UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: September 18, 2013 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: VERSITUDETM Peptide: Summary ofHazard and Science Policy Council 

(HASPOC) Electronic Review: Recommendations on the Need for Additional Toxicity Studies 

PC Code: 006100 DP Barcode: D415147 

Decision No.: N/A Registration No.: N/A 

Petition No.: N/A Regulatory Action: N/A 

Risk Assessment Type: N/A Case No.: N/A 

TXR No.: 0056780 CAS No.: N/A 

MRID No.: N/A 40 CFR: N/A 

FROM: . Kristin Rury, MPH ¥--0 _____. 

Executive Secretary . -c--- 0 

Hazard and Science Policy CoWlcil (HASPOC) 

Health Effects Division (HED 7509P 

THROUGH: Jess Rowland, Co-Chair ~~~ Os::-67 

Anna Lowit, Ph.D, Co-Chair /J _ l/ 

HASPOC ~ 

Health Effects Division (7509P) 

TO: Elissa Reaves, Ph.D., Toxicologist, Chief 

Risk Assessment Branch 4 (RAB4) 

Health Effects Division (HED; 7509P) 

E-RESPONDERS 

HASPOC Members: Anna Lowit, Elizabeth Mendez, John Kough, Jonathan Chen, Michael 

Metzger, Ray Kent. There was additional consultation with Timothy 

Shafer (Office of Research and Development). 

Presenters: Elissa Reaves & PV Shah 

I. PURPOSE OF MEETING 

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

Prevention Division (BPPD) to provide a human health assessment for a new broad spectrum 

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insecticide, GS-U-ACTX-Hvla-SEQ2 Peptide (VERSITUDETM peptide). Currently, only acute 

toxicity studies are available with VERSITUDETM peptide. The HED Hazard and Science 

Policy Council (HASPOC) conducted an electronic review to consider the need for additional 

toxicity studies with VERSITUDETM peptide. 

II. SUMMARY OF USE PROFILE AND HAZARD CONSIDERATIONS 

Use Profile: Vestaron Corp. has submitted a Section 3 request for the new technical active 

ingredient (TGAI) VST-006325 TGAI Spider Venom Peptide (GS-U-ACTX-Hvla-SEQ2 ai) and 

for VST-006330, a new broad spectrum insecticide end-use product to be 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 twf and 

ornamentals. 

Toxicitv Profile: VERSITUDETM peptide is produced by a genetically engineered yeast species, 

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 the lactase enzyme preparation from K. /actis is Generally Recognized as Safe 

(GRAS) as a direct food additive (21 CFR 184.1388). 

VERSITUDETM peptide acts by a dual mode of action that is specific to insects. 

• The first mode of action, inhibiting the voltage-gated insect calcium channels, 

VERSITUDETM peptide shares with the omega peptides. VERSITUDETM peptide 

exhibits a concentration-dependent inhibition of voltage-gated calcium channel currents 

in cockroach neurons with an IC50 =500 nM (King eta!., 2008). Studies show that ooACTX-Hvla blocks insect calcium channels, thereby impairing ganglionic 

neurotransmission, but it is not a potent inhibitor of a variety of mammalian neuronal 

calcium channels in vitro (Fletcher et al., 1997). A homolog of ro-ACTX-Hvla that has 

similar activity at insect calcium channels, named ro-ACTX-Arla, was tested for activity 

in vertebrates using smooth and skeletal nerve-muscle preparations from rats and chicks, 

respectively (Chong eta/., 2007). The results from this testing showed no effects on 

neuromuscular transmission on a· wide range of vertebrate receptors, supporting the 

perspective that the omega peptides interact specifically with insect ion channels and not 

vertebrate ion channels. 

• VERSITUDETM peptide also inhibits insect calcium-activated potassium channels, the 

same as the kappa peptides. The kappa group of peptide toxins blocks insect-specific 

calcium activated potassium channels while having little to no activity at rat dorsal root 

ganglion neuronal calcium-activated potassium channels (Gunning eta/., 2008). Similar 

specific activity has been demonstrated for the hybrid peptide compounds (Sollod, 2006). 

Acute toxicity data support the Registrants' claim that VERSITUDETM peptide 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 

(MRID 48779009), 5 male and 5 female rats were exposed to 2.05 mg!L of the test article in a 

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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 LCSO is> 2.05 

mg/L (Tox Category IV). The primary dermal irritation study (MRID 48779011) 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 III). The primary eye 

irritation study (MRID 487790 I 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 4877901 0). 

The concern for allergenicity has been addressed for the Vestron product (Memo From Gagliardi 

JV to Cerrelli, S, dated June 27,2013, Product characterization ofVERSITUDETM peptide 

consisting ofGS-U-ACTX_Hvla-SEQ2/M-ACTX-HVla+2). The amino acid sequence of the 

VERSITIJDETM peptide 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. The 

Versitude protein 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 VERSITUDETM 

spider venom peptide is not reasonably expected to be an allergen. 

III. RATIONALE FOR THE WAIVER REQUEST 

A waiver is recommended for the additional toxicity studies for VERSITUDETM peptide, based 

on the following considerations: 

• The acute toxicity studies for GS VERSITUDETM peptide indicate no toxicity to 

mammals up to the limit doses. 

• The conduct of additional toxicity studies, including repeat dosing studies, would require 

excessive doses not relevant for risk assessment. 

IV. HASPOC CONCLUSIONS 

Therefore, based on a WOE approach, the HASPOC recommends that no additional toxicity data 

are needed for VERSITUDETM peptide at this time and a quantitative risk assessment is not 

required for the proposed uses ofVERSITUDETM peptide. 

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