### Fenazaquin Human Health Ri s k Assessment DP No. D391819



### UNITED STATES EN VIRONMENTAL PR OTECTI ON AGENCY

WASHINGTON, D

. C

. 20460

MEMORANDUM

Date: Augu s t 29

, 20 1 4 O FFI CE OF
CHEMICAL SAF ETY AND
POLLUTION PREVEN T I ON



### SUBJECT: Fenazaquin: Human Health R i s k Assessment for Proposed New U ses on Almonds and Che rries

.

PC Code: 04450 I

Deci s ion No.: 444200

Pet itio n No.: I F7825

Ri sk Assessment Type: S i n g l e C h e mica l / Aggr eg at e
TXR No.: NA

MRID No.: NA DP Ba rc ode: 03918 1 9 Registrati o n Nos.: 10163-295 ; 10 1 63-GEE

Re g u l a to ry Action: S e cti o n 3R egist ration

Case No.: N A

CAS No.: 1 2 0928

- 09-8

40 CFR : 180.632



### FROM: Cassi Walls, Ph.D.

, Senior Biologist**~** 

### 7-**~** 

### Vincent Chen

, Toxico l og i s t

### ~, _ 

# v; ' z:-

_ Step h en Funk

, Senior

## Scien**~~** (_

_ Kristi n Rury

, Biologist**~ ~-**  

### Risk Assessment Branch III

Health Effect s Division (7509P)

THROUGH: Christine Olinger

, Branch Chief /} / / _,//

, Risk Asse ss m e nt Branch III 

# (_}I / 

# f c/-**~** 

### Health Effect s Divis i on (7509P)

TO: Olga Odio tt, Risk Ma nage r
In secticide and Rodenticide Branch Registration Di v ision (7505P )

The Health E ffects Division ( HED) of the Office of Pe sticide P rograms (OPP ) is c h arged w i th

estimati n g the risk to human health from exposure to pesticides. Gowa n Compa n y, LLC ( G owa n ) h as requested a reg i s tration of new uses of fenazaquin on a lmond s an d c herries. T h e Regi s tr ation Division (RD) of OPP has requested that HED evaluate hazard and exposure data

and conduct di e tary

, occup a ti o nal

, reside n t i a l

, and aggregate exposure assessments

, as needed

, to
estimate the ri s k to human health that will re s ult from the prop os ed uses of fenazaqui n. A

summary o f the findings and an assessment of human health ri s k resulti n g from the proposed

use s of fena z aq uin on almonds an d cherries are provided in this document. The HED team
member s contr ibu t i ng to thi s risk assessment include Ca ssi Walls (risk a ssessme nt and dietar y risk asses s ment)

, Vincent Chen (hazard reevaluation), S t eve Funk (residue c h emistry), and


## Kristin Rur y ( occupational / re s ident ial asses s m e nts)

.

Page 1of45

### Fenazaquin H uman Health R i sk Assessment 

### DP No

. 0391819



### 1.0 Executive Summary

. .. .. .. . ......................... ...... .......................................... ................. .. . ... .. . 4

2.0 HED Recommendations

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

2.1 Data Deficiencies

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

2

. 2 Tolerance Considerations

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

2.2.1 Enforcement Analytical Method

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

2.2.2 Recommended Tolerances

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

2

. 2

. 3 Revisions to Petit ioned-For Tolerances

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

2.2.4 International Harmonization

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

2.3 Label Recommendations

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

3.0 Introduction

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

3.1 Chemical Identity

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

3.2 Physical/Chemical Characteristics

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


### 3 .3 Pesticide Use Pattern

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

3 .4 Anticipated Exposure Pathways

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

3.5 Consideration of Environmental Justice

. ... . .. .. . ........... .. . ....... . ... .. . .............................. 1 0


### 4.0 Hazard Characterization and Dose

- Response Assessment..

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


### 5.0 Dietary Exposure and Risk Assessment

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


### 5.1 Metabolite/Degradate Residue Profile

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



### 5

. 1.1 Summary of Plant and Animal Metabolism Studies

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



### 5

. 1.2 Summary of Environment al Degradation

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



### 5.1.3 Comparison of Metabolic Pathways

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


### 5

. 1.4 Residues of Concern Summary and Rationale

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


### 5

. 2 Food Residue Profile

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

5.3 Water Residue Profile

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


### 5

. 4 Dietary Risk Assessment

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


### 5.4.1 D escri ption of Residue Data Used in Dietary Assessment

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


### 5.4.2 Percent Crop Treated Used in Dietary Assessment

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


### 5.4.3 Acute Dietary Risk Assessment

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


### 5.4.4 Chronic Dietary Risk Assessment

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

5.4.5 Cancer Dietary Risk Assessment..

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


### 5.4.6 Summary Tab le

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

6.0 Residential (Non-Oc cupa tional) Exposure/Risk Characterization

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



### 6.1 Residential Handler Exposure

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


### 6.2 Post-Application Exposure

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



### 6.3 Residential Risk Estimates for Use in Aggregate Assessment..

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



### 6.4 Residential Bystander Post-application Inhalation Exp osu re

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

6.5 Spray Drift

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

7.0 Aggregate Exposure/Risk Characterization

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

7.1 Acute Aggregate Risk

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

7.2 Short-Term Aggregate Risk

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

7.3 Chronic Aggregate Risk

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

7.4 Cancer Aggregate Risk

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

8

. 0 Cumulative Exposure/Risk Characterization

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

9

. 0 Occupational Exposure/Risk Characterization

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

9.1 Short-Term Handler Risk

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

9.2 Short-/lntermediate-Term Post-Application Risk

.................... .. . ... .. . .. ................... . . 28

Page 2 of 45

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 3 of 45 9.2.1 Dermal Post

- application Risk

................................ ................................ .................. 28

9.2.2 Inhalation Post

- application Risk

................................ ................................ ............. 28

10.0 References

................................ ................................ ................................ ......................... 29 Appendix A. Toxicology Profile

................................ ................................ ................................ 30

A.1 Toxicology Data Requirements

................................ ................................ ................... 30 Appendix B. Proposed Metabolic Pathways for Fenazaquin (EL

- 436) in the Rat

............... 35 Appendix C. Physical/Chemical Properties

................................ ................................ ............. 36 Appendix D. Structure of Fenazaquin and its major metabolites/degradates

..................... 37

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 4 of 45 1.0 Executive Summary

Use Profile : Fenazaquin is a quinazoline

- derived insecticide used to control mites and whiteflies, currently registered as an emulsifiable concentrate (EC) for use on outdoor ornamental plants, ornamental plants inside greenhouses, Christmas tree plantations, and non

- b earing fruit and nut trees. There are also existing tolerances for fenazaquin on imported apples, citrus (except grapefruit), citrus oil, and pears.

The Registrant, Gowan Company, has proposed domestic uses of fenazaquin on cherries and

almonds. The p roposed uses will be added to the formulated end use product label (GWN

- 1708 F, 18.79% fe nazaquin, EPA Reg. No. 10163

- GEE ), which is a liquid formulation containing 18.79% fenazaquin by weight and 1.6 lbs active ingredient (ai) per gallon. The product is a foliar spray applied using aerial and ground equipment at a maximum single and seasonal application rate of 0.45 lb ai/A.

Hazard Identification: The most consistently observed effects of fenazaquin exposure across species, sexe s, and

tr e atment durations were decreases in body weight, food consumption, and food efficiency. Fenazaquin was not observed to target a specific tissue. Fenazaquin is classified as “Not likely to be Carcinogenic to Humans.” There was no observed toxicity with resp ect to developmental toxicity, reproductive toxicity, neurotoxicity, mutagenicity, genotoxicity, or immunotoxicity. Based on the available data, toxicity endpoints and points of departure (PODs) have been selected for acute and chronic dietary, short

- term incidental oral, and short

- and intermediate

term inhalation exposure scenarios. A dermal assessment is not required for this chemical

because there was no observed systemic toxicity in rats treated up to the limit dose (1000 mg/kg/day) and no developmenta l toxicity, reproductive toxicity , neurotoxicity, and immunotoxicity effects were observed in the database. The Food Quality Protection Act (FQPA)

Safe ty Factor has been reduced to 1x because the toxicity database is complete, there is no

concern for susce ptibility in infants and young children, there are no neurotoxicity concerns, and

there are no residual unc ertainties regarding exposure.

Dietary Exposure (Food/Water):

Acute: An unrefined acute dietary (food and drinking water) assessment was conducted

. The assumptions of this dietary assessment included tolerance level residues for all registered and proposed crops and 100% crop treated (CT). Default processing factors were used

. The surface

water estimated drinking water concentration ( EDWC ) of 5.74 μ g/L from the Tier II PRZM ( P esticide R oot Z one M odel ) and EXAMS ( EX posure A nalysis M odeling S ystem) modeling was incorporated directly into the dietary assessment

.

T he acute dietary (food and drinking water) exposure to fenazaquin is below HED’s level o f concern [i.e., <100% of the acute Population Adjusted Dose (a PAD)] for the general U.S. population and all po pulation subgroups. The acute dietary exposure estimates at the 95 th


### percentile are 3 % of the a PAD for the general U.S. population and 10% of th e a P AD for children

1

- 2 years old

, the most highly exposed population subgroup.

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 5 of 45 Chronic : An unrefined chronic dietary (food and drinking water) assessment was conducted

. The assumptions of this dietary assessment included tolerance level residues for all registered

and proposed crops and 100% crop treated (CT). Default processing factors were used

. The

surface water EDWC of 2.09 μ g/L from the Tier II PRZM

- EXAMS modeling was incorporated directly into the dietary assessment

.

T he chroni c dietary (food and drinking water) exposure to fenazaquin is below HED’s level of concern [i.e., <100% of the chronic Population Adjusted Dose (c PAD)] for the general U.S. population and all po pulation subgroups. The chronic dietary exposure estimates ar e 2% of the

c PAD for the general U.S. population and 10% of the c PAD for children 1

- 2 years old, the most highly exposed population subgroup.

Residential Exposure: There are no residential uses being requested at this time. However, the existing residen tial

ornamental use was re assessed to incorporate revisions to the Residential Standard Operating Procedures (SOPs) and body weight assumptions

.

Handler Exposures : There are no residential handler risk estimates of concern for the existing uses of fenazaquin using the Revised Residential SOPs. The level of concern (LOC) for residential handler risk

estimates is a margin of exposure (MOE) of 100 (i.e., MOE < 100 are of concern) . Short

- term
inhalati on MOEs for residential handlers range from 190,000 to 19,000,000.

Post

- application Exposures: A quantitative residential post

- application assessment was not conducted for fenazaquin exposure for adults and children because: (1) d ermal endpoints for were not selected ; (2) post

application inhalation exposure is considered negligible from use on ornamentals ; and (3) there is no incidental oral exposure expected from fenazaquin use on ornamental plants.

Aggregate Exposure:

Acute: Aggregate acute ris k is equ ivalent to acute dietary risk ( e.g., food and drinking water

exposure ) where the estimates are not of concern.

Chronic : Aggregate chronic risk is equivalent to ch ronic dietary risk ( e.g., food and drinking

water exposure ) where the estimates are not of concern.

Short

- and Intermediate Term: There is potential short

- term aggregate exposure to fenazaquin

for adults from dietary exposure (which is considered background exposure) and residential dermal and inhalation exposures from handling fenazaqu in

. However, since no hazard was identified for the dermal route of exposure, short

- term ag gregate risk estimate included dietary and inhalation exposures only

. The aggregate MOE for adults is 5,2 00 and not of concern to

HED. Since there is no residenti al exposure for children, there is no potential short

- term aggregate risk.

Intermediate

- term aggregate exposures are not expected based on the use profile of fenazaquin, therefore they were not assessed.

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 6 of 45 Occupational Exposure : Occupational Handler Exposures : Occupational short

- and intermediate

- term dermal and inhalation exposures are expected from fenazaquin handler activities associated with the proposed almond and cherry use s

. Sin ce no hazard was identified for the dermal route of exposure, de rmal exposures were not assessed

. MOEs greater than 100 for the inhalation route is deemed adequate to pr otect occupational fenazaquin handlers. All handler scenarios resulted in MOEs greater than the level of concern (LOC = MOEs ≥ 100) for inhalation ex posures and, therefore are not of concern.

Occupational Post

- application Exposures: Occupational short

- term dermal exposures are expected from fenazaquin post

- application

activities associated with the proposed almond and cherry uses

. However, s in ce no hazard was

identified for the dermal route of exposure, dermal exposures were not quantitatively assessed

. Based on the Agency's current practices, a quantitative non

- cancer post

- application inhalation exposure assessment was not performed for fenazaquin at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for fenazaquin

.

Restricted Entry Interval : The labeled restricted entry interv al (REI ) of 12

- hrs is adequate to protect agricultural workers from post

- applic ation exposures to fenazaquin. Per the Worker Protection Standard (WPS), fenazaquin is classified as Toxicity Category III for acute inhalation

and IV for acute dermal exposure and require s a 12

- hr REI

.

Review of Human Research: This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from

the PHED, AHETF, and Residential SOPs (for the garden/tree SOP); are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at http://www.epa.gov/pesticides/science/handl er

- exposure

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

- app

- exposure

- data.html

.

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

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

.

2.0 HED Recommendations

HED has examined the residue chemistry, toxicity, and exposure database s for fenazaquin and concluded that, provided a revised Section F is submitted, there are no deficiencies that would preclude granting a Section 3 registration on almonds and cherries.

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 7 of 45 2.1 Data Deficiencies

None

2.2 Tolerance Considerations

2.2.1 Enforcement Analytic al Method

An acceptable analytical method exists for the enforcement of plant commodity tolerances. The

HPLC

- MS/MS method is the same as that used for data collection and has been shown acceptable over a range of commodities. The method has undergone suc cessful independent laboratory confirmation. Testing with radiolabeled samples showed that the method recovers adequate amounts of the analyte.

2.2. 2 Recommended Tolerances

Tolerances are established for residues of fenazaquin , including its metabolit es and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified

below for plant commodities is to be determined by measuring only fenazaquin in or on the commodity

.

Table 2.2.2

. Tolerance Summary for Fenazaquin

Commodity Established/Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments

Correct Commodity Definition
Almond, hulls 0.6 4.0 A revised Section F must be submitted to propose a tolerance at

4.0 ppm Almond 0.02 0.02 Almond Cherry 1.5 2.0 A revised Section F must be

submitted to propose a tolerance at

2.0 ppm.



### 2.2. 3 Revisions to Petitioned

- For Tolerances

The use of the Organization of Economic Cooperation and Development (OECD) tolerance derivation procedures indicates the need for the following changes in proposed tolerances:

cherries from 1.5 ppm to 2.0 ppm and almond hull from 0.6 ppm to 4.0 ppm.

The tolerance expression (for plant commodities) should be stated as follows:

Tolerances are established for residues of the insecticide fenazaquin , including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only fenazaquin, or 4

- [2

- [4

- (1,1

- dimethylethyl)phenyl]ethoxy]quinazoline

.

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 8 of 45 2.2

. 4 International Harmonization

There are no established maximum residue limits (MRLs) for fenazaquin in the Codex system. There are no established or pending MRLs in Canada for fenazaquin. Therefore, there are no

harmonization issues.

2.3 Label Recommendations

Based on discussions with the Registrant and the proposed use pattern (foliar insecticide for use in orchards on almond and cherry trees), HED recommends that language regarding chemigation application be removed from the proposed label. Fenazaquin application via chemigation should also be restricted from on the proposed label.

3.0 In troduction

Fenazaquin , 4

- tert

- butylphenethyl quinazolin

- 4

- yl ether, is a q uinazoline class

insecticide/ac aricide used to control mite s and whiteflies. F enazaquin is currently registered in

the U.S. for use on Christmas trees (plantations), outdoor and greenhouse

- grown ornamental plants, established ornamental landscapes (including interiorscapes and around residential premises), and on non

- bearing fruit a nd nut trees. Additionally, fenazaquin has tolerances to
support the importation of apples, pears and citrus fruits treated with fenazaquin that are grown in other countries for exp ort to the U.S.

3.1 Chemical Identity

The structure and nomenclature o f fenazaquin is presented below in Table 3.1. The chemical structure of fenazaquin and its major metabolites/degradates are presented in Appendix D.

T able 3.1

. Fenazaquin Nomenclature.
Compound

Common name Fenazaquin Molecular weight 306.4 Company experimental name s XDE

- 436, EL

- 436, XRD

- 562; DE

- 436

IUPAC name 4

- tert

- butylphenethyl quinazolin

- 4

- yl ether

CAS name 4

- [ 2

- [4

- (1,1

- dimethylethyl)phenyl]ethoxy]quinazoline CAS registry number 120928

- 09

- 8

End

- use products (EP) 10163

- GEE (GWN

- 1708 F, 1.6 pounds ai/gal suspension concentrate)

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 9 of 45 3.2 Physical/Chemical Characteristics

Fenazaquin has a log octanol/water partition coefficient (log K ow 

### ) of > 3 .0 and is slightly water
soluble indicating that it is fat soluble . However, fenazaquin has a molecular weight of 306 .4 g/mol; therefore, the potential to cross biological barriers is somewhat limited. Based on laboratory and field studies, fenazaquin was found to be persistent an d im mobile under most

environmental conditions. The vapor pressure of fenazaquin is c onsidered low ( 1 .4 x10

- 7 

### mm Hg

at 25 oC), limiting the potential for inhalation exposure

. A summary of the physical/chemical characteristics of fenazaquin is provided in Appendix C.

3.3 Pesticide Use Pattern

Gowan has proposed to add al mond and cherry use s to the GWN

- 1708 F label as summarized in

Table 3.3 below

.

Table 3.3 Summary of Proposed Directions for Use of Fenaza quin (Label GWN

- 1708F, 10163

- GEE ).

Application. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate

lb ai/A (fl oz/A) PHI 1

(days) Use Directions and

Limitations

Almonds

Foliar spray GWN

- 1708F;

10163

- GEE; Suspension

concentrate 0.45 1 0.45 ( 36 ) 7 Ground application in a

minimum of 10 0 gallons

water/A Aerial application in a minimum of 5 gallons

water/A. Do not apply more than one application per year.

Cherries

Foliar spray GWN

- 1708F;

10163

- GEE; Suspension

concentrate 0.45 1 0.45 ( 36 ) 3 Groun d application in a

minimum of 50 gallons

water/A Aerial application in a minimum of 5 gallons

water/A. Do not apply more than one application per year

. 1 PHI = Preharvest interval



### 3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new use of fenazaquin on almonds and cherries. Humans may be exposed to fenazaquin in food and drinking water, since fenazaquin may be applied directly to growing crops and application may result in fenazaquin reaching surface and ground water so urces of drinking water . There are

ornament al residential uses of fenazaquin , so there are likely to be exposures in residential or

non

- occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to ap plication, as well as during application. There is a potential for

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 10 of 45 post

- application exposure for workers re

- entering treated fields.

Risk assessments have been previously prepared for the existing uses of fenazaquin. This risk

assessment considers all of the aforementioned exposure pathways based on the proposed new uses of fenazaquin, but also considers the existing uses as well, particularly for the dietary
exposure assessment.

3.5 Consideration of Environmental Justice

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

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

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

- estab lished 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 USDA under the National Health and Nutrition Examination Survey, What We E at in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered fo od uses of a pesticide. These data are analyzed and categorized by subgroups based on age, and ethnic group . Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

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

- application are

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

4.0 Hazard Characterization and Dose

- Response Assessment

Fenazaquin is a quinazoline

- derived insecticide used to control mites and whiteflies. Fenazaquin ’s pesticidal mode of action is through inhibition of the mitochondrial electron transport at the Complex I site (NADH

- ubiquinone reductase). There are no mammalian

molecular data to confirm this mode of action in the test animals.

4.1 Toxicology Studies Available for Analysis

The toxicity studies available for risk assessm ent include an acute toxicity battery; subchronic oral studies in rats, hamsters, and dogs; subchronic dermal study in rabbits; chronic toxicity studies in rats and dogs; carcinogenicity studies in rats and hamsters; developmental toxicity

studies in rats and rabbits; a 2

- generation reproduction study in rats; a battery of mutagenicity and genotoxicity studies; an acute neurotoxicity study in rats; metabolism and pharmacokinetic studies in rats; and an immunotoxicity study in rats.

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 11 of 45 Three studies, a 21

- day dermal toxicity in rabbits, a developmental toxicity in rabbits, and an

a cute neurotoxicity study , were previously identified to have deficiencies. These studies were further evaluated in the context of the toxicity results from the entire database. The re sults of this evaluation were presented to HED Hazard and Science Policy Council (HASPOC). The Council conducted a thorough analysis of all the available toxicity and exposure information for fenazaquin, and recommended upgrading the classification and not requiring new studies with respect to (1) acute neurotoxicity, (2) subchronic dermal toxicity, and (3) developmental toxicity study in rabbits. The requirements for a subchronic inhalation toxicity study and a subchronic neurotoxicity study in rats were a lso waived (HASPOC 10 April 2014; TXR 0056942 ).

4.2 Absorption, Distribution, Metabolism and Excretion (ADME)

ADME was evaluated in rats of both sexes under the following scenarios: A single or repeated

oral low dose administration (1 mg/kg); and a single oral high dose administration (30 mg/kg). Fenazaquin demonstrated rapid absorption, systemic distribution, extensive metabolism, and near complete excretion within 72 hours. Fenazaquin distribution does not correlate with organ

spe cific toxicity nor is it indicat ive of bioaccumulation potential.

Rats absorbed 65% of the orally administered dose (AD) in male rats over 48 hours. The data

collected in male and non

- pregnant female rats at 1 mg/kg suggests a time to peak plasma level (t max 

### ) between 4

- 8 hrs. The plasma elimination half

- life (t 1⁄2 

### ) could not be ascertained due to the limitations of the pharmacokinetic study’s design. Fenaza quin residues were distributed in low

and insubstantial levels (<0.04% AD) throughout the rat carcas s. The majority of the AD was eliminated from the rat within 48 hrs (97% AD); and feces was the primary route of elimination with the parent compound accounting for 1.2

- 4.2% AD.

Fenazaquin was extensively metabolized in rats, and the major metabolites we re AN

- 1 (found in urine), and the fecal metabolites F

- 1, F

- 2 and F

- 3 (as shown in Appendix B)

. Based on characterization of metabolites, metabolism was mostly the result of cleavage separating the two aromatic rings or oxidation of the t ert

- butyl group (to either a hydroxyl or carboxyl group).

4.2.1 Dermal Absorption

The registrant submitted an in vitro dermal penetration study (OECD 428), the results suggests a dermal absorption factor (DAF) of 0.5

- 7.3%. In the absence of an in vivo dermal absorption study, a definitive DAF could not be established for use in risk assessment with respect to the

der mal penetration guideline (OCSPP 870.7600).

4.3 Toxicological Effects

The most consistently observed effects of fenazaquin exposure acro ss species, genders, and

tre atment durations were decreases in body weight, food consumption, and food efficiency. The effects on body weight and food consumption were consistent with the commonly observed findings for compounds which disrupt mitochondrial respiration. Other effects noted were mild dehydration and certain clinical signs seen at relatively high dose levels in the acute neurotoxicity study. These clinical signs, which included increased foot splay, decreased motor

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 12 of 45 activity, sluggish arousal, unusual posture, abnormal gait, and altered response to auditory

stimuli were seen in the absence of any neuropathological changes and were not considered to be related to neurotoxicity

. In a 90

- day study in hamsters, treated animals had an increased

incid ence of testicular hypospermatogenesis and reduced testicular and prostate weight; however, these findings were not replicated in the hamster carcinogenicity study which suggest

the effects were transient or reversible

.

Fenazaquin did not cause any develo pmental or reproductive toxicity at the doses tested in rats and rabbits. In the rat study, developmental toxicity was not observed in the presence of maternal toxicity (i.e. decreases in body weight gain, food consumption, and food efficiency). In the rab bit study, no developmental or maternal toxicity was seen. In the reproduction study, systemic toxicity manifested in parental animals as excessive salivation and decreased body weight and food intake; in offspring as decreased body weight gain; and there was no observed reproductive toxicity. Therefore, there is no developmental toxicity or reproductive susceptibility with respect to fetal and developing young animals with in utero and postnatal exposures.

Carcinogenicity was evaluated in t he hamster in st ead of the mouse because the hamster was found to be more sensitive to the effects of fenazaquin than mice due to slower elimination

kinetics for hamster. In a three

- month feeding study in the mouse, it was found that 6

- 22x higher dose levels were required to elicit a comparable effect in mice than in the hamster. The results of

the rat and hamster carcinogenicity studies demonstrated no increase in treatment

- related tumor incidence. Therefore, fenazaquin was classified as “Not likely to be Carcinogenic to Humans.”

Fenazaqu in did not cause mutagenicity, genotoxicity, neurotoxicity, or immunotoxicity. Fenazaquin did not demonstrate any systemic toxicity in a 21

- day dermal toxicity study in rabbits up to the limit dose (1000 mg/kg/day).

Fenazaquin has high acute oral toxicity (Category II); and low acute toxicity by dermal and inhalation routes of exposure (Categories IV and III, respectively). Fenazaquin is not a skin irritant (Category III), but it is minimally irritating to the eye (Category IV). Fenazaqu in is considered to be a dermal sensitizer; Technical Review Branch ( TRB ) / Registration Division ( RD ) made this recommendation due to the lack of an acceptable dermal sensitization study demonstrating otherwise.

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

The 10 x FQPA Safety Factor can be reduced to 1x because the toxicity database is complete

, there is no evidence of sensitivity/susceptibility in the developing organism

, no evidence of neurotoxicity, and no residual uncer tainty in th e exposure data. The details are discussed below.

4.4.1 Completeness of the Toxicology Database

As de s cribed in Section 4.1, HED HASPOC recommended upgrading and not requiring new

studies for acute neurotoxicity study, subchronic dermal toxicity study, a nd developmental study

in rabbits . In addition, the HASPOC recommended waiving the requirements for a subchronic inhalation study and a subchronic neurotoxicity study . In the presence of these recommendations,

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 13 of 45 the toxicity database for fenazaquin was consi dered complete and sufficient for assessing susceptibility to infants and children as required by FQPA

.

4.4.2 Evidence of Neurotoxicity

There are no indications in any of the studies available that the nervous system is a target for fenazaquin

. In the ac ute neurotoxicity study in rats at the highest dose tested (130 mg/kg/day in males and 120 mg/kg/day in females), the clinical signs such as mild dehydration, increased foot splay, decreased motor activity, sluggish arousal, unusual post u r e , abnormal gait, and altered response to auditory stimuli were observed on Day 1 only. An increase in the incidence of minimal nerve fiber degeneration was also reported in the high dose males, but in females, this incidence was greater in controls than that in the high d ose group. Considering the findings in both genders, the finding of minimal nerve fiber degeneration was considered to be equivocal because when the data for both sexes are combined the incidence for the high dose animals was

no different from the controls . The neuropathology findings seen in this study were also evaluated by EPA’s Office of Research and Development (ORD); the conclusion was that minimal nerve fiber degeneration found in the highest dose animal in this study should not be

considered as a tr eatment

- related effect for the reasons just discussed. Therefore, i n the absence of neuropathology, the observed clinical signs were not considered to be related to neurotoxicity. Additional supporting evidence for this conclusion was that in the repeated dosing studies in rats, dogs, and hamsters, there were no clinical signs indicative of neurotoxicity; no gross/microscopic pathology findings were observed in central or peripheral nervous systems in these studies.

The HASPOC evaluated the available toxicity data in association with the possible need for a subchronic neurotoxicity study, and it was determined that a subchronic neurotoxicity study was

not needed at this time because 1) indications of treatment

- related clinical signs in the ACN were well

- characterized; 2) effects seen in ACN we re observed at doses higher than current PODs; and 3) there was no indication of treatment

- related neurotoxicity observed in any repeated dosing

studies. In the absence of gross neurotoxicity or neuropathology findings in the available database, a developmental neurotoxicity study is not required.

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

Susceptibility/sensitivity in the developing animals w as evaluated in developmental toxicity studies in rats and rabbits as well as a reproduction and fertility study in rats.

In the rabbit developmental toxicity study, toxicity was not observed in dams or fetuses up to 13 mg/kg/day; HED excluded the high do se group (60 mg/kg/day) because of a loss of nearly a third of that dose group due to technical difficulties that were not deemed to be test substance related. Despite the technical difficulties, the surviving animals at the 60 mg/kg/day dose group did not demonstrate any maternal or fetal toxicity. Additionally, there were no fetal effects up to the highest dose tested (100 mg/kg/day) in a range

- finding developmental toxicity study in rabbits. In the rat developmental toxicity study at the highest dose tes ted (40 mg/kg/day), maternal toxicity consisting of decreases in food consumption and body weight gain occurred in the absence of any developmental toxicity in fetuses.

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 14 of 45 In the reproduction study, the offspring effects (i.e., decreased body weight gain du ring lactation) occurred only in the presence of parental toxicity (i.e., excessive salivation and decreased body weight, body weight gain, and food intake). Therefore, there is no e vidence of

s ensitivity/ s usceptibility in the d eveloping or y oung a nimal

. C lear NOAELs and LOAELs are available for all the parental and offspring effects. Therefore, there are no residual pre

- or post

natal concerns.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. Since the dietary and non

- dietary exposure estimates were based on several conservative assumptions, HED does not believe that the exposure estimates are underestimated. The acute and chro n ic dietary assessment s conducted

with DEEM

- FCID were screening level analyse s. The assessment s utilized tolerance values, default processing factors, and assumed that 100% of the registered and proposed crop s were treated w ith fenazaquin . The dietary exposure analys e s also assumed that all drinking water will

contain fenazaquin at the highest EDWC levels modeled by Environmental Fate and Effects Division ( EFED )

. Therefore, the dietary exposure analys es do not underestimate risk from acute

or c hronic dietary exposure to fenazaquin. Similarly, HED does not believe that the non

- dietary

residential exposure s are not underestimated because they are also based on conservative assumptions

, including maximum application rates, and standard values for u nit exposures,

amount handled as described in the Residential SOPs.

4.5 Toxicity Endpoint and Point of Departure Selection

4.5.1 Dose

- Response Assessment

The doses and endpoints selected for dietary risk assessments are shown in Table 4.5.4.1. For

acut e dietary exposure, the results from the immunotoxicity study were considered in selecting toxicity endpoints and points of departure (POD) for risk assessment. The NOAEL of 15 mg/kg/day was selected as the POD based on clinical signs (i.e. general ataxia/ hypoactivity) observed after a single exposure at the LOAEL of 30 mg/kg/day. The endpoint is appropriate for this exposure scenario since the effects were seen after a single oral administration. In addition, it is also protective of the clinical signs (i. e., mild dehydration) seen in the acute neurotoxicity study at 60 mg/kg (LOAEL). An acute reference dose (aRfD) of 0.15 mg/kg/day was derived from the NOAEL with the application of an Uncertainty Factor (UF) of 100x (10x inter

- species extrapolation, 10x in tra

- species variations factor).

A separate endpoint of concern for pregnant females (13

- 49 years of age) was not selected since no endpoints attributable to a single dose were identified in the developmental toxicity studies in

rats and rabbits.

For chro nic dietary exposure, the toxicity endpoints of decreases in body weight, food consumption, and food efficiency were selected, and these effects were seen at similar dose levels in both subchronic (15 mg/kg/day) and chronic (12 mg/kg/day) oral toxicity stu dies in dogs. The NOAELs were the same for both chronic and subchronic toxicity studies in dogs. The results from these two studies demonstrated no increase in severity with increased treatment

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 15 of 45 durations. Hence, the subchronic and chronic toxicity studies in dogs were appropriate to be employed as co

- critical studies for toxicity end point and point of departure selections for the chronic exposure scenario. A chronic reference dose (cRfD) of 0.05 mg/kg/day was derived from a NOAEL of 5 mg/kg/day and an UF o f 100x. While the NOAEL of the chronic toxicity study in the hamster (2 mg/kg/day) is lower than that of dogs, it was not selected because it was

considered to be an artifact of dose

- selection.

For the short term incidental oral exposure risk assessment, the toxicity endpoints and NOAEL seen in the subchronic and chronic dog studies were deemed appropriate for the short term incidental oral exposure scenario since the effects in the dog studies were similar in both subchronic and chronic toxicity studies. Similar effects were also seen in the reproduction study.

Dermal endpoints for both short

- and intermediate

- term exposures were not selected because an

in vitro dermal penetration study suggested that the dermal absorption was less than 8%, and

there were no systemic effects observed in the 21

- day dermal toxicity study in rabbits up to the limit dose (1000 mg/kg/day). There was no treatment related toxic effects observed in the oral studies with respect to developmental and reproductive toxicity or suscept ibility; additionally, no toxic effects were observed with respect to neurotoxicity or immunotoxicity.

An inhalation study is not included in the available database (and the requirement has been waived as discussed in Section 4.1) so inhalation endpoints for occupational and residential exposures were derived from oral studies. For sh ort

- and intermediate

- term inhalation, the NOAEL of 5 mg/kg/day was used as the POD from co

- critical subchronic and chronic toxicity studies in dogs, with LOAELs of 15 and 12 mg/kg/day, respectively, based on decreased body weight and food consumption/efficiency.

There are no long

- term dermal or inhalation scenarios anticipated for this risk assessment

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

HED has considered the potential for concurrent exposure via oral , dermal, and inhalation routes;

HED aggregates exposure from different routes for each population if the same toxic effects are seen for that duration of exposure by each route. Since oral and inhalation endpoints are based on

the same effect s ( i.e., decrease s in body weight , food consumption, and food efficiency ), these routes of exposure may be combined for residential exposure risk assessment.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Fenazaquin is classified as “Not likely to be Carcinogenic to Humans” based on the absence of a

treatment

- related increase in tumor incidence in adequately conducted carcinogenicity studies in

hamsters and rats

.

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 16 of 45 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

Table 4.5.4.1 presents a summary of the endpoints selected for fenazaquin for use in risk

assessments

. A summary of the acute toxicity categories for the technical material are included in Appendix A

.

Table 4.5.4.1

. Summary of Toxicological Doses and Endpoints for use in Dietary and Non

- Occupational Human Health

Risk Assessments Exposure Scenario Point of Departure (POD) Uncertainty / FQPA

Safety Factors RfD, PAD, and

LOC for Risk

Assessment Study and Toxicological Effects

Acute Dietary

G eneral population ( including i nfants and

children )

And Females (13

- 49 years) NOAEL=

15 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x aRfD = 0.15 mg/kg/day

aPAD = 0. 15 mg/kg/day Immunotoxicity

– Rat

LOAEL = 3 0 mg/kg/day Based on clinical signs (general ataxia/hypoactivity) observed in 1 animal on Day 02 and 3 animals on Day 03 of dosing. Chronic Dietary All populations NOAEL= 5 mg/kg/day UF A = 10 x

UF H = 10 x FQPA SF= 1 x c RfD = 0.05 mg/kg/day

cPAD = 0.0 5 mg/kg/day Co

- Critical: Subchronic and Chronic

Toxicity

– Dog

Subchronic Toxicity

– Dog LOAEL = 15 mg/kg/day Based on decreased body weight and food consumption/efficiency.

Chronic Toxicity

– Dog

LOAEL = 12 mg/kg/day

B ased on decreased body weight and food consumption/efficiency

Incidental Oral

Short Term (1

- 30 days) NOAEL = 5 mg/kg/day UF A = 10 x

UF H = 10 x FQPA SF= 1 x LOC =

MOE = 100 Co

- Critical: Subchronic and Chronic

Toxicity

– Dog

Same as Chronic Dietary

Inhalation

Short Term (1

- 30 days )

And

Intermediate Term (1

- 6 months) NOAEL = 5 mg/kg/day UF A = 10 x

UF H = 10 x FQPA SF= LOC =

MOE = 100 Co

- Critical: Subchronic and Chronic

Toxicity

– Dog

Same as Chronic Dietary

Dermal Short Term (1

- 30 days)

And

Intermediate Term (1

- 6 months) T here is no ident ified hazard for this scenario because there was no observed systemic toxicity in rats treated up to the limit dose (1000 mg/kg/day). Additionally, developmental toxicity

, reproductive susceptibility, neurotoxicity, and immunotoxic ity effects were not observed in the database.

Cancer (oral, dermal, and inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

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

= no observed adv erse 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). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 17 of 45 Table 4.5.4.2 : Summary of Toxicological Doses and Endpoints for use in Occupational Human Health Risk Assessments Exposure Scenario Point of Departure (POD) Uncertainty / FQPA

Safety Factors RfD, PAD, and

LOC for Risk

Assessment Study and Toxicological Effects

Inhalation

Short Term (1

- 30 days )

And

Intermediate Term (1

- 6 months) NOAEL = 5 mg/kg/day UF A = 10 x

UF H = 10 x LOC =

MOE = 100 Co

- Critical: Subchronic and Chronic

Toxicity

– Dog

Same as Chronic Dietary exposure

scenario in Table 4.5.4.1

Dermal Short Term (1

- 30 days)

And

Intermediate Term (1

- 6 months) T here is no ident ified hazard for this scenario because there was no observed systemic toxicity in rats treated up to the limit dose (1000 mg/kg/day). Additionally, developmental toxicity

, reproductive susceptibility, neurotoxicity, and immunotoxicity effects were not observed i n the database.

Cancer (oral, dermal, and inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

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

= no observed adverse effect level. LOAEL = lowe st 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). MOE = margin of exposure. LOC = level of conc ern. N/A = not applicable.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Metabolism studies in apples and citrus were previously evaluated to support tolerances in/on imported apple, citrus fruits (except grapefruit), and pear. New metabolism studies conducted with grapes and corn; lettuce, wheat and radish (confine d rotational); poultry and goat. An

aerobic soil metab olism study and aerobic aquatic metabolism s tudy were submitted to support the proposed new uses. It should be noted that subsequent to the completion of the residue chemistry memo (D391810, S. Funk, 07/25/12) and ROCKS meeting decision (D397773, I. Negrón

- Encarnación, 04/18/12) Gowan amended the p roposed label to i nclude only almonds and cherries. There is one livestock (cattle) feed item, almond hulls, however, based on a maximum reasonably based diet (MRBD), no residues are anticipated in the livestock commodities.

The residue chemistry databa se is adequate for determining residues of concern

. Metabolism studies were conducted with fenazaquin radiolabled in the phenyl ring or in the quinazoline ring. Parent fenazaquin is a major residue in corn grain, corn stover, grape, orange, and apple.

F enazaquin dimer , a photolysis product, is absent in grapes, but is a major metabolite in corn stover and apple, and a minor metabolite in corn grain. Other metabolites are generally <10% of the Total Radioactive Residue (TRR) across all matrices and PHIs

. The exceptions are

metabolite I (2

- hydroxy fenazaquin) and metabolite C (fenazaquin alcohol) which were observed in grapes at maximum concentrations of 26% and 12.9 % of the TRR, respectively. However, about half of metabolite I is conjugated. See Appendix D for a list and description of all

metabolites.

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 18 of 45 A confined rotational crop study (1X) was conducted with lettuce, wheat, and radish. Fenazaquin was found at concentrations > 0 .01 ppm only in 30

- day PBI radish root (0.03 ppm)

. Fenazaquin was ex tensively degraded/metabolized in the confined rotational crop study to multiple metabolites/degradates that were also observed in the primary crop metabolism studies.

With a 120

- day plant back interval ( PBI ) for root and tuber and bulb vegetables (and 30 days for all other crops), there will be no significant rotational crop residues.

T he livestock metabolism studies were performed by administrating radiolabeled fenazaquin to poultry and goats. T he highest total radioactive residues (TRR) were in the fat and liver of goats and the fat of poultry, suggesting that fenazaquin partitions into fat and is detoxified via the liver

in ruminants

. In addition, fenazaquin was a major residue in milk. Fenazaquin was absent in goat muscle, kidney, and liver and w as present at low levels (<10% TRR or <0.01 ppm) in poultry muscle and eggs and absent in liver . Major metabolites in goat were metabolite M29 in muscle, kidney, and liver; metabolite M34 in liver; and metabolite J in milk . Metabolite J in

milk was at a low absolute amount, <0.01 ppm

. The major metabolite in muscle, liver, and eggs

of poultry was metabolite I

.

5.1.2 Summary of Environmental Degradation

Fenazaquin is persistent and immobile in terrestrial and aquatic environments. Degradation products of fenazaquin can be classified according to their formation by cleavage of the ether (ethoxy) linkage. This cleavage generates products with only the ter t

- butylphenyl group or the quinazoline group. The quinazoline products form mostly 4

- quinazo linol and 2,4

- quinazoline

diol. Linkage intact products are reactions involving the quinazoline part of the molecule. Major degradation products (> 10% of applied radioactivity) of fenazaquin are 4

- (2

- (4

- (1,1

- imethylethyl)phenyl)ethoxy)quinazolone (Metabol ite 1), and 2

- Methyl

- 2

- (4

- {2

- [(2

- oxo

- 1,2

- dihydroquinazolin

- 4

- yl)oxy]ethyl}phenyl) propanoic acid (Metabolite 2 9 )

.

The environmental fate studies showed that fenazaquin has a half

- life from 51 to 123.8 days in aerobic soil and 58.7 to 133.3 days in aerobic aquatic environments. Two major degradates were

identified in the aerobic aquatic metabolism , metabolite 1 and metabolite 29

. The half

- life of fenazaquin total toxic residues (parent + metabolite 1 + metabolite 29) ranged from 73 to 197 days in aerobic soil metabolism studies, and 65 to 291 days in aerobic aquatic environments. Additionally, the mobility of the metabolites, especially Metabolite 29, is expected to be higher than parent fenazaquin.

5.1.3 Comparison of Metabolic Pathways

Fenazaquin is extensively metabolized in rats, resulting with the major metabolites of AN

- 1 (found in urine) and the fecal metabolites ( F

- 1, F

- 2 and F

- 3 ) (see Appendix B)

. Based on characterization of metabolites, metabolism was mostly the result of cleavage separating the two aromatic rings or oxidation of the t ert

- butyl group (to either a hydroxyl or carboxyl group).

The predominant residues in plants are parent fenazaquin and its dimer

, which is a photolysis product

. The dimer is unlikely to be cleaved back to the parent. Fenazaquin tends to be a

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 19 of 45 surface residue and metabolizes via oxidation of the t

- butyl methyl group, oxidation of the C

- 2 of the quinazoline ring, and hydroxylation/cleavage of the ether linkage.

The aquatic metabolism studies showed metabolite 1 and metabolite 29 as major metabolites. Metabolites are formed via cleavage of the ether linkage.

5.1.4 Residues of Concern Summary and Rationale

The residue of concern for risk assessment and tolerance enforcement in prim ary and rotational crops is pa rent fenazaquin. Parent fenazaquin, metabolite 1 and metabolite M29 are included as residues of concern in drinking water. Table 5.1.4 summarized the residues of concern for fenazaquin.

Plants: The predominant residues in plants are parent fenazaquin and its dimer

. The dimer is excluded as a residue of concern since it is unlikely to be cleaved back to the parent, and is not likely to be bioavailable after ingestion due to its high molecular weight and lipophilic properties. Metabolite I was not co nsidered a residue of concern

, since about half of it is conjugated and it was observed in grapes 76 days after treatment (DAT)

, which is much longer than the proposed PHI of 7 days. Although metabolite C was 12.9% of the TRR in grapes 49 DAT, the absolut e amount (0.046 ppm) is fairly low. Metabolite C was absent or <10% TRR in other crops studied. Therefore, it is not considered a residue of concern. The residue of concern

for risk assessment and tolerance enfo rcement in primary crops is parent fenazaqu in.

Rotational Crops: The confined rotational crop studies showed similar results to those of primary crops. The residue of concern for risk assessment and tolerance enforcement in rotational crops is parent fenazaquin.

Livestock: Metabolism studies i n goat showed parent fenazaquin and metabolite J as the major

metabolites observed in milk. The latter was identified as 4

- hydroxyquinazoline (metabolite J)

, which doesn’t appear to be more toxic than parent fenazaquin. In addition, the absolute amount

o f metabolite J is below 0.01 ppm. Fenazaquin was the major component of the residue in fat, with no single metabolite identified above 1.1% TRR. Based on this, the residue of concern for

risk assessment and tolerance enforcement in f at and milk of rumin ants is parent fenazaquin. Two different major metabolites were observed in meat, liver and/or kidney, metabolite M29 and

met abolite M34. The latter is excluded as a residue of concern since it was only observed as a major metabolite in goat liver (15.3% TRR) and it appears to be very water soluble. The residue of concern for risk assessment and tolerance enforcement in kidney, live r and muscle of

ruminant is parent fenazaquin and metabolite M29. Based on the proposed uses of fenazaquin,

there is no rea sonable expectation of residues in poultry; however, the residues of concern were identified in case new uses are proposed. Parent fenazaquin and metabolite I were the major residues observed in poultry. Both are recommended as residues of concern in pou ltry

commodities for tolerance enforcement and risk assessment.

Water: The aquatic metabolism studies showed metabolite 1 and metabolite 29 as major metabolites. These are structurally similar to parent fenazaquin; therefore, they are not likely to

be less toxic than the parent. The ROCKS recommends that parent fenazaquin, metabolite 1 and

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 20 of 45 metabolite M29 are included as residues of concern in drinking water. For the risk assessment, it

is assumed that the M29 and metabolite 1 have a similar toxicity to the parent. Drinking water exposure is estimated for total residues of fenazaquin, M29 and metabolite 1

.

Table 5.1.4. Summary of Metabolites and Environmental Transformation Products t o be Included in the Risk Assessment and Tolerance Expression 1

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Fenazaquin Fenazaquin

Rotational Crop Fenazaquin Fenazaquin

Livestock Ruminant Milk, Fat: F enazaquin Liver, Kidne y, Meat : F enazaquin and Metabolite M29 Milk, Fat : F enazaquin Liver, Kidne y, Meat : F enazaquin and Metabolite M29

Poultry Fenazaquin and

Metabolite I Fenazaquin and

Metabolite I

Drinking Water Fenazaquin, Metabolite 29 and

Metabolite 1 Not Applicable

1 Fenazaquin is 4

- [[4

- (1,1

- dimethylethyl)phenyl]ethoxy]quinazoline; Metabolite M29 is 2

- (4

- {2

- [(2

- hydroxyquinazolin

- 4

- yl)oxy]ethyl}phenyl)

- 2

- methylpropanoic acid and its tautomer 2

- Methyl

- 2

- (4

- {2

- [(2

- oxo

- 1,2

- dihydroquinazolin

- 4

- yl)oxy]ethyl}phenyl)propanoic acid ; Metabolite I is quinazoline

- 2,4

- diol a nd its tautomer quinazoline

- 2,4(1 H ,3 H

)

- dione ; Metabolite 1 is 4

- [2

- (4

- tert

- butyl

- phenyl)

- ethoxy]

- quinazolin

- 2

- ol a nd its tautomer

4

- [2

- (4

- tert

- butylphenyl)ethoxy]quinazolin

- 2(1 H )

- one

.



### 5 .2 Food Residue Profile

The submitted magnitude of the residue data , summarized in Table 5.2.1, are adequate for risk

assessment and tolerance assessment (D391810, S. Fu nk, 07/25/12 ). Residues of fe nazaquin were detected at low levels, indicating that there will be low exposure to fenazaquin in food. Processing studies were not conducted for processed commodities a ssociated with proposed

crops.

Table 5.2.1 . Summary of Residues from Field Trials w ith Fenazaquin

Crop

Matrix Analyte Applic.

Rate (lb ai/acre) PHI

(days) n 1 Residues (ppm)

Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3

STONE FRUIT, Proposed Cherry Use = 0.45 lb ai/acre total application rate, 3

- day PHI Cherry,

sweet/tart Fenazaq

uin 0.45 3 12 0.233 0.965 0.255 0.914 0.521 0.587 0.246

Cherry,

sweet/tart Dimer 0.45 3 12 <0.01 0.0165 0.01 0.0163 0.01 0.0105 0.0018

TREE NUTS, Proposed Almond Use = 0.45 lb ai/acre total application rate, 7

- day PHI

Almond

Nutmeat Fenazaq

uin 0.44

–

0.45 7 10 <0.01 0.0116 0.01 0.011 0.010 0.010 0.0004

Almond

Nutmeat Dimer 0.44

–

0.45 7 10 <0.01 0.0360 0.01 0.0356 0.01 0.015 0.0114

Almond

Hull Fenazaq

uin 0.44

–

0.45 7 10 0.2174 1.674 0.27 1.47 1.2 0.94 0.567

Almond

Hull Dimer 0.44

–

0.45 7 10 <0.01 0.1647 0.015 0.154 0.034 0.0578 0.0574

1 Number of samples, typically 2X number of trials.

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 21 of 45 2 Values based replicates and not averages.

3 Values based on per

- trial averages. LAFT = Lowest Average Field Trial, HAFT = Highest Average Field Trial, SD = Standard Deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ (0.01 ppm) are assumed

to be at the LOQ.



### 5.3 Water Residue Profile

Estimated surface water and groundwater concentrations we re provided by EFED ( D394030, J.

Hetrick

, 03/08/12 ) and are shown in Table 5.3. The dietary exposure assessment used the peak concentration values of 5.74 ppb for acute and 2.09 ppb for chronic assessments. Th e drinking

water assessment is based PRZM and EXAMS modeling for all currently registered and proposed fenazaquin uses. All Tier II surface water modeling was corrected for default percent cropped area (PCA) of 0.87.

The drinking water assessment was conducted using the total toxic residue (TTR) approach. The

residues con sidered in this assessment include fenazaquin (parent), Metabolite 1 , and Metabolite

2 9

.

Table 5.3

. Summary of Estimated Surface Water and Groundwa ter Concentrations for Fenazaquin

Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute 5.74

0.704 Chronic (non

- cancer) 2.09

Chronic (cancer) 1.33

a From the Tier II PRZM

- EXAMS

- Index Reservoir model. I nput parameters are based on MI cherry scenario

b From the SCI

- GROW model.
It should be noted that based on personal communication with EFED, the PRZM

- GW modeling would not produce EWDCs higher that those presented here ( email from D. Spatz to C. Olinger 5/19/14)



### 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute and chronic dietary analysis for non

- cancer risk assessment assumed tolerance level

residues for all registered and proposed crops

. Default processing factors were used for all processed commodities.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary analyse s assumed that 100% of the crop was treated (100% CT).

5.4.3 Acute Dietary Risk Assessment

A n unrefined acute dietary assessment was conducted. The assumptions of this dietary

assessment included tolerance levels residues for al l proposed and registered crops , default processing factors, and 100% CT was assumed. A tier II (PRZM

- EXAMS) EDWC derived through EFED modeling which is unlikely to underestimate the concentration of fenazaquin in

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 22 of 45 drinking water was utilized. The surface water EDWC (5.74 μ g/L) was incorporated directly into the dietary assessment ( D394030, J. Hetrick

, 03/08/12 )

.

As shown in Table 5.4 .6, the acute dietary (food and drinking water) exposure to fenazaquin is below HED’s level of concern [i.e., <100% of the acute Population Adjusted Dose (a PAD)] for the general U.S. population and all po pulation subgroups. The acute dietary exposure estimates

at the 95 th 

### percentile are 3 % of the aPAD for the general U.S. population and 10% of the aPAD

for children 1

- 2 years of age, the most highly exposed population subgroup.

5.4.4 Chronic Dietary Risk Assessment

A n unrefined chronic dietary assessment was conducted. Tolerance level residues

, 100 % CT

, and default processing factors w ere used to determine the chronic dietary exposure and risk

estimates. A tier II EDWC derived through EFED modeling which is unlikely to underestimate

the concentration of fenazaquin in drinking water was utilized. The ground water EDWC (2

. 0 9

μ g/L) was i ncorporated directly into the dietary assessment ( D394030, J. Hetrick

, 03/08/12 )

. As shown in Table 5.4 .6, the chronic dietary (food and drinking water) exposure to fenazaquin is
below HED’s level of concern (< 100% cPAD) for the general U.S. population and all population subgroups

. The chronic d ietary exposure estimates are 2 % of the cPAD for the general U.S. population and 10 % of the cPAD for children 1

- 2 years of age, the most highly exposed population subgro up.

5.4.5 Cancer Dietary Risk Assessment

A cancer dietary risk assessment was not conducted because there was n o evidence of carcinogenicity to humans based on lack of carcinogenic effects in the rat and mouse carcinogenicity studies

.

5.4.6 Summary Tab le

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure Analysis for Fenazaquin Using

DEEM

- FCID

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary

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

General U.S. Population 0.004348 3 0.000949 2
All Infants (< 1 year old) 0.007455 5 0.001831 4

Children 1

- 2 years old 0.015404 10 0.004753 10

Children 3

- 5 years old 0.011604 8 0.003358 7

Children 6

- 12 years old 0.006134 4 0.001481 3

Youth 13

- 19 years old 0.003965 3 0.000777 2

Adults 20

- 49 years old 0.002985 2 0.000586 1

Adults 50

- 99 years old 0.002568 2 0.000619 1

Females 13

- 49 years old 0.003034 2 0.000613 1
*The subpopulation with the highest risk estimates

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 23 of 45 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no residential uses being requested at this time. H owever, ther e are existing residential

uses that were reassessed using the updates to the 2012 HED Residential SOPs.

6.1 Residential Handler Exposure

T here are existing residential ornamental uses that were reassessed using the updates to the 2012

HED Residential SOPs. It is assumed that most residential uses will result in short

- term (1

- 30 day) exposures. Residential handlers are assumed to be wearing short

- sleeved shirts, short pa nts, shoes, and socks while handling fenazaquin . Because there was no dermal e ndpoint chosen for fenazaquin

, risk from exposure to fenazaquin was assessed for the inhalation route only.

Table 6.1 lists the residential hand ler inhalation risk estimates for ornamental treatments

. Residential handler inhalation MOEs were not of concern to HED, and ranged from 190,000 to 19,000,000.

Table 6.1: Residential Handler Non

- cancer Exposure and Risk Estimates for Fenazaquin

.

Expo sure Scenario Level of

Concern Inhalation Unit

Exposure (mg/lb ai) Maximum

Application

Rate 1 Amount

Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

Mixer/Loader/Applicator to Ornamentals

Manually Pressurized

Handwand

100 0.018

0.003 lb ai/gal 5 gal 0.0000034 1,500,000

Hose

- End Sprayer 0.0014 11 gal 0.00000058 8.700,000

Backpack Sprayer 0.14 5 gal 0.000026 190,000

Sprinkler Can 0.0014 5 gal 0.00000026 19,000,000

1 Based on registered label (EPA Reg. No. 10163

- 297 ).

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/ac re or gal) × Amount Handled (gallons/day)

÷ BW ( 80 kg).

4 Inhalation MOE = Inhalation NOAEL ( 5 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).



### 6.2 Post

- Application Exposure

There is the potential for post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with fenazaquin. However, since there is no adverse systemic hazard vi a the dermal route of exposure, and there is no incidental oral exposure expected from fenazaquin use on ornamental plants, a residential post

- application

ass essment has not been conducted.

6 .3 Residential Risk Estimates for Use in Aggregate Assessment

The recommended residential exposure for use in the adult aggregate assessment reflects inhalation exposure from applications to ornamentals via backpack sprayer ( 0.000026 mg/kg/day) . Since there is no residential incidental oral exposure expected for children 1<2 years old on ornamental pla nts, the aggregate assessment for children will only include exposure

from food and water.

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 24 of 45 6.4 Residential Bystander Post

- application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to

individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP ’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.re gulations.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 fenazaq uin.

6.5 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the gr ound application methods (e.g., groundboom and airblast) employed for fenazaquin. The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data

Call

- In issued by EPA), E PA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information). 1 

### The agency has also developed a policy on how to

app ropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during

the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Standard Operatin g Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification

of indirect non

- occupational exposure to drift.

7.0 Aggregate Exposure/Risk Characterization

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

7.1 Acute Aggregate Risk

The acute aggregate risk is equal to the acute dietary (food and drinking water) exposure

. Refer

to Section 5.4. 3.

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 25 of 45 7.2 Short

- Term Aggregate Risk

There is potential short

- term exposure to fenazaquin via the dietary pathway (which is considered background exposure) and t he residential pathway (which is considered the primary pathway ). Since intermediate

- term residential exposures are not likely to occur, intermediate

term aggregate risks were not assessed. T he short

- term aggregate exposure assessment for adults

include s dietary (food and drinking water) and inhalation handler exposures. The most

conservative scenario was chosen. Since there is no residential incidental oral exposure expected

for children 1<2 years old on ornamental plants, the aggregate assessment for ch ildren will only include exposure from food and water. For a description of the residential exposure scenarios considered in the aggregate assessment, see Section 6.1.

Table 7.2 Short

- Term Aggregate Risk Calculations

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

Adult Male 5 100 0.05 0.000949 0.000026 0.000975 5,2 00

1 LOC = standard inter

- and intra

- species unc ertainty factors totaling 100

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = Inhalation Handler Exposure. Table 6.1

. 4 Total Exposure = Avg Food & Water Exposure + Residenti al Exposure

5 Aggregate MOE = [NOAEL ÷ / (Avg Food & Water Exposure + Residential Exposure)]



### 7.3 Chronic Aggregate Risk

The c hronic aggregate risk is equal to the chronic dietary (food and drinking water) exposure

. Refer to Section 5.4 .4

.

7.4 Cancer Aggreg ate Risk

A cancer aggregate risk assessment was not conducted because there was n o evidence of carcinogenicity to humans based on lack of carcinogenic effects in the rat and mouse carcinogenicity studies

.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxici ty finding as to fenazaquin and any other substances and fenazaquin does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore,

EPA has not assumed that fenazaquin has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common

### Fenazaquin Human Health Risk Assessment DP No. D391819

Page 26 of 45 mechanism determinations and proce dures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short

- Term Handler Risk

O c c upational exposures are expected to occu r from the proposed fenazaquin use on almonds and

cherries

. Only s hort

- term (1

- 30 consecutive days) dermal and inhalation exposures are expected because fenazaquin has been proposed for use only once per season

. Additionally, for inhalation

exposures , the POD selected are considered protective of both short

- and intermediate

- term
durations. Dermal risks were not assessed since a dermal hazard was not identified.

The quantitative exposure/risk assessment developed for occupational handlers is based o n the following scenarios:

 Mixing/Loading liquid formulation for aerial, airblast, and application;

 Applying sprays with aerial, airblast, and handheld equipment;

 Flagging for aerial applications; and

 Mixing/Loading/Applying sprays using mechanically pressurized handgun

.

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., gloves, respirator, etc). Fenazaquin

a pplicators and other handlers must wear long

- sleeved shirts, long pants, chemical resistant gloves, shoes, and socks. For those mixing/loading/applying with a high

- pressure handwand

, coverall s must also be worn.

Short

- and intermediate

- term r isk estimates for occupational h andlers are included in Table 9.1.1.

All handler scenarios resulted in MOEs greater tha n the LOC (MOEs ≥ 1 00) for baseline inhalation exposures

, and therefore a re not of concern

. The short

- term occupational handler inhalation MOEs ranged from 4,700 to 52 0,000.

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 27 of 45 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2014 ); Level of mitigation: Baseline, except for aerial application which is baseline with Eng.

Controls.

2 Based on proposed label (Reg. No. 10163

- GEE ).

3 Exposure Science Advisory Council Policy #9.1.

4 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW ( 80 kg).

5 Inhalation MOE = Inhalation NOAEL ( 5 mg/kg/day) ÷ Inhalation Dose (mg/kg/da y). Table 9 .1 .1 : Occupational Handler Non

- Cancer Exposure and Risk Estimates for Fenazaquin

.

Exposure Scenario Crop or Target Level of Concern Inhalation Unit Exposure ( μ g/lb ai) 1 Maximum

Application Rate 2 Area Treated or

Amount Handled Daily 3 Inhalation

Baseline (no respirator) Dose
(mg/kg/day) 4 MOE 5

Mixer/Loader

Mixing/Loading Liquids for Aerial

Application Almonds and

Cherries 100 0.219 0.45 lb ai/A 350 acres 0.00043 12,000

Mixing/Loading Liquids for Airblast

Application 40 acres 0.000049 100,000

Applicator

Aerial Application Almonds and

Cherries 100 0.0049 0.45 lb ai/A 350 acres 0.0000097 520,000

Airblast Application 4.71 40 acres 0.0011 4,700

Flagger

Flagging for Aerial Application Almonds and

Cherries 100 0.35 0.45 lb ai/A 350 acres 0.00069 7,300

Mixer/Loader/Applicator

Mixing/Loading/Applying using Mechanically Pressurized Handgun Almonds and

Cherries 100 3.9 0.0090 lb ai/gal 1000 gal 0.00044 11,000

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 28 of 45 9.2 Short

- /Intermediate

- Term Post

- Application Risk

9.2.1 Dermal Post

- application Risk

There is the potential for occupational dermal post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with fenazaquin. However, since there is no adverse systemic hazard vi a the dermal rou te of exposure, an occupational post

- application assessment has not been conducted.

Restricted Entry Interval The REI specified on the proposed label is based on the acute toxicity of fenazaquin. Fenazaquin is classified as Toxicity Category IV via the dermal route and Toxicity Category IV for skin irritation potential. It is classified as a skin sensitizer. Under 40 CFR 156.208(c)(2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to fenazaquin.

9.2.2 Inhalation Post

- application Risk

There are multiple potent ial sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on M arch 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studi es, route

- specific inhalation toxicological studies) or further analysis is required for fenazaquin.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force . Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post

- applica tion inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than pos t

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 29 of 45 Furthermore, inhalation exposure during dusty mechanical activitie s such as shaking and mechanical harvesting is another potential source of post

- application inhalation

exposure. However, the airblast applicator scenario is believed to represent a reasonable worst case surrogate estimate of post

- application inhalation e xposure during these dusty mechanical harvesting activities. The non

- cancer inhalation risk estimate for commercial airblast application is not of concern (i.e., MOE > 100).

10.0 References

Funk, S., 07/25/12, DP381810, 401360, Fenazaquin. Petition for the Establishment of Permanent Tolerances and Registration for Use on Alfalfa, Avocado, Berry Fruit Group 13, Citrus Fruits Group 10, Field Corn, Sweet Corn, Cotton, Cucurbit Vegetables Group 9, Edible

Podded Legume Vegetables Sub group 6

- A, Succulent Shelled Pea and Bean Subgroup 6B (Except Soybean), Dry Bean and Pea Subgroup 6

- C, Fruiting Vegetables (Except Cucurbits) Group 8, Grapes, Hops, Mint, Pome Fruits Group 11, Stone Fruits Group 12, Strawberry, and Tree Nuts Group 14. S ummary of Analytical Chemistry and Residue Data.

Hebert, J., DP394030, 03/8/12, Drinking Water Assessment to Support First Fenazaquin (4

- tert

butylphenethyl quinazolin

- 4

- yl ether) Use on Food Crops

.

Negrón

- Encarnación ,I., 04/18/12, DP397773

, Fenazaqui n

. Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS).

Rury, K., 08 /XX /14, DP391813, FENAZAQUIN : Occupational Exposure Assessment for Proposed Use on Almonds and Cherries, and a Re

- Evaluation of Existing Residential Uses.

Walls, C., 06/16/14, DP391808, Fenazaquin: Acute and Chronic Aggregate Dietary Exposure and Risk Assessments for the Section 3 Registration Action on Almonds and Cherries.

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 30 of 45 A ppendix A . Toxicology Profile

A.1 Toxicology Data Requirements

The requirem ents (40 CFR 158.500) for food uses are in the table below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1 : Toxicology Data Requirements

Guideline Study Type Required Submitted Satisfied

870.1100 Acute Oral Toxicity Yes Yes Yes

870.1200 Acute Dermal Toxicity Yes Yes Yes

870.1300 Acute Inhalation Toxicity Yes Yes Y es
870.2400 Acute Eye Irritation Yes Yes Yes

870.2500 Acute Dermal Irritation Yes Yes Yes

870.2600 Skin Sensitization Yes Yes Yes

870.3100 90

- Day Oral Toxicity in Rodents Yes Yes Yes

870.3150 90

- Day Oral Toxicity in Non

- Rodents Yes Yes Yes

870.3200 21/28

- Day Dermal Toxicity Yes Yes Yes

870.3250 90

- Day Dermal Toxicity CR No NA

870.3465 90

- Day Inhalation Toxicity CR No Yes 2

870.3700 Prenatal Developmental Toxicity Study (Ra t) Y es Yes Yes

Prenatal Developmental Toxicity Study ( Rabbit ) Yes Yes No

870.3800 Reproduction and Fertility Effects Yes Yes Yes

870.4100 Chronic Toxicity (Rodent) Yes Yes Yes

870.4200 Carcinogenicity ( Rat ) Yes Yes NA

Carcinogenicity ( Mouse ) Yes Yes Yes

870.5100 Bacterial Reverse Mutation Test Y es Yes Yes

870.5300

870.5375 i n vitro Mammalian Cell Gene Mutation Test

i n vitro Mammalian Chromosome Aberration Test Y es 1 Yes

Yes Yes

870.5385

870.5395 Mammalian Bone Marrow Chromosomal Aberration Test

Mammalian Erythrocyte Micronucleus Test Y es 1 No

Yes Yes

870.6100 Delayed Neurotoxicity of Organophosphorus Substances (Acute, Hen) CR No NA

Delayed Neurotoxicity of Organophosphorus Substances (28

- Day, Hen) CR No NA

870.6200 Neurotoxicity Screening Battery (Acute, Rat) Yes Yes Yes

Neuro toxicity Screening Battery (90

- Day , Rat) Yes No Yes 2

870.6300 Developmental Neurotoxicity Study CR No NA

870.7200 Companion Animal Safety CR No NA

870.7485 Metabolism and Pharmacokinetics Yes Yes Yes

870.7600 Dermal Penetration CR No NA

870.7800 Immunotoxicity Yes Yes Yes

CR : Conditionally Required

NA: Not Applicable

1 Either guideline study type may be used to satisfy the data requirement (e.g., 870.5300 or 870.5375)

2 Requirement waived by HASPOC on 10 April 2014

– TXR 0056942

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 31 of 45 A.2 Toxicity Profiles

Table A.2.1: Acute Toxicity Profile

Guideline Study Type MRID Results Toxicity Category

870.1100 Acute Oral Toxicity 46684003 LD 50 = 134/138 mg/kg II

870.1200 Acute Dermal Toxicity 47097627 LD 50 > 5000 mg/kg IV

870.1300 Acute Inhalation Toxicity 47097628 LC 50 = 1.96 mg/L III

870.2400 Acute Eye Irritation 47097629 Minimal irritation III

870.2500 Acute Dermal Irritation 47097627 Not irritating IV

870.2600 Dermal Sensitization 47097630 P ositive ( unacceptable study ): in lieu of an acceptable dermal sensitization study demonstrating otherwise, TRB/RD recommends

this chemical be labeled a dermal sensitizer. ---

Table A.2. 2: Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

870.3100 90

- Day Oral

Toxicity in Rodents (Rat) 45029904 (1992)

Dietary Concentration (ppm): 0, 15

, 45

, 150

, 450 Dose (mg/kg/day) : M: 0, 1.0, 3.0

, 9.6, 28.7

F: 0, 1.2

, 3.5

, 11.5, 33.0 Acceptable / Guideline NOAEL (mg/kg/day): M = 9.6 F = 11.5

LOAEL (mg/kg/day): M = 28

. 7 F = 33

. 0

B ased on decreased body weight and food consumption.

45029905 (1992) Gavage Dose (mg/kg/day) : M: 0

, 1

, 3

, 10, 30

F: 0

, 1

, 3

, 10, 30 Acceptable / Guideline NOAEL (mg/kg/day): M = 10 F = 10

LOAEL (mg/kg/day): M = 30 F = 3 0 Based on decreased body weight and food consumption/efficiency.

90

- Day Oral Toxicity in

Rodents ( Hamster ) 45029903 (1992)

Gavage Dose (mg/kg/day) : M: 0

, 5

, 25

, 75, 150

F: 0, 5

, 25

, 50, 100 Acceptable / Guideline NOAEL (mg/kg/day) : M = 25 F = 25 LOAEL (mg/kg/day) : M = 75 F = 50

M: Based on decreased body weight, reduced testes and prostate weights, and testicular hypospermatogenesis

F: B ased on decreased body weight

870.3150 90

- Day Oral

Toxicity in Non

R odents (Dog) 45029901 (1992)

Dietary Concentration (ppm):

Information was not available Dose (mg/kg/day) : M: 0

, 1

, 5

, 15

F: 0

, 1

, 5

, 15 Acceptable / Guideline NOAEL (mg/kg/day) : M = 5 F = 5 LOAEL (mg/kg/day) : M = 1 5 F = 1 5

B ased on decreased body weight and food consumption/efficiency.

870.3200 21/28

- Day

Dermal Toxicity (Ra bbi t) 48143805 (1992)

Dose (mg/kg/day) : M: 0

, 100

, 315

, 1000

F: 0

, 100

, 315

, 1000

A cceptable / Non

- G uideline Systemic NOAEL (mg/kg/day) : M = 1000 F = 1000 LOAEL (mg/kg/day) : M > 1000 F > 1000

870.3465 90

- Day

Inhalation Toxicity Study was not submitted Study requirement waived by HASPOC

TXR 0056942 (10 April 2014)

83

- 3

870.3700 Prenatal

Developmental Toxicity Study (Rat) 45029911 (1989)

Gavage Dose (mg/kg/day):

F: 0

, 3

, 10

, 40 Acceptable / Guideline Maternal NOAEL (mg/kg/day) = 10 LOAEL (mg/kg/day) = 40 Based on findings (as early as GD 6

- 9) of

decreased f

ood intake and food efficiency.

Developmental NOAEL (mg/kg/day) = 40 LOAEL (mg/kg/day) > 40

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 32 of 45 Table A.2. 2: Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

Prenatal Developmental Toxicity Study (Rabbit) 45029912 (19 90 )

Gavage Dose (mg/kg/day) : F: 0

, 3

, 13

, 60 Acceptable / Non

- Guideline

The 60 mg/kg/day dose was excluded due to an unusually high number of

mortalities that were not treatment

related. Maternal

NOAEL (mg/kg/day) = 13

L OAEL (mg/kg/day) > 13

Developmental

NOAEL (mg/kg/day) = 13

L OAEL (mg/kg/day) > 13

83

- 4

870.3800 Reproduction and

Fertility Effects (Rat) 46684001 (1991)

Gavage Dose (mg/kg/day):

M: 0

, 1

, 5

, 25

F: 0

, 1

, 5

, 25 Acceptable / Guideline Parental NOAEL (mg/kg/day) = 5 LOAEL (mg/kg/day) = 25 Based on excessive salivation and decreased body weight and food intake.

Reproductive NOAEL (mg/kg/day) = 25 LOAEL (mg/kg/day) > 25

Offspring NOAEL (mg/kg/day) = 5 LOAEL (mg/kg/day) = 25 Based on decreased weight gain during lactation.

83

- 1

870.4100 Chronic T oxicity

(Dog) 45029906 (1993)

Dietary Concentration (ppm):

Information was not available

Dose (mg/kg/day):

M: 0

, 1

, 5

, 1 2

F: 0

, 1

, 5

, 1 2 Acceptable / Guideline NOAEL (mg/kg/day) : M = 5 F = 5 LOAEL (mg/kg/day) : M = 12 F = 12

Ba sed on decreased body weight and food consumption , and food efficiency.

870.4200 Carcinogenicity

( Hamster ) 45029913 (1992)

Gavage Dose (mg/kg/day):

M: 0

, 2

, 1 5

, 30

F: 0, 2, 15, 35 Acceptable / Guideline

The Registrant’s justification for using hamsters can be found in MRID

44742910 NOAEL (mg/kg/day) : M = 2 F = 1 5 LOAEL (mg/kg/day) : M = 15 F = 3 5

M: B ased on decreased body weight gain

F: B a sed on decreased body weight No evidence of carcinogenicity

870.4300 Combined

Chronic Toxicity/ Carcinogenicity ( Rat) 45029907 (1992)

Dietary Concentration (ppm): 0, 10

, 100

, 200

, 400 (M)

45 0 (F)

Dose (mg/kg/day):

M: 0

, 0.46

, 4.5

, 9.2, 18.3

F: 0, 0.57

, 5.7

, 11.5, 25.9 Acceptable / Guideline NOAEL (mg/kg/day) : M = 9.2 F = 11.5 LOAEL (mg/kg/day) : M = 18.3 F = 25.9 Based on decreased body weight, food consumption , and food efficiency.

No evidence of carcinogenicity

870.5100 Bacterial Reverse

Mutation Test ( Salmonella typhimurium ) 44742909 (1989)

Applied Dose ( μg/plate ):

 S9: 0, 187.5, 375, 750, 1500, 3000 Acceptable / G uideline ±S9 : Negative up to 3000 μg/mL in the absence of cytotoxicity with precipitation above this

concentration.

870.5300 i n vitro

Mammalian Cell

Gene Mutation

Test (Mouse Lymphoma Cells) 44742908 (1989)

Applied Dose ( μg/ mL):

- S9: 0, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0,

20.0

+S9: 0, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0

12.0 Acceptable / G uideline - S9: Negative, severely cytotoxic at concentrations up to10 μg/mL +S9: Positive at concentrations (up to 12 μg/mL) that were severely cytotoxic (10

- 20% survival)

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 33 of 45 Table A.2. 2: Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

870.5375 i n vitro

Mammalian

Chromosome

Aberration Test ( C hinese H amster
O vary cells ) 44742907 (1989)

Applied Dose ( μg/ mL):

- S9: 0, 0.1, 0.5, 1.0

+S9: 0, 40 50, 60 Acceptable / G uideline ± S9: Negative for clastogenic/aneugenic activity up to concentrations that reduced cell survival by ≈50% (1 μg/mL

- S9; 60 μg/ mL+S9). Compound precipitation was evident at levels ≥ 24 μg/mL +/

- S9.

870.5395 Mammalian

Erythrocyte

Micronucleus Test (Mouse) 44742904 (1989)

Gavage Dose (mg/kg):

M: 0

, 400

, 800

, 1600

F: 0, 400

, 800

, 1200 Acceptable / G uideline Negative for clastogenic/aneugenic activity in mouse bone marrow up to the highest dose tested in males/females (1600/1200 mg/kg, repeated on two days).

In a preliminary study, the median lethal doses (MLD) were 3191/ 2430 mg/kg (M/F).

870.55 5 0 Unscheduled

DNA Synthesis

in Mammalian

Cells in Culture (Rat Hepatocytes) 44742906 (1989)

Dose ( μg/ mL):

- S9: 0, 0 .001, 0.005, 0.01, 0.05, 0.1, 0.5, 1.0,

5.0 Acceptable / G uideline Negative up to cytotoxic concentrations (≥0.5 to 1.0 μg/mL).

--- Unscheduled

DNA Synthesis ( in vitro and in

vivo ) 45029908 (1989)

Dose ( μg/ mL):

- S9: 0, 180

, 600 Acceptable / N on

- G uideline Negative for DNA damage and repair in this in

vivo / in vitro test system up to the maximum tolerated dose (600 mg/kg).

870.5915 in viv o Sister

Chromatid Exchange Assay (Mouse) 44742905 (1989)

Gavage Dose (mg/kg):

M: 0

, 500

, 1000

, 2000 Unacceptable / G uideline

Unacceptable due to inadequate number of test animals (each data point had 3 males which is lower than the guideline

recommended 5/sex/dose ) Negative in this cytogenetic assay (no increase in SCE) of bone marrow from male CD

- 1 mice treated with doses up to levels that produced death (2000 mg/kg).

870.6200 Neurotoxicity

Screening Battery (Acute Rat) 48814001 (2012)

Gavage Dose (mg/kg):

M: 0

, 20

, 65

, 130

F : 0

, 20

, 60

, 120

A cceptable / G uideline NOAEL (mg/kg/day) : M = 20 F = 20 LOAEL (mg/kg/day) : M = 65 F = 60

Based on mild dehydration in females

.

Neurotoxicity Screening Battery ( Subchronic Rat) Study has not been submitted Study requirement waived by HASPOC

TXR 0056942 (10 April 2014)

870.7485 Metabolism and

Pharmacokinetics (Rat) 44742901 (1992)

Gavage Dose (mg/kg): Single: 1, 30 Repeated: 1

A cceptable / G uideline Absorption Absorption was determined to be 65.09% of the administered dose (AD). The urine contained

3.75% AD.

Distribution Fenazaquin residues were found in low levels throughout the rat with detectable levels in a broad range of organs (i.e. brain, kidneys, and l iver) as

well as in the residual carcass. The residue levels in the rat organs and tissues were <0.04% AD . The rat carcass without the previously mentioned organs

contained ≤1 .6% AD.

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 34 of 45 Table A.2. 2: Subchronic, Chronic, and Other Toxicity Profiles

Guideline Study Type MRID (year) / Doses / Classification Results

48907401 (2 012 )

– Tier 2 Study Gavage Dose (mg/kg): Single: 1

A cceptable / G uideline Metabolism

Non

- metabolized fenazaquin was higher in feces (1.0

- 15.0% A D) than in urine (< 0.5% AD ) and some of the major metabolites were identified including AN

- 1 (urine) in addition to the fecal

metabolites F

- 1, F

- 2 and F

- 3. The metabolic pathway of fenazaquin involved cleavage of the ether bond, resulting in the formation of the respective alcohol (4

- OH quinazoline metabolite) and carboxyl acid (AN

- 1) derivatives. Other

biotransformation reactions included oxidation of one of the methyl groups on the alkyl side chain to produce either an alcohol (F

- 1) or carboxylic acid ( F

- 2) metabolites. Finally, hydroxylation at the O

ether alkyl moiety of F

- 1 or the 2

- position of the quinazoline ring of F

- 2 resulted in F

- 1A and F

- 3 metabolites, respectively.

Elimination The majority (89.5

- 107.7%) of elimination in the

rat occurred within 168 hours. There was no radiolabel in the expired air and no evidence for

bioaccumulation. Based on excretion and tissue residue data, bioavailability is conservatively

estimated at about 20% of an administered d ose. 870.7600 in vitro

Dermal

Penetration (Human & Rat) 48012905 (2007)

Study is not acceptable without an in

vivo guideline OPPTS 870.7600 study

submission Preliminary review of the study indicate s a dermal absorption of 0.48

- 7.33%.

870.7800 Immunotoxicity

(Rat) 48459503 (2011)

Gavage Dose (mg/kg/day):

F: 0

, 1 5

, 30

, 37.5/45 Acceptable / Non

- Guideline Systemic Toxicity NOAEL (mg/kg/day) = 15

LOAEL (mg/kg/day) = 30 Based on clinical signs (general ataxia/hypo

activity) (also seen after a single dose)

.

Immunotoxicity NOAEL (mg/kg/day) = 37.5 LOAEL (mg/kg/day) > 37.5

NA Potential of XDE

436 Analogues to

I nduce H epatic

H ypertrophy and

P eroxisome A cyl

CoA O xidase

A ctivity (Mouse) 44742903 (1993)

Acceptable / N on

- G uideline Fenazaquin and several of its analogs (with varying susceptibilities to metabolism of the ether bond or the alkylbenzene substituents) were assessed for their ability to increase liver peroxisomal fatty acyl

CoA oxidase (FAO, a marker of peroxisomal proliferation) and relative liver weight in groups of

five CD

- 1 female mice. The FAO peroxisomal activity data indicate that oxidation of the t

- butyl substituent on the alkylbenzene m oiety (to the corresponding carboxylic acid) of fenazaquin and related compounds appears to be the critical step for hepatocellular peroxisome proliferation.

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 35 of 45 A ppendix B. Proposed Metabolic Pathways for Fenazaquin (EL

- 436) in the Rat

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 36 of 45 Appendix C. Physical/Chemical Properties

Table C1

. Physicochemical Properties of Fenazaquin.

Parameter Value Reference
Melting point/range 77.5

- 80oC Evaluation on Fenazaquin, Issue No. 150, Pesticides Safety Directorate, Depart. for Environment, Food, and Rural Affairs, U.K.,

March 1996 pH Not determined due to low solubility Relative Density 1.16 at 21oC Water solubility (20°C) 0.102 mg/L at pH 5 & 7 0.135 mg/L at pH 9 Solvent solubility (g/L at 23oC) acetonitrile 33

- 50 acetone 400

- 500

n

- chlorobutane >500 chloroform >500

dichloromethane >600 ethyl acetate 400

- 500 dimethylformamide 300

- 400 ethylene glycol <5

hexane 33

- 50 isopropanol 50

- 100

methanol 50

- 100 toluene >500

N

- methyl

- 2

- pyrrolidone >500 Vapor pressure (25oC) 1.9 x 10

- 5 Pa ; 1.4 x 10

- 7 mmHg

16 x 10

- 5 Pa

35 X 10

- 5 Pa Dissociation constant, pK
a 2.44 Octanol/water partition coefficient, Log(K OW ) 5.71 at 25oC ; 5.51 at 20oC

UV/visible absorption
spectrum A
max 215 nm є = 41,588 L mol

- 1 cm - 1

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 37 of 45 Appendix D. Structure of Fenazaquin and it s major metabolites/ degradates

Summary of Metabolites and Degradates Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1

Matrices

- Major Residue (>10% TRR) Matrices

- Minor Residue (<10% TRR) Fenazaquin Apple (30% mature) (7 DAT) 66.4 (0.363) P

76.0 (0.461) Q

Apple (30% mature) (28 DAT) 48.0 (0.070) P

39.7 (0.085) Q

Orange (63 DAT) 65.5 (0.295) P

55.4 (0.500)Q Grapes (28 DAT) 63.0 (0.939) P

46.4 (1.22) Q Grapes (49 DAT) 39.1 (0.14) P

26.7 (0.662) Q Corn grain (20 DAT) 23.1 (0.003) Q

Not analyzed P

Corn stover (20 DAT) 48.4 (2.95) Q

29.8 (1.98) P

Radish root (rotational) 30 (0.031) Q 30 day PBI 15 (0.007) Q 120 day PBI

27 (0.026) P 16 (0.009) P

Lettuce immature (rotational 30 day PBI) 8.0 (0.004) Q
7.3 (0.004) P

Wheat straw (rotational 30 day PBI) 1.7 (0.002) Q

0.8 (0.002) P

Muscle (Goat) N/D P Not analyzed Q
Fat (Goat) 83.0 (0.073) Q

77.3 (0.085) Q

Kidney (Goat) N/D P and Q

Liver (Goat) N/D P and Q
Milk (Goat) 15.4 (0.004) Q

47.1 (0.016) P Muscle, thigh (Chicken) 68.8 (0.011) P 5.0 (0.003) Q

Fat, subcutaneous (Chicken) 83.2 (0.134) Q

88.8 (0.159) P
Fat, omental (Chicken) 94.9 (0.147) Q

89.2 (0.156) P
Liver (Chicken) 4.6 (0.004) Q

N/D P Eggs (Chicken) 13.0 (0.003) P 2.1 (0.003) Q

Rat 1

– 21% of residue in feces

Water Major residue

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 38 of 45 Summary of Metabolites and Degradates Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1

Matrices

- Major Residue (>10% TRR) Matrices

- Minor Residue (<10% TRR) Fenazaquin Dimer Apple (30% mature) (7 DAT) 24.6 (0.135) P

10.1 (0.061) Q

Apple (30% mature) (28 DAT) 27.4 (0.040) P

19.4 (0.041) Q

Grapes (28 DAT) N/D P and Q

Corn grain (20 DAT) 7.7 (0.001) Q Not analyzed P

Corn stover (20 DAT) 19.8 (1.20) Q

54.3 (3.61) P

Goat Tissues

– not found

Chicken Tissues

– not found

Rat Not found

Water Not found

2

- Methyl

- 2

- {4

- [2

- (quinazolin

4

- yloxy)

- ethyl]

- phenyl}

- propan

- 1

- ol

(Metabolite F1) (Metabolite C) Apple (30% mature) (7 DAT) 1.0 (0.005) P [or metabolite L]
N/D Q

Apple (30% mature) (28 DAT) 3.3 (0.005) P [or metabolite L]
0.4 (0.001) Q

Grapes (28 DAT) 9.1 (0.136) P

4.3 (0.112) Q Grapes (49 DAT) 12.9 (0.046) P

3.3 (0.062) Q

Goat Tissues

– not found

Chicken Tissues

– not found

Rat 5

– 9 .4% residue in feces

Water Not found

Rat 16

– 23% of TRR in feces

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 39 of 45 Summary of Metabolites and Degradates Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1

Matrices

- Major Residue (>10% TRR) Matrices

- Minor Residue (<10% TRR)

2

- Methyl

- 2

- (4

- (2

- ((4

- quinazolinyl)oxy)ethyl)phenyl )

- propionic acid. (Metabolite 5) (Metabolite F2) Water Identified as present

(Metabolite D)
(M29)
(Metabolite F3)
(Metabolite 2 in the drinking water memo)

2

- (4

- {2

- [(2

- hydroxyquinazolin

- 4

- yl)oxy]ethyl}phenyl)

- 2

- methylpropanoic acid

2

- Methyl

- 2

- (4

- {2

- [(2

- oxo

- 1,2

- dihydroquinazolin

- 4

- yl)oxy]ethyl}phenyl) propanoic acid Apple (105 day PHI) 0.8 (<0.001) Q

Corn stover (20 DAT) 0.5 (0.033) Q

N/D P
Radish root (30 day PBI) 3.8(0.004) Q
3.2 (0.003) P
Muscle (Goat) 20.0 (0.005) P

Not analyzed Q
Fat (Goat) 0.9 (0.001) P

N/D Q Kidney (Goat) 28.6 (0.010) Q

25.3 (0.023) P
Liver (Goat) 13.7 (0.054) Q

14.9 (0.106) P
Milk (Goat) 1.8 (0.001) Q
2.9 (0.001) P
Liver (Chicken) 7.0 (0.003) P
N/D Q Eggs (Chicken) 13.0 (0.003) P 1.4 (0.002) Q

Rat 6.5

– 12.5% of TRR in rat

feces

4(2

- (4(1,1dimethylethyl)

- phenyl)ethoxy)quinazolone Orange (191 day PHI) 8.1 (0.029) P
4.9 (0.016) Q

Corn stover (20 DAT) 1.2 (0.073) Q
0.5 (0.030) P

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 40 of 45 Summary of Metabolites and Degradates Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1

Matrices

- Major Residue (>10% TRR) Matrices

- Minor Residue (<10% TRR)

4

- [2

- (4

- tert

- butyl

- phenyl)

- ethoxy]

- quinazolin

- 2

- ol

2

- Oxy

- fenazaquin

2

- Hydroxy

- fenazaquin
(Metabolite F)
(Metabolite 1) Radish root (rotational, 30 day PBI) 3.8 (0.004) Q
4.2 (0.004) P

Radish top (rotational, 30 day PBI) 3.3 (0.001) Q

Wheat straw (rotational, 30 day PBI) 0.9 (0.001) Q

0.4 (0.001) P

Fat (goat) 1.1 (0.001) Q
0.9 (0.001) Liver (goat) Previously reported at 4

– 10%

TRR in a marginal study.

Rat Not found, but implied by

oxidative metabolism and presence of F3 (‘fenazaquin acid’) in feces.

Water 8.1% of applied chemical

2

- (4

- (1,1

- dimethyl)

- phenyl)ethyl

2

- (formylaminobenzoate)

1

- (4

- Tert

- butylphenyl)

- 2

- (quinazolin

- 4

- yloxy)ethanone

(Metabolite H) (Metabolite 4) Grapes (76 DAT) 2.7 (0.028)P
N/D Q

Water Present but not quantified

Goat Not found

Chicken Not found

Rat Not found

Apple (30% mature) (7 DAT) N/D P
1.9 (0.012) Q

N/D P N N O

C H 3 C H 3

C H 3 O H

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 41 of 45 Summary of Metabolites and Degradates Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1

Matrices

- Major Residue (>10% TRR) Matrices

- Minor Residue (<10% TRR) Dihydroxyquinazoline

(Metabolite I)

And its tautomer Quinazolindione or Benzoyleneurea Apple (30% mature) (28 DAT) 4.4 (0.009) Q

Orange N/D Grapes (28 DAT) 3.8 (0.099) Q

Grapes (49 DAT) 4.1 (0.101) Q

Grapes (76 DAT) 26.2 (0.248) Q, including

14% from base hydrolysis. Muscle, thigh (Chicken) 63.3 (0.038) Q

Fat, subcutaneous (Chicken) 14.9 (0.024) Q

Fat, omental (Chicken) 3.2 (0.005) Q

Liver (Chicken) 52.9 (0.046) Q Eggs (Chicken) 82.4 (0.117) Q

Goat Not found

Rat Not found

Water Identified

– amount not reported

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 42 of 4 5 Summary of Metabolites and Degradates Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1

Matrices

- Major Residue (>10% TRR) Matrices

- Minor Residue (<10% TRR)

4

- Hydroxyquinazoline

4

- Quinazolinol

(Metabolite J)

And its tautomer Quinazolidinone Apple (30% mature) (7 DAT) 0.4 (0.003) Q

Apple (30% mature) (28 DAT) 3.2 (0.007) Q

Orange N/D

Grapes (49 DAT) 1.6 (0.040) Q

Corn stover (20 DAT) 6.9 (0.419) Q

Radish root (30 day PBI) 8.7 (0.009) Q

Radish top (30 day PBI) 3.3 (0.001) Q

Lettuce immature (rotational 30 day PBI) 4.0 (0.002) Q

Wheat straw (rotational 30 day PBI) 4.3 (0.005) Q

Wheat hay (rotational 30 day PBI) 8.0 (0.010) Q

Wheat forage (rotational 30 day PBI) 8.1 (0003) Q

Kidney (goat) 5.7 (0.002) Q Liver (goat) 1.9 (0.007) Q Milk (goat) 23.1 (0.006) Q

Rat Minor component of feces reported in the proposed

metabolic scheme

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 43 of 45 Summary of Metabolites and Degradates Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1

Matrices

- Major Residue (>10% TRR) Matrices

- Minor Residue (<10% TRR)

Water Minor to major depending

upon conditions

2

- (4

- (2

- hydroxyethyl)phenyl)

- 2

- methyl propanoic acid

(Metabolite K) Grapes (76 DAT) 4.1 (0.043) P

Tertiarybutylphenyl ethanol or

4

- (1,1

- Dimethylethyl)benzene

ethanol or

4

- tert

- butylphenethyl alcohol

(Metabolite L) Apple (0 DAT) 0.6 (0.005) P

Grapes (28 DAT) 3.0 (0.08) P

Corn stover (20 DAT) 1.8 (0. 11 9) P

Radish root (30 day PBI) 1.0 (0.001) P

Rat Not found, but implied present by general oxidative metabolism and presence of

metabolite AN

- 1

Water Minor to major depending

upon conditions

2

- (4

- carboxymethylphenyl)

- 2

- methylpropanoic acid

(Metabolite G)
(Metabolite M34) Kidney (goat) 8.8 (0.008) P

Liver (goat) 15.3 (0.109) P

Rat Not found (in feces)

Water Minor identified product

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 44 of 45 Summary of Metabolites and Degradates Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1

Matrices

- Major Residue (>10% TRR) Matrices

- Minor Residue (<10% TRR)

Metabolite F1A Rat 0.8

- 2.6% of TRR in rat feces

Metabolite AN

- 1 Rat 24

– 29% TRR in rat urine

(4

- tertbutylphenyl)acetic acid
(Metabolite 6) Water Minor identified product

Rat Not found in feces, but implied by general oxidative metabolism and presence of

metabolite AN

- 1

1

- [3

- (carboxymethyl)phenyl]

- 2

- methylpropionic acid Water Minor identified product

### Fenazaquin Human Health Risk Assessment DP No. 391819

Page 45 of 45 Summary of Metabolites and Degradates Chemical Name (other names in parentheses) and Structure Matrix Percent TRR (PPM) 1

Matrices

- Major Residue (>10% TRR) Matrices

- Minor Residue (<10% TRR)
Methyl

- 2

- [4

- (2

— oxoethyl)phenyl]

- 2

- methylpropanoate Water Minor identified product

Apple ; 45029914 & 45029917; 31 or 125 mg ai/L; unknown X rate ; post

- emergence (spray painted to fruit), early season or late season; 0, 7, 14, 28 and 105

- day PHI (early season) or 0 and 70

- day PHI (late season). Orange ; 45054401 & 44742913; 0.4 lb ai/A; 1X rate; post

- emergence (foliar), early season or late season; 0, 28, 112 and 19 1

- day PHI (early season) or 0, 19, and 63

- day PHI (late season). Grape : 48350005 (1) Early season, 0.013 lb ai/acre, foliar, berry diameter 3

– 6 mm. Samples 0, 49, 76 DAT. (2) Late season, 0.013 lb ai/acre, foliar; berry diameter 10

– 15 mm. Samples 0, 28 DAT.

Corn :48350008. 0.45 lb ai/acre (1X) at milk stage. Samples: corn grain and stover at 20 DAT. Confined Rotational: 48073883. 0.45 lb ai/acre (1X) to ground. Lettuce, wheat, garden beet sowed at PBIs of 30, 120, and 365 days.

Goat : 48350007. 0.79 mg/kg/bw/day [P} and 0.84 mg/kg bw/day [Q] or about 12 ppm based on feed; 5 consecutive days.

Hen: 48350008. 0.97 mg/kg bw/day [Q} and 0.98 mg/kg bw/day [P{ or about 12 ppm based on feed; 7 consecutive days.

1 Fenazaquin radiolabeled in the phenyl ring [P] or on the quinazoline ring [ Q ]. The label positions are depicted

below.

* denotes position of radiolabel, uniformly labeled in

the phenyl ring * denotes position of radiolabel, uniformly labeled in

the phenyl ring of the quinazoline