UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: December 5, 2013 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: GS-omegalkappa-Hxtx-Hvla: Qualitative Human Health Assessment 

PC Code: 006100 DP Barcode: D411505 

Decision No.: 463505 Registration 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: Elissa 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 Division 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 & Pollution Prevention Division (7511P) 

The Health Effect Division (HED) received a request from the Biopesticides and Pollution 

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 new technical active 

ingredient (TGAI) GS-omega!kappa-Hxtx-Hvla, with product names VST-006325 TGAI and 

VST-006330 EP. VST-006330 EP is a new broad spectrum insecticide end-use product to be 

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used on various vegetable and cole crops, herbs, pasture, fruit trees, nut trees, small fruit/berries, 

field crops, ornamentals, and nursery stock. Additional proposed residential uses include turf 

and ornamentals. 

HED has reviewed the available data for the new insecticide and concluded that a qualitative 

human health risk assessment is sufficient. HED is not requiring additional mammalian toxicity 

data due to the low toxicity profile of the compound. HED, therefore, did not conduct a 

quantitative risk assessment for dietary, residential, occupational or aggregate risk. 

Executive Summary 

HED has prepared a human health risk assessment to support a new insecticide, GSomega/kappa-Hxtx-Hvl a, for the BPPD. HED has reviewed the available information and 

because of the lack of toxicity at any of the limit doses, the HED has determined that a 

qualitative risk assessment is appropriate for GS-omegalkappa-Hxtx-Hvla. 

Acute toxicity data for GS-omegalkappa-Hxtx-Hvla are available. Acute oral, dermal, and 

inhalation toxicities for the formulated product are all category IV. No effects were identified in 

these studies up to the limit dose (oral limit of 5,000 mg/kg). GS-omegalkappa-Hxtx-Hvla is 

slightly irritating to skin (Tox Category III) but not the eye (Tox Category TV). It is also not a 

skin sensitizer. Repeated dosing toxicity studies with GS-omega/kappa-Hxtx-Hvl a are not 

available and were not required by the Hazard and Science Policy Council (HASPOC) (Rury 

TXR0056780). 

Vestaron Corporation is requesting an exemption from the requirement of a tolerance for 

residues in and on all food commodities. Since hazard has not been identified, the HED has no 

objection to granting an exemption for the requirement of a tolerance. Therefore, a dietary (food 

and water) assessment is not required and there is no need for an aggregate risk assessment. 

Although there are exposure scenarios relevant to both occupational and residential handlers who 

apply the pesticide, no occupational or residential assessments are needed at this time based on 

the lack of hazard to identify an endpoint for risk assessment. 

Regulatory Recommendations 

Sufficient data are available to support HED's decision to waive generic mammalian toxicity 

data requirements for GS-omegalkappa-Hxtx-Hvla. 

HED recommends the residues ofGS-omegalkappa-Hxtx-Hvla be exempt from the requirement 

of a tolerance when used in accordance with good agricultural practices. Codex has not 

established maximum residue limits for GS-omega/kappa-Hxtx-Hvla. Concern for residential 

and occupational exposure is low because toxicity effects have not identified endpoints for risk 

assessment. GS-omega/kappa-Hxtx-Hvla is also not irritating via the dermal or inhalation route 

of exposure. Therefore, HED has no objection to the petitioned uses of GS-omegalkappa-HxtxHvl a. 

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Introduction 

V estaron Corporation has petitioned for the use of a derived spider peptide fraction as a 

biopesticide. The product characterization ofGS-omegalkappa-Hxtx-Hvla is provided in an 

EPA review by Joel Gagliardi (U.S. EPA. 2013). This active ingredient is proposed for 

formulation in an end use product (EP), VST-006330 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 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 primarily as a 

central nervous inhibitor for use in the control or suppression of many foliar feeding pests 

including caterpillars, foliage feeding coleopteran and whiteflies infesting labeled crops. GSomegalkappa-Hxtx-Hv1 can be used in either the field or greenhouse for the control of any 

labeled pest. 

Potential areas of environmental justice concerns, to the extent possible, were considered in the 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations." The 

Office of Pesticide Programs (OPP) typically considers the 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 agricultural 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-Hxtx-Hv1a is cloned into and expressed from commercial K. lactis 

(Kluyveromyces lactis). The yeast is removed during the manufacturing process of the peptide, 

and is not present in the technical grade active ingredient. K. lactis is commonly used in the 

culturing of dairy products (BoneKamp and Oosterom, 1994). The Food 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 voltage-gated calcium channels] and kappa 

(inhibits voltage-activated potassium channels]. The original source ofthe peptide is a fraction of 

the venom from the Australian Blue Mountains Funnelweb Spider Hadronyche versuta, a species 

that preys mainly on insects in its wild habitat. 

Acute toxicity data support the Registrants' claim that GS-omegalkappa-Hxtx-Hv1a 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 Category IV). In the acute 

inhalation study (MRJD 48779009), 5 male and 5 female rats were exposed to 2.05 mg/L of the 

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test article in a nose-only 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 necropsy. 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). The 

primary eye irritation study (MRID 4877901 0) resulted in no corneal opacity or iritis in any 

treated eye during the study. All animals were free of ocular irritation by 48 hours. The material 

was minimally irritating (Tox Category IV). No dermal sensitization was observed in guinea 

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 assessed for similarity to known 

toxins and allergens. No sequence similarities were found for allergen sequences found in the 

Allergen online database using a 35% similarity over 80 amino acid residues nor on a sliding 

sequence comparison for 8 amino acids. The only toxins showing sequence similarity were other 

spider toxins as could be expected. GS-omega/kappa-Hxtx-Hvla was not significantly degraded 

by pepsin after 4 hours so it is 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 studies with GS-omega/kappa-Hxtx-Hv1a are available. 

Vestaron Corporation submitted waiver requests for repeat exposure toxicity studies (MRID 

48779019). Although repeated dosing toxicity studies with GS-omega/kappa-Hxtx-Hv1a are not 

available, these were not required by the Hazard and Science Policy Council (HASPOC) (Rury 

TXR0056780). Therefore, based on the very low toxicity 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 

studies, however, were provided for surrogate peptides. These literature studies did not identify 

any toxicity data considered critical such that a quantitative assessment would be required. 

Cumulative 

Section 498(b)(2)(D)(v) ofFFDCA require that, when considering whether to establish, 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 toxicity." 

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 

toxicity with other substances. For information regarding EPA's efforts to determine which 

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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 tolerance for 

residues in and on all food commodities. There is potential for exposure from consumption of 

GS-omega/kappa-Hxtx-Hvl a residues in food commodities and/or water. However, GSomega/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/kappaHxtx-Hvla is not toxic via the oral route(> 5,000 mglkg). Submitted literature studies on 

surrogate peptide compounds indicate lack of bioavailability 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 residential handles (homeowners) may 

occur during application. However, HED does not believe that risk from inhalation or dermal 

exposure will be of concern based on the lack of hazard identified in available studies. GSomega/kappa-Hxtx-Hvla 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 Requirements 

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 risk 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. 

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Dermal 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 Science Policy Council 

(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. Unpublished 

study prepared by Technology Sciences Group Inc. 463p. MRID 48779019 

U.S. EPA. 2013. BPPD Review of Product characterization ofVERSITUDETM peptide 

consisting ofGS-U-ACTX_Hvla-SEQ2/M-ACTX-HV1a+2. Memorandum from J. 

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

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