2 I NTRODUCTION

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

R egistration R eview of the harpin proteins

. This FWP follows the Preliminary Work Plan (PWP) posted in the R egistration R evie w docket for the harpin proteins (EPA

- HQ

- OPP

- 2012

- 0641 ).

Thes e 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 plan t growth, and suppress insect, mite and nematode pests.

The EPA is implementing the R egistration R eview program pursuant to Section 3(g) of the Federal Insecticide, Fungici de, 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

R egistration R eview program is inte nded 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 R egistration R eview begins when the initial docket is opened for each case. Informatio n on this program is provided on the EPA’s website

. 1

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

substantive comments recei ved , 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 response s to th o se comments

. This section is followed by the planned data needs, risk assessments expected to be conducted , and the projected

R egistration R eview timeline for the harpin protein s

. Lastly, there is a discussion of next steps.

UPDATES SINCE THE PWP WAS ISSUED

In the PWP, the EPA indicated that th ere 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 s pecified 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 P WP

(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

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

1 See http://www.epa.gov/oppsrrd1/registration_review/

.3 the TGAI. EP testing may also be appropriate.” B ased on PHC’s refer ence to test note #8

under 40 CFR § 158.2030(e) and its explanation that the TGAI (technical grade of the active ingredient) for harpin αβ 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 dat a 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 product s (EP s ) are sufficient to fulfill this data need.

• Partition Coefficient ( n

- Octanol/Water) (Harmon ized 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 pro duct 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

refere nce to test note #16 unde r 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 therefor e 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 (Harmo nized 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 requ ired. 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)

– Ac cording 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 o f the following criteria are met: (i) Data from a 90

- day oral study ar e 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 toxicologica l concern. (iii) The use pattern is such that the dermal exposure would be the primary route of exposure.” Based on

PHC’s refer ence 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.4 • 90

- day Inhalation (Harmonized Guideline 870.3465)

– According to 40 CFR § 158.120,

which d escribes 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 registr ation.” Test note #8 under 40 CFR § 158.2050(e) states the following: “Required if

there is a li kelihood of significant levels of repeated inhalation exposure to the pesticide as a gas, vapor, or aerosol.” Based on PHC’s refer ence to test note #8 under 40 CFR § 158.2050(e) and its explanation for harpinαβ protein, which is structurally, chemically, a nd 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, o ther sections in 40 CFR Part 158 (e.g., 40 CFR § 158.243 (b) ) explain that a comma between test subst ances, such as is found in 40 CFR § 158.2060(d),

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

fo rth 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 is olated 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 it s applicability to the specific product proposed for registr ation.” 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 refer ence 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 , furth er da ta
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 harpin αβ protein EPs are sufficient to fulfill these data need s

.5 • Partition Coefficient (n

- Octanol/Water) (Harmonized Guidelines 830.7550, 830.7560, and 830.7570)

– According to 40 C F R § 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 C FR § 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 insta nce.

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

Guidelin e 870.1200), Acute Inhalation Toxicity (Harmonized Guideline 870.1300), Primary Eye Irritation (Harmonized Guideline 870.2400), and Primary Dermal Irritat ion (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

describe s 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 registr ation.” Test note #7 under 40 CFR § 158.2050(e) states the following: “R equired 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 w ould be the primary route of exposure.” Based on

PHC’s refer ence 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 registr ation.” 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 un der 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.6 • Fish Acute Toxicity, Freshwater (Harmonized Guideline 850.1075) and Terrestrial Plant Toxicity, Seedling Emergence (Harmonized Guideline 850.4100)

– Although no t explained

in 40 CFR § 1 58.2060, other sections in 40 CFR Part 158 (e.g., 40 CFR § 158.243 (b) ) explain that a comma between test substance s, such as is found in 40 CFR § 158.2060(d),

indicate s 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 environmenta l 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 ter restrial 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 biologica lly 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 m entioned 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 . T he EPA expects to require the remaining data needs for both harpin proteins be

fulfilled using EP t est material

. The se 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 Norma l and Elevated Temperatures, Metals and Metal Ions from the List Presented i n 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 t he active ingredient is expected to come into contact with either material during storage.” In its comment, PHC refer red 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. Giv en 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.”7 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 p ublic comments : one from the FIFRA Endangered Species Task Force (FESTF) and one from the registrant of the harpin protein pesticide prod ucts, 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 R eview.

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 th e EPA discussed in the PWP, should not be required or should be adjusted (e.g., substance to be tes ted) according to the test notes in 40 CFR §§ 158.2030,

15 8.2050, 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 ) t he anticipated data need s for the Registration Review of the har pin proteins

. See the “Upda tes Since T he 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 natura lly 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 containin g 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 it s R egistration R eview 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 Rev iew , 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.8 PLANNED DATA NEEDS

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

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

additional information recei ved from PHC during the comment period for the PWP

. 2

Planned D ata 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 Ions 3

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 Temperatures 3

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 R egistration R eview, the EPA will (1) conduct an endangered species assessment for all

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

2 See Section III (“Bibliography”) of the PWP. Also, see the discussion in the “Upd ates 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 o n 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 th e “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 harpin α β protein section of this table; this was done to account for information that is not expected to be required

from PHC

.9 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 R egistration R eview 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 201 2

– Completed

Close Public Comment Period November 2012

– Completed Case Development

Issue Final Work Plan September 2013

– Completed

Issue D ata Call

- in September 201 4

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 D ecision August 2017

Close Public C omment P eriod October 2017 Registration Review Final D ecision and Begin P ost

- d ecision F ollow

up November 2017

Total ( years ) * ~5
* This schedule is subject to revision should unforeseen issues arise during the Registration R eview 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 F WP 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 s tudy 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 b e 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

.