Tebufenozide Human Health Risk Assessment DP No. 414533 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

Date: 9/9/2015 

SUBJECT: Tebufenozide: Draft Human Health Risk Assessment for Registration Review 

PC Code: 129026 

Decision No.: 482454 

Petition No.: NA 

Risk Assessment Type: NA 

TXRNo.: NA 

MRID No.: NA 

DP Barcode: 0414533 

Registration No.: NA 

Regulatory Action: Registration Review 

Case No.: 7416 

CAS No.: 112410-23-8 

40 CFR: § 180.482 

- / ' 

FROM: \___/,';/ 7//--

t./-;;- 6- ~/~ / 

1 

Mohsen Sahafeyan, Chemist and Risk Assessor vi f c /,;,,._ Yung Yang, Ph.D., Toxicologist 

Bridgett Bobowiec, ORE Assessor ~ · V 

Risk 

Health 

Assessment 

Effects Division 

Branch 

(7509P) 

VI ~ ~ 

THROUGH: Donna Davis, Branch Chief 

Risk Assessment Branch VI 

Health Effects Division (7509P) 

TO: Christina Scheltema, Risk Manger Reviewer 

Kelly Sherman, Branch Chief 

Risk Management and Implementation Branch 3 

Pesticide Re-Evaluation Division (7508P) 

This document provides the Health Effects Division's (HED) Draft Risk Assessment to support 

registration-review for the active ingredient, tebufenozide. A summary of the findings and an 

assessment of potential human health risk resulting from the currently registered uses of 

tebufenozide are provided in this document. The HED team members contributing to this risk 

assessment include Mohsen Sahafeyan (risk assessment, residue chemistry, and dietary exposure 

Page 1of55 
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assessments), Bridgett Bobowiec (occupational and residential exposure assessments) and Yung 

Yang (hazard assessment). Jim Carleton of the Environmental Fate and Effects Division (EFED) 

performed the drinking water assessment for tebufenozide.
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Contents

1.0 Executive Summary............................................................................................................. 5

2.0 HED Recommendations....................................................................................................... 7

2.1 Data Deficiencies ............................................................................................................. 7

2.2 Tolerance Considerations................................................................................................. 7

2.2.1 Enforcement Analytical Method............................................................................... 7

2.2.2 Established and Recommended Tolerances.............................................................. 8

2.2.3 International Harmonization ................................................................................... 10

2.3 Label Recommendations................................................................................................ 11

2.3.1 Recommendations from Occupational Assessment................................................ 11

3.0 Ingredient Profile ............................................................................................................... 11

3.1 Chemical Identity and Physical/Chemical Characteristics............................................. 11

3.2 Pesticide Use Pattern...................................................................................................... 12

3.3 Anticipated Exposure Pathways..................................................................................... 17

3.4 Consideration of Environmental Justice ........................................................................ 17

3.5 Incident Reports ............................................................................................................. 17

4.0 Hazard Characterization and Dose-Response Assessment................................................ 18

4.1 Toxicology Studies Available for Analysis ................................................................... 18

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)................................... 18

4.2.1 Dermal Absorption.................................................................................................. 19

4.3 Toxicological Effects ..................................................................................................... 19

4.4 Safety factor for Infants and Children (FQPA Safety Factor) ....................................... 20

4.4.1 Completeness of the Toxicology Database............................................................. 20

4.4.2 Evidence of Neurotoxicity ...................................................................................... 20

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 21

4.4.4 Residual Uncertainty in the Exposure Database..................................................... 21

4.5 Toxicity Endpoint and Point of Departure Selections.................................................... 21

4.5.1 Dose-Response Assessment.................................................................................... 21

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment........ 22

4.5.3 Cancer Classification and Risk Assessment Recommendation.............................. 22

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment ............................................................................................................................ 23

4.6 Endocrine Disruption ..................................................................................................... 23

5.0 Dietary Exposure and Risk Assessment ............................................................................ 24

5.1 Summary of Plant and Animal Metabolism Studies...................................................... 24

5.1.1 Summary of Environmental Degradation ............................................................... 25

5.1.2 Residues of Concern Summary and Rationale........................................................ 26

5.2 Food Residue Profile...................................................................................................... 27

5.3 Water Residue Profile .................................................................................................... 27
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5.4 Dietary Risk Assessment................................................................................................ 28

5.4.1 Description of Residue Data Used in Dietary Assessment..................................... 28

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................ 28

5.4.3 Acute Dietary Risk Assessment.............................................................................. 29

5.4.4 Chronic Dietary Risk Assessment .......................................................................... 29

5.4.5 Summary Table....................................................................................................... 29

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 29

6.1 Residential Handler Exposure/Risk Estimates............................................................... 30

6.2 Residential Post-application Exposure........................................................................... 32

6.3 Combined Exposure ....................................................................................................... 32

6.4 Residential Bystander Post-application Inhalation Exposure ........................................ 32

6.5 Spray Drift...................................................................................................................... 33

6.5.1 Combined Risk Estimates from Lawn Deposition Adjacent to Applications......... 34

7.0 Aggregate Exposure and Risk Assessment........................................................................ 35

7.1 Acute Aggregate Risk .................................................................................................... 35

7.2 Short- Term Aggregate Risk .......................................................................................... 35

7.3 Intermediate-Term Aggregate Risk................................................................................ 36

7.4 Long-Term, Non-Cancer, Aggregate Risk..................................................................... 36

7.5 Cancer Aggregate Risk................................................................................................... 36

8.0 Cumulative Exposure/Risk Characterization..................................................................... 36

9.0 Occupational Exposure/Risk Characterization .................................................................. 36

9.1 Short-/Intermediate Handler Risk .................................................................................. 36

9.2 Short-/Intermediate-term Post-Application Risk ........................................................... 38

9.2.1 Dermal Post-application Risk ................................................................................. 38

9.2.2 Inhalation Post-application Risk............................................................................. 38

10.0 References.......................................................................................................................... 40

Appendix A: Toxicology Assessment....................................................................................... 41

A.1 Toxicology Data Requirements...................................................................................... 41

A.2 Toxicity Profiles............................................................................................................. 42

Appendix B. International Tolerances......................................................................................... 47

B.2 Harmonization - Recommendation .................................................................................. 49

Appendix C. Physical/Chemical Properties................................................................................. 51

C.2. Chemical Identity of Metabolites of Concern................................................................ 51

Appendix D. Spray Drift.............................................................................................................. 53

Appendix E. Occupational Exposure Scenarios and Risk Estimates........................................... 54
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1.0 Executive Summary

HED has conducted a human health risk assessment to support registration review for the active 

ingredient, tebufenozide, an insecticide and miticide used against (and highly specific for) 

lepidopteran species. Tebufenozide is a molting disruptor that kills lepidopteran larvae. 

Tebufenozide is registered for use on a wide range of food and feed commodities as well as 

ornamentals and trees. It is formulated as a flowable liquid concentrate (suspension) and 

wettable powder enclosed in a water-soluble pouch. Tebufenozide is applied via aerial, ground, 

and handheld equipment. Chemigation is allowed on cranberries and ornamentals. Tebufenozide 

is also registered for residential use on ornamental plants. 

The toxicity database of tebufenozide is complete. The available toxicity database for 

tebufenozide is adequate for FQPA and dose-response evaluation.

The toxic effects of tebufenozide in mammalian species arise primarily from 

methemoglobinemia associated with denaturation of hemoglobin and concomitant Heinz

body formation in erythrocytes, resulting in a rapid turnover of red blood cells with increased 

hematopoiesis, splenic discoloration, and other spleen effects. There is no evidence that 

tebufenozide is a developmental, reproductive, neurotoxic, or immunotoxic chemical. 

Tebufenozide is classified as "not likely to be carcinogenic to humans" based on lack of evidence

of carcinogenicity in rats and mice and lack of mutagenicity.

Tebufenozide is rapidly absorbed and excreted within 48 hours mainly through feces. The extent 

of absorption is not established. There is no tendency for bioacculmulation. Tebufenozide has 

low acute toxicity (Toxicity Category III or IV) by the oral, dermal, or inhalation route of 

exposure. It is not an eye or skin irritant, and is not a skin sensitizer.

No appropriate endpoint attributable to a single dose was identified in the toxicity database for 

acute dietary risk assessment. Since there is a lack of progression of toxicity for the period from

90-360 days, a co-critical 90-day and 1-year dog feeding studies were selected for chronic 

dietary, incidental oral and inhalation exposure scenarios based on decreases in body weight 

gains, alterations in hematology parameters, changes in organ weights, and histopathological 

lesions in the bone, spleen, and liver. No dermal endpoint was selected for dermal risk 

assessment based on a lack of systemic toxicity in the dermal study and a lack of developmental 

concern. 

There is no evidence of increased qualitative or quantitative susceptibility in the young, and no 

evidence of neurotoxicity with tebufenozide. Additionally, the exposure estimates are unlikely 

to underestimate risk; therefore, the 10-fold FQPA Safety Factor (SF) can be reduced to 1x.

Tolerances have been established in 40 CFR 180.482 for tebufenozide on a number of food and 

feed commodities. The residue chemistry database for tebufenozide is complete. Validated 

analytical methods are available for tolerance enforcement purposes. The nature of the residue 

in plants, animals, rotational crops, and drinking water is adequately understood. Field trial data 

elucidating the magnitude of the residue in agricultural crops have been submitted. These 
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studies were generated using validated data collection methods, and are supported by adequate 

storage stability data. These studies support the established tolerances in registered crops.

As part of registration review, HED recommends conversion of relevant crop groups to new crop 

groups as well as harmonized tolerances for pome fruits, citrus and almond hulls. In addition, 

because tebufenozide is registered for use on sugarcane, HED recommends that tolerances be 

established for tebufenozide residues in/on molasses and sugarcane. 

The chronic dietary analysis (food and drinking water) assumed tolerance-level residues for all 

foods including harmonized/recommended tolerances, average percent crop treated (% CT), and 

Dietary Exposure Evaluation Model version 7.81 (DEEM 7.81) default concentration factors, as 

well as EFED modelled estimated drinking water concentration (EDWCs). The chronic dietary 

risks estimates are <37% of the chronic population adjusted does (cPAD) for the U.S. general 

population and for all population subgroups, and therefore are not of concern. Since 

tebufenozide has been classified as not likely to be carcinogenic, quantification of dietary cancer 

risk is not required. 

Aggregate risk assessment included short-term and long-term risk assessments only. The shortterm aggregate risk assessment for tebufenozide is appropriate for adults only and includes

average exposure from food, water, and short-term residential handlers’ exposure. Since 

residential uses are limited to application to outdoor ornamentals, there are no expectations of 

residential post-application exposure. The calculated aggregate margin of exposure (MOE) for 

the tebufenozide short-term aggregate risk was 550, which is greater than the level of concern 

(LOC) of 100, and, therefore, is not of concern. The long-term aggregate risk assessment 

included only food and drinking water exposure since there is no reasonable expectation of longterm residential exposure from the registered uses of tebufenozide. Therefore, the long-term 

aggregate assessment is equivalent to the chronic dietary (food and water) risk assessment, and is 

not of concern as noted above. 

A screening level residential spray drift assessment was completed for tebufenozide as part of 

registration review. The spray drift risk estimates are based on an estimated deposited residue 

concentration as a result of the screening level agricultural application scenarios. Children’s 

(ages 1 to < 2 years old) incidental oral risk estimates from indirect exposure to tebufenozide, 

related to spray drift, result in no risks of concern at the edge of a field from groundboom, 

airblast, or aerial applications. Adult and children dermal risk estimates were not calculated 

because a dermal hazard was not identified for tebufenozide.

HED conducted an occupational handler exposure and risk assessment for the inhalation route of 

exposure only as there was no dermal hazard identified. The tebufenozide registrant has 

submitted an amended label for EPA Reg No. 8033-111 (Confirm 2F) requiring use of a PF5 

respirator for greenhouse applications. This label amendment will address risk concerns for 

greenhouse workers. Short- and intermediate-term inhalation occupational MOEs for 

mixers/loaders and applicators are not of concern (i.e. MOE >100) when a PF5 respirator is 

worn; MOEs range from 1,100 to 73,000. 
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Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, the inhalation handler exposure assessment resulting from application of 

tebufenozide is likely to result in higher exposure than post-application exposure. Therefore, it is 

expected that these handler inhalation exposure estimates would be protective of most 

occupational post-application inhalation exposure scenarios. The non-cancer inhalation risk 

estimate for this scenario for airblast application of tebufenozide is not of concern (i.e., MOE > 

100) and is believed to represent a reasonable worst case surrogate estimate of post-application 

inhalation exposure during dusty mechanical harvesting activities.

Potential environmental justice concerns were considered, to the extent possible, in this humanhealth risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to 

Address Environmental Justice in Minority Populations and Low-Income Populations.1

” 

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 data, which include studies from 

the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler 

Exposure Task Force (AHETF) database, and the Agricultural Reentry Task Force (ARTF) 

database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, 

and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review 

may have included review by the Human Studies Review Board. Descriptions of data sources, 

as well as guidance on their use, can be found at the following Agency 

websites: http://www.epa.gov/pesticides/science/handler-exposure-data.html

and http://www.epa.gov/pesticides/science/post-app-exposure-data.html. 

2.0 HED Recommendations

2.1 Data Deficiencies

There are no residue chemistry, toxicology, or occupational/residential exposure data gaps for 

tebufenozide.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Primary Crops - An adequate high-performance liquid chromatography/ultraviolet (HPLC/UV)

method (Method TR 34-94-38, TR 34-94-41 or its variation) is available for determination of 

tebufenozide residues of concern in plants for regulatory enforcement. In this method, residues 

in crop samples are extracted with acidified methanol, filtered, and the filter cake is partitioned 

with hexane and then methylene chloride. The methylene chloride is filtered through sodium 

 

1 http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf
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sulfate and concentrated to dryness by rotary evaporation. Residues are quantitated by HPLC 

analysis with UV detection. The validated method limit of quantitation (LOQ), depending on the 

matrix, is generally between 0.01 to 0.05 ppm. 

Rotational Crops - The original proposed analytical method for the enforcement of tebufenozide 

residues in/on rotated crops is Rohm and Haas Analytical Method TR 34-99-10. However, the 

Analytical Chemistry Branch (ACB) of the Biological and Economic Analysis Division (BEAD)

recommended modification to the method so that the metabolite RH-1788 can be detected. The 

registrant proposed another method (DAS Method GRM 02.20) for the tolerance enforcement; 

this method appeared to be superior to Rohm and Hass Method TR 34-99-10 for quantitation of 

tebufenozide and RH- 1788 residues in/on low-moisture rotational crops. The ACB recently 

conducted a petition method validation (PMV) for DAS Method GRM 02.20 and has 

recommended that this method be conditionally accepted as an enforcement method for the 

analysis of tebufenozide and its metabolite RH-1788 in rotational crops. ACB recommended

that data be provided showing the presence of second MS/MS transitions at or above the LOQ 

level as a confirmatory technique before recommending that DAS Method CRM 02.20 be 

accepted. ACB also noted that because of simplicity of the sample preparation and reliability of 

tandem mass spectrometry, an independent laboratory validation (ILV) study may not be needed 

for tebufenozide and its metabolite RH-1788 in rotational crops (Y. Qian, ACB Project # B15-

05, 6/17/2015).

In DAS Method GRM 02.20, residues in crop samples are extracted with acidified methanol, 

centrifuged and purified on the solid-phase extraction (SPE) plate, washed with solution of 

water/methonal/formic acid and eluted with acetonitrile (ACN). The ACN eluent was 

evaporated at 50°C. Residues are reconstituted in solution of water/ACN containing ammonium 

acetate and quantitated via HPLC/MS/MS. Tebufenozide is monitored via ions (m/z) 351 and 

149, while RH-1788 is monitored via ions 367 and 149. The validated method limit of 

quantitation (LOQ) for both tebufenozide and RH-1788 is 0.020 ppm.

Ruminants - An adequate HPLC/UV method (Method TR 34-96-109) is available for 

determination of tebufenozide residues of concern in ruminants for regulatory enforcement; at 

present there are no tolerances for poultry tissues. This enforcement method determines residues 

of tebufenozide and its metabolites RH-0282, RH- 9886, and RH-2703 in their existing 

molecular form. RH-9526, the stearic acid conjugate of RH- 9886, and other fatty acid 

conjugates of RH-9886, are hydrolyzed and determined as RH-9886. In this method meat 

samples are extracted with acidified methanol, filtered, washed with hexane, partitioned into 

DCM, concentrated, (residues) taken up in EtOAc, cleaned up and quantitated by HPLC/UV. 

The LOQ for tebufenozide and its metabolites in milk is 0.01 ppm. The LOQ for residues in 

liver, meat, and fat is 0.02 ppm. 

2.2.2 Established and Recommended Tolerances

Tolerances are established under 40 CFR: §180.482 for residues of tebufenozide in/on a number 

of agricultural commodities including bushberries, caneberries, brassica (head and stem, and 

leafy green), citrus, canola, cotton, cranberry, fruiting vegetables, grape, leafy greens and 

petioles, mint, nuts, pome fruits, tuberous and corm vegetables except potato, turnips as well as 
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milk and ruminant tissues. Tolerances for inadvertent residues include nongrass animal feed, 

and forage, fodder and straw of cereal grains and grass. The residues of concern and tolerance 

expression under 40 CFR: §180.482 are up to date and comply with the HED Interim Guidance 

on Tolerance Expressions (S. Knizner, 5/27/2009). 

HED notes that as part of registration review, certain crop groups may be converted to the 

updated crop groups with simultaneous revocation of some individual crop tolerances as shown

below (see Table 2.2.2). The currently established tolerances for the converted crop groups 

remain at the same level except for pome fruit crop group 11-10, citrus fruit crop group 10-10

and almond hulls. New tolerances for these crops/crop groups are recommended to harmonize 

with Codex (see section 2.2.3 below). In addition, because tebufenozide is registered for use on 

sugarcane, HED recommends that tolerances be established for tebufenozide residues in/on 

molasses and sugarcane. 

Table 2.2.2 Commodity/Tolerance Updates

Commodity Action Established 

Tolerance

Recommended/harmonized 

Tolerance

Berry group 13 Convert to: 

Caneberry 

Subgroup 13-07A

And 

Bushberry 

subgroup 13-07B

3.0 3.0

Fruit, citrus, group 

101

1) Convert to: 

Fruit, citrus, group 

10-10

2) Harmonize 

tolerance

0.80 2.0

Fruit, pome2 1) Convert to: 

Fruit, pome, group 

11-10

2) Harmonize 

tolerance

1.5 1.0

Nut, tree, group 14 Convert to: Nut, 

tree, group 14-12

0.1 0.1

Vegetable, fruiting, 

group 8

Convert to: 

Vegetable, fruiting, 

group 8-10

1.0 1.0

Pistachio Revoke tolerance 

as it is included in 

the crop group 14-

12

0.1 Revoke

Walnut Revoke tolerance 

as it is included in 

the crop group

0.1 Revoke
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Table 2.2.2 Commodity/Tolerance Updates

Commodity Action Established 

Tolerance

Recommended/harmonized 

Tolerance

14-12

Apple Revoke tolerance 

as it is included in 

crop group 11-10

1.0 Revoke

Kiwifruit Revoke tolerance 

since US 

registration expired 

June 15, 1999

0.5 Revoke

Almond, hulls3 Harmonize

tolerance

25 30

Sugarcane, cane4 Should be 

established.

None 1.0

Sugarcane, 

molasses4

Should be 

established.

None 3.0

1 Tolerance for fruit, citrus, group 10-10 is recommended to be changed from 0.80 ppm to 2.0 ppm to harmonize with Codex. 2 Tolerance for fruit, pome, group 11-10 is recommended to be changed from 1.5 ppm to 1.0 to harmonize with Codex. 3 Tolerance for almond hulls is recommended to be changed from 25 ppm to 30 to harmonize with Codex. The increase in 

almond hulls tolerance is not expected to change the livestock dietary burden significantly; i.e., livestock tolerances are not 

changed.

4 HED recommended tolerances for sugarcane (1.0 ppm) and molasses (3.0 ppm) previously (Yan Donovan, D239395, 6/21/99)

because tebufenozide is registered for use on sugarcane. The recommended sugarcane tolerance of 1.0 ppm harmonizes with 

Codex.

2.2.3 International Harmonization

There are Codex, Canadian, and Mexican Maximum Residue Limits (MRLs) established for 

tebufenozide. The International Residue Limit (IRL) Status sheet is attached as Appendix B. 

A harmonization discussion is only relevant for primary crops since the residue definitions 

(tebufenozide only) for ruminant tissues, milk, and inadvertent residues differ between the US, 

Canada, and Codex. For primary crops, while there are similar tolerances and MRLs (Canadian 

and Codex) for some crops, there are some that are different. In general, HED mainly considers 

raising, as opposed to lowering tolerances to harmonize US tolerances with international MRLs. 

This is because lowering tolerances may result in over-the-tolerance residues in crops treated 

following US registered use patterns. However for pome fruit, crop group 11-10, HED 

determined that because the rate and use pattern in the US and the European Union (EU) are 

similar, the tolerance can be lowered for harmonization purpose. HED has reviewed the 

tolerances for other primary crops that can be adjusted to harmonize with international MRLs. 

Both use rates and use patterns in the US and the EU were examined. The HED recommended 

tolerances for international harmonization purposes as well as other tolerances that need to be 

revised are shown in Table 2.2.3; for detailed discussion see Appendix B.
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Table 2.2.3 HED Recommended Tolerance Revisions for Codex Harmonization

Commodity Established 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comment

Fruit, pome, group 11-101 1.5 1.0 International 

Harmonization 

Fruit, citrus, group 10-102 0.80 2.0 International 

Harmonization

Almond, hulls 25 30 International 

Harmonization 1 The current crop group, “Fruit, pome”, may be converted to “Fruit, pome, group 11-10”. 2 The current crop group, “Fruit, citrus, group 10”, may be converted to “Fruit, citrus, group 10-10”.

2.3 Label Recommendations

2.3.1 Recommendations from Occupational Assessment

During registration review, HED identified potential risk concerns for tebufenozide liquid 

concentrate product labeled for use on greenhouse ornamentals allowing applications to 

ornamentals using a mechanically pressurized handgun. The tebufenozide registrant has 

submitted an amended label for EPA Reg No. 8033-111 (Confirm 2F) that requires the use of

PF5 respirators for greenhouse applications. HED expects that this label amendment will 

address the risk concern. 

3.0 Ingredient Profile

Tebufenozide (CAS Name: 3,5-dimethylbenzoic acid 1-[1,1-dimethylethyl]-2-[4-ethylbenzoyl 

]hydrazide), a member of the diacylhydrazine class of compounds and an insecticide and 

miticide is registered for use on a wide range of food and feed commodities as well as 

ornamentals and trees. Tolerances for tebufenozide residues are under 40 CFR, 180.482 for 

primary crops, ruminant tissues and milk, and inadvertent residues in rotational crops.

Tebufenozide mimics an insect molting hormone that induces lethal molting of lepidopterous 

larvae. There is a potential for residential handler exposure from the registered uses of 

tebufenozide from outdoor ornamental plants, and indirect residential exposure to tebufenozide

via spray drift from use on the various registered agricultural crops.

There are three registered end-use products containing tebufenozide, two liquid concentrates and 

a wettable powder formulated product enclosed in a water-soluble pouch. Maximum single 

tebufenozide application rates range from 0.12 to 0.47 lb ai/A on the various crops. Application 

methods include aerial, ground, and handheld equipment as well as chemigation on cranberries 

and ornamentals. 

3.1 Chemical Identity and Physical/Chemical Characteristics

Tebufenozide is white powder at room temperature with low vapor pressure. It has low 
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solubility in water. Field trial data show that it translocates in plants. In the environment, parent 

tebufenozide is characterized as persistent to very persistent, with laboratory half-lives that range 

up to 179 days. Based upon limited data, tebufenozide major degradates in drinking water (RH112651, RH-112703, and RH-96595) appear to be somewhat less persistent than the parent. 

However, all (parent and the three metabolites) are classified either as mobile or moderately 

mobile and, therefore, have potential to contaminate surface water or leach to groundwater.

Table 3.1 shows the nomenclature for tebufenozide; see Appendix C for a summary of 

tebufenozide physical/chemical properties and chemical identity of its residues of concern.

Table 3.1 Tebufenozide Nomenclature

Chemical Structure

Empirical Formula C22H28N2O2

Common Name Tebufenozide

Company experimental name

IUPAC name N-tert-butyl-N’-(4-ethylbenzoyl)-3,5-dimethylbenzohydrazide 

CAS Name 3,5-dimethylbenzoic acid 1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)hydrazide

CAS Registry Number 112410-23-8

End-use product/EP

CONFIRMTM 2F ( EPA Registration Number: 8033-111)

CONFIRMTM 70 WSP (EPA Registration Number: 8033-112)

MIMICTM 2LV (EPA Registration Number: 8033-113)

Chemical Class diacylhydrazine

3.2 Pesticide Use Pattern

Tebufenozide is registered for a variety of crops including the following: bushberries, 

caneberries, brassica (head and stem, and leafy green), citrus, canola, cotton, cranberry, fruiting 

vegetables, grape, leafy greens and petioles, mint, nuts, ornamentals, pastureland, pome fruits, 

sugarcane, tuberous and corm vegetables except potato, turnips, forests and shrub, as well as 

ornamentals and trees. 

There are three registered products for tebufenozide. ConfirmTM 2F is a flowable liquid 

concentrate (suspension) comprised of 23% ai, MimicTM 2LV is a flowable liquid concentrate 

(suspension) comprised of 24% ai, and ConfirmTM 70WSP is a wettable powder enclosed in 

water-soluble pouches containing 70% ai. The three products can be applied using aerial, 

ground, and handheld equipment; chemigation is allowed on cranberries and ornamentals. 

Application to foliar plants should be uniform and thorough to ensure larvae ingestion of 

product. Reapplication may be required as crops grow with new foliage and expanding fruit. 

The maximum application rates on the labels range from 0.12 lb to 0.47 lb ai/A depending on the 
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crop. The ConfirmTM 2F label includes outdoor ornamental use that does not preclude residential 

consumers/applicators; therefore, a residential assessment was conducted. 
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Table 3.2 Tebufenozide Use Profile

Company

Formulation 

Name

EPA Reg. No.

% a.i Use Sites Application 

Equipment

Max. App. 

Rate

Max. 

No. 

App. per 

Season

Max.

Season 

App 

Rate

Spray Instructions PHI Use Directions 

and Limitations

Liquid Concentrate

NIPPON 

SODA 

CO., LTD

CONFIRMTM

2F (EPA 

Registration 

Number: 8033-

111)

23%

Bushberries1

Aerial and

Ground.

Do not apply 

through 

irrigation 

except on 

cranberries 

and

ornamentals

0.25 lb ai/A

4

(10 to 

14 day 

interval)

1 lb ai/A

Ground boom or airblast with minimum of 30 

gal/A. Aerial application in minimum of 10 

gal/A. Do not apply more than 64 fl. oz./season

14 days

In New York, do 

not apply by 

ground within 25 

feet or by air 

within 150 feet of 

water. Not for use 

in Nassau and 

Suffolk counties 

in NY. A 

minimum of 6 hrs. 

of drying time. Do 

not graze 

livestock in 

treated areas or 

cover crops. 

REI is 4 hrs. 

PPE includes 

long-sleeved shirt 

and long pants, 

waterproof gloves, 

shoes plus socks.

Caneberries2

Canola

Ground boom or airblast with minimum of 8-10 

gal/A. Aerial application in minimum of 5 gal/A. 

Do not apply more than 64 fl. oz./season.

Citrus3 1.25 lb 

ai/A

Ground boom or airblast with minimum of 50 

gal/A to trees 10 feet tall or less and 100 gallons 

for trees greater than 10 feet. Aerial application 

in minimum of 20 gal/A. Do not apply more than 

80 fl. oz. /season.

Cole Crops4, Leafy 

Vegetables5 and 

Turnips (tops and 

roots)

0.12 lb ai/A

1 lb ai/A

Ground boom 10 -20 gal/A by conventional 

ground equipment. Aerial application in 

minimum of 10 gal/A. Do not apply more than 

56 fl. oz./season.

7 days

Cotton

0.25 lb ai/A

Ground boom with minimum of 5 gal/A. Aerial 

application in minimum of 2 gal/A. Do not apply 

more than 64 fl. oz./season.

14 days

Cranberry

Ground boom with minimum of 10-20 gal/A. 

Aerial application in minimum of 10 gal/A. Do 

not exceed 900 gallons of water per acre for 

chemigation.

30 days

Fruiting Vegetables6

Ground boom or airblast with 10-20 gal/A. 

Aerial application in minimum of 10 gal/A. Do 

not apply more than 64 fl. oz. /season.

7 days

Mint

Conventional ground sprayers with minimum of 

8-10 gal/A. Arial application minimum of 5 

gal/A. Do not apply more than 64 fl. oz. /season.

14 days

Ornamentals7 0.25 lb ai/A 16 4 lb ai 

/A

Application with hand sprayers is equivalent to 1 

teaspoon in gallon of water. Hydraulic ground 

application minimum of 50 gal/A. Mist blowers 

or airblast sprayer minimum of 10 gal/A. Aerial 

application minimum of 20 gal/A. Do not exceed 

1200 gallon of water per acre application 

volume.

unknown

Pome Fruit8 0.31 lb ai/A 6 1.9 lb 

ai/A

Ground minimum of 50 gals/A to trees 10 feet 

tall or less and 100 gallons for trees greater than 

10 feet. Aerial application in minimum of 20 

gallons. Do not apply more than 120 fl. oz./ 

season.

14 days 
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Table 3.2 Tebufenozide Use Profile

Company

Formulation 

Name

EPA Reg. No.

% a.i Use Sites Application 

Equipment

Max. App. 

Rate

Max. 

No. 

App. per 

Season

Max.

Season 

App 

Rate

Spray Instructions PHI Use Directions 

and Limitations

Sugarcane 0.25 lb ai/A 1 1 lb ai/A

Conventional ground sprayers with minimum of 

10 gal/A. Arial application minimum of 2 gal/A. 

Do not apply more than 64 oz. /season.

Pecans, 4 1.9 lb 

ai/A

Ground minimum of 50 gal/A trees 4th leaf or 

younger. Trees 5th or older use minimum of 100 

gallons. Aerial application in minimum of 20 

gal/A. Do not apply more than 122 fl. oz./season.

Almonds, Walnuts

0.47 lb ai/A

4

Other tree nut trees. 5 2.4 lb 

ai/A

Forests, trees, shrubs, 

christmas trees,

plantations, conifer 

seed orchards, shade 

tree, woody shrubs 

and vines. 0.12 lb ai/A 4 0.25 lb 

ai/A

Ground minimum of 50 gal/A to trees 10 feet tall 

or less and 100 gallons for trees greater than 10 

feet. Aerial application in minimum of 20 gal/A.

Do not apply more than 16 fl. oz. /year. Apply 

early instar.

unknown

Not registered for 

use on forests in 

state of California.

Pastureland/Rangela

nd NA

Arkansas SLN, 

Oklahoma SLN 

only

REI is 4 hrs.

MIMIC 2LV 

(EPA 

Registration 

Number: 8033-

113)

24%

Canola

Ground and 

aerial

0.25 lb ai/A

4

1 lb ai/A

Apply a minimum of 8-10 gallons/A by ground 

application and a minimum of 5 gal/A fore aerial 

application. Do not apply more than 34 fl. 

oz./season

14 days 

Do not apply 

product through 

irrigation. Not 

registered for 

forests in 

California. REI is 

4 hrs.

Commercial, private, 

and public 

forestland, christmas 

trees, nurseries, 

plantations, conifer 

seed orchards, 

ornamental and 

woody shrubs and 

vines.

0.12 lb ai/A 0.25 lb. 

ai./A

Hydraulic ground sprayer minimum of 50 gal/A. 

Mist blowers a minimum of 10 gal/A. Aerial 

application minimum 1 gal/A. Do not apply more 

than 16 fl. oz./season.

unknown

Water Soluble Powder in Water Soluble Packages

NIPPON 

SODA 

CO., LTD

CONFIRM 70 

WSP 

(EPA 

Registration 

Number: 8033-

112)

70%

Almonds

Ground and 

aerial

No 

chemigation 

except for 

cranberries

0.45 lb ai/A

2

(10 to 

14 day 

interval)

2.4 lb 

ai/A

Ground minimum of 50 gal/A trees 4th leaf or 

younger. Trees 5th or older use minimum of 100 

gallons. Do not apply more than 55 fl. oz./season. 

Minimum of 20 gal/A for aerial application. 14 days

Do not apply 

through irrigation. 

Do not graze 

livestock in 

treated area or 

cover crops. A 

minimum of 6 hrs. 

drying time. REI 

is 4 hrs.

Pecans 0.26 lb ai/A

Walnuts 0.45 lb ai/A

Tree nut crops not 

specified already 0.45 lb ai/A 5.3 lb ai/A Do not apply more than 122 fl. oz./season. 

Fruiting Vegetable6

0.26 lb ai/A 1 lb ai/A

Ground boom or airblast with 10-20 gal/A. 

Aerial application in minimum of 10 gal/A. Do 

not apply more than 24 fl. oz. /season.

7 days

Cotton

Ground boom with minimum of 5 gal/A. Aerial 

application in minimum of 2 gal/A. Do not apply 

more than 24 fl. oz./season

14 days 
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Table 3.2 Tebufenozide Use Profile

Company

Formulation 

Name

EPA Reg. No.

% a.i Use Sites Application 

Equipment

Max. App. 

Rate

Max. 

No. 

App. per 

Season

Max.

Season 

App 

Rate

Spray Instructions PHI Use Directions 

and Limitations

Cranberries Ground boom with minimum of 10-20 gal/A. 

Aerial application in minimum of 10 gal/A. Do 

not apply more than 24 fl. oz. /season.

30 days

Sugarcane 14 days

Cole Crops4 Leafy 

vegetable5 and 

turnips

0.13 lb ai/A

Ground boom with minimum of 10-20 gal/A. 

Aerial application in minimum of 10 gal/A. Do 

not exceed 21 oz./season

7 days

Pome Fruit 0.31 lb ai/A 1.86

Ground minimum of 50 gals/A to trees 10 feet 

tall or less and 100 gallons for trees greater than 

10 feet. Aerial application in minimum of 20 

gallons. Do not apply more than 7oz/A per 

application or 42 oz. /A season. 

14 days

Technical

NIPPON 

SODA 

CO., LTD

EPA 

Registration 

Number: 8033-

110

TEBUFENOZIDE TECHNICAL 99% ai.

1. Bushberries= blueberries high and low, currant, elderberry, gooseberry, and huckleberry.

2. Caneberries =bingleberry, black satin berry, blackberry, boysenberry, Cherokee blackberry, chester berry, lavacberry, loganberry , lowberry, lucretiaberry, mammoth 

blackberry, marionberry, nectarberry, Olallie berry, Oregon evergreen berry, phenomenal berry, rangeberry, ravenberry, red and black raspberry, rossberry, Shawne 

blackberry youngberry.

3. Citrus = calamondin, citrus citron, citrus hybrids, pummelo, Satsuma mandarin, sour orange, sweet orange.

4. Cole crops= broccoli, chinese broccoli, broccoli raab, brussel sprouts, cabbage, bok choy, napa cabbage, chinese mustard cabbage, cauliflower, cavalo broccoli, collards, 

kale, kohlrabi, mizuna, mustard greens, mustard spinach, rape greens.

5. Leafy vegetable= (except Brassica) includes amaranth, arugula cardoon, celery, Chinese celery, celtuce, chervil. chrysanthemum , corn salad, garden cress, upland cress, 

dandelion, dock, endive Florence fennel, lettuce , orach, parsley, garden purslane, winter purslane, radicchio, rhubarb, spinach, vine spinach , Swiss chard. 

6. Fruiting Vegetables =eggplant, ground cherry, pepino, pepper (bell, chili, cooking) pimento, tomatillo and tomato.

Ornamentals= nurseries and greenhouse, outdoor landscape, recreational areas, institutional grounds and interior plantscapes.

7. Pome Fruit = apples, crabapples, loquat, mayhaw, pears including oriental, quince
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3.3 Anticipated Exposure Pathways

Tebufenozide is applied directly to growing crops and application may result in tebufenozide 

reaching surface and ground water sources of drinking water. Therefore, humans may be 

exposed to tebufenozide from eating food that has been directly treated with tebufenozide and 

drinking water which contains residues of the chemical. Additionally, homeowners may apply 

tebufenozide to ornamental and trees grown in outdoor residential settings. Therefore, humans 

may also be exposed to tebufenozide while applying the pesticide to ornamentals at their 

residence. In an occupational setting, workers may be exposed while handling the pesticide prior 

to application, as well as during application. Further, workers may be exposed to tebufenozide 

from contact with treated foliage when conducting activities in the field after application. This 

risk assessment considers all of the aforementioned exposure pathways.

3.4 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://epa.gov/compliance/ej/resources/policy/exec_order_12898.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 (USDA) under the 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.

3.5 Incident Reports

HED completed a review of tebufenozide incidents in the OPP Incident Data System (IDS) and 

the Centers for Disease Control and Prevention/National Institute for Occupational Safety and 

Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk-Pesticides 

(SENSOR) databases. 
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Based on the low frequency and severity of incident cases reported for tebufenozide in both IDS 

and NIOSH SENSOR Pesticides, there does not appear to be a concern at this time that would 

warrant further investigation (S. Recore, Tebufenozide: Tier I Review of Human Incidents for 

Preliminary Risk Assessment, D422657, 9/23/14). The Agency will continue to monitor the 

incident information, and, if a concern is triggered, additional analysis will be conducted. The 

Agricultural Health Study (AHS) is also a potential source of information associated with human 

health effects associated with certain pesticides. Tebufenozide is not included in the AHS.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database for tebufenozide is complete. The Hazard and Science Policy Council 

(HASPOC) determined that a subchronic neurotoxicity study was not needed but a subchronic 

inhalation study was required for tebufenozide (TXR# 0055187, TXR# 0057075). However, the 

HASPOC also recommended use of a PF5 respirator for greenhouse uses in lieu of an inhalation 

study. Because the tebufenozide registrant submitted an amended label for EPA Reg No. 8033-

111 (Confirm 2F), requiring a PF5 respirator for greenhouse uses, HED has determined that an 

inhalation study is not needed at this time. The available toxicity database for tebufenozide is 

adequate to characterize a wide range of effects, including developmental, reproductive, 

neurotoxic, mutagenic, carcinogenic, and immunotoxic effects. The toxicity data requirements 

and toxicity profile are listed in the Appendix A. 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

In the metabolism studies (MRID# 42436233, 42931211, 42931212), the pharmacokinetics and 

metabolism of tebufenozide (RH-5992) were studied in groups of male and female Sprague 

Dawley rats (3-6/sex/group) receiving a single oral dose of 3 or 250 mg/kg of RH-5992 14C 

labeled in one of three positions (A-ring, B-ring, or N-butyl carbon). Absorption, distribution, 

metabolism and excretion also were studied after repeated oral dosing (dietary) with 

nonradioactive RH-5992 followed by a single oral gavage dose (3 mg/kg) of 14C-RH-5992.

The extent of absorption was not established. The majority of the radioactivity was excreted in 

the feces within 48 hours; small amounts (1 to 7% of the administered dose) were excreted in the 

urine and only traces were excreted in expired air or remained in the tissues. There was no 

tendency for bioacculmulation.

A total of 11 metabolites, in addition to the parent compound, were identified in the feces; the 

parent compound accounted for 96 to 99% of the administered radioactivity in the high dose 

group and 35 to 43% in the low dose group. No parent compound was found in the urine; 

urinary metabolites were not characterized. The identity of several fecal metabolites was 

confirmed by mass chromatography with synthetic standards. A pathway of metabolism was 

proposed based on these data. Metabolism proceeded primarily by oxidation of the three benzyl 

carbons, two methyl groups on the B-ring and an ethyl group on the A-ring to alcohols, 
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aldehydes or acids. The type of metabolite produced varies depending on the position oxidized 

and extent of oxidation. The butyl group on the quaternary nitrogen also can be cleaved (minor), 

but there has no fragmentation of the molecule between the benzyl rings.

No qualitative differences in metabolism were observed between sexes, when high or low dose 

groups were compared or when different labeled versions of the molecule were compared.

4.2.1 Dermal Absorption

In a dermal absorption study in rats (MRID# 42991510), 14C-RH5992 was prepared in a 

formulation of 24% a.i. and an end use concentration of 0.024% and administered to a 

group of male rats with a single dermal application of either the undiluted material 

(24% a.i., 6000 μg a.i./cm2, 24 mg total) or an aqueous dilution of the formulation 

(0.024% a.i., 6 μg a.i./cm2, 0.024 mg total) for 10 or 24 hours. Excreta were collected 

at various time intervals for 4 days and analyzed for 14C-label. After 4 days, the 

animals were killed and the skin application sites and remaining carcasses were 

analyzed for 14C-label. 

A total of 5% and 7% of the administered 14C-label was absorbed dermally in rats 

exposed to 24% 14C-RH-5992 formulation for 10 and 24 hours, respectively. 14C-label 

was presented in feces (0.8-1.4% of dose), urine (0.2-0.3% of dose), carcass (0.3-0.6% 

of dose), and skin (3-6% of dose) after 4 days. Total recovery of 14C-label in high dose 

group was 88-97% of administered dose. In comparison, a total of 22% and 26% of the 

administered 14C-label was absorbed dermally in rats exposed to 0.024% 14C-RH-5992 

in diluted formulation for 10 and 24 hours, respectively. 14C-label was presented in 

feces (3-7% of dose), urine (0.5-2% of dose), carcass (2-4% of dose), and skin (14-17% 

of dose) after 4 days. Total recovery of 14C-label in low dose group was 95% of 

administered dose. 

Although a dermal absorption study is available, since no dermal hazard has been 

identified for tebufenozide, a dermal endpoint was not selected for use in risk 

assessment. 

4.3 Toxicological Effects

Tebufenozide is an insecticide, an ecdysone agonist acting as a molting inhibitor, used

against (and highly specific for) lepidopteran species. Because the insect ecdysone nuclear

hormone receptor has no apparent mammalian genomic homolog, a similar mechanism for

toxicity does not exist for humans or other mammalian species. 

The toxic effects of tebufenozide in mammalian species arise primarily from 

methemoglobinemia associated with denaturation of hemoglobin and concomitant Heinz

body formation in erythrocytes, resulting in a more rapid turnover of red blood cells with
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increased hematopoiesis, splenic discoloration and other spleen effects. This type of

toxicity is often typical of compounds with a hydrazine moiety, and is consistent with the

structure of tebufenozide. The hematologic effects have been observed in all mammalian

species tested to date (rat, mouse, dog, and rabbit), with no indication of any significant

differences between sexes. There is no evidence that tebufenozide is neurotoxic, or that it

causes reproductive or developmental toxicity. There is no indication of increased 

susceptibility of fetuses or pups (effects occur above maternally toxic doses). There was 

no toxicity noted in a 21-day dermal toxicity study and no immunotoxicity was observed 

in immunotoxicity studies in both rats and mice.

Tebufenozide is classified as "not likely to be carcinogenic to humans" based on lack of 

evidence of carcinogenicity in rats and mice and no evidence of mutagenicity. Therefore, a

cancer risk assessment is not required.

Tebufenozide has low acute toxicity (Toxicity Category III or IV) by the oral, dermal, or 

inhalation route of exposure. It is not an eye or skin irritant, and is not a skin sensitizer.

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

HED has recommended that the required 10x Food Quality Protection Act (FQPA) Safety Factor 

(SF) be reduced to 1x for tebufenozide. The toxicology database is complete. There is no 

evidence of increased susceptibility, no concerns/residual uncertainties with regard to pre- and/or 

postnatal toxicity, and no concern for neurotoxicity. In addition, in using conservative 

assumptions regarding residues in food and modeled drinking water estimates, HED has 

overestimated the potential for exposure through food and water.

4.4.1 Completeness of the Toxicology Database

The toxicology database for tebufenozide is complete. The available toxicity database for 

tebufenozide is adequate to assess the qualitative or quantitative susceptibility in the young.

4.4.2 Evidence of Neurotoxicity

There was no evidence of neurotoxicity for tebufenozide. No neurotoxicity was seen in an acute 

neurotoxicity study in rats. In addition, the toxicology database does not reveal any evidence of 

neurotoxic clinical signs, changes in brain weight, or histopathology of the nervous system in 

any study with tebufenozide. Accordingly, the HASPOC determined that a subchronic 

neurotoxicity study is not required based on a weight-of-evidence approach considering all the 

available hazard information on tebufenozide (TXR# 0057075).
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4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The toxicology data on tebufenozide provides no indication of enhanced sensitivity of infants 

and children based on the results from developmental studies conducted with rats and rabbits as 

well as two-generation reproduction studies conducted with rats. 

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary and residential 

exposure analyses are conservative in nature. The dietary exposure assessment used tolerancelevel residues. The residential exposure assessment uses the 2012 Residential SOPs and is 

considered health-protective.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Acute Dietary Endpoint for the General Population including Females 13-49 years of Age: There

were no toxicological effects attributable to a single exposure (dose) observed in the oral

toxicity studies, including the developmental toxicity studies in rats and rabbits, where no

toxicity was seen at the limit dose (1000 mg/kg/day). Therefore, no endpoint/PoDs ( Point of 

Departure) were selected for this risk assessment.

Chronic Dietary Endpoint for the General Population: A co-critical 90-day dog feeding study 

(MRID# 42436223) and a 1-year dog study (MRID# 42931203-04) were selected with a PoD 

(NOAEL) of 2 mg/kg/day and a LOAEL of 8.7 mg/kg/day based on decreases in body weight 

gains, alterations in hematology parameters, changes in organ weights, and histopathological 

lesions in the bone, spleen, and liver. The 90-day dog feeding study with a NOAEL of 2.1 

mg/kg/day, taken in conjunction with the NOAEL of 1.8 mg/kg/day in the 1- year dog study,

indicates a lack of progression of toxicity for the period from 90-360 days. In essence, 1.8 

and 2.1 mg/kg/day are not different and can be rounded to 2 mg/kg/day. This dose, therefore, 

would be protective of the effects (decreases in body weight gains, organ weight changes, and 

alterations of the hematological and hematopoietic systems) seen at doses ranging from 8- 20

mg/kg/day in the subchronic and chronic dog studies. An UF of 100x (10x for interspecies 

extrapolation and 10x for intraspecies variation,) is applied to the PoD of 2 mg/kg/day to obtain a 

chronic reference dose (cRfD) of 0.02 mg/kg/day. The FQPA SF is reduced to 1X; therefore, 

the chronic population adjusted dose (cPAD) is 0.02 mg/kg/day.

Incidental Oral Exposure (Short-Term): The same co-critical dog studies described above (under 

chronic dietary endpoint) were selected for incidental oral exposure. HED has considered the 2-

generation reproduction study (MRID# 43797701) for the incidental oral exposure scenario since 

the offspring is the population (infants and children) of concern. However, this study was not 

selected because the toxic effects of concern (increased methemoglobinemia) were not measured 

in the offspring where the NOAEL was 12.6/14.6 mg/kg/day (M/F) and the LOAEL was 
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126.0/143.2 (M/F), based on a reduction in the body weights of the F1 and F2 pups after day 14 

of lactation. The PoD of 2.0 mg/kg/day from the dog studies was considered appropriate for 

incidental oral exposure scenario since the PoD was 60x lower than the offspring LOAEL and 

considered protective of the young from potential adverse hematological effects. An UF of 100x 

(10x for interspecies extrapolation, 10x for intraspecies variation, and 1x for FQPA factor) is 

applied.

Dermal Exposure (Short-, Intermediate-, and Long-Term): A 28-day dermal toxicity study in rats 

(MRID# 42991507) is available and shows no toxic effects on any test parameter including 

hematology; the NOAEL was 1000 mg/kg/day (the highest dose test, HDT). Since no toxicity 

was observed at the limit dose for dermal exposure and no developmental toxicity concern has 

been identified, a quantitative dermal risk assessment for dermal exposure is not necessary. 

Inhalation Exposure (short, Intermediated- and Long Term): With the exception of the acute 

inhalation study (Toxicity Category IV), no other inhalation study was available; therefore, an 

oral toxicity study was selected for the inhalation exposure scenario. The same co-critical dog 

studies previously described (under chronic dietary endpoint) were selected for inhalation 

exposure. Since an oral study was selected, the inhalation absorption rate of 100% was applied 

to the PoD. An UF of 100x (10x for interspecies extrapolation and 10x for intraspecies variation) 

is applied. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Under FQPA, when there are potential residential exposures to a pesticide, HED must aggregate 

exposures from the three routes of exposure: oral, dermal, and inhalation exposures.

Tebufenozide does not pose a dermal risk; therefore, quantification of dermal risk is not required. 

Oral and inhalation exposure can be combined since route specific inhalation data are not 

available, and inhalation toxicity is evaluated based on oral studies.

4.5.3 Cancer Classification and Risk Assessment Recommendation

The Hazard Identification Assessment Review Committee (HIARC) has classified tebufenozide

as "not likely to be carcinogenic to humans" based upon lack of evidence of carcinogenicity in

rats and mice (HIARC Memo, October 6, 2003). Therefore, a cancer risk assessment is not

required.
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4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment 

 Table.4.5.4 Toxicological Doses and Endpoints for Use in Tebufenozide 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

(All Populations)

No appropriate endpoint attributable to a single dose was identified in the toxicity database.

Chronic Dietary

(All Populations)

PoD = 2 mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

cRfD = 0.02

cPAD = 0.02 

mg/kg/day

MRID# 42436223, 42931203, 

42931204

90-day and 1-year Dog Studies (cocritical), LOAEL=8.7 mg/kg/day based 

on decreases in body weight gains, 

alterations in hematology parameters, 

changes in organ weights, and 

histopathological lesions in the bone, 

spleen, and liver.

Incidental Oral-

(Short-term)

PoD= 2.0 mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

Residental LOC

for MOE =100

MRID# 42436223, 42931203, 

42931204

90-day and 1-Year Dog Studies (cocritical), LOAEL=8.7 mg/kg/day based 

on decreases in body weight gains, 

alterations in hematology parameters, 

changes in organ weights, and 

histopathological lesions in the bone, 

spleen, and liver.

Dermal 

(All time period)

No dermal endpoint was selected based on a lack of systemic toxicity in the dermal study 

and no concern for susceptibility.

Inhalation 

(All time period)

Oral, PoD= 2.0 mg/kg/day

(inhalation toxicity assumed 

to be equivalent to oral 

toxicity 100%)

UFA = 10x

UFH = 10x

Occupational 

LOC for 

MOE = 100

MRID# 42436223, 42931203, 

42931204

90-day and 1-year Dog Studies (cocritical), LOAEL=8.7 mg/kg/day based 

on decreases in body weight gains, 

alterations in hematology parameters, 

changes in organ weights, and 

histopathological lesions in the bone, 

spleen, and liver.

Cancer (Oral, 

Dermal, Inhalation)

Classification: This chemical is classified as “not likely” to be a human carcinogen.

A cancer risk assessment is not required.

Point of Departure (POD) = data point or estimated point, 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). UFDB= Database uncertainty. FQPA SF = 

FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). LOC = level of concern. MOE= 

Margin of exposure.

4.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 
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susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision for tebufenozide, EPA 

reviewed these data and selected the most sensitive endpoints for relevant risk assessment 

scenarios from the existing hazard database. However, as required by FFDCA section 408(p), 

tebufenozide is subject to the endocrine screening part of the Endocrine Disruptor Screening 

Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of 

chemicals identified for EDSP screening was published on June 14, 20132 and includes some 

pesticides scheduled for registration review and chemicals found in water. Neither of these lists 

should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website. 3

5.0 Dietary Exposure and Risk Assessment 

5.1 Summary of Plant and Animal Metabolism Studies

 

2 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals.

3 http://www.epa.gov/endo/
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Plant

The qualitative nature of the residue in plants is adequately understood based on acceptable 

apple, sugar beet, and rice metabolism studies. The metabolism of tebufenozide was similar in 

each of the plants studied. The major metabolic pathway involved oxidation of the alkyl 

substituents of the aromatic rings of tebufenozide, primarily at the benzylic positions. The extent

of metabolism and degree of oxidation differed among the plants, and appeared to be a function 

of time. In all studies the parent compound, tebufenozide, comprised the majority of the total 

radioactive residue with various oxidative metabolites present, none in excess of 10% of the 

TRR. 

Livestock

The qualitative nature of the residues in animals is adequately understood based on acceptable 

ruminant and poultry metabolism studies. Two distinct metabolic pathways in ruminants were 

proposed by the registrant. The first involved multiple oxidative transformations of the three 

alkyl substituents present on the two phenyl rings while retaining the intact molecular skeleton of 

the parent compound. The second pathway involved metabolism of tebufenozide with resulting 

cleavage of the diacyl-t-butyl hydrazine backbone resulting in the formation of 4-ethylbenzoic 

and 3,5-dimethylbenozoic acids. These compounds were rapidly excreted through the urine, 

while the t-butyl group was metabolized to isopropanol and acetaldehyde with subsequent 

reincorporation into natural products. Similarly, two distinct metabolic pathways in poultry were 

proposed by the registrant. The first involved multiple oxidative transformations of the three 

alkyl substituents present on the two phenyl rings while retaining the intact molecular skeleton of 

the parent compound. The second pathway involved metabolism of tebufenozide with resulting 

cleavage of the diacyl-t-butyl hydrazine backbone resulting in the formation of 4-ethylbenzoic 

and 3,5-dimethylbenozoic acids. These compounds were rapidly excreted, while the t-butyl 

group was metabolized to isopropanol, acetaldehyde, and acetic acid with subsequent 

reincorporation into natural products.

Rotational Crops

The nature of residues in rotational crops are adequately understood based on metabolism of 

[

14C]tebufenozide in rotated collard, wheat, and turnip. The metabolic pathway proceeds in a 

manner similar to that in primary crops. The parent compound is oxidized to the primary A- and 

B-benzyl alcohols, which are conjugated or further oxidized. In rotated crops the oxidized 

metabolites and metabolite conjugates are somewhat more numerous than in primary crops. No 

cleavage of the molecule has been observed in any study.

5.1.1 Summary of Environmental Degradation

Parent tebufenozide is characterized as persistent to very persistent, with laboratory half-lives 

that range up to 179 days. Based upon limited data, tebufenozide’s major degradates (RH112651, RH-112703 and RH-96595) appear to be somewhat less persistent than the parent, with 

calculated half-lives for summed degradates ranging from 29.3 to 123.8 days in aerobic soil 

studies conducted using applied parent chemical (under which conditions the decay of degradates 
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is confounded by their simultaneous formation from the parent compound). Microbiallymediated degradation is the primary dissipation pathway for parent tebufenozide. Parent 

tebufenozide is stable to hydrolysis (pH 5-9) and is expected to be stable to aqueous photolysis 

based on its UV absorbance spectrum. The compound is also relatively stable to indirect 

photolysis in pond water (t1⁄2 = 67 days) and on soil (t1⁄2 = 98 days). No abiotic degradation data 

are available on any of the major degradates. In an aged soil column leaching study, the parent 

compound was present in four soils at approximately 52-71% of the applied after 30 days of 

aerobic aging. In terrestrial field studies, parent tebufenozide dissipated with half-lives of 39-53 

days. Bioaccumulation studies show that the bioconcentration factor (BCF) for tebufenozide in 

fish was 151X for whole-fish tissue and showed 90% depuration within 15 days. 

Tebufenozide is classified as moderately mobile, based on batch equilibrium Koc values (351-

894 mL/gOC) and using the Food and Agricultural Organization (FAO) soil mobility 

classification scheme. The carboxylic acid metabolite RH-112651 is classified as mobile to 

moderately mobile under the FAO scheme, based on its soil organic carbon-water partitioning 

coefficient (Koc) values (76-156 mL/gOC). A second carboxylic acid metabolite, RH-112703, 

and the ketone metabolite RH-96595, are also mobile, based on column leaching study results. 

Thus, the parent compound and all three major degradates have the potential to contaminate 

surface water via runoff from treated areas after application, through subsurface (e.g., tile drain) 

flow, and as a consequence of spray drift during application. Tebufenozide and its degradates 

also have the potential to leach to groundwater.

5.1.2 Residues of Concern Summary and Rationale

HED (Davis, D., D205283, 7/14/94 and Cutchin, W., D254956, 4/26/99) has concluded that,

based on plant, ruminant, and poultry metabolism data in consideration of the rat metabolism 

data, the residue of concern for tolerance expression and risk assessment are as outlined in Table 

5.1.2, below. For chemical identity and structures of metabolites of concern see Appendix C.

Table 5.1.2 Summary of Metabolites and Degradates to be Included in the Risk Assessment and 

Tolerance Expression for Tebufenozide

Matrix Residues included in Risk Assessment and Tolerance Expression

Plants Primary Crop Tebufenozide

Rotational Crop Tebufenozide + RH-1788

Livestock Ruminant and Milk Tebufenozide + RH-2703, RH-9886, Stearic acid conjugate of RH9886, RH-0282

Drinking Water

For Risk Assessment (not applicable for tolerance):

For ground water: tebufenozide and metabolite RH-112651; this is the 

major route of concern for drinking water at present

For surface waters: tebufenozide and the 3 metabolites, RH-112651, 

RH-112703, and RH-96595

Tebufenozide: benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)hydrazide

RH-1788: benzoic acid, 3,5-dimethyl-1-(1,1dimethylethyl)-2-[4-(1-hydroxyethyl)benzoyl]hydrazide

RH-2703: benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-((4-carboxymethyl)benzoyl)hydrazide)
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RH-9886: benzoic acid, 3-hydroxymethyl,5-methyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)hydrazide

RH-0282: benzoic acid, 3-hydroxymethyl-5-methyl-1-(1,1-dimethylethyl)-2-(4-(1-hydroxyethyl)benzoyl)hydrazide

RH-112651: IUPAC: (4-[N′-(3,5-dimethylbenzoyl)-N′-(1,1-dimethylethyl)hydrazinocarbonyl]benzoic acid

RH-112703: IUPAC: 4-[N′-(3,5-dimethylbenzoyl)-N′-(1,1-dimethylethyl)hydrazinocarbonyl]phenyl acetic acid

RH-96595: IUPAC: N-(1,1-dimethylethyl)-N′-(4-acetylbenzoyl)-3,5-dimethylbenzohydrazide

5.2 Food Residue Profile

Tebufenozide is registered on a wide range of agricultural commodities. Applications are 

conducted post-emergent and as foliar. Timing and frequency of application depends upon the 

severity of target pest infestation. Residues are most likely to be surface residues from direct 

application to crops and quantifiable residues in harvested crops are as likely. However, 

metabolism data suggests that tebufenozide translocates through the plant and residues have been 

found inside of fruits and different parts of other crops. Environmental fate data suggest that 

residues are persistent in soil. Rotational crop data confirm that residues are taken up from soil 

and distributed through the plant when grown in rotation with directly-treated crops. 

Additionally, based on animal metabolism data, residues of tebufenozide may end up in ruminant 

tissues and milk at low levels as a result of feeding livestock treated feed items.

5.3 Water Residue Profile

The residues of concern in drinking water was recently updated to include parent and metabolite 

RH-112651 for ground water and parent plus 3 metabolites, RH-112651, RH-112703, and RH96595 for surface water (M. Sahafeyan, D423156, 10/2/2014). However, for the sake of 

simplicity, saving time and resources, and being more protective, the Environmental Fate and 

Effect Division (EFED), used the Total Toxic Residues (TTR) approach, assuming presence of 

parent tebufenozide plus all three of its major metabolites, RH-112651, RH-112703 and RH9659 in both ground and surface water in its assessment of tebufenozide residues in drinking 

water.(J. N. Carleton, D423306, 2/10/15). In surface water, TTR was conservatively modeled as 

a single conceptual entity with Surface Water Concentration Calculator (SWCC) and with the 

Provisional Cranberry Model, using an aerobic soil half-life representing the degradation of 

parent plus all three degradates, and a KOC reflecting one of the (more mobile than parent) 

degradates, for which data were available. Unlike surface water, groundwater modeling (using 

PRZM-GW) was “refined,” by simulating parent and the three summed degradates as separate 

entities, then combining their resulting EDWCs to represent TTR. 

Table 5.3 contains results of the EFED’s maximum estimated drinking water concentration 

(EDWCs) for different use cites and application rates. The EDWCs values which were 

recommended for use in the human health dietary risk assessment are 279.3 μg/L for acute 

EDWC and 107.2 μg/L for chronic and cancer EDWCs. As there is not an acute toxic end point 

for tebufenozide, the maximum value of 107 ppb (0.107 ppm) modeled from fruiting vegetables, 

mint and ornamentals in Pesticide Root Zone Model for Groundwater (PRZM-GW) model was 

used for chronic analysis for all direct and indirect water in DEEM.
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Table 5.3 Summary of Maximum Estimated Drinking Water Concentration for Tebufenozide 

Drinking Water Source (Model 

Used)

Use (rates modeled) Maximum Estimated Drinking 

Water Concentration (EDWC) 

Acute 

(μg/L)

Chronic 

(μg/L)

Cancer 

(μg/L)

Surface water

(SWCC; LA sugarcane Std scenario, 

ground application for acute; FL

peppers Std scenario, ground 

application for chronic and cancer)

Sugarcane (4 apps at 0.25 

lbs a.i./A, 10 day RTI); 

fruiting vegetables (8 apps 

at 0.25 lbs a.i./A, 10 day 

RTI)

51.8 3.13 2.19

Surface water

(Provisional Cranberry Model)

Cranberries

(4 apps at 0.25 lbs a.i./A, 7 

day RTI)

279.3 105.8  ̄

Groundwater (PRZM-GW)

Fruiting vegetables, mint, 

ornamentals (WI sands) 

(2.0 lb a.i./A/yr: 8 apps at 

0.25 lbs a.i./A, 10 day RTI)

116.4 107.2 107.2

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The chronic analysis assumed tolerance-level residues for all foods, average percent crop treated 

(% CT), and DEEM 7.81 default processing factors. This analysis also includes 

harmonized/recommended tolerances shown in Table 2.2.2. Dietary risk estimates were 

determined considering exposures from food plus drinking water. The estimated drinking water 

concentration (EDWC) value was based on residues of concern in ground water (107 ppb) from 

application to fruiting vegetables, mint, and ornamentals. The assessment shows that the chronic 

dietary risk estimates for food plus drinking water are below HED’s level of concern (i.e., 

<100% of the cPAD). The resulting chronic dietary (food + drinking water) risk estimates 

utilized 18% of the cPAD for the general U.S. population and 37% of the cPAD for children 1-2 

years old population subgroups, the most highly exposed population subgroup. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

The following average percent crop treated estimates (from screening level usage analysis, 

SLUA, provided by BEAD for 2014) were used in the chronic dietary risk assessment for the 

following crops: blueberries: 10%; cabbage, caneberries, cauliflower, celery, lettuce, parsley, 

pecans, peppers, tomatoes and walnuts: each at 5%; almonds, broccoli, pistachios, spinach, and 

turnip roots: each at 2.5%; apples, cotton, grapes and pears: each at 1%. For other registered 

crops not listed in SLUA report, except orange, 100%CT were assumed; for orange and its 

related commodities, the primary analysis showed that orange input parameters in the dietary 

exposure model needed to be refined since it was the major contributor to the dietary risk. HED, 

in coordination with BEAD (e-mail communication with Don Atwood in BEAD, 9/22/2014),

used 1%CT, for orange and its related commodities in the dietary analysis.
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5.4.3 Acute Dietary Risk Assessment

An acute dietary-exposure and risk assessment was not conducted because toxic effects 

attributable to a single exposure to tebufenozide have not been identified.

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary risk estimates reported in Table 5.4.5 are for the general U.S. Population, all 

infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 13-19, females 13-49, 

adults 20-49, and adults 50-99 years. The resulting dietary risk estimates are not of concern; all 

are less than 100% of the cPAD. The most highly exposed population subgroups was children 1-

2 years old, utilizing 37% of the cPAD (see Table 5.4.5 below for a summary of the results). A 

chronic cancer dietary assessment was not conducted since it was determined that tebufenozide 

is not likely to be a human carcinogen.

5.4.5 Summary Table

Table 5.4.5. Summary of Dietary (Food + Drinking Water) Exposure and Risk for 

Tebufenozide1.

Population Subgroup

Chronic Dietary

Dietary Exposure

(mg/kg/day) % cPAD*

General U.S. Population 0.003704 18

All Infants (<1 year old) 0.006852 34

Children 1-2 years old 0.007460 37

Children 3-5 years old 0.005624 28

Children 6-12 years old 0.003728 19

Youth 13-19 years old 0.002755 14

Adults 20-49 years old 0.003466 17

Adults 50-99 years old 0.003582 18

Females 13-49 years old 0.003515 18 1 The most highly-exposed population subgroup is in bold.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

A residential handler assessment was conducted to account for use on ornamental plants in 

outdoor residential areas; ConfirmTM 2F includes ornamental use language that does not preclude 

residential consumers/applicators. Residential post-application exposure from the ornamental 

use was not assessed due to a lack of a dermal hazard identified. However, a post application

(incidental oral) non-occupational spray drift assessment has been conducted for tebufenozide. 
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6.1 Residential Handler Exposure/Risk Estimates

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct tasks related to applications and that 

exposures can vary depending on the specifics of each task. Residential handlers are addressed 

somewhat differently by HED as homeowners are assumed to complete all elements of an 

application without use of any protective equipment. A series of assumptions and exposure 

factors served as the basis for completing the residential handler risk assessments. Each 

assumption and factor is detailed below.

Scenarios and Application Rate: The quantitative exposure/risk assessment developed for 

residential handlers is based on the following scenarios: 

• Mixing/loading/applying liquids with manually pressurized handwand to outdoor garden 

and trees (0.005 lb ai/gallon) and (5.74 E-06 lb ai/ft2

); and

• Mixing/loading/applying liquids with backpack sprayers to garden and trees (0.005 lb 

ai/gallon) and (5.74 E-06 lb ai/ft2

).

Unit Exposures and Area Treated or Amount Handled: Unit exposure values and estimates for 

area treated or amount handled were taken from HED’s 2012 Residential SOPs4

. 

Exposure Duration: Residential handler exposure is expected to be short-term in duration. 

Intermediate-term exposures are not likely because of the intermittent nature of applications by 

homeowners.

Residential Handler Non-Cancer Exposure and Risk Estimate Equations: The algorithms used to 

estimate exposure and dose for residential handlers is according to the 2012 Residential SOPs5

.

Summary of Residential Handler Non-Cancer Exposure and Risk Estimates

Residential handler inhalation MOEs (MOE >100) were not of concern to HED and ranged from 

46,000 to 1,300,000.

Table 6.1.1 presents the residential handler non-cancer inhalation risk estimates of concern for 

application to outdoor ornamental plants including trees, shrubs, foliage plants, and flowers.

 

4 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html 5 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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Table 6.1.1 Residential Handler Non-cancer Exposure for Tebufenozide 

Scenario Formulation Application 

Equipment/Method Type Application Rate1 Units

Area Treated 

or Amount 

Handled 

Daily2

Units 

(per 

day)

Inhalation 

Unit 

Exposure 

(mg/lb ai)

Inhalation 

Absorbed Dose 

(mg/kg/day)3

Inhalation 

MOE4

Ornamentals Liquid 

concentrate

ManuallyPressurized

Handwand

Broadcast

/Spot/

0.005 lb ai/gal. 5 gal. 0.018 0.0000056 360,000

5.74E-06 lb ai/ft2 1,200 ft2 0.018 0.0000015 1,300,000

Backpack 5.74E-06 lb ai/ft2 1,200 ft2 0.14 0.000012 170,000

0.005 lb ai/gal. 5 gal. 0.14 0.000044 46,000

1 Based on registered or proposed label (EPA Reg. No.8033-111 Confirm 2F).

2 Based on HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).

3 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) ÷ BW (kg).

4 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).
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There are no recommended scenarios for inclusion in the aggregate risk assessment for children 

1< 2 years old because no dermal hazard was identified and there were no incidental oral 

scenarios identified based on the current tebufenozide use pattern in residential settings except 

for spray drift which is further discussed in Section 6.5. Therefore, the recommended scenario 

for the aggregate assessment includes adults only and is summarized in the Table 6.1.2. The 

recommended residential exposure for use in the adult aggregate assessment reflects inhalation 

exposure from applications to garden/ trees via backpack sprayer.

Table 6.1.2 Recommendations for the Residential Exposures for the Tebufenozide Aggregate Assessment.

Lifestage Exposure 

Scenario

Dose (mg/kg/day)1 MOE2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult Handler 

backpack to 

ornamentals

NA 0.000044 N/A 0.000044 NA 46,000 N/A 46,000

1. Dose = the highest dose for each applicable Lifestage of all residential scenarios assessed. 

2. MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ (1/Inhalation MOE)

6.2 Residential Post-application Exposure

A dermal residential post-application quantitative exposure assessment is not required from the 

ornamental use due to a lack of a dermal hazard identified. Per the Residential SOPs, a 

quantitative residential post-application inhalation exposure assessment was not performed for 

outdoor residential use. 

6.3 Combined Exposure

The combined residential exposure includes only the handler inhalation exposure since no 

dermal hazard is identified.

6.4 Residential Bystander Post-application Inhalation Exposure

A residential bystander post-application inhalation exposure assessment was not conducted at 

this time for tebufenozide based on the Agency’s current policies.

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby 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, and received the SAP’s final report on 

March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 
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During Registration Review process, the agency will continue to utilize this analysis to 

determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further 

analysis is required for tebufenozide.

6.5 Spray Drift

Off-target movement of pesticides can occur via many types of pathways and it is governed by a 

variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those it may directly contact. They can also deposit on 

surfaces where contact with residues can eventually lead to indirect exposures (e.g., children 

playing on lawns where residues have deposited next to treated fields). The potential risk 

estimates from these residues can be calculated using drift modeling onto 50 feet wide lawns 

coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based 

on a premise of compliant applications which, by definition, should not result in direct exposures 

to individuals because of existing label language and other regulatory requirements intended to 

prevent them.6

 Direct exposures would include inhalation of the spray plume or being sprayed 

directly. Rather, the exposures addressed here are thought to occur indirectly through contact 

with impacted areas, such as residential lawns, when compliant applications are conducted. 

Given this premise, exposures for children (1 < 2 years old) and adults - who have contact with 

turf where residues are assumed to have deposited via spray drift thus resulting in an indirect 

exposure - are the focus of this analysis analogous to how exposures to turf products are 

considered in risk assessment. 

In order to evaluate the drift potential and associated risks, an approach based on drift modeling 

coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, 

a residential turf assessment based on exposure to deposited residues has been completed to 

address drift from the agricultural applications of tebufenozide. In the spray drift scenario, the 

deposited residue value was determined based on the amount of spray drift that may occur at 

varying distances from the edge of the treated field using the AgDRIFT (v2.1.1) model and the 

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift Policy. Once the deposited residue values were determined, the remainder of the 

spray drift assessment was based on the algorithms and input values specified in the recently 

revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs). 

A screening-level approach was developed based on the use of the AgDRIFT model in situations 

where specific label guidance that defines application parameters is not available.7,8 AgDRIFT 

is appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and 

groundboom sprayers. When AgDRIFT was developed, a series of screening values (i.e., the 

 

6 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.

7http://www.agdrift.com/ 

8 Note that for many cases the scenarios outlined in the screening approach represent actual use practice so risk assessors should 

be aware and characterize these appropriately.
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Tier 1 option) were incorporated into the model and represent each equipment type and use 

under varied conditions. The screening options specifically recommended in this methodology 

were selected because they are plausible and represent a reasonable upper bound level of drift for 

common application methods in agriculture. These screening options are consistent with how 

spray drift is considered in a number of ecological risk assessments and in the process used to 

develop drinking water concentrations used for risk assessment. In all cases, each scenario is to 

be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides are 

not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are 

not allowed). 

In many cases, risks are of concern when the screening level estimates for spray drift are used as 

the basis for the analysis. In order to account for this issue and to provide additional risk 

management options additional spray drift deposition fractions were also considered. These drift 

estimates represent plausible options for pesticide labels. 

6.5.1 Combined Risk Estimates from Lawn Deposition Adjacent to Applications

The spray drift risk estimates are based on an estimated deposited residue concentration as a 

result of the screening level agricultural application scenarios. Tebufenozide can be applied via 

groundboom, airblast, and aerial equipment to the various crops listed in the Table 3.2. The 

recommended drift scenario screening level options are listed below:

• Groundboom applications are based on the AgDRIFT option for high boom height and 

using very fine to fine spray type using the 90th percentile results. 

• Orchard airblast applications are based on the AgDRIFT option for Sparse 

(Young/Dormant) tree canopies.

• Aerial applications are based on the use of AgDRIFT Tier 1 aerial option for a fine to 

medium spray type and a series of other parameters which will be described in more 

detail below (e.g., wind vector assumed to be 10 mph in a downwind direction for entire 

application/drift event).9

Dermal risk estimates were not calculated for adults and children because dermal hazard was not 

identified. Incidental oral risk estimates for children 1 to <2 years old were assessed to account 

for hand to mouth behavior on turf adjacent to an application site. The total applicable level of 

concern is 100, so MOEs < 100 represent risk estimates of concern. Children’s (1 to <2 year 

old) incidental oral risk estimates ranged from 1,100 to 2,800 at edge of field, and therefore are

not of concern. Risk estimates are presented in Appendix D Table D.1.

 

9 AgDRIFT allows for consideration of even finer spray patterns characterized as very fine to fine. However, this spray pattern 

was not selected as the screening basis since it is used less commonly for most agriculture including this use pattern for 

tebufenozide.
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7.0 Aggregate Exposure and Risk Assessment 

In accordance with the FQPA, when there are potential residential exposures to a pesticide, 

aggregate risk assessment must consider exposures from three major routes: oral, dermal, and 

inhalation. Additionally, aggregate exposure should consider exposure across both the dietary 

and residential pathways. 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 Aggregate Risk 

An acute dietary exposure and risk assessment was not conducted for tebufenozide because toxic 

effects attributable to a single exposure to tebufenozide have not been identified.

7.2 Short- Term Aggregate Risk

Short term aggregate exposure takes into account residential exposure plus average exposure 

levels to food and water (considered to be a background exposure level). Because endpoints for 

relevant routes of exposure (inhalation, and oral endpoints) are based on the same effects (90-

day and 1-Year Dog Studies (co-critical)) and same LOC (100x), the aggregate risk was 

calculated by summing the exposures from different routes and comparing it to the common 

endpoint (2 mg/kg/day) to get the aggregate MOE. Based on the use pattern, residential shortterm exposure to children is not expected; therefore, a short-term aggregate risk was conducted 

for adults only. From Table 7.2 below, the aggregate MOE for adults is 550 which is above the 

LOC; therefore, the short-term aggregate risk for tebufenozide is not of concern.

Table 7.2 Short-Term Aggregate Risk Calculations for Tebufenozide

Population

Short-Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adults 2 100 0.02 0.003582 0.000044 0.003626 550

1 LOC for all relevant routes is 100x (10x for inter- and 10x for intra-species uncertainty factor); see Table 4.5.4. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]; for tebufenozide it is inhalation exposure only for Handler 

backpack to ornamentals; See Table 6.1.2. 4 Total Exposure = Avg Food & Water Exposure + Residential Exposure; see Table 5.4.5. 5 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)]
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7.3 Intermediate-Term Aggregate Risk 

There are no residential use scenarios that would result in potential intermediate-term exposure 

to tebufenozide; therefore, an intermediate-term aggregate risk assessment is not required.

7.4 Long-Term, Non-Cancer, Aggregate Risk

There are no residential use scenarios that would result in potential long-term (chronic) 

exposure; therefore, the chronic aggregate risk is equivalent to the chronic dietary (food and 

water) risk, and as shown in Section 5.4.4, there are no risks of concern.

7.5 Cancer Aggregate Risk

The HIARC has classified tebufenozide as "not likely to be carcinogenic to humans" based upon 

lack of evidence of carcinogenicity in rats and mice (HIARC Memo, October 6, 2003). 

Therefore, a cancer risk assessment is not required.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to tebufenozide and any other substances and tebufenozide does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that tebufenozide has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short-/Intermediate Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Representative crops were selected to encompass crops with same exposure scenarios and 

application rates. The category “ornamentals” includes nurseries, Christmas tree farms, outdoor 
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landscape, recreational areas, and institutional grounds. Airblast applications to tree nuts will 

encompass the lower application rate orchard crops such as apples and pome fruit. Cotton risk 

estimates represent high acreage agricultural crops such as canola and sugarcane. Fruiting 

vegetable rates and scenarios cover selected variety of registered field crops such as berries and 

cole crops. Based on the anticipated use patterns and current labeling, types of equipment and 

techniques that can potentially be used, occupational handler exposure is expected from the 

proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is 

based on the following scenarios:

• Mixing/loading EC/WSP for aerial application;

• Mixing/loading EC/WSP for groundboom application;

• Mixing/loading EC/WSP for airblast application;

• Mixing/loading EC/WSP for chemigation;

• Applying sprays by aerial application;

• Applying sprays by groundboom application;

• Applying sprays by airblast application;

• Mixing/loading/applying sprays for mechanically pressurized handgun application;

• Mixing/loading/applying sprays for manually pressurized handwand application; 

• Mixing/loading/applying sprays for backpack application; and 

• Flaggers from aerial application of sprays.

HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months 

as intermediate-term. Exposure duration is determined by many things, including the exposed 

population, the use site, the pest pressure triggering the use of the pesticide, and the cultural 

practices surrounding that use site. For most agricultural uses, it is reasonable to believe that 

occupational handlers will not apply the same chemical every day for more than a one-month 

time frame; however, there may be a large agribusiness and/or commercial applicators who may 

apply a product over a period of weeks (e.g., completing multiple applications for multiple 

clients within a region). Occupational exposure to tebufenozide is most likely to be intermittent 

and short-term given the use pattern. Most applications are suggested at onslaught of infestation. 

However as stated previously it is possible that a commercial applicator could apply the product 

over a period of weeks within a region. Therefore, based on the proposed uses short-term and 

intermediate-term exposures were assessed for tebufenozide. The toxicological PODs selected 

are protective of both exposure durations. 

HED conducted an occupational handler exposure and risk assessment for the inhalation route of 

exposure only as there was no dermal hazard identified. Estimates of inhalation exposure were 

calculated for various levels of PPE. Short- and intermediate-term inhalation occupational 

MOEs for mixers/loaders and applicators range from 1,100 to 73,000; see Appendix E. Results 

are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved 

shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline 

with various levels of PPE as necessary (e.g., , respirator, etc.) and engineering control. 

Tebufenozide labels currently include baseline attire (long-sleeve shirt, long pants, shoes, and 

socks) with the addition of waterproof gloves. Based on the assessment of registered uses, there 

are no risk estimates of concern (i.e., all inhalation MOEs are >100). 
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The Agency matches quantitative occupational exposure assessment with appropriate 

characterization of exposure potential. While HED presents quantitative risk estimates for 

human flaggers where appropriate, agricultural aviation has changed dramatically over the past 

two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of 

their membership, the use of GPS for swath guidance in agricultural aviation has grown steadily 

from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide 

applications has decreased steadily from ~15% in the late 1990’s to only 1% in the most recent 

(2012) NAAA survey. The Agency will continue to monitor all available information sources to 

best assess and characterize the exposure potential for human flaggers in agricultural aerial 

applications.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for 

exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, 

and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, 

pilots are not required to wear protective gloves for the duration of the application. With this 

level of protection, there are no risk estimates of concern for applicators.

9.2 Short-/Intermediate-term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1 Dermal Post-application Risk

A post-application dermal assessment has not been conducted for tebufenozide due to the lack of 

dermal hazard endpoint. At this time, a dislodgeable foliar residue (DFR) study is not required 

for tebufenozide. Tebufenozide can retain the 4-hr REI based on the low acute toxicity and 

because it is not a sensitizer. There are no reports of hypersensitivity, incident data, or adverse 

health effects associated with the end use product, e.g., carcinogenicity, developmental effects.

9.2.2 Inhalation Post-application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for tebufenozide at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and low vapor pressure (2 x 10-8 mm hg at 25 degrees 
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Celsius). However, there are multiple potential sources of post-application inhalation exposure 

for individuals performing post-application activities in previously treated fields. These potential 

sources include: volatilization of pesticides and resuspension of dusts and/or particulates that 

contain pesticides. 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, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for tebufenozide. In addition, the Agency is continuing to evaluate the available postapplication inhalation exposure data generated by the Agricultural Reentry Task Force (ARTF). 

Given these two efforts, the Agency will continue to identify the need for and, subsequently, the 

way to incorporate occupational post-application inhalation exposure into the agency's risk 

assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed for tebufenozide, an inhalation exposure assessment was performed for 

occupational/commercial handlers. Handler exposure resulting from application of pesticides 

outdoors is likely to result in higher exposure than post-application exposure. Therefore, it is 

expected that these handler inhalation exposure estimates would be protective of most 

occupational post-application inhalation exposure scenarios.

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and 

mechanical harvesting is another potential source of post-application inhalation 

exposure. However, the airblast applicator scenario is believed to represent a reasonable worst 

case surrogate estimate of post-application inhalation exposure during these dusty mechanical 

harvesting activities. The non-cancer inhalation risk estimate for commercial airblast application 

is not of concern (i.e., MOE > 100).
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10.0 References

Memoranda Relevant to Registration Review for Tebufenozide

Author DP or TXR 

Barcode Date Title

B. Bobowiec D422853 July 2015 Tebufenozide. Occupational and Residential Assessment to 

Support Registration Review

J. Redden D270019 08/23/2004

ADDENDUM TO TEBUFENOZIDE: Human Health Risk 

Assessment for Proposed Uses in/on Grapes and Tuberous 

and Corm Vegetables (Except Potatoes), Subgroup 1-D 

(D285364 and D285366). This revision considers 

Tebufenozide on Citrus (Crop Group 10), Rotational Crops 

(Legume Foliage and Cereal Grain Foliage; Wheat/Barley 

and Soybean), and grass and Non-Grass Animal Feed.

D. Atwood NA 11/30/2011 BEAD Chemical Profile for Registration Review 

Tebufenozide

M. Dow D298756 02/13/2004

Tebufenozide: exposure/Risk Assessment for the Proposed 

Use of Tebufenozide on Grapes and Tuberous and Corn 

Vegetables (Except Potato) Crop Subgroup 1D.

S. Recore TXR 0055187

D363543 05/21/2009

Tebufenozide: Agency’s Responses to Registrant’s 

Requests for Waivers of Toxicity Studies Required in the 

Human Health Risk Assessment Scoping Document 

(D352995).

S. Recore D352995 08/28/2008 Tebufenozide: Human Health Assessment Scoping 

Document in Support of Registration Review

U. Habiba TXR # 0057075 11/18/2014

Tebufenozide: Summary of Hazard and Science Policy 

Council (HASPOC) Meeting of October 9, 2014: 

Recommendations on the requirements of subchronic 

inhalation and subchronic neurotoxicity studies

S. Recore D422657 9/23/14 Tebufenozide: Tier I Review of Human Incidents for 

Preliminary Risk

D. Davis D205283 7/15/94 Tebufenozide: MARC Decision Memorandum

M. Sahafeyan D423156 10/2/2014 Tebufenozide: Residues of Concern in Drinking Water

M. Sahafeyan D414536 9/9/2015

Tebufenozide: Chronic Dietary (Food and Drinking Water) 

Exposure and Risk Assessment to Support Registration 

Review.

Y. Donovan D239395 6/21/99

Tebufenozide-- Proposal for Tolerances on Sugarcane and 

Sugarcane Processed Commodities. Evaluation of 

Analytical Method and Magnitude of the Residue Data.

Y. Qian ACB Project # 

B15-05 6/17/2015

Tebufenozide and its metabolite in/on Rotational crops; 

MRID 458932-01. Petition Method Validation (PMV) 

Review.
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Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The toxicological data requirements (40CFR §158.340) for tebufenozide are in Table A.1, below. 

Use of the new guideline numbers does not imply that the new (1998) guideline protocols were 

used. 

Table A.1 Toxicology Data Requirements for Tebufenozide

Test Technical

Required Conducted

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 (non-rodent)

870.3200 21/28-Day Dermal

870.3250 90-Day Dermal

870.3465 90-Day Inhalation

yes

yes

yes

no

yes

yes

yes

yes

no

waived1

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (non-rodent)

870.3800 Reproduction

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (non-rodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation (bacterial)

870.5300 Mutagenicity—Gene Mutation (mammalian)

870.5375 Mutagenicity—Structural Chromosomal Aberrations

870.5395 Mutagenicity—Other Genotoxic Effects 

870.5500 Mutagenicity—Other Genotoxic Effects

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery (rat)

870.6300 Developmental Neurotoxicity

no

no

yes

yes

no

no

no

yes

waived1

no

870.7485 General Metabolism

870.7600 Dermal Penetration 

870.7800 Immunotoxicity

yes

no

yes

yes

yes

yes

1

The HASPOC determined that a subchronic neurotoxicity study and a subchronic inhalation study could be

waived with additional mitigation on registered label (TXR# 0057075, November 18, 2014). 
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A.2 Toxicity Profiles

Table A.2 Toxicology Profile for Tebufenozide 

Type of Study/

Guideline

Study Title MRID Results

Acute Toxicity Profile

81-1

870.1000

Acute oral LD50, Rat 42436211 (1991)

Acceptable

LD50 > 5000 mg/kg 

Toxicity Category IV

81-2

870.1200

Acute dermal LD50, Rat 42436214 (1991)

Acceptable

LD50 > 5000 mg/kg

Toxicity Category IV

81-3

870.1300

Acute inhalation toxicity, Rat 42436215 (1992)

Acceptable

LC50 > 4.4 mg/L

Toxicity Category IV

81-4

870.2400

Primary eye irritation, Rabbit 42436216 (1988)

Acceptable

Corneal haze in 1/6 at 24 & 48hrs.

Toxicity Category III

81-5

870.2500

Primary dermal irritation, Rabbit 42459802 (1988)

Acceptable

No irritation

Toxicity Category IV

81-6

870.2600

Dermal sensitization, Guinea Pig 42436217 (1992)

Acceptable

Buehler 3-induction protocol; olive oil as 

vehicle; no sensitization 

Not a sensitizer

Subchronic, Chronic and Other Toxicity Profile

82-1 870.3100 13-Week oral toxicity (rat)

0, 20, 200, 2000, 20000

ppm

Equivalent to 0, 1.3, 13.1, 132.9, 

1330 mg/kg/day in males and 0, 

1.6, 15.6, 155.2, 1651 mg/kg/day 

in females

42436219 (1991)

42436218 (1992)

Range-finding

Acceptable - Guideline

Systemic Toxicity NOAEL = 13.1/15.6 

mg/kg/day (M/F)

Systemic Toxicity LOAEL = 132.9/155.2 

mg/kg/day (M/F) based on depression of 

body weight and body weight gain in both 

sexes, there a depression of the RBCs, HGB 

and MCHC and an elevation of the MCV in 

both sexes; a depressed myeloid/erythroid 

ratio and an increased reticulocyte count in 

females. 

82-1 870.3100 13-Week oral toxicity (mouse)

0, 20, 200, 2000, 20000

ppm

Equivalent to 0, 3.4, 35.3, 339, 

3332 mg/kg/day in males and 0, 

4.0, 44.7, 431, 4233 mg/kg/day in 

females

42436221 (1991)

42436220 (1992)

Range-finding

Acceptable - Guideline

Systemic Toxicity NOAEL = 3.4/4.0 

mg/kg/day (M/F)

Systemic Toxicity LOAEL = 35.3/44.7 

mg/kg/day (M/F) based on decreases in the 

body weight gain in male (no effect in 

females). A dose related splenic 

extramedullary hematopoiesis and pigment 

deposition (containing iron) as well as the 

liver and kidney also showed pigment 

deposition (containing iron) in both sexes 

starting at 339/431 mg/kg/day. 

82-1 870.3100 13-Week oral toxicity (dog)

0, 50, 500, 5000 ppm

Equivalent to 0, 2.1, 20.1, 202 

mg/kg/day in males and 0, 2.1, 

21,4, 202 mg/kg/day in females

42436223 (1992)

42436222 (1990)

Range-finding

Acceptable - Guideline

Systemic Toxicity NOAEL = 2.1/2.1 (M/F) 

mg/kg/day; LOAEL = 20.1/21.4 (M/F) 

mg/kg/day based on decreases in the rate of 

body weight gain in females at 21.4 

mg/kg/day and above and males at 202 

mg/kg/day, hematological findings 

(peripheral, blood), presented as a minimal 

depression of HGB, RBC, HCT and a 
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Table A.2 Toxicology Profile for Tebufenozide 

Type of Study/

Guideline

Study Title MRID Results

minimal elevation of MCV, MCH and 

platelets. 

82-2

870.3200

21-Day dermal toxicity (rat)

Technical 96.1% product RH75,992 at 1,000 mg/kg/day 

(Limit-Dose)

Formulation (23.1% a.i.) product 

RH-755,992 2F at 0, 62.5, 250, or 

1,000 mg/kg/day

6 hours/day, 5 days/week for 21 

days. 

42991507 (1993)

Acceptable -Guideline

Technical and Formulation

Systemic Toxicity NOAEL = 1000 

mg/kg/day, LOAEL not established

Dermal Toxicity NOAEL = 1000 

mg/kg/day, LOAEL not established.

83-3

870.3700

Prenatal developmental in (rat)

0, 50, 250, 1000 mg/kg/day

42436225 (1991) 

42436224 (1992)

Range-finding

Acceptable - Guideline

Maternal Systemic Toxicity NOAEL = 

1000 mg/kg/day, LOAEL not established.

Developmental Toxicity NOAEL = 1000 

mg/kg/day, LOAEL not established.

83-3

870.3700

Prenatal developmental in (rabbit)

0, 50, 250, 1000 mg/kg/day 

42436226 (1991) 

range-finding

42436227 (1992)

Acceptable - Guideline

Maternal Systemic Toxicity NOAEL = 

1000 mg/kg/day, LOAEL = not established.

Developmental Toxicity NOAEL = 1000 

mg/kg/day, LOAEL = not established.

83-4

870.3800

Reproduction and fertility effects 

(rat)

0, 10, 150, 2000 ppm 

Equivalent to 0, 0.8, 11.5, 154.8 

mg/kg/day for males and 0, 0.9, 

12.8, 171.1 mg/kg/day for 

females

42931207 (1993)

Acceptable– Guideline

(Note: The HIARC 

expressed more 

confidence in the 

findings of 1995 2-gen 

rat study than this 

1993 study) 

Parental Systemic Toxicity NOAEL = 

0.8/0.9 (M/F) mg/kg/day.

Parental Systemic LOAEL = 11.5/12.8 

(M/F) mg/kg/day based on an increase in 

both incidence and severity of splenic 

pigmentation in both generations.

Reproductive Toxicity NOAEL = 11.5/12.8 

(M/F) mg/kg/day. 

Reproductive Toxicity LOAEL =

154.8/171.2 (M/F) mg/kg/day based on a 

slight increase in the number of pregnant 

females of both generations that either did 

not deliver (P and Fl dams) or experienced 

great difficulty during delivery and, 

therefore, had to be sacrificed (Fl dams). 

Also in Fl dams, the length of gestation 

increased significantly and the number of 

implantation sites decreased significantly. 

The number of pups per litter decreased on 

LD4 to 90% of the controls for the first 

generation and on LDs 0 and 4 (80%) for 

the second generation.

Offspring/Developmental Toxicity NOAEL 

= 154.8/171.2 (M/F) mg/kg/day. 
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Table A.2 Toxicology Profile for Tebufenozide 

Type of Study/

Guideline

Study Title MRID Results

Offspring/Developmental Toxicity LOAEL 

not established.

83-4

870.3800

Reproduction and fertility effects 

(rat)

0, 25, 200 and 2000 ppm

Equivalent to 0, 1.6, 12.6 and 126 

mg/kg/day for males and 0, 1.8, 

14.6 and 143.2 mg/kg/day for 

females

43797701 (1995)

Acceptable - Guideline

Parental Systemic Toxicity NOAEL = 

1.6/1.8 (M/F) mg/kg/day.

Parental Systemic LOAEL = 12.6/14.6 

(M/F) mg/kg/day based on splenic effects 

(increased incidence of splenic congestion 

in males, increased incidence of extramedullary hematopoiesis in females).

Reproductive Toxicity NOAEL 

=126.0/143.2 (M/F) mg/kg/day (HDT). 

Reproductive Toxicity LOAEL was not 

established.

Offspring Toxicity NOAEL = 12.6/14.6 

(M/F) mg/kg/day. 

Offspring/Developmental Toxicity LOAEL 

= 126.0/143.2 (M/F) mg/kg/day based on a 

reduction in the body weights of the F1 and 

F2 pups after day 14 of lactation.

83-1

870.4100

Chronic Toxicity (Dog) – 1 Year

0, 15, 50, 250, 1500 ppm

Equivalent to 0, 0.5, 1.8, 8.7, 52.7 

mg/kg/day in males and 0, 0.6, 

1.9, 8.9, 55.8 mg/kg/day in 

females

42931203 (1992)

42931204 (1992)

photomicrographs

Acceptable - Guideline

Systemic Toxicity NOAEL = 1.8/1.9 (M/F) 

mg/kg/day and LOAEL = 8.7/8.9 (M/F) 

mg/kg/day based on males showing 

decreases in body weight gains, both sexes 

exhibited decreases in RBC, HCT and 

HGB; increases in Heinz bodies, 

methemoglobin, MCV, MCH, reticulocyte, 

platelet, plasma total bilirubin, spleen 

weight and spleen/body weight ratio and 

liver weight and liver/body weight ratio. 

Hematopoiesis and sinusoidal engorgement 

occurred in the spleen and hyperplasia 

occurred in the marrow of the femur and 

sternum.

83-2

870.4200

Carcinogenicity (mouse) -

18 Months

0, 5, 50, 500 or 1000 ppm

Equivalent to 0, 0.8, 7.8, 77.9, 

154.9 mg/kg/day in males and 0, 

0.9, 9.4, 94.3, 185.5 in females

42931206 (1992)

Acceptable - Guideline

Systemic Toxicity NOAEL = 7.8/9.4 

mg/kg/day (M/F)

Systemic Toxicity LOAEL = 77.9/94.3

mg/kg/day (M/F) based on splenic effects 

(increased incidences of moderate and 

moderately severe splenic pigmentation and 

slight but not statistically significant 

increases in methemoglobinemia in both 

sexes and reduced survival in males).

No evidence of carcinogenicity.

83-5

870.4300

Combined Chronic 

Toxicity/Carcinogenicity (rat) – 2 

Years

0, 10, 100, 1000, 2000 ppm 

42931208 (1992)

42931209 (1992)

Photomicrographs

Acceptable - Guideline

Systemic Toxicity NOAEL = 5/6 mg/kg/day 

(M/F), and LOAEL = 48/61 mg/kg/day 

(M/F) based on decreases in body weight 

and body weight gains in both sexes, 

increased splenic pigmentation and 

hemolytic anemia in both sexes, and effects 

on a number of hematological parameters, 
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Table A.2 Toxicology Profile for Tebufenozide 

Type of Study/

Guideline

Study Title MRID Results

Equivalent to 0, 0.5, 5, 48, 97 

mg/kg/day in males and 0, 0.6, 6, 

61, 125 mg/kg/day in females

particularly during the first year of the 

study.

No evidence of carcinogenicity.

84-2

870.5100

Gene Mutation 

(Ames Assay) 42436228 (1991)

Unacceptable -

upgradeable 

Negative

84-2

870.5100

Gene Mutation 

(Ames Assay) 42436229 (1992)

Unacceptable 

Study flaws

84-2

870.5100

Gene Mutation 

(Ames Assay) 42931210 (1988)

Acceptable

Negative

84-2

870.5100

Gene Mutation 

(Ames Assay) 43280104 (1994)

Acceptable

Negative

84-2

870.5100

Gene Mutation 

(E-Coli assay) 43003501 (1992)

Unacceptable but 

supports 42931210

Negative

84-2

870.5375

CHO Assay 42436230 (1990)

Acceptable Negative

84-2

870.5375

CHO Assay 42459803 (1988)

Acceptable Negative

84-2

870.5395

Micronucleus Assay 42436231 (1992) 

Acceptable

Negative 

84-2 870.5550 Unscheduled DNA Synthesis 4243632 (1992) 

Acceptable

Negative

870.6200 Acute neurotoxicity

0, 500, 1000, 2000 mg/kg 43781706 (1991)

Acceptable/ guideline

No neurotoxicity was observed. 

NOAEL=2000 mg/kg.

870.7800 Immunotoxicity (rats)

0, 2.2/2/5, 18.5/22, 150.8/162.9 

mg/kg/day (M/F)

48533006 (2011)

Acceptable/guideline

No Immunotoxicity

NOAEL=150.8/162.9 mg/kg/day (M/F)

870.7800 Immunotoxicity (mice)

0, 5.0/6.2, 41.4/50.3, 316.3/385.3 

mg/kg/day (M/F)

48533005 (2011)

Acceptable/guideline

No Immunotoxicity

NOAEL= 316.3/385.3 mg/kg/day (M/F)

85-1

870.7485

Metabolism and 

Pharmacokinetics (rat)

Single oral dose 3 or 250 mg/kg

Repeated dose 30 ppm (diet) for 

14 days

42436233 (1991)

Single oral dose –

distribution

42931211 (1992)

Pharmacokinetics

42931212 (1992)

Supplement

42931213 (1993)

The extent of absorption was not 

established, although absorption and 

excretion was rapid. The majority of the 

radio-label was excreted in the feces within 

24 hours. There was no tendency towards 

bioaccumulation. Metabolites were 

identified. 
Tebufenozide Human Health Risk Assessment DP No. 414533

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Table A.2 Toxicology Profile for Tebufenozide 

Type of Study/

Guideline

Study Title MRID Results

Supplement

42991508 (1992)

Biliary excretion

42991509 (1993)

Supplement 

Acceptable

Biliary excretion study yield a similar 

metabolic profile to the oral study.

A higher level of metabolism was noted in 

the repeated dose dietary study.

85-2

870.7600

Dermal penetration (rat)

24% and 0.024% formulation

42991510 (1993) 

Acceptable

Following dermal administration of 

24% 14C-RH-5992 formulation to male rats, 

5% and 7% was absorbed for 10 and 24 hr 

exposure, respectively.

Dermal administration of 0.024% 14C-RH5992 formulation resulted in 22% and 26% 

absorption for 10 and 24 hr exposure, 

respectively.

Blood Recovery in dogs

To evaluate the reversibility of 

blood toxicity of RH- 5992, 4 

dogs per dose received either 0 or 

1500 (450 mg/day) RH5992 in their diets for 6 weeks, 

followed by a 4-week recovery 

period.

Histological examinations were 

performed prior to treatment 

(week 0) at the end of treatment 

(week 6) and after recovery 

periods of 2 weeks (week 8) and 4 

weeks (week 10).

43003502 (1992)

Acceptable – Non 

guideline

After 2 weeks of treatment, hemoglobin and 

erythrocyte counts were significantly 

decreased and mean corpuscular volume, 

platelet and reticulocyte counts were 

significantly increased in the blood of the 

dogs. There was also an increased (although 

not statistically significant) of 

methemoglobin. These results are indicative 

of a toxic anemia. Within 4 weeks of 

cessation of treatment, all hematological 

values were similar to controls, i.e. dogs 

recovered from the RB-5992 induced 

anemia.
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Appendix B. International Tolerances 

Table B.1 Summary of US and International Tolerances and Maximum Residue Limits

US Canada Mexico Codex

Residue Definition:

40CFR§180.482

tebufenozide, or benzoic acid, 3,5-

dimethyl-1-(1,1-dimethylethyl)-2-(4-

ethylbenzoyl)hydrazide

3,5-dimethylbenzoic 

acid

1-(1,1-dimethylethyl)-

2-(4-

ethylbenzoyl)hydrazide

tebufenozide

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

Commodity US Canada Mexico Codex

Almond, hulls 25 30

Apple, pomace 3.0

Apple 1.0 1 1 pome fruits

Berry group 13 3.0 3 (Blueberries)

2 (Raspberries, red, black)

Brassica, head and stem, 

subgroup 5A 5.0 0.5 (Broccoli)5 (Cabbages, head)

Brassica, leafy greens, subgroup 

5B 10.0 10 leafy vegetables

Canola, refined oil 4.0

Canola, seed 2.0 2 (Rape seed)

Citrus, oil 15.0

Cotton 1.5

Cotton, gin byproducts 30

Cranberry 1.0 1 0.5

Fruit, citrus, group 10 0.80 2 (excluding kumquats)

Fruit, pome 1.5 1 (Apples)

1 (Pears)

1

Grape 3.0 0.5 2

Kiwifruit1 0.5 0.5 0.5

Leaf petioles subgroup 4B 2.0

Leafy greens subgroup 4A 10.0 6 (Lettuce) 10 leafy vegetables

Peppermint, tops 10.0 20 (Mint)

Spearmint, tops 10.0 20 (Mint)

Tree nut crop group including 

pistachio 0.1 0.05 (Almonds, walnuts0.01* (Pecan)

Turnip, greens 9.0

Turnip, roots 0.3

Vegetable, fruiting, group 8 1.0

0.2 (African 

eggplants), eggplants, 

pea eggplants, peppers, 

scarlet eggplants)

2 (Tomatoes)

1 (Tomato)

1 (Pepper)

Vegetable, tuberous and corm, 

except potato, subgroup 1D 0.015

Walnut 0.1 0.05

MRLs with NO US Equivalent

Avocado - - 1

Nectarine - - 0.5

Peach - - 0.5

Peppers, Chili dried - - 10
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Table B.1 Summary of US and International Tolerances and Maximum Residue Limits

US Canada Mexico Codex

Rice - - 0.1 (Rice, husked)

Sugar cane - - 1

Dried cranberries - 5 -

Raisins - 2.5 2 dried grapes (=currants, 

raisins and sultanas)

Residue Definition:

combined residues of tebufenozide and 

its metabolites benzoic acid, 3,5-

dimethyl-1-(1,1-dimethylethyl)-2-((4-

carboxymethyl)benzoyl)hydrazide), 

benzoic acid, 3-hydroxymethyl,5-methyl1-(1,1-dimethylethyl)-2-(4-

ethylbenzoyl)hydrazide, the stearic acid 

conjugate of benzoic acid, 3-

hydroxymethyl,5-methyl-1-(1,1-

dimethylethyl)-2-(4-

ethylbenzoyl)hydrazide and benzoic acid, 

3-hydroxymethyl-5-methyl-1-(1,1-

dimethylethyl)-2-(4-(1-

hydroxyethyl)benzoyl)hydrazide

As above

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

Commodity US Canada Mexico Codex

Fat of cattle, goat, hog, horse, 

and sheep 0.1

Meat of cattle, goat, hog, horse 

and sheep 0.08 0.05 (fat)

Meat byproducts of cattle, goat, 

hog, horse and sheep 0.08 0.02 *

Milk 0.04 0.01 *

MRLs with NO US Equivalent

Eggs - - 0.02 *

Poultry meat - - 0.02 *

Residue Definition:

indirect or inadvertent combined 

residues of tebufenozide, 

benzoic acid, 3,5-dimethyl-1-

(1,1-dimethylethyl)-2-(4-

ethylbenzoyl)hydrazide and its 

metabolite benzoic acid, 3,5-

dimethyl-1-(1,1dimethylethyl)-

2-[4-(1-

hydroxyethyl)benzoyl]hydrazide

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

Commodity US Canada Mexico Codex

Animal feed, nongrass, group 18 1.0

Grain, cereal, forage, fodder and 

straw, group 16 1.0

Grass, forage, fodder and hay, 

group 17 1.0
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Table B.1 Summary of US and International Tolerances and Maximum Residue Limits

US Canada Mexico Codex

Vegetable, foliage of legume, 

group 7 0.20

1 No US registration as of June 19992 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.

B.2 Harmonization - Recommendation

US tolerances on primary crops that are different from other international MRLs are shown in 

the Table B.2 below. Changes to tolerances on highlighted commodities are recommended for 

harmonization with international MRLs. 

Table B.2 Dissimilar (Primary Crops) Tolerances and MRLs 

US Canada Mexico Codex

Residue Definition:

40CFR§180.482

tebufenozide, or benzoic acid, 3,5-

dimethyl-1-(1,1-dimethylethyl)-2-(4-

ethylbenzoyl)hydrazide

3,5-dimethylbenzoic 

acid

1-(1,1-dimethylethyl)-

2-(4-

ethylbenzoyl)hydrazide

tebufenozide

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

Commodity US Canada Mexico Codex

Almond, hulls 25 30

Brassica, head and stem, 

subgroup 5A 5.0 0.5 (Broccoli)5 (Cabbages, head)

Cranberry 1.0 1 0.5

Fruit, citrus, group 10 0.80 2 (excluding 

kumquats)

Fruit, pome 1.5 1 (Apples)

1 (Pears)

1

Grape 3.0 0.5 2

Leafy greens subgroup 4A 10.0 6 (Lettuce) 10 leafy vegetables

Peppermint, tops 10.0 20 (Mint)

Spearmint, tops 10.0 20 (Mint)

Tree nut crop group including 

pistachio 0.1

0.05 (Almonds, 

walnuts

0.01* (Pecan)

Vegetable, fruiting, group 8 1.0

0.2 (African 

eggplants), eggplants, 

pea eggplants, peppers, 

scarlet eggplants)

2 (Tomatoes)

1 (Tomato)

1 (Pepper)

Walnut 0.1 0.05
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Recommendations: 

• HED recommends that commodity definition for “Fruit, pome” to change to “Fruit, 

pome, group 11-10.” For the purpose of harmonization, HED also recommends that the 

pome fruit group 11-10 tolerance be lowered from 1.5 ppm to 1.0 ppm with 

simultaneous removal of apple tolerance at 1.0 ppm in accordance with ChemSAC 

recommendation on 4/21/99.

• HED recommends that the citrus fruit crop group tolerance be raised from 0.8 ppm to 

2.0 ppm to harmonize with Codex. The Codex MRL was set based on field trials that 

were conducted at seasonal application rates (0.32 lb ai/A) that are lower than field trials 

conducted in US (1.25 lb ai/A). Field trials from Codex had PHIs from 7-45 days while 

those in US had 14 day PHI. The highest residue in the Codex data was 0.18 ppm while 

the highest residue in the US trials was 0.521 ppm.

• HED recommends that the Codex MRL for almond hulls be raised from 25 ppm to 30 

ppm since the Codex MRL is based on US trials for almond hulls. Because almond hulls 

is not a major livestock feed, the change in livestock maximum dietary burden is 

insignificant; therefore, livestock tolerances do not need to be revised.
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Appendix C. Physical/Chemical Properties

Table C.1 Physicochemical Properties of Tebufenozide

Parameter Value

Melting point 191-191.5°C

pH NA

Density 280 kg/m3

Water solubility (25oC) 0.83 mg/L

Solvent solubility (25oC) 650 mg/L in acetone

1080 mg/L in methanol

2400 mg/L in methylene chloride

Vapor pressure (25oC) 3 x 10-6 Pa (2 x 10-8 mm Hg)

Dissociation constant (pKa) No dissociation within the pH range of 5-9

Octanol/water partition coefficient (Log Kow) 4.25

UV/visible absorption spectrum NA

C.2. Chemical Identity of Metabolites of Concern

Table C.2 Chemical Identity of Tebufenozide Metabolites of Concern

(benzoic acid, 3,5-dimethyl-1-[1,1-

dimethylethyl]-2-[[4-carboxymethyl] 

benzoyl]hydrazide)

(referred to as Metabolite RH-2703)

(benzoic acid, 3-hydroxymethyl-5-

methyl-1-[1,1-dimethylethyl]-2-[4-

ethylbenzoyl]hydrazide)

(referred to as Metabolite RH-9886)

stearic acid conjugate of benzoic acid, 3-

hydroxymethyl,5-methyl-1-(1,1-

dimethylethyl)-2-(4-

ethylbenzoyl)hydrazide

(referred to as RH-9526)

Stearic Acid Conjugate of RH-9886

(benzoic acid, 3-hydroxymethyl-5-

methyl-1-[1,1-dimethylethyl]-2-[4-[1-

hydroxyethyl] benzoyl]hydrazide)

(referred to as Metabolite RH-0282)
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(benzoic acid, 3,5-dimethyl-1-[1,1-

dimethylethyl]-2-[4-[1-hydroxyethyl] 

benzoyl] hydrazide)

(referred to as Metabolite RH-1788)

Drinking water degradate:

IUPAC: N-(1,1-dimethylethyl)-N′-(4-

acetylbenzoyl)-3,5-

dimethylbenzohydrazide

(referred to as Metabolite RH-96595)

Drinking water degradate:

IUPAC: (4-[N′-(3,5-dimethylbenzoyl)-

N′-(1,1-

dimethylethyl)hydrazinocarbonyl]benzoi

c acid

(referred to as Metabolite RH-112651)

O

N N

H3C CH3

CH3

O

CH3

CH3 H

O

H3C

O

N N

H3C CH3

CH3

O

CH3

CH3 H

HO2C
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Appendix D. Spray Drift

Table D.4.1 Children Ages 1<2 years HtM Risk Estimates MOEs Related to Indirect Exposure to Spray 

Drift for Tebufenozide2

Crop/Rate Group Spray Type/ Nozzle 

Configuration 

Application Rate 

(lb ai/A)

Estimated or 

Adjusted TTRt

(ug/cm2)

At Edge 

HtM MOE 

Agricultural Crop (i.e. Bushberries, Caneberries, Citrus, Canola, Cotton, Cranberry, Fruiting Vegetables, 

Mint Reg #8033-111)

Groundboom

High Boom Very fine to 

Fine

0.25 0.0277875

 2,800 

Low Boom Very fine to 

Fine 6,200 

High Boom Fine to 

Medium/Coarse 11,000 

Low Boom Fine to 

Medium/Coarse 16,000 

Tree Nuts (Highest Maximum Single Application Rate Taken From Reg # 8033-112)

Aerial

Fine to Medium

0.47 0.0522405

 1,100 

Medium to Coarse 1,300 

Coarse to Very Coarse 1,500 

Very Fine to Fine 750 

AT4011, M, 10 mph, 37% 

SD 1,200 

WASP, M, 10 mph, 37% 

SD 1,300 

AT401, C, 10 mph, 25% 

SD 1,400 

WASP, C, 10 mph, 25% 

SD 1,600 

AT401, VC, 10 mph, 

20% SD 1,600 

WASP, VC, 10 mph, 20% 

SD 2,000 

Airblast3

Sparse 1,900 

Normal 93,000 

Dense 6,600 

Vineyard 35,000 

1. The AT401 is the representative fixed wing aircraft and the WASP is the representative helicopter

2. Spray drift estimates based on WDG formulation maximum rates for ground and aerial application

3. Tree Nut airblast application rates are the highest and therefore risk estimates are protective of the orchards and 

berries crop rates. 
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Appendix E. Occupational Exposure Scenarios and Risk Estimates

Table E.1 Occupational Inhalation Handler Non-Cancer Exposure and Risk Estimates for Tebufenozide

Exposure Scenario Crop / Target 

Category

Application Rate2

Amount 

Handled / Area 

Treated3

Inhalation Exposures 

(ug/lb ai)1 Inhalation Dose (mg/kg/day)8 Inhalation MOE9

Formulation Application 

Equipment Value Units Value Units No Respirator EC No Respirator EC No Respirator EC

Mixer/Loader

L/SC/EC

Aerial

Ornamentals4 0.25

lb ai/A

60

acres 0.219 0.083

0.00000821 0.0000156 49,000 130,000

Nut Trees5 0.47 350 0.00045 0.000171 4,400 12,000

Fruiting 

Vegetables6 0.25 350 0.00024 0.0000908 8,300 22,000

Cotton7 0.25 1200 0.000821 0.000311 2,400 6,400

Groundboom

Ornamentals1 0.25

lb ai/A

60

acres 0.219 0.083

0.00000274 0.0000104 73,000 190,000

Fruiting 

Vegetables6 0.25 80 0.0000548 0.0000208 36,000 96,000

Cotton7 0.25 200 0.000138 0.0000519 14,000 39,000

Airblast

Ornamentals4 0.25

lb ai/A

20 acres

0.219 0.083

0.0000138 0.00000519 140,000 390,000

Nut Trees5 0.47 40 0.0000515 0.0000195 39,000 100,000

Fruiting 

Vegetables6 0.25 40 acres 0.0000274 0.0000104 73,000 190,000

Chemigation

Cranberries 0.25

lb ai/A

350 acres 0.219 0.0830.00024 0.0000908 8,300 22,000

Ornamentals1 0.25 60 0.0000411 0.00001568 4,900 130,000

WSP

Aerial

Nut Trees5 0.45

lb ai/A

350

acres

No Data 0.24 No Data 0.000473 No Data 4,200

Fruiting 

Vegetables6 0.26 350 No Data 0.24 No Data 0.000273 No Data 7,300

Cotton7 0.26 1200 No Data 0.24 No Data 0.000936 No Data 2,100

Groundboom

Fruiting

Vegetables6 0.26 80 No Data 0.24 No Data 0.0000624 No Data 32,000

Cotton7 0.26 200 No Data 0.24 No Data 0.000156 No Data 13,000

Airblast Nuts Trees5 0.45 40 No data 0.24 No Data 0.000054 No Data 37,000

Chemigation Cranberries 0.26 350 No Data 0.24 No Data 0.000273 No Data 7,300

Applicator

All Sprays

Aerial

Ornamentals4 0.25

lb ai/A

60

acres

No Data 0.0049 No Data 0.000000919 No Data 2,200,000

Nut Trees5 0.47 350 No Data 0.0049 No Data 0.0000279 No Data 72,000

Fruiting 

Vegetables6 0.26 350 No Data 0.0049 No Data 0.00000558 No Data 360,000

Cotton7 0.26 1200 No Data 0.0049 No Data 0.0000191 No Data 100,000

Groundboom Ornamentals4 0.25 60 0.34 0.043 0.00000638 0.00000806 31,000 250,000

Nut Trees5 0.47 80 0.000443 0.0000559 4,500 36,000
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Fruiting 

Vegetables6 0.26 80 0.0000884 0.0000112 23,000 180,000

Cotton7 0.26 200 0.000221 0.000028 9,000 71,000

Airblast Ornamentals4 0.25 lb ai/A 20 acres 4.71 0.068 0.000295 0.00000425 6,800 470,000

Nut Trees5 0.47 40 0.00111 0.000016 1,800 130,000

Flagger

All Sprays Aerial

Ornamentals4 0.25

lb ai/a

60

acres 0.35 No Data

0.00000656 No Data 30,000 No Data

Nut Trees5 0.47

350

0.00072 No Data 2,800 No Data

Fruiting 

Vegetables6 0.26 0.000399 No Data 5,000 No Data

Cotton7 0.26 0.000399 No Data 5,000 No Data

Mixer/Loader/Applicator

L/SC/EC

Backpack Ornamentals4 0.005

lb 

ai/gallon

40 gallons

140 No Data 0.000035 No Data 5,700 No Data

Nut Trees5 0.0094 0.000658 No Data 3,000 No Data

Manuallypressurized 

Handwand

Ornamentals4 0.005

30 No Data

0.0000075 No Data 27,000 No Data

Other Nut 

Trees5 0.0094 0.000141 No Data 14,000 No Data

Mechanicallypressurized 

Handgun

Ornamentals4 0.005

1,000 gallons

3.9 No Data 0.000075 No Data 27,000 No Data

Greenhouse

without 

respirator 0.005

120

No Data

0.00075

No Data

270

No Data Greenhouse10 

with

respirator

24

PF5

0.0015

PF5

1,300 

PF5

Nut Trees5 0.0094 3.9 No Data 0.000585 No Data 3,400 No Data

WSP

Backpack Nut Trees5

0.009 lb 

ai/gallon

40 gallons

140 No Data 0.00184 No Data 1,100 No Data

Manuallypressurized 

Handwand

Nut Trees5 30 No Data 0.000135 No Data 15,000 No Data

Mechanicallypressurized 

Handgun

Nut Trees5 1,000 gallons 3.9 No Data 0.00044 No Data 4,600 No Data

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013); Level of mitigation: Baseline PPE includes no respirator, long sleeved shirt, long pants, socks 

plus shoes. Eng. Controls (EC) takes into account the WSP formulation for Mixing/Loading as well as assumes enclosed cockpits for the aerial and ground application of tebufenozide for all 

formulations. 

2 Based on registered labels (Table 3.2.).

3 Exposure Science Advisory Council Policy #9.1.

4 Ornamentals include nurseries and greenhouse, Christmas tree farms, out landscape, recreational areas, and institutional grounds and interior plantscapes. The one exception is for 

mixing/loading/applying with mechanically pressurized handgun. Greenhouse have different exposure units than outdoor landscaping applications. 

5 Nut trees equals the maximum single application to nut trees. These high end application rate should encompass the lower nut trees as well as other fruit orchard applications.

6 Fruiting Vegetables was selected to represent the most common application rate for the variety of field crops of typical acreage (berries, Cole crops). 

7 Cotton was selected to represent the most application rate for the variety of crops of high acreage (sugarcane, mint, pastureland, and canola)

8 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ 80 (kg). 

9 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

10. Greenhouse mechanically pressurized handgun MOE is 1300 with the addition of a PF5 respirator; the label has been revised to require the PF5 respirator.

11.Tree nuts have the highest maximum application rate for airblast scenarios. The risk estimates are protective of lower application rates found for citrus orchards and berries.