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

## f A t UNITE D STATES ENVIRONMENTAL PROTECTION AGENCY

## \S~ "'

... ,t 

### WASHINGTON

, D.C. 20460

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



### MEMORANDUM

Date: September 1 5

, 20 1 5 OFFIC E OF

C H EM I CAL SAFE TY AND

POLLUTION PREVENTION



### SUB J EC T : Flazasulfuron. Human Health Draft Ri sk Assessmen t for Reg i s tration R eview.

PC Co d e: 11 9 011

D ecis i o n No.: 502405

Petition No .: NJ\



### Ri s k As s e ss m e nt T y p e: Single C h emical / Agg r ega t e

TXR No.: NA



### MRID No.: NA DP Barcode: 0426196

R eg i s tration Nos. : 71512-12

, 715 1 2 -18

R eg ulatory Action: R eg i st ration Re v iew

Case No .: 

### N I A

CAS No.: I 

### 04040

- 78-0

40 CF R: § 

### 180 .655

FR OM: Na n cy Dodd

, R i sk Assesso r / Chem i s t

## ~**h'~** Nancy K e ll er
, Occupational/Residential Ex po s ur e

Minerva Mercado

,

### Toxicolog**~** 

# A**~** Ri s k Assessme nt B ra nch 

### III (RAB3)

THROUGH: Christine Olin ger, Branch Chief / / H ea l th Effects Di visio n ( HED ; Zt 7509P) )

,

RAB3/HED (75 09P) 

# r

TO: Thomas Mori a rty / Ricardo Jon es, RM 5 1

R i s k Managemen t a nd Implementation B ranc h 1

P es ticid e Re -Eva lu at i on Divi s ion (7508P)

As part of R eg i s t ra tion Re v i ew
, th e P es ti c ide R e -e va lua tio n Di vis ion ( PRD ) of th e Office of

Pesticide Programs (OP P ) h as requ ested that HED eva lu a t e the h aza rd and ex po s ure d a ta and

co ndu ct occupat i ona l and r eside nti a l exposure assess ment s
, as n eeded

, to est im ate th e risk to

human h ea lth that will r esult from th e currently r eg i s ter ed u ses of p est i c i des. Th i s
memorandum serves as H E D 's draft hum a n h ea lth ri sk assessment of th e die tar y
, occupa t ional

, and residential expos ur e, a nd aggregate ri sk from the r egis t e r e d uses of

n azasu l furon.

P age 1 

### of 3 8

### 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 Environme ntal 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- pyrimidiny l)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 C FR §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 re creational 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 ; t herefore, the endpoints selected for the previous risk assessment are still appropriate. There are no outstanding human health data deficiencies.

The toxicology d atabase for flazasulfuron is adequate to support current registration requirements. Since the last human health risk assessment and scoping document, a new immunotoxicit y 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 th e 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

req uirements. 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 th e currently established tolerances.

The dietary exposure data used in this risk assessment w ere 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,

t he ground water estimated drinking water concentration ( EDWC ) of 90.8 μ g/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, t he ground water EDWC of 55.6 μ g/L from the Tier II PRZM

- GW

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

.

T he ac ute 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 95 th 

### percentile are 1.0% of the a PAD for the general U.S. population

and 3.1% of the a PAD for all infants (<1 year old), the most highly exposed population subgroup. The chronic dietary exposure estimates are 9.1% of the c PAD for the general U.S. population and 23% of the c PAD 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 c hronic aggregate exposure is equal to the chronic dietary (food and drinking water) exposure. T he 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, intermediate

te rm 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 flaza sulfuron 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 f rom 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 Rec ommendations

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 flazasulfu ron , 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 K
ow 

### ) 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 2 0 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

r egistered 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 ) formulation s 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.

T able 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

Limitations 1

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

Pre

- emergence
and Post

emergence; 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 Post

emergence; 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 T able 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

Limitations 1

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

betwe en the last application and the planting of the rotational

crop.

TREE NUTS ( Hazelnut; Pecan; Pistachio; Black Walnut; English Walnut; A frican nut

- tree; Beechnut; Brazil nut; Brazilian pine; Bunya; Bur oak; Butternut; Cajou nut; Candlenut; Cashew; Chestnut; Chinquapin; Coconut; Coquito nut; Dika nut; Ginkgo; Guiana ch es tnut; Heartnut; Hickory nut; Japanese horse

- chestnut; Macadamia nut; Mongongo nut; Monkey

pot; Monkey puzzle nut; Okari nut; Pa chira nut; Peach palm nut; Pequi ; Pili nut; Pine nut; Sapucaia nut; Tropical
almond; Yellowho rn )

Pre

- emergence and post

emergence; 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 post

emergence; 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 c oncentration.

C ONIFER (CHRISTMAS) TREES

### Page 8 of 38 T able 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

Limitations 1

Pre

- emergence
and Post

emergence ; 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

equ ip ment 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

– 0.047 2
( spot treatment) Not reported 0.14 14 (broad

cast);

21 (spot

treat ment) NA Multiple applications can be

made.

T URF

- Residential

Postemergence; Spot treatment

with directed

spray;
Ground equipment Flazasulfuron

25WG
[71512

- 12] 0.024

– 0.047 2

0.0011 lb

ai/gal

1.1 x 10 -6

lb ai/ft 2 Not reported 0.14 21 NA Residential turf grass sites

are limited to targeted or spot treatment wih s pray
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 a n adjuvant

is recommended for p ost emergence 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 assess ment, 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, s pecialized 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 t o bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization

The toxicology database for flaza sulfuron is complete. The latest risk assessment was conducted in 2014 (D411772, C. Walls, 7/29/2014). The data requirement for a n 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

immunotoxicit y study has been reviewed , and the rat developmental studies have been re

evaluated since the previous risk assessment according to current standards for toxicity

evalu ation. Since the new ly 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 li ver hypertrophy to more severe histopathological findings like inflammatory cell infiltration, hepatocellular necrosis and swelling, and bile duct proliferation

. R ats 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 stu dies

.

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 h igh incidence of abortion and decreased food consumption, but no s pecific 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 mi ce. 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 NOAEL s 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 neurotoxi city, 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 re sult in higher NOAEL/LOAEL values and, given the current risk picture, would not impact the overall f indings 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 explai ned 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 wel l above the limi t dose of 1000 mg/kg/day.
Therefore, a dermal risk assessment was not conducted.

Table 4. 3. Summary of Toxicity Endpoints and P oints 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 UF A = 10X

UF H = 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 UF A = 10X

UF H = 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 P oints 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. UF A = 10

UF H = 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, a pplying 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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 gene ral 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 flazasulf uron, 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 oc curring 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 r elationship 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 c ontains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 

### 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 batt ery, 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 t o support current

R egistration Review data req uirements. 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://w ww.epa.gov/endo/

### Page 14 of 38 requirement of a c onfined 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

studi es, 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 T heresa 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 EDWC s 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 Residue s of Concern Knowledge base 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, EDWC s were generated from a Tier II provisional groundwater model (PRZM- GW). The EDWC s for ground water w ere 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 a n assessment was recently completed. The use pattern, POD s, 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)

assessmen ts for flazasulfuron using tolerance-level residues for foods and assuming that 100% of the crops were treated (D41 7419, C. Walls, 2/5/2014 ). For the acute assessment, the ground water EDWC of 90.8 μ g/L from the Tier II PRZM -GW modeling was incorporated

di rectly into the dietary assessment . For the chronic assessment, t he ground water EDWC of 55.6 μ g/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 deriv e 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 (a PAD or cPAD ). T he 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 95 th 

### percentile are 1 .0 % of the a PAD 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 c PAD for the general U.S. population and 23% of the c PA D for all infants (<1 year old), the most highly exposed population subgroup. Because of the conservati ve assumptions used in the analyses, actual exposures and risks are expected t o be lower than shown in Table 5.3. The residue input files

are included in Appendix B.

Flazasulf uron is classified as “no t 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 (95 th 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 SOPs 3 

### 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 resid ential 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 e stimate s 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 h azard 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 Dose a MOE b

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 tre ated 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 i nto 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 a ssociated 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, t he 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 max imum nonturf application rate to a crop/ta rget site multiplied by the adjustment facto r 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 SOP s.

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 estim ates, 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, t he

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 est imate 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 + Re sidential 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 LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day 3 Residential Exposure mg/kg/day 4 Total Exposure mg/kg/day 5 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/201 5/framework

- for

- screening

analysis.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, foll owed 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 f urther 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 -disper sible 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 der mal 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 T TR 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 th e 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 t hat report. No

concern was identified that would warrant further investigation.

11.0 References

A uthor Barcode Date Title

C. Walls D 411772 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/ 20 12 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

I nhalation S tud y

.

### 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 y es

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

--- waived 1

870.3700 Developmental Toxicity (rodent)

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

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

................................ ................................ yes

yes

yes yes

yes

yes

870.4100 a Chronic Toxicity (rodent)

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

....................................... 870.4200 a Carcino genicity (rat)

..................................................... 870.4200 b Carcino genicity (mouse)

............................................... 870.4300 Chronic Toxicity/Carcino genicity (rodent)

.................. yes

yes

yes

yes

no yes 2

yes

yes 2

yes

yes 2

870.5100 Mutagenicity

— Gene Mutation

- bacterial

.................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

............... 870.53 85 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)

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

...................... 870.6200 b 90

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Developmental Neuro toxicity

....................................... no

no

yes

yes

no ---

---
yes

yes

---

870.7485 General Metabolism

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

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

................................ ............................ yes

no

yes y es

--- 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 LD 50 > 5000 mg/kg IV

870.1200 Acute dermal

– rabbit 46220909 LD 50 ≥ 2000 mg/kg III

870.1300 Acute inhalation

– rat 46220910 LC 50 ≥ 5 mg/L IV

870.2400 Acute eye irritation

– rabbit 46220911 Minimal conjunctivitis through

48 hours. Clear by 72 hours. III

870.2500 Ac ute dermal irritation

– rabbit 46220912 Not an irritant IV

870.2600 S kin 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 lev els 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 = 10 00 mg/kg/day

LOAEL could not be established

. Developmental NOAEL = 100 mg/kg/day

LOAEL = 3 00 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 (19 96 )

Acceptable/guideline

0, 100, 300, 1000 mg/kg/day Maternal NOAEL = 10 00 mg/kg/day

LOAEL could not be established

. Developmental NOAEL = 10 0 mg/kg/day

LOAEL = 3 00 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 Materna l NOAEL = 150 mg/kg/day

LOAEL = 450 mg/kg/day based on high incidence of abortion and decrease food consumption.

Developmenta l 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

F 0 M: 0, 14

, 135

, 675

F 0 F: 0, 16 , 1 55

, 760 mg/kg/day

F 1 M: 0, 15

, 148

, 761

F 1 F: 0, 16 , 1 65

, 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 F 0 males, kidney abnormalities in F 1 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

Ch ronic 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 (19 88 )

Acceptable/guideline

0.000021

– 0.00033 M Flazasulfuron did not induce chromosome aberrations in the presence or absence of metabolic

activation.

870.53 9 5

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)

Ac ceptable/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 r apidly absorbed : males 84 -99%

females 93

- 95 % by 48 hr

. P t
max was 30 min at 2 mg/kg both sexes; 4 hr in females and 6 hr in males at 50 mg/kg . Pm t
max 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): u rine was major route : 73-

80% males

, 89

- 94% females ; f eces 18

- 24% male, 9-

10% female; b ile 8.4

- 17.0 % with males slightly more

than females

. Tissue distribution was rapid but incomplete. T otal body burdens ≤4 /2 % males and
≤1/0.3 % females (P/Pm). B lood, 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 5 0 mg/kg P or Pm P arent compound was primary component in urine ( 19

- 40% males

, 51

- 67% females ), feces ( 1- 5%), and bile (0.6

- 2%). M ost prevalent metabolite was HDTG+TPPG ( 6.5 -17 % urine, 0.4

- 9.7 % fec es, 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 bil e except high dose Pm males was 12%; up to 35% in

feces

. Proposed metabolic pathway : intramolecular rearrangement within the sulfo nylur ea bridge, cleavage at the sulf onylurea bridge, pyrimidine hydroxylation followed by glucuronidation at the 5

-
po sition 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/d ose 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 fetusesin 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 , n o treatment -related deaths or clinical signs of toxicity were observed and gross necropsy was unremarkable. Mid dose animals had transient decreases in body w eight gain (50%; p ≤ 0.01) and food consumption (11%; p ≤ 0.05) compared to con trols 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 ; b ody weig ht gain s 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 tim e 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 fornumbers 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 increase s 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 , respecti vely.

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 incide nces 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 14 th 

### rib, compared to no litters in the control and low dose groups, and 2 litters in the mid dose group; however thi s variation is usually reversible as pups mature (Wickramaratne, 1988; J A ppl 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 curren t 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 revers ible effect and is not considered adverse. T he 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, j uice

- 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 Almon d- 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

130417500 0 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 = u nit exposure (μg ai/lb ai),

AR = m aximum application rate according to registered label s (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 A ppendix E

. Nomenclature and Physical/Chemical Properties

Table E.1

. Flazasulfuron Nomenclature.

Chemical Structure

Empirical Formula C 13 H 12 F 3 N 5 O 5 S

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 Sulf ony lurea herbicide

Table E.2. Chemical Names and Structures f or 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 f or 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/cm 3 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(K OW ) K ow = 20.0 in pH 5 buffer

K ow = <10 in pH 7 buffer UV/visible absorption spectrum Not reported

*n

- hexane with various methylpenta nes

### Page 35 of 38 Ap pendix F. International Harmonization

Flazasulfuron (119011; 4/06/2015)
Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 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 Mexico 2 

### 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 andvegetable gardens, pick your own farms, retail tree farms) uses that could result in postapplicati on 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 submitte d 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 fa ctors such as active ingredient, formulation, field conditions in the studies, weat her 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 AR TF 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 gra nular default values for the fraction of the application rate available for transfer after a turf application (F AR 

### ). 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 F AR 

### value seen using a liquid product was 6.1% or 6.1 times higher than the default residue transfer value. The maximum F AR 

### 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 t here was no dermal hazard identified and hand- to -mouth MOE is greater than 1,000 based

on default values fo r 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. 

### S tructure

- Activity Relationship (SAR) Data for Sulfonylureas Technical

Formulations with Available Experimental or Estimated Dermal Absorption Factors (DAF)

Chemical MW Log Kow 1 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

- 90 2 )

.

Chlorimuron

- ethyl 414.8 2.50 4.8% Dermal NOAEL / oral LOAEL extrapolation 3

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%)

.

Iodo sulfuron

- methyl

sodium 529.2

- 0.70 11% 1

- 6% per in vivo rat study; however 11% used because data indicates absorption continues after

exposure.

Mesosulfuron

- m ethyl 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

- final 2 )

.

Nicosulfuron 410.4

- 1.74 0.021

- 0.23% Unpublished in vitro human studies not submitted to EPA (DuPont 21540 and 25519 2 )

.

Oxasulfuron 406.4

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

rat studies not submitted to EPA (EC

SANC0/4323/2002 2 )

.

Primisulfuron 468.3 1.15 (pH 5.0) 30% Dermal NOAEL / oral LOAEL extrapolation 3

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 24600 2 )

.

Tribenuron

- methyl 395.4 0.78 17.7% P er in vivo rat study

Trifloxysulfuron

sodium 459.3

- 0.42 30% Dermal NOAEL / oral LOAEL extrapolation 3

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.1 2 )

.

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.