# I Fenoxaprop-p-ethyl Human Health Risk Assessment DP No

. 403928 and 411289

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

Date: March 20, 2014 OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION



### SUBJECT: Fenoxaprop-p-ethyl. Registration Review Preliminary Risk Assessment and Proposed New Use on Grass Grown for Seed.

PC Code: 129092 DP Barcode: D403928 and D411289 Registration No.: 264-666 Decision No.: 477911; 466648
Petition No

. : 2E8051 Regulatory Action: Registration Review and New Use
Assessment
Risk Assessment Type: Risk Assessment
TXRNo.: NA CaseNo.: NA
CAS No.: 66441-23-4
40 CFR: 180.430 MRIDNo.: NA



### FROM: Shalu Shelat, Industrial Hygienist Christopher Schlosser, Toxicologist
Donald Wilbur, Chemist
Risk Assessment Branch VI
Health Effects Division (7509P)

THROUGH: Donna S. Davis, Acting Branch Chief
Risk Assessment Branch VI

TO: Health Effects Division (7509P)

Andrew Ertman/ Barbara Madden, Risk Managers
Risk Integration Minor Use, and Emergency Response Branch Registration Division (7505P)

And

Molly Clayton, Chemical Review Manager
Risk Management and Implementation Branch III
Pesticide Re-evaluation Division (7508P)

Page 1 of84

### Fenoxaprop

- p

- ethyl Human Health Risk Assessment DP No. 403928 and 411289

Page 2 of 84 

### Introduction
The Health Effects D ivision (HED) of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. Fenoxaprop

- p

- ethyl (FPE) is currently registered for use on barley, cotton, rice, soybeans, and wheat. FPE is also reg istered
for non

- agricultural use on conservation reserve land s, ornamentals, rights

- of

- way, and turf. The Interregional Research Project No. 4 (IR

- 4) has submitted a petition requesting a new use on grass grown for seed in the states of Oregon, Washington , and Utah only. The Registration Division (RD) of OPP has requested that HED evaluate the hazard and exposure data and conduct dietary, residential, occupational, and aggregate exposure assessments, as needed, to
estimate the risk to human health that wi ll result from the existing and newly proposed use of
FPE. The Pesticide Re

- evaluation Division has also requested that an assessment be drafted in support of registration review of the currently registered uses of FPE. This document has been developed t o assess both the new use as well as in support of registration review for FPE.

HED has evaluated the toxicity and exposure databases for FPE and has conducted a human health risk assessment which is provided in this document. Based on this assessment, H ED has determined that there are no potential risk estimates of concern for the proposed use and currently registered uses of FPE with the addition of PPE (i.e., chemical

- resistant gloves)

.

The HED team members contributing to this risk assessment include Donald Wilbur (residue chemistry and dietary exposure assessment), Shalu Shelat (occupational and residential exposure assessments and risk assessment), and Christopher Schlosser (hazard assessment). Chuck Peck
of the Environmental Fate and Effects Divis ion (EFED) performed the drinking water

assessment.

### Fenoxaprop

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### Table of Contents
1.0 Executive Summary

................................ ................................ ................................ ............. 5
2.0 HED Recommendations

................................ ................................ ................................ ....... 8
2.1 Data Deficiencies

................................ ................................ ................................ ............. 8
2.2 Tolerance Considerations

................................ ................................ ................................ . 8
2.2.1 Enforceme nt Analytical Method

................................ ................................ ............... 8
2.2.2 Established Tolerances

................................ ................................ .............................. 9
2.2.2.1 Revisions to Established Tolerances

................................ ................................ ... 10
2.2.3 Petitioned

- For Tolerances

................................ ................................ ....................... 10
2.2.3.1 Revisions to Petitioned

- For Tolerances

................................ .............................. 10
2.2.4 International Harmonization

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

2.3 Label Recommendations

................................ ................................ ................................ 11
2.3.1 Recommendations from Residue Reviews

................................ ............................. 11
2.3.2 Recommendations from Occupational Assessment

................................ ................ 11
2.3.3 Recommendations from Residential Assessment

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

3.0 Introduction

................................ ................................ ................................ ........................ 11
3.1 Chemical Identity

................................ ................................ ................................ ........... 11
3.2 Physical/Chemical Characteristics

................................ ................................ ................. 12
3.3 Pesticide Use Pattern

................................ ................................ ................................ ...... 13
3.4 Anticipated Exposure Pathways

................................ ................................ ..................... 15
3.5 Consideration o f Environmental Justice

................................ ................................ ........ 15
3.6 Incident Reports

................................ ................................ ................................ ............. 15
4.0 Hazard Characterization and Dose

- Response Assessment

................................ ................ 16
4.1 Toxicology Studies Available for Analysis

................................ ................................ ... 16
4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

................................ ... 17
4.2.1 Dermal Absorption

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

4.3 Toxicological Effects

................................ ................................ ................................ ..... 17
4.4 Safety Factor for Infants and Chil dren (FQPA Safety Factor)

................................ ....... 18
4.4.1 Completeness of the Toxicology Database

................................ ............................. 19
4.4.2 Evidence of Neurotoxicity

................................ ................................ ...................... 19
4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

......... 19
4.4.4 Residual Uncertainty in the Exposure Database

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

4.5 Toxicity Endpoint and Point of Departure Selections

................................ .................... 20
4.5.1 Dose

- Response Assessment

................................ ................................ .................... 20
4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

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

.............................. 22
4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment.

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

4.6 Endocrine Disruption

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

................................ ................................ ............ 25
5.1 Metabolite/Degradate Residue Profile

................................ ................................ ........... 25
5.1.1 S ummary of Plant and Animal Metabolism Studies

................................ ............... 25
5.1.2 Summary of Environmental Degradation

................................ ............................... 26
5.1.3 Comparison of Metabolic Pat hways

................................ ................................ ....... 26
5.1.4 Residues of Concern Summary

................................ ................................ ............... 27

### Fenoxaprop

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### 5.2 Food Residue Profile

................................ ................................ ................................ ...... 27
5.3 Water Residue Profile

................................ ................................ ................................ .... 28
5.4 Dietary Risk Assessment

................................ ................................ ................................ 29
5.4.1 Description of Residue Data Used in Dietary Assessme nt

................................ ..... 29
5.4.2 Acute Dietary Risk Assessment

................................ ................................ .............. 29
5.4.3 Chronic Dietary Risk Assessment

................................ ................................ .......... 29
5.4.4 Summary Table

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

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .... 30
6.1 Residentia l Handler Exposure

................................ ................................ ........................ 30
6.2 Post

- Application Exposure

................................ ................................ ............................. 33
6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

......................... 34
6.4 Residential Risk Estimates for Use in Aggregate Assessment

................................ ...... 35
6.5 Residential Bystander Post

- application Inhalation Exposure

................................ ........ 36

6.6 Spray Drift

................................ ................................ ................................ ...................... 36
7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ....... 37
7.1 Acute Aggregate Risk

................................ ................................ ................................ .... 37
7.2 Short

- Term Aggregate Risk

................................ ................................ ........................... 37
7.3 Chronic Aggregate Risk

................................ ................................ ................................ . 38
8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 38
9.0 Occupational Exposure/Risk Characterization

................................ ................................ .. 38
9.1 Short

- and Intermediate

- term Handler Risk

................................ ................................ ... 38
9.2 Short

- and Intermediate

- term Post

- Application Risk

................................ ..................... 47
9.2.1 Dermal Po st

- application Risk

................................ ................................ ................. 47
9.2.2 Inhalation Post

- application Risk

................................ ................................ ............. 49

10.0 References

................................ ................................ ................................ .......................... 49 Appendix A. Toxicology Profile and Executive Summaries

................................ ....................... 51 Appendix B. International Residue Limits Table

................................ ................................ ..... 78 Appendix C. Spray Drift Summary Tables

................................ ................................ .................. 80

### Fenoxaprop

- p

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### 1.0 Executive Summary

Fenoxaprop

- p

- ethyl [FPE; (+)

- ethyl 2

- [4

- [(6

- chloro

- 2

- benzoxazolyl)oxy]phenoxy]propanoate] is a selective aryloxy phenoxy

- propionate herbicide used to contr ol grass weeds after emergence. FPE is an enriched isomer formulation (95% d , the herbicidally active enantiomer). Originally, the product was registered as racemic mixture known as fenoxaprop ethyl (FE, PC Code 128701). FE is no longer a registered act ive ingredient. FPE is currently registered for use on barley, cotton, rice, soybeans, and wheat. FPE is also registered for non

- agricultural use on conservation reserves, ornamentals, rights

- of

- way, and turf. The Interregional Research Project No. 4 (IR

- 4) has submitted a petition requesting a new use on grass grown for seed in the states of Oregon, Washington, and Utah only. This document is being drafted in support of registration review of FPE as well as the assessment of the new use on grass grown f or seed.

The toxicology database for FPE is complete based on studies submitted for both FPE and FE

. Based on the analysis of the submitted studies

, 

### HED found that the toxicological effects of FE and FPE across species, duration, and route of exposure ar e similar. Most of the toxicological data available involved testing of the FE , not FPE . However, HED has con cluded that the similarity between the FE and FPE data is such that the database for FE could be bridged with

FPE. A cute and subchronic neurot oxicity studies were not available; however, HED’s Hazard and Science Policy Council (HASPOC) determined that the studies may be waived

.

The major target organs following short

- term and long

- term oral administration of FE and FPE
in rats and mice are the liver and kidneys, with rats being the most sensitive species. The primary toxic effect is altered lipid metabolism characterized by decreased lipids and cholesterol, and increased liver weights in rats, and slightly increased lipids, cholesterol, proteins , and liver weights in mice. It is also important to note that no increases in toxicity are observed over time for FE when comparing the 28

- day and 90

- day subchronic studies, the 2

- generation reproductive toxicity study, and the 2

- year chronic toxicity/car cinogenicity study in rats, or in FPE when comparing the 28

- day and 90

- day subchronic toxicity studies in rats.

FPE has low acute toxicity following the oral, dermal, and inhalation routes of exposure. No
evidence of Immunotoxicity, reproductive

, or neu rological toxicity was identified in the database. No developmental effects were identified in rabbits. In mice, a treatment

- related increase in tumor incidence of hepatocellular adenomas and carcinomas, mainly adenomas, was
observed in males at 320 ppm (30%) compared to the control (2%). Although a treatment

related increase in tumor incidence of hepatocellular adenomas and carcinomas, mainly adenomas, was observed in male mice and microscopic pathology indicated that hepatocellular hypertrophy was obse rved in the majority of treated animals (both sexes), there was no evidence of a mutagenic effect in a comprehensive battery of genetic toxicology assays with both isomers.
No evidence of tumors was identified in rats. In accordance with EPA’s Final Gui delines for Carcinogen Risk Assessment (2005), CARC classified FE/FPE as “Suggestive Evidence of Carcinogenic Potential”.

For short

- term incidental oral exposure (1

- 30 days), a 28

- day oral toxicity study in rats with a no observed adverse effect level (N OAEL) of 6 mg/kg/day was selected based on altered lipid metabolism (decreased HDL

- cholesterol, HDL

- phospholipids, and total lipids, increased

### Fenoxaprop

- p

- ethyl Human Health Risk Assessment DP No. 403928 and 411289

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### triglycerides, and ketonuria) and increased liver and kidney weights at the study t he Lowest
Observed Adverse Eff

ect Level (LOAEL) of 26/28 (M/F) mg/kg/day

.

For short and intermediate

- term dermal exposure, a 28

- day dermal toxicity study in rats with a NOAEL of 20 mg/kg/day was selected (FPE) based on non

- regenerative anemia, decreased serum cholesterol, total lipi ds, and protein (beta 1 globulins), and increased liver and kidney weights seen at the study LOAEL of 100 mg/kg/day . There is no long

- term exposure from existing or proposed uses; therefore, a risk assessment for long

- term dermal exposure is not required.

For short and intermediate

- term inhalation exposure, a 28

- day inhalation toxicity study in rats with a NOAEL of 0.07 mg/L was selected (FPE). In the study, the LOAEL is 0.3 mg/L (M) based on slight normocytic anemia, decreases in serum cholesterol and t otal lipids, and increases in liver and kidney weights and urea nitrogen. An inhalation study was used therefore the resulting human equivalent concentrations (HECs) are 0.14 mg/L and 0.57 mg/L, respectively. There is no long

- term exposure from existing o r proposed uses; therefore, a risk assessment for long

- term inhalation exposure is not required.

No acute reference dose (aRfD) was established to assess acute dietary risks since there was no evidence of toxicity attributable to a single dose for the ge neral U.S. population, infants and children, or females 13

- 49 years of age in any studies. For the chronic dietary risk assessment, a chronic reference dose (cRfD) of 0.015 mg/kg/day was established for assessments of all populations, with a NOAEL of 1.5 mg/kg/day and a LOAEL of 9 mg/kg/day based on decreased serum lipids and cholesterol, and changes in liver weights

.

For acute and chronic dietary, incidental oral and dermal risk assessments, a 100X uncertainty factor is applied (interspecies factor of 10X and intraspecies factor of 10X). For inhalation risk assessment, a 30X uncertainty factor is applied, which includes interspecies (3X) and intraspecies (10X) extrapolation. The interspecies factor was reduced from l0Xto 3X due to the
HEC calculation a ccounting for pharmacokinetic (not pharmacodynamic) interspecies
differences

The risk assessments conducted for FPE were based on the most sensitive endpoints in the toxicity database, and the NOAELs selected for risk assessment are considered protective of potential developmental, neurotoxic, and immunotoxic eff ects for infants and children. There is no evidence of increased qualitative or quantitative susceptibility in the rat 2

- generation reproduction study or the rat and rabbit developmental studies

. There is no evidence of neurotoxicity in any of the submitted studies for FPE

. There is also no residual uncertainty in the exposure database. T herefore, reduction of the 10X FQPA safety factor to 1X is considered appropriate.

The residue chemistry dat abase is considered complete for FPE for the purposes of the proposed use as well as for registration review . The nature and magnitude of the residue in plants has been adequately delineated. The residue of concern in plants and livestock consists of fen oxaprop

ethyl, its free acid metabolite, and 6

- chloro

- 2,3

-- dihydrobenzoxazol

- 2

- one. No FPE residues are expected in poultry livestock commodities based on the submitted ruminant metabolism study and the calculated dietary burden. The requirements for re sidue analytical methods are fulfilled

### Fenoxaprop

- p

- ethyl Human Health Risk Assessment DP No. 403928 and 411289

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### for the purposes of the proposed use as well as for registration review. Adequate methods are available for tolerance enforcement and data collection purposes for plant and animal
commodities. The enforcement method s are not stereo

- specific and cannot differentiate between FE and FPE ( i.e., cannot distinguish the level of enrichment of the d enantiomer)

.

Since a n acute refer ence dose was not selected for FPE , the Agency conducted only a chronic dietary (food and dri nking water) exposure and risk assessment. This assessment was conducted using tolerance level residues, 100% crop treated, and DEEMTM default processing factors. Using assumptions considered to be highly conservative, the chronic dietary risk estimates a re below HED’s level of concern (<100% of the chronic population adjusted dose (cPAD)), and range from 8.9 % of the cPAD for youth 13

- 19 years old to 27.5 % of the cPAD for the highest exposed population subgroup of all infants < 1 years old.

The registered uses of FPE on ornamentals and turf may result in adult residential handler and
post

- application exposure. This exposure is expected to be only short

- term in duration ( i.e., 1 to 30 days) as intermediate

- or long

- term exposures are not likely based on th e intermittent nature of applications by homeowners

. These assessments were conducted according to HED’s 2012 Residential Standard Operating Procedures (SOPs) . All route specific (dermal and in halation) exposure scenarios do not exceed HED’s level of con cern (LOC) ( MOEs ≥ 100 for dermal and MOEs ≥ 30 for inhalation) and all combined dermal and inhalation exposure scenarios for handlers result in aggregate risk index (ARI) values that are ≥ 1. ARI values were used to illustrate the combined exposures because the inh alation and dermal exposures have different
LOCs. For residential post

- application exposure, there are no risk estimates of concern identified for the dermal or incidental oral routes of exposure (all MOEs ≥ 100) from turf or
ornamental use sites

. Inhala tion post

- application exposure is not assessed for the registered use
scenarios.

A non

- occupational spray drift assessment was conducted for FPE based on the highest agricultural application rate currently registered (0.173 lbs ai/acre for use on sod farms). The edge of field adult dermal and children (1 to < 2 years) dermal and incidental oral MOEs do not
exceed HED’s level of concern (MOEs ≥ 100).

Since there are no acute points of departure identified, an acute aggregate risk assessment was
not conducted. HED has conducted short

- term and long

- term (chronic) ag gregate risk
assessments for FPE

. The short

- term aggregate assessment includes residential post

- application and dietary (food and water) exposures. Short

- term aggregate MOEs do not exceed HED’s level
of concern (MOEs ≥ 100). The long

- term (chronic) aggregate assessment includes only dietary (food and water) expo sure as long

- term residential exposure is not expected. Chronic dietary
risk is not of concern.

O ccupational handler risks were assessed for the inhalation and dermal route of exposure. All
estimated short

- and intermediate

- term handler combined (derm al and inhalation) risk estimates
do not exceed HED’s level of concern ( ARIs ≥ 1 ) with the use of chemical resistant gloves

. Similarly, the short

- and intermediate

- term post

- application dermal risk estimates ranging from
220 to 12,000 do not exceed HED’s of concern (MOEs ≥100) on the day of treatment (i.e., Day 0) for all of the post

- application exposure activities. Based on the Agency's current practices, a

### Fenoxaprop

- p

- ethyl Human Health Risk Assessment DP No. 403928 and 411289

Page 8 of 84 

### quantitative occupational post

- application inhalation exposure assessment was not performed for

FPE at this time.

This risk assessment relies, in part, on data from st udies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Re

- entry Task Force (ARTF) database; and the Residential SOPs ( Handler, Turf,
and Gardens SOP ) are subject to ethics review pursuant to 40 CFR 26, have received that review,
and are compliant with applicable ethics requirements. For certain studies that review may have included review by the Human Studies Review Board.

2.0 HED Recommendations

There are no recommendations based on the toxicological database.

HED has examined the r esidue chemistry database for FPE. Pending submission of a revised Section F (see requirements under Revisions to Petitioned

- For Tolerances below) there are no residue chemistry issues that would preclude the establishment of a tolerance with regional

res triction on grass, hay. Additionally, all regulatory requirements related to residue chemistry for FPE are considered adequate for registration review.

HED recommends that all registered and proposed occupational use labels contain chemical

resistant glo ves for handler exposure activities

.

2.1 Data Deficiencies

There are no data defi ciencies relating to toxicology, residue chemistry , or occupational exposure
associated with this action.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate analytical method is available to enforce tolerances for FE in plant and animal commodities. A gas chromatography with electron capture detection (GD

- ECD) method, based on Hoechst HRAV Analytical Method HRAV

- 4B, was previously reviewed by th e Agency and was incorporated into the Food and Drug Administration (FDA) Pesticide Analytical Manual, Volume II (PAM II). The method has a limit of quantitation (LOQ) of 0.05 ppm in all matrix
types. HED notes that his method is not stereospecific, and therefore, does not distinguish
between residues of FE and FPE in foods.

The method is described as follows. Briefly, samples are refluxed with a solution of acetonitrile, concentrated HCl, and water for 6 hours and filtered through filer paper. An al iquot is transferred onto an Extrelut column and equilibrated with the column matrix. The hydrolysis product 6

- chlorobenzoxazolone is eluted with hexane: diethyl ether and evaporated to dryness.

### Fenoxaprop

- p

- ethyl Human Health Risk Assessment DP No. 403928 and 411289

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### The residue is dissolved with ethyl acetate and the ethyl a cetate evaporated to dryness. The residue is then derivatized in a mixture of toluene, acetic anhydride, and pyridine for 2 hours at 130° C. The residue with reaction product acyl 6

- chlorobenzoxazolone (AE F083312) is dried, and cleaned up on a silica ge l SPE cartridge. FE and its metabolites are then determined as

6

- chlorobenzoxazolone (AE F083312) by GC

- ECD. Total residue is then expressed as FE equivalents.

FE has also been subjected to analysis by the Food and Drug Administration (FDA) multi

residu e method (MRM) protocols. Multi

- residue methods are available for residues of FE and the metabolites of concern under Protocols 1 through 4.

2.2. 2 Established Tolerances

FPE is an enriched isomer formulation (95% d , the herbicidally active enantiomer). Originally, the product was registered as racemic mix ture known as FE

. Tolerances were at that time established under 40CFR 180.30 for FE, and the tolerance expression included both enantiomers ( d and l ) with no ratio specified. Therefore, since both en antiomer s are included in the tolerance expression and the data

- collection and tolerance enforcement methods are not stereo

- specific and cannot differentiate between FE and FPE ( i.e., cannot distinguish the level of enrichment of the d enantiomer), the pre viously established tolerances for FE are adequate to cover residues from the application of FPE. For this reason, any discussion of tolerances with respect to FPE is
described in terms of FE in this document.

Currently there are tolerances established f or residues of FE as listed in Table 2.2. 2 below. The tolerance expression for FE is as follows:

Compliance with the tolerance levels specified is to be determined by measuring only the sum of fenoxaprop

- ethyl, (±)

- ethyl 2

- [4

- [(6

- chloro

- 2

- benzoxazolyl )oxy]phenoxy]propanoate, and its metabolites, 2

- [4

- [(6

- chloro

- 2

- benzoxazolyl)oxy]phenoxy]propanoic acid and 6

- chloro

- 2,3

- dihydrobenzoxazol

- 2

- one, calculated as the stoichiometric equivalent of fenoxaprop

- ethyl.

Table 2.2.2. Tolerance Summary for Feno xaprop
- ethyl

Commodity Tolerance (ppm) Comments Correct Commodity Definition 180.430 (a) General Barley, grain 0.05 Barley, straw 0.1 Cattle, fat 0.05 Cattle, meat byproducts 0.05 Cattle, meat 0.05 Cotton, undelinted seed 0.05 Goat, fat 0.05 Goat, meat byproducts 0.05 Goat, meat 0.05 Hog, fat 0.05 Hog, meat byproducts 0.05 Hog, meat 0.05 Horse, fat 0.05

### Fenoxaprop

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- ethyl Human Health Risk Assessment DP No. 403928 and 411289

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- ethyl

Commodity Tolerance (ppm) Comments Correct Commodity Definition Horse, meat byproducts 0.05
Horse, meat 0.05

Milk 0.02

Peanut 0.05 Peanut, hulls 0.05 Revoke, no longer a regulated

com modity Rice, grain 0.05 Sheep, fat 0.05 Sheep, meat byproducts 0.05 Sheep, meat 0.05 Soybean 0.05 Soybean, seed Wheat, grain 0.05 Wheat, straw 0.05 180.430 (b) Section 18 emergency exemptions Grass, forage 0.05 Expires 12/31/2013 Grass, hay 0.05 Expires 12/31/2013



### 2.2. 2.1 Revisions to Established Tolerances

HED is recommending that certain existing tolerances be amended to reflect current polices. The commodity definition for soybean should be changed from soybean to soybean, seed.
Addi tionally, the tolerance on peanut, hulls may be revoked since that commodity is no longer a regulated raw agricultural commodity (RAC).

2.2.3 Petitioned

- For Tolerances

For the purposes of this petition, tolerances for residues of FE in/on grass, hay were not derived using the Organization for Economic Cooperation and Development Maximum Residue Level (OECD MRL) Calculation Procedures since all of the residue values were less than the limit of quantification (<LOQ) of the analytical method.

Table 2.2.3 Proposed Tolerance Summary for FE Commodity P roposed
Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

180.430 (c) Tolerances with regional restrictions Grass, hay 0.15 0.09 For the states of WA, OR, and UT only



### 2.2.3.1 Revisions to Petition ed

- For Tolerances

HED is recommending that a tolerance with regional restriction be set for grass, hay as requested by the petitioner with the change noted below. The method used for data

- collection (as well as tolerance enforcement) converts the residue s of concern for FE to acyl 6

- chlorobenzoxazolone for detection. It is necessary to then convert this residue value to parent equivalents. Since the residues found on grass, hay were less than the LOQ of 0.05 ppm for acyl

### Fenoxaprop

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- ethyl Human Health Risk Assessment DP No. 403928 and 411289

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### 6

- chlorobenzoxazolone, HED multi plied this 0.05 ppm value by the ratio of the molecular weights (1.71) to arrive at a recommended tolerance of 0.09 ppm.

The requested change to the proposed tolerance level is shown in Table 2.2.3 above.

2.2. 4 International Harmonization

There are no i nternational harmonization issues related to the existing or proposed uses of FPE. Please see Appendix B for a summary of international maximum residue limits (MRLs).

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

There are no labe l recommendations based on residue chemistry identified for this petition.

2.3.2 Recommendations from Occupational Assessment

HED recommends that all registered and proposed occupational use labels contain chemical

resistant gloves for handler exposure activities

.

2.3.3 Recommendations f rom Residential Assessment

There are no label recommendations for the currently registered residential uses of fenoxaprop

- p

ethyl.

3.0 In troduction

FPE is a selective aryloxy phenoxy

- propionate herbicide used to con trol grass weeds after emergence. FPE is currently registered for use on barley, cotton, rice, soybeans, and wheat. FPE is also registered for non

- agricultural use on conservation reserve land s, ornamentals, rights

- of

way, and turf. S ince both enantiomer s are included in the tolerance expression , and the data

collection and tolerance enforcement methods are not stereo

- specific and cannot di fferentiate
between FE and FPE , the previously established tolerances for FE are adequate to cover residues
from the application of FPE

.

The chemical structure and nomenclature of FPE are presented in Table 3.1, and the physicochemical properties of the technical grade of FPE are provided in Table 3.2.

3.1 Chemical Identity

Table 3.1 Fenoxaprop

- p
- ethyl Nomenclature

### Fenoxaprop

- p

- ethyl Human Health Risk Assessment DP No. 403928 and 411289

Page 12 of 84 Table 3.1 Fenoxaprop

- p
- ethyl Nomenclature

Chemical Structure

Empirical Formula

Common Name Fenoxaprop

- p

- ethyl
Company experimental name AE F046360

IUPAC name ethyl ( R )

- 2

- [4

- ( 6

- chloro

- 1,3

- benzoxazol

- 2

- yloxy)phenoxy] propionate

or ethyl ( R )

- 2

- [4

- (6

- chlorobenzoxazol

- 2

- yloxy)phenoxy]propionate

CAS Name ethyl (2 R )

- 2

- [4

- [(6

- chloro

- 2

- benzoxazolyl)oxy]phenoxy]propanoate
CAS Registry Number 71283

- 80

- 2



### 3.2 Physical/Chemical Characte ristics

FPE has low water solubility. Its octanol/water partition coefficient suggests that it is a hydrophobic compound that is more fat soluble than water soluble, exhibiting a tendency to dissolve in fats, oils, lipids, and non

- polar solvents more rea dily than in water. Further, FPE has a low vapor pressure. The full complement of physiochemical properties for this active ingredient is shown in Table 3.2.

Table 3.2. Physicochemical Properties of the Technical Grade FPE

Parameter Value Reference

Melting Point/Range (  C) 86.5 Health Canada Fenoxaprop

- p

- ethyl Proposed Re

Evaluation Decision

(PRVD2011

- 04) Density (g/cm 3 ) 1.32

Water Solubility ( 20  C, pH 5.8) (mg/L) 0.7

Solvent Solubility (g/L at 20  C) n

- hexane 7.0

acetone >400

toluene >480

dichloromethane >400

methanol 43.1
isopropanol 14.2
ethyl acetate >380

Vapor Pressure (Pa) 5.3 x 10

- 7 at 20°C
1.4 x 10

- 6 at 25°C

1.1 x 10

- 4 at 50°C
Dissociation Constant (pK
a ) Not possible to measure in water in the pH range

1

- 13 (no acidic or bas ic groups on the molecule)

Octanol/Water Partition Coefficient Log (K
ow ) 4.58
UV/Visible Absorption Spectrum Not expected to absorb at

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Parameter Value Reference

λ > 300nm



### 3.3 Pesticide Use Pattern

The only FPE end

- use formulation currently registered is as a liquid formulation which may be applied post

- emergent for the use on various agricultural crops (barley, cotton, rice, soybeans, and wheat), ornamentals, turf (resid ential lawns and sod farms), conservation reserve lands, and right

- of

- ways . There is also a proposed new use for grasses grown for seed in Oregon, Washington, and Utah.

A summary of the existing and proposed use patterns for FPE are shown in T able s 3.3 a and 3.3b
below.

Table 3.3a. Summary of Directions for Use of Currently Registered Fenoxaprop

- p
- ethyl Uses

Applic. Timing, Type, and Equip. EPA Reg.

No. Max

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

Applic. per
Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Barley

Groundboom
and Aerial applications 264

- 666

264

- 1073
264

- 1075 0.083 1 0.083 57 No chemigation
24 hour REI

Conservation Reserve Lands

Groundboom
and Aerial applications 264

- 647 0.1 NS 0.142 N/A No ch emigation
24 hour REI

Cotton

Groundboom
and Aerial applications 100

- 1059 0.105 1 0.105 90 No chemigation
24 hour REI

Ornamentals

Groundboom
and handheld applications 432

- 950 0.173
0.002 lbs ai/gal 3 0.531 N/A No chemigation
24 hour REI

Ornamentals (Residential)

Handheld applications 72155

- 74 0.076

0.0009 lbs ai/gal

0.008 lbs
ai/bottle NS 0.531 N/A N/A

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- p
- ethyl Uses

Applic. Timing, Type, and Equip. EPA Reg.

No. Max

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

Applic. per
Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Rice

Groundboom
and Aerial applications 264

- 647

264

- 682 0.108

(SLN) 1 0.142 65 No chemigation
24 hour REI

Right of Way

Groundboom
and Aerial

ap plications 100

- 1059

432

- 950 0.173

0.017 (lbs ai/gal) 3 0.531 N/A No chemigation
24 hour REI

Soybean

Groundboom
and Aerial applications 100

- 1059

264

- 647 0.1 2 0.128 90 No chemigation
24 hour REI

Turf (sod/commercial)

Groundboom
and Aerial applications 432

- 950 0.173 NS 0.531 NS No chemigation
24 hour REI

Turf (residential lawns) Ready to use

Hose

- end sprayer and

concentrate solutions through
handheld equipment 228

- 716 1

72155

- 74
72155

- 77
72155

- 78 0.076

0.0009 lbs ai/gal

0.008 lbs
ai/bottle NS NS N/ A No aerial, groundboom, or chemigation

Wheat

Groundboom
and Aerial applications 100

- 1429

264

- 666
264

- 1073
264

- 1075 0.083 1 0.083 70 No chemigation
24 hour REI

SLN= Special Local Needs
1. The currently registered label 228

- 716 has a maximum application ra te of 0.1 lbs ai/acre for residential lawn applications; however, Bayer Crop Science has submitted a commitment letter to revise the application rate to 0.076 lbs ai/acre for all residential lawn applications. The letter is discussed and appended to D4160 00, D416003 (S. Shelat, 1/ 23/ 201 4 ).

Table 3.3b. Summary of Directions for Use of Proposed Fenoxaprop

- p
- ethyl Uses

Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Max

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

Applic. per
Season Max.

Seasonal Applic.
R ate (lb ai/A) PHI

(days) Use Directions and

Limitations

Proposed Grass grown for seed (Oregon, Washington, Utah)

Groundboom application 264

- 266 0.082 NS NS 60 No chemigation no aerial applications NS= not specified

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### 3.4 Anticipated Exposure Pathways

In addition to the preliminary risk assessment for Registration Review, this document addresses the Registration Division’s request of a human health risk to support the proposed new use of fenoxaprop

- p

- ethyl on grass grown for seed. Humans may be exposed t o fenoxaprop

- p

- ethyl in food and drinking water, since fenoxaprop

- p

- ethyl may be applied directly to growing crops and application may result in fenoxaprop

- p

- ethyl reaching surface and ground water sources of drinking water. There are residential uses of fenoxaprop

- p

- ethyl, so there is likely to be exposure in residential or non

- occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There
is also a po tential for post

- application exposure for workers re

- entering treated fields.

Risk assessments have been previously prepared for the existing uses of fenoxaprop

- p

- ethyl. This risk assessment considers all of the aforementioned exposure pathways based o n the proposed new use of fenoxaprop

- p

- ethyl, but also considers the existing uses as well.

3.5 Consideration of Environmental Justice

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

- Income Populations," ( http://www.eh.doe.gov/oe pa/guidance/justice/eo12898.pdf . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pestic ide 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 t he Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and reg ion of the country. 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 p esticide 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 e xpertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

3.6 Incident Reports

HED completed a review of FPE incide nts in the OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases

. Based on the low frequency and severity of incident cases reported for

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### FPE in both IDS and NIOSH SENSOR

- Pesticides, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident
infor mation and if a concern is triggered, additional analysis will be conducted.

The Agricultural Health Study (AHS) is also a potential source of information associated with human health effects associated with certain pesticides. FPE is included in the AH S, but it is only in phase III and there are no studies available yet to consider. Further detail is provided in
the Tier I Updated Review of Human Incidents for Preliminary Risk Assessment (D416023, November 13, 2013).

4.0 Hazard Characterization and Do se
- Response Assessment

4.1 Toxicology Studies Available for Analysis

FE was first registered as a 50:50 racemic mixture of d and l enantiomers

. Since registration, the

more herbicidally active isomer d, FPE has been registered. HED held a joint Toxicolo gy Science Advisory Committee/Hazard and Science Council (ToxSAC/H ASPOC) meeting on April 17, 2008 to determine if bridging of fenoxaprop

- ethyl (FE) toxicity data was appropriate for FPE (Kidwell, 2008). Based on the analysis of the acute and subchronic t oxicity studies,

HED found that the toxicological effects of FE and FPE across species, duration, and route of exposure are similar. It was, therefore, concluded that the similarity between the FE and FPE
data was such that the database for FE could be br idged with FPE . HED further concluded that the enriched isomer is approximately an order of magnitude less toxic than the racemic mixture.

Based on bridging, the toxicology database on FPE is sufficient for assessing the toxicity and characterizing the h azard of FPE. The toxicology studies for FPE are summarized in Table A.1 in Appendix A. The database includes the following studies.

 Subchronic: 90

- day oral toxicity (rat, mouse, dog)

 Dermal: 30

- day dermal toxicity (rat)

 Inhalation: 28

- day inhalation to xicity (rat)

 Developmental toxicity: developmental toxicity (rat and rabbit)

 Immunotoxicity: 28

- day dietary (rat)

 Other: Mutagenicity battery, metabolism, dermal absorption, in vitro dermal penetration comparison of humans vs. rats

The database for the ra cemic fenoxaprop ethyl (FE) includes the following studies.

 Chronic/Carcinogenicity: 2

- year oral toxicity (rat and mouse)

 Chronic: 1

- year oral toxicity (dog)

 Subchronic: 90

- day oral toxicity (rat, mouse, and dog)

 Dermal: 21

- day and 30

- day dermal toxicity (rat)

 Inhalation: 28

- day inhalation toxicity (rat)

 Developmental toxicity: oral (rat, mouse, and rabbit); dermal (rat and rabbit)

 Reproductive toxicity: 2

- generation (rat)

 Other: Mutagenicity, metabolism, dermal absorption

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### The studies available for consi deration of FPE toxicity provide a comprehensive database, with routes of administration that are consistent with potential exposure scenarios.

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

In studies with the racemic FE, 83

- 109% of the administered radioactivity was recovered in the urine and feces, with the majority of the dose (51

- 65%) being recovered within 24 hours of dosing. Sex

- related differences in the pattern of excretion were apparent. Female rats
metabolized the chemical more rapidly and excreted more of the total radioactivity in the urine (54

- 70% of dose) than the males (37

- 58% of dose). Within 24 hours of dosing, urinary excretion
accounted for 39

- 48% of the dose for females and 22

- 31% of the dose for males. Over the course of the study, radioactivity in feces accounted for 39

- 62% of the dose for males and 30

- 43% of
the dose for females. Dose

- related differences in excretion were not evident in females, but high dose males had a higher level (62% of dose) of excretion in the feces than low

- dose males (39

- 40% of dose). A very small amount of unchanged parent compound is excreted in the feces. No
bioaccumulation occurred.

A comparison and evaluation of the metabolism and pharmacokinetics of FPE was conducted in rats using sin gle and repeat (15 doses, once daily) oral doses of 2 and 10 mg/kg. Excretion via the urine and feces is in the same order of magnitude as FE. At 168 hours after exposure with FPE, ~95% of the administered dose was recovered, with slightly higher urinary e xcretion in females (56.9 to 65.0%) than males (42.8 to 54.1%). The highest residue concentrations were identified in the kidneys at 168 hours following exposure. Comparison of metabolic pathways demonstrated that they are identical for FE and FPE, and tha t the optical activity is preserved in the animal body.

4.2.1 Dermal Absorption

In an in vivo study, a single dermal application of 2.72 ± 0.03 or 617.5 ± 125.6 μg/cm 2 

### was applied to male rats. Each dose was washed after eight hours of exposure and 4/gr oup were sacrificed at 8, 24, 72 and 120 hrs. Recovery of the applied dose (mass balance) was acceptable at both dose levels (96.3 and 90.8%, respectively). Estimates of dermal absorption were based on the sum of residues retained in the urine (including c age wash and rinse), gastrointestinal tract and contents, feces, carcass, and blood and increased in a contact time

- dependent manner from 6.212% of the applied dose at eight hours and 9.6% of the applied dose at 24 hours after
initiation of treatment to 16 .31% of the applied dose at 120 hours after initiation of treatment for the low dose. For the high dose, total absorption was 0.6% of the applied dose eight hours after initiation of treatment, 1.3% after 24 hours, and increased to 2.012% of the applied do se by 120
hours.

4 .3 Toxicological Effects

FPE is a post

- emergent herbicide of the oxyphenoxy acid ester group (aryloxy phenoxy

propionate class). Its pesticidal mechanism of action is to interfere with fatty acid biosynthesis, specifically to inhibit acetyl CoA carboxylase. The major target organs following short

- term and

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### long

- term oral administration of FE and FPE in rats and mice are the liver and kidneys, with rats being the most sensitive species. The primary toxic effect is altered lipid metaboli sm characterized by decreased lipids and cholesterol, and increased liver weights in rats, and slightly increased lipids, cholesterol, proteins, and liver weights in mice. Additionally, increased enzyme activity (ASAT, ALAT, and ALP), hypertrophy, and sing le cell necrosis were observed in mice. In the kidneys, increases in ketones and kidney weights were observed in rats and evidence of proximal renal tubular injury were observed in mice following 90 day administration of FPE. However, no effects on the kid neys were observed following chronic administration of FE to rats, mice, or dogs. In both species, males were slightly more sensitive to the liver effects of FE and FPE. It is also important to note that no increases in toxicity are observed over time for FE when comparing the 28

- day and 90

- day subchronic studies, the 2

- generation reproductive toxicity study, and the 2

- year chronic toxicity/carcinogenicity study in rats, or in FPE when comparing the 28

- day and 90

- day subchronic toxicity studies in rats.

F PE has low acute toxicity following the oral, dermal, and inhalation routes of exposure. No
evidence of immunotoxicity, reproductive or neurological toxicity was identified in the database. Developmental toxicity occurred in rats as evidenced by skeletal a nomalies (longitudinally displaced, fragmented, fused, dysplastic sternebrae or dislocated sternebrae) and skeletal retardations (weak or non

- ossification of one or several cranial bones). Developmental effects only occurred in the rat in the presence of m aternal toxicity (decreased body weight, body weight gain, and heart weight). No developmental effects were identified in rabbits. In mice, a

treatment

- related increase in tumor incidence of hepatocellular adenomas and carcinomas, mainly adenomas, was obse rved in males at 320 ppm (30%) compared to the control (2%). In addition, microscopic pathology indicated that hepatocellular hypertrophy was observed in the majority of treated animals (both sexes). There was, however, no evidence of a mutagenic effect
in a comprehensive battery of genetic toxicology assays with both isomers. No evidence of tumors was identified in rats. In accordance with EPA’s Final Guidelines for Carcinogen Risk Assessment (2005), CARC classified FE/FPE as “Suggestive Evidence of Carcin ogenic
Potential”.

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

The HED recommends that the FQPA Safety Factor be reduced to 1X based on adequate toxicity database and exposure data. There is no evidence of susceptibility/sensitivity and there are no residual uncertainties concerning pre

- or post

- natal toxicity. No evidence of neurotoxicity was identified throughout the database for FE or FPE. All endpoints used in this risk assessment are protective of developmental effects in FE and FPE. The dietary and residential assessments are based on reliable data and will not underestimate exposure.

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### 4.4.1 Completeness of the Toxicology Database

The toxicology database for FPE is complete based on bridging to FE. Acceptable rat and rabbit
dev elopmental toxicity studies, a rat 2

- generation reproduction study, a non

- guideline developmental toxicity study, and an immuno toxicity study are available. The Hazard and Science Policy Council (HASPOC) (Report dated November 27, 2012, TXR 0056489,
deter mined that the acute neurotoxicity study and subchronic neurotoxicity studies may be
waived.

4.4.2 Evidence of Neurotoxicity

No evidence of neurotoxicity was observed in any of the submitted studies for FPE or FE. The
HASPOC determined that the acute n eurotoxicity study and subchronic neurotoxicity studies are not required at this time based on the following rationale: 1) the lack of neurotoxicity in the available toxicology database for FE and FPE ; 2) the target organs of FPE and FE are the kidney
and liver, and the mechanism of action for FPE and the chemical class do not target the nervous system; 3) developmental effects and decreased total blood lipids/cholesterol are the most sensitive effects seen in the FE database and provide the most sensitive POD for risk assessment; 4) there is low concern for neurotoxicity in other members of this class of chemicals ( i.e ., the arloxy phenoxy

- propionate class ); and 5) using an oral POD, the acute and chronic dietary risk estimates (food only) for FE utilize < 1% of the aPAD and cPAD, respectively.

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

The available data do not provide evidence of any increased susceptibility in the offspring in either of the two developmental toxicit y studies for FPE or in the two

- generation reproduction study for FE. Delayed ossification was the primary effect in the developmental toxicity study
and only occurred in the presence of maternal toxicity and a clearly defined NOAEL and
LOAEL were achieve d.

In the rat developmental toxicity study with FPE, longitudinally displaced, fragmented, fused, dysplastic sternebrae or dislocated sternebrae and weak or non

- ossification of one or several cranial bones were noted at 100 mg/kg (highest dose tested). These incidences occurred only in the presence of maternal toxicity ( decreased gestational body weights, body weight gains, and food consumption. ) . No developmental effects occurred in rabbits. In the 2

- generation rat reproductive toxicity study on FE, n o reproductive or developmental effects were observed. An increase in alkaline phosphatase ( ALP ) activity and liver weights were identified in th e offspring at 9.0 mg/kg. These effects occurred in the presence of parental toxicity (increased liver weight

a nd decreased lipids) and are consistent with hepatotoxicity, the primary toxic effect of FPE,
observed across the database.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. Since the diet ary and residential exposure estimates were based on conservative assumptions, HED is confident that this assessment does not underestimate dietary (food and water) or residential exposure.

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### The unrefined chronic analysis is based on tolerance

- level resi dues, 100% crop treated (%CT) assumptions, and DEEM default processing factors. The drinking water assessment used water concentration values generated by models and associated modeling parameters which are designed to produce conservative, health protec tive, high

- end estimates of water concentrations which are not likely to be exceeded. For these reasons it can be concluded that the chronic dietary exposure analysis does not underestimate risk from chronic exposure to FPE.

Similarly, HED does not belie ve that the residential exposure estimates are underestimated because they are also based on conservative assumptions including maximum application rates
and standard values for inputs such as unit exposures, transfer coefficients, and amount handled.

4. 5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

A detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios is presented in Appendix A.

For acute dietary assessment , no appropriate toxicological endpoints attributable to a single exposure were identified for general populations or females age 13 to 49. Consequently, there was no basis for selecting a dose and endpoint for an acute RfD for general populations including infants and children, and females ages 13

- 49.

For chronic dietary exposure and risk assessment, the chronic/carcinogenicity and 2

- generation reproductive toxicity studies in rats, conducted on FE, were selected with a NOAEL of 1.5 mg/kg/day identified in both studies. The LOAEL is 9 mg/kg/day based on decreased serum lipids and cholesterol, and changes in liver weights in both studies, as well as increased ALP and liver weights in pups from the 2

- generation reproductive toxi city study. These studies are considered to be the most appropriate for chronic dietary dose and endpoint selection. A lower NOAEL of 0.375 mg/kg/day was identified in the chronic dog study for FE. However, this was not considered a critical NOAEL as only minimal effects occurred (10

- 12% reduction in body weights ), and subchronic toxicity studies in the dog for FPE showed no effects up to 77.7 mg/kg/day.

For short

- term incidental oral exposure (1

- 30 days), a 28

- day oral toxicity study in rats with a
NOAEL of 6 mg/kg/day was selected (FPE). In the study, t he LOAEL is 26 mg/kg/day (M/F) based on altered lipid metabolism (decreased HDL

- cholesterol, HDL

- phospholipids, and total lipids, increased triglycerides, and ketonuria) and increased liver and kidney weigh ts. Intermediate exposure is not expected based on current use patterns; therefore, risk assessment for intermediate incidental oral exposure is not required.

For short and intermediate

- term dermal exposure, a 28

- day dermal toxicity study in rats with a

N OAEL of 20 mg/kg/day was selected (FPE). In this study, the LOAEL is 100 mg/kg/day (M/F)
based on non

- regenerative anemia, decreased serum cholesterol, total lipids, and protein (beta 1 globulins), and increased liver and kidney weights. There is no long

- term exposure from existing or proposed uses; therefore, a risk assessment for long

- term dermal exposure is not required.

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### For short and intermediate

- term inhalation exposure, a 28

- day inhalation toxicity study in rats with a NOAEL of 0.07 mg/L was select ed (FPE). In the study, the LOAEL is 0.3 mg/L (M) based on slight normocytic anemia, decreases in serum cholesterol and total lipids, and increases in liver and kidney weights and urea nitrogen. There is no long

- term exposure from existing or proposed use s; therefore, a risk assessment for long

- term inhalation exposure is not required.

The methods and dosimetry equations described in EPA's reference concentration (RfC) guidance (1994) are suited for calculating HECs based on the inhalation toxicity NOAEL for use in MOE calculations. The regional

- deposited

- dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter [MMAD] and geometric standard deviation [<σ g 

### ] of aerosols), can be used to estimate the different dose fractions d eposited along the respiratory tract. The RDDR is also based on interspecies differences in ventilation and respiratory

- tract surface areas. Thus, the RDDR can be used to adjust an observed inhalation particulate exposure of an animal to the predicted inha lation exposure for a human. For the 4

- week inhalation study with FPE, a MMAD and geometric standard deviation were not reported due to the type of particle collection system. An MMAD of 1.2 μm and stand ard deviation (<σ g 

### )
of 2.80 were estimated based on the cumulative 50 th 

### percentile (50% of particles being ≤) ranging from 1.2

- 1.5 μm and between 74

- 97% of particles ≤ 4 μm. Therefore, an RDDR of 2.7 was estimated using the above values and the respiratory

- tract surface area of the rat relative to the human (see Appendix A.5 for detailed calculations). Since the rat inhalation study was carried out for 6 hrs/day for 5 days/week, the only exposure adjustment made was in the assumption of 8 hrs/day for human occupational exposures, and 2 hrs/day for human residential exposures. The resulting HECs are 0.14 mg/L and 0.57 mg/L, respectively.

4.5.1. Inhalation Endpoints and Points of Departures for Fenoxaprop

- p
- ethyl

Inhalation
Short

- Term (1

- 30 days) and

Inte rmediate

- Term (1

– 6 months) NOAEL = 0.07

mg/L (males)

0.3 mg/L (females) UF A = 3x

UF H = 10x

FQPA SF= 1X

LOC for MOE

= 30 21

- Day Inhalation toxicity (rat)

MRID 47113307 (1989) LOAEL = 0.3 mg/L (males only) Based on slight normocytic anemia,
decreases in serum cholesterol and total lipids, and increases in liver weight and urea nitrogen. Occupational
HEC = 0.14 mg/L

Residential
HEC = 0.57 mg/L

HED = 6.8 mg/kg/day

NOAEL =no

- observed adverse

- effect level, LOAEL

- lowest

- observed adverse

- effect level

M OE= margin of exposure, HEC =human

- equivalent concentration; HED =human

- equivalent dose. Occupational HEC =rat NOAEL*(daily duration adjustment)*weekly daily duration adjustment *RDDR* = 0.07 mg/L * (6hr/8hr)*(l)*2.7 = 0.1417 or 0.14 mg/L.
Residential HEC =rat NOAEL*(daily duration adjustment)*weekly daily duration adjustment *RDDR* = 0.07 mg/L * (6hr/2hr)*(l)*2.7 = 0.567 or 0.57 mg/L.
HED = HEC*human

- specific conversion factor*daily duration = 0.1417 mg/L • 6.0 l/hr/kg*8hr = 6.81 or 6.8 mg/kg/day.

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### For ac ute and chronic dietary, incidental oral, and dermal risk assessments, a 100X uncertainty factor is applied (interspecies factor of 10X and intraspecies factor of 10X). For inhalation risk assessment, a 30 X uncertainty factor is applied, which includes in terspecies (3X) and intraspecies (10X) extrapolation. The interspecies factor was reduced from l0 X to 3X due to the HEC calculation accounting for pharmacokinetic (not pharmacodynamic) interspecies
differences.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources: incidental oral, dermal, and inhalation. For FPE, inhalation, dermal, and o ral routes can be combined since toxicological
effects are the same.

4.5.3 Cancer Classification and Risk Assessment Recommendation

In accordance with EPA’s Final Guidelines for Carcinogen Risk Assessment (2005), the Cancer Assessment Review Committee (C ARC) classified FPE as “Suggestive Evidence of Carcinogenicity” based on increased liver adenomas and carcinomas observed male mice in the chronic toxicity/carcinogenicity study ( 7/29/2013, TXR 0056683). The liver tumor response induced by FE/FPE occurred only in the male mice; no liver tumors were seen in the female mice or in the guideline chronic/carcinogenicity study in rats. The tumors were benign with no progression to malignancy . Mutagenicity has been ruled out as an MOA for this response.
Additiona lly, t he adrenal cortex subcapsular Type B adenomas were determined to be not

treatment

- related. The CARC concluded that d ata were not sufficient to support the proposed
MOA for liver tumors. When there is suggestive evidence of carcinogenicity, the Agenc y does not attempt a dose

- response assessment as the nature of the data generally would not support one. Therefore, q uantification of risk using a non

- linear approach (i.e. the chronic reference dose (cRfD)) will adequately protect for all chronic toxicity , including carcinogenicity that could result from exposure to FE/ FPE.

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

Table 4.5.4. Summary of Toxicological Doses and Endpoints for Fenoxaprop

- p
- ethyl for Use
in Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety
Factors RfD/PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Acute Dietary (General Population) No appropriate endpoint attributable to a single dose was identified. An acute RfD was not

established. Acute Dietary (Females 13

- 49 years of age)

Chronic Dietary (All Populations) NOAEL = 1.5

mg/kg/day UF A 10X

UF H 10X

FQPA SF = 1X Chronic RfD =

0.015 mg/kg/day

cPAD = 0.015 mg/kg/day Chron ic Toxicity/Carcinogenicity (rat)

MRIDs: 00149664, 0149665, 00151564,
00151565

2

- Generation Reproductive Toxicity (rat)
MRID: 00159920

LOAEL = 9 mg/kg/day, based on decreased serum lipids and cholesterol, and altered liver weights

Incidental Oral
Short

- Term (1

- 30 days) NOAEL = 6

mg/kg/day UF A = 10X

UF H = 10X

FQPA SF = 1X LOC for MOE

= 100 28

- Day Oral Toxicity (rat)

MRID 47113304 (1986) LOAEL = 26 mg/kg/day, based on altered lipid metabolism (decreased HDL

cholesterol, HDL

- phospholipids, and total lipids , increased triglycerides, and ketonuria) and increased liver and kidney

weights.

Dermal
Short

- Term (1

– 30 days) and
Intermediate

- Term (1

– 6 months) NOAEL = 20

mg/kg/day UF A = 10X

UF H = 10X

FQPA SF= 1X LOC for MOE

= 100 28

- Day Dermal Toxicity (rat)

MRI D 47113306 (1987) LOAEL = 100 mg/kg/day, based on non

regenerative anemia, decreased serum cholesterol, total lipids, and protein (beta 1 globulins), and increased liver and kidney weights were observed. Additionally,
cholesterol remained decreased follow ing a

15

- day recovery period.

Inhalation
Short

- Term (1

- 30 days) and
Intermediate

- Term (1

– 6 months) NOAEL = 0.07

mg/L (males)

0.3 mg/L (females) UF A = 3X

UF H = 10X

FQPA SF= 1X LOC for MOE

= 30 21

- Day Inhalation toxicity (rat)

MRID 47113307 (1989)
LOAEL = 0.3 mg/L (males only) Based on slight normocytic anemia,
decreases in serum cholesterol and total

### Fenoxaprop

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### Table 4.5.4. Summary of Toxicological Doses and Endpoints for Fenoxaprop

- p
- ethyl for Use
in Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety
Factors RfD/PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Occupational
HEC = 0.14 mg/L

Residential
HEC = 0.57 mg/L

HED = 6.8 mg/kg/day lipids, and increases in liver weight and urea nitrogen.

Cancer (oral) Classification: "Suggestive evidence of carcinogenic potential"; quantification of risk using a

non

- linear approach; i.e., RfD, for FPE will adequately account for all chronic toxicity, including

carcinogenicity, that could result from exposure to FPE. Point of Departure (POD) = A data point or an estimated point derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL
= no observed ad verse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animals to humans (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA S F = FQPA Safety Factor. cPAD = chronic population adjusted dose. RfD = reference dose. N/A = not applicable. HEC = human equivalent concentration. HED = human equivalent dose.



### 4.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numer ous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or sy stemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision for FP E, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), FPE is subject to the endocrine screening part of the Endocrine Dis ruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estro gen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a
chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the E DSP where EPA

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### will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and
establish a dose

- response relationship betw een the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pestic ide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 20131 and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists sho uld be construed as a list of known or likely endocrine disruptors.

FPE is on List 2. List 2 represents the next set of chemicals for which EPA intends to issue test
orders/data call

- ins in the near future.

5.0 Dietary Exposure and Risk Assessment
See memos D415999, D416002 (D. Wilbur; 11/14/2013) and D 415998 , D416001 (D. Wilbur; 12/5/13) for additional details.

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Plant HED has previously concluded that the me tabolism of fenoxaprop

- ethyl is adequately understood. A comparison of the metabolism of FE and FPE was submitted for soybeans, rice, and wheat (MRID 47113302). The results showed that there is no significant difference in the
metabolism for FE and FPE. Plant metabolism studies have been submitted for barley, soybeans, rice, cotton, peanuts, and wheat. It has been concluded that the metabolic pathway for fenoxaprop

- ethyl is similar in these plants. The parent compound fenoxaprop

- ethyl is cleaved to yiel d 2

- [4

- [(6

- chloro

- 2

- benzoxazolyl)oxy]phenoxy]propanoic acid which subsequently loses phenoxypropionic acid to yield 6

- chloro

- 2,3

-- dihydrobenzoxazol

- 2

- one. The residue of concern in plants consists of fenoxaprop

- ethyl, its free acid metabolite {2

- [4

- [(6

- ch loro

- 2

- benzoxazolyl)oxy]phenoxy]propanoic acid,} and 6

- chloro

- 2,3

-- dihydrobenzoxazol

- 2

- one.

Livestock The nature of the residue in livestock for FPE based on the currently registered and proposed uses is considered to be adequately understood. Both rumi nant and poultry metabolism studies were submitted/reviewed and found to be scientifically acceptable. The metabolic pathway in ruminants and poultry is similar; therefore a swine metabolism study was not required.

The metabolism of fenoxaprop

- ethyl in a nimals has been previously considered in lactating ruminants (PP#6F3316, N. Dodd, 02/04/1986). It was reported that 6

- chloro

- 2,3

- dihydrobenzoxazol

- 2

- one constituted 75% of the residue in milk and 50% of the residue in the tissues of liver and kidney. No in formation was available concerning the relative amounts of parent and the two metabolites in ruminant tissues, since the analytical method used in the ruminant study was the enforcement method resulting in a common analyte, 6

- chloro

- 2,3

-

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### dihydrobenzoxazol

- 2

- one. In HED reviews of 02/02/90 and 12/14/90, (PP#9F3714), it was concluded that the residue of concern in ruminants and swine are parent compound, its free acid, fenoxaprop, and 6

- chloro

- 2,3

- dihydrobenzoxazol

- 2

- one.

A poultry metabolism study (MRID #434 26201, 01/22/1998) was submitted. The nature of the residue in poultry has been adequately delineated. The principal route of metabolism is de

esterification to the free acid, followed by cleavage of the ether linkage to yield 6

- chloro

- 2,3

- dihydrobenzoxaz ol

- 2

- one and phenoxypropionic acid. Further, based on the low levels of TRR found in edible tissues of poultry following dosing at highly exaggerated rates, there is no reasonable expectation of finite residues (180.6(a)(3)). Therefore, a poultry feeding s tudy is not required, nor are tolerances for poultry/eggs required.

Rotational Crops Confined rotational crop data were submitted, reviewed and found to be scientifically acceptable. Based on the results of this study and the results of the studies from EFSA, no field accumulation studies are required.

A confined rotational crop study was submitted and reviewed in support of an experimental use permit (EUP) on soybeans (8340

- EUP

- T, 01/04/1984). Rotational crops were planted at 120 and 364 days after the first application of radiolabeled FE. Wheat, lettuce, carrots, radishes, soybeans, and corn were then allowed to grow to maturity. Samples of these representative rotational crops did not show significant uptake of radiolabeled FE after 120 and 364 days . The parts of the plants that had measurable levels of radioactivity are not used for human consumption. Only total radioactive residue (TRR) was measured in the study.

5.1.2 Summary of Environmental Degradation

FPE has limited solubility in water and is moderately mobile. FPE is also quite lipophilic. Once deposited, either at the site of application or farther afield through spray drift (or through erosion of FPE bearing soil particles), the parent molecule is expected to degrade quickly through

mu ltiple fate processes (half

- lives of hours to several days) under environmental conditions. FPE is hydrolyzed moderately rapidly in acidic conditions and neutral conditions, and quickly in
alkaline conditions. The two major hydrolytic degradates identifi ed were fenoxaprop

- p acid and
chlorobenzoxazolone. Both FPE and fenoxaprop

- p acid may hydrolyze to chlorobenzoxazolone, which was observed in the hydrolysis study. When considering the combined residues, however, they were stable to hydrolysis at all pHs

. While FPE degrades quickly via aqueous photolysis and is quickly biodegraded in aerobic soils and aerobic and anaerobic aquatic systems, the total residues of concern (FPE, fenoxaprop

- p acid (AE F088406), chlorobenzoxazolone (AE F054014), and 4

- (6

- chlor o

- 2

- benzoxazolyloxy) phenol (AE F040356), are relatively stable in the environment (half

- lives > 200 days).

5.1.3 Comparison of Metabolic Pathways

The metabolism of FPE in plants is similar. The parent compound is rapidly metabolized to yield 2

- [4

- [(6

- c hloro

- 2

- benzoxazolyl)oxy]phenoxy]propanoic acid which subsequently loses phenoxypropionic acid to yield 6

- chloro

- 2,3

-- dihydrobenzoxazol

- 2

- one. Residues in plants tend

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### to be surface residues with no translocation to newly formed leaves or plants parts. Th ere is no difference between the metabolic profiles of FE and the enriched FPE.

Metabolism studies performed in rat, goat, and laying hen showed a common metabolic pathway in animals. FPE is metabolized in animals primarily by de

- esterification to the fre e acid, followed by cleavage of the ether linkage to yield 6

- chloro

- 2,3

- dihydrobenzoxazol

- 2

- one and phenoxypropionic acid

.

5.1.4 Residues of Concern Summary

Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk
Assessment and T olerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop fenoxaprop

- ethyl,
2

- [4

- [(6

- chloro

- 2

- benzoxazolyl)oxy]phenoxy]propanoic acid,

6

- chloro

- 2,3 dihydrobenzoxazol

- 2

- one Same as those
included in RA

Rotational Crop Not Applicable Not Applicable

Livestock Ruminant and

Poultry fenoxaprop

- ethyl

2

- [4

- [(6

- chloro

- 2

- benzoxazolyl)oxy]phenoxy]propanoic
acid

6

- chloro

- 2,3 dihydrobenzoxazol

- 2

- one Same as those
included in RA

Drinking Water fe noxaprop

- ethyl and all degradates containing the 6

- chloro

- 2

- benzoxazol moiety Not Applicable



### 5 .2 Food Residue Profile

The results from plant metabolism for FPE indicate that the residues of concern are fenoxaprop

ethyl, its free acid metabolite {2

- [4

- [( 6

- chloro

- 2

- benzoxazolyl)oxy]phenoxy]propanoic acid,}
and 6

- chloro

- 2,3

-- dihydrobenzoxazol

- 2

- one . These data also show that FPE undergoes limited translocation with plants. Supplemental metabolism studies on FE and FPE demonstrated that there is no signifi cant difference in metabolism and no racemisation occurs. The metabolism of FE and FPE follows the same path leading to the metabolic pathway being identical for the two compounds.

Adequate residue chemistry data are available for FPE. Field trials show ed levels of FPE residues to be less than the LOQ (<0.05 ppm) for all crops with the exception of some animal feedstuffs (barley and wheat straw) where very few detects were seen slightly above the LOQ. The data were generated using a validated data collec tion method and are adequately supported by frozen storage stability data. Sufficient processing studies are available to elucidate the fate of FPE in processed commodities, with no concentration seen in any crop matrix. Tolerances
have been set on rumin ant livestock commodities based on the previously calculated high

- end dietary burden. HED believes that these tolerances are protective for all uses of FPE since the method used was much more conservative that the current method of using a maximum

reasona bly balanced diet (MRBD). HED has determined that the uses of FPE are classified as

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### 180.6 (a) (3), no reasonable expectation of finite residues with respect to residues in poultry commodities. Metabolism in rotational crops was seen to be limited; with ra dioactive residues less than the LOQ found at 30

- days, 120

- days, or 365

- days in leafy vegetables, root vegetables, and small grains.

5.3 Water Residue Profile

FPE is partially soluble in water, dissolving at 0.7 mg/L at 20°C and pH 5.8. FPE residues are considered moderately mobile. The compound is not expected to volatilize significantly due to its low vapor pressure of 1.4 x 10

- 8 

### torr (20°C). The octanol

- water partition coefficient of FPE is 38,000, with a relatively high bioconcentration factor (BCF) observed in fish viscera (1021x) compared to the edible fish portions (129x). The BCF for whole fish portions was 510x, which does not exceed reporting thresholds for concern for bioconcentration.

FPE is hydrolyzed moderately rapidly in acidic condition s (t 1⁄2 

### = 19.6 d at pH 5) and neutral conditions (t 1⁄2 

### = 24.6 d at pH 7), and quickly in alkaline conditions (t 1⁄2 

### = 0.7 d at pH 9). Two major hydrolytic degradates were identified: fenoxaprop

- p acid (AE F088406) and chlorobenzoxazolone (AE F054014). Both FPE and fenoxaprop

- p acid may hydrolyze to chlorobenzoxazolone, which was observed in the hydrolysis study at up to 64% of the applied at pH 5(30 DAT), 23% of the applied at pH 7 (30 DAT), and 20% of the applied at pH 9 (30 DAT). When considering the combined residues however, they were stable to hydrolysis at all pHs. FPE also degrades quickly via aqueous photolysis, with an estimated half

- life of 0.95 days. FPE was quickly biodegraded in aerobic soils (t 1⁄2 

### ≤ 1.63 d), in aerobic aquatic systems (t 1⁄2 

### < 1 d) and in anaerobic aquatic systems (t 1⁄2 

### ≤ 2.4 d).

The computer models PRZM and EXAMS and the Tier I Rice model were used to generate surface water EDWCs for use in the human health dietary risk assessment, while the PRZM

- GW
and SCI

- GROW models were used to generate groundwater EDWCs. In 2007, HED identified FPE and its two degradates, fenoxaprop

- p acid ((D+)

- 2

- [4

- (6

- chloro

- 2

- benzoxazolyloxy) phenoxy] propanoate, AE F088406) and chlorobenzoxazolone (4

- (6

- chl oro

- 2

- benzoxazolyloxy) phenol, AE F054014), as residues of concern in drinking water because these residues retained
the 6

- chloro

- 2

- benzoxazol moiety. Newly submitted environmental fate studies indicated that a fourth degradate, 4

- (6

- chloro

- 2

- benzoxazolyl oxy) phenol (AE F040356), also contained the 6

- chloro

- 2

- benzoxazol moiety. This degradate was included as a residue of concern, so the parent plus the three degradates were assessed using a total toxic residue (TTR) approach. Additionally, as high levels ( e.g. , >20%) of non

- extracted residues (NER) were found in all environmental fate studies and these NER were found to contain levels of two degradates of concern (fenoxaprop

- p acid and chlorobenzoxazolone) when subjected to harsh mineral acid extraction, NER were also included in the TTR approach. However, it is uncertain as to how available these residues are to reaching surface water and groundwater drinking water sources. As such, EFED modeled FPE TTR with and without NER to bracket the EDWCs. Descri ptions
of the models are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

The maximum acute and chronic surface EDWCs ( 110 and 69 μg/L , respectively) were
associated wit h application to rice. Surface water EDWCs for the proposed new use of grass grown for seed were much lower than the maximum values (acute EDWC of 1.65 μg/L and a

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### chronic EDWC of 0.62 μg/L). For groundwater sources of drinking water, the maximum acute

an d chronic estimated concentrations of FPE TTR in shallow groundwater from PRZM

- GW for applications to turf were 0.17 and 0.032 μg/L , respectively. The maximum groundwater EDWC reported from SCI

- GROW was 0.096 μg/L for the chemical’s use on turf. Maximum EDWCs for FPE residues in surface water and groundwater recommended for dietary assessment are presented in Table 2. Wat er residues were incorporated in the DEEM

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

Table 5.3 Summary of Estimated Surface Water and Groundwater Concentrations

for Fenoxaprop

- p
- ethyl

Scenario Surfac e Water Conc., ppb a Groundwater Conc., ppb b

Acute 110 0.17

Chronic (non

- cancer) 68.6 0.032

Chronic (cancer) N/A N/A

a From the Tier I Rice Model . I nput parameters are based on foliar rice with 

### first app at 0.108 lbs a.i./A, 14 day RTI, second app at 0.034 lbs a.i./A, and third app at 0.046 lbs a.i./A.

b From the PRZM

- GW model. Input parameters are based on aerial foliar turf with 0.173 lbs a.i./A applied 3 times and fourth app at 0.012 lbs a.i./A. (RTI = 14 days)
Reference: C. Peck, D411291, D404234 , 09/25/2013



### 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

This chronic dietary exposure and risk analysis is based on tolerance

- level residues, 100% crop treated assumptions, and default processing factors.

5.4.2 Acute Dietary Risk Assessment

An acute reference dose has not been established for either the general population or for females
13

- 49 years of age since there were no appropriate studies that demonstrated evidence of toxicity attributable to a singl e dose for these populations.

5.4.3 Chronic Dietary Risk Assessment

The DEEM

- FCID analyses estimate the dietary exposure and risk of the U.S. population and various population subgroups. The results reported in Table 5.4.5 below are for the general U.S

. Population, all infants (<1 year old), children 1

- 2, children 3

- 5, children 6

- 12, youth 13

- 19,
females 13

- 49, adults 20

- 49, and adults 50

- 99 years. C ombined chronic dietary exposure estimates for food and drinking water are below HED’s level of concern f or all population subgroups, including those of infants and children . The most highly exposed population subgroup is all infants at 27.5% of the cPAD, while the general U.S. population utilized 11.7%
of the cPAD.

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### 5.4.4 Summary Table

Table 5.4.5 . Summ ary of Dietary 

### ( Food and Drinking Water Exposure and Risk for Fenoxaprop

- p
- ethyl

Population Subgroup Acute Dietary Chronic Dietary Cancer

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

General U.S. Population



### N/A N/A 0.001757 12



### N/A N/A All Infants (< 1 year old) 0.004121 28

Children 1

- 2 years old 0.003361 22

Children 3

- 5 years old 0.002634 18

Children 6

- 12 years old 0.001810 12

Youth 13

- 19 years old 0.001340 9.0

Adults 20

- 49 years old 0.001671 11

Adults 50+ years old 0.001617 11

Females 13

- 49 years old 0.001646 11



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are currently several registered labels with residential turf and orn amental use sites for FPE. The residential uses have not previously been assessed by HED and therefore, have been
assessed in this risk assessment document and the accompanying occupational and residential exposure risk assessment ( S. Shelat, D 416003 , 1 / 2 3 /201 4 ) to reflect updates to HED’s 2012
Residential SOPs 1 

### along with policy changes for body weight assumptions. The residential exposures assessed will impact the human health aggregate risk assessment for FPE.

6.1 Residential Handler Exposure

HED us es the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residentia l handlers are addressed somewhat differently by HED as homeowners are assumed to complete all elements of an application without use of any protective equipment.

The quantitative exposure/risk assessment developed for residential handlers is based on th e following scenarios:

 Manually

- pressurized handwand

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

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###  Hose

- end Sprayer

 Backpack

 Trigger

- sprayer

The residential handler non

- cancer risk estimates from the registered non

- occupational uses of FPE do not result in risk estimates of concern for dermal (MOEs ≥ 100) nor inhalation routes of exposure (MOEs ≥ 30). Dermal MOEs range from 1,200 to 120,000 and inhalation MOEs range from 420,000 to 190,000,000. An ARI approach was used to calculate the combined dermal and inhalation exposure risk estimates becau se the levels of concern are different for the two routes as determined by the uncertainty factors discussed in Section 4.5.1. The ARIs for the combined dermal and inhalation exposures are ≥ 1 and therefore do not exceed HED’s level of
concern. The ARIs range from 12 to 1200 and are provided below in Table 6.1.

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Page 32 of 84 Table 6.1. Short

- term Residential Handler Non

- cancer Exposure and Risk Estimates for Fenoxaprop

- p
- ethyl.

Exposure Scenario Use Site Dermal Unit Exposure (mg/lb ai) Inhalation

Unit Exposure (mg/l b ai) Maximum

Application

Rate 1 Area Treated or

Amount Handled Daily 2 Dermal Inhalation Combined

Dose (mg/kg/day) 3 MOE 4 Dose (mg/kg/day) 5 MOE 6 ARI 7

Mixer/Loader/Applicator

Manually pressurized
handwand (Liquid Concentrate) Gardens/Trees

63 0.018 0 .0009 lbs ai/gallon 5 gallons 0.0035 5,600 0.000001 6,700,000 56

0.00000174
lbs ai/ft 2 1200 ft 2 0.0016 12,000 0.00000047 14,000,000 120

Lawns/Turf 0.0009 lbs ai/gallon 5 gallons 0.0035 5,600 0.000001 6,700,000 56

Hose

- end sprayer (Liquid Concen trate) Gardens/Trees 58 0.0014 0.00000174
lbs ai/ft 2 1200 ft 2 0.0015 13,000 0.000000037 190,000,000 130

0.0009 lbs ai/gallon 11 gallons 0.0072 2,800 0.00000017 39,000,000 28

Lawns/Turf 13.4 0.022 0.076
lbs ai/acre 0.5 acres 0.0064 3,100 0.00001 65 0,000 31

Hose

- end sprayer (Ready to Use) Gardens/Trees

6.26 0.034 0.00000174
lbs ai/ft 2 1200 ft 2 0.00016 120,000 0.00000089 7,700,000 1200

0.0009 lbs ai/gallon 11 gallons 0.00077 26,000 0.0000042 1,600,000 260

Lawns/Turf 0.076
lbs ai/acre 0.5 a cres 0.003 6,700 0.000016 420,000 67

Backpack (Liquid Concentrate) Gardens/Trees

130 0.14 0.00000174
lbs ai/ft 2 1200 ft 2 0.0034 5,900 0.0000037 1,900,000 59

0.0009 lbs ai/gallon 5 gallons 0.0073 2,700 0.0000079 860,000 27

Lawns/Turf 0.0009
lbs ai/gallon 5 gallons 0.0073 2,700 0.0000079 860,000 27

Trigger

- spray bottle (Ready to Use) Gardens/Trees 85.1 0.061 0.008
lbs ai/bottle 2 bottles 0.017 1200 0.000012 560,000 12

Lawns/Turf 1 bottle 0.0085 2400 0.0000061 1,100,000 23

1 Based on regis tered labels (see Table 3.3 or D411289).
2 Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ).
3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/ft 2 or gal) × Area Treated or Amount Handled (ft 2 /day or gallons/day)÷ Body Weight (kg).
4 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).
5 Inhalation Dose = Inhalation Unit Exposure (mg/ lb ai) × Application Rate (lb ai/ ft 2 or gal) × Area Treated or Amount Handled (ft 2 /day or gallons/day) ÷ Body Weight (kg).

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

7 ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ÷ Derm al MOE) + (Inhalation LOC ÷ Inhalation MOE)].

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### 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 FPE. The quantitativ e exposure/risk assessment for residential post

- application exposures is based on the following scenarios:

 Adults High Contact Lawn Activities

 Children 1 to <2 years old High Contact Lawn Activities

 Adults Mowing Turf

 Children 11 to < 16 years old Mowing Turf

 Adults Ornamental Garden Activities

 Children 6 to < 11 years old Ornamental Garden Activities

The lifestages selected for each post

- application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs 2 

### . While not the o nly lifestage potentially exposed for these post

- application scenarios, the lifestage that is included in the quantitative assessment is health protective for the exposures and risk estimates for any other potentially exposed lifestage.

Dislodgeable Folia r Residues:

T his assessment uses HED’s default assumption that 25% of the application is available for transfer on day 0 following the application to ornamental use sites and the residues dissipate at a rate of 10% each following day. EPA is not requiri ng additional 40CFR DFR data.

Turf Transferable Residue Study: A Turf Transferable Residue (TTR) study for FPE was submitted to the Agency and reviewed
for use in this assessment. For the purposes of this risk assessment, the highest measured TTR
value (0.0091 μg/cm 2 

### ) adju sted for application rate was used in the post

- application exposure
assessment for turf uses of FPE

. ( S.Shelat, D416436, 1/2 3 /2014 )

Table 6 .2.1 Summary of Fenoxaprop

- p
- ethyl Turf Transferable Residue Study (MRID 45251301)

Location Av erage Application

Rates (lbs ai/acre) Highest Mean

Measured Residue (μg/cm 2 ) Timing of Highest

Measured Residue Adjusted TTR
value for
Residential Use 1

North Rose, New

York 0.0885 0.0091 0DAT2

0.0078 μg/cm 2 Columbia, Missouri 0.0867 0.0047 0DAT5

Ivor, Virginia 0.089 0.0067 0DAT2

1. Maximum application rate for residential lawn/turf use is 0.076 lbs ai/acre, therefore the TTR value for the residential lawn/turf assessment was calculated as follows: (0.076 lbs ai/acre * 0.0091 μg/cm 2 )/0.089 lbs ai/acre = 0 .0078 μg/cm 2 ). 0.089 lbs ai/acre represents the application rate during application treatment 2, after which the highest measured residue
was collected.

2 A vailable: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Fenoxaprop

- p

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Page 34 of 84 

### Since dermal and incidental oral exposure routes share a common toxicological endpoint, risk
estimate s have been combined for those routes. The incidental oral scenarios (i.e., hand

- to

mouth and object

- to

- mouth) should be considered inter

- related

. Combining these scenarios with the dermal exposure scenario would be overly

- conservative because of the con servative nature of each individual assessment. Therefore, the post

- application exposure scenarios that were combined for children 1 to < 2 years old are the dermal and hand

- to

- mouth scenarios. This combination should be considered a protective estimate of children’s exposure to pesticides used
outdoors.

Summary of Residential Post

- application Non

- Cancer Exposure and Risk Estimates

Table 6.2

. 2 Short

- term Residential Post

- application Non

- cancer Exposure and Risk Estimates for Fenoxaprop

- p
- ethyl.

Lifest age Post

- application Exposure
Scenario Application
Rate 1 Dose

(mg/kg/day) 2 MOEs 3 Combined Routes (X indicates
included in Combined MOE) Combined

MOEs 4 Use Site Route of

Exposure

Adult

Turf

- High
contact lawn activity Dermal 0.076 0.026 760

Child (1 to <2 years) Dermal 0.076 0.052 390 X

370 Hand to Mouth 0.076 0.001 5,600 X Object to Mouth 0.076 0.00003 190,000 Soil Ingestion 0.076 0.0000034 1,800,000

Adult

Turf

- Mowing
turf Dermal 0.076 0.0005 37,000

Child (11 to < 16 years) Dermal 0.076 0.0006 33,000

Adult

Ornamentals Dermal 0.076 0.049 410

Child (6 to < 11 years) Dermal 0.076 0.033 600

1 Based on registered labels (see Table 3.3 ).
2 Dose (mg/kg/day) equations provided in D411289 and D403926

. 3 MOE = POD (mg/kg/da y) ÷ Dose (mg/kg/day).
4 Combined MOE = 1 ÷ (1/dermal MOE) + (1/incidental oral MOE), where applicable.



### 6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

For FPE, there is the potential for multiple exposure scenarios to be combined. Of the registered

non

- occupational uses of FPE, the use on turf and ornamentals in the residential setting is registered on the same label (72155

- 74), increasing the likelihood that the exposures from these application sites may occur on the same day(s) for both the adult handler and post

- application scenarios. The multiple exposure scenari o risk estimate for the handler, which includes both dermal and inhalation exposures, do not exceed HED’s level of concern (ARI ≥ 1) and the multiple exposure estimate for post

- application

, which includes only dermal exposure, results in
an MOE of 267 and is similarly not of concern. The results are provided in Table 6.3.

### Fenoxaprop

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Page 35 of 84 Table 6.3. Short

- term Adult Residential Combined (Multiple Exposure Scenarios) Non

- Cancer Expo sure and Risk Estimates for Fenoxaprop

- p
- ethyl (EPA Reg No 72155

- 74).

Combined Exposure
Scenario Exposure Scenario Route of Exposure Dose

(mg/kg/day) 1 Combined

Total Dose (mg/kg/day) 2 Total MOEs 3 Total ARI 4

Outdoor
Scenario (Turf/Garden) Handler

Turf

– Sprays with Trigger Pump Sprayer Dermal 0.0085 Dermal:

0.0255 780

8 Inhalation 0.0000061

Garden

– Sprays with Trigger Pump Sprayer Dermal 0.017 Inhalation:

0.000018 376,000 Inhalation 0.000012

Post

- application

Turf

- Sprays Dermal 0.0 26 Dermal:

0.075 267 N/A Garden

- Sprays Dermal 0.049

1 Dose (mg/kg/day) taken from Tables 6.1 and 6.2.2.
2 Combined Total Dose (mg/kg/day) = combined dermal + inhalation doses for handlers or combined dermal + inhalation + incidenta l oral post

appli cation doses. Handler exposures should not routinely be combined with post

- application exposures.
3 Total MOEs = POD (mg/kg/day) ÷ Total Dose (mg/kg/day).
4 ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)]

.



### 6.4 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.4 reflects the residential risk estimates that are recommended for use in the aggregate
assessment for FPE.

 The recommended residential exposure for use in the adult aggregate asses sment reflects
post

- application d ermal exposure from a pplications to turf and gardens via sprays.

 The recommended residential exposure for use in the children 1 to <2 years old aggregate
assessment reflects dermal and hand

- to

- mouth exposures from post

- appl ication high contact lawn activity exposure from turf applications.

Table 6.4 Recommendations for the Residential Exposures for the Fenoxaprop

- p
- ethyl Short

- term Aggregate Assessment. 1

Lifestage Dose (mg/kg/day) 2,4 MOE 3,5

Dermal Inhalation Oral Total Dermal Inhalation Oral Total ARI

or MOE

Residential Handler

Adult 0.0255 0.000018 N/A 0.0255 780 376,000 N/A 8 (ARI)

Residential Post

- application

Adult 0.075 N/A N/A 0.075 267 N/A N/A 267 (MOE)

Child 0.052 N/A 0.001 0.053 390 N/A 5,640 370 (MOE)

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment.
2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all residential handler scenarios assess ed. Total =
dermal + i nhalation.
3 Residential Handler MOE = the MOEs associated with the highest residential handler doses. ARI = Aggregate Risk Index = 1÷ [( Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)].
4 Residential Post

- application Dose = the highest post

- application dose for each applicable lifestage of all post

- application scenarios assessed. Total = dermal + inhalation + incidental oral (where applicable).
5 Residential Post

- application MOE = the MOEs associated with the highest post

- application doses. Total = Dermal MOE + Inhalation MOE + Incidental Oral MOE (where applicable).

### Fenoxaprop

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Page 36 of 84 

### 6.5 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure

assessment was not performed for FPE at this time. However, 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 3 

### . The Agency is in the process of evaluating the SAP report and may, as appropri ate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need f or a quantitative post

- application inhalation exposure assessment
for FPE.

6.6 Spray Drift

Off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors. Sprays that are released and do not deposit in the application area end up off

target and can lead to exposures to those it may directly contact. They can also deposit on surfaces where contact with residues can eventually lead to exposures ( e.g. , children playing on lawns where residues have deposite d next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling coupled with methods employed for residential risk assessments for turf products. The approach to be used for quantitatively incorporating spray drift into risk assessment includes assessing exposures for children (1 to < 2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an exposure scenario. Aside from the predi cted residues available for transfer, the routes of exposure and assessment methodology is analogous to how exposures to turf products are considered in risk assessment.

The spray drift risk estimates are based on an estimated deposited residue concentra tion as a result of the screening level agricultural application scenarios. FPE is used on a variety crops and turf sites and can be applied via groundboom and aerial equipment at a maximum application rates ranging from 0.083 to 0.173 lbs ai/acre. Derma l risk estimates were calculated for adults. Dermal and incidental oral risk estimates for children 1 to <2 years old were combined because the toxicity endpoint for each route of exposure is the same. The total applicable Level of Concern is 100 so MOEs < 100 represent risk estimates that exceed HED’s
level of concern. Adult and children dermal and children’s incidental oral risk estimates from indirect exposure to FPE related to spray drift result in buffers of 0 feet for groundboom and aerial applicat ions, (i.e., all MOEs ≥ 100 at the edge of the field). Results for the drift scenarios of the highest application rate and chemical

- specific TTR values are provided in Appendix C.

3 Available: http:/

/www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Fenoxaprop

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Page 37 of 84 7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQ PA, 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

Acute aggregate risk estima tes include exposure to residues in food and water alone; therefore, the acute aggregate risk estimates are equivalent to the acute dietary risk assessment. However, for FPE, no toxic effects attributable to a single dose were observed in the toxicology d atabase. As a result, an acute aggregate risk assessment is not required for this chemical.

7.2 Short

- Term Aggregate Risk

There is a potential for short

- term exposure to FPE via dietary and residential exposure pathways. To estimate short

- term aggreg ate risk, HED combined chronic dietary ( average food and water) exposures (as a measure of average background dietary exposure) with short

- term residential exposures. These pathways lead to exposure via oral (background), dermal

, and incidental oral (hand to mouth) (primary) routes.

The most conservative residential exposure scenario was chosen for the adult population which reflects dermal exposure from post

- application exposure to turf and gardens (refer to Table 6.3 and 6.4). The residential exposure for use in the children 1 to <2 years old aggregate assessment
reflects dermal and hand

- to

- mouth exposures from post

- application high contact lawn activity exposure from turf applications.

For adult male background dietary exposure, the adult sub

- popula tion with the highest exposure (adults 20

- 4 9) was chosen since this is protective for all other adult sub

- populations. For children 1 to < 2 years old, the children 1 to 2 years old background dietary exposure was chosen
for the short

- term aggregate risk assessment

. The 1/MOE approach was used for the aggregate assessment because route specific toxicological data was available for the different routes of

exposure.

Short

- term aggregate margins of exposure for adults (all adult sub

- populations) and childre n (1 to < 2 years old) are above the LOC of 100 and do not exceed HED’s level of concern (MOEs ≥ 100). Short

- term aggregate risk estimate s are shown below in Table 7.2.

Table 7.2 Short

- Term Aggregate Risk Calculations Population Short

- Term Scenario

### Fenoxaprop

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Page 38 of 84 LOC for Aggregate
Risk 1 Dietary

MOE 2 MOE Oral

Residential Exposure 3 MO E

Dermal
Residential Exposure 4 MOE

Inhalation
Residential Exposure 5 Aggregate

MOE (food, water, and residential) 6

Adult 100 3590 N/A 267 N/A 249
Child 100 1790 5640 390 N/A 302

1 10X inter species uncertainty factor and 10X intraspecies uncertainty facto r totaling 100

2 MOE dietary = [( 6 mg/kg/day)/(chronic dietary exposure)] ( Table 5.4.5 )

. 3 MOE oral = [( 6 mg/kg/day )/(hand

- to

- mouth residential exposure)] (Table 6.4 ).

4 MOE dermal = [( 20 mg/kg/day )/(high end dermal residential exposure)] (Table 6.4 ).

5 N ot applicable

6 MOE Aggregate = 1/[(1/MOE dietary) + (1/MOE oral) + (1/MOE dermal)]



### 7.3 Chronic Aggregate Risk

As there are no uses that are expected to result in long

- term residential exposure, long

- term (chronic) aggregate risk includes only chronic di etary (food and water) exposure. As noted in Section 5.4.4, there are no chronic dietary risks of concern for FPE.

8.0 Cumulative Exposure/Risk Characterization

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

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

to FPE and any other substances and FPE 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 FPE 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 t he policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulati ve/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short

- and Intermediate

- term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection u sed by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposur e is expected from the registered and proposed uses of FPE. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:

### Fenoxaprop

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Page 39 of 84  Mixer/Loader for aerial and groundboom equipment

 Applicators for aerial and gr oundboom equipment

 Flagger for aerial spray applications

 Mixer/Loader/Applicator for backpack equipment

 Mixer/Loader/Applicator for manually

- pressurized handwand equipment

 Mixer/Loader/Applicator for mechanically

- pressurized handgun equipment

The above ex posure scenarios best represent the registered and proposed use patterns for FPE. Chemigation applications are prohibited on the product labels.

For FPE, based on the registered and proposed uses, short

- and intermediate

- term exposures are expected becaus e a number of the registered uses allow for multiple applications over the growing season. The toxicological endpoints for FPE are the same for both the short

- and
intermediate

- term durations, therefore the short

- term assessment is protective for the longe r duration.

Estimates of dermal and inhalation exposure 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. Most of the currently reg istered and proposed labels of FPE require PPE in addition to baseline attire. PPE on the registered labels ranges from the addition of chemical

resistant gloves to also requiring coveralls, goggles and face shields. Respirators are not required

PPE on t he currently registered or proposed FPE labels.

A total aggregate risk index (ARI) was used since the LOC values for dermal exposure (100) and inhalation exposure (30) are different. The target ARI is 1; therefore, ARIs of less than 1 are risk
estimates of concern.

For mixer/loaders with baseline attire, ARIs range from 0.56 to 43. With the addition of gloves, the mixer/loader ARIs range from 3. 1 to 3,900,000. For applicators with baseline attire (except for aerial applicators which are always assesse d with engineering controls), the ARIs range from
9 to 31 and with chemical

- resistant gloves for groundboom applicators the ARIs range from 45 to 150. Flagger ARIs range from 21 to 130 and 23 to 140 for baseline attire and chemical

resistant gloves, respe ctively. For mixers/loaders/applicators the handheld equipment ARIs range from 2 to 28 with baseline attire and 3.1 to 440 with the addition of chemical

- resistant gloves. Risk estimate summary tables are provided below.

### Fenoxaprop

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Page 40 of 84 Table 9 .1.1. Short

- and Intermediate

- term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Fenoxaprop

p
- ethyl

. All estimates are at Baseline Attire*.

Exposure Scenario Crop or Target Dermal Unit Exposure (ug/lb ai) 1 Inhalation Unit

Exposure (ug/lb ai) 1 Maximum

Ap plication

Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Baseline Attire No Respirator Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 ARI 8

Mixer/Loader

Aerial Nursery

220 0.219 0.173 60 0.0285 700 0.0000284 240000 7

Sod 0.173 350 0.166 120 0.000166 41000 1.2

Rice 0.108

1200 0.356 56 0.000355 19000 0.56

Barley and
Wheat 0.083 0.274 73 0.000273 25000 0.73

Cotton 0.105 0.346 58 0.000345 20000 0.58

Soybeans 0.1 0.33 61 0.000329 21000 0.61

Conservation
Reserve Land 0.1 0.33 61 0.000329 21000 0.61

Groundboom Field

- grown

Ornamentals

220 0.219 0.173 40 0.019 1100 0.000019 360000 11

Nursery
Ornamentals 0.173 60 0.0285 700 0.0000284 240000 7

Greenhouse
Ornamentals 0.173 60 0.0285 700 0.0000284 240000 7

Sod 0.173 80 0.038 530 0.0000379 180000 5.3

Rice 0.108

200 0.0594 340 0.0000591 120000 3.4

Barley and
Wheat 0.083 0.0456 440 0.0000455 150000 4.4

Cotton 0.105 0.0578 350 0.0000575 120000 3.5

Soybean 0.1 0.0699 290 0.0000695 98000 2.9

Conservation
Reserve Land 0.1 0.0699 290 0.0000695 98000 2.9

Grass Grown
for Seed 220 0.219 0.082 80 0.018 1100 0.000018 380000 11

Mechanically Pressurized

Handgun Right of Ways 220 0.219 0.0017 1000 gallons 0.00468 4300 0.00000465 1500000 43

Appli cator

### Fenoxaprop

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Page 41 of 84 Table 9 .1.1. Short

- and Intermediate

- term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Fenoxaprop

p
- ethyl

. All estimates are at Baseline Attire*.

Exposure Scenario Crop or Target Dermal Unit Exposure (ug/lb ai) 1 Inhalation Unit

Exposure (ug/lb ai) 1 Maximum

Ap plication

Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Baseline Attire No Respirator Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 ARI 8

Aerial *Engineering Controls Nursery

2.08 0.0049 0.173 60 0.00027 74000 0.000000636 11000000 740

Sod 0.173 350 0.00158 13000 0.00000371 1800000 130

Rice 0.108

1200 0.00338 5900 0.00000794 860000 59

Barley and
Wheat 0.082 0.00256 7800 0. 00000603 1100000 78

Cotton 0.105 0.00328 6100 0.00000771 880000 61

Soybeans 0.1 0.00313 6400 0.00000735 930000 64

Conservation
Reserve Land 0.1 0.00313 6400 0.00000735 930000 64

Groundboom Field

- grown

Ornamentals

78.6 0.34 0.173 40 0.0068 2 900 0.0000294 230000 29

Nursery
Ornamentals 0.173 60 0.0102 2000 0.0000441 150000 20

Greenhouse
Ornamentals 0.173 60 0.0102 2000 0.0000441 150000 20

Sod 0.173 80 0.0136 1500 0.0000589 120000 15

Rice 0.108

200 0.0213 940 0.0000918 74000 9.4

Barley and
Wheat 0.083 0.0163 1200 0.0000705 96000 12

Cotton 0.105 0.0206 970 0.0000893 76000 9.7

Soybean 0.1 0.0196 1000 0.000085 80000 10

Conservation
Reserve Land 0.1 0.0196 1000 0.000085 80000 10

Grass Grown
for Seed 78.6 0.34 0.0 82 80 0.0065 3100 0.0000279 240000 31

Mechanically Pressurized

Handgun Right of Ways 1300 3.9 0.0017 lbs ai/gallon 1000

gallons 0.0276 720 0.0000829 82000 7.2

Flagger

### Fenoxaprop

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Page 42 of 84 Table 9 .1.1. Short

- and Intermediate

- term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Fenoxaprop

p
- ethyl

. All estimates are at Baseline Attire*.

Exposure Scenario Crop or Target Dermal Unit Exposure (ug/lb ai) 1 Inhalation Unit

Exposure (ug/lb ai) 1 Maximum

Ap plication

Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Baseline Attire No Respirator Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 ARI 8

All aerial applications (Flagger) Nursery

11 0.35 0.173 60 0.00143 14000 0.0000454 150 000 140

Sod 0.173 350 0.00833 2400 0.000265 26000 23

Rice 0.108 350 0.0052 3800 0.000165 41000 37

Barley and
Wheat 0.083 350 0.004 5000 0.000128 53000 49

Cotton 0.105 350 0.00505 4000 0.000161 42000 39

Soybeans 0.1 350 0.00481 4200 0.00 0154 44000 41

Mixer/Loader/Applicator

Backpack Sprayer Greenhouse

Ornamentals 13200 140

0.002 lbs ai/gallon 40

gallons 0.0133 1500 0.00014 49000 15

Nursery 13200 11200 0.0133 1500 0.00014 49000 15

Landscape
Turf 8260 2.58 0.00826 2400 0.0000025 8 2600000 24

Right of Ways 8260 2.58 0.0017 lbs ai/gallon 0.00703 2800 0.00000219 3100000 28

Manually

- pressurized
Handwand Greenhouse

Ornamentals

100000 30 0.002 lbs ai/gallon 40

gallons 0.1 200 0.00003 230000 2 Nursery

Landscape
Turf

Mechanically

- pressurized Handgun Greenhouse

Ornamentals 3500 120 0.002 lbs ai/gallon 1000

gallons 0.0875 230 0.003 2300 2.2

Nursery 1300 3.9 0.002 lbs ai/gallon 1000

gallons 0.0325 620 0.0000975 70000 6.2

Landscape
Turf 1300 3.9 0.002

lbs ai/gallon 1000

gallons 0.0325 620 0.0000975 70000 6.2

1140 1.9 0.173 lbs
ai/acre 5 acres 0.0123 1600 0.0000205 330000 16

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( [ May 2013 ] ); Level of mitigation: Baselin e, PPE, Eng. Controls.

### Fenoxaprop

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Page 43 of 84 2 Based on registered and proposed labels (Table 4.1 & 4.2).
3 Exposure Science Advisory Council Policy #9.1.
4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (kg).
5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (kg).
7 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).
8 Aggregate Risk Index (ARI) = 1÷ (1 ÷ RI dermal ) + (1 ÷ RI inhalation ) Where: Risk Index (RI) = MOE ÷ LOC



### Tabl e 9 .1.2. Short

- and Intermediate

- term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Fenoxaprop

p
- ethyl

. All estimates are at Baseline Attire plus Chemical

- Resistant Gloves*.

Exposure Scenario Crop or Target Dermal Unit Exposure (ug/lb ai) 1 Inhalation Unit

Exposure (ug/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Baseline plus gloves No Respirator Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 ARI 8

Mixer/Loader

Aerial Nursery

37.6 0.219 0.173 60 0.00488 4100 0.0000284 240000 41

Sod 0.173 350 0.0285 700 0.000166 41000 7

Rice 0.108

1200 0.0609 330 0.000355 19000 3.3

Barley and
Wheat 0.083 0.0434 460 0.000273 25000 4.3

Cotton 0.105 0.0468 430 0.000345 20000 3.4

Soyb eans 0.1 0.0593 340 0.000329 21000 3.5

Conservation
Reserve Land 0.1 0.0593 340 0.000329 21000 3.5

Groundboom Field

- grown

Ornamentals

37.6 0.219 0.173 40 0.00325 6200 0.000019 360000 62

Nursery
Ornamentals 0.173 60 0.00488 4100 0.0000284 24000 0 41

Greenhouse
Ornamentals 0.173 60 0.00488 4100 0.0000284 240000 41

Sod 0.173 80 0.0065 3100 0.0000379 180000 31

Rice 0.108

200 0.0102 2000 0.0000591 120000 20

Barley and
Wheat 0.083 0.0078 2600 0.0000455 150000 26

Cotton 0.105 0.00 988 2000 0.0000575 120000 20

Soybean 0.1 0.0119 1700 0.0000695 98000 17

### Fenoxaprop

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Page 44 of 84 Tabl e 9 .1.2. Short

- and Intermediate

- term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Fenoxaprop

p
- ethyl

. All estimates are at Baseline Attire plus Chemical

- Resistant Gloves*.

Exposure Scenario Crop or Target Dermal Unit Exposure (ug/lb ai) 1 Inhalation Unit

Exposure (ug/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Baseline plus gloves No Respirator Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 ARI 8

Conservation
Reserve Land 0.1 0.0119 1700 0.0000695 98000 17

Grass Grown
for Seed 37.6 0.219 0.082 80 0.00309 6500 0.000018 380000 65

Mechanically Pressurized

Handgun Righ t of Ways 37.6 0.219 0.0017 1000 gallons 0.0008 25000 0.00000465 1500000 3900000

Applicator

Aerial *Engineering Controls Nursery

2.08 0.0049 0.173 60 0.00027 74000 0.000000636 11000000 740

Sod 0.173 350 0.00158 13000 0.00000371 1800000 130

Rice 0 .108

1200 0.00338 5900 0.00000794 860000 59

Barley and
Wheat 0.082 0.00256 7800 0.00000603 1100000 78

Cotton 0.105 0.00328 6100 0.00000771 880000 61

Soybeans 0.1 0.00313 6400 0.00000735 930000 64

Conservation
Reserve Land 0.1 0.00313 64 00 0.00000735 930000 64

Groundboom Field

- grown

Ornamentals

16.1 0.34 0.173 40 0.00139 14000 0.0000294 230000 140

Nursery
Ornamentals 0.173 60 0.00209 9600 0.0000441 150000 94

Greenhouse
Ornamentals 0.173 60 0.00209 9600 0.0000441 150000 94

Sod 0.173 80 0.00279 7200 0.0000589 120000 71

Rice 0.108

200 0.00435 4600 0.0000918 74000 45

Barley and
Wheat 0.083 0.00334 6000 0.0000705 96000 59

Cotton 0.105 0.00423 4700 0.0000893 76000 46

Soybean 0.1 0.00403 5000 0.000085 80000 49

Co nservation 0.1 0.00403 5000 0.000085 80000 49

### Fenoxaprop

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Page 45 of 84 Tabl e 9 .1.2. Short

- and Intermediate

- term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Fenoxaprop

p
- ethyl

. All estimates are at Baseline Attire plus Chemical

- Resistant Gloves*.

Exposure Scenario Crop or Target Dermal Unit Exposure (ug/lb ai) 1 Inhalation Unit

Exposure (ug/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Baseline plus gloves No Respirator Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 ARI 8

Reserve Land

Grass Grown
for Seed 16.1 0.34 0.082 80 0.00133 15000 0.0000279 240000 150

Mechanically Pressurized

Handgun Right of Ways 390 3.9 0.0017 lbs ai/gallon 1000

gallons 0.00829 2400 0.0000829 8200 0 24

Flagger

All aerial applications (Flagger) Nursery

12 0.35 0.173 60 0.00156 13000 0.0000454 150000 130

Sod 0.173 350 0.00909 2200 0.000265 26000 21

Rice 0.108 350 0.00568 3500 0.000165 41000 34

Barley and
Wheat 0.083 350 0.00436 4600 0.00 0128 53000 45

Cotton 0.105 350 0.00551 3600 0.000161 42000 35

Soybeans 0.1 350 0.00525 3800 0.000154 44000 37

Mixer/Loader/Applicator

Backpack Sprayer Greenhouse

Ornamentals 11200 140

0.002 lbs ai/gallon 40

gallons 0.0112 1800 0.00014 49000 18

Nursery 11200 140 0.0112 1800 0.00014 49000 18

Landscape
Turf 8260 2.58 0.00826 2400 0.00000258 2600000 24

Right of Ways 8260 2.58 0.0017 lbs ai/gallon 40

gallons 0.00703 2800 0.00000219 3100000 28

Manually

- pressurized
Handwand Greenhouse

Orn amentals

430 30 0.002 lbs ai/gallon 40

gallons 0.00043 47000 0.00003 230000 440 Nursery

Landscape
Turf

Mechanically

- pressurized Handgun Greenhouse

Ornamentals 2500 120 0.002 lbs ai/gallon 1000

gallons 0.0625 320 0.003 2300 3.1

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Page 46 of 84 Tabl e 9 .1.2. Short

- and Intermediate

- term Occupational Handler Non

- Cancer Exposure and Risk Estimates for Fenoxaprop

p
- ethyl

. All estimates are at Baseline Attire plus Chemical

- Resistant Gloves*.

Exposure Scenario Crop or Target Dermal Unit Exposure (ug/lb ai) 1 Inhalation Unit

Exposure (ug/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Baseline plus gloves No Respirator Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 ARI 8

Nursery 390 3.9 0.002 lbs ai/gallon 1000

gallons 0.00975 2100 0.0000975 70000 21

Landscape
Turf 390 3.9 0.002 lbs ai/gallon 1000

gallons 0.00975 2100 0.0000975 70000 21

Turf/Sod 880 1.9 0.173 lbs
ai/acre 5 acres 0.00951 2100 0.0000205 330000 21

1 Ba sed on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( [ May 2013 ] ); Level of mitigation: Baseline, PPE, Eng. Controls.
2 Based on registered and proposed labels (Table 4.1 & 4.2).
3 Exposure Science Advisory Council Policy #9. 1.
4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (kg).
5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

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

7 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dos e (mg/kg/day).
8 Aggregate Risk Index (ARI) = 1÷ (1 ÷ RI dermal ) + (1 ÷ RI inhalation ) Where: Risk Index (RI) = MOE ÷ LOC

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### 9.2 Short

- and Intermediate

- t erm Post

- Application Risk

9.2.1 Dermal Post

- application Risk

HED uses the term post

- application to de scribe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job funct ions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

Transfer Coefficients: It is the pol icy of HED to use the best available data to assess post

- application exposure. Sources of generic post

- application data, used as surrogate data in the absence of chemical

specific data, are derived from ARTF exposure monitoring studies, and, as proprietar y data, are subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting post

- application exposure that are used in this assessment, known as “transfer coefficients”, are presented in the ExpoSAC Policy 3 4 

### ” wh ich, along with additional information about the ARTF data, can be found at the Agency website 5



### .

Dislodgeable Foliar Residues:

T his assessment uses HED’s default assumption that 25% of the application is available for transfer on day 0 following the ap plication and the residues dissipate at a rate of 10% each following day.

Turf Transferable Residues:
Chemical

- specific turf transferable residue (TTR) data have been submitted for FPE. Therefore, this assessment uses the highest measured residue adju sted for the maximum commercial sod application rate. A description of the TTR study is provided in Section 6.2

.

Table 9.2: Summary of Occupational/Commercial Post

- application Risk Estimates for Fenoxaprop

- p
- ethyl. Crop/Site Activities DFR/TTR 1 DAT MO E 2

Barley Scouting
0.233 0 780

Mechanical Harvesting/Swathing/non

- Handset

Irrigation/ Baling Straw - -

Cotton Scouting

0.294 0 3200 Hand weeding 0 9700 Mechanical wedding/non

- Handset Irrigation

- -

Ornamentals

– Nursery Crop Handset Irrigation
0.485 0 220

6 410 Hand harvesting, pruning, weeding, transplanting, grafting, propagating, pinching, tying/training, 0 1800

4 Available: http://www.epa.gov/pesticides/science/exposac_policy3.pdf

5 Available: http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

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Page 48 of 84 Table 9.2: Summary of Occupational/Commercial Post

- application Risk Estimates for Fenoxaprop

- p
- ethyl. Crop/Site Activities DFR/TTR 1 DAT MO E 2

Mechanical wedding, harvesting, non

- handset irrigation, fertilizing, spreading bins - -

Ornamentals

– Greenhouse Crop Ha nd harvesting, pruning, weeding, transplanting, grafting, propagating, pinching, tying/training, 0.485 0 1800

Mechanical wedding, harvesting, non

- handset irrigation, fertilizing, spreading bins - -

Rice Scouting

0.303 0 600 Hand weeding 0 9400

Me chanical weeding, non

- hand set irrigation

- -

Sod Maintenance, Slab harvesting, Transplanting /planting 0.0177 0 1700 Roll harvesting

- -

Soybean Scouting

0.28 0 650 Hand weeding 0 10000 Mechanical weeding, non

- hand set irrigation

- -

Wheat, sp ring/winter Scouting

0.233 0 780 Hand weeding 0 12000 Mechanical Harvesting/Swathing/non

- Handset

Irrigation/ Baling Straw - -

Proposed Use

Grass Grown for
Seed (Surrogate: Forage Crop) Handset Irrigation

0.23 0 460 Scouting, 0 790

Non

- handset Irrigation, , Mechanical harvesting,

fertilizing - -

1. Default DFR calculation for liquid formulations was utilized. Chemical specific TTR data was utilized for the commercial sod application. 2. MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Der mal Dose = [DFR/TTR (μg/cm 2 ) x TC x 0.001 mg/μg x 8 hrs/day ]  BW (kg)



### In accordance with 40CFR158, DFR data are required for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your o wn farms, retail tree farms) uses that could result in post

- application exposure to foliage. In the
absence of chemical

- specific DFR data, EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment inclu des an analysis of a number of DFR studies, which resulted in the selection of a revised default values for the fraction of the application rate available for transfer after a foliar application (F AR 

### ). These values are based on an analysis of 19 DFR studi es. The results indicate a range of F AR 

### values from 2% to 89%. In the data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or many other difficult to quantify factors. Although witnessed across multiple chemicals, this range in F AR 

### values is not expected when considering DFR data for a single chemical. EPA selected 25% as the rea sonable, high

- end default value.
Because DFR data are not available for FPE, EPA is using the default value of 25%. Although there may be a small degree of uncertainty in the use of the default DFR value for FPE (i.e., there
is a small chance that the F A R 

### value may exceed the applicable default value), it is likely that the
health

- protective aspects of EPA’s residential and occupational post

- application assessment methodology will more than compensate for this potential uncertainty. For example, when

as sessing residential and occupational post

- application exposure, EPA assumes the following:
exposures occur to zero

- day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn’t rain, etc); individuals perform the same post

- application activities performed in the transfer

### Fenoxaprop

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Page 49 of 84 

### coefficient study day after day (e.g., weeding, harvesting, pruning, etc.); and individuals engage in these post

- application activities for a high

- end amount of time every day (represented by data reflecting time spent gardening based on survey data). In actuality, residues will dissipate to some degree depending on the chemical; in the residential setting, individuals do not garden every day; children do not spend all of their outdoor time in vegetable or ornamental gardens or “pick your own” farms; and high

- end levels of activity will not occur every day even if individuals are in treated areas. In the occupational post

- application setting, i t is possible that individuals may not enter a treated field day 0 after treatment, may not engage in the same type of post

- application activity, and may not conduct those activities throughout the duration
assessed.

Given the conservatisms discussed ab ove and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being underestimated.

T he highest estimated occupational post

- application exposure risk estim ate (i.e., nursery crop hand set irrigation scenario) using default DFR values for FPE is minimal in comparison to the
level of concern

. EPA is not requiring additional 40CFR DFR data.

9.2.2 Inhalation Post

- application Risk

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for FPE at this time. However, there are multiple potential 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 March 2, 2010 6 

### . The Agency is in the process of evaluating the SAP report as well as available post

- applic ation inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk asses sments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment
for FPE.

Although a quantitative occupational post

- application inhalation exposure a ssessment 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 post

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

- application inhalation exposure scenarios.

10.0 References

6 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.ht ml

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### D. Wilbur, December 5, 2013, D415998 and D416001, Fenoxaprop

- p
- ethyl . Peti tion for the Establishment of a Permanent Tolerance and Registration for Use on Grass Grown for Seed (Grass Hay). Summary of Analytical Chemistry and Residue Data for Registration
Review. D. Wilbur. November 14, 2013, D415999 and 416002, Fenoxaprop

- p
- ethy l. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for Registration Review and a New Use on Grass Hay. J. Kidwell. May 13, 2008, FPE/FE: Joint ToxSAC/HASPOC Meeting to Discuss Briding of
Mixed and Enriched Isomers.
S. Shel at, January 23 , 201 4 , D411289 and D403928, Fenoxaprop

- p
- ethyl . Occupational and Residential Exposure Assessment for the Registration Review Preliminary Risk Assessment and Proposed New Use on Grass Grown for Seed. S. Shelat, January 23, 2014, D416436, Fen oxaprop
- p
- ethyl. .Determination of Transferable Turf
Resi dues on Turf Treated with Fenoxa prop

- p

- ethyl. C. Peck, September 25, 2013, D411291 and D404234, Fenoxaprop

- p

- ethyl Drinking Water Assessment for Registration Review and Section 3 New Use Registration S. Recore, November 13, 2013, D416023, Fenoxaprop

- p
- ethyl : Tier I Updated Review of Human Incidents for Preliminary Risk Assessment

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### Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for the food use for FE/FPE are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test Technical Required Satisfied

870.1100 Acute Oral Toxici ty 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation
870.2600 Dermal Sensitization yes
yes
yes
yes
yes
yes yes

yes
yes
yes
yes
yes 870.3100 Oral Su bchronic (rodent) 870.3150 Oral Subchronic (nonrodent)
870.3200 21

- Day Dermal
870.3250 90

- Day Dermal
870.3465 90

- Day Inhalation yes
yes
yes

no

no yes

yes
yes

no
yes a 870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Tox icity (nonrodent) 870.3800 Reproduction yes
yes
yes yes

yes
yes 870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (nonrodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) yes

no
yes
yes yes

yes
yes
yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial 870.5300 Mutagenicity

— Gene Mutation

- mammalian 870.5395 Mutagenicity

— Other Genotoxic Effects yes
yes
yes yes

yes
yes 870.6100a Acute Delayed Neurotox. (hen)
870.6100b 90

- Day Neurotoxicity (hen)
870.620 0a Acute Neurotox. Screening Battery (rat)
870.6200b 90

- Day Neuro. Screening Battery (rat) 870.6300 Developmental Neurotoxicity no

no
yes
yes CR no

no waived b

waived b

no 870.7485 General Metabolism
870.7600 Dermal Penetration
870.7800 Immunotoxicity yes

no
yes yes

yes
yes Special Studies for Ocular Effects no no a) A 28 day inhalation study is suitable for risk assessment based on the current proposed use pattern, and a 90 day inhalati on study is not required at this time. b) Acute and subchronic neurotoxicity studies are not required for FPE (HASPOC TXR#0056489, November 27, 2012)

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### A.2 Toxicity Profiles

Acute Toxicity Profile

– Fenoxaprop

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

870.1100 Acute oral [Rats] 42009612
42009613 LD 50 = 3.04♂/♀2.09 g/kg

LD 50 = 4.0♂ g/kg III

870.1200 Acute dermal [Rat] 42009614 LD 50 > 2.0 g/kg III

870.1300 Acute inhalation 42009615 LD 50 > 0.604 mg/L III

870.2400 Acute eye irritation
42009616 No corneal opacity, no iris effects, irritation reversi ble
within 72 hrs III

870.2500 Acute dermal irritation
42009617 Very slight irritation, resolved by 48 hours Irritancy index 0.33 IV

870.2600 Skin sensitization
42009618 Buehler method

- negative Magnusson & Kligman

allergic potential N/A

Fenoxaprop

- p
- ethyl Toxicity Profile
Guideline
No. Study Type MRID No. (year)/
Classification /Doses Results

870.3100 28

- Day oral

toxicity (Wistar rat) (FPE) 47113304 (1986)

Acceptable/non

- guideline 20, 80, 320 ,1280, 5120

ppm

M: 2, 6, 26, 95, and 126 mg/kg/day

F: 2, 6, 28, 94, and 144 mg/kg/day NOAEL = 80 ppm (6 mg/kg/day)
LOAEL = 320 ppm (26/28 mg/kg/day)

Based on altered lipid metabolism (decreased HDL

cholesterol, HDL

- phospholipids, and total lipids, increased triglycerides, and ketonuria) and increased
li ver and kidney weights.

870.3100 90

- Day oral

toxicity (Wistar rat, feeding) (FPE) 47113310 (1987)

Acceptable/Guideline 10, 80, 640 ppm

M: 0.7, 5.8, 49 mg/kg/day

F: 0.8, 6.3, 51.8 mg/kg/day NOAEL = 5.8/6.3 mg/kg/day
LOAEL = 49/51.8 mg/kg/day

Based on decreased body weights (

- 11 to 19%), increased liver and kidney weights, and altered lipid metabolism (decreased HDL

- cholesterol, HDL

phospholipids, and total lipids, increased triglycerides, and ketonuria).

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- ethyl Toxicity Profile
Guideline
No. Study Type MRID No. (year)/
Classification /Doses Results

870.3100 90

- Day oral

toxicity (NMRI/KFM mice, feeding) (FPE) 47113305 (1987)

47113309 (1987) Acceptable/Guideline

90

- day study: 10, 80, or 640 ppm (M: 1.4, 11.9, and 100.8 mg/kg/day; F: 2.0, 16.5, and 122.4 mg/kg/day)

28

- day study: 20, 80, 320 and 1280 ppm (M: 3, 14, 56, and 260 mg/kg/day; F: 4, 16 , 61, and 280 mg/kg/day) NOAEL = 80 ppm (11.9/14 mg/kg/day)
LOAEL = 320 ppm (56/61 mg/kg/day)

Based on increased liver weight, hepatocellular hypertrophy, single or group cell necrosis in the liver, and proximal renal tubular injury.

870.3150 90

- Day or al

toxicity (Beagle dog, capsule) (FPE) 47113308 (1986)

47113303 (1986) Acceptable/Non

- guideline 80, 400, or 2000 ppm

M: 3.0, 15.6, and 77.7 mg/kg/day

F: 3.2, 16.2, and 83.4 mg/kg/day NOAEL = 77.7 mg/kg/day in males = 83.4 mg/kg/day in fem ales

No LOAEL was achieved. However, this study is acceptable based on bridging to FE.

870.3200 30

- Day dermal

toxicity (Wistar rat) (FPE) 47113306 (1987)

Acceptable/Guideline 10, 20, 100, 500 mg/kg/day Systemic NOAEL = 20 mg/kg/day Systemic LOAEL = 1 00 mg/kg/day

Based on non

- regenerative anemia, decreased serum cholesterol, total lipids, and protein (beta 1 globulins), and increased liver and kidney weights. Cholesterol remained decreased following a 15

- day recovery period.

Dermal Toxicity NOAEL is equal to or greater than 500 mg/kg/day as no toxicologically relevant effects
were identified.

870.3465 28

- Day inhalation

toxicity (Wistar rat) (FPE) 47113307 (1989)

Acceptable/Guideline 0.015, 0.07, 0.3 mg/L NOAEL = 0.07 mg/L in males = 0.3 mg/L in females
LOAEL = 0.3 mg/L in males

Based on slight normocytic anemia, decreases in serum cholesterol and total lipids, and increases in liver and kidney weights and urea nitrogen.

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- ethyl Toxicity Profile
Guideline
No. Study Type MRID No. (year)/
Classification /Doses Results

870.3700a Prenatal

developmental (Wistar rats) (FPE) 47113 318 (1985)

Acceptable/Guideline 10, 32, 100 mg/kg/day
GD 7

- 16 Maternal NOAEL = 32 mg/kg/day LOAEL = 100 mg/kg/day

B ased on decreased gestational body weights, body weight gains, and food consumption.

D evelopmental NOAEL = 32 mg/kg/day

LOAEL = 100 mg/kg/day based

Based on decreased fetal body weight (

- 18%) and crown rump length (

- 10%), and longitudinally displaced, fragmented, fused, dysplastic sternebrae or dislocated sternebrae, and weak ossification or non

ossification of one or several cranial bones.
870.3700b Prenatal

developmental (rabbit) (FPE) 47113319 (1986)

Acceptable/Guideline 10, 32, 100 mg/kg/day
GD 7

- 19 Maternal NOAEL = 32 mg/kg/day LOAEL = 100 mg/kg/day

Based on decreased bo dy weights gain and food consumption.

D evelopmental NOAEL = 100 mg/kg/day

There were no treatment

- related external, visceral, or
skeletal malformations or variations. There were no effects of treatment on fetal body weights, fetal crown to rump lengths, or placental weights. Incidences of skeletal retardations in the treated groups were similar
to the concurrent controls and were within historical control ranges.

Non

Guideline Developmental

Toxicity (Wistar rats) (FPE) 47113320 (1986)

Acceptable/non

- g uideline 10, 32, 100 mg/kg
GD 7

- 16 Materna l NOAEL = 32 mg/kg LOAEL = 100 mg/kg

Based on decreased gestational body weights, body weight gains, and food consumption.

Developmenta l NOAEL = 32 mg/kg/day

LOAEL = 1 00 mg/kg/day

Based on decreased pup body weights.

870.3800 2

- Generation

Reproduction and fertility effects (Wistar rat) (FE) 00159920 (1986)

Acceptable/Guideline 5, 30, 180 ppm (0.25, 1.5, 9.0 mg/kg) Parental NOAEL = 1.5 mg/kg
LOAEL = 9 mg/kg

Based on decreased total lipids and increased liver weights.

Reproductive NOAEL = 9.0 mg/kg

Offspring NOAEL = 1.5 mg/kg

LOAEL = 9.0 mg/kg

Based on increased ALP and liver weights.

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- ethyl Toxicity Profile
Guideline
No. Study Type MRID No. (year)/
Classification /Doses Results

870.4100b Chronic toxicity

(Beagle d og, capsule) (FE) 00151566 (1985)

Acceptable/Guideline 3, 15, 75 ppm 0.075, 0.375, 1.875 mg/kg NOAEL = 0.375 mg/kg/day
LOAEL = 1.875 mg/kg/day

Based on reduced body weights (10

- 12%) and body weight gains.

870.4300 Combined chronic

toxicity/carcinogen
i city (Sprague

Dawley rat) (FE) 00149664

00149665
00151564
00151565 Acceptable/Guideline 5, 30, 180 ppm

~0.25, 1.5, 9 mg/kg NOAEL = 1.5 mg/kg/day
LOAEL = 9 mg/kg/day

Based on decreased serum lipids, cholesterol and relative liver weights in male rats.

No evidence of carcinogenicity.

Note: Dosing was considered adequate by CARC based on the findings of the 90

- day feeding study in rats (MRID 00130028) with data showing liver toxicity at 320 ppm.

870.4200 Carcinogenicity

(NMRI

- mice) (FE) 44157402 (19 96)

Acceptable/Guideline 40, 115, 320 ppm

M: 5.7, 16.6, 44.6 mg/kg

F: 6.8, 19.4, 53.7 mg/kg NOAEL = 5.7/6.8 mg/kg
LOAEL = 16.6/19.4 mg/kg

Based on liver histopathology including hypertrophy, single cell necrosis, pigmentation in microphages and lipofus cin deposit and increased liver weights.

Note: No appreciable differences in survival were reported for the vehicle control and test groups at any dose. All test animals survived to study termination. The only clinical sign of note was an increased
inci dence of swollen abdomens in the mid

- and high

dose males and females. In addition, microscopic pathology indicated that hepatocellular hypertrophy was observed in the majority of male animals treated with 115 or 320 ppm fenoxaprop

- ethyl and the majority of females at 320 ppm. Dosing was, therefore, considered adequate by the CARC based on clinical signs (swollen abdomen), increased liver weights, and histopathology data at the high dose.

Gene
Mutation
870.5100 Bacterial reverse

mutation test (FPE) 471 13314

Acceptable/Guideline 0, 4, 20, 100, 500, 2500, 5000 μg/plate +/

- S9; two independent trials. Negative in S. typhimurium TA1535, TA100, TA1537, and TA98 & E. coli WP2 uvrA up to a cytotoxic limit
dose.

Cytogenetics
870.5300 In vitro

mammalian cell gene mutation test (FPE) 47113316

Acceptable/Guideline 0, 6.25, 12.5, 25.0, 50.0, 100 μg/mL +/

- S9; two independent trials. Negative up to an insoluble concentration (40 μg/mL
+/

- S9). No cytotoxicity at any level.

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- ethyl Toxicity Profile
Guideline
No. Study Type MRID No. (year)/
Classification /Doses Results

Other Effects
870.5375 In vitro

chromo some aberrations in
human lymphocytes assay (FPE) 47113313

Acceptable/Guideline
5.0

- 125 μg/mL +/

- S9. . Cells, treated either continuously for 24 hrs & harvested (

- S9) or for 2
hrs. & harvested at 12 or 24 hrs (+S9). Negative up to an insoluble concentrati on (100 μg/mL
+/

- S9). No cytotoxicity at any level. No clear effects (≥50% ↓) on the mitotic index.

Other Effects
870.5395 Mammalian

Micronucleus assay (NMRI Mouse) (FPE) 47113317

Acceptable/Guideline

0, 1000, 2000, 4000 mg/kg oral gavage. Negative up to a level that exceeds the limit dose (2000 mg/kg). Toxic signs at 4000 mg/kg included: narrowed palpebral fissures & reduced spontaneous activity. No cytotoxic effect on the bone marrow.

Other Effects
870.5550 Unscheduled DNA

synthesis in A 549
hu man HeLa cells (FPE) 47113315

Acceptable/Guideline 0, 0.1, 0.3, 1, 3, 10, 30, 100 μg/mL +/

- S9; two independent trials. Negative up to the highest soluble concentration (100 μg/mL +/

- S9). No cytotoxicity at any level.

Other Effects
870.5575 Mitotic g ene

conversion in Saccharomyces
cerevisiae D4 (FPE) 47113312

Acceptable/Guideline 0, 1.25, 2.50, 5, 10, 20 μg/mL +/

- S9; two independent trials Negative at the ade

- 2 and try

- 5 loci up to an insoluble concentration (20 μg/mL +/

- S9). No cytotoxicity at any l evel.

Other Effects

Non

Guideline Forward mutations

in Schizosaccharomy ces pombe P1

assay (FPE) 47113311

Acceptable/Non

Guideline 0, 2.5, 5.0, 10.0, 20.0, 40.0 μg/mL +/

- S9; two independent trials. Negative up to an insoluble concentration (40 μg/mL
+/

- S9). No cytotoxicity at any level.

870.6200a Acute

neurotoxicity screening battery Waived by HASPOC

870.6200b Subchronic

neurotoxicity screening battery Waived by HASPOC

870.7485 Metabolism and

pharmacokinetics (Sprague

- Dawley rat) (FPE) MRID 4711 3323 (1988)

Acceptable/Non

Guideline HOE 033171 and HOE 046360 were both excreted rapidly. ~75% of admin. Dose was recovered in excreta
0

- 48 hrs sampling interval. Females tend to excrete slightly higher % of admin. Dose via urine than males,
but is not in fluenced by dose or number of admins.
Residue concentrations of several tissues at 168 hrs
showed no sex differences in either HOE 033171 or HOE 046360, highest concern always in kidney. For HOE 046360, no racemization occurs after
administration of dose t o rats. The unchanged parent and its free acid HOE 088406 stay in their D+

- configuration. The metabolism pathway for both HOE
033171 and 046360 is identical.

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Guideline
No. Study Type MRID No. (year)/
Classification /Doses Results

870.7600 Dermal penetration

(Sprague

- Dawley rat) (FPE) 47113321 (2002)

Acceptable/Non

Guideline
2.72 ± 0.03 and 617.5 ± 125.6 μg ai/cm2 skin.

0.0276 and 6.9 mg/animal Estimates of dermal absorption based on the sum of residues retained in the urine (including cage wash and rinse), GIT and contents, feces, carcass, and blood ranged from 6.212% of the applied dose at eight hours after initiation of treatment to 16.31% of the applied
dose at 120 hours after initiation of treatment for the low dose and 0.6% of the applied dose eight hours after
initiation of treatment that increased to 2.012% of the

a pplied dose by 120 hours in the high

- dose group.

In Vitro Dermal penetration

– Rat
vs. Human (FPE) 47113322 (2000)

Acceptable/Non

Guideline Absorption was ~0.34 μg/cm2/hr for human skin and 2.32 μg/cm2/hr for rat skin (or ~6.8 times greater for
rat ski n than human skin) when applied at a nominal concentration of 550 μg/cm2. When the test material was applied diluted 75

- fold as for end use, rat skin was only slightly more permeable (~1.6 times) than human skin. Absorption through human skin was ~0.02

μg /cm2/hr and 0.034 μg/cm2/hr for rat skin when fenoxaprop

- p

- ethyl was applied at a nominal concentration of 7.3 μg/cm2.

870.7800 Immunotoxicity

(Female Wistar Rat) (FPE) 48445201 (2011)

Acceptable/Guideline 70, 210, 630 ppm

5.5, 16, or 47 mg/kg/day Sys temic NOAEL = 210 ppm (16 mg/kg/day)
LOAEL = 630 ppm (47 mg/kg/day)

Based on decreased body weight gains and food consumption.

Under conditions of this study, the immunotoxicity NOAEL is 630 ppm (47 mg/kg/day) (HDT) 

### HDT= highest dose tested

A.3 Hazard Identification and Endpoint Selection

A.3.1 Chronic Reference Dose (cRfD)

Study Selected: Combined Chronic Toxicity/Carcinogenicity Study and 2

- Generation Reproductive Toxicity Study in rats.
MRIDs: 00149664, 0149665, 00151564, and 00151565 (Chronic), and 00159920 (2

- Gen) Dose and Endpoint for Risk Assessment : NOAEL=1.5 mg/kg/day based on decreased serum lipids and cholesterol, and altered liver weights, as well as increased ALP and liver weights in pups from the 2

- generation repro ductive toxicity study at LOAEL of 9 mg/kg/day (M/F). Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor )

Comments on Study/Endpoint/Uncertainty Factors : The studies are of appropriate duration.

T he Chronic Toxicity/Carcinogenicity and 2

- Generation Reproductive Toxicity studies are
considered to be co

- critical as systemic effects from both studies and developmental effects from
the two

- generation study were observed at the same NOAEL and LOAEL. It is also protective of developmental effects seen at LOAEL of 32 mg/kg/day in the rat developmental study, and systemic effects in the rat and mouse subchronic and chronic studies throughout the FE/FPE

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### database. A lower NOAEL of 0.375 mg/kg/day was identifi ed in the chronic dog study with FE. However, this was not considered a critical NOAEL, taking into consideration the minimal effects that occurred in the study (10

- 12% reduction in body weights) and no toxicity was
observed in the 90

- day dog study with FP E.

Chronic RfD = = 0.015 mg/kg/day



### A.3.2 Incidental Oral Exposure (Short

- term, 1

- 30 days)

Study Selected: 28

- Day Feeding Study in Rats (FPE)
MRID No.: 47113304 Dose and Endpoint for Risk Assessment: NOAEL=6 mg/kg/day based on al tered lipid metabolism (decreased HDL

- cholesterol, HDL

- phospholipids, and total lipids, increased triglycerides, and ketonuria) and increased liver and kidney weights. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor )

Comments on Study/Endpoint/Uncertainty Factors: The endpoint of concern in this study is appropriate for the population (infant and children) and the duration of concern.

A.3.3

. Dermal Exposure (Short

- and Intermediate

- Term)

Study Selected: 28

- Day Dermal Toxicity Study in Rats (FPE)
MRID No.: 47113306 Dose and Endpoint for Risk Assessment: NOAEL=20 mg/kg/day based on non

- regenerative anemia, decreased serum cholesterol, total lipids, and protein (beta 1 globulins), and increased
li ver and kidney weights were observed at a LOAEL of 100 mg/kg/day. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor )

Comments: This study is appropriate for the short and intermediate duration a s no increase in toxicity occurred over time throughout the FPE or FE database. There is no proposed long

- term use; therefore, risk assessment for long

- term dermal exposure is not required.

A.3.4 Inhalation Exposure (Short

- , and Intermediate

- Term)

Study Selected: 28

- Day Inhalation Study
MRID No.: 47113307 Dose and Endpoint for Risk Assessment: NOAEL=0.07 mg/L based on slight normocytic anemia, decreases in serum cholesterol and total lipids, and increases in liver and kidney weights and urea nitrogen at LOAEL of 0.03 mg/L (M/F). Uncertainty Factor: 30x (3x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor )

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### Comments on Study/Endpoint/Uncertainty Factors: This study is appropriate for the short
and intermediate duration as no increase in toxicity occurred over time throughout the FPE or FE database. There is no proposed long

- term use; therefore, risk assessment for long

- term inhalation exposure is not required.

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 28

- Day Oral Toxicity

– Rat (FPE)

In a 28

- day oral toxicity study (MRID 47113304) HOE 046360 (Batch no. OH ZC960002; 95.6%) was administered to 5 Wistar, KFM

- han., SPF rats/sex/dose in the diet at levels of 0, 20, 80, 320, 1280 and 5120 ppm (equivalent to 0, 2, 6, 26, 95 and 126 mg/kg/day, in males and 0, 2, 6, 28, 94 and 144 mg/kg/day, in females). The males and females dosed at 5120 ppm were killed due to severe systemic toxicity on exposure day 9; the remaining exposure groups received the
test diets for a t least 28 days.

Based on study results, there were no compound

- related effects on hematology or gross and histological pathology. Animals dosed at 5120 ppm lost body weight and became emaciated; as noted, these animals were killed on day 9 of exposure. Clinical signs in these animals included curved posture and ruffled fur in addition to emaciation. Clinical examinations were not conducted on the remaining animals. Body weights, body weight gain, and food consumption were significantly decreased in the 1280 ppm group in both sexes. Compound

- related changes in clinical chemistry parameters indicated altered lipid metabolism and included decreased levels
of total cholesterol and HDL

- cholesterol at 320 (

- 31.2 and

- 50%, respectively) and 1280 ppm (

- 51.8 an d

- 74.5%, respectively) in males, decreased HDL

- phospholipids at 80 ppm and above in males (

- 17.9,

- 27.8 and

- 42.6%, respectively), increased triglyceride at 320 ppm in females (+47%) and 1280 ppm in both sexes (M: +129%, F: +153%). Additionally, compound

- related changes in urinalysis parameters included detection of ketones at 80 ppm in males and at 320 and 1280 ppm in both sexes. Alkaline phosphatase (M: +61.8%, F: +101%) and leucine aminotransferase activities (M: +14.5%, F: +27%) were increased at 1280 ppm in both sexes without correlative histopathological changes in the liver. Bilirubin and urobilinogen were seen in males at 320/1280 ppm and 80 ppm and above, respectively. Decreased creatinine and creatinine clearance were also seen at 1280 ppm in ma les, which may be an indication of decreased glomerular function. An increased level of lactate dehydrogenase (LDH) was observed in females at 1280 ppm. Absolute and liver relative weights were increased at 320 ppm and above in both sexes. Compound

- relat ed increases in relative kidney weights were seen at 320 and 1280 ppm in both sexes. Clinical chemistry changes at 80 ppm were not considered adverse in the absence of corresponding liver weight changes.

The Systemic Toxicity LOAEL is 320 ppm (26 mg/kg /day), based on altered lipid metabolism (decreased HDL

- cholesterol, HDL

- phospholipids, and total lipids, increased triglycerides, and ketonuria) and increased liver and kidney weights.

The Systemic Toxicity NOAEL is 80 ppm (6 mg/kg/day).

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### This 28

- day ora l toxicity study in the rat is A cceptable/Non

- guideline . There is no guideline for

a range

- finding study. M any parameters that should have been assessed were omitted; deficiencies are listed in the Study/Report Deficiencies section of this DER. This study can be used to support a guideline study in the rat.

870.3100 90

- Day Oral Toxicity

- Rat (FPE)

In a 90

- day oral toxicity study (MRID 47113310), HOE 046360 (Batch no. OH ZC960002; 95.6% a.i.) was administered to 10 Wistar, KFM

- han., SPF rats/sex/dose in t he diet at dietary levels of 0, 10, 80 and 640 ppm (equivalent to 0, 0.7, 5.8 and 49 mg/kg/day, in males and 0, 0.8, 6.3 and 51.8 mg/kg/day, in females) for 13 weeks. Ten additional rats/sex/dose received dietary levels of 0, 80 and 640 ppm for 13 weeks a nd a recovery evaluation was performed on these animals for 4 weeks after the termination of exposure.

There were no significant compound

- related effects on mortality, clinical signs, eyes or gross pathology. The following significant compound

- related ef fects were seen at 640 ppm: decreased body weight (19% in males, 11% in females) and body weight gain (31% in males, 11% females); increased serum alkaline phospha tase activity in both sexes (163% males, 23% females), altered lipid metabolism: decreased c oncentrations of total cholesterol (

- 37%) and

HDL

- phospholipids in males (

- 32%), decreased HDL

- cholesterol in both sexes (

- 61% males,

- 13% females), increased trigly ceride in females (24%), and ketonuria in males; and increased
absolute and relative liver weights in males (23 and 46%, respectively) and females (20 and 32%, respectively). These results suggest a treatment

- related perturba tion in lipid metabolism as well as impaired liver function. Absolute and relative kidney weights were also increased in high

- dose female rats (13 and 25%, respectively).

The LOAEL is 640 ppm (49 and 51.8 mg/kg/day in males and females, respectively) based on decreased body weights (

- 11 to 19%), increased liver and kidney weights, and altered lipid metabolism (decrease d HDL

- cholesterol, HDL

- phospholipids, and total lipids, increased triglycerides, and ketonuria). The Systemic Toxicity NOAEL in this study is 80 ppm (5.8 and 6.3 mg/kg/day in males and females, respectively).

This 90

- day oral toxicity study in the rat i s Acceptable/Guideline and satisfies the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3100; OECD 408) in rat when taken together with MRID 00130028. Although this second subchronic rat study was conducted with
the racemi c Fenoxa prop

- e thyl (FE) rather th an the enriched compound, Fenox prop

- p

- Ethyl (FPE), the ToxSAC and HASPOC determined that FE studies can be bridged with FPE.

870.3100 90

- Day Oral Toxicity

– Mouse (FPE)

In a s ubchronic oral toxicity study, HOE 046360 technical was test ed in NMRI/KFM

- han outbred mice by dietary treatment for 28 or 90 days. Results of both studies are presented in this report. In the dose range

- finding study (MRID 47113305), HOE 046360 Technical (95.6% a.i.,
Batch No. OH ZC06 002) was administered to mi ce (5/sex/dose) in the diet at dose concentrations of 0, 20, 80, 320 and 1280 ppm (equivalent to 0, 3, 14, 56, and 260 mg/kg bw/day

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### for males and 0, 4, 16, 61, and 280 mg/kg bw/day for females) for 28 days. In the 90

- day oral toxicity study (MRID 47113309 ), HOE 046360 Technical (95.6% a.i., Batch No. OH ZC06 002) was administered to mice (10/sex/dose) in the diet at dose concentrations of 0, 10, 80, or 640 ppm (equivalent to 0, 1.4, 11.9, and 100.8 mg/kg/day for males and 0, 2.0, 16.5, and 122.4 mg/kg
bw/d ay for females.

In the 28

- day feeding study, dietary treatment at doses up to 1280 ppm did not cause adverse effects on clinical signs, survival, body weight, body weight gain, or food consumption.

Treatment

- related findings at 1280 ppm included signi ficant increases in aspartate amino

transferase (356%), and alkaline phosphatase (452%) activities in males as well as alanine aminotransferase activity in males (997%) and females (396%), increases in protein concentra

tion (25%) and sodium concentration (10%) in males and albumin (17%

- 33%) concentration in both sexes. Effects on organs included increased liver weights (172%

- 265%) associated with hepatocellular hypertrophy (100%) and single cell necrosis (40%

- 100%), as well as increased
incidences of rena l tubular injury in both sexes (33%

- 100%). At 320 ppm, there were significant increases in sodium concentration (9%) in males, increase in relative liver weights (33%

- 74%) and liver hypertrophy (100%) in both sexes, and single cell necrosis (40%) in males as well as renal tubular injury (20%

- 80%) in both sexes. The statistically significant increase in absolute kidney weights in females at 80 ppm was not considered to be toxicologically relevant. No adverse effects were seen following treatment with 20 p pm.

Following oral administration HOE 046360 Technical for 90 days, there were no adverse effects on survival, body weight and body weight gain, food consumption, and hematology. At 640 ppm, the treatment

- related effects seen in one or both sexes consist ed of significant increases in alanine aminotransferase (102%) and alkaline phosphatase (171%) activities and albumin con

centration (13%) in males

, as well as increased absolute (100

- 137%) and relative (93%

- 140%) liver weights
, hepatocellular hypertrophy (100%), and group cell necrosis (10%

- 20%). These changes were toxicologically significant and indicative of liver toxicity. The liver effects were more pronounced in males than in females. Proximal renal tubular injury noted at 640 ppm (50% in males, 10 0% in females) and renal cortical calcification (100% in females) was accompanied by increase in urea (91% in females) and sodium concentration (13% in males).

Based on the combined results of both studies, t he Systemic Toxicity LOAEL is 320 ppm (61 and 56 mg/kg/day, for females and males, respectively) increased liver weight, hepatocellular hypertrophy, single or group cell necrosis in the liver, and proximal renal tubular injury.

The Systemic Toxicity NOAEL is 80 ppm (16.5 and 14 mg/kg/day, for female s and males, respectively)

The 28

- day oral toxicity study in mice is a dose range

- finding study and therefore, is not intended to meet the guideline requirements. T he 13

- week oral toxicity study in mice is
A cceptable/ Guide line and as such satisfies th e guideline requirements for the 90

- day oral toxicity study (OPPTS 870.3100; OECD 408) in mice

.

870.3150 90

- Day Oral Toxicity

– Dog (FPE)

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### In a 90

- day oral toxicity study (MRID 47113308), HOE 046360 Technical (95.6% a.i., Sample No. 13646) was administere d to four beagle dogs/sex/dose in diet at dose levels of 0, 80, 400, or 2000 ppm (equivalent to 0, 3.0, 15.6, and 77.7 mg/kg bw/day, in males and 0, 3.2, 16.2, and 83.4 mg/kg bw/day, in females). Doses were based on results of a 28

- day range

- finding dieta ry study in beagles (MRID 47113303).

No deaths occurred, no clinical signs related to treatment were observed, and no treatment

related changes were noted in ophthalmoscopic findings, hematologic, clinical chemistry and urinalysis findings, organ weights and their ratios, or macroscopic and microscopic findings.

Body weight gain in high

- dose males was consistently reduced compared to controls, with the body weight gain over the dosing interval of Days 0

- 90 reduced by 41%. However, as the reduced body w eight gain did not follow a clear dose

- response and were not accompanied by changes in absolute body weight, they are not considered to be treatment related. Compared to controls, high

- dose females had a biologically significant reduction in body weight ga in over Days 20

- 42 (

- 50% of controls; not statistically significant) that was accompanied by a reduction in food consumption (reduced by 11% and 7% over weeks 22

- 28 and 36

- 42; respectively). However, as the reduced body weight gain and food consumption wer e transient, and no effects on absolute body weight were reported, these changes were not considered to be adverse.

The study authors considered the decreased alanine aminotransferase activity in the high

- dose male and female groups and increased total protein in the high

- dose male group to be an effect of treatment. However, these values were not biologically significant and were within the historical control range that was supplied in the study report (Attachment 6 of MRID 47113308). Additionally, th e changes were not accompanied by any other indications of toxicity such as gross or microscopic changes. Therefore, the reviewer does not agree that these changes are an
adverse effect of treatment.

The Systemic Toxicity NOAEL is 77.7 mg/kg/day (2000 pp m) and 83.4 mg/kg bw/day (2000 ppm) in females.

This 90

- day oral toxicity study in the dog is Acceptable/Guideline and as such satisfies the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3150; OECD 409) in dogs.
No LOAEL was achieved i n this study. Based on the range

- finding study (no effects up to and including 1280 ppm), the animals could have tolerated a higher dose. However, based on bridging with FE, the study is acceptable.

870.3200 21/28

- Day Dermal Toxicity

– Rat (FPE)

In a 30

- day dermal toxicity study (MRID 47113306), Hoe 046360 (Fenoxaprop

- p

- ethyl; 95.6% a.i., batch/lot# not reported) in sesame oil was applied to the clipped skin of groups of Wistar [Hoe: WISKf(SPF71)] rats, under occlusive conditions, 6 hours/day, 5 day s/week, for a total of 21 treatments during a 30

- day period. Animals were treated at dose levels of 0, 10, 20, 100, or
500 mg/kg bw/day (6/sex/dose were treated at dose levels of 10 or 20 mg/kg bw/day and 12/sex/dose at 100 or 500 mg/kg). Six animals/sex/ dose (all dose levels) were killed on Day 30,

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### and satellite groups of 6 male and 6 female animals from the control, and the 100 and 500 mg/kg groups were killed on Day 44, after a 14

- day recovery period.

There were no deaths during the study, and clini cal signs were limited to local effects (dry, chapped skin, with or without fine or coarse scales) at the application sites. No treatment related toxicologically relevant effects were identified on body weights, food consumption, water consumption, ophtha lmoscopic examination, or sacrifice and pathology.

On day 30, the males in the 100 and 500 mg/kg groups had mild normocytic, normochromic,

non

- regenerative anemia (hematocrit: 48%, 44%, and 43% for control, 100 and 500 mg/kg, respectively; p<0.05). 100 mg/kg males showed partial recovery by Day 44, but the high

- dose males did not (hematocrit: 47%, 45%, and 43% for control, 100 and 500 mg/kg, respectively). In addition, reticulocytes remained decreased in high

- dose males between day 30 (n.s.) and day 44 (2.6% vs. 6.7% for controls; p<0.05). In males, decreased serum cholesterol and a concomitant decrease in total lipids were seen in the 100 and 500 mg/kg groups on day 30 (cholesterol: 1.60, 1.19, and 1.10 mmol/L in ascending dose order), and both paramet ers remained decreased at the high

- dose on Day 44 (cholesterol: 1.58 vs. 1.92 mmol/L in controls). Decreases in serum protein concentration and the β 1



### - globulin fraction were seen in males at 100 and 500 mg/kg on day 30, only. In females, treatment

- relate d effects on clinical pathology parameters occurred only at the high

- dose and on Day 30; these included decreased reticulocytes (2.6% vs. 4.5% for controls; p<0.05) and decreased serum cholesterol (1.05 vs. 1.48 mmol/L for controls; p<0.05).

High

- dose mal es had increased absolute and relative liver and kidney weights and decreased heart and spleen weights (liver: +37%/+40%; kidney: +13%/+15%; heart:

- 17%/

- 16%; spleen:

- 25/

- 23), but by day 44, only the heart weight remained affected (

- 17%/

- 16% absolute/rela tive). In 100 mg/kg males, liver and kidney weights were increased on day 30 only (liver: +16%/+15%; kidney: +10%/+9% absolute/relative). High

- dose females had increased liver and kidney weights on day 30 only (liver: +15%/+20%; kidney: +11%/+16% absolut e/relative).
There were no treatment

- related effects on gross or microscopic pathology, other than local microscopic changes at the application sites.

Decreases in serum cholesterol and total lipids, and increases in liver weight are consistent with
alte red lipid metabolism and were also observed in the 28

- and 90

- day oral toxicity studies. In addition, increases in urine ketone bodies may be indicative of increased breakdown of lipids.
The treatment

- related hematological effects are considered to be toxi cologically relevant as decreases were greater than 5% of the concurrent controls. The fact that the high

- dose males showed little if any increase in erythrocyte mass during recovery, and decreased reticulocytes were observed in high

- dose animals of both s exes is also significant. Decreases in reticulocytes may consistent with a bone marrow alteration and/or kidney dysfunction, and the decrease in high

- dose males is of particular concern, as it is an inappropriate response in the face of anemia.
The decre ased spleen weight in high

- dose males is consistent with impaired erythropoiesis, as well. Additionally, transferrin is the chief component of the β1 globulin fraction, and a decrease in transferrin has the potential to alter iron metabolism and thus erythrocyte production.

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### The Systemic Toxicity LOAEL is 100 mg/kg/day, based on non

- regenerative anemia, decreased serum cholesterol, total lipids , and protein (beta 1 globulins), and increased liver and kidney weights. The Systemic Toxicity NOAEL is 20 mg/kg/day.

The Dermal Toxicity NOAEL is equal to or greater than 500 mg/kg/day as no toxicologically relevant effects were identified.

This study is Acceptable/Guideline and as such satisfies the guideline recommendations for a
28

- day dermal toxicity study (OPPTS 870.3200; OECD 410) in rats.

870.3465 28

- Day Inhalation

– Rat (FPE)

In a 28

- day inhalation toxicity study, (MRID 47113307) [Hoe 046 360 (Code Hoe 046360 OH ZC96 0002, 95.6 % purity)] four groups of rats consisting of 15 males and 15 females per group were administered the test material by nose

- only exposure at concentrations of 0, 0.015, 0.07, or 0.3 mg/L. The exposures were for six h ours per day, 5 days per week for a total of 28 exposures. Ten males and ten females were killed and necropsied one day after the last exposure, and the remainder were killed and necropsied after a recovery period of 29 days.

In males rats, hemoglobin con centration (

- 9.8%), hematocrit (

- 10.9%), and thromboplastin time (

- 17.8%) were decreased (p<0.05) in the 0.3 mg/L group. Thromboplastin time was also
decreased in males in the mid

- dose group (0.07 mg/L). The effects in male rats persisted throughout the 2 9

- day recovery period. Activated partial thromboplastin (APTT) time was increased in females at the high concentration compared to controls (p<0.05). There were no correlating histological findings to the observed hematology changes relative to controls a nd no effects were observed in the female rats following the 29

- day recovery period.

There was a decrease in cholesterol and total lipids in both males and females at the high exposure level accompanied by an increase in urea nitrogen (p<0.05). Males at the high exposure
level showed increases in triglycerides and decreases in α2

- globulin that may be treatment related due to the possible interactions with lipoproteins and lipid metabolism. There were no correlating histological findings to the observed clinical chemistry change s relative to controls. However, at the end of the 4

- week recovery period, the hemoglobin concentration, hematocrit, and thromboplastin time remained decreased (p<0.05) in males relative to controls.

In males, significant increases (p<0.05) in absolute li ver weights were observed at all dose levels, and significant increases in relative liver weights were observed in the mid

- and high

- dose groups. At the high

- dose, significant increases in relative liver weights were also identified following the 29

- day r ecovery period. Significant increases in kidney weights observed for both sexes in the high

- dose group but did not persist following the 29

- day recovery period. Additionally, females showed increased absolute and relative liver weights in the top dose
fo llowing the exposure were comparable to controls following 29

- day recovery.

Decreases in both hemoglobin (

- 9.8%) and hematocrit (

- 0.9%) values, which persisted after the
29

- day recovery period may indicate slight normocytic anemia in male rats. Eviden ce of slight normocytic anemia was also observed in male rats following the 30

- day dermal toxicity study.

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### In both sexes, decreases in serum cholesterol and total lipids, and increases in liver weight and urea nitrogen are consistent with altered lipid me tabolism. These effects were only observed in male rats following the 29

- day recovery period, and were therefore not considered to be adverse
in females.

The Systemic Toxicity LOAEL for male rats is 0.3 mg/L following 28 days of inhalation exposure to H oe 046360 based on slight normocytic anemia, decreases in serum cholesterol and total lipids, and increases in liver and kidney weights and urea nitrogen. The Systemic Toxicity for male rats is NOAEL is 0.07 mg/L.

The Systemic Toxicity NOAEL for female r ats is 0.3 mg/L, the highest

- tested dose.

Submission by Registrant (Dana Sargent, Feb 20, 2008) : Doses selected based on subchronic feeding study (MRID 4713310). Due to the type of particle collection system used in this study,
a calculated MMAD and GS D were not provided for this study. Particle sizes generated in this study were generally very small, as stated in the report, “98% of the particles had an aerodynamic diameter less the 7 microns in all treatment groups, and 22 to 49% were less than 1
micr on.” Pg 25. The reason for the small particle size was that the test substance could not be dispersed in its original state. Therefore, HOE 046360 was micronized and used as a fine dust. Based on the cumulative distribution tables and graphs for median ma ss diameter of the particles collected (starting p 230 of the report) at multiple time points for each dose level, between 74

- 97% of the particles were below 4 μm, with diameter values at the cumulative 50 th 

### percentile (50% of the particles being ≤) rangi ng from 1.2

- 1.5 μm. Therefore, while an overall MMAD was not presented in the study, the distribution of particle size is within the current guideline requirements.

This 28

- day inhalation toxicity study in the rat is Acceptable/Guideline and as such sati sfies the guideline requirement (OPPTS 870.3465 [§82

- 4], OECD 413) for a subchronic inhalation study
in the rat.

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

– Rat (FPE)

In a developmental toxicity study (MRID 4 7113318), HOE 046360 ( fenoxaprop

- p

- ethyl; >99%
a.i. ; Serial No. 0321, OH ZB99 0002) was administered by oral gavage to presumed pregnant Wistar rats (20/sex/dose) at doses of 0, 10, 32, or 100 mg/kg bw/day from gestation days (GD) 7

- 16 . On GD 21, all dams were euthanized, and the uterus was removed via cesarean section and its contents examined. Fetuses were examined for external, visceral, and skeletal malformations
and variations.

All dams survived until the end of the study. At 100 mg/kg, a slight in crease in incidence of increased urinary excretion was noted (20% treated vs 0% controls). Increased urinary excretion was observed in 2 dams during GD 13

- 16 and 20

- 21, in 1 dam during GD 11

- 16, and in 1 dam during GD 19

- 21. The biological relevance for this observation is unclear. The intake of fluids
was not monitored.

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### At 100 mg/kg/day, decreased maternal body weights and maternal body weight gains were observed. Decreased (p≤0.05) body weight was noted on GD 17 (decreased 15% and outside the
normal range of historical control data) and GD 21 (decreased 13%; within the normal range of historical control data). Body weight gains were decreased by 45

- 90% during GD 7

- 14 and GD
14

- 17. Overall body weight gain (GD 0

- 21) was decreased by 30%. Food consum ption differed (p≤0.05 and outside the normal range of historical control data) from controls during GD 14

- 17 (decreased 1%) and 17

- 21 (increased 13%). Thus, during GD 17

- 21, a slight increase in food consumption was noted at the same time there was a sl ight decrease in body weight gain, suggesting decreased food efficiency (not calculated). Decreased (not statistically significant; NS) food consumption was also noted during GD 7

- 14 (decreased 32%), which corresponded to the decrease in body weight gain of 90% observed during this period.

Additionally, heart weight was decreased (p≤0.05; outside of the normal historical control range) at 100 mg/kg (decreased 17%). This may be due to decreased body weights. No histopathology
was available for the heart.

The Maternal Toxicity LOAEL is 100 mg/kg bw/day based on decreased body weight, body weight gain, and heart weight. The Maternal Toxicity NOAEL is 32 mg/kg/day.

At 100 mg/kg/day, the following findings were observed: 2 abortions (vs 0 controls), 2 dead fetuses (vs 0 controls), and 22 resor ptions (vs 11 controls); increased post

- implantati on loss (10.0% treated vs 4.1% controls); and decreased (p≤0.05) placental weight (decreased 16%). One 32 mg/kg/day dam aborted; however, there was no further evidence to corroborate toxicity at this dose level. There were no premature deliveries and no effect on sex ratio at any dose. Also, there was no change in litter size between control and treated groups.

Decreased (p≤0.05) mean fetal weight (decreased 18%) and crown to rump length (decreased 10%) were noted at 100 mg/kg/day. Increased (p≤0.05) i ncidences of retardations were observed as follows: (i) weak ossification or non

- ossification of one or several cranial bones at all doses (30.5

- 65.5% fetuses in 65.0

- 88.9% litters) compared to controls (19.5% fetuses in 60.0% litters); (ii) non

- ossificati on of one sternebra at 100 mg/kg/day (56.4% fetuses in 83.3% litters) compared to controls (5.3% fetuses in 25.0% litters); and (iii) non

- ossification of os metacarpal 5 at all doses (33.6

- 91.8% fetuses in 68.4

- 94.4% litters; NS at 10 mg/kg/day) compared t o controls (23.3% fetuses in 60.0% litters).

Increased incidences of the following developmental anomalies were observed: (i) bent, thickened ribs at 32 mg/kg/day (15.2% fetuses in 47.4% litter; p≤0.05) and 100 mg/kg/day (4.5%
fetuses in 22.2% litters co mpared to controls (1.5% fetuses in 10% litters); (ii) longitudinally displaced, fragmented, fused, dysplastic sternebrae or dislocated sternebrae at 100 mg/kg/day (23.6% fetuses in 66.7% litters) compared to controls (1.5% fetuses in 5.0% litters); and (i ii) anlage of the 14 th 

### thoracic vertebra and of a normal length and/or short 14 th 

### rib on this vertebra at 100 mg/kg/day (4.5% fetuses in 16.7% litters) compared to controls (0%).

No treatment

- related findings were observed on external malformation or anom alies or visceral anomalies. One 100 mg/kg/day fetus (among 104 fetuses) had an abdominal fissure with

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### protruding abdominal coils, and one 100 mg/kg/day fetus (among 110 fetuses) had various
vertebral malformations.

The Developmental Toxicity LOAEL is 100 mg/kg bw/day based on decreased fetal body weight (

- 18%) and crown rump length (

- 10%), and longitudinally displaced, fragmented, fused, dysplastic sternebrae or dislocated sternebrae, and weak ossification or non

ossification of one or several cranial bones. The Developmental Toxicity NOAEL is 32 mg/kg/day.

This study is classified Acceptable/Guideline and as such with the additional information,
satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rats

.

870.3700b Prenatal Developmental Toxicity Study

- Rabbit (FPE)

In a developmental toxicity study (MRID 47113319), HOE 046360 (fenoxaprop

- p

- ethyl; >99%
a.i. ; Serial No. 0321) in sesame oil was administered by oral gavage (0.5 mL/kg) once daily to
insem inated Himalyan rabbits (15/dose group) at dose levels of 0, 10, 32, or 100 mg/kg bw/day from gestation days (GD) 7

- 19 . On GD 29, all dams were euthanized. The uterus was removed via cesarean section, and its contents examined. Fetuses were examined for external, visceral,
and skeletal malformations and variations.

In the dams, no treatment

- related effect was observed on mortality. Furthermore, no macroscopic abnormalities and no adverse effects on organ weights were observed.

At 100 mg/kg/day, decrea sed defecation was noted (4/15 dams in treated group vs 0/15 controls). Decreased body weight gains were observed throughout the treatment period, where body weight gain was approximately 0. Before and after the treatment period body weight gain was simil ar to the controls. Overall body weight gain (GD 0

- 29) was decreased by 24%. Relative food consumption (g/100 g

- bw) was decreased during the treatment period by 22% (not statistically significant) at GD 7

- 14 and by 42% (p≤0.05, but within the normal rang e of historical controls)
at GD 14

- 20.

The Maternal Toxicity LOAEL is 100 mg/kg bw/day based on decreased food consumption and body weight gain. The Maternal Toxicity NOAEL is 32 mg/kg/day.

Abortions were noted in one 32 mg/kg/day dam and two 100 mg/kg/ day dams, and a premature delivery was noted in one 10 mg/kg/day dam; however, these values were within the range of historical controls. There were no effects of treatment on numbers of litters, live fetuses, dead fetuses, or sex ratio.

There were no tr eatment

- related external, visceral, or skeletal malformations or variations. There were no effects of treatment on fetal body weights, fetal crown to rump lengths, or placental weights. Incidences of skeletal retardations in the treated groups were simil ar to the concurrent controls and were within historical control ranges.

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### The Developmental Toxicity NOAEL is equal to or greater than 100 mg/kg/day.

This study is classified Acceptable/Guideline and as such with the additional information,
satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rabbits

.

Non

- Guideline Developmental Toxicity Study

- Rat (FPE)

In a non

- guideline, developmental toxicity study (MRID 47113320), Fenoxaprop

- p

- ethyl (Hoe 046360; 95. 6% a.i.; Serial # 13646, OH ZC96 0002) in sesame oil was administered by daily oral gavage to 20 presumed pregnant Wistar (Hoe WISKf [SPF71]) rats/dose at levels of 0, 10, 32, or 100 mg/kg/day (dose volume 5 mL/kg) on gestation days (GD) 7

- 16. The dams we re allowed to litter normally and rear their offspring for 21 days. Pups were examined daily for viability and clinical signs of toxicity, weighed at regular intervals, and examined for physical development. All animals were killed on post

- natal days (PN D) 21

- 23 and necropsied. The purpose of this study was to determine if repeated doses of Fenoxaprop

- p

- ethyl administered during pregnancy impaired the post

- natal development of offspring.

There were no treatment

- related effects on mortality, clinical obs ervations, organ weights, gross pathology, or reproductive performance.

In the 100 mg/kg/day females, body weights were decreased (statistics not presented) by 7

- 10% during GD 14

- 21, resulting in decrease of 16% in overall (GD 0

- 21) gestational body weigh t gains , and absolute and relative food consumption were decreased by 16

- 25% during treatment (GD 7

- 17).

The Maternal Toxicity LOAEL is 100 mg/kg/day, based on decreased gestational body weights, body weight gains, and food consumption. The Maternal Toxic ity NOAEL is 32 mg/kg/day.

At 100 mg/kg/day, mean pup body weights were decreased by 4

- 8% during PND 0

- 21, and overall (PND 0

- 21) body weight gains were decreased by 3%. As these mean body weights were observed to be near the minimum or slightly below th e range of historical controls, these
decreases were considered adverse.

The Offspring Systemic/Developmental Toxicity LOAEL for offspring toxicity 100 mg/kg/day, based on decreased pup body weights. The Offspring Systemic/Developmental Toxicity NOAEL is 32 mg/kg/day.

This study is classified as Acceptable /Non

- Guideline

.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

– Rat (FE)

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### In a 2

- generation reproduction study (MRID# 00159920) HOE 33171 (97.2% a.i.) was
administered to 3 0 WISTAR/HAN rats/sex/dose in the diet at dose levels of 0, 5, 30, or 180 ppm (calculated by the reviewer to be the equivalent to doses of 0.25, 1.5, or 9.0 mg/kg/day). Exposure to F0 animals began at 7 weeks of age and lasted for 80 days prior to mating t o produce Fla and F1b pups. At 21 days of age, F1b pups were selected to become the parents of the F2a and F2b litters. Fl animals were given test diets for 101 days prior to mating the first time. Exposure of the test material to all animals was continuou s in the diet throughout the study and all pups were given the same concentration of the test diet as their dam.

Parental toxicity was noted at 180 ppm as treatment

- related decreases in total lipids (27

- 56%, p≤0.05, Fl males and females) and total cholesterol (16

- 36%, p≤0.05, Fl males) Decreases (12

- 25%, p≤0.05) in total lipid and cholesterol were also noted at 5 pp m in the Fl parents, however, these effects were considered borderline. In addition for parental males dosed at 180 ppm, increased absolute (8%, p<0.05, Fl), relative to body (5

- 7%, F0 and Fl, p≤0.01), and relative to brain (l0%, p≤0.0l, Fl) liver weights were noted. Treatment

- related increases in the absolute (9

- 12%, p≤0.01, Fl males and females), relative to body (6

- l2%, p≤0.0l or ≤0.05, F0 and Fl males, Fl females), and relative to brain (5

- 13%, p≤0.0l or ≤0.05, F0 and Fl males) kidney weights were
also observed at the high

- dose. Histopathology was not reported for this study, however, increased incidences of nephrocalcinosis at the 180 ppm dose level was reported in the previous study. There were no treatment

- related effects on mortality, clinical signs of toxicity, body weight, food consumption or reproductive parameters at any dose level.

The Parental Systemic Toxicity LOAEL is 180 ppm (9 mg/kg/day) based on decreased blood lipids with increases in liver and kidney weights. The Parental Systemic Toxic ity NOAEL is 30 ppm (1.5 mg/kg/day).

There were no effects on reproductive parameters. The Reproductive Toxicity LOAEL is greater than 180 ppm. The Reproductive Toxicity NOAEL is greater than or equal to 180

ppm.

Offspring toxicity was demonstrated as increased pup liver weights on day 21 postpartum in the all F2 groups at 180 ppm. Several organ weights and organ weight ratios were decreased at the high dose, including lungs and spleen weights. These effects were considered to be secondary to
the debil ity of the animals. Alkaline phosphatase was increased in the pups at the mid

- and high

doses.

The Developmental/Offspring Systemic Toxicity LOAEL is 180 ppm (9 mg/kg/day) based on increased liver weights and increased alkaline phosphatase. The Developm ental/Offspring Systemic Toxicity NOAEL is 30 ppm (1.5 mg/kg/day).

This study is classified Acceptable/Guideline and satisfies the guideline requirements (OPPTS 870.3800; OECD 416) for a multigeneration reproduction study in rats.

A.4.4 Chronic Toxicit y

870.4100b Chronic Toxicity

– Dog (FE)

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### In chronic toxicity study (MRID # 00151566), HOE 33171 (technical, 94% a.i.) was administered in the diet for two years to beagle dogs (6/sex/dose, English beagle dog,
Hoe:BEAK strain ) at dose levels of 0, 3, 15, or 75 ppm (calculated by the reviewers to be equivalent to 0, 0.075, 0.375, or 1.875 mg/kg/day, based on a dry diet).

Treatment with HOE 33171 for up to two years did not affect mortality, behavior, clinical findings, food consumption, hematology, kidney and liver function, or urinalysis. Neurologic, ophthalmologic, otologic, dental, and mucosal health was similar in the treated and control animals. In addition, dosing did not cause toxicologically significant effects on organ weights,

organ

- to

- body weight ratios, or gross and histopathological findings. At termination, the high

dose animals had lower (p ≤ 0.05) mean body weights (10

- 13%) and body weight gains (51

- 53%) than the controls. The mean body weights of the mid

- dose males were also significantly ( p ≤ 0.05) decreased (11%), but mean weight gain did not differ significantly from the controls. Additionally, body weights in the mid

- dose were 8% lower than controls at study initiation. Therefore, the body weight difference at the mid

- dose was not consid ered to be adverse.

The LOAEL is 75 ppm (1.875 mg/kg/day) based on reduced body weights and body weight gains. The NOAEL is 15 ppm (0.375 mg/kg/day).

This study is classified as Acceptable/Guideline and as such satisfies the guideline
recommendations f

or a (OPPTS 870.4100; OECD 452 (1981); EEC 87/302 B) chronic oral toxicity study in dogs.

A.4.5 Carcinogenicity

870.4300a Combined Chronic Toxicity/Carcinogenicity

– Rat (FE)

In combined chronic/carcinogenicity studies (MRID Nos. 00145638, 00149664, 00 149665, 00151564, 00151565), HOE 33171 (technical, 94 and 95.8% a.i.) was administered to 116 Wistar rats/sex/dose in the diet at dose levels of 0, 5, 30, or 180 ppm (calculated by the reviewers to be equivalent to approximately 0, 0.25, 1.5, or 9 mg/kg/da y) for up to 28 months. At each of the 6 and 12 month interim sacrifices, 10 rats/sex/group were terminated and at the 24 month sacrifice, 20 rats/sex/group were terminated. In addition, at 26 months, hepatic and renal (BSP/PSP clearance) function tests we re performed in 6 rats/sex/group, and at 28 months, 60 rats/sex/group were terminated.

Treatment with HOE 33171 for up to 28 months did not affect mortality, behavior, clinical findings, body weight, food consumption, haematology, kidney function, or urin alysis. In addition, dosing did not cause toxicologically important effects on gross and histopathological findings. Significantly decreased absolute and relative liver weights were identified in male rats at 24 months, and significantly decreased relative liver weights only at 28 months. All clinical chemistry parameters were similar in dosed and control groups with the exception that in the high

- dose males, there were significant (p<0.05) decreases in serum cholesterol levels at 26, 54, and 107 weeks (1.1 9

- 22%) and in total lipids at 107 weeks (

- 24%) . The decreases in cholesterol

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### (17

- 18%) and total lipids (19%) observed in the high

- dose females were not statistically significant.

The Chronic Toxicity LOAEL is 180 ppm (equivalent to 9 mg/kg/day) based on decreased serum lipids, cholesterol and relative liver weights in the males and the Chronic Toxicity NOAEL is 30 ppm (equivalent to 1.5 mg/kg/day).

There was no evidence of carcinogenicity (no increase in tumors) in Wistar rats under these study condition s.

Note: Dosing was considered adequate by CARC (TXR #0056683) based on the findings of the
90

- day feeding study in rats (MRID 00130028) with data showing liver toxicity at 320 ppm.

This study is classified Acceptable/Guideline and as such satisfies the guideline recommendations (OPPTS 870.4300; OECD 452) for a chronic oral toxicity/carcinogenicity study in rats.

870.4200b Carcinogenicity (feeding)

– Mouse (FE)

In a carcinogenicity toxicity study in mice (MRID 44157402), Fenoxaprop

- ethyl (96.8% a.i., Lot/Batch 04663) was administered to NMRI mice (50/sex/group, Hoe:NMRI(SPF71) obtained
from Hoechst

- AG, Kastengrund) via the diet at dose levels of 0, 40, 115, or 320 ppm (0, 5.7, 16.6, or 44.6 mg/kg/day for males and 0, 6.8, 19.4, or 53.7 mg/kg/day for f emales, respectively)
for 105 weeks.

Clinical observations indicated an increased, incidence of swollen abdomen in both sexes at 115 and 320 ppm from week 55 onward. No other significant findings were noted on mortality and
clinical observations. Absolute liver weight was increased at 320 ppm (males only) while relative liver weight was increased at 115 and 320 ppm (males only). Microscopic pathology showed that alterations occurred in the liver including hypertrophy, single cell necrosis, pigmentation in macrophages and lipofuscin deposit at 115 ppm (males only) and 320 ppm (both sexes).

The Systemic Toxicity LOAEL is 115 ppm (16.6 mg/kg/day for males and 19.4 mg/kg/day for females) based on histopathological findings in the liver. The Systemic Toxicity NOAEL is 40 ppm (5.7 mg/kg/day for males or 6.8 mg/kg/day for females).

At the doses tested, there was a treatment related increase in tumor incidence of hepatocellular adenoma and carcinoma when compared to controls. A significant increase in liver tumo rs, mainly adenomas, was observed in males at 320 ppm (30%) compared to the ‘control (2%). In addition, microscopic pathology indicated that hepatocellular hypertrophy was observed in: the majority of all treated animals (both sexes). Dosing was considered adequate based on clinical signs (swollen abdomen), increased liver weight, and histopathology data at the high dose.

Note: No appreciable differences in survival were reported for the vehicle control and test groups at any dose. All test animals surviv ed to study termination. The only clinical sign of note was an
increased incidence of swollen abdomens in the mid

- and high

- dose males and females. In

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### addition, microscopic pathology indicated that hepatocellular hypertrophy was observed in the majority of male animals treated with 115 or 320 ppm fenoxaprop

- ethyl and the majority of females at 320 ppm. Dosing was, therefore, considered adequate by the CARC (TXR #0056683) based on clinical signs (swollen abdomen), increased liver weights, and histopatholo gy data at the high dose.

This study is classified as Acceptable

- Guideline and as such satisfies the guideline recommendations for a carcinogenicity study in mice (OPPTS 870.3200; OPP §82

- 2).

A.4.6 Mutagenicity (FPE)

STUDY FPE
870.5100
Bacterial /mamma lian microsome reverse gene mutation assay MRID 47113314: 0, 4, 20, 100, 500, 2500, 5000 μg/plate +/

- S9; two independent
trials. Negative in S. typhimurium TA1535, TA100, TA1537, and TA98 & E.
coli WP2 uvr

A up to a cytotoxic limit
dose.

Non

- Guideline
Forward mutations in Schizosaccharomyces pombe P1 assay MRID 47113311: 0, 2.5, 5.0, 10.0, 20.0, 40.0 μg/mL +/

- S9; two independent trials. Negative up to an insoluble concentration (40 μg/mL +/

- S9). No cytotoxicity at any
level.
870.5300

In vitro gene mutations in
Chinese hamster V79 cells (HGPRT locus) assay MRID 47113316: 0, 6.25, 12.5, 25.0, 50.0, 100 μg/mL +/

- S9; two independent
trials. Negative after a 6

- or 9

- day expression time up to an insoluble concentration (100 μg/mL +/

- S9). No cytotoxicit y at any level.

870.5375

In vitro chromosome
aberrations in human lymphocytes assay MRID 47113313: 5.0

- 125 μg/mL +/

- S9. Cells, treated either continuously for 24 hrs & harvested (

- S9) or for 2 hrs. & harvested at 12 or 24 hrs (+S9). Cells exposed to 0

, 50, 79, 125 μg/mL +/

- S9 were scored. Negative up to an insoluble concentration (100 μg/mL +/

- S9). No cytotoxicity at any level. No clear effects (≥50% ↓) on the
mitotic index.
870.5395 NMRI Mouse (M/F) Micronucleus assay MRID 47113317: 0, 1000, 2000, 4000 mg/kg oral gavage. Negative up to a leve l that exceeds the limit dose (2000 mg/kg). Toxic signs at 4000 mg/kg included: narrowed palpebral fissures & reduced spontaneous activity. No cytotoxic effect
on the bone marrow.
870.5575 MRID 471 13312: 0, 1.25, 2.50, 5, 10, 20

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### STUDY FPE Mitotic gene conversion in Saccharomyces cerevisiae
D4 μg/mL +/

- S9; two independent trials. Negative at the ade

- 2 and try

- 5 loci up to an insoluble concentration (20 μg/mL +/

- S9). No cytotoxicity at any level.
870.5550
Unscheduled DNA synthesis in A 549 human
HeLa cells MRID 47113315: 0, 0.1, 0.3, 1, 3, 10, 30, 100 μg/mL +/

- S9; two independent trials. Negative up to the highest soluble concentration (100 μg/mL +/

- S9). No cytotoxicity at any level.

A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery

- Rat

Waived by HASPOC.

870.6200 Subchronic Neurotoxicity Screening Battery

- Rat

Waived by HASPOC.

A.4.8 Metabolism

870.7485 Metabolism

– Rat (FE)

In a rat metabolism study (MRID 00148476), HOE 33171 (FE) (U

- 14C

- chlorophenyl; 98% radiochemical purity) w as administered to male and female Wistar HOE:WISKf (SPF 71) strain rats (10

- 15 animals/dose/sex) by gavage as a single dose at levels of 2 or 10 mg/kg, or as a single dose at 2 mg/kg following a 14

- day pretreatment with unlabeled HOE 33171 at 2 mg/kg/day.

Within 96 hours of dosing, 83

- 109% of the administered radioactivity was recovered in the urine and feces, with the majority of the dose (51

- 65%) being recovered within 24 hours of dosing.
Sex

- related differences in the pattern of excretion were apparent . Female rats metabolized the chemical more rapidly and excreted more of the total radioactivity in the urine (54

- 70% of dose) than the males (37

- 58% of dose). Within 24 hours of dosing, urinary excretion accounted for 39

- 48% of the dose for females and 22

- 31% of the dose for males. Over the course of the study, radioactivity in feces accounted for 39

- 62% of the dose for males and 30

- 43% of the dose for
females. Dose

- related differences in excretion were not evident in females, but high dose males had a hig her level (62% of dose) of excretion in the feces than low

- dose males (39

- 40% of dose).

The primary metabolite in urine of both sexes in each dose group was 6

- chlorobenzoxazole

- 2

- mercapturic acid, accounting for 22

- 50% of the total radioactivity in urine (15

- 26% of dose). However, urine of female rats dosed either once at 10 mg/kg or repeatedly at 2 mg/kg also contained high levels (23

- 28% of dose) of 2

- (4

- (6

- chloro

- 2

- benzoxazolyloxy)

- phenoxy)

- propionic acid (the free acid of fenoxaprop

- ethyl). This metab olite in urine accounted for 4.7% of the dose from single low

- dose females and ≤ l.3% of the dose from males of all dose groups.

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### The primary fecal metabolite, which was common to both sexes, was the free acid of fenoxaprop

- ethyl, accounting for 21

- 39% of the fecal radioactivity (8.4

- 21.7% of dose). Unchanged parent accounted for approximately 17% of the fecal radioactivity (5.7

- 6.3% of dose) in rats dosed once at 2 mg/kg and approximately 4% of the fecal radioactivity (1.1

- 1.4% of dose) in rats dosed repe atedly at 2 mg/kg. At the 10 mg/kg dose, unchanged parent accounted for 24% of the fecal radioactivity (15% of dose) for male rats and 6% for female rats (1.7% of dose)

870.7485 Metabolism

– Rat (FE)

In a rat metabolism study (MRID 00148477), HOE 33171 (FE) (1

- 14C

- dioxyphenyl; 96% radiochemical purity) was administered by gavage as a single dose to male and female SPF Wistar strain rats (10 animals/sex) at 10 mg/kg body weight and to 15 females at 2 mg/kg body weight.

The administered radioactivity was quantitatively recovered from the urine and feces of rats at each dosing regimen. Within 96 hours of dosing, 101.3% and 87.4% of the 10 mg/kg dose was recovered from male and female rats, respectively, and 108.8% of the 2 mg/kg dose was
recovered from fema le rats. For each sex and dose level, the majority of the dose (66

- 80%) was recovered within 24 hours of dosing. Sex

- and dose

- related differences in excretion were noted. For the 10 mg/kg dose groups, females eliminated 54.9% of the dose in urine and 32.5 % of the dose in feces; whereas, males eliminated 47.9% and 53.4% of the dose in urine and feces, respectively. In addition, females dosed at 2 mg/kg had a higher rate of urinary excretion (70.9% of dose) than did females dosed at 10 mg/kg, although levels of fecal elimination were similar
for females from both dose levels.

Sex

- and dose

- related differences were also apparent in the metabolic profiles. In the 0

- to 24

- hour urine of male rats dosed at. 10 mg/kg, 99% of the radioactivity was identified as 2

- (4

- hydroxyphenoxy)

- propionic acid (HPP

- acid), accounting for 47.5% of the administered dose. In female rats dosed at 10 mg/kg, the primary urinary metabolites were identified as HPP acid (27.5% of dose) and 2

- (4

- (6

- chloro

- 2

- benzoxazolyloxy) phenoxyl

- propio nic acid (the free acid of fenoxaprop

- ethyl; 27% of dose). These metabolites were also identified in the urine of low

dose females at a ratio of approximately 2:1 (49.6 and 21.3% of dose, respectively).

In 0

- to 24

- hour feces from each dose group, 63

- 69% of the radioactivity was identified as either fenoxaprop

- ethyl or its free acid metabolite. In feces of the 10 mg/kg dose groups, fenoxaprop

ethyl and its free acid accounted for 20.1 and 16.6% of the dose for males and 9.0 and 11.3% of
the dose for female s. In feces from the low

- dose females, parent and the free acid metabolite accounted for 6.6 and 17.5% of the dose, respectively. Minor amounts (≤ 1% of dose) of HPP acid metabolite were also detected in feces from each dose group.

870.7600 Dermal Absorpt ion

- Rat (FPE)

I n a dermal penetration study (MRID 47113321), fenoxaprop

- p

- ethyl (~99%) was administered
to four male Sprague Dawley Crl:CD BR rats /dose to a 10.3 cm 2 

### area on the shaved dorso

lumbar surface at concentrations of 2.72 ± 0.03 and 617.5 ± 1 25.6 μg ai/cm 2 

### skin. The applied

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### concentrations were equivalent to 0.0276 and 6.9 mg/animal for the low

- and high

- exposure groups, respectively. The animals were exposed for eight hours. Four rats/exposure interval/group were sacrificed at 8, 24, 72, 12 0 hours after initiation of treatment.

The average recovery of the radiolabel was 96.3% and 90.8% for the low

- and high

- groups, respectively. The maximum concentration of radiolabel recovered in the blood and plasma of
the low

- dose group was 15.4 and 2 5.1 ng equivalents/g at eight hours after initiation of treatment and 403 and 622 ng equivalent/g, respectively, at 24 hours after initia tion of treatment for the high dose. The majority of the administered dose was recover ed from the wash solutions and dressings at both treatment concentrations. Approximately 70

- 80% of the applied low

- dose and
87

- 90% of the high

- dose were retained in these media. Estimates of dermal absorption based on the sum of residues retained in the urine (including cage wash and rinse), GIT and contents, feces, carcass, and blood ranged from 6.212% of the applied dose at eight hours after initiation of treatment to 16.31% of the applied dose at 120 hours after initiation of treatment for the low dose and 0.6% of the applied dose eight hours after initia tion of treatment that increased to 2.012% of the applied dose by 120 hours in the high

- dose group. Following treatment, approximately two

thirds of the absorbed radiolabel was recover ed in the urine/cage wash with the remainder
recovered in the feces. The 250

- fold difference between the low

- dose (meant to simulate the

spray

- strength concen tration) and the high

- dose resulted in a 28

- fold difference in the amount absorbed (444 ng equivalents/cm 2 

### for the low

- dose and 12,445 ng equ ivalents/cm 2 

### for the high

dose) strongly suggested the absorption process was saturated at the high

- dose.

This study in the rat is Acceptable/Nonguideline and does not satisfy the guideline requirement for a dermal penetration study (870.7600) in rats. T he study does provide, however, useful information on the absorption of fenoxaprop

- p

- ethyl at expected use concentrations. Study deficiencies are listed in the Deficiency Section

Non

- Guideline Dermal Absorption

– Rat vs. Human (FPE)

I n an in vitro derma l penetration study (MRID 47113322), fenox aprop

- p

- ethyl (>99% a.i. unlabeled, Lot No. 28283

- 133 and >99% a.i. radiolabeled, Lot No. Z 28084

- 1 uniformly labeled on the phenyl ring) was applied to 0.64 cm 2 

### skin prepara tions from male Sprague Dawley rats

an d from a human female at nominal concentrations of 7.3 and 550 μg/cm 2 

### . The radiolabeled test material was in contact with the epidermal tissue for 24 hours. Absorption through the prepared tissue samples was determined by monitoring the amount of radioa ctivity in the receptor fluid.

Absorption was ~0.34 μg/cm 2 

### /hr for human skin and 2.32 μg/cm 2 

### /hr for rat skin (or ~6.8 times greater for rat skin than human skin) when applied at a nominal concentration of 550 μg/cm 2



### . When the test material was applied dil uted 75

- fold as for end use, rat skin was only slightly more permeable (~1.6 times) than human skin. Absorption through human skin was ~0.02 μg/cm 2 

### /hr and 0.034 μg/cm 2 

### /hr for rat skin when fenoxaprop

- p

- ethyl was applied at a nominal concentration of 7.3 μ g/cm 2



### .

However, following OECD guidelines, calculations should be conducted using the receptor fluid, material left on the skin site, and the cell wash + receptor chamber contents. Using these values,

### Fenoxaprop

- p

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Page 76 of 84 

### the percent absorption from rats and humans is 38.9 an d 59.6%, respectively, indicating high penetration through human skin.

This in vitro study with rat and human skin Acceptable/Nonguideline

.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

- Rat (FPE)

In an immunotoxicity study (MRID 48445201), fenoxaprop

- p

- ethyl (94.5% a.i., batch# EFLC000572) was administered to female Wistar rats (10/dose) via diet at dose levels of 0, 70, 210, or 630 ppm (0, 5.5, 16, or 47 mg/kg/day, respectively) for 4

- weeks. The positive control consisting of 10 female Wistar rats we re administered cyclophosphamide (3.5 mg/kg/day) by gavage for 28 days. Animals were observed daily for mortality and clinical signs. Body weight and food consumption were recorded once weekly. A detailed physical examination was performed once during the acclimatization phase and at least weekly throughout the study.

On Day 26, all animals were immunized with 0.5 mL Sheep Red Blood Cell (2.5 x 10 8 

### SRBC/mL) antigen by intravenous injection via the tail vein. On Day 30, blood samples were
collected from th e retro

- orbital venous plexus of each animal for specific anti

- SRBC IgM analysis with an Enzyme

- Linked Immunosorbent Assay (ELISA).

There were no effects on mortality, clinical signs, organ weight or gross pathology findings. At 630 ppm, mean body weight was reduced 4% to 6% (not statistically significant) during the course of the study, when compared to the controls. Between Study Days 1 to 8, mean body weight gain was reduced by 54% (p<0.01), compared to controls. Between Study Days 8 to 15,
and 15 to 2 2, effect was less pronounced and not statistically significant. Overall mean absolute body weight gain between Study Days 1 and 29 was reduced by 29% (p≤0.05). Mean food consumption was statistically significantly lower than controls (

- 10% to

- 13%, p<0.05 to p≤0.01) throughout the study. At 210 and 70 ppm, there were no treatment

- related effects on any of the parameters assessed.

The systemic toxi city NOAEL is 210 ppm (16 mg/kg/day) and the LOAEL was 630 ppm (47 mg/kg/day) based on decreased body weight gains and food consumption.

For immunotoxicity, mean anti

- SRBC IgM concentrations were similar to the untreated control group at all dose levels t ested. A high inter

- individual variability was noted in all the treatment groups as well as in the control group. Evaluation of individual animal data did not show any trend or distribution that would demonstrate significant suppression of SRBC antibody r esponse.

For positive control group, cyclophosphamide induced no mortalities, clinical signs, body weight or food consumption effects and no gross pathology findings. Lower mean absolute and relative spleen weights were observed, compared with the control group (

- 16% to

- 17%, p≤0.05). Following immunization with SRBC antigen, the mean anti

- SRBC IgM concentration was markedly lower than the corresponding control group (

- 92%, p<0.01). The positive control

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Page 77 of 84 

### animals confirmed the sensitivity of the test system to detect immunosuppressive effects and confirmed the validity of the study design.

The NK cells activity was not evaluated. Evaluation of toxicity database of fenoxaprop

- p

- ethyl
reveals no evidence of treatment

- related effects on the immune system. Unde r the HED guidance, if the TDAR assay is negative and evaluation of observational endpoints from all available toxicology database provide no evidence of immunotoxicity, the test article is considered negative for immunotoxicity and evaluation of NK cells activity is not necessary.

Under conditions of this study, the immunotoxicity NOAEL is 630 ppm (47 mg/kg/day) and
the LOAEL was not established.

This immunotoxicity study in rats is classified as Acceptable / Guideline and satisfies the guideline requireme nt for an immunotoxicity study (OPPTS 870.7800)

.

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### Appendix B. International Residue Limits Table



## Fenoxaprop

- p

- ethyl (129092), Fenoxaprop

- ethyl (128701; 09/09/2013)
Summary of US and International Tolerances and Maximum Residue Limits Residue Definiti on : US Canada Mexico 1 Codex

40 CFR 180.430:
Plant and Livestock: Compliance with the tolerance levels specified is to be determined by measuring only the sum of fenoxaprop

- ethyl, (±)

- ethyl 2

- [4

- [(6

- chloro

- 2

- benzoxazolyl)oxy]phenoxy]propanoate,
and its me tabolites, 2

- [4

- [(6

- chloro

- 2

- benzoxazolyl)oxy]phenoxy]propanoic acid
and 6

- chloro

- 2,3

- dihydrobenzoxazol

- 2

- one, calculated as the stoichiometric equivalent of fenoxaprop

- ethyl ( 

### RS )

- ethyl

- 2

- [4

- (6

- chloro

- 1,3

- benzoxazol

- 2

- yloxy) phenoxy]propanoate, including t he metabolites
2

- [4

- [(6

- chloro

- 2

- benzoxazolyl)

- oxy]phenoxy]propionic
acid and 6

- chloro

- 2,3

- dihydrobenzoxalazol

- 2

-

one None



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

US Canada Mexico 1 

### Codex Barley, grain 0.05 0.05 Barley, straw 0.1 Cattle, fat 0.05 Cattle, meat byproducts 0.05 Cattle, meat 0.05 Cotton, undelinted seed 0.05 Goat, fat 0.05 Goat, meat byproducts 0.05 Goat, meat 0.05 Hog, fat 0.05 Hog, meat byproducts 0.05 Hog, meat 0.05 Horse, f at 0.05 Horse, meat byproducts 0.05 Horse, meat 0.05

Milk 0.02 0.02

Peanut 0.05 Peanut, hulls 0.05 Rice, grain 0.05 0.05 Sheep, fat 0.05 Sheep, meat byproducts 0.05 Sheep, meet 0.05 Soybean 0.05 0.05 dry soybeans

Wh eat, grain 0.05 0.05 Wheat, straw 0.50 Proposed Tolerances Grass, hay** 0.15 Completed: M. Negussie; 9/11/13

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. ** Grass hay is a new use. Grass, hay also has a time

- limit ed tolerance of 0.05 ppm expiring 12/31/2013.

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Page 79 of 84 *** Time limited tolerance expiring 12/31/2013. (b) Section 18 emergency exemptions. Time

- limited tolerances are established for residues of the herbicide fenoxaprop

- ethyl, including its metabolites and degrada tes, in or on the commodities in the table in this paragraph in connection with use of fenoxaprop

- ethyl under section 18 emergency exemptions granted by EPA. Compliance with the tolerance levels specified in this paragraph is to be determined by measuring only the sum of fenoxaprop

- ethyl, (±)

- ethyl 2

- [4

- [(6

- chloro

- 2

- benzoxazolyl)oxy]phenoxy]propanoate, and its metabolites, 2

- [4

- [(6

- chloro

- 2

- benzoxazolyl)oxy]phenoxy]propanoic acid and 6

- chloro

- 2,3

- dihydrobenzoxazol

- 2

- one, calculated as the stoichiometric equ ivalent of fenoxaprop

- ethyl, in or on the commodity. The tolerances expire and are revoked on the dates specified in the table in this paragraph.

Commodity Parts per million Expiration/
revocation date

Grass, forage 0.05 12/31/13

Grass, hay 0.05 12/31/13

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### Appendix C. Spray Drift Summary Tables

The spray drift risk estimates are based on an estimated deposited residue concentration as a result of the screening level agricultural application scenarios. FPE is used on a variety crops
and turf sites and can be applied via groundboom and aerial equipment at a maximum application rates ranging from 0.083 to 0.173 lbs ai/acre. The recommended drift scenario screening level options are listed below:

 Groundboom applications are based on the AgDrift option fo r high boom height and using very fine to fine spray type using the 90 th 

### percentile results.

 Aerial applications are based on the use of AgDrift Tier 1 aerial option for a fine to medium spray type and a series of other parameters which will be described in more detail below (e.g., wind vector assumed to be 10 mph in a downwind direction for entire application/drift event). 7



### In addition to the screening level spray drift scenarios described above, additional results are provided which represent viable dr ift reduction technologies (DRTs) that represent potential risk management options. In particular, different spray qualities have been considered as well as the impact of other application conditions (e.g., boom height, use of a helicopter instead of fix ed wing aircraft, crop canopy conditions).

Dermal risk estimates were calculated for adults. Dermal and incidental oral risk estimates for children 1 to <2 years old were combined because the toxicity endpoint for each route of exposure is the same. The total applicable Level of Concern is 100 so MOEs < 100 represent
risk estimates of concern. Adult and children dermal and children’s incidental oral risk estimates from indirect exposure to FPE related to spray drift result in buffers of 0 feet for groun dboom and aerial applications, (i.e., all MOEs ≥ 100 at the edge of the field). Results for the drift scenarios of the highest application rate and chemical

- specific TTR values (as described in Section 5.2) are presented in Tables C.1 and C.2.

7 AgDrift allows for consideration of even finer spray patterns characterized as very fine to fine. However, this spray pattern was not selected as the common screening basis since it is used less commonly for most agriculture. If assessors identify this use pattern it should be used as the screening criteria and deposition values associated with it are provided in Table 1 below. Justification for including this spray quality should be included in any assessment based on specific label directions for its use.

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Page 81 of 84 Tabl e C.1 Adult Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Fenoxaprop

- p
- ethyl for the Dermal Route of Exposure

Crop/Rate Group Spray Type/

Nozzle Configuration Appl.

Rate (lb ai/A) TTR

(ug/c m2) At Edge 10

Feet 25

Feet 50

Feet 75

Fee t 100

Feet 125

Feet 150

Feet 200

Feet 250

Feet 300

Feet

Right of Way/ Commercial Turf (Sod Farms)/ Ornamentals

Aerial Fine to Medium

0.173 0.018 1,300 1,600 2,000 2,600 3,400 4,400 5,3 0 0 6,200 8,200 9,900 12,000

Medium to Coarse 1 ,600 2,100 2,900 4,100 5,800 7,600 9,600 12,000 16,000 2 1,000 26,000

Coarse to Very

Coarse 1,800 2,700 4,100 6,300 9,100 12,000 15,000 19,000 26,000 34,000 42,000

Very Fine to Fine 900 990 1,100 1,300 1,500 1,700 1,90 0 2,200 2,600 3,100 3,500

AT401, M, 10 mph,

37% SD 1,400 1,800 2,400 3,200 4,300 5,600 6,800 8,000 10,000 13,000 16,000

WASP, M, 10 mph,

37% SD 1,500 2,000 2,600 3,900 5,300 6,800 8,400 9,900 13,000 16,000 19,000

AT401, C, 10 mph,

25% SD 1,700 2,400 3,400 5,000 7,100 9,300 12,000 14,000 20,000 26,000 30,000

WASP, C, 10 mph,

25% SD 2,000 2,800 4,000 6,300 8,800 12,000 15,000 19,000 26,000 34,000 37,000

AT401, VC, 10 mph, 20% SD 1,900 2,900 4,700 7,600 11,000 15,000 19,000 24,000 34,000 42,000 56,000

WASP, VC, 10 mph, 20% SD 2,400 3,800 5,900 9,300 13,000 18,000 24,000 28,000 42,000 48,000 56,000

Groundboom High Boom Very

fine to Fine 1,800 3,600 6,000 9,600 13,000 17,000 20,000 24,000 30,000 42,000 48,000

Low Boom Very

fine to Fine 3,900 10,000 17,000 26,000 34,000 42,000 48,000 56,000 67,000 84,000 110,000

High Boom Fine to

Medium/C oarse 6,800 18,000 26,000 37,000 48,000 56,000 67,000 67,000 84,000 110,000 110,000

Low Boom Fine to

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Table C.2 Children (1 to <2 years old) Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Fe noxaprop
- p
- ethyl for the Combined Dermal and Oral Routes of Exposure

Crop/Rate Group Spray Type/

Nozzle Configuration Appl.

Rate (lb ai/A) TTR

(ug/cm2) At

Edge 10

Feet 25

Feet 50

Feet 75

Feet 100

Feet 125

Feet 150

Feet 200 Feet 250 Feet 300 Feet

Right of Way/ Commercial Turf (Sod Farms)/ Ornamentals

Aerial Fine to Medium

0.173 0.018 620 760 940 1,200 1,600 2,100 2,500 2,900 3,900 4,700 5, 700

Medium to

Coarse 750 1,000 1,400 1,900 2,700 3,600 4,500 5,500 7,500 9,900 12,000

Coarse to Very

Coarse 870 1, 300 1,900 3,000 4,300 5,700 7,200 8,800 12,000 16,000 20,000

Very Fine to

Fine 420 470 520 600 700 800 910 1,000 1,200 1,500 1,700

AT401, M, 10 mph, 37% SD 680 870 1,100 1,500 2,000 2,600 3,200 3,800 4,900 6,100 7,500

WASP, M, 10 mph, 37% SD 730 930 1,200 1,800 2,500 3,200 4,000 4,700 6,100 7,500 8,800

AT 401, C, 10 mph, 25% SD 800 1,100 1,600 2,400 3,400 4,400 5,500 6,600 9,300 12,000 14,000

WASP, C, 10 mph, 25% SD 930 1, 300 1,900 3,000 4,200 5,700 6,900 8,800 12,000 16,000 18,000

AT401, VC, 10 mph, 20% SD 910 1,400 2,200 3,600 5,100 6,900 8,800 11,000 16,000 20,000 26,000

WASP, VC, 10 mph, 20% SD 1,100 1,800 2,800 4,400 6,300 8,300 11,000 13,000 2 0,000 23,000 26,000

Groundboom High Boom

Very fine to 850 1,700 2,800 4,500 6,300 7,900 9,300 11,000 14,000 20,000 23,000

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Lo w Boom Very fine to

Fine 1,900 4,900 7,900 12,000 16,000 20,000 23,000 26,000 32,000 40,000 53,000

High Boom

Fine to

Medium/Coarse 3,200 8,300 12,000 18,000 23,000 26,000 32,000 32,000 40,000 53,000 53,000

Low Boom

Fine to

Medium/Coarse 4,800 13,000 20,000 26,000 32,000 40,000 53,000 53,000 79,000 79,000 79,000

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