pattern specified onthe end-use product labels is summarized below in Table 3.2.

Table3.2. SummaryofDirections for theProposed End-UseProducts for Alpha-cypermethrin. \ Use Site/Application Product/ Timing, Type, and Formulation Max. Single Applic. Rate Use Directions and Limitations Equipment Indoor/Outdoor -Commercial, Residential and Food Handling Establishments Crack & Crevice (Void) TC-327 Residual time using application rates is up to 90 treatmentusing injection tube 0.0033 lb ai/can @I fWsec ortip. (EPA Reg. No. 499- days depending on pests. Reapply as necessary, Spotapplication using RTU LAO) butno morethan 2 times per week. Applications container. Ready-to-use 0

.0033 lb ail can@2 fWsec mustbe at least 3 days apart. Use with the Perimeter application using pressurized liquid 0.0033 lb ail can @ I 0 sec/site or supplied actuator, injection tubes/tip or other RTU container. (0.05%ai) hole BASF equipment. Crack & Crevice (Void) Residual time using application rates range from treatment using injection tube 0.0033 lb ailcan @I ft2/sec ortip. 30- 90 days depending on pests. Reapply as Spotapplication using necessary, but no more than 2 times per week. injection tube or lowpressure TC-305 0.0033 lb ail can@2 fWsec Applications must be at least 3 days apart

. Apply handheld equipment. EPAReg. No. 499- with equipment designed for void applications

. LTN) Product is to be used as a residual/supplemental Microencapsulated treatment. Use higher application rate to inhibit Perimeter, spot (spray) or liquid concentrate wood-infesting insect sand termite infestations in (3.0% ai) exposed tubing, cracks orcoldjoints (this is not a general surface application (0.25 lb ai/gal) 0.0039-0.0059 lb ail gal substitute for othertermite treatments)

. using lowpressure handheld (20-30 fl oz/10 gal) General surface applications for FHE may be used equipment. when the facility is not in operation and food/feed has been covered or removed from the application area. Lawns/Ornamentals TC-305 Not for use in commercial greenhouses or Perimeter (spray) application Microencapsulated using backpack sprayer or liquid concentrate 0.00012 lb ailgal (ornamentals) nurseries. To be used in golfcourses, hobby handheld equipment. (3.0% ai) 0.01 lb ail A (turf) greenhouse, interiorscapes, landscapes and lawns. (0

.25 lb ailgal) Residual Time = 30-90 days depending onpest. LivestockHousing TC-305 0.0085 1b ai/A To be use in and on outside surfaces ofouter Perimeter (spray) application Microencapsulated (1.0 fl oz/1,000 ft2) building. Treata band of6-10 ft around/adjacent using backpack sprayer or liquid concentrate 0.44lb ail A (5.0 fl oz/1,000 ft2 to the building. Use higher application rate to handheld equipment. (3.0%ai) (0.25 lb ailgal) for darkling beetles only) control darklingbeetles only.

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