Page 1 of 34 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION

D ATE : Dece mber 31 , 20 1 3

MEMORANDUM

SUBJECT : Tebuconazole : Human Health Risk Assessment for Tolerance on Imported Oranges

.

PC Code: 128997 DP Barcode: D 412600

Decision No.: 473438 Registration No. : NA

Petition No.: 2E8138 Regulatory Action: Import Tolerance Risk Assessment Type: Single C hemical /

A ggregate Case No.: 7004

T XR No.: NA CAS No.: 107534

- 96

- 3

MRID No.: NA 40 CFR: §180. 474

FROM : Barry O’Keefe

, Senior Biologist Meheret Negussie

, Chemist Whang Phang

, Senior Toxicologist

R isk Assessment Branch III

Health Effects Division (7509P)

THROUGH : Christine Olinger , Branch Chief

R isk Assessment Branch III Health Effects Division (7509P)

TO : Tamue Gibson

, R isk M anager Fungicide Branch Registration Division (7505P)

Introduction

Bayer CropScience (Bayer) has submitted a petition (PP# 2E8138) to establish tolerances on imported oranges and associated orange commodities. The Registration Division (RD) requested

that the HED evaluate toxicology and residue chemistry data and conduct dietary and aggregate

exp osure and risk assessments, as needed, to estimate the risk to human health result ing from

the se additional tolerances. Since new domestic (US) uses are not being proposed , the tebuconazole use pattern is unchanged

. T herefore, no new occupational or resi dential risk

assessments are needed. However, HED has conducted new dietary and aggregate riskPage 2 of 34 assessments to reflect the additional commodity tolerances.

A summary of the findings and an assessment of human risk resulting from the se changes in

tolerance s of tebuconazole are provided in this document. The risk assessment was provided by Barry O’Keefe , the hazard characterization by Whang Phang , the residue chemistry data review and the dietary assessment by Meheret Negussie . The drinking water assessmen t was provided by A ndrew Shelby of the Environmental Fate and Effects Division (EFED).Page 3 of 34 Table of Contents

1.0 Executive Summary

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

2.0 Regulatory Conclusions and Recommendations

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

2.1 Data Deficiencies

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

2.2 Tolerance Considerations

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

2.2. 1 Enforcement method

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

2.2.2 International Harmonization

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

2.2.3 Recommended Tolerances

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

2.2. 4 Revisions to Petitioned

- For Tolerances

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

3.0 Ingredient Profile

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

3.1 Summary of Proposed Uses

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

3.2 Structure and Nomenclature

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

3.3 Physical and Chemical Properties

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

3.4 Anticipated Exposure Pathways

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

3.5 Consideration of Environmental Justice

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

4.0 Hazard Characterization/Assessment

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

4.1 Toxicology Studies Available for Analysis

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

4.2 Summary of Toxicological Effects (including ADME and Absorption)

........ 12

4.3 Safety Factor for Infants and Children (FQPA Safety Factor)

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

4.3.1 Completeness of Toxico logy Database

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

4.3.2 Evidence of Neurotoxicity

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

4.3.3 Evidence of Sensitivity/Susceptibility in the Developing or Young

Animal

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

4.3.4 Residual Uncertainty in the Exposure Database

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

4.4 Toxicity Endpoint and Point of Departure Selections

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

4.4.1 Recommendation for Combining Routes of Exposures for Risk

Assessment

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

4.4.2 Cancer Classification and Risk Assessment Recommendation

.......... 15

5.0 Dietary Exposure/Risk Characterization

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

5.1 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

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

5.2.1 Drinking Water Residue Profile

................................ ............................ 17

5.3 Dietary Exposure and Risk

................................ ................................ ................ 18

5.3.1 Description of Residue Data Used in Dietary Assessment

.................. 18

5.3.2 Percent Crop Treated Used in Dietary Assessment

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

5.3.3 Acute Dietary Risk Assessment

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

5.3.4 Chronic Dietary Risk Assessment

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

5.3.5 Summary Tables

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

6.0 Resident ial (Non

- Occupational) Exposure/Risk Characterization

............................ 21

6.1 Residential Handler Exposure/Risk Characterization

................................ .... 21

6.2 Residential Post

- Application Exposure and Risk Characterization

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

6.3 Other (Spray Drift, etc. )

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

7.0 Aggregate Risk Assessments and Risk Characterization

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

7.1 Acute & Chronic Aggregate Risk

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

7.2 Short

- and Intermediate

- Term Aggregate Risks

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

8.0 Cumulative Risk Characterization/Assessment

................................ ........................... 26Page 4 of 34 9.0 References

................................ ................................ ................................ ........................ 27 Appendix A: Toxicology Assessment

................................ ................................ ....................... 28 Appendix B: EPA Review of Human Research

................................ ................................ ...... 33 Appendix C: Physical and Chemical Properties

................................ ................................ ..... 33 Appendix D: International Residue Limit Status

................................ ................................ ... 34Page 5 of 34 1.0 Exec utive Summary

Tebuconazole is a triazole fungicide currently registered for disease control on a variety of fruit and field crops. The triazoles act by inhibiting C14

- d e methylase, an enzyme which plays a role in sterol production in fungi.

This document evaluates a request by Bayer (PP# 2E8138) to establish tolerances on imported oranges and associated orange commodities. HED has conducted new dietary and aggregate risk assessments to reflect the additional commodity tolerances. Since new uses are not being proposed by th is action, the domestic tebuconazole use pattern is unchanged; and therefore, no new occupational ris k assessments are needed. However, for the existing golf course turf use the residential post

- application dermal exposure and risk assessment was recalculated using HED default assumptions due to a recent decision to invalidate the use of the Bayer turf t ransferability residue (TTR) study.

Exposure Profile There is exposure expected to tebuconazole through food from the proposed uses of tebuconazole. Because the proposed use is only on imported oranges and orange commodities, occupational exposure is n ot expected. However, there are existing residential uses of tebuconazole; therefore there is potential for short

- and intermediate

- term exposure in residential settings.

Toxicity/Hazard The toxicological database for tebuconazole is essentially comple te

. With repeated dosing, the main target organs are the liver, the adrenals, the hematopo i etic system

, and the nervous system. Effects on these target organs were seen in both rodent and non

- rodent species. In addition, ocular lesions are seen in dogs (including lenticular degeneration and increased cataract formation) following subchronic

and chronic ex posure

. The toxicological effects of tebuconazole are consistent with those of other

triazole

- derivative chemicals. In particular, developmental toxicity and hepatocellular tumors are effects common to a number of these pesticides. R eliable data show th at the Food Quality Protection Act ( FQPA ) safety factor (SF) can be reduced to 3 x for all potential exposure scenarios

. The level of concern ( LOC ) for residential risk is for margins of exposure (MOEs) less than 300, based on the uncertainty factors of 10 x for interspecies extrapolation, 10x for intraspecies variation, and a 3x uncertainty factor to account for LOAEL to NOAEL extrapolation.

Tebuconazole is considered a “possible human carcinogen , Group C .” For the purpose of carcinogenic risk assessmen t, the chronic risk assessment is considered protective of any cancer effects; therefore, a separate quantitative cancer risk assessment is not required.

Tebuconazole has low acute toxicity by the oral and dermal route s of exposure (Toxicity Category II I), and moderate toxicity by the inhala tion route (Toxicity Category II). It is not a

dermal sensitizer

, n or a dermal irritant; however, it is slightly to mildly irritating to the eye.

Dietary Exposure (food and drinking water)

Somewhat r efined acute and chronic dietary (food and drinking water) exposure analyses were performed for tebuconazole. For the acute assessment, anticipated residues for grapes, grapePage 6 of 34 juice, and peaches were derived using the latest United States Department of Agriculture (USDA) Pesticide Data Program (PDP) monitoring data. Anticipated residues for all other registered and proposed food commodities were based on field trial data. Anticipated residues for all current uses were further refined using percent crop treated (%CT) data . Estimated drinking water concentrations (EDWCs) from surface water from the Environmental Fate and Effects Division (EFED) were also included. The analyses indicate that acute and chronic dietary exposure to tebuconazole from food and drinking water ar e below HED’s LOC.

Combined acute dietary exposure from food and drinking water at the 99.9 th percentile of

exposure utilized 45 % of the acute population adjusted dose (aPAD) for the general U.S. population and 84% of the aPAD for children 1

- 2 years old

, the highest exposed population subgroup

. Chronic dietary exposure estimates for food and drinking water are below HED’s

LOC for all population subgroups. The chronic dietary exposure from food and drinking water

utilized 6.7 % of the chronic population ad justed dose (cPAD) for the general U.S. population

and 1 4 % of the cPAD for all infants (<1 year old) , the population subgroup with the highest estimated dietary exposure to tebuconazole.

Dietary Assessment of Free Triazole and its Conjugates

Tebuconazole is among the group of pesticides which generate the common triazole metabolites 1,2,4

- triazole (T), triazolylalanine ( triazole alanine; TA), triazolylacetic acid ( triazole acetic acid; TAA), and triazolylpyruvic acid (TP). These triazole residues have be en evaluated for the entire class of triazole compounds. In connection with the pending tolerance s for imported oranges and orange commodities , HED has reviewed the previous triazole dietary assessments to include

the se changes to tebuconazole. HED has d etermined that dietary risk (food and drinking water)

remains unchanged and below HED’s LOC

. There are no dietary exposure considerations for the common triazole metabolites that would preclude granting the tolerance increase requests.

Residential Exposu re No new residential uses are being requested at this time. However, a dults, adolescents and children may be exposed to tebuconazole from currently registered use s on turf

, ornamentals and

treated wood surfaces

.

Aggregate Risk The dietary route (food and drinking water) alone is relevant to assess acute and long

- term aggregate exposure to tebuconazole; therefore, the dietary exposure and risk assessment s described above eval u ate aggregate exposure for these durations. However

, there are residential

uses of tebuconazole that result in exposure that should be considered with background dietary exposure. The aggregate assessment is not of concern, with MOE s rang ing from 3 1 0 to 1, 7 00 (LOC = 300)

.

Updated Aggregate Assessment of Free Triazole & its Conjugates HED has completed an updated aggregate human health risk assessment for 1,2,4

- triazole and the conjugated triazole metabolites (TA, TAA and TP). The only revisions to the components of the previous aggregate exposure and ris k estimates are to the dietary exposure estimates. For the common triazole metabolites, acute and chronic aggregate risks consist only of dietary components and, therefore, are equivalent to the dietary risk estimates. For short

- andPage 7 of 34 intermediate

- term ag gregate scenarios, the revised aggregate estimates are below HED’s level of

concern.

Occupational Exposure and Risk This document presents the risk assessment of the proposed tolerance in or on imported oranges and orange commodities

. There is no occupat ional exposure/ risk to US workers from importation of oranges or orange commodities treated with tebuconazole, and therefore, an

assessment of occupational exposure and risk is not needed.

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent possible, were considered in this

human health risk assessment , in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Population s,” http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

.

Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies (listed in Appendix B ) have been determined to require a review of their ethical conduct, and have received that review.

2.0 Regulatory Conclusions and Recommendations

HED has examined the toxicology and residue chemistry databases for tebuconazole. Pending

submission of a revised Sectio n F , there are no outstanding data deficiencies or conditions of registration that would preclude the establishment of tolerances in or on imported orange s and orange oil as outlined in this document. HED has reviewed the submitted field trial and

process ing study data for oranges for tebuconazole. HED concurs with Bayer ’s proposal for a tolerance of 1 ppm in or on orange, fruit. The proposed tolerance of 0. 7 for orange juice is not

needed. The proposed tolerance of 2 0 ppm for orange oil is not appropriate and should be proposed at 10 ppm.

Additional data are needed, as outlined in Section 2.1. The specific tolerance recommendations

are discussed in Section 2.2.

2.1 Data Deficiencies

There are no data deficiencie s associated with the proposed uses of tebuconazole.

2.2 Tolerance Considerations

2.2.1 Enforcement method

The data collection and enforcement method s for tebuconazole w ere previously discussed (D373948, B. O’Keefe, 12/28/09). A gas chromatography/ n itrogen p hosphorus d etector (GC/NPD) enforcement method for dete rmin ing tebuconazole residues is available and adequate (Method 101341).Page 8 of 34 2.2.2 International Harmonization

The US and Canadian tolerance expressions for plants and livestock are harmon ized ; w hereas

, the US and Codex tolerance expressions are harmon ized for plants only. The Codex tolerance expression for livestock commodities includes parent only. The r esidue definition in the US includes parent and the metabolite; therefore

, harmonization of tolerances/MRLs for livestock

commodities is not possible. There are no Codex or Canadian MRLs for the subject

commodities.

An Intern ational Residue Limit (IRL) status sheet is appended to this document as Appendix D.

2.2.3 Recommended Tolerances

The petitioner proposed a tolerance of 1 ppm on orange fruit based on the European (EU) MRL.

In order to harmonize with the proposed MRL for oranges, HED did not use the Organization for Economic Cooperation and Development (OECD) tolerance calculation spreadsheet to calculate the tolerance. The OECD spreadsheet recommended a tolerance of 0.8 ppm. T he pr oposed

tolerance of 1.0 ppm on orange fruit is acceptable.

The 0.7 ppm tolerance for orange juice is not needed since the raw agricultural commodity tolerance (1 ppm) is higher.

860.1550 Proposed Tolerances

• The proposed tolerance of 0.7 ppm for orange j uice is not needed since the raw agricultural commodity tolerance (1 ppm) is higher.

• The proposed tolerance of 2 0 ppm for orange oil based on the ora nge processing study is not appropriate ; to lerance should be proposed at 1 0 ppm.

The proposed and recommended tolerances are summarized in Table 2.2.3 below.

Table 2.2.3. Tolerance Summary for Tebuconazole

. Crop Commodity Proposed

Tolerance

(ppm) Recommended

Tolerance

(ppm) Comments (Correct Commodity Definition)

Orange, fruit 1.0 1.0 Orange, juice 0. 7 None The RAC tolerance covers the juice. Orange, oil 2 0 10 A lower toleran ce is needed based on available data

.Page 9 of 34 2.2.4 Revisions to Petitioned

- For Tolerances

The proposed tolerance of 20 ppm for orange oil based on using the OECD tolerance calculation spreadsheet is not appropriate; a revised Section F needs to be submitted to propose a tolerance

of 1 0 ppm for residues of tebuconazole on orange oil. HED does n ot use the OECD tolerance calculation spreadsheet to determine tolerances for processed commodities.

3.0 Ingredient Profile

3.1 Summary of Proposed Uses

Bayer submitted a petition (PP# 2E 8138) to establish tolerances on imported oranges and orange

commodities. Therefore, n o new uses, or changes to existing uses, are being proposed by these

actions. The use directions for oranges grown in Spain and Brazil are presented in Table 3. 1

. The use pattern in Spain reflects a single post

- harvest application of tebuconazole to several citrus fruits (spray or drench) at a rate of 0.1 kg a i /hL with a 250 g a i /L emulsion, oil in water, (EW) formulation. For the intended use in citrus fruits

, 5 to 25 g a i per ton of fruits were applied. The submitted use directions are adequate to allow evaluation of the submitted r esidue

data for oranges . The submitted dat a reflect the maximum use rate

. HED has assumed th a t a

s ingle post

- harvest applicatio n of a maximum of 0.214 lb ai/A will be made.

Table 3.1. Summary of Directions for Use of Tebuconazole.

Applic. Timing, Type, and Equip. Formulation [EPA Reg. No.] Applic.

Rate g ai/ha (lb ai/A) Max. No. Applic.

per Season Max.

Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and

Limitations

Citrus Fruits in Post

- Harvest (Oranges) (Spain)

Apply directly onto the fruit by immersion in the fungicide solution or by drenching at the time of receipt, before entry into the

chamber. Tunnel spraying on the conveyor belt either before

wax treatment or mixed with

authorized waxes. 25%; 250 g/L [264

- 7 48 ] 240

(0.214) N/A N/A N/A Post harvest use against fungi causing rot.

Do not contaminate water with the product or its

container.

Folicur 25 EW should be

alternated with other fungicide products of a

different nature.

Citrus Fruits (Brazil)

Broadcast, Foliar Spray, Aerial; Ground Nativo 300 SC MAI; 100 g/L trifloxystrobin

and 200 g/L

tebuconazole 120

- 160

(0.11

- 0.14) 2

- 4 (Implied) N/S 20 For control of black rot, perform the maximum of 3 applications with spaces of 30 days. For black spot, 3 applications with Nativo, alternating with fungicides with different

mechanism of action. For control of postbloom fruit drop, only 2 applications are necessary.
NA = not applicable. N/S = not specified.Page 10 of 34 3.2 Structure and Nomenclature

Structure and nomenclature are reported in Table 3.2

.

Table 3.2

. Nomenclature of Tebuconazole and its Regulated Metabolite

. Compound

Common name Tebuconazole Company experimental name HWG 1608

IUPAC name ( RS )

- 1

- p

- chlorophenyl

- 4,4

- dimethyl

- 3

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)pentan

- 3

- ol

CAS name α

- [2

- (4

- chlorophenyl)ethyl]

- α

- (1,1

- dimethylethyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol CAS registry number 107534

- 96

- 3 Molecular weight 307.8

End

- use products (EP) F OLICUR ® 25EW (25% w/v 250 g/L ; EPA Reg. No. 264

- 7 48 )

Metabolite

Common name t

- butylhydroxy

- tebuconazole Company experimental name HWG 2061

IUPAC name Not available

CAS name 1

- (4

- chlorophenyl)

- 4,4

- dimethyl

- 3

- (1 H

- 1,2,4

- triazole

- 1

- ylmethyl)

- petane

- 3,5

- diol CAS registry number Not available Molecular weight 323.8

3.3 Physical and Chemical Properties

The physicochemical properties of tebuconazole are reported in Appendix C.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed tolerance s for tebuconazole in or on imported oranges and orange commodities . This

risk assessment considers human exposures from residues in or on those commodities and from

exposure pa thways based on the registered uses of tebuconazole

. From registered uses, humans may be exposed to tebuconazole in food and drinking water, since tebuconazole may be applied directly to growing crops and application may result in tebuconazole reaching su rface and ground water sources of drinking water. There are also existing residential uses of tebuconazole

on turf, ornamentals and treated wood surfaces that must be aggregated with dietary exposures

. There is no occupational exposure associated with imported oranges or orange commodities

. Cl O H C H 3

C H 3 C H 3

N N

N

Cl O H C H 3

C H 3 C H 2 O H

N N

NPage 11 of 34 This risk assessment considers all of the aforementioned exposure pathways based on the proposed tolerances of tebuconazole, but also considers existing uses of t ebuconazole, particularly in the dietary and residential exposure assessment s

.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were c onsidered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patte rns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyz ed and categorized by subgroups based on age, and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas

post

- application are evaluated. Further considerations are currently in deve lopment as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Charact erization/Assessment

Tebuconazole is a member of the triazole fungicide g r oup . The triazoles act by inhibiting, C14

- demethylase, an enzyme which plays a role in sterol production in fungi. Sterols, such as ergosterol, are needed for membrane structure and function, making them essential for the development of functional cell walls. Hence, in hi bition of sterol production leads to abnormal fungal growth and eventually death.

4.1 Toxicology Stu dies Available for Analysis

The toxicity studies on tebuconazole are complete

. Refer to a previous HED risk assessment for further details (D 384949, K. Rury, 0 5/24/11).Page 12 of 34 4.2 Summary of Toxicological Effects (including ADME and Absorption)

The toxicological profile of tebuconazole is presented in the Appendix A. With repeated dosing, the main target organs are the liver, t he adrenals, the hematopo i etic system and the nervous system. Effects on these target organs were seen in both rodent and non

- rodent species. In addition, ocular lesions are seen in dogs (including lenticular degeneration and increased cataract

formation ) following subchronic or chronic exposure (D256074 & D276447, S

. Winfield,

0 4/18/08).

Oral administration of tebuconazole caused developmental toxicity in rat s , rabbit s , and m ic e ; with the most prominent effects seen in the developing nervous system. In developmental toxicity studies, these effects were manifested as increases in malformations of the nervous system and skull (including exencephaly and acrania, skull bone and vertebral anomalies). Similar types of malformations were seen in all species e valuated. The developmental toxicity studies, including the developmental neurotoxicity study, demonstrate increase d susceptibility in developing fetuses both quantitatively and qualitatively. In the reproductive toxicity study, adverse effects on offspr ing were manifested only as decreased pup body weight. However, prolonged gestation and dystocia, as well as decreased offspring survival (fewer pups born alive, more stillborn pups, and more pup deaths during the first week after birth), were seen in the developmental neurotoxicity study.

The results o f the carcinogenicity study in mice showed that tebuconazol e induced an increase in the incidence of hepatocellular adenomas, carcinomas and combined a denomas/carcinomas in

male and female mice. Tebuconazole was classified as a Group C “possible human carcinogen”. Submitted mutagenicity studies did not demonstrate any evidence of mutagenic potential for

tebuconazole.

The toxicological effects of tebuconazole are consistent with those of other tr iazole

- derivative chemicals. In particular, developmental toxicity and hepatocellular tumors are effects common to a number of these pesticides. Tebuconazole also shares common metabolites with other chemicals in this group, including free triazole (1,2, 4

- triazole) and triazole

- conjugated plant metabolites (such as triazole alanine). These common metabolites were the subject of a recent

aggregate risk assessment document (D 414592

, T. Morton

, 10 /24/1 3 ) updated to incorporate new

uses of triazole

- derivativ e fungicides.

It should be noted that tebuconazole has low acute toxicity by the oral or dermal route of exposure, and moderate toxicity by the inhalation route. It is not a dermal sensitizer or a dermal irritant; however, it is slightly

, to mildly irrit ating to the eye.

Following o ral administration to rats

, tebuconazole was rapidly and extensively absorbed (approximately 98% of the administered dose), metabolized, and eliminated. At 72 hours post

dosing, >94% of the administered radioactivity was re covered. Approximately 11

- 33% of the

administered dose was eliminated in urine and 61

- 82% was eliminated in the feces. At sacrifice, total radioactivity in the body, excluding the GI tract, amounted to 0.3 to 0.5% of the

administered dose. The data also showed that tebuconazole unde rwent enterohepatic circulation

.Page 13 of 34 Elimination via expired air accounted for 0.03% of the administered dose over a 72

- hour collection period. A total of 10 compounds (metabolites) were identified in the excreta, amounting to 5 1

- 58% of the administered dose. The parent compound was present in relatively

small amount s (0.5

- 2.2% of the administered dose).

Previously, a dermal absorption factor of 23.1 % was derived from a dermal absorption study in

the monkey

. HED recently re

- ex amined the data from this study and determined the absorption factor appropriate for route

- to

- route extrapolation is 13%, rather than 23.1% ( D397518 , B. O’Keefe, 0 4/30/12), and the original DER w as updated with a new Executive Summary (D399045, J. Ryman, 0 2/23/12).

4.3 Safety F actor for Infants and Children (FQPA Safety Factor)

The RAB3 risk assessment team has determined that reliable data show that the FQPA safety

factor can be red uced to 3X for all potential exposure scenarios. That decision is based on the following findings in Sections 4.4.1 through 4.4.4.

4.3.1 Completeness of Toxicology Data b ase

The toxicity database for tebuconazole is considered complete

.

4.3.2 Evidence of Neurotoxicity

Tebuconazole demonstrated neurotoxicity in the acute neurotoxicity study in rats ; the lowest

observable adverse effect le vel ( LOAEL ) of 100 mg/kg/day was based on increased motor activity in male and female rats and decreased footsplay in female rats ; however, the subchronic neurotoxicity study was unacceptable due to inadequate dosing. A new subchronic neurotoxicity study is not needed. Malformations indicative of nervous system development disruption were seen in developmental toxicity studies in mice, rats, and rabbits. Neurotoxicity was also seen in the rat developmental toxicity study as decreases in body weights, decreases in absolute brain weights, changes in brain morphometric parameters, and decreases in motor activity in offspring

at t he LOAEL of 8.8 mg/kg/day a no observable adverse effect leve l ( NOAEL ) could not be

established. However, the LOAEL (8

. 8 mg/kg/day) was employed as the point of departure (POD) for assessing risk for all exposure scenarios

, and the FQPA SF ha s been retained as a n uncertainty factor for use of a LOAEL to extrapolate a NOAEL ( UF L )

. To determine whether

the UF L is protective of any potential neurotoxicity a Benchmark Dose (BMD) analys i s of the datasets relevant to the adverse offspring effects (decreased body weight and brain weight) seen

at the LOAEL in the developme ntal neurotoxicity ( DNT ) study was conducted. All of the

BMDLs (benchmark dose limit ) modeled successfully on statistically significant effects we re 1

- 2X lower than the LOAEL. The refore, an extrapolated NOAEL is not likely to be 10 X lower

than the LOAEL and that use of an UF L of 3 X would not underestimate risk. Using an UF L of

3 X in risk assessment (8.8 mg/kg/day ÷ 3x = 2.9 mg/kg/day) is further supported by other studies in the tebuconazole toxicity database [with the lowest NOAELs being 3 and 2.9 mg/kg /day, from a developmental toxicity study in mice and a chronic toxicity study in dogs, respectively (respective LOAELs 10 and 4.5 mg/kg/day)].Page 14 of 34 4.3.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

Although there is qualitative evidence of increased susceptibility in the prenatal developmental studies in rats, the risk assessment team did not identify any residual uncertainties after

est ablishing toxicity endpoints and traditional UFs that will be protective of effects observed

. The degree of concern for residual uncertainties for prenatal and/or postnatal toxicity is low.

4.3.4 Residual Uncertainty in the Exposure Database

EPA utilized a tiered approach in estimating exposure to tebuconazole. While some refinements were incorporated into dietary and residential exposure calculations, EPA is confident that the aggregate risk from exposure to tebuconazole in food, water and residential pathways will not be

underestimated. The acute and chronic dietary exposure assessments incorporated somewhat

refined estimates of residues in food commodities from reliable field trial data reflecti ng maximum use conditions, recent monitoring data from USDA’s Pesticide Data Program (PDP), and relevant market survey data on the percentage of crops treated. Estimated concentrations of tebuconazole in drinking water were incorporated into the chronic d ietary analysis as the upper bound point estimate and into the probabilistic acute dietary analysis as a distribution. For the residential exposure pathway s (ornamentals, golf course turf, and treated wood products), potential exposure resulting from tebu conazole outdoor uses in the residential setting was assessed using screening

- level inputs that assumes an adult or child will come in contact with turf and other surfaces immediately after application.

4.4 Toxicity Endpoint and Point of Departure Selection s

At this time, the toxicity endpoints and points of depart ure previously selected for risk

assessment (D256074 and D276447, S Winfield, 04/18/08) are valid and will be employed for

this risk assessment

. A full discussion of the endpoints selected for risk assessment may be

found in the above referenced risk assessment. However, it should be reiterated that based on the available toxicity database and the Agency's current practices, the inhalation risk for tebuconazole was assessed using an oral toxicity study (developmental neurotoxicity study in rats). The reasons were: (1) although a 21

- day inhalation toxicity study in rats was available, the study did not assess the potential of tebu conazole on the fetal nervous system; (2) the effects

determined at the LOAEL (155.8 mg/m 3 ) in the inhalation study were minimal (piloerection and induction of liver microsomal enzymes ) ; and (3) the point of departure (8.8 mg/kg/day) and safety factors app lied for the inhalation risk assessment were protective of the effects seen in the

21

- day inhalation toxicity study.

The summary of toxicity endpoints and points of departu re are presented in Table 4. 4

.Page 15 of 34 Table 4

. 4

. Summary of Toxicological Doses and En dpoints for Tebuconazole for Use in Dietary and Non

Occupational Human Health Risk Assessments

. Exposure/

Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD, Level of

Concern for Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) LOAEL = 8.8 mg/kg/day

UF = 300 UF A = 10x

UF H =10x FQPA(UF L )= 3x Acute RfD = 0.029 mg/kg/day

aPAD = 0.029 mg/kg/day Developmental Neurotoxicity Study

- Rat. LOAEL = 8.8 mg/kg/day based on decreases in body weights, absolute brain weights, brain measurements and motor activity in offspring. Chronic Dietary (All Populations) LOAEL = 8.8 mg/kg/day

UF = 300 UF A = 10x

UF H =10x FQPA(UF L )= 3x Chronic RfD = 0.029 mg/kg/day

cPAD =0.029 mg/kg/day Developmental Neurotoxicity Study

- Rat. LOAEL = 8.8 mg/kg/day based on decreases in body weights, absolute brain weights, brain measurements and motor activity in offspring.

Incidental Oral

Short

- Term (1

- 30 days) LOAEL = 8.8 mg/kg/day

UF = 300 UF A = 10x

UF H =10x FQPA(UF L )= 3x Residential LOC for

MOE = 300 Developmental Neurotoxicity Study

- Rat. LOAEL = 8.8 mg/kg/day based on decreases in body weights, absolute brain weights, brain measurements and motor activity in offspring.

Dermal Short

Term (1

- 30 day s) LOAEL = 8.8 mg/kg/day

UF = 300 UF A = 10x

UF H =10x

UF L = 3x

DAF = 1 3% Residential LOC for

MOE = 300 Developmental Neurotoxicity Study

- Rat. LOAEL = 8.8 mg/kg/day based on decreases in body weights, absolute brain weights, brain measurements and motor activity in offspring.

Inhalation Short

Term (1

- 30 days) LOAEL = 8.8 mg/kg/day

UF = 300 UF A = 10x

UF H =10x

UF L = 3x Residential LOC for

MOE = 300 Developmental Neurotoxicity Study

- Rat. LOAEL = 8.8 mg/kg/day based on decreases in body weights, absolute brain weights, brain measurements and motor activity in offspring. Cancer (oral, dermal, inhalation) Classification: Group C

- possible human carcinogen based on statistically significant increase in the incidence of hepatocellular adenoma, carcinoma, and combined adenoma/carcinomas in both sexes of NMRI mice. The chronic risk assessment is considered to be protective of any cancer effects; therefore, a separate quantitative cancer risk assessment is not required. Point of Departure (POD) = A data point o r an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL

= no observed adverse effect level. LOAEL = low est observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NO AEL. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. DAF = dermal absorption factor.

4.4.1 Recommendation for Combining R outes of Exposures for Risk Assessment

As per FQPA, 1996, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. The toxicity endpoints selected for short

- , intermediate

- and long

- term risk

assessments are identical; the oral, dermal

, and inhalation exposures can be combined due to the presence of a co mmo n toxicity endpoint

.

4.4.2 Cancer Classification and Risk Assessment Recommendation

The Carcinogenicity Peer Review Committee concluded that tebuconazole should be classified

as a Gro up C

- possible human carcinogen (TXR No. 0052724). This conclusion was based on

results of a 91

- week carcinogenicity study in NMRI mice (MRID 42175001, 42469301) in whichPage 16 of 34 the following effects were observed: 1) a statistically significant increase in th e incidence of hepatocellular adenomas, carcinomas and combined adenomas/carcinomas in male mice both by positive trend and pairwise comparison at the highest dose tested (279 mg/kg/day); and 2) a statistically significant increase in the incidence of hepa tocellular carcinomas and combined adenomas/carcinomas in female mice both by positive trend and pairwise comparison at the highest dose tested (366 mg/kg/day). The structural relationship of tebuconazole to at least six other triazole fungicides that als o produce hepatocellular tumors in male and/or female mice supported the Committee's conclusion. These compounds include triadimefon, triadimenol, uniconazole, propiconazole, cyproconazole and etaconazole. For the purpose of carcinogenic risk assessment, t he chronic risk assessment is considered to be protective of any cancer effects; therefore, a separate quantitative cancer risk assessment is not required.

5.0 Dietary Exposure/Risk Characterization

5.1 Residues of Concern Summary and Rationale

The residues of concern for the dietary risk assessment and the tolerance expression are

summarized in Table 5.1. In addition to tebuconazole and free and conjugated t

- butylhydroxy tebuconazole, triazole degradates may occur in livestock from the use of tebuconazole and other triazole pesticides. Exposure to these degradates was assessed independently as part of the triazole aggregate risk assessment, and therefore, need not be included as a residue of concern for risk assessment or tolerance expression in the tebuconazole risk assessment.

Table 5.1. Summary of Metabolites and Degradates included in the Tebuconazole Risk Assessment and Tolerance Expression

.

Matrix Residues included in

Risk Assessment 1 Residues included in

Tolerance Expression

Plants Primary Crop Tebuconazole Tebuconazole

Rotational Crop Tebuconazole Tebuconazole

Livestock Ruminant Tebuconazole and Free and Conjugated HWG

- 2061 Tebuconazole and Free and Conjugated HWG

- 2061 2

Poultry Tebuconazole and Free and Conjugated HWG

- 2061 Tebuconazole and Free and Conjugated HWG

- 2061

Drinking Water Tebuconazole Not Applicable

1 HED has determined that 1,2,4

- triazole, triazole alanine (TA) and triazole acetic acid (TAA) are potential residues of concern for all triazole fungicides . Therefore, they are considered in the triazole risk as sessment (D322215, M. Doherty et al. , 2/7/06, which ha s be en updated in D4 14592 ).

2 Although the tolerance expression for livestock commodities does not reference conjugated residues, the conjugated residues are converted to free HWG

- 2061 by the data collection method; HWG

- 2061 is t

- butylhydroxy

tebuconazole or 5

- (4

- chlorophenyl)

- 2,2

- dimethyl

- 3

- (1 H

- 1,2,4

- triazol

- 1

- ylmethyl)pentan

- 1,3

- diol.

5.2 Food Residue Profile

No new metabolism data were submitted with the subject petition. Adequate plant metabolism

studies are available ref lecting the metabolism of [ 14 C] tebuconazole in grapes and [U

14 C

-Page 17 of 34 triazole] tebuconazole in wheat and peanuts. The residue of concern in plants for tolerance and

risk assessment in primary and rotational crops is tebuconazole

. The nature of tebuconazole residues in livestock is adequately understood based on acceptable goat and poultry metabolism studies. The residues of concern in livestock commodities for the tolerance expression include both tebuconazole and free and conjugated t

- butylhydroxy tebuconazole (HWG

- 2061). In addition to tebuconazole and free and conjugated t

- butylhydroxy tebuconazole , triazole degradates may occur in livestock from the use of tebuconazole and other triazole pesticides

. Exposure to these degradates wa s assessed independently as part of the triazole aggregate risk assessment, and therefore, need not be included as a residue of concern for risk assessment or tolerance expression in the tebuconazole risk assessment.

In support of the petition, Bayer su bmitted field trial data, a copy of the European Food Safety Authority’s (EFSA’s) reasoned opinion published in 2010 and non

- Good Laboratory Practices (GLP) residue data from Brazil (D416474, M. Negussie, 12/18/13 ) . The Brazilian data is used as

confirmat ory data to show that the tolerance is not exceeded since Brazil is a major exporter of oranges/processed oranges. For oranges and orange commodities, the number and locations of field trials are adequate. The trials were designed as decline studies with fruit samples collected

at 0

- 14 days and peel and pulp samples collected 3

- 14 days after one post

- harvest application. The orange samples were not analyzed for the triazole metabolites. However, the proposed use is a post

- harvest use and tebuconazole is not likely to degrade to the triazole metabolites under these conditions. Triazoles are assumed to be formed in soil and/or metabolically active plants. HED will wave the requirement of the triazole analysis for this case only.

A processing study with o ranges treated with a post

- harvest application was conducted in the United

States. This study showed that tebuconazole residues concentrate in oil (2 4X ). The study also

showed that residues did no t concentrate in juice. T he maximum expected residue of t ebuconazole

in orange oil resulting from the proposed post

- harvest use is 10 ppm

.

The available storage stability data are adequate to support the storage conditions and intervals of samples from the submitted field trials. Samples of orange (fruit, pu lp, and peel) were stored frozen for up to 8 months prior to extraction. Interval s between extraction and analysis or analysis dates were not provided. For the processed commodities, analysis dates were not provided. Based on the limited chromatograms provided, it is concluded that the samples were analyzed a month after extraction.

There are no rotational crop issues associated with imported oranges.

5.2.1 Drinking Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the EFED (D 412862

, A. Shelby, 0 7 /0 3 /13 ) and incorporated directly into th e dietary assessment. Water residues were incorporated in the DEEM

- FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.”

The drinking water models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

. The EDWCs were calculated for surface water using the Tier II Pesticide Root Zone Model/Exposure Analysis Monitoring SystemPage 18 of 34 (PRZM/EXAMS) surface water modelin g. The assessment was based on the use of the Florida turf scenario as this yielded the highest drinking water estimates from surface water. Because application rates, chemical fate data, and model versions have changed, the ground water EDWC

estimated b y SCI

- GROW in the previous assessment (D311610) is applicable for the current assessment. The ground water EDWC from the previous assessment was 1.56 μg/L. Due to the chemical properties of tebuconazole, surface water EDWCs are much larger than ground wa ter
EDWCs , and therefore, PRZM

- GW estimates do not impact the findings.

Table 5. 2

. 1 is a summary of the maximum drinking water estimates that were used in the dietary exposure assessment. For the acute assessment, the entire 30

- year distribution of estim ated daily surface water concentrations based on Florida turf scenario was used. For chronic dietary exposure, the 1

- in10 year annual mean concentration of 68.8 μg/L was used.

Table 5. 2

. 1 . Maximum Estimated Drinking Water Concentrations (EDWCs)

resultin g from applications of Tebuconazole. Estimated Drinking Water Concentrations (μg/L) 1 in 10 year annual peak 1 in 10 year annual mean 36 year annual mean

87.7 68.8 55.0

5.3 Dietary Exposure and Risk

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments

were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16. This software uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).

Since t ebuconazole is a triazole fungicide

, a separate updated dietary exposure and risk ana lysis (D414521, T. Morton, 10/24/13) for the common triazole metabolites 1,2,4

- triazole (T), triazolylalanine (TA), triazolylacetic acid (TAA), and triazolylpyruvic acid (TP) was conducted. The assessment is an update to address requested Section 3 regist rations for use of the triazole

derivative fungicides propiconazole, difenoconazole, and tebuconazole. For all four analyses, risk estimates are below HED’s level of concern for all population subgroups. There are no dietary exposure considerations for t he common triazole metabolites that would preclude granting the registration requests for propiconazole, difenoconazole, and tebuconazole

.

5.3.1 Description of Residue Data Used in Dietary Assessment

Somewhat r efined acute probabilistic and chronic dietary exposure assessment s were conducted

for all existing and proposed uses of tebuconazole and drinking water. For the acute assessment,

a nticipated residues for grapes
, grape juice, and peaches were derived using the latest USDA Pesticide Data Program (PDP) monitoring data . Anticipated residues for all other registered and proposed food commodities were based on field trial data. Available processing data were used

to refine anticipated residues for apples/pears (dried and juice), apricots (dried), cherry (juice), coffee (roasted bean), grapes (juice), orange (juice), plums (prunes/prune juice), peanut (oil), andPage 19 of 34 tomatoes (paste and puree). For all other processed comm odities, DEEM (ver. 7.81) default processing factors were assumed.

A distribution of estimated concentrations of tebuconazole in drinking water was provided by the Environmental Fate and Effects Divison (EFED) and incorporated directly into the acute

asse ssment. The acute assessment was conducted using the full distribution of estimated residues in surface water generated by the (Pesticide Root Zone Model/Exposure Analysis Modeling System) PRZM

- EXAMS model. The highest exposure in surface water resulted from application of tebuconazole to Florida turf. The 1

- in

- 10 yr annual mean (chronic) concentration is expected not to exceed 68.8 μg/L. For groundwater, based on the ( S creening C oncentration i n Gro und w ater ) SCI

- GROW model, tebuconazole concentration wa s estimated at 1.56 μg/L.

5.3.2 Percent Crop Treated Used in Dietary Assessment

Anticipated residues for all current uses were further refined using percent crop treated (%CT) data, following the guidance provided in HED SOP (Standard Operating Procedures) 99.6 ( Classification of Food Forms with Respect to level of Blending ; 8/20/99) ( D413306, D. Atwood, 12/06/13)

. Screenin g Level Usage Analysis (SLUA) data were used for the following commodities: almonds, apples, apricots, asparagus, barley, green beans, cantaloupes, cherries, corn, cotton, dry beans and peas, garlic, grapes, nectarines, onions, peaches, peanuts, pears,

pec ans, pistachios, plums/prunes, pumpkins, soybeans, squash, sweet corn, watermelons, and wheat. Percentage of imported orange juice and oranges was also provided.

The following maximum percent crop treated estimates were used in the acute dietary risk

as sessment for the following crops that are currently registered for tebuconazole : almonds 2.5 % ; apples 2.5 %; apricots 20%; barley 2.5%; beans green 2.5%; cantaloupes 10%; cherries 45%;

corn 2.5%; cotton 2.5%; dry beans/peas 5%; garlic 95%; grapes 35% ; onio ns 5%; peaches 25%; peanuts 55%; pears 5%; plums/prunes 5%; soybeans 2.5%; sweet corn 5%; and wheat 25%.

The following average percent crop treated estimates were used in the chronic dietary risk

assessment for the following crops that are currently reg istered for tebuconazole : almonds 1 % ; apples 1 %; apricots 10%; asparagus 5%; barley 2.5%; beans green 1%; cantaloupes 5%; cherries 30%; corn 1 %; cotton 1%; dry beans/peas 2.5%; garlic 60%; grapes 20 %; nectarines 10 %; onions 5%; peaches 15%; peanuts 40%; pears 5%; pecans 5%; pistachios 2.5%; plums/prunes 2.5%; pumpkins 2.5%; soybeans 1%; squash 2.5%; sweet corn 2.5%; watermelons 10%; and

wheat 20 %.

The following estimated percent import es timates for the proposed import oranges were used in

the acute an d chron ic dietary risk assessments for the orange juice and oranges: 27.7% and 7.7%, respectively ( D413306, D. Atwood, 12/06/13)

. Since usage data are not available for other countries, the Agency assumes that all of the imported orange commodities are tre ated.Page 20 of 34 5.3.3 Acute Dietary Risk Assessment

Estimated acute dietary exposure to tebuconazole from food and drinking water is below HED’s

level of concern for all population subgroups (< 100% (aPAD) acute Population Adjusted Dose) using time series for drinking water. Combined acute dietary exposure from food and drinking

water at the 99.9 th percentile of exposure utilized 45% of the acute population adjusted dose (aPAD) for the general U .S. population and 84% of the aPAD for children 1 to 2 years old, the highest exposed population subgroup.

5.3.4 Chronic Dietary Risk Assessment

Chronic dietary exposure estimates for food and drinking water are well below HED’s level of concern (<100% (cPAD) chronic Population Adjusted Dose) for all population subgroups. The

chronic dietary exposure from food and drinking water utilized 6.7% of the chronic population adjusted dose (cPAD) for the general U.S. population and 14% of the cPAD for all infants (<1 year old), the highest exposed population subgroup.

5.3.5 Summary Tables

Table 5

. 3 .5.1. Results of Acute Dietary (Food + Drinking Water) Exposure Analysis Using DEEM

- FCID 1

.

Population Subgroup aPAD (mg/kg/day) 95 th Percentile 99th Percentile 99.9 th Percentile

Exposure (mg/kg/day) % aPAD Exposure (mg/kg/day) % aPAD Exposure (mg/kg/day) % aPAD

General U.S. Population

0.029 0.004179 14 0.006949 24 0.013119 45

All Infants (< 1 year old) 0.010313 36 0.014846 51 0.021525 74

Children 1

- 2 years old 0.006971 24 0.012895 44 0.024238 84

Children 3

- 5 years old 0.005917 20 0.009919 34 0.017804 61

Children 6

- 12 years old 0.004080 14 0.006907 24 0.013352 46

Youth 13

- 19 years old 0.003379 12 0.005564 19 0.009307 32

Adults 20

- 49 years old 0.004049 14 0.006073 21 0.009702 34

Adults 50+ years old 0.003692 13 0.005816 20 0.009879 34

Females 13

- 49 years old 0.003950 14 0.005894 20 0.009521 33

1 The population subgroup with the greatest exposure is in boldPage 21 of 34 Table 5. 3

. 5. 2. Summary of Chronic Dietary (Food + Drinking Water) Exposure and Risk for Tebuconazole Using DEEM

- FCID 1

.

Population Subgroup Exposure (mg/kg/day) % cPAD

General U.S. Population 0.001934 6.7

All Infants (<1 year old) 0.004155 14.3

Children 1

- 2 years old 0.003375 11.6

Children 3

- 5 years old 0.002753 9.5

Children 6

- 12 years old 0.001793 6.2

Youth 13

- 19 years old 0.001383 4.8

Adults 20

- 49 years old 0.001903 6.6

Adults 50+ years old 0.001853 6.4

Females 13

- 49 years old 0.001811 6.2

1 The population subgroup with the greatest exposure is in bold

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

No new residential uses are being requested at this time. However, a dults, adolescents

, and children may be exposed to tebuconazole from currently registered use s on turf

, flower gardens, trees, ornamentals, and pressure

- treated wood. Each of these existing residential use patterns has previously been assessed and the resulting exposures and risk estimates did not exceed HED’s LOC (see D346795, B. O’Keefe, 11/27/07 and D349926, B. O’Keefe, 3/13/08). Additionally, HED has recently updated the residential standard operating procedures (SOPs; see http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html for specifics) and body weights to be used in all human health assessments. Therefo re, all of the existing residential use patterns were reassessed for handler and post

- application exposures to adults and children using the updated procedures and data, since the residential exposures can impact the aggregate assessment for tebuconazole ( see DP397518, B. O’Keefe, 4/30/12). The only change in the estimated residential risk estimates is due to the data and procedures used to estimate turf transferrable residue (TTR) for the post

- application exposures from turf.

6.1 Residential Handler Exposure/Risk Characterization

Residential h andler exposure is expected to be short

- term only; i ntermediate

- term exposures are not likely because of the intermittent nature of applications by homeowners. Dermal and inhalation exposures were combined since the same endpoint and POD is used for both routes of exposure. Table 6.1 summarizes the residential handler exposures and risk estimates for

tebuconazole. All combined risk estimates are n ot of concern to HED with MOEs ranging from 2,800 to 91,000.Page 22 of 34 1 Application rates are based on maximum values found on existing labels.

2 Daily Exposure (mg/kg/day) = (Unit Exposure * % Absorption * Application rate * Amount handled daily) / Body Weight of 6 9

- kg; where dermal absorption is 1 3%. and inhalation absorption is 100%.

3 Short

- /Intermediate

- Term MOE = NOAEL / Daily Exposure. The dermal/inhalation NOAEL is 8.8 mg/kg/day. The LOC is 300.

6.2 Residential Post

- A pplication Exposure and Risk Characterization

Adults and children golfing, working in gardens, and performing physical activities on pressure

treated wood after application of tebuconazole may receive exposu re to tebuconazole residues. Exposure is expected to be short

- term in duration. Short

- term dermal and incidental oral

exposure and risk estimate s have been previously assessed and indicate d no risk estimates of

concern. However, for the use of tebuconaz ole on golf course turf the post

- application dermal exposure and risk assessment must be recalculated due to a recent decision to invalidate the use of the Bayer turf transferability residue (TTR) study (MRID 44108303). The TTR data from this study were p reviously used as an estimate of day zero tebuconazole residues on treated turf.

This TTR study was explained in a previous HED document (D361303, B. O’Keefe, 12/28/09). However, based on current practices and updated policies, HED assumes first

- order di ssipation kinetics to generate dissipation curves for tebuconazole. Therefore, HED conducted an extensive review of the study including linear regression analyses for each state evaluated in the TTR study using the natural logarithm of the individual turf residue values collected immediately after the application through the last day of sampling. A complete review of the study is presented in a separate review document (D414822, B. O’Keefe, 10/31/13). However, at this time HED has

concluded that the data from this study should not be used as an estimate of day zero tebuconazole residues on treated turf. Although the study does provide chemical specific data, the study has a number of issues that make its use not appropriate in the current assessment;

spe cifically: 1) The study is based on the old, not the new, C alifornia roller method. Because of this, the data are not a good match for the new inputs in the Residential SOPs; 2) Also, tebuconazole is a systemic fungicide and the labels require that the pr oduct be watered

- in. Watering

- in of the product wasn’t a component of the original study, but should have been; 3) There were several issues with the analytical piece of the TTR study (e.g., very high recoveries for the low fortification samples); and 4) Several rain events were reported either before or after application at the three test sites which may have influenced the resulting TTR values. Consequently, HED’s standard operating procedures and assumptions were used to determine an Table 6.1. Residential Handler Short

- term Exposure and Risk Estimates for Tebuconazole.

Scenario Formulation Equipment/ Application

Method Application

Rate 1 Amount

Treated Exposure

Route Daily Dose (mg/kg/day) 2 MOE Combined

MOE 3

Residential

Handler for

flower gardens,

trees,
ornamentals Liquid Manually

Pressurized

Handwand 0.0053 lb ai/gal 5 gal Dermal 0.00314 2,800 2,800 Inhalation 0.00000690 1.3E+6

Hose

- End

Sprayer 0.0014 lb ai/gal 11 gal Dermal 0.00168 5,200 5,200 Inhalation 0.000000312 2.8E+7

Backpack 0.0014 lb ai/gal 5 gal Dermal 0.00171 5,100 5,100 Inhalation 0.0000142 6.2E+5

Ready To Use (RTU) Liquid Trigger Sprayer 0.0003 lb

ai/bottle 2 bottles Dermal 0.0000961 92,000 91,000 Inhalation 0.000000530 1.7E+7Page 23 of 34 estimate of day ze ro tebuconazole residues on treated turf

. Table 6.2.1 summarizes the re

calculated residential post

- application exposure and risk estimates for tebuconazole for golfers

.

Table 6.2.1 . Residential Post

- Application Dermal Short

- Term Exposure and Risk Estimates from Golfing

.

Scenario Application

Rate TTR 1
(μg/cm 2 ) Exposure Time (hr) Population TC (cm 2 /hr) Daily Dose 2
(mg/kg/day) MOE 3

Golf Course

Turf 1. 35 lb ai/A 0.1 51 4 Adults 5,300 0.00 605 1,5 00

Youths 11 to <16 yr old 4,400 0.00 607 1,4 00

Children 6 to <11 yr old 2,900 0.00 7 13 1, 2 00

1 TTR derived as follows: 1.3 5 lb ai/A x 4.54E+8 μg/lb x 2.47E

- 8 A/cm 2 x 0.01 (fraction of transferable ai) = 0. 151 μg/cm 2

. 2 Daily Dose = [ TT R (μg/cm 2 ) x (0.001 mg/μg) x Dermal Transfer Coefficient x Dermal Absorption Factor ( 1 3%) x Exposure Time ( 4 hr)] / [Body weight (6 9 kg for adults, 57 kg for youths 11 to <16 yr, and 32 kg for children 6 to <11 yr )]

. 3 MOE = LOAEL/Daily Dose. Short

- /Intermediate

- Term LOAEL = 8.8 mg/kg/day.

Table 6.2 .2 summarizes the residential post

- application exposure and risk estimates for

tebuconazole. Residential dermal post

- application MOEs for all life stages range from 3 40 to 6,200. The residential exposure for 1 to 2 year olds coming in contact with pressure treated wood resulted in a dermal MOE of 460, an oral hand

- to

- mouth MOE of 2,600, and a combined dermal plus oral MOE of 390.

Table 6.2 . Residential Post

- Application Short

- Term Exposure and Risk Estimates for Tebuconazole.

Scenario Formu lation Application

Rate Amount

Treated Activity Exposure Route Daily Dose (mg/kg/day) MOE 1

Golf Course

Turf Liquid 1.35 lb ai/A NA Adults Golfing Dermal 0.0 0605 1,500

Children 11 to <16 yr old Dermal 0.0 0607 1, 4 0 0

Children 6 to <11 yr old Dermal 0.0 0 7 13 1,20 0

Gardens,

Tress &

Ornamentals Liquid 0.27 lb ai/ A 1 can Adults to Gardens Dermal 0.0261 340

Adults to Trees Dermal 0.0024 3700

Children 6 to <11 yr old

to Gardens Dermal 0.0155 570

Children 6 to <11 yr old

to Trees Dermal 0.00143 6

, 200

Pressure

Treated

Wood 1 Liquid 1 μg/cm 2 NA Children 1 to 2 yr old Dermal 0.0191 460

Children 1 to 2 yr old Oral hand

- to

- mouth 0.0034 2

, 600

Children 1 to 2 yr old Oral HTM & Dermal 0.0225 390

1 Wood surface residue adjusted for dermal transfer or “transfer efficiency” (EPA high end assumption of 1 μg/cm 2 ) (DP Barcode 330159, 6/20/06, T. Leighton)

.

6.3 Other (Spray Drift, etc. )

Residential Bystander Post

- A pplication Inhalation Exposure Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for tebuconazole at this time because the chemical has low vapor

pressure ( 9.75 x 10 - 9 m m Hg (20oC) ) and is not applied via airblast o r a ircraft . However, volatilization of pesticides may be a potential source of post

- application inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticid es from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010Page 24 of 34 ( ht tp://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ) and is in the process of evaluating the SAP report. The Agency may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- appl ication inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment

for tebuconazole.

Spray Drift Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for the previously

registered uses of tebuconazole . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices

, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. pe sticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast

, and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce

off

- target drift and risk estimates associated with aerial as well as other application types where appropriate.

7.0 Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregat e assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e.g. , a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers b oth the route and duration of exposure.

7.1 Acute & Chronic Aggregate Risk

Refer to Section 5. 3 , which discusses acute and chronic dietary (food and drinking water) exposure in detail. The dietary route alone is relevant for acute exposure and risk assessment; and the acute dietary exposure and risk assessment conducted for tebuconazole is a refined, probabilistic assessment. The dietary route alone is also relevant for long

- term/chronic exposure

and risk assessm ent; and the chronic dietary exposure and risk assessment conducted for tebuconazole is a refined, deterministic assessment.Page 25 of 34 7.2 Short

- and Intermediate

- Term Aggregate Risk s

The short

- term aggrega te risk assessments in this document use a deterministic approach, in that point estimates of exposure from each source are added together; and each of the point estimates used are in turn deterministic [dietary exposure estimates use point estimates for f ood and drinking water residue s (anticipated residues based o n field trial and PDP data, and tolerance level residues) and the residential scenarios also employ point estimates (central to high

- end values considered protective)]. Exposures are assumed to occur over the same time frame, and no use frequency data is considered. There is the potential for residential exposure to co

- occur with background dietary exposure over the short

- term (1

- 30 days) , whereas co

- occurring intermediate exposures (1

- 6 months) are less likely. However, since the POD employed for both durations are the same, the aggregate assessments address both exposure durations. Although there are two adult residential exposure scenarios considered in this document, the likelihood of

a res idential handler treating ornamentals with tebuconazole and then playing golf on a

tebuconazole

- treated course is considered low; therefore, each scenario is considered separately with background dietary exposure. In sum, these aggregate risk assessments are considered protective. Aggregate risk estimate s for all examined population subgroups were not of concern to HED, and above the level of concern (LOC = 300).

These aggregate exposure assessments are considered conservative estimates, that should not underestimate risks, for the following reasons : 1) the dietary analysis used somewhat refined dietary exposure inputs for its acute and chronic dietary assessments, including crop specific (turf) screening level drinking water modeling data (i. e., surface water model ing ); 2) maximum application rates and minimum application intervals were used; and 3) conservative SOPs and upper level estimates of exposure were employed.

Table 7.2 .1

. Short

- Term Aggregate Risk Calculations

Population Residential Scenario Short

- Term Scenarios

LOAEL LOC 1 Max

Allowable Exposure 2
(mg/kg/day) Average Food

& Water Exposure (mg/kg/day) Residential Exposure 3
(mg/kg/day) Aggregate

MOE 4

( dietary and residential)

Residential Post

- Application

Children 11 to <16 yr old Golfer, Turf 8.8 300 0.029 0.00 1383 0.0 0 607 1,2 00

Children 6 to <11 yr old G ardens 8.8 300 0.029 0.00 1793 0.0 155 510

Adults Gardens 8.8 300 0.029 0.00 1934 0.0261 310

Children ( 1

- 2 yr old ) Activities on pressure

treated wood surfaces 8.8 300 0.029 0.00 2753 0.0 225 3 5 0

1. The basis for the LOC are the standard inter

- and intra

- species uncertainty factors totaling 100, as well as an additional uncertainty factor for LOAEL to NOAEL extrapolation (UF L = 3X) 2. Maximum allowable exposure (mg/kg/day) = LOAEL / LOC 3. Residential Exposure = [Oral Exposure + Dermal Exposure + Inhalation Exposure]. See Section 6.0 for derivation of residen tial exposurePage 26 of 34 assessments. 4. Aggregate MOE = [LOAEL/(Average Food & Water Exposure + Residential Exposur e)]

Updated Aggregate Assessment of Free Triazole & its Conjugates

In 2006, HED issued aggregate human health risk assessments for 1,2,4

- triazole ( T ) and the conjugated triazole metabolites ( D322215, M. Doherty, et al., 0 2/ 0 7/ 06). In 201 3 , HED

reviewed the dietary and residential exposure of T and the triazole metabolites for to address requested Section 3 registrations for use of the triazole

- derivative fungicides propiconazole, difenoconazole, and tebuconazole (D 4 14592 , T. Morton, 10 / 24 /1 3 ). The findings of the

assessment s were that risk estimates for all exposure scenarios were below HED’s level of concern. Neither the toxicological information nor the non

- dietary exposure estimates detailed

in the 2006 memorandum have changed; thus

, the only al terations to the previous aggregate exposure and risk estimates in 201 3 are due to changes in the dietary exposure estimates. For complete hazard characterization and non

- dietary exposure assessments for the common triazole metabolites, see the 2006 and 2 01 3 risk assessment s

.

8.0 Cumulative Risk Characterization/Assessment

Tebuconazole is a member of the triazole

- containing class of pesticides. Although conazoles act similarly in plants by inhibiting ergosterol biosynthesis, there is not necessarily a relationship between their pesticidal activity and their mechanism of toxicity in mammals. Structural similarities do not constitute a common mechanism of toxicity. Evidence is needed to establish

that the chemicals operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002). In conazoles, however, a variable pattern of toxicological responses is

found ; s ome are hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some induce developmental, reproductive, and neurological effects in rodents. Furthermore, the conazoles produce a diverse range of biochemical events including altered cholesterol levels, stress responses, and altered DNA methylation. It is not clearly understood whether these biochemical events are directly connected to their toxicological outcomes. Thus, there is currently no evidence to indicate that conazoles share common mechanisms of toxicity

and EPA is not fol lowing a cumulative risk approach based on a common mechanism of toxicity for the conazoles. For information regarding EPA’s procedures for cumulating effects from substances found to have a common mechanism of toxicity, see EPA’s website at http://www.ep a.gov/pesticides/cumulative

.

T riazole

- derived compounds can form the common metabolite 1,2,4

- triazole and two triazole conjugates ( triazolylalanine and triazolylacetic acid ). To support existing tolerances and to

establish new tolerances for triazole

- der ivat ive pesticides, including tebuconazole , U.S. EPA conducted a human health risk assessment for exposure to 1,2,4

- triazole, triazolylalanine, and triazolylacetic acid resulting from the use of all current and pending uses of any triazole

- derived fungicid e. The risk assessment is a highly conservative, screening

- level evaluation in terms of hazards associated with common metabolites (e.g., use of a maximum combination of uncertainty factors) and potential dietary and non

- dietary exposures (i.e., high end estimates of both dietary and non

- dietary exposures). In addition, the Agency retained the additional 10X FQPA safety factor for the protection of infants and children. The assessment includes evaluations of risks for various subgroups, including those c omprised of infants and children.Page 27 of 34 The Agency’s complete risk assessment is found in the propiconazole reregistration docket at http://www.regulations.gov , Docket Identification (ID) Number EPA

- HQ

- OPP

- 2005

- 0497.

9.0 References

Tebuconazole: Human Health Risk Assessment to support tolerances in/on Asparagus, Barley, Beans, Beets, Brassica leafy greens, Bulb Vegetables, Coffee (import), Commercial Ornamentals, Corn, Cotton, Cucurbits, Hops, Lychee, Mango, Okra, Pome fruit, Soybean , Stone fruit, Sunflower, Tree Nut Crop Group, Turf, Turnips and Wheat. DP 256074 and DP276447 , S. Winfield, 4/18/08.

Tebuconazole: Human Health Risk Assessment to Harmonize Tolerances of Tebuconazole in/on Oats and Wheat with Canada. DP384949, K. Rury, 5/24/11.

Tebuconazole: Occupational Exposure and Risk Assessment for Proposed Increase in Application Rate for Golf Course Turf. DP397518, B. O’Keefe, 4/30/12

Tebuconazole. Request to Establish a Tolerance for Imported Oranges . Summary of Analytical

Chem istry and Residue Data. DP 416474

, M. Negussie

, 12 /1 8 / 13

.

Tebuconazole: Acute and Chronic Aggregate Dietary Exposure and Risk Assessments for Establishment of a Tolerance for Imported Oranges. M. Negussie, DP4 16473

, 12 / 1 8 /13

.

Drinking w ater and ecological risk for new use of tebuconazole/fluoxastrobin combination for

turf and ornamental use. DP 412862

, A. Shelby , 0 7 / 03 /1 3.

Common Triazole Metabolites: Updated Dietary (Food + Water) Exposure and Risk Assessment

to Address The New Section 3 Regis tration s For Use of Propiconazole on Oilseeds Crop Subgroup 20A; Use of Difenoconazole on Oilseeds Crop Subgroup 20A; and Use of Tebuconazole on Imported Oranges

. T. Morton. DP4 14591

. 10 / 24/13

.

Common Triazole Metabolites: Updated Aggregate Human Health Risk Assessment to Address

The New Section 3 Registration s For Use of Propiconazole on Rapeseed Crop Subgroup 20A; Use of Difenoconazole on Rapeseed Crop Subgroup 20A; and Use of Tebuconazole on Imported Oranges

. T. Morton. DP4 14592

. 10 / 24 /1 3

.Page 28 of 34 

### Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food and non

- food uses for Tebuconazole are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A. 1 .1 Toxicology Data Requirements for Tebuconazole

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes

no

yes yes

yes

yes

no

yes +

870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... no

yes

no

yes

yes no

yes

- yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

................................ ..... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotox. Screening Battery (rat)

....................... 870.6200b 90

- Day Neuro. Screening Battery (rat)

.......................... 870.6300 Develop. Neuro

................................ .............................. no

no

yes

yes

yes -

- yes

yes

yes

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity............................................... yes

no

yes yes

yes

yes
Special Studies for Ocular Effects Acute Oral (rat)

................................ ........................... Subchronic Oral (rat)

................................ .................. Six

- month Oral (dog)

................................ .................. no

no

no no

no

no

+ An acceptable 21

- day inhalation toxicity study in rats was submitted.Page 29 of 34 A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile for Tebuconazole

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 40700917 LD 50 (fasted) = > 5000 mg/kg (M); 3933 mg/kg (F); (unfasted)=4264 mg/kg (M); 3352 mg/kg (F) III

870.1200 Acute dermal [rat] 40700917

41290801 LD 50 = >5000 mg/kg (M & F) III

870.1300 Acute inhalation [rat] 40700922 LC 50 (4 h, aerosol)= >371 mg/m 3

LC 50 (4 h, dust)= >5093 mg/ m 3 II

870.2400 Acute eye irritation [rabbit] 40700925

40700917 Slight to Mild irritant III

870.2500 Acute dermal irritation [rabbit] 40700917

40995910 Non

- irritant IV

870.2600 Skin sensitization [guinea pig] 40700928

41290802 No evidence of skin sensitization using

the Buehler test NA

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)

Doses/ Classification Results

870.3100

90

- Day oral toxicity

- r at 40700930 (1986) ( 0, 100, 400, 1600 ppm in diet ) ; 0, 8.6, 34.8, 171.7 mg/kg/d (m) ; 0, 10.8, 46.5, 235.2 mg/kg/d (f) Acceptable/guideline Male: NOAEL = 34.8 mg/kg/d ; LOAEL= 171.7 mg/kg/d

based on decreased body wt., body wt. gain, and histopathology findings. Female: NOAEL=10.8 mg/kg/d, LOAEL= 46.5 mg/kg/d

based on histopathological changes in the adrenal gland

. 870.3150

90

- Day oral toxicity

- dog 40700934 (1987) (0, 200, 1000, 5000 ppm in diet); 0, 73.7, 368.3, 1749.1 mg/kg/d (m); 0, 73.4, 351.8, 1724.8 mg/kg/d (f) Acceptable/guideline NOAEL = 73.4/73.7 mg/kg/d (m/ f)

LOAEL = 368.3/ 351.8 mg/kg/d ( m/ f) based on decrease d body wt. gain , food consumption and increased liver enzyme activities.

870.3200

21 /28

- Day dermal toxicity

- rabbit 40700937 (1984) 0, 50, 250, 1000 mg/kg/day Acceptable/guideline NOAEL = 1000 mg/kg/day. No dermal or systemic toxicity was seen.

870.3465

2 1

- Day inhalation toxicity

- rat 40700938 (1985) 0, 1.2, 10. 6, 155.8 mg/m 3
Acceptable/guideline NOAEL = 10.6 mg/m 3 /d (0.0106 mg/L/day)

LOAEL = 155.8 mg/m 3 /d (0.1558 mg/L/day) based on clinical signs and induction of liver microsomal

enzymes.

870.3700a Prenatal developmental

- rat 40700943 (1988) 0, 30, 60 , 120 mg/kg/d, GD 6

- 15 Acceptable/guideline Maternal NOAEL = 3 0 mg/kg/day LOAEL=60 mg/kg/d based on increased liver wt and liver/body weight ratios. Developmental NOAEL=3 0 mg/kg/day

LOAEL =60 mg/kg/d based on delayed ossification of

several bones and increased numbers of fetuses with supernumerary ribs.

870.3700a Prenatal developmental

- rat (Dermal) 41450801 (1988) 0, 100, 300, 1000 mg/kg/d, GD 6

- 15 Acceptable/guideline Maternal NOAEL= 1000 mg/kg/d Developmental NOAEL= 1000 mg/kg/d No evidence of maternal or developmental toxicity seen

via dermal route.Page 30 of 34 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)

Doses/ Classification Results

870.3700a Prenatal developmental

- mouse 40821501 (1988) 0, 10, 30, 100 mg/kg/d, GD 6

- 15 40821500 (1988) Supplementary study 0, 10, 20, 30, 100 mg/kg/d GD 6

- 15 Acceptable/guideline Maternal NOAEL = 30 mg/kg/d LOAEL = 100 mg/kg/d based on increased hepatic triglycerides, pale lobular liver, increased severity of hepatic vacuoles and lipidosis. Developmental NOAEL = 10 mg/kg/d LOAEL = 30 mg/kg/d bas ed on increased number of

runts.

870.3700a Prenatal developmental

- mouse 43776201, 43776202(1995) 0, 10 , 30, 100 mg/kg/d, GD 6

- 15 Supplementary group 0, 1, 3 mg/kg/d GD 6

- 15 Acceptable/ guideline Maternal : NOAEL = 3 mg/kg/d LOAEL = 10 mg/kg/d based on increased hepatic enzyme induction and severity of vacuolization in liver

cells. Developmental : NOAEL= 3 mg/kg/d LOAEL=10 mg/kg/d based on increased external, visceral, and skeletal malformation/variation in the head

and skull.

870.3700a Prenatal developmental

- mouse (Dermal) 42010301 (1990) 0,100,300,1000 mg/kg/d GD 6

- 15 Acceptable/guideline Maternal NOAEL= 1000 mg/kg/d Developmental NOAEL= 1000 mg/kg/d No evidence of maternal or developmental toxicity seen

via dermal route.

870.3700b Prenatal developmental

- rabbit 40700945 (1987) 0, 10, 30,100 mg/kg/d, GD 6

- 18 Acceptable/ guideline Maternal NOAEL = 30 mg/kg/d LOAEL = 100 mg/kg/d based on decreased body weight gain and food consumption. Developmental NOAEL = 30 mg/kg/d LOAEL = 100 mg/kg/d based on increased resorptions and post

- implantation losses, decreased live fetuses/doe,

and external and skeleta l abnormalities

. 870.3700b Prenatal developmental

- rabbit 43776201 (1995) 0, 10, 30, 100 mg/kg/day GD 6

- 18 Acceptable/guideline Maternal NOAEL = Not established (<10 mg/kg/d) LOAEL = 10 mg/kg/d based on increased incidence of single cell necrosis in liver cells. Developmental NOAEL = 1 0 mg/kg/d

LOAEL = 3 0 mg/kg/d based on increased external and

visceral malformation/variations.

870.3800 Reproduction and fertility

effects

- rat 40700946 (1987) 0, 100, 300, 1000 ppm in diet ( equivalent to 0, 5, 15, 50 mg/kg/day ) Acceptable/guideline Parental/Systemic NOAEL = 15 mg/kg/day (m & f) LOAEL = 50 mg/kg/day based on increased severity of splenic hemosiderosis (m & f), increased incidence of splenic hematopoiesis (m), and decreased weight gain during gestation (f) Reproductive NOAEL = 50 mg/kg/day

LOAEL = not determined Offspring NOAEL = 15 mg/kg/day LOAEL = 50 mg/kg/day based on decreased pup body

wt.

870.4300 Chronic/ carcinogenicity

- rat 40700939 , 40816401 (1988) 0, 100, 300, 1000 ppm in diet; M: 0, 5.2, 15.9, 55 mg/kg/d; F: 0, 7.4, 22.8, 86.3 mg/kg/d Acceptable /guideline Males: NOAEL = 15.9 mg/kg/d; LOAEL=55 mg/kg/day based on decreased testes weight.

Females: NOAEL= 7.4 mg/kg/d ; LOAEL=22.8 mg/kg/day based on decreased body wt. & wt. gain, decreased erythrocyte parameters and increased incidence of splenic hemosiderosis (incr eased erythrocyte clearance). No evidence of carcinogenicity at the doses tested.

870.4100b Chronic toxicity

- dog 40700940 (1987) 0, 40, 200, 1000/2000 ppm in diet ; 0, 15.5, 77.3, 483 mg/kg/ d Acceptable/guideline NOAEL = 15.5 mg/ kg/ d ay LOAEL = 77.3 mg /kg /d ay based on ocular lesions and changes in erythrocyte morphology (anisocytosis)Page 31 of 34 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)

Doses/ Classification Results

870.4100b Chronic toxicity

- dog 42030601 (main) (1989) & 42537201 (suppl.) (1992); 0, 100, 150 ppm; M: 0, 2.96, 4.39 mg/kg/d F: 0, 2.94, 4.45 mg/kg/d

A cceptable/guideline together with

40700940 NOAEL = 2.96 mg/kg/day (m), 2.94 mg/kg/d (f )

LOAEL = 4.39 mg/kg/day (m), 4.45 mg/kg/d (f) based

on lesions in the adrenal gland

.

870.4200b Carcinogenicity

- mouse 40700941 (1988) 0, 20, 60, 180 ppm in diet; M: 0, 5.9, 18.2, 53.1 mg/kg/d F: 0, 9.0, 26.1, 80.5 mg/kg/d

42175001 0, 500, 1500 ppm M: 0, 84.9, 279 mg/kg/day F: 0, 103.1, 365.5 mg/kg/day Acceptable/guideline M ale mice had statistically significant, dose

- related increasing trends in hepatocellular adenomas,

carcinomas and combined adenomas and/or carcinomas. There were also statistically significant differences in the pair

- wise comparisons of the controls with the 1500 ppm dose group for hepatocellular adenomas (29% vs. 5% controls), hepatocellular carcinomas (21% vs. 0% controls) and combined adenomas and/or carcinomas (47% vs. 5% controls).

870.5100 Salmonella point mutation 40700947 & 4 0700948 (1988) Acceptable/guideline Negative with or without activation at doses ranging from 39.5 to 450 μg/plate

870.5300

CHO

- HGPRT forward

mutation 40700949 (1988) Unacceptable/guideline Negative with or without activation at concentrations ranging from 12.5

- 200 and 80

- 100 μg/mL, respectively; highest concentration tested did not produce high level of cytotoxicity

. 870.5375 In vitro Cytogenetics (human lymphocytes) 40700953 (1988) Acceptable with activation; Unacceptable without activation Negative for chromosome aberrations with activation (30

- 300 μg/mL) and without activation (10

- 300 μg/mL); highest dose not cytotoxic without activation

. 870.5395 Mammalian erythrocyte

micronucleus 40700951 (1985) Acceptable/guideline Negative at all doses up to 2000 mg/kg bw

870.5450 Mouse dominant lethality 40700950 (1986) Unacceptable/guideline Negative at 2000 mg/kg bw (only dose tested) during 12 serial mating periods; positive control was not included

870.5500 DNA damage and repair ( E.coli) 40700955 (1983) Unacceptable/guideline Negative with or without activation at concentrations ranging from 625

- 10,000 μg/plate); no growth inhibition

zone detected

870.5550

Unscheduled DNA synthesis (rat hepatocytes) 40816402 (1988) Acceptable/guideline No evidence of an increase in unscheduled DNA synthesis at 0.504

- 25.2 μg/mL

870.5900 Sister chromatid exchange (CHO cells in vitro ) 40700952 (1987) Acceptable/guideline Negative with and without activation with S9 at concentrations ranging from 4

- 30 μg/mL and 15

- 120 μg/mL, respectively.

870.6200a

Acute neurotoxicity screening battery

- rat 44449301, 44545701 (1997)

0, 21, 50, 103, 497, 950 mg/kg

Unacceptable/Guideline

(Upgradeable) NOAEL = 50 mg/kg/day

LOAEL = 100 mg/kg/day based on increased motor activity in males and females and decreased footsplay in

females.

870.6200b

Subchronic neurotoxicity screening battery

- rat 44588001 (1998)

0, 100, 400, or 1600 ppm

M: 0.00, 7.57, 29.2, 107 mg/kg/day F: 0.00, 8.81, 34.0, 122 mg/kg/day

Unacceptable/Guideline

(Not upgradeable) NOAEL = 107 mg/kg/day

LOAEL = Not determined [>107 mg/kg/day]Page 32 of 34 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)

Doses/ Classification Results

870.6300

Developmental neurotoxicity

- rat 45074301 (2000)

0, 100, 300, 1000 ppm

[GD/LD 0/0, 8.8/16.3, 22/41.3, 65/125.4 to dams], GD6 to LD11

Acceptable/Guideline Maternal NOAEL = 22 mg/kg/day LOAEL = 65 mg/kg/day based on decreased body weight, body weight gain, and food consumption; prolonged gestation with mortality, increased number of

dead fetuses. Offspring NOAEL = <8.8 mg/kg/ day

LOAEL = 8.8 mg/kg/day based on decreased body weight, decreased absolute brain weights and brain measurements, and decreased motor activity.

870.7485

Metabolism

- rat 40995911, 40995912 (1987)

Acceptable/guideline 98.1% of oral dose is absorbed. Over 87% of dose excreted in urine & feces within 72 hours after dosing. At sacrificed (72 hrs postdosing) total residue (minus GI tract) amounted to 0.63% of the dose. A total of 10 compounds were identified in excreta. A large fraction

of the identified metab olites corresponded to successive oxidation steps of a methyl group of tebuconazole. At higher dose 920 mg/kg) changes in detoxification patterns may result from metabolic saturation.

870.7600

Dermal penetration

- monkey 46634901 (2003)

132 μg/cm 2 tebuconazole in Folicur EW250, single 8 hr administration

A cceptable/non guideline Estimated dermal absorption 23.1%. (including the

fraction of the dose absorbed and the amount of dose remaining in the skin after washing).

Literature study: Developmental neurotoxicity /immunotoxicity 45486901 (2001), 45591701 (2002), 46146701 (2003)

0, 6, 20, 60 mg/kg (gavage) GD14

- PND7 to dams, PND7

- 42 to offspring Study evaluated reproductive, immuno

- , and neurotoxicity in offspring. Identified one effect of

concern: learning deficits in high dose offspring, evaluated starting on PND74. Neuropathological effects identified in the original study were retracted based on a pathology peer

- review.

870.7800 Immunotoxicity 48769501 (2012)

Doses: 0, 100, 300, 1000 ppm 0, 8.1, 24.3, 78.4 m g/ k g/ d ay

Acceptable/Guideline Systemic: NOAEL = 78.4 m g/ k g/ d ay LOAEL > 78.4 m g/ k g/ d ay

Immunotox icity : NOAEL = 78.4 m g/k g/ d ay LOAEL = 78.4 m g/k g/ d ayPage 33 of 34 Appendix B: EPA Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies (which compose PHED,

l isted below) were determined to require a review of their ethical conduct, have received that

review and have been determined to be ethical.

Data from the Outdoor Residential Exposure Task Force (ORETF).

HED Residential Standard Operating Procedures (2 012).

Appendix C: Physical and Chemical Properties

Table C. 1

. Physicochemical Properties of Tebuconazole

. Parameter Value Reference

Melting point/range 104.7 °C PP#9F3724/9F3818, 5/9/91,

G. Otakie pH Not soluble enough

Specific gravity (20 oC) 1.202 g/mL

Water solubility (20 °C) 32 mg/L

Solvent solubility (g/L at 20oC) n

- hexane 2

- 5

dichloromethane >200

2

- propanol 100

- 200

toluene 50

- 100

Vapor pressure 1.3 x 10 - 3 mPa (20 oC)

3.1 x 10 - 3 mPa (25 oC)

Dissociation constant, pK

a does not dissociate

Octanol/water partition coefficient, Log(K OW ) 3.7 at 20 oC

UV/visible absorption spectrum Not availablePage 34 of 34 Appendix D : International Residue Limit Status



### Tebuconazole (PC Code; 9/04/2013 )

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex 3

40 CFR 180.474:

Plant: (1) tebuconazole [α

- [2

- (4

- chlorophenyl) ethyl]

- α

- (1,1

- dimethylethyl)

- 1H

1,2,4

- triazole

- 1

- ethanol]

Livestock: sum of tebuconazole (alpha

- [2

- (4

- chlorophenyl)ethyl]

- alpha

- (1,1

- dimethylethyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol) and its diol metabolite (1

- (4

- chlorophenyl)

- 4,4

- dimethyl

- 3

- (1 H

- 1,2,4

- triazo le

- 1

- yl

- methyl)

- pentane

- 3,5

- diol), calculated as the stoichiometric equivalent of

tebuconzole Plants: (+)

- α

- [2

- (4

- chlorophenyl)ethyl]

- α

- (1,1

- dimethylethyl)

- 1 H

1,2,4

- triazole

- 1

- ethanol

Livestock: (±)

- α

- [2

- (4

- chlorophenyl)ethyl]

- α

- (1,1

- dimethylethyl)

- 1H

1,2 ,4

- triazole

- 1

- ethanol, including the metabolite

5

- (4

- chlorophenyl)

- 2,2

- dimethyl

- 3

- (1H

- 1,2,4

- triazol

- 1

- ylmethyl)

- 1,3

- pentanediol Tebuconazole

The residue is fat

soluble.

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex 3

Orange, whole fruit 1.0 Orange, oil 10 Completed: M. Negussie; 09/04 /2013

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (f at) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.