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 2015

____________________________________

Robert McNally, Director
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TABLE OF CONTENTS

I. EXECUTIVE SUMMARY...........................................................................................................................4

II. ACTIVE INGREDIENT OVERVIEW .......................................................................................................6

III. REGULATORY BACKGROUND ..............................................................................................................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 JUSTICE.................................................................................................................15

VI. RISK MANAGEMENT DECISION .........................................................................................................16

VII. ACTIONS REQUIRED OF THE REGISTRANT...................................................................................17

VIII. GLOSSARY OF ACRONYMS AND ABBREVIATIONS ......................................................................18

IX. BIBLIOGRAPHY .......................................................................................................................................19

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

nucleopolyhedrovirus strain BV-0003 and Pesticide Product, Helicovex, Registration......................................19

B. Environmental Protection Agency Risk Assessment Memoranda .............................................20

C. Other References............................................................................................................................20

APPENDIX A. MICROBIAL PESTICIDES DATA REQUIREMENTS ...........................................................23

APPENDIX B. PESTICIDE PRODUCT................................................................................................................30
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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, Biologist Environmental Effects

Regulations

Kimberly Nesci Chief, Microbial Pesticides Branch

Shannon Borges Team Leader, Microbial Pesticides Branch

Michael Glikes Regulatory Action Leader
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I. EXECUTIVE SUMMARY

Background

In October 2013, SciReg, Inc., on behalf of Andermatt Biocontrol AG, a Swiss company, 

submitted an application for a new end-use product (EP), 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 Lepidopteran pests and a member of the virus 

family Baculoviridae, genus Alphabaculovirus. This non-genetically modified, naturallyoccurring strain was isolated by the Institute of Zoology, Chinese Academy of Sciences, from 

several H. armigera larval cadavers infected with nuclear polyhedrosis disease in a cotton field 

in a suburb of Beijing, China. On April 7, 2006, the applicant deposited a sample with the 

German Collection for Microorganisms and Cell Cultures under the accession number BV-0003. 

This strain 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, were originally isolated from different hosts, 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 common 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 agricultural 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 scientists reviewed product analysis, toxicology, and nontarget organism data and 

information (40 CFR §§ 158.2120, 158.2140, and 158.2150, respectively) submitted to support 

the registration of the pesticide product. They found that, overall, 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 and the EP, Helicovex, 

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

characteristics were fulfilled by acceptable guideline studies.

Toxicology

The applicant submitted adequate mammalian toxicology data and information to support the

proposed pesticide product. Acute oral, pulmonary, and injection toxicity/pathogenicity studies
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showed that, at a single high dose, Helicoverpa armigera NPV strain BV-0003 is not toxic

and/or pathogenic via these routes of exposure. Moreover, the applicant reported that no 

hypersensitivity incidents occurred during research, development, or testing of Helicoverpa 

armigera NPV strain BV-0003. In light 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) already is exempt from this 

requirement and since H. zea NPV and H. armigera NPV are variants of the same virus, the 

applicant did not petition the EPA for an exemption from the requirement of a tolerance for 

residues of the new strain, Helicoverpa armigera nucleopolyhedrovirus strain BV-0003. In 1980 

the EPA granted an exemption from the requirement of a tolerance for residues of the active 

ingredient H. zea 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 tolerance requirement. Hence, the EPA concludes

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 BV0003. Data and information submitted by the applicant support the conclusion that no 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 significant 

exposure to Helicoverpa armigera NPV strain BV-0003 through food and drinking water. Based 

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

determined that, even if Helicoverpa armigera NPV strain BV-0003 were 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, directs handlers working with 

Helicoverpa armigera NPV in 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 rationale bridging studies previously 

submitted for a variant of Helicoverpa armigera NPV strain BV-0003 to support the Agency’s 

waiving nontarget organism testing for the new active ingredient (AI). The 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 Agency accepted 

the bridging rationale and determined that the 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 proposed uses. The risk assessment is limited by 
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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.

Based on data and other information provided by the applicant, the EPA determined that adverse 

effects to nontarget organisms 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 habitats 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 depend 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 in 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 applications: new active ingredients; first food 

uses; first outdoor uses; first residential uses; 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/registrationstatus.html, is EPA-HQ-OPP-2014-0151. The following documents are being made available for 

comment in EPA-HQ-OPP-2014-0151: (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 registrations. 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 believes 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 contains H. armigera NPV strain BV-0003 as a new active ingredient, should 

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

II. ACTIVE INGREDIENT OVERVIEW

Biological Name: Helicoverpa armigera Nucleopolyhedrovirus strain BV0003
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Culture Deposit: German Collection for Microorganisms and Cell Cultures; 

accession number BV-0003

OPP Chemical Code: 107310

Type of Pesticide: Microbial Pesticide – Insecticide

See Appendix B for specific information (e.g.,

use sites, application rates, methods of application, 

formulation types, and target pests) regarding

the pesticide product containing this 

active ingredient.

III. REGULATORY BACKGROUND

A. Applications for Pesticide Product Registration

In October 2013, SciReg, Inc. (address: 12733 Directors Loop, Woodbridge, VA 22192) 

submitted an application on behalf of Andermatt Biocontrol AG (address: Stahlermatten 6, CH6146 Grossdietwil, Switzerland) to register an end-use product, Helicovex (EPA File Symbol 

69553-E), under FIFRA section 3. On April 8, 2014 (79 FR 21919), 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 30-day public comment period pursuant to the provisions of 

FIFRA section 3(c)(4). Following this publication, the Agency received one public comment 

expressing concern about the effects of the proposed product on honey bees and its persistence in 

soil or water. 

B. Food Tolerance Exemption

Under Federal Food, Drug, and Cosmetic Act (FFDCA) section 408(d), the EPA in 1980 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, contamination control, and safety. 

In its application to the EPA in 2013, 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 from the requirement of a tolerance for residues 

of H. zea NPV in or on 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 became 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 for risk assessment. A rating of “acceptable” indicates the study is 

scientifically sound and is useful for risk assessment. A “supplemental” rating indicates the data 
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provide some information that can be useful for risk assessment. The studies may have certain 

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 the study is not required by 40 CFR Part 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 acute toxicity data requirements, Toxicity Categories are assigned based on the 

hazard(s) identified from studies and/or other information submitted to the EPA in support of a 

pesticide registration. The EPA classifies the 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 Assessment (40 CFR § 158.2140)

1. Toxicity

All toxicology data requirements for Helicoverpa armigera 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 similarity between Helicoverpa armigera NPV strain BV0003 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 Helicoverpa armigera NPV strain BV-0003.

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

No 49591502): Researchers assessed the toxicity/infectivity of 5 batches of the test substance on 

mice by intraperitoneal (IP) injection. They randomly divided 30 female mice into six groups of 
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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 animal, 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 abnormalities 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/mouse.

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 (Harmonized 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 their host range is 

exclusively restricted to arthropods. No member of this virus family is infective to plants or 

vertebrates. 

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

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

between baculoviruses and humans without 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 one 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; Surges 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. In the Heliothis zea Reregistration Eligibility Document, the EPA stated that "due 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 Agency concludes there are sufficient data 

to satisfy this requirement without requesting a cell culture study."

6. Although baculovirus uptake has been observed, there has been no evidence that viral DNA 
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replication, production of viral proteins or cytopathological effects have occurred. In vivo, the 

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 (including 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) authorizes 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. Helicoverpa 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 armigera 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 is 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 

requirement 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 tolerance exemption, and 
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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 

pesticide 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.

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

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

the risk posed to adults, infants, and children is likely to be minimal because of the low acute 

oral toxicity/pathogenicity 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-0003in consumed drinking water is unlikely. The use patterns for 

Helicovex are soil directed and/or soil incorporated, thereby 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 chlorination, 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 BV0003 is present in drinking water (e.g., water not subject to treatment systems or facilities), its 
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target pest specificity and available data indicate no toxicity and/or pathogenicity is likely to 

occur with any drinking water exposure to Hz ABA NPV-U that results from pesticide 

applications made in accordance with good agricultural practices (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 exposures to 

the microorganism from pesticidal applications do not exceed EPA’s level of concern, 

particularly in light of available data that demonstrate 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 shares 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 viruses, when used as pesticides, would not contribute to cumulative 

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

NPV do not appear to produce a toxic metabolite against target pests. For the purposes of the 

tolerance action, therefore, the EPA has assumed that Helicoverpa armigera NPV strain BV0003 does not have a common mechanism of toxicity with another 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 mechanism 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 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 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 toxicity 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 this 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.
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Based on the acute toxicity and pathogenicity data/information discussed 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 BV0003 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) will 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, including 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 an 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 demonstrate toxic and/or pathogenic potential 

to mammals, including infants and children. 

3. Occupational Exposure and Risk Characterization

The EPA does not expect handler 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 additional 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 safety factors in FFDCA. The Agency 

determined that no unreasonable 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 information (e.g., scientific literature) submitted and cited by the applicant to 

support requests to waive nontarget organism testing for Helicoverpa armigera NPV strain BV0003 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 II, 

III, and IV) is not required. The EPA performed an environmental risk assessment based on data 

and other information provided by the applicant, 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 federally listed threatened and endangered species and their 

designated critical habitats resulting from these same proposed pesticidal uses. 
Helicoverpa armigera nucleopolyhedrovirus strain BV-0003 Page 14 of 30

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

15), 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 terrestrial and aquatic vertebrates and plants is fairly welldocumented (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 

00062584) 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 applicant 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 49591500), and the baculovirus taxonomy for the microbial pesticide control 

agent (MRID 49239301). 

a. Terrestrial Animals and Plants

Wild Mammals (Harmonized Guideline 885.4150, MRID No. 495915-02), Birds (Harmonized 

Guideline 885.4100), Nontarget Insects (Harmonized Guideline 885.4340, MRID No. 492393-

09), Honey Bees (Harmonized Guideline 885.4380, MRID No. 492393-08) and Plants 

(Harmonized Guideline 885.4300): 

The proposed applications—ground and aerial sprays and sprinkler chemigation –would deposit 

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 environment, 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 conclude 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 mammals 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 NPV
Helicoverpa armigera nucleopolyhedrovirus strain BV-0003 Page 15 of 30

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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 populations of nontarget, non-Lepidopteran insects and other 

arthropods are not anticipated. 

Since baculoviruses 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 

Guideline 885.4240), Estuarine/Marine Fish and Invertebrates (Harmonized Guideline 

885.4280) (MRID No. 492393-01):

The EPA determined that, based 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 

the proposed uses of Helicoverpa armigera NPV strain BV-0003. Freshwater and 

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

NPV BV-003 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 the data and information provided are sufficient to fulfill the Tier I nontarget organism data 

requirements and allow for nontarget organism risk assessment for Helicoverpa armigera NPV 

strain BV-0003, further 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 anticipated for any nontarget 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 habitats also are not 

expected. Moreover, the 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, and 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 from 
Helicoverpa armigera nucleopolyhedrovirus strain BV-0003 Page 16 of 30

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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 

an 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, the EPA sought 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 BV0003 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.

VI. RISK MANAGEMENT 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, has

well-known properties. The EPA has no knowledge that would contradict the claims made on the 

label, and the pesticide 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 

believes that the Helicoverpa armigera NPV strain BV-0003 pesticide product will not cause any 

unreasonable adverse effects on the environment. In fact, Helicovex is likely to provide 

protection against many infestations, 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, which contains 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. 
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VII. ACTIONS 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 the proposed new product. If 

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 produce 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 provisions 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).
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VIII. GLOSSARY OF ACRONYMS AND ABBREVIATIONS

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

LD50 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 pesticide 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 States
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IX. 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 Vertebrates 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 PhysicalChemical 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 prepared 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.
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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 Registration 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. Project 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. 2015a. Review of Product Chemistry, Manufacturing Process, and Acute Toxicity 

Studies of the EP containing Helicoverpa armigera Nucleopolyhedrovirus (Hz NPV) for 

section 3 product registration. Memorandum from Ibrahim S. Barsoum, Ph.D. and John 

L. Kough, Ph.D. to Michael Glikes, dated June 10, 2015.

U.S. EPA. 2015b. 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. 484373; DP#: 426617; 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.
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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 to 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 Polyhedrosis 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 armigera 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 Heliothine 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. 
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Lapointe, R. D., Thumbi and C.J.Lucarotti. 2011 (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 – Current 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/MONO(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. 109-140. As cited in 

Fuxa, 2004.

Centers for Disease Control and Prevention. 2009. Drinking Water - Water Treatment. Available 

from http://www.cdc.gov/healthywater/drinking/public/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 Wastewater Treatment Systems. EPA 832-R-04-001. 

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

Guideline 

Number

Data Requirement Results MRID No.

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

885.1200 Manufacturing 

Process Submitted data fulfill the requirement for manufacturing process. 49239301

N/A

Deposition of a 

Sample in a 

Nationally 

Recognized Culture 

Collection

Helicoverpa armigera NPV strain BV-0003 is 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 Samples Submitted data fulfill the requirement for analysis of samples. 49239302

885.1500

Certification of 

Limits Submitted data fulfill the requirement for manufacturing process. 49239302

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. 49239302
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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 

Guideline Number Data Requirement Results MRID No.

830.6302 Color Grey-brown

830.6303 Physical State Liquid 49239303

830.6304 Odor Typical organic odor

830.6313

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 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.

830.63021 Color Grey-brown

49239303

830.63031 Physical State Liquid

830.63041 Odor Typical organic odor

830.63131

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 49239304
Helicoverpa 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 no hypersensitivity incidents, including 

immediate-type or delayed-type reactions of humans and domestic 

animals, occurred during 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 IV

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 IV

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 IV

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 Helicoverpa 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. Classification: 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 

baculoviruses 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

49591500
Helicoverpa 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). Classification: 

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 invertebrates. 

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/A
Helicoverpa 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) 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. 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 indicated no crossinfectivity even at a high dosage of Helicovex. 

Maximum hazard dosing was not confirmed. 

Classification: Supplemental.

Submitted rationale provides a weight-ofevidence justification (based on information and 

data from the current open literature) 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 listed 

Lepidopteran species or to unmanaged honeybees 

and other pollinating insects. 

Classification: Supplemental.

49239309

49239310

49409702

49591500
Helicoverpa 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 there 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 associated with 

baculovirus activity. Classification: 

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 were 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 tables 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 reported 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-ofevidence 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 PRODUCTS

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)