BIOPESTICIDES REGISTRATION ACTION DOCUMENT



# Tea Tree Oil

PC Code : 028853

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

August 11, 2014Tea Tree Oil Page 2 of 32 Biopesticides Registration Action Document

TABLE OF CONTENTS

I. EXECUTIVE SUMMARY: ................................................................................................ 5

II. ACTIVE INGREDIENT OVERVIEW ............................................................................. 6

III. REGULATORY BACKGROUND...................................................................................... 6

A. Classification ................................................................................................................ ........ 6

B. Food Clearances/Tolerances ............................................................................................... 6

IV. RISK ASSESSMENT ......................................................................................................... 7

A. Active Ingredient Characterization.................................................................................... 7

B. Human Health Assessment.................................................................................................. 8

1. Toxicology .................................................................................................................... .................................. 8

2. Dose Response Assessment ...................................................................................................... ................... 13

3. Food Quality Protection Act (FQPA) Considerations ............................................................................. . 13

4. Occupational, Residential, School and Day Care Exposure and Risk Characterization ...................... 18

5. Aggregate Exposure from Multiple Routes Including Dermal, Oral, and Inhalation ........................... 20

6. Cumulative Effects ............................................................................................................ .......................... 20

7. Risk Characterization ................................................................................................... .............................. 21

C. Environmental Assessment ............................................................................................... 21

1. Ecological Hazards ............................................................................................................ .......................... 21

2. Environmental Fate and Ground Water Data ...................................................................................... .... 21

3. Ecological Exposure and Risk Characterization ................................................................................. ..... 22 4. Endangered Species Assessment ........................................................................................... ..................... 22

D. Product Performance Data .............................................................................................. 22

V. RISK MANAGEMENT DECISION ................................................................................ 23

A. Determination of Eligibility for Registration .................................................................. 23

B. Regulatory Decision ........................................................................................................... 23

C. Environmental Justice ....................................................................................................... 2 3

VI. ACTIONS REQUIRED BY REGISTRANTS................................................................. 23

A. Reporting of Adverse Effects ............................................................................................ 24

B. Reporting of Hypersensitivity Incidents .......................................................................... 24Tea Tree Oil Page 3 of 32 Biopesticides Registration Action Document

VII. APPENDIX A. DATA REQUIREMENTS (40 CFR PART 158-SUBPART U) .......... 24

VIII. APPENDIX B. ............................................................................................................. ....... 29

IX. APPENDIX C. ................................................................................................................. .. 29

X. GLOSSARY OF ACRONYMS AND ABBREVIATIONS ............................................. 30Tea Tree Oil Page 4 of 32 Biopesticides Registration Action Document



### BIOPESTICIDES REGISTRATION AC TION DOCUMENT (BRAD) TEAM



## Branch Chief Linda A. Hollis, M.S.

Product Chemistry/Human Health Effects/Nontarget Organisms Angela L. Gonzales, Biologist

Regulatory Action Leader Colin G. Walsh, M.S., BiologistTea Tree Oil Page 5 of 32 Biopesticides Registration Action Document

I. EXECUTIVE SUMMARY:

Tea tree oil is a new biochemical pesticide act ive ingredient intended for non-food use treatment as a fungicide/bactericide on the following f ood commodities: leafy vegetables (group 4), fruiting vegetables (group 8), cu curbit vegetables (group 9), berri es (group 13), tree nuts (group 14), cereal grains (group 15), avocado, banana, mango, papaya, passion fruit, plantain, and peanuts. The active ingredient is extracted from the leaves and terminal branches of the tea tree ( Melaleuca alternifolia ), which is a member of the plant fa mily Myrtaceae and is indigenous to Australia, New Zealand, and Southeast Asia. Te a tree oil is composed of approximately 100 different compounds which cons ist of terpene hydrocarbons , primarily monoterpenes, sesquiterpenes, and their associat ed alcohols. The active ingredient has antifungal properties and is effective against a broad spectrum of plant- pathogenic fungi. Tea tree oil has been shown to affect cell respiration an d alter cell membrane structure in y east. Based on this information, the Agency considers the mode of action to be nontoxic.

The Biopesticides and Pollution Prevention Divisi on (BPPD) has reviewed all of the data and other information submitted in suppo rt of the registration of tea tr ee oil as a fungicide/bactericide under Section 3(c)(5) of the Fede ral Insecticide, Fungicide and Rodenticide Act (FIFRA), and has determined that the current data requi rements (40 CFR part 158.2010 through 158.2070) for registration of a biochemical pes ticide have been satisfied. Give n that tea tree oil is of low toxicity and presents little, if any, risks to humans, including infa nts and children, and the environment, the U.S. Environmental Protecti on Agency (EPA or the Agency) has concluded

that it is in the best interest of the public to issu e registrations for the manufacturing-use product (MP), Tea Tree Oil Technical (E PA File Symbol No. 86182-E), and the end-use product (EP), Timorex Gold (EPA File Symbol No. 86182-R), wh ich contain this new active ingredient, tea

tree oil. The basis for this decision is described in more detail in section IV of this Biopesticide Registration Action Do cument (BRAD).

On October 1, 2009, EPA announced a policy to provi de a more meaningful opportunity for the public to participate on major regi stration decisions before they occur. According to this policy, EPA provides a public comment period prior to making a registration decision for the following types of applications: new active ingredients, fi rst food use, first outdoor use, first residential use; and any registration decisions for which the Agency believes there may be substantial public

interest.

Consistent with the policy of ma king registration actions more transparent, tea tree oil is subject to a 15-day comment period as a “new active ingr edient.” EPA has established a comment period of 15 days on the basis of tea tree oil’s low toxici ty, the determination that tea tree oil presents low risk of any adverse effects to human health and the environment, and need for this active ingredient. The notice for this comment period includes the draft BRAD a nd draft product labels for the MP, Tea Tree Oil Technical, and EP, Timorex Gold, which contain this new active ingredient, tea tree oil. Th e docket identifica tion (ID) number is EPA-HQ-OPP-2009-0440. The Agency believes that based on the risk assessmen t and information submitted in support of the registration of the MP and EP cont aining tea tree oil, it is in the best interests of the public to issue the registration for Tea Tree Oil Technical and Timorex Gold. The basis for this decision

can be found in the risk assessment for tea tree oil, which is characterized in this BRAD.Tea Tree Oil Page 6 of 32 Biopesticides Registration Action Document

For definitions of scientific terms, please refer to http://www.epa.gov/pesticides/glossary/

.

II. ACTIVE INGREDIENT OVERVIEW

Common Name: Tea Tree Oil

Chemical Names: Tea Tree Oil; Oils, tea-tree

Trade & Other Names: Tea Tree Oil Technical

CAS Registry Number: 68647-73-4

OPP Chemical Code: 028853

Type of Pesticide: Fungicide/Bactericide

III. REGULATORY BACKGROUND

On April 10, 2009, EPA received an applica tion filed by Technology Sciences Group, Inc. (TSG), 1150 18 th Street, NW, Suite 1000, Washington, DC 20036, on behalf of Biomor Israel, Ltd. (Biomor), P.O. Box 81, Qatzrin, 12900 Israel, to register the products, Timorex Gold (EPA File Symbol No. 86182-R) and Tea Tree Oil Technical (EPA File Symbol No. 86182-E), containing the new biochemical activ e ingredient, tea tree oil. A no tice of receipt (NOR) of this application, allowing for a 30-day co mment period, was published in the Federal Register on July 22, 2009 (74 FR 36215). No comments we re received following this publication.

A. Classification

On October 28, 2004, EPA’s Biochemical Classifica tion Committee determined that tea tree oil is a biochemical pesticide. The biochemical classi fication committee indicated that tea tree oil is a fungicide/bactericide. The active ingredient has been shown to disrupt membranes of fungal/bacterial species. Tea tree o il is the essential oil of the Mela leuca tree (tea tree) and is rich in terpene alcohols (such as terp inen-4-ol and eucalpyptol). The o il is manufactured to contain at least 30% terpinen-4-ol (germi cidal) and no more than 15% eucalpyptol (anti-fungal). The terpinen-4-ol is generally accepted to be the acti ve component of tea tree oil. There is a long history of use of tea tree oil as an antiseptic and antifungal agent and it is formulated into creams, soaps, mouthwashes, toothpaste, and other cosmetic products.

B. Food Clearances/Tolerances

The consultant, TSG on behalf of Biomor, filed a petition (PP 9F7558) proposing to establish an exemption from the requirement of a tolerance for residues of tea tree oil in or on all food commodities. A notice of filing (NOF), allowing for a 30-day comment period, was published inTea Tree Oil Page 7 of 32 Biopesticides Registration Action Document

the Federal Register on July 22, 2009 (74 FR 36200). No comme nts were received following this publication.

EPA determined during the review of the petiti on that the data and information submitted was insufficient to support an exemption from the requi rement of a tolerance for residues of tea tree oil in or on all food commodities. However, as no ted in the Risk Assessment section of this BRAD (Section IV), EPA has made a non-food us e determination, with limitations, for the following food commodities: leafy vegetables (gr oup 4), fruiting vegetables (group 8), cucurbit vegetables (group 9), berries (g roup 13), tree nuts (group 14), cerea l grains (group 15), avocado, banana, mango, papaya, passion fru it, plantain, and peanuts. The limitations for the non-food use determination are a pre-harvest interval (PHI) of 48 hours and a maximum application rate of 1.54 lbs a.i./acre (EPA, 2014b).

IV. RISK ASSESSMENT

A. Active Ingredient Characterization

Tea tree oil is a new biochemical pesticide act ive ingredient intended for use to prevent and control diseases such as powdery mildew, Botr ytis, and black sigatoka in horticultural and agricultural crops. The active ingr edient has antifungal pr operties and is effective against a broad spectrum of plant-pathogenic fungi, but the mode of action is not clearly understood. It has been shown to affect cell respirati on and alter cell membrane structure in yeast. Based on this information, the Agency considers th e mode of action to be nontoxic.

The active ingredient is extracted from the leaves and terminal branches of the tea tree ( Melaleuca alternifolia ) which is a member of the plant fa mily Myrtaceae and is indigenous to Australia, New Zealand, and Southeast Asia. Te a tree oil is composed of approximately 100 different compounds which cons ist of terpene hydrocarbons : primarily monoterpenes, sesquiterpenes, and their associated alcohol s. These biogenic chemicals are aromatic hydrocarbons which are found in the essential oils of a multitude of plants and are characterized by their high volatility and low aqueous solubili ty (EPA, 2010). The composition of tea tree oil used in commerce is regulated by an inte rnational standard (ISO 4730, International Organization for Standardisation), which sets maximum and minimum limits for 14 of its components. Of the several vari eties or chemotypes of tea tree oil, only the terpinen-4-ol chemotype, which contains 30-48% terpinen-4-ol, will be used as the TGAI in the proposed MP, Tea Tree Oil Technical (EPA File Symbol No. 86182-E). ISO 4730 defines the main ingredients

as α -terpinine (5-13%); 1,8-cineole (traces to 15%); γ -terpinine (10-28%); p-cymene (0.5-12%); and terpinen-4-ol (30-48%). The sp ecifications for all 14 ingredients are listed in Table 1 below.

TABLE 1. Specifications of Tea Tree O il Components per ISO Standard 4730 1

Name CAS No. Minimum % Maximum %
Terpinen-4-ol 562-74-3 30 48

γ -Terpinine 99-85-4 10 28

α -Terpinine 99-86-5 5 13

α -Terpineol 98-55-5 1.5 8

α -Terpinolene 586-62-9 1.5 5Tea Tree Oil Page 8 of 32 Biopesticides Registration Action Document

α -Pinene 80-56-8 1 6
p-Cymene 99-87-6 0.5 8
1,8-Cineole 470-82-6 Trace 15

Limonene 138-86-3 0.5 1.5

Aromadendrene 489-39-4 0.5 3

δ -Cadinene 483-76-1 Trace 3

Sabinene 3387-41-5 Trace 3.5

Globulol 489-41-8 Trace 1

Viridiflorol 552-02-3 Trace 1

Ledene Trace 3

1 from MRID 47730409

Humans are already naturally exposed to the majo r constituents of tea tree oil (terpinen-4-ol, γ

terpinene, 1,8-cineole, and α -terpinene) in the diet as they ar e found in herbs, spices, fruits, and some vegetables (EPA, 2014b). Huma ns are also exposed to the major constituents of tea tree oil as food additives in the diet, as they have been approved as substances that may directly be added to food by the U.S. Food and Drug Ad ministration (FDA) under 21 CFR § 172.515(b). Tea tree oil is comprised of primarily terpenes and their associated alcohols which are found in the environment as they are emitted by and present in a variety of plant species and water sources. Additionally, tea tree oil has a long hist ory of use as a remedy for acne, eczema, skin infections, cold sores, blisters, and warts; and is used in cosmetic and personal care products such as shampoo, toothpaste, mouthwash, deodorants, lo tions, and bath oils, as well as in animal care products (EPA, 2010).

Descriptions of the product formulation and pr oduction process, formation of impurities, and physical and chemical characterist ics of tea tree oil were exam ined by BPPD and found to be acceptable in meeting current guideline standards.

All product chemistry data requirements for registration of tea tree oil have been satisfied.

For more information regarding product chemistry data requirements, refer to Tables 4 and 5 in Appendix A.

B. Human Health Assessment

1. Toxicology

For acute toxicity data requirements, toxicity categories are assigned based on the hazard(s)

identified from studies and/or information on fi le with the Agency. The active ingredient is classified into Toxicity Category I, II, III, or IV where Toxicity Category I indicates the highest toxicity and Toxicity Category IV indicates the lowest toxicity.

Adequate mammalian toxicology data/information is available to support regi stration of tea tree oil. All toxicology data requireme nts for tea tree oil have been satisfied.Tea Tree Oil Page 9 of 32 Biopesticides Registration Action Document

a. Acute Toxicity

Acute toxicity testing is required to: 1) determine systemic toxici ty from acute exposure via the dermal, inhalation, and oral routes; 2) determine ir ritant effects from exposure to the eyes; and 3) determine the potential for skin sensitiz ation (allergic contact dermatitis).

A Tier I primary dermal irritation study in rabb its submitted and reviewed showed that tea tree

oil is corrosive to the skin at undiluted concentr ations (toxicity category I). Based on the results in the primary dermal irritation study, the primar y eye irritation and derm al sensitization data requirements were waived; therefore, tea tree oil is classified as corrosive to the eye (toxicity category I). Tea tree oil is a toxi city category III (slightly toxic) compound via the acute oral and dermal toxicity routes of exposure based on a median lethal dose (LD 50 ) of 1,752 mg/kg body weight in rats and a LD 50 of greater than 2,000 mg/kg in rabbi ts, respectively. T ea tree oil is a toxicity category IV (not toxic) compound for acute inhalation toxicity ba sed on a medial lethal concentration (LC 50 ) of 3.64 mg/L.

For more information regarding acute toxicity data requirements, refer to Table 6 in Appendix A.

b. Subchronic Toxicity

Subchronic data are required to determine a no-observed-effect-level (NOEL) and any toxic effects associated with repeated or continuous exposure to a test substa nce for a period of 90 days via the oral, dermal, and inhalation routes of exposure

.

A 90-day oral toxicity study (OCSPP 870.3100) wa s conducted on tea tree oil and submitted in MRID 48598702. Adequate supportive information re garding homogeneity testing of the test

substance was submitted in MRID 48878202. Tea tree oil was administered to Wistar rats by gavage at dosages of 0 (peanut oil), 30, 60 or 120 mg/kg/day. An additional 20 rats were included in the high dose group, and an additional 10 rats were included in the control group. To determine the reversibility of any effects observe d, 10 rats from the high dose group and 5 rats from the control group were sacrificed 14 days and 28 days after completion of the 90-day dosing period. No mortality was observed in ma le rats. Two moribund females in the high dose group were sacrificed during the treatment perio d. At all dose levels salivation was observed which persisted for about 30 minutes after dosing. Salivation incidences were dose-related. No treatment-related effects on body weight and body weight gain were observed. Toxicologically relevant hematological, clinical chemistry, or urinalysis findi ngs were not noted at any dose level. In the high dose group, some motor act ivity measurements were statistically (p ≤ 0.05) affected in both sexes; however, the toxicological significance of these observations is unclear as

there was no correlation with abnor mal functional observations. Stat istically significant increases in liver to body weight ratios at the mid- and high-dose levels (+11% and +9%, respectively) were noted in females, and a si gnificant increase in ovary to b ody weight ratio was noted in the 28-day high dose recovery group (+31%). There wa s no microscopic correlation for the organ weight findings in females. Flaccid testes, some with a small appearance, were observed in highdose males (4/10 at the end of treatment; 2/10 afte r the 14-day recovery pe riod; 8/10 after the 28- day recovery period). Absolute organ weight and organ-to-body-weight rati os were significantly reduced in the testes and epididymides of male s in the high-dose 28-day recovery group. TheseTea Tree Oil Page 10 of 32 Biopesticides Registration Action Document

findings were microscopically associated with de generative changes in the seminiferous tubules (loss of germ cells, formation of multinucleated germ cells, presence of cell debris in tubular lumen, atrophic appearance, and sert oli cell vacuolation). The testicular effect s occurred at the same or higher rate of incidence with an overa ll greater degree of severity in the high dose animals in the 14-day and 28-day recovery groups . Sperm granulomas and cellular debris in the lumen (inflammation involving epididymal lumen and interstitium with the presence of large zones of spermatozoa surrounded by a zone of m acrophages, giant cells and fibroblasts) were observed in the epididymides of high dose male s at the end of the 90- day treatment period. The incidence of sperm granulomas peaked in th e 14-day recovery group, but the incidence and severity of cellular debris in the epididymal lumen increased in the 14- and 28-day recovery groups. Minimal cell debris was observed in the lu men of the epididymides in 1/10 male rats dosed at 60 mg/kg/day. No treatme nt-related histological changes we re observed in males dosed at 30 mg/kg/day. Statistically significant treatment-related effects on sperm motility, sperm morphology, and epididymal sperm counts were obser ved at the high dose level at the end of the treatment period and in the 14- and 28-day re covery groups. Sperm counts were significantly lower relative to controls in the mid-dose gr oup, and there was a signifi cant decrease in sperm motility and an insignificant incr ease in abnormal sperm at this dose level. Based on these data, the lowest-observed-adverse-effect level (LOAEL) of tea tree oil in rats was 60 mg/kg/day based on testicular toxicity in male s and increased liver to body wei ght ratios in females. The noobserved-adverse-effect level (NOAEL) is 30 mg/kg/day for males and females (EPA, 2013).

A 90-day dermal toxicity study was not submitted and is not required. Exposure via the dermal route is not anticipated due to the following: 1) prolonged derm al exposure is not expected because the product is not purposely applied to th e skin and handlers/applicators are required to wear appropriate personal protect ive equipment (PPE); 2) a 4-hour restricted-entry interval (REI) requirement has been included on the proposed EP label which will further mitigate exposure; and 3) tea tree oil has a long history of use in a variety of dermally-applied products, including shampoo, deodorants, lotions, and antifungal tr eatments. In a non-guideline 30-day dermal irritation study on rabbits (MRID 47730404), undiluted tea tree oil caused seve re irritation to the skin on the first day of the study. For the remai nder of the study, a 25% solution in paraffin oil was applied to the skin which did not result in visible irritation; however, non-specific microscopic dermatitis consistent wi th irritation was observed (EPA, 2013).

A 90-day inhalation toxicity study was not subm itted for tea tree oil. In lieu of a study, the applicant cited the data from the 90-day or al toxicity study (MRID 48598702). Due to the use pattern of the active ingredient as a spray and th e volatility of the constituents of tea tree oil, exposure to handlers/applicators is possible. Th ere are no PPE requirements regarding mitigation of inhalation exposure on the proposed EP label. A route to route extrapolation using the default assumption that 100% of the tea tree oil is absorbed into th e body has been employed. The Agency is confident that this approach is pr otective of potential rep eat exposure inhalation toxicity for the following reasons: 1) tea tree oil is classified into Toxicity Category IV for acute inhalation toxicity and Toxicity Category III for acute oral toxi city; and 2) humans are already exposed to the constituents of tea tree oil as the oil is used in a variety of dermally-applied cosmetic and pharmaceutical products. Moreover, five of the main com ponents of tea tree oil (terpinen-4-ol, γ -terpinine, α -terpinine, p-cymene, and 1,8-cine ole) are all approved for use by

the FDA as direct food additives under 21 CF R 172.515. Further, in an occupational riskTea Tree Oil Page 11 of 32 Biopesticides Registration Action Document

assessment conducted for applicators and handlers (who may be exposed via inhalation to tea tree oil), margins of exposure (MOEs) were de rived and were significantly higher than the Agency’s level of concern (LOC) of 100 (MOEs ranged from 4,900 to 150,000). Because the MOEs were significantly higher than the LOC, the Agency believes that an adequate margin of safety has been achieved to account for any poten tial difference in toxicity from oral versus inhalation exposure (EPA, 2013).

For more information regarding the subchronic toxi city data requirements, refer to Table 7 in Appendix A.

c. Developmental Toxicity and Mutagenicity

A developmental toxicity study conducted on tea tree oil was submitted in MRID 49166401. In the study, Wistar rats were administered doses of tea tree oil by gavage at 0, 30, 60, or 120 mg/kg/day from day 5 to day 19 of gestation. Ea ch treatment group consisted of 24 female rats; the control group which received peanut oil, the test substance vehicle, also consisted of 24 female rats. Initially, rats were dosed at 75, 150, and 300 mg/kg/day; however, there was a mortality on day two of treatment in the high dos e group and treatment rela ted clinical signs in the mid- and high-dose groups. Consequently, do ses were reduced to 30, 60 and 120 mg/kg/day. At the start of treatment, animals were approxima tely 13-15 weeks old, within a weight range of approximate 224g ± 15g and healthy in appearan ce. Animal acclimatization, housing, diet, and water supply were reported adequately. Test subs tance characterization an d preparation was also reported adequately. Animals were dosed once a day at approximately the same time each day. Physical examinations occurred on day 0 of gestation and at weekly intervals during the gestation period. Clinical observatio ns occurred at leas t twice a day on treatment days (pre- and post-dosing) and once a day on other days. Body weights were measured on days 0, 3 and 5, 8, 11, 14, 17, and 20 after mating and food consum ption was measured throughout the study. Animals were sacrificed on day 20 after mating under isoflurane anesthesia. Gross necropsy was performed on all rats, which consisted of extern al observation and examination of thoracic and

abdomen viscera and examination of uterine cont ents. Gravid uterine weights, the number of corpora lutea in each ovary, the number of impl antation sites, the number of early and late resorptions sites, the number of live and dead fetuses, individua l fetal body weights, fetal sex,

and the fetal sex ratio were recorded. Fetuses we re also examined for external abnormalities, visceral organ abnormalities and skeletal develo pment and abnormalities. Statistical analyses of the data were provided in th e study. Significant reductions in maternal body weight gain and food intake were observed during the treatment period in the mid- and high-dose groups and throughout gestation in the hi gh dose group. These observations were considered treatment related. No gross pathological fi ndings were observed in the dams in any group. At all dose levels, mean gravid uterine wei ghts, the number of corpora lut ea, the number of implantations, and pre and post-implantation losses were all st atistically comparable to the control group. Significant resorption was observed in dams in the high dose group when compared to the control group. At all dose levels, the total number of fetuses, mean litter size, number of live fetuses, and the sex ration were all statistica lly comparable to the control group. Mean fetal body weights of males, females, and total fetuses we re significantly reduced at the mid and high dose level; however, the weights of the fetuses in th e mid dose group were comp arable to historical control data. Any fetal anomalies and abnormalitie s that were observed were routinely observedTea Tree Oil Page 12 of 32 Biopesticides Registration Action Document

in rat fetuses, were comparable to the control group or were comparable to historical control data; none were considered treatment related. Based on the results of the study, the maternal NOAEL is 30 mg/kg/day and the LOAEL is 60 mg /kg/day based on reduced body weight gain and food consumption. The developmental NOAEL is 60 mg/kg/day and the LOAEL is 120 mg/kg/day based on reduced fetal body weight (EPA, 2014a).

In a study published in the New England Jour nal of Medicine (Henley, 2007), study authors reported that repeated topical exposure to lavender and tea tr ee oils may cause prepubertal gynecomastia in boys. Three prepubertal boys who were otherwise healthy and had normal serum concentrations of endogenous steroids exhibited gynecomas tia that coincided with the topical application of products that contained lavender and tea tr ee oils. The effect resolved in each boy shortly after the use of the products was discontinued. The authors also reported that

studies in human cell lines indicated that la vender and tea tree oils had estrogenic and antiandrogenic activities. Although the study suggests that exposure to topi cal applications of products containing lavender and te a tree oils may result in gynecomastia in boys, the Agency

has concluded that the uses of tea tree oil as a pesticide will not result in unreasonable adverse effects to this population subgroup. This conclusion is based upon the following: 1) tea tree oil will not be applied topically to the skin. The ac tive ingredient will be applied to crops as an agricultural use; thus, expos ure is mainly anticipated to be via the oral route, 2) dietary exposure to tea tree oil as a pesticide is anticipated to be minimal as it de grades rapidly in the environment, 3) dermal exposure is not anticipa ted to result in risk as occupational exposure assessments (see subchronic toxicity section a bove) indicate MOEs that do not exceed the Agency’s level of concern, and 4) humans are alr eady exposed to the constituents of tea tree oil as they are found naturally in the diet, are used as food additives, and ar e found in a variety of cosmetic and pharmaceutical products.

A Tier I mutagenicity study [ in vitro reverse gene mutation assay (Ames) using Salmonella typhimurium strains TA98, TA100, and TA102 (MRID 47730404) ] showed that tea tree oil did

not increase the number of revertants at doses of <50 μg in the pres ence or absence of S9

metabolic activation. A Tier II mutagenicity study [ in vivo mammalian erythrocyte micronucleus assay (MRID 47730407)] showed that tea tree oil di d not produce a statistically significant increase in the frequency of micronucleated polyc hromatic erythrocytes in bone marrow of mice given oral doses of 1000-1750 mg/kg body weight . Therefore, under the conditions of both assays, tea tree oil is consid ered to be non-mutagenic.

For more information regarding prenatal develo pmental and mutagenicity data requirements, refer to Table 7 in Appendix A.

d. Tier II/Tier III

Tiers II and III data were not required due to th e nature of the active ingredient and its intended uses in potential new EP produc ts (fungicides/bactericides).

e. Effects on the Endocrine System

As required under Federal Food, Drug, and Cosm etic Act (FFDCA) section 408(p), EPA hasTea Tree Oil Page 13 of 32 Biopesticides Registration Action Document

developed the Endocrine Disrupt or Screening Program (EDSP) to determine whether certain substances (including pesticide ac tive and other ingredients) may have an effect in humans or wildlife similar to an effect pr oduced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two-tiered approach to making the statutorily required dete rminations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substan ce to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will pr oceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse e ndocrine related effects caused by the substance, and esta blish a dose-response relationshi p between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and nine inert ingredients.

This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-applic ation agricultural scenarios.

This list should not be construed as a list of known or likely endocrine disruptors.

Tea tree oil is not among the group of 58 pesticide activ e ingredients on the in itial list to be

screened under the EDSP. Under FFDCA section 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuin g future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pleas e visit our website: http://www.epa.gov/endo/

.

2. Dose Response Assessment

The NOAEL of 30 mg/kg bw/day has been selected as the point of departure (POD) for the

hazard and risk assessment. The NOAEL is based on toxic endpoints observe d in the 90-day oral toxicity study. The POD is prot ective of developmental toxicity because the NOAEL in the 90- day oral toxicity study is lowe r than the developmental (fetal ) toxicity NOAEL of 60 mg/kg bw/day.

3. Food Quality Protection Act (FQPA) Considerations

a. Dietary Exposure and Risk Characterization

EPA has made a non-food use determinati on, with limitations, fo r the following food commodities: leafy vegetables (group 4), fruiti ng vegetables (group 8), cucurbit vegetables (group 9), berries (group 13), tree nuts (group 14), cereal grains (gr oup 15), avocado, banana, mango, papaya, passion fruit, plantain, and p eanuts. The limitations for the non-food use

determination are a PHI of 48 hours and a maximu m application rate of 1.54 lbs a.i./acre (EPA,Tea Tree Oil Page 14 of 32 Biopesticides Registration Action Document

2014b). The Agency’s reasoning for the non-food use determination, with limitations, for tea tree oil is provided below.

As stated earlier in the document, the major co mponents of tea tree oil are moderately to highly volatile substances. A substance with a high vapo r pressure at normal te mperatures is often referred to as volatile. The vapor pressure is an indication of a substance' s evaporation rate and relates to the tendency of particles to escape from the substance. Up to 90% of tea tree oil has

been shown to volatilize with in 24 hours after ap plication (Chadwick, 2008; Gatenio, 2007). Based on these studies, substant ial volatilization is expected within the first 24 hours of application from plant, soil, and water surfaces . Tea tree oil constituents are quickly broken down in air through atmospheric reactions (PMR A, 2014; EFSA, 2012). Further, residue data reviewed by EPA in support of this non-food use determination indi cate the absence of quantifiable residues on tomatoes, peppers, and ba nanas immediately after application when tea tree oil was applied at a proposed application rate of 1.54 pounds of active ingredient per acre. These data demonstrate that tea tree oil, when ap plied at that applicati on rate, volatilizes even faster than what is reported in the Chadwick & Gatenio reports referenced above in this paragraph, and volatilizes complete ly. Volatilization from plant su rfaces and soil can be a major dissipation pathway for pesticides applied to crops. Generally, pe sticides volatilize from plant surfaces faster and to a greater extent than fr om soil (Bedos, 2002). Pesticide volatilization from plant surfaces often occurs rapidly after appl ication (Bedos, 2002). For example, 30 to 50% of lindane (vapor pressure estimat ed at 5 x 10-4 mmHg) was reported to volatilize from plant surfaces within one hour application regardless of the crop species, canopy structure or plant age (Bedos et al., 2002). More than 90% of the linda ne application volatilized from the plant surfaces over a period of 3 days. The data suggest th at over longer periods af ter application, leaf

characteristics do not interfere w ith volatilization (Bedos, 2002). Most of the pesticides evaluated by Bedos for volatilization after application have low vapor pressures, such as diazinon, with a vapor pressure of 5.43 x 10-5 mmH g, or dieldrin with a vapor pressure of 1.77x 10-5 mmHg (as estimated by EpiSuiteTM). These data suggest th at tea tree oil, which has a much higher vapor pressure than the example pesticides presente d by Bedos (2002), would readily volatilize from plant surfaces soon after applica tion, regardless of the surface area of the plant. Table 2 provides information on the vapor pressures of the constituen ts of tea tree oil all of which were measured at or near room temperature. As indicated in the table, the vapor pressure of tea tree oil is significantly higher than (by a ma gnitude of ~ 10,000) diazinon, a pesticide that has a low vapor pressure and therefore is not consider ed to be a volatile substance.

Table 2. Vapor Pressures of Tea Tree Oil Constituents Component Temperature (°C) Vapor Pressure (mmHg) Terpinen-4-ol 20 0.40

ɤ -terpinene 20 0.70

ɤ -terpinene 23.5 0.77

α -terpinene 20 0.80 p-cymene 25 1.50 1,8-cineole 25 1.90

Residue studies were submitted in which products containing varying amounts of tea tree oil (one to seven times the proposed application rate) were applied to tomatoes, peppers, and bananas. Analyses for residues of the three major components in the oil (terpinen-4-ol, γ

-Tea Tree Oil Page 15 of 32 Biopesticides Registration Action Document

terpinene, and 1,8-cineole) were performed in the studies. No detectab le residues (below the limit of quantification [LOQ] which was 0.05 ppm fo r the residue studies) were found in any of the commodities at the proposed application rate. The LOQ is the lowest amount of a substance that can be distinguished from the absence of th at substance for any par ticular analytical method. Residue studies were submitted in which a product was tested at approximately seven times (7X) the proposed application rate on tomatoes and peppers. No dete ctable residues were found in tomatoes. Detectable residues of terpinen-4-ol only were found for up to 48-hours on peppers at the 7X application rate. No detectable re sidues were found at 48-hours post-application. Acceptable residue data have not been submitted for any other crop. The available data indicate

that residues of tea tree oil ar e not likely to be present on edible commodities when tea tree oil is applied at the proposed applica tion rate with a PHI of 48 hours. As stated above, the major

constituents of tea tree oil are found naturally in most of the crops and crop groups listed in this document. Tea tree oil is primarily comprised of terpenes and thei r associated alcohols, all of which are found in a multitude of plants, as they are ubiquitous in the environment. Therefore, based on the rapid volatilization from the plant surfaces , it is likely that ev en if there are any tea tree oil constituent residues, the residues of these substances will not be distinguishable from background levels when tea tree oil is applied at the proposed applic ation rate and at the PHI of

48 hours.

Rationale behind the non-food use dete rmination for each crop group

Fruiting vegetables (group 8): tomatoes and pepp ers are representative commodities in this crop group. Residue studies on these crop s indicate that 1) residues are not likely to be present on treated commodities in this crop group when tea tr ee oil is applied at an application rate of 1.54 lbs a.i./acre and 2) residues ar e not likely to be present on tr eated commodities after 48 hours when tea tree oil is applied at an application rate approximately seven times the proposed rate.

The limitation in the non-food use determination for tea tree oil would be that the active ingredient cannot be applied at more than 1.54 lbs a.i./acre; therefore, re sidues are not likely to be present on these commodities when consumed.

Leafy vegetables (group 4): even though resi due data have not been submitted for leafy vegetables, the residue data on fr uiting vegetables (tomatoes and pe ppers) can be bridged to this crop group and a non-food use determin ation can be made based on th e following: 1) as stated above, the data from Bedos (2002) suggest that leaf characteristics do not interfere with volatilization; thus, the difference in surface textur e between fruiting and leafy vegetables is not likely to affect residue profiles; 2) a 48-hour PH I would give ample time fo r volatilization of the constituents of tea tree oil from plant surfaces. Further, the PHI of 48 hours is further supported because residues of terpinen-4-ol were below the LOQ by 48 hours in the residue study where tea tree oil was applied at the 7X application rate; and 3) the limitation in the non-food use

determination for tea tree oil would be that the ac tive ingredient cannot be applied at more than 1.54 lbs a.i./acre, the level at which no detectab le residues of tea tr ee oil were found. This

information indicates that residues of tea tree oil are not likely to be present when these

commodities are consumed.

Cucurbit vegetables (group 9): even though residue data have not been submitted for cucurbits, the residue data on fruiting vegetables (tomatoe s and peppers) can be bridged to this crop groupTea Tree Oil Page 16 of 32 Biopesticides Registration Action Document

and a non-food use determination can be made ba sed on the following: 1) residue profiles are anticipated to be similar between cucurbits and fruiting vegetables because they have similar surfaces (smooth, non-textured); 2) a 48-hour PHI would give am ple time for volatilization of the constituents of tea tree oil from plant surfaces. Further, the PHI of 48 hours is further supported because residues of terpinen-4-ol we re below the LOQ by 48 hours in the residue study where tea tree oil was applie d at the 7X application rate and 3) the limitation in the nonfood use determination for tea tree oil would be that the active ingredient cannot be applied at more than 1.54 lbs a.i./acre, th e level at which no detectable re sidues of tea tree oil were found.

This information indicates that residues of tea tree oil are not likely to be present when these

commodities are consumed.

Berries (group 13): even though residue data have not been submitted for berries, the residue data on fruiting vegetables (tomatoes and peppe rs) can be bridged to this crop group and a nonfood use determination can be made based on the following: 1) as stated above, the data from Bedos (2002) suggest that leaf characteristics do not interfere with volatilization; thus, the difference in surface texture between fruiting vegetabl es and berries is not likely to affect residue profiles; 2) a 48-hour PHI would give ample time for volatilization of the cons tituents of tea tree oil from plant surfaces. Further, the PHI of 48 hours is furthe r supported because residues of terpinen-4-ol were be low the LOQ by 48 hours in the resi due study where tea tree oil was applied at the 7X application ra te; and 3) the limitati on in the non-food use determination for tea

tree oil would be that the active ingredient cannot be applied at more than 1.54 lbs a.i./acre, the

level at which no detectable resi dues of tea tree oil were found. Th is information indicates that residues of tea tree oil are not likely to be present when these commodities are consumed.

Tree nuts (group 14): even though residue data have not been submitted for tree nuts, the residue data on fruiting vegetables (tomatoes and peppe rs) can be bridged to this crop group and a nonfood use determination can be made based on the following: 1) as stated above, the data from Bedos (2002) suggest that leaf characteristics do not interfere with volatilization; thus, the difference in surface texture between fruiting vege tables and tree nuts is not likely to affect residue profiles; 2) a 48-hour PHI would give ampl e time for volatilization of the constituents of tea tree oil from plant surfaces. Further, the PHI of 48 hours is further supported because residues of terpinen-4-ol were below the LOQ by 48 hours in the residue study where tea tree oil was applied at the 7X applicati on rate; and 3) the limitation in the non-food use determination for

tea tree oil would be that the active ingredient cannot be app lied at more than 1.54 lbs a.i./acre,

the level at which no detectable residues of t ea tree oil were found. This information indicates that residues of tea tree oil are not likely to be present when these commodities are consumed. Additionally, although not anticipa ted, if residues were availabl e, they would be found on the shells of the nuts, wh ich are not consumed.

Cereal grains (group 15): even though residue data have not been submitted for cereal grains, the residue data on fruiting vegetabl es (tomatoes and peppers) can be bridged to this crop group and

a non-food use determination can be made based on the following: 1) as st ated above, the data from Bedos (2002) suggest that l eaf characteristics do not interfer e with volatilization; thus, the difference in surface texture between fruiting vegetabl es and cereal grains is not likely to affect residue profiles; 2) a 48-hour PHI would give ampl e time for volatilization of the constituents of tea tree oil from plant surfaces. Further, the PHI of 48 hours is further supported becauseTea Tree Oil Page 17 of 32 Biopesticides Registration Action Document

residues of terpinen-4-ol were below the LOQ by 48 hours in the residue study where tea tree oil was applied at the 7X applicati on rate; and 3) the limitation in the non-food use determination for

tea tree oil would be that the active ingredient cannot be app lied at more than 1.54 lbs a.i./acre,

the level at which no detectable residues of t ea tree oil were found. This information indicates that residues of tea tree oil are not likely to be present when these commodities are consumed. Additionally, cereal grains are not typically consumed straight fr om the field and are processed and/or cooked prior to consumption which woul d further mitigate the potential for residues due

to the increased time for volatilization and/ or removal of tea tree oil’s constituents.

Avocado, banana, mango, papaya, passion fruit, p eanut, and plantain: residue data have been

submitted for bananas which indicated that no re sidues were found at the proposed application rate. Even though residue data have not been su bmitted for the other crops, the residue data on fruiting vegetables (tomatoes and peppers) can be bridged to this crop group and a non-food use determination can be made based on the following : 1) as stated above, the data from Bedos (2002) suggest that leaf characteristics do not interfere with vo latilization; thus, the difference in surface texture between fruiting vegetables and tree nut s is not likely to affect residue profiles; 2) a 48-hour PHI would give ample time for volatilizati on of the constituents of tea tree oil from plant surfaces. Further, the PHI of 48 hours is further supported because residues of terpinen-4-ol were below the LOQ by 48 hours in the residue st udy where tea tree oil was applied at the 7X application rate; and 3) the limitation in the non -food use determination for tea tree oil would be that the active ingredient cannot be applied at more than 1.54 lbs a.i./acre, the level at which no

detectable residues of tea tree oil were found. This information indicates that residues of tea tree oil are not likely to be present when these comm odities are consumed. Furt her, for the crops for which the skin is not consumed, (avocado, plan tain, and peanuts), the potential for residues available at the time of consumption is further reduced.

There is sufficient justificati on to support a non-food use determ ination for tea tree oil with limitations on the crops and crop groups identifi ed previously in this document. The non-food

use determination is based on the fo llowing: 1) the constituents of tea tree oil are very volatile

which indicates that residues are not likely to be present in or on food; 2) no residues of the major constituents of tea tree oil were found on bananas, peppers, and tomatoes in residue studies at the proposed applica tion rate for the rule; 3) a PH I of 48-hours is sufficient to compensate for the lack of residue data on the ot her listed crops and will provide ample time for dissipation of any residues; 4) the application ra te limitation mitigates the potential for residues because no residues were found on bananas, peppers, and tomatoes at this application rate; 5)

even if residues of tea tree oil’s constituents were found on edible crops they are not likely to be distinguishable from background levels since thes e substances are naturally found in plants; and 6) washing, rinsing, and processi ng of commodities and weather even ts such as rain will further reduce any possibility for residues.

Based on the analysis provided in this BRAD, the Agency concludes that use of tea tree oil in accordance with the limitations specified in the paragraph above will not result in residues on food. For the sake of transparency, the Agency in tends to promulgate an amendment to 40 CFR § 180.2020 to document this finding as follows:Tea Tree Oil Page 18 of 32 Biopesticides Registration Action Document

Pesticide

Chemical CAS Reg. No. Limits Uses

Tea Tree Oil 68647-73-4 Post-harvest interval of 48 hours; maximum application rate of 1.54 lbs a.i./acre Fruiting vegetables (group 8), leafy vegetables (group 4), cucurbit vegetables (group 9), berries (group 13), tree nuts (group 14), cereal grains (group 15), avocados, bananas, mangoes, papaya, passion fruit, peanuts, and plantains

b

. Drinking Water Exposure and Risk Characterization

Residues of the constituents of tea tree oil in drinking water are not expected when pesticide products are used according to label instructions. T ea tree oil and its const ituents are expected to volatilize and degrade rapidl y in the environment and are not dire ctly applied to water; therefore,

residues of tea tree oil in drinking water are unlikely.

c. Acute and Chronic Dietary Risks fo r Sensitive Subpopulations Particularly

Infants and Children

The Agency has made a non-food use determinati on, with limitations, for the active ingredient, tea tree oil; therefore, there are no foreseeable dietary risks to sensitive subpopulations, including infants and children, from the use of tea tree oil in the proposed product when label instructions

are followed. This conclusion is based on the fo llowing: 1) significant dietary exposure is not anticipated when label instruc tions for the proposed product are followed, 2) dietary risk to infants and children is anticipated to be neglig ible based on the results of the dietary risk assessments that the Agency has conducted (see Section IV.B.3.a a bove) and 3) humans are already exposed to tea tree oil in cosmetic a nd personal care products, and its major constituents are found naturally in the diet , in the environment, and are used as food additives.

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

a. Occupational Exposure and Risk Characterization

Dermal exposure to mixers/loaders and applic ators is not anticipated as adequate PPE requirements are on the proposed EP label. Additi onally, the active ingredie nt degrades rapidly in the environment which further mitigates dermal exposure. Due to the potential for inhalation exposure of residues of tea tree oi l to mixers/loaders and applicat ors (the EP is applied as a spray, fog or drench), and the effects observe d in the 90-day oral t oxicity and prenatal developmental studies, an occupational exposur e and risk assessment was conducted. The results

of the risk assessment indicate that risk from inha lation exposure to tea tree oil is negligible for mixers/loaders and applicators wh en the pesticide product (Timorex Gold [EPA File Symbol No. 86182-R]) is used according to label instructions . A summary of the a ssessment is provided

below.Tea Tree Oil Page 19 of 32 Biopesticides Registration Action Document

The assessment was conducted using a POD of 30 mg/kg bw/day (the NOAEL from the 90-day oral and developmental toxicity studies) and the occupational handler exposure calculation spreadsheet developed by OPP’s Health Eff ects Division (HED). Because 90-day inhalation toxicity data are not available, the Agency has bridged the data from the 90-day oral toxicity study and assumed 100% absorption via inhalati on. The standard body weight for females (69 kg) was used for all exposure scenarios in the assessment due to the incidence of developmental

effects. Based on label instruc tions, exposure scenarios consiste d of the following application methods: ground boom, airblast, aerial, and m echanically-pressured ha ndgun. The application rate used for the exposure assessment was the maximum application rate on the label (1.6 lbs a.i./acre on a previously proposed label). Pote ntial daily exposures for occupational handlers (mixer/loaders and applicators) were calculated in the spreadsheet usi ng the following formulas:

Daily exposure to the pesticide:

Daily Exposure (mg ai /day) = UE (μg ai / lb ai ) * AR (lb ai /A) * AT (A /day) * 1E-3 mg/μg

Daily Exposure = amount of the act ive ingredient that is available for i nhalation absorption, UE = Unit Exposure (generic values derived using measurements of exposure data in the field) AR = maximum application rate according to proposed label AT = daily acres treated.

The average daily dose (daily exposure adjust ed for absorption and body weight) was calculated using the following formula:

Average Daily Dose (mg ai/kg/day) = [Daily Exposure (mg ai/day) * Absorption (%)] Body Weight (kg)

Average Daily Dose (ADD) = absorbed dose received from exposure to the active ingredient in a given scenario Daily Exposure = amount of the act ive ingredient that is ava ilable for inhalation absorption Absorption Factor = a measure of the amount of chemical that crosses a biological boundary such as the skin and lungs (%) Body Weight = body weight determin ed to represent the population of interest in a risk

assessment

Risk for each application handler scenario was calculated using a MOE, which is a ratio of the toxicological endpoint to the da ily dose of concern. The daily inhalation dose received by occupational handlers was compared to the POD (i .e.: NOAEL) to assess the risk to occupational

handlers. All MOE values were calcul ated using the following formula:

MOE = POD (i.e.: NOAEL in mg/kg/day) ADD (mg/kg/day)

All MOEs calculated for mixers/loaders a nd applicators using no inhalation PPE were significantly greater than the Agency’s LOC of 100 (10X fo r intraspecies variation and 10x forTea Tree Oil Page 20 of 32 Biopesticides Registration Action Document

interspecies variation). MOEs gr eater than 100 do not exceed the Ag ency’s LOC; therefore, risks

are not considered to be of c oncern. Based on the results of the occupational risk assessment,

unreasonable adverse effects to ha ndlers are not anticipated when the pesticide product is used according to label instructions. A summary of th e exposure scenarios and MOEs is provided in

Table 3 below.

Significant post-application exposure to tea tree oil is no t anticipated as ther e is a 24-hour REI on the EP label and the active ingredient is expe cted to rapidly degrade in the environment.

b. Residential, School and Day Ca re Exposure and Risk Characterization

Significant exposure to tea tree oil is not anticipated in reside ntial, school, and da y care areas, as the product containing this active ingredient is intended for use on horticultural a nd agricultural

crops.

5. Aggregate Exposure from Multiple Routes Including Dermal, Oral, and Inhalation

There is reasonable certainty that no harm to the U.S. population will result from aggregate exposure to tea tree oil. This in cludes all exposures for which ther e is reliable information. The Agency arrived at this conclusion based on th e following: 1) the non-food use determination, with limitations, for the active ingredient, tea tree oil, 2) residential expo sures are not anticipated based on the pesticidal use pattern of tea tree o il, 3) drinking water expos ure is not anticipated based on the rapid degradation of the active ingred ient in the environment and tea tree oil is not directly applied to water. The risks from aggr egate exposure via oral, dermal, and inhalation exposure are a compilation of three low-risk exposure scenarios and are negligible.

6. Cumulative Effects

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “a vailable information” concerning the cumulative TABLE 3. Occupational Risk Asse ssment Summaries for Tea Tree Oil (Inhalation Route of Exposure)
Worker Activity Application Equipment/A pplication Type Application Type MOE

Mixer/Loader Aerial/Broadcast Orchard 17,000

Mixer/Loader Aerial/Broadcast Field crop, typical 17,000

Mixer/Loader Aerial/Broadcast Field crop, high-acreage 4,900 Mixer/Loader Airblast/Broadcast Orchard 150,000

Mixer/Loader Groundboom/Broadcast Field crop, typical 74,000

Mixer/Loader Groundboom/Broadcast Field crop, high-acreage 29,000

Applicator Aerial/Broadcast Orchard Exposure not anticipated
Applicator Aerial/Broadcast Field crop, typical Exposure not anticipated
Applicator Aerial/Broadcast Field crop, high-acreage Exposure not anticipated
Applicator Airblast/Broadcast Orchard 6,900
Applicator Groundboom/Broadcast Field crop, typical 48,000
Applicator Groundboom/Broadcast Field crop, high-acreage 19,000

Flagger Aerial/Broadcast Orchard 11,000
Flagger Aerial/Broadcast Field crop, typical 11,000
Flagger Aerial/Broadcast Field crop, high-acreage 11,000Tea Tree Oil Page 21 of 32 Biopesticides Registration Action Document

effects of a particular pesticid e’s residues and “other substances that have a common mechanism of toxicity.” EPA has not found t ea tree oil to share a common m echanism of toxicity with any other substances, and tea tree oil does not app ear to produce a toxic me tabolite produced by other substances. For the purposes of this tolerance acti on, therefore, EPA has assumed that tea tree oil does not have a common mechanism of toxicity w ith other substances. For information regarding

EPA’s efforts to determine which chemicals ha ve a common mechanism of toxicity and to

evaluate the cumulative effects of su ch chemicals, see EPA’s website at http://www.epa.gov/pesticides/cumulative

.

7. Risk Characterization

The Agency has considered human exposure to tea tr ee oil in light of the re levant 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 chil dren in particular, will result from the use of tea tree oil as a pesticide when label instructions are followed.

C. Environmental Assessment

1. Ecological Hazards

Adequate nontarget toxicology data/information is available to support regi stration of tea tree oil with the submission of nontarget toxicology da ta on the TGAI. All nontarget toxicology data requirements for tea tree oil have been satisfied.

Tea tree oil is highly toxic to a quatic invertebrates. T ea tree oil is practically nontoxic to fish and

insects. Tea tree oil is not phytotoxic. Significant exposure of t ea tree oil to birds is not expected due to volatilization and rapid degradation of the active ingred ient in the environment (EPA, 2013).

For more information regarding nontarget organism toxicity data requirements, refer to Table 8 in Appendix A.

2. Environmental Fate and Ground Water Data

Tea tree oil is expected to degrad e rapidly in the environment. Up to 90% of tea tree oil has been

shown to volatilize within 24 hours after application and residue studies indicate the lack of

detectable residues of three of th e major constituents of tea tree oil at 48 hours post-application (EPA, 2013). In MRID 48275004, a study was submitted in which the biodegradation of tea tree oil was determined in a 28-day ready biodegrad ability assay (OECD Gu ideline 310 and EN ISO 14593) by monitoring the release of carbon dioxide with a non-adap ted activated sewage sludge. Based on the results of the assay, biodegradation of tea tree oil was 10% after 2 days, 60% after 5 days, 87% by day 7, and 106% at study termination.Tea Tree Oil Page 22 of 32 Biopesticides Registration Action Document

3. Ecological Exposure and Risk Characterization

Significant exposure to birds is not expected because the active ingred ient is volatile and degrades rapidly in the environment. Additiona lly, birds are already e xposed to the components of tea tree oil, as they are present in a multitude of plants. Although exposure to fish, insects, and plants is anticipated from use of the product through direct ap plication, accidental application, drift or run-off, results of toxicity testing on pure tea tree oil indicat e that tea tree oil is practically nontoxic to these organisms. The proposed EP wh ich contains 23.8% tea tree oil will also be diluted with water pr ior to application, which will further reduce exposure to these organisms. The aquatic invertebrate toxicity stud y submitted indicates that tea tree oil is highly toxic to these organisms. Because of the potential fo r toxicity to freshwater invertebrates, a risk assessment for these organisms was conducte d for the EP based on nontarget organism toxicology data on the EP (EPA, 2014a). The results of the risk assessment for the EP indicated that mitigation language for aquatic invert ebrates is required on the EP label.

4. Endangered Species Assessment

The Agency has not conducted a risk assessmen t that supports a complete endangered species determination. The ecological risk assessment pl anned during registration review will allow the Agency to determine whether tea tree oil’s use has “no effect” or “may effect” federally listed threatened or endangered species ( listed species) or their designate d critical habitats. When an assessment concludes that a pesticide’s use “may aff ect” a listed species or its designated critical habitat, the Agency will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Services (the Services) as appropriate.

D. Product Performance Data

Product performance data must be developed for a ll pesticides to ensure that pesticide products will perform as intended and that unnecessary pe sticide exposure to the environment will not occur as a result of the use of ineffective products . The Agency reserves the right to require on a case-by-case basis, submission of efficacy data for any pesticide product registered or proposed for registration that are intended to be used to control a pest of significance public health importance and a public health pest as defined in FIFRA section 28(d) and section 2(nn). For further guidance on product performance requirement , refer to Pesticide Registration Notice (PR) Notices 96-7, 2002-1 and Explanatio n of Statutory Framework for Risk-Benefit Balancing for Public Health Pesticides (http:/ /www.epa.gov/PR _Notices/pr1996-7.pdf) (http://www.ea.gov/PR_N otices/pr2002-1.pdf) and ( http://www.epa.gov/pest icides/health/riskbenefit.htm).

The EP submitted with this new active ingredient did not list pests of significant public health importance or a public health pest as define d in FIFRA section 28(d) and section 2(nn). Therefore, product performance (efficacy) was not evaluated.Tea Tree Oil Page 23 of 32 Biopesticides Registration Action Document

V. RISK MANAGEMENT DECISION

A. Determination of Eligibility for Registration

Section 3(c)(5) of FIFRA provides for the regi stration of a new active ingredient if it is determined that: (A) its composition warrants proposed claims; (B) its labeling and other materials comply with the requi rements of FIFRA; (C) it will perform its intended function

without unreasonable adverse eff ects on the environment; and (D) when used in accordance with widespread and commonly recogniz ed practice, it will not genera lly cause unreasonable adverse

effects on the environment.

The four criteria of the Eligibility Determinati on for Pesticidal Active Ingredients are satisfied by the science assessments supporting products contai ning the TGAI, tea tree oil. Such products are not expected to cause unreasonable adverse effects. Therefore, tea tree oil as a TGAI is eligible for registration for the labeled uses.

B. Regulatory Decision

The data submitted fulfill the registration requirements of tea tree oil for use as a fungicide/bactericide

. Refer to Appendix B for product-specific information.

Conditional/Unconditional Registration

All data requirements are fulf illed, and EPA determined that an unconditional registration of tea tree oil is appropriate.

C. Environmental Justice

EPA seeks to achieve environmen tal justice—the fair treatment and meaningful involvement of all people regardless of race, color, national or igin, or income—with respect to the development, implementation, and enforcement of environmental laws, regulations, and po licies. At this time,

EPA does not believe that use of tea tree oil pesticide products will cause harm or a disproportionate impact on at-risk communitie s. For additional information regarding environmental justice issues, please visit EPA’s website at http://www.epa.gov/compliance/en vironmentaljustice/index.html

.

VI. ACTIONS REQUIRED BY REGISTRANTS

EPA evaluated all data submitted in connection with the registration of the tea tree oil pesticide products and determined that these data are su fficient to satisfy curre nt registration data requirements. At this time, no additional data must be submitted to EPA for these particular products. For new uses and/or changes to existi ng uses, EPA may require additional data.

Notwithstanding the information stated in the pr evious paragraph, it should be clearly understood that certain specific data are requi red to be reported to EPA as a requirement for maintaining theTea Tree Oil Page 24 of 32 Biopesticides Registration Action Document

Federal registration for a pesticide product. A br ief summary of these t ypes of data are listed

below.

A. Reporting of Adverse Effects

Pursuant to FIFRA section 6(a)(2), reports of al l incidents of adverse effects to the environment

must be submitted to EPA.

B. Reporting of Hypersensitivity Incidents

Additionally, all incidents of hype rsensitivity (including both suspected and confirmed incidents) must be reported to the Agency unde r the provisions of 40 CFR Part 158.2050(d).

VII. APPENDIX A. DATA REQUIREM ENTS (40 CFR PART 158-SUBPART U)

*NOTE: Master Record Identification (MRID) numbers listed in the following tables are representative of supporting da ta/information for the original registration of the product containing this active ingredient. Subsequent to this registration, there may be additional MRIDs that support registration of other products containing th is active ingredient.

TABLE 4. Product Chemistry Data Requirements for Tea Tree Oil ( 40 CFR § 158.2030 )

OCSPP Guideline Reference No./Study Description of Result MRID

880.1100 Product identity and composition The product identity and composition were adequately addressed. Confidential Business Information (CBI). 47730401

880.1200 Description of starting materials, production, and formulation

process The description of the starting materials, production, and formulation process were adequately addressed. CBI. 47730401

880.1400 Discussion of formation of impurities The discussion of formation of impurities was adequately addressed. CBI. 47730401

830.1700 Preliminary analysis The preliminary analysis of the product was acceptable. CBI. 47730402, 47730403

830.1750 Certified limits The certified limits listed on the CSF are acceptable. 47730401

830.1800 Enforcement analytical method The enforcement analytical method was adequately addressed. CBI. 47730401Tea Tree Oil Page 25 of 32 Biopesticides Registration Action Document

TABLE 5. Physical and Chemical Properties for Tea Tree Oil ( 40 CFR § 158.2030 )

OCSPP Guideline Reference No./Property Description of Result MRID

830.6302 Color Colorless to pale yellow 47730401

830.6303 Physical State Liquid 47730401

830.6304 Odor Characteristic 47730401

830.6313 Stability to normal and elevated temperatures, metals and metal

ions Decomposition temperature is expected to be >200°C (based on values for the individual components). Generally stable to galvanized steel (packaging material) over 8 months at ambient warehouse storage, 10-35  ̊ C. 47730401

Correspondence

between Canada’s Pest Management Regulatory Agency (PMRA) and TSG dated May 11, 2009 and PMRA product chemistry review.

830.6315 Flammability Flashpoint = 55°C

59°C 47918402

47730401

830.6317 Storage Stability Composition of TGAI may vary considerably during storage, with ρ -cymene levels increasing and α - and γ -terpinene levels decreasing. Light, heat, air exposure and

moisture affect oil stab ility. The MP should be stored in dark, cool, dry conditions in an airtight container.

During the 8 month study, of the 5 major

components, α -terpinene decreased ~13% and

ρ -cymene increased ~15.5%, with the other three not changing significantly. Correspondence

between PMRA and TSG dated May 11, 2009, and PMRA product chemistry

review.

830.6319 Miscibility Not applicable, the produc t is not to be mixed with petroleum solvents. 47730401

830.6320 Corrosion Characteristics Generally stable to galvanized steel (packaging material) over 8 months at ambient warehouse storage, 10-35  ̊ C. No visual changes (corrosion, color change) were

observed. Correspondence

between PMRA and TSG dated May 11, 2009, and PMRA product chemistry

review.

830.7000 pH Not applicable 47730401

830.7050 UV/Visible light absorption In propan-2-ol, a single maximum at 265 nm

was observed. 47730409 and

47918403

830.7100 Viscosity 2.47 cSt at 25oC 48275001

830.7200 Melting Range Not applicable, the pr oduct is a liquid. 47730401

830.7220 Boiling Range Expected to be ca. 200°C (derived from values of the individual components) 47730401

830.7300 Density/Relative Density/Bulk Density Minimum density = 0.885 g/mL at 20°C

Maximum density = 0.906 g/mL at 20°C 47730401

830.7520 Particle size, fiber length, and

diameter distribution Not known for TGAI. Relevant components of TGAI are not expected to dissociate. 47730401 and

47730409Tea Tree Oil Page 26 of 32 Biopesticides Registration Action Document

TABLE 5. Physical and Chemical Properties for Tea Tree Oil ( 40 CFR § 158.2030 )

OCSPP Guideline Reference No./Property Description of Result MRID

830.7550 Partition Coefficient (n-Octanol/

830.7560 Water)

830.7570 Not known for TGAI. Component log K ow terpinen-4-ol 2.643

3.33

γ -terpinene 4.47

α -terpinene 4.75 p-cymene 4.44 1,8-cineole 3.13 47730401 and

47730409

830.7840 Water Solubility Not known for TGAI. Component Temp (  ̊ C) Solubility terpinen-4-ol - 1767 mg/L

γ -terpinene 22-25 8.72 mg/L

α -terpinene - 5.92 mg/L p-cymene - 5.0 mg/L 1,8-cineole - 552 mg/L 47730401 and

47730409

830.7950 Vapor Pressure Not known for TGAI.

Component Temp (  ̊ C) VP (Pa) terpinen-4-ol 20 53.2  -terpinene 20 93.1

23.5 103

α -terpinene 20 106.4 p-cymene 25 199.5 1,8-cineole 25 253 47730401 and

47730409Tea Tree Oil Page 27 of 32 Biopesticides Registration Action Document

Table 6: Mammalian Toxicology Data Requirements for Tea Tree Oil (40 CFR § 158.2050)

Study/OCSPP Guideline No. Results Toxicity Category/Description MRID

Acute oral toxicity (rat) (870.1100) LD 50 = 1752 mg/kg (1752-2450 mg/kg) Toxicity Category III 47730404

Acute dermal toxicity (rat) (870.1200) LD 50 > 2000 mg/kg Toxicity Category III 47730404

Acute inhalation toxicity (rat) (870.1300) LC 50 = 3.64 mg/L Toxicity Category IV 48598701

48878201 Primary eye irritation (rabbit) (870.2400) Waived: MP is corrosive to skin. A chorioallantioic membrane vascular assay (chicken egg) was submitted, but is unacceptable as EPA has not established this assay to be appropriate to fulfill the primary eye irritation data requirement. Toxicity Category I 47730405

Primary dermal irritation (rabbit) (870.2500) Corrosive. Well-defined to severe erythema and barely perceptible to slight edema were

noted on the intact sites of 6/6 rabbits at the

24- and 72-hour evaluations. Well-defined to severe erythema and barely perceptible to

moderate edema were noted on the abraded

sites of 6/6 rabbits at the 24 and 72 hour

evaluations. Three animals had erosion on

abraded sites at the 72-hour evaluation. The primary irritation i ndex (PII) was 5.0. Toxicity Category I 47730404

Dermal sensitizati on (guinea pig) (870.2600) Waived: MP is corrosive to skin. A skin sensitization study was submitted. After intradermal and epidermal inductions, the test and control animals showed no signs of reactivity 24 hour s after challenge. However, study classification is unacceptable due to the lack of positive

control data. - 47730404

90-Day oral toxicity (870.3100) LOAEL = 60 mg/kg/day based on testicular toxicity in males and increased liver to body weight ratios in females NOAEL = 30 mg/kg/day for males and

females - 48598702

48878202

90-Day dermal toxicity (870.3250) Waived: prolonged dermal exposure not anticipated. TGAI is corrosive to skin and adequate PPE is required on the label.

Undiluted tea tree oil caused severe irritation to the skin on the first day of a non-guideline 30-day dermal irritation study on rabbits. For the remainder of the study, a 25% solution in paraffin oil was applied to

the skin which did not result in visible irritation; however, non-specific microscopic dermatitis consistent with

irritation was observed. - 47730411

47730404

90-Day inhalation toxicity (870.3465) The data from the 90-data oral toxicity study has been bridged to satisfy this data requirement. A route to route extrapolation will be employed using a 100% absorption assumption. - 48598704

48878201Tea Tree Oil Page 28 of 32 Biopesticides Registration Action Document

Table 6: Mammalian Toxicology Data Requirements for Tea Tree Oil (40 CFR § 158.2050)

Study/OCSPP Guideline No. Results Toxicity Category/Description MRID

Developmental toxicity (870.3700) Maternal: NOAEL = 30 mg/kg/day LOAEL = 60 mg/kg/day based on treatment related decreased body weight gain and food

intake Developmental: NOAEL = 60 mg/kg/day LOAEL = 120 mg/kg/day based on decreased fetal weights - 49166401

Mutagenicity – Tier I (870.5100, 5300 and 5375)

Mutagenicity – Tier II (870.5395) Not mutagenic in Salmonella reverse mutation assay at doses below 50 μg.

Negative in in vivo mouse bone marrow micronucleus assay. - 47730404

47730407

47730409

Table 7: Nontarget Organism Toxicity Data Requirements for Tea Tree Oil (40 CFR § 158.2060)

Study/OCSPP Guideline No. Results Toxicity Category/Description MRID

Avian acute oral toxicity (850.2100) Adequate information to support data requirement: significant exposure to birds is not expected due to vo latilization and rapid degradation of the active ingredient in the

environment. Additiona lly, components of the TGAI are already found in a multitude of plants. Significant exposure not expected 47730411

Avian dietary toxicity (850.2200) Adequate information to support data requirement: significant exposure to birds is not expected due to vo latilization and rapid degradation of the active ingredient in the

environment. Additiona lly, components of the TGAI are already found in a multitude of plants. Significant exposure not expected 47730411

Aquatic invertebrate acute toxicity, freshwater (850.1010) 48-hour EC 50 = 0.591 mg/L (95% CL: 0.499-0.700 mg/L) Highly toxic 48598703

Fish acute toxicity, freshwater (850.1075) LC 50 > 100 mg/L Practically non-toxic

47730408 Terrestrial plant toxicity, Seedling emergence/Vegetative vigor (850.4100 and 850.4150) Adequate information to support data requirement: using the proposed EP in efficacy trials on squash, potatoes, apples, no phytotoxicity was observed. Minor phytotoxicity was observed in one South African grape variety (brown spots) in one trial; however, in nine other trials in grapes no phytotoxicity was observed. Minor phytotoxicity was observed in one trial in tomatoes and cucumbers (small necrotic spots); however, no phytoxicity was

observed in eleven other trials in tomatoes. The components of tea tree oil are volatile and are also already found in a multitude of plants. Not phytotoxic 47730521

Nontarget insect testing Apis millifera : oral LD 50 > 98.5 μ g a.i./bee; 47730520 1Tea Tree Oil Page 29 of 32 Biopesticides Registration Action Document

Table 7: Nontarget Organism Toxicity Data Requirements for Tea Tree Oil (40 CFR § 158.2060)

Study/OCSPP Guideline No. Results Toxicity Category/Description MRID

(880.4350) contact LD 50 > 331 μ g a.i./bee

Bombus terrestris: oral LD 50 > 105.49 μ g a.i./bee; contact LD 50 > 100 μ g a.i./bee Aphidius rhopalosiphi : ER 50 and LR 50 >1.08 L EP /ha Typhlodromus pyri : ER 50 = 1.78 L EP/ha (95% c.i., 1.54-2.09 L EP /ha); 7d LR 50 >4.32 L EP/ha Practically non-toxic 47730519 2

47730518 3

47730517 3

1 Study conducted on the proposed EP, Timorex Gold (EPA File Symbol No. 86182-R), at target doses of 100 μ g a.i./bee (oral) and 18, 32, 56, 100, 180, and 320 μ g a.i./bee (contact)

2 Study conducted on the proposed EP, Timorex Gold (EPA File Symbol No. 86182-R), at a target dose of 100 μ g a.i./bee (nominally equivalent to 423.73 μ g EP/bee)

3 Supplemental data. Values reported are based on the proposed EP, Timorex Gold (EPA File Symbol No. 86182-R), and have not been corrected for active ingredient concentration.

VIII. APPENDIX B.

For product specific informatio n, please refer to http://w ww.epa.gov/pesticides/pestlabels.

IX. APPENDIX C.

REFERENCES

Bedos C, Cellier P, Calvet R, et. al. (2002) Mass transfer of pesticides into the atmosphere by volatilization from soils and plants: overview. Agronomie 22: 21-33.

Chadwick G. (2008). Final Report on Projec t AF/12583/BB. Agrisearch UK Ltd. Laboratory Project ID AF/12583/BB. September 18, 2008. MRID 47730522.

EPA. 2010. Memorandum from Angela L. Gonzales to Colin Walsh. Joint Science Review with Health Canada Pest Management Regulatory Agen cy (PMRA) In Support of the Registration of Tea Tree Oil Technical containing Tea Tree Oil as its active ingredient. U.S. Environmental Protection Agency Office of Pes ticide Programs. February 28, 2010.

EPA. 2013. Memorandum from Angela L. Gonzales thru Felecia A. Fort to Colin Walsh. Joint

Science Review with Health Canada Pest Ma nagement Regulatory Agency In Support of the Registration of Tea Tree Oil Technical Containing Tea Tree Oil as its Ac tive Ingredient. U.S. Environmental Protection Agency Office of Pesticide Programs. January 30, 2013.

EPA. 2014a. Memorandum from Angela L. Gon zales to Colin Walsh. Science Review In Support of the Registration of Tea Tree Oil T echnical Containing Tea Tree Oil as its Active Ingredient. U.S. Environmental Protection Agen cy Office of Pesticide Programs. April 10, 2014.

EPA. 2014b. Memorandum from Angela L. Gonzales to Linda A. Hollis. Nonfood-UseTea Tree Oil Page 30 of 32 Biopesticides Registration Action Document

Determination In Support of the Registration of Tea Tree Oil Technical Containing Tea Tree Oil as its Active Ingredient. U.S. Environmental Pr otection Agency Office of Pesticide Programs. July 23, 2014.

European Food Safety Authority (EFSA). (2012). C onclusion on the peer review of the pesticide

risk assessment of the active substance extract from tea tr ee. EFSA Journal: 10(2):2542. http://www.efsa.europa.eu/en/efsajournal/doc/2542.pdf

.

Gatenio I, Ofer D. (2007). Determination of Tea Tree Oil Residues in Grapes (Treated with BM 608). Bactochem. January 11, 2007. MRID 47730523.

Henley DV, Lipson N, Korach KS, Block CA. 2007. Prepubertal gynecomastia linked to lavender and tea tree oils. N Engl J Med.; 356(5): 479-85

Pest Management Regulatory Agency (PMRA) . Health Canada. (2014). Evaluation Report ERC2014-01, Tea Tree Oil . Catalogue number: H113-26/2014-1E-PDF. http://www.hcsc.gc.ca/cps-spc/pubs/pest/_deci sions/erc2014-01 /index-eng.php

.

REVIEWS AND OTHER REFERENCES

EPA. 2010. Memorandum from Angela L. Gonzales to Colin Walsh. Joint Science Review with Health Canada Pest Management Regulatory Agen cy (PMRA) In Support of the Registration of Timorex Gold containing Tea Tree Oil as its ac tive ingredient. U.S. Environmental Protection Agency Office of Pesticide Programs. February 28, 2010.

EPA. 2013. Memorandum from Angela L. Gonzales to Colin Walsh. Joint Science Review with Health Canada Pest Management Regulatory Agen cy (PMRA) In Support of the Registration of Timorex Gold containing Tea Tree Oil as its ac tive ingredient. U.S. Environmental Protection Agency Office of Pesticide Programs. January 30, 2013.

EPA. 2014. Memorandum from Angela L. Gonzales to Colin Walsh. Scie nce Review in Support of the Registration of Timorex Gold containi ng Tea Tree Oil as its Active Ingredient. U.S. Environmental Protection Agency Offi ce of Pesticide Programs. April 10, 2014.

X. GLOSSARY OF ACRONYMS AND A BBREVIATIONS

a.i. active ingredient ARS Agricultural Research Service (USDA) Biomor Biomor Israel, Ltd. BPPD Biopesticides and Pollu tion Prevention Division BRAD Biopesticide Registration Action Document bw body weight

CBI Confidential Business Information CFR Code of Federal Regulations

cm 3 cubic centimeterTea Tree Oil Page 31 of 32 Biopesticides Registration Action Document

CSF Confidential Statement of Formula

cSt centistokes °C degrees Celsius DEEM-FCID Dietary Exposure Evaluation Mo del - Food Commodity Intake Database

EC 50 median effective concentra tion. A statistically derive d single concentration in environmental medium that can be expected to cause an effect in 50% of the test animals when administrated by the route in dicated (inhalation). It is expressed

as a concentration in ai r or water (e.g. mg/L). EDSP Endocrine Disrupt or Screening Program EDSTAC Endocrine Disruptor Screeni ng and Testing Advisory Committee EP end-use product EPA Environmental Protection Agency (the “Agency”) FDA U.S. Food and Drug Administration FFDCA Federal Food, Drug, and Cosmetic Act FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality Protection Act FR Federal Register

g gram ha hectare kg kilogram Kow octanol-water partition coefficient

L liter

LC 50 median lethal concentration. A statistically derived singl e concentration in air or water that can be expected to cause d eath in 50% of the test animals when administrated by the route indicated (inhalation and environment). It is expressed as a concentration in air or water (e.g. mg/L).

LD 50 median lethal dose. A statistically de rived single dose that can be expected

to cause death in 50% of the test an imals when administered by the route indicated (oral and dermal). It is expressed as a weight of substance per unit weight of animal (e.g., mg/kg).

LOAEL lowest-observed-adverse-effect-level

LOC level of concern LOQ limit of quantification MOE margin of exposure

MRID No. Master Record Identification Number mg milligram mPa millipascal

mL milliliter MP manufacturing-use product N/A not applicable

NE “No Effect”

nm nanometer
NOAEL no-observed-adverse-effect-level

NOEL no-observed-effect-level NOF notice of filing NOR notice of receiptTea Tree Oil Page 32 of 32 Biopesticides Registration Action Document

OPP Office of Pesticide Programs

OCSPP Office of Chemical Safe ty and Pollution Prevention pa pascal PHI pre-harvest interval

PMRA Canada’s Pesticide Mana gement Regulatory Authority POD point of departure PPE personal protective equipment PR Notice Pesticide Registration Notice REI restricted-entry interval

RfD reference dose

TGAI technical grade of the active ingredient TSG Technology Sciences Group, Inc. UF uncertainty factor ug microgram

USDA United Stat es Department of Agriculture

UV ultra-violet