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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

 OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

DATE: December 31, 2013

MEMORANDUM

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

Oranges.

PC Code: 128997 DP Barcode: D412600

Decision No.: 473438 Registration No.: NA

Petition No.: 2E8138 Regulatory Action: Import Tolerance

Risk Assessment Type: Single Chemical/ 

Aggregate

Case No.: 7004

TXR 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

Risk Assessment Branch III

Health Effects Division (7509P)

THROUGH: Christine Olinger, Branch Chief

Risk Assessment Branch III

Health Effects Division (7509P)

TO: Tamue Gibson, Risk Manager

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 

exposure and risk assessments, as needed, to estimate the risk to human health resulting from 

these additional tolerances. Since new domestic (US) uses are not being proposed, the 

tebuconazole use pattern is unchanged. Therefore, no new occupational or residential risk 

assessments are needed. However, HED has conducted new dietary and aggregate risk 
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assessments to reflect the additional commodity tolerances.

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

tolerances 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 assessment was provided 

by Andrew Shelby of the Environmental Fate and Effects Division (EFED).
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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 Toxicology 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 Residential (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........................................................... 26
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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................................................................... 34
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1.0 Executive 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-demethylase, 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 this action, the domestic tebuconazole use pattern is unchanged; and therefore, no 

new occupational risk 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 transferability 

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 not 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 complete. With repeated dosing, the main 

target organs are the liver, the adrenals, the hematopoietic 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 exposure. 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. Reliable data show that the Food Quality Protection 

Act (FQPA) safety factor (SF) can be reduced to 3x 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 10x 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 assessment, 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 routes of exposure (Toxicity 

Category III), and moderate toxicity by the inhalation route (Toxicity Category II). It is not a 

dermal sensitizer, nor a dermal irritant; however, it is slightly to mildly irritating to the eye.

Dietary Exposure (food and drinking water)

Somewhat refined acute and chronic dietary (food and drinking water) exposure analyses were 

performed for tebuconazole. For the acute assessment, anticipated residues for grapes, grape 
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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 are below HED’s LOC. 

Combined acute dietary exposure from food and drinking water at the 99.9th 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 adjusted dose (cPAD) for the general U.S. population 

and 14% 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 been evaluated for the entire 

class of triazole compounds. In connection with the pending tolerances for imported oranges and 

orange commodities, HED has reviewed the previous triazole dietary assessments to include 

these changes to tebuconazole. HED has determined 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 Exposure

No new residential uses are being requested at this time. However, adults, adolescents and 

children may be exposed to tebuconazole from currently registered uses 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 assessments

described above evaluate 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 MOEs ranging from 310 to 1,700

(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 risk 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- and 
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intermediate-term aggregate 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 occupational 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 Populations,” 

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 Section F, there are no outstanding data deficiencies or conditions of 

registration that would preclude the establishment of tolerances in or on imported oranges and 

orange oil as outlined in this document. HED has reviewed the submitted field trial and 

processing 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 20 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 deficiencies associated with the proposed uses of tebuconazole.

2.2 Tolerance Considerations

2.2.1 Enforcement method

The data collection and enforcement methods for tebuconazole were previously discussed 

(D373948, B. O’Keefe, 12/28/09). A gas chromatography/nitrogen phosphorus detector 

(GC/NPD) enforcement method for determining tebuconazole residues is available and adequate 

(Method 101341). 
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2.2.2 International Harmonization

The US and Canadian tolerance expressions for plants and livestock are harmonized; whereas,

the US and Codex tolerance expressions are harmonized for plants only. The Codex tolerance 

expression for livestock commodities includes parent only. The residue 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 International 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. The proposed 

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 juice is not needed since the raw 

agricultural commodity tolerance (1 ppm) is higher.

• The proposed tolerance of 20 ppm for orange oil based on the orange processing study is 

not appropriate; tolerance should be proposed at 10 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 20 10 A lower tolerance is needed based on available data.
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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 10 ppm for residues of tebuconazole on orange oil. HED does not 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# 2E8138) to establish tolerances on imported oranges and orange 

commodities. Therefore, no 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 ai/hL with a 250 g ai/L emulsion, oil in water, 

(EW) formulation. For the intended use in citrus fruits, 5 to 25 g ai per ton of fruits were 

applied. The submitted use directions are adequate to allow evaluation of the submitted residue 

data for oranges. The submitted data reflect the maximum use rate. HED has assumed that a 

single post-harvest application 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

[264-748]

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.
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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-(1H-1,2,4-triazol-1-ylmethyl)pentan-3-ol

CAS name α-[2-(4-chlorophenyl)ethyl]-α-(1,1-dimethylethyl)-1H-1,2,4-triazole-1-ethanol

CAS registry number 107534-96-3

Molecular weight 307.8

End-use products (EP) FOLICUR® 25EW (25% w/v 250 g/L ; EPA Reg. No. 264-748)

Metabolite

Common name t-butylhydroxy-tebuconazole

Company experimental name HWG 2061

IUPAC name Not available

CAS name 1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-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 tolerances 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 pathways 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 surface 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 OH CH3

CH3

CH3

N N

N

Cl OH CH3

CH3

CH2OH

N N

N
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This risk assessment considers all of the aforementioned exposure pathways based on the 

proposed tolerances of tebuconazole, but also considers existing uses of tebuconazole, 

particularly in the dietary and residential exposure assessments. 

3.5 Consideration of Environmental Justice

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 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 patterns 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 analyzed 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 development 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 Characterization/Assessment

Tebuconazole is a member of the triazole fungicide group. 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, inhibition of sterol production leads to abnormal 

fungal growth and eventually death. 

4.1 Toxicology Studies Available for Analysis

The toxicity studies on tebuconazole are complete. Refer to a previous HED risk assessment for 

further details (D384949, K. Rury, 05/24/11).
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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, the adrenals, the hematopoietic 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, 

04/18/08).

Oral administration of tebuconazole caused developmental toxicity in rats, rabbits, and mice;

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 evaluated. The developmental toxicity 

studies, including the developmental neurotoxicity study, demonstrate increased susceptibility in 

developing fetuses both quantitatively and qualitatively. In the reproductive toxicity study, 

adverse effects on offspring 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 of the carcinogenicity study in mice showed that tebuconazole induced an increase in 

the incidence of hepatocellular adenomas, carcinomas and combined adenomas/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 triazole-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 (D414592, T. Morton, 10/24/13) updated to incorporate new 

uses of triazole-derivative 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 irritating to the eye. 

Following oral administration to rats, tebuconazole was rapidly and extensively absorbed 

(approximately 98% of the administered dose), metabolized, and eliminated. At 72 hours postdosing, >94% of the administered radioactivity was recovered. 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 underwent enterohepatic circulation. 
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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 51-58% of the administered dose. The parent compound was present in relatively 

small amounts (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-examined 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, 04/30/12), and the original DER was updated with a new Executive Summary 

(D399045, J. Ryman, 02/23/12). 

4.3 Safety Factor 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 reduced 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 Database

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 level (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 the LOAEL of 8.8 mg/kg/day a no observable adverse effect level (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 has been retained as an 

uncertainty factor for use of a LOAEL to extrapolate a NOAEL (UFL). To determine whether 

the UFL is protective of any potential neurotoxicity a Benchmark Dose (BMD) analysis of the 

datasets relevant to the adverse offspring effects (decreased body weight and brain weight) seen 

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

BMDLs (benchmark dose limit) modeled successfully on statistically significant effects were 1-

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

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

3X 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)].
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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 

establishing 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 reflecting 

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 dietary analysis as the upper 

bound point estimate and into the probabilistic acute dietary analysis as a distribution. For the 

residential exposure pathways (ornamentals, golf course turf, and treated wood products), 

potential exposure resulting from tebuconazole 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 Selections

At this time, the toxicity endpoints and points of departure 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 tebuconazole on the fetal nervous system; (2) the effects 

determined at the LOAEL (155.8 mg/m3

) 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 applied 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 departure are presented in Table 4.4.
Page 15 of 34

Table 4.4. Summary of Toxicological Doses and Endpoints for Tebuconazole for Use in Dietary and NonOccupational 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

UFA= 10x

UFH=10x

FQPA(UFL)= 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

UFA= 10x

UFH=10x

FQPA(UFL)= 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

UFA= 10x

UFH=10x

FQPA(UFL)= 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 ShortTerm (1-30 days)LOAEL = 8.8 

mg/kg/day

UF = 300

UFA= 10x

UFH=10x

UFL= 3x

DAF = 13%

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 ShortTerm (1-30 days)LOAEL = 8.8 

mg/kg/day

UF = 300

UFA= 10x

UFH=10x

UFL= 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 or 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 = lowest observed adverse effect level. UF = uncertainty factor. UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human 

population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. 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 Routes 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 common toxicity endpoint.

4.4.2 Cancer Classification and Risk Assessment Recommendation

The Carcinogenicity Peer Review Committee concluded that tebuconazole should be classified 

as a Group 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 which 
Page 16 of 34

the following effects were observed: 1) a statistically significant increase in the 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 hepatocellular 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 also 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, the 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 Assessment1

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-20612

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 assessment (D322215, M. 

Doherty et al., 2/7/06, which has been updated in D414592). 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-(1H-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 reflecting the metabolism of [14C] tebuconazole in grapes and [U14C-
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 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. 

In support of the petition, Bayer submitted 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 

confirmatory 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 oranges treated with a post-harvest application was conducted in the United 

States. This study showed that tebuconazole residues concentrate in oil (24X). The study also 

showed that residues did not concentrate in juice. The maximum expected residue of tebuconazole

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, pulp, and peel) were stored 

frozen for up to 8 months prior to extraction. Intervals 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 

(D412862, A. Shelby, 07/03/13) and incorporated directly into the 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 System 
Page 18 of 34

(PRZM/EXAMS) surface water modeling. 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 by 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 water 

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 estimated 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) 

resulting 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 tebuconazole is a triazole fungicide, a separate updated dietary exposure and risk analysis 

(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 registrations for use of the triazolederivative 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 the 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 refined acute probabilistic and chronic dietary exposure assessments were conducted 

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

anticipated 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), and 
Page 19 of 34

tomatoes (paste and puree). For all other processed commodities, 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 

assessment. 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 (Screening Concentration in 

Groundwater) SCI-GROW model, tebuconazole concentration was 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). Screening 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, 

pecans, 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 

assessment 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%; onions 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 registered 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 estimates for the proposed import oranges were used in 

the acute and chronic 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 treated.
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 99.9th 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-FCID1. 

Population 

Subgroup

aPAD 

(mg/kg/day)

95th Percentile 99th Percentile 99.9th 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 bold
Page 21 of 34

Table 5.3.5.2. Summary of Chronic Dietary (Food + Drinking Water) Exposure and Risk for 

Tebuconazole Using DEEM-FCID1.

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, adults, adolescents, and 

children may be exposed to tebuconazole from currently registered uses 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. Therefore, 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 handler exposure is expected to be short-term only; intermediate-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 not 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 69-kg; where 

dermal absorption is 13%. 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-Application Exposure and Risk Characterization

Adults and children golfing, working in gardens, and performing physical activities on pressuretreated wood after application of tebuconazole may receive exposure to tebuconazole residues. 

Exposure is expected to be short-term in duration. Short-term dermal and incidental oral 

exposure and risk estimates have been previously assessed and indicated no risk estimates of 

concern. However, for the use of tebuconazole 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 previously 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 dissipation 

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; 

specifically: 1) The study is based on the old, not the new, California 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 product 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 

Rate1

Amount 

Treated

Exposure 

Route

Daily Dose 

(mg/kg/day)2 MOE Combined MOE3

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+7
Page 23 of 34

estimate of day zero tebuconazole residues on treated turf. Table 6.2.1 summarizes the recalculated 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

TTR1

(μg/cm2)

Exposure 

Time (hr) Population TC (cm2/hr)

Daily Dose2

(mg/kg/day) MOE3

Golf Course 

Turf 1.35 lb ai/A 0.151 4

Adults 5,300 0.00605 1,500

Youths 11 to <16 yr old 4,400 0.00607 1,400

Children 6 to <11 yr old 2,900 0.00713 1,200 1 TTR derived as follows: 1.35 lb ai/A x 4.54E+8 μg/lb x 2.47E-8 A/cm2

x 0.01 (fraction of transferable ai) = 0.151 μg/cm2. 2 Daily Dose = [TTR (μg/cm2

) x (0.001 mg/μg) x Dermal Transfer Coefficient x Dermal Absorption Factor (13%) x Exposure Time (4 hr)] / 

[Body weight (69 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 340 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 Formulation Application 

Rate

Amount 

Treated Activity Exposure Route Daily Dose (mg/kg/day) MOE1

Golf Course 

Turf Liquid 1.35 lb ai/A NA

Adults Golfing Dermal 0.00605 1,500

Children 11 to <16 yr old Dermal 0.00607 1,400

Children 6 to <11 yr old Dermal 0.00713 1,200

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 

Wood1

Liquid 1 μg/cm2 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/cm2) (DP 

Barcode 330159, 6/20/06, T. Leighton).

6.3 Other (Spray Drift, etc.)

Residential Bystander Post-Application 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 mm Hg (20oC)) and is not applied via airblast or aircraft. 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 pesticides 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, 2010 
Page 24 of 34

(http://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-application 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 previouslyregistered 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. pesticide 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 aggregate 

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 both 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 assessment; 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 Risks

The short-term aggregate 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 food and 

drinking water residues (anticipated residues based on 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 residential 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 estimates 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 modeling); 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 LOC1

Max 

Allowable 

Exposure2

(mg/kg/day)

Average Food 

& Water 

Exposure 

(mg/kg/day)

Residential 

Exposure3

(mg/kg/day)

Aggregate 

MOE4

(dietary and 

residential)

Residential Post-Application

Children 11 to 

<16 yr old Golfer, Turf 8.8 300 0.029 0.001383 0.00607 1,200

Children 6 to 

<11 yr old Gardens 8.8 300 0.029 0.001793 0.0155 510

Adults Gardens 8.8 300 0.029 0.001934 0.0261 310

Children (1-2

yr old)

Activities on pressure 

treated wood surfaces 8.8 300 0.029 0.002753 0.0225 350

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 (UFL = 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 residential exposure
Page 26 of 34

assessments.

4. Aggregate MOE = [LOAEL/(Average Food & Water Exposure + Residential Exposure)]

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., 02/07/06). In 2013, 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 (D414592, T. Morton, 10/24/13). The findings of the

assessments 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 alterations to the previous aggregate 

exposure and risk estimates in 2013 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 2013 risk assessments.

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; some 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 following 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.epa.gov/pesticides/cumulative.

Triazole-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-derivative 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 

fungicide. 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 comprised 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. DP256074 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 

Chemistry and Residue Data. DP416474, M. Negussie, 12/18/13.

Tebuconazole: Acute and Chronic Aggregate Dietary Exposure and Risk Assessments for 

Establishment of a Tolerance for Imported Oranges. M. Negussie, DP416473, 12/18/13. 

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

turf and ornamental use. DP 412862, A. Shelby, 07/03/13.

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

to Address The New Section 3 Registrations 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. DP414591. 10/24/13.

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

The New Section 3 Registrations 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. DP414592. 10/24/13.
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 LD50 (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

LD50 = >5000 mg/kg (M & F) III

870.1300 Acute inhalation [rat] 40700922 LC50 (4 h, aerosol)= >371 mg/m3

LC50 (4 h, dust)= >5093 mg/ m3

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

- rat

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 

decreased 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

21-Day inhalation toxicity 

- rat

40700938 (1985)

0, 1.2, 10. 6, 155.8 mg/m3

Acceptable/guideline

NOAEL = 10.6 mg/m3/d (0.0106 mg/L/day)

LOAEL = 155.8 mg/m3/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 = 30 mg/kg/day

LOAEL=60 mg/kg/d based on increased liver wt and 

liver/body weight ratios.

Developmental NOAEL=30 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 based 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 skeletal 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 = 10 mg/kg/d

LOAEL = 30 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 (increased 

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/day

LOAEL = 77.3 mg/kg/day 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 

Acceptable/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

Male 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 & 40700948 (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 metabolites 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/cm2 tebuconazole in Folicur 

EW250, single 8 hr administration

Acceptable/nonguideline

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 mg/kg/day

Acceptable/Guideline

Systemic: NOAEL = 78.4 mg/kg/day

 LOAEL > 78.4 mg/kg/day

Immunotoxicity: NOAEL = 78.4 mg/kg/day

 LOAEL = 78.4 mg/kg/day
Page 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, 

listed 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 (2012). 

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, pKa does not dissociate

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

UV/visible absorption spectrum Not available
Page 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 Mexico2 Codex3

40 CFR 180.474:

Plant: (1) tebuconazole [α-[2-

(4-chlorophenyl) ethyl]-α-

(1,1-dimethylethyl)-1H1,2,4-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-triazole-1-yl-methyl)-

pentane-3,5-diol), calculated as the 

stoichiometric equivalent of 

tebuconzole

Plants: (+)-α-[2-(4-

chlorophenyl)ethyl]-α-

(1,1-dimethylethyl)-1H1,2,4-triazole-1-ethanol

Livestock: (±)-α-[2-(4-

chlorophenyl)ethyl]-α-

(1,1-dimethylethyl)-1H1,2,4-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 fatsoluble.

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

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. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.