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.: N A Regulatory Action: Regi s tration Review
Case No.: 7416

CAS No.: 112410-23-8
40 CFR: § 180.482



# - / '

FROM: 

# \___/,' ;/ 7/ /--

t./-;;- 6-

## ~/~ / 1

Mohsen Sahafeyan, Chemist and Risk Assessor 

# v i f c /,;

,,._ Yung Yang, Ph.D.

, Toxicologist Bridgett Bobowiec

, ORE Assessor**~** · 

## V

Risk Assessment Branch VI**~ ~**  Health Effects Division (7509P)

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 1of55Tebufenozide Human Health Risk Assessment DP No. 414533

Page 2 of 55 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.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 3 of 55 

## 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 an d 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 P oints 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

................................ ................................ ................................ .... 27Tebufenozide Human Health Risk Assessment DP No. 414533

Page 4 of 55 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

................................ ........... 54Tebufenozide Human Health Risk Assessment DP No. 414533

Page 5 of 55 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 agains t (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 a s a flowable liquid concentrate (suspension) and wettable powder enclosed in a water

- soluble pouch. Tebufenozide is a pplied via aerial, ground, and handheld equipment . C hemigation is allowed on cranberries and ornamentals. Tebufenozide is also registered for residential use on ornamental plants

.

The t oxicity database of tebufenozide is complete

. T he available to xicity database for
tebufenozide is adequate for FQPA and dose

- response evaluation.

The toxic effects of t ebuf enozide 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 hu m ans" based on lack of evidence
of carcinogenicity in rats and mi ce 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 a cute toxicity (Toxicity Category III or IV) by the or al, 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

- y ear dog feeding studies were selected for chronic dietary, incidental oral and inhalation exposure sce narios 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 sys temic toxicity in the dermal study and a lack of developmental

concern.

T here 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. T he residue chemistry database for te bufenozide 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 magnitu de of the residue in agricultural crops have been submitted. TheseTebufenozide Human Health Risk Assessment DP No. 414533

Page 6 of 55 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 recommend s 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 rec ommends 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 c hronic population adjusted does (c PAD ) f or 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 di etary cancer
risk is not required.

Aggregate risk assessment included short

- term and long

- term risk assessment s only

. The s hort

term aggregate risk a ssessment for tebufenozide is appropriate for adults only and include s average exposure from food, water

, and short

- term res idential handler s ’ 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
include d only food and drinking water exposure since there is no reasonable expectation of long

term residential exposure from the registered uses of tebufenozide. Therefore, t he long

- term aggregate asses s ment is equivalent to the chronic dietary (food and water) ri sk assessment , and is
not of concern as noted above

.

A screening level residential spray drift assessment w as completed for tebufenozide as part of registration re v i ew . The spray drift risk estimates are based on an estimated deposited residue concentration as a result of the screening level agricultural appl ication scenarios. Children’ s ( ages 1 to < 2 year s old) incidental oral risk estimates from indi rect 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 d ermal 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 derma l hazard identified

. T he 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. S hort

- 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

.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 7 of 55 Although a quantitative occupational post

- application inhalati on 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 belie ved 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 human

health ris k 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 we re 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 Studi es 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 ex posure data gaps for
tebufenozide

.

2.2 Tolerance Considerations

**2.2.1 Enforcement Analytical Method** 

Primary Crops

- An adequate high

- performance liquid chromatography/ultraviolet ( HPL C/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.pdfTebufenozide Human Health Risk Assessment DP No. 414533

Page 8 of 55 sulfate and concentrated to dryness by rotary evaporation. Residues are quantitated by HPLC analysis with UV detection. The va lidated method limit of quantitation (LOQ) , depend ing 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 Anal ytical 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 metho d (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 petitio n method validation (PMV) for DAS Method GRM 02.20 and has
recommended that th is 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 provid ed 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

tan dem 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 ext racted 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. T he validated method limit of quantitation (LOQ) f or 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 po ultry tissues. Th is 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, a re 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 vegeta bles except potato, turnips as well asTebufenozide Human Health Risk Assessment DP No. 414533

Page 9 of 55 milk and ruminant tissues

. Tolerances for in advertent 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: § 1 80.482 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 current ly 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 . N ew tolerances for these crops/crop groups are recommended to harmoni ze 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
Toleran ce Recommended/harmonized
Tolerance Berry group 13 Convert to: Caneberry Subgroup 13

- 07A
And Bushberry subgroup 13

- 07B 3.0 3.0

Fruit, citrus, group
10 1 1) Convert to : Fruit, citrus, group
10

- 10 2) H armonize
tolerance 0.80 2.0

Fruit, pome 2 1) Convert to : Fruit, pome, group
11

- 10 2) H armonize
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 RevokeTebufenozide Human Health Risk Assessment DP No. 414533

Page 10 of 55 Table 2.2.2 Commodity/Tolerance Updates Commodity Action Established
Toleran ce 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, hulls 3 Harmonize
tolerance 25 30

Sugarcane, cane 4 Should be
established. None 1.0

Sugarcane,
molasses 4 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 n ot 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 harmonize s with
Codex.

**2.2. 3**  **International Harmonization**

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

te bufenozide . T he International Residue Limit (IRL) Status sheet is attached as Appendix B

. A h armonization 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 oppose d 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, HE D 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 in ternational 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 discu ssion see Appendix B.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 11 of 55 Table 2.2.3 HED Recommended Tolerance Revisions for Codex Harmonization Commodity Established Tolerance (ppm) Recommended Tolerance (ppm) Comment

Fruit, pome, group 11

- 10 1 1.5 1.0 International
Harmonization Fruit, citrus, group 10

- 10 2 0.80 2.0 International
Harmonization Almond, hulls 25 30 International
Harmonization

1 T he 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 concern s 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 o f
PF5 respirator s for greenhouse applications

. HED expects that this label amendment will
address the risk concern.

3.0 Ingredient Profile

Tebufen ozide ( CAS Name: 3,5

- dimethylbenzoic acid 1

- [1,1

- dimethylethyl]

- 2

- [4

- ethylbenzoyl ]hydrazide), a member of the diacyl hydrazine class of com pounds and an insecti cide and
miticide is registered for use on a wide range of food and feed commodities as well as
ornamentals and trees

. T olerances for t ebufen ozide residues are under 40 CFR, 180.482 for primary crops, ruminant tissues and milk, and in advertent 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 ornamen tal plants, and indirect residential exposure to t ebufenozide via spray drift from use on the various registered agricultural crops.

There are three registered end

- use products containing tebufenozide, two liquid concentrate s and a wettable powder formulated product encl osed in a water

- soluble pouch. Maximum single
tebufenozide application rates range from 0.12 t o 0.47 lb ai/A on the various crops. Application
methods include aerial, ground, and handheld equipment as well as chemigation on cranber ries
and ornamentals

.

3.1 Chemical Identity and Physical/Chemical Characteristics

Tebufenozide is white powder at room temperature with low vapor pressure

. It has lowTebufenozide Human Health Risk Assessment DP No. 414533

Page 12 of 55 solubility in water. Field trial data show that it translocate s in plants. In the environment, p arent 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 (RH

112651, 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 show s 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 C 22 H 28 N 2 O 2

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 CONFIRM TM 2F ( EPA Registration Number: 8033

- 111)

CONFIRM TM 70 WSP ( EPA Registration Number: 8033

- 112)

MIMIC TM 2LV ( EPA Registration Number: 8033

- 113)

Chemical Class diacylhydrazine

3.2 Pesticide Use Pattern

Tebufenozide is registered for a variety of cro ps including the following: bushberries, caneberries, brassica (head and stem, and leafy green), citrus, canola, cotton, cranberry, frui ting vegetables, grape, leafy greens and petioles , mint, nuts, or namentals, pastureland, pome fruit s , sugarcane, tuberous and corm vegetables except potato, turnips, forests and shrub, as well as
ornamentals and trees.

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

concentrate (suspension) comprised of 23% ai

, MimicTM 2LV is a flowable liquid concentrate (s uspension) comprised of 24% ai , and ConfirmTM 70WSP is a wettable powder encl osed 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 theTebufenozide Human Health Risk Assessment DP No. 414533

Page 13 of 55 crop . The ConfirmTM 2F label includes outdoor ornamental use that does not p reclude residential consumers/applicators ; therefore, a residential assessment was conducted

.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 14 of 55 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 CONFIRM TM

2F ( EPA Registration
Number: 8033

- 111 ) 23% Bushberries 1

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 inclu des long

- sleeved shirt and long pants, waterproof gloves, shoes plus socks. Caneberries 2

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.

Citrus 3 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 Crops 4 , Leafy Vegetables 5 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 Vegetables 6 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

Ornamentals 7 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 Fruit 8 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 daysTebufenozide Human Health Risk Assessment DP No. 414533

Page 15 of 55 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 4 th leaf or younger. Trees 5 th 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 4 th leaf or younger. Trees 5 th 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 Vegetable 6

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 daysTebufenozide Human Health Risk Assessment DP No. 414533

Page 16 of 55 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 Crops 4 Leafy vegetable 5 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, chest er berry, lavacberry, loganberry , lowberry, lucretiaberry, mammoth blackberry, marionberry, nectarberry, Olallie berry, Oregon evergreen berry, phenomenal berry, rangeberry, ravenberry, red an d black raspberry, rossberry, Shawne blackberry youngberry.

3. Cit rus = 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 cabb age, 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, upl and 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 an d interior plantscapes.

7. Pome Fruit = apples, crabapples, loquat, mayhaw, pears including oriental, quinceTebufenozide Human Health Risk Assessment DP No. 414533

Page 17 of 55 3.3 Anticipated Exposure Pathways

Tebufenozide is applied directly to growing crops and application may result in tebufenozide
reachin g 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 setting s. 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 Or der 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 var iety 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 Ameri ca, (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, youth s, 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 exposur e 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.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 18 of 55 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 Revie w 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 po tential source of i nformation associated with human
health effects assoc iated with certain pesticides. T ebu fenozide is not included in the AHS

.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

T he toxicology database for tebufenozide is complete

. T he Hazard and Scien ce P olicy Council (HASPOC) determined that a subchronic neurotox icit y study wa s not needed but a subchronic inhalation study was required for tebufenozide (TXR# 0055187, TXR# 0057075 ). However, t he

HASPOC also recommended use of a PF5 respirator for greenhouse uses in lieu of an inhalation study . Because the tebufenozide registr ant submitted a n amended label for EPA Reg No. 8033

- 111 (Confirm 2F) , requiring a PF5 respirator for gree nhouse uses

, HED has determined that an inhalation study is not needed at this time. T he available toxicity database for tebufenozide is adequate to characterize a wide range of effects, including developmental, reproductive, neurotoxic, mutagenic, carcin ogenic, 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), t he 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 14 C 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 14 C

- RH

- 5992.

The extent of absorption was not establish ed. The majority of the radioactivity w as excret ed in the feces within 48 hours; small amount s (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, we re 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. Metabol ism 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,Tebufenozide Human Health Risk Assessment DP No. 414533

Page 19 of 55 aldehydes or acids. The type of metabolite produced varies depending on the position oxidized

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

but there h as no fragmentation of the molecule between the benzyl rings.

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

groups wer e 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), 14 C

- RH5992 was prepared in a

formulation of 24% a.i. and an end use concentration of 0.024% and adm inistered to a group of male rats with a single dermal application of either the undiluted material (24% a.i., 6000 μg a.i./cm 2 , 24 mg total) or an aqueous dilution of the formulation (0.024% a.i., 6 μg a.i./cm 2 , 0.024 mg total) for 10 or 24 hours. Excret a were collected at various time intervals for 4 days and analyzed for 14 C

- label. After 4 days, the animals were killed and the skin application sites and remaining carcasses were analyzed for 14 C

- label.

A total of 5% and 7% of the administered 14 C

- label was absorbed dermally in rats exposed to 24% 14 C

- RH

- 5992 formulation for 10 and 24 h ou rs , respectively. 14 C

- 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 14 C

- label in high dose group was 88

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

administered 14 C

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

- RH

- 5992

in diluted formulation for 10 and 24 h ou rs , respectively. 14 C

- 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 14 C

- label in low dose group was 95% of

administered dose.

Although a dermal absorpti on 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 t ebufenozide 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 withTebufenozide Human Health Risk Assessment DP No. 414533

Page 20 of 55 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 t ebufenozide. 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 t ebufenozide is neurotoxic, or that it

causes reproductive or developmental toxicity . T here 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 hu m ans" based on lack of

evidence of carcinogenicity in rats and mi ce and no evidence of m utagenicity

. Therefore, a

cancer risk assess m ent is not required.

Tebufenozide has low acute toxicity (Toxicity Category III or IV) by the or al, 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 recommend ed that the required 10x Food Quality Protection Act (FQPA) Safety Factor (SF) b e reduced to 1x for tebufenozide. The toxicology database is complete. T here 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

over estimated the potential for exposure through food and water.

**4.4. 1**  **Completeness of the Toxicology Database**

The toxic ology database for tebufenozide is complete. T he 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 wei ght, or histopathology of the nervous system in any study with tebufenozide. Accordingly, t he HASPOC determined that a subchronic neurotoxicity study is not required based on a weight

- of

- evidence approach considering all the
available hazard information o n tebufenozide (TXR# 0057075).Tebufenozide Human Health Risk Assessment DP No. 414533

Page 21 of 55 **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 t wo

- 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 tolerance

level 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 /PoD s ( 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 gain s , 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 Ex posure (Short

- Term) : The same co

- critical dog studies described above (under chronic dietary endpoint ) w ere selected for incidental oral exposure

. HED has consider ed the 2

- gen eration 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) w ere not measured in the offspring where the NOAEL was 12.6/14.6 mg/kg/day (M/F) and the LOAEL wasTebufenozide Human Health Risk Assessment DP No. 414533

Page 22 of 55 126.0/143.2 (M/F)

, based on a reduction in the body weights of the F1 and F2 pups after da y 14
of lactation

. The PoD of 2.0 mg/kg/day from the dog studies was consid ered 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 hematologic al 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 availabl e and shows n o toxic effect s on any test parameter including

h ematolog y ; 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 n ecessary.

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 expos ure scenario. The same co

- critical dog
studies previously described (under chronic dietary endpoint ) w ere 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

. T ebufenozide does not pose a dermal risk; therefore

, quantification of dermal r isk is not required.

O ral 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 hu m ans" based upon lack of evidence of carcinogenicity in

rats and mi ce (HIARC Memo, October 6, 2003)

. Therefore, a cancer risk asse ss m ent is not required.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 23 of 55 **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk** 

**Assessment**

Table. 4.5.4 Toxic ological 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 P opulation s ) No appropriate endpoint attributable to a single dose was identified in the toxicity database.

Chronic Dietary ( All P opulations) PoD = 2 mg/kg/day

UF A = 10x

UF H = 10x FQPA SF = 1x cRfD = 0.02
cPAD = 0.02 mg/kg/day MRID# 42436223, 42931203,
42931204
90

- d ay and 1

- y ear Dog Stud ies (co

critical) , 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

UF A = 10x

UF H = 10x FQPA SF = 1x Residental LOC
for MOE =100 MRID# 42436223, 42931203,
42931204
90

- d ay and 1

- Year Dog Stud ies (co

critical) , 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 %)

UF A = 10x

UF H = 10x Occup a tional
LOC for
MOE = 100 MRID# 42436223, 42931203,
42931204
90

- d ay and 1

- y ear Dog Stud ies (co

critical) , 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 ( O ral,

D ermal, I nhalation) Classification : This chemical is classified as “not likely” to be a human carcinogen.

A c ancer 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 adver se effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = Databa se 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 pote ntial 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 st udies include endpoints which may beTebufenozide Human Health Risk Assessment DP No. 414533

Page 24 of 55 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 offspr ing. 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 reg istration 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 Endocr ine 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
ch emical 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 relations hip 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 5 8 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 2 and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these l ists 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 h ttp://www.epa.gov/endo/Tebufenozide Human Health Risk Assessment DP No. 414533

Page 25 of 55 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 regi strant. 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 wit h 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 th e 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

a nd 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 n ature of residues i n rotational crops are adequately understood based on metabolism of [ 14 C]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

- an d

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 (RH

112651, 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 par ent chemical (under which conditions the decay of degradatesTebufenozide Human Health Risk Assessment DP No. 414533

Page 26 of 55 is confounded by their simultaneous formation from the parent compound). Microbiall y

mediated degradation is the primary dissipation pathway for parent tebufenozide. Parent
tebufenozide is stabl e 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 tebufenozi de 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 m obile

, based on batch equilibrium Koc values ( 351

- 894 mL/g OC ) 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 s cheme

, based on its soil organic carbon

- water partitioning
coefficient ( Koc ) values (76

- 156 mL/g OC ). A second carboxylic acid metabolite, RH

- 112703,
and the ketone metabolite RH

- 96595, are also mobile

, based on column leaching study results. Thus, the pa rent 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 Appendi x 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 RH

9886, 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)Tebufenozide Human Health Risk Assessment DP No. 414533

Page 27 of 55 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

Te bu fenozide 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 residue s 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. E nvironmental 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 RH

96595 for surface water (M. Sahafeyan, D 423156, 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 thr ee of its major metabolites

, RH

- 112651, RH

- 112703 and RH

9659 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 Surfac e 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 K OC reflecting one of the (more mobile than parent) degradates, for wh ich 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 resu lts 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 μ g/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

us ed for chronic analysis for all direct and indirect water in DEEM

.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 28 of 55 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 S td scenario, ground application for acute; FL

peppers S td 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 chro nic 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 3 7 % of th e 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, can e berries , cauliflower, celery, lettuce, parsley, pecans, peppers, tomatoes and walnuts: each at 5%; almonds, broccoli, pist achios, 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, t he primary analysis showed th at orange input parameters in the dietary exposure model needed to be refined since it was the major contributor to the dietary risk. HED,
i n coordination with BEAD (e

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

, used 1%CT

, for orange and its r elated commodities in the dietary analysis

.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 29 of 55 **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

- 9 9 years. The resulting dietary risk estimates are not of concern; all

are less than 100 % of the cPAD. The most highly exposed population subgroups w as chil dren 1

- 2 years old

, utilizing 3 7 % of the cPAD ( see Table 5.4.5 below for a summary of the results)

. A

c hronic 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
Tebufenozide 1

.

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.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 30 of 55 6.1 Residential Handler Exposure/Risk Estimates

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application pro cess. 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 element s 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 Applicatio n 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/ft 2 ) ; and

• Mixing/loading/applying liquids with backpack sprayers to garden and trees (0.005 lb ai/gallon) and (5.74 E

- 06 lb ai/ft 2 )

.

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 SOPs 4

.

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 SOPs 5

.

Summary of Residential Handler Non

- Cancer Exposure and Risk Estim ates

Residentia l handler inhalation MOEs (MOE >1 00 ) were not of concern to HED and ranged from 46,000 to 1,300,00 0

.

Table 6 .1 .1 pr e sents 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.htmlTebufenozide Human Health Risk Assessment DP No. 414533

Page 31 of 55 Table 6.1 .1 Residential Handler Non

- cancer Exposure for Tebufenozide

Scenario Formulation Application Equipment/Method Type Application Rate 1 Units Area Treated

or Amount

Handled Daily 2 Units (per day) Inhalation
Unit Exposure (mg/lb ai) Inhalation
Absorbed Dose

(mg/kg/day) 3 Inhalation

MOE 4

Ornamentals Liquid

concentrate Manually

Pressurized
Handwand Broadcast /Spot/ 0.0 05 lb ai/gal. 5 gal. 0.0 18 0.000 0056 360,000

5.74E

- 06 lb ai/ft 2 1

, 200 ft 2 0.0 18 0.00 00015 1

, 300

, 000

Backpack 5.74E

- 06 lb ai/ft 2 1

, 200 ft 2 0.14 0.00 0012 170

, 000

0.0 05 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 Inhalati on MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).Tebufenozide Human Health Risk Assessment DP No. 414533

Page 32 of 55 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

sce narios 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 summariz ed 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 MOE 2

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 quant i t at ive 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 assessmen t 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
indivi duals 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 th e 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://w ww.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219).Tebufenozide Human Health Risk Assessment DP No. 414533

Page 33 of 55 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 analys is 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 off

target 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 po tential 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 drif t 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 exposu res 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.
Giv en 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 exposure s 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 sp ray drift that may occur at varying distances from the edge of the treated field using the Ag DRIFT ( v2.1.1) model and the Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift Policy

. Once the deposited resid ue 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.

7 http://www.agdrift.com/

8 Note that for many cases the scenar ios outlined in the screening approach represent actual use practice so risk assessors should be aware and characterize these appropriately.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 34 of 55 Tier 1 option) were incorporated into the model and represent each equipment type and use under varied conditions. The screening options specifically recommende d 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 ec ological 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 t ypically 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 concen tration 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 T able 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 90 th 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 belo w (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 a djacent 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 Appendi x 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.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 35 of 55 7.0 Aggregate Exposure and Risk Assessment

In accordance with the FQPA, when there are potential resident ial exposures to a pesticide, aggregate risk assessment must conside r 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 Ri sk

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

r eleva nt routes of exposure ( inhalation, and oral endpoints) are based on the same effects ( 90

- d ay and 1

- Year Dog Stud ies (co

- critical)) and same LOC (100x), the aggregate risk was calculated by summing the exposures from different routes and comparin g it to the common endpoint (2 mg/kg/day) to get the aggregate MOE. Based on the use pattern, residential short

term exposure to children is not expected; therefore, a short

- term aggregate risk was conducted for adults only. F rom Table 7.2 below , the aggregate MOE for adults is 550 which is above the

LOC ; therefore, t he short

- term aggregate risk for tebufenoz ide is not of concern.

Table 7.2 Short

- Term Aggregate Risk Calculations for Tebufenozide

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential Exposure mg/kg/day 3 Total Exposure mg/kg/day 4 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 Exp osure ; see Table 5.4.5.

5 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)]Tebufenozide Human Health Risk Assessment DP No. 414533

Page 36 of 55 7.3 Intermediate

- Term Aggregate Risk

There are no residential use scenarios that would result in potenti al 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 hu m ans" based upon lack of evidence of carcinogenicity in rats and mi ce (HIARC Memo, October 6, 2003)

. Therefore, a cancer risk assess m ent is not required.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EP A 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 b y 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 m echanism 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 t o 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 t ask. 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 “ o rnamentals ” include s nurseries, C hristmas tree farms, outdoorTebufenozide Human Health Risk Assessment DP No. 414533

Page 37 of 55 landscape, recreational areas, and institutional grounds. Airblast ap plications 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 sele cted variety of registered field crops such as b erries and

c ole 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 ap plication;

• 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 exposure s 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 produc t over a period of weeks (e.g., completing multiple applications for multiple clients within a region). Occupational e xposure to tebufenozide is most likely to be intermittent
and short

- term given the use pattern. Most applications are suggested at onsla ught 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 f or 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

. Tebufenozi de 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 >1 00 )

.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 38 of 55 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 dramatical ly 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 characte rize 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 re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities r elated 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,

a nd 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 po st

- application dermal ass essment has not been conducted for tebufenozide due to the lack of dermal hazard endpoint. A t this time

, a dislodgeable foliar residue (DFR) study is not required
for tebufenozide. Tebufenozide can retain the 4

- hr REI b ased on the low acute toxicity and
because it is not a sensitizer . T here are no reports of hypersensitivity , i ncident data, or a dverse health effects associated with the end use product, e.g., carcinogenicity, developmental effe cts.

**9.2.2 Inhalation Post** 

**- application Risk** 

Based on the Age ncy's current practices, a quantitative post

- application inhalation exposure

assessment w as 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 degreesTebufenozide Human Health Risk Assessment DP No. 414533

Page 39 of 55 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 p esticides and resuspension of dusts and/or particulates that contain pesticides. The A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory

P anel (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 A gency 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 ). 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 post

application inhalation exposure data generate d 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.

Al though 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 pes ticides 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.

Fu rthermore, 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 reasonabl e 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 > 1 00 )

.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 40 of 55 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 F oliage 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

Hu man 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 Hum an Incidents for Preliminary Risk

D. Davis D205283 7/15/94 Tebufenozide: MARC Decision Memorandum

M. Sahafeyan D 423156 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.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 41 of 55 Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The toxicological data requirements (40CFR §158.3 40) 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.

T able 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 waived 1

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 waived 1

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)

.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 42 of 55 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 LD 50 , Rat 42436211 (1991)

Acceptable LD 50 > 5000 mg/kg Toxicity Category IV

81

- 2
870.1200 Acute dermal LD 50 , Rat 42436214 (1991)

Acceptable LD 50 > 5000 mg/kg
Toxicity Category IV

81

- 3

870.1300 Acute inhalation toxicity, Rat 42436215 (1992) Acceptable LC 50 > 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

- in duction protocol; olive oil as

v ehicle; 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/da y (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 s exes; a depressed myeloid/erythr oid 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 weigh t gain in male (no effect in females). A dose related splenic extramedullary hematopoiesis and pigment deposition (containing i ron) 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 w eight gain in females at 21.4 mg/kg/day and above and males at 202 mg/kg/day , hematological findings (peripheral, blood), presente d as a minimal depression of HGB , RBC, HCT and aTebufenozide Human Health Risk Assessment DP No. 414533

Page 43 of 55 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 RH

75,992 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 , LOA EL 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 Materna l 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

– G uideline ( Note : The HIARC expressed more
confidence in the findings of 1995 2

- gen rat study than t his 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 s everity of splenic pigmentation in b oth 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 deliv ery 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. Offsprin g/Developmental Toxicity NOAEL = 154.8/171.2 (M/F) mg/kg/day.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 44 of 55 Table A.2 Toxicology Profile for Tebufenozide

Type of Study/

Guideline Study Title MRID Results

Offsprin g/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 extra

medullary hematopoiesis in females). Rep roductive 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 NOAE L = 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
exhibi ted decreases in RBC, HCT and

H GB ; increases i n Heinz bodies, methemoglobin, MCV, MCH, r eticulocyte, 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) Syst emic 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 Toxic ity 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,Tebufenozide Human Health Risk Assessment DP No. 414533

Page 45 of 55 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

Page 46 of 55 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 ex cretion 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% 14 C

- RH

- 5992 formulation to male rats,
5% and 7% was absorbed for 10 and 24 hr exposure, respectively.

Dermal administration of 0.024% 14 C

- RH

5992 formulation resulted in 22% and 26% absorption for 10 and 24 hr exposur e, 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) RH

5992 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 erythrocyt e 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.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 47 of 55 Appendix B. International Tolerances

Table B .1 Summary of US and In ternational 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

Kiwifruit 1 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, walnuts 0.01* (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

- - 10Tebufenozide Human Health Risk Assessment DP No. 414533

Page 48 of 55 Table B .1 Summary of US and In ternational 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

- methyl

1

- (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 1.0Tebufenozide Human Health Risk Assessment DP No. 414533

Page 49 of 55 Table B .1 Summary of US and In ternational Tolerances and Maximum Residue Limits
US Canada Mexico Codex Vegetable, foliage of legume, group 7 0.20

1 No US registration as of June 1999 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as proce ssing of treated stored wheat. ( fat) = to be measured on the fat portion of the sample. MRLs i ndicated 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 t olerances on highli ghted commodities are recommended for
harmonization with international MRLs.

Table B.2 Dissimilar (Primary Crops) Tolerance s 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 0.05Tebufenozide Human Health Risk Assessment DP No. 414533

Page 50 of 55 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 insignifica nt; therefore, livestock tolerances do not need to be revised.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 51 of 55 Appendix C

. Physical/Chemical Properties

T able C

. 1 Physicochemical Properties of Tebufenozide

Parameter Value Melting point 191

- 191.5 ° C pH NA Density 280 kg/m 3 Water solubility (25 o C) 0.83 mg/L Solvent solubility (25 o C) 650 mg/L in acetone 1080 mg/L in methanol 2400 mg/L in methylene chloride Vapor pressure (25 o C) 3 x 10

- 6 Pa (2 x 10

- 8 mm Hg) Dissociation constant (pK
a ) No dissociation within the pH range of 5

- 9

Octanol/water partition coefficient (Log K
ow ) 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] be nzoyl]hydrazide)

(referred to as Metabolite RH

- 0282)Tebufenozide Human Health Risk Assessment DP No. 414533

Page 52 of 55 (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

C H 3 C H 3 C H 3 O C H 3

C H 3 H O

C H 3

O

N N

C H 3 C H 3 C H 3 O C H 3

C H 3 H H O 2 CTebufenozide Human Health Risk Assessment DP No. 414533

Page 53 of 55 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 Tebufenozide 2

Crop/Rate Group Spray Type/ Nozzle Configuration Application Rate (lb ai/A) Estimated or Adjusted TTR t (u g/cm 2 ) 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

AT401 1 , 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

Airblast 3 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 aeria l application

3. Tree Nut airblast application rates are the highest and therefore risk estimates are protective of the orchards and berries crop rates.Tebufenozide Human Health Risk Assessment DP No. 414533

Page 54 of 55 Append ix 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 Rate 2 Amount
Handled / Area
Treated 3 Inhalation Exposures (ug/lb ai) 1 Inhalation Dose (mg/kg/day) 8 Inhalation MOE 9

Formulation Application Equipment Value Units Value Units No Respirator EC No Respirator EC No Respirator EC

Mixer/Loader

L/SC/EC Aerial Ornamentals 4 0.25

lb ai/A 60

acres 0.219 0.083 0.00000821 0.0000156 49,000 130,000

Nut Trees 5 0.47 350 0.00045 0.000171 4,400 12,000

Fruiting Vegetables 6 0.25 350 0.00024 0.0000908 8,300 22,000

Cotton 7 0.25 1200 0.000821 0.000311 2,400 6,400

Groundboom Ornamentals 1 0.25

lb ai/A 60

acres 0.219 0.083 0.00000274 0.0000104 73,000 190,000 Fruiting Vegetables 6 0.25 80 0.0000548 0.0000208 36,000 96,000

Cotton 7 0.25 200 0.000138 0.0000519 14,000 39,000

Airblast Ornamentals 4 0.25

lb ai/A 20

acres 0.219 0.083 0.0000138 0.00000519 140,000 390,000

Nut Trees 5 0.47 40 0.0000515 0.0000195 39,000 100,000
Fruiting Vegetables 6 0.25 40 acres 0.0000274 0.0000104 73,000 190,000

Chemigation Cranberries 0.25 lb ai/A 350

acres 0.219 0.083 0.00024 0.0000908 8,300 22,000

Ornamentals 1 0.25 60 0.0000411 0.00001568 4,900 130,000

WSP Aerial Nut Trees 5 0.45

lb ai/A 350

acres No Data 0.24 No Data 0.000473 No Data 4,200 Fruiting Vegetables 6 0.26 350 No Data 0.24 No Data 0.000273 No Data 7,300

Cotton 7 0.26 1200 No Data 0.24 No Data 0.000936 No Data 2,100

Groundboom Fruiting Vegetables 6 0.26 80 No Data 0.24 No Data 0.0000624 No Data 32,000

Cotton 7 0.26 200 No Data 0.24 No Data 0.000156 No Data 13,000

Airblast Nuts Trees 5 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 Ornamentals 4 0.25

lb ai/A 60

acres No Data 0.0049 No Data 0.000000919 No Data 2,200,000

Nut Trees 5 0.47 350 No Data 0.0049 No Data 0.0000279 No Data 72,000 Fruiting Vegetables 6 0.26 350 No Data 0.0049 No Data 0.00000558 No Data 360,000

Cotton 7 0.26 1200 No Data 0.0049 No Data 0.0000191 No Data 100,000

Groundboom Ornamentals 4 0.25 60 0.34 0.043 0.00000638 0.00000806 31,000 250,000

Nut Trees 5 0.47 80 0.000443 0.0000559 4,500 36,000Tebufenozide Human Health Risk Assessment DP No. 414533

Page 55 of 55 Fruiting Vegetables 6 0.26 80 0.0000884 0.0000112 23,000 180,000

Cotton 7 0.26 200 0.000221 0.000028 9,000 71,000

Airblast Ornamentals 4 0.25 lb ai/A 20

acres 4.71 0.068 0.000295 0.00000425 6,800 470,000

Nut Trees 5 0.47 40 0.00111 0.000016 1,800 130,000 Flagger

All Sprays Aerial Ornamentals 4 0.25

lb ai/a 60

acres 0.35 No Data 0.00000656 No Data 30,000 No Data

Nut Trees 5 0.47

350 0.00072 No Data 2,800 No Data Fruiting Vegetables 6 0.26 0.000399 No Data 5,000 No Data

Cotton 7 0.26 0.000399 No Data 5,000 No Data Mixer/Loader/Applicator

L/SC/EC Backpack Ornamentals 4 0.005

lb ai/gallon 40 gallons 140 No Data 0.000035 No Data 5,700 No Data

Nut Trees 5 0.0094 0.000658 No Data 3,000 No Data Manually

pressurized
Handwand Ornamentals 4 0.005

30 No Data 0.0000075 No Data 27,000 No Data
Other Nut

Trees 5 0.0094 0.000141 No Data 14,000 No Data

Mechanically

pressurized Handgun Ornamentals 4 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 Greenhouse 10

with respirator 24
PF5 0.0015
PF5 1,300
PF5

Nut Trees 5 0.0094 3.9 No Data 0.000585 No Data 3,400 No Data

WSP Backpack Nut Trees 5

0.009 lb ai/gallon 40 gallons 140 No Data 0.00184 No Data 1,100 No Data Manually

pressurized
Handwand Nut Trees 5 30 No Data 0.000135 No Data 15,000 No Data

Mechanically

pressurized Handgun Nut Trees 5 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: Baseli ne PPE includes no respirator, long sleeved shirt, long pants, socks

plus shoes. Eng. Controls (EC) takes into account the WSP for mulation for Mixing/Loading as well as assumes enclosed cockpits for the aerial and ground application of tebufenozide for al l
formulations.

2 Based o n 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 pla ntscapes. The one exception is for

mixing/loading/applying with mechanically pressurized handgun. Greenhouse have different exposu re units th a n 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 sel ected 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, pasture lan d, 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/da y) ÷ 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.

1 1.Tree nuts have the highest maximum application rate for airbla st scenarios. The risk estimates are protective of lower application rates found for citrus orchards and berries.