Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: July 18, 2013 

SUBJECT: Fomesafen Sodium: Human Health Risk Assessment for the Section 3 

Registration Action on Cantaloupe, Cucumber, Pea (Succulent), Pumpkin, Summer Squash, 

Winter Squash, Watermelon, Soybean (Succulent) and Lima Bean (Succulent)

PC Code: 123803; 123802 DP Barcode: 403953, 410795

Decision No.: 467057, 477271 Registration No.: 100-993

Petition No.: 2E8061, 3E8167 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical 

Aggregate

Case No.: NA

TXR No.: NA CAS No.: 72178-02-0

MRID No.: NA 40 CFR: §180.433

FROM: Danette Drew, Chemist

Ideliz Negrón Encarnación, Ph.D., Chemist

Alexandra LaMay, Biologist

Ronnie Bever, Ph.D., Toxicologist 

Branch V/VII

Health Effects Division (7509P)

THROUGH: William Irwin, Ph.D., Toxicologist

Michael Metzger, Branch Chief

Branch V/VII

Health Effects Division (7509P)

TO: Laura Nollen, Risk Manager Reviewer

Barbara Madden, Risk Manager

Risk Integration, Minor Use & Emergency Response Branch

Registration Division (RD, 7505P)
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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............................................................................................ 6

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

2.2.4 International Harmonization......................................................................................... 7

2.3 Label Recommendations.................................................................................................. 7

2.3.1 Recommendations from Residue Reviews................................................................... 7

2.3.2 Recommendations from Occupational Assessment ..................................................... 8

3.0 Introduction.......................................................................................................................... 8

3.1 Chemical Identity ............................................................................................................. 8

3.2 Physical/Chemical Characteristics................................................................................... 8

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

3.4 Anticipated Exposure Pathways..................................................................................... 10

3.5 Consideration of Environmental Justice ........................................................................ 10

4.0 Hazard Characterization and Dose-Response Assessment................................................ 11

4.1 Summary of Toxicological Effects ................................................................................ 11

4.2 Safety Factor for Infants and Children (FQPA Safety Factor)....................................... 12

4.2.1 Completeness of the Toxicology Database ................................................................ 12

4.2.2 Evidence of Neurotoxicity.......................................................................................... 13

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal............. 13

4.2.4 Residual Uncertainty in the Exposure Database......................................................... 13

4.3 Toxicity Endpoint and Point of Departure Selections.................................................... 13

5.0 Dietary Exposure and Risk Assessment ............................................................................ 15

5.1 Residues of Concern Summary and Rationale............................................................... 15

5.2 Food Residue Profile...................................................................................................... 15

5.3 Water Residue Profile .................................................................................................... 16

5.4 Dietary Risk Assessment................................................................................................ 17

5.4.1 Description of Residue Data Used in Dietary Assessment......................................... 17

5.4.2 Percent Crop Treated Used in Dietary Assessment.................................................... 17

5.4.3 Acute Dietary Risk Assessment ................................................................................. 17

5.4.4 Chronic Dietary Risk Assessment .............................................................................. 18

5.4.5 Cancer Dietary Risk Assessment................................................................................ 18

5.4.6 Summary Table........................................................................................................... 18

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................... 18

6.1 Residential Bystander Post-application Inhalation Exposure ........................................ 19

6.2 Spray Drift...................................................................................................................... 19

7.0 Aggregate Exposure/Risk Characterization.......................................................................... 19

8.0 Cumulative Exposure/Risk Characterization....................................................................... 20

9.0 Occupational Exposure/Risk Characterization ..................................................................... 20

9.1 Short-/Intermediate -Term Handler Risk ....................................................................... 20

9.2.1 Dermal Post-application Risk..................................................................................... 24

9.2.2 Inhalation Post-application Risk................................................................................. 25

10.0 References.......................................................................................................................... 26
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Appendix A. Toxicology Profile and Executive Summaries....................................................... 27

A.1 Toxicology Data Requirements...................................................................................... 27

A.2 Toxicity Profiles............................................................................................................. 28

A.3 Toxicity Summaries......................................................................................................... 33

Appendix B. Physical/Chemical Properties................................................................................. 47

Appendix C. Review of Human Research ................................................................................... 48
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1.0 Executive Summary

Fomesafen, 5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide), is 

an herbicide used for control of broadleaf weeds, annual grasses, perennial weeds, and sedges. It 

is in the diphenylether chemical class, and its mode of action is via inhibition of 

protoporphyrinogen oxidase (PPO) in the plant. Fomesafen products are formulated as the 

sodium salt, and the concentration of the active ingredient in the formulation is expressed in 

terms of the acid equivalent (ae). It is currently registered for use on peppers, tomatoes, 

potatoes, cotton, dry beans, and field soybeans. There are no residential uses of fomesafen. The 

requested Section 3 registration of Reflex Herbicide (22.8% active ingredient sodium salt of 

fomesafen) is for new uses on cantaloupe, cucumber, pea (succulent), pumpkin, summer squash, 

winter squash, watermelon, and soybean (succulent) (petition #2E8061), and on lima bean 

(succulent) (petition #3E8167). 

The Health Effects Division (HED) has conducted a human health risk assessment to support the 

requested use registrations and the establishment of associated tolerances. Assessments were 

performed for potential dietary (food and drinking water) and occupational worker exposures. 

The dietary risk assessment takes into account all existing and proposed uses of fomesafen. 

The toxicity database for fomesafen is complete. Generally, hyalinization of hepatocytes 

provided the most sensitive toxicological endpoint (short, intermediate, and long term) in 

mammals. In the subchronic and chronic toxicity studies in rats and mice, food consumption, 

food efficiency, body weight, body weight gain, and histopathological changes in the liver were 

parameters that were most often affected. In addition, dogs and mice also showed hematological 

changes. Neurotoxicity may occur at the same dose level as systemic toxicity. Fomesafen was

not considered to be mutagenic. Carcinogenicity was not observed in the rat chronic toxicity/

carcinogenicity study. Liver tumors were produced in the mouse carcinogenicity study; 

however, HED’s Cancer Assessment Review Committee (CARC) determined that fomesafen 

should be classified as “Not Likely to be Carcinogenic to Humans” (HED Doc No. 0053835). 

Post-implantation loss was noted in the developmental study; however, no quantitative or 

qualitative evidence of increased susceptibility was seen following in utero exposure to rats or 

rabbits in developmental studies or in the reproduction study. Fomesafen can result in 

suppression of anti-SRBC IgM response, but this was not the most sensitive endpoint. 

Fomesafen has a low order of acute toxicity by the oral, dermal, and inhalation routes of 

exposure (Toxicity Category IV). Fomesafen is minimally irritating to the eye and is not

irritating to the skin. It is not a sensitizer. 

The fomesafen risk assessments were based on the most sensitive endpoints in the toxicity

database, and the NOAELs selected for risk assessment are considered protective of potential 

developmental, neurotoxic, and immunotoxic effects for infants and children. Further, highly 

conservative exposure estimates were incorporated into the dietary risk assessment and there are 

no residential uses; therefore, reduction of the 10x Food Quality Protection Act (FQPA) safety

factor to 1x is considered appropriate.
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Sufficient residue data are available to support the proposed tolerances for residues of fomesafen 

on cantaloupe, cucumber, pea (succulent), pumpkin, summer squash, winter squash, watermelon, 

soybean (succulent), and lima bean (succulent). The residue of concern is only the parent, 

fomesafen. The residue data are supported by adequate storage stability data, and an analytical 

method is available to support the tolerances. All residues in the magnitude of residue studies 

were below the lowest limit of method validation (LLMV), and recommended tolerances are 

based on this level.

Environmental fate data indicate that fomesafen should be very mobile and highly persistent in 

terrestrial and aquatic environments. The residue of concern in drinking water is parent 

fomesafen. Estimated drinking water concentrations (EDWCs) were based on Tier II PRZMEXAMS screening model.

Conservative acute and chronic dietary (food and drinking water) assessments were performed 

using tolerance level residues, assuming 100% crop treated, and incorporating modeled EDWCs. 

Acute and chronic dietary (food and drinking water) risk estimates are not of concern. 

Because there are no registered residential uses of fomesafen, aggregate risks are identical to the 

food and drinking water dietary risk estimates; there are no acute or chronic aggregate dietary

risk estimates of concern.

For occupational handlers, dermal and inhalation MOEs above 100 are not of concern. All 

occupational exposure risk estimates for short- and intermediate- term exposures for handlers are 

not of concern with single layer dermal PPE (includes long-sleeve shirt and long pants) or with 

engineering control enclosed cab (fixed wing aircraft/aerial applicators). Dermal MOEs ranged 

from 350 to 300,000, and inhalation MOEs ranged from 410 to 360,000.

The applications to most of the proposed crops are for only pre-emergent or directed ground 

sprays; thus, post-application contact with treated foliage is expected to be negligible using these 

applications. The proposed uses for soybean and lima bean include a post-emergent application; 

therefore, a quantitative dermal post-application exposure assessment was only conducted for 

these uses. Post-application worker risk estimates for short- and intermediate- term exposures 

are not of concern (i.e., dermal MOEs are greater than the LOC of 100). Dermal MOEs ranged 

from 3,200 to 59,000 for post-application activities. Based on the Agency's current practices, a 

quantitative non-cancer occupational post-application inhalation exposure assessment was not 

performed for fomesafen sodium. If new policies or procedures are put into place, the Agency

may revisit the need for a quantitative occupational post-application inhalation exposure 

assessment for fomesafen sodium.

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment (see Section 3.5).

See Appendix C for information regarding the use of human research data in this assessment.
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2.0 HED Recommendations

HED recommends for the registration and associated tolerances for the use of fomesafen sodium 

on cantaloupe, cucumber, pea (succulent), pumpkin, summer squash, winter squash, watermelon, 

soybean (succulent), and lima bean (succulent). The specific tolerance recommendations are 

discussed in 2.2, and label modifications are discussed in section 2.3 below.

2.1 Data Deficiencies

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate residue analytical methods are available for the purpose of fomesafen tolerance 

enforcement for plant commodities. A high performance liquid chromatography method with 

tandem mass spectrometry detection (LC/MS/MS) method (GRM045.01A) has previously been 

submitted as an enforcement method. The method uses extraction procedures similar to previous 

methods, SPE cleanup procedures, and the final determination step by LC/MS/MS for analysis of 

fomesafen residues. The validated limit of quantitation (LOQ) of the method is 0.02 ppm. This 

method is similar to the data acquisition methods used for fomesafen on cantaloupe, pea 

(succulent), summer squash, and cucumber, where the LLMV was 0.025 ppm. 

The requirements for multiresidue method testing data for fomesafen are fulfilled. FDA multiresidue methods are not suitable for determining residues of fomesafen. 

Analytical standards for fomesafen are currently available in the EPA National Pesticide 

Standards Repository.

2.2.2 Recommended Tolerances

HED recommends that 40 CFR 180.443 be amended by establishing tolerances for the plant 

commodities listed in the Table 2.2.2 below. The tolerances for plant commodities should be 

defined as follows:

Tolerances are established for residues of the herbicide fomesafen, including its metabolites and 

degradates, in or on the following commodities. Compliance with the tolerance levels specified 

in the table below is to be determined by measuring only fomesafen, 5-[2-chloro-4-

(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide, in or on the commodity.
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Table 2.2.2. Tolerance Summary for Fomesafen.

Commodity Proposed Tolerance 

(ppm)

HED-Recommended 

Tolerance (ppm)

Comments 

(correct commodity definition)

Cantaloupe 0.025 0.025

Cucumber 0.025 0.025

Pea, succulent 0.025 0.025

Pumpkin 0.025 0.025

Squash, summer 0.025 0.025

Winter, Squash 0.025 0.025 Squash, winter

Watermelon 0.025 0.025

Vegetable, soybean, 

succulent 0.05 0.05 Soybean, vegetable, succulent

Lima, bean 0.05 0.05 Bean, lima, succulent

[It is noted that adequate field trial data for cantaloupe, cucumber, and summer squash is 

available to establish tolerances for melon, crop subgroup 9 A, and squash/cucumber, crop 

subgroup 9B. The HED will consider the establishment of tolerances for these two crop 

subgroups upon petition from the registrant.]

2.2.3 Revisions to Petitioned-For Tolerances

Both the proposed and recommended tolerance levels are the same and are based on the 

commodity LLMV, since residues were below this level in the field trial studies. The 

commodity names should be changed to reflect the correct commodity definitions.

2.2.4 International Harmonization

Codex or Mexican MRLs have not been established for residues of fomesafen in/on the 

registered and proposed commodities; therefore, there are no issues with international 

harmonization raised by this action. Canadian MRL has been established for residues of 

fomesafen in/on succulent shelled lima beans at 0.05 ppm which is harmonized with the USA 

tolerance for lima beans. Canada is also currently reviewing a request for the use of fomesafen 

on cucumbers.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

Rotational crop restrictions were not included in the Section B of the petition. The appropriate 

plant-back intervals (PBIs) for rotated crops should be specified in Section B and in the label of 

Reflex® Herbicide. Refer to the residue chemistry chapter for PBIs previously established (I. 

Negron; D407932).
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2.3.2 Recommendations from Occupational Assessment

None.

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Test Compound Nomenclature.

Compound

Common name Fomesafen Sodium

Company experimental name Not provided.

IUPAC name 5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-N-methylsulfonyl-2-nitrobenzamide, sodium salt

CAS name 5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitro-benzamide, sodium 

salt

CAS registry number 108731-70-0

Compound

Common name Fomesafen

Company experimental name Not provided.

IUPAC name 5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-N-methylsulfonyl-2-nitrobenzamide

CAS name 5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide

CAS registry number 72178-02-0

End-use product (EP) Reflex® Herbicide, 2 lb ae/gal SL; EPA Reg. No. 100-993

3.2 Physical/Chemical Characteristics

Fomesafen is not especially volatile and has a low vapor pressure of 7.5 x 10-7 mm Hg at 50 oC. 

The octanol water partition coefficient (Kow = 790 at pH 1) suggests that it is slightly lipophilic. 

Fomesafen is highly soluble in water (600 g/L at 25 °C and pH of 7) and exists as the anionic 

form at environmental relevant conditions (pKa is 2.7). Fomesafen is expected to be highly

mobile in aquatic environments. A table of the physical and chemical properties can be found in 

Appendix B.

F3C

Cl

O

NO2

O

N

S

CH3

O

O

Na

+

F3C

Cl

O

NO2

O

N

H

S

CH3

O

O
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3.3 Pesticide Use Pattern

The end-use product relevant to the current petitions is Reflex® Herbicide (EPA Reg. No. 100-

993), a soluble concentrate liquid (SL) formulation containing 22.8% sodium salt of fomesafen 

as the active ingredient (equivalent to 2 lb ae/gal of fomesafen). Reflex® is a selective 

herbicide, which may be applied preplant surface, pre-emergence, and/or post-emergence for 

control or partial control of broadleaf weeds, grasses, and sedges. In support of the proposed 

uses, the petitioner submitted the proposed use directions of the Reflex® Herbicide in the 

Section B of the petition. A summary of the proposed use directions is presented in Table 3.3.

See section 2.3 for recommended modifications to the proposed label.

Table 3.3. Summary of Proposed Directions for Use of Reflex Herbicide (EPA Reg. No. 10-993)

Applic. Timing, Type, 

and Equip.

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions 

and Limitations

Cantaloupe (transplants only)

Ground equip, prior to 

transplanting 100-993 0.25-0.375 NS 0.375 35

Cucumber (Direct seeded or transplant)

Gound equip, just after 

seeding but before crop 

emergence of prior to 

transplanting

10-993 0.25-

0.375 NS 0.375 42

Peas, succulent

Ground or aerial equip, 

Broadcast, preemergence 

to weeds and crop

100-993 0.125-

0.25 NS 0.375 46

Pumpkin (Direct seeded or transplant)

Ground equip, broadcast 

or direct spray, after 

seeding but prior to crop 

emergence or prior to 

crop transplanting

100-993 0.25-

0.375 NS 0.375 32

Summer squash and winter squash (Direct seeded or transplant)

Ground equip, broadcast 

or directed spray, after 

seeding but prior to crop 

emergence or prior to 

transplanting

100-993 0.25-

0.375 NS 0.375 32

Watermelon (Direct seeded or transplant)

Ground equip, broadcast 

or directed spray, after 

seeding but prior to crop 

emergence or prior to 

transplanting; postemergence as directed 

application to row 

middles just prior to or at 

vine runner initiation

100-993 0.25-

0.375 NS 0.375 35

Bean, lima, succulent
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Broadcast, postemergent 

appl.1 100-993 0.125-0.25 NS 0.25 30

Do not graze 

treated areas or 

harvest for forage 

or hay. Do not 

utilize hay or 

straw for animal 

feed or bedding. 

Soybean, vegetable, succulent

Preplant surface and 

preemergence appl.;2and 

post emergence appl.3

100-993 0.25-

0.375 NS 0.375 30

Do not graze 

treated areas or 

harvest for forage 

or hay. Do not 

utilize hay or 

straw for animal 

feed or bedding.

NS = Not Specified.

1 Do not apply to any field in regions 2, 3, 4 or 5 more than once every two years.

2 Application only allowed in Regions 1, 2, 3 and 4.

3 Applications only allowed in Regions 1, 2, 3, 4 and 5.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed new use of fomesafen sodium on to cantaloupe, cucumber, pea, pumpkin, squash, 

watermelon, soybean (succulent), and lima bean (succulent). Humans may be exposed to 

fomesafen in food and drinking water, since fomesafen may be applied directly to growing crops 

and application may result in fomesafen reaching surface and ground water sources of drinking 

water. There are no residential uses of fomesafen; so, there is not 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 a 

potential for post-application exposure for workers re-entering treated fields. This risk 

assessment considers all of the aforementioned exposure pathways based on the proposed new 

uses of fomesafen but also considers the existing uses as well in regard to the dietary assessment.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income 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 U.S. Department of 

Agriculture’s (USDA’s) 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 
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exposure to smaller, specialized subgroups, and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures are 

evaluated, 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. 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

The toxicological database for fomesafen is complete. The last human health risk assessment 

was performed on October 12, 2010 (A. LaMay, D373600). Since then, several toxicological 

studies have been received and reviewed. An Acute Toxicity 6-Pack (MRIDs 46988901-

46988906) on fomesafen technical (≥98.5% purity) was submitted. An immunotoxicity test was 

submitted. A subchronic oral toxicity study in rats (MRID 49091201) was received in 2012,

which does not demonstrate an adverse effect at 6x the LOAEL of the previous (1981) 

subchronic oral toxicity study in rats (MRID 00103013). A 13-week subchronic dietary

combined toxicity and neurotoxicity study in rats (MRID 48996801) was submitted, as well as 

an acute neurotoxicity study (MRID 48973302). The acute neurotoxicity study provided an 

acute oral endpoint for the general population (including infants and children), but other toxicity

endpoints and points of departure (PODs) remained the same as in the 2010 assessment. 

4.1 Summary of Toxicological Effects

Fomesafen is an herbicide that is absorbed by leaves and roots and inhibits protoporphyrinogen 

oxidase, leading to irreversible cell membrane damage. Generally, hyalinization of hepatocytes 

provided the most sensitive toxicological endpoint (short, intermediate, and long term) in 

mammals. In the subchronic and chronic toxicity studies in rats and mice, food consumption, 

food efficiency, body weight, body weight gain, and histopathological changes in the liver were 

parameters that were most often affected. In addition, dogs and mice also showed hematological 

changes (e.g., decreased erythrocyte count, hemoglobin, or hematocrit). Neurotoxicity

(decreased motor activity) may occur at the same dose level as systemic toxicity. 

Carcinogenicity was not observed in the rat chronic toxicity/ carcinogenicity study. Liver tumors 

were produced in the mouse carcinogenicity study; however, HED’s Cancer Assessment Review 

Committee (CARC) determined that fomesafen should be classified as “Not Likely to be 

Carcinogenic to Humans” (HED Doc No. 0053835). This decision was based on the weight-ofevidence which supports activation of peroxisome proliferator-activated receptor alpha (PPARα) 

as the mode of action for fomesafen-induced hepatocarcinogenesis in mice. Fomesafen was not 

considered to be mutagenic. Post-implantation loss was noted in the developmental study, but no 

quantitative or qualitative evidence of increased susceptibility was seen following in utero

exposure to rats or rabbits in developmental studies or in the reproduction study. Fomesafen can 

result in suppression of anti-SRBC IgM response. Fomesafen has a low order of acute toxicity

by the oral, dermal, and inhalation routes of exposure (Toxicity Category IV). Fomesafen is 

minimally irritating to the eye and is not irritating to the skin. It is not a sensitizer. 
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In a metabolism study in rats, fomesafen was readily absorbed in male and female rats after oral 

dosing. The major route of elimination in females was in the urine; fecal excretion was the 

major route in males, with some enterohepatic recirculation evident. The sex difference was not 

evident at higher doses, where urine was the main route of excretion for both sexes. At higher 

doses, the vast majority was excreted unchanged, but at lower doses a lesser amount (60%) was 

excreted unchanged. The major metabolite (10%) was 5-(2-chloro-α,α,α-trifluoro-tolyloxy)-

anthranilic acid. Part, or all, of the metabolism may be due to action by intestinal

microorganisms. The rat has a very limited capacity to metabolize fomesafen.

In a metabolism study in dogs, peak blood levels occurred within 3 hours, then rapidly declined. 

Excretion in both sexes was predominantly in urine and to a lesser extent in the feces. Most of 

the fomesafen (96%) was excreted within 24 hours in both sexes. Fomesafen was not 

extensively metabolized in the dog and was recovered to a large extent unchanged.

As a dermal penetration study was not provided, the dermal absorption value of 20% was based 

on dermal absorption factors for oxyfluorfen and acifluorfen, which have similar structures.

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

The FQPA safety factor was reduced to 1X for the reasons described in sections 4.2.1 through 

4.2.4. The toxicity and exposure databases for fomesafen are complete. There is no evidence of 

increased susceptibility in developing and young animals, and there are no residual uncertainties 

concerning pre- or post-natal toxicity. Acute and subchronic neurotoxicity studies are available, 

and all points of departure used in this risk assessment are protective of any potential neurotoxic, 

developmental, or immunotoxic effects. The dietary assessments are conservative and are based 

on tolerance level (non-detectable) residues and assume 100% of the crops are treated. There are 

no residential uses of fomesafen.

4.2.1 Completeness of the Toxicology Database

The toxicology database for fomesafen is complete. The requirement for the subchronic 

inhalation toxicity study was waived upon consideration at HASPOC on April 25, 2013 (DOC # 

123803TS.001). A weight of evidence approach indicated that the inhalation toxicity study was 

not necessary due to low compound volatility, high inhalation MOEs, a conservative oral 

endpoint upon which the MOEs were based, and low acute toxicity via oral, dermal, and 

inhalation routes. Although the developmental toxicity study in rabbits was classified 

unacceptable due to mortality from bacterial infections, there was not any evidence of increased 

susceptibility of rabbit fetuses due to the treatment with fomesafen. Therefore, the lack of an 

acceptable developmental toxicity study in non-rodents was not considered a data gap. As a 

dermal penetration study was not provided, the dermal absorption value of 20% was based on 

dermal absorption factors for oxyfluorfen and acifluorfen, which have similar structures. 

Consequently, the dermal penetration study is not considered a data gap.
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4.2.2 Evidence of Neurotoxicity

Decreased motor activity (horizontal and vertical activity and time in central quadrant) was 

observed in rats in the acute neurotoxicity screening battery at the same dose that resulted in 

general systemic toxicity. In the subchronic neurotoxicity test, neither general systemic toxicity

nor neurotoxicity was observed at the highest dose tested. 

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

There is no evidence of increased susceptibility of rat fetuses to in utero exposure to fomesafen. 

The 2-generation reproduction study in rats did not show evidence of increased susceptibility to 

fomesafen. Although the developmental toxicity study in rabbits was classified as unacceptable 

due to mortality from bacterial infections, there was adequate information to show that there was 

not any evidence of increased susceptibility of rabbit fetuses due to the treatment with 

fomesafen. 

4.2.4 Residual Uncertainty in the Exposure Database

There are no residential uses of fomesafen. The dietary assessment is based on conservative 

assumptions, including 100% crop treated and tolerance-level (non-detectable) residues; there 

are no residual uncertainties in the exposure database.

4.3 Toxicity Endpoint and Point of Departure Selections

The most recent risk assessment performed for fomesafen was completed on October 12, 2010 

(A. LaMay, D373600). That hazard characterization and dose response from that assessment has 

been revised in the following ways: An Acute Toxicity 6-Pack (MRIDs 46988901-46988906) 

on fomesafen technical (≥98.5% purity) was submitted and reviewed. Due to the quality of these 

studies, values from the new 6-Pack replaced the previous values. A 13-week dietary combined 

toxicity and neurotoxicity study in rats (MRID 48996801) was submitted, as well as an acute 

neurotoxicity study (MRID 48973302). The acute neurotoxicity study was used to establish an 

acute oral endpoint for the general population, including infants and children. An acute endpoint 

was not selected in the previous assessment. 

Additionally, a subchronic oral toxicity study in rats (MRID 49091201) was received in 2012 

which does not demonstrate an adverse effect at 6x the LOAEL of the previous (1981) 

subchronic oral toxicity study in rats (MRID 00103013). MRID 00103013 provides the most

protective subchronic POD. The current inhalation risk estimates, which are based on this 

protective oral POD, are very low and are not of concern. At this time HED is not electing to use 

the higher PODs from the 2012 study but may consider them for future assessments.

The PODs and toxicity endpoints selected for various exposure scenarios applicable to this risk 

assessment are summarized in Table 4.3 (Dietary and Occupational). 
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Table 4.3 Summary of Toxicological Doses and Endpoints for Fomesafen for Use in Dietary and 

Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

NOAEL = 

100 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

Acute RfD = 

1 mg/kg/day

aPAD = 1

mg/kg/day

Acute neurotoxicity test in rat

LOAEL = 250 mg/kg/day based on 

decreased body weight and motor activity 

(horizontal and vertical activity and time 

in central quadrant) in males

Acute Dietary

(Females 13-

49 years of 

age)

No toxic effects of fomesafen attributable to a single dose and specific to females of ages 13-49 

were found in the database.

Chronic 

Dietary (All 

Populations)

NOAEL = 

0.25 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1x

Chronic RfD 

= 0.0025 

mg/kg/day 

cPAD = 

0.0025 

mg/kg/day

Chronic toxicity/ carcinogenicity in rat 

LOAEL = 5 mg/kg/day based on 

hyalinization of the liver in males

Dermal 

Short-Term

(1-30 days)

IntermediateTerm

(1-6 months)

NOAEL = 

100 

mg/kg/day 

(Dermal 

absorption 

rate = 

20%)a

UFA = 10x

UFH = 10x

Occupational

LOC for 

MOE = 100

Prenatal developmental in rat

LOAEL = 200 mg/kg/day based on postimplantation loss

Inhalation 

Short- Term

(1-30 days)

IntermediateTerm

(1-6 months)

NOAEL =

0.5 

mg/kg/day

(Inhalation 

toxicity is 

assumed to 

be 

equivalent 

to oral 

toxicity) 

UFA = 10x

UFH = 10x

Occupational

LOC for 

MOE = 100

Subchronic oral toxicity study in rat

LOAEL = 10 mg/kg/day based on 

hyalinization of hepatocytes and increased 

hepatocellular peroxisomes in males.

Cancer (oral, 

dermal, 

inhalation)

Classification: The CARC classified Fomesafen as “Not Likely to be Carcinogenic to Humans”

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

a The dermal absorption value of 20% was based on dermal absorption factors for oxyfluorfen and acifluorfen, 

which have similar structures.
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5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

The residues of concern for dietary risk assessment and the tolerance expression are summarized 

in Table 5.1. The parent compound, fomesafen, is an adequate indicator of misuse and is the 

only residue included in the tolerance expression for plant commodities; there are no livestock 

tolerances required based on the current or proposed uses of fomesafen. For risk assessment 

purposes the residue of concern in plant commodities is parent fomesafen. For livestock 

commodities the residues of concern are fomesafen and its metabolites, 5-(2-chloro-α,α,αtrifluoro-p-tolyloxy) anthranilic acid and 5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-Nmethylsulfonylanthranilamide. For the purpose of this registration action, there is no reasonable 

expectation of finite residues of parent fomesafen or its metabolites in livestock commodities. 

However, should future registration actions result in the likelihood of measurable residues in 

animal commodities, an aggregate risk assessment considering these residues may be required.

Metabolism studies are available for tomatoes, soybeans, and cotton, as well as a confined 

rotational crop study. Studies in plants indicate that, in general, fomesafen is absorbed,

translocated, and rapidly and extensively metabolized. Only trace amounts of the parent were 

found to be present in plant commodities at harvest.

Environmental fate data indicate that fomesafen should be very mobile and highly persistent in 

terrestrial and aquatic environments. The residue of concern in drinking water is parent 

fomesafen.

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants Primary Crop Fomesafen Fomesafen

Plants Rotational Crop Fomesafen Fomesafen

Livestock

Fomesafen, 5-(2-chloro-α,α,αtrifluoro-p-tolyloxy) 

anthranilic acid, 5-(2-chloroα,α,α-trifluoro-p-tolyloxy)-Nmethylsulfonylanthranilamide.

Not required at this time.

Drinking Water Fomesafen NA

Fomesafen is 5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitro-benzamide, sodium salt.

5.2 Food Residue Profile

The submitted crop field trial residue data for cantaloupe, cucumber, summer squash, and 

succulent peas are adequate to support the proposed use of fomesafen on cantaloupe, cucumber, 

pea (succulent), pumpkin, summer squash, winter squash, and watermelon. The studies reflect 
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the maximum proposed use pattern, and the number and location of the field trials are sufficient. 

Acceptable methods were used for residue quantitation, and the studies are supported by

adequate storage stability data. Residues of fomesafen (the residue of concern) were below the 

lowest limit of method validation (<LLMV) in all samples of cantaloupe, cucumber, summer 

squash, or succulent peas when treated with fomesafen sodium at the maximum proposed label 

rates and minimum PHIs. 

Residues of fomesafen were also below the LLMV in previously submitted field trials for 

peppers, potatoes, cotton, dry beans, snap beans, and soybeans (field).

The proposal for the use of the existing field trial data on snap beans to support the establishment 

of a tolerance for fomesafen on bean, lima, succulent was considered adequate by the Chemistry

Science Advisory Council (ChemSAC) provided that a maximum rate per year included in the 

label is 0.25 lbs ai/A and the PHI is 30 days. The proposal for the use of snap bean data to 

support a tolerance for soybean, vegetable, succulent is acceptable as well. In crop subgroup 6A 

(edible-podded legume vegetables) any succulent cultivar of edible podded bean covers all beans

under that group. This group includes snap bean and soybean, immature seed. For the latter

soybean, vegetable, succulent is the preferred term.

There is data to support rotation to other crops beyond those commodities that are currently

registered and proposed as primary crops. Plant back intervals (PBIs) for rotational crops were 

not found in the Section B of the petition. Adequate PBI should be proposed by the registrants 

and included in the label of the Reflex Herbicide.

There are no new animal feedstuffs associated with the proposed uses. Feedstuffs are associated 

with succulent soybean; however, uses on field soybean have been registered previously. The 

dietary burdens of fomesafen to beef and dairy cattle were estimated previously according to the 

2008 Revised Table 1 of OPPTS Guideline 860.1000 for constructing maximum reasonably 

balanced diets (A. LaMay, D373544, 10/12/2010). There is no reasonable expectation of finite 

residues in livestock commodities, and no tolerances are required for residues of fomesafen in 

livestock commodities. 

5.3 Water Residue Profile

The Environmental Fate and Effect’s Division (EFED) provided estimated drinking water 

concentrations (EDWCs) generated using computer modeling methods. The screening model 

Tier II PRZM-EXAMS was used to calculate the surface water EDWCs of 34.8 μg/L for peak 

(acute), 13.1 μg/L for annual average (non-cancer chronic). Groundwater EDWCs were 

calculated using the Tier I PRZM-GW (six vulnerable sites modeled) and resulted in the highest 

acute value of 51.8 μg/L and chronic value of 32.3 μg/L for groundwater. The groundwater 

EDWCs were higher than the surface water EDWCs and were therefore selected for use in the 

fomesafen dietary assessment. The groundwater estimates are very conservative. These 

estimates are based on the highest proposed application rate for fomesafen (0.375 lb a.i./acre for 

the crops of cantaloupe, cucumber, pea, succulent, pumpkin, summer squash, watermelon, winter 

squash, and succulent soybean vegetable succulent (i.e. edamame)). These estimates also reflect 

results from the most vulnerable site modeled, the “Florida Citrus scenario.” In addition, the 
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PRZM-GW model is based on a rural drinking water well beneath an agricultural field (a high 

pesticide use area), which draws water from an unconfined, high water-table aquifer. 

There is ground water monitoring data indicating a maximum concentration of 1 μg/L for 

fomesafen in ground water source for drinking water from a vulnerable soybean soil site.

However, since fomesafen can be applied to a wide variety of crops, groundwater monitoring 

from a soybean soil may not be representative of a vulnerable site in an extended fomesafen use 

area and is not recommended for use in risk assessment. 

Table 5.3. Summary of Estimated Surface Water and Groundwater Concentrations for 

Fomesafen.

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

Acute 34.8 51.8

Chronic (non-cancer) 13.1 32.3

a

From the Tier II PRZM-EXAMS - Index Reservoir model. 

b

From the Tier I PRZM-GW model.

(EFED Memo, H.Zhong, D412599, 6/24/13)

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute and chronic aggregate (food and drinking water) dietary exposures and risk assessment 

were conducted using the Dietary Exposure Evaluation Model software with the Food 

Commodity Intake Database (DEEM-FCID) Version 3.16. This software uses 2003-2008 food 

consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and 

Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). For food, 

tolerance level residues were assumed in the assessments; the tolerance levels were based on 

non-detectable residues from the field trials and reflect the method LOQs. For drinking water, 

estimated drinking water concentrations (EDWCs) from highly conservative surface water 

modeling based on the highest proposed use rates were used directly in the assessments. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

An assumption of 100% crop treated (%CT) was used for all commodities (existing and 

proposed uses) in the fomesafen dietary assessment.

5.4.3 Acute Dietary Risk Assessment

A highly conservative acute dietary risk assessment was conducted which used tolerance level 

residues, assumed 100% CT for all commodities and screening EDWCs. The estimated 

exposure (food and drinking water) to the U.S. population and all population subgroups from the 
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established uses and proposed new uses of fomesafen resulted in an estimated risk of <1% of the 

acute population adjusted dose (aPAD) at the 95th percentile and are not of concern (see Table 

5.4.6). 

5.4.4 Chronic Dietary Risk Assessment

A highly conservative chronic dietary risk assessment was conducted which used tolerance level 

residues, assumed 100% CT for all commodities and screening level EDWCs. The estimated 

exposure (food and drinking water) to the U.S. population and all population subgroups from the 

established uses and proposed new uses of fomesafen resulted in risk estimates below the 

Agency’s level of concern. The risk estimate for the general U.S. population is 32% of the 

chronic population adjusted dose (cPAD). The subgroup with the highest chronic exposure and 

risk estimate is infants. For infants, the exposure for food plus drinking water was 0.001915

mg/kg/day, which represents 77% of the cPAD (see Table 5.4.6).

5.4.5 Cancer Dietary Risk Assessment

The Cancer Assessment Review Committee (CARC) classified fomesafen as “Not likely to be 

carcinogenic to humans;” therefore, a quantitative cancer assessment was not performed.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Fomesafen.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD*

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.002999 <1 0.000787 32

All Infants (<1 year 

old)* 0.009060 <1 0.001915 77

N/A N/A

Children 1-2 years old 0.004827 <1 0.001267 51

Children 3-5 years old 0.003915 <1 0.001085 43

Children 6-12 years old 0.002951 <1 0.000755 30

Youth 13-19 years old 0.002455 <1 0.000588 24

Adults 20-49 years old 0.002858 <1 0.000766 31

Adults 50-99 years old 0.002597 <1 0.000754 30

Females 13-49 years old 0.002938 <1 0.000760 30

The population subgroup with the highest risk estimate is bolded

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Residential exposures and risk are not assessed because there are no proposed or registered uses 

of fomesafen in residential settings. 
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6.1 Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for fomesafen at this time, primarily because of the low vapor 

pressure (<7.5 x 10-7 mmHg at 50 °C). However, volatilization of pesticides may be a source of 

post-application inhalation exposure to individuals nearby pesticide applications. The Agency 

sought expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, 

and received the SAP’s final report on March 2, 20101. The Agency is in the process of 

evaluating the SAP report and may, as appropriate, develop policies and procedures to identify

the need for and, subsequently, the way to incorporate post-application inhalation exposure into 

the Agency's risk assessments. If new policies or procedures are developed, the Agency may

revisit the need for a quantitative post-application inhalation exposure assessment for fomesafen.

6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for fomesafen. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices, 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 information2). The Agency has 

completed its evaluation of the new database submitted by the Spray Drift Task Force, a 

membership of U.S. pesticide registrants, and is developing a policy on how to appropriately 

apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied 

by air, orchard airblast, and ground hydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray drift management practices to reduce off-target drift 

with specific products with significant risk estimates associated with 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. 

There are no residential uses for fomesafen; therefore, the aggregate exposure and risk 

assessments include acute and chronic dietary (food and drinking water) only and are shown in 

 

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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Sections 5.4.3 and 5.4.4. There are no aggregate risk estimates of concern for the existing and 

proposed new uses of fomesafen. 

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 fomesafen and any other substances and fomesafen 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 fomesafen 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

No chemical-specific handler exposure data were submitted in support of the proposed 

fomesafen uses. For assessing the occupational handler and post-application risks, generic 

surrogate data were used from sources such as PHED 1.1, the AHETF database, and ORETF 

database.

9.1 Short/Intermediate-Term Handler Risk

Occupational handler exposure to the herbicide fomesafen is expected for individuals involved in 

mixing, applying, or flagging for the proposed fomesafen sodium applications to cantaloupe, 

cucumber, pea, pumpkin, squash, watermelon, soybean, and lima bean. Occupational handlers 

may experience short- and intermediate-term dermal and inhalation exposures.

The quantitative exposure/risk assessment developed for the proposed uses by occupational 

handlers is based on the following scenarios: 

 Mixing/loading for aerial, groundboom, and chemigation applications

 Applying by aerial or groundboom applications

 Flagging in support of aerial application

 Mixing/loading/applying for soil- and ground-directed applications with handheld 

equipment

The maximum application rates for the proposed uses are 0.375 lb ae/acre, except for the 

proposed use on peas and lima beans; the maximum application rate for peas and lima beans is 

0.25 lb ae/acre. Only the maximum application rate of 0.375 lb ae/acre was used in the 

assessment, as this is protective of all proposed uses.

The fomesafen product labels direct applicators and other handlers to wear long-sleeved shirts,
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long pants, chemical-resistant gloves, shoes, plus socks, and protective eyewear. Estimates of 

dermal and inhalation exposure were calculated for various levels of personal protective 

equipment (PPE). Exposures were calculated “baseline”, defined as a single layer of clothing 

consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no 

respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, 

etc). The dermal and inhalation routes of exposure were not combined because the points of 

departure are based on different toxicological endpoints. 

Occupational dermal and inhalation risk estimates are presented in Table 9.1 below. For 

occupational handlers, dermal and inhalation MOEs above 100 are not of concern. All 

occupational exposure risk estimates for short- and intermediate- term exposures for handlers are 

not of concern with single layer dermal PPE (includes long-sleeve shirt and long pants) or with 

engineering control enclosed cab (fixed wing aircraft/aerial applicators). Dermal MOEs ranged 

from 350 to 300,000, and inhalation MOEs ranged from 410 to 360,000.
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Table 9.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Fomesafen.

Exposure Scenario Crop or 

Target

Dermal Unit 

Exposure (μg/lb 

ai)1

Inhalation Unit 

Exposure (μg/lb 

ai)1 Maximum

Application 

Rate2

Area 

Treated 

or 

Amount 

Handled 

Daily3

Dermal Inhalation

Mitigation 

Level: Single 

Layer

Mitigation 

Level: No 

Respirator

Dose 

(mg/kg/day)

4

MOE5

Dose 

(mg/kg/day)

6

MOE7

Mixer/Loader

M/L, Liquid, Aerial, 

Broadcast

Nursery

220 0.219 0.375 lb ae/acre

60 acres 0.0143 7,000 0.0000616 8,100

Typical Field 

Crop 350 acres 0.0838 1,200 0.000359 1,400

HighAcreage Field 

Crop

1200 acres 0.287 350 0.00123 410

M/L, Liquid, 

Chemigation

Field Crop, 

All 350 acres 0.0838 1,200 0.000359 1,400

M/L, Liquid, 

Groundboom, Broadcast

Nursery, 

Greenhouse 60 acres 0.0143 7,000 0.0000616 8,100

Typical Field 

Crop 80 acres 0.0191 5,200 0.0000821 6,100

HighAcreage Field 

Crop

200 acres 0.0478 2,100 0.000205 2,400

Applicator

Applicator, Spray, 

Aerial

Nursery

Eng Control:

5

Eng Control:

0.0049

0.375 lb ae/acre

60 acres 0.000328 300,000 0.0000014 360,000

Field Crop, 

Typical 350 acres 0.0019 53,000 0.000008 62,000

Field Crop, 

High Acreage 1200 acres 0.00652 15,000 0.0000276 18,000

Applicator, Spray, 

Groundboom

Nursery, 

Greenhouse

78.6 0.34

60 acres 0.00513 19,000 0.0000956 5,200

Field Crop, 

Typical 80 acres 0.00684 15,000 0.000128 3,900

Field Crop, 200 acres 0.0171 5,800 0.000319 1,600
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Table 9.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Fomesafen.

Exposure Scenario Crop or 

Target

Dermal Unit 

Exposure (μg/lb 

ai)1

Inhalation Unit 

Exposure (μg/lb 

ai)1 Maximum

Application 

Rate2

Area 

Treated 

or 

Amount 

Handled 

Daily3

Dermal Inhalation

Mitigation 

Level: Single 

Layer

Mitigation 

Level: No 

Respirator

Dose 

(mg/kg/day)

4

MOE5

Dose 

(mg/kg/day)

6

MOE7

High Acreage

Flagger

Flagger

Nursery

11 0.35 0.375 lb ae/acre

60 acres 0.000719 140,000 0.0000985 5,100

Field Crop, 

All 350 acres 0.00417 24,000 0.000574 870

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline; Eng. Controls for aerial applicators.

2 Based on proposed label.

3 Exposure Science Advisory Council Policy #9.1.

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

(kg).

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

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

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

8 10 gallons per acre assumed.
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9.2.1 Dermal Post-application Risk

Post-application dermal exposure is not anticipated for the majority of the proposed fomesafen 

uses since, based on the label directions, it is not likely that the pesticide will contact the foliage. 

The proposed label states that the product is applied as follows: (1) to cantaloupe as a directed 

spray to row middles prior to transplanting; (2) to cucumber as a directed spray to row middles 

just after seeding but before crop emergence or just prior to transplanting; (3) to succulent peas 

as a broadcast pre-emergence application; (4) to pumpkin, squash, and watermelon as a 

broadcast or directed spray to row middles after seeding but prior to crop emergence or prior to 

transplanting; and (5) to watermelon also as a directed post-emergence application to row 

middles. Therefore, a quantitative post-application dermal exposure assessment was not 

conducted for these proposed uses.

This risk assessment for fomesafen sodium evaluates the potential risks associated with its preplant/pre-emergent uses on vegetables. There is a low potential for occupational post-application 

exposure associated with the use of pre-plant/pre-emergent herbicides because there are no hand 

labor activities typically associated with the production of crops that would require significant 

contact with treated soil and no foliage is present that could also lead to exposure via contact. 

There is a possible concern that some level of soil contact could occur during mechanically

assisted transplanting activities; however, this is likely to result in negligible exposures as 

outlined in HED Exposure SAC Policy 8. The rationale is that transplanting activities involve 

moving starter plants onto a rotating wheel while riding upon an implement being moved across 

a field. In such cases, there would be minimal contact with machinery that has field soil on it,

because of the possibility of mechanical injury. These conclusions are appropriate even though 

fomesafen sodium has a long half-life in soil (i.e., ~390 days). 

The applications to the proposed crops are for pre-emergent or directed ground sprays; thus, 

contact with treated foliage is expected to be minimal, except for soybeans and lima beans. 

Therefore, a quantitative dermal post-application exposure assessment was only conducted for 

the proposed new uses with post-emergent applications (i.e., soybeans and lima beans). The 

proposed application rate on soybeans is 0.375 lb ae/acre and for lima beans is 0.25 lb ae/acre. 

All occupational exposure risk estimates for short- and intermediate-term exposures for postapplication workers are not of concern (i.e., dermal MOEs are greater than the LOC of 100). 

Dermal MOEs ranged from 3,200 to 59,000 for post-application workers (soybean and lima bean 

activities). 
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Table 9.2.1. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Fomesafen.

Crop/Site Activities Transfer Coefficient 

(cm2/hr) DFR/TTR1 Dermal Dose (mg/kg/day)2 MOE3

Short and Intermediate-term

Soybean

Hand Weeding 70

1.05

0.002 59,000

Scouting 1100 0.027 3,700

Lima Beans

Scouting 1100

0.7

0.018 5,600

Irrigation 1900 0.031 3,200

1 DFR = Application Rate × F × (1-D)t × 4.54E8 μg/lb × 2.47E-8 acre/cm2; where F = 0.25 and D = 0.10 per day 

2 Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)]  BW (kg).

3 MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm2) × TC × 0.001 mg/μg × 8 hrs/day × dermal 

absorption factor (%)]  BW (kg).

Restricted Entry Interval

The current label specifies a 24-hour REI. Fomesafen has a low order of acute toxicity by the

dermal route of exposure (Toxicity Category IV). Fomesafen is minimally irritating to the eye 

and is not irritating to the skin. It is not a sensitizer. Short- and intermediate-term postapplication risk estimates were not a concern on Day 0 (12 hours following application) for all 

post-application activities. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute IV for 

acute dermal, eye irritation or primary skin irritation are assigned a 12-hour REI. Therefore, the 

[156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect 

agricultural workers from post-application exposures to fomesafen. The REI on the label meets 

the minimum requirement. 

9.2.2 Inhalation Post-application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for fomesafen at this time primarily because of the low vapor 

pressure (<7.5 x 10-7 mmHg at 50 °C). However, there are multiple potential sources of postapplication 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, 20103. The Agency is in the process of evaluating 

the SAP report, as well as available post-application inhalation exposure data generated by the 

ARTF and may, as appropriate, develop policies and procedures, to identify the need for and the

way to incorporate occupational post-application inhalation exposure into the Agency's risk 

assessments. If new policies or procedures are put into place, the Agency may revisit the need 

for a quantitative occupational post-application inhalation exposure assessment for fomesafen.

 

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

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Although a quantitative occupational post-application 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 post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of the fomesafen occupational postapplication inhalation exposure scenarios.

10.0 References

I. Negrón Encarnación, In Process, D407932, Fomesafen Sodium. Petition for the Establishment 

of Tolerances and Registration of New Uses on Cantaloupe, Cucumber, Pea (Succulent), 

Pumpkin, Summer Squash, Watermelon, Winter Squash, Soybean (Succulent) and Fresh Lima 

Bean: Summary of Analytical Chemistry and Residue Data. 

D. Drew, D410439, 7/11/13, Fomesafen Sodium, Acute and Chronic Aggregate Dietary (Food 

and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on 

Cantaloupe, Cucumber, Pea (Succulent), Pumpkin, Summer Squash, Winter Squash, 

Watermelon, Soybean (Succulent) and Lima Bean (Succulent).

A. LaMay, In Process, D407933, Fomesafen Sodium. Occupational and Residential Exposure 

Assessment for Proposed Uses on Cantaloupe, Cucumber, Pea, Pumpkin, Squash, Watermelon, 

Soybean, and Lima Bean.

A. LaMay, 10/12/10, D373600, Fomesafen Sodium: Human Health Risk Assessment for the 

Establishment of Tolerances and Registration of New Uses of Fomesafen Sodium on Potatoes 

and Peppers.

H. Zhong, 6/24/13, D412599, Revised Fomesafen Drinking Water Assessment to Include IR-4 

Use on Lima Bean and Groundwater EDWCs Using a Tier-I PRZM-GW Model.
Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for the food use for fomesafen are in the table below. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Acute Eye Irritation .......................................................

870.2500 Acute Dermal Irritation .................................................

870.2600 Skin Sensitization ..........................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity in Rodents ..................................

870.3150 90-Day Oral Toxicity in Nonrodents.............................

870.3200 21/28-Day Dermal Toxicity...........................................

870.3250 90-Day Dermal Toxicity................................................

870.3465 90-Day Inhalation Toxicity ...........................................

yes

yes

yes

no

no

yes

yes

yes

-

-

870.3700a Prenatal Developmental Toxicity (rodent).....................

870.3700b Prenatal Developmental Toxicity (nonrodent)...............

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

yes

yes

yes

yes

no a

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Carcinogenicity (rat)......................................................

870.4200b Carcinogenicity (mouse)................................................

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Bacterial Reverse Mutation Test...

870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test

870.5375 Mutagenicity—In Vitro Chromosomal Aberrations

870.5385 Mutagenicity—Mammalian Chromosomal Aberrations

870.5395 Mutagenicity—Micronucleus Test

870.5450 Mutagenicity—Dominant Lethal Assay

870.5550 Mutagenicity—Unscheduled DNA Synthesis

yes

yes

yes

yes

yes

no

no

yes

yes

yes

yes c

yes

-

-

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

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

yes

yes

no

yes

yes

-

870.7485 Metabolism and Pharmacokinetics................................

870.7600 Dermal Penetration........................................................

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

yes

yes

yes

yes

no b

yes

a Although the developmental toxicity study in rabbits was classified unacceptable due to mortality from bacterial infections, there was not 

any evidence of increased susceptibility of rabbit fetuses due to the treatment with fomesafen. Therefore, the lack of an acceptable 

developmental toxicity study in non-rodents was not considered a data gap. 

b As a dermal penetration study was not provided, the dermal absorption value of 20% was based on dermal absorption factors for

oxyfluorfen and acifluorfen, which have similar structures. Consequently, the dermal penetration study is not considered a data gap.

c Two studies were Not Classified (because there were no mutagenicity guidelines when the study was conducted), and one study was 

Unacceptable/Guideline. However, there are mutagenicity studies which evaluate both somatic and germinal cells, which is considered 

sufficient to satisfy CFR requirements.
Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Fomesafen

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

870.1100 Acute oral [rat] 46988901 LD50 Females 

>5000 mg/kg bw

IV

870.1200 Acute dermal [rat] 46988902 LD50 Combined > 

5050 mg/kg bw IV

870.1300 Acute inhalation [rat] 46988903 LC50 Combined 

>2.63 mg/L IV

870.2400 Acute eye irritation [rabbit] 46988904 Minimally 

irritating IV

870.2500 Acute dermal irritation [rabbit] 46988905 No irritation IV

870.2600 Skin sensitization [guinea pig] 46988906 Not a sensitizer N/A

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

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3050 

28-Day Oral Toxicity in 

Rodents 

40786709 (1980) 

Acceptable/NonGuideline 

0, 5, 15, 50, 150, 500, 

1500 or 1500 ppm 

M: 0, 0.71, 2.13, 7.20, 

20.7, 68.9, 209.1, or 

917.2 mg/kg/day)

F: 0, 0.94, 2.87, 8.30, 

27.1, 83.4, 246.8, 1247.6 

mg/kg/day

NOAEL = 209/247 mg/kg/day in M/F

LOAEL = 917/1247 mg/kg/day in M/F based on 

decreased body weights and body weight gains, 

decreased food efficiency, hematology (decreased 

erythrocyte count, hemoglobin, mean corpuscular 

volume, and mean corpuscular hemoglobin), bile duct 

hyperplasia, decreased uterine size in females, and 

decreased size of the seminal vesicles in males

870.3100

90-Day Oral Toxicity in 

Rodents

00103013 (1981)

Acceptable/ Guideline

0, 1, 5, 100 or 1000 ppm 

(0, 0.1, 0.5, 10 and 100 

mg/kg/day)

NOAEL = 0.5 mg/kg/day

LOAEL = 10 mg/kg/day based on hyalinization of 

hepatocytes and increased hepatocellular peroxisomes

870.3100

+ 870.6200b

Combined 90-Day oral 

Toxicity and Neurotoxicity 

Screening Battery in 

Rodents

48996801 (2012)

Acceptable/Guideline

0, 100/300, 300/100, or 

1000/3000 ppm in M/F

M: 0, 6.4, 20.3, 67.0

mg/kg/day

F: 0, 23.1, 74.2, 233.2 

mg/kg/day

NOAEL = 67.0/233.2 mg/kg/day in M/F

LOAEL was not observed

870.3150

90-Day Oral Toxicity in 

Nonrodents

00103014 (1981)

Acceptable/Guideline

0, 0.1, 1.0, 25 mg/kg/day

NOAEL = 1.0 mg/kg/day

LOAEL = 25 mg/kg/day based on hematology 

(decreased hemoglobin and hematocrit concentrations 

and erythrocyte count and increased platelet count and 

prothrombin time)
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fomesafen

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3200

21/28-Day Dermal 

Toxicity

00135632 (1983)

Acceptable/ Guideline

0, 10, 100, 1000 

mg/kg/day

NOAEL = 1000 mg/kg/day

LOAEL was not observed

870.3700a

Prenatal developmental in 

(rodent)

00164903 (1981)

Acceptable/Guideline

0, 50, 100, 200 

mg/kg/day

[This study was considered with: (1) Report Nos. 

CTL/P/656 and CTL/P/656S, MRID #001013016, and 

(2) information provided by Syngenta in their 

submission (DP316263, MRID 46527208) in 

establishing the NOAEL and LOAEL. With the 

additional information, the following conclusions were 

made.]

Maternal NOAEL = 100 mg/kg/day

LOAEL = 200 mg/kg/day based on the staining of the 

ventral fur and significantly decreased body weight 

gain (>10%)

Developmental NOAEL = 100 mg/kg/day

LOAEL = 200 mg/kg/day based on postimplantation 

loss observed in study CTL/P/576 (MRID 00164903)

870.3700a

Prenatal developmental in 

(rodent)

00103016 (1982) 

Acceptable/Guideline

0, 1.0, 7.5, 50 mg/kg/day

[The maternal and developmental toxicity LOAEL and 

NOAEL were not established in this study. However, 

in conjunction with (1) another developmental toxicity 

study in rats (CTL/P/576, MRID 00164903), and (2) 

information provided by Syngenta in their submission, 

DP 316263 (MRID 46527208), the following 

LOAELs/NOAELs were established for fomesafen.]

Maternal NOAEL = 100 mg/kg/day

LOAEL = 200 mg/kg/day based on the staining of the 

ventral fur and significantly decreased body weight 

gain (>10%)

Developmental NOAEL = 100 mg/kg/day

LOAEL = 200 mg/kg/day based on postimplantation 

loss observed in study CTL/P/576 (MRID 00164903)

870.3700b

Prenatal developmental in 

(nonrodent)

00109214 (1981)

Unacceptable/Guideline

0, 2.5, 10, 40 mg/kg/day

At 40 mg/kg/day, does appeared thin and had increased 

incidence of stomach erosions. 

No significant difference between controls and treated 

animals for developmental abnormalities. 

The study provided information to assess potential 

developmental toxicity rabbits, but was classified 

unacceptable because of bacterial infection in the 

colony. 

870.3800 

Reproduction and fertility 

effects

00144862 (1984)

Acceptable/Guideline

0, 50, 250, 1000 ppm 

(0, 2.5, 12.5, 50 

mg/kg/day)

Parental/Systemic NOAEL = 12.5 mg/kg/day

LOAEL = 50 mg/kg/day based on liver histopathology 

in males and females of both generations

Reproductive NOAEL = 50 mg/kg/day

LOAEL was not established 

Offspring NOAEL = 12.5 mg/kg/day

LOAEL = 50 mg/kg/day based on increased incidence 

of liver hyalinization in males
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fomesafen

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.4200b

Carcinogenicity (mouse)

00131491 (1983)

Acceptable/Guideline

0, 1, 10, 100, 1000 ppm 

(0, 0.15, 1.5, 15, 150 

mg/kg/day)

NOAEL = 1.5 mg/kg/day

LOAEL = 15 mg/kg/day based on the presence of liver 

tumors and liver weight increases in male and female 

mice

evidence of carcinogenicity

870.4300

Combined Chronic 

Toxicity/Carcinogenicity

00142125 (1984)

Acceptable/Guideline

0, 5, 100, 1000 ppm

(0, 0.25, 5, 50 

mg/kg/day)

NOAEL = 0.25 mg/kg/day

LOAEL = 5 mg/kg/day based on hyalinization of the 

liver in males

no evidence of carcinogenicity

Genetic Toxicity Test 

870.5300

In vitro mammalian cell 

gene mutation test

40910804

Acceptable/Guideline

-S9: 0, 450, 475, 500, 

525, 550, 575, 600 

μg/mL

+S9: 0, 325, 350, 375, 

400, 425, 450, 475 

μg/mL

A technical grade preparation containing 97 percent 

fomesafen was tested for mutagenicity against L5178Y 

mouse lymphoma cells, both in the presence and 

absence of S-9 metabolic activation at concentrations 

ranging between 325 to 600 μg/mL. Two tests were 

performed and each test was performed in duplicate for 

each concentration. There was no indication of 

mutagenicity at any dose level tested, both in the 

presence or absence of metabolic activation. The 

positive controls, including ethylmethanesulphonate, a 

direct mutagen and N nitrosodimethylamine, which 

required metabolic activation, were both responsive in 

these tests.

Genetic Toxicity Test

870.5375

In Vitro Mammalian 

Chromosome Aberration 

Test

44569805

Acceptable/Guideline

-S9: 0, 150, 500, 1000 

μg/mL

+S9: 0, 75, 150, 250 

μg/mL

There was no evidence of chromosome aberrations 

induced over background.

Genetic Toxicity Test

870.5375

In Vitro Mammalian 

Chromosome Aberration 

Test

44569806

Acceptable/Guideline

±S9: 0, 10, 100, 1000 

μg/mL

There was no evidence of chromosome aberrations

induced over background.

Genetic Toxicity Test

870.5385

Mammalian Bone Marrow

Chromosomal Aberration 

Test

00135628

Not Classified

0, 125, 250 mg/kg

The mitotic index is significantly decreased by 250 

mg/kg Fomesafen, indicating toxicity. The percent of 

cells with chromosome abnormalities including gaps is 

significantly increased by 250 mg/kg Fomesafen. Both 

125 and 250 mg/kg Fomesafen slightly (but not 

statistically significantly) increased the number of cells 

with chromosome abnormalities excluding gaps.

Fomesafen is considered to be a weak mutagen.

Genetic Toxicity Test

870.5385

Mammalian Bone Marrow

Chromosomal Aberration 

Test

00164907

Not Classified

0, 125, 250 mg/kg

The product induced statistically significant increase of 

cells with abnormalities at the 125 and 250 mg/kg dose 

level. The responses were similar to the ones observed 

in the cells of animals treated with the positive control 

EMS, and they include gaps and other than gaps as well 

as breaks and fragments. The product induced 

chromosome damage in the bone marrow of the rat 

cells at oral doses of 125 and 250 mg/kg.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fomesafen

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

Genetic Toxicity Test

870.5385

Mammalian Bone Marrow

Chromosomal Aberration 

Test

45048208

Unacceptable/Guideline

0, 25, 125, 250 mg/kg

Fomesafen technical up to 250 mg/kg dose level is not 

clastogenic in this in vivo test system.

Genetic Toxicity Test

870.5395

Mammalian Erythrocyte 

Micronucleus Test

40910805

Acceptable/Guideline

M: 0, 175, 279 mg/kg

F: 0, 215, 344 mg/kg

Fomesafen does not appear to be clastogenic in the 

mouse micronucleus test system.

Genetic Toxicity Test

870.5450

Rodent Dominant Lethal 

Assay

00103019

Not Classified

0, 25,100, 250 

mg/kg/day

Fomesafen possesses no dominant lethality at any one 

of the dose levels assayed.

Genetic Toxicity Test

870.5550

Unscheduled DNA 

Synthesis in Mammalian 

Cells in Culture

40786703

Unacceptable/Guideline

Up to 1000 μg/mL

At 1000 μg/mL, the compound was toxic to the cells. 

It is difficult to interpret the UDS results as provided.

870.6200a

Acute Neurotoxicity 

Screening Battery

48973302 (2012)

Acceptable/Guideline

0, 100, 250, 800 mg/kg

NOAEL = 100 mg/kg

LOAEL = 250 mg/kg based on decreased motor 

activity (horizontal and vertical activity and time in 

central quadrant) in males

870.6200b

+ 870.3100

Combined 90-Day oral 

Toxicity and Neurotoxicity 

Screening Battery in 

Rodents

48996801 (2012)

Acceptable/Guideline

0, 100/300, 300/100, 

1000/3000 ppm in M/F 

M: 0, 6.4, 20.3, 67.0 

mg/kg/day

F: 0, 23.1, 74.2, 233.2 

mg/kg/day

NOAEL = 67.0/233.2 mg/kg/day in M/F

LOAEL was not observed
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fomesafen

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.7485

Metabolism and 

Pharmacokinetics in Rat

00103017 (1982)

00135633 (1983)

00164904 (1982)

00164905 (1982)

00164906 (1982)

00164939 (1982)

Not Classified or 

Acceptable/Guideline

The overall mean recovery of radioactivity by Day 7 

was 99.9% for males and 98.5% for females in MRID 

00103017. The study, MRID 00135633, is acceptable 

to prove that no meaningful accumulation of the

material was left in the body; most (up to 95%) was 

excreted via urine, feces or bile. The liver did not 

accumulate the material in meaningful amounts. In 

MRID 00164904, there was not a great difference 

between male and female rats in the excretion of (14C)-

PP021, and most of the material was excreted. The 

liver was the organ with more accumulation, ± 0.5% 

males. ± 0.4% females. In MRID 00164905, 

widespread tissue distribution of radioactivity was 

observed throughout the 28 day dosing period (5 mg/kg 

doses). Radioactivity in the liver was increased as 

dosing proceeded and decreased progressively after the 

21 or 28 last dose. In MRID 00164939, Animals were 

treated with a single dose by intravenous injection (5 

mg/kg), and recovery was 94% in both sexes. There 

was a difference observed in fomesafen excretion 

between male and female rats. The liver was the organ 

with the most residues. MRID 00164906 and its DER 

were not found.

870.7485

Metabolism and 

Pharmacokinetics in Dog

00135634 (1983)

Acceptable/Guideline

Fomesafen is excreted via urine or feces. The feces 

showed a large amount of biliary product elimination. 

No substantial differences were observed between male 

and female dogs. The largest part of the product or the 

metabolite was eliminated via urine. The only 

metabolite found was the same product, fomesafen. 

870.7485

Metabolism and 

Pharmacokinetics in 

Marmoset

00141525 (1984) Not evaluated; MRID nor DER were found.

870.7485

Metabolism and 

Pharmacokinetics in Mouse

00144861 (1983) Not evaluated; MRID nor DER were found.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Fomesafen

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.7485

Metabolism and 

Pharmacokinetics in 

Hamster

40910803 (1984)

Supplementary

5 mg/kg/day

A single dose of radiolabeled compound (5 mg/kg) was 

administered orally to three male and three female 

hamsters. Urinary and fecal samples were collected at 

24-hour intervals for 3 days. The animals were killed at 

72 hours to collect tissues and carcass for analysis of 

radioactivity. In males, excretion based on dose of 

radioactivity recovered, amounted to 55 percent in 

urine and 28 percent in feces; in females, 47 percent 

was excreted in urine and 27 percent in feces. There 

were no differences in amount excreted by either route 

between the two sexes. Within the first 24 hours, about 

36 percent of the dose was recovered in urine and 15 

percent of the dose in feces for both the male and 

female. At 72 hours, radioactivity remaining in the 

entire organism amounted to about 3.0 percent in males 

and 2.5 percent in females; no sex differences. Of the 

four tissues in which radioactivity was measured, 

including liver, kidneys, lung, and blood, uptake was 

highest by the liver, based on percent of dose in the 

entire organ and μg equivalents/g of tissue.

870.7800

Immunotoxicity

48762301 (2011)

Acceptable/Guideline

0, 100, 1000, 4000 ppm 

(0, 16, 176, 791 

mg/kg/day)

NOAEL = 16 mg/kg/day

LOAEL = 176 mg/kg/day based on dose-related 

suppression of anti-SRBC IgM response

A.3 Toxicity Summaries

MRID No. 00103013 

Citation : Wade, J.; Banham, P.; Chart, I.; et al. (1981) PP021: 90 Day Feeding Study in 

Rats: Report No. CTL/P/554. (Unpublished study received May 28, 1982 under 10182-

EX-30; prepared by Imperial Chemical Industries, Ltd., Eng., submitted by ICI Americas, 

Inc., Wilmington, DE; CDL:247589-E). Unpublished. 

EXECUTIVE SUMMARY - In this subchronic toxicity study (MRID 00103013), Fomesafen 

(97.5% a.i.; PPO21) was administered in the diet for 90 days to 20 Alderley Park rats/sex/dose at 

doses of 0, 1, 5, 100, or 1000 ppm (approximately equivalent to 0, 0.1, 0.5, 10, and 100 

mg/kg/day using a conversion factor of 0.1). The animals were observed daily for clinical signs 

of toxicity. Body weights and food consumption were determined initially and at 2-week 

intervals, thereafter. Hematology, clinical chemistry and urinalysis were conducted. At 

termination, animals were necropsied, organs weighed and representative tissues examined 

microscopically. Election microscopy was conducted on selected tissues.

No mortality occurred. Animals in the 1000 ppm group gained less weight than the controls. 

Plasma alkaline phosphatase, alanine transaminase and aspartate transaminase were increased in 
Fomesafen Sodium Human Health Risk Assessment DP No. D403953, 410795

Page 34 of 48

males in the 1000 ppm group. Liver weights were increased in male and females at 1000 ppm. 

Hyalinization of hepatocytes, characterized by increased eosinophilia and reduced basophilic 

granulation and reduced vacuolization, was observed at 100 and 1000 ppm. Electron microscopy 

revealed an increase in peroxisomes in centrilobular hepatocytes at 100 and 1000 ppm. 

The LOAEL is 100 ppm (10 mg/kg/day) based on hyalinization of hepatocytes and

increased hepatocellular peroxisomes in males. The NOAEL is 5 ppm (0.5 mg/kg/day).

This study is classified as Acceptable/Guideline and satisfies the guideline requirements 

(OPPTS 870.3100; OECD 408) for a 90-day toxicity study in rats.

MRID No. 00103014 

Citation: Kalinowski AE, Chalmers DT, Chart IS, et al. (1981) PP021: 26 week oral 

dosing study in dog. Central Toxicology Laboratory (Alderley Park, Cheshire, UK). 

Laboratory Report No. CTL/P/591, March 5, 1981. Unpublished.

EXECUTIVE SUMMARY - In a 26-week oral toxicity study (MRID 00103014), fomesafen 

(97.5% a.i., batch #Y00053/001/005) was administered to 6 Beagle dogs/sex/dose in gelatin 

capsules at dose levels of 0, 0.1, 1, or 25 mg/kg bw/day. There were no treatment-related effects 

on survival, clinical parameters, body weight, or food consumption. Mean hemoglobin 

concentrations and erythrocyte counts were slightly decreased in both sexes combined (6-10%), 

relative to controls, at 25 mg/kg from weeks 4-20. Mean hematocrit was also slightly decreased 

(6-9%), relative to controls, in both sexes combined at 25 mg/kg during the same period. At 25 

mg/kg in both sexes combined, mean platelet counts increased by 10-23% from week 8-20, while 

from weeks 4-16 mean prothrombin time was increased only slightly (3-4%), relative to controls. 

Taken together, these results are suggestive of slight anemia at 25 mg/kg. 

Mean absolute and relative liver weights were increased in males by 10% and 13%, respectively, 

at 25 mg/kg. The slight increase in liver weights in males was regarded as non- adverse. The 

adaptive nature of the liver changes was also supported by a 19% (males) and 15% (females) 

increase in smooth endoplasmic reticulum (SER), indicative of increased protein synthesis. 

Mean plasma cholesterol levels were decreased by 31-40%, relative to controls, in both sexes 

combined from weeks 1-26, while mean plasma triglycerides were decreased by 45- 56% over 

the same period. A 3- and 2-fold increase, relative to controls, in the mean number of 

peroxisomes in centrilobular hepatocytes was also observed in males and females, respectively, 

at 25 mg/kg. Peroxisome proliferation is an adaptive response to hypolipidemic compounds. 

Changes in the “tinctorial properties of hepatocytes” was also observed in 4/6 males and 4/6 

females at 25 mg/kg; these changes in staining reflect the observed changes at the organelle 

level, i.e., increase in peroxisome number and SER, and while treatment-related, are considered 

non-adverse.

The LOAEL is 25 mg/kg bw/day, based on hematology (decreased hemoglobin and 

hematocrit concentrations and erythrocyte count and increased platelet count and 

prothrombin time). The NOAEL is 1 mg/kg bw/day.
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This chronic oral toxicity study in the dog is Acceptable/Guideline and satisfies the guideline 

requirements for a chronic oral toxicity study in non-rodents (OPPTS 870.4100; OECD 452).

MRID No. MRID 00164903

EXECUTIVE SUMMARY - In a developmental toxicity study (MRID 00164903), Fomesafen 

(97.5% a.i.) was administered to 17-24 pregnant rats/dose in corn oil by gavage at dose levels of 

0, 50, 100 or 200 mg/kg bw/day from days 6 through 15 of gestation. 

Maternal toxicity was evident at dose of 200 mg/kg bw/day (the highest dose tested) and was 

associated with staining of the ventral fur in 15 of 20 animals and significantly decreased body 

weight gain (>10%) during the dosing period (Days 7-16; Days16-21). Food consumption in 

the high-dose group was also significantly decreased as compared to the control group during the 

dosing period (Days 7-16; Days 16-21).

However, this study should be considered with: 1) Report Nos. CTL/P/656 and CTL/P/656S, 

MRID #001013016, and 2) information provided by Syngenta in their submission (DP 316263, 

MRID 46527208) in establishing the NOAEL and LOAEL (see Discussion/Added Information 

Section). With the additional information, the following conclusions can be made. The 

maternal LOAEL is 200 mg/kg bw/day, based on staining of the ventral fur and 

significantly decreased body weight gain (>10%). The maternal toxicity NOAEL is 100 

mg/kg bw/day. The developmental LOAEL is 200 mg/kg bw/day based on 

postimplantation loss. The developmental NOAEL is 100 mg/kg bw/day.

This developmental toxicity study is classified Acceptable/Guideline and satisfies the guideline 

requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat in 

combination with another developmental toxicity in rat (MRID 001013016).

MRID No. 00103016 

Citation: Wickeramaratne, G.A., Richards, D., Babham, P.B. (1982) Fomesafen: 

Teratogenicity study in the rat. CTL/P/656 and CTL/P/656S prepared by Central 

Toxicology Laboratory, Imperial Chemical Industries PLC, Alderley Park, Macclesfield, 

Cheshire, UK. Unpublished Study.

EXECUTIVE SUMMARY - In a developmental toxicity study (MRID 00103016), Fomesafen 

(97.5% a.i.) was administered to 19-21 pregnant rats/dose in corn oil by gavage at dose levels of 

0, 1.0, 7.5 or 50 mg/kg bw/day from days 6 through 15 of gestation. 

There was no maternal and/or fetal toxicity evident at any dose level tested. However, this study

should be considered with: 1) Report No. CTL/P/576, MRID #00164903, and 2) information 

provided by Syngenta in their submission (DP 316263, MRID 46527208) in establishing the 

NOAEL and LOAEL (see Discussion/Added Information Section). With the additional 

information, the following conclusions can be made. The maternal LOAEL is 200 mg/kg 

bw/day, based on staining of the ventral fur and significantly decreased body weight gain 

(>10%). The maternal toxicity NOAEL is 100 mg/kg bw/day. The developmental 
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LOAEL is 200 mg/kg bw/day based on postimplantation loss observed in study CTL/P/576 

(MRID 00164903). The developmental NOAEL is 100 mg/kg bw/day.

This developmental toxicity study is classified Acceptable/Guideline and satisfies the guideline 

requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat in 

combination with another developmental toxicity in rat (CTL/P/576, MRID 00164903).

MRID No. 00109214 

Citation: Wickeramaratne, G. A., Richards, D., Imartin, M., Doss, A., Ishmail, J., 

Taylor, D., Forbes, D., smf Godley, W.J. PP021: Teratogenicity Study in the Rabbit. 

Unpublished Report No. CTL/P/578. Central Toxicology Laboratory, Imperial Chemical 

Industries PLC, Alderley Park, Macclesfield, Cheshire, UK. Unpublished.

EXECUTIVE SUMMARY- In a developmental toxicity study (MRID 00109214), fomesafen 

(97.5% a.i.) was administered to at least 13 pregnant Dutch rabbits/group orally (in gelatin 

capsules) at dose levels of 0, 2.5, 10, or 40 mg/kg/day from days 6 through 18 of gestation. Due 

to the low number of pregnant does in the low and high dose groups after the initial mating, 6 

mated rabbits were added to the control, low, and mid dose groups and 7 to the high dose group. 

The remaining does were sacrificed on GD 29; their fetuses were removed by cesarean section 

and examined. A total of 17 animals died on study. Total mortality (including sacrifice in 

extremis) was 3/24, 3/24, 4/24, and 7/25 at 0, 2.5, 10, and 40 mg/kg/day, respectively. The 

incidence of mucous around the nose and/or forepaws increased in a dose- dependent manner: 

3/24, 3/24, 4/24 and 8/25 at 0, 2.5, 10 and 40 mg/kg/day, respectively. Pasteurella multocida 

was isolated from two animals found dead or removed from the study prior to GD 29. However, 

no other animal was tested for infection with Pasteurella multocida. In the high dose group only, 

6/25 does appeared thin, although body weight gain was not affected overall. Mean food 

consumption was 34% higher (p<0.05) than controls in the 40 mg/kg/day group during days 20-

29. An increased incidence (6/25) of erosion of the stomach (hemorrhagic foci) was observed 

macroscopically in high dose females versus 1/24 in controls, 2/24 at 2.5 mg/kg/day, and 0/24 at 

10 mg/kg/day. Erosion of the stomach was also observed in a separate, preliminary study at 75 

and 150 mg/kg/day with an incidence of 7/12 animals at each dose.

The maternal LOAEL was unable to be determined due to the occurrence of an apparent 

bacterial infection in the animal colony.

There was no significant difference between the control and treated groups in pregnancy rate or 

abortions. While the mean number of implantations/dam was similar across dose, the number of 

corpora lutea/dam was significantly (p<0.05) increased in the high dose group (10.6) relative to 

controls (7.7). This resulted in an increase in pre-implantation loss at the high dose only. This 

observation was not considered toxicologically significant, because it suggested that dosing took 

place before the completion of implantation, resulting in maternal-stress-induced embryo 

lethality. Early and late fetal deaths increased in the mid-dose group only (7/24, 3/24, 

respectively) relative to controls (4/24, 1/24, respectively). There was an increased frequency of 

partially ossified hyoid (7.1%) and right vestigial rib (#13, 5.4%) at 40 mg/kg/day relative to 

controls (2.9 and 0%, respectively). However, these variants are not regarded as toxicologically 

significant.
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The developmental LOAEL was unable to be determined due to the occurrence of an 

apparent bacterial infection in the animal colony.

Because of an apparent bacterial infection in the animal colony; individual animal data were not 

reported; all fetuses were not examined for both soft tissue and skeletal alterations; and historical 

control data were not provided, the developmental toxicity study in the rabbit is classified 

Unacceptable/guideline. This study does not satisfy the guideline requirement for a 

developmental toxicity study [OPPTS 870.3700; §83-3(b)] in the rabbit.

MRID No. 00131491 

Citation: Colley, J.; Slater, N.; Heywood, R.; et al. (1983) Fomesafen: 2- Year Feeding 

Study in Mice: HRC Report No. ICI 318/82754; Sponsor's Study No. PM 0386; 

CTL/C/1207A through E. Final rept. (Unpublished study received Oct 13, 1983 under 

10182-EX-33; pre- pared by Huntingdon Research Centre, Eng., submitted by ICI

Americas, Inc., Wilmington, DE; CDL:071999-A; 072000; 072001). Unpublished.

EXECUTIVE SUMMARY- In a chronic feeding/oncogenicity study (MRID 00131491), 

Fomesafen (Batch No. P28 and ICI Part No. Y00053/001/007, 97.2%) was administered in the 

diet to CD-1 mice (52/sex/group; control group contained 104 mice/sex) for up to 104 weeks at 

doses of 0, 1, 10, 100 or 1000 ppm (equivalent to 0, 0.15, 1.5, 1.5 or 15 mg/kg/day). An interim 

sacrifice was scheduled at 52 weeks utilizing additional groups of 12 mice/sex, except for the 

control group which contained 24 mice/sex. 

Male mice in the 1000 ppm group were terminated after 80 treatment weeks (80% survival) and 

female mice were terminated after 90 treatment weeks (70% survival). No significant increases 

in mortality were observed at the lower treatment doses. There was a high incidence of male

and female mice with swollen abdomens in the 1000 ppm group by terminal sacrifice. 

Erythrocyte counts, hemoglobin levels and hematocrits were decreased in male and female mice 

in the 1000 ppm group at terminal sacrifice. AP and GPT activities were significantly increased 

in males and females in the 100 and 1000 ppm groups at 52 weeks. Liver weights and liver-tobody weight ratios were significantly increased in both sexes receiving 100 and 1000 ppm 

Fomesafen. Kidney, adrenal, and heart weights were significantly increased at 1000 ppm. 

Because the organ-to-body weight ratios were not significantly different from the controls, 

fomesafen was not considered to have a significant toxicological affect on these organ weights. 

The incidence of liver masses was significantly increased in males receiving 1, 100 and 1000 

ppm fomesafen and in females receiving 100 and 1000 ppm fomesafen. The increase in liver 

masses was accompanied by increases in enlarged and discolored livers and by increases in 

eosinophilic hepatocytes and pigmented macrophages and/or Kupffer cells. The incidence of 

malignant liver cell tumors was significantly (p< 0.001) increased in males and females receiving 

1000 ppm fomesafen. The LOAEL is 100 ppm (equivalent to 1.5 mg/kg/day) based on the 

presence of liver tumors and liver weight increases in male and female mice. The NOAEL 

is 10 ppm (equivalent to 0.15 mg/kg/day).

The submitted study is classified as Acceptable/Guideline and does satisfy the requirements for 

a chronic feeding/oncogenicity study in mice (OPPTS 870.4300; OECD 453). 
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MRID No. 00135632 

Citation: Henderson, C., Parkinson, G., Oliver, G., et al. (1983) Subacute Dermal 

Toxicity in Rabbits. Imperial Chemical Industries, PLC Central Toxicology Laboratory, 

UK. Laboratory Report Number CTL/P/555, March 15, 1983. Unpublished.

EXECUTIVE SUMMARY - In a 21-day dermal toxicity study (MRID 00135632), fomesafen 

(90.8% a.i.; Batch/Lot # P 21 C4915/26/1) in propylene glycol suspension was applied to shaved 

intact or abraded skin of New Zealand white rabbits (10/sex/dose; 5 intact and 5 abraded 

skin/sex) at dose levels of 0, 10, 100, or 1000 mg/kg bw/day (limit dose), 6 hours/day, 5 

days/week for 3 weeks. 

No treatment-related effects were observed on mortality, body weight, body weight gain, food 

consumption, hematology, clinical chemistry and urinalysis at any dose in either sex. Clinical 

signs (subdued behavior) was observed only in the high-dose animals immediately after the 

application of test material. Clinical signs in the high-dose group were not considered as 

toxicologically significant since they were observed immediately after treatment. A slight 

reduction in food consumption and an increase in thyroid weight were also observed. However, 

these effects were not considered treatment-related, since there was no dose response. 

Fomesafen produced moderate to severe skin reactions manifested as erythema, edema, scaling 

and crust in the treated area in the 100 and 1000 mg/kg/day dose groups.

The systemic toxicity LOAEL was not observed in this study. The systemic toxicity 

NOAEL is 1000 mg/kg/day (limit dose).

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3200; OECD 410) for a 21-day dermal toxicity study in rats.

MRID No. 00142125 

Citation: Milburn, G., Banham, et al. (1984) Fomesafen: 2 year feeding in rats: Report 

no. CTL/P/863. Unpublished study prepared by ICI Americas, Inc. 550p. Unpublished.

EXECUTIVE SUMMARY - In this combined chronic toxicity/carcinogenicity study (MRID 

00142125), Fomesafen (97.5% a.i.; CTL Reference No. Y00053/001; Batch No. P28) was 

administered in the diet for 2 years to 52 Wistar albino rats/sex/dose at doses of 0, 5, 100 or 1000 

ppm (equivalent to 0, 0.25, 5 and 50 mg/kg/day). In addition, groups of 12 rats/sex received the 

same dietary concentrations for up to 52 weeks (interim sacrifice).The actual concentrations of 

fomesafen in the test diets were in the acceptable range of 10% of the nominal concentrations. 

There was an increased incidence of coat staining in males treated with 100 and 1000 ppm 

fomesafen and in all females treated with fomesafen. Body weights were significantly decreased 

in males in the 1000 ppm group from weeks 3 through 76. Decreased food utilization 

efficiencies were observed in males treated with 100 and 1000 ppm fomesafen during the first 14 

weeks of the study. Significant increases in the activities of plasma alkaline phosphatase, alanine 

transaminase and aspartate transaminase, and in plasma albumin were observed in male rats 

treated with 1000 ppm fomesafen. Significant reductions in plasma cholesterol and triglycerides
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were observed in males and females treated with 1000 ppm fomesafen. Male and female rats 

treated with 1000 ppm fomesafen had depressed protein excretion in urine. Mean liver weights 

were significantly increased in males and females administered 1000 ppm fomesafen in the diet. 

Hyalinization of the liver was observed in rats administered 100 and 1000 ppm fomesafen in the 

diet. Biliary hyperplasia, bile duct dilatation and portal fibrosis were decreased in groups treated 

with 1000 ppm fomesafen. Pigmentation of portal macrophages, Kupffer cells, and hepatocytes 

was substantially increased in males and slightly increased in females treated with 1000 ppm 

fomesafen. The LOAEL is 100 ppm (5 mg/kg/day), based on hyalinization of the liver in 

males. The NOAEL is 5 ppm (0.25 mg/kg/day).

This study is classified as Acceptable/Guideline and satisfies the guideline requirements 

(OPPTS 870.4300; OECD 453) for a combined chronic toxicity/carcinogenicity study in rats.

MIRD No. 00144862 

Citation: Tenston, D.J. et al (1984) Fomesafen: Two-Generation Reproduction Study in 

the Rat. Central Toxicology Laboratory, Imperial Chemical Industries PLC, Alderley

Park, Macclesfield, Cheshire, UK. Study number RR0199, 1984. Unpublished. 

EXECUTIVE SUMMARY - In a two-generation reproduction toxicity study (MRID 

00144862) Fomesafen (P28; 97.5% a.i.) was administered in diet to 30 Wistar rats (Alderley

Park-derived)/sex/dose at dose levels of 0, 50, 250, or 1000 ppm (equivalent to 0, 2.5, 12.5, or 50 

mg/kg/day) , for 2 generations. The F1A pups were weaned on postnatal day (PND)22 and F1B, 

F2B and F2A pups were weaned PND 29. Thirty F1B females and 15 males were selected to 

become F1 parents and produced F2B litters. Brother-sister matings were avoided in each 

parental generation.

In the parental animals, no treatment-related effects were observed on body weights, or food 

consumption.

At 1000 ppm, increased incidences of liver alterations were seen male and female F0 and F1 

parents. These include congestion (M & F), multifocal necrosis (M), Kupffer cell pigmentation 

(M), hyalinization (diffuse and centrilobular; M & F) and biliary hyperplasia (M & F). An 

increased incidence of liver hyalinization was observed in the livers of F1b males, however, 

these effects are considered to be of systemic effect rather than offspring toxicity. No liver 

alterations were observed at 250 ppm.

The parental LOAEL = 1000 ppm (50 mg/kg bw/day), based on liver histopathology in 

males and females of both generations. The maternal toxicity NOAEL = 250 ppm (12.5 

mg/kg bw/day).

An increased incidence of liver hyalinization was observed in the livers of F1b male pups. 

[Although, representative samples of liver from pups in the mid- and low-dose groups were not 

microscopically examined, hyalinization would not be expected to be observed since it was not 

observed in the livers of the parental animals in the low- and mid-dose groups.]

The offspring LOAEL = 1000 ppm (50 mg/kg/day), based on increased incidence of liver 

hyalinization in males. The offspring NOAEL = 250 ppm (12.5 mg/kg bw/day).
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No treatment-related reproductive parameters were affected due to treatment with fomesafen. 

Reductions of litter size (15 - 20%) was observed in F1and F2 A litter at 250 ppm. A significant 

reduction 20% in litter size was observed at 1000 ppm F2B litters, however, there was no 

reduction in litter sizes in other 3 1000 ppm groups. A 13% reduction in litter size was also 

observed at 50 ppm in F1 B litters. These litter reductions were sporadic, not dose-related, and 

therefore, considered to be of no toxicological significance. At 1000 ppm, an increased 

incidence of hyalinization of the liver was observed in F1B pups in the 1000 ppm group. 

The reproductive NOAEL = 1000 ppm (50 mg/kg/day). The LOAEL was not established.

The study is classified Acceptable/Guideline and satisfies the guideline requirement for a 

reproduction toxicity (OPPTS 870.3800; OECD 416) for a two-generation reproduction study in 

the rat.

MRID No. 00164903 

Citation: Wickeramaratne, G.A., Richards, D., Babham, P.B. (1981) PP021: 

Teratogenicity study in the rat. CTL/P/576 and CTL/P/567S prepared by Central 

Toxicology Laboratory, Imperial Chemical Industries PLC, Alderley Park, Macclesfield, 

Cheshire, UK. Unpublished.

EXECUTIVE SUMMARY - In a developmental toxicity study (MRID 00164903), Fomesafen 

(97.5% a.i.) was administered to 17-24 pregnant rats/dose in corn oil by gavage at dose levels of 

0, 50, 100 or 200 mg/kg bw/day from days 6 through 15 of gestation. 

Maternal toxicity was evident at dose of 200 mg/kg bw/day (the highest dose tested) and was 

associated with staining of the ventral fur in 15 of 20 animals and significantly decreased body 

weight gain (>10%) during the dosing period (Days 7-16; Days16-21). Food consumption in 

the high-dose group was also significantly decreased as compared to the control group during the 

dosing period (Days 7-16; Days 16-21).

However, this study should be considered with: 1) Report Nos. CTL/P/656 and CTL/P/656S, 

MRID #001013016, and 2) information provided by Syngenta in their submission (DP 316263, 

MRID 46527208) in establishing the NOAEL and LOAEL (see Discussion/Added Information 

Section). With the additional information, the following conclusions can be made. The 

maternal LOAEL is 200 mg/kg bw/day, based on staining of the ventral fur and 

significantly decreased body weight gain (>10%). The maternal toxicity NOAEL is 100 

mg/kg bw/day. The developmental LOAEL is 200 mg/kg bw/day based on 

postimplantation loss. The developmental NOAEL is 100 mg/kg bw/day.

This developmental toxicity study is classified Acceptable/Guideline and satisfies the guideline 

requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat in 

combination with another developmental toxicity in rat (MRID 001013016).

MRID No. 40786709 
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Citation: Colley, J., Cladee, S., Street, A., Heywood, R., Gibson, W., Prentice, D., 

Buckley, P., and Offer, J. (1980) Preliminary Assessment of PP 021 Toxicity to Mice by

Dietary Administration for 4 weeks. Huntingdon Research Center, Huntingdon, U.K. 

Study No. ICI/317/80148, September 13, 1980. Unpublished.

EXECUTIVE SUMMARY - In a 28-day range finding oral toxicity study (MRID 40786709), 

fomesafen (94% a.i., Batch/Lot # P 21 and ICI TSC No. Y00053/001/004) was administered to 

CD-1 mice (10/sex/dose) in the diet at doses of 0, 5, 15, 50, 150, 500, 1500, or 5000 ppm (equal 

to 0/0, 0.71/0.94, 2.13/2.87, 7.20/8.30, 20.7/27.1, 68.9/83.4, 209.1/246.8, or 917.2/1247.6 

mg/kg/day [M/F]) for up to 28 days.

Clinical signs consisting of emaciation were noted in two females in the high dose group (5000 

ppm) and in one female in the 150 ppm dose group. Since there was no dose response, the effect 

was not considered treatment-related. Mortality was seen in one male at 15 ppm in week 2, one 

male at 50 ppm during week 4 and one female at 5000 ppm during week 4. Statistically

significant decreased body weights and body weight gains were observed in high-dose animals 

only. Food efficiency was also decreased in high-dose animals only. Clinical chemistry

parameters were not evaluated in this study. A slight decrease in erythrocytes, hemoglobin, 

mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) was observed in 

high- dose females, while decreased MCH and a slight increase in erythrocytes were seen in 

high-dose males. These changes in hematological parameters were indicative of slight anemia 

and were therefore regarded as toxicologically significant. Statistically significant increases in 

liver weights were observed in males at ~50 ppm and in females at ~150 ppm. Enlarged 

hepatocytes were also observed. However, since there were no corroborating adverse 

histopathological findings, these effects were considered adaptive changes. All high-dose 

animals exhibited bile duct hyperplasia. Small seminal vesicles were observed in 2/10 highdose males, while small uteri were observed in 4/10 females at 1500 ppm and in 9/10 high-dose 

females.

Under the conditions of this study, the LOAEL was 5000 ppm (equal to 917/1247 

mg/kg/day in M/F) based on decreased body weights and body weight gains, decreased food 

efficiency, hematology (decreased erythrocyte count, hemoglobin, mean corpuscular 

volume, and mean corpuscular hemoglobin), bile duct hyperplasia, decreased uterine size 

in females, and decreased size of the seminal vesicles in males. The NOAEL is 1500 ppm 

(equal to 209/247 mg/kg/day in M/F).

This 28-day oral study is acceptable/non-guideline, because treatment was less than 90 days (or 

10% of the animal’s lifespan), as required by Guideline OPPTS 870.3100 for a subchronic oral 

toxicity study in rodents.

MRID No. 44569805 

Citation: Howard, C.A., Richardson, C.R. (1989) Fomesafen: An evaluation in the in 

vitro cytogenetic assay in human lymphocytes. Central Toxicology Laboratory, Alderley

Park, Macclecsfield, Cheshire, UK SK104TJ. Laboratory Project ID: CTL/P/2378, April 

4, 1988. Unpublished.
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EXECUTIVE SUMMARY - In a mammalian cell cytogenetics assay (chromosomal 

aberrations) (MRID 44569805), human lymphocytes (obtained from one male and one female 

donor) in culture were exposed to fomesafen (96.7% a.i.) in dimethyl sulfoxide (DMSO) at 

concentrations of 0, 150, 500, and 1000 μg/ml in the absence of S9-mix and 75, 150, and 250 

μg/ml in the presence of S9 mix for 3-3.5 hours and harvested 72 hours after the beginning of 

treatment. Two-hundred cells (100 per duplicate coded slide) were evaluated for metaphases 

with structural aberrations. The S9-fraction was obtained from Aroclor 1254 induced male 

Sprague Dawley rat liver.

Fomesafen was tested at concentrations ranging from 150-1000 μg/mL (S9) and 75-250 μg/mL

(+S9). A significant increase in chromosome fragments was observed in lymphocytes from 

donor 1 at 1000 μg/mL (S9). However, the clastogenic response is most likely secondary to 

cytotoxicity as the MI was reduced by 57% in these cells. In the repeat experiment (S9, donor 

1), the MI decreased by 56% and clastogenicity was not observed. Proper experimental protocol 

was followed and the solvent and positive control values were appropriate. There was no 

evidence of chromosome aberrations induced over background.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for Test 

Guideline OPPTS 870.5375; OECD 473 for in vitro cytogenetic mutagenicity data. 

MRID No. 44569806 

Citation: Mellano, D., Berruto, G. (1984) Fomesafen: In vitro study of chromosome 

aberration induced by fomesafen in cultured human lymphocytes. Istituto Di Ricerche 

Biomediche, “Antoine Marxer” S.p.A., Casella Postale 226, 10015 Ivrea. Laboratory

Project ID: CTL/C/1262, May 16, 1984. Unpublished.

EXECUTIVE SUMMARY - In an in vitro mammalian cell cytogenetics assay (Chromosomal 

aberrations) (MRID 44569806), human lymphocytes (obtained from 1 male donor) in culture 

were exposed to fomesafen (97.5% a.i.) in dimethyl sulfoxide (DMSO) at concentrations of 0, 

10, 100, and 1000 μg/ml in the absence and presence of metabolic activation for 3 hours and 

harvested 26 hours after the beginning of treatment. One-hundred cells (duplicate slides) were 

evaluated for metaphases with structural aberrations. The S9-fraction was obtained from Aroclor 

1254 induced male Sprague Dawley rat liver.

Fomesafen was tested up to a cytotoxic concentration for this assay. Cytotoxicity was observed 

at 1000 μg/ml with and without S-9 mix. No statistically or biologically significant increases in 

chromosomal damage were observed at any of the dose levels either in the presence or absence 

of metabolic activation. The solvent and positive controls induced the appropriate response. 

There was no evidence of chromosome aberrations induced over background.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for Test 

Guideline OPPTS 870.5375; OECD 473 for in vitro cytogenetic mutagenicity data. 

MRID No. 48762301 

Citation: Donald L., Marr C., (2011). Fomesafen – A 28 Day Immunotoxicity Study of 

Fomesafen by Oral (Dietary) Administration in Mice using Sheep Red Blood Cells as the Antigen
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Charles River Laboratories, Tranent, Edinburgh EH 33 2NE, UK. Study number 520005, 

October 31, 2011. MRID 48762301. Unpublished.

EXECUTIVE SUMMARY - In an immunotoxicity study (MRID 48762301), Fomesafen 

(98.8%, Batch/Lot no. 517927) was administered to female CD-1mice (10/group) in diets at dose 

levels of 0, 100, 1000 or 4000 ppm (0, 16, 176, 791 mg/kg/day, respectively) for 28 consecutive 

days. Positive control group consisted of 10 females received cyclophosphamide (CPH) by oral 

gavage (10 mg/kg/day) for 28 consecutive days. All animals in all groups received a single 

intravenous injection of the antigen, 2x108sheep red blood cells (SRBC) in Earles balanced salt 

solution, on Day 25. On day 29, blood samples were collected from the orbital sinus under 

isoflurane anesthesia. Measurement of the SRBC IgM antibody levels were performed with an 

Enzyme Linked Immunobsorbent Assay (ELISA). The animals were monitored for mortality and 

for treatment related symptoms daily. Body weights were recorded twice weekly from Day (-7) 

until necropsy. Additionally, all animals were assessed by gross pathology; the weights of liver

(with gall bladder), spleen and thymus were measured.

There were no treatment related signs and symptoms and no differences in food consumption. 

There were no deaths during the study period. Body weights were not affected in animals in 100 

or 1000 ppm groups. However, treatment related lower body weight and body weight gain

occurred in 4000 ppm group. Animals in positive control group that received (CPH) showed 

statistically significant lower body weight and body weight gain (p<0.05).

Increased liver weights (p<0.01) were found at 100 ppm and above groups. Lower spleen and 

thymus weights were observed in animals at 4000 ppm. Histologically, mild to mark diffuse or 

centrilobular hepatocytes hypertrophy was found in animals at 100 ppm and above groups. 

There was a dose response in severity of histopathology. These findings correlated with higher 

liver weights and macroscopic findings. The selected doses were approved by the HED Dose 

Adequacy and Review Team (DART, TXR No. 0055484, dated 14 September 2010).

The systemic NOAEL is not established (<100 ppm). The systemic LOAEL was 100 ppm 

(equivalent to 16 mg/kg/day) based on increased liver weights and histological changes.

For immunotoxicity, there is a dose-dependent suppression of the immune response to sheep red 

blood cells after the treatment with Fomesafen. IgM levels in animals at 1000 and 4000 ppm 

groups were approximately 2-3 folds lower than that of the control animals. A high interindividual variability was noted in all the treatment groups as well as in the control group. 

Evaluation of individual animal data of this study showed a distribution and trend that 

demonstrated a significant suppression of anti-SRBC IgM response. Animals in positive control 

group showed decreased antibody response which confirmed the ability of the test system to 

detect immunosuppressive effects and validated the study design. 

The Natural Killer (NK) cells activity was not evaluated. However, under the HED guidance 

when the test substance produces dose-related suppression of the TDAR (anti-SRBC response), 

then the test substance is considered as immunotoxic and no further study is required. NK cells 

activity assay is not required.
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Under conditions of this study, the immunotoxicity NOAEL is 100 ppm (equivalent to 16

mg/kg/day). The LOAEL is 1000 ppm (equivalent to 176 mg/kg/day) based on dose-related 

suppression of anti-SRBC IgM response.

This immunotoxicity study is classified acceptable guideline and satisfies the guideline 

requirement for an immunotoxicity study (OPPTS 870.7800) in mice. 

MRID No. 48973302 

Citation: Rached, E. 2012. Fomesafen technical - Acute oral (gavage) neurotoxicity study in 

rats. Harlan laboratories, Ltd. Itingen, Switzerland. Laboratory Report No. D41528, October 

16, 2012. MRID 48973302. Unpublished. 

Rached, E. 2012. Fomesafen technical - preliminary acute oral (gavage) neurotoxicity study in 

rat. Harlan laboratories, Ltd. Itingen, Switerland. Laboratory Report No. D41517, October 12, 

2012. MRID 48973301. Unpublished. 

EXECUTIVE SUMMARY - In an acute neurotoxicity study (MRID 48973302), fomesafen

(98.8% a.i., Batch No. 517927) was administered in a single oral gavage dose to 10 non-fasted

Wistar rats/sex/group at dose levels of 0, 100, 250, or 800 mg/kg bw in 0.5% (w/v) aqueous 

carboxymethylcellulose (10 mL/kg). The animals were observed for 15 days after dosing, and 

the survivors were sacrificed on Day 16. Neurobehavioral assessments, consisting of a modified

functional observational battery (FOB) and locomotor activity testing, were performed on all 

animals of both sexes before dosing and on Days 1 (day of dosing), 8, and 15. Cholinesterase 

activity was not determined in this study. At study termination, 5 rats/sex/group were 

anesthetized and perfused in situ for neuropathological examination. The tissues from the 

perfused animals in the control and 800 mg/kg groups were subjected to histopathological 

evaluation of brain, spinal cord, and peripheral nervous system tissues. 

No adverse, treatment-related effects were observed on mortality, clinical signs, or gross or 

microscopic pathology. No treatment-related effects were observed during the brain weight or 

neuropathology assessments.

Systemic toxicity was noted in the males for a day or two after treatment, but recovery did occur. 

In the 800 mg/kg male rats, a net loss in bodyweight was observed on Day 2 (-13.2 g in treated 

group vs 2.98 g in controls) and Day 3 (-9.39 g in treated group vs 7.61 g in controls). Body 

weights at Day 15 and overall (Days 1-15) body weight gains in the 800 mg/kg males were 

similar to controls. Body weights were affected to a lesser degree in the 250 mg/kg males. A net 

loss of weight was observed in the 250 mg/kg males on Day 2 (-7 g in treated group); however, 

body weights at Day 3 and later were similar to controls. Body weights in the 100 mg/kg males 

and in all treated female groups were similar to controls. During the first 24 hours after 

treatment, mean food consumption was decreased (statistical analysis not performed) by 62% in 

the 800 mg/kg males and by 22% and 43% in the 250 and 800 mg/kg females, respectively. No 

notable effect was observed on food consumption during Days 8-9 and 14-15 in the treated 

groups. Food consumption as a mean of means over the treatment period was decreased by 
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17-18% in the 800 mg/kg group. The effect on food consumption in the females was not 

considered adverse due to the transient nature and the minimal impact on body weight.

Neurotoxicity was observed, but not in the absence of systemic toxicity. In the 250 and 800 

mg/kg males on Day 1, decreased (p≤0.05, except as noted) motor activity compared to controls 

was observed as follows: (i) horizontal activity by 36-41%; (ii) time in central quadrant by 

46-59% (not statistically significant [NS] at 250 mg/kg); and (iii) vertical activity by 61-64%. 

The effect on the females was much less apparent. In the 800 mg/kg females on Day 1, 

horizontal activity was decreased (NS) by 24%, and vertical activity was decreased (NS) by 

28%. Motor activities in all other animals on Day 1 and in all animals on Days 8 and 15 were

similar to controls. Habituation was demonstrated, and unaffected by treatment. Reduced 

activity and decreased rearing was also assessed during the FOB; however, these findings 

demonstrated an equivocal effect on Day 1, marginal increases in incidence or severity without 

an effect that was clearly related to dose. 

At 800 mg/kg on Day 1, one male rat had a hunched posture (#34) and piloerection (#34), and 

another rat had a reduced righting response (#31). Piloerection, hunched posture, and abnormal 

gait were observed in one female (#72). These findings were not observed in other animals at 

any other time. As systemic toxicity was noted at this dose, these findings were considered 

equivocally treatment-related.

The LOAEL was 250 mg/kg, based on decreased body weight and motor activity 

(horizontal and vertical activity and time in central quadrant) in males. The NOAEL is 

100 mg/kg.

This study is classified as acceptable/guideline and satisfies the guideline requirement 

(870.6200; OECD 424) for an acute neurotoxicity study in rats.

MRID No. 48996801 

Citation: Rached, E. (2012) Formesafen technical – 13-week dietary combined toxicity and 

neurotoxicity study in Wistar rats. Harlan Laboratories Ltd., Itingen, Switzerland. Laboratory

Project ID: D41541, November 15, 2012. MRID 48996801. Unpublished.

EXECUTIVE SUMMARY - In a subchronic neurotoxicity and oral toxicity study (MRID 

49091201, replacing MRID 48996801), fomesafen (98.8% a.i., Batch No. 517927) was 

administered in the diet to 15 Wistar rats/sex/group at dose levels of 0, 100/300, 300/1000, or 

1000/3000 ppm in males/females (equivalent to 0/0, 6.4/23.1, 20.3/74.2, and 67.0/233.2

mg/kg/day [M/F], respectively) for 13 weeks. Neurobehavioral assessment (functional 

observational battery [FOB] and motor activity testing) was performed prior to treatment and 

during Weeks 2, 5, 9, and 13 on 10 rats/sex/group. At study termination, 5 rats/sex/group were 

anesthetized and perfused in situ for neuropathological examination. The tissues from the 

perfused animals in the control and 1000 (males)/3000 (females) ppm groups were subjected to 

histopathological evaluation of brain, spinal cord, and peripheral nervous system tissues. 

Additionally, required evaluations for a subchronic dietary toxicity study were fulfilled. 

Standard toxicity observations (such as body weight) were recorded for all animals (n=15). 

Clinical diagnostics and standard histopathology were performed on 10 rats/sex/group.
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No adverse, treatment-related effect was observed on mortality, clinical signs, body weight, body 

weight gains, food consumption, food utilization, ophthalmoscopic examination, hematology, 

clinical chemistry, urinalysis, or gross or microscopic pathology. No treatment-related effect 

was observed during the functional observational battery, motor activity, brain weight or 

neuropathology assessments.

There were no deaths or clinical signs of toxicity in either sex. Slight decreases in terminal body

weights (Day 92) and body weight gains (Days 1-85) were observed in males at 300 ppm (decr 

4-5%) and 1000 ppm (decr 6-7%), but the magnitude of the reductions were not considered 

adverse. Female body weights were comparable among the groups. The liver appears to be the 

target organ, as evidenced by the dose-related increase in liver weight in both sexes. Adjusted 

(for terminal body weight) liver weights were increased (p<0.01) dose-dependently in all treated 

male groups by 14-42% and in the 1000 and 3000 ppm females by 12-28%. Absolute and 

relative to body liver weights were also similarly increased dose-dependently in both sexes. At 

1000 ppm, enlarged livers were seen in 4 of 10 males, and minimal centrilobular hypertrophy 

was seen in 1 of 10 males. These responses were considered treatment-related, but adaptive in 

the absence of other pathological or clinical chemistry findings.

The systemic and neurotoxicity LOAELs were not observed. The systemic and 

neurotoxicity NOAELs are 1000/3000 ppm (equivalent to 67.0/233.2 mg/kg/day in M/F).

The study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 

870.6200b; OECD 424) for a subchronic neurotoxicity study in rats and the guideline 

requirement (OPPTS 870.3100; OECD 408) for a subchronic toxicity study in rats. Although a 

LOAEL was not determined, previous studies in rats with this test compound have demonstrated 

toxic effects at lower doses. Consequently, the dose selection was considered justified.
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Appendix B. Physical/Chemical Properties

Table B.1 Physicochemical Properties of Fomesafen.

Parameter Value Reference

Melting point/range 220-221 C HED Memo, 9/3/82, W. Anthony

pH 8.2 (94% TGAI) CSF (EPA Reg. No. 100-1017; 10/13/00)

Density 1.28 g/cm3

at 20 C HED Memo, 9/10/86, C. Trichilo

Water solubility at 25 °C 600 g/L at pH 7

<10 ppm at pH 1-2

50 mg/L

HED Memo, 9/3/82, W. Anthony

HED Memo, 9/10/86, C. Trichilo

Solvent solubility g/L

Acetone 

300

Cyclohexanone 

150

Methanol 

25

Hexane 

0.5

Xylene 1.9

HED Memo, 9/10/86, C. Trichilo

Vapor pressure <7.5 x 10-7 mm Hg at 50 C The Pesticide Manual 1

Dissociation constant, pKa 2.7 at 20 C

Octanol/water partition 

coefficient, Log(KOW)

Log KOW = 2.9 at pH 1

UV/visible absorption spectrum Not available

1 The Pesticide Manual, A World Compendium, The British Crop Protection Council (toxnet.nlm.nih.gov).
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Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

PHED 1.1; the AHETF database; and the ARTF database, are (1) subject to ethics review 

pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable 

ethics requirements. For certain studies, the ethics review may have included review by the 

Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, 

can be found at the Agency website4. 

 

4

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

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