Isofetamid Human Health Risk Assessment DP No. 411106 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: September 24, 2014 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Isofetamid. Aggregate Human Health Risk Assessment for the Proposed New 

Uses of the New Active Fungicide, including Agricultural Uses on Almonds, 

Lettuce, Small Vine Climbing Fruits (Crop Subgroup l 3-07F), Low Growing 

Berries (Crop Subgroup 13-07G), and Rapeseed (Crop Subgroup 20A); and Uses 

on Turf grass (including Golf Courses, Sod Farms, Seed Farms, Recreational 

Fields, and Commercial/Residential Lawns). 

PC Code: 270000 DP Barcode: 0411106 

Registration Nos.: 71512-EE, 71512-EG Decision No.: 474283 

Petition No.: 3F8142 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Aggregate Human Health CaseNo.: NA 

TXRNo.: NA CAS No.: 875915-78-9 

MRIDNo.: NA 40 CFR: to be determined (new active ingredient) 

FROM: Nancy J. Keller, Chemist, Risk Assessor l \Ullil/£1.<.r 

Myron Ottley, Senior Toxicologist ~ 

Minerva Mercado, Toxicologist --..._ --~:::;..;--~ (_. - Nancy Dodd, Chemist :;·/..-...,~ ~~?'/ 

Risk Assessment Branch 3 (RA'B3) 

Health Effects Division (7509P) 

THROUGH: Christine Olinger, Branch Chief W(/~ Risk Assessment Branch 3 (RAB3) 

and 

Anna Lowit, Designated Reviewer 

Michael Metzger, Designated Reviewer 

Risk Assessment Review Committee 

Health Effects Division (7509P) 

TO: Heather Garvie/Tony Kish, RM #22 

Fungicide Branch (FB) 

Registration Division (7505P) 

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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 Considerations ................................................................................................. 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 

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Isofetamid Human Health Risk Assessment DP No. 411106

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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 Aggregate 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 Health Risk Assessment DP No. 411106

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1.0 Executive Summary

Isofetamid is a new broad spectrum fungicide currently undergoing joint review with the 

Pesticide Management Regulatory Agency (PMRA) in Canada. It is a systemic fungicide 

belonging to the thiophene class of chemistry. Isofetamid is a phenyl-oxo-ethyl thiophene amide 

that acts as a succinate dehydrogenase inhibitor (SDHI), which causes adverse effects on 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/residential turf uses. The 

agricultural 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 

occupational sources. Non-occupational exposures to isofetamid are 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 intermediateterm durations only. The dermal route of exposure is not assessed because a dermal hazard was 

not identified. The proposed residential uses on turf result in inhalation exposures for adults

(handlers) and post-application incidental oral exposures for children (1 to <2 years old).

Toxicity/Hazard

The risk assessment for isofetamid is based on a well-characterized and 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 compared 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, neurotoxicity, 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 the multigeneration 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 Health Risk Assessment DP No. 411106

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Dietary Exposure (Food and Water) and Risk Estimates

An acute dietary assessment was not conducted because there 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 estimated 

drinking water concentration (EDWC) of 110 μg/L was incorporated directly into the chronic 

dietary assessment. The results of the chronic dietary (food and drinking water) analysis are not 

of concern 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 of concern (LOC = 100). The short-term residential 

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

incidental oral post-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 

inhalation 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 dermal route of 

exposure was not assessed because there is no dermal hazard. For adults and children, the shortterm aggregate risk estimates are not of concern; the MOEs are 24,000 and 3,900, 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 quantitatively assessed. The results of the occupational handler exposure and risk 

assessment indicate that short- and intermediate-term inhalation risk estimates are not of concern 

at baseline (long-sleeved shirt, long pants, shoes plus socks) without mitigation from any 

personal protective equipment (PPE). Both labels require PPE of chemical-resistant gloves. The 

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

intermediate-term inhalation MOEs range from 24,000 to 8,500,000 (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, the proposed

12-hour REI is adequate to protect agricultural workers from potential post-application risks.
Isofetamid Human Health Risk Assessment DP No. 411106

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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 databases 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 specific tolerance recommendations are discussed in Section 2.2.

2.1 Data Deficiencies

There 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 studies.

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 tandem mass spectrometry (LC-MS/MS) method (Document 

Number JSM0119; MRID49011967) is acceptable as an enforcement method for determination 

of isofetamid in plant matrices. In brief, isofetamid and the metabolite GPTC in crop 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 expressed as isofetamid 

equivalents). A livestock enforcement method is not required since livestock tolerances have not 

been recommended. Multiresidue methods testing data have been submitted for isofetamid and 
Isofetamid Human Health Risk Assessment DP No. 411106

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GPTC. The data indicate that multiresidue 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 tolerances 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 

5/27/2009. A revised 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 recommends revisions to some of the petitioned-for tolerance levels based on the following 

reasons: (1) Organization for Economic Cooperation and Development (OECD) tolerance 

calculation procedures; (2) the ROCKS decision that parent only is the residue of concern for 

primary crop tolerances rather than parent 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 Health Risk Assessment DP No. 411106

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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 tolerance 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 significantly 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 canola 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 the 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 Introduction

Isofetamid is a systemic, broad-spectrum thiophene fungicide. It acts as a succinate 

dehydrogenase inhibitor (SDHI), adversely affecting respiration in plants and fungi. Isofetamid 

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.
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3.1 Chemical Identity

Table 3.1 Test Compound Nomenclature

Chemical Structure

Common Name isofetamid

Company Experimental Name 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

Chemical 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 

Appendix C. Isofetamid is a solid and based on its low vapor pressure (3.15×10-9 mm Hg at 

25°C) and its Henry’s Law constant (1.2×10-5 Pa·m3/mol at 20°C), isofetamid is unlikely to 

volatilize significantly. 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 

bioaccumulation in fatty tissue or milk fat. The low octanol/water coefficient also suggests low 

potential for dermal absorption. 

H3C O

CH3

CH3 O

H3C

N

H

CH3 O

S

H3C

O

CH3 O

H3C

N

H

CH3 O

S

H3C

O

OH

HO

HO

OH
Isofetamid Human Health Risk Assessment DP No. 411106

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3.3 Pesticide Use Pattern

Isofetamid has been developed by ISK, with a proposal for one technical product and two US EP

registrations, which include agricultural food-uses. The only proposed formulation is an SC. 

The agricultural uses consist of broadcast foliar sprays via ground, aerial, or chemigation 

equipment; and the proposed residential use includes 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 Namea

Maximum 

Application 

Rate

Max. No. 

of

Apps per

Season

Max. 

Seasonal 

Application 

Rate

RTIc

Use Directions and Limitationsd

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 hybrids 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; lingonberry; 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/Ae 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.
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Table 3.3 Summary of Proposed Directions for Use of Isofetamid

Application 

Timing, Type, 

and Equipment

Formulation

[EPA Reg. No.]

Trade Namea

Maximum 

Application 

Rate

Max. No. 

of

Apps per

Season

Max. 

Seasonal 

Application 

Rate

RTIc

Use Directions and Limitationsd

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 radish; 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 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 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/Ae

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 fungicide 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 not 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

Humans 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 residential 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. 
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This is the first aggregate risk assessment prepared for the proposed uses of isofetamid. This risk 

assessment considers all of the exposure pathways based on the proposed 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 Actions 

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 risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the 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 risks for adult applicators and for toddlers, youths, and adults 

entering or playing on treated areas post-application are evaluated. Further considerations are 

currently in development as OPP has committed resources and expertise to the development of 

specialized software and models that consider exposure to bystanders and farm workers as well 

as lifestyle and traditional dietary patterns among specific subgroups.

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 

consumption, 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 higher 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 rats and dogs, oral

carcinogenicity studies in the rats and mice, oral developmental studies in rats and rabbits, a 

mutagenicity battery, a neurotoxicity battery in rats, an immunotoxicity study in mice, and a

dermal subchronic study in rats. Also available are a battery of in vitro dermal penetration 

studies in rat and human skin and an in vivo dermal penetration study in rats. Furthermore, rat 
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metabolism studies are available. A subchronic inhalation study was not included in the 

database, but the requirement has been waived (HASPOC memo, J. Leshin, TXR0057008, 

08/11/2014).

4.2 Absorption, 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 elimination half-lives were 

about 38 hours regardless 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 rats. Males, regardless of 

dose, eliminated most of the radiolabel in the feces while females eliminated approximately five 

times more radiolabel in the urine than males. Elimination was rapid in both sexes with the 

majority of the radiolabel recovered within 96 hours of treatment. Repeated dosing had little 

effect on the route or rate of elimination, suggesting lack of induction or inhibition of 

metabolizing enzymes. Biliary excretion was the major route of elimination for males and 

females. However, greater urinary excretion 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 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. Furthermore, 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 compared with the respective subchronic 

studies, showing an absence 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 
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toxicity. The mutagenicity battery was negative, and there was no evidence of carcinogenicity 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

reproduction study in the presence of parental toxicity. The immunotoxicity study in the mouse 

was negative. Neurotoxic 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 Factor for Infants and Children (FQPA Safety Factor)

Based on the currently available toxicity and exposure data, the risk assessment team 

recommends that the FQPA Safety Factor be reduced to 1X for the following reasons: there is a

complete toxicity database for isofetamid, there 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 of the Toxicology Database

The isofetamid toxicology 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 not 

included in the database, but the requirement has been waived (HASPOC memo, J. Leshin, 

TXR0057008, 08/11/2014). Although isofetamid produced 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 such 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 Neurotoxicity

In all of the available studies, there are no indications that the nervous system is a target 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 and a developmental 

neurotoxicity study is not required.
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4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There are no residual uncertainties regarding increased susceptibility. In the rat and rabbit 

developmental studies, there were no indications of toxicity in the dams or fetuses up to the limit 

dose. In the rat reproduction study, the offspring effects (decreased pup body weight in both 

generations and sexes) only occurred 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) were used to assess 

post-application exposure to children including incidental oral exposure. The residential postapplication assessment assumes that maximum application rates are applied and that hand-tomouth activities occur on the day of application. All of the exposure estimates are based on 

conservative, health-protective assumptions and are not likely to underestimate risk.

4.5 Toxicity Endpoint and Point of Departure Selections

The toxicity endpoints and PODs are summarized in Tables 4.5.4a and 4.5.4b, and detailed 

rationale for the selections is presented 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 quantified.

The chronic dietary endpoint was chosen from the rat multi-generation reproduction study

(MRID 49011940). The NOAEL of 76.6 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 inclusion bodies in the liver of F1 males, and decreased pup body 

weight in both sexes and generations. This study was chosen because 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/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.
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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% presents 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 below 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 F1 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 exposure 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 route. 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 F1 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 dermal endpoint was 

not identified.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Isofetamid is classified as “Not Likely to be Carcinogenic to Humans” based on the absence of 

significant tumor increases in two adequate rodent carcinogenicity 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 used in the study did not reach the 

limit dose of 1000 mg/kg bw/day. However, this study is considered adequate to assess 

carcinogenicity potential for risk assessment of the following reasons: 1) toxicity was not seen 
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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 adverse effects at levels up to the 

limit dose; 3) there was no evidence of carcinogenicity in the rat chronic/carcinogenicity study at 

otherwise toxic dose levels; and 4) any effects seen in a repeat mouse carcinogenicity study at 

levels greater than the current 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 F1 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 Doses and Endpoints for Isofetamid for Use in NonOccupational/Residential Human Health Risk Assessmentsa

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.

Toxicological effects attributable to a single exposure (dose) were not observed in oral toxicity 

studies.

Chronic 

Dietary (All 

Populations)

NOAEL = 

76.6

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 

1X

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 sexes and generations.

Incidental 

Oralb

Short-Term 

(1-30 days)

and 

Intermediate

-Terms (1-6 

months)

NOAEL = 

76.6

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 

1X

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.

Systemic toxicity was not seen in 28-day dermal toxicity in rats up to the limit dose (1000 

mg/kg/day). There are no concerns for developmental or reproductive toxicity or neurotoxicity in 

rat and rabbit studies.
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Table 4.5.4a Summary of Toxicological Doses and Endpoints for Isofetamid for Use in NonOccupational/Residential Human Health Risk Assessmentsa

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

UFA = 10X

UFH = 10X

FQPA SF = 

1X

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.

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 = lowest observed adverse effect level. UF = uncertainty factor. UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human 

population (intraspecies). FQPA SF = FQPA Safety Factor. LOC = level of concern.

b For Incidental Oral risk assessments, the adult female body weight (69 kg) is used because the toxicity endpoint (decreases in 

pup body weight) may have resulted from in utero exposures of the offspring in pregnant dams.

Table 4.5.4b Summary of Toxicological Doses and Endpoints for Isofetamid for Use in Occupational 

Human Health Risk Assessmentsa

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.

Systemic toxicity was not seen in 28-day dermal toxicity in rats up to the limit dose (1000 

mg/kg/day). There are no concerns for developmental or reproductive toxicity or neurotoxicity in 

rat and rabbit studies.

Inhalation 

Short-Term 

(1-30 days)

and 

Intermediate

-Term 

(1–6 months

NOAEL = 

76.6

mg/kg/day

UFA = 10X

UFH = 10X

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.

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 = lowest observed adverse effect level. UF = uncertainty factor. UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human 

population (intraspecies). UFDB = database uncertainty factor: use of a short-term study for intermediate-term risk assessment.

FQPA SF = FQPA Safety Factor. LOC = level of concern.
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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. The metabolic fate of this fungicide is complex with the formation of many low 

level metabolites. Numerous metabolites were detected in various crop matrices. In general, 

isofetamid was first metabolized by O-dealkylation to form 4HP or by cleavage between the 

benzene and thiophene rings to form 3-MTCAM (see Appendix B.1 for structures). The 

metabolite 4HP was further converted by conjugation to form GPTC or by cleavage between 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 milk and fat; PPA was the major

residue in liver and kidney; and the minor metabolites were 4HP, 5-HPPA, IBA, and 3-MTCAM. 

Major metabolites were not identified in poultry matrices. Minor residues included 4HP, 

isofetamid, PPA, IBA, and 3-MTCAM in egg yolk; 4HP, PPA, isofetamid, 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 of 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 in water (5.33 mg/L at 20oC), it may move from treated fields to 

surface water through run-off occurring shortly after application (i.e. rainfall events), and may 

also move into ground water. Isofetamid rapidly degrades as a result of aqueous photolysis, and 

degradation is expected to occur as a result of aerobic metabolism in soil and water. However, 

laboratory studies indicate that isofetamid is stable to hydrolysis and soil photolysis, and very 

persistent in anaerobic environments. No degradation of isofetamid occurred in the hydrolysis 

study. The half-lives for soil photolysis ranged from 294 days for dry soil to 354 days for moist 
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soil. The half-life calculated for the anaerobic soil metabolism study was 572 days, while the 

half-lives calculated for anaerobic aquatic metabolism 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. Parent isofetamid is the major 

residue in most matrices (see Appendix B). Not 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 metabolism 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 (ROCs) for tolerance enforcement and risk assessment for 

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,

05/21/2014):

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 appropriate marker of misuse. For risk 

assessment purposes, the ROCs are parent 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 isofetamid. 

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. 
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Processed Commodities: Based 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: For ruminant commodities, parent 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 toxicity 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 not observed in poultry, parent isofetamid was observed as a minor residue in hen 

commodities.

Water: Parent isofetamid is the only ROC for risk assessment. Based on structural similarity, 

PPA and 4HP are assumed to have similar toxicity as compared to parent 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 ROCs. 

Furthermore, although 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 

Expressiona

Matrix Residues included in 

Risk Assessmenta

Residues included in 

Tolerance Expression

Plants Primary Crop Isofetamid and GPTC Isofetamid

Rotational Crop NSb NSb

Livestock Ruminant Isofetamid and PPA Isofetamid

Poultry Isofetamid Isofetamid

Drinking Water Isofetamid NAc

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 Appendix 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.
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Processing studies have 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 to simulated processing procedures, therefore

degradation would not be expected during food processing involving pasteurization, 

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 isofetamid 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), high 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 unnecessary

because data are not required for samples analyzed within 6 months.

Livestock 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 confined 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 for 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, 05/21/2014). Thus, inadvertent or indirect tolerances for these rotational 

crops are not required at this time. If additional field rotational crop studies are conducted 

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 

(DP422934, M. Biscoe, 09/22/2014). This drinking water 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, and representative application 

methods and exposure estimates. EDWCs for the chronic assessment were estimated using the 

Pesticide Flooded Application Model (PFAM version 1.0). Detailed descriptions, 

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-
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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 value was the 1-in-10 year 

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

Wisconsin 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 Usesa

Drinking Water 

Source (Model)

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 Water 

(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 denotes 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. Since 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 juice 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 μg/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
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The results indicate that chronic dietary (food and drinking water) exposure and risk estimates 

are not of concern for the U.S. population and all population subgroups. The risk estimates 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.

The chronic dietary assessment does not underestimate risk to the general U.S. population or any 

population subgroup. The dietary exposure and risk estimates are somewhat refined since they 

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

additional 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 Isofetamida

Population Subgroup cPAD

Chronic Dietary

Dietary Exposure cPAD

mg/kg/day mg/kg/day %

General U.S. Population

0.766

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. 

However, 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 current policies which include HED’s 

2012 Residential SOPs1along with policy changes for body weight assumptions (DP411113, N. 

Keller, 07/25/2014).

The only EP that may lead to residential exposures (handler and/or post-application exposures) is 

the SC formulation: 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
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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 all 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. Since 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 indicates

that a maximum of eight applications are allowed per year. Thus, intermediate-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 SOPs2(Lawns/Turf). The algorithms used to estimate exposure and dose for 

residential handlers can be found in the 2012 Residential SOPs2(Lawns/Turf).

Risk estimates of all possible scenarios are not of concern. Short-term inhalation MOEs range 

from 850,000 to 18,000,000 as summarized in Table 6.1.

Table 6.1 Residential Handler Non-Cancer Exposure and Risk Estimates for Isofetamid

Application 

Equipment Crop or Target

Inhalation 

Unit 

Exposure

Maximum 

Application 

Ratea

Amount 

Handled 

Dailyb

Inhalation

Dosec

MOEd

mg/lb ai mg/kg/day

Mixer/Loader/Applicator for Liquid Formulations

ManuallyPressurized 

Handwand

Outdoor Broadcast: Lawns/Turf 0.018 0.00650

lb ai/gal

5

gal 0.00000850 9,000,000

Hose-End 

Sprayer

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 Can 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 rates on proposed label, EPA Reg. No. 71512-EG, for liquid applications to turf. 

b Based on HED’s 2012 Residential SOPs: Lawns/Turf (http://www.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 = 100.

6.2 Post-Application Exposure

There is the potential for post-application exposure for individuals as a result of being in an 

environment that has been previously treated with isofetamid. EPA Reg. No. 71512-EG is 

 

2 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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proposed for use on turf areas associated with golf courses (greens, tees, and fairways), college 

and professional sports fields, and residential lawns. 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 experience 

short-term incidental 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) selected for each post-application scenario is based on 

an analysis provided as an Appendix in the 2012 Residential SOPs3. This lifestage is not the 

only lifestage that could be potentially exposed for these post-application scenarios; however, the 

assessment 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 

SOPs4(Lawns/Turf). The algorithms used to estimate residential post-application exposure and 

dose can be found in the 2012 Residential SOPs5(Lawns/Turf).

In accordance with 40CFR158, 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 exposure to turf. Thus, in addition to the SOPs, the 

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/cm2. 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-application 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). The 

incidental oral scenarios (i.e. hand-to-mouth and object-to-mouth) should be considered interrelated and it is likely that they occur interspersed amongst each other across time. However, 

combining these scenarios would be overly-conservative because of the conservative 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.gov/pesticides/science/residential-exposure-sop.html
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Table 6.2 Residential Post-Application Non-Cancer Exposure and Risk Estimates for Isofetamid

Lifestage

Post-Application Exposure Scenario Application 

Ratea

Doseb

MOEsc

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

0.0130 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 (μg/cm2) × fraction of hand mouthed (0.127) × surface area of 1 hand (150 cm2) 

× 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 per hour (13.9 events/hr) ÷ # of replenishment intervals/hr)) ÷ body weight (11 kg).

Object-to-Mouth Dose = object residue loading (μg/cm2) × unit conversion factor (0.001 mg/μg) × object surface area mouthed 

/ event (10 cm2/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/day) × 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/cm2.

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 proposed 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 DoseaMOEb

mg/kg/day

Adults 

Residential Handler Inhalation Exposure

(Applying Liquids to Lawns/Turf with a Hose-End Sprayer) 0.0000900 850,000

Children (1 to <2 Years Old)

Post-Application Incidental Oral Exposure: Hand-to-Mouth

(After Liquid Application to Lawns/Turf) 0.0130 5,900

a Daily Dose = See Table 6.1 for adult handler scenarios 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-Application Inhalation Exposure

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

individuals nearby pesticide applications. The agency sought expert advice and input on issues 
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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 inhalation toxicological studies) or further 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 methods (e.g. groundboom and airblast) 

employed for isofetamid. The agency has been working with the Spray Drift Task Force (a task 

force composed of various registrants which was developed as a result of a Data Call-In issued 

by EPA), EPA Regional Offices, and State Lead Agencies for pesticide regulation, and other 

parties to develop the best spray drift management practices (see the agency’s Spray Drift 

website for more information). 6 The agency has also developed a policy on how to 

appropriately consider spray drift as a potential source of exposure in risk assessments for 

pesticides. 

The potential for spray drift will be quantitatively evaluated for each pesticide during the 

Registration Review process which ensures that all uses for that pesticide will be considered 

concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures 

For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating 

Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification 

of indirect non-occupational exposure to drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

7.1 Acute Aggregate Risk

An acute aggregate risk assessment was not conducted since adverse effects attributable to a 

single dose were not identified.

 

6 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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7.2 Short-Term Aggregate Risk

There is potential short-term exposure to isofetamid via the dietary (which is considered 

background 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 shortterm aggregate risk estimates are not of concern, as shown in Table 7.2 (MOEs = 24,000 and 

3,900, respectively).

Table 7.2 Short-Term Aggregate Risk Calculations

Population

Short-Term Scenario

NOAEL 

mg/kg/day LOCa

Max 

Allowable 

Exposureb

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/dayc

Total 

Exposure 

mg/kg/dayd

Aggregate 

MOE (food, 

water, and 

residential)e

Adults

76.6 100 0.766

0.003070 0.0000900 0.003160 24,000

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 Residential Exposure = Handler Inhalation Only for Adults and Post-Application Incidental Oral Only for 

Children (See Table 6.3).

d Total 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, intermediate-term exposure is not expected 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 incidental 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 chronic 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 likely to be carcinogenic to humans.” Therefore, an aggregate 

cancer assessment was not conducted.
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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, therefore, 

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 chemicals, see the 

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

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

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

9.0 Occupational Exposure/Risk Characterization

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 estimates are not of concern

(DP411113, N. Keller, 07/25/2014). Appendix E summarizes 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, occupational handler exposure is expected from the proposed

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

is based on several scenarios which include mixing/loading/applying an SC formulation of 

isofetamid. The use sites are summarized in Section 3.0. Methods of application include aerial, 

airblast, chemigation, groundboom, and handheld equipment (refer to Appendix E for a detailed 

list of scenarios).

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

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

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

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

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

time frame; however, there may be a large agribusiness and/or commercial applicators who may 

apply a product over a period of several weeks (e.g. completing multiple applications for 

multiple 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 area treated or 

amount handled is based on HED ExpoSAC 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 
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Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler 

Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force 

(ORETF) database; the 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 

predicting handler exposure that are used in this assessment, known as “unit exposures”, are 

outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table7”, 

which, along with additional information on HED policy on use of surrogate data, including 

descriptions of the various sources, can be found at the Agency website8.

Both proposed labels require chemical-resistant gloves as PPE. The results of the occupational 

handler exposure and risk assessment indicate that short- and intermediate-term inhalation risks 

are not of concern (i.e. MOEs 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 only 

engineering control (enclosed cockpit) data are available to assess risks to handlers operating 

aircrafts.

The Agency matches quantitative occupational exposure assessment with appropriate 

characterization of exposure potential. While HED presents quantitative risk estimates for 

human flaggers when appropriate, agricultural aviation has changed dramatically over the past 

two decades. According to the 2012 National Agricultural Aviation Association (NAAA) survey 

of their membership, the use of GPS for swath guidance in agricultural aviation has grown 

steadily from the mid 1990’s. Over the same time period, the use of human flaggers for aerial 

pesticide applications has decreased steadily from ~15% in the late 1990’s to only 1% in the 

most recent (2012) NAAA survey. The Agency will continue to monitor all available 

information sources to best assess and characterize the exposure potential for human flaggers in 

agricultural aerial applications.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for 

exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, 

and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, 

pilots are not required to wear protective gloves for the duration of the application. With this 

level of protection, there are no risk estimates of concern for applicators.

9.2 Short- 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 reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

 

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 Health Risk Assessment DP No. 411106

Page 32 of 48

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1 Dermal Post-Application Risk

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 hours for the REI. Thus, the 12-hour REI on the proposed labels is 

acceptable for all proposed uses.

9.2.3 Inhalation Post-Application Risk

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has 

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

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agency will utilize this analysis to determine 

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

required for 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, inhalation exposure during dusty mechanical 

activities such as shaking and mechanical harvesting is another potential source of postapplication inhalation exposure. However, the airblast applicator scenario is believed to 

represent a reasonable worst case surrogate estimate of post-application inhalation exposure 
Isofetamid Human Health 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 References

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 13-07G), 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 of 

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 (ToxSAC) Meeting of May 8, 2014.”

N. Dodd, 06/20/2014, DP411108, “Isofetamid. First 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, 09/23/2014, DP411109, “Isofetamid Chronic Aggregate Dietary (Food and Drinking 

Water) 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 

20A.”

I. Encarnacion, 05/21/2014, DP411110, “Isofetamid. Report of the Residues of Concern 

Knowledgebase Subcommittee (ROCKS).”

N. Keller, 07/25/2014, DP411113, “Isofetamid. Occupational and Residential Exposure and 

Risk Assessment for the Proposed New Uses of the New Active Fungicide, including 

Agricultural Uses 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 (including 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) Meetings on October 25, 2012 and November 8, 2012: 

Recommendations on the Requirement of 28-Day and 90-Day Inhalation Studies.”
Isofetamid Human Health Risk Assessment DP No. 411106

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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

CRa

Y

Y

Y

N

Nb

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

49011929c

49011930c

--

49011932

49011933c

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 Chromosomal 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.............................................................

870.7600 Dermal Penetration - Human.......................................................

870.7800 Immunotoxicity - Mice................................................................

Y

N

CRa

CRa

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/oncogenicity 

(rat) study. In addition, a one-year chronic study was submitted (MRID 49011929).
Isofetamid Human Health Risk Assessment DP No. 411106

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A.2 Toxicity Profiles

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 LD50 > 2000 mg/kg III

Acute dermal (rat) 49032505 LD50 > 2000 mg/kg III

870.1300 Acute inhalation (rat) 49032506 LC50 > 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 

clinical 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, 933 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/guideline

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 21/28-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.
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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 levels).

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/day

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)

acceptable/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 Health Risk Assessment DP No. 411106

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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 background.

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 concentrations 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 

T1/2 ~38 hrs. Metabolized mainly by Odealkylation, hydroxylation, and subsequent 

glucuronidation. 

870.7600 In vivo dermal 

penetration (rat)

49011953 (2012)

acceptable/guideline

3.2, 7.5, 4000 μg/cm2/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/cm2/hr

Did not readily penetrate rat skin. Steady-state 

absorption rates were low: 0.2, 0.010, and 0.009 

μg/cm2/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/cm2/hr

Did not readily penetrate human skin. Steady-state 

absorption rates were low: 0.08-0.30, 0.0026, and 

0.0008 μg/cm2/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 Health Risk Assessment DP No. 411106

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Appendix B. Isofetamid Metabolite Profile

B.1 Isofetamid Metabolites Summary Table

Table B.1 Summary Table of Parent and Metabolites/Degradates

Common Name/Code 

(ID No.) Chemical Name Chemical Structure

Isofetamid/ISK-5411

CAS #875915-78-9

IUPAC: N-[1,1-dimethyl-2-(4-isopropoxy-otolyl)-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 Health Risk Assessment DP No. 411106

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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 (1st)

92.5 B/91.0 T

(20.695 B/23.146 T) --

Forage (2nd)

77.1 B/76.7 T

(8.121 B/8.889 T) --

Straw (3rd)

52.6 B/62.0 T

(1.718 B/3.066 T) --

Pods (2nd)

80.9 B/68.7 T

(0.212 B/0.284 T) --

Pods (3rd)

26.3 B/18.2 T

(0.077 B/0.068 T) --

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

(0.072 B/0.113 T) --

Seeds (3rd; 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 Health Risk Assessment DP No. 411106

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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 / 4.9c

Water

4HP

French beans

Whole plant (1st) --

0.3 T

(0.069 T)

Forage (2nd) --

0.2 T

(0.019 T)

Straw (3rd) --

1.1 T

(0.053 T)

Pods (2nd) -- --

Pods (3rd) -- --

Seeds (2nd; immature) -- --

Seeds (3rd; 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 Health Risk Assessment DP No. 411106

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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 / 6.93

Water

IBA

French beans

Whole plant (1st) --

0.5 B

(0.107 B)

Forage (2nd) --

0.5 B

(0.057 B)

Straw (3rd) -- --

Pods (2nd) -- --

Pods (3rd) -- --

Seeds (2nd; immature) -- --

Seeds (3rd; 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 Health Risk Assessment DP No. 411106

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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 (1st) -- --

Forage (2nd) --

0.1 T

(0.001 T)

Straw (3rd) -- --

Pods (2nd) -- --

Pods (3rd) -- --

Seeds (2nd; immature) -- --

Seeds (3rd; 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 (1st) --

3.3 T

(0.832 T)

Forage (2nd) --

6.6 T

(0.763 T)

Straw (3rd) --

4.6 T

(0.277 T)

Pods (2nd) --

0.6 T

(0.002 T)

Pods (3rd) -- --

Seeds (2nd; immature) 14.3 T

(0.058 T) --

Seeds (3rd; 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 Health Risk Assessment DP No. 411106

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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 (1st) -- --

Forage (2nd) --

1.7 B/1.7 T

(0.17 B/0.20 T)

Straw (3rd) --

5.0 B/4.8 T

(0.16 B/0.24 T)

Pods (2nd) --

4.7 B/7.4 T

(0.01 B/0.02 T)

Pods (3rd) -- --

Seeds (2nd; immature) -- --

Seeds (3rd; 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 -- --
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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 F3 6.8 M3

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 Health Risk Assessment DP No. 411106

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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.

Goats: 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
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Appendix C. Physical/Chemical Properties

Table C. Physicochemical 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/cm3

pH 6.8 for 1% w/v dispersion

Water solubility (20°C) 5.33 mg/L

Solvent solubility (mg/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 (25°C) 4.2×10-7 Pa

3.15×10-9 mm Hg

Henry’s Law Constant (20 °C) at pH7 = 1.25×10-5 Pa.m3/mole

Dissociation constant, pKa (20°C) The pure active ingredient did not dissociate in pH 4 to 

10.

Octanol/water partition 

coefficient, log KOW (20°C) log Kow = 2.5

UV/visible absorption spectrum The UV/visible absorption maxima (λmax) 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 Studies Review Board. 

Descriptions of data sources, as well as guidance on their use, can be found at the Agency 

website9.

 

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 Health Risk Assessment DP No. 411106

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Appendix E. Occupational Exposure/Risk Summary Tables

Table E. Occupational Handler Non-Cancer Exposure and Risk Estimates for Isofetamid.

Exposure Scenario Crop or Targeta

Baseline 

Inhalation 

Unit 

Exposureb

Maximum

Application 

Ratec

Area 

Treated or 

Amount 

Handled 

Dailyd

Baseline Inhalation

Dosee MOEf

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

0.0049

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 Health Risk Assessment DP No. 411106

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Table E. Occupational Handler Non-Cancer Exposure and Risk Estimates for Isofetamid.

Exposure Scenario Crop or Targeta

Baseline 

Inhalation 

Unit 

Exposureb

Maximum

Application 

Ratec

Area 

Treated or 

Amount 

Handled 

Dailyd

Baseline Inhalation

Dosee MOEf

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 0.000650lb ai/gal

40

gallons 0.000113 680,000

M/L/A Liquids for 

MechanicallyPressurized 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 “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation = Baseline.

c Based on the maximum application rates on the proposed labels (Reg. Nos. 71512-EE and 71512-EG).

d Exposure Science Advisory Council Policy #9.1.

e Inhalation Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or 

Amount Handled Daily (A or gal/day) ÷ BW (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.