..,E.Otl"t<41~..,, 

f A t UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

\S~ "' ... ,t WASHINGTON, D.C. 20460 

"'"""{ Pf'r(Jlf.<1-" 

MEMORANDUM 

Date: September 15, 20 15 

OFFICE OF 

CH EMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJ ECT: Flazasulfuron. Human Health Draft Risk Assessment for Registration Review. 

PC Code: 11 9011 

Decision No.: 502405 

Petition No.: NJ\ 

Risk Assessment Type: Single Chemical/ 

Aggregate 

TXR No.: NA 

MRID No.: NA 

DP Barcode: 0426196 

Registration Nos.: 71512-12, 715 12-18 

Regulatory Action: Registration Review 

Case No.: NIA 

CAS No.: I 04040-78-0 

40 CFR: § 180.655 

FROM: Nancy Dodd, Risk Assessor/Chemist ~ h'~ Nancy Keller, Occupational/Residential Exposure 

Minerva Mercado, Toxicolog ~ A ~ 

Risk Assessment Branch III (RAB3) 

THROUGH: Christine Olinger, Branch Chief / / 

Health Effects Division (HED;Zt 7509P) ) , 

RAB3/HED (7509P) r 

TO: Thomas Mori arty/Ricardo Jones, RM 51 

Risk Management and Implementation Branch 1 

Pesticide Re-Evaluation Division (7508P) 

As part of Registration Review, the Pesti cide Re-evaluation Division (PRD) of the Office of 

Pesticide Programs (OPP) has requested that HED evaluate the hazard and exposure data and 

conduct occupational and residenti al exposure assessments, as needed, to estimate the risk to 

human health that will result from the currently registered uses of pesticides. This 

memorandum serves as HED's draft human health risk assessment of the dietary, 

occupational, and residential exposure, and aggregate risk from the registered uses of 

nazasulfuron. 

Page 1 of 38 
Page 2 of 38 

Table of Contents 1.0 Executive Summary ........................................................................................................ 3

2.0 HED Recommendations ................................................................................................. 5

2.1 Tolerance Considerations ........................................................................................... 5

2.2 Label Considerations .................................................................................................. 5

2.3 Data Deficiencies ......................................................................................................... 5

3.0 Introduction ..................................................................................................................... 5

3.1 Chemical Identity and Physical/Chemical Characteristics ..................................... 5

3.2 Pesticide Use Patterns and Anticipated Exposure Pathways .................................. 5

3.3 Consideration of Environmental Justice ................................................................... 9

4.0 Hazard Characterization................................................................................................ 9

4.1 Summary of Toxicological Effects ........................................................................... 10

4.2 Safety Factor for Infants and Children (FQPA Safety Factor) ............................ 10

4.3 Toxicity Endpoint and Point of Departure Selections ........................................... 11

4.4 Endocrine Disruption ................................................................................................ 12

5.0 Dietary Exposure and Risk Assessment ...................................................................... 13

5.1 Residue Chemistry .................................................................................................... 13

5.2 Drinking Water Residue Profile .............................................................................. 14

5.3 Dietary (Food and Drinking Water) Exposure Assessment .................................. 14

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .......................... 16

7.0 Aggregate Exposure/Risk Characterization ............................................................... 17

7.1 Acute Aggregate Risk................................................................................................ 17

7.2 Short- and Intermediate-Term Aggregate Risk ..................................................... 18

7.3 Chronic Aggregate Risk ........................................................................................... 18

7.4 Cancer Aggregate Risk ............................................................................................. 18

8.0 Cumulative Exposure/Risk Characterization ............................................................ 18

9.0 Occupational Exposure/Risk Characterization ......................................................... 19

10.0 Public Health and Pesticide Epidemiology Data ........................................................ 19

11.0 References ...................................................................................................................... 20

Appendix A. Toxicology Profile and Executive Summaries ............................................. 21

A.1. Toxicology Data Requirements ................................................................................... 21

A.2. Toxicity Profiles............................................................................................................ 22

Appendix B. Dietary Exposure/Risk Modeling Input Files .............................................. 28

Appendix C. Review of Human Research .......................................................................... 31

Appendix D. Occupational Non-cancer Handler Exposure Estimates and Algorithms.32

Appendix E. Nomenclature and Physical/Chemical Properties ....................................... 33

Appendix F. International Harmonization ........................................................................ 35

Appendix G. DFR and TTR Data Waiver Rationales ....................................................... 36

Appendix H. Estimated Dermal Absorption Factors (DAF) .............................................. 38
Page 3 of 38 

1.0 Executive Summary

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

pyridinesulfonamide) is a sulfonylurea herbicide which controls certain broad-leaf weeds and 

grasses. Flazasulfuron acts by inhibiting acetolactate synthase (ALS), which is not present in 

humans. 

Flazasulfuron is currently registered (40 CFR §180.655) for use on citrus, grapes, sugarcane, 

and tree nuts. It is also registered for use on conifer (Christmas) trees, vegetation around 

industrial sites, and turf grass (including residential and recreational areas). ISK is the only 

registrant with flazasulfuron end-use products at this time.

A human health scoping document was conducted for flazasulfuron in 2012 (D399094, C. 

Walls, 4/26/2012). The most recent risk assessment was conducted in 2014 (D411772, C. 

Walls, 7/29/2014). Since the last risk assessment, there have been no changes to the 

flazasulfuron use, residue, or residential/occupational profile. Changes in the hazard profile 

since the previous risk assessment do not change the dose-response assessment; therefore, the 

endpoints selected for the previous risk assessment are still appropriate. There are no 

outstanding human health data deficiencies. 

The toxicology database for flazasulfuron is adequate to support current registration 

requirements. Since the last human health risk assessment and scoping document, a new 

immunotoxicity study has been reviewed; the rat developmental studies have been reevaluated according to current standards for toxicity evaluation; and the estimated maximum 

dermal absorption factor (DAF) has been changed from 45% to 20%. Since the new 

information does not change the dose-response assessment, endpoints selected for the previous 

risk assessment are still appropriate. The liver was the main target organ of flazasulfuron in 

most species tested, with effects ranging from non-adverse liver hypertrophy to more severe 

histopathological findings like inflammatory cell infiltration, hepatocellular necrosis and

swelling, and bile duct proliferation. There was no evidence of neurotoxicity, reproductive 

toxicity, or carcinogenicity in the database. No dermal hazard has been identified. The Food 

Quality Protection Act (FQPA) Safety Factor has been reduced to 1X.

The residue chemistry database is adequate to support current Registration Review data 

requirements. Adequate metabolism, storage stability, magnitude of the residue, and 

processing data are available to support the registered uses. Adequate methods are available 

for enforcement of the currently established tolerances. 

The dietary exposure data used in this risk assessment were taken unchanged from the 

previous dietary assessment (D417419, C. Walls, Ph.D., 2/5/2014). The unrefined acute and 

chronic dietary (food and drinking water) assessments for flazasulfuron used tolerance-level 

residues for foods and assumed that 100% of the crops were treated. For the acute assessment, 

the groundwater estimated drinking water concentration (EDWC) of 90.8 μg/L (ppb) from the 

Tier II Pesticide Root Zone Model – Ground Water (PRZM-GW) modeling system was used. 
Page 4 of 38 

For the chronic assessment, the groundwater EDWC of 55.6 μg/L from the Tier II PRZM-GW 

model was used. The EDWCs were incorporated directly into the dietary assessments. 

The acute and chronic dietary (food and drinking water) exposures to flazasulfuron are below 

HED’s level of concern (i.e., <100% of the acute or chronic population-adjusted dose (aPAD 

or cPAD) for the general U.S. population and all population subgroups. The acute dietary 

exposure estimates at the 95th percentile are 1.0% of the aPAD for the general U.S. population 

and 3.1% of the aPAD for all infants (<1 year old), the most highly exposed population 

subgroup. The chronic dietary exposure estimates are 9.1% of the cPAD for the general U.S. 

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

population subgroup. 

The existing residential uses on turf have been adequately assessed. Residential handler and 

post-application scenarios resulted in margins of exposure (MOEs) greater than the level of 

concern (i.e., the LOC is an MOE <100); therefore, the exposures are not of concern to HED. 

Aggregate risks were assessed. The acute aggregate exposure is equal to the acute dietary 

(food and drinking water) exposure. Similarly, the chronic aggregate exposure is equal to the 

chronic dietary (food and drinking water) exposure. The short-term aggregate exposures for 

adults and children include dietary (food and drinking water) exposures and residential 

exposures to turf. The short-term aggregate exposures are not of concern to HED (i.e., MOEs 

> 100). Since intermediate-term residential exposures are not likely to occur, intermediateterm aggregate risks were not assessed. 

The occupational handler and post-application exposure and risk estimates include dermal and 

inhalation exposures. However, dermal exposure during handling and post-application 

activities was not assessed for flazasulfuron because systemic toxicity was not observed at the 

limit dose in the 21-day dermal toxicity study. The occupational handler exposure and risk 

estimates indicate that short- and intermediate-term non-cancer inhalation MOEs are not of 

concern to HED (i.e., MOEs > 100) at baseline (no respirator) attire. Based on the Agency's 

current practices, a quantitative occupational post-application inhalation exposure assessment 

was not performed for flazasulfuron at this time. If new policies or procedures are put into 

place, the Agency may revisit the need for a quantitative occupational post-application 

inhalation exposure assessment for flazasulfuron.

HED has not identified any risk concerns associated with the registered uses of flazasulfuron. 

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

the preliminary human health risk assessment for flazasulfuron. Dietary and non-dietary 

exposures were considered.

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

intentionally exposed to a pesticide or other chemical. As indicated in Appendix C, these 
Page 5 of 38 

studies have been determined to require a review of their ethical conduct, and have received 

that review.

2.0 HED Recommendations

2.1 Tolerance Considerations 

The existing tolerances (40 CFR §180.655) are supported by the available residue chemistry 

data.

No Codex, Canadian, or Mexican maximum residue limits (MRLs) have been established for 

residues of flazasulfuron, as shown in Appendix F; therefore, there are no international 

tolerance/MRL harmonization issues. 

2.2 Label Considerations 

There are no label recommendations for registered products containing flazasulfuron. 

2.3 Data Deficiencies

There are no data deficiencies for registered products containing flazasulfuron. 

3.0 Introduction

3.1 Chemical Identity and Physical/Chemical Characteristics

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

pyridinesulfonamide) is a pyrimidinylsulfonylurea herbicide. Flazasulfuron has a log 

octanol/water partition coefficient (log Kow) of <1.0 and is considered relatively soluble in 

water. However, flazasulfuron has a molecular weight of 407.4 g/mol; therefore, the potential 

to cross biological barriers is somewhat limited. Based on laboratory and field studies, 

flazasulfuron was found to be long-lived and persistent under most environmental conditions. 

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

potential for inhalation exposure to vapor. Refer to Appendix E for chemical identity and 

physical/chemical characteristics of flazasulfuron.

3.2 Pesticide Use Patterns and Anticipated Exposure Pathways 

Flazasulfuron is currently registered (40 CFR §180.655) for use on citrus, grapes, sugarcane, 

and tree nuts. It is also registered for use on conifer (Christmas) trees, vegetation around 

industrial sites, and turf grass (including residential and recreational areas). Currently 

registered labels include one technical label and two formulated end use products. ISK 

Flazasulfuron Herbicide (EPA Reg. No. 71512-18) and Flazasulfuron 25WG (EPA Reg. No. 
Page 6 of 38 

71512-12) are both water-dispersible granular (WDG/WG) formulations containing 25% 

active ingredient (ai). 

In general, multiple applications may be made by ground, air, or chemigation up to a 

maximum yearly rate of 0.15 lb ai/A. Application timing varies depending on the target weed. 

For both formulated products, the restricted entry interval (REI) is 12 hours, and the personal 

protective equipment (PPE) includes long-sleeved shirt and long pants, shoes plus socks, 

protective eyewear and waterproof gloves. The uses are tabulated in Table 3.2 below. 

Exposure to flazasulfuron is possible via the dietary, residential, and occupational pathways. 

Additionally, there is the potential for indirect exposure (incidental oral and dermal) to 

flazasulfuron related to spray drift. 

Table 3.2. Summary of Directions for Use of Flazasulfuron 

Applic. Timing, 

Type, and Equip.

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. per 

Year

Max. 

Yearly 

Applic. 

Rate

(lb ai/A)

Min. RTI 

(days)

PHI

(days)

Use Directions and 

Limitations1 

CITRUS 

(Navel Orange, Valencia Orange, Lemon, Mandarin, and Tangerine)

Pre-emergence 

and Postemergence; Soil 

application using 

ground spray 

equipment

ISK 

Flazasulfuron 

Herbicide, 

WDG/WG

[71512-18]

0.033 -

0.045

Not 

reported

0.15 3 months 1 Apply only as a directed spray 

to the soil beneath the trees. 

Multiple applications can be 

made.

Do not apply more than 2 

applications at the maximum 

rate.

Do not apply to stony soils or 

sandy soils (greater than 85% 

sand).

GRAPE

Pre-emergence 

and Postemergence; Soil 

application using 

ground spray 

equipment

ISK 

Flazasulfuron 

Herbicide, 

WDG/WG

[71512-18]

0.033 -

0.045

Not 

reported

0.15 3 months 75 Apply only as a directed spray 

to the soil beneath the vines. 

Multiple applications can be 

made.

Do not apply more than 2 

applications at the maximum

rate.

Do not apply to stony soils.

SUGARCANE

Postemergence;

Over-the-Top; 

Ground 

equipment

ISK 

Flazasulfuron 

Herbicide, 

WDG/WG

[71512-18]

0.014 Not 

reported

0.15 14 180 Over-the top::

Apply prior to spiking or on 

ratoon up to 24 inches tall.

Post-directed: 

Apply to sugarcane that is 18 

inches tall up through layby. 
Page 7 of 38 

Table 3.2. Summary of Directions for Use of Flazasulfuron 

Applic. Timing, 

Type, and Equip.

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. per 

Year

Max. 

Yearly 

Applic. 

Rate

(lb ai/A)

Min. RTI 

(days)

PHI

(days)

Use Directions and 

Limitations1 

Postemergence;

Directed spray;

Ground 

equipment

ISK 

Flazasulfuron 

Herbicide, 

WDG/WG

[71512-18]

0014 - 0.045 Not 

reported

0.15 14 180 Applications should minimize 

contact with the whorl of the 

sugarcane.

Multiple applications can be 

made.

Allow a 12 month interval 

between the last application and 

the planting of the rotational 

crop.

TREE NUTS

(Hazelnut; Pecan; Pistachio; Black Walnut; English Walnut; African nut-tree; Beechnut; Brazil nut; Brazilian pine; 

Bunya; Bur oak; Butternut; Cajou nut; Candlenut; Cashew; Chestnut; Chinquapin; Coconut; Coquito nut; Dika nut; 

Ginkgo; Guiana chestnut; Heartnut; Hickory nut; Japanese horse-chestnut; Macadamia nut; Mongongo nut; Monkeypot; Monkey puzzle nut; Okari nut; Pachira nut; Peach palm nut; Pequi; Pili nut; Pine nut; Sapucaia nut; Tropical 

almond; Yellowhorn)

Pre-emergence 

and postemergence; Soil 

application 

using ground 

spray 

equipment.

ISK 

Flazasulfuron 

Herbicide, 

WDG/WG

[71512-18]

0.033 -

0.045

Not 

reported

0.15 3 months 130 Apply as a directed spray to 

the soil beneath the trees.

Multiple applications can be 

made.

Do not apply more than 2 

applications at the maximum 

rate.

Do not apply to stony soils.

ALMOND in California

Pre-emergence 

or postemergence; Soil 

application 

using ground 

spray 

equipment.

ISK 

Flazasulfuron 

Herbicide, 

WDG/WG

[71512-18]

0.023 -

0.045

1 0.045 NA Not 

reported

Apply as a directed spray to 

the soil beneath the trees. 

Apply in Oct. Nov, Dec. or 

Jan.

Do not apply to stony soils 

or soils with 90% or greater 

sand concentration.

CONIFER (CHRISTMAS) TREES
Page 8 of 38 

Table 3.2. Summary of Directions for Use of Flazasulfuron 

Applic. Timing, 

Type, and Equip.

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ai/A)

Max. No. 

Applic. per 

Year

Max. 

Yearly 

Applic. 

Rate

(lb ai/A)

Min. RTI 

(days)

PHI

(days)

Use Directions and 

Limitations1 

Pre-emergence 

and Postemergence; 

Over the top or 

directed sprays; 

Ground 

equipment

ISK 

Flazasulfuron 

Herbicide, 

WDG/WG

[71512-18]

0.033 -0.045 Not 

reported

0.15 3 months 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. 

Multiple applications can be 

made.

INDUSTRIAL VEGETATION MANAGEMENT/NON-AGRICULTURAL USES

Post-emergence;

Broadcast or 

directed spray; 

Ground 

equipment

ISK 

Flazasulfuron 

Herbicide, 

WDG/WG

[71512-18]

0.047 Not 

reported

0.15 45 days NA Do not use near residential 

properties.

Multiple applications can be 

made.

TURF - Non-residential

Postemergence;

Broadcast or 

spot treatments;

Ground 

equipment

Flazasulfuron 

25WG

[71512-12]

0.0078 -

0.047

(broadcast)

0.024 – 

0.0472 

(spot 

treatment)

Not 

reported

0.14 14

(broadcast);

21

(spot 

treatment) 

NA Multiple applications can be 

made.

TURF - Residential

Postemergence;

Spot treatment 

with directed 

spray;

Ground 

equipment

Flazasulfuron 

25WG

[71512-12]

0.024 –

0.0472 

 

0.0011 lb

ai/gal

1.1 x 10-6 

lb ai/ft2

Not 

reported

0.14 21 NA Residential turf grass sites 

are limited to targeted or 

spot treatment wih spray 

directed to the weeds only.

Spot treatments are limited 

to not more than 10% of a 

residential lawn.

Multiple applications can be 

made.
Page 9 of 38 

1 For both labels and all sites: Do not apply by air. Do not apply through any irrigation system. Use of an adjuvant 

is recommended for postemergence applications. 2 Spot treatment rates are 0.03–0.068 oz product (1-2 g product) per 1000 sq ft.

3.3 Consideration of Environmental Justice 

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

the preliminary human health risk assessment for flazasulfuron, in accordance with U.S. 

Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority 

Populations and Low-Income Populations," 

http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf. As a part of 

every pesticide risk assessment, OPP considers a large variety of consumer subgroups 

according to well-established procedures. In line with OPP policy, HED estimates risks to 

population subgroups from pesticide exposures that are based on patterns of that subgroup’s 

food and water consumption, and activities in and around the home that involve pesticide use 

in a residential setting. Extensive data on food consumption patterns are compiled by the 

USDA under the National Health and Nutrition Examination Surveys/What We Eat in 

America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food 

uses of a pesticide. These data are analyzed and categorized by subgroups based on age and 

ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized 

subgroups and exposure assessments are performed when conditions or circumstances warrant. 

Whenever appropriate, non-dietary exposures based on home use of pesticide products and 

associated risks for adult applicators and for toddlers, youths, and adults entering or playing on 

treated areas post-application are evaluated. Further considerations are currently in 

development as OPP has committed resources and expertise to the development of specialized 

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

and traditional dietary patterns among specific subgroups. 

4.0 Hazard Characterization

The toxicology database for flazasulfuron is complete. The latest risk assessment was 

conducted in 2014 (D411772, C. Walls, 7/29/2014). The data requirement for an inhalation

toxicity study is waived (TXR: 0056483, 10/04/2012) based on a weight of evidence approach, 

considering the low acute inhalation toxicity and low vapor pressure of flazasulfuron, and the 

use of an oral POD that results in MOEs below the level of concern to HED. A new 

immunotoxicity study has been reviewed, and the rat developmental studies have been reevaluated since the previous risk assessment according to current standards for toxicity 

evaluation. Since the newly submitted toxicity information, toxicity study waiver, and revised 

DAF do not change the dose-response assessment, endpoints selected for the previous risk 

assessment are still appropriate. A summary of the acute, subchronic, and chronic toxicity 

profile of flazasulfuron is presented in Appendix A. 
Page 10 of 38 

4.1 Summary of Toxicological Effects 

After oral administration to rats, more than 84% of the dose of flazasulfuron was excreted 

within 72 hours, mostly as parent compound. Urinary elimination accounted for about 80-90% 

of the dose and fecal elimination for about 10-20%. Females tended to eliminate more in the 

urine, and slightly more rapidly, than males. Tissue distribution was rapid but incomplete. 

While levels in tissue were generally low, the tissues with highest concentrations were the 

blood, liver, and muscle. Dermal absorption studies are not available for flazasulfuron; 

however, an estimated maximum DAF of 20% is used in this risk assessment, based on the 

range of DAFs available from dermal penetration studies for other sulfonylureas (9.1-17.7%; 

see Appendix H). 

The liver was the main target organ of flazasulfuron in most species tested, with effects 

ranging from non-adverse liver hypertrophy to more severe histopathological findings like 

inflammatory cell infiltration, hepatocellular necrosis and swelling, and bile duct proliferation. 

Rats also showed kidney toxicity (nephropathy) after chronic exposure. No adverse effects 

were observed in most short and intermediate duration (≤ 90 days) studies; only reduced body 

weight gain and non-adverse liver effects (increased weight and hepatocellular hypertrophy) 

were observed in some of the subchronic toxicity studies. 

Developmental toxicity was observed in rats and abortions in rabbits; however, findings in rats 

were not consistent across strains. A small increase in the incidence of intraventricular septal 

defect was observed in Wistar rats but not in Sprague-Dawley rats. Significant decreases in 

mean fetal body weight were observed in both rat strains at the limit dose. In the same studies, 

the maternal animals showed no adverse effects. A high incidence of abortion and decreased 

food consumption, but no specific fetal effects, were observed in rabbits. While the 

developmental studies indicate there is offspring susceptibility in rats, both rat studies provide 

clear no-observed-adverse-effect levels (NOAELs) for the adverse fetal effects. Furthermore, 

the points of departure (PODs) used for risk assessment are lower than doses associated with 

fetal effects; therefore, the assessments are protective of the observed offspring effects. 

No increase in tumor incidence was seen in rats or mice. Flazasulfuron was not genotoxic. 

There was no evidence of neurotoxicity or reproductive toxicity in the database. The acute 

toxicity data indicate that flazasulfuron has low acute oral, dermal, and inhalation toxicity. It 

was not found to be a skin irritant, but was a moderate eye irritant. Flazasulfuron was not a 

dermal sensitizer.

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

The toxicity database for flazasulfuron is complete and adequate to assess susceptibility in the 

young. While there is evidence of increased qualitative and quantitative susceptibility in the 

young based on rat developmental malformation and decreased fetal weight, the FQPA Safety 

Factor is reduced to 1X and is protective of the observed offspring susceptibility because: (1) 

there are clear NOAELs for the developmental effects in two rat studies and the PODs selected 
Page 11 of 38 

for risk assessment are protective of those effects, (2) there is no evidence of neurotoxicity, 

and (3) exposure estimates are unlikely to underestimate risk. 

4.3 Toxicity Endpoint and Point of Departure Selections

There have been no changes to the prior toxicity endpoint selections and cancer classification; 

however, the developmental studies were re-evaluated which resulted in re-evaluation of the 

dermal PODs. Some studies used for endpoint selection have conservative NOAEL/LOAEL 

values that have not been updated to reflect current standards for evaluating toxicity studies. 

Updates would result in higher NOAEL/LOAEL values and, given the current risk picture, 

would not impact the overall findings of the risk assessment. 

Dermal Endpoints for Occupational and Non-Occupational Exposure Scenarios: A dermal 

endpoint was not selected. No effects were observed in the 21-day dermal toxicity study up to 

the limit dose (1000 mg/kg/day). After re-evaluation of the developmental toxicity of 

flazasulfuron, quantitative offspring susceptibility was identified in two rat oral studies (as 

explained in section 4.1 above). In utero offspring susceptibility in animal studies is generally 

of concern for occupational risk assessment since in utero effects are not evaluated in the 

dermal toxicity study. However, in the case of flazasulfuron, dermal absorption is expected to 

be equal to or less than 20% of the oral absorption (as explained in section 4.1 above). 

Applying the 20% dermal absorption rate to the LOAELs of the rat and rabbit developmental 

studies gives estimated dermal equivalent doses well above the limit dose of 1000 mg/kg/day. 

Therefore, a dermal risk assessment was not conducted. 

Table 4.3. Summary of Toxicity Endpoints and Points of Departure for Flazasulfuron for Use in Human 

Risk Assessment. 

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

NOAEL =50 

mg/kg

UFA = 10X

UFH = 10X

FQPA SF = 

1X

Acute RfD = 0.5 

mg/kg

aPAD = 0.5 

mg/kg

Acute Neurotoxicity – Rat

LOAEL = 1000 mg/kg based on

transient decrease in motor 

activity 5 hours post-dosing. 

Chronic Dietary:

All populations

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/ 

Carcinogenicity – Rat

LOAEL = 13 mg/kg/day based 

on kidney effects (chronic 

nephropathy).
Page 12 of 38 

Table 4.3. Summary of Toxicity Endpoints and Points of Departure for Flazasulfuron for Use in Human 

Risk Assessment. 

Exposure

Scenario

Point of 

Departure

Uncertainty/

FQPA 

Safety 

Factors

RfD, PAD, Level 

of Concern for 

Risk Assessment

Study and Toxicological 

Effects

Incidental Oral: 

Short- and 

Intermediate-Term)

and

Inhalation 

Exposure: Short-, 

Intermediate- and 

Long-Term

NOAEL= 2 

mg/kg/day 

Inhalation 

toxicity assumed 

to be equivalent 

to oral.

UFA = 10

UFH = 10

FQPA SF = 

1X

Residential LOC 

for MOE = 100

Occupational 

LOC for MOE = 

100 

90-day toxicity study – Dog

LOAEL = 10 mg/kg/day based 

on based on liver effects 

(inflammatory cell infiltration, 

hepatocellular necrosis, 

hepatocellular swelling, bile duct 

proliferation).

Dermal Exposure: 

Short-, 

Intermediate- and 

Long-Term

No dermal toxicity was observed in the 21-day dermal toxicity study up to the limit dose. 

Increased susceptibility was seen in rat developmental studies; however, applying a 20% 

dermal absorption rate to developmental LOAELs gives estimated dermal equivalent doses 

well above the limit dose of 1000 mg/kg/day. Therefore, a dermal risk assessment was not 

conducted.

Cancer (oral, 

dermal, inhalation)

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 = Food Quality Protection Act 

Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin 

of exposure. LOC = level of concern. 

4.4 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic 

and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of Registration Review for flazasulfuron, EPA reviewed these data 

and selected the most sensitive endpoints for relevant risk assessment scenarios from the 

existing hazard database. However, as required by FFDCA section 408(p), flazasulfuron is 

subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 
Page 13 of 38 

EPA has developed the 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. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second 

list of chemicals identified for EDSP screening was published on June 14, 20131

 and includes 

some pesticides scheduled for Registration Review and chemicals found in water. Neither of 

these lists should be construed as a list of known or likely endocrine disruptors. 

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

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website.2

5.0 Dietary Exposure and Risk Assessment

5.1 Residue Chemistry

The nature of the residue in plants and ruminants is adequately understood based on 

metabolism studies in grapes, sugarcane, tomatoes, and goats. The residue of concern for 

plants and ruminants for both the tolerance expression and risk assessment is parent. Since no 

poultry feed items have been registered or proposed, residues in poultry have not been defined. 

Resides in the drinking water exposure assessment include parent and all identified 

degradates/metabolites (i.e., flazasulfuron, DTPU, DTPP, HTPP, TSPA, ADMP, and 2,3-

GTF). Refer to Appendix E for chemical names and structures of the flazasulfuron degradates. 

The existing residue chemistry database for flazasulfuron is adequate to support current 

Registration Review data requirements. Adequate metabolism, enforcement methods, storage 

stability, field trials, and processing data are available to support the registered uses. The 

 

1 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list 

of chemicals.

2 http://www.epa.gov/endo/
Page 14 of 38 

requirement of a confined rotational crop study to support the use on sugarcane (the only 

registered crop which is rotated) has been waived since an adequate 12-month plant-back 

restriction was placed on the label. (This waiver was based on low residues in metabolism 

studies, no detectable residues in field studies, and limited sugarcane acreage.) An analytical 

reference standard for flazasulfuron with an expiration date of 5/3/2018 is available at EPA’s 

National Pesticide Standards Repository (e-mail dated 2/4/2014 from Theresa Cole, Analytical 

Chemistry Branch/Biological and Economic Analysis Division). 

5.2 Drinking Water Residue Profile

Flazasulfuron may reach surface and/or groundwater. The drinking water residues used in the 

dietary assessment were provided by the Environmental Fate and Effects Division (EFED) in 

the following memorandum: “Drinking Water Assessment for Flazasulfuron Use on Tree 

Nuts” (A. Shelby, D411771, 12/3/2013) and were incorporated directly into the dietary 

assessment. Water residues were incorporated in the DEEM Food Commodity Intake 

Database (FCID) into the food categories “water, direct, all sources” and “water, indirect, all 

sources.” The EDWCs were determined for groundwater and surface water based on the 

Delmarva corn scenario (0.045 lb ai/A with 3 applications per year). EDWCs include total 

toxic residues of flazasulfuron in accordance with the most recent memo of the Residues of 

Concern Knowledgebase Subcommittee (ROCKS; D386767, 2/15/2011). The toxic residues 

include DTPU, DTPP, HTPP, TPSA, ADMP, and 2,3-GTF. For surface water, EDWCs were 

generated from the Pesticide Root Zone Model and Exposure Analysis Modeling System 

(PRZM-EXAMs). For groundwater, EDWCs were generated from a Tier II provisional 

groundwater model (PRZM-GW). The EDWCs for groundwater were used in the dietary 

assessment since they were higher than those for surface water. The surface and groundwater 

EDWCs are shown in Table 5.2. 

Table 5.2. Summary of Estimated Surface Water and Groundwater Concentrations for Flazasulfuron

Surface Water Conc., ppb a Tier II Groundwater Conc., 

ppb b

Acute 26.9 90.8

(highest daily value)

Chronic 4.67

(non-cancer, 1 in 10 year annual average)

55.6

(post breakthrough average)

a From the Tier I PRZM-EXAMs modeling system.

b From the Tier II provisional groundwater model (PRZM-GW). 

5.3 Dietary (Food and Drinking Water) Exposure Assessment 

An updated dietary exposure assessment is not needed for flazasulfuron for the draft risk 

assessment since an assessment was recently completed. The use pattern, PODs, and residue 

inputs to the dietary assessment have not changed since the previous assessment. 
Page 15 of 38 

The recent assessment included unrefined acute and chronic dietary (food and drinking water) 

assessments for flazasulfuron using tolerance-level residues for foods and assuming that 100% 

of the crops were treated (D417419, C. Walls, 2/5/2014). For the acute assessment, the 

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

directly into the dietary assessment. For the chronic assessment, the groundwater EDWC of 

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

assessment. 

Exposure and risk estimates were obtained from the Dietary Exposure Evaluation Model using 

the Food Commodity Intake Database (DEEM-FCID, version 3.16). The model uses food 

consumption data from the 2003-2008 NHANES/WWEIA (National Health and Nutrition 

Examination Survey, What We Eat in America) database, coupled with recipe files and

residues in foods, to derive estimates of dietary exposure and risk. Generally, HED is 

concerned when the dietary exposure estimates exceed 100% of the acute or chronic 

population adjusted dose (aPAD or cPAD). The acute and chronic dietary (food and drinking 

water) exposures to flazasulfuron are below HED’s level of concern (i.e., <100% of the aPAD 

or cPAD) for the general U.S. population and all population subgroups. The acute dietary 

exposure estimates at the 95th percentile are 1.0% of the aPAD for the general U.S. population 

and 3.1% of the aPAD for all infants (<1 year old), the most highly exposed population 

subgroup. The chronic dietary exposure estimates are 9.1% of the cPAD for the general U.S. 

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

population subgroup. Because of the conservative assumptions used in the analyses, actual 

exposures and risks are expected to be lower than shown in Table 5.3. The residue input files 

are included in Appendix B. 

Flazasulfuron is classified as “not likely to be carcinogenic to humans”; therefore, a cancer 

dietary assessment was not conducted.

Table 5.3. Summary of Dietary (Food and Drinking Water) Exposure Analysis for Flazasulfuron Using 

DEEM-FCID

Population Subgroup

Acute Dietary 

(95th Percentile) Chronic Dietary

Dietary Exposure 

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

General U.S. Population 0.004982 1.0 0.001187 9.1

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

Children 1-2 years old 0.007755 1.6 0.001769 14

Children 3-5 years old 0.006309 1.3 0.001485 11

Children 6-12 years old 0.004777 <1.0 0.001054 8.1

Youth 13-19 years old 0.004142 <1.0 0.000867 6.7

Adults 20-49 years old 0.004891 <1.0 0.001177 9.1

Adults 50-99 years old 0.004370 <1.0 0.001165 9.0

Females 13-49 years old 0.004969 <1.0 0.001173 9.0
Page 16 of 38 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are existing residential uses that have been previously assessed to reflect HED’s 2012 

Residential SOPs3

 along with policy changes for body weight assumptions (DP399890, C. 

Walls, 10/09/2012). Residential handler scenarios resulted in margins of exposure (MOEs) 

greater than the level of concern (i.e., the LOC is an MOE <100), ranging from 27,000 to 

6,800,000, and therefore are not of concern to HED. The residential short-term postapplication incidental oral scenario for children resulted in an MOE greater than the LOC of 

100 and therefore is not of concern to HED (MOEs ranged from 2,900 to 1,300,000). A 

summary of the worst-case residential exposure estimates are provided in Table 6.0. The 

recommended residential exposure for use in the adult aggregate assessment reflects inhalation 

exposure from applications to turf via backpack or manually pressurized handwand. The 

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

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

treatments. A turf transferable residues (TTR) study is not required for flazasulfuron at this 

time since there was no dermal hazard identified and the hand-to-mouth MOE is greater than 

1,000 based on default values for the fraction of application rate available for transfer after a 

turf application.

Table 6.0. Scenarios Recommended for Aggregate Risk Assessment of Flazasulfuron (Short-Term Only)

Scenario Daily Dosea MOEb

mg/kg/day LOC = 100

Adults

Handler: Inhalation Only Exposure

(Mixer/Loader/Applicator of Liquids via Backpack or 

Manually Pressurized Handwand to Residential Turf)

0.000073 27,000

Children 1 to < 2 years old

Post-Application: Hand-to-Mouth Only Exposure

(Liquid Application to Residential Turf) 0.00069 2,900

a Daily Dose = inhalation dose for adults, hand-to-mouth dose for children 1 to <2 years old. b MOE = NOAEL/Daily Dose (mg/kg/day). ST Inhalation NOAEL = ST Incidental Oral NOAEL = 2 mg/kg/day.

LOC = 100.

Spray Drift

Off-target movement of pesticides can occur via many types of pathways and it is governed by 

a variety of factors. Sprays that are released and do not deposit in the application area end up 

off-target and can lead to exposures to those it may directly contact. They can also deposit on 

surfaces where contact with residues can eventually lead to indirect exposures (e.g. children 

playing on lawns where residues have deposited next to treated fields). The potential risk 

estimates from these residues can be calculated using drift modeling coupled with methods 

employed for residential risk assessments for turf products. 

 

3 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
Page 17 of 38 

The approach to be used for quantitatively incorporating spray drift into risk assessment is 

based on a premise of compliant applications which, by definition, should not result in direct 

exposures to individuals because of existing label language and other regulatory requirements 

intended to prevent them.4

 Direct exposures would include inhalation of the spray plume or 

being sprayed directly. Rather, the exposures addressed here are thought to occur indirectly 

through contact with impacted areas, such as residential lawns, when compliant applications 

are conducted. Given this premise, exposures for children (1 to 2 years old) and adults who 

have contact with turf where residues are assumed to have deposited via spray drift thus 

resulting in an indirect exposure are the focus of this analysis analogous to how exposures to 

turf products are considered in risk assessment. 

EPA Reg. No. 71512-12 is an existing label for use on turf; thus, it was evaluated to determine 

whether the risk assessment for that use may be considered protective of any type of exposure 

that would be associated with spray drift. If the maximum application rate on crops, adjusted 

by the amount of drift expected, is less than or equal to existing turf application rates, the 

existing turf assessment is considered protective of spray drift exposure. For flazasulfuron, the 

registered residential uses on turf result in estimated exposure levels that are greater than the 

potential exposure from spray drift; therefore, no new residential assessment needs to be 

completed. The currently registered maximum single application rate of flazasulfuron for all 

registered crops is 0.047 lb ai/A. The highest degree of spray drift noted for any application 

method immediately adjacent to a treated field (Tier 1 output from the aerial application using 

fine to medium spray quality) results in a deposition fraction of 0.26 of the application rate. A 

quantitative spray drift assessment for flazasulfuron is not required because the maximum nonturf application rate to a crop/target site multiplied by the adjustment factor for drift of 0.26 is 

less than the maximum registered direct spray residential turf application rate of 0.047 lb ai/A

for any flazasulfuron products. The turf post-application MOEs have been previously assessed 

and are based on the 2012 Residential SOPs. 

7.0 Aggregate Exposure/Risk Characterization

The Food Quality Protection Act of 1996 directs EPA to assess aggregate exposure to 

pesticide chemical residues, including all anticipated dietary exposures and all other exposures 

for which there is reliable information. Aggregate exposure and risk estimates, as calculated in 

D411772 (C. Walls, 7/29/2014), are shown below. 

7.1 Acute Aggregate Risk

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

Refer to Section 5.3. 

 

4 This approach is consistent with the requirements of the EPA’s Worker Protection Standard which, when 

included on all labels, precludes direct exposure pathways.
Page 18 of 38 

7.2 Short- and Intermediate-Term Aggregate Risk

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

(which is considered background exposure) and the residential pathway (which is considered 

the primary pathway). Since intermediate-term residential exposures are not likely to occur, 

intermediate-term aggregate risks were not assessed. Since there is no dermal endpoint, the 

short-term aggregate exposure assessment for adults includes dietary (food and drinking water)

and inhalation handler exposures. The most conservative scenario was chosen for each 

population (e.g., hand-to-mouth exposure from treated turf for children 1-2 years old). For a 

description of the residential exposure scenarios considered in the aggregate assessment, see 

Section 6.0. 

1 LOC includes standard inter- (10X) and intra- (10X) species uncertainty factors totaling 100. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Table 5.4.6

4 Residential Exposure (with no dermal exposure) = [Oral exposure + Inhalation Exposure]. Source of residential 

exposure values used in the aggregate assessment (Table 7.0). Exposure estimate for adults (general U.S. 

population) includes handler exposures from treating turf with flazasulfuron. Exposure estimate for Children 1-2 

years old includes post-application exposure via hand-to-mouth to treated turf. 5 Total Exposure = (Avg Food & Water Exposure + Residential Exposure)

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

7.3 Chronic Aggregate Risk

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

Refer to Section 5.3. 

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

In 2015, EPA’s Office of Pesticide Programs released a guidance document entitled, Pesticide 

Cumulative Risk Assessment: Framework for Screening Analysis 

Table 7.2. Short-Term Aggregate Risk Calculations.

Population

Short-Term Scenario

NOAEL 

mg/kg/day LOC1 

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day3

Residential 

Exposure 

mg/kg/day4 

Total 

Exposure 

mg/kg/day5 

Aggregate 

MOE (food, 

water, and 

residential)6 

Adult 2 100 0.02 0.001187 0.000073 0.001259 1,600

Child 2 100 0.02 0.001769 0.00069 0.002459 810
Page 19 of 38 

[http://www.epa.gov/oppfead1/cb/csb_page/updates/2015/framework-for-screeninganalysis.html]. This document provides guidance on how to screen groups of pesticides for 

cumulative evaluation using a two-step approach beginning with the evaluation of available 

toxicological information and if necessary, followed by a risk-based screening approach. This 

framework supplements the existing guidance documents for establishing common mechanism 

groups (CMGs)[1] and conducting cumulative risk assessments (CRA)[2]. The Agency has 

utilized this framework to evaluate the SUs of which flazasulfuron is a member (J. 

D’Agostino; D428798; 9/9/15). Although the SUs share some chemical and toxicological 

characteristics, the toxicological database does not support a testable hypothesis for a common 

mechanism of action. No further mechanistic data are required and no further cumulative 

evaluation is necessary.

9.0 Occupational Exposure/Risk Characterization

Although exposures are expected for occupational handlers from the agricultural and turf uses 

of flazasulfuron, dermal exposure during handling activities was not considered in this 

assessment because systemic toxicity was not observed at the limit dose in the dermal study. 

The occupational handler exposure and risk estimates (Appendix D) indicate that short- and 

intermediate-term non-cancer inhalation MOEs are not of concern to HED (i.e., MOEs > 100) 

at baseline (no respirator) attire. The lowest MOE of 4,800 represents the most protective 

worst-case occupational scenario: mixing/loading dry flowables (water-dispersible granules) to 

support groundboom applications to sod. These risk estimates are not of concern to HED. 

Dermal exposure during post-application activities was not considered because no systemic 

toxicity was observed at the limit dose in the 21-day dermal toxicity study. Based on the 

Agency's current practices, a quantitative occupational post-application inhalation exposure 

assessment was not performed for flazasulfuron at this time. Since there was no dermal POD 

selected for flazasulfuron, no additional Dislodgeable Foliar Residue (DFR) data are required 

and the 40 CFR DFR data requirement (discussed in Appendix G) is waived. Also, a TTR 

study is not required for flazasulfuron at this time since there was no dermal hazard identified 

and the hand-to-mouth MOE is greater than 1,000 based on default values for the fraction of 

application rate available for transfer after a turf application (also discussed in Appendix G). 

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. 

10.0 Public Health and Pesticide Epidemiology Data

 

[1] Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common 

Mechanism of Toxicity (USEPA, 1999)

[2] Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common 

Mechanism of Toxicity (USEPA, 2002)
Page 20 of 38 

The evaluation of the OPP Incident Data System (IDS) indicated no incidents identified in the 

United States for flazasulfuron in either Main or Aggregate IDS, from January 1, 2006 to 

December 14, 2011 (D399369, S. Recore, 02/14/2012). Flazasulfuron is not included in the 

Agricultural Health Study (AHS); therefore, no information is provided in that report. No 

concern was identified that would warrant further investigation.

11.0 References

Author Barcode Date Title

C. Walls D411772 7/29/2014 Flazasulfuron: Human Health Risk Assessment for Proposed 

Uses on Tree Nuts

N. Dodd D412475 7/29/2014 Flazasulfuron. Petition for the Establishment of Permanent 

Tolerances and Registration for Use on Tree Nuts. Summary 

of Analytical Chemistry and Residue Data.

C. Walls D417419 2/5/2014 Flazasulfuron: Acute & Chronic Aggregate Dietary (Food and 

Drinking Water) Exposure and Risk Assessment for a 

Proposed New Use on Tree Nuts

C. Walls D417418 1/31/2014 Flazasulfuron: Occupational and Residential Exposure 

Assessment for a Proposed Use on Tree Nuts.

C. Walls D399358 10/15/2012 Flazasulfuron: Human Health Risk Assessment for First 

Residential Use on Turf Grass

C. Walls D399890 10/9/2012 Flazasulfuron: Occupational and Residential Exposure/Risk 

Assessment for the First Residential Use on Turf Grass.

C. Walls D399094 4/26/2012 Flazasulfuron. Human Health Assessment Scoping Document 

in Support of Registration Review

N. Dodd D394885 11/8/2011 Flazasulfuron. Amendment to Review of Analytical 

Chemistry and Residue Data for Use on Citrus, Grapes and 

Sugarcane

C. Walls D372903 6/12/2011 Flazasulfuron: Human Health Risk Assessment for Proposed 

Uses on Citrus, Grapes, Sugarcane, Christmas Trees, and 

Industrial Vegetation Management 

N. Dodd D372901 2/16/2011 Flazasulfuron. Summary of Analytical Chemistry and 

Residue Data for Use on Citrus, Grapes and Sugarcane.

K. Rury TXR #

0056483 

10/4/2012 Flazasulfuron: Summary of Hazard and Science Policy 

Council (HASPOC) Meeting of October 4, 2012: 

Recommendations on the Requirement of Repeated Exposure 

Inhalation Study.
Page 21 of 38 

Appendix A. Toxicology Profile and Executive Summaries 

A.1. Toxicology Data Requirements 

Table A.1. Flazasulfuron Data Requirements

Test Technical

Required Satisfied

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

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

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

yes

yes

yes

no

yes

yes

yes

yes

---

waived1

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

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

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

yes

yes

yes

yes

yes

yes

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

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

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

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

870.4300 Chronic Toxicity/Carcinogenicity (rodent) .................. 

yes

yes

yes

yes

no

yes2

yes

yes2 

yes

yes2

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

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

870.5385 Mutagenicity—Structural Chromosomal Aberrations.. 

870.5550 Mutagenicity—Other Genotoxic Effects...................... 

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

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

no

no

yes

yes

no

---

---

yes

yes

---

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

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

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

yes

no

yes

yes

---

yes
Page 22 of 38 

1 The requirement for this study has been waived by the HASPOC (TXR: 0056483, 10/04/2012). 2 A chronic/oncogenicity study is available for the rat, thus separate chronic and oncogenicity studies are not necessary. 

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 IV

870.1200 Acute dermal – rabbit 46220909 LD50 ≥ 2000 mg/kg III

870.1300 Acute inhalation – rat 46220910 LC50 ≥ 5 mg/L IV

870.2400 Acute eye irritation – rabbit 46220911 Minimal conjunctivitis through 

48 hours. Clear by 72 hours.

III

870.2500 Acute dermal irritation – rabbit 46220912 Not an irritant IV

870.2600 Skin sensitization – guinea pig 46220913 Not a sensitizer NA

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

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3100

90-Day Oral Toxicity in 

Rodents (rat)

46220920 (1988)

Acceptable/guideline

0, 40, 200, 1000, 5000 ppm

M: 0, 2.3, 11.7, 57, 287

F: 0, 2.5, 12.8, 62, 309 

mg/kg/day

NOAEL = 11.7/62 mg/kg/day (M/F)

LOAEL = 57/309 mg/kg/day based on reduced body 

weight gains in both sexes and slight anemia due to 

decrease in hemoglobin in females.

870.3150

90-Day Oral Toxicity in 

nonrodent (dog)

46220921 (1994)

Acceptable/guideline

M: 0, 2, 10, 50, 250

F: 0, 2, 10, 50, 100 

mg/kg/day (capsule)

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

LOAEL = 10/50 mg/kg/day based on liver effects 

(brown pigments deposition, inflammatory cell 

infiltration, microgranulomas; increased serum levels 

of glutamic pyruvic transaminase, creatine 

phosphokinase).

870.3200

21-Day dermal toxicity 

(rabbit)

46220922 (1994)

Acceptable/guideline

M: 0, 250, 500, 250, 1000 

mg/kg/day 

NOAEL = 1000 mg/kg/day 

LOAEL could not be established

870.3700a

Prenatal developmental 

in rodent (rat) 

Wistar

46220924 (1988)

Acceptable/non-guideline

0, 100, 300, 1000 mg/kg/day

Maternal NOAEL = 1000 mg/kg/day

LOAEL could not be established. 

Developmental NOAEL = 100 mg/kg/day

LOAEL = 300 mg/kg/day based on increased 

incidence of interventricular septal defect.
Page 23 of 38 

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

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3700a

Prenatal developmental 

in rodent (rat) 

Sprague-Dawley

46220925 (1996)

Acceptable/guideline

0, 100, 300, 1000 mg/kg/day

Maternal NOAEL = 1000 mg/kg/day

LOAEL could not be established. 

Developmental NOAEL = 100 mg/kg/day

LOAEL = 300 mg/kg/day based on reduced fetal 

weights.

870.3700b

Prenatal developmental 

in nonrodent (rabbit)

46220923 (1988)

Acceptable/guideline

0, 50, 150, 450 mg/kg/day

Maternal NOAEL = 150 mg/kg/day

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

abortion and decrease food consumption.

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)

Acceptable/guideline

0, 200, 2000, 10000 ppm

F0 M: 0, 14, 135, 675

F0 F: 0, 16, 155, 760

mg/kg/day

F1 M: 0, 15, 148, 761

F1 F: 0, 16, 165, 842

mg/kg/day

Parental NOAEL = 155 mg/kg/day in females only; 

was not established in males

LOAEL = 14/760 mg/kg/day (male/female) based on 

increased incidence of nephropathy in F0 males, 

kidney abnormalities in F1 females and decreased 

body weights in both generations of females. 

Reproductive NOAEL = 842 mg/kg/day

LOAEL could not be established.

Offspring NOAEL = 135 mg/kg/day 

LOAEL = 675 mg/kg/day based on decreased body 

weight during lactation in both sexes and generations.

870.4100

Chronic toxicity (dog)

46220927 (1995)

Acceptable/guideline

M: 0, 0.4, 2, 10, 50

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

(capsule)

NOAEL = 2 mg/kg/day

LOAEL = 10 mg/kg/day based on based on liver 

effects (inflammatory cell infiltration, hepatocellular 

necrosis, hepatocellular swelling, bile duct 

proliferation).

870.4200

Carcinogenicity (mouse)

46220928 (1995)

Acceptable/guideline

0, 500, 3500, 7000 ppm

M: 0, 77, 553, 1054

F: 0, 94, 660, 1208 

mg/kg/day

NOAEL = 77 mg/kg/day

LOAEL = 553 mg/kg/day based on decreased body 

weight, body weight gain, food consumption, and 

liver effects (increased weight and hepatocellular 

hypertrophy).

No evidence of carcinogenicity.

870.4300

Chronic 

Toxicity/Carcinogenicity 

(rat)

46220929 (1995)

Acceptable/guideline

0, 40, 400, 2000 ppm 

M: 0, 1.3, 13, 70

F: 0, 1.6, 16., 173 mg/kg/day

NOAEL = 1.3 mg/kg/day

LOAEL = 13 based on kidney effects (chronic 

nephropathy, enlargement, dark color).

No evidence of carcinogenicity.
Page 24 of 38 

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

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.5100

Bacterial Reverse 

Mutation Test (S. 

typhimurium and E. coli) 

46220933 (1987)

Acceptable/guideline

20 -5000 μg/plate 

Flazasulfuron was not cytotoxic with or without 

metabolic activation in four S. typhimurium strains 

and one strain of E. coli, and did not induce a 

genotoxic response in any strain. 

870.5300 

In vitro Mammalian Cell 

Gene Mutation Test

(mouse lymphoma cells)

46220930 (1993)

Acceptable/guideline

20 - 5000 μg/mL

There was no evidence of biologically significant 

induction of mutant colonies.

870.5375 

In vitro Mammalian 

Chromosome Aberration 

Test (Chinese hamster 

lung cells) 

46220931 (1988)

Acceptable/guideline

0.000021 – 0.00033 M 

Flazasulfuron did not induce chromosome 

aberrations in the presence or absence of metabolic 

activation.

870.5395

Mammalian Erythrocyte 

Micronucleus Test 

(mouse)

46220932 (1995)

Acceptable/guideline

0, 1250, 2500, 5000 mg/kg

There was no statistically significant increase in the 

frequency of micronucleated polychromatic 

erythrocytes in mouse bone marrow at any dose or 

collection time. 

870.6200a

Acute Neurotoxicity 

Screening Battery (rat)

46220934 (2002)

Acceptable/non-guideline 

0, 50, 1000, or 2000 mg/kg

NOAEL = 50 mg/kg/day

LOAEL = 1000 mg/kg based on transient decrease in 

motor activity observed 5 hours post-dosing. 

870.6200b

Subchronic 

Neurotoxicity Screening 

Battery (rat)

49030001 (2012)

Acceptable/guideline 

0, 300, 3000, or 10000 ppm

M: 0, 19, 190, 649

F: 0, 22, 229, 732 mg/kg/day

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

LOAEL = 732 mg/kg/day based on decreased body 

weight and body weight gain.
Page 25 of 38 

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

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.7485

Metabolism and 

Pharmacokinetics (rat)

46220936 (1995)

46220938 (1994)

46220940 (1994)

46220942 (1995)

Acceptable/guideline

2 or 50 mg/kg pyridinyl ring 

label (P)

46220937 (1995) 

46220939 (1995)

46220941 (1995)

46220943 (1995)

Acceptable/guideline

2 or 50 mg/kg pyrimidinyl 

ring label (Pm)

Generally no difference between dose levels or single 

versus repeated dose, but differences were noted 

between males and females, and between P and Pm 

labels. Both labels rapidly absorbed: males 84-99% 

females 93-95% by 48 hr. P tmax was 30 min at 2 

mg/kg both sexes; 4 hr in females and 6 hr in males 

at 50 mg/kg. Pm tmax was slightly higher: 6 hrs at 2 

mg/kg and 4 hrs at 50 mg/kg. Males had slightly 

longer t1⁄2 (27/28 and 36/26 hr, for P/Pm) than 

females (18.8/17 and 33.8/17 hr); and greater AUC 

(304/361 and 4440/6630 μg-eq/g·hr) than females 

(189/259 and 3080/5710 μg-eq/g·hr). Excretion was 

also rapid (48-72 hrs): urine was major route: 73-

80% males, 89-94% females; feces 18-24% male, 9-

10% female; bile 8.4-17.0% with males slightly more 

than females. Tissue distribution was rapid but

incomplete. Total body burdens ≤4/2% males and 

≤1/0.3% females (P/Pm). Blood, liver, and muscle 

had highest concentrations (0.03-1.0% per tissue); the

carcass had up to 2.5%. 

870.7485

Metabolism and 

Pharmacokinetics (rat)

46220935 (1995)

Acceptable/guideline

2 or 50 mg/kg P or Pm

Parent compound was primary component in urine 

(19-40% males, 51-67% females), feces (1-5%), and 

bile (0.6-2%). Most prevalent metabolite was 

HDTG+TPPG (6.5-17% urine, 0.4-9.7% feces, 6.5-

14% in bile), with minor amounts (<5%) of DTPU, 

HDPU and HTTP for both labels; TPSA and MTMG

for P only; and ADMP and HDU for Pm only. 

Unidentified fraction < 2% of dose in urine and bile 

except high dose Pm males was 12%; up to 35% in 

feces. Proposed metabolic pathway: intramolecular

rearrangement within the sulfonylurea bridge, 

cleavage at the sulfonylurea bridge, pyrimidine 

hydroxylation followed by glucuronidation at the 5-

position or the at methoxy group, displacement 

reaction by glutathione at the 2-position of the 

pyridine ring followed by formation of glucuronic 

acid conjugate of pyridine thiol.

870.7800

Immunotoxicity (female 

mouse)

48870301 (2012)

Acceptable/guideline

0, 600, 3000, 6000 ppm

0, 123, 663, 1198 mg/kg/day

NOAEL = 1198 mg/kg/day

LOAEL could not be established.
Page 26 of 38 

A.3 Hazard Identification and Endpoint Selection

The Hazard Identification and Endpoint Selection sections are presented a previous risk 

assessment document (D303573, Burke G.V., 11/16/05).

 

A.4 Executive Summaries

The following executive summaries are from studies that have been recently re-evaluated, 

leading to changes in their NOAEL/LOAEL statements. Executive summaries for other 

flufenacet studies are presented in the previous risk assessment document (D303573, Burke G.V., 

11/16/05). 

A.4.1 Prenatal Developmental Toxicity

 870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRID 46220924), SL-160 Technical (96.3% a.i., lot # 

8706) was administered to 23 female Wistar rats/dose by gavage at dose levels of 0, 100, 300, 

or 1000 mg/kg bw/day on days 6 through 15 of gestation. On gestational day (GD) 21, all 

surviving dams were sacrificed and examined grossly. Each fetus was weighed and examined 

externally for abnormalities and for sex determination. Approximately one-half of the fetuses 

in each litter were examined viscerally after fixation in Bouin’s solution. The remaining onehalf of the fetuses in each litter were eviscerated and processed for skeletal examination.

In maternal animal, no treatment-related deaths or clinical signs of toxicity were observed and 

gross necropsy was unremarkable. Mid dose animals had transient decreases in body weight 

gain (50%; p ≤ 0.01) and food consumption (11%; p ≤ 0.05) compared to controls during GD 

6-9, but mean absolute body weight was not different from controls. Absolute body weight of 

the high dose group was significantly less than that of the controls (6-7%; p ≤ 0.01) beginning 

on GD 9 and continuing until termination; body weight gains and food consumption were also 

less than controls for the GDs 6-9 and 12-15 intervals. However mean food consumption for 

the high dose group increased significantly (13%) on GD 18-21 and body weight gain was 

similar to controls during the same time period, suggesting a recovery. There were no 

abortions or other indications of maternal toxicity. The maternal LOAEL for Wistar rats 

was not observed. The maternal NOAEL is ≥ 1000 mg/kg/day. 

No treatment-related differences were noted between the treated and control groups for 

numbers of corpora lutea and implantations, placental weight, fetal sex ratios, and preimplantation losses. Male and female fetal body weights of the high-dose group were 

significantly less (8% for each sex; p ≤ 0.01) than control. The high-dose group showed a 

non-statistically significant increases in fetal mortality (20.8% vs 5.5% for controls), 
Page 27 of 38 

resorptions (69 vs 19 for controls), and post-implantation loss (21.6% vs 6% for controls). 

While most dams in the control, low and mid dose groups had 10-17 live fetuses and 0-3 

resorptions each, two high dose dams had complete litter resorption of 16 and 17 

implantations, respectively, and two other dams had partial but significant resorptions of 9/12 

implants and 5/18, respectively. 

Only a few malformations/variations seemed to increase with dose, and the incidence was 

generally low. A significantly (p≤0.05) greater number of high dose litters contained fetuses 

with interventricular septal defect (ISD), and the litter incidences seem to be dose-dependent 

starting at the mid dose (p > 0.5), with 1, 1, 6, and 7 litters in control, low, mid, and high dose 

groups, respectively. The fetal incidence of ISD at the high dose (6.6%, 8/122 fetuses) was 

slightly higher than the laboratory historical control incidence (0-5.3%). A significantly (p ≤ 

0.05) greater number of high dose litters contained fetuses with an extra 14th rib, compared to 

no litters in the control and low dose groups, and 2 litters in the mid dose group; however this 

variation is usually reversible as pups mature (Wickramaratne, 1988; J Appl Toxicol. 1988 

Apr;8(2):91-4) especially when it does not co-occurs with sacral vertebrae variations (Foulon 

et. al., 2000 J. Appl. Toxicol. 20, 205–209) as is noted in the current study, and is therefore not 

considered adverse. Delayed ossification in high dose fetuses was indicated by a significantly 

(p ≤ 0.05) lower percentage of fetuses with 5 ossified metatarsals (72.8% vs 99.4% for the 

controls), however this is also a reversible effect and is not considered adverse. The 

developmental LOAEL in Wistar rats is 1000 mg/kg/day based on increased incidence of 

interventricular septal defect. The developmental toxicity NOAEL is 300 mg/kg/day. 

This developmental toxicity study in the rat is classified acceptable (non-guideline) and only 

partially satisfies the guideline requirements for a developmental toxicity study (OPPTS 

870.3700; OECD 414) in rats. This study is upgradable if laboratory methods and data are 

provided for concentration and homogeneity analyses of the test substance in the dosing 

solution. 
Page 28 of 38 

Appendix B. Dietary Exposure/Risk Modeling Input Files

Acute Food and Water Residue Input File 

Filename: C:\Documents and Settings\cwalls\My Documents\Cassi\HED\Flazasulfuron\2014 tree 

nuts\acute FLAZ 012914.R08

Chemical: Flazasulfuron

RfD(Chronic): .013 mg/kg bw/day NOEL(Chronic): 1.3 mg/kg bw/day

RfD(Acute): .5 mg/kg bw/day NOEL(Acute): 50 mg/kg bw/day

Date created/last modified: 01-23-2014/16:41:25 Program ver. 3.16, 03-08-d 

-----------------------------------------------------------------------------------

 EPA Crop Def Res Adj.Factors Comment

 Code Grp Commodity Name (ppm) #1 #2 

---------- ---- ------------------------------- ---------- ------ ------ -------

1001106000 10A Citron 0.010000 1.000 1.000 

1001107000 10A Citrus hybrids 0.010000 1.000 1.000 

1001108000 10A Citrus, oil 0.010000 1.000 1.000 

1001240000 10A Orange 0.010000 1.000 1.000 

1001241000 10A Orange, juice 0.010000 1.000 1.000 

1001241001 10A Orange, juice-babyfood 0.010000 1.000 1.000 

1001242000 10A Orange, peel 0.010000 1.000 1.000 

1001369000 10A Tangerine 0.010000 1.000 1.000 

1001370000 10A Tangerine, juice 0.010000 1.000 1.000 

1002197000 10B Kumquat 0.010000 1.000 1.000 

1002199000 10B Lemon 0.010000 1.000 1.000 

1002200000 10B Lemon, juice 0.010000 1.000 1.000 

1002200001 10B Lemon, juice-babyfood 0.010000 1.000 1.000 

1002201000 10B Lemon, peel 0.010000 1.000 1.000 

1002206000 10B Lime 0.010000 1.000 1.000 

1002207000 10B Lime, juice 0.010000 1.000 1.000 

1002207001 10B Lime, juice-babyfood 0.010000 1.000 1.000 

1003180000 10C Grapefruit 0.010000 1.000 1.000 

1003181000 10C Grapefruit, juice 0.010000 1.000 1.000 

1003307000 10C Pummelo 0.010000 1.000 1.000 

1304175000 13D Grape 0.010000 1.000 1.000 

1304176000 13D Grape, juice 0.010000 1.000 1.000 

1304176001 13D Grape, juice-babyfood 0.010000 1.000 1.000 

1304179000 13D Grape, wine and sherry 0.010000 1.000 1.000 

1400003000 14 Almond 0.010000 1.000 1.000 

1400003001 14 Almond-babyfood 0.010000 1.000 1.000 

1400004000 14 Almond, oil 0.010000 1.000 1.000 

1400004001 14 Almond, oil-babyfood 0.010000 1.000 1.000 

1400059000 14 Brazil nut 0.010000 1.000 1.000 

1400068000 14 Butternut 0.010000 1.000 1.000 

1400081000 14 Cashew 0.010000 1.000 1.000 

1400092000 14 Chestnut 0.010000 1.000 1.000 

1400155000 14 Hazelnut 0.010000 1.000 1.000 

1400156000 14 Hazelnut, oil 0.010000 1.000 1.000 

1400185000 14 Hickory nut 0.010000 1.000 1.000 

1400213000 14 Macadamia nut 0.010000 1.000 1.000 

1400269000 14 Pecan 0.010000 1.000 1.000 

1400278000 14 Pine nut 0.010000 1.000 1.000 

1400282000 14 Pistachio 0.010000 1.000 1.000 

1400391000 14 Walnut 0.010000 1.000 1.000 

8601000000 86A Water, direct, all sources 0.090800 1.000 1.000 

8602000000 86B Water, indirect, all sources 0.090800 1.000 1.000 

9500177000 O Grape, leaves 0.010000 1.000 1.000 

9500178000 O Grape, raisin 0.010000 1.000 1.000 

9500362000 O Sugarcane, sugar 0.010000 1.000 1.000 

9500362001 O Sugarcane, sugar-babyfood 0.010000 1.000 1.000 
Page 29 of 38 

9500363000 O Sugarcane, molasses 0.010000 1.000 1.000 

9500363001 O Sugarcane, molasses-babyfood 0.010000 1.000 1.000 
Page 30 of 38 

Chronic Food and Water Residue Input File 

Filename: C:\Documents and Settings\cwalls\My Documents\Cassi\HED\Flazasulfuron\2014 tree 

nuts\chronic FLAZ 012914.R08

Chemical: Flazasulfuron

RfD(Chronic): .013 mg/kg bw/day NOEL(Chronic): 1.3 mg/kg bw/day

RfD(Acute): .5 mg/kg bw/day NOEL(Acute): 50 mg/kg bw/day

Date created/last modified: 01-23-2014/16:40:39 Program ver. 3.16, 03-08-d 

-----------------------------------------------------------------------------------

 EPA Crop Def Res Adj.Factors Comment

 Code Grp Commodity Name (ppm) #1 #2 

---------- ---- ------------------------------- ---------- ------ ------ -------

1001106000 10A Citron 0.010000 1.000 1.000 

1001107000 10A Citrus hybrids 0.010000 1.000 1.000 

1001108000 10A Citrus, oil 0.010000 1.000 1.000 

1001240000 10A Orange 0.010000 1.000 1.000 

1001241000 10A Orange, juice 0.010000 1.000 1.000 

1001241001 10A Orange, juice-babyfood 0.010000 1.000 1.000 

1001242000 10A Orange, peel 0.010000 1.000 1.000 

1001369000 10A Tangerine 0.010000 1.000 1.000 

1001370000 10A Tangerine, juice 0.010000 1.000 1.000 

1002197000 10B Kumquat 0.010000 1.000 1.000 

1002199000 10B Lemon 0.010000 1.000 1.000 

1002200000 10B Lemon, juice 0.010000 1.000 1.000 

1002200001 10B Lemon, juice-babyfood 0.010000 1.000 1.000 

1002201000 10B Lemon, peel 0.010000 1.000 1.000 

1002206000 10B Lime 0.010000 1.000 1.000 

1002207000 10B Lime, juice 0.010000 1.000 1.000 

1002207001 10B Lime, juice-babyfood 0.010000 1.000 1.000 

1003180000 10C Grapefruit 0.010000 1.000 1.000 

1003181000 10C Grapefruit, juice 0.010000 1.000 1.000 

1003307000 10C Pummelo 0.010000 1.000 1.000 

1304175000 13D Grape 0.010000 1.000 1.000 

1304176000 13D Grape, juice 0.010000 1.000 1.000 

1304176001 13D Grape, juice-babyfood 0.010000 1.000 1.000 

1304179000 13D Grape, wine and sherry 0.010000 1.000 1.000 

1400003000 14 Almond 0.010000 1.000 1.000 

1400003001 14 Almond-babyfood 0.010000 1.000 1.000 

1400004000 14 Almond, oil 0.010000 1.000 1.000 

1400004001 14 Almond, oil-babyfood 0.010000 1.000 1.000 

1400059000 14 Brazil nut 0.010000 1.000 1.000 

1400068000 14 Butternut 0.010000 1.000 1.000 

1400081000 14 Cashew 0.010000 1.000 1.000 

1400092000 14 Chestnut 0.010000 1.000 1.000 

1400155000 14 Hazelnut 0.010000 1.000 1.000 

1400156000 14 Hazelnut, oil 0.010000 1.000 1.000 

1400185000 14 Hickory nut 0.010000 1.000 1.000 

1400213000 14 Macadamia nut 0.010000 1.000 1.000 

1400269000 14 Pecan 0.010000 1.000 1.000 

1400278000 14 Pine nut 0.010000 1.000 1.000 

1400282000 14 Pistachio 0.010000 1.000 1.000 

1400391000 14 Walnut 0.010000 1.000 1.000 

8601000000 86A Water, direct, all sources 0.055600 1.000 1.000 

8602000000 86B Water, indirect, all sources 0.055600 1.000 1.000 

9500177000 O Grape, leaves 0.010000 1.000 1.000 

9500178000 O Grape, raisin 0.010000 1.000 1.000 

9500362000 O Sugarcane, sugar 0.010000 1.000 1.000 

9500362001 O Sugarcane, sugar-babyfood 0.010000 1.000 1.000 

9500363000 O Sugarcane, molasses 0.010000 1.000 1.000 

9500363001 O Sugarcane, molasses-babyfood 0.010000 1.000 1.000 
Page 31 of 38

Appendix C. Review of Human Research

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

intentionally exposed to a pesticide or other chemical. These data are subject to ethics review 

pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics 

requirements. For certain studies that review may have included review by the Human Studies 

Review Board. Descriptions of data sources as well as guidance on their use can be found at: 

http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html. 
Page 32 of 38

Appendix D. Occupational Non-cancer Handler Exposure Estimates and Algorithms. 

Potential daily exposures for occupational handlers are calculated using the following formulas: 

E=UE * AR * A * 0.001 mg/ug

where:

E = exposure (mg ai/day), 

UE = unit exposure (μg ai/lb ai), 

AR = maximum application rate according to registered labels (lb ai/A), and 

A = area treated or amount handled (e.g., A/day). 

 

The daily doses are calculated using the following formula:

ADD= 

E * AF

BW

where:

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day), 

E = exposure (mg ai/day), 

AF = absorption factor (inhalation), and 

BW = body weight (kg). 

Margin of Exposure: Non-cancer risk estimates for each application handler scenario are 

calculated using a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint to 

the daily dose of concern. The daily inhalation dose received by occupational handlers is

compared to the appropriate POD (i.e., NOAEL) to assess the risk to occupational handlers. All 

MOE values are calculated using the following formula: 

MOE= 

POD

ADD

where:

MOE = margin of exposure: value used by HED to represent risk estimates (unitless),

POD = point of departure (mg/kg/day), and

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day). 
Page 33 of 38

Appendix E. Nomenclature and Physical/Chemical Properties

Table E.1. Flazasulfuron Nomenclature.

Chemical Structure

Empirical Formula C13H12F3N5O5S

Common Name flazasulfuron

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

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

pyridinesulfonamide

CAS Registry Number 104040-78-0

Chemical Class Sulfonylurea herbicide

Table E.2. Chemical Names and Structures for Flazasulfuron Metabolites

Common name/code Chemical name Chemical structure

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
Page 34 of 38

Table E.2. Chemical Names and Structures for Flazasulfuron Metabolites

Common name/code Chemical name Chemical structure

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

pyridinyl]amino]-4-pyrimidinol

TPSA 3-(trifluoromethyl)-2-

pyridinesulfonamide

2,3-GTF 3-trifluoromethyl-2-pyridylguanidine

Table E.3. Physical/Chemical Properties of Flazasulfuron.

Parameter Value Reference (MRID)

Color Cream 46220905

Physical State Granular solid

Odor Strong lawn fertilizer

Melting point 150°C

pH 4.01 at 25°C (1% w/w)

Density 0.66 g/cm3 at 25°C (bulk density)

Water solubility at 20°C pH 5 buffer 0.027 mg/mL

pH 7 buffer 2.1 mg/mL

pH 9 buffer not stable

Solvent solubility at 20°C Acetone 22.7 mg/mL

Acetonitrile 8.7 mg/mL

Dichloromethane 22.1 mg/mL

Ethyl acetate 6.9 mg/mL

Hexanes* 0.50 μg/mL

Methanol 4.2 mg/mL

Octanol 0.20 mg/mL

Toluene 0.56 mg/mL

Vapor pressure <1 x 10-7 mmHg (<1.33 x 10-5 Pa) at 25, 35, and 45°C

Dissociation constant, pKa 4.37 at 20°C

Octanol/water partition 

coefficient, Log(KOW)

Kow = 20.0 in pH 5 buffer

Kow = <10 in pH 7 buffer

UV/visible absorption spectrum Not reported

*n-hexane with various methylpentanes
Page 35 of 38

Appendix F. International Harmonization 

Flazasulfuron (119011; 4/06/2015) 

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex

40 CFR §180.655

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)

None None

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

US Canada Mexico2 Codex

Almond, hulls 0.01

Fruit, citrus, group 10-10 0.01

Grape 0.01

Nut, tree, group 14-12 0.01

Sugarcane 0.01

Completed: M. Negussie; 4/10/2015 1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
Page 36 of 38

Appendix G. DFR and TTR Data Waiver Rationales 

Dislodgeable Foliar Residue (DFR): In accordance with 40 CFR §158, DFR data are required 

for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and 

vegetable gardens, pick your own farms, retail tree farms) uses that could result in postapplication exposure to foliage. In the absence of chemical-specific DFR data, EPA uses default 

values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment 

includes an analysis of a number of DFR studies, which resulted in the selection of revised 

default values for the fraction of the application rate available for transfer after a foliar 

application (FAR). These values are based on an analysis of 19 DFR studies. Since that time, 

the Agricultural Re-entry Task Force has submitted information (MRID 49299201) that corrects 

an application rate error made in the original submission of “ARF039 – Determination of Dermal 

and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a Greenhouse” 

(EPA MRID 45344501). As a result, the range of FAR values was revised from 2% - 89% to 2% 

- 47%. In the data, a large range of transferability is observed and this variability can potentially 

be attributable to many factors such as active ingredient, formulation, field conditions in the 

studies, weather conditions (e.g., humidity), or many other difficult to quantify 

factors. Although witnessed across multiple chemicals, this range in FAR values is not expected 

when considering DFR data for a single chemical. At this time, the ARTF submission did not 

alter the selection of 25% as the reasonable, high-end default value. 

Since there was no dermal POD selected for flazasulfuron, an occupational post-application 

assessment is not required at this time. Therefore, no additional DFR data are required and the 

40 CFR DFR data requirement is waived. 

Turf Transferable Residue (TTR): In accordance with the updated Part 158 data requirements 

(2007), a TTR study is required for all occupational (e.g., sod farms, golf courses, parks, and 

recreational areas) or residential turf uses. As part of the recent revision to the Health Effects 

Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, 

HED analyzed all available data and selected new liquid and granular default values for the 

fraction of the application rate available for transfer after a turf application (FAR).5

 These 

defaults are 1% for formulations applied as liquids (i.e., emulsifiable concentrates, liquids, 

wettable powders, dry flowables, etc.) and 0.2% for granular formulations. Of the available TTR 

studies submitted to the Agency, the maximum FAR value seen using a liquid product was 6.1% 

or 6.1 times higher than the default residue transfer value. The maximum FAR value seen in a 

TTR study using a granular product was 0.69% or 3.5X the default residue transfer value. 

Therefore, for both liquid and granular formulations, a calculated MOE of approximately 10 

times higher than the level of concern (e.g., an MOE > 1,000 if the LOC = 100) using the default 

residue transfer values would provide an adequate margin of safety for any potentially higher 

residues seen in a chemical-specific TTR study (Guidance for Requiring/Waiving Turf 

Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies. 6/7/2012, 

Exposure Science Advisory Council). A TTR study is not required for flazasulfuron at this time 

 

5 http://www.epa.gov/pesticides/science/residential-exposure-sop.html
Page 37 of 38

since there was no dermal hazard identified and hand-to-mouth MOE is greater than 1,000 based 

on default values for the fraction of application rate available for transfer after a turf application.
Page 38 of 38

Appendix H. Estimated Dermal Absorption Factors (DAF)

Table H. Structure-Activity Relationship (SAR) Data for Sulfonylureas Technical 

Formulations with Available Experimental or Estimated Dermal Absorption 

Factors (DAF)

Chemical MW Log Kow1 DAF DAF Basis/Dermal Penetration

Bensulfuron-methyl 410.4 0.79 4.7% Unpublished in vivo rat study not submitted to 

EPA (DuPont HLR 120-902). 

Chlorimuron-ethyl 414.8 2.50 4.8% Dermal NOAEL / oral LOAEL extrapolation3

Flazasulfuron 407.3 1.08 20% Estimated maximum per SAR analysis (Log Kp 

= -4.46) based on tribenuron-methyl (Log Kp = -

4.51, DAF = 17.7%).

Iodosulfuron-methylsodium 529.2 -0.70 11% 1-6% per in vivo rat study; however 11% used 

because data indicates absorption continues after 

exposure. 

Mesosulfuron-methyl 503.6 -0.48 NA An unacceptable/guideline rat in vivo study 

indicates 11.9-26.3%. European document 

indicates 9% (SANCO/1 0298/2003-final2).

Nicosulfuron 410.4 -1.74 0.021-

0.23%

Unpublished in vitro human studies not 

submitted to EPA (DuPont 21540 and 255192).

Oxasulfuron 406.4 -0.81 1% Unpublished in vitro rat and human, and in vivo

rat studies not submitted to EPA (EC 

SANC0/4323/20022).

Primisulfuron 468.3 1.15 (pH 5.0) 30% Dermal NOAEL / oral LOAEL extrapolation3

Rimsulfuron 431.4 -1.46 20% Estimated maximum per SAR analysis (Log Kp 

= -6.41) based on iodosulfuron (Kow = -6.24, 

DAF = 11%). 0.18-0.4% per unpublished in 

vitro human skin not submitted to EPA (DuPont 

24335, 25519 and 246002).

Tribenuron-methyl 395.4 0.78 17.7% Per in vivo rat study

Trifloxysulfuronsodium 459.3 -0.42 30% Dermal NOAEL / oral LOAEL extrapolation3

Tritosulfuron 445.3 0.62 1% Unpublished in vitro rat and human, and in vivo

rat studies not submitted to EPA (EC 

SANC0/1256/08-rev.12).

1 Log Kow measured at pH=7 unless otherwise indicated.

2 Concentrate chemical data excerpted in a DuPont submission, MRID 48904001. That document also has some 

dilute formulation DAFs, which were not considered here.

3 Calculated by dividing the dermal study NOAEL (when no LOAEL was observed) by a subchronic oral LOAEL. 

Because no dermal toxicity was observed, this will lead to an artificially high DAF.