**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 March 22 , 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 Biopestic**  **ides Registration Action Docum ent** **TA BLE OF CONTENTS**  **I. EXECUTIVE SUMMARY**  **................................ ................................**  **................................ ..**  **5 II.**  **ACTIVE INGREDIENT OV ERVIEW**  **................................ ................................**  **............... 6**  **III. REGULATORY BACK**  **GROUND ................................**  **................................ ......................**  **6 A.**  **Classification ................................**  **................................ ................................**  **................................ .....................**  **7 B.**  **Food Clearances/Tolerances ................................**  **................................ ................................**  **............................ 7**  **IV. RISK ASSESSMENT**  **................................ ................................**  **................................ ...........**  **7 A.**  **Active Ingredient Characterization ................................**  **................................ ................................**  **................. 7**  **B. Hum**  **an Health Assessm ent**  **................................ ................................**  **................................ ...............................**  **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 Assessm**  **ent ................................**  **................................ ................................**  **............................. 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 Children
............... 11 **4. Occupational, Residential, School and Day Care Exposure and Risk Characterization**  **.......................... 11**  a. Occupational Exposure and Risk Characterization
................................ ................................ ........................ 11 b. Residential, School and Day Care Exposure and Risk Characterization
................................ ....................... 11 **5. Cum**  **ulative Effects ................................**  **................................ ................................**  **................................ ..........**  **12 6.**  **Risk Characterization ................................**  **................................ ................................**  **................................ .....**  **12 C.**  **Environm ental Assessm**  **ent ................................**  **................................ ................................**  **............................. 12**  **1. Ecolo**  **gical Hazards ................................**  **................................ ................................**  **................................ .........**  **12 2.**  **Environm ental Fate and Ground Water Data**  **................................ ................................**  **.............................. 12**  **3. Ecological Exposure and Risk Characterization**  **................................ ................................**  **.......................... 13**  **4. Endangered Species Assessm**  **ent ................................**  **................................ ................................**  **.................... 13**  **D. Product Perform**  **ance (Efficacy) ................................**  **................................ ................................**  **.................... 13**  **V. RISK MANAGEMENT DECI**  **SION ................................**  **................................ .................**  **14 A.**  **Determ ination of Eligibility for Registration**  **................................ ................................**  **................................ 14** **Cold Pressed Neem Oil**  **Page 3**  **of 21**  **Biopestic ides Registration Action Docum**  **ent B.**  **Regulatory Decision ................................**  **................................ ................................**  **................................ ........**  **14 C.**  **Environm ental Justice**  **................................ ................................**  **................................ ................................**  **.... 14**  **VI. ACTIONS REQUIRED BY**  **REGISTRANTS ................................**  **................................ .**  **15 A.**  **R eporting of Adv**  **erse Effects ................................**  **................................ ................................**  **......................... 15**  **B. Reporting of Hypersensitivity Incidents**  **................................ ................................**  **................................ .......**  **15 VII.**  **APPENDIX A ................................**  **................................ ................................**  **...................... 16**  **VIII. APPENDIX B**  **................................ ................................**  **................................ .....................**  **19 IX.**  **APPENDIX C ................................**  **................................ ................................**  **...................... 20** **Cold Pressed Neem Oil**  **Page 4**  **of 21**  **Biopestic ides Registration Action Docum**  **ent BIOPESTICIDES REGISTRATION ACTION DOCUMENT TEAM**  **Office of Pesticide Programs: Biopesticides and Poll**  **ution Prevention Division Biochemical Pesticides Branch (BPB)**  Driss Benmhend Regulatory Action L eader Gina Burnett , M.S. Regulatory Action L eader Li nda Hollis , M.S. Branch Chief Jacob Moore Chemist Manying Xue , M.S Chemist Clara F uentes, Ph.D. Entemologist Russell Jones , Ph.D. Senior Biologist**Cold Pressed Neem Oil**  **Page 5**  **of 21**  **Biopestic ides Registration Action Docum**  **ent I.**  **EXECUTIVE SUMMARY** The active ingredient 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 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 in secticide
. InOctober 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 registration 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 lac k of toxicity 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 II requirements. InMarch 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 to xicology data/information was submitted to fulfill the biochemical pesticide data requirements of 90
- day dermal toxicity

and 90
- day

inhalation toxicity
. Based on the data available to the Agency , it has been determined that no unreasonable adverse effect s 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

studies 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, rheumatism, 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, the pesticidal usage of Cold Pressed Neem Oil will not have any harmful environmental effects. Stud ies 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 concerns 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 In secticide, Fungicide and Rodenti cide Act (FIFRA) , as amended, and is thus eligible for unconditional registration. Itwas determined that the data/informat ion submitted adequately satisfy applicable data requirements at 40 C
. F
. R
. Subpart U §158.2000
.**Cold Pressed Neem Oil**  **Page 6**  **of 21**  **Biopestic ides Registration Action Docum**  **ent II.**  **ACTIVE INGREDIENT OVERVIEW Common Name:**  Neem Oil **Chemical Names:** Cold Pressed Neem Oil **Trade & Other Names** : Cold Pressed Neem Oil **CAS Registry Numbe r:**  8002
- 65
- 1 **OPP Chemical Code:** 0 25006 **Type of Pesticide:** In sect repellent, insect growth regulator ( anti
- feedant ), insecticide
. Application rates and methods vary depending on the product. For specific information regarding the product (s) refer t o Appendix B
. **III. REGULATORY BACKGROUND**  On August 02, 2007 , Plasma Power of India, submitted an application for the registration of the end use product (EP) Plasma NeemTM Oil (azadirachtin 3000 ppm) Insecticide (84185
- U), and Plasma NeemTM Oil Manufacturing Us e 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 published 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 Co ld 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 products(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 regi stration of the TER
- RTU1 and TER
- CX1 EPs is subject to a 30
- day comment period as a “ first indoor use.” While a final decision on registration of these EPs is contingent upon review and consideration of public comments, EPA presently believes that, based o n the preliminary risk assessment and information submitted in support of the registration of Cold Pressed Neem Oil for indoor use , that 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 Cold Pressed Neem Oil , which is characterized in this BRAD.**Cold Pressed Neem Oil**  **Page 7**  **of 21**  **Biopestic ides Registration Action Docum**  **ent 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 Nee m Oil in or on all food commodities. 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 toler ance in or on all food commodities
. **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 countries . 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 used 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 skin diseases , including eczema, psoriasis, and skin allergies
. Cold Pressed Neem Oil is a mixture of several C 26 terpenoids th at are naturally occurring organic compounds composed of a five
- carbon skeleton (simple terpenoids) or complex terpenoids with structures that possess between 20 and 40 carbon atoms . A zadirachtin , the most common ter penoid in Cold Pressed Neem Oil and the most thoroughly characterized , is a federally registered active ingredient pesticide. Cold Pressed Neem Oil also contains steroids, 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 standards. A preliminary analy sis 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 analy

tical method used to determine the content of the active ingredient is also acceptable. Phy sical 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 phy sical and chemical 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**  **Biopestic ides Registration Action Docum**  **ent 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, I II or IV, in wh ich Toxicity Category I indicates the highest toxicity and Toxicity Category IV indicates the lowest tox icity
. Adequate mammalian toxicology 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 sy stemic toxicity from 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 Itoxicity

dat a submitted and reviewed showed 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 I II (slightly

toxic) for acute dermal irritation. Cold Pressed Neem Oil is 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 Appendix A
. **b. Sub**  **- chronic**  **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 day s . To address the 90
- day

oral toxicity

the data 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 c linical 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 pe riod. 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 published scientific literature. Specifically , d ermal metabolism of the product is not expected to differ from its oral metabolism ( EPA, 2009 ). Inthe acute guideline studies, the product was demonstrated to have no acute**Cold Pressed Neem Oil**  **Page 9**  **of 21**  **Biopestic ides Registration Action Docum**  **ent** derma l toxicity

(LD 50 >4000 mg/kg), was not a dermal irritant, and was not a dermal sensitizer. Similarly , there is a lack of inhalation toxicity (Toxicity Category IV) demonstrated in the submitted acute inhalation toxicity study (LC 50 >2.11 mg/L ). Inaddition , 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, humans are regularly exposed to this substance in medicinal and cosmetic products, via the oral, 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, includin g 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 re quirements for developmental toxicity

and mutagenicity

(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 Oil 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, dem onstrates that chronic oral ingestion 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

expo sed 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 o f use. In addition, an extensive literature search of several scientific databases (i.e. ChemIDPlus, HSDB, Toxline, CCCRI S, DART, GENETOX, I RI S, I TER, L actMed, Multi
- Database, TRI , HazMap, Household Products, TOXMAP and TOXNET) for the period 1980 to 2008 failed to locate any other data / 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 required 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 s imilar to an effect produced by a**Cold Pressed Neem Oil**  **Page 10**  **of 21**  **Biopestic ides Registration Action Docum**  **ent** 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 basis for including, as part of the program, the androgen and thy roid hormone sy stems, in addition to the estrogen hormone sy stem. EPA also adopted EDSTAC’s recommendation that the p rogram include evaluations of potential effects in wildlife. When the appropriate 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 test ing to better characterize effects 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 require d. **3. Food Quality Protection 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 m odeling (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 maxi mum dietary residues present would 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
- 49 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 theoretical 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 2 0
- fold less than chronic laboratory

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, humans are regularly exposed to 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 foliar**Cold Pressed Neem Oil**  **Page 11**  **of 21**  **Biopestic ides Registration Action Docum**  **ent** 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 water. In the unlikely event that exposure via drinking water did occur from accidental spray ing , the health risk would be expected to be minimal, based on the low acute oral toxicity and the long history

of human exposure to Col d Pressed Neem Oil without adverse 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** FFD CA section 408 provides that the 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 Agen cy 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 c oncluded that there is reasonable 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**  **Charac terization** 
**a. Occupational Exposure 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 wil l require labels to include the 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 Chara**  **cterization** 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, humans are regularly

exposed to this substance in medicinal an d cosmetic products, via the oral, 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 exposure. 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 pes ticide's] residues and other substances 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**  **Biopestic ides Registration Action Docum**  **ent 5**  **. Cumulative Effects**  EPA has considered the potential for cumulat ive effects of Cold Pressed Neem Oil and other substances in relation to a common mechanism of toxicity . However, because of its low toxicity to mammalian sy stems, the Agency does not expect any

cumulative or incremental effects from exposure to residues o f Cold Pressed Neem Oil when applied/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. Environmen**  **tal 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 organisms 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 a re well below any

L evels of Concern (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 th at will be pesticidal. Honey bees 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 day s in terrestrial matrices and 8 to 13 day s in water (Sundaram et al., 1999). In laboratory studies, azadirachtin A**Cold Pressed Neem Oil**  **Page 13**  **of 21**  **Biopestic ides Registration Action Docum**  **ent** was shown to have temperature dependent degradation rates in sandy loam soi ls with half

- lives of 43.9 and 19.8 day s 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 day s (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 photoly sis half lives of 48 min to 3.98 day s in thin films under UV light, and 2.47 day s on leaf surfaces (Johnson et al., 2003). In field trials with olives, azadiractin residues had a half
- life of 0.8 day s (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/inf ormation presented in the Environmental 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 moveme nt through the soil. Cold Pressed 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 Spec**  **ies Assessment** A nontarget organism 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) (the MP and the EP are identical formulations ) . 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 L D 50 s >5000 mg/kg and 5000 ppm, respectively ) and birds (acute oral and dietary

toxicity L D 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. Calculated Risk Quotients (RQs) fish and aquatic invertebrates are well below any L evels 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)**  Submission of product performance data (OP PTS 810.3000) is listed as a requirement for all pesticide products. Customarily , the Agency requires efficacy

data to be submitted for review only in connection with the registration of products directly pertaining to the mitigation of disease bearing hum an health organisms and certain designated quarantine p ests, i.e., ticks, mosquitoes, fleas, Mediterranean fruit flies, gyp sy m oths, Japanese b eetles , etc. For a list of**Cold Pressed Neem Oil**  **Page 14**  **of 21**  **Biopestic ides Registration Action Docum**  **ent** organisms considered by

the Agency

as “public health pests”, please refer to Pesticide Registration Notice 2002
- 1 ( http://www.epa.gov/PR_Notices/pr2002
- 1.pdf ). **V. Risk Management Decision**  **A. Determination of Eligibility for Registration**  Section 3(c)(5) of FIFRA provides for the reg istration of new active ingredients if it is determined that (A) its composition is such as to warrant the proposed claims for it; (B) its labeling and other materials required to be submitted comply with the requirements of FIFRA; (C) it will perform its intended function without unreasonable adverse effects on the environment; and (D) when used in accordance with widespread and commonly recognized practice it will not generally cause unreasonable adverse effects on the environment. 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 Cold 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 s ubchronic 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 directions. EPA has not identified any toxic endpoints for non
- target mammals, birds, plants, aquatic, or soil organisms. Nor are there concerns for any threatened and endangered species. Thus, given that Cold Pressed Neem Oil has very low toxicity

and presents little 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 making these registration actions more transparent, EPA ha s p rovid 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. Currently , EPA is providing a 30
- day public comment period on the decision to approve the “first i ndoor use” of Cold Pressed Neem Oil. 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 equipment 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 inc ome, 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**Cold Pressed Neem Oil**  **Page 15**  **of 21**  **Biopestic ides Registration Action Docum**  **ent** population who, as a result of their location, cultural practices, or other factors, may have aty pical, 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 aty pical, unusually

high ex posure 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 data 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 information stated in the previous paragra ph, 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 ty

pes of data are listed below. **A. R**  **epor ting 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**  Additionally , all incidents of hy persen sitivity

(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**  **Biopestic ides Registration Action Docum**  **ent VII.**  **Appendix A**

**TABLE 1. Product Chem istry Data Requirem**  **ents for**  **Cold Pressed Neem Oil**  **(40 CFR § 158.2030) Biochem**  **ical Data Requirem ent by**  **OCSPP Guideline Num ber**  **MRID (s)**  **Description of R**  **esult** 880.110 0 Product identity; 880.1200 Manufacturing process; 880.1400 Discussion of formation of

unintentional ingredients 47538701 Submitted data sati sfy 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. 830.1750 Certified l imits 47538701 Not required for TGAIs. 830.1800 Enforcement analytical

method 47538701 Not required for TGAIs.

a Data submitted via self certification per Pesticide Registration Notice (PRN) 98
- 1
. **TABLE 2. Physical and Chem ical Properties of Cold Pressed Neem**  **Oil (40 CFR § 158.2030)**  **Biochem ical Data Requirem**  **ent by OCSPP**  **Guideline Num ber**  **MRID(s) Description of**  **R esult**  830.6302 Color a Yellowish brow n 830.6303 Physical State a Liquid at 20°C 830.6304 Odor a Strong, garlic
- like 830.6313 Stability 47476701 10% degradation at 11months under unregulated storage conditi ons/shipment 830.7000 pH a 5.3 at 21°C (70°F) 830.7050 UV/Visible Absorption a 215 nm 830.7200 Melting Range a Not applicable; product is a liquid 830.7220 Boiling Range a BP > 2 00 o C (392 o F) 830.7300 Density/Relative

Density/Bulk Density a 0.922 g/mL ( 8.27 lb/gal) at 22°C (72°F)
830.7370 Dissociation Constant in

Water a Not applicable; the product does not su bstantially dissociate in water 830.7550 Partition Coefficient a Log K ow = 6.26 830.7840 Water Solubility a 52.3 mg/L 830.7950 Vapor Pres sure a 2.5 x 10 **- 7**  mm Hg at 25oC**Cold Pressed Neem Oil**  **Page 17**  **of 21**  **Biopestic ides Registration Action Docum**  **ent**
**Table 3. Hum an Toxicology Data Requirem**  **ents for Cold Pressed Neem Oil**  **(40 CFR § 158.2050) Biochem**  **ical Da ta**  **Requirem ent by OCSPP**  **Guideline Num ber**  **MRID(s) Description of Result**  **Toxicity Category**  870.1100 Acute oral [rat]

toxicity 47088002 1

47208801 **2** LD 50 = >5000 mg/kg for female IV 870.1200 Acute dermal

[rabbits] toxicity 47088003 1

47208802 2 LD 50 = >2000 mg/kg for males,

females, and combined III
870.1300 Acute inhalation

[rat] toxicity 47088005 1

47208803 2 The inhalation LC 50 for males, females,

and combined wa s > 2.53 mg/L & > 2.11 mg/L, respectively, at concentrations of azadirachtin of 0.30% & 0.15% IV

870.2400 Acute eye

irritation [rabbit] 47088006 1

47208804 2 No irritation w as noted on any rabbit

throughout the study. Plasma NeemTM Oil was non
- irritating. IV
870.2500 Acute dermal

irritation [rabbit] 47088007 1 No irritation w as noted on any rabbits throughout the study. The primary irritation index was 0.0. Plasma NeemTM Oil was non
- irritati ng. IV

870.2600 Skin sensitization

[guinea pig] 47088004 1 After three consecutive weekly inductions, the test and control animals showed no signs of reactivity at 24 and 48 hours after challenge. Not a dermal sensitizer
870.310 0 90
- Day Oral

f eeding [mouse] Awad (2003) LD 50 = >5000 mg/kg No subchronic oral toxicity 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**  **Biopestic ides Registration Action Docum**  **ent**
**Table 4: Estim**  **ated Cold Pressed Neem Oil residues on terrestrial m**  **atrices using the Terrestrial Exposure mo**  **del (T -**  **Rex; EPA, 2005)**  **Terrestrial m a**  **trix Dietary**  **- based Estim**  **ated Environm ental 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 1 47208801 **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 >10 00 mg/kg

(highest acute dose tested) No effects at highest dose tested 850.2100 Avian Dietary

Toxicity (redwinged
blackbird) Schafer & Jacobsen.

(1983); (47633502) LD 50 > 10000 ppm (1.0%) Practically non - toxic Avian Dietary Toxicity (Leghorn hen) Verm a et al. (1998)

(474787
- 05) 12
- we ek LD 50 > 12000 ppm (6.0%

neem oil in neem cake feed) Practically non - toxic 850.1075 Fish Toxicity Awad (2003) (476335
- 01) 96
- hr LC 50 s= 70.6

– 84.3 ppm Slightly Toxic 850.1300 Aquatic

Invertebrates Awad (2003) (476335
- 01 ) 48
- hr LC 50 s= 57.5
- 63.9 ppm Slightly Toxic 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 3 Practically non - toxic 850.3020 Honey bees Melathoupoulos et al. (2 000) Contact LD 50 > 45 ug/bee (adult) Practically non - toxic 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 Requirem ents for**  **Cold Pressed Neem Oil**  **(40 CFR § 158.2060) Cold Pressed Neem**  **Oil Page**  **19 of**  **21 Biopestic**  **ides Registration Action Docum ent**  **VIII. Appendix B**  For product specific information, please ref er to : http://oaspub.epa.gov/pestlabl/ppls.home**Cold Pressed Neem Oil**  **Page 20**  **of 21**  **Biopestic ides Registration Action Docum**  **ent 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: Pentatomidae). J ournal of Agricultural Urban Entomol ogy . 21(1): 9

– 13
. Canadian Honey

Council (CHC). 2005. Essential oils and their toxicity to honey bees. 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/ ) Lo wery , D. T. and M. B. I sman. 1995. Toxicity of neem to natural enemies of aphids. Phy toparasitica 23(4): 297
- 306. Methathopoulos, A. P., M. L . Winston, R. Whittington, T. Smith, C. L indberg, A. Mukai, M. Moore. 2 000. Comparative laboratory toxicity of neem pesticides to honey bees (Hy menoptera: 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 Phy siology 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. I sman. 1996. Toxicity of a neem (Azadirachta indica A. Juss) insecticide to larval honey bees. 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 contaminants, and agricultural wastes. 30: 685
- 698.**Cold Pressed Neem Oil**  **Page 21**  **of 21**  **Biopestic ides Registration Action Docum**  **ent**
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. Pest 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
- REX, 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 Manufacturing Use Product and Plasma Neem Oil Biological Insecticide. Each Product is I dentical and Contains 100% Neem Oil (w/0.3% Azadirachtin) As Its Active In gredient. March 9, 2009.