Flazasulfuron Human Health Risk Assessment DP No. 372903

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

MEMORANDUM

Date: June 12, 2011

SUBJECT: Flazasulfuron: Human Health Risk Assessment for Proposed Uses on Citrus, 

Grapes, Sugarcane, Christmas Trees, and Industrial Vegetation Management

PC Code: 119011 DP Barcode: D372903

Decision No.: 425253 Registration No.: 71512-RI

Petition No.: 9F7666 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single 

Chemical/Aggregate

Case No.: NA

TXR No.: NA CAS No.: 104040-78-0

MRID No.: NA 40 CFR: 180.xxx (pending)

FROM: Cassi L. Walls, Ph.D., Senior Biologist

Myron S. Ottley, Ph.D., Toxicologist

Nancy Dodd, Chemist

Kristin Rury, Biologist

Risk Assessment Branch III (RAB3)

Health Effects Division (7509P)

THROUGH: Paula Deschamp, Branch Chief 

RAB3/HED (7509P)

TO: Hope Johnson/Kable Davis, RM#25

Registration Division (7505P)
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1.0 Executive Summary................................................................................................................. 4

2.0 Regulatory Conclusions and Recommendations................................................................... 7

2.1 Data Deficiencies/Conditions of Registration .................................................................... 7

2.2 Tolerance Considerations.................................................................................................... 8

2.2.1 Enforcement Analytical Method ..................................................................................... 8

2.2.2 International Harmonization........................................................................................... 9

2.2.3 Recommended Tolerances............................................................................................... 9

2.2.4 Revisions to Petitioned-For Tolerances.......................................................................... 9

2.3 Label Recommendations...................................................................................................... 9

2.3.1 Recommendations from Residue Reviews...................................................................... 9

2.3.2 Recommendations for Worker Safety .......................................................................... 10

2.3.3 Recommendations for Residential Safety..................................................................... 10

3.0 Ingredient Profile................................................................................................................... 10

3.1 Structure and Nomenclature............................................................................................. 10

3.2 Physical/Chemical Characteristics ................................................................................... 11

3.3 Summary of Existing/Proposed Uses................................................................................ 11

4.0 Hazard Characterization and Dose-Response Assessment................................................ 13

4.1 Toxicology Studies Available for Analysis....................................................................... 13

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)................................... 14

4.2.1 Dermal Absorption......................................................................................................... 15

4.3 Toxicological Effects .......................................................................................................... 15

4.4 Safety factor for Infants and Children (FQPA Safety Factor) ...................................... 16

4.4.1 Completeness of the Toxicology Database.................................................................... 16

4.4.2 Evidence of Neurotoxicity.............................................................................................. 16

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.............. 16

4.4.4 Residual Uncertainty in the Exposure Database ......................................................... 17

4.5 Toxicity Endpoint and Point of Departure Selections.................................................... 17

4.5.1 Dose-Response Assessment............................................................................................ 17

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment........... 18

4.5.3 Cancer Classification and Risk Assessment Recommendation.................................. 18

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment..................................................................................................................................... 18

4.6 Endocrine Disruption......................................................................................................... 21

5.0 Dietary Exposure and Risk Assessment............................................................................... 21

5.1 Metabolite/Degradate Residue Profile ............................................................................. 21

5.1.1 Summary of Plant and Animal Metabolism Studies................................................... 21

5.1.2 Summary of Environmental Degradation.................................................................... 22

5.1.3 Comparison of Metabolic Pathways............................................................................. 22

5.1.4 Residues of Concern Summary and Rationale ............................................................ 23

5.2 Food Residue Profile .......................................................................................................... 25

5.3 Water Residue Profile........................................................................................................ 26

5.4 Dietary Risk Assessment.................................................................................................... 26

5.4.1 Description of Residue Data Used in Dietary Assessment.......................................... 26

5.4.2 Percent Crop Treated Used in Dietary Assessment .................................................... 26

5.4.3 Acute Dietary Risk Assessment..................................................................................... 26

5.4.4 Chronic Dietary Risk Assessment................................................................................. 27
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5.4.5 Cancer Dietary Risk Assessment................................................................................... 27

5.4.6 Summary Table............................................................................................................... 27

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................... 28

6.1 Residential Handler Exposure .......................................................................................... 28

6.2 Post-Application Exposure................................................................................................ 28

6.3 Combined Exposure........................................................................................................... 29

6.4 Spray Drift.......................................................................................................................... 29

7.0 Aggregate Exposure/Risk Characterization........................................................................ 29

7.1 Acute Aggregate Risk......................................................................................................... 29

7.2 Short- and Intermediate-Term Aggregate Risk .............................................................. 29

7.3 Chronic Aggregate Risk .................................................................................................... 30

7.4 Cancer Aggregate Risk ...................................................................................................... 30

8.0 Cumulative Exposure/Risk Characterization ..................................................................... 30

9.0 Occupational Exposure/Risk Characterization .................................................................. 30

9.1 Short-/Intermediate-Term Handler Risk......................................................................... 30

9.2 Short-/Intermediate-Term Post-Application Risk .......................................................... 33

10.0 Environmental Justice Considerations................................................................................ 33

11.0 References............................................................................................................................... 34

Appendix A. Toxicology Profile and Executive Summaries ........................................................ 35

A.1 Toxicology Data Requirements......................................................................................... 35

A.2 Toxicity Profiles.................................................................................................................. 36

A.3 Hazard Identification and Endpoint Selection................................................................ 39

A.4 Executive Summaries......................................................................................................... 39

A.5 Endpoint Selection Worksheet: Flazasulfuron................................................................ 40

Appendix B. Metabolism Summary Table ..................................................................................... 44

Appendix C. Review of Human Research...................................................................................... 47

Appendix D. International Residue Limits.................................................................................... 48

Appendix E. Chemical Names and Structures for Flazasulfuron and its Metabolites.............. 49
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1.0 Executive Summary

Use Profile: ISK BIOSCIENCES CORPORATION (ISK) has proposed first new food uses for 

flazasulfuron on citrus, grapes and sugarcane as well as uses on Christmas trees and industrial 

vegetation management areas. It is currently registered for use on non-residential turf such as golf 

courses, sod farms, athletic fields, and commercial lawns. 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 relevant for this petition is ISK Flazasulfuron Herbicide which is a water 

dispersible granular (WDG/WG) formulation containing 25% active ingredient (ai). Soil directed 

spray application for citrus and grapes and over-the-top applications and post-directed applications 

for sugarcane are proposed at a maximum seasonal rate of 0.15 lb ai/A. Over-the-top and soil 

directed spray applications are proposed for Christmas trees at rates of 0.033 – 0.045 lb 

ai/A/application. Application rates for vegetation management in nonagricultural areas are proposed 

at 0.047 lb ai/A/application where these applications may not be made near residential properties or 

near sensitive desired plants.

Human Health Risk Assessment:

In the longer-term studies of the mammalian toxicology database, the kidney and liver were the 

primary target organs of flazasulfuron toxicity. Subchronic studies in animals indicated decreased 

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

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

in motor activity 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) 

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). Although there was a 21-day dermal study, 

no effects were seen up to the limit dose (1000 mg/kg/day). Therefore, no dermal hazard was 

identified. 

Based on the lack of carcinogenic effects in the two-year combined chronic toxicity and 

carcinogenicity studies, flazasulfuron is classified as “no evidence of carcinogenicity to humans”.

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. 

Dietary Exposure (Food/Water):

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 
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through food and drinking water. No residues of parent were found in field trials on/in citrus, grapes

and sugarcane field trials or processed commodities after treatment at an exaggerated rate (10x the 

seasonal application rate). The estimated drinking water concentrations (EDWCs) were determined 

for ground water and surface water; 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 proposed crops and 

100% crop treated (CT). DEEMTM default processing factors were used. The ground water 

estimated drinking water concentration (EDWC) of 102 μg/L resulting from the Tier II PRZM-GW 

model 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 1.1% of 

the aPAD for the general U.S. population and 4.0% 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 proposed crops and 

100% crop treated (CT). DEEMTM default processing factors were used. The ground water 

estimated drinking water concentration (EDWC) of 102 μg/L resulting from the Tier II PRZM-GW 

model 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 17% of the 

cPAD for the general U.S. population and 54% of the cPAD for all infants (<1 year old), the most 

highly exposed population subgroup. 

Residential Exposure:

This document only presents the assessment of the proposed new agricultural uses of flazasulfuron. 

No residential uses are being requested at this time; therefore, a residential risk assessment has not

been conducted.

Flazasulfuron is currently registered for use on golf courses and other non-residential turf areas such 

as industrial parks, tank farms, sod farms, seed farms, and professionally managed sports fields. 

However, since no hazard was identified for the dermal route of exposure, dermal risks were not 

assessed. 
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Aggregate Risk:

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 at the 95th percentile are 1.1% of the aPAD for the general U.S. population and 4.0% of 

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

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 17% of the cPAD for the general U.S. population and 54% of the cPAD for 

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

Short- and Intermediate Term: There is potential short-term exposure to flazasulfuron via the dietary 

pathway (which is considered background exposure) and the post-application dermal residential 

pathway (which is considered the primary pathway). However, since no hazard was identified for 

the dermal route of exposure, short- and intermediate-term aggregate risks were not assessed. 

Furthermore, for children, exposure includes only food and drinking water since dermal and 

incidental oral exposure to children from treated golf and athletic field turf is considered to be 

negligible.

Cancer: 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.

Occupational Exposure/Risk:

Agricultural Handlers: Occupational short-term (1 - 30 days) and intermediate-term (1 - 6 months) 

dermal and inhalation exposures are expected from flazasulfuron handler activities associated with 

both the proposed agricultural and ornamental uses. HED used data from the Pesticide Handlers 

Exposure Database (PHED) Version 1.1 as presented in the PHED Surrogate Exposure Guide (8/98) 

to assess handler exposures (HED Science Advisory Council for Exposure (ExpoSAC) Standard 

Operating Procedure (SOP) No. 7, dated 01/28/1999). Since no hazard was identified for the dermal 

route of exposure, dermal risks were not assessed. A Margin of Exposure (MOE) 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) (i.e., MOEs ≥ 100) for 

inhalation exposures and, therefore are not of concern. 

Agricultural Post-application: Occupational short- and intermediate-term dermal exposures are 

expected from post-application activities. However, since no hazard was identified for the dermal 

route of exposure, dermal risks were not assessed

Environmental Justice Considerations: Potential areas of environmental justice concerns, to the 

extent possible, were considered in this human health risk assessment. Dietary and non-dietary 

exposures were considered.
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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 studies 

(listed in Appendix C) have been determined to require a review of their ethical conduct, and one of 

these studies is also subject to review by the Human Studies Review Board. All of the listed studies 

have received the appropriate review.

2.0 Regulatory Conclusions and Recommendations

Provided revised Sections B (OPPTS 860.1200) and F (OPPTS 860.1550) are submitted, HED can 

recommend for a conditional registration of flazasulfuron for use on Christmas trees and for 

industrial vegetation management, and permanent tolerances for the proposed uses of flazasulfuron

on citrus, grapes, and sugarcane. Additional data are needed as conditions of registration as outlined 

in Section 2.1 below. The specific tolerance recommendations are discussed in Section 2.2, and 

label modifications are discussed in Section 2.3.

2.1 Data Deficiencies/Conditions of Registration

The following must be provided prior to a tolerance being established or registration allowed:

A revised Section B is requested to clarify/revise the minimum retreatment interval (RTI). 

The general label application restrictions state that repeat applications may be made at 2 to 6 

weeks after application. However, the label also states that split applications should be made 

at 4 to 6 weeks after the first application, and that sequential applications are made on a 

longer term interval such as spring followed by a fall application. The petitioner should also 

consider that the label directions regarding the RTI should reflect the field trials. The 

retreatment intervals in the field trials were 95-308 days for citrus and 14-118 days for 

grapes. Based on the residue data, the retreatment interval should be at least 3 months for 

citrus and at least 2 weeks for grapes. 

860.1200 Directions for Use

Note: The proposed label for sugarcane requires a 12-month interval between the last 

application and the planting of the rotational crop. While HED considers this restriction to 

be adequate for conditional registration of flazasulfuron based on the fact that no detectable 

residues of flazasulfuron were found in the primary crops, the restriction will need to be reevaluated after submission and review of the confined rotational crop study which is required 

to support permanent registration of sugarcane.

A revised Section F must be submitted to reflect tolerances with correct commodity 

definitions as listed in Table 2.2.4.

860.1550 Proposed Tolerances
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The following data are required as a condition of registration:

TOXICOLOGY

The subchronic neurotoxicity screening battery is required to fulfill current 40 CFR Part 158 

data requirements. 

870.6200 Neurotoxicity Battery (Subchronic Studies) 

The immunotoxicity study is required to fulfill current 40 CFR Part 158 data requirements. 

870.7800 Immunotoxicity

RESIDUE CHEMISTRY

Multiresidue methods data must be submitted since tolerances will be established. 

860.1360 Multiresidue Methods

For MRID 47939903 (Howald, M., Ullrich-Mitzel, A. (1997) Storage Stability of SL-160 

Residues in Grapes. Document Number: 634713), the dates of sample spiking and analysis 

must be submitted to verify reported storage intervals.

860.1380 Storage Stability Data

A confined rotational crop study is required to support permanent registration of sugarcane. 

Depending on the results, a study to determine field accumulation in rotational crops may be 

required.

860.1850/860.1900 Confined/Field Accumulation in Rotational Crops

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Flazasulfuron is not listed in the FDA PESTDATA database (Pesticide Analytical Manual, Volume 

I, Appendix I, 3rd edition, 1994, revised October 1999); therefore, a multiresidue method study must 

be submitted. 

Adequate residue analytical methodology is available for tolerance enforcement. The method uses 

high performance liquid chromatography/tandem mass spectrometry with multiple reaction 

monitoring (HPLC/MS-MS/MRM) (ADME study code S09-03106; MRID 48092201). 

Adequate residue analytical methodology is available for data collection. In the field trials and 

processing studies submitted, residues of flazasulfuron and/or DTPU were determined using an 

adequate HPLC-MS/MS method from Central California Research Laboratories, Inc., titled 

“Analytical Method for Determination of SL-160 and Its Metabolite in Soil” (CCRL-MTH-045).
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2.2.2 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. An International Residue Limit Status sheet is attached (Appendix D).

2.2.3 Recommended Tolerances

HED recommends for the following tolerances and residue definition:

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

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

specified below is to be determined by measuring only flazasulfuron (N-[[(4,6-dimethoxy-2-

pyrimidinyl)amino]carbonyl]-3-(trifluoromethyl)-2-pyridinesulfonamide).”

Fruit, citrus, group 10-10 .........................................0.01 ppm

Grape........................................................................0.01 ppm

Sugarcane.................................................................0.01 ppm

2.2.4 Revisions to Petitioned-For Tolerances

Table 2.2.4 compares proposed and recommended tolerance levels. The recommended tolerance 

levels are based on the submitted magnitude of the residue data. The Agency’s tolerance 

spreadsheet from the Guidance for Setting Pesticide Tolerances Based on Field Trial Data was not 

used because all of the treated samples bore residues below the LOQ.

Table 2.2.4. Tolerance Summary for Flazasulfuron

Commodity Established/Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Citrus 0.01 0.01 Fruit, citrus, group 10-10

Grapes 0.01 0.01 Grape

Sugarcane 0.01 0.01

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

A revised Section B/label is requested for ISK Flazasulfuron Herbicide (EPA File Symbol 71512-

RI) to clarify/revise the minimum retreatment interval. The general label application restrictions 

state that repeat applications may be made at 2 to 6 weeks after application. However, the label also 

states that split applications should be made at 4 to 6 weeks after the first application, and that 

sequential applications are made on a longer term interval such as spring followed by a fall 

application. The label directions regarding the retreatment interval should reflect the field trials. 

The retreatment intervals in the field trials were 95-308 days for citrus and 14-118 days for grapes. 

Based on the residue data, the retreatment interval should be at least 3 months for citrus and at least 

2 weeks for grapes. 
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2.3.2 Recommendations for Worker Safety

The ISK Flazasulfuron Herbicide label proposes a 4-hour reduced reentry interval (REI). In 

accordance with criteria for reduced REI candidates, an active ingredient cannot elicit reproductive, 

developmental, neurotoxic or carcinogenic effects. Flazasulfuron elicits developmental effects, and 

therefore cannot be a candidate for a reduced REI. Per the Worker Protection Standard (WPS), 

chemicals classified as Toxicity Categories III and IV require a 12-hr restricted entry interval (REI). 

HED recommends that RD ensure that the REI on the label be corrected to 12 hours.

2.3.3 Recommendations for Residential Safety

There are currently no residential uses being proposed at this time.

3.0 Ingredient Profile

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

pyridinesulfonaminde] 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. 

ISK has proposed the first food/feed uses for flazasulfuron on in citrus, grapes, and sugarcane, as 

well as, uses on Christmas trees and industrial vegetation management in nonagricultural areas. 

Flazasulfuron is currently registered for use on golf courses and other non-residential turf areas.

The flazasulfuron end-use product relevant for this petition is ISK Flazasulfuron Herbicide which is 

formulated as a water dispersible granular (WDG/WG) formulation containing 25% active 

ingredient (ai). The product is proposed for use on citrus, grapes, and sugarcane at a maximum 

single application rate of 0.045 lb ai/A or a maximum seasonal application rate of 0.15 lb ai/A. The 

use of a non-ionic surfactant is recommended for post-emergence applications to citrus and grapes. 

The pre-harvest intervals (PHIs) for these crops are 1 day for citrus, 75 days for grapes, and 180 days 

for sugarcane. 

3.1 Structure and Nomenclature

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
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Table 3.1 Flazasulfuron Nomenclature

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, a WDG/WG formulation containing 25% active ingredient (ai)

(EPA File Symbol 71512-RI), for use on citrus, grapes, and sugarcane; Flazasulfuron 25WG 

(EPA Reg. No 71512-12), registered on turf

3.2 Physical/Chemical Characteristics

Table 3.2 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/cm3 at 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 torr (<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

3.3 Summary of Existing/Proposed Uses

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

for flazasulfuron. However, in the U.S., flazasulfuron is currently registered to control annual and 

perennial grasses, sedges, and broadleaf weeds on golf courses and other non-residential turf areas 

such as industrial parks, tank farms, sod farms, seed farms, and professionally managed sports fields. 

The formulated end use product is a water dispersible granule, also called dry flowable, containing 

25% flazasulfuron.

ISK Biosciences Corporation has proposed the first food/feed uses for flazasulfuron on citrus, 

grapes, and sugarcane, as well as, uses on Christmas trees and industrial vegetation management in 

nonagricultural areas as summarized in Table 3.3 below. The flazasulfuron end-use product relevant 

for this petition is ISK Flazasulfuron Herbicide which is formulated as a water dispersible granular 

(WDG/WG) containing 25% active ingredient (ai). 
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The submitted label for ISK Flazasulfuron Herbicide (EPA File Symbol 71512-RI) is adequate to 

allow evaluation of the residue data relative to the proposed uses. Refer to Section 2.3 for 

recommended modifications to the proposed label. 

Table 3.3 Summary of Directions for Use of Flazasulfuron 

Applic. Timing, 

Type, and Equip.

Application 

Rate 

(lb ai/A)

Max. No. 

Applications 

per Season

Max. Seasonal 

Application 

Rate

(lb ai/A)

Minimum 

RTI 

(days)

PHI

(days) Use Directions and Limitations

Citrus

Pre-emergence and 

Post-emergence; 

Soil application 

using ground spray 

equipment

0.045 Not reported 0.15 Not 

reported1 1

Apply only as a directed spray to the 

soil beneath the trees. 

Use a non-ionic surfactant at 0.25% v/v 

for post-emergence applications.

Grapes

Pre-emergence and 

Post-emergence; 

Soil application 

using ground spray 

equipment

0.045 Not reported 0.15 Not 

reported1 75

Apply only as a directed spray to the 

soil beneath the vines. 

Use a non-ionic surfactant at 0.25% 

v/v.

Sugarcane

Over-the-Top or 

Post-directed 0.023 Not reported 0.15 14 180

Apply prior to spiking or on ratoon up 

to 24 inches tall at a 0.014 lb ai/A rate.

Use a non-ionic surfactant at 0.25% 

v/v.

Allow a 12 month interval between the 

last application and the planting of the 

rotational crop.

Post-Directed 0.045 Not reported 0.15 14 180

Apply to sugarcane that is 18 inches tall 

up through layby. Applications should 

minimize contact with the whorl of the 

sugarcane.

Use a non-ionic surfactant at 0.25% 

v/v.

Allow a 12 month interval between the 

last application and the planting of the 

rotational crop.

Christmas Trees
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Table 3.3 Summary of Directions for Use of Flazasulfuron 

Applic. Timing, 

Type, and Equip.

Application 

Rate 

(lb ai/A)

Max. No. 

Applications 

per Season

Max. Seasonal 

Application 

Rate

(lb ai/A)

Minimum 

RTI 

(days)

PHI

(days) Use Directions and Limitations

Pre-emergence and 

Post-emergence 0.045 Not reported Not reported Not 

reported NA

Do not apply to conifer seedbeds. Do 

not apply to trees within 1 year of 

seeding. May be applied over-the-top 

to conifers prior to spring bud break or 

when conifers are sufficiently hardened

off. Directed sprays must be made to 

conifers that have new growth or are 

not sufficiently hardened off. Directed 

sprays are preferred and recommended 

to reduce phytotoxicity potential

Use a non-ionic surfactant at 0.25% 

v/v.

Industrial Vegetation Management

Post-emergence 0.047 Not reported Not reported

4 to 6 

weeks NA

Do not use near residential properties.

Use a non-ionic surfactant at 0.25% 

v/v. 1 A retreatment interval specifically for citrus and grapes was not provided. A generic retreatment interval was provided.

General application information on the label states that pre-emergence and post-emergence 

applications should be made in 15 to 50 gallons of water per acre. For directed post-emergence 

sprays, a spray volume of 20 gallons or more per acre is recommended. Applications should be 

made using conventional low pressure ground spray equipment. Applications cannot be made 

aerially or through any irrigation system. The general label application restrictions also state that 

repeat applications may be made at 2 to 6 weeks after application. However, the label also states 

that split applications should be made at 4 to 6 weeks after the first application, and that sequential 

applications are made on a longer term interval such as spring followed by a fall application. 

4.0 Hazard Characterization and Dose-Response Assessment

Flazasulfuron belongs to the pyrimidinylsulfonylurea class of herbicides and controls weeds by 

inhibiting the acetolactate synthase (ALS) biochemical process. Since ALS is a component in 

synthesis of some essential amino acids, weed survival and growth are inhibited. A direct 

correlation of this mode of action in plants to a mode of action in mammals is not clear because ALS 

is not present in mammals.

4.1 Toxicology Studies Available for Analysis

The existing database is deemed sufficient for characterizing the hazard of flazasulfuron. The 

database contains studies evaluating toxicity following oral exposure in rats, mice, dogs and rabbits 

and dermal exposure in rabbits, which help to characterize toxicity associated with oral, dermal, and 

inhalation exposure routes in humans.
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The available studies consist of an acute neurotoxicity study in the rat; 90-day oral studies in the rat 

and dog and a 21-day dermal study in the rabbit; developmental studies in the rat and rabbit and a 

multi-generation study in the rat; chronic and/or cancer studies in the rat and mouse; a battery of in 

vitro and in vivo mutagenicity studies; and a battery of metabolism and pharmacokinetics studies in 

the rat.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Absorption. Differences in absorption rates were generally not noted between dose levels or 

between single versus repeated dose administration, but were noted between males and females. The 

bile cannulation study, demonstrated that Flazasulfuron [

14C-SL-160(P)] is rapidly absorbed 

following a single oral dose of 2 or 50 mg/kg. By 48 hours post exposure, males and females 

absorbed 94% and 93% of the low dose, respectively, and 86% and 93% of the high dose, 

respectively. A similar pattern was observed when low- and high-dose animals were followed up to 

168 hours with little differences being noted between a single or repeated exposure. Tmax values of 

30 minutes to 6 hours were dose and sex dependent, being shorter at low doses and in females. T1/2

in blood ranged from 18.8 to 36 hours and was slightly shorter in females.

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

concentrations (0.03- 1.0 % of dose depending on tissue, dose regimen, and sex) while the carcass 

had up to 2.5% of the administered dose. These findings might be explained by binding of some of 

the radiolabel to tissue macromolecules such as proteins and/or DNA. In general, the pattern of 

radiolabel distribution in tissues seemed to be similar irrespective of the dosing regimen.

Metabolism. In the single and repeated dose studies, the parent compound was the primary 

component in the metabolite profiles for urine (males: 19-40%; females: 51-67% of administered 

dose), with lesser amounts in feces (males and females: 2-5% of administered dose), and bile (males 

and females: 0.6-2% of administered dose). Including parent compound, up to 11 fractions were 

detected among these matrices. The most prevalent metabolite (expressed as percent of administered 

dose) was HDTG-i-TPPG (—6.5-12% in urine, —0.4-2% in feces, and —6.5-14% in bile), with 

minor amounts (<5%) of DTPU, HDPU, HTTP, TPSA, and MTMG. Individually, unidentified 

fractions generally accounted for less than 2% of the administered dose in the urine and biliary 

metabolite profile. The fecal metabolite profile had up to 35% unidentified of the recovered fecal 

radiolabel. In aquatic and soil environmental simulation media, there were several hydrolysis 

products that were generated from SL-160 including DTPU, DTPP, HTPP, TPSA, and ADMP all of 

which were either identified as isolated rat metabolites or as an intermediate metabolite (DTPP).

Elimination. 14C-SL-160(P) is rapidly, though not completely, excreted from the animal; total body 

burdens at seven days post dosing were equal to or less than 4% and 1% of the administered 

radioactivity in males and females, respectively. Elimination via the urine was the major route of 

excretion, accounting for 74-80% and 90-94% in males and females, respectively, irrespective of 

dosing regimens with a significant portion of the radioactivity being excreted within 48-72 hrs. 

Feces were the secondary route of elimination, accounting for 21- 24% and 9-10% in males and 

females, respectively, following both low- and high-dose and single and repeated dose 

administration. The biliary excretion study determined that, relative to the administered dose, 9.5% 
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of appeared in bile by 48 hours in low-dose males and low- and high-dose females while 16.5% 

appeared in the high-dose males. 

4.2.1 Dermal Absorption

No dermal absorption study is available for flazasulfuron. However, a 21-day dermal toxicity study

(rabbit) was submitted. In this study, no systemic toxicity occurred at the limit dose (1000 

mg/kg/day) and the primary toxic effects of concern were adequately assessed in the study. In the 

absence of a dermal absorption study, a conservative dermal absorption factor (DAF) was estimated 

based on available oral and dermal toxicity data. HED estimated a DAF of no more than 45% based 

on the ratio of the LOAEL from the oral rabbit developmental study (450 mg/kg/day) and the 

NOAEL from the 21-day dermal toxicity study in rabbits (1000 mg/kg/day). This is a conservative 

estimate because the 21-day dermal study did not present an adverse effect at the highest dose tested 

in order to produce a LOAEL.

 Dermal Absorption Factor (DAF) = 450 mg/kg/day (LOAEL)

 1000 mg/kg/day (NOAEL) 

 x 100 = 45%

4.3 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 kidney physiology (enlargement, dark color of kidney), increases in liver weight 

and 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 be associated with neurotoxicity.

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.

Flazasulfuron exhibits low acute toxicity in rats and rabbits. The oral LD50 is greater than 5000 

mg/kg, the acute inhalation LD50 is greater than 4.0 mg/L, and the acute dermal LD50 is greater than 
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2000 mg/kg. All studies are in Toxicity Category III or IV. Flazasulfuron is not irritating to the skin 

or eyes and is not a sensitizer.

4.4 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.

4.4.1 Completeness of the Toxicology Database

The toxicity database for flazasulfuron is complete except for an immunotoxicity study (OPPTS 

Guideline 870.7800), and a subchronic neurotoxicity study (OPPTS Guideline 870.6200b). These 

studies are now requirements under 40 CFR §158.500 for pesticide registration. In the absence of 

specific immunotoxicity and subchronic neurotoxicity studies, HED has evaluated the available 

flazasulfuron toxicity database to determine whether an additional database uncertainty factor is 

needed to account for potential immunotoxicity or neurotoxicity. 

With the exception of a transient decrease in motor activity at a high dose level (1000 mg/kg/day) in 

the acute neurotoxicity study, which may be associated with a systemic effect, there is no evidence 

of neurotoxicity. There is no evidence of immunotoxicity in the database, as indicated by 

hematology, lymphoid organ weights and histopathology in standard studies. 

Consequently, HED believes the existing data are 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.

4.4.2 Evidence of Neurotoxicity

A guideline 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 different 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 

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

As previously mentioned, the acute neurotoxicity study demonstrated reversible adverse effects at 

high dose levels, with no accompanying histopathologic changes, and these effects may be 

associated with systemic toxicity and not neurotoxicity. The available subchronic and chronic data 

did not show any adverse effects that could be considered as neurotoxicity.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal
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The available data indicate that flazasulfuron produced developmental and reproductive effects only 

at maternally/parentally toxic dose levels. 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 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.

4.4.4 Residual Uncertainty in the Exposure Database

Data have been requested to verify the reported storage intervals in the grape storage stability study. 

Also, a confined rotational crop study has been requested for a permanent registration. Although 

these data have been requested, there are no residual uncertainties in the exposure database for the 

following reasons: 

Grape Storage Stability Study: Dates of sample spiking and analysis in the grape storage 

stability study are required only to confirm the reported storage intervals.

Confined Rotational Crop Study: The 12-month plant-back restriction on the sugarcane label 

will be adequate for a conditional registration.

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 and default processing factors, 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 exposure to flazasulfuron. Similarly, HED does not believe that the non-dietary 

occupational exposures are underestimated because they are also based on conservative assumptions,

including maximum application rates, labeled PPE, and standard values for unit exposures, acreage 

treated/amount handled.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

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

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

study with a transient decrease in motor activity at 1000 mg/kg/day. This endpoint is a single-dose 

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.
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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 

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.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Residential or occupational exposures from different routes (dermal, oral, and inhalation) can be 

combined if the toxicological effects are the same. Because the same toxicity study (and same 

effect) was used to select the endpoint for the oral and inhalation routes, these routes of exposure can 

be combined to estimate aggregate risk. 

4.5.3 Cancer Classification and Risk Assessment Recommendation

Based on lack of carcinogenic effects in the rat and mouse carcinogenicity studies and lack of a 

mutagenicity concern, flazasulfuron can be classified as “No evidence of carcinogenicity to 

humans”.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

The selection of toxicity endpoints and points of departure is presented in the previous risk 

assessment (D303573, G. Burke, 11/16/2005). The short-term incidental oral and occupational, 
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and the dermal endpoints have been updated for this risk assessment and the rationales presented in 

an attached Worksheet (see Appendix A.5). The current endpoints are summarized in Tables 4.5.4a 

and b.

Table 4.5.4a. Summary of Toxicological Doses and Endpoints for Flazasulfuron for Use in Residential and 

Non-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/day

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/day 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

Residential:

LOC for MOE = 

100

90-Day oral toxicity in (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)

NOAEL = 

N/A

UFA = N/A

UFH = N/A

Residential:

LOC for MOE = 

N/A

21-day Dermal study

NOAEL > 1000 mg/kg/day.

No hazard was identified at the limit dose 

following dermal exposure and there are no 

concerns for developmental or neurotoxicity; 

therefore, there is no risk potential for this 

exposure scenario.

Inhalation 

Short-Term

(1 - 30 days)

And 

IntermediateTerm

(1 - 6 

months)

NOAEL = 2 

mg/kg/day

(inhalation 

absorption 

rate = 100%)

UFA = 10x

UFH = 10x

Residential:

LOC for MOE = 

100

90-Day oral toxicity in (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
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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 

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

applicable.

Table 4.5.4b. Summary of Toxicological Doses and Endpoints for Flazasulfuron for Use in 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

Dermal 

Short-Term

(1 - 30 days)

IntermediateTerm

(1-6 months)

NOAEL = 

N/A

UFA = N/A

UFH = N/A

Residential:

LOC for MOE = 

N/A

21-day Dermal study

NOAEL > 1000 mg/kg/day.

No hazard was identified at the limit dose 

following dermal exposure and there are no 

concerns for developmental or neurotoxicity; 

therefore, there is no risk potential for this 

exposure scenario.

Inhalation 

Short-Term

(1 - 30 days)

And 

IntermediateTerm

(1 - 6 

months)

NOAEL = 2 

mg/kg/day

(inhalation 

absorption 

rate = 100%)

UFA = 10x

UFH = 10x

Occupational:

LOC for MOE = 

100

90-Day oral toxicity in (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 

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 
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an inhalation toxicity study for flazasulfuron and/or a reexamination of the inhalation toxicity risk 

assessment.

4.6 Endocrine Disruption

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

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

ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally 

occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP 

employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a 

battery of 11 screening assays to identify the potential of a chemical substance to interact with the 

estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 

screening and are found to have the potential to interact with E, A, or T hormonal systems will 

proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests 

are necessary based on the available data. Tier 2 testing is designed to identify any adverse 

endocrine related effects caused by the substance, and establish a dose-response relationship

between the dose and the E, A, or T effect.

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

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

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

food and water, residential activity, and certain post-application agricultural scenarios. This list 

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

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

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

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

pesticide active ingredients. 

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

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

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

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

PRIMARY CROPS: Acceptable metabolism studies on grapes, sugarcane, and tomatoes are 

available. Residues of the parent (flazasulfuron) were not detected in the tomato study and were 

only detected as a trace or minor component in the grape and sugarcane studies. The major 

metabolites (>10% total radioactive residues [TRR]) which were identified were DTPU in grape 

leaves and grape fruit, DTPP in grape leaves, and HTPP (primarily conjugated) and TPSA in tomato 

fruit. There were no major metabolites (>10% TRR) in sugarcane but the primary minor metabolites 

(<10% TRR) were HTPP, TPSA, and ADMP. (Refer to Appendix E for chemical names and 
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structures). The metabolic pathways for grapes, tomatoes, and sugarcane are similar. The pathways 

involve intramolecular rearrangement of the sulfonylurea bridge to form DTPU, followed by 

hydrolysis to form DTPP and HTPP, and cleavage of the sulfonylurea bridge to form TPSA and 

ADMP.

ROTATIONAL CROPS: There are no rotational crop data requirements associated with the use on 

citrus or grapes (OPPTS 860.1850). The rotational crop guidelines are applicable for sugarcane; 

however, rotational crop data have not been submitted. The proposed label for sugarcane specifies a 

12-month interval between the last application and the planting of the rotational crop in the absence 

of rotational crop data.

RUMINANTS: An acceptable goat metabolism study is available. The major metabolites identified 

in goat kidney were the parent (flazasulfuron), HTPP, and DTPU. HTPP was the major residue in 

goat liver and muscle. Parent was not found in goat liver and muscle. DTPP was identified as a 

minor metabolite only. Chromatographic analysis showed that the radioactivity extracted from a 

tissue type was consistent regardless of label position and yielded little evidence of cleavage of the 

parent molecule by the goat, elimination of the sulfonyl moiety and reconnection of the urea bridge 

notwithstanding.

POULTRY: There are no poultry feedstuffs associated with the subject petition; therefore, data 

requirements pertaining to poultry are not relevant to this petition. 

5.1.2 Summary of Environmental Degradation

Several flazasulfuron degradates were detected in the environmental fate studies, including DTPU, 

DTPP, TPSA, ADMP, HTPP, 2,3-GTP, bound residues, and carbon dioxide (see appendix for names 

and structures). 

The degradates of flazasulfuron are persistent in both aquatic and soil environments. Hydrolysis 

(abiotic; enzyme-mediated) is the major route of transformation of flazasulfuron, but metabolic 

products were also observed in soil and water-sediment systems. The abiotic hydrolysis study 

showed that the rates of hydrolysis and the mechanism of formation of products are pH-dependent. 

Mobility is expected to increase with increasing pH. However, the soils selected for the 

environmental fate studies had a narrow range of pH that does not allow an adequate correlation of 

persistence and mobility with pH. Like all sulfonylurea herbicides, flazasulfuron can exhibit high 

mobility in soil. Direct photolysis in water is likely associated with hydrolytic products rather than 

with parent flazasulfuron. Flazasulfuron has low potential to volatilize from soil or water. 

Potentially, soil particulates containing flazasulfuron could be transported away from the treatment 

site by wind erosion or runoff. 

5.1.3 Comparison of Metabolic Pathways

In plants flazasulfuron is degraded by cleavage of the sulfonylurea bridge to TPSA and ADMP and 

extrusion of sulfur dioxide by intramolecular rearrangement to DTPU. The degradation is very 

extensive since flazasulfuron is not detected in tomato and only traces of the parent compound are 

present in grape and sugarcane. No confined rotational crop study has been conducted.
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In the goat, flazasulfuron appears mainly to be degraded by the intramolecular rearrangement 

pathway; however, the degradation is not as extensive as in plants since a substantial amount of 

flazasulfuron is present in the kidney. No metabolism data on poultry were submitted.

In both plants and goat, DTPU is further hydrolyzed and demethylated to HTTP. The latter is 

conjugated as the glucoside in tomato (HTPP conjugate) and it is postulated that HTTP forms the 

glucuronic acid conjugate in the goat (TPPG). It is also postulated that hydroxylation in the 

pyrimidine ring occurs in the goat to yield a conjugate with glucuronic acid (HDTG).

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.

For drinking water, the residues of concern for risk assessment were parent, DTPU, DTPP, TPSA, 

ADMP, HTPP, and 2,3-GTP.

5.1.4 Residues of Concern Summary and Rationale

Table 5.1.4. 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 applicable1

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

tolerance action. No tolerance is to be established for water.

2 See Appendix E for metabolite names and structures. 3 Rotational crop studies are not available at this time. Parent only is included as an interim recommendation pending 

submission of an adequate study.

Rationale:

Plants

Primary Crops: Metabolism studies were conducted on grape, sugarcane, and tomato while the 

proposed uses are citrus, grape, and sugarcane. Quantifiable residues of flazasulfuron parent were 

not found in the tomato metabolism study, but were observed in the grape and sugarcane metabolism 

studies as minor residues (<10% of the total radioactive residue (TRR)). Several metabolites were 

observed as major residues (>10% TRR): HTPP: tomato; DTPP: grape leaves; DTPU: grape fruit 

and leaves; TPSA: tomato). Minor residues (<10% TRR) were found as follows: HTPP: grape fruit 
Flazasulfuron Human Health Risk Assessment DP No. 372903

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and leaves, sugarcane, tomato; DTPP: grape fruit and leaves, sugarcane; DTPU: grape leaves, 

sugarcane, tomato; TPSA: grape fruit and leaves, sugarcane; ADMP: sugarcane, tomato). 

However, based on submitted field trial and processing studies, the proposed seasonal use rate of 

0.15 lb ai/A is expected to result in residues of <LOQ (<0.01 ppm) for parent and <LOQ (<0.01 

ppm) for DTPU in all raw agricultural commodities and processed commodities of citrus, grapes, 

and sugarcane. No parent was detected in citrus, grape, or sugarcane field trials or processing 

studies. DTPU was not detected in citrus field trials or processing studies or in grape field trials and 

was not tested for in sugarcane. Although quantifiable residues of DTPU were observed in raisins 

(0.01 ppm), given the exaggerated use rate of the grape processing rate (~10X the proposed use rate) 

there is no expectation of finite residues under the proposed use pattern. Furthermore, the primary 

metabolites DTPU, HTPP + conjugates, and TPSA + conjugates are not expected to be more toxic 

than parent flazasulfuron (ROCKS memo, D386767, E. Holman, 2/28/11). Therefore, the use of 

parent flazasulfuron only is an adequate measure for tolerance enforcement and risk assessment 

purposes in primary crops. 

Rotational Crops: No confined rotational crop study has been conducted. Sugarcane, the only 

rotated crop, has a 12-month crop rotation restriction on the proposed label; a confined rotational 

crop study will be required for permanent registration. Parent only is considered to be the residue of 

concern pending submission of an adequate study.

Livestock 

Ruminants: For the proposed use pattern associated with this petition, no secondary residues are 

expected to occur in livestock commodities. Based on the goat metabolism study and the low 

residues (0.0024 ppm) calculated to be in the ruminant diet from feeding dried citrus pulp and 

sugarcane molasses (the only ruminant feed items associated with citrus, grapes, and sugarcane), no 

residues are expected to occur in ruminant commodities from use on citrus, grapes, and sugarcane. 

Hence a 40 CFR 180.6(a)(3) situation (no expectation of finite residues) exists. 

Poultry and Swine: No residues are expected to occur in poultry or swine commodities, as there are 

no poultry or swine feed items associated with citrus, grapes, and sugarcane. However, this decision 

may also need to be revisited for future uses of flazasulfuron that involve significant livestock feed 

items. 

Drinking Water: The parent compound and all identified metabolites are included in the drinking 

water exposure assessment, which is consistent with the previous risk assessment (DP Barcode 

D303573, G.V. Burke, Ph.D., 11/16/05). 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. 
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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. Residues of flazasulfuron were not detectable in any 

commodity at a limit of detection, indicating that there will be minimal exposure to flazasulfuron in 

food. Processing studies were conducted in oranges, grapes, and sugarcane; residues of 

flazasulfuron did not concentration in any commodity. 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. The magnitude of residue and 

processing studies are supported by adequate storage stability data for flazasulfuron. 

Table 5.2.1 Summary of Residue Data from Crop Field Trials with Flazasulfuron

Commodity Analyte

Total Applic. 

Rate

(lb ai/A)

PHI 

(days)

Residue Levels (ppm) 1

n Min. Max. HAFT1 Median Mean Std.

Dev.

Citrus (proposed use = 0.15 lb ai/A total application rate, 1-day PHI)

Orange, 

fruit

Flazasulfuron 

(parent) 0.154 – 0.159

1 24 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ

(ND) --

29-30 24 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) --

DTPU 0.154 – 0.159

1 24 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) --

29-30 24 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) --

Grapefruit, 

fruit

Flazasulfuron

(parent) 0.153 – 0.161

1 12 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) --

28-30 12 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) --

DTPU 0.153 – 0.161

1 12 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) --

28-30 12 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) --

Lemon, fruit

Flazasulfuron 

(parent) 0.154 – 0.156

1 8 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) --

30 8 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) --

DTPU 0.154 – 0.156

1 8 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) --

30 8 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) --

Grapes (proposed use = 0.15 lb ai/A total application rate, 75-day PHI)

Grapes, fruit

Flazasulfuron 

(parent) 0.149-0.158 74-77 24 <LOQ (ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) -

DTPU 0.149-0.158 74-77 24 <LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

Sugarcane (proposed use = 0.15 lb ai/A total application rate, 180-day PHI)

Sugarcane Flazasulfuron 

(parent) 0.152-0.164 179-180 16 <LOQ (ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND)

<LOQ 

(ND) --

1 The LOQ is 0.010 ppm. The calculated LOD for flazasulfuron is 0.003 ppm.
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5.3 Water Residue Profile

Estimated surface water and groundwater concentrations are shown in Table 5.3.

The dietary exposure assessment used the peak concentration value of 102 ppb for acute and chronic

assessments. The drinking water assessment is based on Tier II groundwater model (PRZM-GW)

simulations for all currently registered and proposed flazasulfuron uses. 

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. 

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 26.9 102

Chronic (non-cancer) 4.67 102 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 assuming a maximum use rate of 3 applications at 0.045 lb ai/A/application, a Koc of 

10 mL/g, and an aerobic soil metabolism half-life of 10,398 days, applied to corn in the Delmarva Peninsula to 

represent uses on citrus, grapes, Christmas trees, and industrial vegetation management. c DP#372897, Andrew Shelby, 4/4/2011.

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 proposed crops. Processing studies did not show any concentration of flazasulfuron 

in the commodities tested after processing. . Therefore, processing factors were excluded from 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 crops 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 (102 μg/L) 

was incorporated directly into the dietary assessment (A. Shelby, D372897, 4/4/11).
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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 1.1% of the aPAD for the general U.S. population and 4.0% 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 

DEEMTM 7.81 default 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 concentration of flazasulfuron in drinking water was utilized. The ground water EDWC (102 

μg/L) was incorporated directly into the dietary assessment (A. Shelby, D372897, 4/4/11).

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 17% of the cPAD for the general U.S. 

population and 54% 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 and Risk 

for Flazasulfuron

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

General U.S. Population 0.0054 1.1 0.0022 17

All Infants (< 1 year old) 0.0201 4.0 0.0071 54

Children 1-2 years old 0.0084 1.7 0.0033 25

Children 3-5 years old 0.0077 1.5 0.0031 24

Children 6-12 years old 0.0053 1.1 0.0021 16

Youth 13-19 years old 0.0044 <1.0 0.0016 12

Adults 20-49 years old 0.0049 <1.0 0.0020 16
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Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk 

for Flazasulfuron

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

Adults 50+ years old 0.0045 <1.0 0.0020 16

Females 13-49 years old 0.0050 1.00 0.0020 16

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

This document only presents the assessment of the proposed new agricultural uses of flazasulfuron. 

No new residential uses are being requested at this time; therefore, a residential risk assessment has

not been conducted.

6.1 Residential Handler Exposure

Residential handler exposure was not assessed since flazasulfuron is only applied to use sites such as 

industrial parks, tank farms, sod farms, seed farms, and professionally managed sports fields which 

are not treated by residential handlers.

6.2 Post-Application Exposure

Flazasulfuron is currently registered for use on golf courses and other non-residential turf areas such 

as industrial parks, tank farms, sod farms, seed farms, and professionally managed sports fields.

Post-application short-term dermal exposure was previously assessed for recreational golfers or 

players of various sports who use a golf course or athletic field after flazasulfuron has been applied

(D316614, Burke, G., 11/23/05). However, since a revised hazard assessment was performed for 

fluzazsulfruon, a dermal hazard was not identified and dermal exposures and risks are no longer 

required. 

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 torr). 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.
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6.3 Combined Exposure

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.

For the short- and –intermediate term scenarios, combined exposures were not necessary to assess 

for flazasulfuron since residential handler exposures do not occur, no dermal hazard was identified,

and post-application inhalation exposures were not quantitatively assessed.

6.4 Spray Drift

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

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

of exposure from the ground application method employed for flazasulfuron. The Agency has been 

working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for 

pesticide regulation and other parties to develop the best spray drift management practices (see the 

Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed on 

product labels/labeling. The Agency has completed its evaluation of the new database submitted by 

the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on 

how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 

off-target drift with specific products with significant risks associated with drift.

7.0 Aggregate Exposure/Risk Characterization

Under FQPA, HED must consider and aggregate pesticide exposures and risk from three major 

sources: food, drinking water, and residential exposures. 

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 
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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) and dermal exposures; however, they were not assessed because a dermal hazard 

was not identified. For children, exposure includes only food and drinking water since dermal and 

incidental oral exposure to children from treated golf and athletic field turf is considered to be 

negligible. 

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 citrus, 

grapes, sugarcane, Christmas trees, and industrial vegetation management areas. 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. However, dermal risks were not assessed since a dermal 

hazard was not identified.

9.1 Short-/Intermediate-Term Handler Risk

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

• mixing/loading dry flowable powder to support groundboom applications,

• mixing/loading dry flowable powder to support groundboom applications,

• applying sprays with groundboom equipment,

• applying sprays with right-of-way sprayer equipment,

• mixing/loading/applying sprays with backpack sprayers, and

• wettable powder mixing/loading/applying with low pressure handwand.

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. 

 

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
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Table 9.1.1. Summary Of Short- and Intermediate-Term Occupational Handler Exposures And Risks

Exposure Scenario Crop Grouping

Application 

Ratea

(lb ai/A)

Area Treated 

Dailyb 

(A/day)

Baseline 

Inhalationc

Unit Exposure 

(μg/lb ai)

Baseline 

Inhalation Dose 

(mg/kg/day)

Baseline Inhalation 

ST/IT MOEd

(LOC ≥ 100)

Mixer/Loader

Mixing/Loading Dry 

Flowable for 

Groundboom 

Applications

Citrus

0.045 80 0.77 0.000040 51,000 Grapes

Sugarcane

Christmas Trees

Non-crop 0.047 80 0.77 0.000041 48,000

Mixing/Loading Dry 

Flowable for Right-ofWay Applications

Non-crop 0.047 40 0.77 0.000021 97,000

Applicator

Applying Sprays via 

Groundboom 

Equipment (open cab)

Citrus

Grapes

Sugarcane

Christmas Trees

0.045 80 0.74 0.000038 53,000

Non-crop 0.047 80 0.74 0.000040 50,000

Applying Sprays via 

Right-of-Way

Equipment 

Non-crop

0.0024

(lb ai/gal)

1000

(gal/day) 3.9 0.00013 15,000

Mixer/Loader/Applicator

Backpack

Christmas Trees 0.0023 40 30 0.000039 52,000

Non-crop 0.0024 40 30 0.000040 50,000

(lb ai/gal) (gal/day)

Low Pressure 

Handwand

Christmas Trees 0.0023 40 1100 0.0014 1,400

Non-crop

0.0024 40 1100 0.0015 1,400

(lb ai/gal) (gal/day)

a Application rates are the maximum application rates determined from proposed labels for flazasulfuron.

b Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard 

Values for Daily Acres Treated in Agriculture,”

c Baseline Inhalation: no respirator.

d Inhalation ST/IT MOE = ST/IT NOAEL (2 mg/kg/day) / inhalation daily dose (mg/kg/day), where inhalation dose = daily 

unit exposure (μg/lb ai) x application rate (lb ai/A) x area treated (A/day) x 100% inhalation absorption / body weight (70 

kg adult). LOC = 100
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9.2 Short-/Intermediate-Term Post-Application Risk

There is a possibility for agricultural workers to have post-application dermal exposure to 

flazasulfuron following its proposed new uses. However, a dermal hazard was not identified,

therefore, post-application dermal exposures were not 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 torr). However, there 

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

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: Flazasulfuron elicits developmental effects. Per the Worker Protection 

Standard (WPS), a 12-hr restricted entry interval (REI) is required for chemicals that exhibit adverse 

health effects. The ISK Flazasulfuron Herbicide label indicates an REI of 4 hrs, which is not in 

compliance with the WPS. The REI on the label needs to be corrected to 12 hours.

10.0 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).

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 
Flazasulfuron Human Health Risk Assessment DP No. 372903

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the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk 

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

subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, 

OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments 

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

exposures based on home use of pesticide products and associated risks for adult applicators and for 

toddlers, youths, and adults entering or playing on treated areas post-application are evaluated. 

Further considerations are currently in development as OPP has committed resources and expertise 

to the development of specialized software and models that consider exposure to bystanders and 

farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

11.0 References

Dodd, N., 2/16/11, DP#372901, Flazasulfuron: Summary of Analytical Chemistry and Residue Data 

for Use on Citrus, Grapes and Sugarcane.

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

Subcommittee (ROCKS). 

Rury, K., 4/12/11, DP#378629, Flazasulfuron: Acute & Chronic Aggregate Dietary (Food and 

Drinking Water) Exposure and Risk Assessment for the first food use, Section 3 Registration Action 

(Citrus, Grapes and Sugarcane). 

Shelby, A., 2/1/11, DP#386353, The Drinking Water Degradates Identification Memorandum for 

Flazasulfuron.

Shelby, A., 4/4/11, DP#372897, Flazasulfuron: Refined Drinking Water Assessment for First Food 

Uses on citrus, grapes and sugarcane and new outdoor non-food uses on Christmas trees and 

industrial vegetation management.

Walls, C., Ph.D., 3/19/11, DP#378633, FLAZASULFURON: Occupational and Residential 

Exposure/Risk Assessment for Use on Citrus, Grapes, Sugarcane, Christmas Trees, and Industrial 

Vegetation Management.
Flazasulfuron Human Health Risk Assessment DP No. 372903

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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

--

--

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....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

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

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

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

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

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

no

no

yes

yes

no

-

-

yes

no

--

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

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

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

yes

yes

yes

yes

yes

no

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) = No systemic toxicity was observed at the 

limit dose. No localized dermal effects were observed.
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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 in 

(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 in 

(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).

870.4300

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
Flazasulfuron Human Health Risk Assessment DP No. 372903

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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.4200

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

870.5500

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 

Cytogenetics 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

870.7485

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.

A.3 Hazard Identification and Endpoint Selection

The Hazard Identification and Endpoint Selection sections are presented in the previous Risk 

Assessment document. Please refer to D303573, G.V. Burke, Ph.D., 11/16/05.

A.4 Executive Summaries

The executive summaries of the studies used in this risk assessment are presented in the previous 

Risk Assessment document. Please refer to D303573, G.V. Burke, Ph.D., 11/16/05.
Flazasulfuron Human Health Risk Assessment DP No. 372903

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A.5 Endpoint Selection Worksheet: Flazasulfuron

Table A.5.1 Toxicity Endpoint Selection Worksheet 

Exposure 

Scenario

Study Candidate(s) Rationale for Selection of Dose/Endpoint/Study

Acute Dietary, 

General Population

Acute Neurotoxicity—Rat

Developmental Toxicity--

Rat

Developmental Toxicity--

Rabbit

The NOAEL was 50 m/k/d. The LOAEL was 1000 mg/kg based on a transient decrease in motor activity 

observed 5 hours post-dosing. SELECTED

Maternal NOAEL = 100 m/k/d. LOAEL= 300 m/k/d based on increased relative liver weight and decreased 

body weight gain and food consumption

Developmental NOAEL = 100 m/k/d. LOAEL= 300 m/k/d based on increased incidence of visceral 

malformations (interventricular septal defect).

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.

Acute Neurotoxicity—Rat was selected because it is a single-dose effect and provides the lowest and most 

protective point of departure. 

Both developmental toxicity studies qualify for candidacy because intraventular septal defect (rat) and 

abortion (rabbit) both can be a single-dose effect.

Acute Dietary,

Females 13+

Acute Neurotoxicity—Rat

Developmental Toxicity--

Rat

Developmental Toxicity--

Rabbit

The NOAEL was 50 m/k/d. The LOAEL was 1000 mg/kg based on a transient decrease in motor activity 

observed 5 hours post-dosing. SELECTED

Maternal NOAEL = 100 m/k/d. LOAEL= 300 m/k/d based on increased relative liver weight and decreased 

body weight gain and food consumption

Developmental NOAEL = 100 m/k/d. LOAEL= 300 m/k/d based on increased incidence of visceral 

malformations (interventricular septal defect).

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.

Acute Neurotoxicity—Rat was selected because it is a single dose study and also is protective of the 

developmental effects seen at 300 m/k/d in the rat, and 450 m/k/d in the rabbit. 

The two developmental toxicity studies qualify for candidacy because the developmental effects observed, 

interventral septal defect in the rat and abortion in the rabbit, both qualify as single-dose effects.
Flazasulfuron Human Health Risk Assessment DP No. 372903

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Table A.5.1 Toxicity Endpoint Selection Worksheet 

Exposure 

Scenario

Study Candidate(s) Rationale for Selection of Dose/Endpoint/Study

Chronic Dietary, 

General Population

Chronic/Carcinogenicity 

study in rats

Chronic (1 year) Study in 

dogs

Carcinogenicity study in 

mice

Multigeneration 

Reproduction study in rats

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) SELECTED

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). 

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).

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)

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.

Chronic/Oncogenicity Study--Rat was selected because its NOAEL was the lowest of the candidates, and 

provides the most protective point of departure. 

The chronic dog and mouse carcinogenicity studies are candidates because their duration is long-term and 

therefore appropriate. The mouse reproduction study is a candidate because its duration spans three 

generations.
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Table A.5.1 Toxicity Endpoint Selection Worksheet 

Exposure 

Scenario

Study Candidate(s) Rationale for Selection of Dose/Endpoint/Study

Incidental Oral, 

Short-term (1-30 days)

and

Inhalation

Short-term (1-30 days)

90-Day oral toxicity--dog

Multi-generation 

reproduction--Rat

Acute Neurotoxicity—Rat

Developmental Toxicity—

Rabbit

Developmental Toxicity—

Rat

NOAEL = 2 mg/kg/day. 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). SELECTED

Parental NOAEL = 8.7 mg/kg/day. LOAEL = 87.5 mg/kg/day based on based on changes in kidney 

parameters (Bilateral discoloration, enlargement, mild nephropathy) and reductions in body weight in both 

generations (F0, F1).

Offspring NOAEL = 87.5 mg/kg/day. LOAEL = 430 mg/kg/day based on reduction in lactational body 

weights in F1 and F2 offspring. 

The NOAEL was 50 m/k/d. The LOAEL was 1000 mg/kg based on a transient decrease in motor activity 

observed 5 hours post-dosing.

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.

Maternal NOAEL = 100 m/k/d. LOAEL= 300 m/k/d based on increased relative liver weight and decreased 

body weight gain and food consumption.

Developmental NOAEL = 100 m/k/d. LOAEL= 300 m/k/d based on increased incidence of visceral 

malformations (interventricular septal defect).

90-Day oral toxicity—dog was selected because the NOAEL of 2 mg/kg/day is the lowest dose of any nonchronic study available, and is protective of all adult and developmental/offspring effects observed in the 

available non-chronic studies, including the developmental, reproductive and acute neurotoxicity studies.

The acute neurotoxicity study is a candidate (incidental oral and inhalation) because it is short-term and, 

while showing effects only in adults, provided a point of departure which is protective of short-term effects 

seen in offspring in the developmental and reproductive studies. The multi-generation study is a candidate 

(for incidental oral) because it shows short-term effects in young animals which is a population of concern in 

humans for incidental oral exposure. The developmental (rat and rabbit) studies are candidates (for 

incidental oral and inhalation) because they show effects in adults over short-term duration.
Flazasulfuron Human Health Risk Assessment DP No. 372903

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Table A.5.1 Toxicity Endpoint Selection Worksheet 

Exposure 

Scenario

Study Candidate(s) Rationale for Selection of Dose/Endpoint/Study

Incidental Oral, 

Intermediate-term (1 –

6 months)

and

Inhalation

Intermediate-term (1 –

6 months)

90-Day oral toxicity--dog

90-Day oral toxicity--rat

NOAEL = 2 mg/kg/day. 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). SELECTED

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).

90-Day oral toxicity—dog was selected because it provided a lower NOAEL than the subchronic rat study 

and therefore provides a more protective point of departure.

The 90-day rat study is a candidate because the study duration is appropriate for the intermediate-term 

exposure duration.

Dermal Absorption None The Dermal absorption factor is calculated < 45%, based on the ratio of the LOAEL from the oral rabbit 

developmental study (450 mg/kg/day) and the NOAEL from the 21-day dermal toxicity study in rabbits 

(1000 mg/kg/day). This is a conservative estimate because the 21-day dermal study did not present an 

adverse effect at the highest dose tested in order to produce a LOAEL.

Dermal, 

Short-term, 

(1-30 days)

and

Dermal

Intermediate-term 

(1-6 months)

21-day dermal—rabbit Dermal and systemic NOAEL=1000 mg/kg/day (Limit Dose). LOAEL > 1000 mg/kg/day. SELECTED

21-day dermal—rabbit is chosen because it is route-specific and 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.

Dermal, Long-term

(> 6 months)

and

Inhalation, Long-term

(> 6 months)

None Long-term dermal and inhalation exposures are not anticipated, therefore, endpoints were not selected.
Flazasulfuron Human Health Risk Assessment DP No. 372903

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Appendix B. Metabolism Summary Table

Table B1. Tabular Summary of Metabolites and Degradates

Common 

Name/Code 

Name

Matrix

Percent TRR (PPB) 1

Matrices Structure - Major 

Residue 

(>10%TRR)

Matrices - Minor 

Residue 

(<10%TRR)

Flazasulfuron/

SL-160

Grape (fruit) -- 2.40 (0.1) Pm/F

1.10 (<0.05) P/GH

1.86 (<0.05) Pm/GH

Grape leaves -- 0.22 (0.4) P/F

0.59 (0.3) Pm/F

2.04 (0.4) P/GH

1.16 (0.5) Pm/GH

Sugarcane -- 1.53 (0.153) P/GH

1.02 (0.08) Pm/GH

Tomato -- --

Rotational Crops Not Available (NA) NA

Goat

 Kidney 16.6 (0.028) P 

59.7 (0.016) Pm 

--

Poultry Not Available (NA) NA

Rat2

Water3

HTPP Grape (fruit) -- 1.11 (<0.05)Pm/F

2.56 (<0.05) P/GH

4.21 (0.1) Pm/GH

Grape leaves -- 0.70 (1.1) P/F

0.82 (0.4) Pm/F

1.67 (0.3) P/GH

1.72 (0.8) Pm/GH

Sugarcane -- 2.57 (0.26) P/GH

3.80 (0.29) Pm/GH

Tomato Conjugate:

33 (0.5) P/F

18.7 (0.2) Pm/F

Free:

4.3 (<0.05) P/F

2.0 (<0.05) Pm/F

Rotational Crops NA NA

Goat

 Liver

 Kidney

 Muscle 

40.2 (0.142) P 

31.5 (0.017) Pm 

13.4 (0.022) P 

89.6 (0.044) P 

--

Poultry NA NA

Rat2

Water3

DTPP Grape (fruit) -- 7.10 (0.2)Pm/F

2.54 (<0.05) P/GH

2.25 (<0.05) Pm/GH
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Table B1. Tabular Summary of Metabolites and Degradates

Common 

Name/Code 

Name

Matrix

Percent TRR (PPB) 1

Matrices Structure - Major 

Residue 

(>10%TRR)

Matrices - Minor 

Residue 

(<10%TRR)

Grape leaves 10.21 (5.3) Pm/F 1.16 (1.9) P/F

4.00 (0.8) P/GH

7.16 (3.4) Pm/GH

Sugarcane -- 0.22 (0.022) P/GH

0.67 (0.05 ) Pm/GH

Tomato -- --

Rotational Crops NA NA

Goat

 Kidney 4.5 (0.007) P 

9.1 (0.002) Pm 

Poultry NA NA

Rat2

Water3

DTPU Grape (fruit) 43.38 (1.1)Pm/F

10.96 (0.1) P/GH

19.64 (0.4) Pm/GH

--

Grape leaves 50.90 (26.2)Pm/F

28.47 (5.4) P/GH

34.86 (16.4) Pm/GH

5.78 (9.5) P/F

Sugarcane -- 0.72 (0.072) P/GH

1.14 (0.09) Pm/GH

Tomato -- 7.8 (0.1) P/F

7.8 (0.1) Pm/F

Rotational Crops NA NA

Goat

 Kidney 50.2(0.083) P 

17.6 (0.005) Pm 

--

Poultry NA NA

Rat2

Water3

TPSA Grape (fruit) -- 1.42 (<0.05) P/GH

Grape leaves -- 1.74 (2.9) P/F

2.36 (0.4) P/GH

Sugarcane -- 5.91 (0.591) P/GH

Tomato 13.6 (0.2) P/F --

Rotational Crops NA NA

Goat -- --

Poultry NA NA

Rat2

Water3
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Table B1. Tabular Summary of Metabolites and Degradates

Common 

Name/Code 

Name

Matrix

Percent TRR (PPB) 1

Matrices Structure - Major 

Residue 

(>10%TRR)

Matrices - Minor 

Residue 

(<10%TRR)

ADMP Grape (fruit) -- --

Grape leaves -- --

Sugarcane -- 6.68 (0.51) Pm/GH

Tomato -- 3.3 (0.0) Pm/F

Rotational Crops NA NA

Goat -- --

Poultry NA NA

Rat2

Water3

Grape; 47939905; 2 x 0.045 lb ai/A = 0.089 lb ai/A; 0.59x seasonal application label rate of 0.15 lb ai/A/season; the first application 

was made at early bud break or at post bud break when vines were approximately 10 feet in height and the second application was made 

seven or eight weeks after the first; 85-day PHI in the field, 34-day PHI in the greenhouse.

Sugarcane; 47939906 lb ai/A; 2 x 0.20 = 0.40 lb ai/A; 2.7x seasonal application label rate of 0.15 lb ai/A/season; the first application 

was at the 2-3 leaf stage and the second application was 23-25 days later at the 5-6 leaf stage; 364-367-day PHI.

Tomato; 47939907; 1 application at 0.045 lb ai/A; there is no proposed use on tomato but the rate is 0.30x the seasonal rate of the 

proposed plants; the application was made to immature plants with no fruit, 40 days after the seed was planted; 83-day PHI.

Goat; 47939908; 11.4 ppm [

14C-pyridyl] label; 14.3 ppm14C-pyrimidinyl] label; 4750x or 5958x MRBDB; 3 days; 23-24 hour PSI.

Rat Metabolism; 46220940, 46220941, 46220938, 46220939; single dose: 2 mg/kg or 50 mg/kg; multiple dose: 2 mg/kg 1 P= pyridyl14C label; Pm = pyrimidinyl14C label; GH = greenhouse; F = field 2 Rat metabolites: The most prevalent metabolites (expressed as percent of administered dose) were HDTG+TPPG (~6.5-17.7% in 

urine, ~0.4-9.7% in feces, and ~6.5-14% in bile), with minor amounts (<5%) of other compounds. Individually, unidentified fractions 

generally accounted for less than 2% of the administered dose in the urine and biliary metabolite profile. The fecal metabolite profile 

had up to 35% unidentified of the recovered dose.

3 Water metabolites: The previous risk assessment (DP Barcode D303573, G.V. Burke, Ph.D., 11/16/05) included residues 

of the following compounds in water for the risk assessment: Parent, DTPU, DTPP, HTPP, TSPA, and ADMP.
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Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such 

studies, involving exposure to many different pesticides, comprise generic pesticide exposure 

databases such as PHED. EPA has reviewed all the studies supporting these multi-pesticide generic 

exposure databases, and has found no clear and convincing evidence that the conduct of any of them 

was either fundamentally unethical or significantly deficient relative to the ethical standards 

prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for 

the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no 

regulatory barrier to continued reliance on these studies.
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Appendix D. International Residue Limits 

Flazasulfuron (PC Code 119011)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.xxx:

Plant/Livestock: N-[[(4,6-dimethoxy-2-

pyrimidinyl)amino]carbonyl]-3-

(trifluoromethyl)-2-pyridinesulfonamide

None None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Fruit, citrus, group 10-10 0.01

Grape 0.01

Sugarcane 0.01

Completed: M. Negussie; 1/12/2010

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not 

those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed 

postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of 

the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.
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Appendix E. 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