
	BIOPESTICIDES REGISTRATION ACTION DOCUMENT
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                                       
                      Lysophosphatidylethanolamine (LPE)
                               (PC Code 105120)














	U.S. Environmental Protection Agency
	Office of Pesticide Programs
	Biopesticides and Pollution Prevention Division
                      Lysophosphatidylethanolamine (LPE)
	(PC Code 105120)
                                       
                                       
                             Updated November 2011

                                       
	Table of Contents

I.	Executive Summary
   A.  IDENTITY
   B.  USE/USAGE
   C.  RISK ASSESSMENT
   D.  DATA GAPS / LABELING RESTRICTIONS

II.	Overview
   A.  ACTIVE INGREDIENT OVERVIEW
   B.  USE PROFILE
   C.  DATA REQUIREMENTS
   D.  REGULATORY HISTORY
   E.  CLASSIFICATION
   F.  FOOD CLEARANCES/TOLERANCES
   
III.	Science Assessment
   A.  PHYSICAL/CHEMICAL PROPERTIES ASSESSMENT 
      1.  Product Identity and Mode of Action	
      2.  Physical and Chemical Properties Assessment
   B.  HUMAN HEALTH ASSESSMENT
      1.  Toxicology Assessment
         	a. Acute Toxicology
   		b. Genotoxicity, Immune Response, Mutagenicity, Developmental,                                 
   		Oncogenicity, Subchronic and Chronic Toxicity
          c. Effects on the Endocrine System
      2.  Dose Response Assessment
      3.  Dietary Exposure and Risk Characterization
      4.  Occupational, Residential, School and Day care Exposure and Risk   Characterization
           a. Occupational Exposure and Risk Characterization
           b. Residential, School and Day Care Exposure and Risk Characterization
      5.  Drinking Water Exposure and Risk Characterization
      6.  Acute and Chronic Dietary Risks for Sensitive Subpopulations Particularly Infants and Children
      7.  Aggregate Exposure from Multiple Routes Including Dermal, Oral, and Inhalation
      8.  Cumulative Effects
      9.  Risk Characterization 
   C.  ENVIRONMENTAL ASSESSMENT
      1.  Ecological Effects Hazard Assessment
      
      2.  Environmental Fate and Ground Water Data
      3.  Ecological Exposure and Risk Characterization
   D.  EFFICACY DATA 
   
IV.	Risk Management Decision
   A.  DETERMINATION OF ELIGIBILITY FOR REGISTRATION
   B.  REGULATORY POSITION
      1.  Conditional/Unconditional Registration
      2.  CODEX Harmonization
      3.  Nonfood Re/Registrations
      4.  Risk Mitigation
      5.  Endangered Species Statement
   C.  LABELING RATIONALE
      1.  Human Health Hazard
          a. Worker Protection Standard
          b. Non-Worker Protection Standard
          c. Precautionary Labeling
      2.  Environmental Hazards Labeling
          a. End-Use Product Environmental Hazards Labeling
      3.  Application Rate
   D.  LABELING

V.	Actions Required by Registrants

VI.	Approved Use Sites

VII. References

BIOPESTICIDES REGISTRATION ACTION DOCUMENT TEAM

Office of Pesticide Programs:
Biopesticides and Pollution Prevention Division

Biochemical Pesticides Branch 

Sheryl K. Reilly, Ph.D.					Biologist, Branch Chief
Freshteh Toghrol, Ph.D.					Chemist, Senior Scientist 
Linda Hollis								Microbiologist, Team Leader
Russell S. Jones, Ph.D. 					Biologist, Health Effects/Nontarget Organisms
Carol E. Frazer, Ph.D.						Toxicologist, Regulatory Action Leader
Chris Pfeifer								Regulatory Action Leader

 Executive Summary

A.	IDENTITY

The technical grade active ingredient (TGAI) consists of 94% lysophosphatidylethanolamine (LPE), a natural constituent of all living cell membranes, created when phosphatidylethanolamine is broken down by a phospholipase. Fifty percent of the membrane is phospholipid and the LPE is one to ten percent of the lipid content of the cell, depending on cell type. The end-use product, LPE-94 10% Aqueous Growth Regulator, contains 10% LPE.

B.	USE/USAGE

LPE-94 10% Aqueous Growth Regulator is a pre-harvest spray for use on various fruit and vegetable crops to enhance ripening mechanisms. The product may also be used in a post-harvest bath application to increase the shelf life of fruits, vegetables and cut flowers. The use is classified as a food crop application.
   
C.	RISK ASSESSMENT

No unreasonable adverse effects on humans or the environment are anticipated from aggregate exposure to LPE-94 10% Aqueous Growth Regulator. This includes all anticipated exposures for which there is reliable information.

On October 1, 2009, 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, 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 EPA believes there may be significant public interest.
  
Consistent with the policy of making registration actions more transparent, the proposed pesticide products containing LPE, a new active ingredient, are subject to a 30-day comment period. In addition to containing a new active ingredient, the registration of these products would result in the first outdoor use and first food use for LPE. The docket identification number associated with these registration actions, EPA-HQ-OPP-2011-0899, can be accessed through http://www.regulations.gov/. The following documents are available for comment in the docket: (1) LPE Biopesticides Registration Action Document; (2) a draft label for the manufacturing-use product, LPE E94T (EPA File Symbol 73652-R); and (3) a draft label for the end-use product, Signa-Fresh 10EC (EPA File Symbol 73652-E). While a final decision on registration is contingent upon review and consideration of public comments, EPA presently believes that, based upon the risk assessment and information submitted in support of LPE, it is in the best interest of the public and the environment to issue these registrations. The basis for this preliminary decision can be found in the risk assessment for LPE, which is presented in this document.   

1.	Human Health Risk Assessment

a.	Toxicological Endpoints

No toxicological endpoints were identified. Mammalian toxicology data requirements were submitted and adequately satisfy data requirements to support the registration. Submitted data for the TGAI and the end-use product indicate Toxicity Category IV for acute oral and acute inhalation toxicity. Acute dermal toxicity data is represented by a Toxicity Category III as the limit dose tested, only 2,000 mg/kg, had no toxic effects. The data reported for primary eye irritation studies showed that the test substance was minimally irritating, and is thus a Toxicity Category III when the TGAI is used and Toxicity Category IV when the end use product is used as the test material. Exposure to either the TGAI or the end-use product produced no skin irritation in animal tests; as a result, a Toxicity Category IV is given for dermal irritation. Both the technical grade and end-use product are dermal sensitizers.

b.	Human Exposure


Exposure to the general population would be low but worker exposure is expected. Appropriate protective wear and precautionary label language will mitigate handler risk. 

c.	Risk Assessment

The Biopesticides and Pollution Prevention Division (BPPD) has not identified, and is not aware of, any subchronic, chronic, immune, dietary or nondietary toxicity associated with exposure of children or the general U.S. population to LPE.  Dermal sensitization risk to applicators is mitigated provided that label directions are followed. No toxicological endpoints have been identified, and there is limited exposure of the general public to this product when used according to the label instructions. The Agency has considered LPE in light of relevant safety factors in the under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and determined there are no unreasonable adverse effects from the use of this product.

2.	Ecological Risk Assessment

a.	Ecological Toxicity Endpoints

The data requirements for ecological testing were waived because no toxic endpoints were identified from the submitted mammalian data or literature review.

b.	Ecological Exposure

The active ingredient is a natural constituent found in biological organisms. Sprayed LPE residues are low, and are reduced further by catabolism through the lipid metabolic system found in most organisms.

c.	Risk Assessment

Risk to non-target organisms is expected to be minimal due to the low degree of exposure. Moreover, the active ingredient is a metabolic degradation product of most biological entities. BPPD concludes that when LPE is used according to label directions, it will not result in significant adverse effects to wildlife or other organisms.

   D. DATA GAPS / LABELING RESTRICTIONS


There are no data gaps or special labeling restrictions. 

II.	Overview

 ACTIVE INGREDIENT OVERVIEW

      Common Name:		LPE

      Chemical Name:		Lysophosphatidylethanolamine

      CAS Number:		95046-40-5

      Trade and Other Names:	LPE E94T; LPE-94 10% Aqueous; phospholipid; lyso-PE

      OPP Chemical Code:	105120
  		
B.  USE PROFILE

Proposed uses and application methods for LPE include the following:  

      Type of Pesticide: Plant Growth Regulator
      
      Use Sites: LPE is approved for field use on any type of agricultural commodity, for storage of harvested crops and on cut flowers.
      
      Formulation Types: Liquid 
 	
      Method and Rates of Application: Conventional spray application equipment should be used in the field. The maximum concentration is 1 gallon (0.1 gallon of the active ingredient) per 100 gallons of spray solution (400 ppm LPE).


      When used for post-harvest treatment, raw agricultural commodities are dipped into or sprayed with a solution and air dried prior to storage. 

      Use Practice Limitations: Do not allow workers into treated areas for four hours following application.

      Timing: Application in the field should start at 20 to 30 days before first harvest, depending on crop. Repeat at 7 to 10 day intervals.

   C. DATA REQUIREMENTS

BPPD reviewed data requirements for granting this registration under Section 3(c)(5) of FIFRA. Mammalian toxicology and ecological effects data requirements for LPE were fulfilled. Product analysis data requirements are adequately satisfied. 

   D. REGULATORY HISTORY

On July 18, 1997, EPA received an application from JP BioRegulators, Inc. for an Experimental Use Permit (EUP) covering the use of lysophosphatidylethanolamine to enhance ripening and extend storage time. On September 25, 1998, the Agency granted the EUP (63 FR 51352) to use 72 kilograms/year of the biochemical phospholipid: Lyso-PE (lysophosphatidylethanolamine) on 570 acres of apples, citrus, cranberries, grapes, nectarines, peaches, pears, strawberries, and tomatoes in nine states at a concentration of 100-500 ppm active ingredient. This was to evaluate ripening and storage shelf life. On June 2, 2001, three additional crops, blueberries, cherries and peppers, were added to the exemption from the requirement for a tolerance. The EUP was extended to include 2,475 acres in 10 states for two years at a rate of 12-500 ppm active ingredient (66 FR 39648). 

On November 21, 2000, the Agency received an application for two new products with the new active ingredient, lysophosphatidylethanolamine. A notice of receipt of the application for registration of lysophosphatidylethanolamine was published in the Federal Register on 19 September 2001 (66 FR 48256) with a 30-day comment period. No comments were received following this publication. On January 3, 2001, EPA published a Notice of Filing Petition to Establish an Exemption from the Requirement of a Tolerance (67 FR 323) with a 30-day comment period. No comments were received. On April 11, 2002, an Exemption from the Requirement of a Tolerance was established for the residues of LPE on all food commodities (40 CFR 180.1199); and on June 12, 2002 a Notice of Issuance (67 FR 113) was published in the Federal Register announcing the first registrations containing LPE.

In 2008, the registrant, Nutra-Park, Inc., went out of business. Their registered products containing LPE (EPA Reg. Nos. 70515-2 and 70515-3) were cancelled for non-payment of maintenance fees. Upon dissolution of Nutra-Park, Doosan Corporation, a partner in manufacturing Nutra-Park Inc.'s products, was granted all rights to the original registrations (including rights to data). On September 20, 2010 Doosan Corpooration submitted an application to register anew the former LPE registrations (EPA Reg Nos. 73652-R and 73652-E). No new data evaluations were developed because no new data were required, and the exemption from the requirement of a tolerance was still active. This LPE BRAD with its updated `Regulatory History' is considered to be the current risk assessment for LPE.  As part of the Agency's Public Participation Process, EPA will open a 30-day comment period on November 30, 2011 to provide the public an opportunity to comment on the Agency's draft risk assessment and its intention to re-register this pesticide product.   

   E.    CLASSIFICATION	

In 1995, the Biochemical Classification Committee determined that LPE is a biochemical pesticide, a plant growth regulator, because it is naturally occurring with a non-toxic, indirect mode of action.

   F. FOOD CLEARANCES/TOLERANCES

On June 12, 1998 (63 FR 32134), Phospholipid: Lyso-PE (lysophosphatidylethanolamine) was exempted from tolerance, on a temporary basis, until June 1, 200l. On August 1, 2001 (66 FR 39648), the temporary exemption was extended to June 1, 2003. On January 3, 2001, EPA published a Notice of Filing Petition to Establish an Exemption from the Requirement of a Tolerance (67 FR 323) with a 30-day comment period. No comments were received. A Final Rule establishing an Exemption from the Requirement of a Tolerance (67 FR 70) was published on April 11, 2002. There are no Codex tolerances for lysophosphatidylethanolamine.  

III.  Science Assessment

A.  PHYSICAL/CHEMICAL PROPERTIES ASSESSMENT 

All product chemistry data requirements for the technical grade and the end-use product are met.

1.  Product Identity and Mode of Action

   a. Product Identity:
            
The technical grade active ingredient, LPE E94T consists of 94% LPE and the end-use product, LPE-94 10% Aqueous Growth Regulator, 10% LPE.  
    
   b. Mode of Action:

The precise mode of action is unknown, but LPE has been shown to enhance ripening and extend the shelf life of certain fruits by increasing ethylene production without increasing respiration. It has also been shown to inhibit senescence of ornamental flowers by inhibiting ethylene production and the activity of certain phospholipase enzymes.  


2.	Physical and Chemical Properties Assessment

The physical and chemical characteristics of the TGAI and the end-use product were submitted to support the registration. They are summarized in Table 1. 

Table 1. Product chemistry data requirements:

                               Product Chemistry

                           TGAI/MP (MRID 454357-02)

                              EP (MRID 452736-06)

151B-10 (880.1100): Product identity

LPE E94T, the technical product, consists of 94% lysophosphatidylethanolamine and 6% impurities

LPE-94 10% Aqueous, the end-use product, contains 10% lysophosphatidylethanolamine

151B-11 (880.1620): Formulation process 

An acceptable description of the manufacturing process was submitted.  

The product is formulated via a simple mixing process without any chemical reactions.  

151B-12 (880.1400):  Discussion of  formulation of unintentional impurities 

Acceptable nominal concentrations and certified limits were reported for the manufacturing impurities. 

No impurities of toxicological concern are formed during the formulation process.  

151B-13 (880.1700):  Preliminary analysis

Data obtained from the five-batch analysis demonstrate that the analytical method is precise and accurate.  (MRID 452740-06)

No five-batch preliminary analysis data were submitted, but none are required since the end-use product is not manufactured via an integrated system, and because the TGAI/MP will be registered simultaneously with the EP.

880.1750:  Certified limits

The certified limits for the active ingredient and other impurities are acceptable.  

Acceptable nominal concentrations and certified limits were reported for the other (inert) ingredient in the formulation. 

880.1800:  Enforcement analytical method

The analytical method is HPLC with an evaporative light scattering detector (ELSD).  

An acceptable HPLC/ELSD analytical method was submitted.  

                         Physical/Chemical Properties

                           TGAI/MP (MRID 454357-02)

                              EP (MRID 454361-03)

880.6302:  Color

Off white to yellow

Off white to faint yellow

880.6303:  Physical State

Fine powder (solid)

Suspension

880.6304:  Odor

Faint lipid (vegetable oil) aroma

Faint characteristic odor of lipid (vegetable oil)

880.7200:  Melting Point

Melts over a range of temperatures (MRID 4444534-01)

N/A, not a solid

880.7220:  Boiling Point

N/A, not a liquid

Not required under 40 CFR §158.190

880.7300:  Density, Bulk Density, or Specific Gravity

Approximately 1 g/cc

~1.2 g/cc[3]
(MRID 443399-02)

880.7840:  Solubility

Forms micelles in water

Not reported, but required for TGAI under 40 CFR §158.190

880.7050:  Vapor Pressure

< 2.1 x 10[-4] Pa at 25C (MRID 452740-07)

Not required for EP

880.7370:  Dissociation constant

N/A, does not dissociate

N/A, does not dissociate

880.7550:  Octanol/water partition coefficient

log Pow > 6.2 (MRID 452740-07)

Not required for EP

880.7000:  pH

6-8

6.5-7.0

Stability

Over an extended period of time the unsaturated acyl chains will slowly oxidize (MRID 4444534-01)

Not reported, but required for TGAI under 40 CFR §158.190

880.6314:  Oxidizing or Reduction Action

N/A, does not contain an oxidizing or reducing agent

N/A, does not contain an oxidizing or reducing agent.

880.6315:  Flammability/Flame Extension

N/A, is not a combustible liquid.

N/A, is not a combustible liquid.

880.6316:  Explodability

N/A, is not a potential explosive.

N/A, does not contain explosive material.

880.6317:  Storage Stability

Stable at -20C for 6 months

Interim reports show the end-use formulation is stable for more than 30 days under normal storage conditions.

880.7100:  Viscosity

N/A, is not a liquid.

7.3 cps (at 60 rpm) at 20C
6.2 cps (at 60 rpm) at 40C

880.6319:  Miscibility

N/A, is not an emulsifiable liquid.

N/A, is not to be diluted with petroleum solvents.

880.6320:  Corrosion Characteristics

Non-corrosive

Non-corrosive

880.6321:  Dielectric Breakdown Voltage

N/A, is not a liquid used around electrical equipment

N/A, is not to be used around 
electrical equipment

B.  HUMAN HEALTH ASSESSMENT

Information submitted to support the registration application of the technical grade active ingredient LPE E94T and the end-use product LPE-94 10% Aqueous adequately satisfies the food and non-food use requirements set forth in 40 CFR 158.690 (c) for biochemical pesticides. The overall toxicological risk from human exposure to LPE is negligible.

   1. Toxicology Assessment

Adequate mammalian toxicology data are available and support registration of the product containing the active ingredient LPE.

a.	Acute Toxicity

The registrant submitted acceptable acute toxicity studies. Based on a lack of mortality observed in albino rats, the oral LD50 of both the technical grade LPE E94T and the liquid end-use product LPE-94 10% Aqueous were >5,000 mg/kg, placing them in Toxicity Category IV. Based on a lack of mortality observed in albino rabbits dermally dosed with 2,000 mg/kg of both the technical and the end-use liquid product, the LD50 was >2,000 mg/kg, placing them in Toxicity Category III.  All animals lived and gained weight after inhaling the product for 4 hours. The LC50 for LPE E94T is >2.50, while for the end-use product it is >4.63 mg/L; placing them in Toxicity Category IV.  


With a dose of 0.1 ml of liquid LPE-94 10% Aqueous only, one rabbit demonstrated conjunctivitis at the first reading which cleared by 24 hours. This classifies LPE-94 10% Aqueous as practically non-irritating with a Toxicity Category IV. However, when the TGAI was used as a test material, all rabbits had iritis and conjunctivitis one hour after instillation of LPE; all symptoms cleared by 48-hours post-instillation. Based on the data, LPE Technical was considered a minimal irritant and classified as Toxicity Category III. Dermal application of 0.5 g of liquid product did not cause any dermal irritation symptoms up to 72 hours postdosing, placing it in Toxicity Category IV. Based on the data submitted for dermal sensitization, both the technical and the end-use product are definite contact sensitizers in guinea pigs by the Maximization method. Agency reviews are available in the docket (Refs. 1 and 2)

b.	Genotoxicity, Immune Response, Mutagenicity, Developmental, Oncogenicity, Subchronic and Chronic Toxicity 
      
These studies are required, or conditionally required, for all food use biochemical pesticides, however, the registrant submitted published information to justify waivers for these studies (Refs. 3 and 4), based on its presence in all cellular organisms. LPE is present in all cells in all organisms as part of the cell membrane metabolites, from 1-10% depending on cell type. It is also present in high quantities in food products containing egg yolk and meat as well as in human breast milk (Ref. 5). Because of the ubiquitous nature of LPE and non-toxicity of the acute studies, further studies are waived (Refs. 1 and 6).

      Data Waivers (Ref. 3) were requested for the following studies:

      Studies to detect genotoxicity (OPPTS 870.5300)
      Immune Response (OPPTS 880.3800
      Mammalian mutagenicity test (OPPTS 870.5195
      90-Day feeding (1 species) (OPPTS 870.3100)
      90-Day dermal (1 species) (OPPTS 870.3250)
      90-Day inhalation (1 species) (OPPTS 870.3465)
      Teratogenicity (1 species) (OPPTS 870.3700)
      Chronic exposure (OPPTS 870.4100) (Tier III)
      Oncogencity (OPPTS 870.4200) (Tier III)


Much of these data regarding LPE and related phospholipids were submitted in support of similar waivers for additional acute toxicity testing, subchronic toxicity testing, and chronic toxicity testing in conjunction with a temporary tolerance exemption (see 40 CFR §180.1199)(Ref. 4) for the use of this active ingredient under an Experimental Use Permit (EPA Reg. No. 70515-EUP-1).  The registrant's rationale to support the waivers is that LPE is ubiquitous in nature, and this and related phospholipids are synthesized by microorganisms, plants, and animals. These compounds are also ubiquitous in the human diet.  Also, phospholipids have specific roles in cellular functions and in maintaining the integrity of cell membranes. See also memo from Russell Jones, Ph.D. to Sheila Moats, Ph.D., 8 Oct. 1997 (Ref. 6).  The aforementioned data may be bridged to support the current waiver requests. In addition, there is a long history of consumption by humans of lipids in food and the Agency known of no instance where lipids have been associated with any toxic effects related to the consumption of food. Due to this knowledge of LPE's presence and function in the human system (Ref. 5) and the recent acute testing, EPA believes LPE is unlikely to be carcinogenic or have other long-term toxic effects.

Mammalian toxicity data for LPE are summarized in Table 2. 

Table 2.  Toxicity data requirements

                                 GUIDELINE NO.

                                     STUDY

                                    RESULTS

                                   MRID NO.


152-10, 870.1100

Acute oral toxicity in rats

Both TGAI and EU:
LD50 is > 5000 mg/kg Toxicity  Category  IV

452740-01
452736-01

152-11, 870.1200

Acute dermal toxicity in rabbits

Both TGAI and EU:
LC50 is >2000 mg/Kg Toxicity Category III

452740-02
454361-01

152-12, 870.1300

Acute inhalation toxicity in rats

TGAI LC50 is >2.50 mg/L, EU LC50 is >4.63;
 Both TGAI and EU: Toxicity Category IV

452740-05
452736-04
 

152-13, 870.2400

Primary eye irritation in rabbits

TGAI: Toxicity Category III
EU:  Toxicity Category IV

452740-04
452736-03

152-14, 870.2500

Primary dermal irritation in rabbits

Both TGAI and EU:
Toxicity Category IV

452740-03
452736-02

152-15, 870.2600

Dermal sensitization in guinea pigs

Both TGAI and EU are considered to be contact sensitizers in guinea pigs by the Maximization method.  

454357-01
452736-05

152-17, 870.5300

Studies to detect genotoxicity  

Waived

N/A


152-18, 870.8700

Cellular immune response

Waived

N/A

152-19, 870.5195

Mammalian mutagenicity test

Waived



N/A

152-20, 870.3100

90-day feeding study

Waived

N/A

152-21, 870.3200

90-day dermal study

Waived

N/A

152-22, 870.3250

90-day inhalation study

Waived

N/A

152-23, 870.3700

Developmental toxicity

Waived

N/A

83-1, 870.4100

Chronic exposure

Waived

N/A

83-2, 870.4200

Oncogenicity

Waived

N/A

c.	Effects on the Endocrine Systems


As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) 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." The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA is issuing test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activity, and certain post-application agricultural scenarios.  This list should not be construed as a list of known or likely endocrine disruptors.

LPE is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals.  Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all pesticide active ingredients. 

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/.

While no data are presently being required for LPE, the Agency reserves the right to require new information, should the program require it. Presently, based on the lack of exposure and the negligible toxicity profile of the extract, no adverse effects to the endocrine or immune systems are known or expected. The Agency intends to issue a complete EDSP assessment in the Registration Review process or as might be required earlier.

2.	Dose Response Assessment

No toxicological endpoints are identified.    
   
3.	Aggregate Exposure and Risk Characterization

 Dietary

 Food

In the absence of any toxicological endpoints, risk from the consumption of residues is not expected for the general population including infants and children. Sprayed LPE on food crops is relatively low (examples from 0.06-0.18% over native content [Ref. 7]) and are reduced further by catabolism through the lipid metabolic system found in most organisms (Ref.5). Further, commercial phospholipid products containing LPE are in use already and approved by FDA for food use, animal feed and for dietetics (Ref. 5).

 Drinking Water

Treatment of crops in the fields may include run-off to surface and ground water, but the compound is a natural metabolite further metabolized by microbial organisms (Ref. 5). Significant exposure to LPE in drinking water is not expected. 

 Other Non-occupational Exposure

LPE is a naturally occurring lipid metabolite and exposure is expected to be universal. In addition, FDA has approved LPE-containing substances for use for many other purposes (Ref. 5).
      



4.	Occupational, Residential, School and Day Care Exposure and Risk                      Characterization


Significant additional human exposure to LPE is not expected in residential, school and day care areas. Commercial phospholipid products containing LPE have been approved by FDA for pharmaceuticals and cosmetic uses (Ref. 5).
            
a.	Occupational Exposure	

Agricultural use of LPE is subject to the Worker Protection Standards (WPS), requiring Personal Protective Equipment (PPE), a long-sleeved shirt, long pants, socks, shoes and gloves, plus a 4 hour Restricted Entry Interval (REI). 
            
b.	Residential, School and Day Care Exposure and Risk Characterization

In the absence of any toxicological endpoints, risk from the consumption of residues is not expected for populations in residential, school and day care facilities.  

5.	Acute and Chronic Dietary Risks for Sensitive Subpopulations Particularly Infants and Children
       	
FFDCA section 408 provides that EPA shall apply an additional tenfold margin of exposure (safety) for infants and children in the case of threshold effects to account for pre- and post-natal toxicity and the completeness of the database unless EPA determines that a different margin of exposure (safety) will be safe for infants and children. Margins of exposure (safety) are often referred to as uncertainty (safety) factors. In this instance, based on all the available information, the Agency concludes that LPE is practically non-toxic to mammals, including infants and children. Thus, there are no threshold effects of concern and, as a result the provision requiring an additional margin of safety does not apply. Further, the provisions of consumption patterns, special susceptibility, and cumulative effects do not apply. LPE is found naturally in many foods already consumed by infants and children - human breast milk, eggs, and fruits and vegetables.  No toxic endpoints have been identified for LPE. As a result, EPA has not used a margin of exposure (safety) approach to assess the safety of LPE.
              
6.	Aggregate Exposure from Multiple Routes Including Dermal, Oral, and Inhalation

Aggregate exposure to LPE by field workers and applicators may occur via oral, dermal and inhalation routes. These risks are measured via the acute toxicity studies submitted to support registration.  The oral toxicity studies for LPE showed no toxicity (Toxicity Category IV), the risks anticipated from oral exposure are considered minimal. Because the inhalation toxicity studies for LPE showed no toxicity (Toxicity Category IV), the risks anticipated for this route of exposure are also considered minimal.  


Results of the acute dermal toxicity study indicated no toxicity at the maximum dose tested (2,000 mg) (Toxicity Category III) and no significant dermal irritation (Toxicity Category IV). Based on these results, the anticipated risks from dermal exposure are also considered minimal. Therefore, the risks from aggregate exposure via oral, dermal and inhalation exposure are a compilation of three low risk exposure scenarios and are negligible.  

Dermal sensitization may occur, as the products are sensitizers. However, this risk is mitigated as long as the product is used according to label directions, which requires the use of protective equipment (a long-sleeved shirt and long pants, socks, shoes and gloves) by users and a 4-hour restricted re-entry interval into treated areas. Aggregate exposure to LPE by the consumer would include other sources in addition to the limited amount on the agricultural products. Commercial phospholipid products containing LPE are used in the technical industry, and have been approved by FDA for food use, pharmaceuticals, cosmetics and dietetics and animal feed (Ref. 5).  

7.	Cumulative Effects	

LPE is not toxic and it is not anticipated that there would be cumulative effects from a common mechanism of toxicity.

 Risk Characterization

The Agency has considered LPE in light of the relevant safety factors in FQPA and FIFRA. A determination has been made that no unreasonable adverse effects to the U. S. population in general, and to infants and children in particular, will result from the use of LPE-94 10% Aqueous when label instructions are followed.

C.	ENVIRONMENTAL ASSESSMENT

1.	Ecological Effects Hazard Assessment

The end use product LPE-94 10% Aqueous is intended for agricultural and horticultural use. When applied according to the proposed label directions, no direct exposure of birds or aquatic organisms to LPE-94 10% Aqueous is expected to occur. Moreover, the active ingredient is a natural metabolite of a common biological lipid. Many published studies were supplied to the Agency (Ref. 8), which indicate that the potential environmental/ecological effects LPE-94 10% Aqueous are likely to be negligible. As a result, nontarget organism/ecological effects studies were waived for these particular uses of LPE-94 10% Aqueous. However, standard precautionary label statements under "Environmental Hazards" are presented on the label.






2.	Environmental Fate and Ground Water Data 

The need for environmental fate and groundwater data (Tier II, (40 CFR Section 158.690(d)(2)(vii through xv)) was not triggered because the Tier I studies were waived. Risk is minimal due to the lack of exposure, low toxicity, use pattern, and application methods.

3.	Ecological Exposure and Risk Characterization

Sprayed LPE residues are low (examples are from 0.06-0.18% over native content [Ref. 7]), and are reduced further by catabolism through the lipid metabolic system found in most organisms (Ref. 5). Minimal potential for exposure exists to insects, fish and other nontarget wildlife as a result of LPE-94 10% Aqueous use.

D.	EFFICACY DATA

No efficacy data are required, because no public health uses are involved.

IV.	Risk Management Decision

A.	DETERMINATION OF ELIGIBILITY FOR REGISTRATION

Section 3(c)(5) of FIFRA provides for the registration of new active ingredients if it is determined that (A) its composition is such as to warrant the proposed claims for it; (B) its labeling and other materials required to be submitted comply with the requirements of FIFRA; (c) it will perform its intended function without unreasonable adverse effects on the environment and  (D) when used in accordance with widespread and commonly recognized practice it will not generally cause unreasonable adverse effects on the environment.

To satisfy criteria "A" above, LPE is not expected to cause unreasonable adverse effects when used according to label instructions.  Criteria "B" is satisfied by the current label and by the data presented in this document. It is believed that this new pesticidal active ingredient will not cause any unreasonable adverse effects, will enhance fruit, hasten ripening and increase shelf life, satisfying Criteria "C". Criteria "D" is satisfied by the data submitted and the low exposure to the product when used according to the label's directions.

Therefore, LPE is eligible for registration. The uses are listed in Table 4, Appendix A. 





B.	REGULATORY POSITION


1.	Unconditional Registration

All data requirements have been fulfilled and/or waived by the Agency and the Biopesticides and Pollution Prevention Division supports unconditional registration of products which contain LPE as their sole active ingredient.

Tolerances for food uses and/or exemptions

40 CFR 180.1199 establishes an exemption from the requirement of a tolerance for the residues of LPE in or on all food commodities.    
      
2.	CODEX Harmonization

There are no CODEX values for LPE.

3.	Nonfood Re/Registrations

There are no non-food issues at this time. The non-food uses are listed in Appendix A, Table 4.

4.	Risk Mitigation

There are no significant risk issues. Risks to workers are mitigated by protective clothing requirements and a 4-hour re-entry interval restriction.

5.	Endangered Species Statement

Given LPE's non-toxic mode of action, its negligible potential for exposure to non-target organisms, and its lack of toxicological endpoints, the Agency has determined that the pesticidal use of LPE will have "no effect" on currently listed endangered and threatened species. 

C.	LABELING RATIONALE

It is the Agency's position that the labeling of LPE-94 10% Aqueous and the technical grade active ingredient LPE E94T containing, respectively, 10% and 94% LPE complies with current pesticide labeling requirements.





1.	Human Health Hazard

a.	Worker Protection Standard

This product comes under the provisions of the Worker Protection Standards (WPS).  PPE (long-sleeved shirt and long pants, socks, shoes, and gloves) and REI (4-hour) required.

b.	Non-Worker Protection Standard

There are no non-WPS human health hazard issues.

c.	Precautionary Labeling

The Agency has examined the toxicological data base for LPE E94T and LPE-94 10% Aqueous product and concluded proposed precautionary labeling (i.e. Signal Word, Statement of Practical Treatment and other label statements) adequately mitigates any risks associated with the proposed uses. 

Technical Product Precautionary Labeling:  "Caution"

Hazards to Humans and Domestic Animals:

Harmful if absorbed through skin. Causes moderate eye irritation. Avoid contact with skin, eyes or clothing. Wear protective eyewear. Wash thoroughly with soap and water after handling and before eating, drinking, chewing gum, or using tobacco. Wear long-sleeved shirt and long pants, socks, shoes, and gloves. Remove and wash contaminated clothing before reuse. 

Prolonged or frequently repeated skin contact may cause allergic reactions in some individuals.

First Aid:

If on skin:
-Take off contaminated clothing.
-Rinse skin immediately with plenty of water for 15-20 minutes.
-Call a poison control center or doctor for treatment advice.

If in eyes:
-Hold eye open and rinse slowly and gently with water for 15-20 minutes.
-Remove contact lenses, if present, after the first 5 minutes, then continue rinsing.

-Call a poison control center or doctor for treatment advice.

End-Use Product Precautionary Labeling:  "CAUTION." 

Hazards to Humans and Domestic Animals:

Harmful if absorbed through skin. Avoid contact with skin, eyes or clothing. Wash thoroughly with soap and water after handling and before eating, drinking, chewing gum, or using tobacco.  Remove and wash contaminated clothing before reuse. Wear: long-sleeved shirt and long pants, socks, shoes, and gloves.

Prolonged or frequently repeated skin contact may cause allergic reactions in some individuals.

First Aid:

If on skin:
-Take off contaminated clothing.
-Rinse skin immediately with plenty of water for 15-20 minutes.
-Call a poison control center or doctor for treatment advice.

Have the product container or label with you when calling a poison control center or doctor or going for treatment. 

2.	Environmental Hazards Labeling

End-Use Product Environmental Hazards Labeling: Although LPE is considered to be non-toxic, the environmental hazard statement is nevertheless required on the end-use product's label.

3.	Application Rate

Labeling for the pesticide product containing LPE complies with current pesticide labeling requirements. The Agency has not stipulated a maximum number of applications for the active ingredient.  Pre-harvest applications should use conventional spray or foliar application equipment at a rate of 100-400 ppm depending on crop. Begin applications at 30 to 20 days before harvest and continue at 7 to 10 day intervals. Post-harvest dips or sprays are applied immediately after harvest, before storage, at a rate of 25-100 ppm LPE, while use as a solution for maintenance of cut flowers is at the same rate.

      
D.	LABELING 

      (1)  Product name: LPE E94T

            Active Ingredient:
            Lysophosphatidylethanolamine (LPE). . . . . . . . . . . . . . . . ........94.0%
            Other Ingredients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........6.0%
           ______________________________________________________
            Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100.00%
       (2) Product name: LPE-94 10% Aqueous

            Active Ingredient:
            Lysophosphatidylethanolamine . . . . . . . . . . . . . . . . . . . . . . . .10.0%
            Other Ingredients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .....90.0%
           ______________________________________________________
            Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100.00%
 		
The Signal Word is "CAUTION".  Dermal toxicity and hypersensitivity warning is appropriate.
      
      The product shall contain the following information:
         -	Product Name
         -	Ingredient Statement
         -	Registration Number
         -	Signal Word (CAUTION)	

V.	Actions Required by Registrants

There are no data requirements, label changes or other responses necessary for the reregistration of the end-use product since the product is being registered after November 1984 and is, therefore, not subject to reregistration.  There are also no existing stocks provisions at this time.

VI.	Approved Use Sites

Agency Recognized Use Sites for LPE: Field Crops, Storage Facilities, Horticultural Facilities
      
VII.  References

USEPA; Science Review in Support of Registration of LPE E94T Technical and LPE 94 20% Aqueous Growth Regulator, memo from Jones, Russell S., Ph.D., to Carol E. Frazer, Ph.D., 13 Sep. 2001.

USEPA; Data Evaluation Record: Skin Sensitization (MRID 454357-01), memo from Reilly, Sheryl K., Ph.D., to Carol E. Frazer, Ph.D., 21 Jan. 2002.

JP BioRegulators, Inc.: Waiver Request from Biochemical Pesticides Toxicology Data Requirements, 2000.
      
Palta, Jiwan, Dr. and Hartman, Christina L., Dr.: Phospholipid Safety Data in Support of a Petition Proposing a Temporary Exemption from the Requirement of a Tolerance for Phospholipid for Use in Grapes, Tomatoes, Apples, Pear, Peaches, Nectarines, Citrus, Cranberries and Strawberries, 1997 (MRID 443399-05).

JP BioRegulators, Inc.: A Review on Lysophosphatidylethanolamine and Related Phospholipids, 2000.

USEPA.  An Experimental Use Permit (EUP) and Petition for a Temporary Tolerance Exemption for Phospholipid; memo from Jones, Russell S., Ph.D., to Sheila Moats, Ph.D., 8 October 1997.

Nutra-Park, Inc., 2002:  Effect of LPE Applications; Memo to Carol E. Frazer, Ph.D.

Palta, Jiwan, Dr. and Hartman, Christina L., Dr.: Phospholipid   -  Safety Data for Environmental Effects, 1997 (MRID 443399-06).
             
