**BIOPESTICIDES REGISTRATION ACTION DOCUMENT**



## L **ysophosphatidylethanolamine (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** Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

2 **Table of Contents I.**  **Executive Summary** A. I DENT ITY B. U SE/USAGE C. R IS K ASSESSMENT D. D ATA GAPS / LABELING RESTRI CTI ONS **II. Overview**  A. A CTIVE INGREDIENT OVERVIEW B. U SE PROFILE C . D ATA REQUIREMENTS D . REGULATORY HISTORY E . C LASS IF IC ATION F . F OOD CLEARANCES/TOL ERANCES **III. Science Assessment**  A. P HYSI CAL/CHEMICALPROPERTIES ASSESSMENT 1. P roduct Identity and Mode of Action 2. P hy sical and Chemical Properties Assessment B. HUMAN HEALTH ASSESSMENT 1. T oxicology

Assessment a. Acute Toxicology b. Genotoxicity , Immune Response, Mutagenicit y, Developmental, O ncogenicit y, Subchronic and Chronic Toxicity c. Effects on the Endocrine Sy stem 2. D ose Response Assessment 3. D ietary

Exposure and Risk Characterization 4. O ccupational, Residential, School and Day c are Exposure and Risk Characterization a. Occupational Exposure and Risk Characterization b. Residential , School and Day Care Exposure and Risk Characterization 5. D rinking Water Exposure and Risk Characterization 6. A cute and Chronic Dietary Risks for Sensitive Subpopulations Particularly Infants and Children 7. A ggregate Exposure from Multiple Routes Including Dermal, Oral, and Inhalation 8. C umulative Effects 9. Risk Characterization C. ENVIRONMENTAL ASSESSMENT 1. E cological Effects Hazard Assessment 2. E nvironmental Fate and Ground Water Data 3. E cological Exposure and Risk Characterization D. E FFICACY DATALysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

3 **IV. Risk Management Decision**  A. D ETERMINATION OF ELIGIBILITY FOR REGI STRATION B. REGULATORY POSI TI ON 1. C onditional/Unconditional Registration 2. C ODEX Harmonization 3. N onfood Re/Registrations 4. Risk Mitigation 5. E ndangered Species Statement C. LABELING RATIONALE 1. Human Health Hazard a. Worker Protectio n Standard b. Non - Worker Protection Standard c. Precautionary Labeling 2. E nvironmental Hazards L abeling a. End - Use Product Environmental Hazards Labeling 3. Application Rate D. LABELING **V. Actions Required by Registrants**  **VI. Approved Use**  **Sites VII. References** Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

4 **BIOPESTICIDES REGISTRATION ACTION DOCUMENT TEAM Office of Pesticide Programs:**  **Biopesticides and Pollution Prevention Division** Biochemical Pesticides Branch Sheryl K. Reill y, 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 Pfeif

er Regulatory Action LeaderLysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

5 **I. Executive Summary**  **A. IDENTITY**  The technical grade active ingredient (TGAI) consists of 94% ly sophosphatidylethanolamine (LPE), a natural constituent of all living cell membranes, created when phosphatidylethanolamine is b roken down b y a phospholipase. Fift y percent of the membrane is phospholipid and the LPE is one to ten percent of the lipid content of the cell, depending on cell t ype. The end - use product, LPE - 94 10% Aqueous Growth Regulator, contains 10% LPE. **B. USE/USAGE**  LPE - 9 4 10% Aqueous Growth Regulator i s a pre - harvest spray for use on various fruit and vegetable crops t o enhance ripening mechanisms. The product may also be used in a post - harvest bath application to increase the shelf l ife of fruit s, 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 Gro wth 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 opportunit y for the public to participate in major registration decisions before they o ccur. Accor ding to this policy , EPA intends to provide a public comment period prior to making a registration decision for, at minimum, the following ty pes 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. Th e docket identification number associated with these registration actions , EPA - HQ - OPP - 2011 - 08 99, can be accessed through http://www.regulations.gov/ . The following documents are available for comment in the docket : (1) LP E Biopesticides Registration Action Doc ument; (2) a draft label for the manufacturing - use product, LP E E94T (EPA File Sy mbol 7 3652 - R) ; and (3 ) a draft label for the end - use product, Signa - Fresh 10EC (EPA File Sy mbol 7 3652 - E ). While a final decision on registration is contingent upon review and consideration of public comme nts, EPA presently b elieves that, based upon the risk assessment and information submitted in support of LP E , 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 LP E , which is presented in this document.Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

6 **1. Human Health Risk Assessmen**  t **a. Toxicological Endpoints**  No toxicologi cal endpoints were identified. Mammalian toxicology data requirements were submitted and adequatel y satisfy data requirement s 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 d ata is represented by

a T oxicity C ategory I II as the limit dose tested, only

2,00 0 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 C ategory 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 i s given for dermal irritation. Both th e 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 Biop esticides and Pollution Prevention Division (BPPD) has not identified , and is not aware of, an y subchronic, chronic, immune, dietary or nondietary toxicity associated with exposure of chil dren o r the general U.S. population to LPE . Dermal sensitization ri sk to ap plicators 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 instructio ns. The Agency has c onsidered LPE in light of relevant safet y 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. Ecologi**  **cal 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** Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

7 The active ingredient is a natural constituent found in biological organisms. Sprayed LPE residues are low, and are reduced further b y 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 o f exposure. Moreover, the active ingredient is a metabolic degradation produc t of most biological entities. BPPD concludes that when LP E is used according to label directions , it will not result in significant adverse effects to wildlife or other organis ms. **D. DATA GAPS / LABELING RESTRICTIONS**  There are no data gaps or special labeling restrictions. **II. Overview**  **A. ACTIVE INGREDIENT OVERVIEW**  **Common Name:** LPE **Chemical Name:** Lys ophosphatidylethanolamine **CAS Number:** 95046 - 40 - 5 **Trade and Other Names:**  LPE E94T; LPE - 94 10% Aqueous; phospholipid; ly so - 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 t ype of agricultural commodity , for storage of harvested crops and on cut flowers. **Formulation Types:** Li quid **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).Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

8 When used for post - harvest treatment, raw agricultural commodities are dipped into or sprayed with a solution and air dried prio r 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 day s before fir st 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 requir ements for LPE were fulfilled. Product anal ys is data requirements are adequatel y sat isfied. **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 l ys ophosphatidylethanolamine to enhance rip ening and extend storage time. On September 25, 1998, the Agency g ranted the EUP (63 FR 51352) to use 72 kilograms/ ye ar of the biochemical phospholipid: Lys o - PE (l ys ophosphatidylethanolamine) 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 requirem ent for a toleranc e. The EUP was extended to include 2,475 acres in 10 states for two ye ars 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 ingredi ent, l ys ophosphat idylethanolamine. A notice of receipt of the applicatio n for registration of l ys ophosphatidylethanolamine was published in the Federal Register on 19 September 2001 (66 FR 48256) with a 30 - day comment period. No comments were received foll owing 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 th e 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 11 3) was published in the Federal Register announcing the first registrations containing LPE. In 2008, the registrant , Nutra - Park, In c. , went out of busi ness. T heir registered products containing LPE (EPA Reg. Nos. 70515 - 2 and 70515 - 3) were cancelled for non - pay ment of maintenance fees. Upon dissolution of Nutra - Park , Doosan Corporation , a partner in manufacturing Nutra - ParkLysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

9 In c.’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. 736 52 - 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. T his LPE BRAD with its updated ‘Regulatory History ’ is considered to be the current risk as sessment for LPE . As part of the Agency ’s Public Participation Process, E PA 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 CLEARANCE**  **S/TOLERANCES** On June 12, 1998 (63 FR 32134), Phospholipid: Lyso - PE (l ys ophosphatidylethanolamine) was exempted from tolerance, on a tempor ary 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 R ul e establishing an Exemption from the Requirement of a T olerance (67 FR 70) was published on April 11, 2002 . There are no Codex tolerances for ly sophosphatidylethanolamine. **III .**  **Science Assessment**  **A. P**  **HYSICAL/CHEMICAL PROPERTIES ASSESSMENT** All product chemistry

data requirements for the technica l grade and the end - use product are met. **1. P**  **roduct 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 Ac**  **tion:** 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 eth yl ene production without increasing respiration. ItLysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

10 has also been shown to inhibit senescence of ornamenta l flowers by i nhibiting ethylene production and the activit y of certain phospholipase enzymes. **2. Physical a**  **nd Chemical Properties Assessment**  The ph ys ical and chemical characteristics of the TGAI and the end - use product were submitte d 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% ly sophosphatidylethanolamine and 6% impurities LPE - 94 10% Aqueous, the end - use product, contains 10% ly sophosphatidylethanolamine 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): D iscussion of f ormulation of unintentional im purities Acceptable nominal concentrations and certified limits we re reported for the manufacturing impurities. No impurities of toxicological concern are formed during the formulation process. 151B - 13 (880.1700): P reliminary 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, an d because the TGAI/MP will be registered simultaneously with the EP. 880.1750: C ertified limits The certified limits for the active ingredient and other impurities are acceptable. Acceptable nominal concentrations and certified limits we re reported for the other (inert) ingredient in the formulation. 880.1800: E nforcement 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: C olor Off white to yellow Off white to faint yellow 880.6303: P hysical State Fine powder (solid) Suspension 880.6304: O dor Faint lipid (vegetable oil) aroma Faint characteristic odor of lipid (vegetable oil)Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

11 **Product Chemistry TGAI/MP (MRID 454357**  **- 02)**  **EP (MRID 452736 -**  **06)** 880.7200: M elting Point Melts over a range of temperatures (MRID 4444534 - 01) N/A, not a solid 880.7220: B oiling Point N/A, not a liquid Not required under 40 CFR §158.190 880.7300: D ensity, Bulk Density, or Specific Gravity Approximately 1 g/cc ~1.2 g/cc 3 (MRID 443399 - 02) 880.7840: S olubility Form s micelles in water Not reported, but required for TGAI under 40 CFR §158.190 880.7050: V apor Pressure < 2.1 x 10 - 4 Pa at 25  C (MRID 452740 - 07) Not required for EP 880.7370: D issociation constant N/A, does not dissociate N/A, does not dissociate 880.7550: O ctanol/water partition coefficient log P ow > 6.2 (MRID 452740 - 07) Not required for EP 880.7000: p H 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: O xidizing 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: F lammability/Flame Extension N/A, is not a combustible liquid. N/A, is not a combustible liquid. 880.6316: E xplodability N/A, is not a potential explosive. N/A, does not contain explosive material. 880.6317: S torage Stability Stable at - 20  C for 6 months Interim reports show the end - use formulation is stable for more than 30 days under normal storage conditions. 880.7100: V iscosity N/A, is not a liquid. 7.3 cps (at 60 rpm) at 20  C 6.2 cps (at 60 rpm) at 40  C 880.6319: M iscibility N/A, is not an emulsifiable liquid. N/A, is not to be diluted with petroleum solvents. 880.6320: C orrosion Characteristics Non - corrosive Non - corrosive 880.6321: D ielectric Breakdown N/A, is not a liquid used around N/A, is not to be used aroundLysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

12 **Product Chemistry TGAI/MP (MRID 454357**  **- 02)**  **EP (MRID 452736 -**  **06)** Voltage electrical equipment electrical equipment **B. HUMAN HEALTH ASSESSMENT**  In formation 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 s tudies. Based on a lack of mortality o bserved in albino rats, the oral LD 50 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 C ategory IV. Based on a lack of mortality

observed in alb ino rabbits dermally dosed with 2,000 mg/kg of both the technical and the end - use liquid product, the LD 50 was >2,000 mg/kg, placing them in Toxicity Category I II. All animals lived and gained weight after inh aling the product for 4 hours. The LC 50 for LP E 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 read ing which cleared b y 24 hours. This classifies LPE - 94 10% Aqueous as practicall y non - irritatin g 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 sy mptoms cleared b y 48 - hours post - instillation. Based on the data, LPE Technical was considered a minimal irritant and classi fied as Toxicity

C ategory III. Dermal application of 0.5 g of liquid product did not cause any dermal irritation s ymptoms up to 72 hours postdosing, pl aci ng 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 pi gs b y 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 publ ished information to justify waivers for these studies (Refs. 3 and 4), based on its presence in al l cellular organisms. LP E is present in all cells in all organismsLysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

13 as part of the cell membrane metabolites, from 1 - 10% depending on cell type. Itis also pr esent in high quantities in food products containing egg yo lk 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) Oncogencit y (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 (se e 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 sy nthesized by

microo rganisms, plants, and animals. These compounds are also ubiquitous in the human diet. Also, phospholipids have specific roles in cellular functions and in maintaining th e integrit y of cell membranes. See also memo from Russell Jones, Ph .D. to Sheila Moats, Ph.D., 8 Oct. 1997 (Ref. 6). T he 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 lipi ds have been associated with an y toxic effects relat ed to the consumption of food. Due to this knowledge of LPE’s presence and function in the human sy stem (Ref. 5) and the recent acute testing, EPA believes LP E is unlikely t o be carcinogenic or have other long - term toxic effects. Mammalian toxicity

data for LPE are summarized in Table 2. Table 2. T oxicity

data requirements **GUIDELINE NO. STUDY**  **RESULTS MRID NO.**  152 - 10, 870.1100 Ac ute oral toxicity in rats Both TGAI and EU: LD 50 is > 5000 mg/kg Toxicity Category I V 452740 - 01 452736 - 01Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

14 **GUIDELINE NO. STUDY**  **RESULTS MRID NO.**  152 - 11, 870.1200 Ac ute dermal toxicity in

rabbits Both TGAI and EU: LC 50 is >2000 mg/Kg Toxicity Category III 452740 - 02 454361 - 01 152 - 12, 870.1300 Ac ute inhalation toxicity

in rats TGAI LC 50 is >2.50 mg/L, EU LC 50 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: T oxicity 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/ALysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

15 **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

h ave an effect in humans or wildlife similar to an eff ect produced by a “naturall y occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery

of 11 screening ass ay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or th yr oid (E, A, or T) hormonal s ys tems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal sy s tems 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 b y 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 ingre dients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathway s such as food and water, residential activity , and certain post - application agricultural scenarios. T his list should not be construed as a lis t 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. Accordingl y, EPA anticipat es 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 LP E , 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

p rofile of the extract, no adverse effects to the endocrine or immune sy stems are known or expected. The Agency intends to issue a complete EDSP assessment in the Registration Review process or as might be required e arlier . **2. Dose Response Assessment**  No toxicological endpoints are identified. **3. Aggregate Exposure and Risk Characterization**  **a. Dietary** Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

16 **ii. Food**  In the absence of an y toxicological endpoints, risk from the consumption of residues is not expected for the general population i ncluding infants and children. Sprayed LPE on food crops is relativel y l ow (examples from 0.06 - 0.18% over native content [Ref. 7]) and are reduced further by catabolism through the lipid metabolic sy stem fo und in most organisms (Ref.5). Further, commercial phospholipid products containing LPE are in use already and approved b y FDA for food use, animal feed and for dietetics (Ref. 5). **iii. 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. **b. Other Non**  **- occupational Exposure**  LPE is a naturally occurring lipid metabolite and exposure is expected to be universal. Inaddition, FDA has approved LP E - containing substances for use for man y other purposes (Ref. 5).

**4. Occupational, Residential, School and Day Care Exposure a**  **nd Risk Characterization**  Significant additional human exposure to LPE is not expected in residenti al, 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 a**  **nd Day Care Exposure and Risk Characterization** In the absence of an y toxicological endpoints, risk from the consumption of residues is not expected for populations in residential, school and day care facilities .Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

17 **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 (safet y) for infants and children in the case of threshold effects to account for pre - and post - natal tox icity and the completeness of the database unless EPA determines that a different margin of exposure (safet y) will be safe for infants and children. Margins of exposure (safet y) are often referred to as uncertainty (safet y) factors. In this instance, based on all the available information, the Agency

concludes that LPE is practicall y non - toxic to mammals, i ncluding infants and children. Thus, there are no threshold effects of concern and, as a result the provision requiring an additional margin of safety do es not appl y. Further, the provisions of consumption patterns, special susceptibility , and cumulative effects do not apply . LPE is found naturally in many foods already co nsumed b y infants and children - human breast milk, eggs, and fruits and vegetables . N o toxic endpoints have been identified for LPE . As a result, EPA has not used a margin of exposure (safet y) approach to assess the safet y 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, de rmal and inhalation routes. These risks are measured via the acute toxicity studies submitted to support registration. T he oral toxicity studies for LPE showed no toxicity (Toxicity Category IV), the risks anticipated from oral exposure are considered mi nimal. 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. Resul ts of the acute dermal toxicity s tudy i ndicated 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 exposur e are al so 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 i nto 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 appro ved 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 o f toxicity .Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

18 **8. Risk Characterization**  The Agency

has considered LPE in light of the relevant saf ety 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 LP E - 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 likel y t o be negligible . As a result, nontarget organism/ecological effects studies were waived for these particul ar us es 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 wer e 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 b y catabolism through the lipid metabolic system found in most organisms (Ref. 5). Minimal potential for exposure exists to insects, fish an d 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** Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

19 **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 F IFRA; (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 generall y cause unreasonable adverse effects on the enviro nment. To satisfy criteria “A” above, LPE is not expected to cause unreasonable adverse effects when used according to label instructions. C riteria “B” is satisfied by the current label and by

the data presented in this document. Itis 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 whe n 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 b y the Agency and the Biopesticides and Pollution Prevention Division supports unconditional registration of products which contain LPE as their sole active ingredient. **2. Tolerances for food uses and/o**  **r 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** Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

20 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 b y protective clothing requirements and a 4 - hour re - entry interval restriction. **5. Endangered Species Statement**  Given LP E’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 currentl y listed endangered and threatened species. **C. LABELING RATIONALE**  It is the Agency ’s position that the labeling of LP E - 94 10% Aqueous and the technical grade active ingredient LPE E94T containing, respectivel y, 10% and 94% LPE complies with cur rent 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) adequatel y mitigates an y risks ass ociated with the proposed uses. **Technical P roduct Precautionary Labeling:**  “Caution”Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

21 **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 frequ ently

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 P roduct Precautionary Labeling:**  “CAUTION.” **Hazards to Humans and Domestic Animals:** Harmful if absorbed through skin. Avoid contact with skin, ey es or clothing. Wash thoroughl y with soap and water after handling and before eating, drinking, chew ing gum, or using tobacco. Remove and wash contaminate d clothing before reuse. Wear: l ong - 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 o r doctor or going for treatment. **2. Environmental Hazards Labeling** Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

22 **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**  L abeling for the pesticide product containing LPE complies with current pe sticide labeling requirements. The Agency has not stipulated a maximum number of applications for the active ingredient. P re - 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 cont inue at 7 to 10 day intervals. Post - harvest dips or spray s 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) P roduct name: **LP E E94T**  Active Ingredient: Ly sophosphatidylethanolamine (LPE). . . . . . . . . . . . . . . . ........94.0% Other Ingredients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........6.0%

______________________________________________________ Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100.00% (2) Product name: **LP E**  **- 94 10% Aqueous**  Active Ingredient: Ly sophosphatidylethanolamine . . . . . . . . . . . . . . . . . . . . . . . .10.0% Other Ingredients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... .90.0%

______________________________________________________ Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100.00% The Signal W ord is "CAUTION". D ermal toxicity and h yp ersensitivity

warning is appropriate. The product shall contain the following information:

- Product Name

- In gredient Statement

- Registration Number

- Signal Word (CAUTION) **V. Actions Required by Registrants** Lysophosphatidylethanolamine (LP E)

Biopesticides Registration Action Document

23 There are no data requirements, label changes or other responses necessary f or the reregistration of the end - use product since the product is being registered after November 1984 and is, therefore, not subject to reregistration. T here 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. R**  **eferences** 1. USEPA; Science Review in Support of Registration of LPE E94T Technical and LPE 94 20% Aqueous Growth Regulator, memo from Jones, Russell S., P h.D., to Carol E. Frazer, Ph.D., 13 Sep. 2001. 2. 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. 3. JP BioRegulators, Inc.: Waiver Request from Biochemical Pesticides Toxicology Data Requirements, 2000. 4. Palta, Jiwan, Dr. and Hartman, Christina L ., Dr.: Phospholipid Safety Data in Support of a Petition Proposing a Temporary E xemption 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). 5. JP BioRegulators, Inc.: A Review on Ly sophosphatidylethanolamine and Related Phospholipids, 2000. 6. 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. 7. Nutra - Park, Inc., 2002: E ffect of LPE Applications; Memo to Carol E. Frazer, Ph.D. 8. Palta, Jiwan , Dr. and Hartman, Christina L ., Dr.: Phospholipid

– Safety Data for Environmental Effects, 1997 (MRID 443399 - 06).