BIOPESTICIDES REGISTRATION ACTION DOCUMENT



# Tea Tree Oil

PC Code : 028853

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

May 2 3 , 201 4Tea Tree Oil

Page 2 of 34 Biopesticides Registration Action Document

TABLE OF CONTENTS

I. EXECUTIVE SUMMARY:

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

II. ACTIVE INGREDIENT OV ERVIEW

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

III. REGULATORY BACKGROUN D

................................ ................................ ...................... 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

...................... 20

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

........................... 22

6. Cumulative Effects

................................ ................................ ................................ ................................ ...... 23

7. Risk Characterization

................................ ................................ ................................ ................................ . 23

C. Environmental Assessment

................................ ................................ ............................... 23

1. Ecological Hazards

................................ ................................ ................................ ................................ ...... 23

2. Environmental Fate and Ground Water Data

................................ ................................ .......................... 23

3. Ecological Exposure and Risk Characterization

................................ ................................ ...................... 24

4. Endangered Species Assessment

................................ ................................ ................................ ................ 24

D. Efficacy Data

................................ ................................ ................................ ..................... 24

V. RISK MANAGEMENT DECI SION

................................ ................................ ................ 25

A. Determination of Eligibility for Registration

................................ ................................ .. 25

B. Regulatory Decision

................................ ................................ ................................ ........... 25

C. Environmental Justice

................................ ................................ ................................ ....... 26

VI. ACTIONS REQUIRED BY REGISTRANTS

................................ ................................ . 26

A. R eporting of Adverse Effects

................................ ................................ ............................ 26

B. Reporting of Hypersensitivity Incidents

................................ ................................ .......... 26Tea Tree Oil

Page 3 of 34 Biopesticides Registration Action Document

VII. APPENDIX A. DATA REQ UIREMENTS (40 CFR PA RT 158

- SUBPART U)

.......... 26

VIII. APPENDIX B.

................................ ................................ ................................ .................... 32

IX. APPENDIX C.

................................ ................................ ................................ ................... 32

X. G LOSSARY OF ACRONYMS AND ABBREVIATIONS

................................ ............. 33Tea Tree Oil

Page 4 of 34 Biopesticides Registration Action Document



### BIOPESTICIDES REGISTRATION ACTION 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

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I. EXECUTIVE SUMMARY:

Tea tree oil is a new biochemical pesticide active ingredient intended for use as a fungicide/bactericide on the following food commodities: leafy vegetables (group 4), fruiting vegetables (group 8), cucurbit vegetables (group 9), berries (group 13), cereal grains (group 15), avocado, banana, mango, papaya, plantain, kiwi, an d passion fruit. The active ingredient is extracted from the leaves and terminal branches of the tea tree ( Melaleuca alternifolia )

, which is a member of the plant family Myrtaceae and is indigenous to Australia, New Zealand, and

Southeast Asia. Tea tree oi l is composed of approximately 100 different compounds which consist of terpene hydrocarbons, primarily monoterpenes, sesquiterpenes, and their associated

alcohols. The active ingredient has antifungal properties and is effective against a broad

spectrum o f plant

- pathogenic fungi, but the mode of action is not clearly understood. It has been shown to affect cell respiration and alter cell membrane structure in yeast. Based on this information, the Agency considers the mode of action to be nontoxic.

The Biopesticides and Pollution Prevention Division (BPPD) has reviewed all of the data and other information submitted in support of the registration of t ea t ree o il as a fungicide/bactericide under Section 3(c)(5) of the Federal Insecticide, Fungicide and Ro denticide Act (FIFRA), and has determined that the current data requirements (40 CFR part 158.2010 through 158.2070) for registration of a biochemical pesticide have been satisfied. Given that tea tree oil is of low toxicity and present s little, if any, ri sks to humans , including infants and children, and the environment, the U.S. Environmental Protection Agency ( EPA or the Agency) has concluded that it is in the best interest of the public to issue registrations for the manufacturing

- use product (MP), Tea Tree Oil Technical ( EPA File Symbol No. 86182

- E )

, and the end

- use product (EP),

Timorex Gold (EPA File Symbol No. 86182

- R ), which contain this new active ingredient, t ea

t ree o il

. The basis for this decision is described in more detail in section IV of thi s Biopesticide Registration Action Document (BRAD).

On October 1, 2009, EPA announced a policy to provide a more meaningful opportunity for the public to participate on major registrati on decisions before they occur. According to this policy, EPA provid e s a public comment period prior to making a registration decision for the following types of applications: new active ingredients, first 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 making registration actions more transparent, t ea t ree o il is subject

to a 15

- day comment period as a “new active ingredient

. ” EPA has established a comment period of 15 days on the basi s of t ea t ree o il’s low toxicity, the determination that t ea t ree o il presents low risk of any adverse effects to human health and the environment, and critical need for this active ingredient. The notice for this comment period include s the draft BRAD and draft product

label s for the M P, Tea Tree Oil T echnical, and EP, Timorex Gold , which contain this new active ingredient, t ea t ree o il

. The docket identification ( ID ) number is EPA

- HQ

- OPP

- 20 09

- 0 440 . The Agency believes that based on the risk assessment and information submitted in support of the registration of the MP and EP containing t ea t ree o il , 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 t ea t ree o il , which is characterized in this BRAD.Tea Tree Oil

Page 6 of 34 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, 20 09 , EPA received an application 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 product s, Timorex Gold ( EPA File Symbol No. 86182

- R) and Tea Tree Oil Technical (EPA File Symbol No. 86182

- E )

,

co ntaining the new biochemical active ingredient, t ea t ree o il . A notice of receipt (NOR) of this appl ication, allowing for a 30

- day comment period, was published in the Federal Register o n July 22 , 2 009 (7 4 FR 36215 )

. No comments were received following this publication

.

A. Classification

On October 28, 2004

, EPA’s B iochemical C lassification C ommittee determined that t ea t ree o il

is a biochemical pesticide. The biochemical classification committee indicated that t ea t ree o il is a fungicide/bactericide . The mode of action is not clearly understood, but has been shown to disrupt membrane s of fungal/bacterial species. Tea t ree o il is the essential oil of the Melaleuca tree (tea tree) and is rich in terpene alcohols (such as terpinen

- 4

- ol and eucalpyptol). The oil is manufactured to contain at least 30% terpinen

- 4

- ol (germicidal) and no more than 15% eucalpyptol (anti

- fungal). The terpinen

- 4

- ol is generally accepted to be the active component of

t ea t ree o il. There is a long history of use of te a t ree o il as an antiseptic and antifungal agent and

it is formulated into creams, soaps, mouthwash es, toothpaste, and other cosmetic products.

B. F ood Clearances/Tolerances

The consultant , TSG on behalf of Biomor, filed a petition (PP 9F 7558 ) proposing to establish an exemption from the requirement of a tolerance for residues of t ea t ree o il in or on all food commodities. A notice of filing (NOF)

, allowing for a 30

- day comment period , was published inTea Tree Oil

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the Federal Register on July 22 , 20 09 (7 4 FR 36200 )

. No comments were received following this publication

.

EPA determined during the review of the petition that the data and information submitted was insufficient to support an exemption from the requirement of a tolerance for residues of t ea t ree

o il in or on all food commodities . However, as noted in the Risk Ass essment section of this BRAD (Section IV), EPA has determined , based on the data submitted, that the active ingredient,

t ea t ree o il, can be exempt from the requirement of a tolerance of residues in or on the following

food commodities: leafy vegetables (group 4), fruiting vegetables (group 8), cucurbit vegetables (group 9), berries (group 13), cereal grains (group 15), avocado, banana, mango, papaya, plantain, kiwi, and passion fruit.

IV. RISK ASSESSMENT

A. Active Ingredient Characterization

Tea t ree o il is a new biochemical pesticide active ingredient intended for use to prevent and control diseases such as powdery mildew, Botrytis, and black sigatoka in horticultural and agricultural crops. The active ingredient has antifungal properties and is e ffective against a broad spectrum of plant

- pathogenic fungi, but the mode of action is not clearly understood. It has been shown to affect cell respiration and alter cell membrane structure in yeast. Based on this information, the Agency considers the 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 family Myrtaceae and is indigenous to Australia, New Zealand, and Southeast Asia. T ea t ree o il is composed of approximately 100 different compounds which consist of terpene hydrocarbons, primarily monoterpenes, sesquiterpenes

, and their associated alcohols. These biogenic chemicals are aromatic hydrocarbons which are found in the essenti al oils of a multitude of plants and are characterized by their high volatility and low aqueous solubility (EPA, 2010) . The composition of t ea t ree o il used in commerce is regulated by an international standard (ISO 4730, International Organization for Sta ndardisation)

, which sets maximum and minimum limits for 14 of its components. Of the several varieties or chemotypes of t ea t ree o il , only the terpinen

- 4

- ol chemotype

, which contains 30

- 48% terpinen

- 4

- ol

, will be used as the TGAI in the proposed MP,

Tea T ree 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 specifications for all 14 ingredients are listed in Table 1 below.

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

Name CAS No. Minimum % Maximum %
Terpinen

- 4

- ol 562

- 74

- 3 30 48

γ

- T erpinine 99

- 85

- 4 10 28

α

- T erpinine 99

- 86

- 5 5 13

α

- T erpin eol 98

- 55

- 5 1.5 8

α

- T erpin olene 586

- 62

- 9 1.5 5

α

- Pinene 80

- 56

- 8 1 6Tea Tree Oil

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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 major constituents of t ea t ree o il (terpinen

- 4

- ol, γ

terpinene, 1,8

- cineole, and α

- terpinene ) in the diet as they are found in herbs, spices, citrus and some vegetables (EPA, 2014). Humans are also exposed to the major constituents of t ea t ree o il as food additives in the diet, as they have been approved as substances that may directly be

added t o food by the U.S. Food and Drug Administration ( FDA ) under 21 CFR § 172.515(b).

Tea t ree o il 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 speci es and water sources. Additionally, t ea t ree o il has a long history 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 , lotions

, and bath oils, as well as in animal care products (EPA, 2010).

Descriptions of the product formulation and production process, formation of impurities, and physical and chemical characteristics of t ea t ree o il were examined by BPPD and found to be acceptable in meeting current guideline standards

.

All product chemistry data requirements for registration of t ea t ree o il have been satisfied.

For more information regarding product chemistry data requirements, refer to Tables 6 and 7 i n 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 file 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 registration of t ea t ree

o il

. All toxicology data requirements for t ea t ree o il have been satisfied.

a

. Acute Toxicity

Acute toxicity testing is required to : 1) determine systemic toxicity from acute exposure via theTea Tree Oil

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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).

A Tier I primary dermal irritation study in rabbits submitted and reviewed showed that t ea t ree

o il is corrosive to the skin at undiluted co ncentrations (toxicity category I). Based on the results in the primary dermal irritation study, the primary eye irritation and dermal sensitization data requirements were waived ; therefore, t ea t ree o il is classified as corrosive to the eye (toxicity

cate gory I). Tea t ree o il i s a toxicity category II I (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 bod y weight in rats and a LD 50 of greater than 2,000 mg/kg in rabbits, respectively

. Tea t ree o il is a

t oxicity c ategory IV (not toxic) compound for acute inhalation toxicity based on a medial lethal concentration (LC 50 ) of 3.64 mg/L

.

For more information regarding acute toxicity data requirements, refer to Table 8 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 te st substance for a period o f 90 days via the oral, dermal, and inhalation routes of exposure

.

A 90

- day oral toxicity study (OCSPP 870.3100) was conducted on t ea t ree o il and submitted in MRID 48598702. Adequate supportive information regarding homogeneity testing of the test

substance was submitted in MRID 48878202 . Tea t ree o il 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 observed, 10 rats from the high dose group and 5 rats from the control group were s acrificed 14 days and 28 days after completion of the 90

- day dosing period. No mortality was observed in male rats. Two moribund females in the high dose group were sacrificed during the treatment period

. At all dose levels salivation was observed which pe rsisted 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 findings were not noted at any dose

level. In the high dose group, some motor activity 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 abnormal functio nal observations. Statistically 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 significant increase in ovary to body weight ratio was noted in the

28

- day high dose recovery group (+31%). There was no microscopic correlation for the organ weight findings in females. Flaccid testes, some with a small appearance, were observed in high

dose males (4/10 at the end of treatment; 2/10 after the 14

- day recovery period; 8/10 after the 28

- day recovery period). Absolute organ weight and organ

- to

- body

- weight ratios were significantly reduced in the testes and epididymides of males in the high

- dose 28

- day recovery group. These findings were microscopically associated with deg enerative changes in the seminiferous tubules (loss of germ cells, formation of multinucleated germ cells, presence of cell debris in tubular lumen, atrophic appearance, and sertoli cell vacuolation). The testicular effects occurred at theTea Tree Oil

Page 10 of 34 Biopesticides Registration Action Document

same or higher r ate of incidence with an overall 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 macrophages, giant cells and fibroblasts) were observed in the epididymides of high dose males at the end of the 90

- day treatment period. The incidence of sperm granulomas peaked in the 14

- day recovery gro up, 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 lumen of the epididymides in 1/10 male rats dosed at 60 mg/kg/day. No treatment

- related h istological changes were observed in males dosed at 30 mg/kg/day. Statistically significant treatment

- related effects on sperm motility, sperm morphology, and epididymal sperm counts were observed at the high dose level at the end of the treatment period a nd in the 14

- and 28

- day recovery groups. Sperm counts were significantly

lower relative to controls in the mid

- dose group, and there was a significant decrease in sperm motility and an insignificant increase in abnormal sperm at this dose level. Based on these data,

the lowest

- observed

- adverse

- effect level ( LOAEL ) of t ea t ree o il in rats was 60 mg/kg/day based on testicular toxicity in males and increased liver to body weight ratios in females

. The no

observed

- 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 dermal exposure is not expected because the product is not purposely applied to the skin and handlers/applicators are required to wear appropriate personal protective 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) t ea t ree o il has a long history of use in a variety of dermally

- applied products, including shampoo, deodorants, lotions, and antifungal treatments. In a non

- guideline 30

- day dermal irritation study on rabbits (MRID 47730404) , undiluted t ea t ree o il caused severe irritation to the skin on the first day of the study. 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 consisten t with irritation was observed (EPA, 2013).

A 90

- day inhalatio n toxicity study was not submitted for t ea t ree o il . In lieu of a study, the applicant cited the data from the 90

- day oral toxicity study (MRID 48598702 ) . Due to the use pattern of the active ingredient as a spray and the volatility of the constituents of t ea t ree o il

, exposure to handlers/applicators is possible. There 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 t ea t ree o il is abs orbed into the body has been employed. The Agency is confident that this approach is protective of potential repeat exposure inhalation toxicity for the following reasons: 1) t ea t ree o il is classified into Toxicity Category IV for acute

inhalation toxicit y and Toxicity Categ ory III for acute oral toxicity; and 2) humans are already exposed to the constituents of t ea t ree o il as the oil is used in a variety of dermally

- applied cosmetic and pharmaceutical products. Moreover , five of the main components of t ea t ree o il (terpinen

- 4

- ol, γ

- terpinine, α

- terpinine, p

- cymene
, and 1,8

- cineole) are all approved for use by

th e FDA as direct food ad ditives under 21 CFR 172.515. Further, in a n occupational risk assessment conducted for applicators and handlers (who m ay be exposed via inhalation to t ea

t ree o il )

, margins of exposure ( MOEs ) were derived and were significantly higher than the Agency’s level of concern ( LOC ) of 100 (MOEs ranged from 4,900 to 150,000). Because theTea Tree Oil

Page 11 of 34 Biopesticides Registration Action Document

MOEs were significantly higher than the LOC, the Agency believes that an adequate margin of safety has been achieved to account for any potential difference in toxicity from oral versus inhalation exposure (EPA, 2013)

.

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

c. Developmental Toxicity and Mutagenicity

A developmental toxicity study conducted on t ea t ree o il was submitted in MRID 49166401. In the study, Wistar rats were administered doses of t ea t ree o il by gavage at 0, 30, 60

, or 120 mg/kg/day from day 5 to day 19 of gestation. Each 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 dose group and treatment related clinical signs in

the mid

- and high

- dose groups. Consequently, doses were reduced to 30, 60 and 120 mg/kg/day. At the start of treatment, animals were approximately 13

- 15 weeks old, within a weight range of approximate 224g ± 15g and healthy in appearance. Animal acclimatization, housing, diet, and water supply were reported adequately. Test substance characterization and preparation was al so 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 observations occurred at least 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 consumption was measured throughout the study. Animals were sacrificed on day 20 after mating und er isoflurane anesthesia. Gross necropsy was performed on all rats, which consisted of external observation and examination of thoracic and abdomen viscera and examination of uterine contents. Gravid uterine weights, the number of corpora lutea in each ova ry, the number of implantation sites, the number of early and late resorptions sites, the number of live and dead fetuses, individual fetal body weights, fetal sex

, and the fetal sex ratio were recorded. Fetuses were also examined for external abnormalitie s, visceral organ abnormalities and skeletal development and abnormalities. Statistical analyses of the data were provided in the study

. Significant reductions in maternal body weight gain and food intake were observed during the treatment period in the mi d

- and high

- dose groups and throughout gestation in the high dose group. These observations were considered treatment related. No gross pathological findings were observed in the dams in any group. At all dose levels, mean gravid uterine weights, the numbe r of corpora lutea, the number of implantations

, and pre and post

- implantation losses were all statistically 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 statistically comparable to the control group. Mean fetal body weights of males, females

, and total fetuses were significantly reduced at the mid an d high dose level; however, the weights of the fetuses in the mid dose group were comparable to historical control data. Any fetal anomalies and abnormalities that were observed were routinely observed in rat fetuses, were comparable to the control group o r 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 gainTea Tree Oil

Page 12 of 34 Biopesticides Registration Action Document

and food consumption. The developmen tal NOAEL is 60 mg/kg/day and the LOAEL is 120 mg/kg/day based on reduced fetal body weight (EPA, 2014)

.

In a study published in the New England Journal of Medicine (Henley, 2007)

, study authors reported that repeated topical exposure to lavender and tea tree oils may cause prepubertal gynecomastia in boys. Three prepubertal boys who were otherwise healthy and had normal serum concentrations of endogenous steroids exhibited gynecomastia that coincided with the topical application of products that contained lavender and tea tree 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 lavender and tea tree oils had estrogenic and antiandrogenic acti vities. Although the study suggests that exposure to topical applications of products containing lavender and tea 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 unreaso nable adverse effects to this population subgroup. This conclusion is based upon the following: 1) t ea t ree o il will not be applied topically to the skin. The active ingredient will be applied to crops as an agricultural use; thus, exposure is mainly antic ipated to be via the oral route, 2) dietary exposure

to t ea t ree o il as a pesticide is anticipated to be minimal as it degrades rapidly in the environment, 3) dermal exposure is not anticipated to result in risk as occupational exposure assessments ( see su bchronic toxicity section above) indicate MOEs that do not exceed the Agency’s level of concern

, and 4) humans are already exposed to the constituents of t ea t ree o il as they are found naturally in the diet, are used as food add itives

, and are found in a variety of cosmetic and pharmaceutical products.

A Tier I mutagenicity stud y [ in vitro reverse gene mutation assay (Ames) using Salmonella typhimurium strains TA98, TA100, and TA102 (MRID 47730404)] showed that t ea t ree o il did

not increase the numb er of revertants at doses of <50 μg in the presence or absence of S9

metabolic activation. A Tier II mutagenicity study [ in vivo mammalian erythrocyte micronucleus assay (MRID 47730407)] showed that t ea t ree o il did not produce a statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow of mice given oral doses of 1000

- 1750 mg/kg body weight. Therefore, under the conditions of both

assays
, t ea t ree o il is considered to be non

- mutagenic.

For more inform ation regarding prenatal developmental and mutagenicity data requirements,

refer to Table 8 in Appendix A

.

d. Tier II/Tier III

Tiers I I and II I data were not required due to the nature of the active ingredient and its intended

uses in potential new EP products ( fungicides/bactericides).

e. Effects on the Endocrine System

As required under F ederal Food, Drug, and Cosmetic Act (F FDCA ) section 408(p), EPA has developed the Endocrine Disruptor Screening Pro gram (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrineTea Tree Oil

Page 13 of 34 Biopesticides Registration Action Document

effects as the Adminis trator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose

- response relationship between the dose and the E, A, or T effect.

Between Oc tober 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 the potential for human exposur e through pathways such as food and water, residential activity, and certain post

- application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors.

Tea t ree o il is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA section 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call

- ins for all pesticide active ingredie nts.

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

.

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 observed in the 90

- day oral toxicity study. The POD is protective of developmental toxicity because the NOAEL in the 90

- day oral toxicity study is lower 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

Human exposure to t ea t ree o il may occur via dietary exposure to some treated commodities, although exposure is anticipated to be minimal. A risk assessment was conducted for t ea t ree o il, specifically for the residue of concern, terpinen

- 4

- ol (the main constituent of t ea t ree o il) , to assess potential risks (if any) from dietary exposure. T he Agency has determined that there is reasonable certainty of no harm to humans when exposed to residues of the active ingredient (specifically, residues of terpinen

- 4

- ol) from pesticidal use when label instructions are followed.

T his conclusion is based on the following: 1) although toxic endpoints have been identified in

studies on t ea t ree o il, significant dietary exposure is not expected because t ea t ree o il is anticipated to degrade rapidly in the environment; 2) humans are already exposed to theTea Tree Oil

Page 14 of 34 Biopesticides Registration Action Document

cons tituents of t ea tr ee o il in the diet from foods that naturally contain the compounds and from foods to which the compounds have been added as food additives; and 3) quantitative dietary

risk assessment s suggest that dietary exposure to t ea t ree o il when us ed as a pesticide is not likely to pose unreasonable risk to the U.S. population in general, or sensitive subpopulations

, including infants and children

. A detailed discussion of how the Agency arrived at its conclusion is provided in the subsequent paragr aphs.

Residues

Data on residues of the major constituents of t ea t ree o il (terpinen

- 4

- ol, γ

- terpinene

, and 1,8

- cineole) in crop field trials indicate that when label instructions are followed, residues are not likely to be found on peppers, tomatoes, or bananas. Based on the available data, residues of the constituent terpinen

- 4

- ol are likely to be found on peppers when t ea t ree o il is applied at higher application rates than those provided on the EP label.

Residue data have been submitted for applications of products containing t ea t ree o il on tomatoes, peppers, and bananas (EPA, 2014) . Analysis for residues of the three major components in the oil (terpinen

- 4

- ol, γ

- terpinene

, and 1,8

- cineole) was performed in the studies. No detectable residues (below the limit of quantification [LOQ]) were found in tomatoes at application rates higher than those on the proposed label ( approximately three to seven times the proposed application rate ) . No detectable residues were found in bananas at the proposed application rate. Detectable residues of terpinen

- 4

- ol only (maximum of 0.10 mg/kg at 24

- hours) were found for up to 48

- hours on peppers at a higher application rate than that proposed on the

EP label

, but no detectabl e residues of any components, including terpinen

- 4

- ol

, were found at the proposed application rate.

Dietary Exposure from Natural Sources

Tea tree oil is not considered to be an edible oil; however, its major constituents are found in a variety of edibl e commodities (EPA, 2014)

. H umans are already naturally exposed to the major

constituents of t ea t ree o il (terpinen

- 4

- ol, γ

- terpinene, 1,8

- cineole

, and α

- terpinene) in the diet as they are found in herbs, spices, citrus

, and some vege tables. Additionally, t ea t ree o il is comprised primarily of terpene s 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. Quantitative and qualitative assessments regarding the nat ural occurrence of gamma

- terpinene and 1,8

- cineole have not been performed due to the lack of anticipated dietary exposure based on the absence of residues observed in the residue studies submitted by the applicant. Quantitative and qualitative assessments have been performed for terpinen

- 4

- ol because residues of the compound were observed in the studies (albeit at a significantly higher application rate), thus the potential for dietary exposure (anticipated to be minimal) exists.

According to information on the U.S. Department of Agriculture

– Agricultural Research Service ( USDA

- ARS ) website ( http://www.ars

- grin.gov/duke/ )

, terpinen

- 4

- ol, gamma

- terpinene, 1,8

- cineole

, and alpha

- terpinene (present in tea t ree o il at 5

- 13%) are found in a variety of foods including spices, herbs, and citrus at varying concentrations (EPA, 2014) . Terpinen

- 4

- ol is also found in a variety of foods. The information provided in Table 2 below is a summary of theTea Tree Oil

Page 15 of 34 Biopesticides Registration Action Document

approximate concentrati ons of terpinen

- 4

- ol in foods.

Table 2. Approximate Co ncentrations of Terpinen

- 4

- ol of Tea Tree Oil in Foods

Food Concentration Reference 2

Raspberries 23

- 175 μg/kg (ppb) 1 Malowicki, 2008 Apples and juices Concentration not quantified 1 Ferreira, 2009; Schmutzer, 2011

Carrots Concentration not quantified 1 Varming, 2004 Grapes Concentration not quantified 1 Ugliano, 2008

Bananas Concentration not quantified 1 Jordán, 2000

Lemons 10,000

- 11,000 ppm USDA

- ARS, 2014 Oranges and juices Concentration not quantified 1 Eman, 2006; Gonzales

- Mas, 2011; Qiao, 2008 Tangerines and juices Concentration not quantified 1 Miyazaki, 2011

Tomatoes Concentration not quantified 1 Strano, 2011 Celery Concentration not quantified 1 ; 1,000 ppm D’Antuono, 2002; USDA

- ARS, 2014 Nutmeg 4,800 ppm (seed) USDA

- ARS, 2014 Thyme oil Concentration not quantified but was identified as a major constituent of the oil Kulkarni, 2013

Marjoram oil 0.2

- 51.7% of the oil depending on the

source Nowak, 2010

Peppercorn oils ( Piper nigrum ) 0

- 13.2% of the oils Orav, 2004

Licorice 0

- 72,000 ppm of the rhizome essential oil USDA

- ARS, 2014

1 Measured as a volatile component, generally using GC/MS

2 Information from MRIDs 49166403 and 49273601

Dietary Exposure from Food Additives

Terpinen

- 4

- ol, γ

- terpinene

, and 1,8

- cineole are all approved by the FDA for use for direct addition to food under 21 CFR 172.515(b).

Dietary Risk Assessment

A quantitative risk assessment was conducted by th e Agency using the available toxicity and

residue data as inputs into the Agency’s Dietary Exposure Evaluation Model

- Food Commod ity Intake Database (DEEM

- FCID TM ) to determine the potential for risk to the general U.S. population and sensitive subpopulations. DEEM

- FCID is used by the Agency to provide probabilistic assessments of dietary pesticide exposure. The exposure asses sment is then used to

calculate dietary risk. Two separate types of conservative assessments were conducted, each of

which is discussed b elow.

Assessment # 1: DEEM

- FCID using Tea Tree Oil residue data

For its assessment, the Agency used the measured residue of terpinen

- 4

- ol from the field trials on peppers of 0.36 mg/kg (which was detected immediately after pesticide application) for all crops listed on the EP label since residue data are absent for all listed crops except for tomatoes,

peppers
, and bananas. Although the applicant has included a Pre

- Harvest Interval ( PHI ) of 48 hours on the label to mitigate risk (no residues of any major constituent for which analysis was conducted was found on treated crops at 48 hours), the Agency used the residue value found on treated peppers at time zero for its assessment . This conservative approach was utilized to
increase confidence in the risk as sessment because of the lack of residue data for the other cropsTea Tree Oil

Page 16 of 34 Biopesticides Registration Action Document

listed on the label.

For the risk assessment, the reference dose (RfD) was calculated using the available toxicity data

for t ea t ree o il . An RfD is an estimate (with consistent applications of generally order

- of

magnitude uncertainty factors) of daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. The uncertainty factor (UF) that is g enerally used is 100, which includes a 10X uncertainty factor for interspecies variation (extrapolation from animal data to humans) and a 10X uncertainty factor for intraspecies variation (variability between humans). The RfD is represented by the equation below:

Point of Departure (e.g., NOAEL)

RfD =

------------------------------------------

Uncertainty Factors (e.g., 100)

The RfD was calculated by dividing the NOAEL of 30 mg/kg/day from the 90

- day oral toxicity study on t ea t ree o il by the uncerta inty factor of 100, which resulted in the RfD of 0.3 mg/kg/day.

To express risk, the percent of the RfD (%RfD) for each population subgroup is calculated by dividing the exposure (estimated in DEEM

- FCID) by the RfD and multiplying the result by

100%. For risk characterization, a %RfD or %PAD less than 100 is desired and indicates that the dietary risk for humans from pesticidal exposure is expected to be negligible. The %RfD is represented by the equation below:

Exposure

%RfD =

------------- * 100%

RfD

The results of the DEEM analysis and risk assessment are summarized in Table 3 below.Tea Tree Oil

Page 17 of 34 Biopesticides Registration Action Document

Table 3: DEEM

- FCID Chronic Analysis for Tea Tree Oil (specifically terpinen

- 4

- ol)

Population Subgroups (age in years) Estimated Dietary Exposure (mg/kg bw/day) Percent RfD

U.S. Population 0.002306 0.8% Hispanics 0.002608 0.9%

Non

- hispanics whites 0.002274 0.8%

Non

- hispanic blacks 0.002066 0.7%

Non

- hispanic/Non

- white/Non

- black 0.002520 0.8%

Nursing infants 0.002089 0.7%

Non

- nursing infants 0.004178 1.4% Females (13+) pregnant 0.002051 0.7%
Children (1

- 6) 0.005629 1.9%
Children (7

- 12) 0.003220 1.1%

Male 13

- 19 0.002190 0.7%
Females (13

- 19) not pregnant 0.001901 0.6%
Male (20+) 0.001913 0.6% Females (20+) not pregnant 0.001756 0.6%
Seniors (55+) 0.001672 0.6%

All infants 0.003533 1.2%
Females (13

- 50) 0.001842 0.6%
Children (1

- 2) 0.006413 2.1%
Children (3

- 5) 0.005369 1.8%
Children (6

- 12) 0.003440 1.1%
Youth (13

- 19) 0.002043 0.7%
Adults (20

- 49) 0.001942 0.6%
Adults (50

- 99) 0.001687 0.6%
Females (13

- 49) 0.001848 0.6%

The %RfD values ranged from 0.6% to 2.1%; the highest %RfD being for children aged 1

- 2

years . These values are all significantly below 100 and therefore do not exceed the Agency’s

LOC . These results indicate that the dietary risk for humans from pesticidal exposure to t ea t ree

o il i s expected to be negligible.

Assessment # 2 : DEEM

- FCID using surrogate information (ultra

- conservative approach)

To further support the finding that dieta ry risk to humans from pesticidal exposure to t ea t ree o il is expected to be negligible and subsequently justify the exemption from the requirement of a

tolerance for t ea t ree o il on certain food commodities , the Agency conducted an extremely

conservative estimate of dietary risk. In the absence of specific residue data, the Agency has developed an approach which uses surrogate information to derive upper bound exposure estimates for an ingredient in a pesticide product. The exposure estimates are based on the highest tolerance for a given commodity from a list of high

- use conventional insecticides,

herbicides

, and fungicides. A complete description of the general approach taken to assess ingredient risks in the absence of residue data is contained in the me morandum entitled “Alkyl Amines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and Drinking Water) Dietary Exposure and Risk Assessments for the Inerts.” (D361707, S. Piper, 2/25/09)

, and can be

found at http://www.regulations.gov in docket ID number EPA

- HQ

- OPP

- 2008

- 0738. The document pertains to the dietary risk assessment of an inert ingredient, but the methodology is being employed by BPPD for use in the dietary risk assessment for a biopesticide active ingredient.Tea Tree Oil

Page 18 of 34 Biopesticides Registration Action Document

In its assessment, The Agency assumed that the residue level of t ea t ree o il (specifically, terpinen

- 4

- ol) would be no higher than the highest tolerance for a given commodity. Implicit in this assumption is that there would be similar r ates of degradation (if any) between the conventional and biopesticide active ingredients and that the concentration of the biopesticide in the scenarios leading to these highest of tolerances would be no higher than the concentration of

the conventional a ctive ingredient. The Agency believes that the assumptions used to estimate dietary exposures lead to an extremely conservative estimate of dietary risk due to a series of compounded conservatisms: 1) the assumption that the residue level of the biopestici de is equal to the level of residue for the conventional pesticide will significantly overstate exposure. The

constituents of t ea t ree o il are expected to degrade rapidly in the environment and it is highly unlikely that residue levels of t ea t ree o il would be similar to those of the conventional active ingredients

, which the tolerances used in the dietary assessment are based upon; 2) the assumption that for each commodity, the conventional active ingredient that will serve as a guide to the potential level of biopesticide residues is th e conventional active ingredient with the highest tolerance level. The assumption overstates residue values because it would be highly unlikely that a biopesticide, specifically, te a t ree o il, would be present at the level of the

convent ional active ingredient in the highest tolerance for every commodity for which an exemption is requested; and 3) the assumption that all foods contain the biopesticide at the highest tolerance level. In other words, the Agency assumes that 100 percent of c ommodities are treated with the biopesticide at the rate and manner necessary to produc e the highest residue legally possible for a conventional active ingredient. In summary, the Agency cho se a very conservative method for estimating what level of the bio pesticide residue could be in or on food and then used the methodology to choose the highest possible residue that could be found on

food and assumed that all food contained this residue. No consideration was given to the potential degradation between harv est and consumption even though monitoring data shows that tolerance level residues are typically one to two orders of magnitude higher than actual residues in food when distributed in commerce. Accordingly, although sufficient information to quantify

actu al residue levels of a biopesticide, e.g.: t ea t ree o il, is not available, the compounding of the conservative assumption will lead to a significant exaggeration of actual exposures. The Agency does not believe that this approach underestimates exposure in the absence of residue data.

The results of the DEEM

- FCID analysis and risk assessment are presented in Table 4 below.Tea Tree Oil

Page 19 of 34 Biopesticides Registration Action Document

Table 4: DEEM

- FCID Chronic Analysis for Tea Tree Oil (specifically terpinen

- 4

- ol)

- Ultra

- Conservative

Population Subgroups (age in years) Estimated Dietary Exposure (mg/kg bw/day) Percent RfD

U.S. Population 0.095133 31.7% Hispanics 0.090487 30.2%

Non

- hispanics whites 0.099301 33.1%

Non

- hispanic blacks 0.072545 24.2%

Non

- hispanic/Non

- white/Non

- black 0.105237 35.1%

Nursing infants 0.074365 24.8%

Non

- nursing infants 0.128558 42.9% Females (13+) pregnant 0.082419 27.5%
Children (1

- 6) 0.208179 69.4%
Children (7

- 12) 0.102048 34.0%

Male 13

- 19 0.065080 21.7%
Females (13

- 19) not pregnant 0.070148 23.4%
Male (20+) 0.079670 26.6% Females (20+) not pregnant 0.089827 29.9%
Seniors (55+) 0.087060 29.0%

All infants 0.111827 37.3%
Females (13

- 50) 0.084436 28.1%
Children (1

- 2) 0.249669 83.2%
Children (3

- 5) 0.193070 64.4%
Children (6

- 12) 0.111120 37.0%
Youth (13

- 19) 0.067516 22.5%
Adults (20

- 49) 0.083857 28.0%
Adults (50

- 99) 0.086492 28.8%
Females (13

- 49) 0.084518 28.2%

The %RfD values ranged from 21.7% to 83.2%; the highest %RfD being for children aged 1

- 2

years

. These values are all below 100 and therefore do not exceed the Agency’s LOC . These results indicate that even under extremely conservative dietary exposure scenarios, the dietary risk for the U.S. population in general, including sensitive subpopulations, is expected to be negligible.

b

. Drinking Water Exposure and Risk Characterization

Residues of the constituents of t ea t ree o il in drinking water are not expected when the product is used according to label instructions. The constituents of the active ingredient are mostly volatile compounds that are already present in the environment in plants and water. They are expected to

volatilize and degra de rapidly in the environment and are n ot directly applied to water ; therefore,

residues of t ea t ree o il in drinking water are unlikely.

c

. Acute and Chronic Dietary Risks for Sensitive Subpopulations Particularly

Infants and Children

The Agency has determined that there are no foreseeable d ietary risks to sensitive subpopulations, including infants and children, from the use of tea t ree o il in the proposed product when labe l instructions are followed. This conclusion is based on the following : 1) significant dietary exposure is not anticipat ed when label instructions for the proposed product are followed, 2) dietary risk to infants and children is anticipated to be negligible based on the results of the dietary risk assessments that the Agency has conducted (see Section IV. B

. 3 .aTea Tree Oil

Page 20 of 34 Biopesticides Registration Action Document

above) and 3) humans are already exposed to t ea t ree o il in cosmetic and 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 applicators is not anticipated as adequate PPE requirements are on the proposed EP label. Additionally, the active ingredient degrades rapidly in the environment which further mitigates dermal exposure. Due to the pote ntial for inhalation

exposure of residues of t ea t ree o il to mixers/loaders and applicators (the EP is applied as a spray, fog or drench)

, and the effects observed in the 90

- day oral toxicity and prenatal developmental studies, a n occupational exposure and risk assessment was conducted

. The results of the risk assessment indicate that risk from inhalation exposure to t ea t ree o il is negligible for mixers/loaders and applicators when the pesticide product (Timorex Gold [EPA File Symbol No.

86182

- R]) is used according to label instructions. A summary of the assessment is provided

below.

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 calc ulati on spreadsheet developed by OPP’s Health Effects 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 inhalation. The standard body we ight for females (69 kg) was used for all exposure scenarios in the assessment due to the incidence of developmental effects. Based on label instructions, exposure scenarios consisted of the following application methods: ground boom, airblast, aerial

, and mechanically

- pressured handgun. The application rate used for the exposure assessment was the maximum application rate on the label (1.6 lb

a.i. /acre). Potential daily exposures for occupational handlers (mixer/loaders and applicators)

were calculated in the spreadsheet using 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 active ingredient that is available for inhalation 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 adjusted for absorption a nd body weight) was calculated using the following formula:

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

Page 21 of 34 Biopesticides Registration Action Document

Average Daily Dose (ADD) = a bsorbed dose recei ved from exposure to the active ingredient in a given scenario

Dail y Exposure = amount of the active ingredient that is available for inhalation absorption Absorption Factor = a measure of the amount of chemical that crosses a biological boundary such as the skin and lungs (%) Body Weigh t = b ody weight determined to represent the population of interest in a risk

assessment

Risk for each application handler scenario was calculated using a M OE, which is a ratio of the toxicological endpoint to the daily dose of concern. The daily inhalatio n dose receiv ed by occupational handlers was compared to the POD (i.e. : NOAEL) to assess the risk to occupational

handlers . All MOE values were calculated using the following formula:

MOE = PO D (i.e.: NOAEL in mg/kg/day)

ADD (mg/kg/day)

All MOEs calculated for mixers/loaders and applicators using no inhalation PPE were significantly greater than the Agency’s LOC of 100 (10X for intraspecies variation and 10x for interspecies variation). MOEs greater than 100 do not exceed the Agency’s LOC ; therefore, risks are not considered to be of concern. Based on the results of the occupational risk assessment, unreasonable adverse effects to handlers are not anticipated when the pesticide product is used according to label instructions. A summary of the exposure scenarios and MOEs is provided in

Table 5 below.

Significant post

- application exposure to t ea t ree o il is not anticipated as there is a 4

- hour REI on

the EP label and the active ingredient is expected to rapidly degrade in the environment.

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

Significant exposure to t ea t ree o il is not anticipated in residential, school, and day care areas, as

TABLE 5

. Occupational Risk Assessment Summaries for Tea Tree Oil (Inhalation Route of Exposure)
Worker Activity Application Equipment/Application 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 22 of 34 Biopesticides Registration Action Document

the product containing this active ingredient is intended for use on horticultural and agricultural

crops.

5

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

The Food Quality Protection Act amendments to the Federal Food, Drug, and Cosmetic Act (FFDCA, Section 408(b)(2)(A)(ii)) require “that there is a reasonable certainty that no harm will result from aggregate exposure to pesticide chemical residue, including all anticipated dietary exposures and other exposures for which there are reliable inf ormation.” Aggregate exposure will typically include exposures from food, drinking water, residential uses of a pesticide, and

other non

- occupational sources of exposure.

For t ea t ree o il, qualitative aggregate exposure and risk assessments were conducted . For the pesticidal uses, dietary exposures were evaluated. Residential exposures are not anticipated based on the use pattern of tea tree oil. Drinking water exposure is not anticipated based on the rapid degradation of the active ingredient in the envir onment. Additionally, tea tree oil is not directly applied to water. For the aggregate assessment, the routes of exposure evaluated were oral (via dietary exposure). Significant dermal and inhalation exposures are not anticipated based on the use pattern o f the pesticide; tea tree oil is for agricultural use only.

The active ingredient is not currently used and is not proposed for use as an inert ingredient in pesticide products. Based on the known current uses of tea tree oil in the cosmetic and pharmace utical industries, the general population is likely to be exposed to tea tree oil. Exposures to tea tree oil in these products are likely to be at lower concentrations because tea tree oil is corrosive to the skin and eyes at higher concentrations accordin g to the data available to the Agency. As stated earlier in this document, the general population is also exposed to the major constituents of tea tree oil in the diet, as they are found naturally in foods and are intentionally added to foods as food addit ives. Reliable data on exposures to tea tree oil via food, cosmetic and pharmaceutical uses are not available; thus

, a quantitative aggregate exposure and risk assessment was not conducted. Instead, EPA conducted a qualitative aggregate exposure and

risk a ssessment. Dietary exposure from use as a pesticide is anticipated to be minimal based on the anticipated rapid degradation of the active ingredient in the environment. The constituents of tea tree oil are volatile and degrade quickly once the pesticide is applied. As part of the qualitative aggregate exposure and risk assessment, the Agency used the dietary risk assessment that was conducted for tea tree oil (refer to Section IV.3.B.a ). The highest dietary exposure estimated in the assessment was 0.006 mg/ kg/day. The calculated risk was 2.1% of the reference dose (RfD). Generally, risks from exposures that are less than 100% of the RfD are not a risk

concern.

The Agency believes that the dietary risk assessment is very conservative and protective of any

ad ditional exposures to tea tree oil via foods, cosmetics

, and pharmaceuticals because the potential pesticide

- exposed population utilizes only approximately 2% of the RfD, leaving 98% of the RfD for exposure from non

- pesticidal uses (e.g.: foods, cosmetics, and pharmaceuticals). Based on the Agency’s risk assessments, pesticidal exposure via the oral, dermal and inhalation routes is anticipated to be negligible and not expected to contribute significantly to the overall exposure of tea tree oil to the U.S. p opulation.Tea Tree Oil

Page 23 of 34 Biopesticides Registration Action Document

In consideration of the above information, the Agency has determined the risk from aggregate exposure (via oral, dermal, and inhalation exposures) is negligible; there is reasonable certainty that no harm will result to the general population o r to infants and children from aggregate exposure to tea tree oil.

6

. Cumulative Effects

EPA has considered the potential for cumulative effects of t ea t ree o il and other substances in relation to a common mechanism of toxicity. Unlik e other pesticides for which EPA has followed a cumulative risk approach based on a c ommon mechanism of toxicity, the Agency has

not made a common mechanism of toxicit y finding for t ea t ree o il and any other substances and

t ea t ree o il does not appear to produce a toxic meta bolite produced by other substances. The active ingredient is a biopesticide that has a nontoxic mode of action. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to

evaluate the cumulative effects of such chemicals, see the pol icy statements released by the Agency’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on

EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

7. Risk Characterization

The Agency has considered human exposure to t ea t ree o il 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

t ea t ree o il as a pes ticide when label instructions are followed.

C. E nvironmental Assessment

1. Ecological Hazards

Adequate nontarget toxicology data /information is available to support registration of t ea t ree o il with the submission of nontarget toxicology data on the TGAI. All nontarget toxicology data requirements for t ea t ree o il have been satisfied.

Tea t ree o il i s highly toxic to aquatic invertebrates. Tea t ree o il is practically nontoxic to fish and

insects . Tea t ree o il is not phytotoxic. Significant exposure of t ea t ree o il to birds is not expected due to volatilization and rapid degradation of the active ingredient in the environment (EPA, 2013).

For more information regarding nontarget organism toxicity data requirements, refer to Tabl e 9 in Appendix A

.

2. Environmental Fate and Ground Water Data

Tea t ree o il is expected to degrade rapidly in the environment. Up to 90% of t ea t ree o il has beenTea Tree Oil

Page 24 of 34 Biopesticides Registration Action Document

shown to volatilize within 24 hours after application and residue studies indicate the lack of detectable residues of three of the major constituents of t ea t ree o il at 48 hours post

- application ( EPA, 2013 ) . In MRID 48275004, a study was submitted in which the biodegradation of t ea t ree

o il was determined in a 28

- day ready biodegradability assay (OECD Guideline 310 and EN ISO 14593) by monitoring the release of carbon dioxide with a non

- adapted activated sewage sludge. Based on the results of the assay, bio degradation of t ea t ree o il was 10% after 2 days, 60% after 5 days, 87% by day 7

, and 106% at study termination.

3. Ecological Exposure and Risk Characterization

Significant exposure to birds is not expected because the active ingredient is volatile and degrades rapidly in the environment. Additionally, birds are already exposed to the components

of t ea t ree o il , as they are present in a multitude of plants. Althou gh exposure to fish, insects

, and plants is anticipated from use of the product through direct application, accidental application,

drift or run

- off, results of toxicity testing on pure t ea t ree o il indicate that t ea t ree o il is practical ly nontoxic to the se organisms. The proposed EP which contains 23.8% t ea t ree o il will also be diluted with water prior to application, which will further reduce exposure to these organisms. The aquatic invertebrate toxicity study submitted indicates that t ea t ree o il is highly toxic to these organisms. Because of the potential for toxicity to freshwater invertebrates, risk assessments for these organisms will need to be conducted for products containing t ea t ree o il as an active ingredient. Since nontarget organism to xicology data on the proposed EP are available,

a risk assessment was conducted for the EP (EPA, 201 4 ). The results of the risk assessment for the EP indicated that mitigation language for aquatic invertebrates is required on the EP label.

4. Endangered Species Assessment

The Agency has not conducted a risk assessment that supports a complete endangered species determination. The ecological risk assessment planned during registration review will allow the Agency to determine whether t ea t ree o il’s use has “no effect” or “may effect” federally listed threatened or endangered species (listed species) or their designated critical habitats. When an assessment concludes that a pesticide’s use “may affect” 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. Efficacy Data

Product performance data must be developed for all pesticides to ensure that pesticide products will perform as intended and that unnecessary pesticide 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 pestic ide 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 perfor mance requirement, refer to Pesticide Registration Notice (PR)

Notices 96

- 7, 2002

- 1 and Explanation 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_Notices/pr2002

- 1.pdf ) and ( http://www.epa.gov/pesticides/health/risk

-Tea Tree Oil

Page 25 of 34 Biopesticides Registration Action Document

benefit.htm ).

The EP submitted with this new active ingredient did not list pests of significance public health importance or a public health pest as defined in FIFRA section 28(d) and section 2(nn). Therefore, product performance (efficacy) was not evaluated.

V. R ISK MANAGEMENT DECISION

A. Determination of Eligibility for Registration

Section 3(c)(5) of FIFRA provides for the registration of a new active ingredient if it is

determined that : (A) its composition warrant s proposed claims; (B) its labeling and other materials 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 re cognized 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 t he TGAI

, t ea t ree o il . Such products are not expected to cau se unreasonable adverse effects

. Therefore, t ea t ree o il as a TGAI is eligible for registration for the labeled uses.

B. Regulatory Decision

The data submitted fulfill the registration require ments of t ea t ree o il for use as a fungicide/bactericide

. Refer to Appendix B for product

- specific information.

Conditional/Unconditional Registration

All data requirements are fulfilled, and EPA determined that an unconditional registration of t ea

t ree o il is appropriate.

Consistent with the policy of making registration actions more transparent, t ea t ree o il is subject

to a 15

- day comment period as a “new active ingredient.” EPA has established a comment period of 15 days on the basis of t ea t ree o il minimal toxicity, the determination that t ea t ree o il presents low risk of any adverse effects to human health and the environment, and critical need for this active ingredient. The notice for this comment period includes the draft BRAD and draft produc t labels for the MP, Tea Tree Oil Technical , and EP, Timorex Gold , which contain this new active ingredient, t ea t ree o il . The docket identification (ID) number is EPA

- HQ

- OPP

- 20 09

- 0 440 . The Agency believes that based on the risk assessment and information submitted in support of the registration of the MP and EP containing t ea t ree o il , it is in the best interests of the public to issue the registration for Tea Tree Oil Technical and Ti morex Gold . The basis for this decision

can be found in the risk assessment for t ea t ree o il , which is characterized in this BRAD.Tea Tree Oil

Page 26 of 34 Biopesticides Registration Action Document

C. Environmental Justice

EPA seeks to achieve environmental justice

— the fair treatment and meaningful involvement of

all people regardless of race, color, national origin, or income

— with respect to the development, implementation, and enforcement of environmental laws, regulations, and policies. At this time

, EPA does not believe that use of t ea t ree o il pesticide products will cause harm or a disproportionate impact on at

- risk communities. For additional information regarding environmental justice issues, please visit EPA’s website at http://www.e

pa.gov/compliance/environmentaljustice/index.html

.

V I

. ACTIONS REQUIRED BY REGISTRANTS

EPA evaluated all data submitted in connection with the registration of the t ea t ree o il pesticide products and determined that these data are sufficient to satisfy current registration data requirements. At this time, n o additional data must be submi tted to EPA for these particular products. For new uses and/or changes to existing uses, EPA may require addition al data.

Notwithstanding the information stated in the previous paragraph, it should be clearly understood that certain specific data are required to be reported to EPA as a requirement for maintaining the Federal registration for a pesticide product. A brief summary of these types of data are listed

below.

A. R eporting of Adverse Effects

Pursuant to FIFRA section 6(a)(2), r eports of all incidents of adverse effects to the environment

must be submitted to EPA

.

B. Reporting of Hypersensitivity Incidents

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

VI I

. A PPENDIX A. DATA REQUIREMENTS (40 CFR P ART 158

- S UBPART U)

*NOTE: Master Record Identification (MRID) numbers listed in the following tables are representative of supporting data/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 this active ingredient.Tea Tree Oil

Page 27 of 34 Biopesticides Registration Action Document

TABLE 6 . P roduct Chemistry Data Requirements for Tea Tree Oil ( 40 CFR § 158.2030 )

OCSPP Guideline Reference No./ Study Description of Result MRID

8 8 0. 1100 Product identity and composition The product identity and composition were adequately addressed. Confidential Business

Information (CBI). 47730401

8 8 0. 1200 Description of starting materials,

production, and formulation

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

8 8 0. 1400 Discussion of formation of

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

8 3 0. 1700 Preliminary analysis The preliminary analysis of the product was acceptable. CBI. 47730402, 47730403

8 3 0. 1750 Certified limits The certified limits listed on the CSF are acceptable. 47730401

8 3 0. 1800 Enforcement analytical method The enforcement analytical method was adequately addressed. CBI. 47730401Tea Tree Oil

Page 28 of 34 Biopesticides Registration Action Document

TABLE 7

. 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 pr oduct chemistry review.

830.6315 Flammability Flashpoint = 55 °C

59°C 47918402

47730401

830.6317 Storage Stability C omposition 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 stability. 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 i ncreased ~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 product 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 product 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

830.7 520 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 29 of 34 Biopesticides Registration Action Document

TABLE 7

. 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 30 of 34 Biopesticides Registration Action Document

Table 8 : 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 index (PII) was 5.0. Toxicity Category I 47730404

Dermal sensitization (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 hours 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 ba sed 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 (870.325 0) Waived: prolonged dermal exposure not anticipated. TGAI is corrosive to skin and adequate PPE is required on the label.

Undiluted t ea t ree o il 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

irri t ation; 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 31 of 34 Biopesticides Registration Action Document

Table 8 : 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

D evelopmental : 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 9 : 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 volatilization and rapid degradation of the active ingredient in the environment. Additionally, components of the TGAI are already found in a multitude o f 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 volatilization and rapid degradation of the active ingredient in the environment. Additionally, components of the TGAI are already found in a multitude o f 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

F ish acute toxicity, freshwater (850.1075) LC 50 > 100 mg/L Practically non

- toxic

47730408 Terrestrial plant toxicity, Seedling emergence/Vegetative vigor (850.4 1 00 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 t ea t ree o il 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 32 of 34 Biopesticides Registration Action Document

Table 9 : 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. A PPENDIX B

.

For product specific information, please refer to http://www.epa.gov/pesticides/pestlabels

.

IX

. APPENDIX C.

REFERENCES

EPA. 2010. Memorandum from Angela L. Gonzales to Colin Walsh. Joint Science Review with Health Canada Pest Management Regulatory Agency (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 Pesticide 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 Management Regulatory Agency 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 Pesticide Programs. January 30, 2013.

EPA. 2014. Memorandum from Angela L. Gonzales to Colin Walsh. Science Review In Support of the Registration of Tea Tree Oil Technical Containing Tea Tree Oil as its Active Ingredient.

U.S. Environmen tal Protection Agency Office of Pesticide Programs. April 10, 2014.

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

REVIEWS AND OTHER REFERENCES

EPA. 2010. Mem orandum from Angela L. Gonzales to Colin Walsh. Joint Science Review withTea Tree Oil

Page 33 of 34 Biopesticides Registration Action Document

Health Canada Pest Management Regulatory Agency (PMRA) In Support of the Registration of

Timorex Gold containing Tea Tree Oil as its active 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 Agency (PMRA) In Support of the Registr ation of

Timorex Gold containing Tea Tree Oil as its active ingredient

. U.S. Environmental Protection Agency Office of Pesticide Programs. January 30, 2013.

EPA. 2014. Memorandum from Angela L. Gonzales to Colin Walsh. Science Review i n Support of the Registration of Timorex Gold containing Tea Tree Oil as its Active I ngredient

. U.S. Environmental Protection Agency Office of Pesticide Programs. April 10, 2014.

X. GLOSSARY OF ACRONYMS AND ABBREVIATIONS

a.i. a ctive i ngredient

ARS Ag ricultural Research Service (USDA)

Biomor Biomor Israel, Ltd.

BPPD Biopesticides and Pollution Prevention Division

BRAD Biopesticide Registration Action Document

bw body weight

CBI Confidential Business Information

CFR Code of Federal Regulations

cm 3 cubic centimeter

CSF Confidential Statement of Formula

cSt centistokes

°C degrees Celsius

DEEM

- FCID Dietary Exposure Evaluation Model

- Food Commod ity Intake Database

EC 50 median effective concentration. A statistically derived single concentration in

env ironmental medium that can be expected to cause an effect in 50% of the test animals when administrated by the route indicated (inhalation). It is expressed as a concentration in air or water (e.g. mg/L).

EDSP Endocrine Disruptor Screening Program

EDSTAC Endocrine Disruptor Screening 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 Ro denticide Act FQPA Food Quality Protection Act

FR Federal Register

g gram ha hectare kg kilogram

Kow octanol

- water partition coefficient

L literTea Tree Oil

Page 34 of 34 Biopesticides Registration Action Document

LC 50 median lethal concentration. A statistically derived single concentration in air or

water that can be expected to cause death 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 derived si ngle dose that can be expected

to cause death in 50% of the test animals 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

- effec t

- level

LOC level of concern

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 receipt

OPP Office of Pesticide Programs

O CSPP Office of Chemical Safety and Pollution Prevention

pa pascal

PMRA Canada’s Pesticide Management Regulatory Authority

POD point of departure

PPE personal protective equipment

PR Notice Pesticide Registration Notice

REI restricted

- entry interval

R f D reference dose

TGAI technical grade of the active ingredient

TSG Technology Sciences Group, Inc.

UF uncertainty factor

ug microgram

USDA United States Department of Agriculture

UV ultra

- violet