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INTRODUCTION

This is the U.S. Environmental Protection Agency’s (EPA) Final Work Plan (FWP) for the 

Registration Review of the harpin proteins. This FWP follows the Preliminary Work Plan (PWP) 

posted in the Registration Review docket for the harpin proteins (EPA-HQ-OPP-2012-0641).

These substances elicit a complex natural defense mechanism in plants and are registered for use 

on a wide array of plants (e.g., fruiting vegetables, pome fruit, tobacco, and turf) in agricultural 

and residential settings to manage plant disease, enhance plant growth, and suppress insect, mite 

and nematode pests.

The EPA is implementing the Registration Review program pursuant to Section 3(g) of the 

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered 

pesticide every 15 years to determine whether it continues to meet the FIFRA standard for 

registration. Changes in science, public policy, and pesticide use practices occur over time. The 

Registration Review program is intended to make sure that, as the ability to assess risk evolves 

and as policies and practices change, all registered pesticides continue to meet the statutory 

standard of no unreasonable adverse effects to human health or the environment. The public 

phase of Registration Review begins when the initial docket is opened for each case. Information 

on this program is provided on the EPA’s website.

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The FWP begins with any updates since the PWP was issued. Next, it provides a summary of 

substantive comments received, if any, during the public comment period for the PWP 

concerning anticipated data needs, expected risk assessments, or the estimated timeline identified 

in the PWP, and a summary of the EPA’s responses to those comments. This section is followed 

by the planned data needs, risk assessments expected to be conducted, and the projected

Registration Review timeline for the harpin proteins. Lastly, there is a discussion of next steps.

UPDATES SINCE THE PWP WAS ISSUED

In the PWP, the EPA indicated that there were several data gaps for the harpin proteins. During 

the 60-day public comment period on the harpin proteins PWP, Plant Health Care, Inc. (PHC), 

the registrant for all of the harpin protein pesticide products, provided a comment about the data 

gaps specified by the EPA. After considering PHC’s detailed comment, the EPA adjusted the 

planned data needs for the harpin proteins as follows:

(1) Removal of Certain Data Needs from the List Presented in Section I(H) (“Summary of 

Anticipated Data Needs”) of the PWP 

(a) Harpin Protein

• Density/Relative Density/Bulk Density (Harmonized Guideline 830.7300) – According to 40 

CFR § 158.120, which describes how to determine data requirements, applicants/registrants 

are to “[r]eview the notes for each requirement to determine its applicability to the specific 

product proposed for registration.” Test note #8 under 40 CFR § 158.2030(e) states the 

following: “If the TGAI cannot be isolated, data are required on the practical equivalent of 

 1 See http://www.epa.gov/oppsrrd1/registration_review/.
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the TGAI. EP testing may also be appropriate.” Based on PHC’s reference to test note #8 

under 40 CFR § 158.2030(e) and its explanation that the TGAI (technical grade of the active 

ingredient) for harpinαβ protein, which is structurally, chemically, and biologically similar to 

harpin protein, is produced by industrial fermentation in an integrated production process 

wherein it is never isolated in stable form, further data done with the TGAI are not expected 

to be required. The EPA believes that previously submitted bulk density data on harpin 

protein end-use pesticide products (EPs) are sufficient to fulfill this data need.

• Partition Coefficient (n-Octanol/Water) (Harmonized Guidelines 830.7550, 830.7560, and 

830.7570) – According to 40 CFR § 158.120, which describes how to determine data 

requirements, applicants/registrants are to “[r]eview the notes for each requirement to 

determine its applicability to the specific product proposed for registration.” Test note #16 

under 40 CFR § 158.2030(e) states the following: “Required for organic chemicals unless 

they dissociate in water or are partially or completely soluble in water.” Based on PHC’s 

reference to test note #16 under 40 CFR § 158.2030(e) and its explanation that harpinαβ 

protein, which is structurally, chemically, and biologically similar to harpin protein, is 

partially soluble in water, the EPA believes that partition coefficient data are not applicable 

and therefore not expected to be required in this instance.

• Acute Dermal Toxicity (Harmonized Guideline 870.1200), Acute Inhalation Toxicity 

(Harmonized Guideline 870.1300), Primary Eye Irritation (Harmonized Guideline 870.2400), 

and Primary Dermal Irritation (Harmonized Guideline 870.2500) – Based on PHC’s 

explanation that the TGAI for harpinαβ protein, which is structurally, chemically, and 

biologically similar to harpin protein, is produced by industrial fermentation in an integrated 

production process wherein it is never isolated in stable form, further data done with the 

TGAI are not expected to be required. The EPA believes that previously submitted 

toxicological data on harpin protein EPs are sufficient to fulfill these data needs. 

• 90-day Dermal (Harmonized Guideline 870.3250) – According to 40 CFR § 158.120, which 

describes how to determine data requirements, applicants/registrants are to “[r]eview the 

notes for each requirement to determine its applicability to the specific product proposed for 

registration.” Test note #7 under 40 CFR § 158.2050(e) states the following: “Required to 

support uses involving purposeful application to the human skin or which would result in 

comparable prolonged human exposure to the product (e.g., insect repellents) and if any of 

the following criteria are met: (i) Data from a 90-day oral study are not required. (ii) The 

active ingredient is known or expected to be metabolized differently by the dermal route of 

exposure than by the oral route and the metabolite is of toxicological concern. (iii) The use 

pattern is such that the dermal exposure would be the primary route of exposure.” Based on 

PHC’s reference to test note #7 under 40 CFR § 158.2050(e) and its explanation that

harpinαβ protein, which is structurally, chemically, and biologically similar to harpin protein, 

is not purposefully applied to the skin, does not result in comparable prolonged human 

exposure when mixed and applied according to label directions, and does not meet any of the 

three criteria listed directly above, the EPA believes that 90-day dermal data are not 

applicable and therefore not expected to be required in this instance.
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• 90-day Inhalation (Harmonized Guideline 870.3465) – According to 40 CFR § 158.120, 

which describes how to determine data requirements, applicants/registrants are to “[r]eview 

the notes for each requirement to determine its applicability to the specific product proposed 

for registration.” Test note #8 under 40 CFR § 158.2050(e) states the following: “Required if 

there is a likelihood of significant levels of repeated inhalation exposure to the pesticide as a 

gas, vapor, or aerosol.” Based on PHC’s reference to test note #8 under 40 CFR § 

158.2050(e) and its explanation for harpinαβ protein, which is structurally, chemically, and 

biologically similar to harpin protein, that EPs are dry wettable granules that do not result in 

significant levels of repeated inhalation exposure when mixed or applied according to label 

directions, the EPA believes that 90-day inhalation data are not applicable and therefore not

expected to be required in this instance.

• Fish Acute Toxicity, Freshwater (Harmonized Guideline 850.1075) and Terrestrial Plant 

Toxicity, Seedling Emergence (Harmonized Guideline 850.4100) – Although not explained 

in 40 CFR § 158.2060, other sections in 40 CFR Part 158 (e.g., 40 CFR § 158.243(b)) 

explain that a comma between test substances, such as is found in 40 CFR § 158.2060(d), 

indicates that data may be required on either test substance depending on the conditions set 

forth in the test note(s). Given this description found in 40 CFR § 158.243(b), the EPA 

reevaluated the type of data anticipated as needed to address these two environmental data 

requirements and determined that data could be generated using either the TGAI or EP test 

substance. Because PHC explained that the TGAI for harpinαβ protein, which is structurally, 

chemically, and biologically similar to harpin protein, is produced by industrial fermentation 

in an integrated production process wherein it is never isolated in stable form, further data 

done with the TGAI are not expected to be required. The EPA believes that previously 

submitted fish acute toxicity, freshwater and terrestrial plant toxicity, seedling emergence 

data on a harpin protein EP are sufficient to fulfill these data needs.

(b) Harpinαβ Protein

• Preliminary Analysis (Harmonized Guideline 830.1700), Color (Harmonized Guideline 

830.6302), Physical State (Harmonized Guideline 830.6303), Odor (Harmonized Guideline 

830.6304), pH (Harmonized Guideline 830.7000), and Density/Relative Density/Bulk 

Density (Harmonized Guideline 830.7300) – According to 40 CFR § 158.120, which 

describes how to determine data requirements, applicants/registrants are to “[r]eview the 

notes for each requirement to determine its applicability to the specific product proposed for 

registration.” Test note #8 under 40 CFR § 158.2030(e) states the following: “If the TGAI 

cannot be isolated, data are required on the practical equivalent of the TGAI. EP testing may 

also be appropriate.” Based on PHC’s reference to test note #8 under 40 CFR § 158.2030(e) 

and its explanation that the TGAI for harpin proteinαβ is produced by industrial fermentation 

in an integrated production process wherein it is never isolated in stable form, further data 

done with the TGAI are not expected to be required. The EPA believes that previously 

submitted preliminary analysis, color, physical state, odor, pH, and bulk density data on 

harpinαβ protein EPs are sufficient to fulfill these data needs.
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• Partition Coefficient (n-Octanol/Water) (Harmonized Guidelines 830.7550, 830.7560, and 

830.7570) – According to 40 CFR § 158.120, which describes how to determine data 

requirements, applicants/registrants are to “[r]eview the notes for each requirement to 

determine its applicability to the specific product proposed for registration.” Test note #16 

under 40 CFR § 158.2030(e) states the following: “Required for organic chemicals unless 

they dissociate in water or are partially or completely soluble in water.” Based on PHC’s 

reference to test note #16 under 40 CFR § 158.2030(e) and its explanation that harpinαβ 

protein is partially soluble in water, the EPA believes that partition coefficient data are not 

applicable and therefore not expected to be required in this instance. 

• Acute Oral Toxicity (Harmonized Guideline 870.1100), Acute Dermal Toxicity (Harmonized 

Guideline 870.1200), Acute Inhalation Toxicity (Harmonized Guideline 870.1300), Primary 

Eye Irritation (Harmonized Guideline 870.2400), and Primary Dermal Irritation (Harmonized 

Guideline 870.2500) – Based on PHC’s explanation that the TGAI for harpinαβ protein is 

produced by industrial fermentation in an integrated production process wherein it is never 

isolated in stable form, further data done with the TGAI are not expected to be required. The 

EPA believes that previously submitted toxicological data on a harpinαβ protein EP are 

sufficient to fulfill these data needs. 

• 90-day Dermal (Harmonized Guideline 870.3250) – According to 40 CFR § 158.120, which 

describes how to determine data requirements, applicants/registrants are to “[r]eview the 

notes for each requirement to determine its applicability to the specific product proposed for 

registration.” Test note #7 under 40 CFR § 158.2050(e) states the following: “Required to 

support uses involving purposeful application to the human skin or which would result in 

comparable prolonged human exposure to the product (e.g., insect repellents) and if any of 

the following criteria are met: (i) Data from a 90-day oral study are not required. (ii) The 

active ingredient is known or expected to be metabolized differently by the dermal route of 

exposure than by the oral route and the metabolite is of toxicological concern. (iii) The use 

pattern is such that the dermal exposure would be the primary route of exposure.” Based on 

PHC’s reference to test note #7 under 40 CFR § 158.2050(e) and its explanation that 

harpinαβ protein is not purposefully applied to the skin, does not result in comparable 

prolonged human exposure when mixed and applied according to label directions, and does 

not meet any of the three criteria listed directly above, the EPA believes that 90-day dermal 

data are not applicable and therefore not expected to be required in this instance.

• 90-day Inhalation (Harmonized Guideline 870.3465) – According to 40 CFR § 158.120, 

which describes how to determine data requirements, applicants/registrants are to “[r]eview 

the notes for each requirement to determine its applicability to the specific product proposed 

for registration.” Test note #8 under 40 CFR § 158.2050(e) states the following: “Required if 

there is a likelihood of significant levels of repeated inhalation exposure to the pesticide as a 

gas, vapor, or aerosol.” Based on PHC’s reference to test note #8 under 40 CFR §

158.2050(e) and its explanation for harpinαβ protein that EPs are dry wettable granules that 

do not result in significant levels of repeated inhalation exposure when mixed or applied 

according to label directions, the EPA believes that 90-day inhalation data are not applicable 

and therefore not expected to be required in this instance.
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• Fish Acute Toxicity, Freshwater (Harmonized Guideline 850.1075) and Terrestrial Plant 

Toxicity, Seedling Emergence (Harmonized Guideline 850.4100) – Although not explained 

in 40 CFR § 158.2060, other sections in 40 CFR Part 158 (e.g., 40 CFR § 158.243(b)) 

explain that a comma between test substances, such as is found in 40 CFR § 158.2060(d), 

indicates that data may be required on either test substance depending on the conditions set 

forth in the test note(s). Given this description found in 40 CFR § 158.243(b), the EPA 

reevaluated the type of data anticipated as needed to address these two environmental data 

requirements and determined that data could be generated using either the TGAI or EP test 

substance. Because PHC explained that the TGAI for harpinαβ protein, which is structurally, 

chemically, and biologically similar to harpin protein, is produced by industrial fermentation 

in an integrated production process wherein it is never isolated in stable form, further data 

done with the TGAI are not expected to be required. The EPA believes that previously 

submitted fish acute toxicity, freshwater and terrestrial plant toxicity, seedling emergence 

data on a harpin protein EP are sufficient to fulfill these data needs.

(2) Modification of the Test Substance Required for Data Needs from the List Presented in 

Section I(H) (“Summary of Anticipated Data Needs”) of the PWP 

In the PWP, the EPA stated that the test material for the anticipated data needs would be the 

TGAI. In response to this specification, PHC’s comment emphasized that the TGAI for 

harpinαβ protein, which is structurally, chemically, and biologically similar to harpin protein, 

is produced by industrial fermentation in an integrated production process wherein it is never 

isolated in stable form. For some of the anticipated data needs (e.g., UV/visible light 

absorption and vapor pressure), PHC only mentioned this particular point and that it would 

consider conducting a study with the EP or seeking a data waiver if a data call-in were issued 

by the EPA. The EPA expects to require the remaining data needs for both harpin proteins be 

fulfilled using EP test material. These remaining data needs, which now cite to using EP test 

material instead of TGAI test material, are listed in the “Planned Data Needs” section of this 

document.

(3) Clarification of the Data Required for Harpinαβ Protein’s Stability to Normal and Elevated 

Temperatures, Metals and Metal Ions from the List Presented in Section I(H) (“Summary of 

Anticipated Data Needs”) of the PWP

According to 40 CFR § 158.120, which describes how to determine data requirements, 

applicants/registrants are to “[r]eview the notes for each requirement to determine its 

applicability to the specific product proposed for registration.” Test note #17 under 40 CFR § 

158.2050(e) states the following: “Data on the stability to metals and metal ions is required 

only if the active ingredient is expected to come into contact with either material during 

storage.” In its comment, PHC referred to test note #17 under 40 CFR § 158.2030(e) and 

mentioned that harpinαβ protein is not stored in contact with metals or metal ions. Given this 

explanation, the EPA does not expect to require further data on stability to metals and metal 

ions for harpinαβ protein. Stability data is still expected to be required for normal and 

elevated temperatures, however. The EPA clarified this data need for harpinαβ protein by

mentioning the following study title in the “Planned Data Needs” section of this document: 

“Stability to Normal and Elevated Temperatures.” 
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SUMMARY OF COMMENTS AND THE EPA’S RESPONSES

During the 60-day public comment period on the harpin proteins PWP, which opened on 

September 26, 2012, and closed on November 26, 2012, the EPA received two public comments: 

one from the FIFRA Endangered Species Task Force (FESTF) and one from the registrant of the 

harpin protein pesticide products, PHC.

The EPA received FESTF’s comment, which was a letter dated November 30, 2012, via regular 

mail. This letter expresses concern about data compensation issues related to any future 

endangered species assessments. The EPA placed the November 30, 2012 letter in the public 

docket (EPA-HQ-OPP-2012-0641) and will take note of the information provided in this letter 

while conducting this Registration Review.

 

The EPA received PHC’s comment in a November 26, 2012 document that was posted directly 

to www.regulations.gov. PHC’s comment primarily provides explanation as to how certain 

anticipated data needs, which the EPA discussed in the PWP, should not be required or should be 

adjusted (e.g., substance to be tested) according to the test notes in 40 CFR §§ 158.2030, 

158.2050, and 158.2060 and/or are already fulfilled with other data. The EPA considered this 

portion of the comment and responded appropriately by updating (i.e., removing, modifying, or 

clarifying) the anticipated data needs for the Registration Review of the harpin proteins. See the 

“Updates Since The PWP Was Issued” and “Planned Data Needs” sections of this document for 

further details. PHC’s comment also focuses upon the following items: 

(1) PHC plans to respond to any ecological risk assessments that the EPA undertakes.

(2) PHC agrees with the EPA’s preliminary assessment that harpin proteins are likely substances 

that would not produce any effects in humans similar to an effect produced by a naturally 

occurring estrogenic substance.

(3) PHC provides or plans to provide use- and usage-related information on the harpin protein 

products.

(4) PHC states that Mighty Plant with Messenger Gold (EPA Reg. No. 71771-10) was 

incorrectly cited in the PWP as containing the active ingredient, harpin protein. Mighty Plant 

with Messenger Gold actually contains harpinαβ protein as the active ingredient. 

Regarding all of the points mentioned above, the EPA plans to consider the information provided 

during its Registration Review process. The EPA also plans to integrate relevant changes (e.g., 

active ingredient correction for Mighty Plant with Messenger Gold) into its internal tracking 

systems and documents generated during the later stages of Registration Review, such as a

Proposed Registration Review Final Decision.

 

In the PWP, the EPA also solicited comments on the specific topics of environmental justice, 

water quality concerns, and trade irritants, but no comments or information were received on 

those issues. 
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PLANNED DATA NEEDS

The table below summarizes the current planned data needs for the harpin proteins based on the 

EPA’s risk assessment memoranda, other references associated with the harpin proteins, and 

additional information received from PHC during the comment period for the PWP.

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Planned Data Needs for the Registration Review of the Harpin Proteins

Harmonized 

Guideline Number Study Title Test Material

Estimated 

Timeframe

(Months from 

Receipt of DCI)

Harpin Protein

830.6304 Odor

EP 8 months

830.6313 Stability to Normal and Elevated Temperatures, 

Metals and Metal Ions3

830.7220 Boiling Point/Boiling Range

830.7520 Particle Size, Fiber Length, and Diameter 

Distribution

830.7840 Water Solubility

830.7950 Vapor Pressure

850.4150 Terrestrial Plant Toxicity, Vegetative Vigor 12 months

Harpinαβ Protein

830.6313 Stability to Normal and Elevated Temperatures3

EP 8 months

830.7050 UV/Visible Light Absorption

830.7200 Melting Point/Melting Range

830.7520 Particle Size, Fiber Length, and Diameter 

Distribution

830.7840 Water Solubility

830.7950 Vapor Pressure

850.4150 Terrestrial Plant Toxicity, Vegetative Vigor 12 months

EP = end-use pesticide product

RISK ASSESSMENTS FOR REGISTRATION REVIEW

During Registration Review, the EPA will (1) conduct an endangered species assessment for all 

uses of the harpin proteins; (2) revise/update the product chemistry and environmental risk

 2 See Section III (“Bibliography”) of the PWP. Also, see the discussion in the “Updates Since The PWP Was Issued” section of 

this document for a listing of data that were previously identified as anticipated data needs for the harpin proteins but which are 

no longer needed or have been changed/modified by the EPA based on PHC’s comment. 3 PHC provided packaging information on its harpinαβ protein pesticide products, but it did not provide the same information for 

its harpin protein pesticide product. Therefore, the EPA expects to require different types of stability data on the two active 

ingredients discussed in this document: (1) stability to normal and elevated temperatures stability data for harpinαβ protein and 

(2) stability to normal and elevated temperatures, metals and metal ions for harpin protein. As explained in the “Updates Since 

The PWP Was Issued” section of this document, the EPA modified the normal study title for Harmonized Guideline Number 

830.6317 in the harpinαβ protein section of this table; this was done to account for information that is not expected to be required

from PHC. 
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assessments for the harpin proteins; and (3) determine whether, pursuant to Section 408(p)(4) of 

the Federal Food, Drug, and Cosmetic Act, the harpin proteins qualify for exemption from the 

Endocrine Disruptor Screening Program (EDSP). The EPA believes that the harpin proteins are 

likely not endocrine disruptors; as such, the EPA may exempt them from the EDSP (if exempted, 

an order will be issued).

TIMELINE

EPA has created the following estimated timeline for the completion of the Registration Review

for the harpin proteins.

Registration Review for the Harpin Proteins – Projected Registration Review Timeline

Activities Estimated Month/Year

Opening the Docket

Open Docket and 60-day Public Comment Period for the Harpin 

Proteins

September 2012 – Completed

Close Public Comment Period November 2012 – Completed

Case Development

Issue Final Work Plan September 2013 – Completed

Issue Data Call-in September 2014

Data Submission September 2015

Open 30-day Public Comment Period for Draft Risk Assessments March 2017

Close Public Comment Period April 2017

Registration Review Decision

Open 60-day Public Comment Period for Proposed Registration 

Review Final Decision August 2017

Close Public Comment Period October 2017

Registration Review Final Decision and Begin Post-decision Followup

November 2017

Total (years)* ~5

* This schedule is subject to revision should unforeseen issues arise during the Registration Review process. In the 

event an issue arises, such as the failure to acquire an EDSP exemption, an amended FWP will be issued at that 

time. That FWP will identify any newly planned data needs and set forth a new timeline.

NEXT STEPS

As noted previously, the EPA plans to require several product chemistry studies and a nontarget 

organisms and environmental fate study for the harpin proteins likely through a data call-in, 

expected to be issued in September 2014. The EPA believes that the harpin proteins are likely 

not endocrine disruptors; as such, the EPA may exempt them from the EDSP (if exempted, an 

order will be issued). If the harpin proteins are exempted pursuant to FFDCA section 408(p)(4)

by the end of May 2017, EPA anticipates issuing a Proposed Registration Review Final Decision 

for public comment in August 2017.