Harpin Protein - Conditional Registration of Messenger® 4/01

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Harpin Protein - Conditional Registration of Messenger® 4/01

Harpin Protein - Conditional Registration of Messenger® 4/01

New York State Department of Environmental Conservation
Division of Solid and Hazardous Materials
Bureau of Pesticides Management, 9th Floor
625 Broadway, Albany, New York 12233-7254
Phone: (518) 402-8788 FAX: (518) 402-9024
Website: www.dec.state.ny.us

April 23, 2001

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Mr. Fred Betz
Director of Regulatory Affairs and Environmental Stewardship
EDEN Bioscience Corporation
121 Cathedral Street
Annapolis, MD 21401-2703

Dear Mr. Betz:

Re: Conditional Registration of the New Active Ingredient Harpin Protein Contained in the Pesticide Product Messenger® (EPA Reg. No. 69834-2)

The New York State Department of Environmental Conservation ("The Department") has completed review of your application (received 11/02/00) and supplemental information supplied to date regarding registration of the referenced pesticide product in New York State. Messenger® (EPA Reg. No. 69834-2) contains the new active ingredient harpin protein.

Messenger®, containing 3.0% harpin protein, is labeled as a biochemical pesticide for plant disease management, insect suppression, and plant growth enhancement. Messenger® may be used for greenhouse, shadehouse, nursery, and field production of a broad spectrum of crops. Representative product application rates are listed as 2.25-9.00 oz/acre for vegetable or field crops, 4.50-13.35 oz/acre for vine crops and 6.67-13.35 oz/acre for tree crops. Product is applied as a foliar spray at approximately 14-day intervals. A maximum annual use rate is not specified on the Messenger® labeling.

The subject application and data package were deemed complete for purposes of technical review on December 28, 2000. Pursuant to the review time frame specified in Environmental Conservation Law (ECL) §33-0704.2, a registration decision date of May 27, 2001 was established.

The Department conducted toxicological, ecological effects and environmental fate risk assessments for harpin protein and the Messenger® formulation.

TOXICOLOGICAL RISK ASSESSMENT:
Harpin protein is apparently produced naturally by certain bacteria and other microbes and reportedly stimulates the plant's own pest suppression systems and also enhances plant growth. The protein does not have any direct pesticidal effect on insects or pathogens.

The active ingredient harpin protein is unstable and is stabilized by formulation into the end product Messenger®. Because of the instability, no toxicity studies were conducted on harpin protein alone. Instead, the registrant submitted oral, dermal and inhalation acute toxicity data as well as eye and skin irritation data on the Messenger® product. These data indicate that this pesticide product was not very toxic or irritating by the above noted routes of exposure. No laboratory dermal sensitization study was conducted. However, the registrant indicates that there have been no reported incidents of Messenger®-induced hypersensitivity in individuals exposed to this pesticide product during its research, production or field testing. Based on the low acute toxicity of the Messenger® product, the United States Environmental Protection Agency (USEPA) waived any further toxicity studies and granted an exemption from the requirement of a tolerance for residues of this biochemical pesticide when used in or on all food commodities.

Because harpin protein is commercially produced by E. coli, some strains of which can be pathogenic and produce endotoxin, testing to evaluate the potential for Messenger® use to pose associated risks was conducted. The strain of E. coli used for production of harpn protein (strain K12) is reportedly incapable of surviving long enough in the intestines of various mammals, including humans, to colonize and become pathogenic. In addition, while some endotoxin remains in the Messenger® product, the levels present when mixed with water were determined to not exceed the naturally occurring levels in tap water and creek water sampled for this study. Nevertheless, the USEPA required several studies as a condition of Messenger® registration, including studies on the survival of pathogenic microorganisms in the Messenger® product and on the presence of residual plasmids. These studies are due for submission to USEPA by April 19, 2001.

ECOLOGICAL RISK ASSESSMENT:
The application rate of Messenger® is 2.25 - 9 ounces of product mixed with 25 - 150 gallons of water per acre. For tree and vine crops, as much as 13.35 ounces of Messenger® can be applied per acre. At these maximum label application rates (9 & 13.35 oz/acre) the active ingredient harpin protein is being applied at rates of 7.7 - 11.4 grams per acre. Researchers report that harpin residues on target plants are practically non-detectable almost immediately after application.

Harpin protein degrades within 4-10 days on plant surfaces. Although it is heat stable, it is subject to microbial degradation, photolysis, and degradation by oxidative agents such as chlorinated water. Detailed studies which have been USEPA-reviewed demonstrate that the E. coli K-12 strain is not likely to be accidentally applied along with Messenger®, and that if it were, it would not survive long or reproduce.

Results of acute toxicity testing with Messenger® are listed in the table below. Acute toxicity thresholds for Messenger® typical end-use product (TEP) are so far above expected environmental concentrations (EECs), either on treated vegetation that could be consumed by terrestrial mammals and birds or that could occur in water from direct application, spray drift, or runoff, that further modeling was deemed unnecessary.

Species Test	Test	LD/LC50 (mg/L)	NOEC (mg/L
Rat	Acute oral	>5 g TEP/kg bw
Bobwhite quail	Acute oral single dose	>4,000 mg ai/kg bw	4,000 mg ai/kg bw
Bobwhite quail	Acute dietary	>100,000 mg ai/kg bw	100,000 mg ai/kg bw
Rainbow trout	Acute 96 hour	>3,270 mg TEP/L	378 mg TEP/L
Daphnia magna	Acute 48 hour	1173 mg TEP/L (EC50)	325 mg TEP/L 120 mg ai/L
Selenastrum capricornutum	Acute 96 hour	182 mg TEP/L (EC50, growth)	120 mg TEP/L (growth effects)

When applied as labeled, Messenger® does not appear to pose any risk to exposed non-target organisms. Harpin protein will degrade completely in four to ten days, so it will not accumulate on treated vegetation, even when re-applied every 14 days throughout the growing season.

ENVIRONMENTAL FATE RISK ASSESSMENT:
Due to the low toxicity of Messenger®, USEPA did not require environmental fate data. The only mention made of environmental fate studies was in the notes of a meeting held on February 24, 1999, where it was proposed that hydrolysis and aqueous photolysis studies be performed. However, the Notice of Pesticide Registration did not require these studies to be performed.

In an Ecological Risk Assessment, dated April 5, 2000, USEPA states:

"The active ingredient of MessengerTM is a non-persistent protein which acts as an inducer of the plant's natural defense reaction; and has been shown to degrade rapidly from plant surfaces (within 4 to 10 days). Other naturally-occurring Gram negative bacteria, e.g. Erwinia herbicola and Xanthomonas also produce proteins similar to the harpin from the source strain of Erwinia amylovora.

Harpin is manufactured by fermentation of a strain of E. coli K-12, which produces low levels of endotoxin(s); however under defined conditions, levels of endotoxin in MessengerTM were found to be lower than those found in potable water.

Also, levels of E-coli K-12 in the MessengerTM product will not significantly add to the level of antibiotic resistant bacteria, or to bacterial populations in general, in the environment. The reported studies showed that E. coli K-12 cells which may survive the manufacture and preparation of the end-product, MessengerTM, will likely die over time (about 6-8 days under experimental conditions), rather than perpetuate in the natural environment."

CONCLUSION:
When used as labeled, Messenger® should not cause unreasonable adverse effects to humans or the environment. The Department hereby accepts Messenger® (EPA Reg. No. 69834-2) for registration in New York State subject to the following conditions:

1. EDEN Bioscience Corporation must submit USEPA reviews of the data specified in the letter accompanying the FIFRA section 3(c)(7)(C) conditional registration of Messenger® issued on April 19, 2000;

2. The federal registration of Messenger® expires at midnight, April 30, 2002. USEPA will reevaluate before this date, whether to convert the registration to a non-expiring registration. USEPA's decision will impact the registration status of Messenger® in New York State. In any event, the Department will not renew the registration of Messenger® prior to evaluation of the USEPA reviews specified in condition 1.

Enclosed for your files are the Certificate of Pesticide Registration and New York State stamped-"ACCEPTED" labeling.

Please note that a proposal by EDEN Bioscience Corporation or any other registrant to register a product containing harpin protein, whose labeled uses are likely to increase the potential for significant impact to humans, property or the environment, would constitute a major change in labeled (MCL) use pattern. Such an application must be accompanied by a new application fee and meet the requirements listed in Appendix 1.B. of "New York State Pesticide Product Registration Procedures" (August 1996).

Please contact Frank Hegener, Chief of our Pesticide Product Registration Section, at (518) 457-7446, if you have any questions.

Sincerely,

Maureen P. Serafini
Director
Bureau of Pesticides Management

Enclosures
cc: w/enc. - N. Kim/D. Luttinger, NYS Dept. of Health
R. Zimmerman/R. Mungari, NYS Dept. of Ag. & Markets
G. Good/W. Smith, Cornell PMEP

Disclaimer: Please read the pesticide label prior to use. The information contained at this web site is not a substitute for a pesticide label. Trade names used herein are for convenience only; no endorsement of products is intended, nor is criticism of unnamed products implied. Most of this information is historical in nature and may no longer be applicable.

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