### 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 onthe Need for Additional Toxicity Studies PC Code: 006100 DPBarcode: D415147 Decision No.: N/A Registration No.: N/A Petition No.: N /A Regulatory Action: N/A Risk Assessment Type: N /A CaseNo.: 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 RiskAssessment 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 consultationwithTimothy Shafer (Office ofResearch and Development). Presenters: ElissaReaves 

### & 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 newbroad spectrum
Page I of3insecticide, 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 onvarious vegetable andcole crops, herbs, pasture, fruit trees, nut trees, small fruit/berries, field crops, ornamentals, and nursery stock. Additional proposed residential uses include 

### twfand ornamentals. Toxicitv Profile: VERSITUDETM peptide is produced by a geneticallyengineered yeast species, K. lactis 

### (Kluyveromyces lactis). The yeast is removed during the manufacturing process ofthe peptide, andis not present in the technical grade active ingredient. 

### K. lactis is commonly used in the culturing ofdairy 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 ofaction that is specific to insects.

• The first mode ofaction, inhibiting the voltage-gated insect calcium channels, VERSITUDETM peptide shares withthe omegapeptides. VERSITUDETM peptide exhibits a concentration-dependent inhibition ofvoltage-gated calcium channel currents in cockroach neurons with an IC50 =500 nM (King 

### eta!., 2008). Studies show thatooACTX-Hvlablocks insect calcium channels, thereby impairing ganglionic neurotransmission, butit is not a potent inhibitor ofa variety ofmammalian neuronal calcium channels 

### in vitro (Fletcher

### etal., 1997). A homolog ofro-ACTX-Hvlathat has similaractivity at insect calcium channels, named ro-ACTX-Arla, was tested for activity in vertebrates using smoothand skeletal nerve-muscle preparations from rats and chicks, respectively (Chong 

### eta/., 2007). The results from this testing showedno effects on neuromuscular transmission on a· wide range ofvertebrate receptors, supporting the perspective thatthe omegapeptides interact specifically with insect ion channels and not vertebrate ionchannels.

• VERSITUDETM peptide also inhibits insect calcium-activated potassium channels, the same as the kappa peptides. The kappa group ofpeptide toxins blocks insect-specific calcium activated potassium channels while having little to no activity atrat 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 toxicitydata 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). Inthe acute inhalation study (MRID 48779009), 

### 5 male and 

### 5 female rats were exposed to 2.05 mg!L ofthe test article in a
Page2of3nose-only chamber for 4 hours. The mass median aerodynamic diameteroftheparticles 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 edemain all treated sites butthe skin was clear by day 7. Therefore, the test material is moderately irritating to the skin (Tox Category III). Theprimaryeye irritation study (MRID 487790I0) resulted inno corneal opacity oriritis in any treated eye during the study. All animals were free ofocularirritation by48 hours. The material was minimally irritating (Tox Category IV). No dermal sensitization was observed inguinea pigs (MRID 48779010). The concern for allergenicity 

### has been addressed for the Vestron product (Memo From Gagliardi JV to Cerrelli, S, dated June 27,2013, Product characterization ofVERSITUDETMpeptide consisting ofGS-U-ACTX_Hvla-SEQ2/M-ACTX-HVla+2). The amino acid sequence ofthe VERSITIJDETM peptide was assessed for similarity to knowntoxins andallergens. No sequence similarities were found for allergen sequences found inthe Allergenonline database using a 35% similarity over 80 amino acid residues nor ona sliding sequence comparison for 8 amino acids. The only toxins showing sequence similarity were otherspider toxins as could be expected. The Versitude protein was not significantly degraded bypepsin after4 hours so it is a stable protein. It was nottested for trypsin degradation. Overall, the data indicate that the VERSITUDETM spidervenom peptide is not reasonably expected to be an allergen. 

### III. RATIONALE FORTHE 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 limitdoses. • The conduct ofadditional 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 atthis time and a quantitative risk assessment is not required for the proposed uses ofVERSITUDETMpeptide.

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