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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF PREVENTION, PESTICIDE

AND TOXIC SUBSTANCES

MEMORANDUM

Date: February 19, 2010

SUBJECT: Fomesafen Sodium: Human Health Risk Assessment for the Establishment of 

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

Tomatoes.

PC Code: 123802 DP Barcode: D373963

Decision No.: 409397 Registration No.: 100-993

Petition No.: 9F7563 Regulatory Action: New Use/Tolerance

Risk Assessment Type: Human Health Risk 

Assessment

Case No.: NA

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

MRID No.: NA 40 CFR: §180.433

 

 

FROM: Alexandra LaMay, Risk Assessor

Christine Olinger, Chemist

Kit Farwell, Toxicologist

Risk Assessment Branch VII

Health Effects Division (7509P)

THROUGH: Michael Metzger, Branch Chief

Risk Assessment Branch VII

Health Effects Division (7509P)

TO: Dan Kenny/ Michael Walsh, PM Team 23

Herbicide Branch, Registration Division (7505P)

This document provides the Health Effects Division (HED) human health risk assessment for the 

proposed establishment of tolerances and registration of the new uses of herbicide fomesafen

sodium on potatoes and tomatoes.
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Table of Contents 

1.0 Executive Summary.......................................................................................................... 3

2.0 Ingredient Profile.............................................................................................................. 7

2.1 Summary of Registered and Proposed Uses....................................................... 7

2.2 Structure and Nomenclature ............................................................................... 9

2.3 Physical and Chemical Properties..................................................................... 10

3.0 Hazard Characterization/Assessment........................................................................... 10

3.1 Hazard and Dose-Response Characterization.................................................. 10

3.1.1 Database Summary................................................................................. 10

3.1.2 Toxicological Effects............................................................................... 11

3.2 Absorption, Distribution, Metabolism and Excretion..................................... 11

3.3 FQPA Considerations......................................................................................... 11

3.3.1 Adequacy of the Toxicity Database ....................................................... 11

3.3.2 Evidence of Neurotoxicity ...................................................................... 12

3.3.3 Studies Assessing Offspring Sensitivity ................................................ 12

3.3.4 Degree of Concern Analysis for Pre and Postnatal Susceptibility ..... 13

3.4 FQPA Safety Factor for Infants and Children................................................. 13

3.5 Hazard Identification and Toxicity Endpoint Selection.................................. 14

3.5.1 Level of Concern for Margin of Exposure............................................ 14

3.5.2 Recommendation for Aggregate Exposure Risk Assessments............ 14

3.5.3 Classification of Carcinogenic Potential ............................................... 14

3.5.4 Toxicological Doses and Endpoints....................................................... 14

3.6 Endocrine Disruption ......................................................................................... 15

4.0 Public Health and Pesticide Epidemiology Data.......................................................... 16

5.0 Dietary Exposure/Risk Characterization ..................................................................... 16

5.1 Residues of Concern ........................................................................................... 16

5.2 Residue Profile .................................................................................................... 17

5.2.1 Drinking Water Residue Profile............................................................ 17

5.2.2 Food Residue Profile............................................................................... 18

5.3 Dietary Exposure and Risk ................................................................................ 19

5.3.1 Acute Dietary Exposure/Risk................................................................. 19

5.3.2 Chronic (Non-Cancer and Cancer) Dietary Exposure/Risk ............... 19

5.4 Anticipated Residue and Percent Crop Treated (%CT) Information........... 20

5.5 Tolerance Assessment......................................................................................... 20

5.5.1 Enforcement Analytical Method ........................................................... 20

5.5.2 Tolerance Recommendation .................................................................. 20

5.5.3 International Harmonization................................................................. 21

6.0 Residential (Non-Occupational) Exposure ................................................................... 21

7.0 Aggregate Risk Assessments.......................................................................................... 21

8.0 Occupational Exposure and Risk .................................................................................. 21

8.1 Occupational Handler Exposure ....................................................................... 21

8.1.1 Occupational Handler Risk.................................................................... 23

8.2 Occupational Post-application Exposure.......................................................... 25

9.0 Environmental Justice .................................................................................................... 25

10. 0 Data Needs........................................................................................................... 26

11.0 References............................................................................................................................ 27
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Appendix A: Toxicology Assessment ....................................................................................... 28

A.1 Toxicology Data Requirements.......................................................................... 28

A.2 Toxicity Profiles .................................................................................................. 29

Appendix B. Toxicity Summaries.............................................................................................. 32

Appendix C: Review of Human Research ............................................................................... 42

Appendix D: Rationale for Toxicology Data Requirements.................................................. 43

1.0 Executive Summary

The Health Effects Division (HED) has conducted a human health risk assessment for the active 

ingredient fomesafen 5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-

nitrobenzamide) for the purpose of establishing a tolerance and registering a new use on potatoes 

and tomatoes. Fomesafen sodium is an herbicide used for control of broadleaf weeds. 

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). Fomesafen 

sodium is in the diphenylether chemical class and it mode of action is via inhibition of 

protoporphyrinogen oxidase (PPO) in the plant. There are no residential uses for fomesafen. 

Reflex Herbicide (22.8% active ingredient sodium salt of fomesafen) is applied at a maximum 

rate of 1 pt of product per acre (0.25 lb ae/A) on potatoes and at a maximum rate of 1.5 pt of 

product per acre (0.375 lb ae/A) on transplanted tomatoes. The product is applied to potatoes as 

a broadcast pre-emergence application after planting but before potato emergence for control of 

weeds; the product is applied to transplanted tomatoes as a pre-plant non-incorporated preemergence broadcast applications up to seven days prior to transplanting tomatoes for control of 

weeds. 

Hazard Characterization

The toxicological database for fomesafen is considered complete and adequate for the purposes 

of this risk assessment. Fomesafen has a low order of acute toxicity by the oral route of 

exposure (Toxicity Category III), is severely irritating to the eye and is moderately irritating to 

the skin. In the subchronic and chronic toxicity study in rats and mice, food consumption or 

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

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

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

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”. This decision was based on the weight-of-evidence 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, nor did this chemical show signs of neurotoxicity. 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. Immunotoxicity, acute neurotoxicity, and 

subchronic neurotoxicity studies are now required. 
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There was no evidence of increased susceptibility of fetuses or offspring in developmental or 

reproductive toxicity studies and the FQPA safety factor was reduced to 1X. 

There were no observed toxic effects which were attributable to a single dose of fomesafen; 

therefore, an endpoint for acute dietary risk was not selected. The point of departure used to 

establish the chronic population adjusted dose (cPAD) was microscopic liver changes in the 

chronic toxicity study in rats. An endpoint for incidental oral exposure (short and intermediate 

term) for infants and children was microscopic liver changes, increased liver weights in males 

and females, and increases in liver enzymes in a 90-day study in rats.

The endpoint to assess short- and intermediate-term dermal risk was postimplantation loss and 

decreased maternal body weight gain in the developmental toxicity study in rats. A dermal 

absorption value of 20% (based on dermal absorption factors for similarly structured 

compounds) was applied. The endpoint to assess long-term dermal and inhalation risk was 

microscopic liver changes in the chronic toxicity study in rats. 

The endpoint to assess short and intermediate term inhalation exposure was microscopic liver 

changes, increased liver weights in males and females, and increases in liver enzymes in a 90-

day study in rats. 

The CARC has classified fomesafen as “Not Likely to be Carcinogenic to Humans”. 

Residue Data

Sufficient residue data are available to support the proposed tolerance in/on tomatoes. The 

residue of concern is only the parent, fomesafen. Crop metabolism data are not available to 

support the proposed tolerance in/on potatoes. A root and tuber metabolism study is needed 

before HED can recommend for a tolerance. The residue data are supported by adequate storage 

stability data and an analytical method is available to support the proposed tolerance in/on 

tomatoes.

Dietary Exposure and Risk

The environmental fate data indicated that fomesafen is likely to be persistent and mobile in 

aquatic and terrestrial environments. EFED has calculated estimated drinking water

concentrations (EDWCs) in surface water using PRZM-EXAMS modeling and has 

recommended the use of a prospective groundwater water study to estimate concentrations in 

drinking water derived from groundwater sources. Since the only dietary assessment relevant to 

this action is a chronic dietary assessment, HED used the maximum annual average 

concentration value from PRZM- EXAMS of 10.5 ppb for surface water EDWCs; since the 

prospective groundwater monitoring concentration of 1.0 ppb is lower than the surface water 

value, dietary assessment using the surface water residue will be protective for residues in 

groundwater.
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Acute dietary risk assessments were not required as there were no endpoints identified 

attributable to a single exposure of fomesafen. Additionally, aggregate acute risk assessments 

were not required.

 

Chronic dietary risk assessments were conducted for fomesafen sodium using the Dietary

Exposure Evaluation Model (DEEM-FCIDTM), Version 2.03, which used food consumption data 

from the United States Department of Agriculture’s (USDA’s) Continuing Surveys of Food 

Intakes by Individuals (CSFII) from 1994-1996 and 1998. The assumptions of these unrefined 

assessments were tolerance level residues and 100% crop treated. Estimated drinking water 

concentrations (EDWCs) from the Environmental Fate and Effects Division were also included. 

The dietary exposure analyses in this assessment result in dietary risk estimates for food and 

water that are below the Agency’s level of concern for chronic dietary exposure for all 

population groups. The subgroup with the highest exposure and risk estimates is infants. The 

exposure for food plus surface water was 0.000791 mg/kg/day, which is 32% of the chronic 

population adjusted dose (cPAD) (D372850, C. Olinger, 1/21/2010). 

The Cancer Assessment Review Committee (CARC) classified fomesafen as "not likely to be 

carcinogenic to humans"; therefore, a cancer risk assessment was not required. 

Aggregate Risk Assessment

There are no residential uses for products formulated with fomesafen sodium, therefore an 

incidental oral exposure and risk assessment (short and intermediate term) was not required. 

Further, short-/intermediate- and long-term dermal and inhalation risk assessments were not 

required for residential exposures. Based on the lack of a relevant exposure scenario, short- and 

intermediate-term aggregate risk assessments are not required.

Since no acute endpoint was selected, a quantitative acute assessment is not required. Since 

there are no residential uses for fomesafen, the chronic aggregate risk assessment would combine 

food and water only. As described above, the chronic dietary assessment is below the level of 

concern.

Occupational Risk Assessment

There is potential for occupational exposure to fomesafen during mixing, loading, and 

application activities; therefore, short- and intermediate-term worker exposure and risk 

assessments were conducted. The Margin of Exposure (MOE) for determining the level of 

concern (LOC) for occupational populations is 100, which includes the standard safety factors of 

10X for intraspecies variability and 10X for interspecies variability. When the MOE is greater 

than 100, the risks are not of concern. The MOEs for occupational exposures were calculated for 

short/intermediate term dermal and inhalation exposures. These MOEs were calculated 

separately because the dermal and inhalation endpoints were different. Occupational exposure 

was evaluated by following Exposure Science Advisory Council SOPs and data from the 

Pesticide Handlers Exposure Database (PHED). Data from adult human subjects in the PHED 

study has received ethical review and all regulatory requirements were met. 
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Occupational Handler Risk: Occupational dermal and inhalation daily dose values were 

calculated and presented. For occupational handlers, dermal and inhalation MOEs above 100 are 

not of concern. All occupational exposure risk estimates for Reflex, for short- and 

intermediate- term exposures for handlers, are not of concern with single layer dermal Personal 

Protective Equipment (PPE) (includes long-sleeve shirt, long pants, gloves) or with engineering 

control enclosed cab (fixed wing aircraft). Dermal MOEs ranged from 12,000 to 130,000 and 

inhalation MOEs ranged from 220 to 5,900.

Occupational Post-application Risk: As the herbicide is applied pre-emergence for potato and 

tomato crops, no occupational post-application exposures are expected.

Human Studies: 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 studies, which 

comprise the Pesticide Handlers Exposure Database (PHED), have been determined to require a 

review of their ethical conduct, have received that review, and are considered ethically and 

scientifically acceptable for use in risk assessment.

Regulatory Recommendations

Pending resolution of the deficiency pertaining to directions for use, there are no residue 

chemistry issues that would preclude granting a conditional registration for the use of sodium 

fomesafen on tomatoes and establishing a tolerances for fomesafen in/on tomatoes at 0.025 ppm. 

Confined rotational crops studies should be required as a condition of registration.

At this time, data are not available to support rotation to other crops beyond those commodities 

that are currently registered and proposed as primary crops; therefore, the petitioner must revise 

the Reflex® Herbicide label to permit immediate replanting of soybeans, cotton, dry beans, snap 

beans, and tomatoes only (phytotoxicity concerns permitting) with a restriction that other crops 

can only be planted 12 months after treatment or 18 months after treatment if based on 

phytotoxicity concerns.

The registrant’s most recent Reflex® Herbicide label reflects regional use of fomesafen on 

tomatoes. However, the residue chemistry data submitted in support of this action are of 

sufficient geographic representation to support full U.S. registration; therefore, HED 

recommends that these tolerances be listed in the general section of 40 CFR §180.433.

Note to PM: According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. 

Knizner), the tolerance expression for fomesafen should be revised to state:

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

degradates, in or on the commodities in the table below. Compliance with the tolerance levels 

specified below is to be determined by measuring only fomesafen [5-[2-chloro-4-

(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide].”

HED cannot recommend for the requested tolerance in/on potatoes due to the lack of an adequate 

root/tuber metabolism study. 
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Label Recommendations

The proposed label should be revised to remove the use on potatoes based on lack of an adequate 

root/tuber metabolism study. The label should be revised to permit immediate replanting of 

soybeans, cotton, dry beans, snap beans, and tomatoes only (phytotoxicity concerns permitting) 

with a restriction that other crops can only be planted 12 months after treatment or 18 months 

after treatment if based on phytotoxicity concerns.

The label should be revised to remove the requirement of use of a respirator for mixer/loaders in 

support of aerial application handling more than 140 gallons of product per day. This 

requirement is not enforceable and should be removed from the label since there is no viable 

system in place for inspectors to validate daily use patterns for applicators that would ensure this 

requirement is properly implemented.

According to the label, applications are not to be made through any type of irrigation equipment 

except center pivot systems. The PM should note that there are other permanent systems outside 

of center pivot irrigation equipment which are essentially culturally equivalent (e.g. drip 

irrigation systems for tomatoes in raised bed culture).

2.0 Ingredient Profile

2.1 Summary of Registered and Proposed Uses

Background on Currently Registered Use Pattern: Fomesafen (5-[2-chloro-4-

(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide) is a selective herbicide which 

may be applied pre-plant, pre-emergence, and/or postemergence for control and suppression of 

broadleaf weeds, grasses, and sedges. Fomesafen sodium is a contact herbicide for control of 

broadleaf weeds. Fomesafen is currently registered for pre-plant, pre-emergence and early

postemergence use on cotton, dry beans and soybeans. There are no residential uses of 

fomesafen. The existing labels allow ground and aerial application. 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). Fomesafen sodium is in the diphenylether 

chemical class and it mode of action is via inhibition of protoporphyrinogen oxidase (PPO) in the 

plant. 

Summary of Proposed New Use Pattern: A human health risk assessment has been conducted

for the active ingredient fomesafen 5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-

2-nitrobenzamide) for the purpose of registering a new use on potatoes and tomatoes. Reflex

Herbicide (22.8% active ingredient sodium salt of fomesafen) will be applied at a maximum rate 

of 1 pt of product per acre (0.25 lb ae/A) on potatoes and at a maximum rate of 1.5 pt. of product 

per acre (0.375 lb ae/A) on transplanted tomatoes. The product is applied to potatoes as a 

broadcast pre-emergence application after planting but before potato emergence for control of 

weeds; the product is applied to transplanted tomatoes as a pre-plant non-incorporated preemergence broadcast applications up to seven days prior to transplanting tomatoes for control of 

weeds. The current label for Reflex® Herbicide, the sole label proposed for amendment in this 

action, specifies a 24- hr reentry interval for workers. 
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The draft label specifies that use is restricted to the eastern half of the U.S. Syngenta’s regional 

use map for Reflex® is subdivided into five regions. Reflex® may be applied at a maximum of 

0.375 lb ae/A per year in Region 1, 0.375 lb ae/A in alternate years in Region 2, 0.313 lb ae/A in 

alternate years in Region 3, 0.25 lb ae/A in alternate years in Region 4, and 0.1875 lb ae/A in 

alternate years in Region 5.

Spray additives: The draft label specifies that spray additives cleared for use on growing crops 

under 40 CFR §180.1001 may be used in the spray mixture. A nonionic surfactant (NIS), crop 

oil concentrates (COC), or other adjuvants may be used for postemergence applications only. 

Since the proposed uses on potatoes and tomatoes are either pre-emergence or pre-transplant, the 

use of surfactants is not needed when Reflex® is applied to these crops.

Application equipment: Ground applications are to be made in a minimum of 10 gal/A, and 

aerial applications are to be made in a minimum of 5 gal/A. Applications are not to be made 

through any type of irrigation equipment except center pivot systems. Reflex® alone or in tank 

mixture with other herbicides on the label, which are registered for center pivot application, may

be applied in irrigation water pre-emergence (after planting but before weeds or crop emerge) at 

label-recommended rates.

Tank mixtures with other products registered for use on potatoes and tomatoes: The draft label 

provides mixing procedures for tank mixes but does not specify specific tank mix partners for 

potatoes and tomatoes. The use directions state that, for tank mix combinations, the 

recommendations, restrictions, and limitations for all products must be followed and that the 

most restrictive labeling is to apply. For pre-emergence application in potatoes, Reflex® may be 

tank mixed with other pesticide products registered for use in this way and timing in potatoes. 

For pre-plant non-incorporated pre-emergence applications prior to transplanting tomatoes, 

Reflex® may also be tank mixed with other pesticide products registered for use in this way and 

timing in tomatoes. 

Table 2.1. Use Pattern Summary of Proposed New Use of Fomesafen on Potatoes and 

Tomatoes

Formulations Liquid

Pests Broadleaf weeds, grasses, and sedges

Application Methods Groundboom; chemigation (center pivot only); fixed-wing aircraft

Application Rates and 

Intervals

Potato: 1 pt/A (0.25 lb ae/A); Max 1 pt/A/season

Tomato: 1.5 pt/A (0.375 lb ae/A); Max 1.5 pt/A/season

Frequency No minimum rotation interval for potatoes and transplanted tomatoes

Pre-Harvest Interval 

(PHI)

Potatoes and tomatoes should not be harvested within 70 days after application.

Personal Protective 

Equipment (PPE)

Applicators and other handlers must wear: long sleeved shirt and long pants, chemicalresistant gloves, shoes plus socks, and protective eyewear.

Aerial applications mixers and loaders handling more than 140 gallons of Reflex ® 

Herbicide in a single workday must wear: dust/must filtering NIOSH-approved respirator 
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with any N, R, P or HE filter. (Note: it is recommended that this requirement be removed 

from the label).

Restricted Entry Interval 

(REI)

24 hours

Use Directions and 

Limitations

Potato: Broadcast pre-emergence application after planting but before potato emergence. 

Refer to Syngenta’s Regional Use Map for Reflex® * for determination of maximum use 

rate that may be applied in each geographic region. Do not apply to any field in Regions 

2, 3, 4, or 5 more than once every two years. Do not apply to sweet potatoes or yams. Do 

not apply as a pre-plant incorporated application as crop injury may occur. Do not apply 

to emerged potato plants or severe crop injury will occur.

Tomato: Broadcast pre-plant non-incorporated pre-emergence application up to 7 days 

prior to transplanting tomatoes.

Refer to Syngenta’s Regional Use Map for Reflex® 1(summarized in the ‘General Use 

Directions’ below) for determination of maximum use rate that may be applied in each 

geographic region. Do not apply to any field in Regions 2, 3, 4, or 5 more than once 

every two years.

*The draft label specifies five use regions with specific seasonal maximum application rates. The rates range with the label use 

Region 1 having the highest seasonal application rate reflects application at 0.375 lb ae/A each year and label use Region 5 with 

the lowest seasonal application rate reflects application of up to 0.1875 lb ae/A in alternate years. 

2.2 Structure and Nomenclature

Tables 2.2a and 2.2b provide structures and nomenclature for fomesafen and sodium salt of 

fomesafen.

Table 2.2a. Fomesafen Nomenclature.

Compound Chemical Structure

F3C

Cl

O

NO2

O

N

H

S

CH3

O

O

Common name Fomesafen

Company experimental name N/A

Molecular Formula C15H10ClF3N2O6S

Molecular Weight 438.77

PC code N/A

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 # 72178-02-0

Table 2.2b. Sodium Salt of Fomesafen Nomenclature.
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Table 2.2b. Sodium Salt of Fomesafen Nomenclature.

Compound Chemical Structure

F3C

Cl

O

NO2

O

N

S

CH3

O

O

Na

+

Common name Sodium Salt of Fomesafen

Company experimental name N/A

Molecular Formula C15H9ClF3NaN2O6S

Molecular Weight 460.75

PC code 123802

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 # 108731-70-0

End-use product/(EP) Reflex® Herbicide

2.3 Physical and Chemical Properties

Table 2.3. 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/cm3at 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 mmHg 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 Provided

1 The Pesticide Manual; A World Compendium, The British Crop Protection Council (toxnet.nlm.nih.gov) 

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

The toxicological database for fomesafen is considered adequate for hazard characterization.
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3.1.2 Toxicological Effects 

Fomesafen has a low order of acute toxicity by the oral route of exposure (Toxicity Category

III). Fomesafen is severely irritating to the eye and is moderately irritating to the skin. In the 

subchronic and chronic toxicity studies in rats and mice food consumption or food efficiency, 

body weight and 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). 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-of-evidence 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.

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.

3.2 Absorption, Distribution, Metabolism and Excretion 

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 whereas in males, it was in the 

feces, with some enterohepatic recirculation evident. The sex difference was not evident at 

higher doses where the 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.

3.3 FQPA Considerations

3.3.1 Adequacy of the Toxicity Database

The toxicology database for fomesafen is adequate for FQPA assessment. The following 

acceptable studies are available:

• Developmental toxicity study in rats

• 2 - Generation reproduction toxicity studies in rats
Page 12 of 44

An unacceptable developmental toxicity study in rabbits provided information that fomesafen 

does not pose a hazard to the developing embryo.

 

3.3.2 Evidence of Neurotoxicity

No neurotoxicity was observed in the studies. Acute and subchronic neurotoxicity studies are 

now required under 40 CFR Part 158. 

3.3.3 Studies Assessing Offspring Sensitivity

Developmental Toxicity Studies in Rats (MRID 00164903)

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. 

The maternal LOAEL was 200 mg/kg bw/day, the highest dose tested, based on staining of the 

ventral fur and significantly decreased body weight gain (>10%). The maternal toxicity

NOAEL was 100 mg/kg bw/day. The developmental LOAEL was 200 mg/kg bw/day based on 

postimplantation loss. The developmental NOAEL was 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).

Developmental Toxicity Study in Rabbits (MRID 00109214)

In a developmental toxicity study (MRID 00109214), fomesafen (97.5% a.i.) was administered 

to at least 13 pregnant Dutch rabbits/group orally at doses 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. 

In the high dose group only, 6/25 does appeared thin, although body weight gain was not 

affected overall. An increased incidence of erosion of the stomach was observed in high dose 

females. Mortality due to a bacterial infection was 3/24, 3/24, 4/24, and 7/25 in the respective 

dose groups. There was no significant difference between the control and treated groups in 

pregnancy rate or abortions or for developmental abnormalities. 

This study provided information to assess potential developmental toxicity rabbits, but was 

classified unacceptable because of bacterial infection in the colony. 

Reproductive Toxicity Study

Rat 2-Generation Reproduction Study (MRID 00144862) 
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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. 

At 1000 ppm, an increased incidence of liver alterations was 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). 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).

The offspring LOAEL = 1000 ppm (50 mg/kg/day), based on increased incidence of liver 

hyalinization in F1b male pups. The offspring NOAEL = 250 ppm (12.5 mg/kg bw/day).

No treatment-related reproductive parameters were affected due to treatment with fomesafen. 

The reproductive NOAEL = 1000 ppm (50 mg/kg/day), the highest dose tested. 

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.

3.3.4 Degree of Concern Analysis for Pre and Postnatal Susceptibility 

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 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. 

Therefore, it is concluded that there is no evidence of increased susceptibility to fomesafen 

following pre- and/or post-natal exposure and there are no concerns for residual uncertainties for 

increased susceptibility.

3.4 FQPA Safety Factor for Infants and Children

EPA began requiring functional immunotoxicity testing of all food and non-food use pesticides 

on December 26, 2007. Since this requirement went into effect after the tolerance petition was 

submitted, these studies are not yet available for fomesafen. In the absence of specific 

immunotoxicity studies, the toxicity database was evaluated to determine whether a database 

uncertainty factor is needed to account for potential immunotoxicity. No evidence of 

immunotoxicity was found in the database. Due to the lack of evidence of immunotoxicity for 

fomesafen, it was concluded that a database uncertainty factor is not needed to account for 

potential immunotoxicity.

EPA began requiring acute and subchronic neurotoxicity studies for all food and non-food use 

pesticides on December 26, 2007. Since this requirement went into effect after the tolerance 
Page 14 of 44

petition was submitted, these studies are not yet available for fomesafen. The toxicity database 

was evaluated for evidence of neurotoxicity and no evidence for neurotoxicity was found in the 

database. It was therefore concluded that a database uncertainty factor is not needed to account 

for potential neurotoxicity. 

For the above reasons, and because there are no concerns and/or residual uncertainties for 

pre- and/or postnatal increased susceptibility, the FQPA safety factor was reduced to 1X. 

3.5 Hazard Identification and Toxicity Endpoint Selection

3.5.1 Level of Concern for Margin of Exposure

A summary of the levels of concern for risk assessment may be found in Table 3.5.1. The level 

of concern (MOEs ≥ 100) is based on 10x for interspecies extrapolation from animals to humans 

and 10x for variation in sensitivity between humans. 

Table 3.5.1. Levels of Concern for Risk Assessment.

Route

Short-Term

(1 - 30 Days)

Intermediate-Term

(1 - 6 Months)

Occupational (Worker) Exposure

Dermal 100 100

Inhalation 100 100

Residential Exposure

Not applicable. There are no residential uses for fomesafen. 

3.5.2 Recommendation for Aggregate Exposure Risk Assessments

No residential uses are proposed for fomesafen at this time. Therefore, aggregate risk consists of 

exposure from food and drinking water sources only. Only chronic aggregate risk was assessed 

since no acute toxicity is likely to result from exposure to fomesafen.

3.5.3 Classification of Carcinogenic Potential

In accordance with the EPA Final Guidelines for Carcinogen Risk Assessment (March 29, 2005), 

the CARC classified Fomesafen as “Not Likely to be Carcinogenic to Humans”. This decision 

was based on the weight-of-evidence which supports activation of peroxisome proliferatoractivated receptor alpha (PPARα) as the mode of action for fomesafen-induced 

hepatocarcinogenesis in mice. The data did not support either mutagenesis or cytotoxicity

followed by regenerative proliferation as alternative modes of action. While the proposed mode 

of action for liver tumors in mice is theoretically plausible in humans, it is quantitatively 

implausible and unlikely to take place in humans based on quantitative species differences in 

PPARα activation and toxicokinetics. The quantification of risk is not required. 

3.5.4 Toxicological Doses and Endpoints
Page 15 of 44

A summary of the hazard endpoints selected may be found in Table 3.5.4. 

TABLE 3.5.4 Toxicological Doses and Endpoints for Fomesafen Human Health Risk Assessments. 

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

Special FQPA 

SF* and Level of 

Concern for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(Females 13-49)

- - No toxic effects attributable to a single dose of 

fomesafen were found in the database.

Acute Dietary

(General US Pop.)

- - No toxic effects attributable to a single dose of 

fomesafen were found in the database.

Chronic Dietary

(all populations)

NOAEL = 0.25 

mg/kg/day 

UF = 100

Chronic RfD = 0.0025 

mg/kg/day

FQPA SF = 1X

(cPAD) = 0.00025 

mg/kg/day

Chronic toxicity – rat

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

liver in males

Dermal 

Short-Term

(1 - 30 days)

Intermediate-Term

(1 - 6 months)

NOAEL = 100 

mg/kg/day 

(Dermal absorption 

rate = 20%)*

LOC for MOE = 

100 

(Occupational)

LOC for MOE = 

100 (Residential)

Prenatal development – rat

LOAEL = 200 mg/kg/day based on postimplantation 

loss

Inhalation 

Short-Term

(1 - 30 days)

Intermediate-Term

(1 - 6 months)

NOAEL = 0.5 

mg/kg/day

(Inhalation absorption 

rate = 100% oral 

equivalent)

LOC for MOE = 

100 

(Occupational)

LOC for MOE = 

100 (Residential)

90-Day – rat

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

hepatocytes, increased eosinophilia, reduced 

granulation, increased liver weights in males and 

females, and increases in plasma alkaline 

phosphatase, alanine transminase and aspartate 

transaminase in males

Long-Term

(Dermal &

Inhalation)

NOAEL = 0.25 

mg/kg/day

(Dermal absorption 

rate = 20%)*

LOC for MOE = 

100 

(Occupational)

LOC for MOE = 

100 (Residential)

Chronic toxicity – rat

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

liver 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 

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse-effect level, 

LOAEL = lowest observed adverse-effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = 

reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable

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

which have similar structures. 

3.6 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by 

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may

designate.” The EDSP employs a two-tiered approach to making the statutorily required 
Page 16 of 44

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA is issuing test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Fomesafen is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

In the available toxicity studies on fomesafen, there was no estrogen, androgen, and/or thyroid 

mediated toxicity.

4.0 Public Health and Pesticide Epidemiology Data

At this time there is no information in the incident reports that affect this risk assessment.

5.0 Dietary Exposure/Risk Characterization

5.1 Residues of Concern

The registrant submitted a new tomato metabolism study in support of this petition that is 

acceptable and supports the proposed use on tomatoes. The metabolism in tomatoes is 

submitted to the previously submitted studies on soybeans and cotton. HED generally

recommends that three metabolism studies on diverse crops be conducted when a pesticide is to 

be used on several different commodities. Although three metabolism studies have been 

submitted, soybeans and cotton are not sufficiently diverse to support the proposed use on 

potatoes. A potato metabolism study, in which both the root and tops/foliage are analyzed, is 

required to support the proposed use on potatoes. HED cannot recommend for a tolerance in/on 

potatoes until an adequate metabolism study is submitted. The residues of concern for food and

drinking water are summarized in Table 5.1 below.
Page 17 of 44

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 Not determined1 Not determined1

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. 2

Drinking Water Fomesafen NA

1 The nature of the residue in rotational crops has not been adequately delineated. For this action rotation is limited only to the

primary crops that are the subject of this action.

2 HED has determined that use of fomesafen on the primary crops that are the subject of this action will not likely result in finite 

residues in livestock commodities (180.6 (a)(3)).

5.2 Residue Profile

5.2.1 Drinking Water Residue Profile

Environmental Fate and Effects Division’s (EFED) assessments of potential drinking water 

impacts from the proposed uses of fomesafen are detailed in the memorandums entitled Tier II 

Drinking Water Assessment for Fomesafen use on cotton, soybeans, dry beans and snap beans (J. 

Hetrick, 9/27/2005, D314014) and Drinking Water Assessment for Fomesafen use on cotton, 

soybeans, dry beans, snap beans, potato and tomato (J. Lin, 12/10/2009, D365204).

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

terrestrial and aquatic environments. The major routes of dissipation from the application site 

are expected to be runoff and leaching. 

The surface water assessment was conducted using environmental fate data in the PRZMEXAMS model. There is a complete environmental fate data base except for the sediment halflife value. The surface water modeling was conducted on standard EFED scenarios for cotton in 

TX, NC, MS; soybeans in MS; dry beans and snap beans in IL, MI; potato in ME, FL; tomato in 

Fl, PA; and nursery crop in FL, TN. These scenarios were selected because they are expected to 

be representative of use sites prone to high runoff as well as representative of the highest 

regional use rates for fomesafen. Application rates were selected to reflect maximum application 

rates of 0.375 lbs ae/A for soybean, dry and snap bean, cotton, and tomato; 0.25 lbs ae/A for 

potato; and 0.5 lb ae/ A for nursery crop. Fomesafen aerial applications were simulated to 

account for spray drift of fomesafen to surface waters. The half life of fomesafen in sediment 

was assumed to be stable. No surface water monitor data were available for fomesafen. The 

scenario leading to the highest EDWC in surface water for chronic exposure (1 in 10 year annual 

mean concentration) using PRZM-EXAMS was MD cotton, aerial application, with a 

concentration of 10.535 μg/L (ppb), adjusted for Percent Crop Area (PCA) of 0.87 (D314014). 

This value was used directly in the dietary exposure assessment.
Page 18 of 44

EFED conducted a ground water assessment using the available environmental fate data and the 

SCI-GROW model. EFED notes that although the Koc model is inappropriate for estimation of 

fomesafen soil-water partitioning, the lowest reported Koc was used in the assessment. The SCIGROW modeling indicated that peak and long-term average concentrations of fomesafen in 

shallow ground water were not expected to exceed 11.2 μg/L (ppb). No USGS groundwater 

monitoring data were located for fomesafen, however, the registrant submitted a prospective 

monitoring study for fomesafen use on soybeans in North Carolina which clearly showed that 

fomesafen has a potential to leach to ground water. Fomesafen was detected at concentrations of 

1 μg/L (ppb), which is the detection limit for the compound. The detections were confirmed 

using an alternate analytical technique. EFED recommends using the ground water monitoring 

concentration of 1 μg/L (ppb) as the benchmark concentration for fomesafen in ground water 

source drinking water because it represents actual use conditions of fomesafen on soybeans on a 

vulnerable soil. Since this value was lower than the surface water EDWC, only the surface water 

value was incorporated into the dietary assessment.

Surface and ground water estimated drinking water concentrations (EDWCs) for fomesafen are 

described below:

 The scenario leading to the highest EDWC in surface water for chronic exposure (1-in10 year annual mean concentration) using PRZM-EXAMS was MS cotton, aerial 

application, with a concentration of 10 ppb, adjusted for a Percent Crop Area (PCA) of 

0.87. This value was used directly in the dietary exposure assessment.

 Syngenta submitted a prospective ground water monitoring study for fomesafen use on 

soybeans. EFED recommended using the ground water monitoring concentration of 1 

ppb, since it represents actual use conditions of fomesafen on soybeans on a vulnerable 

soil. Since this value was lower than the surface water EDWC, only the surface water 

value was incorporated into the assessment.

 The model and its description are available at the EPA internet site: 

http://www.epa.gov/oppefed1/models/water/. 

5.2.2 Food Residue Profile

Twelve crop field trials were submitted in support of the proposed tolerance in/on tomatoes. 

Residues in all trials were non-detectable at a limit of quantitation of 0.025 ppm. This is 

consistent with trials on other crops. Processing factors could not be calculated for tomatoes as 

residues were non-detectable in/on the raw and processed commodities. The metabolism, crop 

field trial, and processing studies are supported by adequate storage stability studies. The multiresidue methods are not suitable for the analysis of fomesafen. An adequate analytical method is 

available for the enforcement of tolerances. Syngenta submitted a new LC/MS/MS method 

(GRM045.01A) for analysis of fomesafen residues, which has been adequately validated in 

various crop commodities. 

Confined rotational crop data remain outstanding. Limited rotational crop field trials reflecting 
Page 19 of 44

analysis of only the parent compound are available.

There are no livestock feed items associated with the use on tomatoes. The existing uses of 

fomesafen result in a 180.6 (a)(3) situation, that there is no reasonable expectation of finite 

residues and no tolerances in/on livestock commodities are needed.

5.3 Dietary Exposure and Risk

Please see DP Barcode: D372850, Fomesafen Sodium: Chronic Dietary Exposure Assessment to 

Support Proposed New Use on Tomatoes, January 21, 2010 by Christine Olinger for the

complete fomesafen sodium dietary assessment.

Chronic dietary risk assessments were conducted using the Dietary Exposure Evaluation Model 

(DEEM-FCIDTM), Version 2.03, which used food consumption data from the United States 

Department of Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by Individuals 

(CSFII) from 1994-1996 and 1998. The analyses were performed to support a proposed new use 

of fomesafen sodium (commonly called fomesafen) on tomatoes. See Table 5.2 below for a 

summary of fomesafen chronic dietary exposure risk estimates for food and drinking water.

5.3.1 Acute Dietary Exposure/Risk

No toxic affects attributable to a single dose of fomesafen were found in any study; therefore no 

acute dietary exposures risks assessment was required.

5.3.2 Chronic (Non-Cancer and Cancer) Dietary Exposure/Risk

Chronic dietary exposure assessments were performed for fomesafen. The assessments resulted 

in dietary risk estimates for food alone and food and drinking water that are below the HED’s 

level of concern for chronic dietary exposure. For non-cancer exposure, the highest exposure 

and risk estimates were for all infants (<1 year old), with a cPAD of 32% including food and 

drinking water. 

Table 5.3.2. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Fomesafen.

Population Subgroup Acute Dietary1 Chronic Dietary Cancer2

Dietary 

Exposure 

(mg/kg/day)

% aPAD Dietary 

Exposure

(mg/kg/day)

% cPAD Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population NA NA 0.000282 11.3 NA NA

All Infants (< 1 year old) 0.000791 32

Children 1-2 years old 0.000480 19

Children 3-5 years old 0.000441 18

Children 6-12 years old 0.000302 12
Page 20 of 44

Youth 13-19 years old 0.000221 8.8

Adults 20-49 years old 0.000258 10

Adults 50+ years old 0.000260 10

Females 13-49 years old 0.000255 10

1 No toxic affects attributable to a single dose of fomesafen were found in any study.

2

Fomesafen classified as “not likely to be carcinogenic”.

aPAD = acute population adjusted dose; cPAD = chronic population adjusted dose

5.4 Anticipated Residue and Percent Crop Treated (%CT) Information

Neither anticipated residues nor percent crop treated were used in the dietary assessment.

5.5 Tolerance Assessment

5.5.1 Enforcement Analytical Method

Syngenta Crop Protection has submitted descriptions and validation data for a new proposed 

enforcement method, Method GRM045.01A, which is entitled “Fomesafen Analytical Method 

for the Determination of Residues of Fomesafen in Crop Commodities by LC-MS/MS.” This 

high performance liquid chromatography with tandem mass spectrometry detection (LC/MS/MS) 

method is based on previously submitted gas chromatography with nitrogen phosphorus 

detection (GC/NPD) methods (refer to DP# 325801, D. Davis, 4/25/06) developed by Zeneca 

AG.

Method GRM045.01A uses extraction procedures modified from the previous GC/NPD methods. 

In the revised method, fomesafen residues are extracted with 1% hydrochloric acid in 

acetonitrile. An aliquot is subjected to an SPE cleanup and analyzed using LC/MS/MS. A 

second ion transition may be monitored for confirmation. The LOQ is 0.02 ppm for fomesafen 

in each matrix. Representative spectra and linearity data were submitted demonstrating adequate 

sensitivity.

Adequate multi-residue method testing data are available, which indicate that the FDA multiresidue methods are not suitable for determining residues of fomesafen.

5.5.2 Tolerance Recommendation

Sufficient residue data are available to support a tolerance of 0.025 ppm in/on tomatoes. 

Processed commodity tolerances are not needed since detectable residues were not found in 

either raw or processed tomato commodities. 

According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the 

tolerance expression for fomesafen should be revised to state:

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

degradates, in or on the commodities in the table below. Compliance with the tolerance levels
Page 21 of 44

specified below is to be determined by measuring only fomesafen [5-[2-chloro-4-

(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide].”

5.5.3 International Harmonization

No Codex, Canadian, or Mexican MRLs have been established for residues of fomesafen in/on 

tomato. 

6.0 Residential (Non-Occupational) Exposure

There are no residential uses for fomesafen sodium; therefore, an evaluation of exposures 

resulting from home uses was not required.

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 

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

and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices. On a chemical by chemical basis, the Agency is now requiring interim 

mitigation measures for aerial applications that must be placed on product labels/labeling. 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 risks associated with drift.

7.0 Aggregate Risk Assessments

A typical aggregate risk assessment may include residential, food, and drinking water exposure. 

Because there are no residential uses for fomesafen, the aggregate assessment includes food and 

drinking water only, as discussed in Section 5.2. 

8.0 Occupational Exposure and Risk 

This section presents a summary of the occupational exposure and risk estimates for fomesafen.

Please see DP Barcode: D373961, Fomesafen Sodium: Occupational Exposure Assessment for a 

Proposal to Add New Uses on Potatoes and Tomatoes, Alexandra LaMay, February 19, 2010,

for the complete fomesafen occupational exposure and risk assessment.

This section describes the occupational exposure and risk assessments conducted to support 

applications of fomesafen on potatoes and tomatoes. HED determined that the potential for 

occupational exposure to Reflex Herbicide exists in a variety of scenarios. The anticipated use 

patterns indicate several occupational exposure scenarios based on the types of equipment and 

techniques that can potentially be used for Reflex Herbicide applications.

8.1 Occupational Handler Exposure 
Page 22 of 44

Occupational handler scenarios include handling of Reflexduring mixing, loading, and 

applying processes. The proposed label states loaders, applicators, and other handlers must wear 

a long-sleeved shirt, long pants, shoes plus socks and chemical-resistant gloves as personal 

protective equipment (PPE). Therefore, these scenarios were assessed. Also, for aerial 

applications, mixers/loaders handling more that 140 gallons of product per day must wear a dust/ 

mist filtering NIOSH respirator (80% protection factor, PF5) according to the proposed label. 

For the uses on potatoes and tomatoes, it is assumed that a mixer/loader would not handle more 

than 140 gallons of product per day; therefore this scenario was not assessed with use of a 

respirator. However, it is recommended that this requirement be removed from the label as it is 

not an enforceable requirement.

Short-term and intermediate-term exposures may occur; long term exposures are not expected. 

Exposure and risk were evaluated using the Pesticide Handlers Exposure Database (PHED).

In this exposure assessment, the use parameters were based on the label instructions and default 

exposure assumptions for quantity handled per day (ExpoSAC SOPs). The potential absorbed 

dose and MOEs were calculated using standard EPA exposure algorithms and generic unit 

exposure values from the PHED Version 1.1 (US EPA, 1998). The following exposure scenarios 

were assessed for agricultural workers: 

Mixer/Loaders (M/L):

(1) M/L liquids for Aerial Application/ Chemigation;

(2) M/L liquids for Groundboom Applications;

Applicators:

(3) Applying by Enclosed Fixed Wing Aircraft;

(4) Applying by Groundboom [open cab];

Flagging

(5) Flagging in Support of Aerial Application;

Based on handler’s activity use pattern, the duration of exposure is expected to be short-term (1 

to 30 days) and intermediate term (1 to 6 months) for occupational handlers. Occupational 

workers may be exposed to fomesafen sodium during the mixing/loading and/or application 

process. Based on the product labels, fomesafen sodium can be applied at a maximum rate of 

0.25 lbs ae/A on potatoes and 0.375 lbs ae/A on tomatoes. Maximum application rates have been 

assessed in this document to more inform risk managers about the specific conditions of the 

proposed label amendments. The adverse affects for short- and intermediate-term dermal risk 

assessment are female-specific; therefore the body weight of an average female (60 kg) was used 

to estimate dermal exposure. Since the adverse effects for the short- and intermediate-term 

inhalation endpoints are not gender specific, the body weight of an average adult (70 kg) was 

used to estimate inhalation exposure. Assumptions for the area treated per day were based on the 

EPA default values listed in ExpoSAC SOP #9.1. The work day was assumed to be 8 hours for 

all agricultural workers. For all use scenarios, the product application rates and amount handled 

per day are listed in Table 8.1.
Page 23 of 44

Table 8.1. Application Rates Assessed and Quantity Handled per Day

Use Scenario Crop Group Application Rates 

Assessed (lb ae/A)

Area Treated 

per Day

Liquid: Aerial/ Chemigation

Mixer/ Loader

Potato 0.25 350 Tomato 0.375

Liquid: Aerial Applicator Potato 0.25 350 Tomato 0.375

Liquid: Groundboom 

Mixer/Loader; Applicator

Potato 0.25 80 Tomato 0.375

Flagging

Potato 0.25

350

Tomato 0.375

Risks were calculated as a MOE, which is a ratio of the toxicological Point of Departure (POD) 

to the daily dose. Daily dose values were calculated by first calculating exposures by

considering application parameters (i.e., rate and area treated) along with unit exposures. 

Exposures were then normalized by body weight. 

8.1.1 Occupational Handler Risk 

The proposed label indicates that applications are made pre-emergence to potatoes and tomatoes. 

The proposed label allows for liquid application with a groundboom or an enclosed fixed wing 

aircraft. See Table 8.1.1 below.

For mixer/loaders at single layer dermal PPE (gloves, no respirator):

 For mixer/loader exposure scenarios, dermal and inhalation risks do not exceed HED’s 

level of concern (i.e., the MOEs are greater than 100) at the proposed maximum 

application rate of 0.25 lbs ae /A for potatoes and 0.375 lb ae/A for tomatoes:

o For mixer/loaders for aerial application/ chemigation on potatoes, the dermal 

MOE is 15,000 and the inhalation MOE is 330.

o For mixer/loaders for aerial application/chemigation on tomatoes, the dermal 

MOE is 9,900 and the inhalation MOE is 220.

o For mixer/loader for groundboom application on potatoes, the dermal MOE is 

65,000 and the inhalation MOE is 1,500.

o For mixer/loader for groundboom application on tomatoes, the dermal MOE is 

43,000 and the inhalation MOE is 970.

For applicators at single layer dermal PPE (gloves, no respirator) for groundboom 

applicators or engineering control of enclosed cab for aerial applicators:

 For applicator scenarios, dermal and inhalation risks do not exceed HED’s level of 

concern (i.e., the MOEs are greater than 100) at the maximum proposed application rate 

of 0.25 lbs ae /A for potatoes and 0.375 lb ae/A for tomatoes:

o For applicators using engineering control of enclosed fixed wing aircraft

application on potatoes, the dermal MOE is 62,000 and the inhalation MOE is 

5,900.
Page 24 of 44

o For applicators using engineering control of enclosed fixed wing aircraft

application on tomatoes, the dermal MOE is 42,000 and the inhalation MOE is 

3,900.

o For applicators using groundboom open cab on potatoes, the dermal MOE is 

110,000 and the inhalation MOE is 2,400.

o For applicators using groundboom open cab on tomatoes, the dermal MOE is 

71,000 and the inhalation MOE is 1,600.

For flagging at single layer dermal PPE (gloves, no respirator):

 For flagging scenarios, dermal and inhalation risks do not exceed HED’s level of concern 

(i.e., the MOEs are greater than 100) at the maximum proposed application rate of 0.25 

lbs ae /A for potatoes and 0.375 lb ae/A for tomatoes:

o For flaggers open cab for tomatoes, the dermal MOE is 29,000 and the inhalation 

MOE is 1,100.

o For flaggers open cab for tomatoes, the dermal MOE is 19,000 and the inhalation 

MOE is 760.

The proposed label requires single layer clothing and chemical-resistant gloves for all loaders,

applicators, and other handlers. HED notes that the risk estimates on the proposed label PPE 

would have MOEs that do not exceed the LOC. Refer to Table 8.1.1 for detailed information.

Table 8.1.1. Short- and Intermediate-Term Fomesafen Sodium Occupational Handler 

Risk Estimates

Exposure Scenario Crop

Application 

Rate1(lb 

ae/ acre)

Min PPE 

Dermal 

Unit 

Exposure2

(mg/lb ae)

Baseline 

Inhalation 

Unit 

Exposure3

(μg/lb ae)

Area 

Treated 

Daily 4

(acres)

Single Layer + 

Gloves Dermal 

Daily Dose 

(mg/kg/ day)5

Inhalation 

Daily 

Dose 

(mg/kg/ 

day)6

Single 

Layer + 

Gloves 

Dermal 

MOE7

Baseline 

Inhalation 

MOE8

Mixer/Loader Scenarios

Mix/Load Liquids 

for Aerial 

Application / 

Chemigation

Potato 0.25

With 

Gloves: 

0.023

1.2

350

0.0067 0.0015 15,000 330

Tomato 0.375 0.01 0.00225 9,900 220

Mix/Load Liquids 

for Groundboom 

Application

Potato 0.25

80

0.0015 0.00034 65,000 1,500

Tomato 0.375 0.0023 0.000514 43,000 970

Applicator Scenarios

Applying Sprays by 

Enclosed FixedWing Aircraft9

Potato 0.25 Eng.

Control:

0.0055

Eng. 

Control: 

0.068

350 0.0016 0.000085 62,000 5,900

Tomato 0.375 0.0024 0.00013 42,000 3,900

Applying Sprays by 

Open Cab 

Groundboom

Potato 0.25 With 

Gloves: 

0.014

0.74 80

0.00093 0.00021 110,000 2,400

Tomato 0.375 0.0014 0.00032 71,000 1,600

Flagger Scenario

Flagging for Liquid 

Aerial Application

Potato 0.25 With 

Gloves: 

0.012

0.35 350

0.0035 0.00044 29,000 1,100

Tomato 0.375 0.00525 0.00066 19,000 760

1Application rates are based on maximum values found on the label.
Page 25 of 44

2Minimum PPE dermal unit exposure represent long pants, long sleeved shirts, shoes, socks and chemical-resistant gloves. 

Engineering control unit exposures represent use of enclosed cab. Values are reported in the PHED Surrogate Exposure Guide 

dated August 1998.

3 Baseline Inhalation unit exposures represent no respirator protection (baseline). Engineering control unit exposures represent 

use of enclosed cab. Values are reported in the PHED Surrogate Exposure Guide dated August 1998.

4Area treated daily values are from the EPA HED estimates of acreage treated in a single day for each exposure scenario of 

concern.

5Daily Dermal Dose = (Dermal Unit Exposure (mg ae /lb ae) * Application Rate (lb ai /A) * Area Treated (A /day)) / Body 

Weight (60 kg) * 20% Dermal Absorption (0.20)

6 Daily Inhalation Dose = (Inhalation Unit Exposure (μg ae /lb ae) * Conversion Factor (1 mg /1000 μg) * Application Rate (lb 

ae/A) * Area Treated (A/day))/ Body Weight (70 kg) 

7 Dermal MOE = PoD (NOAEL of 100 mg/kg/day)/ Daily dermal dose (mg/kg/day)

8

Inhalation MOE = PoD (NOAEL of 0.5 mg/kg/day) / Daily inhalation dose (mg/kg/day)

9 Application by fixed-wing aircraft has engineering control of enclosed cab.

8.2 Occupational Post-application Exposure

As the proposed label states that the product is applied to potatoes as a broadcast pre-emergence 

application after planting but before potato emergence, post-application exposures are not 

anticipated for this use. Also, as the product is applied as a pre-plant non-incorporated preemergence broadcast application prior to transplanting tomatoes; post-application exposures are 

not anticipated for this use; therefore a quantitative post-application exposure assessment was not 

conducted. 

This risk assessment for fomesafen sodium evaluates the potential risks associated with its preplant/pre-emergent uses on tomatoes and potatoes. 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 including potatoes and tomatoes. There is a possible concern that some 

level of soil contact could occur during mechanically assisted tomato transplanting activities, 

however, but this is likely to result in negligible exposures as outlined in HED Exposure SAC 

Policy 8. This is because 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 small amounts of field soil on it because of the 

possibility of mechanical injury. Also, commercial tomato cultivation is typically in tarped,

raised beds with small planting holes punched in the tops of the raised beds which also 

minimizes the potential for contact with treated soil because of the physical barrier. These 

conclusions are appropriate even though fomesafen sodium has a long half-life in soil (i.e., mean 

soil half life of ~390 days). 

9.0 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.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf. The Office of 

Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use 

of a pesticide when conducting human health risk assessments, including, but not limited to, 

people who obtain drinking water from sources near agricultural areas, the variability of diets 
Page 26 of 44

within the U.S., and people who may be exposed when harvesting crops. Should these high 

exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure 

that the risk estimates are based on the best available information.

10. 0 Data Needs 

Toxicology

The following toxicology data gaps exist:

869.1200 Acute Dermal Toxicity Study

870.1300 Acute Inhalation Toxicity Study

869.2600 Skin Sensitization Study

870.7200 Acute Neurotoxicity Study

870.7200 Subchronic Neurotoxicity Study

870.7800 Immunotoxicity Study

Residue Chemistry

Provided the following deficiencies are addressed as a condition of the registration, HED 

concludes that the residue chemistry database is sufficient to support requested Section 3 

registration and establishment of tolerances for residues of fomesafen sodium in/on tomatoes.

860.1200 Directions for Use

· At this time, data are not available to support rotation to other crops beyond those 

commodities that are currently registered and proposed as primary crops; 

therefore, the petitioner must revise the Reflex® Herbicide label to permit 

immediate replanting of soybeans, cotton, dry beans, snap beans, and tomatoes 

only with a restriction that other crops can only be planted 12 months after 

treatment or 18 months after treatment if based on phytotoxicity concerns.

860.1850 Confined Accumulation in Crops

· The ongoing confined rotational crop study, which was expected to be completed 

by 12/2009, should be submitted. Based on this future submission, HED will 

determine the terminal residues of concern in rotational crops and will re-evaluate 

the existing field rotational crop studies for determination of appropriate 

plantback restrictions.

HED cannot recommend for the requested tolerance in/on potatoes due to the lack of an adequate 

root/tuber metabolism study. The following study must be submitted to support the proposed 

tolerance.
Page 27 of 44

860.1300 Plant Metabolism

· A potato metabolism study in which both the roots and tops are analyzed is 

required to support the proposed use and tolerance on potatoes.

Occupational and Residential Exposure

None.

11.0 References

Occupational/Residential Exposure: 

Fomesafen Sodium: Occupational Exposure Assessment for a Proposal to Add New Uses on 

Potatoes and Tomatoes, D373961, A. LaMay, 2/19/2010.

Dietary: 

Fomesafen Sodium. Petition for the Establishment of Tolerances and Registration of New Uses 

on Potato and Tomato; and Response to Data Gaps for Conditional Registration on Cotton, Dry

Bean, and Snap Bean. Summary of Analytical Chemistry and Residue Data, D365199, C. 

Olinger, 1/21/2010.

Fomesafen Sodium: Chronic Dietary Exposure Assessment to Support Proposed New Use on 

Tomatoes, D372850, C. Olinger, 1/21/2010.

Water: 

Tier II Drinking Water Assessment for Fomesafen use on cotton, soybeans, dry beans, and snap 

beans, D314014, J. Hetrick, 9/27/2005.

Drinking Water Assessment for Fomesafen use on cotton, soybeans, dry beans, snap beans, 

potato and tomato, D365204, J. Lin, 12/10/2009.

Endpoint Selection: 

Fomesafen: Second Report of the Cancer Assessment Review Committee, TXR No. 0053835, J. 

Kidwell, 11/3/2005.

Fomesafen Sodium: Response to a request by Syngenta Crop Protection, Inc. for revision of the 

toxicity endpoints and unit exposures for the occupational exposure assessment, D337945, W. 

Phang and M. Lloyd, 4/29/08. 
Page 28 of 44

Appendix A: Toxicology Assessment

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for food use for fomesafen are presented below. Use of the new guideline 

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

Test Technical

Required Satisfied

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

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

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

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

no

no

yes

yes

no

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 21-Day Dermal ..............................................................

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

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

yes

yes

yes

no

no

yes

yes

yes

-

-

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

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

870.3800 Reproduction .................................................................

yes

yes

yes

yes

no

yes

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

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

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation – mammalian ...............

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen).....................................

870.6100b 90-Day Neurotoxicity (hen)...........................................

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

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

870.6300 Develop. Neuro..............................................................

no

no

yes

yes

no

-

-

no

no

-

870.7485 General Metabolism ......................................................

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

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

yes

yes

yes

yes

no

no
Page 29 of 44

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile- Fomesafen

Guideline Study Type (Date) MRID Results Tox.

Cat.

870.1100

(§ 81-1)

Acute Oral 00247589 LD50 = 1250-2000 mg/kg III

870.1200 

(§ 81-2) Acute Dermal - - -

870.1300 

(§ 81-3)

Acute Inhalation 

- - -

870.2400 

(§ 81-4) Primary Eye Irritation 00247589 Severe Irriation -

870.2500 

(§ 81-5) Primary Dermal Irritation 00247589 Moderate Irriation -

870.2600 

(§ 81-6) Dermal Sensitization -

-

-

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

Guideline 

No./Study 

Type

MRID No. (year)/ 

Classification/Doses Results

870.3050 28-

day mice- diet

40786709 (1980) 

Acceptable/Non-Guideline 

0, 5, 15, 50, 150, 500, 1500 or 1500 

ppm (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]

NOAEL = 1500 ppm (209/247 mg/kg/day)

LOAEL = 5000 ppm (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 rats- diet

00103013 (1981)

Acceptable/ Guideline

0, 1, 5, 100 or 1000 ppm (0, 0.1, 0.5, 

10 and 100 mg/kg/day)

NOAEL = 5 ppm (0.5 mg/kg/day)

LOAEL = 100 ppm (10 mg/kg/day) based on 

hyalinization of hepatocytes, increased eosinophilia, 

reduced granulation, increased liver weights in males 

and females, and increases in plasma alkaline 

phosphatase, alanine transaminase and aspartate 

transminase in males

870.3150 26-

Week dogs- diet

0.00103014 (1981)

Acceptable/Guideline

0, 0.1, 1.0 or 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)
Page 30 of 44

Guideline 

No./Study 

Type

MRID No. (year)/ 

Classification/Doses Results

870.3200 21-

day dermalrabbit

00135632 (1983)

Acceptable/ Guideline

0, 10, 100 or 1000 mg/kg/day

NOAEL = 1000 mg/kg/day

LOAEL was not observed

870.3700 

Prenatal 

development 

toxicity- rabbit

00109214 (1981)

Unacceptable/Guideline

0, 2.5, 10 or 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. 

Study provided information to assess potential 

developmental toxicity rabbits, but was classified 

unacceptable because of bacterial infection in the 

colony. 

870.3700 

Prenatal 

development 

toxicity- rat

00164903 (1981)

Acceptable/Guideline

0, 50, 100 or 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

Maternal 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

Developmental LOAEL = 200 mg/kg/day based on 

postimplantation loss observed in study CTL/P/576 

(MRID 00164903)

870.3700 

Prenatal 

developmental 

toxicity - rat

00103016 (1982) 

Acceptable/Guideline

0, 1.0, 7.5 or 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 fomesagen.]

Maternal NOAEL = 100 mg/kg/day

Maternal 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

Developmental LOAEL = 200 mg/kg/day based on 

postimplantation loss observed in study CTL/P/576 

(MRID 00164903)

870.3800 

Reproduction 

and fertility 

effects- rat (2-

generation)

00144862 (1984)

Acceptable/Guideline

0, 50, 250 or 1000 ppm (0, 2.5, 12.5 

and 50 mg/kg/day)

Paternal NOAEL = 250 ppm (12.5 mg/kg/day)

Paternal LOAEL = 1000 ppm (50 mg/kg/day) based 

on liver histopathology in males and females of both 

generations

Offspring NOAEL = 250 ppm (12.5 mg/kg/day)

Offspring LOAEL = 1000 ppm (50 mg/kg/day) based 

on increased incidence of liver hyalinization in males

Reproductive NOAEL = 1000 ppm (50 mg/kg/day)

Reproductive LOAEL was not established
Page 31 of 44

Guideline 

No./Study 

Type

MRID No. (year)/ 

Classification/Doses Results

870.4200 

Carcinogenicity 

mice- diet

00131491 (1983)

Acceptable/Guideline

0, 1, 10, 100 or 1000 ppm 

(0, 0.15, 1.5, 15 and 150 mg/kg/day)

NOAEL =10 ppm (1.5 mg/kg/day)

LOAEL = 100 ppm (15 mg/kg/day) based on the 

presence of liver tumors and liver weight increases in 

male and female mice

870.4300 

Chronic 

toxicity/ 

carcinogenicity 

rats- feeding

00142125 (1984)

Acceptable/Guideline

0, 5, 100 or 1000 ppm (0, 0.25, 5 and 

50 mg/kg/day)

NOAEL = 5 ppm (0.25 mg/kg/day)

LOAEL = 100 ppm (5 mg/kg/day) based on 

hyalinization of the liver in males
Page 32 of 44

Appendix B. 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 (equivalent to 0, 0.1, 0.5, 10 and 100 mg/kg/day). 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 

169, 149 and 131%, respectively, in males in the 1000 ppm group. Liver weights were increased 

in male and females at 1000 ppm. Hyalinization of hepatocytes, increased eosinophilia and 

reduced basophilic granulation 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, increased 

eosinophilia, reduced granulation, increased liver weights in males and females, and 

increases in plasma alkaline phosphatase, alanine transaminase and aspartate 

transaminase 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 
Page 33 of 44

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.

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.
Page 34 of 44

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 

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, 
Page 35 of 44

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.

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. 
Page 36 of 44

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 females in the 100 and 1000 ppm groups at 52 weeks. Liver weights and liver-to-body

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). 

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).
Page 37 of 44

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

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 
Page 38 of 44

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).

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.
Page 39 of 44

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 

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 
Page 40 of 44

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.

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 ug/ml in the absence of S9-mix and 75, 150, and 250 

ug/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 ug/mL (!S9) and 75-250 ug/mL 

(+S9). A significant increase in chromosome fragments was observed in lymphocytes from 

donor 1 at 1000 ug/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 
Page 41 of 44

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 ug/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 ug/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. 
Page 42 of 44

Appendix C: Review of Human Research

In the PHED study, adult human subjects were intentionally exposed to a pesticide and it has 

been determined that a review of their ethical conduct is required. 

 The PHED Task Force, 1995. The Pesticide Handler Exposure Database (PHED), 

Version 1.1. Task Force members Health Canada, U.S. Environmental Protection 

Agency, and the National Agricultural Chemicals Association, released February 1995.

The PHED study has received the appropriate ethical review. 
Page 43 of 44

Appendix D: Rationale for Toxicology Data Requirements

Guideline Number: 870.7800

Study Title: Immunotoxicity

Rationale for Requiring the Data

The immunotoxicity study is a new data requirement under 40 CFR Part 158 as a part of the data 

requirements for registration of a pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity 

testing and is designed to evaluate the potential of a repeated chemical exposure to produce 

adverse effects (i.e., suppression) on the immune system. Immunosuppression is a deficit in the 

ability of the immune system to respond to a challenge of bacterial or viral infections such as 

tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the 

immune system is highly complex, studies not specifically conducted to assess immunotoxic 

endpoints are inadequate to characterize a pesticide’s potential immunotoxicity. While data from 

hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity 

studies may offer useful information on potential immunotoxic effects, these endpoints alone are 

insufficient to predict immunotoxicity. 

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to characterize potential 

hazard to the human population on the immune system from pesticide exposure. Since 

epidemiologic data on the effects of chemical exposures on immune parameters are limited and are 

inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal studies are 

used as the most sensitive endpoint for risk assessment. These animal studies can be used to select 

endpoints and doses for use in risk assessment of all exposure scenarios and are considered a 

primary data source for reliable reference dose calculation. For example, animal studies have 

demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD 

(2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive, and endocrinologic 

toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide 

(TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a greater or a diminished risk 

than that given in the interim decision’s conclusion, the risk assessments for the test material may 

need to be revised to reflect the magnitude of potential risk derived from the new data.

Guideline Number: 870.7200

Study Title: Acute and Subchronic Neurotoxicity

Rationale for Requiring the Data

Acute and subchronic neurotoxicity studies are now required under 40 CFR Part 158 as a part of 

the data requirements for registration of a pesticide for (food and non-food uses). 

The Neurotoxicity Test Guideline (OPPTS 870.6200) require a functional observational battery, 

motor activity, and neuropathology evaluation. The functional observational battery consists of 

noninvasive procedures designed to detect gross functional deficits in animals and to better 

quantify behavioral or neurological effects detected in other studies. The motor activity test uses 

an automated device that measures the level of activity of an individual animal. The 

neuropathological techniques are designed to provide data to detect and characterize 
Page 44 of 44

histopathological changes in the central and peripheral nervous system. This battery is designed to 

be used in conjunction with general toxicity studies and changes should be evaluated in the 

context of both the concordance between functional neurological and neuropatholgical effects, and 

with respect to any other toxicological effects seen.

Practical Utility of the Data

How will the data be used? Neurotoxicity studies provide critical scientific information needed 

to characterize potential hazard to the human population of neurotoxicity from pesticide exposure. 

How could the data impact the Agency's future decision-making? 

If the neurotoxicity study shows that the test material poses either a greater or a diminished risk 

than that given in the risk assessments's conclusion, the risk assessments for the test material may 

need to be revised to reflect the magnitude of potential risk derived from the new data.