Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 2 of 36 1.0 Executive Summary

................................ ................................ ................................ ................. 4

2.0 HED Recommendations

................................ ................................ ................................ .......... 7

2.1 Data Deficiencies

................................ ................................ ................................ .................. 7

2.2 Tolerance Considerations

................................ ................................ ................................ .... 7

2.3 Label Recommendations

................................ ................................ ................................ ...... 8

3.0 Introduction

................................ ................................ ................................ .............................. 8

3.1 Chemical Identity

................................ ................................ ................................ ................. 9

3.2 Physical/Chemical Characteristics

................................ ................................ ..................... 9

3.3 Pesticide Use Pattern

................................ ................................ ................................ ............ 9

3.4 Anticipated Exposure Pathways

................................ ................................ ....................... 10

3.5 Consideration of Environmental Justice

................................ ................................ .......... 10

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ................ 11

4.1 Summary of Toxicological Effects

................................ ................................ .................... 11

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

................................ ...... 12

4.2.1 Completeness of the Toxicology Database

................................ ................................ .... 12

4.2.2 Evidence of Neurotoxicity

................................ ................................ .............................. 13

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

.............. 13

4.2.4 Residual Uncertainty in the Exposure Database

................................ ......................... 13

4.3 Toxicity Endpoint and Point of Departure Selections

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

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ............... 16

5.1 Residues of Concern Summary and Rationale

................................ ................................ 16

5.2 Food Residue Profile

................................ ................................ ................................ .......... 17

5.3 Water Residue Profile

................................ ................................ ................................ ........ 17

5.4 Dietary Risk Assessment

................................ ................................ ................................ .... 18

5.4.1 Description of Residue Data Used in Dietary Assessment

................................ .......... 18

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .................... 18

5.4.3 Acute Dietary Risk Assessment

................................ ................................ ..................... 18

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ................. 18

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ................... 19

5.4.6 Summary Table

................................ ................................ ................................ ............... 19

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ ... 19

6.1 Residential Handler Exposure

................................ ................................ .......................... 19

6.2 Post

- Application Exposure

................................ ................................ ................................ 20

6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

......................... 21

6.4 Residential Risk Estimates for Use in Aggregate Assessment

................................ ........ 21

6.5 Residential Bystander Post

- application Inhalation Exposure

................................ ....... 22

6.6 Spray Drift

................................ ................................ ................................ .......................... 22

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ........ 23

7.1 Acute Aggreg ate Risk

................................ ................................ ................................ ......... 23

7.2 Short

- and Intermediate

- Term Aggregate Risk

................................ .............................. 23

7.3 Chronic Aggregate Risk

................................ ................................ ................................ .... 24

7. 4 Cancer Aggregate Risk

................................ ................................ ................................ ...... 24

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 24

9.0 Occupational Exposure/Risk Characterization

................................ ................................ .. 24

9.1 Occupational Handler Exposures

................................ ................................ ..................... 24

9.2 Occupational Post

- application Exposures

................................ ................................ ....... 25Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 3 of 36 10.0 References

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

................................ ........................ 27

A.1 Toxicology Data Requirements

................................ ................................ ......................... 27

A.2 Toxicity Profiles

................................ ................................ ................................ .................. 28

A.3 Executive Summaries

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

.............. 34 Appendix C. Physical/Chemical Properties of Flazasulfuron

................................ ...................... 36Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 4 of 36 1.0 Executive Summary

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

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

- 12

. Permanent tolerances are currently established for f lazasulfuron in/on citrus, grapes and sugarcane (CFR § 180. 655)

. Additionally it is registered for use on residential and non

- residential turf such as golf courses, sod fa rms, professionally managed athle tic fields, commercial lawns

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

control certain broad

- leaf weeds and grasses, and acts by inhibiting the acetolactate synthase (ALS) biochemical p rocess.

The end

- use product

, ISK Flazasulfuron Herbicide (EPA Registration Number 71512

- 18)

, is a water dispersible granular (WDG/WG) formulation containing 25% active ingredient (ai). The product is proposed for use on tree nuts at a maximum single ap plication rate of 0.045 lb ai/A with two applications for a maximum seasonal application rate of 0. 09 lb ai/A. The use of a n adjuvant is recommended for post emergence applications. The minimum retreatment interval is three months. The pre

- harvest interval (PHI) is 130 days.

Hazard Identification:

The risk assessment for flazasulfuron is based on a well

- characterized and nearly complete toxicology database. The data

- gaps noted in the previous risk assessment have been satisfied wit h the exception of an immunotoxicity study which has been received and is currently under review.

In repeated dose studies, t he most consistently observed effects of flazasulfuron exposure across species, genders, and treatment durations were the kidney and liver toxicity. In addition, s ubchronic studies indicated decreased body weight gain and slight anemia in rats and liver abnormalities in dogs. While transient decreases in motor activity were observed at high dose levels in the acute neurotoxicity study, flazasulfuron did not produce significant neurotoxicity in the subchronic neurotoxicity study or other repeated dose studies. Flazasulfuron produced developmental and reproductive effects only at maternally and parentally toxic dose levels, respect ively; in addition, since clear NOAELs and LOAELs have been established for these effects, so there are no concerns for quantitative or qualitative susceptibility. Flazasulfuron did not demonstrate mutagenicity or carcinogenicity in the available databas e. There was no evidence of immunotoxicity in the repeated dose studies in the database, nor in a preliminary assessment of the new immunotoxicity study. Flazasulfuron has low acute toxicity via the oral, dermal and inhalation routes of exposure. It is no t irritating to the skin or eyes and is not a sensitizer.

A NOAEL of 50 mg/kg was selected for the acute dietary endpoint based on a transient decrease in motor activity at the LOAEL in the rat acute neurotoxicity study. The NOAEL of 1.3 mg/kg/day

was selected for the chronic dietary endpoint based on adverse change in kidney function (chronic nephropathy) at the LOAEL in a combined chronic toxicity and carcinogenicity study in rats. For

short

- and intermediate

- term residential and occupational (incide ntal oral and inhalation) exposure scenarios, the NOAEL of 2 mg/kg/day from the oral subchronic in dogs was selected which was

based on changes in liver (increase in: deposition of brown pigments, glutamic pyruvic transaminase, creatine phosphokinase, infl ammatory cell infiltration, and microgranulomas) at theFlazasulfuron Human Health Risk Assessment DP No. 411772

Page 5 of 36 LOAEL

. N o dermal hazard was identified because no effects were seen up to the l imit d ose (1000 mg/kg/day) in a 21

- day dermal toxicity study

. The Food Quality Protection Act (FQPA) Safety

Factor has be en reduced to 1X because 1) the toxicity database is complete, 2) there is no concern for quantitative or qualitative susceptibility in offspring, 3) there are no neurotoxicity concerns, and 4) there are no residual uncertainties regarding exposure.

Dietary Exposure (Food/Water):

F lazasulfuron may reach surface and/or groundwater from the proposed tree nut use and affect the drinking water component of the dietary exposure. The residue chemistry data and drinking water data are adequate to assess di etary exposure. The dietary exposure assessment relies on conservative inputs to model exposure to flazasulfuron through food and drinking water. The estimated drinking water concentrations ( EDWC s) were determined for ground water and surface water based on the

Delmarva corn scenario which also covers the tree nut scenario ; the EDWC for ground water was used since it is higher than that for surface water. The assessments are based on reliable data and

will not underestimate exposure/risk.

Acute: An unr efined acute dietary (food and drinking water) assessment was conducted

. The assumptions of this dietary assessment included tolerance level residues for all registered and proposed crops and 100% crop treated (CT). Empirical processing factors were used

. The ground

water EDWC of 90.8 μ g/L from the Tier II PRZM

- GW model ing was incorporated directly into the dietary assessment

.

T he acute dietary (food and drinking water) exposure to flazasulfuron is below HED’s level of concern [i.e., <100% of the acute Population Adjusted Dose (a PAD)] for the general U.S. population and all po pulation subgroups. The acute dietary exposure estimates at the 95 th percentile are 1% of

the a PAD for the general U.S. population and 3 % of the a PAD for all infants (<1 year old)

, the most highly exposed population subgroup.

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

. The assumptions of this dietary assessment included tolerance level residues for all registered and proposed crops and 100% crop treated (CT). Empirical processing factors were used

. The ground

water EDWC of 55.6 μ g/L from the Tier II PRZM

- GW model ing was incorporated directly into the dietary assessment

.

T he chronic dietary (food and drinking water) exposure to flazasulfuron is below HED’s level of concern [i.e., <100% of the chronic Population Adjusted Dose ( c PAD)] for the general U.S. population and all po pulation subgroups. The chronic dietary exposure estimates are 9 % 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.

Residential Exposure: There are no residential uses being requested at this time. Therefore, residential handler and post

application scenarios were not assessed. H owever, there are existing residential turf uses that have been previously assessed using the most recent Residential SOPs and were not of concern to HED.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 6 of 36 Aggregate Exposure : Acute: Aggregate acu te risk is equ ivalent to acute dietary risk. There is potential acute exposure via the diet (food and drinking water) as determined in Section 5.4

. The acute aggregate exposure estimates are not of concern.

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

exposure via the diet (food and drinking water) as determined in Section 5.4

. The chronic aggregate exposure estimates are not of concern

.

Short

- and Intermediate Term: There is potential short

- term aggregate exposure to flazasulfuron for

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

- application

dermal and incidental oral residential pathway (which is considered the primary pathway ). S ince no hazard was identified for the dermal route of exposure, short

- term ag gregate risks included dietary and incidental oral exposures only

. The aggregate margin of exposure ( MOE ) for children 1

- 2 years

old is 810 and not of concern to HED.

There is potential short

- term aggregate exposure to flazasulfuron for adults via the dietary pathway (which is considered background exposure) and the handler dermal and inhalation pathway s

. However, since no hazard was identifi ed for the dermal route of exposure, short

- term ag gregate risks included dietary and inhalation exposures only

. The aggregate MOE for adults is 1,6 00 and not of

concern to HED.

Intermediate

- term aggregate exposures are not expected based on the use pro file of flazasulfuron

, therefore they were not assessed.

Occupational Exposure : Occupational Handler Exposures : Occupational short

- and intermediate

- term dermal and inhalation exposures are expected from

flazasulfuron handler activities associated with the proposed tree nut use

. Sin ce no hazard was

identified for the dermal route of exposure, dermal exposures were not assessed

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

handle r scenarios resulted in MOEs greater than the level of concern (LOC = MOEs ≥ 100) for inhalation exposures and, therefore are not of concern.

Occupational Post

- application Exposures: Occupational short

- term dermal exposures are expected from flazasulfuron post

- application

activities associated with the proposed tree nut use

. However, s in ce no hazard was identified for the

dermal route of exposure, dermal exposures were not quantitatively assessed

.

Based on the Agency's current practices, a quantitative non

- cancer post

- application inhalation exposure assessment was not performed for flazasulfuron at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for flazasulfuron

.

Restricted Entry Interval : The labeled restricted entry interval (REI ) of 12

- hrs is adequate to protect agricultural workers from post

- application exposures to flazasulfur on

. Per the Worker ProtectionFlazasulfuron Human Health Risk Assessment DP No. 411772

Page 7 of 36 Standard (WPS), flazasu l f uron is classified as Toxicity Categories III and IV and require s a 12

- hr

REI

.

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

at http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html

.

Environmental Justice Considerations: Potential areas of environmental justice concerns, to the extent possible, were considered in this

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://ww w.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

.

2.0 HED Recommendations

HED can recommend for a registration of flazasulfuron for use on tree nuts

. Additional data needed prior to registration are outlined in Section 2.1, specific tolerance recommendations are discussed in Section 2.2, and label modifications are discussed in Section 2.3.

2.1 Data Deficiencies

RESIDUE CHEMISTRY

860.1380 Storage Stability Storage stability data for flazasulfuron are required for tree nuts for up to 186 days (6.1 months) of frozen storage. The petitioner has indicated that a study to determine the stability of flazasulfuron in

the pecan crop matrix under frozen conditions is in progress.

860.1550 Proposed Tolerances The petitioner mu st submit a revised Section F to propose a tolerance for almond, hulls at 0.01 ppm.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate enforcement method is available. The method uses high performance liquid chromatography/tan dem mass spectrometry with multiple reaction monitoring (HPLC/MS

MS/MRM) ( ADME study code S09

- 03106 ; MRID 48092201 ) . T he validated limit of quantification ( LOQ ) is 0.01 ppm

.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 8 of 36 2.2.2 Recommended Tolerances

The petitioner, ISK B iosciences Corporation, prop ose d establishment of a tolerance for residues of

the herbicide f

lazasulfuron in or on nut, tree, group 14

- 12 . The established residue definition (tolerance expression) for flazasulfuron in 40 CFR §180.655 is in accordance with the S. Knizner

memo dated 5 /27/09.

HED is recommending tolerances as shown in Table 2.2.2.

Table 2.2.2 . Tolerance Summary for Flazasulfuron

. Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition )
Almond, hulls None 0.01
Nut, tree, g roup 14

- 12 0.01 0.01

2.2.3 Revisions to Petitioned

- For Tolerances

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

2.2.4 International Harmonization

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

for flazasulfuron

. Therefore, there are no issues regarding international harmon ization raised by this

action.

2.3 Label Recommendations

There are no recommended label modifications

.

3.0 In troduction

Flazasulfuron [ N

- [[4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (trifl uoromethyl)

- 2

- pyridinesulfonami de] belongs to the pyrimidinylsulfonylurea class of herbicides. It is used to
control certain broadleaf weeds and grasses and acts by inhibit ing the acetolactate synthase (ALS) biochemical process.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 9 of 36 3.1 Chemical Identity

Table 3.1 Flazasulfuron N omenclature
Compound Chemical Structure

Common name Flazasulfuron
Company experimental name SL

- 160

IUPAC name 1

- (4,6

- dimethoxypyrimidin

- 2

- yl)

- 3

- (3

- trifluoromethyl

- 2

- pyridylsulfonyl)urea

CAS name N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (trifluoromethyl)

- 2

- pyridinesulfonamide
CAS registry number 104040

- 78

- 0

End

- use product (EP) ISK Flazasulfuron Herbic ide (EPA Reg. No. 71512

- 18)

3.2 Physical/Chemical Characteristics

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 env ironmental

conditions

. The vapor pressure of flazasulfuron is considered low (<1 x10

- 7 mm Hg at 20 oC), limiting the po tential for inhalation exposure to vapor. A summary of the physical/chemical characteristics of flazasulfuron is provided in Appendix C.

3.3 Pesticide Use Pattern

F lazasulfuron is currently registe red to control annual and perennial grasses , sedges, and broadleaf

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

non

- residential turf areas such as industrial parks, tank farms, sod farms, seed farms, pr ofessio nally managed sports fields and industrial vegetation management in nonagricultural areas. The

flazasulfuron end

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

. 71512

- 18 ] which is formulated as a water dispersible granular (WDG/WG) formulation containing 25% active ingredient (ai). The tree nut use rate is proposed at a maximum single application rate of

0.045 lb ai/A with a maximum of 2 applications at a maximum seasonal application rate of 0. 09 lb

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

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

3.3 below

.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 10 of 36 Table 3.3. Use Profile for Proposed New Flazasulfuron Use

Use Site Max. Rate for

Single Appl. Max.

Rate per

Season Retreatment

Interval and

Maximum No. of Applications PHI Application Method and

Instructions

Flazasulfuron Herbicide [ EPA Reg. No 71512

- 1 8 ]

Tree nuts 0.045 lb ai/acre

0.0011 lb ai/gal 0.09 lb

ai /acre 3 months

2 130

days S pray directed to the weeds.

General application information for pre

- and postemergence weed control states that applications

should be made in 15 to 50 gallon s of water per acre

. Directed sp ray applications using low

- pressure coarse spray equipment should be made in at least 20 gallons of water per acre. Applications should be made using conventional spray equipment. Applications cannot be made aerially or through any irrigation system.

3.4 Anticipated Exposu re Pathways

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

new use of flazasulfuron on tree nuts . Humans may be exposed to flazasulfuron in food and drinking water, since flazasulfuron may be applied di rectly to growing crops and application may result in flazasulfuron reaching surface and ground water sources of drinking water. Th e existing

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

those enteri ng treated areas following application. In occupational settings, applicators may be exposed while handling flazasulfuron . There is a potential for post

- application exposure for workers

re

- entering treated fields.

Risk assessments have been completed for existing uses of flazasulfuron . This risk assessment considers all of the aforementioned exposure pathway s based on the proposed new use of flazasulfuron, but also considers e xisting uses of flazasulfuron

, particularly in the dietary, residential,

and aggregate assessment s

.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide ri sk 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 a nd water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the National Health and Nutrition Examination Survey, What We E at i n 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 toFlazasulfuron Human Health Risk Assessment DP No. 411772

Page 11 of 36 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 toddler s, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

This assessment updates the previous hazard characterization of flazasulfuro n; the last comprehensive risk assessment was conducted in 2012 ( D399358, C. Walls, 10/15/12) . At that time, the toxicity database was judged complete with the exception of the subchronic neurotoxicity battery (§870.6200b) and an immunotoxicity study (§87 0.7800). The neurotoxicity studies have been received and reviewed and are discussed in the sections below; the immunotoxicity study has been received and is currently in detailed review.

4.1 Summary of Toxicological Effects

Chronic oral studies in the rat, mouse and dog indicate that the kidney and liver are the target organs for chronic oral exposure. Observed effects include adverse changes in kidney function (chronic nephropathy) and physiology (enlargement, dark color of kidney), changes in liver physiology (increased weight) and histology (hepatocellular hypertrophy, increases in inflammatory cell infiltration, hepatocellular necrosis, hepatocellular swelling, and bile duct proliferation). Subchronic oral studies indicated decreased body weight g ain, slight anemia in rats and liver abnormalities in dogs. Dermal or systemic toxicity was not seen in a subchronic dermal study in rabbits at dose levels up to the Limit Dose.

Developmental toxicity was observed in rats and rabbits. Reduced fetal weig hts and delays in ossification are the effects observed in a Sprague

- Dawley rat developmental study. A n earlier developmental rat study ( Wistar rats) showed increased incidence of visceral malformations (interventricular septal defect). The deve lopmental study in rabbits showed high incidences of abortion at the highest dose tested (450 mg/kg/day) . Decreases in body weight and chronic nephropathy were observed in offspring in a 2

- generation rat reproduction study. The effects on offspring in these devel opmental and reproductive studies occurred at dose levels which were toxic to the parents.

A transient decrease in motor activity on Day 0 (5 hours post

- dosing) was observed at the mid

- dose of 1000 mg/kg in an acute neurotoxicity study. This observation may be associated with a systemic effect and not with neurotoxicity since there was no corroborating indication of neurotoxicity in the subchronic neurotoxicity study. There are no indications of immunotoxicity potential from the repeated dose studies in the toxicity database. In addition, preliminary assessment of the available immunotoxicity study (currently under detailed review) shows no immunotoxicity in female mice when tested up to levels near the limit dose (1198 mg/kg/day). Therefore, there are n o concerns for immunotoxicity.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 12 of 36 I n vitro and in vivo mutagenicity studies showed no genotoxic potential . The mouse oncogenicity study and the rat combined chronic toxicity and carcinogenicity study both showed n o evidence of carcinogenicity.

The metabo lism of flazasulfuron in the rat is similar to that in plants and the goat, which includes breaking of the sulfonylurea bridge, extrusion of sulfur dioxide, demethylation and hydroxylation in the pyrimidine ring, and conjugation with glucuronic acid

. Compo unds of toxicological significance in rats, plants, and livestock included parent only. Several other environmental transformation products ( DTPU, DTPP, TPSA, ADMP, HTPP, and 2,3

- GTP ) (See Appendix B for the names and structures) , predicted to be present in water, are also considered of toxicological significance, with toxicity profiles assumed to be similar to flazasulfuron.

Radiolabeled kinetic studies in the rat show that flazasulfuron is rapidly absorbed irrespective of the dosing regime. At seven days, blood, liver, and muscle were the tissues with the highest concentrations while the carcass had up to 2.5% of the administered dose. Elimination via the urine was the major route of excretion and feces were the secondary route of elimination.

Flazasulfuron has low acute toxicity via the oral (Tox Category IV), dermal (Tox Category III) and inhalation (Tox Category IV) routes of exposure. It is not irritating to the skin or eyes and is not a

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

and treatment durations were the kidney and liver toxicity. Subchronic studies indicated decreased body weight gain and slight anemia in rats, and liver abnormalities in dogs.

4.2 Safety factor for Inf ants and Children (FQPA Safety Factor)

Based on the hazard and exposure data, the flazasulfuron risk assessment team has recommended that the FQPA Safety Factor be reduced to 1X. There are no quantitative susceptibility concerns based on the developmenta l and reproductive studies. A potential qualitative concern from one rat developmental study (intraventricular septal defect seen at minimally toxic maternal dose levels) is addressed by the presence of clear NOAELs and LOAELs, and by the selection of regu latory endpoints that are protective of this effect. The data base is considered sufficient and there are no

residual uncertainties.

4.2.1 Completeness o f the Toxicology Database

The toxicity database for flazasulfuron is considered to be complete and suf ficient for endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements under FQPA, and an additional database uncertainty factor does not need to be applied.

The required inhalation toxicity study for flazasulfuron has been waived based on flazasulfuron’s use pattern, physical chemical properties, and low acute inhalation toxicity (K. Rury , TXR#0056483,

10/04/ 12). In the absence of a route specific inhalation toxicity study, a point of departure ( POD ) for inhalation exposure risk assessment h as been extrapolated from an oral study. EPA does not believe

the risk assessments are under

- protective of adult handlers.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 13 of 36 4.2.2 Evidence of N eurotoxicity

An acute neurotoxicity study was conducted with flaz asulfuron at dose levels up to 2000 mg/kg. Mean motor activity measurements for 1000 and 2000 mg/kg males and females were statistically significantly decreased from the respective control groups five hours post

- dosing. Animals were less

active with more r esting time than controls. The effect was reversed by the next scheduled observation (Day 7). Neurohistopathologic evaluation did not demonstrate any test material

- related neurotoxic lesions following the examination of tissues from the central and peri pheral nervous systems of high dose and control animals. The NOAEL was 50 mg/kg.

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

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

tested.

The available neurotoxicity battery, therefore, did not raise concern for neurotoxicity. Similarly, the subchronic and chronic data in the database did not show any adverse effects that could be considered as neurotoxicity.

4.2.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

The available data indicate that flazasulfuron produced developmental and reproductive effects only at maternally/parentally toxic dose levels, respectively. In addition, clear NOAELs and LOAELs have been established for these effects. Therefore, HED has no concerns for quantitative susceptibility. A potential qual itative susceptibility concern was identified from the dev elopmental study in Wistar rats (intraventricular septal defect seen at minimally toxic maternal dose levels). However, this effect was not seen in the developmental study in Sprague

- Dawley rats tested up to the limit dose, and this concern is further addressed by the presence of clear NOAELs and LOAELs, and by the selection of regulatory endpoints that are protective of this effect. Theref ore, HED has no concerns for qu alitative susceptibility.

4.2 .4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. S ince the dietary and non

- dietary exposure estimates were based on several conservative assumptions, HED does not believe that the exposure estimates are underestimated. The acute and chro n ic dietary assessment s conducted with

DEEM

- FCID were screening leve l analyse s. The assessment s utilized tolerance values and 100% crop treated was assumed for all commodities. The DEEM analysis also assumed that all drinking

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

surface water. For these reasons it can be concluded that the DEEM

- FCID analysis does not

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

b elieve that the non

- dietary occupational and residential exposure s are underestimated because they are also based on conservative assumptions

, including maximum application rates, labeled PPE (where applicable) , and standard values for unit exposures, acre age treated/amount handled as described in the Residential SOPs.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 14 of 36 4.3 Toxicity Endpoint and Point of D eparture Selections

For acute dietary exposure, an acute reference dose (aRfD) of 0.50 mg/kg was selected for assessment of all populations, based on a NOAEL of 50 mg/kg in the rat acute neurotoxicity study with a transient decrease in motor activity at the LOAEL of 1000 mg/kg. This endpoint is a single

dose effect and is appropriate for all populations. The endpoint is also protective of other adverse effects seen in the database, such as increased incidence of abortions in pregnant rabbits and decreased lactational body weights of F 1 and F 2 offspring. In addition, since the dose interval between the NOAEL and LOAEL is 40x and not the 3x to 5x normally used, it is likely that the no

effect level for the study is significantly higher than 50 mg/kg and the reported NOAEL is

conservative.

A separate acute dietary endpoint for females 13

- 49 was not selected from the available developmental toxicity studie s because the NOAEL of 50 mg/kg/day from the acute neurotoxicity study is the lowest NOAEL for any available acute study, and is protective of the developmental effects seen in the prenatal developmental (Wistar) rat study with a NOAEL of 100 mg/kg/day and a LOAEL of 300 mg/kg/day. Therefore, a separate endpoint for females 13

- 49 based on developmental effects is not considered necessary.

For chronic dietary exposure, a chronic reference dose (cRfD) of 0.013 mg/kg/day was selected for assessment of all po pulations, based on a NOAEL of 1.3 mg/kg/day with adverse change in kidney function (chronic nephropathy) observed at the LOAEL of 13.3 mg/kg/day in a rat chronic dietary study. This provided the most sensitive endpoint available for chronic dietary expos ure.

For short

- and intermediate

- term residential and occupational exposure scenarios (incidental oral and inhalation), the NOAEL of 2 mg/kg/day from the oral subchronic study in dogs was selected. The LOAEL of 10 mg/kg/day was based on changes in live r (increases in: deposition of brown pigments, glutamic pyruvic transaminase, creatine phosphokinase, inflammatory cell infiltration, and microgranulomas). The systemic NOAEL of 2 mg/kg/day is the lowest dose of any non

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

the available non

- chronic studies.

For all short

- and intermediate

- term dermal exposures, a dermal study is available and showed no local or systemic effects at dose levels of 250

– 1000 mg/kg/day. This study is chosen because it is a

route

– specific study which measures the same parameters as an oral subchronic study, and because there is no concern for developmental effects in the absence of maternal effects. Since no effect s were seen at the Limit Dose, a quantitative dermal risk assessment is not required.

Long

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

The selection of toxicity endpoints and points of departure are presented in a previous risk assessment ( D303573, G. Burke, 11/16/05). The short

- term incidental oral and the occupational dermal endpoints were updated in the most recent risk assessment which provides rationale in detail ( D372903, C. Walls, 6/12/11) . T he current endpoints are summarized in Tables 4.3.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 15 of 36 Table 4. 3 Summary of Toxicological Doses and Endpoints for Flazasulfuron for Use in Residential and

Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (all populations including

Females 13

- 49) NOAEL =50

mg/kg 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 observed at Day 0 (5 hours post

dosing).

Chronic Dietary (all populations) Oral

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 Toxicity/ Carcinogenicity rats

LOAEL= 13.3 mg/kg/day based on a dverse change in kidney function (chronic nephropathy)

Incidental

Oral

Short

- Term (1

- 30 days)

and

Intermediate

Term (1

- 6 months) NOAEL = 2

mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1X LOC for MOE =

100 90

- Day oral toxicity (dog)

LOAEL= 10 mg/kg/day based on changes in liver (increase in: deposition of brown pigments, glutamic pyruvic transaminase, creatine phosphokinase, i nflammatory cell infiltration, microgranulomas).

Dermal

Short

- Term (1

- 30 days)

and

Intermediate

Term (1

- 6 months) No hazard was identified at the limit dose following dermal exposure

.

Inhalation

Short

- Term (1

- 30 days)

And

Intermediate

Term (1

- 6 months) NOAEL = 2

mg/kg/day UF A = 10x

UF H = 10x FQPA SF = 1X LOC for MOE =

100 90

- Day oral toxicity (dog)

LOAEL = 10 mg/kg/day based on changes in liver (increase in: deposition of brown pigments, glutamic pyruvic transaminase, creatine phosphokinase, inflammatory cell infiltration, microgranulomas).

Cancer (oral, dermal, inhalation) Classification: No evidence of carcinogenicity to humans based on lack of carcinogenic effects in the

rat and mouse carcinogenicity studies and lack of a mutagenicity concern

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human po pulation (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjustedFlazasulfuron Human Health Risk Assessment DP No. 411772

Page 16 of 36 dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Based on the available toxicity database an d the Agency's current practices, the inhalation risk for flazasulfuron was assessed using an oral toxicity study. The Agency sought expert advice and input on issues related to this route to route extrapolation approach (i.e.

, the use of oral toxicity st udies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/ 120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, reexamine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data. If any new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity stu dy for flazasulfuron and/or reexamine the inhalation toxicity risk

assessment.

5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Conce rn Summary and Rationale

The residues of concern for dietary risk assessment and the tolerance expression are summarized in

Table 5.1. HED has concluded that the residues of concern in plants and livestock commodities

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

The parent compound and all identified metabolites are included in the drinking water exposure assessment, which is consistent with the previous risk assessment

. The current assessment include s residues of the following compounds in drinking water: p arent flazasulfuron, DTPU, DTPP, HTPP, TSPA, ADMP , and 2,3

- GTF

. Based on submitted studies, there is potential for exposure to all of these metabolites through drinking water and; therefore, they should be included for risk assessment purposes. ROCKS noted that the metabolite GTF was not observed in submitted plant and livestock metabolism studies, but was a significant route for dissipation through anaerobic aquatic

metabolism. While there is no toxicity data available for GTF, the use of the total residue approach should account for any potential contribution of GTF.

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

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop Flazasulfuron parent only Flazasulfuron parent only

Rotational Crop Flazasulfuron parent only 3 Flazasulfuron parent only 3

Livestock Ruminant Flazasulfuron parent only Flazasulfuron parent only

Poultry Not Applicable 1 Not applicable 1

Drinking Water Total residues (parent + identified metabolites) 2 Not applicable

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

tolerance action.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 17 of 36 2 S ee Appendix B for metabolite names and structures.

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

.

5 .2 Food Residue Profile

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

assessment and tolerance assessment (D412475, N. Dodd, 2/6/14)

. Residues of flazasulfuron were

not detectable in any commodity at the limit of detection, indicating that there will be minimal exposure to flazasulfuron in food. Processing studies were not conducted since there are no processed commodities associated with tree nuts. There is no reasonable expectation of f inite

residues in livestock commodities based on the non

- detectable residues of flazasulfuron in/on animal feed items and the results of the ruminant metabolism study. No storage stability data were submitted for tree nuts. Pending submission of storage stability data for tree nuts, the available field trial data are adequate.

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

Commodity Analyte Total

Rate (lb ai/A) PHI

(days) Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

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

- day PHI)

Almond

Hulls Flazasulfuron 0.0948

- 0.0978 123

- 155 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Almond

Nutmeat Flazasulfuron 0.0948

- 0.0978 123

- 155 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Pecan

Nutmeat Flazasulfuron 0.0466

- 0.0483 154

- 272 5 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

1 Except for sample min/max, values reflect per trial averages; n = no

. of field trials . N/A = Not applicable. For calculation of median and mean, the LOQ (0.01 ppm) was used for any results reported as <LOQ

. Because parent only is the residue of concern,

DTPU was not c onverted to parent equivalents and combined residues of parent and DTP U were not determined.

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

5.3 Water Residue Profile

Estimated surface water and groundwater concentrations were provided by the Environmental Fate and Effects Division (EFED) ( D411771

, A. Shelby, 12/3/13 ) and are shown in Table 5.3. The dietary exposure assessment used the peak concentration value s of 90.8 ppb for acute and 55.6 ppb for

chronic assessments. Th e drinking water assessment is based on Tier I I groundwater model (PRZM

GW) simulations for all currently registered and proposed flazasulfuron uses. EFED concluded that

the EWDCs calculated for the existing flazasulfuron uses did not need to change and are protective to cover the proposed tree nut use.

Th e drinking water asses sment takes into account flazasulfuron and its degradates DTUP, DTPP, HTPP, TPSA, ADMP, and 2,3

- GTF. These compounds are referred to collectively as total toxic

flazasulfuron residues.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 18 of 36 Table 5. 3 Summary of Estimated Surface Water and Groundwater Concentrations

for Flazasulfuron c

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

Acute 26.9 90.8
(highest daily value)

Chronic (non

- cancer) 4.67 55.6
(post breakthrough average)

a From the Tier II PRZM

- EXAMS

- Index Reservoir model. I nput parameters are based on are based on 3 applications at 0.045 lbs ai/A/application to California industrial vegetation management impervious area using a percent cropped area (PCA) correction of 100 %.

b From the PRZM

- GW model

c A. Shelby, D41171, 12/3 /1 3

.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute and chronic dietary analysis for non

- cancer risk assessment assumed tolerance level

residues for all registered and proposed crops

. Processing studies for grapes, citrus, and sugarcane did not show any concentration of flazasulfuron in the commo dities tested after processing. Therefore, the processing factors were used set at 1 in the dietary exposure assessment.

5.4.2 Percent Crop Treated Used in Dietary Assessment

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

5.4.3 Acute Dietary Risk Assessment

A n unrefined acute dietary assessment was conducted. The assumptions of this dietary assessment

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

and 100% CT was assumed. A tier II (PRZM

- GW) EDWC derived through EFED modeling which

is unlikely to underestimate the concentration of flazasulfuron in drinking water was utilized. The ground water EDWC (90.8 μ g/L) was incorporated directly into the dietary assessment ( D411771, A. Shelby, 12/3/13 )

.

As shown in Table 5.4 .6, the acute dietary (food and drinking water) exposure to flazasulfuron is below HED’s level of concern [i.e., <100% of the acute Population Adjusted Dose (a PAD)] for the general U.S. population and all po pulation subgroups. The a cute dietary exposure estimates at the

95 th percentile are 1 % of the a PAD for the general U.S. population and 3 % of the aPAD for all infants (<1 year old), the most highly exposed population subgroup.

5.4.4 Chronic Dietary Risk Assessment

A n unrefined chronic dietary assessment was conducted. Tolerance level residues

, 100 % CT , and empirical processing factors were used to determine the chronic dietary exposure and risk estimates.

A tier II EDWC derived through EFED modeling which is unlikely to under estimate theFlazasulfuron Human Health Risk Assessment DP No. 411772

Page 19 of 36 concentration of flazasulfuron in drinking water was utilized. The ground water EDWC (55.6 μ g/L) was incorporated directly into the dietary assessment ( D411771, A. Shelby, 12/3/13 )

. As shown in Table 5.4 .6, the chronic dietary (food and drink ing water) exposure to flazasulfuron is

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

. The chronic d ietary exposure estimates are 9 % of the c PAD for the general U.S. population and 23 % of the cPAD f or all infants (<1 year old), the most highly exposed population subgroup.

5.4.5 Cancer Dietary Risk Assessment

A cancer dietary risk assessment was not conducted because there was n o evidence of carcinogenicity to humans based on lack of carcinogenic effects in the rat and mouse carcinogenicity

studies

.

5.4.6 Summary Table

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

- FCID

Population Subgroup Acute Dietary (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

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure

There are no residential uses being requested at this time. Therefore, residential handler and post

application scenarios were not assessed for the proposed tree nut use . H owever, there are existing

residential turf uses tha t have been previously assessed and are used in the aggregate assessment presented in this document ( D 3 99890, C. Walls

, 10/9/12 )

.

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

Residential SOPs. It is assu med that most residential uses will result in short

- term (1

- 30 day) exposures. Residential handlers are assumed to be wearing short

- sleeved shirts, short pants, shoes, and socks during flazasulfuron application. Because there was no dermal endpoint chose n for flazasulfuron, non

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

Page 20 of 36 only. Although PODs from an oral study were used to assess residential handler inhalation risks to flazasulfuron, HED does not believe this assessmen t is under protective of adult handlers.

Table 6.1 lists the residential handler non

- cancer inhalation risk estimates for spot application to turf

. Residential handler inhalation MOEs were not of concern to HED, and ranged from 27,000 to 6,800,000.

Table 6.1. Residential Handler Non

- cancer Exposure and Risk Estimates for Flazasulfuron.

Exposure

Scenario Application

Equip Inhalation Unit

Exposure
(μg/lb ai) Maximum

Application

Rate 1 Area Treated

or Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

LOC =

100

Mixer/Loader/Applicator

Lawn/Turf
Spot or targeted

treatment Manually

pressurized

handwand 0.0011 0.0011
lb ai/gal 5 gal 0.000073 27,000

Backpack 0.0011 0.0011 l
b ai/gal 5 gal 0.000073 27,000

Sprinkler can 0.000022 1.1E

- 6 lb ai/ft 2 1000 ft 2 2.9E

- 7 6,800,000

1 Based on proposed use on the Flazasulfuron 25WG label [ EPA Reg. No 71512

- 12 ]

2 Exposure Science Advisory Council Policy #9.1.

3 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai ) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/ft 2 or gal) x Area Treated or Amount Handled (ft 2 or gallons/day) / BW (80 kg).

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

6.2 Post

- Application Exposure

W hen determining the potential for residential exposure, the Agency considers residues, leaf to skin/hand residue transfer, children’s hand

- to

- mouth transfer, and exposure time. Residential short

term dermal exposures for adults and children and short

- term incidental oral exposures for children are considered to be negligible from the proposed residential spot treatment use of flazasulfuron. However, for the broadcast turf use, the revised Flazasulfuron 25WG label replaced “college and professional sports fields” with “sports fields” in the use sites. The generic “sports fields” use site includes recreational parks therefore, there is a potential for short

- term dermal and incidental oral exposures to occur to children from the existing broadcast use of fla zasulfuron which now needs to

be assessed

. No dermal endpoint was chosen for flazasulfuron; therefore, a dermal post

- application risk assessment was not conducted. Table 6.2 summarizes the incidental oral exposures and risks resulting from residential po st

- application exposures. Children incidental ora l risk estimates ranged from 2,900 to 1,3 00,000 on the day of application using default input values, and were not of

concern to HED.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 21 of 36 Table 6 .2. Residential Post

- application Non

- cancer Exposure and Risk Estimates for

Flazasulfuron

Lifestage Post

- application Exposure Scenario Dose mg/kg/day MOEs

Child Turf

- sprays Dermal NA NA

Inhalation NA NA

Hand to Mouth 0.00069 2,900
Object to Mouth 0.000021 94,000
Incidental Soil Ingestion 1.6E6 1,300,000

1 Hand

- to

- Mouth = [Hand residue loading (mg/cm 2 ) x (fraction hand surface area mouthed/event (0.127/event) x typical surface area of one hand (150 cm 2 )) x (exposure time (1.5 hrs/day)*number of replenishment intervals/hr (4 intervals/hr) x (1

- (1

- saliva extraction factor (0.5)^(number of

hand

- to

- mouth contact events per hour (13.9 events/hr); Hand Residue Loading = (fraction of ai on hands compared to total surface residue from dermal TC study (0.06) x dermal exposure (mg))/typical surface ar ea of one hand (150 cm 2 ). Object

- to

- Mouth = ((Object Residue (μg/cm 2 ) x CF1 (1.0E

- 3 mg/μg) x Object Surface Area Mouthed/Event (10 cm 2 /event)) x (Exposure Time (1.5 hrs/day) x #Replenishment I ntervals/hr (4)) x (1

- ((1

- Extraction by Saliva (0.48))^(#Object

- to

- Mouth Events/hr (8.8 events/hr)/#Replenishment intervals/hr))))/Body Weight (11kg)

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

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

6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

Residential post

- application pesticide exposure can occur within a scenario from multiple routes of exposure (e.g., dermal, inhalation, and oral). These exposures to pesticides do not occur as single, isolated events, but rather as a series of sequential or concurrent events that may overlap or be linked in time and space. Based on this, r isk estimates resulting from different exposure routes may be

combi ned when it is likely that they can occur simultaneously based on the use pattern and when the toxicological effects across different routes of exposure are the same. If appropriate for an exposure scenario, the recommended routes of exposure for combinin g include dermal, inhalation, and hand

to

- mouth.

The incidental oral scenarios (i.e., hand

- to

- mouth, object

- to

- mouth, and soil ingestion) should be

considered inter

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

How ever, combining these scenarios together would be overly

- conservative because of the conservative nature of each individual assessment. Therefore, the post

- application incidental oral exposure scenarios were not combined for children 1 < 2 years old.

6 .4 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.4 reflects the residential risk estimates that are recommended for use in the agg regate
assessment for flazasulfuron

.

 The recommended residential exposure for use in the adult aggregate assessment reflects inhalation exposure from applications to turf via backpack or manually pressurized

handwand.

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

- to

- mouth exposures from post

- application exposure to turf

treatments.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 22 of 36 Table 6

. 4 Recommendations for the Residential Exposures for the Flazasulfuron Aggregate Assessment. 1

Lifestage Handler Exposure

(mg/kg/day) 2 Res idential

Handler

Total Exposure (mg/kg/day) 3 Residential

Handler

Total

MOE Post

- application

Exposure (mg/kg/day) 4 Residential

Post

application

Total Exposure (mg/kg/day)

5 Residential

Post

application

MOE Dermal Inhal

. Dermal Inhal

. Oral

Short

- Term

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

Child N A N A N A NA NA NA 0.00069 0.00069 2,900

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

2 Handler exposure repre sents high

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

. 3 R esidential Handler total exposure combines the highest dermal a nd inhalation exposures (Table 6.1 ), where applicable

. 4 Post

- application exposure represents high

- end dermal, inhalation and/or incidental oral exposure for the relevant exposure duration (Table 6 .2)

5 F or adults, r esidential total exposure combines the highest dermal a nd inhalation exposures (Table 6.1 ), where applicable . For young

c hildren, total residential exposure combines high

- end post application incidental oral AND dermal exp osure, where applicable (Table 6 .2)

6.5 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for flazasulfuron at this time primarily because of the low acute inhalation toxicity (Toxicity Categ ory IV) and low vapor pressure (< 1 x10

- 7 mm Hg). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from it s Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov /scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalati on exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for flazasulfuron

.

6.6 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application method s (e.g., groundboom ) employed for flazasulfuron. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pestic ide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information) 1 . The Agency has also developed a policy on how to appropriately consider spray drift as a potential source o f exposure in risk assessments for pesticides.

The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently

.Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 23 of 36 I t is noted that the 0.045 lb ai/acre application rate for turf was previously modeled to estimate post

application residential exposure of children. As this rate is equal to or higher than many of agricultural application rates, this scenario is protectiv e of any exposure of farm children via spray drift from agricultural flazasulfuron applications.

7.0 Aggregate Exposure/Risk Characterization

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

exposure. For flazasulfuron, potential exposures from food, drinking water, and residential scenarios

we re aggregated.

7.1 Acute Aggregate Risk

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

. Refer to

Section 5.4.

7.2 Short

- and Intermediate

- Term Aggregate Risk

There is potential short

- term exposure to flazasulfuron via the dietary pathway (which is considered background exposure) and the residential pathway (which is considered the primary pathway ). Since

intermediate

- term residential exposures are not likely to occur, intermediate

- term aggregate risks

were not ass essed. T he short

- term aggregate exposure assessment for adults include s dietary (food

and drink ing water), dermal and inhalation handler exposures, and post

- application dermal

exposures

. The most conservative scenario was chosen for each population (e.g. , hand

- to

- mouth exposure from treated turf for children 1

- 2 years old). For a description of the residential exposure scenarios considered in the aggregate assessment, see Section 6.4.

1 LOC includes standard inter

- (10X) and intra

- (10X) species uncertainty factors totaling 100.

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

3 Table 5.4.6

4 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Source of residential exposure values used in the aggregate ass essment (Table 6.4) . Exposure estimate for adults includes handler exposures from

tre ating turf with flazasulfuron . Exposure estimate for Children 1

- 2 years includes post

- application exposure via hand

to

- mouth to treated turf.

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

6 (Avg Food & Water Exposure + Re sidential Exposure) , NOAEL = 2 mg/kg/day 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 810Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 24 of 36 7.3 Chronic Aggregate Risk

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

. Refer

to Section 5.4.

7.4 Cancer Aggreg ate Risk

A cancer aggregate risk assessment was not conducted because there was n o evidence of carcinogenicity to humans based on lack of carcinogenic effects in the rat and mouse carcinogenicity

studies

.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to

flazasulfuron and any other substances and flazasulfuron does not appear t o produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA

has not assumed that flazasulfuron has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to d etermine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cu mulating effects from substances found to have a common mechanism on EPA’s

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

9.0 Occupational Exposure/Risk Characterization

Occupational exposures are expected to occu r from the proposed flazasulfuron uses on tree nuts

. Short

- (1

- 30 consecutive days) and intermediate

- term (1

- 6 consecutive months) dermal and inhalation exposures are expected from handler activities while only short

- and intermediate

- term dermal exposures are expected from post

- application activities. D ermal risks were not assessed

since a dermal hazard was not identified.

9.1 Occupational Handler Exposures

Chemical

- specific exposure data were not submitted to s upport the proposed flaza sulfuron uses. When chemical

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

PHED

, Version 1.1 as presented in the PHED Surrogate Exposure Guide (8/98) 1 to assess handler exposures for regulatory actions. Additionally, typical HED standard values were used for the amount treated per day (ExpoSAC Policy No. 9, 07/05/2000).

Based upon the proposed flazasulfuron use patterns, HED assessed risks to occupa tional pesticide handlers in the following scenarios:

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

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

and Chemical

- S pecific Data” HED, OPP, 1/28/99Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 25 of 36  Applicator of liquid formulation for groundboom application to tree nuts,

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

 Mixer/loader/applicator of WDG formulation for mechanically

- pressurized handgun application to tree nuts.

Short

- and intermediate

- term r isk estimates for occupational handlers are included in Table 9.1.1.

All handler scena rios resulted in MOEs greater tha n the LOC (MOEs ≥ 1 00) for baseline inhalation

exposures
, and therefore a re not of concern

.

Table 9 .1. 1 Occupational Handler Exposure and Risk Estimates for Flazasulfuron.

Exposure

Scenario Application

Equip Inhalation Unit

Exposure
(μg/lb ai) Maximum

Application

Rate 1 Area Treated

or Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

LOC =

100

Mixer/Loader

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

Applicator

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

Mixer/Loader/Applicator

Tree nuts Manually

pressurized

handwand 3.9 0.0022
lb ai/gal 1000 gal 0.00011 19,000

Backpack 2.58 0.0022
b ai/gal 40 gal 0.0000029 690,000

1 Based on proposed use on the ISK Flazasulfuron Herbicide label [ EPA Reg. No 71512

- 18 ]

2 Exposure Science Advisory Council Policy #9.1.

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

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

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

9.2 Occupational Post

- application Exposures

Occupational short

- term dermal exposures are expected from flazasulfuron post

- application

activities associated with the proposed tree nut use

. However, s in ce no hazard was identified for the

dermal route of exposure, dermal exposures were not quantitatively assessed

.

Based on the Agency's current practices, a quantitative post

- application inhalation exposure

assessment was not performed for flazasulfuron at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressu re ( < 1 x 10

- 7 mmHg ). However, there are multiple potential sources of post

- application inhalation exposure to individuals performing

post

- application activities in previously treated fields. These potential sources include volatilization of pesticides a nd resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in theFlazasulfuron Human Health Risk Assessment DP No. 411772

Page 26 of 36 process of evaluating the SAP report as well as available post

- application inhalation exposure d ata generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate occupational post

application inhalation exposure into the Agency's risk assess ments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application

inhalation ex posure assessment for flazasulfuron

.

Although a quantitative occupational post

- application inhalation e xposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than

post

- application exposure. The refore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

Restricted Entry Interval: The labeled restricted entry interval (REI ) of 12

- hrs is adequate to protect agricultural workers from post

- application exposures to flazasulfuron

. Per the Worker Protection Standard (WPS), flazasu l f uron is classified as Toxicity Categories III and IV and require s a 12

- hr REI

.

10.0 References

Dodd, N., 2/6/14 , DP# 412475

, Flazasulfuron: Petition for the Establishment of Permanent Tolerances and Registration for Use on Tree Nuts. Summary of Analytical Chemistry and Residue

Data

.

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

.

Shelby, A., 12/3/13 , DP# 411771

, Drinking Water Assessment for Flazasulfuron U s e on Tree Nuts.

Walls, C., 2/5/14 , DP# 417419

, Flazasulfuron: Acute & Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for a Proposed Use on Tree Nuts

.

Walls, C., Ph.D., 1/16/14

, D P# 417418

, FL AZASULFURON : Occupation al and Residential Exposure Assessment for a Proposed Use on Tree Nuts

.

Walls, C., Ph.D., 10/9 /12

, D P# 3 99890

, FL AZASULFURON : Occupation al and Residential Exposure Assessment for the First Residential Use on Turf Grass

.

Walls, C., Ph.D., 10/15/12

, D P# 399358

, FL AZASULFURON : Human Health Risk Assessment for

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

Page 27 of 36 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for Food Use for Flazasulfuron are in the following table. Use of the new guideline numbers does not imply that th e new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

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

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

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

yes

yes

no

no yes

yes

yes

-- waived

870.3700a Developmental Toxicity (rodent)

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

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

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

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

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

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

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

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

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

yes

no

yes

yes yes

yes

yes

yes

yes
870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

................ 870.5375 Mutagenicity

— Chromosomal Aberrations

.................... 870.5395 Mutagenicity

— In Vivo micronucleus

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

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

................................ ..... 870.6100b 90

- Day Neurotoxicity (hen)

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

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

- Day Neuro. Screening Battery (rat)

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

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

no

yes

yes

no -

- yes

yes

--

870.7485 General Metabolism

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

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

................................ ............................. y es

yes

yes yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)

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

................................ .................. Six

- month Oral (dog)

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

no

no --

--

--Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 28 of 36 A.2 Toxicity Profile s

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 (male and females) IV

870.1200 Acute dermal [rat] 46220909 LD 50 > 2000 mg/kg (male and females) III

870.1300 Acute inhalation [rat] 46220910 LC 50 > 5 mg/L (male and females) IV

870.2400 Acute eye irritation

[rabbit] 46220911 Minimal conjunctivitis through 48 hours. Free by 72

hours. III

870.2500 Acute dermal

irritation [rabbit] 46220912 No erythema, edema, or

dermal effects observed at application site. IV

870.2600 Skin sensitization

[guinea pig] 46220913 Not a sensitizer

-

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100

90

- Day oral toxicity (rat) 46220920 (1988)

M/F: 0, 40, 200, 1000, 5000 ppm M: 0, 2.31, 11.66, 57.1, 287 mg/kg/day F: 0, 2.53, 12.8, 61.5, 309 mg/kg/day Acceptable/Guideline NOAEL (M/F) = 11.66/61.5 mg/kg/day LOAEL (M/F) = 57.1/309 mg/kg/day based on depression of body weight gain (M/F) and slight anemia due to decrease in hemoglobin (F).

870.3150

90

- Day oral toxicity (dog)

- capsule 46220921 (1994)

M: 0, 2, 10, 50, 250 mg/kg/day F:0, 2, 10, 50, 100 mg/kg/day Acceptable/Guideline NOAEL (M/F) = 2/10 mg/kg/day LOAEL (M/F) = 10/50 mg/kg/day based on changes in liver (increase in: deposition of brown pigments, glutamic pyruvic transaminase, creatine phosphokinase, inflammatory cell infiltration, microgranulomas).

870.3200

21

- Day dermal toxicity (rabbit) 46220922 (1994)

0, 250, 500, 1000 mg/kg/day Acceptable/Guideline NOAEL (M/F) = 1000/1000 mg/kg/day LOAEL (M/F) > 1000 mg/kg/day. No systemic toxicity was

observed at the limit dose. No localized dermal effects were

observed.

870.3465

90

- Day inhalation toxicity (rat) Not Applicable The requirement for a subchronic inhalation toxicity study has been waived (K. Rury, TXR#0056483, 10/04/2012).Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 29 of 36 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3700a

Prenatal developmental (rat)

Wistar 46220924 (1988)

0, 100, 300, 1000 mg/kg/day Acceptable/Guideline Maternal NOAEL = 100 mg/kg/day LOAEL = 300 mg/kg/day based on increase in maternal relative liver weight and decreased body weight gain and food consumption. Developmental NOAEL = 100 mg/kg/day LOAEL = 300 mg/kg/day based on increased incidence of visceral malformations (interventricular septal defect).

870.3700a

Pre na tal developmental (rat) : Sprague

- Dawley 46220925 (1996)

0, 100, 300, 1000 mg/kg/day Acceptable/Guideline Maternal NOAEL = 300 mg/kg/day LOAEL =1000 mg/kg/day based on transient decreased body weight gain and food consumption. Developmental NOAEL = 300 mg/kg/day LOAEL = 1000 mg/kg/day based on reduced fetal weights

and retardation in ossification.

870.3700b

Prenatal developmental in

rabbit 46220923 (1988)

0, 50, 15 0, 450 mg/kg/day Acceptable/Guideline Materna l NOAEL = 150 mg/kg/day LOAEL = 450 mg/kg/day based on high incidences of abortion and decrease in food consumption after initial

administration. Developmental NOAEL = 150 mg/kg/day LOAEL = 450 mg/kg/day based on high incidences of

abortion.

870.3800 Reproduction and fertility effects (rat) 46220926 (1995)

0, 200, 2000, 10000 ppm M: 0, 8.7, 87.5, 473.0 mg/kg/day F: 0, 11.7, 124.5, 613.7 mg/kg/day Acceptable/Guideline Parental/Systemic NOAEL (M/F) = 8.7/124.5 mg/kg/day LOAEL (M/F) = 87.5/613.7 mg/kg/day based on changes in kidney parameters (M/F: Bilateral discoloration, enlargement, mild nephropathy) and reductions in body weight in both generations (F 0 , F 1 ). Reproductive NOAEL (M/F) =473.0/613.7mg/kg/day LOAEL (M/F) =not established. Offspring NOAEL (M/F) = 87.5/124.5 mg/kg/day LOAEL (M/F) = 473.0/613.7 mg/kg/day based on reduction in lactational body weights of the F 1 and F 2 offspring.

870.4100b Chronic toxicity (dog)

- capsule 46220927 (1995)

M: 0, 0.4, 2, 10, 50 mg/kg/day F: 0, 2, 10, 50 mg/kg/day Acceptable/Guideline NOAEL = 2 mg/kg/day

LOAEL = 10 mg/kg/day based on changes in liver (increase in: inflammatory cell infiltration, hepatocellular necrosis, hepatocellular swelling, and bile duct proliferation).

870.4200 Carcinogenicity (mouse) 46220928 (1995)

0, 500, 3500, 7000 ppm
M: 0, 77.3, 552.7, 1053.8 mg/kg/day F: 0, 93.7, 659.8, 1208.2 mg/kg/day Acceptable/Guideline NOAEL (M/F) = 77.3/93.7 mg/kg/day LOAEL (M/F) = 552.7/659.8 mg/kg/day based on decrease in body weight, body weight gain, food consumption and an increase in liver effects ( liver weight and hepatocellular hypertrophy).

no evidence of carcinogenicityFlazasulfuron Human Health Risk Assessment DP No. 411772

Page 30 of 36 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.4300

Combined Chronic Toxicity/ Carcinogenicity (rat) 46220929 (1995)

M: 0, 40, 400, 2000 ppm F: 0, 40, 400, 4000 ppm M: 0, 1.3, 13.3, 70.1 mg/kg/day
F: 0, 1.6, 16.4, 172.6 mg/kg/day Acceptable/Guideline NOAEL = 1.3 mg/kg/day LOAEL = 13.3 mg/kg/day based on : Adverse change in kidney function (chronic nephropathy) and kidney physiology (enlargement, dark color of kidney)

no evidence of carcinogen icity

870.51 00

Salmonella typhimurium and

Escherichia coli

Reverse Mutation Assay 46220933 (1987)

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

1000  g/ plate ( S. typhimurium ); 0, 100, 200, 500, 1000, 2000, 5000 ( E. coli ) in the presence and absence of

metabolic activation ( + S9) Acceptable/Guideline Flazasulfuron was not cytotoxic with or without S9

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

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

Negative

870.5300

in vitro Mouse Lymp homa Mutagenesis Assay 46220930 (1993)

0, 20, 30, 40, 50, 60, 70, 80, 90, 100, 500  g/ml in the presence and

absence of metabolic

activation ( + S9) Acceptable/Guideline There was no evidence of biologically significant induction

of mutant colonies.

Negative

870.5375

in vitro mammalian

chromosome

aberration test 46220931 (1988)

0, 3.3 x 10

- 4 , 1.7 x 10

- 4

, 8.3 x 10

- 5 , 4.1 x 10

- 5

, 2.1 x 10

- 5 M, with and

without metabolic activation ( + S9) Acceptable/Guideline Flazasulfuron did not induce chromosome aberrations in Chinese hamster lung cells, in the presence and absence of

S9activation.

Negative

870.5395

in vivo Mammalian Erythrocyte

Micronucleus Test:

Mouse 46220932 (1995)

0, 1250, 2500, 5000 mg/kg Acceptable/Guideline There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in mouse bone marrow at any dose or collection time.

Negative

870.6200a Acute neurotoxicity screening battery (rat) 46220934 (2002)

0, 50, 1000, 2000 mg/kg/day Acceptable pending data

submission /Guideline NOAEL (M/F) = 50 mg/kg LOAEL = 1000 mg/kg based on: transient decrease in motor activity observed at Day 0 (5 hours post

- dosing)Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 31 of 36 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.6200b

Subchronic neurotoxicity screening battery (rat) 49030001(2012)

0, 300, 3000, or 10000

ppm (M) 0, 19, 190, 649 mg/kg/day (F) 0, 22, 229, 732 mg/kg /day Acceptable/Guideline NOAEL = 19 / 229 mg/kg/day (M / F) LOAEL = 190 / 732 mg/kg/day (M / F) based on decreased body weight and body weight gain.

870.7485

Metabolism and pharmacokinetics (rat) 46220940 (1994),

46220941 (1995), 46220942 (1995), 46220943 (1995) single dose: 2, 50 mg/kg multiple dose: 2 mg/kg

Radiolabel: (first ring: Pyridine second ring: Pyrimidine) Acceptable/Guideline Radiolabeled flazasulfuron (Pyridine/Pyrimidine) was rapidly distributed and excreted in the urine and feces following multiple dosing. Urinary elimination, calculated from a total collection of 168 hours, occurred slower in males (74/73%) compared to females (90/91%). Fecal

elimina tion, calculated from a total collection of 168 hours, was greater in males (23/23%) than in females (10/9%).

Radiolabel was detected at low concentrations in carcass (M:1.7/1.1%; F:0.30/0.23%)), blood (M: 0.74/0.35%; F: 0.16/0.02), liver (M: 0.23/0.14%; F : 0.04/0.04%), and kidney (M: 0.13/0.02%; F: 0.02/ <0.005%). Peak plasma concentration following single dose administration occurred

at 6 hours in both sexes.

870.7800 Immunotoxicity (female mouse) 48870301 (2012)

0, 600, 3000, 6000 ppm, 0, 122.5, 662.9, 1198.3 mg/kg/day

Guideline classification not yet determined. Systemic NOAEL = 1198 mg/kg/day Systemic LOAEL = >1198 mg/kg/day, not established

Immunotoxicity NOAEL = 1198 mg/kg/day Immunotoxicity NOAEL = not established

Preliminary assessment only. Detailed review pending

A.3 Executive Summaries

The executive summaries of the neurotoxicity studies represent new data and are presented below; the executive summaries of the other studies used in this risk assessment and/or appearing in Table

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

11/16/2005.

870. 6200 Acute and Subchronic Neurotoxicity (rat)

– two studies

MRID 46220934 In an acute neurotoxicity study (MRID 46220934), groups of 7

- week old Sprague

- Dawley rats (10/sex/group) were given a single oral dose by gavage of SL

- 160 (98.5 % a.i., batch/lot #303) in 0.5% aqueous methylcellulose at doses of 0, 50, 1000, or 2000 mg/kg bw and observed for 14 days. Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in 5 animals/sex/group. This assessment occurred on each of the four days, one week prior to the initiation of exposure, on Day 0 at five hours postdosing (the time of peak effect), and on Days 7 and 14 postdosing. At study termination, 5 animals/sex/group were euthanized and perfusedFlazasulfuron Human Health Risk Assessment DP No. 411772

Page 32 of 36 in situ for neuropathological examination. Of the perfused animals, all were subjected to histopathological evaluation of brain and peripheral nervous system tissues. No deaths occurred during the study.

No abnormal clinical observations were recorded in male animals. Anogenital staining, decreased feces and dried red material around the ey es, mouth, and forepaws were observed on Days 1 through

4 for two mid

- dose and two high

- dose females. Mean body weights for males and females in groups receiving the test material were not statistically significantly different from the controls at pre

- tes t,

pre

- fast, or on Days 0, 7 and 14. There were no differences in the observations made as part of the FOB that were considered treatment related. Mean forelimb and hind limb grip strengths and mean

foot

- spread for males and females in groups receiving t he test material showed no treatment

- related differences from the controls at any of the observation times. Mean motor activity measurements for mid and high dose males and females were statistically significantly different from the respective control gro ups [Distance traveled measurement

- M:(mid = 51.2% decrease), (high = 59.3% decrease); F: (high = 58.5% decrease)] on Day 0 (5 hours post

- dosing). Animals were less active with more resting time than controls. The effect was reversed by the next schedule d observation (Day 7). Neurohistopathologic evaluation did not demonstrate any test material

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

dose and control animals.

Based on the t ransient loss of motor activity observed in this study, the NOAEL was 50 mg/kg bw. The LOAEL was 1000 mg/kg bw.

This neurotoxicity study is classified as Acceptable /Guideline (pending submission of analytical data verifying homogeneity and stability

.

D ose and Endpoint for Establishing aRfD: The NOAEL of 50 mg/kg bw based on the transient decrease in motor activity observed at Day 0 (5 hours post

- dosing) at the LOAEL of 1000 mg/kg bw was selected for the acute RfD.

MRID 49030001

In an subchronic neuro toxicity study (MRID 49030001 )

, four groups of Crl:CD(SD) rats (12/sex/group; ~6 weeks of age) were administered 0, 300, 3000, or 10000 ppm of Flazasulfuron [98.95% (Lot No. 0208)] in the diet and observed for 90 days. The respective dose levels based on food consumption were 0, 19, 190, and 649 mg/kg bw/day for males and 0, 22, 229, and 732 mg/kg bw/day for females. Clinical examinations were conducted weekly, and a n eurobehavioral

assessment [functional observational battery (FOB) and motor activity (MA) testing] were performed on all rats during weeks

- 1, 3, 7, and 12 ( first week of administration = week 0 ) . At study termination, all rats were euthanized and perfused in situ

, tissues collecte d for possible neuropathological examination , and brain weights and brain measurements were conducted. The

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

.

There were no mortalities or test

- substance

- related clinical findings during the study. Statistically lower (p≤0.01) body weight (

- 18 to

- 22%) throughout the experimental period) and weight gain (forFlazasulfuron Human Health Risk Assessment DP No. 411772

Page 33 of 36 the first half of the experimental period) were observed in males at the high dose beginning on day 7. Body weight tended to be somewhat lower relative to controls in females at the high dose (

- 8 to

- 9%), but did not reach statistical significance (p≤0.05) until day 49. Weight gain in females at the high dose was statistically lower (p≤0.01) during the 0

- 7 day interval and the cumulative weight gain was lower (p≤0.05) at the end of the experimental period (

- 21%). Statistically lower weight gain (p≤0.01) was observed in males at the mid

- dose during the 0

- 7 day interval, which resulted in a 5.2% lower body weight (not statistically significant). Statistically lower food consumption was observed in both males (p≤0.01) and females (p≤0.05) at the high dose throughout most of the experimental period as well as cumulatively at the end of the study. No statistic ally significant or test substance

related FOB findings were observed in any of the Flazasulfuron

- treated groups. Statistically higher (p<0.05) ambulatory counts were observed in females during separate intervals at 3000 ppm (51

- 60 minutes, week 7) and at 10000 ppm (31

- 40 minutes and 51

- 60 minutes, week 7). The ambulatory findings in females were not toxicologically significant, since they were limited to week 7 and were not accompanied by associated FOB findings or by neuropathology results. There were no findings during the gross examination at necropsy, and no statistically significant or treatment

- related

differences in brain measurements in either sex. Sporadic instances of minimal axonal degeneration were observed in peripheral nerves and in spinal ne rve roots (common background lesions). There

were no test substance

- related or other remarkable findings in the microscopic examination of neurological tissues.

Based on the body weight effects seen in this study, the LOAEL for Flazasulfuron in the diet was 3000 ppm for males (equivalent to 190 mg/kg bw/day ), and 10000 ppm for females (equivalent to 732 mg/kg bw/day) for subchronic neurotoxicity in Crl:CD(SD) rats. The NOAEL was 300 ppm for males (equivalent to 19 mg/kg bw/day), and 3000 ppm for females (equivalent to 229 mg/kg bw/day).

This neurotoxicity study is classified as Acceptable/Guideline and satisfies the guideline requirement for subchronic neurotoxicity study in rats (OCSPP 870.6200; OECD 424).Flazasulfuron Human Health Risk Assessment DP No. 411772

Page 34 of 36 Appendix B

. Chemical Names and Structures for Flazasulfuron and its Metabolites

Chemical Names and Structures f or Flazasulfuron and its Metabolites

Common name/code Chemical name Chemical structure

Flazasulfuron /SL

- 160 N

- [[4,6

- dimethoxy

- 2

- pyrimidinyl)amino]c arbonyl]

- 3

- (trifluoromethyl)

- 2

- pyridinesulfonamide

ADMP 2

- amino

- 4,6

- dimethoxypyrimidine

DTPU N

- (4,6

- dimethoxy

- 2

- pyrimidinyl)

- N

- [3

- ( trifluoromethyl)

- 2

- pyridinyl]urea

DTPP 4,6

- dimethoxy

- N

- [3

- ( trifluoromethyl)

- 2

- pyridinyl]

- 2

- pyrimidinamine

HTPP 6

- methoxy

- 2

- [[ 3

- ( trifluoromethyl )

- 2

- pyridinyl]amino]

- 4

- pyrim idinol

TPSA 3

- ( trifluoromethyl )

- 2

- pyridinesulf

onamideFlazasulfuron Human Health Risk Assessment DP No. 411772

Page 35 of 36 2,3

- GTF 3

- trifluor o methyl

- 2

- pyridylguanidineFlazasulfuron Human Health Risk Assessment DP No. 411772

Page 36 of 36 Appendix C

. Physical/Chemical Properties of Flazasulfuron

Physico

- Chemical Properties of Flazasulfuron

Parameter Value Reference

Melting point 150°C MRID 46220905

pH 4.01 at 25°C (1% w/w)

Density 0.66 g/cm 3 at 25°C (bulk density)

Water solubility (25  C) pH 5 buffer 0.027 mg/mL pH 7 buffer 2.1 mg/mL pH 9 buffer not stable

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

Acetonitrile 8.7 mg/mL

Dichloromethane 22.1 mg/mL Ethyl acetate 6.9 mg/mL

Hexanes* 0.50 μg/mL

Methanol 4.2 mg/mL

Octanol 0.20 mg/mL

Toluene 0.56 mg/mL

Vapor pressure <1 x 10

- 7 mmHg (<1.33 x 10

- 5 Pa) at 25, 35,

and 45°C

Dissociation constant (pK a ) at 20°C 4.37

Octanol/ water partition coefficient

K OW at 25°C 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