 Federal Food, Drug, and Cosmetic Act (FFDCA) Considerations for GS-omega/kappa-Hxtx-Hv1a

                                Docket ID Number: EPA-HQ-OPP-2012-0389
                                              Date: December 20, 2013

Section 408(c)(2)(A)(i) of FFDCA allows the 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 the EPA determines that the exemption is "safe." Section 408(c)(2)(A)(ii) of FFDCA defines "safe" to mean that "there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information." This includes exposure through drinking water and in residential settings but does not include occupational exposure. Pursuant to FFDCA section 408(c)(2)(B), in establishing or maintaining in effect an exemption from the requirement of a tolerance, the EPA must take into account the factors set forth in FFDCA section
408(b)(2)(C), which require the EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance exemption, 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, FFDCA section 408(b)(2)(D) requires that the EPA consider "available information concerning the cumulative effects of [a particular pesticide's] . . . residues and other substances that have a common mechanism of toxicity."

The EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. First, the EPA determines the toxicity of pesticides. Second, the EPA examines exposure to the pesticide through food, drinking water, and through other exposures that occur as a result of pesticide use in residential settings.

I. Summary of Petitioned-for Tolerance Exemption

In the Federal Register of July 25, 2012 (77 FR 43562) (FRL-9353-6), the EPA issued a notice pursuant to FFDCA section 408(d)(3), 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide tolerance petition (PP 2F8014) by Vestaron Corporation, 4717 Campus Drive, Ste. 1200, Kalamazoo, MI 49008. The petition requested that 40 CFR part 180 be amended by establishing an exemption from the requirement of a tolerance for residues of GS-omega/kappa-Hxtx-Hv1a. The notice referenced a summary of the petition prepared by the petitioner, Vestaron Corporation, which is available in Docket ID Number EPA-HQ-OPP-2012-0389 via http://www.regulations.gov.

II. Toxicological Profile

Consistent with section 408(b)(2)(D) of FFDCA, the EPA reviewed the available scientific data and other relevant information on GS-omega/kappa-Hxtx-Hv1a, and considered its validity, completeness, and reliability, as well as the relationship of this information to human risk. The EPA also considered available information concerning the variability of the sensitivities of major identifiable subgroups of consumers, including infants and children.

A.  Overview of GS-omega/kappa-Hxtx-Hv1a

The active ingredient GS-omega/kappa-Hxtx-Hv1 (Versitude(TM) peptide) acts as an insecticide for use on specified ornamental plants, turf and edible crops against cabbage looper. GS-omega/kappa-Hxtx-Hv1 (Versitude(TM) peptide) functions primarily as a central nervous system inhibitor in insects, and is intended for use in the suppression of cabbage looper.  The end use product, VST-006330 EP, is mixed with water and applied as a foliar spray with ground or aerial pesticide equipment, and it can be used in either the field or greenhouse for the suppression of cabbage looper.

GS-omega/kappa-Hxtx-Hv1a, is a peptide derived from one of the toxicologically active components of Australian funnel spider (Hadronyche versuta) venom.  It is a large molecule made up of a chain of 41 amino acids which will be produced in and isolated from yeast.  Its surface is covered in hydrophilic residues, making it highly soluble in water, but insoluble in ethanol.  The active ingredient GS-omega/kappa-Hxtx-Hv1 acts as an insecticide for use on labeled ornamental plants, turf and edible crops against cabbage looper.  GS-omega/kappa-Hxtx-Hv1 functions primarily as a central nervous system inhibitor in insects, and is intended for use in the suppression of cabbage looper.  Acute toxicity data support the registrants' claim that GS-omega/kappa-Hxtx-Hv1a acts specifically on insects and not on mammals.  

B.  Biochemical / Microbial Pesticide Toxicology Data Requirements

All applicable mammalian toxicology data requirements supporting the request for an exemption from the requirement of a tolerance for residues of GS-omega/kappa-Hxtx-Hv1a in or on all food commodities have been fulfilled with data submitted by the petitioner or data waiver requests that have been granted by the EPA.

The toxicity tests (acute oral, dermal, and inhalation toxicity) and irritation tests (acute eye and primary dermal irritation) that address potential routes of exposure to the active ingredient are all classified in Toxicity Category IV (see below or Ref. 1), with the exception of mild skin irritation (Category III), and revealed little to no toxicity attributed to GS-omega/kappa-Hxtx-Hv1a. Finally, the petitioner reported that no hypersensitivity incidents occurred during the research, development, and testing of this active ingredient.

The overall conclusions from all toxicological information submitted by the petitioner are briefly described below, and more in-depth synopses of study results can be found in the associated draft Biopesticides Registration Action Document (BRAD) for GS-omega-kappa-Hxtx-Hv1a, provided as a reference in Section VII of this document (Ref. 1).

1. Acute oral toxicity  -  rat (Harmonized Guideline 870.1100; Master Record Identification Number (MRID No. 487790-07)). An acceptable acute oral toxicity study demonstrated that GS-omega/kappa-Hxtx-Hv1a was not toxic to female rats when dosed at 5,000 milligrams per kilogram (mg/kg) of body weight. The oral median lethal dose (LD50), which is a statistically derived single dose that can be expected to cause death in 50% of test animals, was greater than 5,000 mg/kg for female rats (Toxicity Category IV) (Ref. 2).

2. Acute oral toxicity/pathogenicity (Harmonized Guideline 885.3050; MRID No. 487790-19). Upon consideration of results of other definitive toxicological data submitted by the petitioner, the EPA waived acute oral toxicity/pathogenicity testing for GS-omega/kappa-Hxtx-Hv1a. The acute oral toxicity/pathogenicity study was not required because products containing GS-omega/kappa-Hxtx-Hv1 are purified. The production of this peptide in a yeast does not present a hazard of infectivity or pathogenicity from the yeast itself based on information provided in the product analysis and manufacturing process.  The final product presents no infectivity or pathogenicity hazard since the yeast is inactivated (or killed) during the purification process to yield the final peptide product. 
 An acute oral toxicity study conducted on female rats (MRID No. 487790-07) demonstrated that GS-omega/kappa-Hxtx-Hv1a was not toxic (LD50 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 monitored for microbial contamination have been negative. The EPA believes these data, when taken together, indicate that this peptide would not be toxic, infective, and/or pathogenic through the oral route of exposure and that further testing is not necessary (Ref. 2).

3. Acute inhalation toxicity  -  rat (Harmonized Guideline 870.1300; MRID No. 487790-09). An acceptable acute inhalation toxicity study demonstrated that GS-omega/kappa-Hxtx-Hv1a was not toxic to male and female rats when exposed to 2.05 milligrams per liter (mg/L). The inhalation median lethal concentration (LC50), which is a statistically derived concentration that can be expected to cause death in 50% of test animals, was greater than 2.05 mg/L for female rats, male rats, and both female and male rats combined (Toxicity Category IV) (Ref. 2).

4. Acute pulmonary toxicity/pathogenicity (Harmonized Guideline 885.3150; MRID No. 487790-19). Upon consideration of results of other definitive toxicological data submitted by the petitioner, the EPA waived acute pulmonary toxicity/pathogenicity testing for GS-omega/kappa-Hxtx-Hv1a because products containing GS-omega/kappa-Hxtx-Hv1 are purified  and do not contain yeast. An acute inhalation toxicity study conducted on rats (MRID No. 487790-09) demonstrated that GS-omega/kappa-Hxtx-Hv1a was not toxic (LC50 greater than 2.05 mg/L; 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 monitored for microbial contamination have been negative. The EPA believes these data, when taken together, indicate that this peptide would not be toxic, infective, and/or pathogenic through the inhalation route of exposure and that further testing is not necessary (Ref. 2).
 
5. Acute injection toxicity/pathogenicity (intravenous)  -  rat (Harmonized Guideline 885.3200; MRID No. 487790-19). Upon consideration of results of other definitive toxicological data submitted by the petitioner, the EPA waived acute injection toxicity/pathogenicity testing for GS-omega/kappa-Hxtx-Hv1a because products containing GS-omega/kappa-Hxtx-Hv1 are purified and do not contain yeast. GS-omega/kappa-Hxtx-Hv1a peptide is low in acute toxicity. The acute oral, dermal and inhalation toxicity studies conducted on GS-omega/kappa-Hxtx-Hv1a peptide all reported no deaths at the limit dose. In addition, the yeast used to produce the peptide is not pathogenic, the yeast is removed during the manufacturing process, and samples monitored for microbial contamination have been negative. (Ref. 2). 

6. Hypersensitivity incidents (Harmonized Guideline 885.3400; MRID No. 487790-19). The petitioner reported that no hypersensitivity incidents, including immediate-type or delayed-type reactions of humans and domestic animals, occurred during research, development, or testing of GS-omega/kappa-Hxtx-Hv1a (Ref. 2).
 
7. Acute dermal toxicity  -  rat (Harmonized Guideline 870.1200; MRID No. 487790-08). An acceptable acute dermal toxicity study demonstrated that GS-omega/kappa-Hxtx-Hv1a was not toxic to male and female rats when dosed at 5,000 mg/kg of body weight for 24 hours. The dermal LD50 was greater than 5,000 mg/kg for female and male rats (Toxicity Category IV) (Ref. 2).
 
8. Primary dermal irritation  - rabbit (Harmonized Guideline 870.2500; MRID No. 487790-11). An acceptable primary dermal irritation study demonstrated that GS-omega/kappa-Hxtx-Hv1a was a moderate irritant to the skin of rabbits (Toxicity Category III) (Ref. 2).

9. Primary dermal sensitization  -  guinea pig (Harmonized Guideline 870.2600; MRID No. 487790-12). An acceptable primary dermal sensitization study demonstrated GS-omega/kappa-Hxtx-Hv1a to be a non-sensitizing agent (Toxicity Category IV) (Ref. 2).

10. Acute eye irritation  -  rabbit (Harmonized Guideline 870.2400; MRID No. 487790-10). An acceptable eye irritation study demonstrated that GS-omega/kappa-Hxtx-Hv1a was minimally irritating to the eyes of rabbits.  No corneal opacity or iritis was observed in any treated eye during this study.  However, one hour after test substance instillation, two treated eyes exhibited `positive' conjunctivitis.  All animals were free of ocular irritation by 48 hours (Toxicity Category IV) (Ref. 2).

III.  Aggregate Exposure

In examining aggregate exposure, FFDCA section 408 directs the EPA to consider available information concerning exposures from the pesticide residue in food and all other non-occupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor uses).

Food Exposure: Exposure to residues of GS-omega/kappa-Hxtx-Hv1a, a 41 amino acid peptide derived from one of the toxicologically active components of Australian funnel spider (Hadronyche versuta) venom and isolated from yeast (Ref. 3), in consumed food is possible.  GS-omega/kappa-Hxtx-Hv1a may be applied foliarly to edible plants, turf and ornamentals. Since GS-omega/kappa-Hxtx-Hv1a is applied as a foliar insecticide to crops, it is possible that edible food commodities may retain residues of GS-omega/kappa-Hxtx-Hv1a. Further, treated crops could be diverted for food or feed purposes; therefore, exposure to GS-omega/kappa-Hxtx-Hv1a in this situation is also plausible. Regardless of the scenario, should GS-omega/kappa-Hxtx-Hv1a be present on food, supporting toxicological data and product analysis data indicate that no toxicity, pathogenicity, and/or infectivity is likely to occur with any food exposure resulting from the use of GS-omega/kappa-Hxtx-Hv1a as a pesticide when applied in accordance with label directions and good agricultural practices (see additional discussion in Section II of this document).

Drinking Water Exposure: Like consumed food, exposure to residues of GS-omega/kappa-Hxtx-Hv1a, a 41 amino acid peptide, in consumed drinking water is anticipated to be possible but negligible. However, GS-omega/kappa-Hxtx-Hv1a interacts specifically with the insect nervous system and does not interact with vertebrate systems.  The submitted and reviewed acute oral data suggest GS-omega/kappa-Hxtx-Hv1a is not toxic via the oral route (> 5,000 mg/kg).  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.  

Other Non-occupational Exposure: Based on the lack of acute toxicity and pathogenicity, residential exposure to GS-omega/kappa-Hxtx-Hv1a is not expected to pose undue risk provided the product is applied or used in accordance with label directions.  In addition, potential handler exposure is reduced through the requirement of personal protection equipment (PPE) on the label, including long-sleeved shirt and long pants, waterproof gloves and shoes plus socks.   



IV.  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, the EPA consider "available information concerning the cumulative effects of [a particular pesticide's] . . . residues and other substances that have a common mechanism of toxicity."

The EPA has not found GS-omega/kappa-Hxtx-Hv1a to share a common mechanism of toxicity with any other substances, and GS-omega/kappa-Hxtx-Hv1a does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, the EPA has assumed
that GS-omega/kappa-Hxtx-Hv1a does not have a common mechanism of toxicity with other substances. Following from this, therefore, the EPA concludes that there are no cumulative effects associated with GS-omega/kappa-Hxtx-Hv1a that need to be considered. For information regarding the EPA's efforts to determine chemicals that have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the EPA's website at http://www.epa.gov/pesticides/cumulative.

V.  Determination of Safety for the United States Population, Infants and Children

FFDCA section 408(b)(2)(C) provides that, in considering the establishment of a tolerance or tolerance exemption for a pesticide chemical residue, the EPA shall assess the available information about consumption patterns among infants and children, special susceptibility of infants and children to pesticide chemical residues, and the cumulative effects on infants and children of the residues and other substances with a common mechanism of toxicity. In addition, FFDCA section 408(b)(2)(C) provides that the EPA shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure, unless the 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 Food Quality Protection Act Safety Factor. In applying this provision, the EPA either retains the default value of 10X, or uses a different additional or no safety factor when reliable data are available to support a different additional or no safety factor.

Based on the acute toxicity and product analysis data discussed in Section II of this document, the EPA concludes that there are no threshold effects of concern to infants, children, or adults when GS-omega/kappa-Hxtx-Hv1a is applied or used in accordance with label directions and good agricultural practices.. As a result, the EPA concludes that no additional margin of exposure (safety) is necessary.

Moreover, based on the same data and the EPA analysis as presented directly above, the Agency concludes that there is a reasonable certainty that no harm will result to the U.S. population, including infants and children, from aggregate exposure to the residues of GS-omega/kappa-Hxtx-Hv1a in or on all food commodities when applied or used in accordance with label directions and good agricultural practices.  Such exposure includes all anticipated dietary exposures and all other exposures for which there is reliable information. The EPA has arrived at this conclusion because, considered collectively, the data and information available on GS-omega/kappa-Hxtx-Hv1a do not demonstrate toxic, pathogenic, and/or infective potential to mammals, including infants and children.

VI.  Conclusions

The EPA concludes that there is a reasonable certainty that no harm will result to the U.S. population, including infants and children, from aggregate exposure to residues of GS-omega/kappa-Hxtx-Hv1a. Therefore, an exemption from the requirement of a tolerance is established for residues of GS-omega/kappa-Hxtx-Hv1a in or on all food commodities when applied or used in accordance with label directions and good agricultural practices.

VII.  References

1.  Draft Biopesticides Registration Action Document (BRAD) for GS-omega/kappa-Hxtx-Hv1a 

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

3.  U.S. EPA.  2013b. "Product characterization of Versitude(TM) peptide consisting of 30% GS-omega/kappa-Hxtx-Hv1a." Memorandum from J. Gagliardi, Ph.D. to S. Cerrelli dated September 11, 2013.




