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1.0 Executive Summary ................................................................................................................. 4

2.0 HED Recommendations .......................................................................................................... 7

2.1 Data Deficiencies .................................................................................................................. 7

2.2 Tolerance Considerations.................................................................................................... 7

2.3 Label Recommendations...................................................................................................... 8

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

3.1 Chemical Identity ................................................................................................................. 9

3.2 Physical/Chemical Characteristics ..................................................................................... 9

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

5.0 Dietary Exposure and Risk Assessment............................................................................... 16

5.1 Residues of Concern Summary and Rationale ................................................................ 16

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

5.3 Water Residue Profile........................................................................................................ 17

5.4 Dietary Risk Assessment.................................................................................................... 18

5.4.1 Description of Residue Data Used in Dietary Assessment.......................................... 18

5.4.2 Percent Crop Treated Used in Dietary Assessment .................................................... 18

5.4.3 Acute Dietary Risk Assessment..................................................................................... 18

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

5.4.5 Cancer Dietary Risk Assessment................................................................................... 19

5.4.6 Summary Table............................................................................................................... 19

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................... 19

6.1 Residential Handler Exposure .......................................................................................... 19

6.2 Post-Application Exposure ................................................................................................ 20

6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)......................... 21

6.4 Residential Risk Estimates for Use in Aggregate Assessment........................................ 21

6.5 Residential Bystander Post-application Inhalation Exposure ....................................... 22

6.6 Spray Drift.......................................................................................................................... 22

7.0 Aggregate Exposure/Risk Characterization........................................................................ 23

7.1 Acute Aggregate Risk......................................................................................................... 23

7.2 Short- and Intermediate-Term Aggregate Risk .............................................................. 23

7.3 Chronic Aggregate Risk .................................................................................................... 24

7.4 Cancer Aggregate Risk ...................................................................................................... 24

8.0 Cumulative Exposure/Risk Characterization ..................................................................... 24

9.0 Occupational Exposure/Risk Characterization .................................................................. 24

9.1 Occupational Handler Exposures..................................................................................... 24

9.2 Occupational Post-application Exposures ....................................................................... 25
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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 Executive Summaries......................................................................................................... 31

Appendix B. Chemical Names and Structures for Flazasulfuron and its Metabolites.............. 34

Appendix C. Physical/Chemical Properties of Flazasulfuron...................................................... 36
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1.0 Executive Summary

Use Profile: 

ISK has submitted an application to modify the Flazasulfuron Herbicide label (EPA Reg. No. 71512-

18) to include a new use on tree nuts and establish permanent tolerances on the tree nut group 14-12. 

Permanent tolerances are currently established for flazasulfuron in/on citrus, grapes and sugarcane

(CFR §180.655). Additionally it is registered for use on residential and non-residential turf such as

golf courses, sod farms, professionally managed athletic fields, commercial lawns, Christmas trees, 

and industrial vegetation management areas. Flazasulfuron is a sulfonylurea herbicide used to

control certain broad-leaf weeds and grasses, and acts by inhibiting the acetolactate synthase (ALS) 

biochemical process. 

The end-use product, ISK Flazasulfuron Herbicide (EPA Registration Number 71512-18), is a water 

dispersible granular (WDG/WG) formulation containing 25% active ingredient (ai). The product is 

proposed for use on tree nuts at a maximum single application rate of 0.045 lb ai/A with two 

applications for a maximum seasonal application rate of 0.09 lb ai/A. The use of an adjuvant is 

recommended for postemergence applications. The minimum retreatment interval is three months. 

The pre-harvest interval (PHI) is 130 days.

Hazard Identification:

The risk assessment for flazasulfuron is based on a well-characterized and nearly complete 

toxicology database. The data-gaps noted in the previous risk assessment have been satisfied with 

the exception of an immunotoxicity study which has been received and is currently under review. 

In repeated dose studies, the most consistently observed effects of flazasulfuron exposure across 

species, genders, and treatment durations were the kidney and liver toxicity. In addition, subchronic 

studies indicated decreased body weight gain and slight anemia in rats and liver abnormalities in 

dogs. While transient decreases in motor activity were observed at high dose levels in the acute 

neurotoxicity study, flazasulfuron did not produce significant neurotoxicity in the subchronic 

neurotoxicity study or other repeated dose studies. Flazasulfuron produced developmental and 

reproductive effects only at maternally and parentally toxic dose levels, respectively; in addition, 

since clear NOAELs and LOAELs have been established for these effects, so there are no concerns 

for quantitative or qualitative susceptibility. Flazasulfuron did not demonstrate mutagenicity or 

carcinogenicity in the available database. There was no evidence of immunotoxicity in the repeated 

dose studies in the database, nor in a preliminary assessment of the new immunotoxicity study. 

Flazasulfuron has low acute toxicity via the oral, dermal and inhalation routes of exposure. It is not 

irritating to the skin or eyes and is not a sensitizer. 

A NOAEL of 50 mg/kg was selected for the acute dietary endpoint based on a transient decrease in 

motor activity at the LOAEL in the rat acute neurotoxicity study. The NOAEL of 1.3 mg/kg/day 

was selected for the chronic dietary endpoint based on adverse change in kidney function (chronic 

nephropathy) at the LOAEL in a combined chronic toxicity and carcinogenicity study in rats. For 

short- and intermediate-term residential and occupational (incidental oral and inhalation) exposure 

scenarios, the NOAEL of 2 mg/kg/day from the oral subchronic in dogs was selected which was 

based on changes in liver (increase in: deposition of brown pigments, glutamic pyruvic 

transaminase, creatine phosphokinase, inflammatory cell infiltration, and microgranulomas) at the 
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LOAEL. No dermal hazard was identified because no effects were seen up to the limit dose (1000 

mg/kg/day) in a 21-day dermal toxicity study. The Food Quality Protection Act (FQPA) Safety 

Factor has been reduced to 1X because 1) the toxicity database is complete, 2) there is no concern 

for quantitative or qualitative susceptibility in offspring, 3) there are no neurotoxicity concerns, and 

4) there are no residual uncertainties regarding exposure. 

Dietary Exposure (Food/Water):

Flazasulfuron may reach surface and/or groundwater from the proposed tree nut use and affect the 

drinking water component of the dietary exposure. The residue chemistry data and drinking water

data are adequate to assess dietary exposure. The dietary exposure assessment relies on conservative 

inputs to model exposure to flazasulfuron through food and drinking water. The estimated drinking 

water concentrations (EDWCs) were determined for ground water and surface water based on the 

Delmarva corn scenario which also covers the tree nut scenario; the EDWC for ground water was 

used since it is higher than that for surface water. The assessments are based on reliable data and 

will not underestimate exposure/risk.

Acute: An unrefined acute dietary (food and drinking water) assessment was conducted. The 

assumptions of this dietary assessment included tolerance level residues for all registered and 

proposed crops and 100% crop treated (CT). Empirical processing factors were used. The ground

water EDWC of 90.8 μg/L from the Tier II PRZM-GW modeling was incorporated directly into the 

dietary assessment.

The acute dietary (food and drinking water) exposure to flazasulfuron is below HED’s level of 

concern [i.e., <100% of the acute Population Adjusted Dose (aPAD)] for the general U.S. population 

and all population subgroups. The acute dietary exposure estimates at the 95th percentile are 1% of 

the aPAD for the general U.S. population and 3% of the aPAD for all infants (<1 year old), the most 

highly exposed population subgroup. 

Chronic: An unrefined chronic dietary (food and drinking water) assessment was conducted. The 

assumptions of this dietary assessment included tolerance level residues for all registered and 

proposed crops and 100% crop treated (CT). Empirical processing factors were used. The ground

water EDWC of 55.6 μg/L from the Tier II PRZM-GW modeling was incorporated directly into the 

dietary assessment.

The chronic dietary (food and drinking water) exposure to flazasulfuron is below HED’s level of 

concern [i.e., <100% of the chronic Population Adjusted Dose (cPAD)] for the general U.S. 

population and all population subgroups. The chronic dietary exposure estimates are 9% of the 

cPAD for the general U.S. population and 23% of the cPAD for all infants (<1 year old), the most 

highly exposed population subgroup. 

Residential Exposure:

There are no residential uses being requested at this time. Therefore, residential handler and postapplication scenarios were not assessed. However, there are existing residential turf uses that have 

been previously assessed using the most recent Residential SOPs and were not of concern to HED.
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Aggregate Exposure:

Acute: Aggregate acute risk is equivalent to acute dietary risk. There is potential acute exposure via 

the diet (food and drinking water) as determined in Section 5.4. The acute aggregate exposure 

estimates are not of concern.

Chronic: Aggregate chronic risk is equivalent to chronic dietary risk. There is potential chronic 

exposure via the diet (food and drinking water) as determined in Section 5.4. The chronic aggregate

exposure estimates are not of concern. 

Short- and Intermediate Term: There is potential short-term aggregate exposure to flazasulfuron for 

children via the dietary pathway (which is considered background exposure) and the post-application 

dermal and incidental oral residential pathway (which is considered the primary pathway). Since no 

hazard was identified for the dermal route of exposure, short-term aggregate risks included dietary 

and incidental oral exposures only. The aggregate margin of exposure (MOE) for children 1-2 years 

old is 810 and not of concern to HED. 

There is potential short-term aggregate exposure to flazasulfuron for adults via the dietary pathway 

(which is considered background exposure) and the handler dermal and inhalation pathways. 

However, since no hazard was identified for the dermal route of exposure, short-term aggregate risks 

included dietary and inhalation exposures only. The aggregate MOE for adults is 1,600 and not of 

concern to HED. 

Intermediate-term aggregate exposures are not expected based on the use profile of flazasulfuron, 

therefore they were not assessed.

Occupational Exposure:

Occupational Handler Exposures:

Occupational short- and intermediate- term dermal and inhalation exposures are expected from 

flazasulfuron handler activities associated with the proposed tree nut use. Since no hazard was 

identified for the dermal route of exposure, dermal exposures were not assessed. MOEs greater than 

100 for the inhalation route is deemed adequate to protect occupational flazasulfuron handlers. All 

handler scenarios resulted in MOEs greater than the level of concern (LOC = MOEs ≥ 100) for 

inhalation exposures and, therefore are not of concern. 

Occupational Post-application Exposures:

Occupational short-term dermal exposures are expected from flazasulfuron post-application 

activities associated with the proposed tree nut use. However, since no hazard was identified for the 

dermal route of exposure, dermal exposures were not quantitatively assessed. 

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

exposure assessment was not performed for flazasulfuron at this time. If new policies or procedures 

are put into place, the Agency may revisit the need for a quantitative post-application inhalation 

exposure assessment for flazasulfuron.

Restricted Entry Interval: The labeled restricted entry interval (REI) of 12-hrs is adequate to protect 

agricultural workers from post-application exposures to flazasulfuron. Per the Worker Protection 
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Standard (WPS), flazasulfuron is classified as Toxicity Categories III and IV and requires a 12-hr 

REI. 

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 the 

PHED, AHETF, and Residential SOPs (for the turf grass SOP); 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 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

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

Environmental Justice Considerations: 

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

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

Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. 

2.0 HED Recommendations

HED can recommend for a registration of flazasulfuron for use on tree nuts. Additional data needed 

prior to registration are outlined in Section 2.1, specific tolerance recommendations are discussed in 

Section 2.2, and label modifications are discussed in Section 2.3.

2.1 Data Deficiencies

RESIDUE CHEMISTRY

860.1380 Storage Stability

Storage stability data for flazasulfuron are required for tree nuts for up to 186 days (6.1 months) of 

frozen storage. The petitioner has indicated that a study to determine the stability of flazasulfuron in 

the pecan crop matrix under frozen conditions is in progress.

860.1550 Proposed Tolerances

The petitioner must submit a revised Section F to propose a tolerance for almond, hulls at 0.01 ppm.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate enforcement method is available. The method uses high performance liquid 

chromatography/tandem mass spectrometry with multiple reaction monitoring (HPLC/MSMS/MRM) (ADME study code S09-03106; MRID 48092201). The validated limit of quantification 

(LOQ) is 0.01 ppm.
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2.2.2 Recommended Tolerances

The petitioner, ISK Biosciences Corporation, proposed establishment of a tolerance for residues of 

the herbicide flazasulfuron in or on nut, tree, group 14-12. The established residue definition 

(tolerance expression) for flazasulfuron in 40 CFR §180.655 is in accordance with the S. Knizner 

memo dated 5/27/09. 

HED is recommending tolerances as shown in Table 2.2.2.

Table 2.2.2. Tolerance Summary for Flazasulfuron.

Commodity Proposed Tolerance 

(ppm)

HED-Recommended 

Tolerance (ppm)

Comments 

(correct commodity definition)

Almond, hulls None 0.01

Nut, tree, group 14-12 0.01 0.01

2.2.3 Revisions to Petitioned-For Tolerances

The petitioner must submit a revised Section F to propose a tolerance for almond, hulls at 0.01 ppm.

2.2.4 International Harmonization

There are currently no maximum residue limits (MRLs) established by Codex, Canada, or Mexico 

for flazasulfuron. Therefore, there are no issues regarding international harmonization raised by this 

action. 

2.3 Label Recommendations

There are no recommended label modifications.

3.0 Introduction

Flazasulfuron [N-[[4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-3-(trifluoromethyl)-2-

pyridinesulfonamide] belongs to the pyrimidinylsulfonylurea class of herbicides. It is used to 

control certain broadleaf weeds and grasses and acts by inhibiting the acetolactate synthase (ALS) 

biochemical process. 
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3.1 Chemical Identity

Table 3.1 Flazasulfuron Nomenclature

Compound Chemical Structure

Common name Flazasulfuron

Company experimental name SL-160

IUPAC name 1-(4,6-dimethoxypyrimidin-2-yl)-3-(3-trifluoromethyl-2-pyridylsulfonyl)urea

CAS name N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-3-(trifluoromethyl)-2-

pyridinesulfonamide

CAS registry number 104040-78-0

End-use product (EP) ISK Flazasulfuron Herbicide (EPA Reg. No. 71512-18)

3.2 Physical/Chemical Characteristics

Flazasulfuron has a log octanol/water partition coefficient (log Kow) of <1.0 and is considered 

relatively soluble in water. However, flazasulfuron has a molecular weight of 407.4 g/mol; 

therefore, the potential to cross biological barriers is somewhat limited. Based on laboratory and 

field studies, flazasulfuron was found to be long-lived and persistent under most environmental 

conditions. The vapor pressure of flazasulfuron is considered low (<1x10-7 mm Hg at 20 oC), 

limiting the potential for inhalation exposure to vapor. A summary of the physical/chemical 

characteristics of flazasulfuron is provided in Appendix C.

3.3 Pesticide Use Pattern

Flazasulfuron is currently registered to control annual and perennial grasses, sedges, and broadleaf 

weeds in citrus, grapes, sugarcane and Christmas tree fields as well as, on golf courses and other 

non-residential turf areas such as industrial parks, tank farms, sod farms, seed farms, professionally 

managed sports fields and industrial vegetation management in nonagricultural areas. The 

flazasulfuron end-use product relevant for this petition is Flazasulfuron Herbicide [EPA Reg. No. 

71512-18] which is formulated as a water dispersible granular (WDG/WG) formulation containing 

25% active ingredient (ai). The tree nut use rate is proposed at a maximum single application rate of 

0.045 lb ai/A with a maximum of 2 applications at a maximum seasonal application rate of 0.09 lb 

ai/A, and a retreatment interval of 3 months. The PHI is 130 days.

ISK has proposed to add a tree nut use to the Flazasulfuron Herbicide label as summarized in Table 

3.3 below. 
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Table 3.3. Use Profile for Proposed New Flazasulfuron Use

Use Site

Max. Rate for 

Single Appl.

Max. 

Rate per 

Season

Retreatment 

Interval and 

Maximum No. of 

Applications

PHI Application Method and 

Instructions

Flazasulfuron Herbicide [EPA Reg. No71512-18]

Tree nuts

0.045 lb ai/acre

0.0011 lb ai/gal

0.09 lb 

ai/acre

3 months

2

130 

days Spray directed to the weeds.

General application information for pre- and postemergence weed control states that applications 

should be made in 15 to 50 gallons of water per acre. Directed spray applications using low-pressure 

coarse spray equipment should be made in at least 20 gallons of water per acre. Applications should 

be made using conventional spray equipment. Applications cannot be made aerially or through any 

irrigation system. 

3.4 Anticipated Exposure Pathways

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

new use of flazasulfuron on tree nuts. Humans may be exposed to flazasulfuron in food and 

drinking water, since flazasulfuron may be applied directly to growing crops and application may 

result in flazasulfuron reaching surface and ground water sources of drinking water. The existing 

residential turf use of flazasulfuron is expected to result in exposure to residential handlers, and 

those entering treated areas following application. In occupational settings, applicators may be 

exposed while handling flazasulfuron. There is a potential for post-application exposure for workers 

re-entering treated fields. 

Risk assessments have been completed for existing uses of flazasulfuron. This risk assessment 

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

flazasulfuron, but also considers existing uses of flazasulfuron, particularly in the dietary, residential, 

and aggregate assessments. 

3.5 Consideration of Environmental Justice

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

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

Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

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

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

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

and around the home that involve pesticide use in a residential setting. Extensive data on food 

consumption patterns are compiled by the USDA under the National Health and Nutrition 

Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk 

assessments for all registered food uses of a pesticide. These data are analyzed and categorized by 

subgroups based on age, and ethnic group. Additionally, OPP is able to assess dietary exposure to
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smaller, specialized subgroups and exposure assessments are performed when conditions or 

circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of 

pesticide products and associated risks for adult applicators and for toddlers, youths, and adults 

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

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

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

lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

This assessment updates the previous hazard characterization of flazasulfuron; the last 

comprehensive risk assessment was conducted in 2012 (D399358, C. Walls, 10/15/12). At that time, 

the toxicity database was judged complete with the exception of the subchronic neurotoxicity battery 

(§870.6200b) and an immunotoxicity study (§870.7800). The neurotoxicity studies have been 

received and reviewed and are discussed in the sections below; the immunotoxicity study has been 

received and is currently in detailed review. 

4.1 Summary of Toxicological Effects

Chronic oral studies in the rat, mouse and dog indicate that the kidney and liver are the target organs 

for chronic oral exposure. Observed effects include adverse changes in kidney function (chronic 

nephropathy) and physiology (enlargement, dark color of kidney), changes in liver physiology 

(increased weight) and histology (hepatocellular hypertrophy, increases in inflammatory cell 

infiltration, hepatocellular necrosis, hepatocellular swelling, and bile duct proliferation). Subchronic 

oral studies indicated decreased body weight gain, slight anemia in rats and liver abnormalities in 

dogs. Dermal or systemic toxicity was not seen in a subchronic dermal study in rabbits at dose 

levels up to the Limit Dose.

Developmental toxicity was observed in rats and rabbits. Reduced fetal weights and delays in 

ossification are the effects observed in a Sprague-Dawley rat developmental study. An earlier

developmental rat study (Wistar rats) showed increased incidence of visceral malformations 

(interventricular septal defect). The developmental study in rabbits showed high incidences of 

abortion at the highest dose tested (450 mg/kg/day). Decreases in body weight and chronic 

nephropathy were observed in offspring in a 2-generation rat reproduction study. The effects on 

offspring in these developmental and reproductive studies occurred at dose levels which were toxic 

to the parents.

A transient decrease in motor activity on Day 0 (5 hours post-dosing) was observed at the mid-dose 

of 1000 mg/kg in an acute neurotoxicity study. This observation may be associated with a systemic 

effect and not with neurotoxicity since there was no corroborating indication of neurotoxicity in the 

subchronic neurotoxicity study. There are no indications of immunotoxicity potential from the 

repeated dose studies in the toxicity database. In addition, preliminary assessment of the available 

immunotoxicity study (currently under detailed review) shows no immunotoxicity in female mice 

when tested up to levels near the limit dose (1198 mg/kg/day). Therefore, there are no concerns for 

immunotoxicity. 
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In vitro and in vivo mutagenicity studies showed no genotoxic potential. The mouse oncogenicity 

study and the rat combined chronic toxicity and carcinogenicity study both showed no evidence of 

carcinogenicity.

The metabolism of flazasulfuron in the rat is similar to that in plants and the goat, which includes 

breaking of the sulfonylurea bridge, extrusion of sulfur dioxide, demethylation and hydroxylation in 

the pyrimidine ring, and conjugation with glucuronic acid. Compounds of toxicological significance 

in rats, plants, and livestock included parent only. Several other environmental transformation 

products (DTPU, DTPP, TPSA, ADMP, HTPP, and 2,3-GTP) (See Appendix B for the names and 

structures), predicted to be present in water, are also considered of toxicological significance, with 

toxicity profiles assumed to be similar to flazasulfuron.

Radiolabeled kinetic studies in the rat show that flazasulfuron is rapidly absorbed irrespective of the 

dosing regime. At seven days, blood, liver, and muscle were the tissues with the highest 

concentrations while the carcass had up to 2.5% of the administered dose. Elimination via the urine 

was the major route of excretion and feces were the secondary route of elimination.

Flazasulfuron has low acute toxicity via the oral (Tox Category IV), dermal (Tox Category III) and 

inhalation (Tox Category IV) routes of exposure. It is not irritating to the skin or eyes and is not a 

sensitizer. The most consistently observed effects of flazasulfuron exposure across species, genders, 

and treatment durations were the kidney and liver toxicity. Subchronic studies indicated decreased 

body weight gain and slight anemia in rats, and liver abnormalities in dogs. 

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

Based on the hazard and exposure data, the flazasulfuron risk assessment team has recommended 

that the FQPA Safety Factor be reduced to 1X. There are no quantitative susceptibility concerns 

based on the developmental and reproductive studies. A potential qualitative concern from one rat 

developmental study (intraventricular septal defect seen at minimally toxic maternal dose levels) is 

addressed by the presence of clear NOAELs and LOAELs, and by the selection of regulatory 

endpoints that are protective of this effect. The database is considered sufficient and there are no 

residual uncertainties.

4.2.1 Completeness of the Toxicology Database

The toxicity database for flazasulfuron is considered to be complete and sufficient for endpoint 

selection for exposure/risk assessment scenarios and for evaluation of the requirements under FQPA, 

and an additional database uncertainty factor does not need to be applied.

The required inhalation toxicity study for flazasulfuron has been waived based on flazasulfuron’s 

use pattern, physical chemical properties, and low acute inhalation toxicity (K. Rury, TXR#0056483,

10/04/12). In the absence of a route specific inhalation toxicity study, a point of departure (POD) for 

inhalation exposure risk assessment has been extrapolated from an oral study. EPA does not believe 

the risk assessments are under-protective of adult handlers. 
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4.2.2 Evidence of Neurotoxicity

An acute neurotoxicity study was conducted with flazasulfuron at dose levels up to 2000 mg/kg. 

Mean motor activity measurements for 1000 and 2000 mg/kg males and females were statistically 

significantly decreased from the respective control groups five hours post-dosing. Animals were less 

active with more resting time than controls. The effect was reversed by the next scheduled 

observation (Day 7). Neurohistopathologic evaluation did not demonstrate any test material-related 

neurotoxic lesions following the examination of tissues from the central and peripheral nervous 

systems of high dose and control animals. The NOAEL was 50 mg/kg.

A subchronic neurotoxicity study was conducted with flazasulfuron at up to 732 mg/kg bw/day in 

the diet for 90 days. No biologically relevant neurotoxic effects were observed at the dose levels 

tested.

The available neurotoxicity battery, therefore, did not raise concern for neurotoxicity. Similarly, the 

subchronic and chronic data in the database did not show any adverse effects that could be 

considered as neurotoxicity.

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

The available data indicate that flazasulfuron produced developmental and reproductive effects only 

at maternally/parentally toxic dose levels, respectively. In addition, clear NOAELs and LOAELs 

have been established for these effects. Therefore, HED has no concerns for quantitative 

susceptibility. A potential qualitative susceptibility concern was identified from the developmental 

study in Wistar rats (intraventricular septal defect seen at minimally toxic maternal dose levels). 

However, this effect was not seen in the developmental study in Sprague-Dawley rats tested up to 

the limit dose, and this concern is further addressed by the presence of clear NOAELs and LOAELs, 

and by the selection of regulatory endpoints that are protective of this effect. Therefore, HED has no 

concerns for qualitative susceptibility.

4.2.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. Since the dietary and non-dietary 

exposure estimates were based on several conservative assumptions, HED does not believe that the 

exposure estimates are underestimated. The acute and chronic dietary assessments conducted with 

DEEM-FCID were screening level analyses. The assessments utilized tolerance values and100% 

crop treated was assumed for all commodities. The DEEM analysis also assumed that all drinking 

water will contain flazasulfuron at the highest EDWC levels modeled by EFED for ground water or 

surface water. For these reasons it can be concluded that the DEEM-FCID analysis does not 

underestimate risk from acute or chronic dietary exposure to flazasulfuron. Similarly, HED does not 

believe that the non-dietary occupational and residential exposures are underestimated because they 

are also based on conservative assumptions, including maximum application rates, labeled PPE

(where applicable), and standard values for unit exposures, acreage treated/amount handled as 

described in the Residential SOPs.
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4.3 Toxicity Endpoint and Point of Departure Selections

For acute dietary exposure, an acute reference dose (aRfD) of 0.50 mg/kg was selected for 

assessment of all populations, based on a NOAEL of 50 mg/kg in the rat acute neurotoxicity study 

with a transient decrease in motor activity at the LOAEL of 1000 mg/kg. This endpoint is a singledose effect and is appropriate for all populations. The endpoint is also protective of other adverse 

effects seen in the database, such as increased incidence of abortions in pregnant rabbits and 

decreased lactational body weights of F1 and F2 offspring. In addition, since the dose interval 

between the NOAEL and LOAEL is 40x and not the 3x to 5x normally used, it is likely that the noeffect level for the study is significantly higher than 50 mg/kg and the reported NOAEL is 

conservative.

A separate acute dietary endpoint for females 13-49 was not selected from the available 

developmental toxicity studies because the NOAEL of 50 mg/kg/day from the acute neurotoxicity 

study is the lowest NOAEL for any available acute study, and is protective of the developmental 

effects seen in the prenatal developmental (Wistar) rat study with a NOAEL of 100 mg/kg/day and a 

LOAEL of 300 mg/kg/day. Therefore, a separate endpoint for females 13-49 based on 

developmental effects is not considered necessary.

For chronic dietary exposure, a chronic reference dose (cRfD) of 0.013 mg/kg/day was selected for 

assessment of all populations, based on a NOAEL of 1.3 mg/kg/day with adverse change in kidney 

function (chronic nephropathy) observed at the LOAEL of 13.3 mg/kg/day in a rat chronic dietary 

study. This provided the most sensitive endpoint available for chronic dietary exposure. 

For short- and intermediate-term residential and occupational exposure scenarios (incidental oral and 

inhalation), the NOAEL of 2 mg/kg/day from the oral subchronic study in dogs was selected. The 

LOAEL of 10 mg/kg/day was based on changes in liver (increases in: deposition of brown pigments, 

glutamic pyruvic transaminase, creatine phosphokinase, inflammatory cell infiltration, and 

microgranulomas). The systemic NOAEL of 2 mg/kg/day is the lowest dose of any non-chronic 

study available, and is protective of all the parental and developmental/offspring effects observed in 

the available non-chronic studies.

For all short- and intermediate-term dermal exposures, a dermal study is available and showed no 

local or systemic effects at dose levels of 250 – 1000 mg/kg/day. This study is chosen because it is a 

route –specific study which measures the same parameters as an oral subchronic study, and because 

there is no concern for developmental effects in the absence of maternal effects. Since no effects 

were seen at the Limit Dose, a quantitative dermal risk assessment is not required.

Long-term dermal and inhalation exposures are not expected; therefore, no endpoints were selected.

The selection of toxicity endpoints and points of departure are presented in a previous risk 

assessment (D303573, G. Burke, 11/16/05). The short-term incidental oral and the occupational 

dermal endpoints were updated in the most recent risk assessment which provides rationale in detail 

(D372903, C. Walls, 6/12/11). The current endpoints are summarized in Tables 4.3.
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Table 4.3 Summary of Toxicological Doses and Endpoints for Flazasulfuron for Use in Residential 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

(all 

populations 

including 

Females 13-

49)

NOAEL =50 

mg/kg

UFA = 10x

UFH = 10x

FQPA SF = 1X

Acute RfD = 0.5 

mg/kg

aPAD = 0.5 

mg/kg

Acute neurotoxicity (rat) LOAEL = 

1000 mg/kg based on: transient decrease in 

motor activity observed at Day 0 (5 hours postdosing).

Chronic 

Dietary

(all 

populations)

Oral

NOAEL = 

1.3 mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1X

Chronic RfD = 

0.013 mg/kg/day

cPAD = 0.013 

mg/kg/day

Combined Chronic Toxicity/ Carcinogenicity rats

LOAEL= 13.3 mg/kg/day based on adverse 

change in kidney function (chronic nephropathy)

Incidental 

Oral 

Short-Term

(1 - 30 days) 

and

Intermediate 

Term (1 - 6 

months)

NOAEL = 2 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1X

LOC for MOE = 

100

90-Day oral toxicity (dog)

LOAEL= 10 mg/kg/day based on changes in 

liver (increase in: deposition of brown pigments, 

glutamic pyruvic transaminase, creatine 

phosphokinase, inflammatory cell infiltration, 

microgranulomas).

Dermal 

Short-Term

(1 - 30 days) 

and

IntermediateTerm

(1 - 6 

months)

No hazard was identified at the limit dose following dermal exposure.

Inhalation 

Short-Term

(1 - 30 days)

And 

IntermediateTerm

(1 - 6 

months)

NOAEL = 2 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 1X

LOC for MOE = 

100

90-Day oral toxicity (dog)

LOAEL = 10 mg/kg/day based on changes in 

liver (increase in: deposition of brown pigments, 

glutamic pyruvic transaminase, creatine 

phosphokinase, inflammatory cell infiltration, 

microgranulomas).

Cancer (oral, 

dermal, 

inhalation)

Classification: No evidence of carcinogenicity to humans based on lack of carcinogenic effects in the 

rat and mouse carcinogenicity studies and lack of a mutagenicity concern

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

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity 

among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted 
Flazasulfuron Human Health Risk Assessment DP No. 411772

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dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not 

applicable.

Based on the available toxicity database and the Agency's current practices, the inhalation risk for 

flazasulfuron was assessed using an oral toxicity study. The Agency sought expert advice and input 

on issues related to this route to route extrapolation approach (i.e., the use of oral toxicity studies for 

inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific 

Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 

2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, reexamine and develop new policies 

and procedures for conducting inhalation risk assessments, including route to route extrapolation of 

toxicity data. If any new policies or procedures are developed, the Agency may revisit the need for 

an inhalation toxicity study for flazasulfuron and/or reexamine the inhalation toxicity risk 

assessment.

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. HED has concluded that the residues of concern in plants and livestock commodities

include the parent only for purposes of tolerance enforcement and risk assessment. 

The parent compound and all identified metabolites are included in the drinking water exposure 

assessment, which is consistent with the previous risk assessment. The current assessment includes

residues of the following compounds in drinking water: parent flazasulfuron, DTPU, DTPP, HTPP, 

TSPA, ADMP, and 2,3-GTF. Based on submitted studies, there is potential for exposure to all of 

these metabolites through drinking water and; therefore, they should be included for risk assessment 

purposes. ROCKS noted that the metabolite GTF was not observed in submitted plant and livestock 

metabolism studies, but was a significant route for dissipation through anaerobic aquatic 

metabolism. While there is no toxicity data available for GTF, the use of the total residue approach 

should account for any potential contribution of GTF. 

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

Expression for Flazasulfuron.

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants Primary Crop Flazasulfuron parent only Flazasulfuron parent only

Rotational Crop Flazasulfuron parent only3

Flazasulfuron parent only3

Livestock Ruminant Flazasulfuron parent only Flazasulfuron parent only

Poultry Not Applicable1 Not applicable1

Drinking Water Total residues (parent + 

identified metabolites)2

Not applicable

1 No poultry feed items have been registered or proposed; therefore, residues in poultry are not applicable for this 

tolerance action. 
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2 See Appendix B for metabolite names and structures. 

3 Rotational crop studies are not required for the existing or proposed uses. 

5.2 Food Residue Profile

The submitted magnitude of the residue data, summarized in Table 5.2.1, are adequate for risk 

assessment and tolerance assessment (D412475, N. Dodd, 2/6/14). Residues of flazasulfuron were 

not detectable in any commodity at the limit of detection, indicating that there will be minimal 

exposure to flazasulfuron in food. Processing studies were not conducted since there are no 

processed commodities associated with tree nuts. There is no reasonable expectation of finite 

residues in livestock commodities based on the non-detectable residues of flazasulfuron in/on animal 

feed items and the results of the ruminant metabolism study. No storage stability data were 

submitted for tree nuts. Pending submission of storage stability data for tree nuts, the available field 

trial data are adequate.

TABLE 5.2.1. Summary of Residue Data from Tree Nut Field Trials with Flazasulfuron. 

Commodity Analyte Total

Rate

(lb ai/A)

PHI 

(days)

Residue Levels (ppm)1

n Sample 

Min.

Sample 

Max.

LAFT2 HAFT2 Median Mean Std. 

Dev.

Tree Nuts (proposed use = 0.09 lb ai/A total application rate; 130-day PHI)

Almond 

Hulls

Flazasulfuron 0.0948-0.0978 123-155 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Almond 

Nutmeat

Flazasulfuron 0.0948-0.0978 123-155 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Pecan 

Nutmeat

Flazasulfuron 0.0466-0.0483 154-272 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. N/A = Not applicable. For calculation of 

median and mean, the LOQ (0.01 ppm) was used for any results reported as <LOQ. Because parent only is the residue of concern, 

DTPU was not converted to parent equivalents and combined residues of parent and DTPU were not determined.

2

 LAFT = lowest average field trial; HAFT = highest average field trial.

5.3 Water Residue Profile

Estimated surface water and groundwater concentrations were provided by the Environmental Fate 

and Effects Division (EFED) (D411771, A. Shelby, 12/3/13) and are shown in Table 5.3. The dietary 

exposure assessment used the peak concentration values of 90.8 ppb for acute and 55.6 ppb for 

chronic assessments. The drinking water assessment is based on Tier II groundwater model (PRZMGW) simulations for all currently registered and proposed flazasulfuron uses. EFED concluded that 

the EWDCs calculated for the existing flazasulfuron uses did not need to change and are protective 

to cover the proposed tree nut use.

The drinking water assessment takes into account flazasulfuron and its degradates DTUP, DTPP, 

HTPP, TPSA, ADMP, and 2,3-GTF. These compounds are referred to collectively as total toxic

flazasulfuron residues. 
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Table 5.3 Summary of Estimated Surface Water and Groundwater Concentrations 

for Flazasulfuron c

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

Acute 26.9 90.8

(highest daily value)

Chronic (non-cancer) 4.67 55.6

(post breakthrough average)

a From the Tier II PRZM-EXAMS - Index Reservoir model. Input parameters are based on are based on 3 

applications at 0.045 lbs ai/A/application to California industrial vegetation management impervious area using a 

percent cropped area (PCA) correction of 100%.

b From the PRZM-GW model 

c A. Shelby, D41171, 12/3/13.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute and chronic dietary analysis for non-cancer risk assessment assumed tolerance level

residues for all registered and proposed crops. Processing studies for grapes, citrus, and sugarcane 

did not show any concentration of flazasulfuron in the commodities tested after processing.

Therefore, the processing factors were used set at 1 in the dietary exposure assessment.

 

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary analyses assumed that 100% of the crop was treated (100% CT). 

5.4.3 Acute Dietary Risk Assessment

An unrefined acute dietary assessment was conducted. The assumptions of this dietary assessment 

included tolerance levels residues for all proposed and registered crops, empirical processing factors,

and 100% CT was assumed. A tier II (PRZM-GW) EDWC derived through EFED modeling which 

is unlikely to underestimate the concentration of flazasulfuron in drinking water was utilized. The 

ground water EDWC (90.8 μg/L) was incorporated directly into the dietary assessment (D411771, 

A. Shelby, 12/3/13).

As shown in Table 5.4.6, the acute dietary (food and drinking water) exposure to flazasulfuron is 

below HED’s level of concern [i.e., <100% of the acute Population Adjusted Dose (aPAD)] for the 

general U.S. population and all population subgroups. The acute dietary exposure estimates at the 

95th percentile are 1% of the aPAD for the general U.S. population and 3% of the aPAD for all 

infants (<1 year old), the most highly exposed population subgroup. 

5.4.4 Chronic Dietary Risk Assessment

An unrefined chronic dietary assessment was conducted. Tolerance level residues, 100% CT, and 

empirical processing factors were used to determine the chronic dietary exposure and risk estimates. 

A tier II EDWC derived through EFED modeling which is unlikely to underestimate the 
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concentration of flazasulfuron in drinking water was utilized. The ground water EDWC (55.6 μg/L) 

was incorporated directly into the dietary assessment (D411771, A. Shelby, 12/3/13).

As shown in Table 5.4.6, the chronic dietary (food and drinking water) exposure to flazasulfuron is 

below HED’s level of concern (<100% cPAD) for the general U.S. population and all population 

subgroups. The chronic dietary exposure estimates are 9% of the cPAD for the general U.S. 

population and 23% of the cPAD for all infants (<1 year old), the most highly exposed population 

subgroup. 

5.4.5 Cancer Dietary Risk Assessment

A cancer dietary risk assessment was not conducted because there was no evidence of 

carcinogenicity to humans based on lack of carcinogenic effects in the rat and mouse carcinogenicity 

studies.

5.4.6 Summary Table

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

Flazasulfuron Using DEEM-FCID

Population Subgroup

Acute Dietary 

(95th Percentile) Chronic Dietary

Dietary Exposure 

(mg/kg/day) % aPAD Dietary Exposure (mg/kg/day)

% 

cPAD

General U.S. Population 0.004982 1.0 0.001187 9.1

All Infants (< 1 year old) 0.015502 3.1 0.003022 23

Children 1-2 years old 0.007755 1.6 0.001769 14

Children 3-5 years old 0.006309 1.3 0.001485 11

Children 6-12 years old 0.004777 <1.0 0.001054 8.1

Youth 13-19 years old 0.004142 <1.0 0.000867 6.7

Adults 20-49 years old 0.004891 <1.0 0.001177 9.1

Adults 50-99 years old 0.004370 <1.0 0.001165 9.0

Females 13-49 years old 0.004969 <1.0 0.001173 9.0

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure

There are no residential uses being requested at this time. Therefore, residential handler and postapplication scenarios were not assessed for the proposed tree nut use. However, there are existing 

residential turf uses that have been previously assessed and are used in the aggregate assessment 

presented in this document (D399890, C. Walls, 10/9/12).

Residential exposure and risks from use on turf were assessed using the updates to the 2012 HED 

Residential SOPs. It is assumed that most residential uses will result in short-term (1-30 day) 

exposures. Residential handlers are assumed to be wearing short-sleeved shirts, short pants, shoes, 

and socks during flazasulfuron application. Because there was no dermal endpoint chosen for 

flazasulfuron, non-cancer risk from exposure to flazasulfuron was assessed for the inhalation route 
Flazasulfuron Human Health Risk Assessment DP No. 411772

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only. Although PODs from an oral study were used to assess residential handler inhalation risks to 

flazasulfuron, HED does not believe this assessment is under protective of adult handlers.

Table 6.1 lists the residential handler non-cancer inhalation risk estimates for spot application to turf. 

Residential handler inhalation MOEs were not of concern to HED, and ranged from 27,000 to 

6,800,000. 

Table 6.1. Residential Handler Non-cancer Exposure and Risk Estimates for Flazasulfuron.

Exposure 

Scenario 

Application 

Equip

Inhalation Unit 

Exposure 

(μg/lb ai)

Maximum 

Application 

Rate1

Area Treated 

or Amount 

Handled Daily2

Inhalation

Dose 

(mg/kg/day)3

MOE4

LOC = 

100

Mixer/Loader/Applicator

Lawn/Turf

Spot or targeted 

treatment

Manuallypressurized 

handwand

0.0011 0.0011 

lb ai/gal 5 gal 0.000073 27,000

Backpack 0.0011 0.0011 l

b ai/gal 5 gal 0.000073 27,000

Sprinkler can 0.000022 1.1E-6 lb ai/ft2 1000 ft2 2.9E-7 6,800,000

1 Based on proposed use on the Flazasulfuron 25WG label [EPA Reg. No71512-12]

2 Exposure Science Advisory Council Policy #9.1.

3 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/ft2

or gal) x Area Treated or Amount Handled (ft2 or gallons/day) / BW (80 kg).

4

Inhalation MOE = Inhalation NOAEL (2 mg/kg/day) / Inhalation Dose (mg/kg/day).

6.2 Post-Application Exposure

When determining the potential for residential exposure, the Agency considers residues, leaf to 

skin/hand residue transfer, children’s hand-to-mouth transfer, and exposure time. Residential shortterm dermal exposures for adults and children and short-term incidental oral exposures for children 

are considered to be negligible from the proposed residential spot treatment use of flazasulfuron. 

However, for the broadcast turf use, the revised Flazasulfuron 25WG label replaced “college and 

professional sports fields” with “sports fields” in the use sites. The generic “sports fields” use site 

includes recreational parks therefore, there is a potential for short-term dermal and incidental oral 

exposures to occur to children from the existing broadcast use of flazasulfuron which now needs to 

be assessed. No dermal endpoint was chosen for flazasulfuron; therefore, a dermal post-application 

risk assessment was not conducted. Table 6.2 summarizes the incidental oral exposures and risks 

resulting from residential post-application exposures. Children incidental oral risk estimates ranged 

from 2,900 to 1,300,000 on the day of application using default input values, and were not of 

concern to HED. 
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Table 6.2. Residential Post-application Non-cancer Exposure and Risk Estimates for 

Flazasulfuron

Lifestage Post-application Exposure Scenario Dose

mg/kg/day MOEs

Child Turf - sprays

Dermal NA NA

Inhalation NA NA

Hand to Mouth 0.00069 2,900

Object to Mouth 0.000021 94,000

Incidental Soil Ingestion 1.6E6 1,300,000

1 Hand-to-Mouth = [Hand residue loading (mg/cm2

) x (fraction hand surface area mouthed/event (0.127/event) x typical surface area of one hand 

(150 cm2)) x (exposure time (1.5 hrs/day)*number of replenishment intervals/hr (4 intervals/hr) x (1-(1-saliva extraction factor (0.5)^(number of 

hand-to-mouth contact events per hour (13.9 events/hr); Hand Residue Loading = (fraction of ai on hands compared to total surface residue from 

dermal TC study (0.06) x dermal exposure (mg))/typical surface area of one hand (150 cm2). 

 Object-to-Mouth = ((Object Residue (μg/cm2) x CF1 (1.0E-3 mg/μg) x Object Surface Area Mouthed/Event (10 cm2/event)) x (Exposure Time (1.5 

hrs/day) x #Replenishment Intervals/hr (4)) x (1-((1-Extraction by Saliva (0.48))^(#Object-to-Mouth Events/hr (8.8 events/hr)/#Replenishment 

intervals/hr))))/Body Weight (11kg).

Soil Ingestion = (Soil Residue (0.34 μg/g) x Ingestion Rate (50 mg/kg/day) x CF(0.000001))/Body Weight (11 kg).

2 MOE = NOAEL/Daily Dose (mg ai/kg/day); Oral NOAEL = 2 mg/kg/day. 

6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

Residential post-application pesticide exposure can occur within a scenario from multiple routes of 

exposure (e.g., dermal, inhalation, and oral). These exposures to pesticides do not occur as single, 

isolated events, but rather as a series of sequential or concurrent events that may overlap or be linked 

in time and space. Based on this, risk estimates resulting from different exposure routes may be 

combined when it is likely that they can occur simultaneously based on the use pattern and when the 

toxicological effects across different routes of exposure are the same. If appropriate for an exposure 

scenario, the recommended routes of exposure for combining include dermal, inhalation, and handto-mouth.

The incidental oral scenarios (i.e., hand-to-mouth, object-to-mouth, and soil ingestion) should be 

considered inter-related and it is likely that they occur interspersed amongst each other across time. 

However, combining these scenarios together would be overly-conservative because of the 

conservative nature of each individual assessment. Therefore, the post-application incidental oral 

exposure scenarios were not combined for children 1 < 2 years old. 

6.4 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.4 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for flazasulfuron.

 The recommended residential exposure for use in the adult aggregate assessment reflects 

inhalation exposure from applications to turf via backpack or manually pressurized

handwand. 

 The recommended residential exposure for use in the children 1<2 years old aggregate 

assessment reflects hand-to-mouth exposures from post-application exposure to turf 

treatments.
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Table 6.4 Recommendations for the Residential Exposures for the Flazasulfuron Aggregate Assessment.1

Lifestage

Handler Exposure 

(mg/kg/day)2 Residential 

Handler 

Total 

Exposure 

(mg/kg/day)3

Residential 

Handler 

Total 

MOE

Post-application 

Exposure (mg/kg/day)4

Residential 

Postapplication 

Total 

Exposure 

(mg/kg/day)

5

Residential 

Postapplication 

MOE Dermal Inhal. Dermal Inhal. Oral

Short-Term

Adult NA 0.000073 0.000073 27,000 NA NA N/A NA NA

Child NA NA NA NA NA NA 0.00069 0.00069 2,900

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 

2 Handler exposure represents high-end handler exposure (i.e., the highest handler exposure of all scenarios assessed).

3 Residential Handler total exposure combines the highest dermal and inhalation exposures (Table 6.1), where applicable. 

4 Post-application exposure represents high-end dermal, inhalation and/or incidental oral exposure for the relevant exposure duration

(Table 6.2)

5 For adults, residential total exposure combines the highest dermal and inhalation exposures (Table 6.1), where applicable. For young 

children, total residential exposure combines high-end post application incidental oral AND dermal exposure, where applicable 

(Table 6.2)

6.5 Residential Bystander Post-application Inhalation Exposure

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

assessment was not performed for flazasulfuron at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and low vapor pressure (<1x10-7 mm Hg). 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

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

6.6 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential 

source of exposure from the ground application methods (e.g., groundboom) employed for 

flazasulfuron. The Agency has been working with the Spray Drift Task Force (a task force 

composed of various registrants which was developed as a result of a Data Call-In issued by EPA), 

EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop 

the best spray drift management practices (see the Agency’s Spray Drift website for more 

information)1. The Agency has also developed a policy on how to appropriately consider spray drift 

as a potential source of exposure in risk assessments for pesticides. 

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

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

concurrently. 
Flazasulfuron Human Health Risk Assessment DP No. 411772

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It is noted that the 0.045 lb ai/acre application rate for turf was previously modeled to estimate postapplication residential exposure of children. As this rate is equal to or higher than many of 

agricultural application rates, this scenario is protective of any exposure of farm children via spray 

drift from agricultural flazasulfuron applications.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate flazasulfuron 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. For flazasulfuron, potential exposures from food, drinking water, and residential scenarios 

were aggregated. 

7.1 Acute Aggregate Risk

The acute aggregate risk is equal to the acute dietary (food and drinking water) exposure. Refer to 

Section 5.4.

7.2 Short- and Intermediate-Term Aggregate Risk

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

background exposure) and the residential pathway (which is considered the primary pathway). Since 

intermediate-term residential exposures are not likely to occur, intermediate-term aggregate risks 

were not assessed. The short-term aggregate exposure assessment for adults includes dietary (food 

and drinking water), dermal and inhalation handler exposures, and post-application dermal 

exposures. The most conservative scenario was chosen for each population (e.g., hand-to-mouth 

exposure from treated turf for children 1-2 years old). For a description of the residential exposure 

scenarios considered in the aggregate assessment, see Section 6.4. 

1 LOC includes standard inter- (10X) and intra- (10X) species uncertainty factors totaling 100. 

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Table 5.4.6

4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Source of residential exposure 

values used in the aggregate assessment (Table 6.4). Exposure estimate for adults includes handler exposures from 

treating turf with flazasulfuron. Exposure estimate for Children 1-2 years includes post-application exposure via handto-mouth to treated turf. 

5 Total Exposure = (Avg Food & Water Exposure + Residential Exposure)

6

(Avg Food & Water Exposure + Residential Exposure), NOAEL = 2 mg/kg/day

Table 7.2 Short-Term Aggregate Risk Calculations.

Population

Short-Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day3

Residential 

Exposure 

mg/kg/day4

Total 

Exposure 

mg/kg/day5

Aggregate 

MOE (food, 

water, and 

residential)6

Adult 2 100 0.02 0.001187 0.000073 0.001259 1,600

Child 2 100 0.02 0.001769 0.00069 0.002459 810
Flazasulfuron Human Health Risk Assessment DP No. 411772

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7.3 Chronic Aggregate Risk

The chronic aggregate risk is equal to the chronic dietary (food and drinking water) exposure. Refer 

to Section 5.4.

7.4 Cancer Aggregate Risk

A cancer aggregate risk assessment was not conducted because there was no evidence of 

carcinogenicity to humans based on lack of carcinogenic effects in the rat and mouse carcinogenicity 

studies.

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 

flazasulfuron and any other substances and flazasulfuron 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 flazasulfuron has a common mechanism of toxicity with other substances. For 

information regarding EPA’s efforts to determine which chemicals have a common mechanism of 

toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released 

by EPA’s Office of Pesticide Programs concerning common mechanism determinations and 

procedures for cumulating effects from substances found to have a common mechanism on EPA’s 

website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Occupational exposures are expected to occur from the proposed flazasulfuron uses on tree nuts. 

Short- (1-30 consecutive days) and intermediate-term (1-6 consecutive months) dermal and 

inhalation exposures are expected from handler activities while only short- and intermediate-term 

dermal exposures are expected from post-application activities. Dermal risks were not assessed 

since a dermal hazard was not identified.

9.1 Occupational Handler Exposures

Chemical-specific exposure data were not submitted to support the proposed flazasulfuron uses. 

When chemical-specific monitoring data are not available, it is the policy of HED to use data from 

PHED, Version 1.1 as presented in the PHED Surrogate Exposure Guide (8/98)1to assess handler 

exposures for regulatory actions. Additionally, typical HED standard values were used for the 

amount treated per day (ExpoSAC Policy No. 9, 07/05/2000). 

Based upon the proposed flazasulfuron use patterns, HED assessed risks to occupational pesticide 

handlers in the following scenarios:

 Mixer/Loader of WDG formulation for groundboom application to tree nuts,

 

1 HED Science Advisory Council for Exposure (ExpoSAC) Policy .007, “Use of Values from PHED Surrogate Table 

and Chemical-Specific Data” HED, OPP, 1/28/99
Flazasulfuron Human Health Risk Assessment DP No. 411772

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 Applicator of liquid formulation for groundboom application to tree nuts,

 Mixer/loader/applicator of WDG formulation for backpack application to tree nuts, and

 Mixer/loader/applicator of WDG formulation for mechanically-pressurized handgun 

application to tree nuts.

Short- and intermediate-term risk estimates for occupational handlers are included in Table 9.1.1. 

All handler scenarios resulted in MOEs greater than the LOC (MOEs ≥ 100) for baseline inhalation 

exposures, and therefore are not of concern. 

Table 9.1.1 Occupational Handler Exposure and Risk Estimates for Flazasulfuron.

Exposure 

Scenario 

Application 

Equip

Inhalation Unit 

Exposure 

(μg/lb ai)

Maximum 

Application 

Rate1

Area Treated 

or Amount 

Handled Daily2

Inhalation

Dose 

(mg/kg/day)3

MOE4

LOC = 

100

Mixer/Loader

Tree nuts Groundboom 8.96 0.045 lb ai/A 80 acres 0.00040 5,000

Applicator

Tree nuts Groundboom 0.34 0.045 lb ai/A 80 acres 0.000015 130,000

Mixer/Loader/Applicator

Tree nuts

Manuallypressurized 

handwand

3.9 0.0022

lb ai/gal 1000 gal 0.00011 19,000

Backpack

2.58 0.0022

b ai/gal 40 gal 0.0000029 690,000

1 Based on proposed use on the ISK Flazasulfuron Herbicide label [EPA Reg. No71512-18]

2 Exposure Science Advisory Council Policy #9.1.

3 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/A 

or gal) x Area Treated or Amount Handled (A or gallons/day) / BW (80 kg).

4

Inhalation MOE = Inhalation NOAEL (2 mg/kg/day) / Inhalation Dose (mg/kg/day).

9.2 Occupational Post-application Exposures

Occupational short-term dermal exposures are expected from flazasulfuron post-application 

activities associated with the proposed tree nut use. However, since no hazard was identified for the 

dermal route of exposure, dermal exposures were not quantitatively assessed. 

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

assessment was not performed for flazasulfuron at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and low vapor pressure (< 1 x 10 -7 mmHg). 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 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 
Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 26 of 36

process of evaluating the SAP report as well as available post-application inhalation exposure data 

generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and 

procedures to identify the need for and, subsequently, the way to incorporate occupational postapplication 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 flazasulfuron.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational 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 most occupational post-application inhalation exposure scenarios.

Restricted Entry Interval: The labeled restricted entry interval (REI) of 12-hrs is adequate to 

protect agricultural workers from post-application exposures to flazasulfuron. Per the Worker 

Protection Standard (WPS), flazasulfuron is classified as Toxicity Categories III and IV and requires

a 12-hr REI. 

10.0 References

Dodd, N., 2/6/14, DP#412475, Flazasulfuron: Petition for the Establishment of Permanent 

Tolerances and Registration for Use on Tree Nuts. Summary of Analytical Chemistry and Residue 

Data.

Holman, E., 2/28/11, DP#386767, Flazasulfuron: Report of the Residues of Concern Knowledgebase 

Subcommittee (ROCKS). 

Shelby, A., 12/3/13, DP#411771, Drinking Water Assessment for Flazasulfuron Use on Tree Nuts.

Walls, C., 2/5/14, DP#417419, Flazasulfuron: Acute & Chronic Aggregate Dietary (Food and 

Drinking Water) Exposure and Risk Assessment for a Proposed Use on Tree Nuts.

Walls, C., Ph.D., 1/16/14, DP#417418, FLAZASULFURON: Occupational and Residential 

Exposure Assessment for a Proposed Use on Tree Nuts.

Walls, C., Ph.D., 10/9/12, DP#399890, FLAZASULFURON: Occupational and Residential 

Exposure Assessment for the First Residential Use on Turf Grass.

Walls, C., Ph.D., 10/15/12, DP#399358, FLAZASULFURON: Human Health Risk Assessment for 

First Residential Use on Turf Grass.
Flazasulfuron Human Health Risk Assessment DP No. 411772

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for Food Use for Flazasulfuron are in the following table. 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 Primary Eye Irritation....................................................

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

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

yes

yes

yes

no

no

yes

yes

yes

--

waived

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

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

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

yes

yes

yes

yes

yes

yes

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

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

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

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

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

no

yes

no

yes

yes

yes

yes

yes

yes

yes

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

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5375 Mutagenicity—Chromosomal Aberrations....................

870.5395 Mutagenicity— In Vivo micronucleus..........................

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

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

no

no

yes

yes

no

-

-

yes

yes

--

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

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

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

yes

yes

yes

yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

no

no

no

--

--

--
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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Flazasulfuron 

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

870.1100 Acute oral [rat] 46220908 LD50 > 5000 mg/kg (male and 

females)

IV

870.1200 Acute dermal [rat] 46220909 LD50 > 2000 mg/kg (male and 

females)

III

870.1300 Acute inhalation [rat] 46220910 LC50 > 5 mg/L (male and 

females)

IV

870.2400 Acute eye irritation 

[rabbit]

46220911 Minimal conjunctivitis 

through 48 hours. Free by 72 

hours.

III

870.2500 Acute dermal 

irritation [rabbit]

46220912 No erythema, edema, or 

dermal effects observed at 

application site.

IV

870.2600 Skin sensitization 

[guinea pig]

46220913 Not a sensitizer -

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.3100

90-Day oral toxicity 

(rat)

46220920 (1988)

M/F: 0, 40, 200, 1000, 

5000 ppm

M: 0, 2.31, 11.66, 57.1, 

287 mg/kg/day 

F: 0, 2.53, 12.8, 61.5, 309 

mg/kg/day

Acceptable/Guideline

NOAEL (M/F) = 11.66/61.5 mg/kg/day

LOAEL (M/F) = 57.1/309 mg/kg/day based on depression of 

body weight gain (M/F) and slight anemia due to decrease in 

hemoglobin (F).

870.3150

90-Day oral toxicity 

(dog)-capsule

46220921 (1994)

M: 0, 2, 10, 50, 250 

mg/kg/day 

F:0, 2, 10, 50, 100 

mg/kg/day

Acceptable/Guideline

NOAEL (M/F) = 2/10 mg/kg/day

LOAEL (M/F) = 10/50 mg/kg/day based on changes in liver 

(increase in: deposition of brown pigments, glutamic pyruvic 

transaminase, creatine phosphokinase, inflammatory cell 

infiltration, microgranulomas).

870.3200

21-Day dermal 

toxicity (rabbit)

46220922 (1994)

0, 250, 500, 1000 

mg/kg/day

Acceptable/Guideline

NOAEL (M/F) = 1000/1000 mg/kg/day

LOAEL (M/F) > 1000 mg/kg/day. No systemic toxicity was 

observed at the limit dose. No localized dermal effects were 

observed.

870.3465

90-Day inhalation 

toxicity (rat)

Not Applicable The requirement for a subchronic inhalation toxicity study 

has been waived (K. Rury, TXR#0056483, 10/04/2012). 
Flazasulfuron Human Health Risk Assessment DP No. 411772

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.3700a

Prenatal 

developmental (rat)

Wistar

46220924 (1988)

0, 100, 300, 1000 

mg/kg/day

Acceptable/Guideline

Maternal NOAEL = 100 mg/kg/day

LOAEL = 300 mg/kg/day based on increase in maternal 

relative liver weight and decreased body weight gain and 

food consumption.

Developmental NOAEL = 100 mg/kg/day

LOAEL = 300 mg/kg/day based on increased incidence of 

visceral malformations (interventricular septal defect).

870.3700a

Prenatal 

developmental (rat): 

Sprague-Dawley

46220925 (1996)

0, 100, 300, 1000 

mg/kg/day

Acceptable/Guideline

Maternal NOAEL = 300 mg/kg/day

LOAEL =1000 mg/kg/day based on transient decreased 

body weight gain and food consumption.

Developmental NOAEL = 300 mg/kg/day

LOAEL = 1000 mg/kg/day based on reduced fetal weights 

and retardation in ossification.

870.3700b

Prenatal 

developmental in 

rabbit

46220923 (1988)

0, 50, 150, 450 

mg/kg/day

Acceptable/Guideline

Maternal NOAEL = 150 mg/kg/day

LOAEL = 450 mg/kg/day based on high incidences of 

abortion and decrease in food consumption after initial 

administration.

Developmental NOAEL = 150 mg/kg/day

LOAEL = 450 mg/kg/day based on high incidences of 

abortion. 

870.3800

Reproduction and 

fertility effects

(rat)

46220926 (1995)

0, 200, 2000, 10000 ppm

M: 0, 8.7, 87.5, 473.0 

mg/kg/day

F: 0, 11.7, 124.5, 613.7 

mg/kg/day

Acceptable/Guideline

Parental/Systemic NOAEL (M/F) = 8.7/124.5 mg/kg/day

LOAEL (M/F) = 87.5/613.7 mg/kg/day based on changes in 

kidney parameters (M/F: Bilateral discoloration, 

enlargement, mild nephropathy) and reductions in body 

weight in both generations (F0, F1).

Reproductive NOAEL (M/F) =473.0/613.7mg/kg/day

LOAEL (M/F) =not established.

Offspring NOAEL (M/F) = 87.5/124.5 mg/kg/day

LOAEL (M/F) = 473.0/613.7 mg/kg/day based on reduction 

in lactational body weights of the F1 and F2 offspring.

870.4100b

Chronic toxicity 

(dog)-capsule

46220927 (1995)

M: 0, 0.4, 2, 10, 50 

mg/kg/day

F: 0, 2, 10, 50 mg/kg/day

Acceptable/Guideline

NOAEL = 2 mg/kg/day

LOAEL = 10 mg/kg/day based on changes in liver (increase 

in: inflammatory cell infiltration, hepatocellular necrosis, 

hepatocellular swelling, and bile duct proliferation).

870.4200

Carcinogenicity

(mouse)

46220928 (1995)

0, 500, 3500, 7000 ppm

M: 0, 77.3, 552.7, 1053.8 

mg/kg/day

F: 0, 93.7, 659.8, 1208.2 

mg/kg/day

Acceptable/Guideline

NOAEL (M/F) = 77.3/93.7 mg/kg/day

LOAEL (M/F) = 552.7/659.8 mg/kg/day based on decrease 

in body weight, body weight gain, food consumption and an 

increase in liver effects (liver weight and hepatocellular 

hypertrophy).

no evidence of carcinogenicity
Flazasulfuron Human Health Risk Assessment DP No. 411772

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.4300

Combined Chronic 

Toxicity/ 

Carcinogenicity

(rat)

46220929 (1995)

M: 0, 40, 400, 2000 ppm

F: 0, 40, 400, 4000 ppm

M: 0, 1.3, 13.3, 70.1 

mg/kg/day

F: 0, 1.6, 16.4, 172.6 

mg/kg/day

Acceptable/Guideline

NOAEL = 1.3 mg/kg/day

LOAEL = 13.3 mg/kg/day based on : Adverse change in 

kidney function (chronic nephropathy) and kidney 

physiology (enlargement, dark color of kidney)

no evidence of carcinogenicity

870.5100

Salmonella 

typhimurium and 

Escherichia coli

Reverse Mutation 

Assay

46220933 (1987)

0, 20, 50, 100, 200, 500, 

1000 g/ plate (S. 

typhimurium); 0, 100, 

200, 500, 1000, 2000, 

5000 (E. coli) in the 

presence and absence of 

metabolic activation

(+ S9)

Acceptable/Guideline

Flazasulfuron was not cytotoxic with or without S9 

activation in four S. typhimurium strains and one strain of E. 

coli, and did not induce a genotoxic response in any strain.

Negative

870.5300

in vitro Mouse 

Lymphoma 

Mutagenesis Assay

46220930 (1993)

0, 20, 30, 40, 50, 60, 70, 

80, 90, 100, 500 g/ml 

in the presence and 

absence of metabolic 

activation 

(+ S9)

Acceptable/Guideline

There was no evidence of biologically significant induction 

of mutant colonies. 

Negative

870.5375

in vitro mammalian 

chromosome 

aberration test

46220931 (1988)

0, 3.3 x 10-4, 1.7 x 10-4, 

8.3 x 10-5, 4.1 x 10-5, 

2.1 x 10-5 M, with and 

without metabolic 

activation (+ S9) 

Acceptable/Guideline

Flazasulfuron did not induce chromosome aberrations in 

Chinese hamster lung cells, in the presence and absence of 

S9activation.

Negative

870.5395

in vivo Mammalian 

Erythrocyte 

Micronucleus Test: 

Mouse

46220932 (1995)

0, 1250, 2500, 5000 

mg/kg

Acceptable/Guideline

There was no statistically significant increase in the 

frequency of micronucleated polychromatic erythrocytes in 

mouse bone marrow at any dose or collection time.

Negative

870.6200a

Acute neurotoxicity 

screening battery

(rat)

46220934 (2002)

0, 50, 1000, 2000 

mg/kg/day

Acceptable pending data 

submission /Guideline

NOAEL (M/F) = 50 mg/kg

LOAEL = 1000 mg/kg based on: transient decrease in motor 

activity observed at Day 0 (5 hours post-dosing)
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.6200b

Subchronic 

neurotoxicity 

screening battery

(rat)

49030001(2012)

0, 300, 3000, or 10000 

ppm

(M) 0, 19, 190, 649 

mg/kg/day

(F) 0, 22, 229, 732 

mg/kg /day

Acceptable/Guideline

NOAEL = 19 / 229 mg/kg/day (M / F)

LOAEL = 190 / 732 mg/kg/day (M / F) based on decreased 

body weight and body weight gain.

870.7485

Metabolism and 

pharmacokinetics

(rat)

46220940 (1994), 

46220941 (1995), 

46220942 (1995), 

46220943 (1995)

single dose: 2, 50 mg/kg

multiple dose: 2 mg/kg

Radiolabel: 

(first ring: Pyridine

second ring: Pyrimidine)

Acceptable/Guideline

Radiolabeled flazasulfuron (Pyridine/Pyrimidine) was 

rapidly distributed and excreted in the urine and feces 

following multiple dosing. Urinary elimination, calculated 

from a total collection of 168 hours, occurred slower in 

males (74/73%) compared to females (90/91%). Fecal 

elimination, calculated from a total collection of 168 hours, 

was greater in males (23/23%) than in females (10/9%). 

Radiolabel was detected at low concentrations in carcass 

(M:1.7/1.1%; F:0.30/0.23%)), blood (M: 0.74/0.35%; F: 

0.16/0.02), liver (M: 0.23/0.14%; F: 0.04/0.04%), and 

kidney (M: 0.13/0.02%; F: 0.02/ <0.005%). Peak plasma 

concentration following single dose administration occurred 

at 6 hours in both sexes.

870.7800

Immunotoxicity 

(female mouse)

48870301 (2012)

0, 600, 3000, 6000 ppm, 

0, 122.5, 662.9, 1198.3 

mg/kg/day

Guideline classification 

not yet determined.

Systemic NOAEL = 1198 mg/kg/day

Systemic LOAEL = >1198 mg/kg/day, not established

Immunotoxicity NOAEL = 1198 mg/kg/day

Immunotoxicity NOAEL = not established

Preliminary assessment only. Detailed review pending

A.3 Executive Summaries

The executive summaries of the neurotoxicity studies represent new data and are presented below; 

the executive summaries of the other studies used in this risk assessment and/or appearing in Table 

A.2.2 are presented in a previous Risk Assessment document. Please refer to G.V. Burke, D303573, 

11/16/2005.

870.6200 Acute and Subchronic Neurotoxicity (rat) – two studies

MRID 46220934

In an acute neurotoxicity study (MRID 46220934), groups of 7-week old Sprague-Dawley rats 

(10/sex/group) were given a single oral dose by gavage of SL-160 (98.5 % a.i., batch/lot #303) in 

0.5% aqueous methylcellulose at doses of 0, 50, 1000, or 2000 mg/kg bw and observed for 14 days. 

Neurobehavioral assessment (functional observational battery and motor activity testing) was 

performed in 5 animals/sex/group. This assessment occurred on each of the four days, one week 

prior to the initiation of exposure, on Day 0 at five hours postdosing (the time of peak effect), and on 

Days 7 and 14 postdosing. At study termination, 5 animals/sex/group were euthanized and perfused 
Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 32 of 36

in situ for neuropathological examination. Of the perfused animals, all were subjected to

histopathological evaluation of brain and peripheral nervous system tissues. No deaths occurred 

during the study.

No abnormal clinical observations were recorded in male animals. Anogenital staining, decreased 

feces and dried red material around the eyes, mouth, and forepaws were observed on Days 1 through 

4 for two mid-dose and two high-dose females. Mean body weights for males and females in groups 

receiving the test material were not statistically significantly different from the controls at pre-test, 

pre-fast, or on Days 0, 7 and 14. There were no differences in the observations made as part of the 

FOB that were considered treatment related. Mean forelimb and hind limb grip strengths and mean 

foot-spread for males and females in groups receiving the test material showed no treatment-related 

differences from the controls at any of the observation times. Mean motor activity measurements for 

mid and high dose males and females were statistically significantly different from the respective 

control groups [Distance traveled measurement- M:(mid = 51.2% decrease), (high = 59.3% 

decrease); F: (high = 58.5% decrease)] on Day 0 (5 hours post-dosing). Animals were less active 

with more resting time than controls. The effect was reversed by the next scheduled observation 

(Day 7). Neurohistopathologic evaluation did not demonstrate any test material-related neurotoxic 

lesions following the examination of tissues from the central and peripherial nervous systems of high 

dose and control animals.

Based on the transient loss of motor activity observed in this study, the NOAEL was 50 mg/kg 

bw. The LOAEL was 1000 mg/kg bw.

This neurotoxicity study is classified as Acceptable /Guideline (pending submission of analytical 

data verifying homogeneity and stability.

Dose and Endpoint for Establishing aRfD: The NOAEL of 50 mg/kg bw based on the transient 

decrease in motor activity observed at Day 0 (5 hours post-dosing) at the LOAEL of 1000 

mg/kg bw was selected for the acute RfD.

MRID 49030001

In an subchronic neurotoxicity study (MRID 49030001), four groups of Crl:CD(SD) rats 

(12/sex/group; ~6 weeks of age) were administered 0, 300, 3000, or 10000 ppm of Flazasulfuron 

[98.95% (Lot No. 0208)] in the diet and observed for 90 days. The respective dose levels based on 

food consumption were 0, 19, 190, and 649 mg/kg bw/day for males and 0, 22, 229, and 732 mg/kg 

bw/day for females. Clinical examinations were conducted weekly, and a neurobehavioral 

assessment [functional observational battery (FOB) and motor activity (MA) testing] were

performed on all rats during weeks -1, 3, 7, and 12 (first week of administration = week 0). At study 

termination, all rats were euthanized and perfused in situ, tissues collected for possible 

neuropathological examination, and brain weights and brain measurements were conducted. The 

tissues collected from 6 rats/sex from the control and high dose groups were examined 

microscopically. 

There were no mortalities or test-substance-related clinical findings during the study. Statistically 

lower (p≤0.01) body weight (-18 to -22%) throughout the experimental period) and weight gain (for 
Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 33 of 36

the first half of the experimental period) were observed in males at the high dose beginning on day 7. 

Body weight tended to be somewhat lower relative to controls in females at the high dose (-8 to -

9%), but did not reach statistical significance (p≤0.05) until day 49. Weight gain in females at the 

high dose was statistically lower (p≤0.01) during the 0-7 day interval and the cumulative weight gain 

was lower (p≤0.05) at the end of the experimental period (-21%). Statistically lower weight gain 

(p≤0.01) was observed in males at the mid-dose during the 0-7 day interval, which resulted in a 5.2% 

lower body weight (not statistically significant). Statistically lower food consumption was observed 

in both males (p≤0.01) and females (p≤0.05) at the high dose throughout most of the experimental 

period as well as cumulatively at the end of the study. No statistically significant or test substancerelated FOB findings were observed in any of the Flazasulfuron-treated groups. Statistically higher 

(p<0.05) ambulatory counts were observed in females during separate intervals at 3000 ppm (51-60 

minutes, week 7) and at 10000 ppm (31-40 minutes and 51-60 minutes, week 7). The ambulatory 

findings in females were not toxicologically significant, since they were limited to week 7 and were 

not accompanied by associated FOB findings or by neuropathology results. There were no findings 

during the gross examination at necropsy, and no statistically significant or treatment-related 

differences in brain measurements in either sex. Sporadic instances of minimal axonal degeneration 

were observed in peripheral nerves and in spinal nerve roots (common background lesions). There 

were no test substance-related or other remarkable findings in the microscopic examination of 

neurological tissues.

Based on the body weight effects seen in this study, the LOAEL for Flazasulfuron in the diet 

was 3000 ppm for males (equivalent to 190 mg/kg bw/day ), and 10000 ppm for females 

(equivalent to 732 mg/kg bw/day) for subchronic neurotoxicity in Crl:CD(SD) rats. The 

NOAEL was 300 ppm for males (equivalent to 19 mg/kg bw/day), and 3000 ppm for females 

(equivalent to 229 mg/kg bw/day).

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

requirement for subchronic neurotoxicity study in rats (OCSPP 870.6200; OECD 424).
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Appendix B. Chemical Names and Structures for Flazasulfuron and its Metabolites

Chemical Names and Structures for Flazasulfuron and its Metabolites

Common name/code Chemical name Chemical structure

Flazasulfuron/SL-160 N-[[4,6-dimethoxy-2-

pyrimidinyl)amino]carbonyl]-3-

(trifluoromethyl)-2-

pyridinesulfonamide

ADMP 2-amino-4,6-dimethoxypyrimidine

DTPU N-(4,6-dimethoxy-2-pyrimidinyl)-N-

[3-(trifluoromethyl)-2-pyridinyl]urea

DTPP 4,6-dimethoxy-N-[3-

(trifluoromethyl)-2-pyridinyl]-2-

pyrimidinamine

HTPP 6-methoxy-2-[[3-(trifluoromethyl)-2-

pyridinyl]amino]-4-pyrimidinol

TPSA 3-(trifluoromethyl)-2-

pyridinesulfonamide
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2,3-GTF 3-trifluoromethyl-2-pyridylguanidine
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Appendix C. Physical/Chemical Properties of Flazasulfuron

Physico-Chemical Properties of Flazasulfuron

Parameter Value Reference

Melting point 150°C MRID 46220905

pH 4.01 at 25°C (1% w/w)

Density 0.66 g/cm3at 25°C (bulk density)

Water solubility (25C) pH 5 buffer 0.027 mg/mL

pH 7 buffer 2.1 mg/mL

pH 9 buffer not stable

Solvent solubility (25C) Acetone 22.7 mg/mL

Acetonitrile 8.7 mg/mL

Dichloromethane 22.1 mg/mL

Ethyl acetate 6.9 mg/mL

Hexanes* 0.50 μg/mL

Methanol 4.2 mg/mL

Octanol 0.20 mg/mL

Toluene 0.56 mg/mL

Vapor pressure <1 x 10-7 mmHg (<1.33 x 10-5 Pa) at 25, 35, 

and 45°C

Dissociation constant (pKa) at 20°C 4.37 

Octanol/water partition coefficient 

KOW at 25°C

Kow = 20.0 in pH 5 buffer

Kow = <10 in pH 7 buffer

UV/visible absorption spectrum Not reported

*n-hexane with various methylpentanes