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



### MEMORANDUM DATE : December 5, 2013 

### OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUBJECT: GS-omegalkappa-Hxt x-Hvla: Qualitative Human Health Assessment 

### PC Code: 006100 

### DP Barcode: D411505 

### Decision No. : 463505 

### R egistration No.: 88847-R-VST-006325 TGAI 

### Petition No.: 2F8014 

### Regulatory Action: PRIA 

### Risk Assessment Type: Qualitative 

### Case No. : NA 

### TXR No
. : N/ A 

### CAS No .: NA 

### MRID No. : N/ A 40 

### CFR: N/ A 

### FROM: E lis s a Reaves , Ph.D
. , Toxicologist

# ~ 

# D - - -"'< Chief, RAB IV, Health Effects Division (7509P) 

### AND PV Shah , Ph
.D., Toxicologist Chief, Inerts,**Registr io**  

### Divisio I

. 

### THROUGH : Dana Vogel , . Associate D ivis ion Director , Health Effects Division (7509P) 

### TO : Debra Rate, Mark Suarez, Product Manager 13 Deborah McCall , Chief Insecticides Branch, Registration Division (7505P) Susanne CerreUi, Regulatory Action Leader Kimberly Nesci, Chief Microbial Pesticides Branch Biopesticides 

### & Po llution Prevention Division (7511P) The Health Effect Division (HED) receiv ed a request from the Biopesticides and Pollut ion Prevention Division (BPPD) to provide a human health assessment for a new broad spectrum insecticide. Vestaron Corporation has submitted a Section 3 request for the ne w technical active ingredient (TGAI) GS-omega!kappa-Hxtx-Hvla, with product names VST-006325 T GAI and VST-006330 EP
. VST-006330 EP is a new broad s pectrum insecticide end- use product to be Page 1 of6used on various vegetable and co le crops, herb s, pasture, fruit tree s , nut trees , s mall fruit/berries , field crops, ornamental s, and nur sery stock. Add itional proposed residential uses include turf and ornamenta ls
. HED has reviewed the availab le data for the new insecticide and concluded that a qualitative human health risk assessment is sufficient. HED is not requiring additi o na l mammalian toxicity data due to the low toxicity profile of the compound. HED , therefore , did not conduct a quantitati ve risk assessment fo r dietary , residential , occ up ati onal or aggregate risk. Executive Summary HED has prepared a hum an health risk assessment to s upport a new in secti c ide, GSomega/ka ppa-Hxtx-Hv l a, for the BPPD. HED ha s rev iewed the av ailabl e information and b ec ause of the lack of t ox ic ity at any of the limit d oses, the HED has d etermin ed that a qualitative risk assessment is appropriate for GS-omegalkappa-Hxtx-Hvla. Acute to xicity dat a for GS-o megalkappa-H xtx -H vla are available. Acute oral , dermal , and inhal ation toxiciti es for the formulated produ c t are all category IV. No effects were identified in these stu dies up to the limit dose (oral limit of 5,0 00 mg/kg). GS-omegalkappa-Hxtx-Hv la i s s lightl y irritating to skin (To x Category 

### III) but n ot the eye (Tox Category 

### T V). It is also not a skin se ns itizer. Repeated dosing toxicity studies with GS-omega/kappa

- Hxtx-Hv l a are not availab le and were not required by t he Hazard and Sc ience Policy Counc il (HASP OC) (Rury TXR0056780). Vestaron C orp oration is requ est ing an exempti on from the requirement of a to lerance for residues in and on all food commoditie s. Since hazard has not been ide ntifi ed , the HED has no ob

jec tion to granting an exem ption for the requirement of a tolerance. T h erefo re , a dietary (food and water) assessment i s not required and there is no n eed for an ag gregate ri sk assessment. A lthough there are exposure scenarios rel ev ant to both occupational and residential handlers who apply the pesticide , no occupationa l or re s idential assess ments are needed at this time based on the lack of hazard to identify an endpoint for ri sk assessment. Regulatory Recommendations Sufficient data are avail ab le to s upport HED ' s decision to waive generic mammalian toxicity data requirements fo r GS

- omegalkappa-Hxtx-Hvla. HED recommends th e residues ofGS

- omegalkappa-Hxtx -H vla be exempt from th e requirement of a tolerance when used in accordance with good agricu ltural practi ces. Co dex has not esta bli shed maximum residue limits for GS-omega/kappa-Hxtx- Hvla. Concern for residential and occupational exposure is lo w because tox ic ity effects have not identified endpoints for ri sk assessment. GS- ome ga/kappa- Hxtx-Hvla i s also not irritating v ia the dermal or inhalation route of expo sure . Theref o re , HE D has no objection to the p etitioned u ses of GS-omegalkappa-Hxtx
H v l a.
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### Introduction Vestaron Corpora tion has peti tioned for the use of a derived spider peptide fraction as a biopesticide. The product characterization ofGS

- omegalkappa-Hxtx-Hvla is provided in an EPA re view by Joel Gagliardi (U.S
. EPA. 2013). This active ingredient is proposed for formu lation in an end use product (EP), VST-0 06330 will contain the TGAI at a concentration of 20%. The EP is proposed for dilution with app lication as a fo li ar spray, intended as a new broad spectrum pesticide to be used (pre -harvest, up to day ofharvest) on various vegetable and cole crops, herbs, pasture, fruit trees, nut trees , small fruit/berries, field crops, ornamentals , and nursery stock to control chewing insects. GS

- omegalkappa-Hxtx-Hv1a functions primar il y as a centra l nervous inhibitor for use in the control or supp re ss ion of many foliar fee ding pests including caterpillars, foliage fe eding coleopteran and whiteflies infestin g labeled crops. GSomegalkappa-Hxtx -Hv 1 can be used in either the field or greenhouse for the control of any labeled pest. Potential areas of environmenta l justice concerns, to the extent possible, were considered in the human health ri sk assessment, in accordance with U.S. Exec utive Order 12898 , "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations
. " The Office of Pesticide Programs (OPP) typically considers th e highest potential exposures from the legal use of a pesticide when conducting human health risk assessments , including, but not limited to, people who obtain drinking water from sources near ag ricultural areas , the variability of diets within the U.S., and people who may be exposed when harvesting crops . Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information
. Hazard Identificatio-n and Dose Response Assessment GS-omegalkappa-Hxt x-Hv1a is cloned into and expressed from commercial K. 

### lactis (Kluyveromyces lactis). The yeas t is removed during th e manufacturing process of the peptide , and is not present in the technical grade active ingredient. K. 

### lactis i s commonly used in the culturing of dairy products (BoneKamp and Oosterom, 1 994). The Foo d and Drug Administration (FDA) considers K. 

### lactis a "nonpathogenic and nontoxicogenic yeast" (21 CFR 184.1388), and lactase enzyme preparations produced from similar K. 

### lactis strains are Generally Recognized as Safe (GRAS) as a direct food additive (21 CFR 184
. 1388). GS-omegalkappa

- Hxtx

- Hv1a acts by inhibiting two channels thought highly specific to insects, specifically a combination of omega [inhibits vo ltage
- gated calcium channels] and kappa (inhibits vo ltage-activated potassium channels]. The original source ofthe peptide is a fraction of the venom from the Aust ra lian Blue Mountains Fu nne lweb Spider 

### Hadronyche versuta, a species that preys mainly on in sects in its wild habitat. Acute toxicity data support the Registrants' claim that GS-omegalkappa-Hxtx -Hv 1a acts specifically on insects and not to mammals. The acute oral (MRID 48779007) and dermal (MRID 48779008) limit dose (LD)so was >5,000 mglkg (Tox Ca tegory IV)
. In the acute inhalation study (MRJD 48779009), 5 male and 5 female rats were exposed to 2.05 mg/L of the Page 3 of6test article in a nose-o n ly chamber for 4 hours. The mass median aerodynamic diameter of the particles was 3. 7 m. All animals survived the exposure and gained body weight during the 14- day observation period. There were no gross abnormalities observed at n ecropsy. Therefore, the LC50 is > 2.05 mg/L (Tox Category IV). The primary dermal irritation study (MRID 4877901 1) resulted in erythema and very slight edema 

### in all treated sites but the skin was clear by day 7. Therefore, the test material is moderately irritating to the skin (Tox Category Ill). T he primary eye irritation study (MRID 4877901 0) resulted in no corneal opacity or iriti s in any treated eye during the study. All animals were free of ocular irritation by 48 hours. The material was minimally irritating (T ox Category IV). No dermal sensit ization was observed in gu inea pigs (MRID 48779010). The concern for allergenicity has been addressed for the Vestaron product (U .S. EPA, 2013). The amino acid sequence ofGS-omega/kappa-Hxtx-Hv1a was assesse d for similarity to known tox ins and allergens. No sequence similarities were found for allergen sequences found in the A llergen online database using a 35% similarity over 80 amino acid residues nor on a s liding sequence comparison for 8 amino acids. The only toxins showing sequence si mi larity were other spider toxins as could be expected. GS

- omega/kappa-Hxtx-Hvla was not s ignificantly degraded by pepsin after 4 hours so it i s a stable protein. It was not tested for trypsin degradation. Overall , the data indicate that the GS-omega/kappa-Hxtx-Hv1a is not reasonably expected to be an allergen. No oral repeat subchronic or chronic st udie s with GS-omega/kappa-Hxtx-Hv1a are available. Vestaron Corporation submitted waiver requests for repeat exposure toxic ity studies (MRID 48779019). Although repeated dosing toxicity studies w ith GS-omega/kappa-Hxtx -Hv1a are not available, these were not required by the Hazard and Science Po licy Council (HASPOC) (Rury TXR0056780). Therefore, based on the very low t oxicity of the compound in the acute studies (e.g. , no effects at the limit dose), repeat exposure to GS-omega/kappa-Hxtx-Hv1a is not of concern and additional toxicity studies are not warranted at this time. A search of the open literature was not performed for GS-omega/kappa-Hxtx-Hvla. Literature s tudies , however, were pro v ided for surrogat e peptides. These literature studies did not identify any toxicity data considered critical such that a quantitative assessment would be required. Cumulative Sec tion 498(b)(2)(D)(v) ofFFDCA require that , when considering w hether to es tablish , modify, or revoke a tolerance, the Agency considers "available information" concerning the cumulative effects of a particular pesticide's residues and " other substances that have a common mechanism of tox icity." Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism oftoxicity, EPA has not made a common mechanism of toxicity finding as to GS-omega/kappa-Hxtx-Hv1a. In addition, GS-omega/kappa-Hxtx-Hvla does not convert to toxic metabolites resulting in other substances. For the purposes of this registration review, therefore, EPA has not assumed that GS

- omega.lkappa-Hxtx-Hv1a has a common mechanism of toxic it y with other substances. For information regarding EP A's efforts to determine which Page 4 of6

### chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals , see the policy statements released by EPA ' s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http: //www.epa.gov /pesticides/cumulative /
. 

### Dietary Exposures Vestaron Corporation is requesting an exemption from the requirement of a to lerance for residues in and on all food commodities. There is potential for exposure from consumption of GS -omega/kappa-Hxtx

- Hv l a residues in food commodities and/or water. However, GS

omega/kappa-Hxtx-Hvla interacts specifically to the insect nervous system and does not interact with vertebrate systems. The submitted and reviewed acute oral data suggest GS-omega/kappa

Hxtx-Hvla is not toxic via the oral route(> 5,000 mglkg). Submitted li terature stud ies on surrogate peptide compounds indicate l ack ofbioavailability by mammals via the oral route (MRID 48779019). Based on the low toxicity profile of the compound and low bioavailability , exposure to this compound from treated food or residues in water is not of concern . Therefore, HED has not identified any toxicological points of departure and a quantitative human health risk assessment is not warranted. 

### Occupational and Residential Exposures Dermal and inhalation exposures to occupational and residenti al handles (homeowners) may occur during appli cation. However, HED does not beli eve that risk from inhalation or dermal exposure will be of concern based on the lack of hazard identified in avai l able studies. GSomega/kappa-Hxtx -H vla is not dermally irritating or toxic (Tox Category III), not a sensitizer, and is not toxic via the inhalation route (Tox Category IV). HED has not indentified any dermal or inhalation endpoints for risk assessment. Therefore, residential and occupational assessments (dermal and inhalation) are not warranted. 

### Data Requ i rements Additional data are not required at this time. 

### Conclusions Due to the lack of mammalian toxicity ofGS-omega/kappa-Hxtx

- Hvla, the HED has determined that a qualitative ri sk assessment is sufficient. Since toxicological points of departure have not been identified for any route of exposure (oral, dermal, inhalation) a dietary assessment is not warranted and there is no need for an aggregate risk assessment. HED has no objection to granting an exemption for the requirement of a tolerance. Additional data are not required at this time.

Page 5 of6Dermal and inhalation exposures to occupational and residential handlers can occur during application; however , there are no risk concerns due to the lack of hazard identified in the available toxicity studies.

References BoneKamp FJ, and Oosterom J. 1994 On the safety of Kluyveromyces lactis- a review. Appl. Microbiol Biotechnol. 41:1-3. HASPOC. VERSITUDETM Peptide: Summary of Hazard and Scienc e Po licy Counci l (HASPOC) Electronic Review: Recommendations on the Need for Additional Toxicity Studies TXR0056780. Mileson, B. (2012) Response to Tier 1 Data Requirements for VST-006325 TGAI. U npubli shed st

udy prepared by Techno lo gy Sciences Group Inc. 463p. MRID 487790 19 U.S. EPA. 2013. BPPD Review of Product characterization ofVERSITUDETM peptide consisting ofGS-U-ACTX

_ Hvla

- SEQ2/M-ACTX -HV 1 a+2. Memorandum from J. Gagliardi,Ph.D.and 

### J, Kough, Ph.D
. to S. Cerrelli , S, dated June 27, 2013.

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