BIOPESTICIDES REGISTRATION ACTION DOCUMENT



## Helicoverpa armigera Nucleopolyhedrovirus strain BV

- 0003

Pesticide Chemical (PC) Code: 107310

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

September 201 5

____________________________________
Robert McNally, DirectorHelicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 2 of 30

Biopesticides Registration Action Document

TABLE OF CONTENTS

I. EXECUTIVE SUMMARY

................................ ................................ ................................ ........................... 4

II. ACTIVE INGREDIENT OV ERVIEW

................................ ................................ ................................ ....... 6

III. REGULATORY BACKGROUN D

................................ ................................ ................................ .............. 7

A. Applications for Pesticide Product Registration

................................ ................................ ............ 7

B. Food Tolerance Exemption

................................ ................................ ................................ .............. 7

IV. RISK ASSESSMENT

................................ ................................ ................................ ................................ .... 7

A. Product Analysis Assessment (40 CFR § 158.2120)

................................ ................................ ....... 8

B. Human Health Assessment (40 CFR § 158.2140)

................................ ................................ ........... 8

C. Environmental Assessment (40 CFR § 158.2150)

................................ ................................ ......... 13

V. ENVIRONMENTAL JUSTIC E

................................ ................................ ................................ ................. 15

VI. RISK MANAGEMENT DECI SION

................................ ................................ ................................ ......... 16

VII. ACTIONS REQUIRED OF THE REGISTRANT

................................ ................................ ................... 17

VIII. GLOSSARY OF ACRONYMS AND ABBREVIATIONS

................................ ................................ ...... 18

IX. BIBLIOGRAPHY

................................ ................................ ................................ ................................ ....... 19

A. Stud ies Submitted to Support the Active Ingredient, Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 and Pesticide Product

, Helicovex

, Registration

................................ ...... 19

B. Environmental Protection Agency Risk Assessme nt Memoranda

................................ ............. 20

C. Other References

................................ ................................ ................................ ............................ 20

APPENDIX A. MICROBI AL PESTICIDES DATA R EQUIREMENTS

................................ ........................... 23

APPENDIX B. PESTICI DE PRODUCT

................................ ................................ ................................ ................ 3 0Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 3 of 30

Biopesticides Registration Action Document

BIOPESTICIDES REGISTRATION ACTION DOCUMENT TEAM

Office of Pesticide Programs (OPP) Biopesticides and Pollution Prevention Division

Microbial Pesticides Branch

Science Reviews

Ibrahim S. Barsoum, Ph.D. Product Analysis, Human Health

John L. Kough, Ph.D. Product Analysis, Human Health Gail Tomimatsu, Ph.D. Environmental Effects

Milutin Djurickovic, B iologist Environmental Effects

Regulations

Kimberly Nesci Chief, Microbial Pesticides Branch Shannon Borges Team Leader, Microbial Pesticides Branch

Michael Glikes Regulatory Action LeaderHelicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 4 of 30

Biopesticides Registration Action Document

I. EXECUTIVE SUMMARY

Background

In October 201 3

, SciReg , Inc., on behalf of Andermatt Biocontrol AG, a Swiss company, submitted an application for a new end

- use product ( E P)

, Helicovex (EPA File Symbol 69553

- E), containing a new active ingredient, to the United States Environmental Protection Agency (EPA) under section 3 of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA).

The new active ingredient in the proposed EP, Helicoverpa armigera nucleopolyhedrovirus ( NPV ) strain BV

- 0003, is a virus specific to L epidopteran pests and a member of the virus family Baculoviridae, genus Alphabaculovirus

. This non

- genetically modified, naturally

occurring strain was isolated by the Institute of Zoology, Chinese Academy of Sciences, from

several H

. armigera larval cada vers infected with nuclear polyhedrosis disease in a cotton field in a suburb of Beijing, China. O n April 7, 2006, the applicant deposited a sample with the German Collection for Microorganisms and Cell Cultures under the accession number BV

- 0003.

This str ain has a similar, if not identical, host range and virulence with Heliothis zea single NPV,

which was first detected in infected H. zea larvae in South Africa in 1891. Since the two viruses

, H. armigera NPV and H. zea NPV

, w ere originally isolated from di fferent h osts, they were previously classified as different species. By using DNA restriction analysis , researchers showed that the genomes of both viruses are very similar

. This similarity was corroborated by genome sequencing , which demonstrated a 97% nucleotide identity and a 99% amino acid identity. Because they share c ommon host range

, virulence, physical properties, and genome sequence, H

.
zea NPV and H

. armigera NPV are “variants of the same virus species.”

Helicovex is proposed for agricu ltural use in the United Sates in greenhouses and field applications to control the corn earworm ( Helicoverpa zea ), tobacco budworm ( Helicoverpa

virescens ), and African cotton bollworm ( Helicoverpa armigera ) on a wide variety of food and

non

- food crops

. It is proposed for application by ground or aerial spray or by chemigation. In addition, a sub

- label is proposed for use on a subset of these food crops, flowers, and ornamentals in home gardens.

EPA s cientists reviewed product analysis, toxicology, and nontarget organism data and information ( 40 CFR §§ 158.2120, 158.2140, and 158.2150, respectively) submitted to su pport the registration of the pesticide product. They found that, o verall, such data and information are adequate for risk assessment purposes , fulfill the current microbial pesticide data requirements,

and support registration of the product under FIFRA section 3(c)(5)

.

Product Analysis

For the purposes of FIFRA section 3(c)(5) registration, the product analysis data requirements

for Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 a nd the EP

, Helicovex

, including product chemistry and composition, analysis of samples, physical and chemical

characteristics were fulfilled by acceptable guideline studies.

Toxicology

The applica nt submitted a dequate mammalian toxicology data and information to support the proposed pesticide product. A cute oral, pulmonary, and injection toxicity/pathogenicity studiesHelicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 5 of 30

Biopesticides Registration Action Document

showed that, at a single high dose, Helicoverpa armigera NPV strain BV

- 0003 is not toxic and/or p athogenic via these route s of exposure

. Moreover, the applicant reported that no hypersensitivity incidents occurred during rese arch, development, or testing of Helicoverpa armigera NPV strain BV

- 0003

. In l ight of the results of the acute toxicity/pathogenicity data and the absence of hypersensitivity incidents, testing at higher tiers (i.e., Tiers II and III) was not required.

Tolerance Exemption

Because Helicoverpa zea (H. zea) nucleopolyhedrovirus (NPV) a lready is exempt from this requirement and since H. zea NPV and H. armigera NPV are va riants of the same virus, t he applicant did not petition the EPA for an exemption fr om the requirement of a tolerance for

residues of the new strain, Helicoverpa armigera nucleopolyhedrovirus strai n BV

- 0003

. In 1 980

t he EPA granted an exemption from the requirement of a tolerance for residues of the active ingredient H

. z ea NPV in or on all agricultural commodities ( 7 CFR 180.1027) as long as the manufacturer meets certain specifications related to identity, contamination control, and safety. In its application to the EPA , the applicant provided data and other information to support coverage by the existing exemption from the toler a nce requirement

. Hence, t he EPA conclude s that there is reasonable certainty that no harm will result to the U.S. population, including infants and children, from aggregate exposure to residues of Helicoverpa armigera NPV strain BV

0003

. Data and informati on submitted by the applicant support the conclusion that n o dietary

risks are expected to occur as a result of the use of Helicoverpa armigera NPV strain BV

- 0003 as an active ingredient in pesticide products. The EPA concludes that there will not be s ignificant

exposure to Helicoverpa armigera NPV strain BV

- 0003 through food and drinking water

. Based

on the review of acute oral toxicity and pathogenicity d ata by EPA scientists , the Agency

determined that, even if Helicoverpa armigera NPV strain BV

- 0003 w ere present on food or in drinking water, human exposure to this insect virus would not result in unreasonable adverse

effects.

Occupational Exposure

Despite the low toxicological profile of residues of the active ingredient

, Helicoverpa armigera

NPV strain BV

- 0003

, the EPA is requiring baseline personal protective equipment (PPE) for handlers that, due to their occupation

, may be subject to prolonged or repeated exposure to the active ingredient

. The label on Helicovex , the end

- use product, direc ts h andlers working with Helicoverpa armigera NPV i n agricultural settings to wear a long

- sleeved shirt, long pants, socks, shoes , and a dust/mist filtering respirator meeting National Institute for Occupational Safety and Health (NIOSH) standards of at least N

- 95, R

- 95, or P

- 9

.

Nontarget Organisms

The applicant submitted guideline studies and scientific rational e bridging studies previously

submitted for a variant of Helicoverpa armigera NPV strain BV

- 0003 t o support the Agency’s waiving nontarget organism testing for the new active ingredient (AI)

. T he EPA determined that this new AI is substantially similar to the previously registered AI and that previously submitted data would provide an adequate measure of hazard for the new AI. Hence, the Agen cy accepted

th e bridging rational e and determined that t he information provided is sufficient to satisfy most of the Tier I nontarget organism data requirements and support a limited ecological risk assessment for this new active ingredient and its propose d uses. The risk assessment is limited byHelicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 6 of 30

Biopesticides Registration Action Document

uncertainties associated with baculovirus persistence and spread in the environment, which

include complex ecological relationships, such as insect host

- viral parasite, host plant

- insect interactions, and variable environmental factors

. Further testing of nontarget organisms at higher tier levels (i.e., Tiers II, III, and IV) is not required.

B ased on data and other information provided by the ap plicant, the EPA determined that adverse effects to nontarget organis ms are not anticipated from the proposed pesticidal uses of

Helicovex , which contains the active ingredient Helicoverpa armigera NPV strain BV

- 0003

. Moreover, the EPA made a “No Effect” determination for direct and indirect effects to federally

listed threatened and endangered species and their designated critical habi tats resulting from

these same pesticidal uses. Direct effects to individuals of listed lepidopteran insect species cannot be precluded, nor can indirect effects to listed species that dep end specifically on a listed lepidopteran insect. Additional analysis of the potential effects to these species is necessary to make a determination for these species.

Public Participation On October 1, 2009, the EPA announced a new policy to provide a more meaningful opportunity for the public to participate i n major registration decisions before they occur. According to this policy, the EPA intends to provide a public comment period prior to making a registration decision for, at minimum, the following types of appli cations: new active ingredients; first food uses; first outdoor uses; first residential use s; or any other registration actions for which the Agency believes there may be significant public interest

.

Consistent with the policy of making registration actions more transparent, the proposed pesticide product containing Helicoverpa armigera NPV strain BV

- 0003

, is subject to a 15

- day comment period. In addition to containing a new active ingredient, the registration of the pesticide product would result in the first outdoor and food uses for H. armigera NPV BV

- 0003

. The docket identification number associated with these registration actions

, and accessed through

either http://www.regulations.gov or http://www.epa.gov/pesticides/regulating/registration

status.html , is EPA

- HQ

- OPP

- 201 4

- 0 151 . The following documents are being made availa ble for

comment in EPA

- HQ

- OPP

- 201 4

- 0 151 : (1) draft Helicoverpa armigera NPV strain BV

- 0003 Registration Action Document (BRAD); ( 2 ) draft label for the end

- use pesticide product,

Helicovex (EPA File Symbol 69553

- E ) ; (3) risk assessment for product chemistry and human health; and (4) environmental risk assessment . EPA believes that, based upon the data and information submitted in support of H

. armigera NPV strain BV

- 0003 and Helicovex

, it is appropriate to issue the registration s

. The basis for this decision can be found in the risk

assessment for H

. armigera NPV strain BV

- 0003 which is characterized throughout this BRAD.

Registration Decision

The EPA believe s that the use of Helicoverpa armigera NPV strain BV

- 0003 pesticide products

will not cause any unreasonable adverse effects on the environment. Therefore, the proposed EP,

Helicovex , which contain s H

. armigera NPV strain BV

- 0003 as a new active ingredient, s hould

be eligible for registration under FIFRA section 3(c)(5) for the labeled uses

.

II. ACTIVE INGREDIENT OVERVIEW

Biological Name: Helicoverpa armigera Nucleopolyhedrovirus strain BV

0003Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 7 of 30

Biopesticides Registration Action Document

Culture Deposit: German Collection for Microorganisms and Cell Cultures;

accession number BV

- 0003

OPP Chemical Code: 107310

Type of Pesticide: Mi crobial Pesticide

– Insecticide

See Appendix B for specific information (e.g., use sites, application rate s , methods of application, formulation type s , and target pests) regarding

the pesticide product containing this active ingredient.

III. REGULATORY BACKGROUND

A. Applications for Pesticide Product Registration

In October 201 3

, SciReg , Inc. (address: 12733 Directors Loop

, Woodbridge

, VA 22192 )

submitted an application on behalf of A ndermatt Biocontrol AG (address: Stahlermatten 6, CH

6146 Grossdietwil, Switzerland ) to register a n end

- use product, Helicovex (EPA File Symbol

69553

- E)

, under FIFRA section 3. On April 8 , 201 4 ( 79 FR 2 1 919 )

, the EPA announced receipt

of the application to register a pesticide product containing a new active ingredient for use in agriculture

. The EPA opened a 3 0

- day public comment period pursuant to the provisions of FIFRA section 3(c)(4). F ollowing this publication , t he Agency received one p ublic comment expressing concern about the effects of the proposed product on honey bees and its persistence in

soil or water

.

B. Food Tolerance Exemption

U nder Federal Food, Drug, and Cosmetic Act (FFDCA) section 408(d), the EPA in 1 980 granted an exemption from the requirement of a tolerance for residues of the active ingredient Helicoverpa zea NPV in or on all agricultural commodities ( 40 CFR 180.1027) as long as the manufacturer meets certain specifications related to identity, contami nation control, and safety. In its application to the EPA in 201 3

, SciReg , on behalf of the Swiss company Andermatt

Biocontrol

, provided data and other information to support coverage of Helicoverpa armigera

NPV strain BV

- 0003 by the existing exemption fro m the requirement of a tolerance for residues

of H

. z ea NPV in or o n all agricultural commodities because H. armigera NPV is a variant of H.

zea NPV.

IV. RISK ASSESSMENT

In the Federal Register of October 26, 2007 ( 72 FR 61002 )

, the EPA issued a Final Rule on the data requirements to support registration of microbial pesticides and updated the definition for microbial pesticides

. The rule becam e effective on December 26, 2007. The data and information evaluated for this BRAD were considered in light of these requirements.

The EPA classifies each data submission with an indication of the usefulness of the information

contained in the documents f or risk assessment. A rating of “ acceptable ” indicates the study is scientifically sound and is useful for risk assessment. A “ supplemental ” rating indicates the dataHelicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 8 of 30

Biopesticides Registration Action Document

provide some information that can be useful for risk assessment. The studies may have cer tain aspects determined not to be scientifically acceptable (“ supplemental : upgradeable ”). If a study

is rated as “supplemental: upgradeable,” EPA always provides an indication of what is lacking or what can be provided to change the rating to “ acceptable

. ” If there is simply a “ supplemental ” rating, the reviewer will often state that t he study is not required by 40 CFR P art 158. Both

“ acceptable” and “supplemental ” studies may be used in the risk assessment process as appropriate. An “unacceptable ” rating indicates that new data must be submitted.

For the acu te toxicity data requirements, Toxicity C ategories are assigned based on the hazard(s) identified from studies and/or other infor mation submitted to the EPA in support of a pesticide registration. The EPA classifies t he active ingredient or particular product into Toxicity Category I, II, III, or IV, where Toxicity Category I indicates the highest toxicity and Toxicity Category IV indicates the lowest toxicity (see 40 CFR § 156.62 )

.

A. Product Analysis Assessment ( 40 CFR § 158.2120 )

For purposes of registration under FIFRA section 3(c)(5), the EPA determined that all product analysis data requirements for Helicoverpa armigera NPV strain BV

- 0003 have been fulfilled. Refer to Tables 1, 2, 3, and 4 in Appendix A for a summary of the data requirements, including both generic and product

- specific information.

B. Human Health Asses sment ( 40 CFR § 158.2140 )

1. Toxicity

All toxicology data requirements for Helicoverpa armiger a NPV strain BV

- 0003 have been

fulfilled. Acceptable Tier I mammalian toxicology data and information support registration of

the proposed pesticide product, Helicovex

. Furthermore, Tier II and Tier III studies were not required for Helicoverpa armigera NPV strain BV

- 0003 because of the lack of acute toxicity/ pathogenicity in the Tier I studies.

For a summary of the toxicology data for Helicoverpa armigera NPV strain BV

- 0003 described in sections IV(B)(1)(a) and IV(B)(1)(b) (see pages 8

– 10 ), refer to Table 5 in Appendix A

.

a. Acute Toxicity/Pathogenicity

– Tier I

The applicant evaluated the identity or sim ilarity between Helicoverpa armigera NPV strain BV

0003 and Helicoverpa zea NPV by using DNA restriction analysis to show that the genomes of both viruses are very similar (Gettig and McCarthy, 1982). This was corroborated by genome sequencing. The sequence identity of HzSNPV and HearNPV showed a 97% nucleotide identity and a 99% amino acid identity (Chen et al., 2002 ). On the basis of common host range and virulence, the common physical properties, and the common sequence, Chen et al. (2002)

concluded that Helicoverpa armigera NPV and Helicoverpa zea NPV are “variants of the same virus species.” Based on this conclusion , data previously submitted to support the registration of Helicoverpa zea NPV can be bridged to H elicoverpa armigera NPV strain BV

- 0003

.

Acute Injection Toxicity/Pathogenicity (Intra venous ) (Harmonized Guideline 885.3200; MRID

No 4 9591502) : R esearchers assess ed the toxicity/infectivity of 5 batches of the test substance on

mice by intraperitoneal (IP) injection. They randomly divided 30 female mice into s ix groups ofHelicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 9 of 30

Biopesticides Registration Action Document

five mice

. They administered 5 groups one batch of the test substance by IP injection at a dose of approximately 106 Viral Occlusion Bodies (OB) per ani mal, and they dosed a control group with an equivalent volume of sterile saline. Observations for mortality and signs of pharmacologic

and/or toxicological effects were made twice on Day 0 and once daily through Day 7. Body weights were recorded on Day 0 and at study termination. All mice were sacrificed on Day 7 and gross necropsies were performed. The researchers observed no mortality or abno rmalities during the study. The necropsy conducted at termination of the study revealed no observable

abnormalities. The researchers concluded that the test substance is not toxic to mice when administered by intraperitoneal injection at a dose of l06 OB/m ouse.

The applicant submitted a scientific rationale to waive all of the other toxicity/pathogenicity data requirements (MRID No. 49409700):

Acute Oral Toxicity/Pathogenicity (Harmonized Guideline 885.3050) Acute Pulmonary Toxicity/Pathogenicity (Harm onized Guideline 885.3150; Hypersensitivity Incidents (Harmonized Guideline 885.3400; Cell Culture (Harmonized Guideline 885.3500) Acute Oral Toxicity (Harmonized Guideline 870.1100 ; Acute Inhalation Toxicity (Harmonized Guideline 870

- 1300 ; Acute Dermal Toxicity (Harmonized Guideline 870.1200; Acute Eye Irritation Study (Harmonized Guideline 870.2400; Acute Dermal Irritation Study (Harmonized Guideline 870.2500.

The EPA accepted the applicant’s scientific rationale for the following reasons:

1. Baculoviruses are naturally occurring pathogens of arthropods , and t heir host range is exclusively restricted to arthropods. No member of this virus family is infective t o plants or

vertebrates.

2. Baculoviruses are present in the environment and have been used for biological insect control

for over 100 years. E vidence for the safety of baculoviruses emerges from the history of contact

between baculoviruses and humans wi thout any detrimental effect. During the 1970s, the EPA

established “ Guidance for Safety Testing of Baculoviruses, ” which also became a guideline of baculovirus safety tests.

3 . Helicoverpa zea NPV was the first commercial baculovirus insecticide and is o ne of the most extensively tested entomopathogenic viruses (Ignoffo, 1975). Safety tests of more than 51 entomopathogenic viruses including more than 30 baculoviruses resulted in a long and complete safety record (extensively reviewed by Ignoffo, 1973; Sur ges et al.1980a, 1980b; Groner, 1986).

4. No adverse effect on human health has been observed in any of these investigations indicating that the use of baculovirus is safe and does not cause any health hazards.

5. I n the Heliothis zea Reregistration Eligibility Document , the EPA stated that " d ue to the overall results of Tier III toxicology testing and the additional toxicology data which support the negative response of viral replication in mammals, the A gency concludes there are sufficient data

to s atisfy this requirement without requesting a cell culture study."

6. Although baculovirus uptake has been observed, there has been no evidence that viral DNAHelicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 10 of 30

Biopesticides Registration Action Document

replication, production of viral proteins or cytopathological effects have occurred. In vivo, th e uptake of baculovirus occlusion bodies by various animals did not lead to the production of

baculovirus

- specific antibodies.

b. Acute Toxicology and Subchronic Toxicity/Pathogenicity

– Tier II; ReproductiveFertility Effects, Carcinogenicity, Immunotoxicity, and Infectivity/Pathogenicity Analysis

– Tier III

Tier II and Tier III studies were not required for Helicoverpa armigera NPV strain BV

- 0003 based on the lack of acute toxicity/pathogenicity in the Tier I data requirements.

c. Endocrine Disruptors

As required by the Administrator under the Federal Food, Drug, and Cosmetic Act ( FFDCA )

, the EPA has developed the Endocrine Disruptor Screening Program (EDSP) and has begun to implement the screening program that is to be used to test all pesticides to determine whether certain substances (in cluding pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” FFDCA section 408(p)(4) authoriz es the Administrator, by order, to exempt from the requirements of the Endocrine Disruptor Screening Program a biologic substance or other substance if a determination is made that the substance is anticipated to not produce any effect in humans similar to an effect produced by a naturally occurring estrogenic substance. Between October 2009 and February 2010, EPA issued test

orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. He licoverpa armigera NPV strain BV

- 0003 is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP.

The EPA believes that Helicoverpa armigera NPV strain BV

- 0003 is a substance that would not produce any effect in humans similar to an effect produced by a naturally occurring estrogenic substance. As such, and pursuant to Section 408(p)(4), the EPA will determine in the future whether it can exempt Helicoverpa armig era NPV strain BV

- 0003 from the requirements of the Section 408(p)(4) EDSP. In the event the EPA does determine to exempt this substance from the EDSP, an order will be issued. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

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

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 i s reliable information.” This includes exposure through drinking water and in residential settings

, but it does not include occupational exposure. Pursuant to section 408(c)(2)(B) of FFDCA, in establishing or maintaining in effect an exemption from the

req uirement of a tolerance, the EPA must take into account the factors set forth in section 408(b)(2)(C) of FFDCA, which require the EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tole rance exemption

, andHelicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 11 of 30

Biopesticides Registration Action Document

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 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

pe sticide residues. First, the Agency determines the toxicity of a pesticide . 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.

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

Based on the acute toxicity/pathogenicity data and information discussed previously and presented in Table 5 in Appendix A , t he data required for a FFDCA risk assessment for Helicoverpa armigera NPV strain BV

- 0003 have been fulfilled.

a. Aggregate Exposure

In examining aggregate exposure, section 408 of FFDCA directs the EPA to consider available information concerning exposures from the pesticide residue in food and all other nonoccupational 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 and Risk Characterization : The EPA found that d ietary exposure to Helicoverpa armigera NPV strain BV

- 0003

, a naturally occurring insect virus

, is anticipated to be negligible

. Due to the ubiquitous nature of the organism and the concentrations of H

. armigera NPV strain

BV

- 0003 and other closely related viruses that already exist in the environment, the likelihood of

increased risk to humans or animals from the use of Helicov ex is low. The EPA concluded that

t he risk posed to adults, infants, and children is likely to be minimal because of the low acute oral toxicity/ p athogenicity potential of Helicoverpa armigera NPV strain BV

- 0003 and any potential exposure to the virus also would be minimal.

Drinking Water Exposure and Risk Characterization : Exposure to residues of Helicoverpa armigera NPV strain BV

- 0003 in consumed drinking water is unlikely. The use patterns for

Helicovex are soil directed and/or soil incorporated , ther eby limiting contact with surface water by drift and runoff. Furthermore, ground water is not expected to have significant exposure to the

virus since, like other microorganisms, this microbial pesticide would likely be filtered out by the particulate nature of many soil types. If it were to be transferred to surface or ground waters that are intended for eventual human consumption (e.g., through spray drift or runoff) and directed to

wastewater treatment systems or drinking water facilities, it likely would not survive the conditions water is subjected to in such systems or facilities, including chlor ination, pH adjustments, filtration , and/or occasionally high temperatures (Centers for Disease Control and Prevention 2009; U.S. EPA 2004). In the remote likelihood that H. armigera NPV strain BV

0003 is present in drinking water (e.g., water not subject to treatment systems or facilities), itsHelicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 12 of 30

Biopesticides Registration Action Document

target pest specificity and available data indicate no toxicity an d/or pathogenicity is likely to occur with any drinking water exposure to Hz ABA NPV

- U that results from pesticide application s made in accordance with good agricultural practice s (see section IV(B)(1)(a) on pages 8

– 10 and Table 5 in Appendix A ).

Non

- occupational, Residential Risk Characterization : Given that Helicoverpa armigera NPV

strain BV

- 0003 is naturally

- occurring and usually not stable outside of its insect host

, the EPA

determined that non

- occupational exposure to the bacterium is unlikely

. Repeated exposure s to the microorganism from pesticidal applications do not exceed EPA’s level of concern, particularly in light of available data that demonstra te that the virus is not toxic (acute dermal toxicity and acute pulmonary toxicity/ pathogenicity), non

- irritating (primary dermal irritation),

and not pathogenic (acute pulmonary toxicity/pathogenicity) (see section IV(B)(1)(a) on pages 8

– 10 and Table 5 in Appendix A ).

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, 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.”

Helicoverpa armigera NPV strain BV

- 0003 share s a common mechanism of toxicity with strains

of Helicoverpa zea NPV because the insect viruses are variants of the same insect virus . The

EPA concluded that the two v iruses, when u sed as pesticides, would not contribute to cumulative

effects to human health or the environment. Helicoverpa armigera NPV and Helicoverpa zea

NPV d o not appear to produce a toxic metabolite against target pest s . For the purposes of the tolerance action, therefore, the EPA has assumed that Helicoverpa armigera NPV strain BV

0003 does not have a common mechanism of toxicity with an other substance because the two viruses basically are the same substance . Thus, section 408(b)(2)(D)(v) of the FFDCA does not apply. For information regarding the EPA’s efforts to determine which chemicals have a

common mechani sm of toxicity and to evaluate the cumulative effects of such chemicals, see the

EPA’s website at http://www.epa.gov/pesticides/cumulative

.

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

In considering the establishment of a tolerance or tolerance exemption for a pesticide chemical residue, FFDCA section 408(b)(2)(C) provides that the EPA shall assess the available information about consumption patterns am ong 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 exposure ( 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 toxicit y and exposure

unless the EPA determines that a different margin of exposure ( safety ) will be safe for infants and children. This additional margin of exposure ( safety ) is commonly referred to as the Food Quality Protection Act Safety Factor. In applying t his provision, the EPA either retains the default value of 10X or uses a different additional safety factor when reliable data available to

the EPA support the choice of a different factor.Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 13 of 30

Biopesticides Registration Action Document

Based on the acute toxicity an d pathogenicity data/information di scussed in section IV(B)(1)(a) (see pages 8

– 10 ) and Table 5 in Appendix A

, the EPA concludes that there are no threshold effects of concern to infants, children, or adults when Helicoverpa armigera NPV strain BV

0003 is used as labeled in accordance with good agricultural practices. As a result, the EPA concludes that no additional margin of exposure (safety) is necessary to protect infants and children and that not adding any additional margin of exposure (safety) wil l be safe for infants

and children.

Moreover, based on the same data /information and EPA analysis as presented directly above, the Agency is able to conclude that there is a reasonable certainty that no harm will result to the

United States population, in cluding infants and children, from aggregate exposure to the residues

of Helicoverpa armigera NPV strain BV

- 0003 when it is used

— as labeled and in accordance with good agricultural practices

— as a n insecticide . 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 Helicoverpa armigera NPV strain BV

- 0003 do not demons trate toxic and/ or pathogenic potential to mammals, including infants and children.

3. Occupational Exposure and Risk Characterization

The EPA does not expect h andler exposure to Helicoverpa armigera NPV strain BV

- 0003 to pose any undue risk. Regardless, appropriate personal protective equipment (PPE) and precautionary statements are required on pesticide product labels to mitigate any potential risks to pesticide handlers due to prolonged or numerous exposures. Handlers applying Helicovex in agricultural settings must wear a dust/mist filtering respirator , waterproof gloves, long

- sleeved shirt, long pants, socks and shoes. For future products containing this insect virus as an active ingredient

, the EPA may require a dditional PPE (e.g., protective eyewear ) on a product

- specific

basis.

4. Human Health Risk Characterization

The EPA considered human exposure to Helicoverpa armigera NPV strain BV

- 0003 in light of the standard for registration in FIFRA and the relevant s afety factors in FFDCA. The Agency

determin ed that no unrea sonable adverse effects to the United States population in general, and to infants and children in particular, will result when Helicoverpa armigera NPV strain BV

- 0003

is used in accordance with EPA

- approved labeling.

C. Environmental Assessment ( 40 CFR § 158.2150 )

Data and other informat ion (e.g., scientific literature) submitted and cited by the applicant to

support requests to waive nontarget organism testing for Helicoverpa armigera NPV strain BV

0003 are sufficient to fulfill the relevant microbial pesticide data requirements and for risk

assessment purposes. Further testing of nontarget organisms at higher tier levels (i.e., Tiers I I, III, and IV) is not required. The EPA performed an environmental risk assessment based on data

and other information provided by the ap plicant, and the Agency determined that adverse effects to nontarget organisms are not anticipated from the proposed pesticidal uses of Helicoverpa armigera NPV strain BV

- 0003 . Moreover, the EPA has made a “No Effect” determination for

direct and indirect effects to fed erally listed threatened and endangered species and their designated critical habitats resulting from these same proposed pesticidal uses.Helicoverpa armigera nucleopolyhedrovirus strain BV

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Biopesticides Registration Action Document

For a summary of the generic data requirements described in sections IV(C)(1) (see pages 14

– 1 5 ) , refer to Table 6 in Appendix A

.

1. Ecological Exposure and Risk Characterization

Baculoviruses are host

- specific within certain arthropod orders (seven insect orders, predominantly the Lepidopteran and Hymenopteran insects to date and Crustacea (Fuxa, 2004) );

however

, they may persist in the environment (either in soil and/or suitable insect host populations) for several years and even decades. The environmental safety of currently registered baculovirus products to nontarget terrestria l and aquatic vertebrates and plants is fairly well

documented (OECD, 2002; Lapointe, et al., 2011)

, and the EPA does not know of adverse effects to nontarget organisms such as honeybees.

For this strain of Helicoverpa armigera NPV, information from the open literature to date are sufficient to address the majority of the nontarget organism data requirements for microbial pesticides (40 CFR 158.2150). The applicant cited older studies conducted on a different NPV baculovirus, Heliothis zea (synonomous to Helicoverpa zea NPV). The cited document ( MRID

000 62584) listed several studies (some were unpublished) in which different species of test organisms (plants; insects, including honeybee; freshwater and estuarine invertebrates and several vertebrates) were exposed via contact, oral or inhalation routes to Heliothis zea NPV

without adverse effects. The applica nt also submitted a published study to support that Helicoverpa zea NPV and Helicoverpa armigera NPV are practically the same virus species ( 98

- 99% sequence identity )

, that the host range specificity is limited to the Lepidopteran order of insects (MRID 49 591500)

, and the baculovirus taxonomy for the microbial pesticide control

agent (MRID 49239301).

a. Terrestrial Animals and Plants

Wild Mammals (Harmonized Gui deline 885.4150, MRID No. 495915

- 0 2 ), Birds (Harmonized

Guideline 885.4 10 0), Nontarget Insects (Harmonized Guideline 885.4340 , MRID No. 492393

- 09 ), Honey Bees (Harmonized Guideline 885.4380

, MRID No. 4 9 2393

- 0 8 ) and Plants (Harmonized Guideline 885.4300) :

The proposed applications

— ground and aerial sprays and sprinkler chemigation

– would de posit Helicoverpa armigera NPV strain BV

- 0003 on foliar and other above ground plant surfaces. The EPA expects deposition onto these surfaces to occur within the intended area of treatment, as well as surrounding areas. Persistence of the virus in the envi ronment, particularly in soil, is possible as long as conditions are favorable, but it does not pose risks to nontarget species because of its specificity. Birds and mammals would be exposed to Helicoverpa armigera NPV

Strain BV

- 003 primarily through ingestion of treated prey or plants. Contact with these surfaces is not expected to result in significant exposure, though oral exposure may occur incidentally through grooming. The submitted data and information are sufficient to con clude that Helicoverpa armigera NPV Strain BV

- 003 is unlikely to infect birds or cause adverse effects. Data with laboratory mammals were also submitted, and concerns are not raised that would indicate potential risk to wild mammals. While birds and mammal s may be exposed to Helicoverpa armigera NPV Strain BV

- 003, there is sufficient evidence to show that this exposure will not result in adverse direct effects to birds and mammals. Therefore, risk to birds and mammals is expected to be minimal. The proposed uses of Helicoverpa armigera NPVHelicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 15 of 30

Biopesticides Registration Action Document

Strain BV

- 003 are also not expected to significantly affect the food supply for these nontarget animals, because the range of species affected is expected to be narrow and widespread reductions in the majority of populatio ns of nontarget, non

- Lepidopteran insects and other arthropods are not anticipated.

Since b aculoviruses are not taxonomically related to any known plant pathogens, the EPA did not require the applicant to submit data on testing Helicoverpa armigera NPV BV

- 003 on plants

. Risk to nontarget plants is not anticipated as a result of the proposed uses of Helicoverpa armigera NPV BV

- 003.

b. Aquatic Animals and Plants

Freshwater Fish (Harmonized Guideline 885.4200 ), Freshwater Invertebrates (Harmonized

Gui deline 885.4240) , Estuarine/Marine Fish and Invertebrates (Harmonized Guideline 885.4280) (MRID No. 4 9 2393

- 0 1 ) :

The EPA determined that , b ased on the information cited from the literature, risks to freshwater

fish and invertebrates and estuarine/marine fish and invertebrates are not expected as a result of

t he proposed uses of Helicoverpa armigera NPV strain BV

- 0003. F reshwater and

e stuarine /marine fish and invertebrates are not likely to be exposed to Helicoverpa armigera

NPV BV

- 0 03 from runoff and drift into aquatic areas

, and the virus is not pathogenic to aquatic organisms. Baculoviruses have a history of safe use as microbial pesticides, and they generally have narrow host ranges with no adverse effects on nontarget organisms ( OECD 2002). Typically, NPVs only infect the genus or perhaps family from which they were originally

isolated.

2. Environmental Fate Data

As t he data and information provided are sufficient to fulfill the Tier I nontarget organism data requirements and allow for nontarget organism risk asse ssment for Helicoverpa armigera NPV

strain BV

- 0003

, f

urther testing at higher levels (Tiers II, III, and IV) is not required.

3. Threatened and Endangered Species Assessment

Since the EPA has determined that no effects are ant icipated for any non target species exposed

to Helicoverpa armigera NPV strain BV

- 0003 as a result of the labeled uses , effects to federally

listed threatened and endangered species and their designated critical ha bitats also are not expected. Moreover, t he EPA made a “No Effect” determination for direct and indirect effects to all federally listed threatened and endangered species and their designated critical habitats resulting from the use of the proposed pesticide.

V. ENVIRONMENTAL JUSTICE

The EPA seeks to achieve environmental justice

— the fair treatment and meaningful involvement of all people regardless of race, color, national origin, or income

— with respect to the development, implementation, and enforcement of environmental laws, regulations, a nd policies. Fair treatment means that no group of people, including racial, ethnic, or socioeconomic groups, should bear a disproportionate share of the negative environmental consequences resulting fromHelicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 16 of 30

Biopesticides Registration Action Document

industrial, municipal, and commercial operations or the execution of federal, state, local, and tribal environmental programs and policies. Meaningful involvement means that (1) potentially affected community residents have an appropriate opportunity to participate in decisions about

a n activity that will affect their environment and/or health; (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. The EPA has this goal for all communities and persons across the United States.

To help address potential environmental justice issues, t he EPA s ought information on any groups or segments of the population who, as a result of their location, cultural practices, or other factors, may have atypical, unusually high exposure to Helicoverpa armigera NPV strain BV

0003 compared to the general population.

For additional information regarding environmental justice issues, please visit the EPA’s web

site at http://www.epa.gov/compliance/environmentaljustice/index.html

.

V I

. RISK MA NAGEMENT DECISION

Section 3(c)(5) of FIFRA permits for the registration of a pesticide provided that all the following determinations are made:

(1) Its composition is such as to warrant the claims for it; (2) Its labeling and other material required to be submitted comply with the requirements of FIFRA; (3) It will perform its intended function without unreasonable adverse effects on the environment; AND (4) When used in accordance with widespread and commonly recognized practice, it will not generally cause unreasonable adverse effects on the

environment.

To satisfy criterion 1, the Helicoverpa armigera NPV strain BV

- 0003 product

, Helicovex

, ha s well

- known properties. The EPA has no knowledge that would contradict the claim s made on the

label

, and th e p esticide product is not expected to cause unreasonable adverse effects on the

environment when used according to label instructions. Criterion 2 is satisfied by the current product label , as well as the data and information presented in this document. The Agency

believe s that the Helicoverpa armigera NPV strain BV

- 0003 p esticide product will not cause any

unreasonable adverse effects on the environment . I n fact

, Helicovex is likel y to provide protection against many infestat ions , satisfying criterion 3. Criterion 4 is satisfied in that the Helicoverpa armigera NPV strain BV

- 0003 pesticide product is not expected to cause unreasonable adverse effects when used according to label instructions. Therefore, the EP,

Helicovex

, whic h contain s Helicoverpa armigera NPV strain BV

- 0003 as a new active ingredient, is eligible for registration under FIFRA section 3(c)(5) for the labeled uses.Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 17 of 30

Biopesticides Registration Action Document

V II

. A CTIONS REQUIRED OF THE REGISTRANT

A. Final Printed Labeling

Before the end

- use product, Helicovex , may be released for shipment, the applicant is required to provide appropriate final printed labeling to the EPA

.

B. Terms of Registration

The EPA is requiring additional information on the registration of th e proposed n ew product. I f the product is to be manufactured in a country other than Switzerland, then the registrant must provide official documentation from the other country’s government that microbial

contamination is not a concern and that the water used to produ ce Helicovex (e.g., public drinking water) is tested for pathogens such as Shigella and Vibrio

.

C. Reporting of Adverse Effects and Hypersensitivity Incidents

Notwithstanding the information stated in the previous sections, it should be clearly understood

that certain specific data must be reported to the EPA as a requirement for maintaining the federal registration for a pesticide product. Reports of all incidents of adverse effects to the

environment must be submitted to the EPA under the provi sions stated in FIFRA section 6(a)(2). Additionally, all incidents of hypersensitivity (including both suspected and confirmed incidents) must be reported to the EPA under the provisions of 40 CFR § 158.2140(d).Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 18 of 30

Biopesticides Registration Action Document

VIII. GLOSSARY OF ACRONYMS AND ABBREVIATIO NS

BRAD Biopesticides Registration Action Document

CFR Code of Federal Regulations

cSt centistokes

EDSP Endocrine Disruptor Screening Program

EP end

- use pesticide product

EPA United States Environmental Protection Agency (the “Agency”)

FFDCA Federal Food, Drug, and Cosmetic Act

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FR Federal Register g/mL grams per milliliter lb/gal pounds per gallon

LD 50 median lethal dose. A statistically derived single dose that can be expected

to cause death in 50% of the test animals 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

MP manufacturing

- use pesti cide product

MRID No. Master Record Identification Number

NIOSH National Institute for Occupational Safety and Health

OPP Office of Pesticide Programs

PC Code Pesticide Chemical Code

PP Pesticide Petition

PPE personal protective equipment

TGAI technical grade of the active ingredient

U.S. United StatesHelicoverpa armigera nucleopolyhedrovirus strain BV

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Biopesticides Registration Action Document

I X. BIBLIOGRAPHY

A. Studies Submitted to Support the Active Ingredient, Helicoverpa armigera NPV strain

BV

- 0003 , and Pesticide Product Registration for the EP

, Helicovex

.

MRID No. Study Information

62584 International Minerals & Chemical Corporation (1967) Published and

Unpublished Studies Demonstrating Specificity of Heliothis Virus to Other Insects, Invertebrates and Vertebra tes Including Humans. (Unpublished study received Oct 2, 1968 under 8G0697; CDL: 091209

- G)

.

48624718 Organisation for Economic Co

- operation and Development (2002) Consensus

Document on Information Used in the Assessment of Environmental Applications Involving Baculoviruses. Series on Harmonization of Regulatory Oversight in Biotechnology 87p.

49239301 SciReg, Inc. (2013) Helicovex: Product Identity, Manufacturing Process,

Deposition of Sample in a Nationally Recognized Culture Collection, Discussion of the Formation of Unintentional Ingredients. Unpublished study. 104p.

49239302 SciReg, Inc. (2013) Helicovex: Analysis of Samples and Certification of Limits.

Unpublished study. 20p.

49239303 SciReg, Inc (2013) Helicovex: Summary of the OPPTS 830 Series Physical

Chemical Properties Test Guidelines. Unpublished study. 5p.

49239304 Aversa, S. (2013) Physical

- Chemical Properties: pH, Viscosity and Relative

Density of Test Item Helicovex: Final Report. Project Number: BT/109/13. Unpublished study prep ared by BioTecnologie BT S.r.l. 28p.

49239305 Walter, D. (2011) 3 Year Storage Stability of the Formulation Helicovex at

5(degrees) Celsius: Final Report. Project Number: 20061550/01/PCTY. Unpublished study prepared by Eurofins

- GAB GmbH. 59p.

49239308 Verge, E. (2010) Acute Oral and Contact Toxicity to the Honey Bee Apis

mellifera L. in the Laboratory: Final Report. Project Number: S10/00139, S10/00139/L1/BLEU. Unpublished study prepared by Eurofins

- GAB GmbH. 30p.

49239309 Klug, T. (2010) Helicovex: Toxicity to the Aphid Parasitoid, Aphidius

rhopalosiphi De Stefani Perez (Hymenoptera, Braconidae) in the Laboratory (Limit Test): Final Report. Project Number: S10/00142, S10/00142/L1/NLAP. Unpublished study prepared by Eurofins

- GAB GmbH. 28p.

49239310 Klug, T. (2010) Helicovex: Toxicity to the Predatory Mite, Typhlodromus pyri

Scheuten (Acari, Phytoseiidae) in the Laboratory (Limit Test): Final Report. Project Number: S10/00143, S10/00143/L1/NLTP. Unpublished study prepared by Eurofins

- GAB GmbH. 28p.Helicoverpa armigera nucleopolyhedrovirus strain BV

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Biopesticides Registration Action Document

49239311 SciReg, Inc. (2013) Helicovex: Nontarget Organisms and Environmental Fate

Waiver Requests. Unpublished study. 34p.

49409700 Andermatt Biocontrol AG (2014) Submission of Product Chemistry and Toxicity

Data in Support of the Application for Regi stration of Helicovex. Transmittal of 2

Studies.

49409701 Smith, F. (2014) Helicovex: Analysis of Samples. Unpublished study prepared by

SciReg, Inc. 14p.

49409702 Konrad, R. (2014) Helicovex Nontarget Insect Testing. Unpublished study

prepared by Andermatt Biocontrol AG. 14p.

49591501 Smith, F. (2015) Helicovex: Manufacturing Process. Unpublished study prepared

by SciReg, Inc. 8p.

49591502 Murphy, V. (2015) Helicovex (Helicoverpa armigera NPV) Intraperitoneal Acute

Mouse Toxicity/Infectivity. Pr oject Number: 18596/14. Unpublished study prepared by Stillmeadow, Inc. 20p.

49591503 Minei, C. (2015) Helicovex: Honeybees (Apis mellifera), Acute Oral Toxicity

Test: Final Report. Project Number: PL12868/2014/28/0AB0/B, 12868/2014ABO. Unpublished study prepared by TECAM Technologia Ambiental Ltda. 27p.

B. Environmental Protection Agency Risk Assessment Memoranda

U.S. EPA. 201 5 a. Review of Product Chemistry , Manufacturing Process, and Acute Toxicity

Studies of the EP containing Helicoverpa armigera N ucleopolyhedrovirus (H z NPV) for

section 3 product registration. Memorandum from Ibrahim S. Barsoum, Ph.D. and John L. Kough, Ph.D. to Michael Glikes

, dated Ju ne 10 , 201 5

.

U.S. EPA. 201 5b

. Environmental Risk Assessment for Section 3 Registration of an End

- Use Product (Helicovex, EPA File Symbol 69553

- E), manufactured by Andermatt Biocontrol AG) containing baculovirus, Helicoverpa zea NPV strain BV

- 0003 (PC Code 10730) ; Decision No. 48 4 3 73; D P # : 4 26617; Submission No. 965729.

U.S. EPA. Registration Eligibility Decision (RED) Facts: Heliothis Zea NPV, January 1991.

C. Other References

Annals of the Entomological Society of America. 2004. A New Synonym of Helicoverpa zea (Boddie) and Differentiation of Adult Males of H. zea and H. armigera (Hubner). Vol.
97, no. 6.Helicoverpa armigera nucleopolyhedrovirus strain BV

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Biopesticides Registration Action Document

Chen, X., I.J. Wu, R. Tarchine, et al. 2001. The Sequence of the Heliocoverpa armigera Single Nucleocapsid NPV Genome. J. Gen. Virol 82:241

- 257.

Chen, X., W .J. Zhang, J. Wong, et al. 2002. Comparative Analysis of the Complete Genome Sequences of Helicoverpa zea and Heliocoverpa armigera Single

- Nucleocapsid NPVes. J.

Gen. Virol. 83:673

- 684.

Hamm, J.J. 1982. Relative Susceptibility of Several Noctuid Species t o a Nuclear Polyhedrosis Virus from Heliothis armigera. Journal of Invertebrate Pathology 39:255

- 256.

Hughes, P.R., R.R. Gettig, and W.J. McCarthy. 1983. Comparison of the Time

- Mortality Response of Heliothis zea to 14 Isolates of Heliothis Nuclear Polyhe drosis Virus. Journal of Invertebrate Pathology 41:256

- 261.

Ignoffo, C.M., A.H. McIntosh, and C. Garcia. 1983. Susceptibility of Larvae of Heliothis zea, H. virescens, and H. armigera (Lep: Noctuidae) to 3 Baculoviruses. Entomophaga 28:1

- 8.

Jehle, J.A., M. Lange, H. Wang, et al. 2006. Molecular Identification and Phylogentic Analysis of Baculoviruses of Lepidoptera. Virology 346:180

- 196.

Ogembo, J.G., B.L. Caoili, M. Shikata, et al. 2009. Comparative Genomic Sequence Analysis of Novel Heliocoverpa armige ra NPV (NPV) Isolated from Kenya and Three Other Previously Sequenced Helicoverpa spp. NPVs Virus Genes. Reference not provided.

Rowley, D.L., H.J. Popham, and R.L. Harrison. 2011. Genetic Variation and Virulence of NPVes

Isolated Worldwide from the Helio thine Pests Helicoverpa armigera, Heliocoverpa zea,

and Heliothis virescens. J. Invertebr. Pathol. 107: 112

- 126.

Williams, C.F., and C.C. Payne. 1984. The Susceptibility of Heliothis armigera Larvae to Three Nuclear Polyhedrosis Viruses. Annals of Applied Biology 104: 405

- 412.

Zhang, C.S., S.C. Ma, and Z.J. Guo. 2005. Comparison of the Complete Genome Sequence between C1 and G4 Isolates of the Helicoverpa armigera Single Nucleocapsid NPV. Virology 333:190

- 199.

Burges, H.D. G.Croizier and J.Huber. 1980(? ). A Review of Safety Tests on baculoviruses. Entomophaga (?): 25:329

- 349. Portions of the document were illegible due to faded

Xerox.

Doyle, C.J., M.L. Hirst, J.S.Cory, P.F.Entwistle. 1990. Risk Assessment Studies: Detailed Host Range Testing of Wild

- Type Cabbage Moth, Mamestra brassicae (Lepidoptera: Noctuidae), Nuclear Polyhedrosis Virus. Applied and Environmental Microbiology 56:2704

- 2710.

Fuxa, J.R. 2004. Ecology of Insect Nucleopolyhedroviruses. Agriculture , ecosystems and the

environment. 103:27

- 43.

Gröner, A. 1986. “Safety of nontarget invertebrates of baculoviruses”, Chapter in book: Safety of Microbial Insecticides, M.Laird, L.A.Larey, and E.W.Davidson, eds.Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 22 of 30

Biopesticides Registration Action Document

Lapointe, R. D., Thumbi and C.J.Lucarotti. 2 011 (year not confirmed). Recent Advances in our knowledge of Baculovirus Molecular Biology and Its Relevance for the Registration of

Baculovirus

- based Products for Insect Pest Population Control. p.481

- 522, Integrated Pest Management and Pest Control

– Cu rrent and Future Tactics. Available at: http: www.intechopen.com

Organization for Economic Cooperation and Development (OECD). 2002. Consensus Document on Information Used in the Assessment of Environmental Applications Involving Baculoviruses. ENV/JM/M ONO(2002)1, 08 January 2002. Available at: http://www.oecd.org/science/biotrack/46815698.pdf.

Possee and, R.D., G.F. Rohrmann. 1997. Baculovirus genome organization and evolution. In: Miller, L.K.(Ed). The Baculoviruses. Plenum Press, New York, pp. 109

- 1 40. As cited in
Fuxa, 2004.

Centers for Disease Control and Prevention. 2009. Drinking Water

- Water Treatment. Available

from http://www.cdc.gov/healthywater/drinking/pu blic/water_treatment.html

.

DeFelice K, Wollenhaupt N, Buchholz D. 1993. Aquifers and Soil Filter Effect. Available from http://extension.missouri.edu/p/WQ24

.

U.S. EPA. 2004. Primer for Municipal Wastew ater Treatment Systems. EPA 832

- R

- 04

- 001.

Available from http://www.epa.gov/npdes/pubs/primer.pdf

.Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 23 of 30

Biopesticides Registration Action Document

APPENDIX A. MICROBIAL PESTICIDES DATA REQUIREMENTS

(40 CFR PART 158

– SUBPART V)

TABLE 1. Product Analysis Data Requirements for the Active Ingredient (TGAI), Helicoverpa armigera NPV strain BV

- 0003 (40 CFR § 158.2120)

Harmonized

G uideline

N umber Data Requirement Results MRID No.

885.1100 Product Identity Submitt ed data fulfill the requirement for product identity and composition. 49239301

885.1200 Manufacturing

Process Submitted data fulfill the requiremen t for manufacturing process

. 49239301

N/A Deposition of a

Sample in a Nationally Recognized Culture

Collection Helicoverpa armigera NPV strain BV

- 0003 i s on deposit with the German

Collection for Microorganisms and Cell Cultures under the accession number

BV

- 0003 49239301

885.1300 Discussion of

Formation of

Unintentional Ingredients Submitted data fulfill the requirement for preventing and detecting any

microbial contaminants. 49239301

885.1400 Analysis of S amples Submitted data fulfill the requirement for analysis of samples. 4 9239302

8 85 .1 50 0 Certification of

L imits Submitted data fulfill the requirement for manufacturing process. 4 9239302

TABLE 2 . Product Analysis Data Requirements for the End

- Use Pesticide Product (EP), Helicovex (40 CFR § 158.2120)

Harmonized

Guideline

Number Data Requirement Results MRID No.

885.1100 Product Identity Submitted data fulfill the requirement for product identity. 49239301

885.1200 Manufacturing Process Submitted data fulfill the requirement for manufacturing

process. 49239301

49591501

N/A Deposition of a Sample in a

Nationally Recognized

Culture Collection Submitted data fulfill the requirement for deposition of a sample

in a culture collection. N/A

885.1300 Discussion of Formation of

Unintentional Ingredients Submitted data fulfill the requirement for preventing and detecting any microbial contaminants. 49239301

885.1400 Analysis of Samples Submitted data fulfill the requirement for analysis of samples for purposes of FIFRA section 3(c)(5) registration. 49239302

885.1500 Certification of Limits Limits listed on the confidential statement of formula are adequate/acceptable. 49239302Helicoverpa armigera nucleopolyhedrovirus strain BV

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Biopesticides Registration Action Document

TABLE 3

. Physical and Chemical Characteristics for the Technical Grade of the Active Ingredient (TGAI)

, Helicoverpa armigera

NPV strain BV

- 0003 (40 CFR § 158.2120)

Harmonized

G uideline N umber Data Requirement Results MRID No.

830.6302 Color Grey

- brown

49239303 830.6303 Physical State Liquid

830.630 4 Odor Typical organic odor

830.6313 Stability to Normal and

E levated Temperatures, Metals,

and Metal I ons N/A N/A

830.6317 Storage Stability Stable at 5 degrees C for 36 months 49239305

830.6319 Miscibility Non emulsifiable liquid N/A

830.6320 Corrosion

Characteristics Non

- corrosive to PET container when stored at 5 degrees for

36 months 49239305

830.7000 pH 6.43

– 6.92 6.92 (1% w/v aqueous solution at 24.1°C) 49239304

830.7100 Viscosity Non

- Newtonian fluid.

2863.7 mPa/s at 2.5 rpm at 20°C

690.1 mPa/s at 50 rpm at 20°C

1490.3 mPa/s at 2.5 rpm at 40°C

405.00 mPa/s at 50 rpm at 40°C 49239304

830.7300 Density/Relative

Density/Bulk Density (Specific Gravity) 1. 163 g/mL at 20 degrees Celsius 49239304

TABLE 4. Physical and Chemical Characteristics for the End

- Use Pesticide Product (EP), Helicovex (40 CFR § 158.2120)

Harmonized

Guideline Number Data Requirement Results MRID No.

830.6302 1 Color Grey

- brown

49239303

830.6303 1 Physical State Liquid

830.6304 1 Odor Typical organic odor

830.6313 1 Stability to Normal and

Elevated Temperatures, Metals, and Metal Ions N/A N/A

830.6317 Storage Stability Stable at 5 degrees C for 36 months 49239305

830.6319 Miscibility Non emulsifiable liquid N/A

830.6320 Corrosion Characteristics Non

- corrosive to PET container when stored at 5 degrees

for 36 months 49239305

830.7000 pH 6.43

– 6.92 6.92 (1% w/v aqueous solution at 24.1°C) 49239304

830.7100 Viscosity Non

- Newtonian fluid.

2863.7 mPa/s at 2.5 rpm at 20°C

690.1 mPa/s at 50 rpm at 20°C

1490.3 mPa/s at 2.5 rpm at 40°C

405.00 mPa/s at 50 rpm at 40°C 49239304

830.7300 Density/Relative

Density/Bulk Density (Specific Gravity) 1.163 g/mL at 20 degrees Celsius 49239304Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 25 of 30

Biopesticides Registration Action Document

TABLE 5. Toxicology Data Requirements for the Active Ingredient Helicoverpa armigera NPV strain BV

- 0003

and the End Use Pesticide Product Helicovex (40 CFR § 158.2140)

Harmonized

Guideline

Number Data Requirement Results MRID No.

Tier I

885.3050 Acute Oral

Toxicity/Pathogenicity Waived based on extensive list of toxicology studies on other strains

of NPV. Classification: Acceptable

TOXICITY CATEGORY IV 49409700

885.3150 Acute Pulmonary

Toxicity/Pathogenicity Waived based on extensive list of toxicology studies on other strains

of NPV. Classification: Acceptable 49409700

885.3200 Acute Injection

Toxicity/ Pathogenicity Submitted study on intraperitoneal injection in mice demonstrated no

toxicity or pathogenicity. Classification: Acceptable 49591502

885.3400 Hypersensitivity

Incidents The applicant reported that n o hypersensitivity incidents, including

immediate

- type or delayed

- type reactions of humans and domestic animals, occurred durin g research, development, or testing of the

TGAI. Any future hypersensitivity incidents must be reported to EPA (refer to test note #3 of 40 CFR § 158.2140(d))

. 49409700

885.3500 Cell Culture Waived due to results of toxicology testing and additional toxicology data which support the negative replication of viral replication in

mammals. Classification: Acceptable 49409700

870.1100 Acute Oral Toxicity Waived based on extensive list of toxicology studies on other strains

of NPV. Classification: Acceptable

TOXICITY CATEGORY I V 49409700

870.1200 Acute Dermal Toxicity Waived based on extensive list of toxicology studies on other strains

of NPV. Classification: Acceptable

TOXICITY CATEGORY IV 49409700

870.1300 Acute Inhalation Toxicity Waived based on extensive list of toxicology studies on other strains

of NPV. Classification: Acceptable

TOXICITY CATEGORY I V 49409700

870.2400 Acute Eye Irritation Waived based on extensive list of toxicology studies on other strains

of NPV. Classification: Acceptable

TOXICITY CATEGORY IV 49409700

870.2500 Primary Dermal Irritation Waived based on extensive list of toxicology studies on other strains

of NPV. Classification: Acceptable

TOXICITY CATEGORY I V 49409700

Tiers II and III

Not required for Helicoverpa armigera NPV strain BV

- 0003 based on the lack of acute toxicity/pathogenicity in the Tier I studies.Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 26 of 30

Biopesticides Registration Action Document

TABLE 6

. Nontarget Organism Toxicity and Environmental Fate Data Requirements for the Technical Grade of the Active

Ingredient (TGAI), Helicoverpa armigera NPV strain BV

- 0003 (40 CFR § 158.2150)

Harmonized Guideline

Number Data Requirement Results MRID No.

Tier I

885.4050 Avian Oral Toxicity No biological response from chickens or eggs when exposed to Helicoverpa zea NPV; no quantitative information was provided in the cited study (62584). A study cited from the literature (Chen et al., 2002) provided data to support that Helicoverpa zea and H

elicoverpa armigera are variants of the same virus species. (49591500) Classification: Acceptable

.

The OECD consensus document (OECD 2002)

contains a review of information and states that effects on birds are not expected from exposure to

baculoviruses. C lassification: Supplemental (acceptable for avian risk assessment) 62584

49239301

49591500

48624718

885.4100 Avian Inhalation Toxicity/Pathogenicity Not required as the nature of the microbial pesticide does not indicate potential pathogenicity

to birds or relatedness to any known bird pathogens (refer to test note #3 of 40 CFR § 158.2150(e)).

Submitted rationale cited literature that was for

bac uloviruses in general. Classification: Supplemental N/A

49239311

885.4150 Wild Mammal Toxicity/Pathogenicity Tests required by 40 CFR § 158.2140 are adequate and appropriate for assessment of

hazards to wild mammals. The review of

information submitted to fulfill those data requirements does not indicate concerns for

adverse effects on wild mammals. Classification: Acceptable for environmental

risk assessment

Submitted rationale cited literature that was for baculoviruses in general. Classification: Supplemental 49591502

49409700

49239311

885.4200 Freshwater Fish Toxicity/Pathogenicity No biological response from minnow, killifish, and spotfish when exposed to Helicoverpa zea NPV; no quantitative information were provided in the study citation (62584). A study cited from the literature (Chen et al., 2002) provided data to support that Helicoverpa zea and Helicoverpa armigera are variants of the same virus species. (49591500). Classification: Acceptable.

A study cited from the literature (Gröner et al. 1981) and the OECD consensus document (OECD 2002) provide information to show that baculoviruses are generally understood not to be toxic or pathogenic to fish.

Classification: Supplemental 62584

49591500

49239301

49591500Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 27 of 30

Biopesticides Registration Action Document

TABLE 6

. Nontarget Organism Toxicity and Environmental Fate Data Requirements for the Technical Grade of the Active

Ingredient (TGAI), Helicoverpa armigera NPV strain BV

- 0003 (40 CFR § 158.2150)

Harmonized Guideline

Number Data Requirement Results MRID No.

885.4240 Freshwater Invertebrate Toxicity/Pathogenicity No biological response from grass shrimp, brown shrimp, or oyster when exposed to Helicoverpa

zea NPV; no quantitative information were provided in the study citation (62584). A study cited from the literature (Chen et al., 2002) provided data to support that Helicoverpa zea and Helicoverpa armigera are variants of the same virus species. (49591500). C lassification: Acceptable.

A study cited from the literature (Gröner et al. 1981) and the OECD consensus document provide additional information that baculoviruses specific to Lepidoptera are not expected to cause

adverse effects in freshwater invertebrat es. Classification: Supplemental 62584,

49239301

49591500

49591500

885.4280 Estuarine/Marine Fish and Invertebrate Testing The product is not intended for direct application

into estuarine or marine environments. Data are not required since agricultural applications of Helicovex are not expected to enter these environments in significant amounts. Classification: Acceptable 49239311

885.4300 Nontarget Plant Testing Not required as the microbial pesticide is not taxonomically related to any known plant pathogens (refer to test note #7 of 40 CFR § 158.2150(e)). N/AHelicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 28 of 30

Biopesticides Registration Action Document

TABLE 6

. Nontarget Organism Toxicity and Environmental Fate Data Requirements for the Technical Grade of the Active

Ingredient (TGAI), Helicoverpa armigera NPV strain BV

- 0003 (40 CFR § 158.2150)

Harmonized Guideline

Number Data Requirement Results MRID No.

885.4340 Nontarget Insect Testing A submitted study conducted on parasitic wasps (Aphidius rhopalosiphi) indicated uncertainty in the toxicity and/or viral activity because of the test material or experimental design. Reported results were not consistent with published literature on baculovirus biology and pathology

. There were scientific issues with the method and duration of exposure to determine potential baculovirus infectivity and replication in parasitic

wasps . Classification: Unacceptable.

A submitted study conducted on predatory mites (Typhlodromus pyri) ind icated uncertainty in the toxicity and/or viral activity because of the test material or experimental design. Reported results were not consistent with published literature on baculovirus biology and pathology. The duration of exposure to test material may have been too short to determine potential baculovirus infectivity and replication in parasitic wasps. Classification: Unacceptable.

A bioassay conducted on 3 Lepidopteran pest species: Agrotis ipsilon, Cydia pomonella, and Plutella xylostella larvae ind icated no cross

infectivity even at a high dosage of Helicovex. Maximum hazard dosing was not confirmed. Classification: Supplemental.

Submitted rationale provides a weight

- of

evidence justification (based on information and data from the current open lit erature) that there will be minimal risks to the majority of nontarget insect populations, because of the host specificity of NPV baculoviruses, such as HaNPV. However, the submitted rationale is not sufficient to preclude potential adverse effects to list ed Lepidopteran species or to unmanaged honeybees and other pollinating insects. Classification: Supplemental. 49239309

49239310

49409702

49591500Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 29 of 30

Biopesticides Registration Action Document

TABLE 6

. Nontarget Organism Toxicity and Environmental Fate Data Requirements for the Technical Grade of the Active

Ingredient (TGAI), Helicoverpa armigera NPV strain BV

- 0003 (40 CFR § 158.2150)

Harmonized Guideline

Number Data Requirement Results MRID No.

885.4380 Honey Bee Testing A submitted guideline study provided an LD50 > 10 μL/bee (i.e., ≥ 106 Helicoverpa armigera NPV/bee), since it was the highest dose tested and ~22% bee mortalities were reported in a

dose

- response contact exposure test for 72 hours.

Bee mortalities were noted in the contact exposure test; however ther e were no bee

mortalities after 48 hr of continuous oral exposure to Helicovex. Potential infectivity or pathogenicity of HaMNPV strain BV003 was not

evaluated in this short test. The LD50 value is

uncertain because of deficiencies with the test

material , lack of appropriate controls and other issues in the experimental design and reporting of results. Maximum hazard dosing was not confirmed. Results of the submitted study are

Inconclusive because bee mortalities did not exhibit overt symptomatology asso ciated with baculovirus activity. C lassification: Unacceptable due to inconclusive results.

A submitted guideline study provided a median

oral LD50 > 2.96 x 108 OB H. armigera NPV strain BV003/mL, in a 96

- hr laboratory test. Although bee mortalities wer e noted in all groups, including the negative control, the differences in mortality were not significant. No significant toxic effect was observed in the treatment group compared with the negative and inactivated control groups. However, no

statistical ta bles were included in the data set to

confirm that no statistical differences were present between treatment and control groups. Classification: Unacceptable ; as bee mortality was noted in all experimental groups and the results are inconclusive. The repor ted results are not typical of expected baculovirus symptomatology and may have been confounded by impure test material or experimental design flaws. According to the guidelines, testing should not be stopped when control mortality reaches 20%, as outlined for other non

- target insect testing.

The submitted rationale provides a weight

- of

evidence justification that exposures of Helicovex to honeybee populations are not likely to cause irreversible adverse effects, because of the host specificity of NPV baculoviruses, and that baculovirus insecticides have a limited activity in the environment because of their sensitivity to sunlight and ultraviolet radiation. Classification: Supplemental. 49239308

49591503

49591500

Tiers II, III, and IV Not required for Helicoverpa armigera NPV strain BV

- 0003 based on the acceptability of data and other information provided for Tier I

.Helicoverpa armigera nucleopolyhedrovirus strain BV

- 0003 Page 30 of 30

Biopesticides Registration Action Document

APPENDIX B. PESTICIDE PRODUCT S

EPA File Symbol Registration

Name Percenta

ge Active Ingredie

nt Formulation

Type Use Site(s) Method(s) of Application Application Rate (s) Target Pest

69553

- E Helicovex 0.60 % End

- use product Agricultural Ground application

Aerial Chemigation

Greenhouse

Residential 1

. 0

– 2. 5 fl. oz./ acre

depending on the crop corn earworm (Helicoverpa zea),

tobacco budworm (Helicoverpa virescens) , and

African cotton

bollworm (Helicoverpa armigera)