GS-omega/kappa-Hxtx-Hv1a Page 1 of 29 Biopesticides Registration Action Document - DRAFT

BIOPESTICIDES REGISTRATION ACTION DOCUMENT



### GS-omega/kappa-Hxtx-Hv1a Pesticide Chemical (PC) Code: 006100

DRAFT DOCUMENT

U.S. Environmental Protection Agency Office of Pesticide Programs Biopesticides and Pollution Prevention Division

Dated 01/09/14GS-U-ACTX-Hv1a-SEQ2 Page 2 of 29 Biopesticides Registration Action Document - DRAFT

TABLE OF CONTENTS

I. EXECUTIVE SUMMARY .............................................................................................. 4

II. ACTIVE INGREDIENT OVERVIEW ................................................................................ 5

III. REGULATORY BACKGROUND ................................................................................ 5

A. Applications for Pe sticide Registration ................................................................................... ............................. 5

B. Food Tolerance Exemption .................................................................................................. ................................. 6

IV. RISK ASSESSMENT ...................................................................................................... 6

A. Product Analysis Assessment (40 CFR § 158.2120) ............................................................................... ........ 7

B. Human Health Assessm ent (40 CFR § 158.2140) ............................................................................... ................. 7

C. Environmental Assessm ent (40 CFR § 158.206 0) .............................................................................. ................ 12

V. ENVIRONMENTAL JUSTICE .......................................................................................... 15

VI. RISK MANAGEMENT DECISION ................................................................................. 15

VII. ACTIONS REQUIRED BY THE REGISTRANT ......................................................... 16

VIII. GLOSSARY OF ACRONYMS AND ABBREVIATIONS ........................................... 17

IX. BIBLIOGRAPHY.............................................................................................................. .. 18

APPENDIX A. BIOCHEMICAL/MICROBIAL PESTICIDES DATA REQUIREMENTS
.........................................................................................................21

APPENDIX B. PESTICIDE PRODUCTS ............................................................................... 28GS-U-ACTX-Hv1a-SEQ2 Page 3 of 29 Biopesticides Registration Action Document - DRAFT

BIOPESTICIDES REGISTRATION ACTION DOCUMENT TEAM

Office of Pesticide Programs (OPP)

Science Reviews

Sheryl K. Reilly, Ph.D. Acute Mammalian Toxicity, Biopesticid es and Pollution Prevention Division Elissa Reeves, Ph.D. Human Health, Health Effects Division Joel Gagliardi, Ph.D. Product Analysis, Biopesticides a nd Pollution Prevention Division Meghan Radtke, Ph.D. Environmental Effects, Environmen tal Fate and Effects Division

Regulations Biopesticides and Pollution Prevention Division Kimberly Nesci Chief, Microbial Pesticides Branch Shannon Borges Team Leader, Microbial Pesticides Branch Susanne Cerrelli Regulatory Action Leader

Registration Division Deborah McCall Chief, Insecticide Branch Debra Rate, Ph.D. BiologistGS-U-ACTX-Hv1a-SEQ2 Page 4 of 29 Biopesticides Registration Action Document - DRAFT

I. EXECUTIVE SUMMARY

The active ingredient GS-omega/kappa-Hxtx-H v1a (VersitudeTM peptide, formerly GS-UACTX-Hv1a-SEQ2) acts as an insecticide agains t cabbage looper for use on ornamental plants and edible crops. The cabbage looper inse ct is also known by the scientific name Trichoplusia ni and feeds on a wide variety of cultivated pl ants and weeds. GS-omega/kappa-Hxtx-Hv1a (VersitudeTM peptide) functions primarily as a cent ral nervous system inhibitor in insects, and is intended for use in the suppression of foliage feeding cabbage looper insects. The end-use product, VST-006330 EP, is mixed with water and a pplied as a pre-harves t, foliar spray with ground or aerial pesticide equipment, and it can be used in either the field or greenhouse to suppress cabbage looper.

On October 1, 2009, EPA announced a new policy to provide a more meani ngful opportunity for the public to participate in majo r registration decisions before th ey occur. Under this policy, EPA provides a public comment period prior to maki ng a registration decision for the following types of applications: new active ingredie nts; first food uses; first outdoor uses; first residential uses; or any other registration actions for which EPA beli eves there may be significant public interest.

Consistent with the policy of making regist ration actions more transparent, the proposed pesticide products containing the new active ingredient, GS-omega/kappa-Hxtx-Hv1a, are subject to a 15-day comment period prior to re gistration of the manufacturing and end-use products. In addition to contai ning a new active ingredient, the registration of these products represents the first food use for GS-omega/kappa -Hxtx-Hv1a. The docket identification number associated with these registration actions and accessed through either http://www.regulations.gov/ or http://www.epa.gov/pesticides/regul ating/registration-status.html

, is EPA-HQ-OPP-2012-0391 for GS-omega/kappa-Hxtx-Hv1a. The following documents are available in EPA-HQ-OPP-2012-0391:

1) Draft GS-omega/kappa-Hxtx- Hv1a Biopesticides Registrati on Action Document (BRAD) for VersitudeTM peptide,

2) U.S. EPA. 2013a “ VERSITUDETM Peptide: Summary of Hazard and Science Policy Council (HASPOC) Electronic Review: Recommendations on the Need for Additional Toxicity Studies” Memorandum from K. Rury, MPH to E. Reaves, Ph.D. dated September 18, 2013.

3) U.S. EPA. 2013b. “ Ecological Risk Assessment for the Proposed New Chemical Registration of GS-U-ACTX-Hv1a-SEQ2 (VersutideTM peptide) on Vegetables and Cole Crops; Herbs, Spices, and Mints; Pasture and Hay Crops; Fruit, Nut, and Vine Crops; Field Crops; Commercial Flowers and Ornamental Plants; Forest, Shade Tree, and Nursery Stock; and Turf.” Memorandum from M. Radtke, Ph.D., F. Khan, Ph.D., E. Odenkirchen, Ph.D., and S. Sankula, Ph.D. dated May 30, 2013,

4) U.S. EPA. 2013c. “ Ecological Risk Assessment for the Proposed New Chemical Registration of GS-U-ACTX-Hv1a-SEQ2 (VersutideTM peptide) on Vegetables and Cole Crops; Herbs, Spices, and Mints; Pasture and Hay Crops; Fruit, Nut, and Vine Crops; Field Crops; Commercial Flowers and Ornamental Plants; Forest, Shade Tree, and Nursery Stock; and Turf -

AMENDMENT.” Memorandum from M. Radtke, Ph.D., and S. Sankula, Ph.D. to M. Suarez and S Cerrelli dated September 24, 2013.GS-U-ACTX-Hv1a-SEQ2 Page 5 of 29 Biopesticides Registration Action Document - DRAFT

5) U.S. EPA. 2013d. “GS-omega/kappa-Hxtx-Hv1a: Qual itative Human Health Assessment.” Memorandum from E . Reaves, Ph.D. and P. Shah, Ph.D. dated December 6, 2013.

6) U.S. EPA. 2013 e. “ Ecological Risk Assessment for the Proposed New Chemical Registration of GS-U-ACTX-Hv1a-SEQ2 (VersutideTM peptide) on Vegetables and Cole Crops; Herbs, Spices, and Mints; Pasture and Hay Crops; Fruit, Nut, and Vine Crops; Field Crops; Commercial Flowers and Ornamental Plants; Forest, Shade Tree, and Nursery Stock; and Turf –

AMENDMENT 2” Memorandum from M. Radtke, Ph.D., M. Wait and S. Sankula, Ph.D. to S Cerrelli, S. Borges, and K. Nesci dated December 5, 2013.

7) VST 006325 TGAI -DRAFT Label

8) VST-006330 EP -DRAFT Label

While a final decision on regist ration is contingent upon review and consideration of public comments, EPA presently believes that the risk assessment and information submitted support registration of the VST- 006325 TGAI, and VS T-006330 EP. The basis for this preliminary
decision can be found in the risk assessmen t for GS-omega/kappa-Hxtx-Hv1a, which is characterized throughout this BRAD.

II. ACTIVE INGREDIENT OVERVIEW

Chemical Name: GS-omega/kappa-Hxtx-Hv1a

Synonym: VersitudeTM peptide

OPP Chemical Code: 006100

Type of Pesticide: Insecticide

See Appendix B for specific information (e.g., use sites, application rates, methods of application, formulation types, and target pest) regarding the proposed pesticide pr oducts containing this active ingredient.

III. REGULATORY BACKGROUND

A. Applications for Pesticide Registration

On April 26, 2012, Vestaron Corporation (addres s: 4717 Campus Dr., Suite 1200, Kalamazoo, MI 49008) submitted applications to register one end-use product, VST-006330 EP (EPA File Symbol 88847-E), and one manufacturing use product, VST-006325 TGAI (EPA File Symbol 88847-R) to the U.S. Environmental Protection Agency (EPA or the Agency) to be registered in
accordance with section 3 of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). EPA announced receipt of these applications to register pesticide pr oducts containing a new active ingredient, GS-U-ACTX-Hv1a-SEQ2 ( now GS-omega/kappa-Hxtx-Hv1a), in the FederalGS-U-ACTX-Hv1a-SEQ2 Page 6 of 29 Biopesticides Registration Action Document - DRAFT

Register on August 14, 2012 (77 Federal Register (FR) 48519), and opened a 30-day public comment period pursuant to the pr ovisions of FIFRA section 3(c )(4). No substantive comments were received during the comment period concer ning this announcement. A correction for the current recognized name of the active ingredie nt (GS-omega/kappa-Hxtx-Hv1a ) was published
in the Federal Register of December 18, 2013 (78 FR 76613).

B. Food Tolerance Exemption

Concurrent with its registra tion applications and under Federal Food, Drug, and Cosmetic Act (FFDCA) section 408(d), Vestaron Corporation su bmitted a petition to establish an exemption from the requirement of a tolerance for residue s of the pesticide active ingredient, GS-U-ACTXHv1a-SEQ2 (now GS-omega/kappa -Hxtx-Hv1a) (Pesticide Petiti on (PP) 2F8014) in or on all
food commodities

. EPA published a Notice that Vestar on Corporation filed a petition to establish an exemption from the requirement of a tolerance for residues of the insecticide in the Federal Register of July 25, 2012 (77 FR 43562 ), and opened a 30-day comment period. No comments to the petition for GS-U-ACTX-Hv 1a-SEQ2 (now GS-ome ga/kappa-Hxtx-Hv1a) tolerance exemption were receiv ed. A correction for the name of the active ingredient was published in the Federal Register of December 18, 2013 (78 FR 76589). The active ingredient, previously known as GS-U-ACT X-Hv1a-SEQ2, was revised to GS-omega/kappa-Hxtx-Hv1a, based on acceptable nomenclature for nami ng peptide toxins from spiders.

IV. RISK ASSESSMENT

In the Federal Register of October 26, 2007, EPA issued a Final Rule on the data requirements to support registration of biochemical pesticid es and updated the defi nition for microbial pesticides ( 72 FR 61002 ). The rule became effective on December 26, 2007. The data and information evaluated for this BRAD were considered in light of these requirements.

The classifications for each data submission are assigned by EPA science re viewers, and indicate
the usefulness of the information contained in the documents for risk assessment. A rating of “acceptable” indicates the study is scientifically sound and is useful for risk assessment. A “supplemental” rating indicates the data provide so me information that can be useful for risk assessment. The studies may have certain aspects determined not to be scientifically acceptable (“supplemental: upgradeable”). If a study is ra ted as “supplemental: upgradeable,” EPA always provides an indication of what is lacking or what can be prov ided to change the rating to “acceptable.” If there is simply a “supplemental” rating, the review er often will state that the study is not required by 40 CFR Part 158. Both “accep table” and “supplemental” studies may be used in the risk assessment process as appropria te. An “unacceptable” ra ting indicates that new
data need to be submitted.

For assessing the risks to human health, toxici ty or other adverse e ffects are based on the hazard(s) identified from mammalian toxicity and irritation studies conduc ted with and/or other information pertaining to the ac tive ingredient and proposed pest icide products submitted to EPA in support of registration. The active ingredie nt and formulated ma nufacturing and end-use products are classified as Toxicity Category I, II, III, or IV according to the results of studies conducted with the TGAI and proposed pesticide pr oducts to determine the acute toxicity by the oral, dermal, and inhalation routes of exposure, and th eir potential for dermal and eye irritation, Toxicity Category I represents the highest level of toxicity or potential fo r eye and skin irritation (corrosion, permanent damage), while Toxicity Cate gory IV indicates the lowe st level of toxicityGS-U-ACTX-Hv1a-SEQ2 Page 7 of 29 Biopesticides Registration Action Document - DRAFT

or irritation.

A. Product Analysis Assessment ( 40 CFR § 158.2120 )

The product characterization of GS-omega/kappa -Hxtx-Hv1a is provided in an EPA review (U.S. EPA. 2013g). This active ingredient is pr oposed for formulation in an end use product (EP), VST-006330, which will contain the TGAI at a concentration of 20%. The EP is proposed for dilution with application as a foliar spray, intended as a new broad spectrum pesticide to be used (pre-harvest, up to day of harvest) on va rious vegetable and cole crops, field crops, ornamentals, and nursery stock to suppress cabbage looper. GS-omega/kappa-Hxtx-Hv1a functions primarily as a central nervous syst em inhibitor for suppressing cabbage looper caterpillars that feed on the foliage of labeled crops. GS-omega/kappa-Hxtx-Hv1 can be used in either the field or greenhouse fo r suppression of cabbage looper.

A summary of the data requirement s is located in Tables 1-4 in Appendix A

.

B. Human Health Assessment ( 40 CFR § 158.2140 )

1. Toxicity

All Tier I mammalian toxicology data require ments for GS-omega/kappa-Hxtx-Hv1 were fulfilled. For a comprehensive summary of the toxicology data requirements described in sections IV(B)(1)(a) and IV(B)(1 )(b), as well as additional product-specific data and other information submitted to support the individu al registrations, refer to Table 5 in Appendix A

.

a. Acute Toxicity/Pathogenicity – Tier I

Acute Oral Toxicity/Pathogenicity [Office of Chemical Safety and Pollution Prevention (OCSPP)
Guideline 885.3050 and Acute Pulmonary Toxicity/Pathogenicity (OCSPP Guideline 885.3150 ; Master Record Identification Number (MRID No.) 487790-19]

Upon consideration of results of other definitiv e toxicological data submitted by the petitioner, the EPA waived acute oral toxicity/pathogenici ty testing for GS-omega/kappa-Hxtx-Hv1a. An acute oral toxicity study conducted on female rats (MRID No. 487790-07) demonstrated that GSomega/kappa-Hxtx-Hv1 a was not toxic (LD 50 greater than 5,000 mg/kg; Toxicity Category IV). In addition, the yeast used to produce the peptide is not pathogenic, the yeast is removed during the manufacturing process, and samples monito red for microbial contamination have been negative. These data indicate that this peptide would not be to xic through the oral route of exposure and that further te sting is not necessary (U.S. EPA. 2013d). The acute oral toxicity/pathogenicity and acute pulmonary toxi city/pathogenicity stud ies were not required because products containing GS-omega/kappa -Hxtx-Hv1 do not cont ain microorganisms.

Acute Injection Toxicity/Pathogenicity (OCSPP Guideline 885.3200 ; MRID No 487790-19): Upon consideration of results of other definitiv e toxicological data submitted by the petitioner, the EPA waived acute injection toxicity/pathogenicity testing for GS-omega/kappa-Hxtx-Hv1a. GS-omega/kappa-Hxtx-Hv1a is low in acute t oxicity. The acute oral, dermal and inhalation toxicity studies conducted on GS-o mega/kappa-Hxtx-Hv1a all re ported no deaths at the limit dose. In addition, the yeast used to produce the peptide is not pa thogenic, the yeast is removedGS-U-ACTX-Hv1a-SEQ2 Page 8 of 29 Biopesticides Registration Action Document - DRAFT

during the manufacturing process, and samples monitored for microbi al contamination have been negative.

b. Hypersensitivity Incidents (OCSPP Guideline 885.3400 ):

Cell Culture (OCSPP Guideline 885.3500) : This study was not required becau se GS-omega/kappa-Hxtx-Hv1a is not a virus (refer to test note #4 of 40 CFR § 158.2140(d)).

Acute Oral Toxicity (OCSPP Guideline 870.1100; MRID No. 487790-07) : An acute oral toxicity test (Up and Down procedure) was conducted with rats to determine the potential for VST-006325 to produce toxicity from a single dose via the oral route. Under the conditions of this study, the acute oral

LD 50 of the test substance is greater than 5,000 mg /kg of body weight in female rats. This study is
classified as Acceptable/Toxicity Category IV.

Acute Dermal Toxicity (OCSPP Guideline 870.1200; MRID No. 487790-08) : An acute dermal toxicity test was conducted with rats to determine the pot ential for VST-006325 to produce toxicity from a single topical application. Under the conditions of this study, the single dose acute dermal LD 50 of the test substance is greater than 5,000 mg/kg of body weight in male and female rats. This study is classified Acceptable/Toxicity Category IV

.

Acute Inhalation Toxicity (OCSPP Guideline 870.1300; MRID No. 487790-08) : An acute inhalation toxicity test was conducted with ra ts to determine the pot ential for VST-006325 to produce toxicity by the inhalation (nose-only) exposure rout e. Under the conditions of this study, the single exposure acute
inhalation LC 50 of the test substance is greater than 2.05 mg/L in male and female rats. This study is
classified as Acceptable/Toxicity Category IV.

Acute Eye Irritation (OCSPP Guideline 870.2400; MRID No. 487790-10) : A primary eye
irritation test was conducted w ith New Zealand white rabbits to determine the potential for VST006325 to cause eye irritation. Under the conditions of this study, the test substance is minimally irritating to the eye. This study is classified as Acceptable/Toxicity Category IV

.

Primary Dermal Irritation (OCSPP Guideline 870.2500; MRID No. 487790-11 : A primary skin
irritation test was conducted w ith New Zealand white rabbits to determine the potential for VST006325 to produce irritation after a single topical application. Under the conditions of this study, the test substance is classi fied as moderately irritating to the skin. This study is Acceptable/Toxicity Category III.

c. Acute Toxicology and Subchronic Toxicity/Pathogenicity – Tier II; Reproductive Fertility Effects, Carcinogenicity, Immunotoxicity, and Infectivity/Pathogenicity Analysis – Tier III

Tier II and Tier III studies we re not required for GS-omega/ka ppa-Hxtx-Hv1a based on the lack of acute toxicity in the Tier I studies.

d. Endocrine Disruptors

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide activeGS-U-ACTX-Hv1a-SEQ2 Page 9 of 29 Biopesticides Registration Action Document - DRAFT

and other ingredients) may have an effect in humans or wildlife si milar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered ap proach to making the statutorily required
determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects caused by the substance, and establish a quantitative relationship betw een the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticid e active ingredients and 9 inert ingredients.
This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-app lication agricultural scenarios.
This list should not be construed as a lis t of known or likely e ndocrine disruptors.

GS-omega/kappa-Hxtx-Hv1a is not among the gr oup of 58 pesticide active ingredients on the
initial list to be screened unde r the EDSP. Under FFDCA secti on 408(p), EPA must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP orders/data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pl ease visit our website: http://www.epa.gov/endo/

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2. Federal Food, Drug, and Cosmet ic Act (FFDCA) Considerations

Section 408(c)(2)(A)(i) of FFDCA allows EPA to establish an exemption from the requirement for a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the exemption is “safe.” Sect ion 408(c)(2)(A)(ii) of FFD CA defines “safe” to mean that “there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, incl uding all antic ipated dietary exposures a nd all other exposures for
which there is reliable information.” This includes exposure through drinking water and in residential settings but does not include occupa tional exposure. Pursuant to secti on 408(c)(2)(B) of FFDCA, in establishing or maintaining in e ffect an exemption from the requirement of a tolerance, EPA must take into account the f actors set forth in sect ion 408(b)(2)(C) of FFDCA, which require EPA to give special consideratio n to exposure of infants and children to the pesticide chemical residue in establishing a tole rance and to “ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue....” Additionally, section 408(b)(2 )(D) of FFDCA requires that EPA consider “available information concerning the cumulative eff ects of [a particular pesticide's] residues and
other substances that have a co mmon mechanism of toxicity.”

EPA performs a number of analyses to determin e the risks from aggregate exposure to pesticide residues. First, EPA determines the toxicity of pesticides. Second, EPA examines exposure to the pesticide through food, drinking water, and throu gh other exposures that occur as a result of pesticide use in residential settings.GS-U-ACTX-Hv1a-SEQ2 Page 10 of 29 Biopesticides Registration Action Document - DRAFT

Consistent with section 408(b)(2 )(D) of FFDCA, EPA has reviewed the available scientific data and other relevant information, and considered it s validity, completeness, and reliability and the relationship of this information to human risk. EPA has also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children.

Based on the acute toxicity data and information discussed previ ously and presented in Table 5
in Appendix A , the data required for a FQPA risk assessment for GS-omega/kappa-Hxtx-Hv1a have been fulfilled, and EPA has determined that there is a reasonable certainty that no harm will result from exposure to GS-o mega/kappa-Hxtx-Hv1a residues.

a. Aggregate Exposure

In examining aggregate exposure, section 408 of FFDCA directs EPA to consider available information concerning exposures from the pesticide residue in food and all other nonoccupational exposures, including drinking wa ter from ground water or surface water and exposure through pesticide use in gardens, lawn s, or buildings (reside ntial and other indoor uses).

Dietary Exposure and Risk Characterization : GS-omega/kappa-Hxtx-Hv1a is a 41 amino acid peptide derived from one of the toxicologically active components of Australian funnel spider ( Hadronyche versuta ) venom and isolated from yeast, and ex posure to residues of this peptide, in consumed food is possible. GS -omega/kappa-Hxtx-Hv1a may be applied foliarly to edible plants, turf and ornamentals. Si nce GS-omega/kappa-Hxtx-Hv1a is applied as a foliar insecticide to crops, it is possible that edible food comm odities may retain residues of GS-omega/kappaHxtx-Hv1a. Further, treated crops could be di verted for food or feed purposes; therefore, exposure to GS-omega/kappa-Hxtx-Hv1a in this situation is also plau sible. Although residues from the use of pesticides c ontaining GS-omega/kappa-Hxtx-Hv1a may be present on certain food commodities, processing procedures (e.g., pe eling and washing) may reduce such residues. Regardless of the scenario, should GS-omega /kappa-Hxtx-Hv1a be present on food, EPA
concludes that there is a reasona ble certainty that no harm will result from exposure to such
residues because of the lack of toxicity in the previously desc ribed toxicological studies (see Appendix A ).

Drinking Water Risk Characterization : Like consumed food, exposure to residues of GS-omega/kappa-Hxtx- Hv1a, a 41 amino acid peptide, in consumed drinking water is anticipa ted to be possible but negligible. However, GSomega/kappa-Hxtx-Hv1a interact s specifically with the insect nervous system and does not interact with vertebrate systems. The subm itted and reviewed acute oral data suggest GSomega/kappa-Hxtx-Hv1a is not toxic via the or al route (> 5,000 mg/kg). Submitted literature studies on surrogate peptide compounds indicate lack of bioavailabi lity by mammals via the oral route (MRID 48779019). Based on the low toxi city profile of the compound and low bioavailability, exposure to this compound from treated food or residues in water is not of

concern.

Non-occupational, Residentia l Risk Characterization : Residential exposure to GS-omega/kappa-Hxtx-H v1a is not expected to pose any undue risk provided the product is used in accordance with la bel directions. Appropr iate personal protectiveGS-U-ACTX-Hv1a-SEQ2 Page 11 of 29 Biopesticides Registration Action Document - DRAFT

equipment and precautionary statements are requir ed on pesticide product labels to mitigate any potential risks to pesticid e handlers due to prolonged or repeated exposures.

b. Cumulative Effects from Substances with a Common Mechanism of Toxicity

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance exemption, EPA consid er “available information concerning the cumulative effects of [a particular pesticide’s] residues and other substanc es that have a common mechanism of toxicity.”

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for GS-omega/kappa-Hxtx-Hv1a. In addition, GS-o mega/kappa-Hxtx-Hv1a does not convert to toxic metabolites resulting in other substan ces; therefore, EPA has not assumed that GSomega/kappa-Hxtx-Hv1a has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determ ine which chemicals have a common mechanism of toxicity and to evaluate th e cumulative effects of such chem icals, see the policy statements released by EPA’s Office of Pesticide Program s concerning common mechanism determinations and procedures for cumulating effects from s ubstances found to have a common mechanism on
EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

c. Determination of Safety for the U.S. Population, Infants and Children

FFDCA section 408(b)(2)(C ) provides that EPA shall assess the available information about consumption patterns among infants and children, speci al susceptibility of infants and children to pesticide chemical residues, and the cumulative effects on infants and ch ildren of the residues
and other substances with a common mechanis m of toxicity. In a ddition, FFDCA section 408(b)(2)(C) provides that EPA shall apply an ad ditional tenfold (10X) margin of safety for
infants and children in the case of threshold effect s to account for prenatal and postnatal toxicity and the completeness of the database on toxic ity and exposure unless EPA determines that a different margin of safety will be safe for infants and children. This additional margin of safety is commonly referred to as the FQPA Safety Factor. In applying this provis ion, EPA either retains
the default value of 10X or uses a different addi tional safety factor when reliable data available to EPA support the choice of a different factor.

Based on the lack of toxicity in mammals demo nstrated in the studies summarized in section IV(B)(1)(a) and Table 5 in Appendix A , EPA concludes that there is a reasonable certainty that no harm will result to the U.S. population, in cluding infants and children, from aggregate exposure to the residues of GS-o mega/kappa-Hxtx-Hv1a. This in cludes all anticipated dietary exposures and all other exposures for which there is reliable information. EPA has arrived at this
conclusion because the data and information available on GS-omega/kappa-Hxtx-Hv1a do not demonstrate toxic potential to mammals. Because there are no threshold effects of concern, the provision requiring an additional margin of safety does not apply.

3. Occupational Exposure and Risk Characterization

Occupational exposure to GS-omega/kappa-Hxtx-H v1a is not expected to pose undue risks to pesticide handlers (mixer/loader /applicators), but EPA requires appropriate personal protective equipment and precautionary statements to mitigate any potential risks to pesticide handlers fromGS-U-ACTX-Hv1a-SEQ2 Page 12 of 29 Biopesticides Registration Action Document - DRAFT

prolonged or repeated exposures. Potential ha ndler exposure is redu ced through the use of required personal protection equipment (PPE), including long-sleeved shirt and long pants, waterproof gloves and shoes plus socks.

4. Human Health Risk Characterization

EPA considered human exposure to GS-omega/ka ppa-Hxtx-Hv1a in light of the standard for registration in FIFRA and the rele vant safety factors in FFDCA. A determination has been made
that no unreasonable advers e effects to the U.S. population in ge neral, and to infants and children in particular, will result when GS-omega/ka ppa-Hxtx-Hv1a pesticide products are used in accordance with EPA-approved labeling.

C. Environmental Assessment ( 40 CFR § 158.2060 )

For a comprehensive summary of the generic data requirements described in sections IV(C),
refer to Table 6 in Appendix A . The ecological and environmen tal assessment (Section IX (B)) listed the following studies as data gaps: 835.2129 (hydrolysis), 835.2240 (photodegradation in water), 835.2410 (photodegradation in soil), 835. 2370 (photodegradation in air – conditional, depending on chemical’s properties), 835.4100 (aerobic soil metabolism), 835.4200 (anaerobic soil metabolism), 835.4300 (aerobic aquati c metabolism), 835.4400 (anaerobic aquatic metabolism), 835.1230/835.1240 (leaching adsorption/ desorption), 835.6100 (terrestrial field dissipation), 835.1410 (volatility laboratory – cond itional, depending on chemical’s properties). However, these data are not required unde r 40 CFR § 158.2060 for this pesticide because no
adverse effects were noted in the Tier I studies. These environmental fate data listed above may be conditionally required only wh en potential adverse effects ar e indicated in the Tier I nontarget organism studies.

Ecological risk characterization in tegrates the results of the e xposure and ecotoxicity data to
evaluate the likelihood of adverse ecological effects. In some cases, toxicity is noted as nondefinitive since testing concentrations were either not high enough or not low enough and an exact value was not determined. Although an act ual value can’t be note d, a bound can be put on the potential toxicity based on available information.

No direct risk concerns were identified for the following: aq uatic-phase amphibians, aquatic plants, birds, freshwater and estuarine/marine fis h, freshwater and estuarin e/marine invertebrates, mammals, reptiles, terrestrial-pha se amphibians, terrestrial pl ants, or contact exposure to terrestrial invertebrates.

Risks to Aquatic Organisms

Fish and Invertebrates

The LC 50 for freshwater fish is > 100 mg ai/L. Co mpared to the peak EEC of 0.044 mg ai/L, the

LC 50 is at least four orders of ma gnitude higher. This indicates th at risk concerns to freshwater fish on an acute exposure basis are unlikely. Acute toxicity data we re not available for estuarine/marine fish. In lieu of this, freshwater fish are used as a surrogate. This adds some uncertainty to the analysis; however, given that no effects (including sub- lethal) were seen in freshwater fish and the extremely large difference between the LC 50 value and the peak EEC, it is unlikely that estuarine/marine fish would be markedly differe nt in their sensitivity to GS-GS-U-ACTX-Hv1a-SEQ2 Page 13 of 29 Biopesticides Registration Action Document - DRAFT

omega/kappa-Hxtx-Hv1a. Conseque ntly, estuarine/marine fish are not expected to be at risk on an acute exposure basis.

The EC 50 for freshwater invertebrate s is >1000 mg ai/L. Compared to the peak EEC of 0.044 mg ai/L, the EC 50 is at least five orders of magnitude la rger. Therefore, acute risk concerns to
freshwater invertebrates are unlikel y. Acute toxicity data were not available for estuarine/marine invertebrates, thus, the freshwater invertebrate data were used as a surrogate. For the same reasons identified for fish, the freshwater inverteb rate data are considered a reasonably protective surrogate for estuarine/marine invertebrates. Based on this, EPA does not have acute risk
concerns for estuarine/ marine invertebrates.

Toxicity data were not availabl e for chronic exposures to fish or invertebrates. One of the uncertainties in the acute aquatic studies was the possibility that GS -omega/kappa-Hxtx-Hv1a degraded very quickly and the ac tual exposure experienced by th e test organism was far lower
than the nominal concentration of active ingredient. Hydrolysis data for the peptide are not available, but it is likely that degradation rapidly occurs in water. The quaternary structure (protein folding) of GS-omega/ka ppa-Hxtx-Hv1a is very complex; conditions that even slightly alter the protein’s configuration (e.g., exposure to water) will interfere wi th its receptor binding.
Terrestrial data indicate that the half-life of GS-omega/kappa-Hxtx-Hv1a is only 4 days. If a similar or shorter half-life occurs in water, a quatic organisms would not reasonably be expected to experience chronic exposure c onditions. Therefore, risk concerns from chronic exposures are considered unlikely.

Aquatic Plants Toxicity data were not available for aquatic vasc ular and non-vascular plants. At an application rate of 0.8 lb ai/A, terrest rial plants showed no effects. As wi th the aquatic invertebrate and fish analysis, if the 0.8 lb ai/A were sp rayed directly onto a 1 ha 20,000,000 L pond, the concentration is expected to be 0.044 mg ai/L. Given the specificity of GS-omega/kappa-HxtxHv1a to insects, the low probability that aquatic pl ants have this same receptor, and the peptide’s predicted instability in water, EPA does not have risk concerns for aquatic plants.

Risk to Terrestrial Organisms
Birds and Mammals The highest acute dose-based EEC generated for birds is 424.72 mg ai/kg-bw (20 g bird eating short grass). The LD 50 of > 630 mg ai/kg-bw, when compar ed with the EEC, is approximately one-third higher. Thus, acute ri sks to birds are not expected. Similarly, the acute dose-based EEC for mammals is 355.56 mg ai/kg-bw (15 g mammal eating short grass). The corresponding

LD 50 is > 5000 mg ai/kg-bw, which is one order of magnitude higher than the EEC. Therefore,
EPA does not have acute risk concerns for mammals.

Toxicity data were not available for chr onic exposures to birds and mammals. The bioavailability of GS-omega/ka ppa-Hxtx-Hv1a is expected to be low, based on the physical structure of the peptide. Spider venoms are de signed to be injected in to their prey. Oral ingestion is likely to result in a drastic decrease in the toxicity of the compound or eliminate it altogether; peptides are rapidly dige sted in the gut. As an exampl e, peptide drugs that have been developed for human oral administration are gene rally limited to a bioavailability of 1-2 % because of their molecular size (large), hydrophilic nature, and physical stab ility in the digestive tract. Consequently, absorption enhancing agents and chemical a nd physical modifications to theGS-U-ACTX-Hv1a-SEQ2 Page 14 of 29 Biopesticides Registration Action Document - DRAFT

peptide molecules are made to increase the ab sorption. Drugs derived from the cone shell ( Conus fulmen ) are based on a peptide with the similar cy stine knot of 3 disulf ide bonds that is found in GS-omega/kappa-Hxtx-Hv1a; they also share similar physical chemical characteristics. The drug is delivered intrathecally (into the spinal canal) because of a lack of bioavailability through the oral route. The limite d bioavailability and similarity of the cone shell peptide and GS-omega/kappa-Hxtx-Hv1a further supports the premise that the oral exposure route poses little chance of toxicity to vert ebrates. Consequently, EPA does not have chronic risk concerns
for birds and mammals.

Acute Risks to Honeybees EECs were generated for both the oral and contact exposure pathways for honeybees. Toxicological data were availabl e for the contact route; the LD 50 is > 25 μg ai/bee for adult honeybees. The contact EEC (convert ed to a dose) is 18.7 μg ai/b ee, which is lower than the

LD 50 . Consequently, direct risks to honeybees vi a the contact exposure route are not considered likely. The insecticide is intended to be delivered to its targets through the oral route; therefore, risk concerns (via ingestion) are identified for honeybees (a dult and larval). A study was submitted to complete the suite of toxicity informa tion needed to evaluate potential risks to adult honeybees and non-target terrestrial invertebrates from the proposed new pesticide. Based on the high LD 50 (> 100 μg ai/bee) and no observed sub-lethal effects, acute direct risks to terrestrial invertebrates, including honey bees, through the oral exposure route are no longer expected, based on the recently evaluated toxicity data. Di rect risks to larval terrestrial invertebrates remain an uncertainty because no toxicity informati on is yet available for this life stage. Indirect risks may be possible for terrestrial plants that rely on larval terrestrial invertebrates for pollination and other ecological services. Indirect effects are also possible for taxa that rely on
larval terrestrial invertebrate s as a food source (amphibians, birds, fish, mammals, reptiles, terrestrial invertebrates).

Risk to Non-Target Organisms Non-target Terrestrial and Semi-Aquatic Plants Toxicity data for terrestrial plants were availa ble; however the solubility information for GSomega/kappa-Hxtx-Hv1a needed to run the Terr Plant model was not available. The plant toxicity studies did not exhib it reductions in seedling emergen ce and vegetative vigor endpoints that were greater than 25%. Given that they were conducted at the hi ghest application rate, effects to plants are probably unlikely for the pr oposed uses. Consequently, no risk concerns are identified for plants from the pr oposed application rate and uses.

Endangered Species
Terrestrial Invertebrates Based on the endangered species anal ysis, no direct risk concerns ha ve been identified. There is a potential concern for indirect effects to te rrestrial plants that have obligate pollinator requirements or other dependencies on terrestria l invertebrates. Species that depend on
terrestrial invertebrates for f ood (amphibians, birds, fish, mammals, reptiles, terrestrial invertebrates) may also be at indirect risk.GS-U-ACTX-Hv1a-SEQ2 Page 15 of 29 Biopesticides Registration Action Document - DRAFT

V. ENVIRONMENTAL JUSTICE

EPA seeks to achieve environmen tal justice—the fair treatment and meaningful involvement of all people regardless of race, color, national or igin, or income—with respect to the development, implementation, and enforcement of environmen tal laws, regulations, and policies. Fair treatment means that no group of people, includi ng racial, ethnic, or socioeconomic groups, should bear a disproportionate sh are of the negative environmenta l consequences resulting from industrial, municipal, and commercial operations or the execution of federal, state, local, and tribal environmental programs and policies. Mean ingful involvement mean s that (1) potentially affected community residents have an appropriate opportunity to participat e in decisions about a proposed activity that will aff ect their environment and/or heal th; (2) the public’s contribution can influence the regulatory agency’s decision; (3) the concerns of all participants involved will be considered in the decision-making process; and (4) the decision-makers seek out and facilitate the involvement of those potentially affected. EPA has this goal for all communities and persons
across the United States.

To help address potential envir onmental justice issues, EPA seeks information on any groups or segments of the population who, as a result their location, cultural practic es, or other factors, may have atypical, unusually high exposure to GS-omega/kappa-Hxtx-Hv1a, compared to the general population. Please comm ent if you are aware of any subpopulations that may have atypical, unusually high exposure co mpared to the ge neral population.

For additional information regarding environmental justice issues, please vi sit EPA’s web site at http://www.epa.gov/compliance/en vironmentaljustice/index.html

.

VI. RISK MANAGEMENT DECISION

Section 3(c)(5) of FIFRA authorizes the Agency to approve the regist ration of a pesticide without condition, if the Administra tor determines that (i) its composition is such as to warrant the proposed claims for it, (ii) its labeling and other material required to be submitted comply with the requirements of this Act, (iii) it will perfor m its intended function without unreasonable adverse effects on the environment, and (iv) wh en used in accordance with widespread and commonly recognized practice it will not genera lly cause unreasonable adverse effects on the
environment.

In reference to the first and second determina tions above, the compositions of the pesticides (VST-006325 TGAI and VST-006339 EP) are such that the proposed claims are warranted and the Agency received satisfact ory data to conduct risk asse ssments for the uses proposed.

In reference to the third dete rmination above, the Agency believes that the use of GSomega/kappa-Hxtx-Hv1a will not cause any unreasonable adverse human health or ecological
effects. This determination is based on the findi ngs in the Agency’s conservative human health
and environmental risk assessments.

The screening level assessment identified potenti al risks to bee larvae . The registrant has adopted the following pollinator protection langua ge for the environmental hazards section and
the directions for use for the labels.GS-U-ACTX-Hv1a-SEQ2 Page 16 of 29 Biopesticides Registration Action Document - DRAFT

Environmental Hazard : Exposure of adult bees to direct treatment or residues on blooming crops can lead to effects on hone ybee larvae. See the "Directions for Use" section of this label for application instruc tions that minimize risk to honey bee larvae.

Directions for Use: To minimize potential exposure to bee larvae: Do Not apply this product at any time between 4 days prior to bloo m and until after petal fall, or if bees are foraging in the treatment area.

These restrictions prohibit application while be es are foraging and crops are in bloom. The advisory statements highlight the potential risks and exposure to bees if applied. Minimization of adult honey bee exposure to GS-omega/kappa-Hxtx-Hv1a residues through application restrictions is expected to mitigate po tential risk to both adults and larvae.

In reference to the fourth determination above , the product label that includes the mitigation measures described above provide s adequate directions for use that when used in accordance with widespread and commonly recognized prac tice it will not generally cause unreasonable
adverse effects on the environment.

The Agency believes that with the revised labeli ng as described above, i) the composition of the GS-omega/kappa-Hxtx-Hv1a products are such as to warrant the proposed claims for them, (ii) the labeling and other material required to be submitted comply with the requirements of this Act, (iii) these pesticides w ill perform their intended func tion without unreasonable adverse effects on the environment, and (iv) when used in accordance with widespread and commonly recognized practice these pesticid es will not generally cause unreasonable adverse effects on the environment. Therefore, the Agency proposes to grant these unconditi onal registrations and establish an exemption to the requirement of a to lerance for use on ornamental plants, and edible crops, provided that the label statements de scribed in this secti on are incorporated.

VII. ACTIONS REQUIRED BY THE REGISTRANT

A. Final Printed Labeling

Before releasing pesticide pr oducts containing GS-omega/kappa -Hxtx-Hv1a for shipment, the registrant is required to provide appropriate final printed labeling to EPA.

B. Reporting of Adverse Effects and Hypersensitivity Incidents

Notwithstanding the information stated in the prev ious sections, it should be clearly understood that certain, specific data are requi red to be reported to EPA as a requirement for maintaining the federal registration for a pesticid e product. A brief summary of thes e types of data are described
below.

Reports of all incidents of adverse effects to the environment must be submitted to EPA under the provisions stated in FIFRA section 6(a)(2 ). Additionally, all inci dents of hypersensitivity (including both suspected and confirmed inci dents) must be reported to EPA under the provisions of 40 CFR § 158.2140(d).GS-U-ACTX-Hv1a-SEQ2 Page 17 of 29 Biopesticides Registration Action Document - DRAFT

VIII. GLOSSARY OF ACRONYMS AND ABBREVIATIONS

ASAE American Society of Agricultural Engineers BPPD Biopesticides and Po llution Prevention Division BRAD Biopesticides Registration Action Document bw body weight of animal CFR Code of Federal Regulations cfu colony-forming unit(s) cfu/kg colony-forming units per kilogram cfu/mL colony-forming units per milliliter cP centipoise DSMZ Deutsche Sammlung von Mi kroorganismen und Zellkulturen (the German Strain Collection for Microorganisms) EDSP Endocrine Disrupt or Screening Program EP end-use product EPA Environmental Protection Agency (the “Agency”) FFDCA Federal Food, Drug, and Cosmetic Act FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality Protection Act FR Federal Register g/mL gram per milliliter

LC 50 median lethal concentration. A statis tically derived concentration of a substance that can be expected to cause death in 50% of test animals. It is usually expressed as the weight of subs tance per weight or volume of water, air, or feed (e.g., mg/L, mg/kg, or ppm).

LD 50 median lethal dose. A statistically de rived single dose that can be expected
to cause death in 50% of the test an imals when administered by the route indicated (oral, dermal, or inhalation) . It is expressed as a weight of substance per unit weight of animal (e.g., mg/kg). mg/kg milligrams per kilogram mg/L milligrams per liter MP manufacturing-use product
MRID No. Master Record Identification Number NIOSH National Institute for Occupational Safety and Health NRRL Northern Regional Research Laboratory
OCSPP Office of Chemical Safe ty and Pollution Prevention OPP Office of Pesticide Programs
PC Code Pesticide Chemical Code
PP Pesticide Petition PPE personal protective equipment ppm parts per million TGAI technical grade of the active ingredient
ULV ultra low volumeGS-U-ACTX-Hv1a-SEQ2 Page 18 of 29 Biopesticides Registration Action Document - DRAFT

IX. BIBLIOGRAPHY

A. Studies Submitted to Support the GS-o mega/kappa-Hxtx-Hv1a Pesticide Product Registrations

MRID Citation Reference

48779000 Vestaron Corporation (2012) Submission of Product Chemistry and Toxicity Data in Support of the Application for Registration of VST-006325 TGAI. Transmittal of 19 Studies.

48779001 Kennedy, R. (2012) Product Chemistry for VST-006325 TGAI. Unpublished study prepared by Vestaron Co. 271p.

48779002 Wo, C. (2012) Physical and Chem ical Characteristics: Color, Ph ysical State, Odor, pH and Density/Bulk Density. Project Number: 33617/OCR, P801. Unpublished study prepared by Eurofins/Product Safety Laboratories. 12p.

48779003 Kennedy, R. (2012) Review of Development an d Identity of VST-006325 TGAI. Project Number: US005763568A/OCR, 5763568. Unpublished study prepared by Vestaron Corporation. 425p.

48779004 Stoneburner, A.; Pilar, C. (2012) Evaluation of Vestaron Samples for the Detection of Foodborne Pathogens. Project Number: 02/06/2012/VESTARON/OCR. Unpublished study prepared by Micromyx, LLC. 14p.

48779005 Stoneburner, A.; Pilar, C. (2012) Evaluation of Vestaron Samples for the Detection of Vibrio cholera. Project Number: 03/09/2012/VESTARON2/OCR. Unpublished study prepared by Micromyx, LLC. 13p.

48779006 Telforrd, W.; Cavey, G. (2012) Simulated Gastric Fluid Treatment of GS-U-ACTX-Hv1a-SEQ2 Peptide. Unpublished study prepared by Core Lab. 34p.

48779007 Durando, J. (2011) Acute Oral Toxicity Up and Down Procedure in Rats. Project Number: 32855/OCR P320/UDP. Unpublished study prepared by Product Safety Laboratories. 15p.

48779008 Durando, J. (2011) VST-006325: Acute Dermal Toxicity Study in Rats. Project Number: 33040/OCR, P322/RAT. Unpublished study prepared by Product Safety Laboratories. 15p.

48779009 Lowe, C. (2012) VST-006325: Acute Inhalation Toxicity Study in Rats. Project Number: 33305, P330/OCR. Unpublished study prepared by Product Safety Laboratories. 22p.

48779010 Durando, J. (2012) VST-006325: Primary Eye Irritation Study in Rabbits. Project Number: 33041, P324/OCR. Unpublished study prepared by Product Safety Laboratories. 15p.

48779011 Durando, J. (2011) VST-006325: Primary Skin Irritation Study in Rabbits. Project Number: 33042, P326/OCR. Unpublished study prepared by Product Safety Laboratories. 15p.

48779012 Durando, J. (2012) VST-006325: Dermal Sensitization Study in Guinea Pigs (Buehler Method). Project Number: 33045, P328/OCR. Unpublished study prepared by Product Safety Laboratories. 25p.

48779013 Younger, C. (2012) VST-006325: Acute Oral Toxicity Study in Bobwhite Quail: Final Report. Project Number: 15676/11/OCR. Unpublished st udy prepared by Stillmeadow, Inc. 16p.

48779014 Mikulas, J. (2012) VST-006325: Rainbow Trout (Oncorhynchus mykiss) 96-hour Acute Toxicity Test: Final Report. Project Number: 15677/11/O CR. Unpublished study prepared by Stillmeadow, Inc. 16p.

48779015 Mikulas, J. (2012) VST-006325: Daphnia magna 48-hour Acute Toxicity Test: Final Report. Project Number: 15678/11/OCR. Unpublished st udy prepared by Stillmeadow, Inc. 19p.

48779016 Younger, C. (2012) VST-006325: Terrestrial Plant Toxicity, Seedling Emergence. Project Number: 15959/12/OCR. Unpublished stu dy prepared by Stillmeadow, Inc. 44p.GS-U-ACTX-Hv1a-SEQ2 Page 19 of 29 Biopesticides Registration Action Document - DRAFT

48779017 Younger, C. (2012) VST-006325: Terrestrial Plant Toxicity, Vegetative Vigor: Final Report. Project Number: 15680/11/OCR. Unpublished st udy prepared by Stillmeadow, Inc. 46p.

48779018 Younger, C. (2012) VST-006325: Honey Bee, Apis mellifera, Acute Contact Toxicity Limit Test: Final Report. Project Number: 15681/11/OCR. Un published study prepared by Stillmeadow, Inc. 12p.

48779019 Mileson, B. (2012) Response to Tier 1 Data Requirements for VST-006325 TGAI. Unpublished study prepared by Technology Sciences Group Inc. 463p.

49123400 Vestaron Corporation (2013) Submission of Product Chemistry Data in Support of the Application for Registration of VST-006325 TGAI. Transmittal of 1 Study.

49123401 Roberts, A. (2013) Supplemental Product Chemistry for VST-006325 TGAI. Unpublished study prepared by Technology Science Group, Inc. 55p.

49174500 Vestaron Corporation (2013) Submission of Product Chemistry Data in Support of the Applications for Registration of VST-006325 TG AI and VST-006330 EP. Transmittal of 1 Study.

49174501 Kennedy, R. (2013) Supplemental Product Chemistry for VST-006325 TGAI and VST-006330 EP. Unpublished study prepared by Vestaron Corporation. 85p.

49174600 Vestaron Corporation (2013) Submission of Toxicity Data in Support of the Application for Registration of VST-006325 TGAI. Transmittal of 1 Study.

49123400 Vestaron Corporation (2013) Submission of Product Chemistry Data in Support of the Application for Registration of VST-006325 TGAI. Transmittal of 1 Study.

49174601 Sindermann, A.; Porch, J. (2013) GS-U-ACTX-HV1a-SEC2: An Acute Oral Toxicity Study with the Honey Bee: Final Report. Project Number: 745P/101/OCR. Unpublished study prepared by Wildlife International, Ltd. 33p.

49199300 Vestaron Corporation (2013) Submission of Product Chemistry Data in Support of the Application for Registration of VST-006325 TGAI. Transmittal of 2 Studies.

49199301 Kennedy, R. (2013) Supplemental Product Chemistry for VST-006325 TGAI and VST-006330 EP. Unpublished study prepared by Vestaron Corporation. 28p.

49199302 Foune, C. (2013) Validation of Bioactivity of VST-006325 TGAI Lot 1234603. Unpublished study prepared by Vestaron Corporation. 12p.

B. Environmental Protection Ag ency Risk Assessment Memoranda

U.S. EPA. 2013a “ VERSITUDETM Peptide: Summary of Ha zard and Science Policy Council (HASPOC) Electronic Review: Recommendations on the Need for Additional Toxicity Studies” Memorandum from Kristin Rury, MPH to E lissa Reaves, Ph.D. dated September 18, 2013.

U.S. EPA. 2013b. “ Ecological Risk Assessment for the Pr oposed New Chemical Registration of GS-U-ACTX-Hv1a-SEQ2 (VersutideTM peptide) on Ve getables and Cole Crops; Herbs, Spices, and Mints; Pasture and Hay Crops; Fruit, Nut, and Vine Crops; Field Crops; Commercial Flowers and Ornamental Plants; Forest, Shade Tree, and Nursery Stock; and Turf.” Memorandum from M. Radtke, Ph.D., F. Khan, Ph.D , E. Odenkirchen, Ph.D., and S. Sankula, Ph.D. dated May 30,

2013.GS-U-ACTX-Hv1a-SEQ2 Page 20 of 29 Biopesticides Registration Action Document - DRAFT

U.S. EPA. 2013c. “ Ecological Risk Assessment for the Pr oposed New Chemical Registration of GS-U-ACTX-Hv1a-SEQ2 (VersutideTM peptide) on Ve getables and Cole Crops; Herbs, Spices, and Mints; Pasture and Hay Crops; Fruit, Nut, and Vine Crops; Field Crops; Commercial Flowers and Ornamental Plants; Forest, Shade Tree, and Nursery Stock; and Turf - AMENDMENT.” Memorandum from M. Radtke, Ph.D., and S. Sankul a, Ph.D. to M. Suarez and S Cerrelli .dated September 24, 2013.

U.S. EPA. 2013d. Reaves, E. and Shah, P., “GS-omega/kappa-Hxtx-Hv1a: Qualitative Human
Health Assessment.” Memorandum from E . Reaves, Ph.D. and P. Shah, Ph.D dated December 6,

2013.

U.S. EPA. 2013 e. “ Ecological Risk Assessment for the Pro posed New Chemical Registration of GS-U-ACTX-Hv1a-SEQ2 (VersutideTM peptide) on Ve getables and Cole Crops; Herbs, Spices, and Mints; Pasture and Hay Crops; Fruit, Nut, and Vine Crops; Field Crops; Commercial Flowers and Ornamental Plants; Forest, Shade Tree, and Nursery Stock; and Turf – AMENDMENT 2” Memorandum from M. Radtke, Ph.D., M. Wait and S. Sankula, Ph.D. to S Cerrelli, S. Borges, and K. Nesci dated December 5, 2013.

U.S. EPA. 2013 f. “ BEAD Review of Efficacy Data for Versutide peptide (DP # 416207, MRID 49225101) ” Memorandum from D. Brassard to D. Rate, D. Walsh, D. McCall, S. Cerrelli, and K. Nesci. dated December 18, 2013.

U.S. EPA. 2013g. “Product characterization of Versitu deTM peptide consisting of 30% GSomega/kappa-Hxtx-Hv1a.” Memorandum from J. Gagliardi, P h.D. to S. Cerrelli dated September 11, 2013.GS-U-ACTX-Hv1a-SEQ2 Page 21 of 29 Biopesticides Registration Action Document - DRAFT

APPENDIX A. BIOCHEMICAL/MICROBIAL PESTICIDES DATA REQUIREMENTS (40 CFR PART 158 – SUBPART V)

TABLE 1. Product Analysis Data Requirements for the Technical Grade of the Active Ingredient

(TGAI; GS-omega/kappa-Hxtx-H v1a) and Manufacturing Prod uct (MP; VST-006325 TGAI) (40 CFR § 158.2120)

OCSPP
Guideline

Number Data Requirement Results MRID No.

885.1100 Product Identity Submitted data fulfill the requirement for product identity. 487790-01, 487790-03, 491745-01, 491993-01

885.1200 Manufacturing Process Submitted data fulfill the requirement for manufacturing

process. 487790-01, 487790-04,

487790-05

Not applicable Deposition of a Sample in a Nationally Recognized Culture
Collection Not applicable

885.1300 Discussion of Formation of Unintentional Ingredients Submitted data fulfill the requirement for discussion of
formation of unintentional ingredients 487790-01

885.1400 Analysis of Samples Submitted data fulfill the requirement for analysis of samples 491745-01, 491993-01

885.1500 Certification of Limits Acceptable CSFs dated 8/23/2013

Additional Studies 830.1800 Enforcement Analytical Method Submitted data fulfill the requirement for an enforcement analytical method. 491993-01GS-U-ACTX-Hv1a-SEQ2 Page 22 of 29 Biopesticides Registration Action Document - DRAFT

TABLE 2. Physical and Chemical Characterist ics for the Technical Grade of the Active Ingredient (TGAI)/MP (40 CFR § 158.2120)

OCSPP Guideline

Number Data Requirement Results MRID No.

830.6302 Color Off-white to light tan 487790-02

830.6303 Physical State Powder 487790-02
830.6304 Odor Faint odor 487790-02 830.6313 Stability to Normal
and Elevated Temperatures, Metals,
and Metal Ions The VST-006325 TGAI is stable after storage at 45°C for 49 days.

The product is expected to be stable at normal temperatures. The product is not expected to
come into contact with metal or metal ions during storage. 487790-02

830.6317 Storage Stability Preliminary data supports storage for 1 year, though production
batch data is needed.. 491993-01

830.6319 Miscibility Not required per OCSPP 830.1000(e)(2), the product is not an emulsifiable liquid. NA

830.6320 Corrosion
Characteristics Only required if MP packaged in metal, plastic or paper containers. NA

830.7000 pH 4.89 (1% w/w) 487790-02

830.7100 Viscosity Not applicable. NA 830.7300 Density/Relative Density/Bulk Density (Specific Gravity) Pour density 0-.2 g/cc and tap density 0.4 g/cc @ 20°C 487790-02GS-U-ACTX-Hv1a-SEQ2 Page 23 of 29 Biopesticides Registration Action Document - DRAFT

TABLE 3. Product Analysis Data Requirements for the End-Use Product (EP), VST 006330 (40 CFR § 158.2120)

OCSPP Guideline

Number Data Requirement Results MRID No.

885.1100 Product Identity Submitted data fulfill the requirement for product identity. 487791-01

885.1200 Manufacturing

Process Submitted data fulfill the requirement for manufacturing process. 487791-01

Not applicable Deposition of a Sample in a Nationally Recognized Culture
Collection Not applicable

885.1300 Discussion of
Formation of
Unintentional

Ingredients Submitted data fulfill the requirement
for discussion of formation of unintentional ingredients for the current
use sites. . 487791-01

885.1400 Analysis of Samples Submitted data fulfill the requirement for analysis of samples 487791-01

885.1500 Certification of
Limits Acceptable CSF dated
8/23/2013

Additional Studies

830.1800 Enforcement Analytical Method An analytical method is not required for enforcement purposes since the Agency is establishing an exemption from the requirement of a tolerance without any numerical limitation. 491993-01GS-U-ACTX-Hv1a-SEQ2 Page 24 of 29 Biopesticides Registration Action Document - DRAFT

*TGAI TABLE 4. Physical and Chemical Characteristic s for the End-Use Product (EP), VST 006330 (40 CFR § 158.2120)

OCSPP Guideline

Number Data Requirement Results MRID No.

830.6317 Storage Stability Storage Stability demonstrated for up to 1 year. 491993-01,

830.6319 Miscibility Not applicable per 40 CFR 158.2030(e)(10) – EP is not an emulsifiable liquid and is not to be diluted with petroleum solvents. 487791-01

830.6320 Corrosion Characteristics Will be submitted upon completion. 487791-01 830.7100 Viscosity Not applicable per 40 CFR 158.2030(e)(12) – EP is a solid. 487791-01

830.7300* Density/Relative Density/Bulk Density

(Specific Gravity) Pour density 0.2 g/cc and tap density 0.4 g/cc @ 20oC 487790-02GS-U-ACTX-Hv1a-SEQ2 Page 25 of 29 Biopesticides Registration Action Document - DRAFT

TABLE 5. Toxicology Data Requirements for the Technica l Grade of the Active Ingredient (TGAI)/ and for the End-Use Product VST-006330 (40 CFR § 158.2140)

OCSPP
Guideline

Number Data Requirement VST-006325 TGAI VST-006330 (EP) MRID No.

885.3050 Acute Oral Toxicity/ Pathogenicity Not required. Only required for microbial pesticides. Not required. Only required for microbial pesticides. 487790-19

885.3150 Acute Pulmonary Toxicity/Pathogenicity Not required. Only required for microbial pesticides. Not required. Only required for microbial pesticides. 487790-19

885.3200 Acute Injection Toxicity/Pathogenicity Not required. Only required for microbial pesticides. Not required. Only required for microbial pesticides. 487790-19

885.3400 Hypersensitivity
Incidents Reporting is required when incidents occur during testing or production of the pesticide, or are otherwise known or reported to the registrant. Reporting is required when incidents occur during testing or production of the pesticide,
or are otherwise known or reported to the registrant. 487790-19

885.3500 Cell Culture Not required since the TGAI is not a
virus Not required since the TGAI
is not a virus

870.1100 Acute Oral Toxicity Oral LD 50 > 5,000 mg/kg bw

Classification: Toxicity Category IV Waiver accepted, based upon
the data submitted for the manufacturing product and the low toxicity of the inert ingredients. 487790-07

870.1200 Acute Dermal Toxicity The LD 50 > 5,000 mg/kg bw.

Classification: Toxicity Category IV Waiver accepted, based upon
the data submitted for the manufacturing product and the low toxicity of the inert ingredients. 487790-08

870.1300 Acute Inhalation Toxicity The LC
50 > 2.05mg/L

Classification: Toxicity Category IV Waiver accepted, based upon
the data submitted for the manufacturing product and the low toxicity of the inert ingredients. 487790-09

870.2400 Acute Eye Irritation Mildly Irritating
Classification: Toxicity Category IV Eye irritation information for some of the inert ingredients
in the formulation was insufficient to rely solely on
the results of the TGAI.
Provided the label includes Toxicity Category III precautionary language for eye irritation, a separate study is not required for the end product formulation. 487790-10

870.2500 Primary Dermal
Irritation Moderately Irritating Classification: Toxicity Category III Skin irritation information for some of the inert ingredients
in the formulation was insufficient to rely solely on
the results of the TGAI.
Provided the label includes Toxicity Category III precautionary language for dermal irritation, a separate study is not required for the end product formulation. 487790-11

870.2600 Dermal Sensitization Not a dermal sensitizer. Waiver accepted, based upon
the data submitted for the manufacturing product and the low potential of the inert 487790-12GS-U-ACTX-Hv1a-SEQ2 Page 26 of 29 Biopesticides Registration Action Document - DRAFT

TABLE 5. Toxicology Data Requirements for the Technica l Grade of the Active Ingredient (TGAI)/ and for the End-Use Product VST-006330 (40 CFR § 158.2140)

OCSPP
Guideline

Number Data Requirement VST-006325 TGAI VST-006330 (EP) MRID No.

ingredients in the formulation
to cause dermal sensitization. Hypersensitivity 487790-19

870.3100 90-day Oral - rat

Human Health Risk analysis of available data concluded that this additional mammalian toxicity data was not required. 487790-19

870.3250 90-day Dermal - rat 487790-19

870.3465 90-day Inhalation - rat 487790-19

870.3700 Prenatal developmental – rat 487790-19

870.5100 Bacaterial reverse
mutation test 487790-19

870.5300

870.5375 In vitro mammalian cell assay 487790-19GS-omega/kappa-Hxtx-Hv1a Page 27 of 29 Biopesticides Registration Action Document - DRAFT

TABLE 6. Nontarget Organism Toxicity and Environmental Fate Data Requirements for the Technical Grade of the Active Ingred ient (TGAI), GS-omeg a/kappa-Hxtx-Hv1a (40 CFR § 158.2060) OCSPP Guideline Number Data Requirement Results MRID No.

Tier I

850.2100 Avian Acute Oral Toxicity LD 50 > 630 mg ai/kg-bw NOAEC = 630 mg ai/kg-bw
No effects 487790-13;

850.2200 Avian Dietary Toxicity Waiver granted. 487790-19

850.1075 Fish Acute Toxicity,
Freshwater LC 50 > 100 mg ai/A NOAEC = 100 mg ai/L
No sub-lethal effects 487790-14

850.1010 Aquatic Invertebrate Acute Toxicity EC 50 > 1000 mg ai/L NOAEC = 1000 mg ai/L
No sub-lethal effects 487790-15

850.4100 Terrestrial Plant Toxicity, Seedling Emergence EC 25 > 0.8 lb ai/A
NOAEC = 0.8 lb ai/A
No effects 487790-16

850.4150 Terrestrial Plant Toxicity, Vegetative Vigor EC 25 > 0.8 lb ai/A
NOAEC = 0.8 lb ai/A >25% root weight decrease in
onion and lettuce that was not
considered reliable 487790-17

880.4350 Nontarget Insect Testing Contact LD 50 > 25 μ g ai/bee

NOAEC = 25 μ g ai/bee
No sub-lethal effects 487790-18

OECD 213 Honeybee acute oral toxicity

test LD 50 > 100 μg ai/bee NOAEC = 100 μg ai/bee
No sub-lethal effects 49174600

Tiers II, III, and IV Not required for GS-omega/kappa-Hxtx-Hv1a based on the current uses and application methods.GS-U-ACTX-Hv1a-SEQ2 Page 28 of 29 Biopesticides Registration Action Document - DRAFT

APPENDIX B. PESTICIDE PRODUCTS

EPA File Symbol Registration

Name Percentage
Active Ingredient Formulation Type Use Site(s) Methods of Application Application

Rate Target

Pest

88847-R VST-006325
TGAI 30% TGAI Manufacturi ng use N/A N/A N/A

88847-E VST-006330

EP 20.0% End-use
Product Artichokes Arugula Asparagus Beans- including

garden, dried,

succulent, adzuki, fava, field, garbanzo, pinto, kidney, lentil, lima, moonbeam,

navy, runner, snap, teary, wax, yard long Beets-including garden Bok Choy
Broccoli
Broccoli Raab Brussels Sprouts Cabbage
Cardoni

Carrots
Cassava
Cauliflower

Cavalo
Celeriac Celery Chayote root

Chervil Chick peas

Chicory China greens
Chinese artichoke
Chinese broccoli Chinese cabbage (Napa)
Chinese mustard cabbage
Collards
Corn salad

Cotton

Cress
Cucumber
Cucurbits
Dandelion dock Dry bulb onions
Edible burdock Edible chrysanthemum Edible gourds

Eggplant
Escarole
Endive
Garlic Ginger Ginseng
Green onions Greens: Beets, China, Dandelion, Mustard, Turnip, Rape Ground cherry Foliar spray via ground

or aerial equipment. As directed
on label Cabbage looper nymphsGS-U-ACTX-Hv1a-SEQ2 Page 29 of 29 Biopesticides Registration Action Document - DRAFT

EPA File Symbol Registration

Name Percentage
Active Ingredient Formulation Type Use Site(s) Methods of Application Application

Rate Target

Pest

Horseradish
Jerusalem artichoke
Kale
Kohlrabi

Leeks
Lentils Lettuce: Head, Leaf,
Romaine Lupine Malanga Melons: Cantaloupe, Crenshaw, Honeydew, Muskmelon, Watermelon, etc.
Mizuna Mustard spinach Napa
Okra
Olives
Onions Parsley Parsnips Peas-including garden, dried, succulent, blackeyed, chickpea,

cowpea, crowder, edible-pod, English, field, green, pigeon,

snow, sugar snap, Pepino Peppers

Potatoes Pumpkins
Purslane
Radicchio
Radishes
Rhubarb Rutabaga

Salsify
Shallots
Skirret Soybean foliage Soybean Spinach Squash Sugar beets Sweet potatoes

Swiss chard

Tobacco
Tomatillo

Tomatoes
Turmeric Turnips Turnip-rooted chervil Turnip-rooted parsley

Watercress

Yams Flowers; Green house
and field