Document ID: EPA-HQ-OPP-2012-0589-0009
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-11-01T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION

MEMORANDUM

Date: July 18, 2013 

SUBJECT:	Fomesafen Sodium: Human Health Risk Assessment for the Section 3 Registration Action  on Cantaloupe, Cucumber, Pea (Succulent), Pumpkin, Summer Squash, Winter Squash, Watermelon, Soybean (Succulent) and Lima Bean (Succulent) 
 

PC Code:  123803; 123802
DP Barcode: 403953, 410795
Decision No.: 467057, 477271
Registration No.: 100-993
Petition No.:  2E8061, 3E8167
Regulatory Action: Section 3 Registration
Risk Assessment Type: Single Chemical Aggregate
Case No.: NA
TXR No.: NA
CAS No.: 72178-02-0
MRID No.: NA
40 CFR: §180.433

FROM:	Danette Drew, Chemist
		Ideliz Negrón Encarnación, Ph.D., Chemist
		Alexandra LaMay, Biologist
      Ronnie Bever, Ph.D., Toxicologist 
		Branch V/VII
		Health Effects Division (7509P)

THROUGH:	William Irwin, Ph.D., Toxicologist 
      Michael Metzger, Branch Chief
		Branch V/VII
		Health Effects Division (7509P)

TO:	Laura Nollen, Risk Manager Reviewer
      Barbara Madden, Risk Manager
            Risk Integration, Minor Use & Emergency Response Branch
            Registration Division (RD, 7505P)

		

1.0	Executive Summary	4
2.0	HED Recommendations	6
2.1	Data Deficiencies	6
2.2	Tolerance Considerations	6
2.2.1	Enforcement Analytical Method	6
2.2.2	Recommended Tolerances	6
2.2.3	Revisions to Petitioned-For Tolerances	7
2.2.4	International Harmonization	7
2.3	Label Recommendations	7
2.3.1	Recommendations from Residue Reviews	7
2.3.2	Recommendations from Occupational Assessment	8
3.0	Introduction	8
3.1	Chemical Identity	8
3.2	Physical/Chemical Characteristics	8
3.3	Pesticide Use Pattern	9
3.4	Anticipated Exposure Pathways	10
3.5	Consideration of Environmental Justice	10
4.0	Hazard Characterization and Dose-Response Assessment	11
4.1	Summary of Toxicological Effects	11
4.2	Safety Factor for Infants and Children (FQPA Safety Factor)	12
4.2.1	Completeness of the Toxicology Database	12
4.2.2	Evidence of Neurotoxicity	13
4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	13
4.2.4	Residual Uncertainty in the Exposure Database	13
4.3	Toxicity Endpoint and Point of Departure Selections	13
5.0	Dietary Exposure and Risk Assessment	15
5.1	Residues of Concern Summary and Rationale	15
5.2	Food Residue Profile	15
5.3	Water Residue Profile	16
5.4	Dietary Risk Assessment	17
5.4.1	Description of Residue Data Used in Dietary Assessment	17
5.4.2	Percent Crop Treated Used in Dietary Assessment	17
5.4.3	Acute Dietary Risk Assessment	17
5.4.4	Chronic Dietary Risk Assessment	18
5.4.5	Cancer Dietary Risk Assessment	18
5.4.6	Summary Table	18
6.0       Residential (Non-Occupational) Exposure/Risk Characterization	18
6.1	Residential Bystander Post-application Inhalation Exposure	19
6.2	Spray Drift	19
7.0   Aggregate Exposure/Risk Characterization	19
8.0    Cumulative Exposure/Risk Characterization	20
9.0   Occupational Exposure/Risk Characterization	20
9.1	Short-/Intermediate -Term Handler Risk	20
9.2.1	Dermal Post-application Risk	24
9.2.2	Inhalation Post-application Risk	25
10.0	References	26
Appendix A.  Toxicology Profile and Executive Summaries	27
A.1	Toxicology Data Requirements	27
A.2	Toxicity Profiles	28
A.3   Toxicity Summaries	33
Appendix B.  Physical/Chemical Properties	47
Appendix C.  Review of Human Research	48

1.0	Executive Summary

Fomesafen, 5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide), is an herbicide used for control of broadleaf weeds, annual grasses, perennial weeds, and sedges.  It is in the diphenylether chemical class, and its mode of action is via inhibition of protoporphyrinogen oxidase (PPO) in the plant.  Fomesafen products are formulated as the sodium salt, and the concentration of the active ingredient in the formulation is expressed in terms of the acid equivalent (ae).  It is currently registered for use on peppers, tomatoes, potatoes, cotton, dry beans, and field soybeans. There are no residential uses of fomesafen.  The requested Section 3 registration of Reflex Herbicide (22.8% active ingredient sodium salt of fomesafen) is for new uses on cantaloupe, cucumber, pea (succulent), pumpkin, summer squash, winter squash, watermelon, and soybean (succulent) (petition #2E8061), and on lima bean (succulent) (petition #3E8167).  

The Health Effects Division (HED) has conducted a human health risk assessment to support the requested use registrations and the establishment of associated tolerances.  Assessments were performed for potential dietary (food and drinking water) and occupational worker exposures. The dietary risk assessment takes into account all existing and proposed uses of fomesafen. 

The toxicity database for fomesafen is complete.  Generally, hyalinization of hepatocytes provided the most sensitive toxicological endpoint (short, intermediate, and long term) in mammals.  In the subchronic and chronic toxicity studies in rats and mice, food consumption, food efficiency, body weight, body weight gain, and histopathological changes in the liver were parameters that were most often affected.  In addition, dogs and mice also showed hematological changes.  Neurotoxicity may occur at the same dose level as systemic toxicity.  Fomesafen was not considered to be mutagenic.  Carcinogenicity was not observed in the rat chronic toxicity/ carcinogenicity study.  Liver tumors were produced in the mouse carcinogenicity study; however, HED's Cancer Assessment Review Committee (CARC) determined that fomesafen should be classified as "Not Likely to be Carcinogenic to Humans" (HED Doc No. 0053835).  Post-implantation loss was noted in the developmental study; however, no quantitative or qualitative evidence of increased susceptibility was seen following in utero exposure to rats or rabbits in developmental studies or in the reproduction study.  Fomesafen can result in suppression of anti-SRBC IgM response, but this was not the most sensitive endpoint.  Fomesafen has a low order of acute toxicity by the oral, dermal, and inhalation routes of exposure (Toxicity Category IV).  Fomesafen is minimally irritating to the eye and is not irritating to the skin.  It is not a sensitizer.  

The fomesafen risk assessments were based on the most sensitive endpoints in the toxicity database, and the NOAELs selected for risk assessment are considered protective of potential developmental, neurotoxic, and immunotoxic effects for infants and children.  Further, highly conservative exposure estimates were incorporated into the dietary risk assessment and there are no residential uses; therefore, reduction of the 10x Food Quality Protection Act (FQPA) safety factor to 1x is considered appropriate.

Sufficient residue data are available to support the proposed tolerances for residues of fomesafen on cantaloupe, cucumber, pea (succulent), pumpkin, summer squash, winter squash, watermelon, soybean (succulent), and lima bean (succulent).  The residue of concern is only the parent, fomesafen.  The residue data are supported by adequate storage stability data, and an analytical method is available to support the tolerances.  All residues in the magnitude of residue studies were below the lowest limit of method validation (LLMV), and recommended tolerances are based on this level.

Environmental fate data indicate that fomesafen should be very mobile and highly persistent in terrestrial and aquatic environments.  The residue of concern in drinking water is parent fomesafen.  Estimated drinking water concentrations (EDWCs) were based on Tier II PRZM-EXAMS screening model.

Conservative acute and chronic dietary (food and drinking water) assessments were performed using tolerance level residues, assuming 100% crop treated, and incorporating modeled EDWCs. Acute and chronic dietary (food and drinking water) risk estimates are not of concern. 
Because there are no registered residential uses of fomesafen, aggregate risks are identical to the food and drinking water dietary risk estimates; there are no acute or chronic aggregate dietary risk estimates of concern. 

For occupational handlers, dermal and inhalation MOEs above 100 are not of concern.  All occupational exposure risk estimates for short- and intermediate- term exposures for handlers are not of concern with single layer dermal PPE (includes long-sleeve shirt and long pants) or with engineering control enclosed cab (fixed wing aircraft/aerial applicators).  Dermal MOEs ranged from 350 to 300,000, and inhalation MOEs ranged from 410 to 360,000.

The applications to most of the proposed crops are for only pre-emergent or directed ground sprays; thus, post-application contact with treated foliage is expected to be negligible using these applications.  The proposed uses for soybean and lima bean include a post-emergent application; therefore, a quantitative dermal post-application exposure assessment was only conducted for these uses.  Post-application worker risk estimates for short- and intermediate- term exposures are not of concern (i.e., dermal MOEs are greater than the LOC of 100).  Dermal MOEs ranged from 3,200 to 59,000 for post-application activities.  Based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment was not performed for fomesafen sodium.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for fomesafen sodium.

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment (see Section 3.5).

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

2.0	HED Recommendations

HED recommends for the registration and associated tolerances for the use of fomesafen sodium on cantaloupe, cucumber, pea (succulent), pumpkin, summer squash, winter squash, watermelon, soybean (succulent), and lima bean (succulent).  The specific tolerance recommendations are discussed in 2.2, and label modifications are discussed in section 2.3 below.
2.1	Data Deficiencies

None.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

Adequate residue analytical methods are available for the purpose of fomesafen tolerance enforcement for plant commodities.  A high performance liquid chromatography method with tandem mass spectrometry detection (LC/MS/MS) method (GRM045.01A) has previously been submitted as an enforcement method.  The method uses extraction procedures similar to previous methods, SPE cleanup procedures, and the final determination step by LC/MS/MS for analysis of fomesafen residues.  The validated limit of quantitation (LOQ) of the method is 0.02 ppm.  This method is similar to the data acquisition methods used for fomesafen on cantaloupe, pea (succulent), summer squash, and cucumber, where the LLMV was 0.025 ppm.  

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

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

2.2.2	Recommended Tolerances

HED recommends that 40 CFR 180.443 be amended by establishing tolerances for the plant commodities listed in the Table 2.2.2 below.  The tolerances for plant commodities should be defined as follows:
Tolerances are established for residues of the herbicide fomesafen, including its metabolites and degradates, in or on the following commodities.  Compliance with the tolerance levels specified in the table below is to be determined by measuring only fomesafen, 5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide, in or on the commodity.

Table 2.2.2.  Tolerance Summary for Fomesafen.
Commodity
                           Proposed Tolerance (ppm)
                        HED-Recommended Tolerance (ppm)
                                   Comments 
                        (correct commodity definition)
Cantaloupe
                                     0.025
                                     0.025

Cucumber
                                     0.025
                                     0.025

Pea, succulent
                                     0.025
                                     0.025

Pumpkin
                                     0.025
                                     0.025

Squash, summer
                                     0.025
                                     0.025

Winter, Squash
                                     0.025
                                     0.025
Squash, winter
Watermelon
                                     0.025
                                     0.025

Vegetable, soybean, succulent
                                     0.05
                                     0.05
Soybean, vegetable, succulent
Lima, bean
                                     0.05
                                     0.05
Bean, lima, succulent

[It is noted that adequate field trial data for cantaloupe, cucumber, and summer squash is available to establish tolerances for melon, crop subgroup 9 A, and squash/cucumber, crop subgroup 9B.  The HED will consider the establishment of tolerances for these two crop subgroups upon petition from the registrant.]

2.2.3	Revisions to Petitioned-For Tolerances

Both the proposed and recommended tolerance levels are the same and are based on the commodity LLMV, since residues were below this level in the field trial studies.  The commodity names should be changed to reflect the correct commodity definitions.

2.2.4	International Harmonization

Codex or Mexican MRLs have not been established for residues of fomesafen in/on the registered and proposed commodities; therefore, there are no issues with international harmonization raised by this action.  Canadian MRL has been established for residues of fomesafen in/on succulent shelled lima beans at 0.05 ppm which is harmonized with the USA tolerance for lima beans.  Canada is also currently reviewing a request for the use of fomesafen on cucumbers.

2.3	Label Recommendations

2.3.1	Recommendations from Residue Reviews

Rotational crop restrictions were not included in the Section B of the petition.  The appropriate plant-back intervals (PBIs) for rotated crops should be specified in Section B and in the label of Reflex(R) Herbicide.  Refer to the residue chemistry chapter for PBIs previously established (I. Negron; D407932).

2.3.2	Recommendations from Occupational Assessment

None.

3.0	Introduction

3.1	Chemical Identity

Table 3.1.   Test Compound Nomenclature.
Compound
                                       
Common name
Fomesafen Sodium
Company experimental name
Not provided.
IUPAC name
5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-N-methylsulfonyl-2-nitrobenzamide, sodium salt
CAS name
5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitro-benzamide, sodium salt
CAS registry number
108731-70-0
Compound
                                       
Common name
Fomesafen
Company experimental name
Not provided.
IUPAC name
5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-N-methylsulfonyl-2-nitrobenzamide
CAS name
5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitrobenzamide
CAS registry number
72178-02-0
End-use product (EP)
Reflex(R) Herbicide, 2 lb ae/gal SL; EPA Reg. No. 100-993

3.2	Physical/Chemical Characteristics

Fomesafen is not especially volatile and has a low vapor pressure of 7.5 x 10[-][7] mm Hg at 50 ºC.  The octanol water partition coefficient (Kow = 790 at pH 1) suggests that it is slightly lipophilic.  Fomesafen is highly soluble in water (600 g/L at 25 °C and pH of 7) and exists as the anionic form at environmental relevant conditions (pKa is 2.7).  Fomesafen is expected to be highly mobile in aquatic environments.  A table of the physical and chemical properties can be found in Appendix B.
3.3	Pesticide Use Pattern

The end-use product relevant to the current petitions is Reflex(R) Herbicide (EPA Reg. No. 100-993), a soluble concentrate liquid (SL) formulation containing 22.8% sodium salt of fomesafen as the active ingredient (equivalent to 2 lb ae/gal of fomesafen).  Reflex(R) is a selective herbicide, which may be applied preplant surface, pre-emergence, and/or post-emergence for control or partial control of broadleaf weeds, grasses, and sedges.  In support of the proposed uses, the petitioner submitted the proposed use directions of the Reflex(R) Herbicide in the Section B of the petition.  A summary of the proposed use directions is presented in Table 3.3. 

See section 2.3 for recommended modifications to the proposed label.

Table 3.3.  Summary of Proposed Directions for Use of Reflex Herbicide (EPA Reg. No. 10-993)
Applic. Timing, Type, and Equip.
                                  Formulation
                                [EPA Reg. No.]
                                 Applic. Rate 
                                   (lb ai/A)
                          Max. No. Applic. per Season
                          Max. Seasonal Applic. Rate
                                   (lb ai/A)
                                      PHI
                                    (days)
                        Use Directions and Limitations
                         Cantaloupe (transplants only)
Ground equip, prior to transplanting
100-993
0.25-0.375
NS
0.375
35

                    Cucumber (Direct seeded or transplant)
Gound equip, just after seeding but before crop emergence of prior to transplanting
10-993
0.25-0.375
NS
0.375
42

                                Peas, succulent
Ground or aerial equip, Broadcast, preemergence to weeds and crop
100-993
0.125-0.25
NS
0.375
46

                     Pumpkin (Direct seeded or transplant)
Ground equip, broadcast or direct spray, after seeding but prior to crop emergence or prior to crop transplanting
100-993
0.25-0.375
NS
0.375
32

         Summer squash and winter squash (Direct seeded or transplant)
Ground equip, broadcast or directed spray, after seeding but prior to crop emergence or prior to transplanting
100-993
0.25-0.375
NS
0.375
32

                   Watermelon (Direct seeded or transplant)
Ground equip, broadcast or directed spray, after seeding but prior to crop emergence or prior to transplanting; post-emergence as directed application to row middles just prior to or at vine runner initiation
100-993
0.25-0.375
NS
0.375
35

                             Bean, lima, succulent
Broadcast, postemergent appl.[1]
100-993
0.125-0.25
NS
0.25
30
Do not graze treated areas or harvest for forage or hay.  Do not utilize hay or straw for animal feed or bedding. 
                         Soybean, vegetable, succulent
Preplant surface and preemergence appl.;[2] and post emergence appl.[3]
100-993
0.25-0.375
NS
0.375
30
Do not graze treated areas or harvest for forage or hay.  Do not utilize hay or straw for animal feed or bedding.
NS = Not Specified.
1 Do not apply to any field in regions 2, 3, 4 or 5 more than once every two years.
[2] Application only allowed in Regions 1, 2, 3 and 4.
[3] Applications only allowed in Regions 1, 2, 3, 4 and 5.

3.4	Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use of fomesafen sodium on to cantaloupe, cucumber, pea, pumpkin, squash, watermelon, soybean (succulent), and lima bean (succulent). Humans may be exposed to fomesafen in food and drinking water, since fomesafen may be applied directly to growing crops and application may result in fomesafen reaching surface and ground water sources of drinking water.  There are no residential uses of fomesafen; so, there is not likely to be exposure in residential or non-occupational settings.  In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application.  There is a potential for post-application exposure for workers re-entering treated fields.  This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of fomesafen but also considers the existing uses as well in regard to the dietary assessment.

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture's (USDA's) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups, and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures are evaluated, based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application.  Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.
4.0	Hazard Characterization and Dose-Response Assessment

The toxicological database for fomesafen is complete.  The last human health risk assessment was performed on October 12, 2010 (A. LaMay, D373600).  Since then, several toxicological studies have been received and reviewed.  An Acute Toxicity 6-Pack (MRIDs 46988901-46988906) on fomesafen technical (>=98.5% purity) was submitted.  An immunotoxicity test was submitted.  A subchronic oral toxicity study in rats (MRID 49091201) was received in 2012, which does not demonstrate an adverse effect at 6x the LOAEL of the previous (1981) subchronic oral toxicity study in rats (MRID 00103013).  A 13-week subchronic dietary combined toxicity and neurotoxicity study in rats (MRID 48996801) was submitted, as well as an acute neurotoxicity study (MRID 48973302).  The acute neurotoxicity study provided an acute oral endpoint for the general population (including infants and children), but other toxicity endpoints and points of departure (PODs) remained the same as in the 2010 assessment.  

4.1	Summary of Toxicological Effects

Fomesafen is an herbicide that is absorbed by leaves and roots and inhibits protoporphyrinogen oxidase, leading to irreversible cell membrane damage.  Generally, hyalinization of hepatocytes provided the most sensitive toxicological endpoint (short, intermediate, and long term) in mammals.  In the subchronic and chronic toxicity studies in rats and mice, food consumption, food efficiency, body weight, body weight gain, and histopathological changes in the liver were parameters that were most often affected.  In addition, dogs and mice also showed hematological changes (e.g., decreased erythrocyte count, hemoglobin, or hematocrit).  Neurotoxicity (decreased motor activity) may occur at the same dose level as systemic toxicity.  Carcinogenicity was not observed in the rat chronic toxicity/ carcinogenicity study.  Liver tumors were produced in the mouse carcinogenicity study; however, HED's Cancer Assessment Review Committee (CARC) determined that fomesafen should be classified as "Not Likely to be Carcinogenic to Humans" (HED Doc No. 0053835).  This decision was based on the weight-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.  Post-implantation loss was noted in the developmental study, but no quantitative or qualitative evidence of increased susceptibility was seen following in utero exposure to rats or rabbits in developmental studies or in the reproduction study.  Fomesafen can result in suppression of anti-SRBC IgM response.  Fomesafen has a low order of acute toxicity by the oral, dermal, and inhalation routes of exposure (Toxicity Category IV).  Fomesafen is minimally irritating to the eye and is not irritating to the skin.  It is not a sensitizer.  

In a metabolism study in rats, fomesafen was readily absorbed in male and female rats after oral dosing.  The major route of elimination in females was in the urine; fecal excretion was the major route in males, with some enterohepatic recirculation evident.  The sex difference was not evident at higher doses, where urine was the main route of excretion for both sexes.  At higher doses, the vast majority was excreted unchanged, but at lower doses a lesser amount (60%) was excreted unchanged.  The major metabolite (10%) was 5-(2-chloro-α,α,α-trifluoro-tolyloxy)-anthranilic acid.  Part, or all, of the metabolism may be due to action by intestinal microorganisms.  The rat has a very limited capacity to metabolize fomesafen.

In a metabolism study in dogs, peak blood levels occurred within 3 hours, then rapidly declined.  Excretion in both sexes was predominantly in urine and to a lesser extent in the feces.  Most of the fomesafen (96%) was excreted within 24 hours in both sexes.  Fomesafen was not extensively metabolized in the dog and was recovered to a large extent unchanged.

As a dermal penetration study was not provided, the dermal absorption value of 20% was based on dermal absorption factors for oxyfluorfen and acifluorfen, which have similar structures.

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

The FQPA safety factor was reduced to 1X for the reasons described in sections 4.2.1 through 4.2.4.  The toxicity and exposure databases for fomesafen are complete.  There is no evidence of increased susceptibility in developing and young animals, and there are no residual uncertainties concerning pre- or post-natal toxicity.  Acute and subchronic neurotoxicity studies are available, and all points of departure used in this risk assessment are protective of any potential neurotoxic, developmental, or immunotoxic effects.  The dietary assessments are conservative and are based on tolerance level (non-detectable) residues and assume 100% of the crops are treated.  There are no residential uses of fomesafen. 

4.2.1	Completeness of the Toxicology Database

The toxicology database for fomesafen is complete.  The requirement for the subchronic inhalation toxicity study was waived upon consideration at HASPOC on April 25, 2013 (DOC # 123803TS.001).  A weight of evidence approach indicated that the inhalation toxicity study was not necessary due to low compound volatility, high inhalation MOEs, a conservative oral endpoint upon which the MOEs were based, and low acute toxicity via oral, dermal, and inhalation routes.  Although the developmental toxicity study in rabbits was classified unacceptable due to mortality from bacterial infections, there was not any evidence of increased susceptibility of rabbit fetuses due to the treatment with fomesafen.  Therefore, the lack of an acceptable developmental toxicity study in non-rodents was not considered a data gap.  As a dermal penetration study was not provided, the dermal absorption value of 20% was based on dermal absorption factors for oxyfluorfen and acifluorfen, which have similar structures.  Consequently, the dermal penetration study is not considered a data gap.

4.2.2	Evidence of Neurotoxicity

Decreased motor activity (horizontal and vertical activity and time in central quadrant) was observed in rats in the acute neurotoxicity screening battery at the same dose that resulted in general systemic toxicity.  In the subchronic neurotoxicity test, neither general systemic toxicity nor neurotoxicity was observed at the highest dose tested. 

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

There is no evidence of increased susceptibility of rat fetuses to in utero exposure to fomesafen.  The 2-generation reproduction study in rats did not show evidence of increased susceptibility to fomesafen.  Although the developmental toxicity study in rabbits was classified as unacceptable due to mortality from bacterial infections, there was adequate information to show that there was not any evidence of increased susceptibility of rabbit fetuses due to the treatment with fomesafen.     

4.2.4	Residual Uncertainty in the Exposure Database

There are no residential uses of fomesafen.  The dietary assessment is based on conservative assumptions, including 100% crop treated and tolerance-level (non-detectable) residues; there are no residual uncertainties in the exposure database.

4.3	Toxicity Endpoint and Point of Departure Selections

The most recent risk assessment performed for fomesafen was completed on October 12, 2010 (A. LaMay, D373600).  That hazard characterization and dose response from that assessment has been revised in the following ways:  An Acute Toxicity 6-Pack (MRIDs 46988901-46988906) on fomesafen technical (>=98.5% purity) was submitted and reviewed.  Due to the quality of these studies, values from the new 6-Pack replaced the previous values.  A 13-week dietary combined toxicity and neurotoxicity study in rats (MRID 48996801) was submitted, as well as an acute neurotoxicity study (MRID 48973302).  The acute neurotoxicity study was used to establish an acute oral endpoint for the general population, including infants and children.  An acute endpoint was not selected in the previous assessment. 

Additionally, a subchronic oral toxicity study in rats (MRID 49091201) was received in 2012 which does not demonstrate an adverse effect at 6x the LOAEL of the previous (1981) subchronic oral toxicity study in rats (MRID 00103013).  MRID 00103013 provides the most protective subchronic POD.  The current inhalation risk estimates, which are based on this protective oral POD, are very low and are not of concern. At this time HED is not electing to use the higher PODs from the 2012 study but may consider them for future assessments. 

The PODs and toxicity endpoints selected for various exposure scenarios applicable to this risk assessment are summarized in Table 4.3 (Dietary and Occupational).  

Table 4.3  Summary of Toxicological Doses and Endpoints for Fomesafen for Use in Dietary and Occupational Human Health Risk Assessments
                              Exposure/ Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary (General Population, including Infants and Children)
NOAEL = 100 mg/kg/day
UFA = 10x
UFH = 10x
FQPA SF = 1x
Acute RfD = 1 mg/kg/day

aPAD = 1 mg/kg/day
Acute neurotoxicity test in rat
LOAEL = 250 mg/kg/day based on decreased body weight and motor activity (horizontal and vertical activity and time in central quadrant) in males
Acute Dietary
(Females 13-49 years of age)
No toxic effects of fomesafen attributable to a single dose and specific to females of ages 13-49 were found in the database.
Chronic Dietary (All Populations)
NOAEL = 0.25 mg/kg/day
UFA = 10x
UFH = 10x
FQPA SF = 1x
Chronic RfD = 0.0025 mg/kg/day 

cPAD = 0.0025 mg/kg/day
Chronic toxicity/ carcinogenicity in rat LOAEL = 5 mg/kg/day based on hyalinization of the liver in males
Dermal Short-Term (1-30 days)

Intermediate-Term 
(1-6 months)
NOAEL = 100 mg/kg/day 
(Dermal absorption rate = 20%)[a]
UFA = 10x
UFH = 10x
Occupational LOC for MOE = 100

Prenatal developmental in rat
LOAEL = 200 mg/kg/day based on post-implantation loss
Inhalation Short- Term (1-30 days)

Intermediate-Term 
(1-6 months)
NOAEL = 0.5 mg/kg/day
(Inhalation toxicity is assumed to be equivalent to oral toxicity) 
UFA = 10x
UFH = 10x
Occupational LOC for MOE = 100
Subchronic oral toxicity study in rat
LOAEL = 10 mg/kg/day based on hyalinization of hepatocytes and increased hepatocellular peroxisomes in males.
Cancer (oral, dermal, inhalation)
Classification:  The CARC classified Fomesafen as "Not Likely to be Carcinogenic to Humans"
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key data (i.e., lack of a critical study).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.
a	The dermal absorption value of 20% was based on dermal absorption factors for oxyfluorfen and acifluorfen, which have similar structures.
5.0	Dietary Exposure and Risk Assessment 

5.1	Residues of Concern Summary and Rationale

The residues of concern for dietary risk assessment and the tolerance expression are summarized in Table 5.1.  The parent compound, fomesafen, is an adequate indicator of misuse and is the only residue included in the tolerance expression for plant commodities; there are no livestock tolerances required based on the current or proposed uses of fomesafen.  For risk assessment purposes the residue of concern in plant commodities is parent fomesafen.  For livestock commodities the residues of concern are fomesafen and its metabolites, 5-(2-chloro-α,α,α-trifluoro-p-tolyloxy) anthranilic acid and 5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-N-methylsulfonylanthranilamide.  For the purpose of this registration action, there is no reasonable expectation of finite residues of parent fomesafen or its metabolites in livestock commodities.  However, should future registration actions result in the likelihood of measurable residues in animal commodities, an aggregate risk assessment considering these residues may be required.

Metabolism studies are available for tomatoes, soybeans, and cotton, as well as a confined rotational crop study.  Studies in plants indicate that, in general, fomesafen is absorbed,
translocated, and rapidly and extensively metabolized.  Only trace amounts of the parent were found to be present in plant commodities at harvest.

Environmental fate data indicate that fomesafen should be very mobile and highly persistent in terrestrial and aquatic environments.  The residue of concern in drinking water is parent fomesafen.

Table 5.1.  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression
Matrix
Residues included in Risk Assessment
Residues included in Tolerance Expression
Plants
Primary Crop
Fomesafen
Fomesafen
Plants
Rotational Crop
Fomesafen
Fomesafen
Livestock
Fomesafen, 5-(2-chloro-α,α,α-trifluoro-p-tolyloxy) anthranilic acid, 5-(2-chloro-α,α,α-trifluoro-p-tolyloxy)-N-methylsulfonylanthranilamide.
Not required at this time.
Drinking Water
Fomesafen
NA
Fomesafen is 5-[2-chloro-4-(trifluoromethyl)phenoxy]-N-(methylsulfonyl)-2-nitro-benzamide, sodium salt.

5.2	Food Residue Profile

The submitted crop field trial residue data for cantaloupe, cucumber, summer squash, and succulent peas are adequate to support the proposed use of fomesafen on cantaloupe, cucumber, pea (succulent), pumpkin, summer squash, winter squash, and watermelon.  The studies reflect the maximum proposed use pattern, and the number and location of the field trials are sufficient.  Acceptable methods were used for residue quantitation, and the studies are supported by adequate storage stability data.  Residues of fomesafen (the residue of concern) were below the lowest limit of method validation (<LLMV) in all samples of cantaloupe, cucumber, summer squash, or succulent peas when treated with fomesafen sodium at the maximum proposed label rates and minimum PHIs.  

Residues of fomesafen were also below the LLMV in previously submitted field trials for peppers, potatoes, cotton, dry beans, snap beans, and soybeans (field).

The proposal for the use of the existing field trial data on snap beans to support the establishment of a tolerance for fomesafen on bean, lima, succulent was considered adequate by the Chemistry Science Advisory Council (ChemSAC) provided that a maximum rate per year included in the label is 0.25 lbs ai/A and the PHI is 30 days.  The proposal for the use of snap bean data to support a tolerance for soybean, vegetable, succulent is acceptable as well.  In crop subgroup 6A (edible-podded legume vegetables) any succulent cultivar of edible podded bean covers all beans under that group.  This group includes snap bean and soybean, immature seed.  For the latter soybean, vegetable, succulent is the preferred term.

There is data to support rotation to other crops beyond those commodities that are currently registered and proposed as primary crops.  Plant back intervals (PBIs) for rotational crops were not found in the Section B of the petition.  Adequate PBI should be proposed by the registrants and included in the label of the Reflex Herbicide.

There are no new animal feedstuffs associated with the proposed uses.  Feedstuffs are associated with succulent soybean; however, uses on field soybean have been registered previously.  The dietary burdens of fomesafen to beef and dairy cattle were estimated previously according to the 2008 Revised Table 1 of OPPTS Guideline 860.1000 for constructing maximum reasonably balanced diets (A. LaMay, D373544, 10/12/2010).  There is no reasonable expectation of finite residues in livestock commodities, and no tolerances are required for residues of fomesafen in livestock commodities. 

5.3	Water Residue Profile

The Environmental Fate and Effect's Division (EFED) provided estimated drinking water concentrations (EDWCs) generated using computer modeling methods.  The screening model Tier II PRZM-EXAMS was used to calculate the surface water EDWCs of 34.8 μg/L for peak (acute), 13.1 μg/L for annual average (non-cancer chronic).  Groundwater EDWCs were calculated using the Tier I PRZM-GW (six vulnerable sites modeled) and resulted in the highest acute value of 51.8 μg/L and chronic value of 32.3 μg/L for groundwater.  The groundwater EDWCs were higher than the surface water EDWCs and were therefore selected for use in the fomesafen dietary assessment.  The groundwater estimates are very conservative.  These estimates are based on the highest proposed application rate for fomesafen (0.375 lb a.i./acre for the crops of cantaloupe, cucumber, pea, succulent, pumpkin, summer squash, watermelon, winter squash, and succulent soybean vegetable succulent (i.e. edamame)).  These estimates also reflect results from the most vulnerable site modeled, the "Florida Citrus scenario."  In addition, the PRZM-GW model is based on a rural drinking water well beneath an agricultural field (a high pesticide use area), which draws water from an unconfined, high water-table aquifer.  

There is ground water monitoring data indicating a maximum concentration of 1 μg/L for fomesafen in ground water source for drinking water from a vulnerable soybean soil site. However, since fomesafen can be applied to a wide variety of crops, groundwater monitoring from a soybean soil may not be representative of a vulnerable site in an extended fomesafen use area and is not recommended for use in risk assessment. 

Table 5.3.  Summary of Estimated Surface Water and Groundwater Concentrations for Fomesafen.
Scenario
Surface Water Conc., ppb a
Groundwater Conc., ppb b
Acute
34.8
51.8
Chronic (non-cancer)
13.1
32.3
[a] From the Tier II PRZM-EXAMS - Index Reservoir model.  
[b] From the Tier I PRZM-GW model.
(EFED Memo, H.Zhong, D412599, 6/24/13)

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

Acute and chronic aggregate (food and drinking water) dietary exposures and risk assessment were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID) Version 3.16.  This software uses 2003-2008 food consumption data from the U.S. Department of Agriculture's (USDA's) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).  For food, tolerance level residues were assumed in the assessments; the tolerance levels were based on non-detectable residues from the field trials and reflect the method LOQs.  For drinking water, estimated drinking water concentrations (EDWCs) from highly conservative surface water modeling based on the highest proposed use rates were used directly in the assessments. 

5.4.2	Percent Crop Treated Used in Dietary Assessment

An assumption of 100% crop treated (%CT) was used for all commodities (existing and proposed uses) in the fomesafen dietary assessment.

5.4.3	Acute Dietary Risk Assessment

 A highly conservative acute dietary risk assessment was conducted which used tolerance level residues, assumed 100% CT for all commodities and screening EDWCs.  The estimated exposure (food and drinking water) to the U.S. population and all population subgroups from the established uses and proposed new uses of fomesafen resulted in an estimated risk of  <1% of the acute population adjusted dose (aPAD) at the 95[th] percentile and are not of concern (see Table 5.4.6).  

5.4.4	Chronic Dietary Risk Assessment

 A highly conservative chronic dietary risk assessment was conducted which used tolerance level residues, assumed 100% CT for all commodities and screening level EDWCs.  The estimated exposure (food and drinking water) to the U.S. population and all population subgroups from the established uses and proposed new uses of fomesafen resulted in risk estimates below the Agency's level of concern.  The risk estimate for the general U.S. population is 32% of the chronic population adjusted dose (cPAD).  The subgroup with the highest chronic exposure and risk estimate is infants.  For infants, the exposure for food plus drinking water was 0.001915 mg/kg/day, which represents 77% of the cPAD (see Table 5.4.6). 

5.4.5	Cancer Dietary Risk Assessment

The Cancer Assessment Review Committee (CARC) classified fomesafen as "Not likely to be carcinogenic to humans;" therefore, a quantitative cancer assessment was not performed.

5.4.6	Summary Table

 Table 5.4.6.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Fomesafen.
                              Population Subgroup
                                 Acute Dietary
                               (95th Percentile)
                                Chronic Dietary
                                     Cancer
                                        
                          Dietary Exposure (mg/kg/day)
                                     % aPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
 General U.S. Population
                                    0.002999
                                     <1
                                    0.000787
                                       32
 
 
 All Infants (<1 year old)*
                                    0.009060
                                     <1
                                    0.001915
                                       77
                                      N/A
                                      N/A
 Children 1-2 years old
                                    0.004827
                                     <1
                                    0.001267
                                       51
 
 
 Children 3-5 years old
                                    0.003915
                                     <1
                                    0.001085
                                       43
 
 
 Children 6-12 years old
                                    0.002951
                                     <1
                                    0.000755
                                       30
 
 
 Youth 13-19 years old
                                    0.002455
                                     <1
                                    0.000588
                                       24
 
 
 Adults 20-49 years old
                                    0.002858
                                     <1
                                    0.000766
                                       31
 
 
 Adults 50-99 years old
                                    0.002597
                                     <1
                                    0.000754
                                       30
 
 
 Females 13-49 years old
                                    0.002938
                                     <1
                                    0.000760
                                       30
 
 
The population subgroup with the highest risk estimate is bolded
6.0       Residential (Non-Occupational) Exposure/Risk Characterization

Residential exposures and risk are not assessed because there are no proposed or registered uses of fomesafen in residential settings. 

6.1	Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for fomesafen at this time, primarily because of the low vapor pressure (<7.5 x 10[-7] mmHg at 50 °C).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010.  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for fomesafen.

6.2	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fomesafen.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, State Lead Agencies for pesticide regulation, and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information).  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risk estimates associated with drift.
 7.0   Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  

There are no residential uses for fomesafen; therefore, the aggregate exposure and risk assessments include acute and chronic dietary (food and drinking water) only and are shown in Sections 5.4.3 and 5.4.4.  There are no aggregate risk estimates of concern for the existing and proposed new uses of fomesafen.  
8.0    Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to  fomesafen and any other substances and fomesafen does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that fomesafen has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.
9.0   Occupational Exposure/Risk Characterization

No chemical-specific handler exposure data were submitted in support of the proposed fomesafen uses.  For assessing the occupational handler and post-application risks, generic surrogate data were used from sources such as PHED 1.1, the AHETF database, and ORETF database.

9.1	Short/Intermediate-Term Handler Risk

Occupational handler exposure to the herbicide fomesafen is expected for individuals involved in mixing, applying, or flagging for the proposed fomesafen sodium applications to cantaloupe, cucumber, pea, pumpkin, squash, watermelon, soybean, and lima bean.  Occupational handlers may experience short- and intermediate-term dermal and inhalation exposures.  
The quantitative exposure/risk assessment developed for the proposed uses by occupational handlers is based on the following scenarios: 

   * Mixing/loading for aerial, groundboom, and chemigation applications
   * Applying by aerial or groundboom applications
   * Flagging in support of aerial application
   * Mixing/loading/applying for soil- and ground-directed applications with handheld equipment

The maximum application rates for the proposed uses are 0.375 lb ae/acre, except for the proposed use on peas and lima beans; the maximum application rate for peas and lima beans is 0.25 lb ae/acre.  Only the maximum application rate of 0.375 lb ae/acre was used in the assessment, as this is protective of all proposed uses.

The fomesafen product labels direct applicators and other handlers to wear long-sleeved shirts, long pants, chemical-resistant gloves, shoes, plus socks, and protective eyewear. Estimates of dermal and inhalation exposure were calculated for various levels of personal protective equipment (PPE).  Exposures were calculated "baseline", defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc).  The dermal and inhalation routes of exposure were not combined because the points of departure are based on different toxicological endpoints.  

Occupational dermal and inhalation risk estimates are presented in Table 9.1 below.  For occupational handlers, dermal and inhalation MOEs above 100 are not of concern.  All occupational exposure risk estimates for short- and intermediate- term exposures for handlers are not of concern with single layer dermal PPE (includes long-sleeve shirt and long pants) or with engineering control enclosed cab (fixed wing aircraft/aerial applicators).  Dermal MOEs ranged from 350 to 300,000, and inhalation MOEs ranged from 410 to 360,000.

Table 9.1.  Occupational Handler Non-Cancer Exposure and Risk Estimates for Fomesafen.
                               Exposure Scenario
                                Crop or Target
                      Dermal Unit Exposure (μg/lb ai)[1]
                    Inhalation Unit Exposure (μg/lb ai)[1]
                                    Maximum
                              Application Rate[2]
                    Area Treated or Amount Handled Daily[3]
                                    Dermal
                                  Inhalation
                                       
                                       
                        Mitigation Level: Single Layer
                        Mitigation Level: No Respirator
                                       
                                       
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                              Dose (mg/kg/day)[6]
                                    MOE[7]
                                 Mixer/Loader
                        M/L, Liquid, Aerial, Broadcast
                                    Nursery
                                      220
                                     0.219
                               0.375 lb ae/acre
                                   60 acres
                                    0.0143
                                     7,000
                                   0.0000616
                                     8,100
                                       
                              Typical Field Crop
                                       
                                       
                                       
                                   350 acres
                                    0.0838
                                     1,200
                                   0.000359
                                     1,400
                                       
                            High-Acreage Field Crop
                                       
                                       
                                       
                                  1200 acres
                                     0.287
                                      350
                                    0.00123
                                      410
                           M/L, Liquid, Chemigation
                                Field Crop, All
                                       
                                       
                                       
                                   350 acres
                                    0.0838
                                     1,200
                                   0.000359
                                     1,400
                      M/L, Liquid, Groundboom, Broadcast
                              Nursery, Greenhouse
                                       
                                       
                                       
                                   60 acres
                                    0.0143
                                     7,000
                                   0.0000616
                                     8,100
                                       
                              Typical Field Crop
                                       
                                       
                                       
                                   80 acres
                                    0.0191
                                     5,200
                                   0.0000821
                                     6,100
                                       
                            High-Acreage Field Crop
                                       
                                       
                                       
                                   200 acres
                                    0.0478
                                     2,100
                                   0.000205
                                     2,400
                                  Applicator
                           Applicator, Spray, Aerial
                                    Nursery
                                 Eng Control:
                                       5
                                 Eng Control:
                                    0.0049
                               0.375 lb ae/acre
                                   60 acres
                                   0.000328
                                    300,000
                                   0.0000014
                                    360,000
                                       
                              Field Crop, Typical
                                       
                                       
                                       
                                   350 acres
                                    0.0019
                                    53,000
                                   0.000008
                                    62,000
                                       
                           Field Crop, High Acreage
                                       
                                       
                                       
                                  1200 acres
                                    0.00652
                                    15,000
                                   0.0000276
                                    18,000
                         Applicator, Spray, Groundboom
                              Nursery, Greenhouse
                                     78.6
                                     0.34
                                       
                                   60 acres
                                    0.00513
                                    19,000
                                   0.0000956
                                     5,200
                                       
                              Field Crop, Typical
                                       
                                       
                                       
                                   80 acres
                                    0.00684
                                    15,000
                                   0.000128
                                     3,900
                                       
                           Field Crop, High Acreage
                                       
                                       
                                       
                                   200 acres
                                    0.0171
                                     5,800
                                   0.000319
                                     1,600
                                    Flagger
                                    Flagger
                                    Nursery
                                      11
                                     0.35
                               0.375 lb ae/acre
                                   60 acres
                                   0.000719
                                    140,000
                                   0.0000985
                                     5,100
                                       
                                Field Crop, All
                                       
                                       
                                       
                                   350 acres
                                    0.00417
                                    24,000
                                   0.000574
                                      870
1	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March 2013); Level of mitigation: Baseline; Eng. Controls for aerial applicators. 
2	Based on proposed label.
3	Exposure Science Advisory Council Policy #9.1.
4	Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) x DAF (%) / BW (kg).
5	Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day).
6	Inhalation Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) / BW (kg).
7	Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day).
8 10 gallons per acre assumed.

9.2.1	Dermal Post-application Risk

Post-application dermal exposure is not anticipated for the majority of the proposed fomesafen uses since, based on the label directions, it is not likely that the pesticide will contact the foliage. The proposed label states that the product is applied as follows:  (1) to cantaloupe as a directed spray to row middles prior to transplanting; (2) to cucumber as a directed spray to row middles just after seeding but before crop emergence or just prior to transplanting; (3) to succulent peas as a broadcast pre-emergence application; (4) to pumpkin, squash, and watermelon as a broadcast or directed spray to row middles after seeding but prior to crop emergence or prior to transplanting; and (5) to watermelon also as a directed post-emergence application to row middles.  Therefore, a quantitative post-application dermal exposure assessment was not conducted for these proposed uses.

This risk assessment for fomesafen sodium evaluates the potential risks associated with its pre-plant/pre-emergent uses on vegetables.  There is a low potential for occupational post-application exposure associated with the use of pre-plant/pre-emergent herbicides because there are no hand labor activities typically associated with the production of crops that would require significant contact with treated soil and no foliage is present that could also lead to exposure via contact.  There is a possible concern that some level of soil contact could occur during mechanically assisted transplanting activities; however, this is likely to result in negligible exposures as outlined in HED Exposure SAC Policy 8.  The rationale is that transplanting activities involve moving starter plants onto a rotating wheel while riding upon an implement being moved across a field.  In such cases, there would be minimal contact with machinery that has field soil on it, because of the possibility of mechanical injury.  These conclusions are appropriate even though fomesafen sodium has a long half-life in soil (i.e., ~390 days).  

The applications to the proposed crops are for pre-emergent or directed ground sprays; thus, contact with treated foliage is expected to be minimal, except for soybeans and lima beans.  Therefore, a quantitative dermal post-application exposure assessment was only conducted for the proposed new uses with post-emergent applications (i.e., soybeans and lima beans).  The proposed application rate on soybeans is 0.375 lb ae/acre and for lima beans is 0.25 lb ae/acre.  

All occupational exposure risk estimates for short- and intermediate-term exposures for post-application workers are not of concern (i.e., dermal MOEs are greater than the LOC of 100).  Dermal MOEs ranged from 3,200 to 59,000 for post-application workers (soybean and lima bean activities).  

Table 9.2.1.  Occupational Post-application Non-Cancer Exposure and Risk Estimates for Fomesafen.
                                   Crop/Site
                                  Activities
                        Transfer Coefficient (cm[2]/hr)
                                  DFR/TTR[1]
                                 Dermal Dose 
                                (mg/kg/day)[2]
                                    MOE[3]
                          Short and Intermediate-term
                                    Soybean
                                 Hand Weeding
                                      70
                                     1.05
                                     0.002
                                    59,000
                                       
                                   Scouting
                                     1100
                                       
                                     0.027
                                     3,700
                                  Lima Beans
                                   Scouting
                                     1100
                                      0.7
                                     0.018
                                     5,600
                                       
                                  Irrigation
                                     1900
                                       
                                     0.031
                                     3,200
1	DFR = Application Rate x F x (1-D)t x 4.54E8 ug/lb x 2.47E-8 acre/cm[2]; where F = 0.25 and D = 0.10 per day  
2	Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 8 hrs/day x dermal absorption (%)]  BW (kg).
3	MOE = POD (mg/kg/day) / Daily Dermal Dose.  Daily Dermal Dose = [DFR/TTR (ug/cm[2]) x TC x 0.001 mg/ug x 8 hrs/day x dermal absorption factor (%)]  BW (kg).

Restricted Entry Interval
 The current label specifies a 24-hour REI.  Fomesafen has a low order of acute toxicity by the dermal route of exposure (Toxicity Category IV).  Fomesafen is minimally irritating to the eye and is not irritating to the skin.  It is not a sensitizer.  Short- and intermediate-term post-application risk estimates were not a concern on Day 0 (12 hours following application) for all post-application activities.  Under 40 CFR 156.208 (c) (2) (iii), ai's classified as Acute IV for acute dermal, eye irritation or primary skin irritation are assigned a 12-hour REI.  Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to fomesafen.  The REI on the label meets the minimum requirement.   

9.2.2	Inhalation Post-application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for fomesafen at this time primarily because of the low vapor pressure (<7.5 x 10[-7] mmHg at 50 °C).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010. The Agency is in the process of evaluating the SAP report, as well as available post-application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for fomesafen.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of the fomesafen occupational post-application inhalation exposure scenarios.
10.0	References

I. Negrón Encarnación, In Process, D407932, Fomesafen Sodium.  Petition for the Establishment of Tolerances and Registration of New Uses on Cantaloupe, Cucumber, Pea (Succulent), Pumpkin, Summer Squash, Watermelon, Winter Squash,  Soybean (Succulent) and Fresh Lima Bean: Summary of Analytical Chemistry and Residue Data. 

D. Drew, D410439, 7/11/13, Fomesafen Sodium, Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action  on Cantaloupe, Cucumber, Pea (Succulent), Pumpkin, Summer Squash, Winter Squash, Watermelon, Soybean (Succulent) and Lima Bean (Succulent).

A. LaMay, In Process, D407933, Fomesafen Sodium.  Occupational and Residential Exposure Assessment for Proposed Uses on Cantaloupe, Cucumber, Pea, Pumpkin, Squash, Watermelon, Soybean, and Lima Bean.

A. LaMay, 10/12/10, D373600, Fomesafen Sodium: Human Health Risk Assessment for the Establishment of Tolerances and Registration of New Uses of Fomesafen Sodium on Potatoes and Peppers.

H. Zhong, 6/24/13, D412599, Revised Fomesafen Drinking Water Assessment to Include IR-4 Use on Lima Bean and Groundwater EDWCs Using a Tier-I PRZM-GW Model.
 

Appendix A.  Toxicology Profile and Executive Summaries
A.1	Toxicology Data Requirements
The requirements (40 CFR 158.340) for the food use for fomesafen are in the table below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity	
870.1200    Acute Dermal Toxicity	
870.1300    Acute Inhalation Toxicity	
870.2400    Acute Eye Irritation	
870.2500    Acute Dermal Irritation	
870.2600    Skin Sensitization	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    90-Day Oral Toxicity in Rodents	
870.3150    90-Day Oral Toxicity in Nonrodents	
870.3200    21/28-Day Dermal Toxicity	
870.3250    90-Day Dermal Toxicity	
870.3465    90-Day Inhalation Toxicity	
                                      yes
                                      yes
                                      yes
                                      no
                                      no
                                      yes
                                      yes
                                      yes
                                       -
                                       -
870.3700a  Prenatal Developmental Toxicity (rodent)	
870.3700b  Prenatal Developmental Toxicity (nonrodent)	
870.3800    Reproduction and Fertility Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                     no a
                                      yes
870.4100a  Chronic Toxicity (rodent)	
870.4100b  Chronic Toxicity (nonrodent)	
870.4200a  Carcinogenicity (rat)	
870.4200b  Carcinogenicity (mouse)	
870.4300    Combined Chronic Toxicity/Carcinogenicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Bacterial Reverse Mutation Test...
870.5300    Mutagenicity -- Mammalian Cell Gene Mutation Test
870.5375    Mutagenicity -- In Vitro Chromosomal Aberrations
870.5385    Mutagenicity -- Mammalian Chromosomal Aberrations
870.5395    Mutagenicity -- Micronucleus Test
870.5450    Mutagenicity -- Dominant Lethal Assay
870.5550    Mutagenicity -- Unscheduled DNA Synthesis
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      no
                                      no
                                      yes
                                      yes
                                      yes
                                     yes c
                                      yes
                                       -
                                       -
870.6200a  Acute Neurotoxicity Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Developmental Neurotoxicity	
                                      yes
                                      yes
                                      no
                                      yes
                                      yes
                                       -
870.7485    Metabolism and Pharmacokinetics	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                     no b
                                      yes
a	Although the developmental toxicity study in rabbits was classified unacceptable due to mortality from bacterial infections, there was not any evidence of increased susceptibility of rabbit fetuses due to the treatment with fomesafen.  Therefore, the lack of an acceptable developmental toxicity study in non-rodents was not considered a data gap.  
b	As a dermal penetration study was not provided, the dermal absorption value of 20% was based on dermal absorption factors for oxyfluorfen and acifluorfen, which have similar structures.  Consequently, the dermal penetration study is not considered a data gap.
c	Two studies were Not Classified (because there were no mutagenicity guidelines when the study was conducted), and one study was Unacceptable/Guideline.  However, there are mutagenicity studies which evaluate both somatic and germinal cells, which is considered sufficient to satisfy CFR requirements.

A.2	Toxicity Profiles

Table A.2.1	Acute Toxicity Profile - Fomesafen
Guideline No.
Study Type
MRID(s)
                                    Results
                               Toxicity Category
870.1100
Acute oral [rat]
                                   46988901
                        LD50 Females >5000 mg/kg bw
                                      IV
870.1200
Acute dermal [rat]
                                   46988902
                       LD50 Combined > 5050 mg/kg bw
                                      IV
870.1300
Acute inhalation [rat]
                                   46988903
                          LC50 Combined >2.63 mg/L
                                      IV
870.2400
Acute eye irritation [rabbit]
                                   46988904
                             Minimally irritating
                                      IV
870.2500
Acute dermal irritation [rabbit]
                                   46988905
                                 No irritation
                                      IV
870.2600
Skin sensitization [guinea pig]
                                   46988906
                               Not a sensitizer
                                      N/A

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile for Fomesafen
                           Guideline No./ Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
870.3050 
28-Day Oral Toxicity in Rodents 
40786709 (1980) 
Acceptable/Non-Guideline 
0, 5, 15, 50, 150, 500, 1500 or 1500 ppm 
M: 0, 0.71, 2.13, 7.20, 20.7, 68.9, 209.1, or 917.2 mg/kg/day)
F: 0, 0.94, 2.87, 8.30, 27.1, 83.4, 246.8, 1247.6 mg/kg/day
NOAEL = 209/247 mg/kg/day in M/F
LOAEL = 917/1247 mg/kg/day in M/F based on decreased body weights and body weight gains, decreased food efficiency, hematology (decreased erythrocyte count, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin), bile duct hyperplasia, decreased uterine size in females, and decreased size of the seminal vesicles in males
870.3100
90-Day Oral Toxicity in Rodents
00103013 (1981)
Acceptable/ Guideline
0, 1, 5, 100 or 1000 ppm (0, 0.1, 0.5, 10 and 100 mg/kg/day)
NOAEL = 0.5 mg/kg/day
LOAEL = 10 mg/kg/day based on hyalinization of hepatocytes and increased hepatocellular peroxisomes
870.3100
+ 870.6200b
Combined 90-Day oral Toxicity and Neurotoxicity Screening Battery in Rodents
48996801 (2012)
Acceptable/Guideline
0, 100/300, 300/100, or 1000/3000 ppm in M/F M: 0, 6.4, 20.3, 67.0 mg/kg/day
F: 0, 23.1, 74.2, 233.2 mg/kg/day
NOAEL = 67.0/233.2 mg/kg/day in M/F
LOAEL was not observed
870.3150
90-Day Oral Toxicity in Nonrodents
00103014 (1981)
Acceptable/Guideline
0, 0.1, 1.0, 25 mg/kg/day
NOAEL = 1.0 mg/kg/day
LOAEL = 25 mg/kg/day based on hematology (decreased hemoglobin and hematocrit concentrations and erythrocyte count and increased platelet count and prothrombin time)
870.3200
21/28-Day Dermal Toxicity
00135632 (1983)
Acceptable/ Guideline
0, 10, 100, 1000 mg/kg/day
NOAEL = 1000 mg/kg/day
LOAEL was not observed
870.3700a
Prenatal developmental in (rodent)
00164903 (1981)
Acceptable/Guideline
0, 50, 100, 200 mg/kg/day
[This study was considered with: (1) Report Nos. CTL/P/656 and CTL/P/656S, MRID #001013016, and (2) information provided by Syngenta in their submission (DP316263, MRID 46527208) in establishing the NOAEL and LOAEL.  With the additional information, the following conclusions were made.]
Maternal NOAEL = 100 mg/kg/day
LOAEL = 200 mg/kg/day based on the staining of the ventral fur and significantly decreased body weight gain (>10%)
Developmental NOAEL = 100 mg/kg/day
LOAEL = 200 mg/kg/day based on postimplantation loss observed in study CTL/P/576 (MRID 00164903)
870.3700a
Prenatal developmental in (rodent)
00103016 (1982) 
Acceptable/Guideline
0, 1.0, 7.5, 50 mg/kg/day
[The maternal and developmental toxicity LOAEL and NOAEL were not established in this study.  However, in conjunction with (1) another developmental toxicity study in rats (CTL/P/576, MRID 00164903), and (2) information provided by Syngenta in their submission, DP 316263 (MRID 46527208), the following LOAELs/NOAELs were established for fomesafen.]
Maternal NOAEL = 100 mg/kg/day
LOAEL = 200 mg/kg/day based on the staining of the ventral fur and significantly decreased body weight gain (>10%)
Developmental NOAEL = 100 mg/kg/day
LOAEL = 200 mg/kg/day based on postimplantation loss observed in study CTL/P/576 (MRID 00164903)
870.3700b
Prenatal developmental in (nonrodent)
00109214 (1981)
Unacceptable/Guideline
0, 2.5, 10, 40 mg/kg/day
At 40 mg/kg/day, does appeared thin and had increased incidence of stomach erosions.  
No significant difference between controls and treated animals for developmental abnormalities.  
The study provided information to assess potential developmental toxicity rabbits, but was classified unacceptable because of bacterial infection in the colony.   
870.3800 
Reproduction and fertility effects
00144862 (1984)
Acceptable/Guideline
0, 50, 250, 1000 ppm 
(0, 2.5, 12.5, 50 mg/kg/day)
Parental/Systemic NOAEL = 12.5 mg/kg/day
LOAEL = 50 mg/kg/day based on liver histopathology in males and females of both generations
Reproductive NOAEL = 50 mg/kg/day
LOAEL was not established 
Offspring NOAEL = 12.5 mg/kg/day
LOAEL = 50 mg/kg/day based on increased incidence of liver hyalinization in males

870.4200b
Carcinogenicity (mouse)
00131491 (1983)
Acceptable/Guideline
0, 1, 10, 100, 1000 ppm 
(0, 0.15, 1.5, 15, 150 mg/kg/day)
NOAEL = 1.5 mg/kg/day
LOAEL = 15 mg/kg/day based on the presence of liver tumors and liver weight increases in male and female mice 
evidence of carcinogenicity
870.4300
Combined Chronic Toxicity/Carcinogenicity
00142125 (1984)
Acceptable/Guideline
0, 5, 100, 1000 ppm
(0, 0.25, 5, 50 mg/kg/day)
NOAEL = 0.25 mg/kg/day
LOAEL = 5 mg/kg/day based on hyalinization of the liver in males
no evidence of carcinogenicity
Genetic Toxicity Test 870.5300
In vitro mammalian cell gene mutation test
40910804
Acceptable/Guideline
-S9: 0, 450, 475, 500, 525, 550, 575, 600 ug/mL
+S9: 0, 325, 350, 375, 400, 425, 450, 475 ug/mL
A technical grade preparation containing 97 percent fomesafen was tested for mutagenicity against L5178Y mouse lymphoma cells, both in the presence and absence of S-9 metabolic activation at concentrations ranging between 325 to 600 ug/mL. Two tests were performed and each test was performed in duplicate for each concentration. There was no indication of mutagenicity at any dose level tested, both in the presence or absence of metabolic activation. The positive controls, including ethylmethanesulphonate, a direct mutagen and N nitrosodimethylamine, which required metabolic activation, were both responsive in these tests.
Genetic Toxicity Test
870.5375
In Vitro Mammalian Chromosome Aberration Test
44569805
Acceptable/Guideline
-S9: 0, 150, 500, 1000 ug/mL
+S9: 0, 75, 150, 250 ug/mL
There was no evidence of chromosome aberrations induced over background.
Genetic Toxicity Test
870.5375
In Vitro Mammalian Chromosome Aberration Test
44569806
Acceptable/Guideline
+-S9: 0, 10, 100, 1000 ug/mL
There was no evidence of chromosome aberrations induced over background.
Genetic Toxicity Test
870.5385
Mammalian Bone Marrow Chromosomal Aberration Test
00135628
Not Classified
0, 125, 250 mg/kg
The mitotic index is significantly decreased by 250 mg/kg Fomesafen, indicating toxicity. The percent of cells with chromosome abnormalities including gaps is significantly increased by 250 mg/kg Fomesafen. Both 125 and 250 mg/kg Fomesafen slightly (but not statistically significantly) increased the number of cells with chromosome abnormalities excluding gaps. Fomesafen is considered to be a weak mutagen.
Genetic Toxicity Test
870.5385
Mammalian Bone Marrow Chromosomal Aberration Test
00164907
Not Classified
0, 125, 250 mg/kg
The product induced statistically significant increase of cells with abnormalities at the 125 and 250 mg/kg dose level.  The responses were similar to the ones observed in the cells of animals treated with the positive control EMS, and they include gaps and other than gaps as well as breaks and fragments.  The product induced chromosome damage in the bone marrow of the rat cells at oral doses of 125 and 250 mg/kg.
Genetic Toxicity Test
870.5385
Mammalian Bone Marrow Chromosomal Aberration Test
45048208
Unacceptable/Guideline
0, 25, 125, 250 mg/kg
Fomesafen technical up to 250 mg/kg dose level is not clastogenic in this in vivo test system.
Genetic Toxicity Test
870.5395
Mammalian Erythrocyte Micronucleus Test
40910805
Acceptable/Guideline
M: 0, 175, 279 mg/kg
F: 0, 215, 344 mg/kg
Fomesafen does not appear to be clastogenic in the mouse micronucleus test system.
Genetic Toxicity Test
870.5450
Rodent Dominant Lethal Assay
00103019
Not Classified
0, 25,100, 250 mg/kg/day
Fomesafen possesses no dominant lethality at any one of the dose levels assayed.
Genetic Toxicity Test
870.5550
Unscheduled DNA Synthesis in Mammalian Cells in Culture
40786703
Unacceptable/Guideline
Up to 1000 ug/mL
At 1000 ug/mL, the compound was toxic to the cells.  It is difficult to interpret the UDS results as provided.
870.6200a
Acute Neurotoxicity Screening Battery
48973302 (2012)
Acceptable/Guideline
0, 100, 250, 800 mg/kg
NOAEL = 100 mg/kg
LOAEL = 250 mg/kg based on decreased motor activity (horizontal and vertical activity and time in central quadrant) in males
870.6200b
+ 870.3100
Combined 90-Day oral Toxicity and Neurotoxicity Screening Battery in Rodents
48996801 (2012)
Acceptable/Guideline
0, 100/300, 300/100, 1000/3000 ppm in M/F M: 0, 6.4, 20.3, 67.0 mg/kg/day
F: 0, 23.1, 74.2, 233.2 mg/kg/day
NOAEL = 67.0/233.2 mg/kg/day in M/F
LOAEL was not observed
870.7485
Metabolism and Pharmacokinetics in Rat
00103017 (1982)
00135633 (1983)
00164904 (1982)
00164905 (1982)
00164906 (1982)
00164939 (1982)
Not Classified or Acceptable/Guideline

The overall mean recovery of radioactivity by Day 7 was 99.9% for males and 98.5% for females in MRID 00103017.  The study, MRID 00135633, is acceptable to prove that no meaningful accumulation of the material was left in the body; most (up to 95%) was excreted via urine, feces or bile. The liver did not accumulate the material in meaningful amounts.  In MRID 00164904, there was not a great difference between male and female rats in the excretion of (14C)-PP021, and most of the material was excreted.  The liver was the organ with more accumulation, +- 0.5% males.  +- 0.4% females.  In MRID 00164905, widespread tissue distribution of radioactivity was observed throughout the 28 day dosing period (5 mg/kg doses).  Radioactivity in the liver was increased as dosing proceeded and decreased progressively after the 21 or 28 last dose.  In MRID 00164939, Animals were treated with a single dose by intravenous injection (5 mg/kg), and recovery was 94% in both sexes.  There was a difference observed in fomesafen excretion between male and female rats.  The liver was the organ with the most residues.  MRID 00164906 and its DER were not found.
870.7485
Metabolism and Pharmacokinetics in Dog
00135634 (1983)
Acceptable/Guideline

Fomesafen is excreted via urine or feces. The feces showed a large amount of biliary product elimination.  No substantial differences were observed between male and female dogs. The largest part of the product or the metabolite was eliminated via urine.  The only metabolite found was the same product, fomesafen. 
870.7485
Metabolism and Pharmacokinetics in Marmoset
00141525 (1984)

Not evaluated; MRID nor DER were found.
870.7485
Metabolism and Pharmacokinetics in Mouse
00144861 (1983)

Not evaluated; MRID nor DER were found.
870.7485
Metabolism and Pharmacokinetics in Hamster
40910803 (1984)
Supplementary
5 mg/kg/day
A single dose of radiolabeled compound (5 mg/kg) was administered orally to three male and three female hamsters. Urinary and fecal samples were collected at 24-hour intervals for 3 days. The animals were killed at 72 hours to collect tissues and carcass for analysis of radioactivity. In males, excretion based on dose of radioactivity recovered, amounted to 55 percent in urine and 28 percent in feces; in females, 47 percent was excreted in urine and 27 percent in feces. There were no differences in amount excreted by either route between the two sexes. Within the first 24 hours, about 36 percent of the dose was recovered in urine and 15 percent of the dose in feces for both the male and female. At 72 hours, radioactivity remaining in the entire organism amounted to about 3.0 percent in males and 2.5 percent in females; no sex differences. Of the four tissues in which radioactivity was measured, including liver, kidneys, lung, and blood, uptake was highest by the liver, based on percent of dose in the entire organ and ug equivalents/g of tissue.
870.7800
Immunotoxicity
48762301 (2011)
Acceptable/Guideline
0, 100, 1000, 4000 ppm 
(0, 16, 176, 791 mg/kg/day)
NOAEL = 16 mg/kg/day
LOAEL = 176 mg/kg/day based on dose-related suppression of anti-SRBC IgM response

A.3   Toxicity Summaries

MRID No. 00103013 
      Citation : Wade, J.; Banham, P.; Chart, I.; et al. (1981) PP021: 90 Day Feeding Study in Rats: Report No. CTL/P/554.  (Unpublished study received May 28, 1982 under 10182-EX-30; prepared by Imperial Chemical Industries, Ltd., Eng., submitted by ICI Americas, Inc., Wilmington, DE; CDL:247589-E).   Unpublished. 

EXECUTIVE SUMMARY - In this subchronic toxicity study (MRID 00103013), Fomesafen (97.5% a.i.; PPO21) was administered in the diet for 90 days to 20 Alderley Park rats/sex/dose at doses of 0, 1, 5, 100, or 1000 ppm (approximately equivalent to 0, 0.1, 0.5, 10, and 100 mg/kg/day using a conversion factor of 0.1).   The animals were observed daily for clinical signs of toxicity.  Body weights and food consumption were determined initially and at 2-week intervals, thereafter.  Hematology, clinical chemistry and urinalysis were conducted.  At termination, animals were necropsied, organs weighed and representative tissues examined microscopically.  Election microscopy was conducted on selected tissues.

No mortality occurred.  Animals in the 1000 ppm group gained less weight than the controls.  Plasma alkaline phosphatase, alanine transaminase and aspartate transaminase were increased in males in the 1000 ppm group.  Liver weights were increased in male and females at 1000 ppm.  Hyalinization of hepatocytes, characterized by increased eosinophilia and reduced basophilic granulation and reduced vacuolization, was observed at 100 and 1000 ppm.  Electron microscopy revealed an increase in peroxisomes in centrilobular hepatocytes at 100 and 1000 ppm.  

The LOAEL is 100 ppm (10 mg/kg/day) based on hyalinization of hepatocytes and increased hepatocellular peroxisomes in males.   The NOAEL is 5 ppm (0.5 mg/kg/day).

This study is classified as Acceptable/Guideline and satisfies the guideline requirements (OPPTS 870.3100; OECD 408) for a 90-day toxicity study in rats.

MRID No. 00103014 
      Citation: Kalinowski AE, Chalmers DT, Chart IS, et al. (1981) PP021: 26 week oral dosing study in dog. Central Toxicology Laboratory (Alderley Park, Cheshire, UK).  Laboratory Report No. CTL/P/591, March 5, 1981. Unpublished.
 
EXECUTIVE SUMMARY  - In a 26-week oral toxicity study (MRID 00103014), fomesafen (97.5% a.i., batch #Y00053/001/005) was administered to 6 Beagle dogs/sex/dose in gelatin capsules at dose levels of 0, 0.1, 1, or 25 mg/kg bw/day.  There were no treatment-related effects on survival, clinical parameters, body weight, or food consumption.  Mean hemoglobin concentrations and erythrocyte counts were slightly decreased in both sexes combined (6-10%), relative to controls, at 25 mg/kg from weeks 4-20.  Mean hematocrit was also slightly decreased (6-9%), relative to controls, in both sexes combined at 25 mg/kg during the same period.  At 25 mg/kg in both sexes combined, mean platelet counts increased by 10-23% from week 8-20, while from weeks 4-16 mean prothrombin time was increased only slightly (3-4%), relative to controls.  Taken together, these results are suggestive of slight anemia at 25 mg/kg.    

Mean absolute and relative liver weights were increased in males by 10% and 13%, respectively, at 25 mg/kg.  The slight increase in liver weights in males was regarded as non- adverse.  The adaptive nature of the liver changes was also supported by a 19% (males) and 15% (females) increase in smooth endoplasmic reticulum (SER), indicative of increased protein synthesis.  Mean plasma cholesterol levels were decreased by 31-40%, relative to controls, in both sexes combined from weeks 1-26, while mean plasma triglycerides were decreased by 45- 56% over the same period.  A 3- and 2-fold increase, relative to controls, in the mean number of peroxisomes in centrilobular hepatocytes was also observed in males and females, respectively, at 25 mg/kg.  Peroxisome proliferation is an adaptive response to hypolipidemic compounds.  Changes in the "tinctorial properties of hepatocytes" was also observed in 4/6 males and 4/6 females at 25 mg/kg; these changes in staining reflect the observed changes at the organelle level, i.e., increase in peroxisome number and SER, and while treatment-related, are considered non-adverse.

The LOAEL is 25 mg/kg bw/day, based on hematology (decreased hemoglobin and hematocrit concentrations and erythrocyte count and increased platelet count and prothrombin time).  The NOAEL is 1 mg/kg bw/day.

This chronic oral toxicity study in the dog is Acceptable/Guideline and satisfies the guideline requirements for a chronic oral toxicity study in non-rodents (OPPTS 870.4100; OECD 452).

MRID No.  MRID  00164903

EXECUTIVE SUMMARY - In a developmental toxicity study (MRID 00164903), Fomesafen (97.5% a.i.) was administered to 17-24 pregnant rats/dose in corn oil by gavage at dose levels of 0, 50, 100 or 200 mg/kg bw/day from days 6 through 15 of gestation. 

Maternal toxicity was evident at dose of 200 mg/kg bw/day (the highest dose tested) and was associated with staining of the ventral fur in 15 of 20 animals and significantly decreased body weight gain (>10%) during the dosing period (Days 7-16; Days16-21).   Food consumption in the high-dose group was also significantly decreased as compared to the control group during the dosing period (Days 7-16; Days 16-21).

However, this study should be considered with: 1) Report Nos. CTL/P/656 and CTL/P/656S, MRID #001013016, and 2) information provided by Syngenta in their submission (DP 316263, MRID 46527208) in establishing the NOAEL and LOAEL (see Discussion/Added Information Section).  With the additional information, the following conclusions can be made.   The maternal LOAEL is 200 mg/kg bw/day, based on staining of the ventral fur and significantly decreased body weight gain (>10%).    The maternal toxicity NOAEL is 100 mg/kg bw/day.   The developmental LOAEL is 200 mg/kg bw/day based on postimplantation loss.  The developmental NOAEL is 100 mg/kg bw/day.

This developmental toxicity study is classified Acceptable/Guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat in combination with another developmental toxicity in rat (MRID 001013016).

MRID No. 00103016 
      Citation:  Wickeramaratne, G.A., Richards, D., Babham, P.B. (1982) Fomesafen: Teratogenicity study in the rat. CTL/P/656 and CTL/P/656S prepared by Central Toxicology Laboratory, Imperial Chemical Industries PLC, Alderley Park, Macclesfield, Cheshire, UK.  Unpublished Study.

EXECUTIVE SUMMARY - In a developmental toxicity study (MRID 00103016), Fomesafen (97.5% a.i.) was administered to 19-21 pregnant rats/dose in corn oil by gavage at dose levels of 0, 1.0, 7.5  or 50 mg/kg bw/day from days 6 through 15 of gestation. 

There was no maternal and/or fetal toxicity evident at any dose level tested.  However, this study should be considered with: 1) Report No. CTL/P/576, MRID #00164903, and 2) information provided by Syngenta in their submission (DP 316263, MRID 46527208) in establishing the NOAEL and LOAEL (see Discussion/Added Information Section).  With the additional information, the following conclusions can be made.   The maternal LOAEL is 200 mg/kg bw/day, based on staining of the ventral fur and significantly decreased body weight gain (>10%).    The maternal toxicity NOAEL is 100 mg/kg bw/day.   The developmental LOAEL is 200 mg/kg bw/day based on postimplantation loss observed in study CTL/P/576 (MRID 00164903).  The developmental NOAEL is 100 mg/kg bw/day.

This developmental toxicity study is classified Acceptable/Guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the rat in combination with another developmental toxicity in rat (CTL/P/576, MRID 00164903).

MRID No.  00109214  
      Citation:  Wickeramaratne, G. A., Richards, D., Imartin, M., Doss, A., Ishmail, J., Taylor, D., Forbes, D., smf Godley, W.J.   PP021: Teratogenicity Study in the Rabbit. Unpublished Report No. CTL/P/578.  Central Toxicology Laboratory, Imperial Chemical Industries PLC, Alderley Park, Macclesfield, Cheshire, UK.  Unpublished.

EXECUTIVE SUMMARY-    In a developmental toxicity study (MRID 00109214), fomesafen (97.5% a.i.) was administered to at least 13 pregnant Dutch rabbits/group orally (in gelatin capsules) at dose levels of 0, 2.5, 10, or 40 mg/kg/day from days 6 through 18 of gestation.  Due to the low number of pregnant does in the low and high dose groups after the initial mating, 6 mated rabbits were added to the control, low, and mid dose groups and 7 to the high dose group.  The remaining does were sacrificed on GD 29; their fetuses were removed by cesarean section and examined.  A total of 17 animals died on study.  Total mortality (including sacrifice in extremis) was 3/24, 3/24, 4/24, and 7/25 at 0, 2.5, 10, and 40 mg/kg/day, respectively.  The incidence of mucous around the nose and/or forepaws increased in a dose- dependent manner: 3/24, 3/24, 4/24 and 8/25 at 0, 2.5, 10 and 40 mg/kg/day, respectively.  Pasteurella multocida was isolated from two animals found dead or removed from the study prior to GD 29.  However, no other animal was tested for infection with Pasteurella multocida.  In the high dose group only, 6/25 does appeared thin, although body weight gain was not affected overall.  Mean food consumption was 34% higher (p<0.05) than controls in the 40 mg/kg/day group during days 20-29.  An increased incidence (6/25) of erosion of the stomach (hemorrhagic foci) was observed macroscopically in high dose females versus 1/24 in controls, 2/24 at 2.5 mg/kg/day, and 0/24 at 10 mg/kg/day.  Erosion of the stomach was also observed in a separate, preliminary study at 75 and 150 mg/kg/day with an incidence of 7/12 animals at each dose.

The maternal LOAEL was unable to be determined due to the occurrence of an apparent bacterial infection in the animal colony.

There was no significant difference between the control and treated groups in pregnancy rate or abortions.  While the mean number of implantations/dam was similar across dose, the number of corpora lutea/dam was significantly (p<0.05) increased in the high dose group (10.6) relative to controls (7.7).  This resulted in an increase in pre-implantation loss at the high dose only.  This observation was not considered toxicologically significant, because it suggested that dosing took place before the completion of implantation, resulting in maternal-stress-induced embryo lethality.  Early and late fetal deaths increased in the mid-dose group only (7/24, 3/24, respectively) relative to controls (4/24, 1/24, respectively).  There was an increased frequency of partially ossified hyoid (7.1%) and right vestigial rib (#13, 5.4%) at 40 mg/kg/day relative to controls (2.9 and 0%, respectively).  However, these variants are not regarded as toxicologically significant.

The developmental LOAEL was unable to be determined due to the occurrence of an apparent bacterial infection in the animal colony.

Because of an apparent bacterial infection in the animal colony; individual animal data were not reported; all fetuses were not examined for both soft tissue and skeletal alterations; and historical control data were not provided, the developmental toxicity study in the rabbit is classified Unacceptable/guideline.  This study does not satisfy the guideline requirement for a developmental toxicity study [OPPTS 870.3700; §83-3(b)] in the rabbit.

MRID No. 00131491  
      Citation:  Colley, J.; Slater, N.; Heywood, R.; et al. (1983) Fomesafen: 2- Year Feeding Study in Mice: HRC Report No. ICI 318/82754; Sponsor's Study No. PM 0386; CTL/C/1207A through E.  Final rept. (Unpublished study received Oct 13, 1983 under 10182-EX-33; pre- pared by Huntingdon Research Centre, Eng., submitted by ICI Americas, Inc., Wilmington, DE; CDL:071999-A; 072000; 072001).  Unpublished.

EXECUTIVE SUMMARY-  In a chronic feeding/oncogenicity study (MRID 00131491), Fomesafen (Batch No. P28 and ICI Part No. Y00053/001/007, 97.2%) was administered in the diet to CD-1 mice  (52/sex/group; control group contained 104 mice/sex) for up to 104 weeks at  doses of 0, 1, 10, 100 or 1000 ppm (equivalent to 0, 0.15, 1.5, 1.5 or 15  mg/kg/day).  An interim sacrifice was scheduled at 52 weeks utilizing additional groups of 12 mice/sex, except for the control group which contained 24 mice/sex. 

Male mice in the 1000 ppm group were terminated after 80 treatment weeks (80% survival) and female mice were terminated after 90 treatment weeks (70% survival).  No significant increases in mortality were observed at the lower treatment doses.   There was a high incidence of male
and female mice with swollen abdomens in the 1000 ppm group by terminal sacrifice. 
 
Erythrocyte counts, hemoglobin levels and hematocrits were decreased in male and female mice in the 1000 ppm group at terminal sacrifice.  AP and GPT activities were significantly increased in males and females in the 100 and 1000 ppm groups at 52 weeks.  Liver weights and liver-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).

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 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.

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 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 high- dose 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 
      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. 

MRID No. 48762301 
Citation:  Donald L., Marr C., (2011). Fomesafen  -  A 28 Day Immunotoxicity Study of Fomesafen by Oral (Dietary) Administration in Mice using Sheep Red Blood Cells as the Antigen  Charles River Laboratories, Tranent, Edinburgh EH 33 2NE, UK.  Study number 520005, October 31, 2011. MRID 48762301. Unpublished.

EXECUTIVE SUMMARY -  In an immunotoxicity study (MRID 48762301), Fomesafen (98.8%, Batch/Lot no. 517927) was administered to female CD-1mice (10/group) in diets at dose levels of 0, 100, 1000 or 4000 ppm (0, 16, 176, 791 mg/kg/day, respectively) for 28 consecutive days.  Positive control group consisted of 10 females received cyclophosphamide (CPH) by oral gavage (10 mg/kg/day) for 28 consecutive days.  All animals in all groups received a single intravenous injection of the antigen, 2x10[8] sheep red blood cells (SRBC) in Earles balanced salt solution, on Day 25. On day 29, blood samples were collected from the orbital sinus under isoflurane anesthesia. Measurement of the SRBC IgM antibody levels were performed with an Enzyme Linked Immunobsorbent Assay (ELISA). The animals were monitored for mortality and for treatment related symptoms daily. Body weights were recorded twice weekly from Day (-7) until necropsy. Additionally, all animals were assessed by gross pathology; the weights of liver (with gall bladder), spleen and thymus were measured.

There were no treatment related signs and symptoms and no differences in food consumption. There were no deaths during the study period.  Body weights were not affected in animals in 100 or 1000 ppm groups.  However, treatment related lower body weight and body weight gain occurred in 4000 ppm group. Animals in positive control group that received (CPH) showed statistically significant lower body weight and body weight gain (p<0.05).

Increased liver weights (p<0.01) were found at 100 ppm and above groups. Lower spleen and thymus weights were observed in animals at 4000 ppm.  Histologically, mild to mark diffuse or centrilobular hepatocytes hypertrophy was found in animals at 100 ppm and above groups.  There was a dose response in severity of histopathology. These findings correlated with higher liver weights and macroscopic findings. The selected doses were approved by the HED Dose Adequacy and Review Team (DART, TXR No. 0055484, dated 14 September 2010).

The systemic NOAEL is not established (<100 ppm). The systemic LOAEL was 100 ppm (equivalent to 16 mg/kg/day) based on increased liver weights and histological changes.

For immunotoxicity, there is a dose-dependent suppression of the immune response to sheep red blood cells after the treatment with Fomesafen.  IgM levels in animals at 1000 and 4000 ppm groups were approximately 2-3 folds lower than that of the control animals. A high inter-individual variability was noted in all the treatment groups as well as in the control group. Evaluation of individual animal data of this study showed a distribution and trend that demonstrated a significant suppression of anti-SRBC IgM response. Animals in positive control group showed decreased antibody response which confirmed the ability of the test system to detect immunosuppressive effects and validated the study design.  

The Natural Killer (NK) cells activity was not evaluated. However, under the HED guidance when the test substance produces dose-related suppression of the TDAR (anti-SRBC response), then the test substance is considered as immunotoxic and no further study is required. NK cells activity assay is not required.

Under conditions of this study, the immunotoxicity NOAEL is 100 ppm (equivalent to 16 mg/kg/day). The LOAEL is 1000 ppm (equivalent to 176 mg/kg/day) based on dose-related suppression of anti-SRBC IgM response.

This immunotoxicity study is classified acceptable guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in mice.  

MRID No. 48973302 
Citation:  Rached, E.  2012.  Fomesafen technical - Acute oral (gavage) neurotoxicity study in rats.  Harlan laboratories, Ltd.  Itingen, Switzerland.  Laboratory Report No. D41528, October 16, 2012.  MRID 48973302.  Unpublished.  
		
Rached, E.  2012.  Fomesafen technical - preliminary acute oral (gavage) neurotoxicity study in rat.  Harlan laboratories, Ltd.  Itingen, Switerland.  Laboratory Report No. D41517, October 12, 2012.  MRID 48973301.  Unpublished.  

EXECUTIVE SUMMARY -  In an acute neurotoxicity study (MRID 48973302), fomesafen (98.8% a.i., Batch No. 517927) was administered in a single oral gavage dose to 10 non-fasted Wistar rats/sex/group at dose levels of 0, 100, 250, or 800 mg/kg bw in 0.5% (w/v) aqueous carboxymethylcellulose (10 mL/kg).  The animals were observed for 15 days after dosing, and the survivors were sacrificed on Day 16.  Neurobehavioral assessments, consisting of a modified functional observational battery (FOB) and locomotor activity testing, were performed on all animals of both sexes before dosing and on Days 1 (day of dosing), 8, and 15.  Cholinesterase activity was not determined in this study.  At study termination, 5 rats/sex/group were anesthetized and perfused in situ for neuropathological examination.  The tissues from the perfused animals in the control and 800 mg/kg groups were subjected to histopathological evaluation of brain, spinal cord, and peripheral nervous system tissues.   

No adverse, treatment-related effects were observed on mortality, clinical signs, or gross or microscopic pathology.  No treatment-related effects were observed during the brain weight or neuropathology assessments.
   
Systemic toxicity was noted in the males for a day or two after treatment, but recovery did occur.  In the 800 mg/kg male rats, a net loss in bodyweight was observed on Day 2 (-13.2 g in treated group vs 2.98 g in controls) and Day 3 (-9.39 g in treated group vs 7.61 g in controls).  Body weights at Day 15 and overall (Days 1-15) body weight gains in the 800 mg/kg males were similar to controls.  Body weights were affected to a lesser degree in the 250 mg/kg males.  A net loss of weight was observed in the 250 mg/kg males on Day 2 (-7 g in treated group); however, body weights at Day 3 and later were similar to controls.  Body weights in the 100 mg/kg males and in all treated female groups were similar to controls.  During the first 24 hours after treatment, mean food consumption was decreased (statistical analysis not performed) by 62% in the 800 mg/kg males and by 22% and 43% in the 250 and 800 mg/kg females, respectively.  No notable effect was observed on food consumption during Days 8-9 and 14-15 in the treated groups.  Food consumption as a mean of means over the treatment period was decreased by 17-18% in the 800 mg/kg group.  The effect on food consumption in the females was not considered adverse due to the transient nature and the minimal impact on body weight.

Neurotoxicity was observed, but not in the absence of systemic toxicity.  In the 250 and 800 mg/kg males on Day 1, decreased (p<=0.05, except as noted) motor activity compared to controls was observed as follows:  (i) horizontal activity by 36-41%; (ii) time in central quadrant by 46-59% (not statistically significant [NS] at 250 mg/kg); and (iii) vertical activity by 61-64%.  The effect on the females was much less apparent.  In the 800 mg/kg females on Day 1, horizontal activity was decreased (NS) by 24%, and vertical activity was decreased (NS) by 28%.  Motor activities in all other animals on Day 1 and in all animals on Days 8 and 15 were similar to controls.  Habituation was demonstrated, and unaffected by treatment.  Reduced activity and decreased rearing was also assessed during the FOB; however, these findings demonstrated an equivocal effect on Day 1, marginal increases in incidence or severity without an effect that was clearly related to dose.  
   
At 800 mg/kg on Day 1, one male rat had a hunched posture (#34) and piloerection (#34), and another rat had a reduced righting response (#31).  Piloerection, hunched posture, and abnormal gait were observed in one female (#72).  These findings were not observed in other animals at any other time.  As systemic toxicity was noted at this dose, these findings were considered equivocally treatment-related.

The LOAEL was 250 mg/kg, based on decreased body weight and motor activity (horizontal and vertical activity and time in central quadrant) in males.  The NOAEL is 100 mg/kg.
	
This study is classified as acceptable/guideline and satisfies the guideline requirement (870.6200; OECD 424) for an acute neurotoxicity study in rats.

MRID No. 48996801 
Citation:  Rached, E. (2012) Formesafen technical  -  13-week dietary combined toxicity and neurotoxicity study in Wistar rats.  Harlan Laboratories Ltd., Itingen, Switzerland. Laboratory Project ID:  D41541, November 15, 2012.  MRID 48996801.  Unpublished.

EXECUTIVE SUMMARY - In a subchronic neurotoxicity and oral toxicity study (MRID 49091201, replacing MRID 48996801), fomesafen (98.8% a.i., Batch No. 517927) was administered in the diet to 15 Wistar rats/sex/group at dose levels of 0, 100/300, 300/1000, or 1000/3000 ppm in males/females (equivalent to 0/0, 6.4/23.1, 20.3/74.2, and 67.0/233.2 mg/kg/day [M/F], respectively) for 13 weeks.  Neurobehavioral assessment (functional observational battery [FOB] and motor activity testing) was performed prior to treatment and during Weeks 2, 5, 9, and 13 on 10 rats/sex/group.  At study termination, 5 rats/sex/group were anesthetized and perfused in situ for neuropathological examination.  The tissues from the perfused animals in the control and 1000 (males)/3000 (females) ppm groups were subjected to histopathological evaluation of brain, spinal cord, and peripheral nervous system tissues.   Additionally, required evaluations for a subchronic dietary toxicity study were fulfilled.  Standard toxicity observations (such as body weight) were recorded for all animals (n=15).  Clinical diagnostics and standard histopathology were performed on 10 rats/sex/group.

No adverse, treatment-related effect was observed on mortality, clinical signs, body weight, body weight gains, food consumption, food utilization, ophthalmoscopic examination, hematology, clinical chemistry, urinalysis, or gross or microscopic pathology.  No treatment-related effect was observed during the functional observational battery, motor activity, brain weight or neuropathology assessments.

There were no deaths or clinical signs of toxicity in either sex.  Slight decreases in terminal body weights (Day 92) and body weight gains (Days 1-85) were observed in males at 300 ppm (decr 4-5%) and 1000 ppm (decr 6-7%), but the magnitude of the reductions were not considered adverse.  Female body weights were comparable among the groups.  The liver appears to be the target organ, as evidenced by the dose-related increase in liver weight in both sexes.  Adjusted (for terminal body weight) liver weights were increased (p<0.01) dose-dependently in all treated male groups by 14-42% and in the 1000 and 3000 ppm females by 12-28%.  Absolute and relative to body liver weights were also similarly increased dose-dependently in both sexes.  At 1000 ppm, enlarged livers were seen in 4 of 10 males, and minimal centrilobular hypertrophy was seen in 1 of 10 males.  These responses were considered treatment-related, but adaptive in the absence of other pathological or clinical chemistry findings.

The systemic and neurotoxicity LOAELs were not observed.  The systemic and neurotoxicity NOAELs are 1000/3000 ppm (equivalent to 67.0/233.2 mg/kg/day in M/F).

The study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 870.6200b; OECD 424) for a subchronic neurotoxicity study in rats and the guideline requirement (OPPTS 870.3100; OECD 408) for a subchronic toxicity study in rats.  Although a LOAEL was not determined, previous studies in rats with this test compound have demonstrated toxic effects at lower doses.  Consequently, the dose selection was considered justified.

Appendix B.  Physical/Chemical Properties

Table B.1   Physicochemical Properties of Fomesafen.
Parameter
Value
Reference
Melting point/range
220-221 C
HED Memo, 9/3/82, W. Anthony
pH
8.2 (94% TGAI)
CSF (EPA Reg. No. 100-1017; 10/13/00)
Density
1.28 g/cm[3] at 20 C
HED Memo, 9/10/86, C. Trichilo
Water solubility at 25 °C
600 g/L at pH 7
<10 ppm at pH 1-2
50 mg/L
HED Memo, 9/3/82, W. Anthony

HED Memo, 9/10/86, C. Trichilo
Solvent solubility
                  g/L
Acetone	                                300
Cyclohexanone	                150
Methanol	                                  25
Hexane	                                  0.5
Xylene                                      1.9
HED Memo, 9/10/86, C. Trichilo

Vapor pressure
<7.5 x 10[-7] mm Hg at 50 C
The Pesticide Manual [1]
Dissociation constant, pKa
2.7 at 20 C

Octanol/water partition coefficient, Log(KOW)
Log KOW = 2.9 at pH 1

UV/visible absorption spectrum
Not available

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

Appendix C.  Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from PHED 1.1; the AHETF database; and the ARTF database, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements.  For certain studies, the ethics review may have included review by the Human Studies Review Board.  Descriptions of data sources, as well as guidance on their use, can be found at the Agency website.