BIOPESTICIDES REGISTRATION ACTION DOCUMENT



## Cold Pressed Neem Oil
PC Code 025006

U.S. Environmental Protection Agency Office of Pesticide Programs Biopesticides and Pollution Prevention Div ision

( Last updated May 7 , 2012 )

This document is for informational purposes only and is representative of the Agency’s justification in registering products containing this active ingredient. This is not a legal document.Cold Pressed Neem Oil Page 2 of 21 Biopesti cides Registration Action Document

TABLE OF CONTENTS

I. EXECUTIVE SUMMARY

................................ ................................ ................................ .. 5

II. ACTIVE INGREDIENT OV ERVIEW

................................ ................................ ............... 6

III. REGULATORY BACKGROU ND

................................ ................................ ...................... 6

A. Classification

................................ ................................ ................................ ................................ ..................... 7

B. Food Clearances/Tolerances

................................ ................................ ................................ ............................ 7

IV. RIS K ASSESSMENT

................................ ................................ ................................ ........... 7

A. Active Ingredient Characterization

................................ ................................ ................................ ................. 7

B. Human Health Assessment

................................ ................................ ................................ ............................... 8

1. Toxicology

................................ ................................ ................................ ................................ .......................... 8

a. Acute Toxicity

................................ ................................ ................................ ................................ ................. 8

b. Sub

- chronic Toxicity

................................ ................................ ................................ ................................ ....... 8

c. Developmental Toxicity and Mutagenicity

................................ ................................ ................................ ...... 9

d. Effects on the Endocrine System

................................ ................................ ................................ ..................... 9

2. Dose Response Assessment

................................ ................................ ................................ ............................. 10

3. Food Quality Protection Act (FQPA) Consideration

................................ ................................ ................... 10

a. Dietary Exposure and Risk Characterization

................................ ................................ ................................ . 10

b. Drinking Water Exposure and Risk Characterization

................................ ................................ .................... 10

c. Acute and Chronic Dietary Risks for Sensitive Subpopulations Particularly Infants and Chil dren

............... 11

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

.......................... 11

a. Occupational Exposure and Ris k Characterization

................................ ................................ ........................ 11

b. Residential, School and Day Care Exposure and Risk Characterization

................................ ....................... 11

5. Cumulative Effects

................................ ................................ ................................ ................................ .......... 12

6. Risk Characterization

................................ ................................ ................................ ................................ ..... 12

C. Environmental Assessment

................................ ................................ ................................ ............................. 12

1. Ecologica l Hazards

................................ ................................ ................................ ................................ ......... 12

2. Environmental Fate and Ground Water Data

................................ ................................ .............................. 12

3. Ecological Exposure and Risk Characterization

................................ ................................ .......................... 13

4. Endangered Species Assessment

................................ ................................ ................................ .................... 13

D. Product Performance (Efficacy)

................................ ................................ ................................ .................... 13

V. RISK MANAGEMENT DECISION

................................ ................................ ................. 14

A. Determination of Eligibility for Registration

................................ ................................ ................................ 14Cold Pressed Neem Oil Page 3 of 21 Biopesti cides Registration Action Document

B. Regulatory Decision

................................ ................................ ................................ ................................ ........ 14

C. Environmental Justice

................................ ................................ ................................ ................................ .... 15

VI. ACTIONS REQUIRED BY REGISTRANTS

................................ ................................ . 15

A. R eporting of Adverse Effects

................................ ................................ ................................ ......................... 15

B. Reporting of Hypersensitivity Incidents

................................ ................................ ................................ ....... 15

VII. APPENDIX A

................................ ................................ ................................ ...................... 16

VIII. APPENDIX B

................................ ................................ ................................ ..................... 19

IX. APPENDIX C

................................ ................................ ................................ ...................... 20Cold Pressed Neem Oil Page 4 of 21 Biopesti cides Registration Action Document

BIOPESTICIDES REGISTRATION ACTION DOCUMENT TEAM

Office of Pesticide Programs

Biopesticides and Pollution Prevention Division

Bio chemical Pesticides Branch:

Driss Benmhend Regulatory Action Leader

Gina Burnett , M.S. Regulatory Action Leader

Linda Hollis , M.S. Branch Chief

Jacob Moore Chemist Manying Xue , M.S Chemist Clara Fuentes, Ph .D. Entemologist

Russell Jones , Ph.D. Senior BiologistCold Pressed Neem Oil Page 5 of 21 Biopesti cides Registration Action Document

I. EXECUTIVE SUMMARY

The active ingredien t Cold Pressed Neem Oil is pressed directly from seeds of the Neem tree ( Azadirachta indica ), which is a tropical evergreen tree native to India and a lso found in other

Southeast Asian and African countries

. Cold Pressed Neem Oil has a brown color, a bitter taste and a garlic/sulfur smell. Cold pressed Neem Oil h as demonstrated properties as an insect repell e nt

, insect growth regulator , and insecticide

.

In October 2009, the Biopesticides and Pollution Prevention Division (BPPD) reviewed data require d to support the registration of this biochemical active ingredient, under Section 3(c)(5) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA )

, for use on outdoor and greenhouse agricultural food and ornamental crops

. At that time, p roduct chemistry data requirements were satisfied by acceptable guideline studies. Adequate mammalian toxicology

data /information was submitted to support registrat ion of Cold Pressed Neem Oil for outdoor uses on crops and ornamentals

. Specifically, a cceptable acute toxicity guideline studies were submitted, and data waivers were granted by the Agency for the remaining toxicity requirements

based on the lack of toxic ity of the active ingredient

. E cological effects data requirements for

Cold Pressed Neem Oil were fulfilled by acceptable guideline studies and additional data/information from the scientific literature sufficient to support the remaining Tier I and Tier

I I requirements.

In March 2012, BPPD review ed data required to support the addition of a “ new use ” to the Cold Pressed Neem Oil registration. The “ new use ” is indoor use for the control of bed bugs. In support of this use, additional mammalian toxicology d ata/information was submitted to fulfill the biochemical pesticide data requirements of 90

- day dermal toxicity and 90

- day inhalation toxicity

. Product performance (efficacy data) was submitted to support label claims.

Based on the data available to the A gency, it has been determined that no unreasonable adverse effects to the U.S. population and the environment will result from the use of the active ingredient when label instructions are followed and good agricultural practices are employed. Laboratory s tudies indicate that the active ingredient is not toxic following oral, inhalation or dermal exposure

. Cold Pressed Neem Oil and neem extracts are widely used in cosmetics (soap, hair products, hand creams, etc.), traditional folk medicine (acne, fevers, r heumatism, diuretics, inflammations, etc.), as an insect repellent

, insecticide, nematicide

, fungicide, and as a fertilizer. There are no reports of adverse effects following human exposure to this biochemical

. Moreover,

t he pesticidal usage of Cold Press ed Neem Oil will not have any harmful environmental effects.

Studies indicate that Cold Pressed Neem Oil will not cause adverse effects to mammals, birds, fish and aquatic invertebrates, other non

- target insects, or plants.

Due to the negligible risk co ncerns when used as an insect repellent , insect growth regulator, and

insecticide

, Cold Pressed Neem Oil meets the criteria as specified in §3(c)(5) of the Federal Insecticide, Fungicide and Rodenti cide Act (FIFRA) , as amended, and is thus eligible for

unc onditional registration. It was determined that the data/information submitted adequately satisfy applicable data requirements at 40 C

. F

. R

. Subpart U §158.2000

.Cold Pressed Neem Oil Page 6 of 21 Biopesti cides Registration Action Document

II. ACTIVE INGREDIENT OVERVIEW

Common Name: Neem Oil

Chemical Names: Cold Pressed Neem Oi l

Trade & Other Names : Cold Pressed Neem Oil

CAS Registry Number: 8002

- 65

- 1

OPP Chemical Code: 0 25006

Type of Pesticide: Insect repellent, insect growth regulator ( anti

- feedant ), insecticide

.

Application rates and methods vary depending on the pr oduct. For specific information regarding the product (s) refer to Appendix B

.

III. REGULATORY BACKGROUND

On August 2, 2007 , Plasma Power of India, submitted an application for the registration of the end use product (EP) Plasma NeemTM Oil (azadirachtin 3000 p pm) Insecticide (84185

- U), and Plasma NeemTM Oil Manufacturing Use Product (84185

- G). Both products contain 100% Cold

Pressed Neem Oil

. A notice of receipt of the application for registration of Cold Pressed Neem Oil as a new active ingredient was publishe d in the Federal Register on October 24, 2007 (7 2 FR

60365 )

, with a 30

- day comment period. No comments were received following this publication.

Consistent with the Agency’s new policy for making pesticide registration a ctions more transparent, EPA provid ed a 30

- day public comment period on the decision to regist e r Cold

Pressed Neem Oil

. No comments were received during the 30 day public comment period

On September 19, 2011, Terramera, Inc., submitted an application for the registration of end

- use product s(EPs) TER

- R T U1 (88760

- R), containing 5.5% Cold Pressed Neem Oil, and TER

- CX1 (88760

- E), containing 22.0% Cold Pressed Neem Oil. These EPs indicate a “ new use ” for this active ingredient (indoor use for the control of bed bugs ). A notice of receipt of the application for registration of Cold Pressed Neem Oil for indoor use was published in the Federal Register on November 9, 2011 ( 76 FR 69730) , with a 30

- day comment period. No comments were received following this publication.

Consistent with the Agency’s policy of making registration actions more transparent, the registration of the TER

- RTU1 and TER

- CX1 EPs was subject to a 30

- day comment period as a

“ first indoor use ” for Cold Pressed Neem Oil. No comments were received following this publication. EPA bel ieves that, based on the information submitted in support of the registration

of Cold Pressed Neem Oil for indoor use
, it is in the best interest of the public and the

environment to issue these registrations. The basis for this decision can be found in th e risk

assessment for Cold Pressed Neem Oil , which is characterized in this BRAD.Cold Pressed Neem Oil Page 7 of 2 1 Biopesti cides Registration Action Document

A. Classification

T he Biochemical Classification Committee determined that Cold Pressed Neem Oil is a biochemical pesticide due to its app arent non

- toxic mode of action and natural occurrence in the

environment

.

B. Food Clearances/Tolerances

Plasma Power of India filed a petition (PP 7F7249) proposing to establish an exemption from the requirement of a tolerance for residues of Cold Pressed Neem Oil in or on all food commod ities. A notice of filing was published on November 2, 2007 (72 FR 62237). On October 13, 2009, EPA promulgated a final rule exempting residues of the biochemical pesticide Cold Pressed

Neem Oil , from the requirement for tolerance in or on all food commodi ties

.

IV. RISK ASSESSMENT

A. Active Ingredient Characterization

Cold Pressed Neem Oil is pressed directly from seeds of the Neem tree ( Azadirachta indica ),

which is a tropical evergreen tree native to India and also found in other Southeast Asian and

African co untries . Cold Pressed Neem Oil has a brown color, a bitter taste and a garlic/sulfur smell. A single seed may contain up to 50 percent oil by weight. Cold Pressed Neem Oil contains various compounds that have insecticidal and medicinal properties. It is us ed in making shampoos, toothpaste, soaps, cosmetics, mosquito repell e nts, creams and lotions, and pet products such as pet shampoo. It also contains vitamin E, other essential amino acids and fatty acids. Cold Pressed Neem Oil is used for treating many ski n diseases , including eczema, psoriasis, and skin allergies

.

Cold Pressed Neem Oil is a mixture of several C 26 terpenoids t h at are naturally occurring organic compounds composed of a five

- carbon skeleton (simple terpenoids) or complex terpenoids with

st ructures that possess between 20 and 40 carbon atoms . A zadirachtin

, the most common

terpenoid in Cold Pressed Neem Oil and the most thoroughly characterized

, is a federally registered active ingredient pesticide. Cold Pressed Neem Oil also contains steroi ds, fatty acids,

and a number of essential oils.

D escription s of the technical grade active ingredient (TGAI) product formulation and production

process
, as well as the formation of impurities, were examined by the Agency and found to meet

current stand ards. A preliminary analysis was conducted to determine Cold Pressed Neem Oil content in five batches of the product, and the results were determined to be acceptable by the Agency. The analytical method used to determine the content of the active ingredi ent is also acceptable. Physical and chemical properties were submitted for the TGAI and are adequate.

Refer to Table 1 in Appendix A for a summary of product chemistry data requirements. Refer to

Table 2 in Appendix A for the summary of physical and ch emical characteristics

. All product chemistry data requirements for registration of Cold Pressed Neem Oi l have been satisfied.Cold Pressed Neem Oil Page 8 of 21 Biopesti cides Registration Action Document

B. Human Health Assessment

1. Toxicology

T oxicity categories are assigned based on the hazard(s) identified from studies and /or information on file with the Agency. An active ingredient is classified into Toxicity Category I

, II, III or IV, in wh ich Toxicity Category I indicates the highest toxicity and Toxicity Category IV indicates the lowest toxicity

.

Adequate mammalian t oxicology data /information is available to support registration of Cold

Pressed Neem Oil

. All toxicology data requirements for Cold Pressed Neem Oil have been

satisfied.

a. Acute Toxicity

Acute toxicity testing is required to 1) determine systemic toxicity f rom acute exposure via the dermal, inhalation and oral routes, 2) determine irritant effects from exposure to the eyes and 3) determine the potential for skin sensitization (allergic contact dermatitis).

Tier I toxicity data submitted and reviewed showe d that Cold Pressed Neem Oil is a toxicity
category IV (low toxicity) compound via acute oral and acute inhalation routes of exposure. Cold Pressed Neem Oil is in Toxicity Category III (slightly toxic) for acute dermal irritation.

Cold Pressed Neem Oil i s not an eye or skin irritant, and it is not a dermal sensitizer. N o additional toxici ty data are required to support us age of this biochemical.

For more information regarding the acute toxicity data requirements, refer to Tab le 3 in

A ppendix A

.

b. Sub

- ch ronic Toxicity

Subchronic data is required to determine a no

- observed

- effect

- level (NOEL) and toxic effects (if any) associated with repeated or continuous exposure to a test substance for a period of 90 days

.

To address the 90

- day oral toxicity the d ata requirement as appropriate for an agricultural registration , the applicant submitted data obtained from the technical public literature in lieu of a guideline study. The study showed that test animals did not exhibit any clinical signs of toxicity

that were statistically different from untreated controls. There were no significant changes in body weight, serum liver damage indicators, direct bilirubin and total bilirubin, or other blood parameters during the 90

- day study period. The 90

- day oral feeding LD 50 is higher than 5000 mg crude Cold Pressed Neem Oil/kg body weight. Based on the review of this data, the Agency concluded that no subchronic oral toxicity is expected to occur when this compound is used in accordance with good agricultural practices.

The 90

- day dermal and 90

- day inhalation toxicity data requirements were waived for the initial agricultural use of Cold Pressed Neem Oil. For the addition of a “first indoor use,” these data requirements have been fulfilled using rationale supported by p ublished scientific literature. Specifically, d ermal metabolism of the product is not expected to differ from its oral metabolism ( EPA, 2009 ). In the acute guideline studies, the product was demonstrated to have no acuteCold Pressed Neem Oil Page 9 of 21 Biopesti cides Registration Action Document

dermal toxicity (LD 50 >4000 mg/kg), was not a dermal irritant, and was not a dermal sensitizer.
Similarly, t here is a lack of inhalation toxicity (Toxicity Category IV) demonstrated in the

submitted acute inhalation toxicity study (LC 50 >2.11 mg/L ). In addition, repeated inhalation

e xposure is mitigated by indoor use label language requiring a four hour re

- entry period after application of the product

. Alongside the low toxicity present in the acute and subchronic studies, the Agency concludes that no subchronic dermal or inhalation toxicity is expected to occur when used in accordance with good agricultural practice and when used indoors in accordance with

label instructions.

Furthermore, h umans are regularly exposed to this substance in medicinal and cosmetic products, via the oral, inhal ation and dermal routes, and at comparatively high levels ( Schmutterer, 1995 ). These uses are also expected to result in exposures that are significantly greater than that which would be expected from pesticidal uses, including both agricultural and indoor uses.

For more information regarding the subchronic data requirements, refer to Table 3 in Appendix

A

.

c. Developmental Toxicity and Mutagenicity

S tudies from technical public literature were submitted to address the data requirements for developmental t oxicity and m utagenicity (OPPTS 870.3700 ).

Based on In vitro and in vivo studies, and subcutaneous and intravaginal applications of Cold Pressed Neem Oil, it seems that developmental toxicity may occur in test animals when expose d
to Cold Pressed Neem O il by intravaginal, intrauterine, subcutaneous injection, or by direct exposure to mammalian sperm and eggs in in vitro laboratory studies. T he three generation study
in rats fed Cold Pressed Nee m Oil in the diet, however, demonstrates that chronic oral in gestion of food commodities containing Cold Pressed Neem Oil residues does not result in any mammalian developmental toxicity. T aken together, these data demonstrate that no developmental toxicity is expected to occur from the use of Cold Pressed Neem Oil as a pesticide.

Furthermore, Cold Pressed Neem Oil and its components are not structurally related to known mutagens, nor do they belong to any chemical class of compounds containing known mutagens. Humans are regularly exposed to this substance via oral exposure (as a traditional folk medicinal product) and dermal exposure (when used on skin and hair) at levels that are significantly greater than that which would be expected from the product as a pesticide under conditions of use. In addition, an extensi ve literature search of several scientific databases (i.e. ChemIDPlus, HSDB, Toxline, CCCRIS, DART, GENETOX, IRIS, ITER, LactMed, Multi

- Database, TRI, HazMap, Household Products, TOXMAP and TOXNET) for the period 1980 to 2008 failed to locate any

other dat a / information regarding mutagenicity or genotoxicity of Cold Pressed Neem Oil. As a result, EPA concludes that Cold Pressed Neem Oil is not mutagenic or genotoxic.

d. Effects on the Endocrine System

EPA is requ ired under the Federal Food, Drug, and Cosmetics Act (FFDCA) to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) “may have an effect in humans that is similar to an effect produced b y aCold Pressed Neem Oil Page 10 of 21 Biopesti cides Registration Action Document

naturally

- occurring estrogen, or other such endocrine effects as the Administrator may designate.” Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there was scientific basi s for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC’s recommendation that the p rogram include evaluations of potential effects in wildlife. When the appropri ate screening and/or testing protocols being considered under the Agency’s Endocrine Disrupter Screening Program (EDSP) have been developed and vetted, Cold Pressed Neem Oil may be subjected to additional screening and/or testing to better characterize eff ects related to endocrine disruption.

2. Dose Response Assessment

No meaningful toxicological endpoints were identified on Cold Pressed Neem Oil when used as a pesticide ; therefore, a dose respon se assessment was not required.

3. Food Quality Protecti on Act (FQPA) Consideration

a. Dietary Exposure and Risk Characterization

The most likely human exposure to Cold Pressed Neem Oil will occur via dietary exposure (consumption) to treated fruits, seeds, or leafy vegetables. EPA modeling (using the Terrestrial Exposure model (T

- REX; EPA, 2005) of potential residues of Cold Pressed Neem Oil following terrestrial treatments indicated that following 12 consecutive applications of 100% Cold Pressed

Neem Oil at 7

- day intervals, the maximum dietary residues present w ould be approximately 881 ppm on broadleaf plant foliage; and approximately 98 ppm on fruits, pods, and seeds. The modeling indicated that residues would decline rapidly between foliar applications (approximately 245

- 440 ppm on broadleaf foliage; and 27

- 4 9 ppm on fruits, pods, and seeds) and following the final application (see Table 4 in appendix A) . As stated in section B (a) of this document, Cold Pressed Neem Oil is a toxicity category IV for oral exposure ( LD 50 = >5000 mg/kg) . The estimated maximum th eoretical residues likely to be present on edible commodities are 882 ppm. This residue level is approximately 5

- fold less than the highest doses used in acute and subchronic laboratory testing (5000 mg/kg) and approximately 20

- fold less than chronic

labor atory testing (10% in the diet) at which no mortalities or other signs of clinical toxicity were observed. Therefore, based on a lack of acute, subchronic, or chronic toxicity in laboratory testing, estimated maximum residues that are well below the doses used in laboratory testing, and the rapid degradation of Neem Oil in the environment, it is highly unlikely that that there will be any adverse effects to humans resulting from dietary exposure to Neem Oil residue

.

Moreover, h umans are regularly exposed t o this compound via consumption of Cold Pressed Neem Oil medicinal products, and at levels that are significantly greater than what would be expected from pesticide applications. EPA has determined that dietary exposure is not a concern

because of the low toxicity of this active ingredient and the history of its use without any reports

of adverse effects.

b. Drinking Water Exposure and Risk Characterization

No significant drinking water exposure or residues are expected to result from the pesticidal usage of Cold Pressed Neem Oil. The outdoor use of this active ingredient is intended as a foliarCold Pressed Neem Oil Page 11 of 21 Biopesti cides Registration Action Document

application on food commodities and not to be applied directly to water. If used in accordance

with EPA

- approved labeling, is not likely to accumulate in drinking wat er. In the unlikely event that exposure via drinking water did occur from accidental spraying

, the health risk would be expected to be minimal, based on the low acute oral toxicity and the long history of human exposure to Cold Pressed Neem Oil without adv erse effects. As a result, dietary and drinking water exposure to residue of Cold Pressed Neem Oil are expected to be minimal

.

c. Acute and Chronic Dietary Risks for Sensitive Subpopulations Particularly Infants

and Children

FFDCA section 408 provides that t he Agency 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 the Agency 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 has concluded that there is reasona ble certainty that no harm to

infants and children or adults will result from the use of Cold Pressed Neem Oil when label

instructions are followed.

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

Characterization

a. Occupational Exposu re and Risk Characterization

The potential for dermal, eye, and inhalation exposure to Cold Pressed Neem Oil for handlers and applicators is mitigated as long as products are used according to label directions. The Agency will require labels to include th e appropriate signal word , re

- entry interval and precautionary statements

, including the requirement for personal protective equipment, to mitigate any risk of exposure

.

b. Residential, School and Day Care Exposure and Risk Characterization

As stated above, 90

- day oral data show very low toxicity

, indicating no concern for oral exposure, such as hand

- to

- mouth, that may occur during indoor residential use. Furthermore,

h umans are regularly exposed to this substance in medicinal and cosmetic products, via the o ral, inhalation and dermal routes, and at comparatively high levels ( Schmutterer, 1995 ). These uses are also expected to result in exposures that are significantly greater than that which would be expected from pesticidal uses, including hand

- to

- mouth expo sure.

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to establish an exemption from a tolerance, the Agency consider “available information concerning the cumulative effects of [a particular pesticide's] residues and other s ubstances that have a common mechanism of toxicity.'' These considerations include the possible cumulative effects of such

residues on infants and children.Cold Pressed Neem Oil Page 12 of 21 Biopesti cides Registration Action Document

5

. Cumulative Effects

EPA has considered the potential for cumulative effects of Cold Pressed Ne em Oil and other substances in relation to a common mechanism of toxicity. However, because of its low toxicity to mammalian systems, the Agency does not expect any cumulative or incremental effects from exposure to residues of Cold Pressed Neem Oil when a pplied/used as directed on the label and in accordance with good agricultural practices.

6

. Risk Characterization

The Agency considered human exposure to Cold Pressed Neem Oil 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 Cold Pressed Neem Oil when label instructions are followed.

C. Environmental Assessment

1. Ecological Hazards

Adequate non

- target toxicology data /information are available to support registration of Cold

Pressed Neem Oil

. All non

- target toxicology data requirements for Cold Pressed Neem Oil have

been satisfied.

There are no concerns for any non

- target or ganisms when 100% Cold Pressed Neem oil is applied in accordance with EPA

- approved label use directions. No toxic endpoints have been

identified for non

- target birds, non

- target plants, and non

- target soil organism such as earthworms. Although Cold Pressed Neem Oil is slightly toxic to aquatic organisms in laboratory testing, as a result of the rapid biodegradation of Neem Oil under approved conditions of use, calculated Risk Quotients (RQs) for fish and aquatic invertebrates are well below any Levels of

Co ncern (LOCs) for threatened and endangered species. There are no concerns for non

- target
insects. O nly insects that feed directly on treated plant foliage or roots will be directly exposed to
Cold Pressed Neem Oil at levels that will be pesticidal. Honey b ees and other pollinators that

feed on nectar , and predators of insect pests are unlikely to consume sufficient quantities of Cold

Pressed N eem Oil to cause adverse effects . Bees have been reported to avoid foods that contain >100 ppm Cold Pressed N eem Oil

.

For more information regarding the non

- target toxicity data requirements, refer to Table 4 in Appendix A.

2. Environmental Fate and Ground Water Data

Since Cold Pressed N eem Oil is a multicomponent mixture, a zadirachtin A was used as a
surrogate when evaluating environmental fate for all of the insecticidally active liminoid components in 100% Cold Pressed N eem Oil

.

A number of studies have addressed the degradation of Cold Pressed N eem Oil components in the environment. In forest environments, azadirachtin A persisted 3 to 6 days in terrestrial matrices and 8 to 13 days in water (Sundaram et al., 1999). In laboratory studies, azadirachtin ACold Pressed Neem Oil Page 13 of 21 Biopesti cides Registration Action Document

was shown to have temperature dependent degradation rates in sandy loam soils with half

- lives

of 43.9 and 19.8 days at 15 o C and 25 o C, respectively (Stark and Walter, 1995). When the soil was autoclaved, half

- lives increased to 91.2 (15 o C) and 31.5 days (25 o C), demonstrating the significant influence of microbial activity in the degradation of Cold Pressed N eem Oil. Half lives for azadirachtin B in sandy loam soil were comparable to that of azadirachtin A. Azadirachtin is extremely labile in light with photolysis half lives of 48 min to 3.98 days in thin films under UV light, and 2.47 days on leaf surfaces (Johnson et al., 2003). In field trials with olives, azadiractin residues had a half

- life of 0.8 days (Caboni et al., 2002).

Based on the submitted data, Cold Pressed N eem Oil is readily biodegradable in soil, water and

on foliar surfaces. As a result, Cold Pressed N eem Oil and its components are not likely to persist

in the environment.

3. Ecological Exposure and Risk Characterization

The potential for exposure to non

- target wildlife is minimal. Based on the results/information presented in the Envi ronmental Fate and Groundwater Data section above, it is highly unlikely

that non

- target organisms, particularly aquatic organisms, would be exposed to potentially toxic

levels of Cold Pressed Neem Oil via runoff and/or movement through the soil. Cold Pres sed

Neem Oil undergoes rapid biodegradation in soil and water, and no unreasonable adverse effects to the environment are expected from the use of Cold Pressed Neem Oil when label instructions

are followed.

4. Endangered Species Assessment

A nontarget or ganism hazard assessment and an Endangered Species Assessment has been conducted to support registration of Plasma Neem Oil Manufacturing Use Product and Plasma Neem Oil Biological Insecticide (an end

- use product, EP) (t he MP and the EP are identical

formu lations ) . There are no concerns for non

- target mammals and birds, including threatened and endangered species. No toxic endpoints were identified for non

- target terrestrial mammals (acute oral and dietary toxicity LD 50 s >5000 mg/kg and 5000 ppm, respectiv ely) and birds (acute oral and dietary toxicity LD 50 s >1000 mg/kg and 12000 ppm, respectively. Moreover, based on submitted laboratory studies, no concerns were identified for non

- target aquatic organisms, including threatened and endangered species. Calcu lated Risk Quotients (RQs) fish and aquatic invertebrates are well below any Levels of Concerns (LOCs) for threatened and endangered species.

Based on the fact that Cold Pressed Neem Oil is not toxic to non

- target organisms and on its use pattern and use instructions, EPA has determined it will have "No Effect" on any currently listed threatened or endangered species or any designated critical habitat

.

D. Product Performance (Efficacy)

Customarily, the Agency requires product performance (efficacy) data to be submitted for review only in connection with the registration of products directly pertaining to the mitigation of disease bearing human health organisms and certain designated q uarantine pests, collectively referred to as “publ ic h ealth pests

. ” For a l ist of organisms considered by the Agency as “publicCold Pressed Neem Oil Page 14 of 21 Biopesti cides Registration Action Document

health pests”, please refer to Pesticide Registration Notice 2002

- 1 ( http://www.epa.gov/PR_Notices/pr2002

- 1.pdf )

.

In accordance with Agenc y policy regarding “public health pests,” Terramera, Inc. , has submitted efficacy data in support of the registrat ion of the TER

- RTU1 and TER

- CX1 EPs for indoor use to control bed bugs . T rials conducted at product label rates showed control of bed bug adul ts, nymphs and eggs. Treatment residues on various substrates (painted and unpainted wood, carpet, mattress swatches and filter paper) killed all adults in less than 24 hours, and direct spray killed all adults in less than 8 hours. Bed bug eggs exposed to dried residues, wet residues and direct sprays of treatment all did not hatch. Treatment on wood substrate remained active in preventing nearly all egg hatch for up to 19 days post treatment. Retreatment interval for control of adults and nymphs was found to be 14 days (up to 100% for 10 days and 90% or greater for 14 days on wood), and for control of eggs was found to be 21 days (up to 100% for 18 days and 80% or greater for up to 21 days).

V. Risk Management Decision

A. Determination of Eligibility for Regi stration

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 adv erse effects on the environment.

The four criteria of the Eligibility Determination for Pesticidal Active Ingredients are satisfied by the science assessments supporting products containing Cold P ressed Neem Oil . Such products are not expected to cause unreasonable adverse effects, and are likely to provide protection as claimed when used according to label instructions. Therefore, Cold Pressed Neem Oil is eligible for registration for the labeled uses.

B. Regulatory Decision

EPA has determined that Col d Pressed Neem Oil , in either agricultural or indoor use practices

, presents no issues of toxicological, ecological, or environmental concern. As discussed above, acute toxicity data for Cold Pressed Neem Oil demonstrate that it is either toxicity category IV or

III. Cold Pressed Neem Oil does not demonstrate subchronic or developmental toxicity, and it is not mutagenic or genotixic. EPA has no concerns for any non

- target organisms exposed to Cold Pressed Neem Oil in accordance with approved label direction s. EPA has not identified any toxic endpoints for non

- target mammals, birds, plants, aquatic, or soil organisms. Nor are t here

concerns for any threatened and endangered species. Thus, given that Cold Pressed Neem Oil has very low toxicity and presents lit tle if any risk to non

- target organisms, EPA concludes that it is in the best interests of the public and the environment to both issue the registration for Cold

Pressed Neem Oil and to approve its use indoors

. C onsistent with the Agency’s policy for

makin g these registration actions more transparent, EPA ha s provid ed one 30

- day public comment period on the decision to regist e r Cold Pressed Neem Oil and an additional 30

- day public comment period on the decision to approve the “first indoor use” of Cold Pres sed NeemCold Pressed Neem Oil Page 15 of 21 Biopesti cides Registration Action Document

Oil. No comments were received during either comment period.

The data submitted fulfill the requirements of registration of Cold Pressed Neem Oil for use in on

all outdoor and greenhouse ornamental and food crops to control insects using ground equipmen t

, and indoors for the control of bed bugs

. Refer to Appendix B for product

- specific

information.

C. Environmental Justice

EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all people, regardless of race, color, national origin, or income, in the development, implementation, and enforcement of environmental laws, regulations, and policies. To help address potential environmental justice issues, the Agency seeks information on any groups or segments of the population who, as a result of their location, cultural practices, or other factors, may have atypical, unusually high exposure to Cold pressed Neem Oil , compared to the general population. Please comment if you are aware of any sub

- populations that may have atypical, unusually high exposure compared to the general population.

VI. ACTIONS REQUIRED BY REGISTRANTS

The Agency evaluated all of the data submitted in connection with the initial registration of Cold

Pressed Neem Oil and determined that these d ata are sufficient to satisfy current registration data requirements. No additional data are required to be submi tted to the Agency at this time. For new uses and/or changes to existing uses, additional data may be required.

Not withstanding the inform ation stated in the previous paragraph, it should be clearly understood that certain, specific, data are required to be reported to the Agency as a requirement for maintaining the Federal registration for a pesticide product. A brief summary of these types of

data are listed below.

A. R eporting of Adverse Effects

Reports of all incidents of adverse effects to the environment must be submitted to the Agency under the provisions stated in FIFRA, Section 6(a)(2).

B. Reporting of Hypersensitivity Incidents

Add itionally, all incidents of hypersensitivity (including both suspected and confirmed incidents) must be reported to the Agency under the provisions of 40 CFR Part 158.2050(d).Cold Pressed Neem Oil Page 16 of 21 Biopesti cides Registration Action Document

VII. Appendix A

TABLE 1. Product Chemistry Data Requirements for Cold Pressed Ne em Oil (40 CFR § 158.2030)
Biochemical Data Requirement by

OCSPP Guideline Number MRID (s) Description of R esult

880.110 0 Product identity;

880.1200 Manufacturing process;

880.1400 Discussion of formation of unintentional ingr edients 47538701 Submitted data satisfy the requirements for product identity, manufacturing process, and discussion of formation of impurities.

830.1700 Analysis of samples 47538701 Submitted data satisfy the requirements for analysis of samples.

83 0.1750 Certified l imits 47538701 Not required for TGAIs.

830.1800 Enforcement a nalytical

method 47538701 Not required for TGAIs.

a TABLE 2. Physical and Chemical Properties of Cold Pressed Neem Oil (40 CFR § 158.2030)

Data submitted via self certification per Pesticide Registration Notice (PRN) 98

- 1

. Bi ochemical Data Requirement by

OCSPP Guideline Number MRID(s) Description of R esult

830.6302 Color Yellowish brown a

830.6303 Physical State Liquid at 20°C a

830.6304 Odor Strong, garlic

- like a

830.6313 Stability 47476701 10% degradation at 11mont hs under unregulated storage conditions/shipment

830.7000 pH 5.3 at 21°C (70°F) a

830.7050 UV/Visible Absorption 215 nm a

830.7200 Melting Range Not applicable; product is a liquid a

830.7220 Boiling Range BP > 2 00 a o C (392 o F)

830.7300 Density/Relative Density/Bulk Density 0.922 g/mL (8.27 lb/gal) at 22°C (72°F) a

830.7370 Dissociation Constant in

Water Not applicable; the product does not su bstantially

dissociate in water a

830.7550 Partition Coefficient Log K a

ow = 6.26

830.7840 Water Solubilit y 52.3 mg/L a

830.7950 Vapor Pressure 2.5 x 10 a

- 7 mm Hg at 25oCCold Pressed Neem Oil Page 17 of 21 Biopesti cides Registration Action Document

Table 3. Human Toxicology Data Requirements for Cold Pressed Neem Oil (40 CFR § 158.2050)

Biochemical Data Requirement by OCSPP

Guideline Number MRID(s) Description of Result Toxicity Category

870.1100 Acute oral [rat] toxicity 47088002 1

47208801 LD

2 50 = >5000 mg/kg for female IV

870.12 00 Acute dermal [rabbits] toxicity 47088003

47208802 1 LD

2 50 = >2000 mg/kg for males, females, and combined III

870.1300 Acute inhalation [rat] toxicity 47088005

47208803 1 The inhalation L C

2 50 IV for males, females, and combined was > 2.53 mg/L & > 2.11 mg/L, respectively, at

concentrations of azadirachtin of

0.30% & 0.15%

870.2400 Acute eye irritation [rabbit] 47088006

47208804 1 No irritation was noted on any rabbit throughout the study. Plasma NeemTM

Oil was non

- irritating. 2 IV

870.2500 Acute dermal irritation [rabbit] 47088007 No irritation was noted on any rabbits throughout the study. The primary

irritation index was 0.0. Plasma

NeemTM Oil was non

- irritati ng. 1 IV

870.2600 Skin sensitization [guinea pig] 47088004 After three consecutive weekly inductions, the test and control animals showed no signs of reactivity at 24 and 48 hours after challenge. 1 Not a dermal

sensitizer

870.310 0 90

- Day Oral

f eeding [mouse] Awad (2003) LD 50 No subchronic oral toxicity = >5000 mg/kg

870.3250 90

- Day Dermal 47195705

48606014

48751001 The product is not intended for purposeful application to human skin.

Neem oil is not known nor expected to be metabolized differently by the dermal route of exposure than by the oral route of exposure. No literature reports of subchronic dermal toxicity. No subchronic dermal toxicity

870.5100 90

- Day Inhalation 47195705

48606014

4 8751001 The use patterns will not result in significant levels of repeated inhalation exposure to the pesticid e as a gas, vapor, or aerosol. Indoor use label language includes 4hr re

- entry interval following application. No literature reports of subchronic inhalation toxicity. No subchronic

inhalation

toxicity

870.3500 Developmental Toxicity [Teratogenicity] 47195706 (see refs

within this

MRID) No reproductive/developmental effects

in a 3

- gen rat study with 10% Neem Oil in diet. Reproductive/developmental effects occur only in in vitro studies on sperm or eggs, subcutaneous exposure; contraceptive effects with intrauterine/intravaginal exposure Not a developmental

toxicant when

used in

accordanc e with approved labeling.

870.5100 Mutagenicity Testing [Ames Assay] 47088008 &

Polasa &

Rukmini

(1987) No evidence of mutagenicity with or

without S

- 9 activation in S. typhimurim Not a mutagen

1 The test material contains 0.30% azadirachtin.

2 The test material contains 0.15% azadirachtin.Cold Pressed Neem Oil Page 18 of 21 Biopesti cides Registration Action Document

Table 4: Estimated Cold Pressed Neem Oil residues on terrestrial matrices using the Terrestrial Exposure model (T

- Rex; EPA, 2005)

Terrestrial ma trix Dietary

- based Estimated Environmental Concentrations (ppm)
0 days after last app 86 days after last app 106 days after last app

Edible broadleaf plant foliage 881.20 0.04 0.00

Fruits. pods, and seeds 97.91 0.00 0.00

TABLE 1 Tier I Non

- Target Organism Profile

Guideline

No. Study Type References and/or

MRID ( s) Results Toxicity Category

870.1100 Acute oral (rat) toxicity 47088002

47208801 1

2 LD 50 = >5000 mg/kg for female IV

870.3100 90

- Day Oral Feeding

(mouse) Awad (2003)

(476335

- 01) LD 50 = >5000 mg/kg No

subchronic oral toxicity

850.2100 Avian Acute Oral Toxicity (redwinged

blackbird) Schafer & Jacobsen. (1983); (47633502) LD 50 (highest acute dose tested) >10 00 mg/kg No effects at highest dose

tested

850.2100 Avian Dietary Toxicity (redwinged

blackbird) Schafer & Jacobsen. (1983); (47633502) LD 50 Practically

non

- toxic > 10000 ppm (1.0%)

Avian Dietary Toxicity (Leghorn hen) Verm a et al. (1998)

(474787

- 05) 12

- week LD 50 Practically > 12000 ppm (6.0% neem oil in neem cake feed) non

- toxic

850.1075 Fish Toxicity Awad (2003)

(476335

- 01) 96

- hr LC 50 Slightly Toxic s= 70.6

– 84.3 ppm

850.1300 Aquatic

Invertebrates Awad (2003)

(476335

- 01 ) 48

- hr LC 50 Slightly Toxic s= 57.5

- 63.9 ppm

850.4150 Non

- target Plants

(vegetative vigor) 476335

- 04 &

- 05 No toxicity observed in plants treated with up to 11000 ppm (1.1%)

Neem Oil Practically

non

- toxic

3

850.3020 Honey bees Melathoupoulos et al. (2 000) Contact LD 50 Practically

non

- toxic > 45 ug/bee (adult)

Canadian Honey Council (2005) -

1 The test material contains 0.30% azadirachtin.

2 The test material contains 0.15% azadirachtin

. TABLE 5 . Non

- Target Organis m Toxicity Requirements for Cold Pressed Neem Oil (40 CFR § 158.2060)Cold Pressed Neem Oil Page 19 of 21 Biopesti cides Registration Action Document

VIII. Appendix B

For product specific information, please ref er to : http://oaspub.epa.gov/pestlabl/ppls.homeCold Pressed Neem Oil Page 20 of 21 Biopesti cides Registration Action Document

IX. Appendix C

REFERENCES

Abudulai, M., B. Merle Shepard, and Paula Levin Mitchell. 2004. Effects of neem ( Azadirachta
indica A. Juss.) on predators of Nezara viridula (L.) (Hemiptera: Heteroptera: Penta tomidae).
J ournal of Agricultural Urban Entomol ogy . 21(1): 9

– 13

.

Canadian Honey Council (CHC). 2005. Essential oils and their toxicity to honeybees.

November

- December. http:/ /www.honeycouncil.ca/users/folder.asp?FolderID=5220

Da Silva, F. A. C. and S. S. Maritnez. 2004. Effect of neem seed oil aqueous solutions on survival and development of the predator Cycloneda sanguinea (L) (Coleoptera: Coccinellidae).

Extension Tox icology Network (EXTOXNET). 1995. Pesticide Information Profile: Azadirachtin. Cornell University Cooperative Extension. http://pmep.cce.cornell.edu/profile s/extoxnet/24d

- captan/azadirachtin

- ext.html

Food and Agriculture Organization of the United Nations (FAO). 2003. Azadirachtin. FAO Specifications and Evaluations for Agricultural Pesticides. http:/ /www.fao.org/ag/agpp/pesticid/ )

Lowery, D. T. and M. B. Isman. 1995. Toxicity of neem to natural enemies of aphids. Phytoparasitica 23(4): 297

- 306.

Methathopoulos, A. P., M. L. Winston, R. Whittington, T. Smith, C. Lindberg, A. Mukai, M.

Moore. 2 000. Comparative laboratory toxicity of neem pesticides to honey bees (Hymenoptera: Apidae), their mite parasites Varroa jacobsoni (Acari: Varroidae) and Acarapis woodi (Acari: Tarsonemidae), and brood pathogens Paenibacillus larvae and Ascophaera apis . Entomological Society of America 93(2):199

- 209.

Mordue, J. A. and A. Blackwell. 1993. Azadirachtin: An update. Journal of Insect Physiology

39: 903

- 924.

N ational Research Council. 1992. Neem: A tree for solving global problems. National Academy Press, Washington, DC.

Naumann, K. and M. B. Isman. 1996. Toxicity of a neem (Azadirachta indica A. Juss) insecticide to larval honeybees. American Bee Journal. 7: 518

- 520.

Rembold, H., G. K. Sharma, C. Czoppelt, and H. Schmutterer. Evidence of gro wth disruption in insects without feeding inhibition by neem azadirachta

- indica seed fraction. Journal of Plant

Diseases and Protection 87:290

- 297.

Schmutterer, H. 1995

. Chapter 6: Medicinal Uses in Asia . The Neem Tree and Other Meliaceous

Plants. New York: VCH Publishers, 1995. p. 518

- 525.

Stark, J. D. and J. F. Walter. 1995. Persistence of azadirachtin A and B in soil: Effects of temperature and microbial activity. Journal of Environmental Science and Health: Part B. Pesticides, food contaminan ts, and agricultural wastes. 30: 685

- 698.Cold Pressed Neem Oil Page 21 of 21 Biopesti cides Registration Action Document

Sundaram, K. M. S., A. Sundarum, J. Curry, and L. Sloane. 1999. Formulation selection, and investigation of azadirachtin

- A persistence in some terrestrial and aquatic components of a forest

environment. Pes t Management Science 51(1):74

- 90.

EPA. 2001. Generic Environmental Estimated Concentration (GENEEC) Version 2.0. Tier One Screening Model for Pesticide Aquatic Ecological Exposure Assessment. Environmental Fate and Effects Division/Office of Pesticide Programs. August 1, 2001.

EPA. 2005. T

- R EX, Version 1.2.3. Terrestrial Biology and Exposure Teams, Environmental Fate and Effects Division/Office of Pesticide Programs. August 8, 2005.

EPA. 2009. Memo from R. Jones to D. Benmhend. Tolerance Exemption Petition Review

Plasma Neem Oil Manufactu ring Use Product and Plasma Neem Oil Biological Insecticide. Each Product is Identical and Contains 100% Neem Oil (w/0.3% Azadirachtin) As Its Active Ingredient. March 9, 2009.