### Iso fe tam i d Human Health Risk Assessment DP No. 41110 6



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

DATE: Septembe r 24, 20 1 4 OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION



### SUBJECT : Isofetamid. 

### Aggrega t e Human Hea l th Risk Assessment for the Proposed New

Uses of the New Active Fungicide, including Agricultural Uses on Al mond s, Lettuce, Small Vine Climbing Fruits (Crop Subgroup l 3-07F), Lo w Growing

Berries (Cro p Subgroup 1 3-07G), and Rapeseed (Crop S ub grou p 20A); and Uses

on Turf grass (including Golf Courses, So d Farms, Seed Farms, Recreational

Fields

, and Commercial/Residentia l Lawns).

PC Code: 270000 DP Barcode: 04 11106

D e cision No

. : 474283 Registration N os. : 71512-EE, 71512 -EG

Petition N o. : 3F8142 Regulatory Ac tion : Sect i o n 3 Registration


### Cas eNo.: NA Risk Asses sment T ype : Aggregate Hu m an H ealth



### TXRNo.: NA CAS No.: 8 75915- 78-9

MRIDNo.: NA 40 C FR: to b e d ete rmin ed ( n ew active in g redi e nt )



### FRO M: Nancy 

### J. Keller

, Chemist

, Risk Assessor 

# l

\Ullil/£1.<.r 

### Myron Ottley, Senior

### To**xicologist ~**  Minerva Mercado, Toxicologi st --..._**--~:::;. .;--** **~** (_. 

### - Nancy Dodd

, Chem i st**:;·/..-...,~ ~~?'/**  

### Risk Assessme n t Bran ch 3 (RA'B3)

Health Effects Divis ion (7509P)

THROUGH: C hri st in e Olinger, Branch Ch i ef

# W(/~ Ri s k Assessmen t Branch 3 (RAB3)

and

Anna Lowit

, Designated Review e r Michael Metzger, De signated Reviewer

Ri s k Assessme n t Review Committee

Hea l th Effects Di vis ion (7509P)

TO : H eather Garv i e/Tony Kish, RM #22 Fungicide Branch (FB) Regi s tration Di visi on (7505P)

Pa ge 1of48

### Isofetamid Human Health Risk Assessment DP No

. 411106



### Table of Contents

1.0 Executive Summary

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

2.0 HED Recommendations

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

2.1 Data Deficiencies

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

2

. 2 Tolerance Considerat i ons

................................................................................................. 6
2.2.1 Enforcement Analytical Method

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

2.2.2 Recommended Tolerances

... ...... ...... . ... ......... ... ...... ... . ... . .. ....... .. .. ... .. .. .. .. ... .. ... ... ........ 7
2.2.3 Revisions to Petitioned-For Tolerances

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

2.2.4 International Harmonization

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

3.0 Introduction

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

3 .1 

### Chemical Identity

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

3 .2 Physical/Chemical Characteristics

................................................................................... 9
3.3 Pesticide Use Pattern

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

3 .4 Anticipated Exposure Pathways

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

3.5 Consideration of Environmental Justice

........................................................................ 12

4.0 Hazard Characterization and Dose-Response Assessment..

.............................................. 12

4

. 1 Toxicology Studies Available for Analysis

................................................................... 12

4.2 Absorption, Distribution, Metabolism, & 

### Elimination (ADME)

................................... 13

4.3 Toxicological Effects

......................................................................................... ....... .. ... 13

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

.. ..................................... 14

4.4.1 Completeness of the Toxicology Database

............................................................. 14

4.4.2 Evidence ofNeurotoxicity

....................................................... . ... ... ...... ... ............... 14

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

......... 15

4.4.4 Residual Uncertainty in the Exposure Database

..................................................... 15

4

. 5 Toxicity Endpoint and Point of Departure Selections

........................ . ........................... 15

4.5.1 Dose-Response Assessment

.... . ... .. .. .. .. ...... .. .. .. .. .. ... . ... .. .. .. .. .. .. .. ... .. .. .. ... .. .. ... .. .. ... .. ... 15

4

. 5.2 Recommendation for Combining Routes of Exposures for Risk Assessment..

...... 16

4.5.3 Cancer Classification and Risk Assessment Recommendation

....... ... .. ... ... . ........... 16

4

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

Assessment

..................... .. . . ...... .. .. .. ... . .. .. .. .. .. .. .. .. .. . ... . ... .. .. .. ... . ... . ... ...... .................................. 17
5.0 Dietary Exposure and Risk Assessment

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

5.1 Metabolite / Degradate Residue Profile

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

5.1.1 Summary of Plant and Animal Metabolism Studies

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

5 .1.2 Summary of Environmental Degradation

............................................................... 19
5.1.3 Comparison of Metabolic Pathways

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

5.1.4 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

.................... . ........................................ .. .. .. ................................... 21
5 .3 Water Residue Profile

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

5.4 Dietary Risk Assessment..

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

5.4. l Description of Residue Data Used in Dietary Assessment..

....... ...... ............ .. ... .. ... 23
5.4.2 Acute Dietary Risk Assessment..

................................................ . ........................... 23
5.4.3 Chronic Dietary Risk Assessment

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

5.4.4 Summary Table

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

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Residential Handler Exposure

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

Page 2 of 48

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 3 of 48 6.2 Post

- Application Exposure

................................ ................................ ............................. 25
6.3 Residential Risk Estimates for Use in Aggregate Assessment

................................ ...... 27
6.4 Residential Bystander Post

- Application Inhalation Exposure

................................ ....... 27
6.5 Spray Drift

................................ ................................ ................................ ...................... 28
7.0 Aggregat e Exposure/Risk Characterization

................................ ................................ ....... 28
7.1 Acute Aggregate Risk

................................ ................................ ................................ .... 28
7.2 Short

- Term Aggregate Risk

................................ ................................ ........................... 29
7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ................ 29
7.4 Chronic Aggregate Risk

................................ ................................ ................................ . 29
7.5 Cancer Aggregate Risk

................................ ................................ ................................ ... 29
8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 30
9.0 Occupational Exposure/Risk Characterization

................................ ................................ .. 30
9.1 Short

- and Intermediate

- Term Handler Risk

................................ ................................ .. 30
9.2 Short

- and Intermediate

- Term Post

- Application Risk

................................ ................... 31
9.2.1 Dermal Post

- Application Risk

................................ ................................ ................ 32
9.2.2 Restricted Entry Interval

................................ ................................ ......................... 32
9.2.3 Inhalation Post

- Application Risk

................................ ................................ ............ 32
10.0 References

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

................................ .................... 34
A.1 Toxicology Data Requirements

................................ ................................ ...................... 34
A.2 Toxicity Profiles

................................ ................................ ................................ ............. 35 Appendix B. Isofetamid Metabolite Profile

................................ ................................ .............. 38
B.1 Isofetamid Metabolites Summary Table

................................ ................................ ........ 38
B.2 Tabular Summary of Isofetamid Metabolites and Degradates

................................ ...... 39 Appendix C. Physical/Chemical Properties

................................ ................................ .............. 46 Appendix D. Review of Human Research

................................ ................................ ................ 46 Appendix E. Occupational Exposure/Risk Summary Tables

................................ ................... 47

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 4 of 48 1.0 Executive Summary

Isofetamid i s a new broad spectrum fungicide currently undergoing joint review with the Pesticide Management Regulatory Agency (PMRA) in Canada

. It is a systemic f ungicide belonging to the thiophen e class of chemistry. Isofetamid is a phenyl

- oxo

- ethyl thiophene amide that acts as a succinate dehydrogenase inhibitor (SDHI) , which causes adverse effects o n plant and fungi respiration

.

Proposed Use Profile Isofetamid has been developed by ISK Biosciences Corporation (ISK), with a proposal for one technical product and two end

- use product (EP) registrations in the United States (PP#3F8142). The proposed uses include agricultural food

- uses and commercial/resi dential turf uses. The

ag ricultural uses include foliar treatment to various crops including almonds, berries, grapes, lettuce, and oilseeds

.

Exposure Profile Exposure pathways for isofetamid include residential, dietary (food and drinking water), and

oc cupational sources. Non

- occupational e xposures to isofetamid a re expected for short

- and
intermediate

- term durations based on the persistence of isofetamid

. Dietary exposures are also expected for chronic duration. Occupational exposures are expected for short

- and intermediate

term durations only. The dermal route of exposure is not assessed because a dermal hazard was not identified

. The proposed residential u se s on turf result in inhalation exposures for adults ( handlers ) and post

- application inci dental oral exposure s for children (1 to <2 years old)

.

Toxicity/Hazard
The risk assessment for isofetamid is based on a well

- characterized an d complete toxicology
database. In repeated dose studies, the liver was the primary target organ in the rat, mouse, and dog, as indicated by increased liver weights, changes in the clinical chemistry values, and liver hypertrophy. A second target organ was the thyroid in the rat and dog , as indicated by changes in thyroid weights and histopathology. Adrenal weight changes were observed in the subchronic

rat and dog studies. In the rat and dog, the dose levels where toxicity was observed were similar or higher in the chronic studies com pared with the respective subchronic studies, showing an absence of progression of liver toxicity with time. There was no evidence of carcinogenicity in the rat or mouse cancer studies; the mutagenicity battery was negative. There are no genotoxicity, ne urotoxicity, or immunotoxicity concerns observed in the available toxicity
studies

. Developmental toxicity was not observed in the rat or rabbit, and offspring effects such as decreased body weight were seen only in the presence of parental toxicity in th e multi

generation rat study

. Therefore, the data support a reduction of the Food Quality Protection Act (FQPA) safety factor to 1X. The level of concern (LOC) for all durations and routes of exposure
is 100. Isofetamid is classified as “ Not Likely to be Carcinogenic to Humans” based on the absence of increased tumor incidence in acceptable/guideline carcinogenicity studies in rats and
mice. Isofetamid is not acutely toxic; it is classified as Toxicity Category III for acute oral and dermal exposure, and Toxicity Category IV for inhalation exposure. Furthermore, it is not irritating to the eye or skin, and it is not a dermal sensitizer.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 5 of 48 Dietary Exposure (Food and Water) and Risk Estimates An acute dietary assessment was not conducted because t here was no indication of an adverse effect attributable to a single dose

. A partially refined chronic dietary (food and drinking water)
assessment was conducted for all proposed crops, assuming average residues and 100% crop treated (CT). Empirical and default processing factors were used as available. The e stimated drinking water concentration (EDWC) of 110 μ g/L was incorporated directly into the chronic dietary assessment

. The results of the chronic dietary (food an d drinking water) analysis are not
of conce rn for the general U.S. population and all population subgroups. The chronic dietary (food and drinking water) exposure is estimated at <1 % of the chronic Population Adjusted Dose (cPAD) for the general U.S. population and <1 % of the cPAD for children 1

- 2 years old, the population subgroup with the highest estimated chronic dietary exposure to isofetamid

.

Residential Exposure and Risk Estimates Residential exposure may occur by the dermal, oral, and inhalation routes of exposures. The proposed uses do not result in residential handler inhalation (adults) or post

- application incidental oral (children) risk estimates o f concern (LOC = 100)

. T he s hort

- term residential
handler inhalation margins of exposure ( MOEs ) range from 850,000 to 18, 000,000

. Short

- term incidental oral p ost

- application risk estimates for all scenarios are not of concern to HED (MOEs range from 5 ,900 to 4,000,000). Intermediate

- term incidental oral post

- application exposures are possible (i.e. from soil ingestion due to the persistence of isofetamid ); however, the short

- term incidental oral exposures are protective of the possible intermediate

- term incidental oral exposures because the point of departure ( POD ) for both durations is the same. Post

- application
inhalatio n exposure is expected to be negligible for the proposed residential uses.

Residential Aggregate Exposure Risk Estimates There is potential for short

- term aggregate exposure to isofetamid via the dietary and residential pathways

. Since dietary, incidental oral

, and inhalation endpoints are based on the same effects, these routes of exposure may be combined for aggregate risk assessment. The d ermal route of

exposure was not assessed because there is no dermal hazard

. For adults and children, the short

term aggregate risk estimate s are not of concern; the MOE s are 2 4,000 and 3,9 00, respectively (LOC = 100 )

. The short

- term incidental oral exposures are protective of the possible
intermediate

- term incidental oral exposures because the POD for both durations is the same.

Occupational Exposure and Risk Estimates Occupational handler and post

- application exposure may occur by the dermal and inhalation routes of exposure only. Since a dermal hazard was not identified , only inhalation exposures

were qu antitatively assessed. The results of the occupational handler exposure and risk

assessment indicate that short

- and intermediate

- term inhalation risk estimate s are not of concern
at baseline (long

- sleeved shirt, long pants, shoes plus socks) without mitigation from any personal protective equipment ( PPE)

. Both l abels require PPE of chemical

- resistant gloves. The proposed level of clothing and PPE are adequate for protection of workers. Short

- and
interme diate

- term inhalation MOEs range from 24,000 to 8,500,0 00 (LOC = 100)

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

- cancer occupational post

- application inhalation exposure assessment was not performed for isofetamid at this time. Furthermore, t he proposed

12

- hour REI is adequate to protect agricultural workers from potential post

- application risks

.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 6 of 48 Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

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

2.0 HED Recommendations

HED has examined the toxicology, residue chemistry , and exposure database s for isofetamid

. The databases are complete and there are no label recommendations for ISK. Provided Section F (tolerances) is revised

, there are no data deficiencies that would preclude granting Section 3 registration for the requested uses of isofetamid, or establishment of tolerances for residues of
isofetamid. The spec ific tolerance recommendation s are discussed in Section 2.2.

2.1 Data Deficienc ies

The re are no data deficiencies to prevent establishing a tolerance or allowing registration.

Data That May Be Required For Future Uses

For future uses on cereal grains or other crops dissimilar to beans, grapes, and lettuce, additional metabolism studies may be required.

Future uses involving livestock feedstuffs with quantifiable residues in livestock commodities would require a livestock enforcement method and livestock feeding stu dies.

Any future ruminant feeding studies should include analysis for parent and the metabolite known

as PPA (see Appendix B for detailed description)

.

If additional field rotational crop studies are conducted because higher application rates or
shorter plant

- back intervals ( PBIs ) are proposed, the petitioner should determine parent, GPTC (metabolite , see Appendix B ) , and malonyl

- GPTC (metabolite , see Appendix B ) in the rotational

crops.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The liquid chromatography with tand em mass spectrometry ( LC

- MS/MS) method ( Document Number JSM0119; MRID 49011967 ) is acceptable as an enforcement method for determination
of isofetamid in plant matrices. In brief, isofetamid and the metabol ite GPTC in cr op samples were extracted by homogenization in acetonitrile/water (80/20, v/v) or in acetone (for oilseed sample only)

. The extracts were analyzed by LC

- MS/MS

. The method limit of quantitation ( LOQ ) for each analyte was 0.010 ppm (0.0075 ppm for GPTC exp ressed as isofetamid equivalents) . A livestock enforcement method is not req uired since livestock tolerances have not been recommended. Multiresidue methods testing data have been submitted for isofetamid and

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 7 of 48 GPTC. The data indicate that m ultiresidue methods are not suitable for analysis of isofetamid and GPTC, so the multiresidue methods cannot serve as enforcement methods. The multiresidue
data have been sent to FDA.

2.2. 2 Recommended Tolerances

ISK proposed the establishment of tolera nces for residues of the fungicide isofetamid including its metabolites and degradates, in or on the raw agricultural commodities (RACs) shown in Table
2.2.2 below. A compliance statement was not included as per the S

. Knizner memo dated
5/27/ 20 09. A rev ised Section F is needed to propose tolerances as recommended in Table 2.2.2 and to state the following: “ Tolerances are established for residues of the fungicide isofetamid, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only isofetamid, N

- [1,1

- dimethyl

- 2

- [2

- methyl

- 4

- (1

- methylethoxy)phenyl]

- 2

- oxoethyl]

- 3

- methyl

- 2

- thiophenecarboxamide , in or on the commodity. ”

Table 2.2.2 Tolerance Summary for Isofetamid

Commodity Proposed
Tolerance Recommended

Tolerance Comments

Correct Commodity Definition ppm ppm

Almond 0.02 0.01

Almond, hulls 0.2 0.01

Canola, refined oil none 0.03

Flax

, seed, oil none 0.03
Grape, raisin none 5.0

Lettuce, head 6.0 5.0

Lettuce, leaf 7.0 7.0
Low Growing Berry Crop Subgroup 13

- 7G 4.0 4.0 Berry, low growing, subgroup 13

- 07G

Mustard

, seed, oil none 0.03
Rapeseed, Crop Subgroup 20A 0.04 0.015 Rapeseed subgroup 20A

Sesame, oil none 0.03
Small Fruit Vine Climbing Crop Subgroup 13

- 7F 3.0 3.0 Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F



### 2.2. 3 Revisions to Petitioned

- For Tolerances

HED recommend s revisions to some of the petitioned

- for tolerance levels based on the following reasons: (1) O rganization for Economic Cooperation and Development (OECD) t olerance calculation procedures; (2) the ROCKS decision that parent only is the residue of concern for primary crop toleran ces rather than p arent and GPTC; and (3) concentration of residues in two processed commodities.

Since all residues of isofetamid (parent) were nondetectable (<0.01 ppm) in almond nutmeat and hulls, the proposed tolerances of 0.02 ppm for almond (nutmeat) and 0.2 ppm for almond hulls should both be reduced to 0.01 ppm , the limit of quantitation of the analytical method

.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 8 of 48 Based on the OECD tolerance calculation procedures, the proposed tolerance for head lettuce of
6.0 ppm should be reduced to 5.0 ppm.

Based on the OECD to lerance calculation procedures, the proposed tolerance for the rapeseed subgroup 20A of 0.04 ppm should be reduced to 0.015 ppm.

The petitioner did not propose tolerances for the processed commodities, canola oil and raisins.
Since residues concentrate s ignificantly in canola oil and raisins, tolerances should be proposed at 0.03 ppm for canola, refined oil

, and 5.0 ppm for grape, raisin . These HED recommendations are based on the highest average field trial (HAFT) residues for canola seed and grape and the processing factors for canola oil and raisins.

The petitioner did not propose tolerances for flaxseed oil, mustard seed oil, or sesame oil. Flaxseed, mustard seed, and sesame are members of the rapeseed subgroup 20A, with canola as the representative crop. Sesame oil and refined c anola oil are included as processed commodities in Table 1 of OCSPP 860.1000; mustard seed oil and flaxseed oil are not included in Table 1. However, HED is recommending for tolerances on flaxseed oil, mustard seed oil,
and sesame oil. Tolerances should be proposed at 0.03 ppm, the same as for refined canola oil.
These tolerances will harmonize with Canada.

2.2. 4 International Harmonization

Canadian, Mexican, or Codex maximum residue limits (MRLs) are not established

. Canada is concurrently establishing tolerances for all of the same commodities proposed for the US except
almond hulls because Canada does not set tolerances on livestock feed commodities . Canada’s
recommended tolerance levels for these commodities are th e same as the US

- recommended
tolerance levels. The tolerance expression for the US and Canada is the same, with isofetamid as the residue of concern for primary crops.

3.0 In troduction

Isofetamid is a systemic, broad

- spectrum thiophene fungicide. It ac ts as a succinate dehydrogenase inhibitor (SDHI) , adversely affecting respiration in plants and fungi. I sofetamid
is effective against brown rot blossom blight ( Monilinia spp .), anthracnose ( Colletotrichum spp .), gray mold and bunch rot ( Botrytis cinerea ) , shot hole ( Wilsonomyces carpophilus ), Sclerotinia ( Sclerotinia spp .), and powdery mildew ( Erysiphe necator and Podosphaera aphanis ) in a variety of crops.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 9 of 48 3.1 Chemical Identity

Table 3.1 Test Compound Nomenclature

Chemical Structure

Common Name isofetamid
Company E xperimental Na me IKF

- 5411
Molecular Weight 359.49 g/mol

IUPAC Name N

- [1,1

- dimethyl

- 2

- (4

- isopropoxy

- o

- tolyl)

- 2

- oxoethyl]

- 3

- methylthiophene

- 2

- carboxamide

CAS Name N

- [1,1

- dimethyl

- 2

- [2

- methyl

- 4

- (1

- methylethoxy)phenyl]

- 2

- oxoethyl]

- 3

- methyl

- 2

- thiophenecarboxamide CAS Registry Number 875915

- 78

- 9

End

- Use Product/EP Isofetamid 400SC Fungicide (EPA Reg. No. 71512

- EE); 3.34 lb ai/gal (400 g ai/L) suspension concentrate

Ch emical Class thiophene
Known Impurities of Concern none

Chemical Structure

Common Name GPTC
Molecular Weight 479.55 g/mol

Chemical Name N

- [l,l

- dimethyl

- 2

- (4

- β

- D

- glucopyranosyloxy

- 2

- methylphenyl)

- 2

- oxoethyl]

- 3

- methyl

- 2

- thiophenecarboxamide



### 3.2 Physical/Chemical Characteristics

The physicochemical properties of the technical grade of isofetamid are summarized in

A ppendix C

. Isofetamid is a solid and b ased on its low vapor pressure ( 3.15×10

- 9 

### mm Hg a t 25°C) and its Henry’s Law con stant ( 1. 2 × 10

- 5 

### Pa

· m 3 

### /mol at 20°C), isofetamid is unlikely to volatilize significa ntly

. Isofetamid is stable to hydrolysis and soil photolysis, very persistent in
anaerobic environments

, and is soluble in water ( 5.33 g/L) which suggests persistence in ground

water. The log of the octanol/water partition coefficient is 2.5, which indicates lesser concern for
bioaccumulat ion in fatty tissue or milk fat . The low octanol/water coefficient also suggests low potential for dermal absorption.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 10 of 48 3.3 Pesticide Use Pattern

Is ofetamid has been developed by ISK , with a proposal for one t echnical product and two US EP registrations, which include agricultural food

- uses. The only proposed formulation is an SC. The agricultural use s consist of broadcast foliar sprays via ground, aerial, or chemigation equipment ; and th e proposed resi dential use include s turfgrass

. A detailed summary of all the proposed use pattern is summarized in Table 3.3

.

Table 3.3 Summary of Proposed Directions for Use of Isofetamid

Application Timing, Type, and Equipment Formulation

[EPA Reg. No.]
Trade Name a Maximum

Application

Rate Max. No.

of Apps per
Season Max.

Seasonal Application

Rate RTI c
Use Directions and Limitations d

days

Almond

Foliar (ground, aerial, chemigation) 36.0% SC

[71512

- EE ]
Isofetamid
400SC Agricultural Fungicide

3.33 lb ai/gal 17 fl oz/A

0.442 lb
ai/A

0.0442 lb ai/gal 4 68 fl oz/A 7

- 14 Spray volume will usually range from 20 to 100 gallons per acre for dilute sprays, and 5 to 10 gallons per acre for concentrate ground and aerial sprays. Do not make more than 2 sequential applications of Isofetamid 400SC before rotating to a fungicide with a different mode of action. Do not apply after first cover. The PHI is not specified.

Lettuce (Head and Leaf)

Foliar (ground, aerial, chemigation) 36.0% SC

[71512

- EE ]
Isofetamid
400SC Agricultural Fungicide

3.33 lb ai/gal 12.3 fl

oz/A

0.320 lb
ai/A

0.0320 lb ai/gal 2 24.6 fl
oz/A 14 Spray volume will usually range from 20 to 100

gallons per acre for dilute sprays, and 5 to 10 gallons per acre for concentrate ground and aerial sprays. Do not make more than 2 sequential applications of Isofetamid 400SC before rotating to a fungicide with a different mode of action. The PHI is 14 days.

Fruit, Small Vine Climbing, except Fuzzy Kiwifruit, Subgroup 13

- 07F (including Amur river grape; gooseberry; grape; kiwifruit, hardy; maypop; schisandra berry; and cultivars, varieties and/or h ybrids of these)

Foliar (ground, aerial, chemigation) 36.0% SC

[71512

- EE ]
Isofetamid
400SC Agricultural Fungicide

3.33 lb ai/gal 22 fl oz/A

0.572 lb
ai/A

lb ai/gal 3 66 fl oz/A 7

- 14 Spray volume will usually range from 20 to 100 gallons per acre for dilute sprays, and 5 to 10 gallons per acre for concentrate ground and aerial sprays. Do not make more than 2 sequential applications of Isofetamid 400SC before rotating to a fungicide with a different mode of action. The PHI is 14 days.

Berry, Low Growing, Subgroup 13

- 07G (includes bearberry; bilberry; blueberry, lowbush; cloudberry; cranberry; lingonber ry; muntries; partridgeberry; strawberry; and cultivars, varieties, and/or hybrids of these)

Foliar (ground, aerial, chemigation) 36.0% SC

[71512

- EE ]
Isofetamid
400SC Agricultural Fungicide

3.33 lb ai/gal 17 fl oz/A

0.442 lb
ai/A

0.0442 lb ai/gal 5 87.5 fl
oz/A e 7

- 14 Spray volume will usually range from 20 to 100

gallons per acre for dilute sprays, and 5 to 10 gallons per acre for concentrate ground and aerial sprays. Do not make more than 2 sequential applications of Isofetamid 400SC before rotating to a fungicide with a different mode of action. The PHI is 0 days.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 11 of 48 Table 3.3 Summary of Proposed Directions for Use of Isofetamid

Application Timing, Type, and Equipment Formulation

[EPA Reg. No.]
Trade Name a Maximum

Application

Rate Max. No.

of Apps per
Season Max.

Seasonal Application

Rate RTI c
Use Directions and Limitations d

days

Rapeseed, Subgroup 20A (includes borage; carambe; cuphea; echium; flax seed; gold of pleasure; hare’s ear mustard; lesquerella; lunaria; meadowfarm; milkweed; mustard seed; oil r adish; poppy seed; rapeseed ( Brassica napus

, B. campestris , and Crambe abyssinica (oilseed

- producing varieties only

which include canola and crambe)); sesame; sweet rocket; and cultivars varieties, and/or hybrids of these)

Foliar (ground, aerial, chemigation) 36.0% SC

[71512

- EE ]
Isofetamid
400SC Agricultural Fungicide

3.33 lb ai/gal 12 fl oz/A

0.312 lb
ai/A 2 24 fl oz/A 14 Spray volume will usually range from 20 to 100 gallons per acre for dilute sprays, and 5 to 10 gallons per acre for concentra te ground and aerial sprays. Do not make more than 2 sequential applications of Isofetamid 400SC before rotating to a fungicide with a different mode of action. The PHI is not specified.

Turfgrass (including golf courses, sod farms, seed farms, college and professional sports fields, residential and commercial lawns )

Foliar (ground only) 36.0% SC

[ 71512

- EG ]
Isofetamid Turf Fungicide

3.33 lb ai/gal 21.8 fl oz/A

0.5
fl oz /1000 sq ft

0.567
lb ai/A

0.0000130
lb ai/1000 sq ft

0.00650 lb ai/gal 8 140 fl oz/A e

3.2 fl oz /1000 sq ft 14 Isofetamid may be applied with all types of spray

equipment normally used for ground applications on turfgrasses . Do not apply isofetamid through any type of irrigation system. Do not apply isofetamid by aerial application. Do not apply more than two consecutive applications of isofetamid. Subsequent applications should be alternated with another registered fung icide with a
different mode of action.

a Formulation code: SC = suspension concentrate.
b Based on the label for Reg. No. 71512

- EG, the most concentrated dilution spray volume is 25 fl oz of Isofetamid Turf Fungicide per 100 gallons of spray solution.

c RTI = retreatment interval.
d PHI = pre

- harvest interval. The plant

- back interval (PBI) restriction for rotational crops is 30 days for crops not registered on the label.

e The maximum seasonal application rates for low growing berries and turfgrass are n ot consistent with the single maximum application rate multiplied by the maximum number of applications per season. The label must reflect the proper use rates (i.e. 85 fl oz/A for low growing berries and 174.4 for turfgrass).



### 3.4 Anticipated Exposure Pathways

H umans may be exposed to isofetamid in food and drinking water because isofetamid may be applied directly to growing crops

, and application may result in isofetamid reaching surface and ground sources of drinking water. There are also residentia l uses of isofetamid , 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 potential for post

- application exposure for workers re

- entering treated fields.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 12 of 48 This is the first aggregate risk assessment prepared for the p roposed uses of isofetamid . This risk assessment considers all of the exposure pathways based on the propo sed new uses of
isofetamid

.

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 Ac tions to Address Environmental Justice in Minority Populations and Low

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

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

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food an d water consumption, and activities in and around the home that involve pesticide use in a residential setting.
Extensive data on food co nsumption patterns are compiled by the USDA under the National Health and Nutrition Examination Survey / What We Eat in America ( NHANES/WWEIA), and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region 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 pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of

spec ialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Isofetamid belongs to the thiophene class of pesticides , which act as SDHIs and adversely affect respiration in plants and fungi. There are no mammalian molecular data to specifically show this mode of action in the test animals; however, effects such as decreased body weight, food

consump tion, and food efficiency are frequently found in test animals treated with compounds which disrupt mitochondria respiration with the subsequent disruption of energy production, and similar effects are also demonstrated in isofetamid treated animals at hig her dose levels.

4.1 Toxicology Studies Available for Analysis

All of the required toxicity studies have been submitted to support the proposed food

- use registrations for isofetamid and the potential exposure scenarios associated with this action

. The available toxicology database is sufficient to characterize the hazard of isofetamid. Available repeated dose studies include oral subchronic and chronic studies in rat s and dog s , oral carcinogenicity studies in the rat s and mic e, o ral developmental studies in rat s and rabbit s , a mutagenicity battery, a neurotoxic ity battery in r at s , an immunotoxicity study in mic e, and a dermal subchronic study in rat s. Also available are a battery of in vitro dermal penetration
studies in rat and human skin and an in vivo dermal penetration study in rat s

. Furthermore, rat

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 13 of 48 metabolism studies a re available. A subchronic inhalation study w as not included in the database, but the requirement has been waived (HASPOC memo, J. Leshin, TXR0057008

, 08/11/2014 )

.

4.2 Absor ption, Distribution, Metabolism, & Elimination (ADME)

In a standard series of ADME tests with single and multiple gavage dosing at various dose levels, isofetamid was readily absorbed, with up to 93% of the radioactivity eliminated in bile and urine at the low dose. Maximum plasma concentrations were achieved 2

- 6 hours post dosing at the low dose, and about 8 hours at the high dose. Plasma elimi nation half

- lives were
about 38 hours regard less of dose, sex

, or radiolabel position. Distribution studies showed the radiolabel did not accumulate in any of the tissues. The single and repeat dose elimination
studies showed a sex

- related difference between male and female rat s . Males, regardles s of dose, eliminated most of the radiolabel in the feces while females eliminated approximately five
time s more rad iolabel in the urine than males . Elimination was rapid in both sexes with the majority of the radiolabel recovered with in 96 hours of treat ment. Repeated dosing had little
effect on the route or ra te of elimination, suggesting lack of induction or inhibition of metabolizing enzymes. Biliary excretion was the major route of elimin ation for males and
females . However, greater urinary excreti on of metabolites was seen in females than males

, suggesting reabsorption of biliary metabolites in females . Little or no radiolabel was recovered in expired air. Isofetamid underwent extensive metabolism following oral administration with no qualitative sex or radiolabel differences in metabolism. The test material was rapidly metabolized by three main routes; O

- dealkylation, hydroxylation, and subsequent glucuronidation. Minor routes included methylation, sulfation and cleavage between the
benzene and thiophene

- ring

.

Dermal Absorption Available dermal absorption studies included in vitro human and rat penetration data, and in vivo

rat penetration data. The total absorbable dose at 24 hours from each in vitro study ( 23.1% for the rat study and 23.6% for the human study ) were compared, resulting in a ratio of essentially
1:1. This indicated that the values derived from the in vivo rat study require no adjustment in the calculation of a dermal absorption factor (DAF) for risk assessment. The DAF of 8% was derived from the low

- dose of the in vivo rat study, adding together the radioactivity found in excreta, tissues and stratum corneum at 24 hours

.

4.3 Toxicological Effects

In repeated dose studies, the liver was the primary target organ in the r at, mouse , and dog; as indicated by increased liver weights, changes in the clinical chemistry values, and liver hypertrophy. A second target organ was the thyroid in the rat and dog, as indicated by changes in thyro id weights and histopathology. Further more, a drenal weight changes were observed in
the subchronic rat and dog studies. In the rat and dog, the dose levels where toxicity was observed were similar or higher in the chronic studies compared with the respective subchronic studies, showing an abs ence of progression of liver toxicity with time. There was no evidence of
liver tumors in the rat cancer study , further supporting the absence of progression of liver

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 14 of 48 toxicity

. T he mutagenicity battery was negative , and there was no evidence of carcinoge nicity of any type in the rat and mouse cancer studies.

Developmental toxicity was not seen in the rat or rabbit. Decreased offspring body weight and decreased body weight gain was observed in both sexes and generations in the multi

- generation reproduc tion study in the presence of parental toxicity. The immunotoxicity study in the mouse

was neg ative. N eurotoxic effects were not observed in any toxicity study including the neurotoxicity battery.

In acute studies, isofetamid is categorized as Toxicity Category III following oral and dermal exposure, and Toxicity Category IV following inhalation exposure; it is not irritating to the eye or skin (Toxicity Category IV) and is not a dermal sensitizer.

4.4 Safety F actor for Infants and Children (FQPA Safe ty Factor)

Based on the currently available toxicity and exposure data, the risk assessment team
recommend s that the FQPA Safety Factor be reduced to 1X for the following reasons: there is a complete toxicity database for isofetamid, t here is no evidence of developmental toxicity or reproductive susceptibility

, and there are no residual uncertainties concerning pre

- or post

- natal toxicity or exposure . Acute and subchronic neurotoxicity studies are available, and did not demonstrate any neurotoxic effects. The dietary and residential assessments are based on reliable data and will not underestimate exposure. The details for reducing the FQPA safety
factor to 1X are described further below.

4.4 .1 Completeness o f the Toxicology Database

The isofetamid tox icology database for FQPA assessment is considered complete and includes developmental toxicity studies, a multi

- generation reproduction study, an acute and subchronic neurotoxicity battery

, and an immunotoxicity study

. A subchronic inhalation study was n ot included in the database, but the requirement has been waived (HASPOC memo, J. Leshin,
TXR0057008 , 08/11/2014 ). Although isofetamid produce d adverse effects on the thyroid in the rat and dog, an assay to detect and measure the potential for isofetamid in the developing offspring is not indicated because of the following reasons: 1) thyroid toxicity (follicular cell hypertrophy) occurred only in the presence of liver toxicity (hepatocellular hypertrophy) in all cases, as well as other adverse effects suc h as decrease spleen weight, changes in clinical chemistry, or the presence of eosinophilic inclusion bodies ; and 2) there was no evidence of developmental toxicity or susceptibility in the developmental or reproduction studies (see
detailed discussion in Section 4.4.3)

.

4.4.2 Evidence of N eurotoxicity

In all of the available studies, t here are no indications that the nervous system is a targ et for
isofetamid

. Effects attributed to neurotoxicity were not observed in the acute or subchronic neurotoxicity studies up to the limit dose, nor in any other studies in the database. Therefore, there are no neurotoxicity concerns for adults or the developing offspring a nd a developmental neurotoxicity study is not required

.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 15 of 48 4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

T here are no residual uncertainties regarding increased susceptibility. I n the rat and rabbit developmental stud ies, t here were no indications of toxicity in the dam s or fetus es up to the limit
dose . In the rat reproduction study, the offspring effect s (decreased pup body weight in both generations and sexes ) o nly o ccurred in the presence of parental toxicity (liver and thyroid histopathology, and decreased spleen weights in males). Clear NOAELs and LOAELs are available for all parental and offspring effects

.

4.4.4 Residual Uncertainty in the Exposure Database

Potential exposures are not underestimated . The chronic dietary food exposure assessment was conservatively based on 100% crop treated (CT) assumptions

, and conservative ground drinking water modeling estimates. The most up

- to

- date Residential SOPs (2012) we re used to assess
post

- application exposure to childr en including incidental oral exposure. The residential post

application assessment assumes that maximum application rates are applied and that ha nd

- to

mouth activities occur on the day of application . All of the exposure esti mates are based on
conservati ve, health

- protective assumptions and are not likely to underestimate risk.

4.5 Toxicity Endpoint and Point of D eparture Selections

The toxicity e ndpoints and PODs are summarized in Tables 4.5.4a and 4.5.4b, and detailed rationale for the selections is p resented in Appendix A, Section A.3.

4.5.1 Dose

- Response Assessment

For acute dietary exposure (all populations)

, an adverse effect attributable to a single dose was not identified in the available toxicity database. Therefore, acute risk was not quanti fied

.

The chronic dietary endpoint was chosen from the rat multi

- generation reproduction study (MRID 49011940)

. T he NOAEL of 7 6.6 mg/kg/day was used as the POD, with the LOAEL of 679/775 mg/kg/day based on hepatocellular hypertrophy in the liver and follicular cell hypertrophy in the thyroid in both sexes and generations, decreased spleen weights and cytoplasmic eosinophilic in clusion bodies in the liver of F1 males , and decreased pup body weight in both sexes and generations

. This study was chosen be cause the dosing period is appropriate for long

- term exposure scenarios, the study protocol covers all populations, and because the POD is protective of all adverse effects seen in other toxicity studies in the database.

For the incidental oral endpoints (both short

- and intermediate

- term), the population of concern is infants and children, and the multi

- generation reproduction study was chosen because dosing regimens include young offspring treated during the appropriate exposure duration (1

- 30 days
and 1

- 6 months) of concern. The NOAEL is 76.6 mg/kg/day and the LOAEL is 679 mg/kg/d ay based on hepatocellular hypertrophy in the liver and follicular cell hypertrophy in the thyroid in both sexes and generations, decreased spleen weights and cytoplasmic eosin ophilic in clusion
bodies in the liver of F1 males , and decreased pup body weight in both sexes and generations

.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 16 of 48 Dermal endpoints (both short

- and intermediate

- term) were not selected for the following

reasons: 1) there were no systemic effects noted in a dermal subchronic study up to the limit dose of 1000 mg/kg/day; 2) there are no concerns that developmental toxicity, neurotoxicity or immunotoxicity could potentially occur by the dermal route because there is no concern for these
effects via oral exposure, and a DAF of 8% present s an even lower level of concern . Similarly, offspring effects (decreased body weights) seen in the multi

- generation reproduction study at 679 mg/kg/day are not expected to be observed by the dermal route at dose levels be low the limit
dose because of the low DAF

. There are no long

- term dermal scenarios anticipated for this risk

assessment.

An inhalation study is not included in the available database so inhalation endpoints for occupational and residential exposures were derived from oral studies. For short

- and intermediate inhalation scenarios, the NOAEL of 76.6 mg/kg/day was used as the POD from a
multi

- generation reproduction rat study, with the LOAEL of 679/775 mg/kg/day (males/females)
based on microscopic changes in the liver and thyroid in both sexes and generations and decreased spleen weights in F 1 

### males, and decreased pup body weight in both sexes and generations

. This study was chosen because the duration is appropriate for short

- and
intermediate

- term exposu re scenarios, and the POD is protective of all adverse effects seen in other toxicity studies in the database. There are no long

- term inhalation scenarios anticipated for
this risk assessment.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

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

HED aggregates exposure from different routes for each population if the same toxic effects are seen for that duration of exposure by each ro ute. Since oral and inhalation endpoints are taken from the same oral study ( i.e. microscopic changes in the liver and thyroid in both sexes and generations and decreased spleen weights in F 1 

### males, and decreased pup body weight in both
sexes and generations ), these routes of exposure were combined for residential exposure risk

assessment. For both the residential and occupational exposure scenarios the dermal route of

exposure was not aggregated with oral or inhalation routes because there a derm al endpoint was
not identified.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Isofetamid is classified as “ Not L ikely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate rodent carcinogenicit y studies.

Isofetamid did not produce a significant increase in tumors in a two

- year rat carcinogenicity study at dosages up to the limit dose. In an 18

- month mouse carcinogenicity study, no tumors were noted at dose levels up to 502 mg/kg/day, or 1⁄2 the limit dose. Based on 870.4200b guidelines, dosing would generally not be considered adequate to assess carcinogenic potential because a LOAEL was not demonstrated, and dose levels use d in the study did not reach the limit dose of 1000 mg/kg bw/day. Howev er, this study is considered adequate to assess carcinogenicity potential for risk assessment of the following reasons : 1) toxicity was not seen

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 17 of 48 either in the 18

- month mouse carcinogenicity up to one

- half the limit dose, nor in the 13

- week

mouse oral subchronic study up to the limit dose; 2) the toxicity profile of isofetamid in the rat and dog also demonstrates it has low toxicity , often failing to produce significant overt effects (such as body weight decrements or clinical signs) or other adver se effects at levels up to the limit dose; 3) there was no evidence of carcinogenicity in the rat chronic/carcinogenicity study at
othe rwise toxic dose levels; and 4) any effects seen in a repeat mouse carcinogenicity study at levels greater than the curre nt NOAEL of 502 mg/kg/day are expected to be protected against by
the Chronic RfD for isofetamid of 0. 77 mg/kg/day (based on microscopic changes in the liver and thyroid in both sexes and generations and decreased spleen weights in F 1 

### males, and
decreased pup body weight in both sexes and generations at the LOAEL in a multi

- generation reproduction study )

.

4. 5

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

Table 4.5.4a Summary of Toxicological Do ses and Endpoints for Isofetamid for Use in Non

Occupational /Residential Human Health Risk Assessments a

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD,

Level of
Concern for
Risk

Assessment Study and Toxicological Effects

Acute Dietary (All Populations ) A toxicity endpoint was not identified.

T oxicological effects attributable to a single exposure (dose) were not observed in oral toxicity
studies

.

Chronic Dietary (All Populations) NOAEL =

76.6 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1 X Chronic

RfD = 0.77 mg/kg/day

cPAD =
0.77 mg/kg/day Reproduction and fertility effects (rat)

LOAEL = 679/775 mg/kg/day based on hepatocellular hypertrophy in the liver and follicular cell hypertrophy in the thyroid in both sexes and generations, decreased spleen weights and cytoplasmic eosinophilic inclusion bodies in the liver of F1 males, and decreased pup body weight in
both sex es and generations

. Incidental
Oral b

Short

- T erm (1

- 30 days)
and

I ntermediate

- T erms (1

- 6 months) NOAEL =

76.6 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1 X Residential

LOC for
MOE = 100 Reproduction and fertility effects (rat)

LOAEL = 679/775 mg/kg/day based on hepatocellular hypertrophy in the liver and follicular cell hypertrophy in the thyroid in both sexes and generations, decreased spleen weights and cytoplasmic eosinophilic inclusion bodies in the liver of F1 males, and decreased pup body weight in both sexes and generations

.

Dermal
Short

- Term (1

- 30 days) A toxicity endpoint was not identified

.

S ystemic toxicity was not seen in 2 8

- day dermal toxicity in rats up to the limit dose (1000 mg/kg/day) . T here are no concerns f or developmental or reproductive toxicity or neurotoxicity in
rat and rabbit studies

.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 18 of 48 Table 4.5.4a Summary of Toxicological Do ses and Endpoints for Isofetamid for Use in Non

Occupational /Residential Human Health Risk Assessments a

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD,

Level of
Concern for
Risk

Assessment Study and Toxicological Effects

Inhalation
Short

- Term (1

- 30 days) NOAEL =

76.6 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1 X Residential

LOC for
MOE = 100 Reproduction and fertility effects (rat)

LOAEL = 679/775 mg/kg/day based on hepatocellular hypertrophy in the liver and follicular cell hypertrophy in the thyroid in both sexes and generations, decreased spleen weights and cytoplasmic eosinophilic inclusion bodies in the liver of F1 males, and de creased pup body weight in both sexes and generations

. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant

tumor increases in two adequate rodent carcinogenicity studies.

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.
NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety F actor. LOC = level of concern.
b For Incidental Oral risk assessments, the adult female body weight (69 kg) is used because the toxicity endpoint (decreases i n pup body weight) may have resulted from in utero exposures of the offspring in pregnant dams.

Table 4.5.4b Summary of Toxicolo gical Do ses and Endpoints for Isofetamid for Use in Occupational
Human Health Risk Assessments a

Exposure/
Scenario Point of

Departure Uncertainty/

Safety

Factors RfD, PAD,

Level of
Concern for
Risk

Assessment Study and Toxicological Effects

Dermal
Short

- Term (1

- 30 days) A toxicity endpoint was not identified

.

S ystemic toxicity was not seen in 2 8

- day dermal toxicity in rats up to the limit dose (1000 mg/kg/day) . T here are no concerns for developmental or reproductive toxicity or neurotoxicity in
rat and r abbit studies

.

Inhalation
Short

- Term (1

- 30 days)
and
Intermediate

- Term (1

– 6 months NOAEL =

76.6 mg/kg/day UF A = 10X

UF H = 10 X Residential

LOC for
MOE = 100 Reproduction and fertility effects (rat)

LOAEL = 679/775 mg/kg/day based on hepatocellular hypertrophy in the liver and follicular cell hypertrophy in the thyroid in both sexes and generations, decreased spleen weights and cytoplasmic eosinophilic inclusion bodies in the liver of F1 males, and decreased pup body weight in
both sex es and generations

. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant

tumor increases in two adequate rodent carcinogenicity studies.

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.
NOAEL = no observed adverse effect level. LOAEL = l owest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = database uncertainty factor: use of a short

- term study for intermediate

- term risk assessment. FQPA SF = FQPA Safety F actor. LOC = level of concern.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 19 of 48 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

Metabolism of parent isofetamid results in several metabolites: 4HP, PPA, 3

- MTCAM, IBA, 3

- MTCA, GPTC, malonyl

- GPTC,

- HPPA, and MW

- 209. The chemical names and structures of
each metabolite /degradate are summarized in Appendix B .1

.

5.1.1 Summary of Plant and Animal Metabolism Studies

The plant metabolism studies are adequate to support the proposed uses of isofetamid

. Detailed tabular results of metabolites in various matrices can be found in Appendix B.2. Studies indicate
that metabolism of isofetamid is similar following foliar application to grapes, lettuce, and
French beans. T he metabolic fate of this fung icide is complex with the formation of many low
level metabolites. Numerous metabolites were detected in various crop matrices. In general,
i sof etamid was first metabolized by O

- dealkylation to form 4HP or by cleavage between the benzene and thiop hene rings to form 3

- MTCAM (see Appendix B .1 for structures) . T he metabolite 4HP was further converted by conjugation to form GPTC or by cleavage betwee n the rings to form 3

- MTCAM. In goats and hens, isofetamid was metabolized by carboxylation to form PPA, by O

- dealkylation to form 4HP, and by cleavage of the benzene and thiophene rings to form IBA. In goats, PPA was further metabolized by hydroxylation of the thiophene ring to
form 5

- HPPA. The plant metabolites 3

- MTCAM and IBA are not found in rats.

In the goat study, parent isofetamid was the major residue in mi lk and fat; PPA was the major residue in liver and kidney; and the m inor metabolites were 4HP, 5

- HPPA, IBA, and 3

- MTCAM. Major metabolites were not identified in poultry matrices . M inor residues included 4HP, isofetamid, PPA, IBA, and 3

- MTCAM in egg yolk; 4HP, PPA, isofe tamid, and IBA in poultry
liver ; 4HP in poultry muscle ; and isofetamid and 4HP in poultry fat.

The main metabolic pathway of isofetamid in rotational crops is the O

- dealkylation of isofetamid to yield the metabolite 4HP, which is then conjugated to form the metabolites GPTC and malonyl

- GPTC. Carboxylation o f isofetamid also occurs to result in the metabolite PPA. In addition, cleavage of isofetamid occurs between the benzene and thiophene ring structures
results in the metabolite IBA.

5.1.2 Summary of Environmental Degradation

Since isofetamid is soluble i n water (5.33 mg/L at 20oC) , it may move from treated field s t o surface water through run

- off occurring shortly after app lication (i.e. rain fall events) , and may
also move into ground water . Isofetamid rapidly degrades as a result of aqueous photolysis, a nd degradation is expected to occur as a result of aerobic metabolism in soil and water. However,
l aboratory studies indicate that isofetamid is stable to hydrolysis and soil photolysis, and very persistent in anaerobic environments. No degradation of is ofetamid occurred in the hydrolysis study. The half

- lives for soil photolysis ranged from 294 days for dry soil to 354 days for moist

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 20 of 48 soil. The half

- life calculated for the anaerobic soil metabolism study was 572 days, while the
half

- lives calculated for anaerobic aquatic m etabolism exceeded 1,000 days.

5.1.3 Comparison of Metabolic Pathways

A comparison of the proposed metabolic pathways indicates that the metabolic pathways among plants, livestock, and rotational crops are similar. Noted differences include the following: 1) the carboxylation product PPA was not identified in primary plants

, but was found in rotational crops and livestock; and 2) malonyl

- GPTC (a further conjugate of GPTC) was not identified in primary plants or livestock but was found in rotational crops. P arent isofetamid is the major
residue in most matrices (see Appendix B ) . N ot all plant metabolites are not found in rats (e.g.
3

- MTCAM and IBA).

5.1.4 Residues of Concern Summary and Rationale

Compliance with the recommended tolerance levels is to be determined by measuring only isofetamid, N

- [1,1

- dimethyl

- 2

- [2

- methyl

- 4

- (1

- methylethoxy)phenyl]

- 2

- oxoethyl]

- 3

- methyl

- 2

- thiophenecarboxamide , in or on the commodity. Parent isofetamid was detected as a main
residue in the metaboli sm studies, crop field trials

, and livestock feeding studies. Based on this

, it is considered an appropriate marker for primary crops, rotational crops

, and livestock
commodities

. Residues of concern ( ROC s ) for tolerance enforcement and ri sk assessment f or each matrix , as shown in Table 5.1.4, were recommended by the Residues of Concern and Knowledgebase Subcommittee, and are described below ( DP411110, I. Negrón

- Encarnación,
0 5/21/2014 ):

Primary Crops: Parent isofetamid is recommended as the ROC for tolerance enforcement.
Parent isofetamid was identified as a major residue in most primary crop metabolism studies
and/or crop field trials, and is therefore considered an appro priate marker of misuse. For risk assessment purposes, the ROCs are pare nt isofetamid and GPTC

. GPTC was also observed in the metabolism studies and crop field trials. The crop field trials show that residues of GPTC
in/on almond hulls at harvest are at higher concentrations than parent isofetamid (<0.01 ppm)

. Based on the available metabolism data in the rat, there is a reasonable expectation that the conjugate can be cleaved in vivo , resulting in exposure to parent (or a structurally similar metabolite). Therefore, the toxicity of GPTC is assumed to be similar to parent i sofetamid.

Rotational Crops: As with primary crops, parent isofetamid and GPTC were identified as main components in the confined rotational crop studies. In addition, malonyl

- GPTC was observed as a major residue in most matrices. Because the limited rotational field trials showed that parent isofetamid, GPTC and malonyl

- GPTC were below the LOQ at all PBIs and the registrant is proposing a 30

- day PBI restriction in the label, it is not necessary to define the residues of

concern at this time. If a shorter PBI or higher application rate is pursued by the registrant in the future, a limited rotational field study analyzing for parent isofetamid, GPTC and malonyl

- GPTC in the plant matrices may be needed.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 21 of 48 Processed Commodities: B ased on the isofetamid hydrolysis study which indicated that isofetamid was stable to simulated processing procedures, the ROCs for tolerance enforcement and risk assessment are the same as for the primary crops.

Livestock: F or ruminant commodities, pare nt isofetamid is the only ROC for tolerance enforcement, whereas isofetamid and PPA are the ROCs for risk assessment. Parent isofetamid and PPA were the main residues identified in the lactating goat metabolism study. PPA is
assumed to have similar toxic ity to the parent isofetamid based on structural similarity. For poultry commodities, parent isofetamid is recommended as the only ROC for tolerance enforcement and risk assessment. Although major residues (>10% of the total radioactive
residues ) were no t observed in poultry, parent isofetamid was observed as a minor residue in hen
commodities.

Water: Pa rent isofetamid is the only ROC for risk assessment. Based on structural similarity, PPA and 4HP are assumed to have similar toxicity as compared to pa rent isofetamid. However, these degradates were observed at levels <11.8% of the applied radioactivity. Based on the low levels expected relative to parent isofetamid, these degradates are not considered ROC s

. Furthermore, a lthough IBA was observed as a major metabolite in the aqueous photolysis study, it is a cleavage product with a carboxylic acid moiety which is likely to be rapidly excreted. Therefore, it is not considered a ROC.

Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression a

Matrix Residues included in
Risk Assessment a Residues included in Tolerance Expression

Plants Primary Crop Isofetamid and GPTC Isofetamid

Rotational Crop NS b NS b

Livestock Ruminant Isofetamid and PPA Isofetamid Poultry Isofetamid Isofetamid Drinking Water Isofetamid N A c

a Isofetamid is N

- [1,1

- dimethyl

- 2

- (4

- isopropoxy

- o

- tolyl)

- 2

- oxoethyl]

- 3

- methylthiophene

- 2

- carboxamide . The
names and chemical structures of the metabolites can be found in A ppendix B

. b Not specified at this time. If field accumulation studies are performed in the future , then the levels of isofetamid, GPTC, and malonyl

- GPTC should be determined.

c Not applicable

.



### 5 .2 Food Residue Profile

Adequate field trial data, reflecting the proposed use patterns in geographically representative regions, were submitted for almonds, canola, grapes, lettuce (head and leaf), and strawberries. Canola, grapes, and strawberries are the representative commodities for subgroups 20A, 13

- 07F,
and 13

- 07G, respectively. Residues of parent were quantifiable in most samples of lettuce and in all samples of grapes and strawberries. In almond nutmeat, all residues were <LOQ

. In almond
hulls , parent was not found

, but GPTC was found at low levels. In canola seed, only parent was detected; quantifiable parent was found in only three of seventeen studies. Some decline studies indicated that residues decrease over time; others did not indicate a trend.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 22 of 48 Processing studies h ave been submitted for canola (meal and refined oil) and grapes (raisins and juice) and tolerances are needed for canola oil and raisins. A hydrolysis study with radiolabeled
isofetamid indicated that isofetamid was stable t o simulated processing procedures , therefore degradation would not be expected during food processing involving pasteuri z ation, baking / brewing / boiling

, or sterilization. Quantifiable residues of isofetamid (parent) did not
concentrate in canola meal

, but did concentrate 2.0X in canola oil. Quantifiable residues of
isofetamid (parent) did not concentrate in grape juice or wine but did concentrate 2.3X in raisins.

The available storage stability data are adequate to support the storage conditions and intervals of samples from the field trials , processing studies, and field rotational crop studies. The freezer storage stability data indicate that residues of isofeta mid and the metabolite GPTC are stable in almonds, canola (oilseed rapeseed), grapes, lettuce, potatoes and dry beans for at least 12 months when stored under frozen conditions. These data include five different crop types: high water content (lettuce), h igh acid content (grape), high protein content (dry bean), high oil content (almond and canola), and high starch content (potato). Based on the livestock metabolism
studies , HED concludes that storage stability data for the livestock matrices are unnecess ary because data are not required for samples analyzed within 6 months

.

L ivestock feeding studies were not submitted and are not required. Tolerances are not required
for livestock commodities because there is no reasonable expectation of finite residues

.

The confined rotational crop studies are adequate. Because residues were found in rotational crops in the conf

ined study at >0.01 ppm at all PBIs, a field accumulation study on rotational crops was conducted. The results from this study support the 30

- day PBI f or crops without registered uses, as stated on the proposed label. Furthermore

, since the limited rotational field trials showed that all residues (parent, GPTC, and malonyl

- GPTC) were below the LOQ at all

PBIs

, a residue of concern is not identified for risk assessment for rotational crops ( DP411110, I. Negrón

- Encarnación, 0 5/21/2014 )

. Thus, i nadvertent or indirect tolerances for these rotational

crops are not required at this time

. If additional field rotational crop studies are c onducted because higher application rates or shorter PBIs are proposed in the future, the petitioner should determine residue levels of parent, GPTC, and malonyl

- GPTC in the rotational crops.

5.3 Water Residue Profile

Since isofetamid is a new chemical, there are no monitoring data regarding the concentrations of
the parent isofetamid in surface or ground water. The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division, EFED (DP 4 22934

, M

. Biscoe

, 0 9 / 22 /2014 ). This drinking w ater assessment was only conducted on
parent isofetamid

.

The EDWCs for use in the human health risk assessment are based on the maximum proposed single and annual application rates specified in the product labels

, an d representative application methods and exposure estimates

. EDWCs for the chronic assessment were estimated using the Pesticide Flooded Application Model (PFAM version 1.0 ). Detailed description s , documentation, and links for running the PFAM model may found at http://www.epa.gov/oppefed1/models/water/index.htm

. The PFAM generates daily, 1

- in

- 10

-

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 23 of 48 year, and 30

- year average EDWCs of isofetamid that may occur in and downstream of flooded fields through dry

- field runoff, overflows, and manual releases of water. PFAM simulates pesticide application, movement and transformation in a watershed and the resultant pesticide loadings to a receiving water body via runoff, erosion, and spray drift, and then simulates the fate of the pesticide and resulting concentrations in the water body.

The ground water value of 110 μg/L ( ppb ) was the EDWC chosen for chronic dietary assessment because it was higher than the surface water chronic value. This val ue was the 1

- in

- 10 year annual average EDWCs in surface water residue value, based on the cranberry use and the

W isconsin rice scenario , as presented in Table 5.3

.

Table 5.3 Maximum Estimated Drinking Water Concentrations (EDWCs) in parts per billion (μg /L) Resulting from Applications of Isofetamid on the Proposed Low

- Growing Berries Subgroup 13

- 07G and
Turf Uses a

Drinking Water Source ( M odel) Model Scenario, Use Modeled, and Application Method Acute Chronic

μg/L

Surface Water ( PFAM ) Wisconsin Rice Scenario
Cranberries 5 Aerial Applications @ 0.442 lb ai/A Peak

1

- in

- 10 Year Chronic

1

- in

- 10 Year

136 110

Ground W ater (PRZM

- GW 30

- year simulation) Wisconsin Corn Scenario Turf 7 Ground Applications Total:
6 @ 0.567 lb ai/A; 1 @ 0.248 lb ai/A Peak Post

- Breakthrough Average

49 43

a Bolded value denote s maximum EDWC for chronic dietary assessment

. b NA = not applicable.



### 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

A partially refined chronic (food and drinking water) dietary assessment was conducted assuming mean field trial residues of the combined residues of parent and GPTC for all proposed

crops and 100% CT

. The anticipated residues used for crop commodities included parent and
GPTC

. Sin ce processing studies were available on canola and grapes, empirical processing
factors were used for rapeseed oil, flax seed oil, and sesame oil (all 1.97X based on the canola processing study) and raisins (2.2X). Residues did not concentrate in grape ju ice and wine, so a processing factor of 1X was applied

. A DEEM default processing factor was used for cranberry juice (1.1X), and other default processing factors were not applicable. The EDWC of 110 μ g/L was incorporated directly into the dietary assessment

.

5.4. 2 Acute Dietary Risk Assessment

An acute dietary endpoint was not selected for quantitative risk assessment because acute hazard attributable to a single dose was not identified.

5.4.3 Chronic Dietary Risk Assessment

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 24 of 48 The results indica te that chronic dietary (food and drinking water) exposure and risk estimates
are not of concern for the U.S. population and all population subgroups. T he risk estimate s are <1 % of the cPAD for the general U.S. population and <1 % of the cPAD for children (1

- 2 years old), the most highly exposed subgroup. Table 5.4. 4 summarizes the dietary exposure and risk
estimates for isofetamid

.

Th e chronic dietary assessment does not underestimate risk to the general U.S. population or any population subgroup. The d ietary exposure and risk estimates are somewhat refined since they

assume mean residues for most crops and include empirical processing factors. For future uses,

a dditional refinements could be implemented such as the incorporation of %CT data.

5.4. 4 Summary Table

Table 5.4. 4 Summary of Dietary (Food and Drinking Water) Exposure and Risk for Isofetamid a

Population Subgroup cPAD Chronic Dietary
Dietary Exposure cPAD
mg/kg/day mg/kg/day % General U.S. Population

0.7 66 0.003070 <1 All Infants (< 1 year old) 0.006959 <1

Children 1

- 2 years old 0.006560 <1

Children 3

- 5 years old 0.004900 <1

Children 6

- 12 years old 0.002986 <1

Youth 13

- 19 years old 0.002140 <1

Adults 20

- 49 years old 0.002875 <1 Adults 50+ years old 0.002916 <1

Females 13

- 49 years old 0.002913 <1

a The subpopulation with the highest risk estimate is bolded

.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Residential exposure may occur by the dermal, oral, and inhalation routes of exposures.

H owever, since dermal hazard has not been identified for isofetamid , the only exposure scenarios quantitatively assessed are handler inhalation ( for adults ) , and post

- application incidental oral ( for children ) . These exposures have been assessed with curre nt policies which include HED’s
2012 Residential SOPs 1 

### along with policy change s for body weight assumptions ( DP411113, N. Keller, 07 / 25 /2014 )

.

The only EP t hat may lead to residential exposures (handler and/or post

- application exposure s ) is
the SC formul ation: EPA Reg. No. 71512

- EG (foliar and systemic insect control in turfgrass including golf courses, residential lawns, and recreational turfgrass).

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

- exposure

- sop.html

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 25 of 48 6.1 Residential Handler Exposure

Since the proposed turf label (EPA Reg. No. 71512

- EG) includes residential use sites, prohibition of use by homeowners is not enforceable, and use by homeowners is possible. Thus, residential handler exposure and risk estimates have been calculated for al l possible residential exposure scenarios. Including all possible residential exposure scenarios provides a conservative and health protective assessment for the potential for homeowners to use the professionally labeled products on residential use sites. S ince there is no dermal toxicity endpoint , the residential handler assessment only includes the inhalation route of exposure.

Residential handler exposure is expected to be short

- term in duration. The turf label indicate s that a maximum of eight appli cations are allowed per year . Thus, i ntermediate

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

. Unit exposure
values and estimates for area treated or amount handled were taken from HED’s 2012
Residential SOPs 2 

### (Lawns/Turf ). The algorithms used to estimate exposure and dose for
residential handlers can be found in the 2012 Residential SOPs 2 

### (Lawns/Turf ).

Risk estimates of all possible scenarios are not of concern. Short

- term inhalation MOEs range
from 85 0,000 to 18,000,000 as summarized in Table 6.1

.

Table 6.1 Residential Handler Non

- C ancer Exposure and Risk Estimates for Isofetamid

Application Equipment Crop or Target Inhalation
Unit Exposure Maximum

Application

Rate a Amount
Handled Daily b Inhalation

Dose c MOE d

mg/lb ai mg/kg/day

Mixer/Loader/Applicator for Liquid Formulations
Manually

Pressurized

H andwand Outdoor Broadcast: Lawns/Turf 0.018 0.00650 lb ai/gal 5

gal 0.00000850 9,000,000

Hose

- End
S prayer Outdoor Broadcast: Lawns/Turf 0.022 0.567
lb ai/A 0.5

acres 0.0000900 850,000

Backpack Outdoor Broadcast: Lawns/Turf 0.14 0.00650 lb ai/gal 5

gal 0.0000660 1,200,000

Sprinkler C an Outdoor Broadcast: Lawns/Turf 0.022 0.00650 lb ai/sq ft 1000

sq ft 0.00000410 18,000,000

a Based on maximum application rate s on proposed label , EPA Reg. No. 71512

- EG, for liquid applications to turf.
b Based on HED’s 2012 Residential SOPs: Lawns/Turf ( http://ww w.epa.gov/pesticides/science/residential

- exposure

- sop.html ).

c Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or lb ai/ gal) × Amount Handled ( A/day or gallons/day) ÷ BW ( 69 kg adult ).
d Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Short

- Term Inhalation NOAEL = 76.6 mg/kg/day . Level of concern = 10 0.



### 6.2 Post

- Application Exposure

There is the potential for post

- application exposure for individuals as a res ult of being in an environment that has been previously treated with isofetamid. E PA Reg. No. 71512

- EG is

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

- exposure

- sop.html

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 26 of 48 proposed for use on turf areas associated with golf courses (greens, tees, and fairways), college and professional sports fields, and residential law ns. Since dermal hazard has not been identified for isofetamid, a quantitative assessment for dermal exposure is not necessary and the only exposure scenarios quantitatively assessed are for children 1 to <2 years old who may exp erience
short

- term inciden tal oral exposure to isofetamid from treated turf. Intermediate

- term incidental oral post

- application exposures are possible (i.e. from soil ingestion due to the persistence of
isofetamid ); however, the short

- term incidental oral exposures are protective of the possible
intermediate

- term incidental oral exposures because the POD for both durations is the same.

Post

- application inhalation exposure is expected to be negligible for the proposed residential

uses.

The lifestage (children 1 to <2 years old) se lected for each post

- application scenario is based on an analysis provided as an Appendix in the 2012 Residential SOPs 3 

### . This lifestag e is not the only lifestage that could be potentially exposed for these post

- application scenarios; however, the

assessme nt of these lifestages is health protective for the exposures and risk estimates for any other potentially exposed lifestages.

A series of assumptions and exposure factors served as the basis for completing the residential
post

- application risk assessment. Each assumption and factor is detailed in the 2012 Residential
SOPs 4 

### (Lawns/Turf

). The algorithms used to estimate residential post

- application exposure and
dose can be found in the 2012 Residential SOPs 5 

### (Law ns/Turf).

In accordance with 40C FR158, turf transferrable residue (TTR) data are required for all occupational (e.g. sod farms, golf courses, parks, and recreational areas) or residential turf uses that could result in post

- application exp osure to turf. Thus, in addition to the SOPs, th e registrant has submitted chemical

- specific TTR data ( DP411110, DP411111, DP411112, N. Keller, 10/30/2013 ). The high

- end TTR value chosen to be protective of all exposure scenarios (regardless of formulation applied), is the predicted Day 0 residue from the Pennsylvania site of 0.0761 μg/cm 2 

### . This value is based on a target application rate of 0.454 lb ai/A, and must be adjusted for the proposed application rates in quantitative post

- application risk estimate
calculations.

Table 6.2 presents the post

- ap plication incidental oral MOE values calculated based on the scenario of liquid application of isofetamid to turf. Post

- application risk estimates for all
incidental oral scenarios are not of concern (MOEs range from 5 ,900 to 4,000,000). T he
incidental o ral scenarios (i.e. hand

- to

- mouth and object

- to

- mouth) should be considered inter

related and it is likely that they occur interspersed amongst each other across time. However, combining these scenarios would be overly

- conservative because of the conserva tive nature of each individual assessment. Therefore, the hand

- to

- mouth post

- application exposure scenario for children 1 < 2 years old should be considered a protective estimate of children’s exposure to pesticides used indoors. Furthermore, incidental oral risk estimates are highly conservative
because the short

- and intermediate

- term incidental oral POD is based on a 90

- day exposure
duration which represents daily exposure for 90 days

.

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

- exposure

- sop.html

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

- exposure

- sop.html

5 Available: http://www.epa.go v/pesticides/science/residential

- exposure

- sop.html

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 27 of 48 Table 6

. 2 Residential Post

- Application Non

- Cancer Exposure and Risk Estimates for Isofetamid

Lifestage Post

- Application Exposure Scenario Application

Rate a Dose b MOEs c Use Site Route of Exposure mg/kg/day

Children 1 to <2 years old Liquid Application

to Turf Hand to Mouth 0.567

lb ai/A 0.0 130 5 ,900 Object to Mouth 0.000262 290,000 Incidental Soil Ingestion 0.0000192 4,000,000

a Based on proposed label: EPA Reg. No. 71512

- EG for liquid applications to turf.
b Dose (mg/kg/day) equations:
Hand

- to

- Mouth Dose = hand residue loading ( μ g/cm 2 ) × fraction of hand mouthed (0.127) × surface area of 1 hand (150 cm 2 ) × exposure time (1.5 hrs/day) × # of replenishment intervals/hr (4 int/hr) × (1

- ((1

- saliva extraction factor (0.5))^(Number of
hand

- to

- mouth events p er hour (13.9 events/hr) ÷ # of replenishment intervals/hr)) ÷ body weight (11 kg). Object

- to

- Mouth Dose = object residue loading ( μ g/cm 2 ) × unit conversion factor (0.001 mg/ μ g) × object surface area mouthed / event (10 cm 2 /event) × exposure time (1.5 hrs /day) × # replenishment intervals/hr (4 int/hr) × (1

- ((1

- saliva extraction factor (0.50))^(# Object

- to

- Mouth Events/hr (8.8 events/hr) ÷ # replenishment intervals/hr)) ÷ body weight (11 kg). Soil Ingestion = soil residue (μg/g) × ingestion rate (50 mg/da y) × conversion factor (0.000001 g/μg) ÷ body weight (11 kg). TTR for liquid application rate of 0. 567 lb ai/A calculated based on chemical

- specific study = 0.0950 μg/cm 2

.
c MOE = NOAEL ÷ Daily Dose (mg/kg/day). ST/IT Incidental Oral NOAEL = 76.6 mg/kg/day. Level of concern = 100.



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

For the purpose of the isofetamid aggregate human health risk assessment, a summary of the most protective residential exposure risk estimates for all prop osed residential uses is provided in
Table 6. 3

. Since a dermal endpoint wasn’t selected , only short

- term inhalation residential
handler exposures (for adults) and short /intermediate

- term incidental oral post

- application exposures (for children) should be included in the aggregate risk assessment

.

The recommended exposure contribution for aggregate risk assessment is based on the most protective risk estimate from liquid application to turf (MOE = 850,000 for adults and MOE = 8.900 for children).

Table 6. 3 Scenarios Recommended for Aggregate Risk Assessment of Isofetamid

Scenario Daily Dose a MOE b mg/kg/day

Adults

Residential Handler Inhalation Exposure (Applying Liquids to Lawns/Turf with a Hose

- End Sprayer) 0.0000900 850,0 00

Children (1 to < 2 Years Old)

Post

- Application Incidental Oral Exposure : Hand

- to

- Mouth (After Liquid Application to Lawns/Turf) 0.0 130 5 ,900

a D aily Dose = See Table 6.1 for a dult h andler s cenarios and Table 6.2 for post

- application incidental oral
scenarios. Adults and children based on EPA Reg. No. 71512

- EG (SC).
b MOE = NOAEL/ Daily Dose (mg/kg/day)

. ST/IT Incidental Oral = 76.6 mg/kg/day. ST Incidental Oral LOC = 100.



### 6.4 Residential Bystander Post

- A pplication Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 28 of 48 related to volatilization of pesticides from its Federal Insecticide, Fu ngicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has develope d a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

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

stu dies, route

- specific inhalation toxicological studies) or fu rther analysis is required for
isofetamid

.

6.5 Spray Drift

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

- In issued by EPA), EPA Regional Offices

, and State Lead Agencies for pesticide regulation

, and other parties to develop the best spray drift management practices (see the ag ency’s Spray Drift website for more information). 6 

### The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessm ents for pesticides.

The potential for spray drift will be quantitat ively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures
For Residential Risk Ass essment (SOPs)

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification
of indirect non

- occupa tional exposure to drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together an d compared to quantit ative 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

A n ac ute aggregate risk assessment was not conducted since adverse effect s a ttributable to a single dose were not identified

.

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

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 29 of 48 7.2 Short

- Term Aggregate Risk

There is potential short

- term exposure to isofetamid via the dietary (which is considered backgroun d exposure) and residential (which is considered primary exposure ) pathways. For all populations , the oral and inhalation routes of exposure should be aggregated since the endpoints
of concern are the same

. For adults, the pathways lead to exposure via the dietary oral (background) and inhalation (primary) routes. For children, the pathways lead to exposure via the dietary oral (background) and incidental oral (primary) routes. The adults and children short

term aggregate risk estimates are not of concern, as shown i n Table 7.2 (MOEs = 2 4,000 and 3,9 00, respectively).

Table 7.2 Short

- Te rm Aggregate Risk Calculations

Population Short

- Term Scenario

NOAEL mg/kg/day LOC a Max

Allowable Exposure b mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day c Total

Exposure mg/kg/day d Aggregate

MOE (food, water, and residential) e

Adults

76.6 100 0. 766 0. 003070 0.0000900 0.00 3160 2 4,000

Children

1

- 2 years old 0.006560 0.0130 0.01956 3,900

a Adults and Children LOC = 100 (based on inter

- and intra

- species uncertainty factors, each at 10X).
b Maximum Allowable Exposure (mg/kg/day) = NOAEL ÷ LOC.

c Re sidential Exposure = Handler Inhalation Only for Adults and Post

- Application Incidenta l Oral Only for
C hildren (See Table 6.3).
d T otal Exposure = Average Food and Water Exposure + Residential Exposure.

e Aggregate MOE = NOAEL ÷ Total Exposure. ST Adult and Children NOAEL = 76.6 mg/kg/day. LOC = 100.



### 7.3 Intermediate

- Term Aggregate Risk

For adults, i ntermediate

- term exposure is not expe cted for the residential exposure pathway. Therefore, the intermediate

- term aggregate risk would be equivalent to the chronic dietary exposure estimate. Refer to Section 5.4.3. For children, the incident al oral POD is the same for
both short

- and intermediate

- term durations. Thus, the short

- term aggregate risk estimate is protective of potential intermediate

- term exposures and risks. Refer to section 7.2.

7.4 Chronic Aggregate Risk

There are no chroni c residential exposure scenarios; therefore , the chronic aggregate risk would be equivalent to the chronic dietary (food and drinking water) risk estimate . Refer to Section
5.4. 3.

7.5 Cancer Aggregate Risk

Isofetamid is classified as “not like ly to be c arcinogenic to humans. ” T herefore, an aggregate
cancer assessment was not conducted.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 30 of 48 8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to isofetamid and any other substances and isofetamid does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, there fore,
EPA has not assumed that isofetamid 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 chem icals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pestici des/cumulative.

9.0 Occupational Exposure/Risk Characterization

Occupational handler and post

- application exposure may occur by the dermal and inhalation
routes of exposure only. Since a dermal hazard was not identified , only inhalation exposures were quantitatively assessed. The results of the occupational handler exposure and risk

assessment indicate that short

- and intermediate

- term inhalation risk estimate s are not of concern (DP411113, N. Keller, 07 /25/2014)

. Appe ndix E summarize s all assessed occupational exposure
and risk estimates.

9.1 Short

- and Intermediate

- Term Handler Risk

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupationa l handler exposure is expected from the proposed agricultural uses. The quantitative exposure/risk assessment developed for occupational handlers
is ba sed on several scenarios which include mixing/loading/applying an SC formulation of
isofetamid. The use sites are sum marized in Section 3 .0. Methods of application include aerial, airblast, chemigation, groundboom, and handheld equipment (refer to Appendix E for a detailed
list of scenario s )

.

HED classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months
as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use si te. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one

- month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a produ ct over a period of several weeks (e.g. completing multiple applications for
mult iple clients within a region). Short

- term exposures are protective of the possible
intermediate

- term exposures because the POD for both durations is the same. The are a treated or
amount handled is b ased on HED Exp oSAC Policy No. 9.1 (refer to Appendix E for these assumptions for each scenario).

It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include the

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 31 of 48 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; t he Residential SOPs ( Lawns/Turf ) ; and or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in

p redicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 7 

### ”, which, along with additional information on HED policy on use of surrogat e data, including descriptions of the various sources, can be found at the Agency website 8



### .

Both proposed labels require chemical

- resistant gloves as PPE

. The results of the occupational handler exposure and risk assessment indicate that short

- and inter mediate

- term inhalation risks
are not of concern (i.e. MOE s are greater than the LOC of 100 for short

- and intermediate

- term

exposures ) at baseline mitigation (no PPE)

. Since the short

- and intermediate

- term PODs are the same, the inhalation MOEs are also the same, ranging from 24,000 to 8,500,000

. Note that o nly engineering control (enclosed cockpit) data are available to assess risks to handlers operating
aircrafts.

The Agency matches quantitative occupational exposure assessment with appropriate
chara cterization of exposure potential. While HED presents quantitative risk estimates for human flaggers whe n appropriate, agricultural aviation has changed dramatically over the past
two decades. According to the 2012 National Agricultural Aviation Associat ion (NAAA) survey of their membership, the use of GPS for swath guidance in agricultural aviation has grown steadily from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15 % in the late 1990’s to only 1% in the most recent (2012) NAAA survey. The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long

- sl eeve shirt, long pants, shoes, and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application. With this level of protection, there are n o risk estimates of concern for applicators.

9.2 Short

- and Intermediate

- Term Post

- Application Risk

HED uses the term post

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

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

- app licatio n 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,

7 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf

8 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 32 of 48 and the chemical’s degradation properties. In addition, the timing of pesticide appli cations, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9.2.1 Dermal Post

- A pplication Risk

An occupational post

- application exposure and risk assessment was not conducted because a
dermal hazard was not identified for isofetamid

.

9.2.2 Restricted Entry Interval

Isofetamid is classified as Toxicity Category III via the dermal route. It is not irritating to the eye or skin, nor a skin sensitizer. Typically, the REI specified on the proposed label is based on the acute toxicity of the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), active ingredients
classified as Acute III or IV for acute dermal, eye irritation

, and primary skin irrigation are assigned a minimum of 12 hour s for the REI . Thus, the 12

- hour REI on the proposed labels is acceptable for all proposed uses.

9.2.3 Inhalation Post

- A pplication Risk

There are multiple po tential 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 con tain pesticides. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

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

- specific inhalati on toxicological studies) or further analysis is required for isofetamid

.

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

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

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

Although a quantitative occupational postapplication inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than postapplication exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational postapplication inhalation exposure scenarios. Furthermore, i nhalat ion exposure during dusty mechanical activities such as shaking and mechanical harvesting is another potential source of post

application inhalation exposure. However, the airblast applicator scenario is believed to represent a reasonable worst case surro gate estimate of post

- application inhalation exposure

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 33 of 48 during these dusty mechanical harvesting activities. The non

- cancer inhalation risk estimate for commercial airblast application is not of concern (i.e. the MOE is greater than the LOC of 100 )

.

10.0 R eferences

M. Biscoe, 06/11/2014, DP410179 , “ Isofetamid : Drinking Water Exposure Assessment for the Section 3 Registration of the New Chemical Isofetamid, in Support of Proposed Almond, Lettuce, Grapes (Subgroup 13

- 07F), Low Growing Berries (Subgroup 13

- 07 G), Rapeseed (Subgroup 20A), and Turf Uses (EPA File Symbols 71512

- ER,

- EE, and

- EG). ”

M. Biscoe, 09/22/2014, DP422934, “ Isofetamid : ADDENDUM to Drinking Water Exposure

Assessment for the Section 3 Registration of the New Chemical Isofetamid, in Support o f Proposed Almond, Lettuce, Grapes (Subgroup 13

- 07F), Low Growing Berries (Subgroup 13

- 07G), Rapeseed (Subgroup 20A), and Turf Uses.”

J. D’Agostino, 07/28/2014, ToxSAC Report PC Code 270000 , “ Isofetamid

- Summary of Toxicology Science Advisory Council (To xSAC) Meeting of May 8, 2014. ”

N. Dodd, 0 6 /2 0 /201 4

, DP 411108

, “ Isofetamid. F irst Food Use Petition for the Establishment of Permanent Tolerances and Registration for Use on Almonds, Lettuce (Head and Leaf), Small Vine Climbing Fruit, except Fuzzy Kiwifruit, Subgroup 13

- 07F

, Low Growing Berry Subgroup 13

- 07G, and Rapeseed Subgroup 20A. Summary of Analytical Chemistry and
Residue Data. ”

N. Dodd

, 0 9 /2 3 /2014 , DP4 11109 , “ Isofetamid C hronic Aggregate Dietary (Food and Drinking

Wate r ) Exposure and Risk Assessment for the Section 3 Registration Action for Uses on Almonds, Lettuce (Head and Leaf), the Small Vine Climbing Fruit, except Fuzzy Kiwifruit, Subgroup 13

- 07F; the Low Growing Berry Subgroup 13

- 07G; and the Rapeseed Subgroup
20 A. ”

I. E ncarnacion, 05/21/2014, DP411110 , “ Isofetamid. Report of the Residues of Concern Knowledgebase Subc ommittee (ROCKS)

. ”

N. Keller, 07/25/2014, DP 411113, “ Isofetamid

. Occupational and Residential Exposure and
Risk Assessment for the Proposed New Uses of the New Active Fungicide, including Agricultural Use s on Almonds, Lettuce, Small Vine Climbing Fruits (Crop Subgroup 13

- 07F), Low Growing Berries (Crop Subgroup 13

- 07G), and Rapeseed (Crop Subgroup 20A); and Uses on Turfgrass (incl uding Golf Courses, Sod Farms, Seed Farms, Recreational Fields, and Commercial/Residential Lawns).”

J. Leshin, 08/11/2014, TXR0057008 , “Isofetamid : Summary of Hazard and Science Policy Council (HASPOC) Meeting s o n October 25, 2012 and November 8, 2012 : Recommendations on the R equirement of 28

- Day and 90

- Day I nhalation S tud ies

. ”

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 34 of 48 Appendix A

. Toxicology Profile and Executive Summaries

A .1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food and non

- food uses for isofetamid are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were
used.

Table A.1 Summary of Toxicology Data Requirements

Guideline No. / Study Type Technical MRID No. Required Submitted

870.3100 Subchronic (Oral) Toxicity

- Rodent

................................ ........... 870.3150 Subchronic (Oral) Toxicity

- Non

- Rodent

................................ ... 870.3200 21/28

- Day Dermal Toxicity

................................ ........................ 870.3250 90

- Day Dermal Toxicity

................................ ............................. 870.3465 90

- Day Inhalation Toxicity

................................ ......................... Y

Y

Y

N
CR a Y

Y

Y

N

N b 49011923

49011924
49011928

--

-- 870.3700a Prenatal Developmental Toxicity

- Rodent

................................ .. 870.3700b Prenatal Developmental Toxicity

- Non

- Rodent

......................... 870.3800 Reproduction and Fertility Effects

................................ .............. Y

Y

Y Y

Y

Y 49011935

49011937
49011940

870.4100a Chronic (Oral) Toxicity

- Rodent

................................ ................ 870.4100b Chronic (Oral) Toxicity

- Non

- Rodent

................................ ........ 870.4200a Carcinogenicity

- Rat

................................ ................................ .... 870.4200b Carcinogenicity

- Mouse

................................ ............................. 870.4300 Combined Chronic Toxicity /Carcinogenicity

............................. N

N

N

Y

Y Y

Y

N

Y

Y 49011929 c

49011930 c

-- 49011932
49011933 c

870.6100a Neurotoxicity

- Acute Delayed Neurotox.

- Hen

.......................... 870.6100b Neurotoxicity

- Subchronic

- Hen

................................ .............. 870.6200a Neurotoxicity Screening Battery

- Acute

- Rat

............................ 870.6200b Neurotoxicity Screening Battery

- Subchronic

- Rat

.................... 870.6300 Developmental Neurotoxicity

................................ .................... N

N

Y

Y

N N

N

Y

Y

N --

-- 49011945
49011946

-- 870.5100 Bacterial Reverse Mutation Test

................................ ................. 870.5300 In Vitro Mammalian Gene Mutation Test

– Mouse Lymphoma Cells

................................ ................... 870.5375 In Vitro Mammalian Chromosome Aberration Test

.................... 870.5395 In Vivo Erythrocyte Micronucleus Test

- Mice

........................... 870.5385 In Vivo Mammalian Chro mosomal Aberration Test

................... Y

Y

N

Y

N Y

Y

Y

Y

N 49011941

49011942
49011943
49011944

-- 870.7485 Metabolism and Pharmacokinetics

................................ .............. 870.7200 Companion Animal Safety

................................ .......................... 870 .7600 Dermal Penetration

- Rat

................................ ............................. 870.7 600 Dermal Penetration

- Human

................................ ....................... 870.7800 Immunotoxicity

- Mice

................................ ................................ Y

N
CR a
CR a

Y Y

N

Y

Y

Y 49011950

-- 49011951
49011953
49011952
49011956
49011955

a CR = conditionally required

. b The requirement for a subchronic inhalation study has been waived ( HASPOC memo, J. Leshin, TXR0057008 , 08/11/2014 )

.
c The requirements for the chronic oral (rat) and carcinogenicity (rat) studies are satisfied by the combined chronic/oncogenic ity (rat) study. In addition, a one

- year chronic study was submitted (MRID 49011929)

.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 35 of 48 A .2 Toxicity Profile s

Table A .2 .1 Acute Toxicity Profile

– Technical Isofetamid

Guideline No. Study Type MRID Results Toxicity Category

870.1100
870.1200 Acute oral (rat) 49032504 LD 50 > 2000 mg/kg III

Acute dermal (rat) 49032505 LD 50 > 2000 mg/kg III

870.1300 Acute inhalation (rat) 49032506 LC 50 > 4.28 mg/L IV

870.2400 Acute eye irritation (rabbit) 49032507 Non

- irritating IV

870.2500 Acute dermal irritation (rabbit) 49032508 Non

- irritating IV

870.2600 Skin sensitization (mouse) 49032509 Not a dermal
sensitizer N/A

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Isofetamid

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

870.3050 28

- day oral diet

toxicity (rat) 49011919 (2011)

49011920 (2009) 49011921 (2009) 49011922 (2010) acceptable/guideline 0, 100, 500, 2500, or 15,000 ppm M: 0, 8.4, 42, 210, 1271 mg/kg bw/day F: 9.3, 45, 215, 1322 mg/kg bw/day NOAEL = 42/45 (M/F) mg/kg bw/day LOAEL = 210/215 (M/F) mg/kg bw/day based on elevated relative liver weight and changes in
clini cal chemistry (GGTP and total bilirubin; total cholesterol in females only).

None 28

- day oral diet

toxicity (dog) 49011926 (2011)

acceptable/non

- guideline 0, 1000, 3000, 10,000, 30,000 ppm M: 0, 30.3, 89.8, 299, 987 mg/kg bw/day F: 0, 34.8, 90.9, 315, 93 3 mg/kg bw/day This was a range

- finding study not designed to establish a NOAEL/ LOAEL. However, the data on liver weight, histopathology and clinical chemistry (ALP and GTTP) indicate that the liver is a target organ.

870.3100 90

- Day oral toxicity

(rat) 49011923 (2011)

acceptable/guideline 0, 100, 1000, 10000 ppm M: 0, 6.65, 68.9, 637 mg/kg bw/day F: 0, 7.83, 78.0, 741 mg/kg bw/day NOAEL = 68.9/78.0 (M/F) mg/kg bw/day
LOAEL = 637/ 741 (M/F) mg/kg bw/day based on hepatocellular and thyroid follicular cell hypertrophy, changes in clinical chemistry (GGPT, cholesterol and bilirubin) and increased activated partial thromboplastin time in both sexes, and adrenal hypertrophy in females

.

870.3150 90

- Day oral toxicity

(dog) 49011924 (2011)

acceptable/guide line 0, 100, 1000 or 10,000 ppm M: 0, 2.95, 29.3, 301 mg/kg bw/day F: 0, 3.07, 32.7, 314 mg/kg bw/day NOAEL = 29/33 (M/F) mg/kg bw/day LOAEL = 301/314 (M/F) mg/kg bw /day based on increased liver weight, changes in clinical chemistry (ALP, albumin, triglycerides; GGTP in females only), hepatic centrilobular hypertrophy;
these effects co

- occurred with thyroid follicular cell hypertrophy in a few animals.

870.3200 21/2 8

- Day dermal

toxicity (rat) 49011928 (2011)

acceptable/guideline 0, 100, 300, or 1000 mg/kg bw/day NOAEL = 1000 mg/kg bw/day LOAEL > 1000 mg/kg bw/day, not established.

870.3700a Prenatal

developmental in (rat) 49011935 (2010), 49011934 (2010)

acceptable/guideline 0, 100, 300, or 1000 mg/kg bw/day Maternal NOAEL = 1000 mg/kg bw/day LOAEL > 1000 mg/kg bw/day, not established. Developmental NOAEL = 1000 mg/kg bw/day LOAEL > 1000 mg/kg bw/day, not established.

870.3700b Prenatal

developmental in (rabbit) 49011937 (2012)

49011936 (2010) acceptable/guideline 0, 100, 300, or 1000 mg/kg bw/day Maternal NOAEL = 1000 mg/kg bw/day LOAEL > 1000 mg/kg bw/day, not established. Developmental NOAEL = 1000 mg/kg bw/day LOAEL > 1000 mg/kg bw/day, not established.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 36 of 48 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Isofetamid

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

870.3800 Reproduction and

fertility effects (rat) 49011940 (2013), 49011938 (2011)

Acceptable/guideline 0, 100, 1000, or 10,000 ppm M: 0, 6.58, 65.8, 679 mg/kg bw/day F: 0, 7.49, 76.6, 775 mg/kg bw/day Parental/Systemic NOAEL = 65.8/76.6 (M /F) mg/kg bw/day LOAEL = 679/775 mg/kg bw/day based on hepatocellular hypertrophy in the liver and follicular cell hypertrophy in the thyroid in both sexes and generations, decreased spleen weights and cytoplasmic eosinophilic inclusion bodies in
the liver of F1 males, and decreased pup body weight in both sexes and generations.. Reproductive NOAEL = 679/775 mg/kg bw/day LOAEL > 679/775 mg/kg bw/day, not established Offspring NOAEL = 65.8/76.6 (M/F) mg/kg bw/day LOAEL = 679/775 mg/kg bw/day based on decreased pup body weight in both sexes and generations

.

870.4100a Chronic toxicity

One

- year (rat) 49011929 (2012)

Acceptable/guideline 0, 30, 100, 500, or 5000 ppm M: 0, 1.39, 4.68, 22.7, 237 mg/kg bw/day F: 0, 1.82, 5.92, 30.0, 311 mg/kg bw/day NOAEL = 22.7/30 (M/F) mg/kg bw/day LOAEL = 237/311 mg/kg bw/day based on liver toxicity (increased liver weight, centrilobular hepatocellular hypertrophy, and changes in blood chemistry (increased ALP and GGTP activity,
increased TG levels and decreased Alb lev els).

870.4100b Chronic toxicity

(dog) 49011930 (2012)

Acceptable/guideline 0, 60, 200 or 6000 ppm M: 0, 1.61, 5.34 or 166.0 mg/kg bw/day F: 0, 1.57, 5.58 or 178.0 mg/kg bw/day NOAEL = 5.34/5.58 (M/F) mg/kg bw/day LOAEL = 166/178 (M/F) mg/kg bw /day based on increased liver weight, centrilobular hepatocellular hypertrophy, and changes in blood chemistry.

870.4200 Carcinogenicity

(rat) 49011932 (2012)

Acceptable/guideline 0, 30, 100, 500, or 5000 ppm M: 1.21, 4.07, 20.3, 210 mg/kg bw/day F: 0, 1.55, 5.02, 26.1, 263 mg/kg bw/day NOAEL = 20.3/26.1 mg/kg bw/day LOAEL = 210/263 (M/F) mg/kg bw/day based on microscopic changes in the liver (diffuse hepatocyte hypertrophy and hepatocellular cytoplasmic eosinophilic inclusion bodies in
males and hepatocyte brown pigment [lipofuscin] in females) and microscopic changes in the thyroid (follicular cell hypertrophy in both sexes and follicular cysts in males). These findings are supported by similar liver and thyroid microscopic changes in the 1

- year rat study (MRID 49011929). No evidence of carcinogenicity

870.4300 Carcinogenicity

(mouse) 49011933 (2012), 49011931 (2011)

0, 100, 800, 4000/3000 (M/F) ppm M: 0, 12, 92, 502 mg/kg bw/day F: 0, 14, 118, 431 mg/kg bw/day NOAEL = 502/431 (M/F) mg/kg bw/da y LOAEL > 502/431 (M/F) mg/kg bw/day, not
established No evidence of carcinogenicity

Gene Mutation
870.5100 In vitro bacterial

gene mutation ( S. typhimurium and E.
coli ) 49011941 (2009)

acceptable/guideline Experiment 1: 0, 61.7, 185, 556, 1667, and 5000 μg/plate Experiment 2: 0, 313, 625, 1250, 2500, 5000 μg/plate There was no evidence of induced mutant colonies over background.

Cytogenetics
870.5300 In vitro mammalian

cells in Culture Gene mutation (mouse lymphoma L5178Y cells) 49011942 (2011)

acceptab le/guideline 0, 14.1, 28.1, 56.3, 112.5, 225 μg/mL There was no evidence of induced mutant colonies over background.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 37 of 48 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Isofetamid

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

Other Effects
870.5375 In vitro Mammalian

Chromosome
Aberration Test (Chinese hamster lung cells) 49011943 (2010)

acceptable/guideline Experiment #1: 0, 33.3, 100, 300, and 900 μg/mL Experiment #2: 0, 16.7, 50, 150, and 450 μg/mL Experiment #3: 0, 16.7, 50, 150, and 450 μg/mL Experiment #4: 0, 3.3, 10, 30, and 90 μg/mL There was no evidence of chromosome aberrations induced over backgrou nd.

Other Effects
870.5395 In vivo mammalian

cytogenetics

- erythrocyte
micronucleus (mouse) 49011944 (2010)

acceptable/guideline 0, 500, 1000, or 2000 mg/kg There was no biologically significant increase in the frequency of micronucleated polychromatic erythrocytes in mouse bone marrow at any dose or
sacrifice time.

870.6200a Acute neurotoxicity

screening battery (rat) 49011945 (2012)

acceptable/guideline 0, 500, 1000, 2000 mg/kg bw/day NOAEL = 2000 mg/kg bw/day LOAEL > 2000 mg/kg bw/day, not established.

870.6200b Subchronic

neurotoxicity screening battery 49011946 (2011)

acceptable/non

- guideline 0, 500, 3000, or 15,000 ppm M: 0, 34, 207, and 1049 mg/kg bw/day F: 0, 40, 245, and 1213 mg/kg bw/day NOAEL = 1049 mg/kg bw/day

LOAEL > 1049 mg/kg bw/day, not established.

870.7485 Metabolism and

pharmacokinetics (rat) 49011950 (2011)

acceptable/guideline 0, 5, 200 mg/kg Rapid absorption at low dose (~93%); saturated at the high

- dose. Did not accumulate in any of the tissues. Maximum plasma concen trations at 2

- 6
hr at low

- dose, ~8 hr at high dose. Rapidly eliminated in bile and urine, majority by 48 hours
of treatment. Males eliminated most in the feces
while females eliminated ~5X more in urine. Little to no recovery in expired air. The plasma

T 1/2 ~38 hrs. Metabolized mainly by O

dealkylation, hydroxylation, and subsequent glucuronidation.

870.7600 In vivo dermal

penetration (rat) 49011953 (2012)

acceptable/guideline 3.2, 7.5, 4000 μg/cm 2 /hr After 6 hours of treatment, amount in excreta was
about 3

- 6% of the administered dose at 6 hr, 1

- 6% at 24 hr, 1

- 8% at 72 hr, 1

- 7% at 120 hrs and 1

- 10% at 168 hrs. A larger percent of the dose was excreted at lower treatment doses than at higher
treatment doses for all time points.

In vitro dermal penetration study (rat skin) 49011951 (2012)

acceptable/non

- guideline 3.2, 7.5, 4000 μg/cm 2 /hr Did not readily penetrate rat skin. Steady

- state absorption rates were low: 0.2, 0.010, and 0.009 μg/cm 2 /hr after treatment with high mid or low dose, respectively.

In vitro dermal penetration study (human skin) 49011952, 49011956 (2012)

acceptable/non

- guideline 3.2, 7.5, 4000 μg/cm 2 /hr Did not readily penetrate human skin. Steady

- state absorption rates were low: 0.08

- 0.30, 0.0026, a nd 0.0008 μg/cm 2 /hr after treatment with high mid or low dose, respectively.

870.7800 Immunotoxicity

(female mouse) 49011955 (2012)

acceptable/guideline 0, 1000, 3000, or 7000 ppm F: 0, 197, 644, 1380 mg/kg bw/day Systemic NOAEL = 1380 mg/kg bw/day LOAEL > 1380 mg/kg bw/day, not established.
Immunotoxic NOAEL = 1380 mg/kg bw/day LOAEL > 1380 mg/kg bw/day; not established.

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 38 of 48 Appendix B

. Isofetamid Metabolite Profile

B

. 1 Isofetamid Metabolites Summary Table

Table B

. 1 Summary Table of Parent and Metabolites/Degradates

Common Name/C ode (ID No.) Chemical N ame Chemical S tructure

Isofetamid/ ISK

- 5411

CAS # 875915

- 78

- 9 IUPAC: N

- [1,1

- dimethyl

- 2

- (4

- isopropoxy

- o

tolyl)

- 2

- oxoethyl]

- 3

- methylthiophene

- 2

- carboxamide
CAS: N

- [1,1

- dimethyl

- 2

- [2

- methyl

- 4

- (1

- methylethoxy)phenyl]

- 2

- oxoethyl]

- 3

- methyl

- 2

- thiophenecarboxamide

4HP (YN

- 5394) N

- [1,1

- dimethyl

- 2

- (4

- hydroxy

- 2

- methylphenyl)

- 2

- oxoethyl]

- 3

- methyl

- 2

- thiophenecarboxamide

PPA (YN

- 6187) 2

- [3

- methyl

- 4

- [2

- methyl

- 2

- (3

- methylthiophene

- 2

- carboxamido)propanoyl]phenoxy]propanoic acid

3

- MTCAM 3

- methyl

- 2

- thiophenecarboxamide

IBA (HM

- 939) 2

- methyl

- 4

- (2

- propyloxy)benzoic acid

3

- MTCA (minor deg) 3

- methyl

- 2

- thiophenecarboxylic acid

GPTC

M3

4HP glucuronide N

- [1 ,1

- dimethyl

- 2

- (4

- β

- D

- glucopyranosyloxy

- 2

- methylphenyl)

- 2

- oxoethyl]

- 3

- methyl

- 2

- thiophenecarboxamide

Malonyl

- GPTC

5

- HPPA 2

- [3

- methyl

- 4

- [2

- methyl

- 2

- (5

- hydroxy

- 3

- methylthiophene

- 2

- carboxamido)propanoy]phenoxy]propanoic acid

MW 209

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 39 of 48 B

. 2 Tabular Summary of Isofetamid Metabolites and Degradates

Table B.2 Tabular Summary of Metabolites and Degradates Chemical Name (other names in parenthesis)
and Structure Matrix Percent TRR (PPM) a,b

Matrices

- Major Residue (>10%TRR) Matrices

- Minor Residue (<10%TRR)

Isofetamid French beans

Whole plant (1 st ) 92.5 B/91.0 T (20.695 B/23.146 T) --

Forage (2 nd ) 77.1 B/76.7 T (8.121 B/8.889 T) --

Straw (3 rd ) 52.6 B/62.0 T (1.718 B/3.066 T) --

Pods (2 nd ) 80.9 B/68.7 T (0.212 B/0.284 T) --

Pods (3 rd ) 26.3 B/18.2 T (0.077 B/0.068 T) --

Seeds (2 nd ; immature) 49.8 B/28.0 T (0.072 B/0.113 T) --

Seeds (3 rd ; mature)

-- 1.1 B/0.5 T (<0.001 B/<0.001 T) Grapes

Foliage 38.2 B/61.1 T (6.478 B/9.749) --

Fruit 46.0 B/60.2 T (0.332 B/0.388 T) --

Lettuce

Wrapper leaves 72.9 B/61.8 T (1.865 B/1.04 T) --

Heads 66.4 B/56.9 T (0.043 B/0.051 T) --
Rotational Crops (PBI = 30 days)

Carrot foliage mature)

-- 9.7 B/1.2 T (0.022 B/0.001 T)

Carrot root (mature) 25.2 B (0.023 B/ 4.7 T (0.002 T)

Lettuce, head (mature)

-- 5.4 B/1.4 T (0.004 B/0.001 T)

Wheat forage

-- 4.4 B/4.3 T (0.014 B/0.009 T)

Wheat hay 10.4 T (0.112 T) 2.2 B (0.026 B)

Wheat straw

-- 1.9 B/2.2 T (0.027 B/0.020 T) Wheat grain

-- -- Ruminant (Goat)

Fat 62.2 B/44.4 T (0.0328 B/0.0059 T) --

Kidney

-- 0.6 B (0.0004 B)

Liver

-- 2.3 B/1.9 T (0.0100 B/0.007 T)

Meat

-- --
Milk aqueous 17.2 B (0.0019 B) --

Milk fat 76.1 B/25.6 T (0.0992 B/0.0123 T) --

Poultry (Laying Hen)

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 40 of 48 Table B.2 Tabular Summary of Metabolites and Degradates Chemical Name (other names in parenthesis)
and Structure Matrix Percent TRR (PPM) a,b

Matrices

- Major Residue (>10%TRR) Matrices

- Minor Residue (<10%TRR)

Egg yolk

-- 0.9 B/1.1 T (0.0019 B/0.002 T)

Fat

-- 6.2 B/1.1 T (0.0009 B/0.0011 T)

Meat

-- --

Liver

-- 0.4 B (0.0008 B)

Rat

-- 5.2 / 4.9 c

Water

4HP French beans

Whole plant (1 st )

-- 0.3 T (0.069 T)

Forage (2 nd )

-- 0.2 T (0.019 T)

Straw (3 rd )

-- 1.1 T (0.053 T) Pods (2 nd )

-- -- Pods (3 rd )

-- -- Seeds (2 nd ; immature)

-- -- Seeds (3 rd ; mature)

-- -- Grapes Foliage

-- -- Fruit

- -- Lettuce

Wrapper leaves

-- 1.0 B/1.5 T (0.034 B/0.025 T)

Heads

-- 3.1 B/3.3 T (0.002 B/0.003 T)

Rotational Crops (PBI = 30 days)

Carrot foliage mature)

-- 6.1 B/3.3 T (0.014 B/0.002 T)

Carrot root (mature)

-- 3.7 B (0.003 B)

Lettuce, head (mature)

-- 2.6 B/1.7 T (0.002 B/0.001 T)

Wheat forage

-- 1.7 B/2.4 T (0.005 B/0.005 T)

Wheat hay

-- 2.0 B/3.5 T (0.024 B/0.038T)

Wheat straw

-- 4.7 B/2.5 T (0.067 B/0.023 T) Wheat grain

-- -- Ruminant (Goat)

Fat

-- 1.0 T (0.0004T)

Kidney

-- 4.1 B/4.9 T (0.0029 B/0.0051 T)

Liver

-- 2.5 B/2.9 T (0.0107 B/0.0105 T)

Meat

-- -- Milk aqueous

-- -- Milk fat

-- -- Poultry (Laying Hen)

Egg yolk

-- 4.1 B/1.8 T (0.0089 B/0.0031 T)

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 41 of 48 Table B.2 Tabular Summary of Metabolites and Degradates Chemical Name (other names in parenthesis)
and Structure Matrix Percent TRR (PPM) a,b

Matrices

- Major Residue (>10%TRR) Matrices

- Minor Residue (<10%TRR)

Fat

-- 3.4 B/0.4 T (0.0005 B/0.0004 T)

Meat

-- 0.9 B (0.0001 B)

Liver

-- 1.8 B/2.8 T (0.0039 B/0.0050 T)

Rat

-- 1.7 / 6.9 3

Water

IBA French beans

Whole plant (1 st )

-- 0.5 B (0.107 B)

Forage (2 nd )

-- 0.5 B (0.057 B) Straw (3 rd )

-- -- Pods (2 nd )

-- -- Pods (3 rd )

-- -- Seeds (2 nd ; immature)

-- -- Seeds (3 rd ; mature)

-- -- Grapes Foliage

-- -- Fruit

-- -- Lettuce Wrapper leaves

-- -- Heads

-- --

Rotational Crops (PBI = 30 days)

Carrot foliage mature)

-- 2.0 B (0.004 B) Carrot root (mature)

-- --
Lettuce, head (mature)

-- 2.2 B (0.002 B)

Wheat forage

-- 1.8 B (0.006 B)

Wheat hay

-- 2.4 B (0.029 B)

Wheat straw

-- 1.3 B (0.018 B) Wheat grain

-- -- Ruminant (Goat)

Fat

-- -- Kidney

-- --

Liver

-- 1.3 B (0.0056 B)

Meat

-- -- Milk aqueous

-- -- Milk fat

-- -- Poultry (Laying Hen)

Egg yolk

-- 0.5 B (0.001 B)

Fat

-- -- Meat

-- --

Liver

-- 2.3 B (0.0048 B)

Rat

-- -- Water

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 42 of 48 Table B.2 Tabular Summary of Metabolites and Degradates Chemical Name (other names in parenthesis)
and Structure Matrix Percent TRR (PPM) a,b

Matrices

- Major Residue (>10%TRR) Matrices

- Minor Residue (<10%TRR)

3

- MTCA French beans Whole plant (1 st )

-- --
Forage (2 nd )

-- 0.1 T (0.001 T) Straw (3 rd )

-- -- Pods (2 nd )

-- -- Pods (3 rd )

-- -- Seeds (2 nd ; immature)

-- -- Seeds (3 rd ; mature)

-- -- Grapes Foliage

-- -- Fruit

-- -- Lettuce Wrapper leaves

-- -- Heads

-- --

Rotational Crops (PBI = 30 days) Carrot, lettuce, wheat

-- -- Ruminant (Goat) Fat, kidney, liver, meat, milk aqueous, milk fat -- --
Poultry (Laying Hen) Egg yolk, fat, meat, liver

-- --

Rat

-- -- Water

3

- MTCAM French beans

Whole plant (1 st )

-- 3.3 T (0.832 T)

Forage (2 nd )

-- 6.6 T (0.763 T)

Straw (3 rd )

-- 4.6 T (0.277 T)

Pods (2 nd )

-- 0.6 T (0.002 T) Pods (3 rd )

-- --
Seeds (2 nd ; immature) 14.3 T (0.058 T) --
Seeds (3 rd ; mature)

-- -- Grapes

Foliage

-- 4.1 T (0.645 T)

Fruit

-- 1.7 T (0.011 T)

Lettuce

Wrapper leaves

-- 2.4 T (0.04 T)

Heads

-- 1.1 T (0.001 T) Rotational Crops (PBI = 30 days) Carrot, lettuce, wheat

-- -- Ruminant (Goat)

Fat

-- -- Kidney

-- --

Liver

-- 1.2 T (0.0041 T)

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 43 of 48 Table B.2 Tabular Summary of Metabolites and Degradates Chemical Name (other names in parenthesis)
and Structure Matrix Percent TRR (PPM) a,b

Matrices

- Major Residue (>10%TRR) Matrices

- Minor Residue (<10%TRR)

Meat

-- -- Milk aqueous

-- -- Milk fat

-- -- Poultry (Laying Hen)

Egg yolk

-- 1.1 T (0.002 T)

Fat

-- -- Meat

-- -- Liver

-- -- Rat

-- -- Water

GPTC French beans Whole plant (1 st )

-- --
Forage (2 nd )

-- 1.7 B/1.7 T (0.17 B/0.20 T)

Straw (3 rd )

-- 5.0 B/4.8 T (0.16 B/0.24 T)

Pods (2 nd )

-- 4.7 B/7.4 T (0.01 B/0.02 T) Pods (3 rd )

-- -- Seeds (2 nd ; immature)

-- -- Seeds (3 rd ; mature)

-- -- Grapes

Foliage

-- 4.8 B/3.1 T (0.812 B/0.501 T)

Fruit 10.0 B (0.072 B) 3.4 T (0.022 T)

Lettuce

Wrapper leaves

-- 5.3 B/6.6 T (0.136 B/0.111 T)

Heads 10.1 B (0.007 B) 9.4 T (0.008 T) Rotational Crops (PBI = 30 days)

Carrot foliage (mature) 14.5 T (0.011 T) 4.0 B (0.009 B)

Carrot root (mature) 17.0 T (0.007 T) 5.9 B (0.005 B)

Lettuce, head (mature) 32.5 B/35.9 T (0.025 B/0.016 T) --

Wheat forage

-- 3.3 B/5.2 T (0.011 B/0.011 T)

Wheat hay

-- 2.6 B/5.7 T (0.031 B/0.062 T)

Wheat straw

-- 3.4 B/3.7 T (0.049 B/0.034 T) Wheat grain

-- -- Ruminant (Goat)

Fat, kidney, liver, meat, milk aqueous, milk fat -- --

Poultry (Laying Hen) Egg yolk, fat, meat, liver

-- --

Rat 23.09 (urine) 3 5.1 (bile) 3

Water

PPA French beans

-- --

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 44 of 48 Table B.2 Tabular Summary of Metabolites and Degradates Chemical Name (other names in parenthesis)
and Structure Matrix Percent TRR (PPM) a,b

Matrices

- Major Residue (>10%TRR) Matrices

- Minor Residue (<10%TRR) Grapes

-- -- Lettuce

-- --

Rotational Crops (PBI = 30 days)

Carrot foliage mature)

-- 1.8 B/4.7 T (0.004 B/0.003 T)

Carrot root (mature)

-- 1.1 B/5.4 T (0.001 B/0.002 T)

Lettuce, head (mature)

-- 3.1 T (0.001 T)

Wheat forage

-- 4.7 B/4.0 T (0.015 B/0.008 T)

Wheat hay

-- 1.8 B/4.2 T (0.021 B/0.045 T)

Wheat straw 10.0 T (0.092 T) 9.1 B (0.130 B)

Wheat grain

-- 0.3 B/3.3 T (0.001 B/0.002 T) Ruminant (Goat)

Fat

-- 6.0 T (0.0008 T)

Kidney 19.6 T (0.0205 T) 6.4 B (0.0046 B)

Liver 17.3 T (0.0618 T) 6.7 B (0.0287 B)

Meat

-- --

Milk aqueous

-- 1.8 B (0.0002 B)

Milk fat

-- 1.0 B/5.2 T (0.0013 B/0.0025 T) Poultry (Laying Hen)

Egg yolk

-- 2.8 B/0.8 T (0.006 B/0.0014 T)

Fat

-- -- Meat

-- --

Liver

-- 4.0 B/1.6 T (0.0085 B/0.0029 T)

Rat 17.6 F 3 6.8 M 3

Water

Malonyl

- GPTC French beans

-- -- Grapes

-- -- Lettuce

-- --

Rotational Crops (PBI = 30 days)

Carrot foliage mature) 12.3 T (0.009 T) 6.8 B (0.015 B)

Carrot root (mature) 11.4 B/28.5 T (0.010 B/0.011 T) --

Lettuce, head (mature) 11.4 B/18.9 T (0.009 B/0.009 T) --

Wheat forage 18.8 B/27.4 T (0.060 B/0.058 T) --

Wheat hay 16.1 B/15.5 T (0.193 B/0.167 T) --

Wheat straw 10.3 B/19.0 T (0.147 B/0.175 T) --

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 45 of 48 Table B.2 Tabular Summary of Metabolites and Degradates Chemical Name (other names in parenthesis)
and Structure Matrix Percent TRR (PPM) a,b

Matrices

- Major Residue (>10%TRR) Matrices

- Minor Residue (<10%TRR)

Wheat grain

-- 3.7 B/2.6 T (0.003 B/0.002 T) Ruminant (Goat) Fat, kidney, liver, meat, milk aqueous, milk fat -- --
Poultry Egg yolk, fat, meat, liver

-- --

Rat

-- --
Water

5

- HPPA French beans

-- -- Grapes

-- -- Lettuce

-- -- Rotational Crops

-- -- Ruminant (Goat)

Fat

-- -- Kidney

-- --

Liver

-- 1.9 B/5.6 T (0.0083 B/0.0199 T)

Meat

-- -- Milk aqueous

-- -- Milk fat

-- -- Poultry (Laying Hen) Egg yolk, fat, meat, liver

-- --

Rat

-- -- Water

a Maximum seasonal application rates on the label for proposed crops are as follows: 1.8 lb ai/A for almonds, 2.3 lb ai/A for the berry, low growing, subgroup 13

- 07G, 1.7 lb ai/A for fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F, 0.64 lb ai/A for lettuce, and 0.63 lb ai/A for rapeseed.
b Metabolism studies: French bean: MRID 49011962; 2.0 lb ai/A; 68

- day PHI. Grape: MRID 49011960; 2.0 lb ai/A; 43

- day PHI. Lettuce: MRID 49011961l; 2.0/2.1 lb ai/A (3.1x/3.3x); 18

- day PHI. Confined rotational crops: MRIDs 49011975 and 49018433; 2.0 lb ai/A; applied to bare soil; 30

- .120

- , and 365

- day PBIs.
G oats: MRID 49011964; 10 ppm; 7 days; 23

- hour PSI. Hens: MRID 49011963; 10 ppm; 14 days; 23

- hour PSI. Rats: MRID 49011950; 5ppm; 96 hours; values represent total in urine and feces; M/F = males/females

c Percent of dosage

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 46 of 48 Appendix C

. Physical/Chemical Properties

Table C

. Physicoc hemical Properties of the Technical Grade of Isofetamid

Parameter Value Reference
Molecular Weight 359.49 g/mol

MRID 49011905 Physical state solid
Melting point 103.5

– 105.0°C
Density (21oC) 1.18 g/cm 3

pH 6.8 for 1% w/v dispersion
Water solubility (20°C) 5.33 mg/L

Solvent solubility ( m g/L at 20°C) water 5.33

n

- heptane 1.2 xylene 61.4 1,2

- dichloroethane >250

acetone >250
methanol >250

n

- octanol 31.7 ethyl acetate >250

Vapor pressure (2 5 °C) 4.2× 10

- 7 Pa
3. 1 5×10

- 9 mm Hg Henry’s Law Constant (20 °C) at pH7 = 1.25 × 10

- 5 Pa .m 3 /mole

Dissociation constant, pKa (20°C) The pure active ingredient did not dissociate in pH 4 to
10. Octanol/water partition coefficient, log K OW (20°C) log K
ow = 2.5

UV/visible absorption spectrum The UV/visible absorption maxima (λ
max ) in purified
water is 264.3 nm.



### Appendix D

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include 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; and
the Residential SOPs ( Lawns/Turf ), are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human S tudies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency
website 9



### .

9 http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 47 of 48 Appendix E

. Occupational Exposure/Risk Summary Tables

Table E. Occupational Handler Non

- Cancer E xposure and Risk Estimates for Isofetamid

.

Exposure Scenario Crop or Target a Baseline
Inhalation
Unit Exposure b Maximum

Application

Rate c Area

Treated or

Amount
Handled Daily d Baseline Inhalation

Dose e MOE f

μg/lb ai lb ai/A Acres mg/kg/day ST/IT LOC = 100

Mixer/Loader

Mixing/Loading Liquids for Aerial Application Orchard Crops

0.219 0.572 350 0.000636 120,000

Sod Farms 0.567 350 0.000630 120,000

Typical Field Crops 0.442 350 0.000491 160,000

High

- Acreage Field Crops 0.312 1200 0.00119 64,000

Mixing/Loading Liquids for Airblast Application Orchard Crops 0.572 40 0.0000726 1,100,000

Mixing/Loading Liquids for Chemigation Orchard Crops 0.572 350 0.000636 120,000

Sod Farms 0.567 350 0.000630 120,000

Typical Field Crops 0.442 350 0.000491 160,000

High

- Acreage Field Crops 0.312 350 0.000346 220,000

Mixing/Loading Liquids for
Groundboom Application Golf Courses

(tees and greens only) 0.567 5 0.00000900 8,500,000

Golf Courses (fairways, tees, and greens) 0.567 40 0.0000720 1,100,000

Sod Farms 0.567 80 0.000144 530,000

Typical Field Crops 0.442 80 0.000112 680,000

High

- Acreage Field Crops 0.312 200 0.000199 380,000

Applicator

Applying Sprays for Aerial Application Orchard Crops

0.0 049 0.572 350 0.0000142 5,400,000

Sod Farms 0.567 350 0.0000141 5,400,000 Typical Field Crops 0.442 350 0.0000110 7,000,000 High

- Acreage Field Crops 0.312 1200 0.0000267 2,900,000 Applying Sprays for Airblast Application Orchard Crops 4.71 0.572 40 0.00157 49,000

Applying Sprays for
Groundboom Application Golf Courses

(tees and greens only)

0.34 0.567 5 0.0000140 5,500,000

Golf Courses (fairways, tees, and greens) 0.567 40 0.000112 680,000

Sod Farms 0.567 80 0.000223 340,000 Typical Field Crops 0.442 80 0.000174 440,000 High

- Acreage Field Crops 0.312 200 0.000307 250,000

Flagger

Flagging for Aerial Applications Orchard Crops

0.35 0.572 350 0.00102 75,000

Sod Farms 0.567 350 0.00101 76,000 Typical Field Crops 0.442 350 0.000786 97,000
High

- Acreage Field Crops 0.312 350 0.000554 140,000

### Isofetamid Human Heal th Risk Assessment DP No. 411106

Page 48 of 48 Table E. Occupational Handler Non

- Cancer E xposure and Risk Estimates for Isofetamid

.

Exposure Scenario Crop or Target a Baseline
Inhalation
Unit Exposure b Maximum

Application

Rate c Area

Treated or

Amount
Handled Daily d Baseline Inhalation

Dose e MOE f

μg/lb ai lb ai/A Acres mg/kg/day ST/IT LOC = 100

Mixer/Loader/Applicator

M/L/A Liquids for Backpack Sprayers Landscaping (turf, lawns,

athletic fields, parks, etc) (Broadcast and Spot) 2.58 0.000650 lb ai/gal 40

gallons 0.00000972 7,900,000

M/L/A Liquids for Manually

- Pressurized Handwand Sprayers Landscaping (turf, lawns,

athletic fields, parks, etc) 30 0.000650 lb ai/gal 40

gallons 0.000113 680,000

M/L/A Liquids for Mechanically

Pressurized Handgun Sprayers Orchard Crops (Foliar)

3.9 0.0572 lb ai/gal 1000

gallons 0.00323 24,000

Typical Field Crops (Foliar) 0.0442 lb ai/gal 0.00249 31,000

Golf Courses (tees and greens only)

1.9 0.567 5

acres 0.0000781 980,000 Golf Courses (fairways, tees, and greens) Landscaping (turf, lawns, athletic fields, parks, etc)

a “Typical Field Crops” include lettuce (head and leaf ) and low growing berry crop subgroup 13

- 07G

. “Orchard Crops” include almonds and small fruit vine climbing crop subgroup 13

- 07F. “High

- Acreage Field Crops” includes rapeseed (canola).
b Based on the “Oc cupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2012 ); Level of mitigatio n = Baseline.

c Based on the maximum application rates on the proposed label s (Reg. No s

. 71512

- EE and 71512

- EG ).
d Exposure Science Advisory Council Policy #9.1.

e Inhalation Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW ( 69 kg).
f Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). ST/IT NOAEL = 76.6 mg/kg/day. ST/IT LOC = 100.