Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 1 of 50 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

MEMORANDUM

Date : June 12 , 2011

SUBJECT: Flazasulfuron : Human Health Risk Assessment for Proposed Uses on Citrus, Grapes, Sugarcane, Christmas Trees, and Industrial Vegetation Management

PC Code: 119011 DP Barcode: D372903

Decision No.: 42525 3 Registration No. : 71512

- RI

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

Risk A ss essment Type: Single Chemical/Aggregate Case No.: NA

T XR No.: NA CAS No.: 104040

- 78

- 0

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

FROM: Cassi L. Walls

, Ph.D., Senior Biologist Myron S. Ottley , Ph.D., Toxicologist Nancy Dodd, Chemist Kristin Rury, Biologist

R isk Assessment Branch III (RAB3) Health Effects Division (7509P)

THROUGH: Paula Deschamp, Branch Chief RAB3/HED (7509P)

TO: Hope Johnson /Kable Davis, RM #25 Registration Division (7505P)Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 2 of 50 1.0 Executive Summary

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

2.0 Regulatory Conclusions and Recommendations

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

2.1 Data Deficiencies/Conditions of Registration

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

2.2 Tolerance Considerations

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

2.2.1 Enforcement Analytical Method

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

2.2.2 International Harmonization

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

2.2.3 Recommended Tolerances

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

2.2.4 Revisions to Petitioned

- For Tolerances

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

2.3 Label Recommendations

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

2.3.1 Recommendations from Residue Reviews

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

2.3.2 Recommendations for Worker Safety

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

2.3.3 Recommendations for Residential Safety

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

3.0 Ingredient Profile

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

3.1 Structure and Nomenclature

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

3.2 Physical/Chemical Characteristics

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

3.3 Summary of Existing/Proposed Uses

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

4.0 Hazard Characterization and Dose

- Response Assessment

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

4.1 Toxicology Studies Available for Analysis

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

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

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

4.2.1 Dermal Absorption

................................ ................................ ................................ ......... 15

4.3 Toxicological Effects

................................ ................................ ................................ .......... 15

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

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

4.4.1 Completeness of the Toxicology Database

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

4.4.2 Evidence of Neurotoxicity

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

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

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

4.4.4 Residual Uncertainty in the Exposure Database

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

4.5 Toxicity Endpoint and Point of Departure Selections

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

4.5.1 Dose

- Response Assessment

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

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

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

4.5.3 Cancer Classification and Risk Assessment Recommendation

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

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

Assessment

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

4.6 En docrine Disruption

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

5.0 Dietary Exposure and Risk Assessment

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

5.1 Metabolite/Degradate Residue Profile

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

5.1.1 Summary of Plant and Animal Metabolism Studies

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

5.1.2 Summary of Environmental Degradation

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

5.1.3 Comparison of Metabolic Pathways

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

5.1.4 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

................................ ................................ ................................ .......... 25

5.3 Water Residue Profile

................................ ................................ ................................ ........ 26

5.4 Dietary Risk Assessment

................................ ................................ ................................ .... 26

5.4. 1 Description of Residue Data Used in Dietary Assessment

................................ .......... 26

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .................... 26

5.4.3 Acute Dietary Risk Assessment

................................ ................................ ..................... 26

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ................. 27Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 3 of 50 5.4.5 Cancer Dietary Risk Assessment

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

5.4.6 Summary Table

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

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Residential Handler Exposure

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

6.2 Post

- Application Exposure

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

6.3 Combined Exposure

................................ ................................ ................................ ........... 29

6.4 Spray Drift

................................ ................................ ................................ .......................... 29

7.0 Aggregate Ex posure/Risk Characterization

................................ ................................ ........ 29

7.1 Acute Aggregate Risk

................................ ................................ ................................ ......... 29

7.2 Short

- and Intermediate

- Term Aggregate Risk

................................ .............................. 29

7.3 Chronic Aggregate Risk

................................ ................................ ................................ .... 30

7.4 Cancer Aggregate Risk

................................ ................................ ................................ ...... 30

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 30

9.0 Occupational Exposure/Risk Characterization

................................ ................................ .. 30

9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ......... 30

9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ .......................... 33

10.0 Environmental Justice Considerations

................................ ................................ ................ 33

11.0 References

................................ ................................ ................................ ............................... 34 Appendix A. Tox icology Profile and Executive Summaries

................................ ........................ 35

A.1 Toxicology Data Requirements

................................ ................................ ......................... 35

A.2 Toxicity Profiles

................................ ................................ ................................ .................. 36

A.3 Hazard Identification and Endpoint Selection

................................ ................................ 39

A.4 Executive Summaries

................................ ................................ ................................ ......... 39

A.5 Endpoint Selection Worksheet: Flazasulfuron

................................ ................................ 40 Appendix B. Metabolism Summary Table

................................ ................................ ..................... 44 Appendix C. Review of Human Research

................................ ................................ ...................... 47

A ppendix D. International Residue Limits

................................ ................................ .................... 48

A ppendix E. Chemical Names and Structures for Flazasulfuron and its Metabolites

.............. 49Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 4 of 50 1.0 Executive Summary

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

flazasulfuron on citrus, g rapes and s ugarcane as well as uses on Christmas trees and industrial vegetation management areas. It is currently registered for use on non

- residential turf such as golf courses, sod farms, athletic fields, and commercial lawns. Flazasulfuron is a sulfonylurea herbicide

used to control certa in broad

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

The end

- use product relevant for this petition is ISK Flazasulfuron Herbicide which is a water dispersible granular (WDG/WG) formulation contain ing 25% active ingredient (ai). Soil directed spray application for citrus and grapes and over

- the

- top applications and post

- directed applications for sugarcane are proposed at a maximum seasonal rate of 0.15 lb ai/A. Over

- the

- top and soil directed spray applications are proposed for Christmas trees at rates of 0.033

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

at 0.047 lb ai /A/application where these applications ma y not be made near resi dential properties or near sensitive desired plants.

Human Health Risk Assessment :

In the longer

- term studies of the mammalian toxicology database, the kidney and liver were the primary target organs of flazasulfuron toxicity. Subchronic studies in animals indicated decreased body weight gain, slight anemia in rats and liver abnormalities in dogs.

A NOAEL of 50 mg/kg/day was selected for the acute dietary endpoint based on a transient decrease in motor activity in the rat acute neurotox icity study. The NOAEL of 1.3 mg/kg/day was selected for the chronic dietary endpoint based on adverse change in kidney function (chronic nephropathy) in a combined chronic toxicity and carcinogenicity study in rats. For short

- and intermediate

- term
resid ential and occupational (incidental oral and inhalation) exposure scenarios, the NOAEL of 2 mg/kg/day from the oral subchronic in dogs was selected which was based on changes in liver (increase in: deposition of brown pigments, glutamic pyruvic transaminas e, creatine phosphokinase, inflammatory cell infiltration, and microgranulomas). Although there was a 21

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

identified.

Based on the lack of ca rcinogenic effects in the two

- year combined chronic toxicity and carcinogenicity studies , flazasulfuron is classified as “no evidence of carcinogenicity to humans”.

Flazasulfuron has low acute toxicity via the oral, dermal and inhalation routes of exposure. It is not irritating to the skin or eyes and is not a sensitizer.

Dietary Exposure (Food/Water):

The residue chemistry data and drinking water data are adequate to assess dietary exposure. The dietary exposure assessment relies on conservative inputs to model exposure to flazasulfuronFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 5 of 50 through food and drinking water. No residues of parent were found in field trials on /in citrus, grapes and sugarcane field trials or proce ssed commodities after treatment at an exaggerated rate (10x th e seasonal application rate). The estimated drinking water concentrations ( EDWC s) were determined for ground water and surface water; the EDWC for ground water was used since it is higher than that

for surface water. The assessments are based on reliable data and will not underestimate exposure/risk.

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

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

. The ground water estimated drinking water concentration ( EDWC ) of 102 μ g/L resulting from the Tier II PRZM

- GW

model was incorporated d irectly 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 subgr oups. The acute dietary exposure estimates at the 95 th percentile are 1 .1 % of

the a PAD for the general U.S. population and 4.0 % 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 proposed crops and 100% crop treated (CT). DEEMTM default processing factors were used

. The ground water

est imated drinking water concentration ( EDWC ) of 102 μ g/L resulting from the Tier II PRZM

- GW

model 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 1 7 % of the

c PAD for the general U.S. population and 54 % of the c PAD for all infants (< 1 year old), the most highly exposed population subgroup.

Residential Exposure:

This document only presents the assessment of the proposed new ag ricultural uses of flazasulfuron

. N o residential uses are being reque sted at this time; therefore, a residential risk assessment has not
been conducted.

F lazasulfuron is currently registered for use on golf courses and other non

- residential turf areas such as industrial parks, tank farms, sod farms, seed farms, and professionally managed sport s fields

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

assessed.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 6 of 50 Aggregate Risk:

Acute: Aggregate acu te risk is equivalent to acute dietary risk. There is potential acute exposure via the diet (food and drinking water) as determined in Section 5.4

. The acute aggregate exposure estimates at the 95th percentile are 1.1% of the a PAD for the general U.S. population and 4.0% of

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

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

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

. The chronic aggregate exposure estimate s are 17% of the c PAD for the general U.S. population and 54% of the c PAD for all infants (<1 year old), the most highly exposed population subgroup.

Short

- and Intermediate Term: There is potential short

- term exposure to flazasulfuron via the dietary

p athway (which is considered background exposure) and the post

- application dermal residential pathway (which is considered the primary pathway ). However, since no hazard was identified for the dermal route of exposure, short

- and intermediate

- term ag gregate risks were not assessed. Furthermore, for children, exposure includes only food and drinking water since dermal and incidental oral exposure to children from treated golf and athletic field turf is considered to be negligible.

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

studies

.

Occupational Exposure/Risk:

Agricultural Handlers: Occupational short

- term (1

- 30 days) and intermediate

- term (1

- 6 months) dermal and inhalation exposure s are expected from flazasulfuron handler activities associated with both the proposed ag ricultural and ornamental uses. HED used data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in the PHED Surrogate Exposure Guide (8/98) to assess handler exposures (HED Science Advisory Council for Exposure (ExpoSAC) Standard Operating Procedure (SOP) No. 7, dated 01/28/1999). Since no hazard was identified for the dermal route of exposure, dermal risks were not assessed

. A Margin of Exposure (MOE) greater than 100

for the inhalation route is deemed adequate to protect occupational flazasulfuron handlers. All handler scenarios resulted in MOEs g reater tha n the level of concern ( LOC ) (i.e., MOEs ≥ 1 00) for

inhalation exposures and, therefore a re not of concern

.

Agricultural Post

- application: Occupational short

- and intermediate

- term dermal exposures are expected from post

- application activitie s. However, since no hazard was identified for the dermal route of exposure, dermal risks were not assessed

Environmental Justice Considerations : Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment . Dietary and non

- dietary exposures were considered.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 7 of 50 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. The se studies (listed in Appendix C) have been determined to require a review of their ethical conduct, and one of these studies is also subject to review by the Human Studies Review Board. All of the listed studies have received the appropriate review.

2.0 Regulatory Conclusions and Recommendations

Provided revised Sections B (OPPTS 860.1200) and F (OPPTS 860.1550) are submitted, HED can recommend for a conditional registration of flazasulfuron for use on Christmas trees and for industrial vegetation manag ement, and permanent tolerances for the proposed uses of flazasulfuron

on citrus, grapes, and sugarcane. Additional data are needed as condition s of registration as outlined in Section 2.1 below. The specific tolerance recommendations are discussed in Se ction 2.2, and

label modifications are discussed in Section 2.3.

2.1 Data Deficiencies/Conditions of Registration

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

A revised Section B is requested to clarify/revise the minimum retreatment interval (RTI). The general label application restrictions state that repeat applications may be made at 2 to 6 weeks after application. However, the label also states that split applications should be made at 4 to 6 weeks after the first application, and that sequential applications are made on a longer term interval such as spring followed by a fall application. The petitioner should also

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

re treatment intervals in the field trials were 95

- 308 days for citrus and 14

- 118 days for grapes. Based on the residue data, the re treatment interval should be at least 3 months for

citrus and at least 2 weeks for grapes. 860.1200 Directions for Use

Note : The proposed label for sugarcane requires a 12

- month interval between the last application and the planting of the rotational crop. While HED considers this restriction to be adequate for conditional registration of flazasulfuron based on the fact that no detectable

residues of flazasulfuron were found in the primary crops, the restriction will need to be re

evaluated after submission and review of the confined rotational crop study which is required to support permanent registrat ion of sugarcane.

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

definitions as listed in Table 2.2.4. 860.1550 Proposed TolerancesFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 8 of 50 The following d ata are required as a condition of registration :

TOXICOLOGY

The subchronic neurotoxicity screening battery is required to fulfill current 40 CFR Part 158 data requirements. 870.6200 Neurotoxicity Battery (Subchronic Studies)

The immunotoxicity study is required to fulfill current 40 CFR Part 158 data requirements. 870.7800 Immunotoxicity

RESIDUE CHEMISTRY

Multiresidue methods data must be submitted since tolerances will be established. 860.1360 Multiresidue Methods

For MRID 47939903 ( Howald, M., Ullrich

- Mitzel, A. (1997) Storage Stability of SL

- 160 Residues in Grapes. Document Number: 634713), t he dates of sample spiking and analysis must be submitted to verify reported storage intervals. 860.1380 Storage Stability Data

A confined rotational crop study is required to support permanent registration of sugarcane. Depending on the results, a study to determine field accumulation in rotational crops may be required. 860.1850/860.1900 Confin ed/Field Accumulation in Rotational Crops

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Flazasulfuron is not listed in the FDA PESTDATA database ( Pesticide Analytical Manual , Volume I, Appendix I, 3 rd edition, 1994, revised October 1999) ; therefore, a multiresidue method study must

be submi tted.

Adequate residue analytical methodology is available for tolerance enforcement. The method uses high performance liquid chromatography/tandem mass spectrometry with multiple reaction monitoring (HPLC/MS

- MS/MRM) ( ADME study code S09

- 03106 ; MRID 48 092201 )

.

Adequate residue analytical methodology is available for data collection. In the field trials a nd processing studies submitted , residue s of flazasulfuron and/or DTPU were determined using an adequate HPLC

- MS/MS method from Central California Research Laboratories, Inc., titled “Analytical Method for Determination of SL

- 160 and Its Metabolite in Soil” ( C CRL

- MTH

- 045).Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 9 of 50 2.2.2 International Harmonization

There are currently no maximum residue limits (MRLs) established by Codex, Canada, or Mexi co for flazasulfuron

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

action. An International Residue Limit Status sheet is attached ( Appendix D).

2.2.3 Recommended Tolerances

HED recommends for the following tolera nces and residue definition:

“Tolerances are established for residues of flazasulfuron, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by mea suring only flazasulfuron ( N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (trifluoromethyl)

- 2

- pyridinesulfonamide).”

Fruit, citrus, group 10

- 10

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

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

................................ ................................ . 0.01 ppm

2.2.4 Revisions to Petitioned

- For Tolerances

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

levels are based on the submitted magnitude of the residue data . T he Agency’s tolerance spreadsheet from the Guidance for Setting Pesticide Tolerances Based on Field Trial Data was not used because all of the treated samples bore residues below the LOQ

.

Table 2.2.4 . Tolerance Summary for Flazasulfuron

Commodity Established/Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments Correct Commodity Definition

C itrus 0.01 0.01 Fruit, citrus, group 10

- 10 Grape s 0.01 0.01 Grape Sugarcane 0.01 0.01

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

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

- RI) to clarify/revise the minimum retreatment interval. The general label application restrictions state that repeat applications may be made at 2 to 6 weeks after application. However, the label also states that split applications should be made a t 4 to 6 weeks after the first application, and that sequential applications are made on a longer term interval such as spring followed by a fall application. T he label directions regarding the retreatment interval should reflect the field trials.

The re treatment intervals in the field trials were 95

- 308 days for citrus and 14

- 118 days for grapes. Based on the residue data, the re treatment interval should be at least 3 months for citrus and at least 2 weeks for grapes.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 10 of 50 2.3.2 Recommendations for Worker Safety

T he ISK Flazasulfuron Herbicide label proposes a 4

- hour reduced reentry interval ( REI ). In accordance with criteria for reduced REI candidates, an active ingredient cannot elicit reproductive, developmental, neurotoxic or carcinogenic effects. Fl azasulfuron elicits developmental effects, and

therefore cannot be a candidate for a reduced REI. Per the Worker Protection Standard (WPS), chemicals classified as Toxicity Categories III and IV require a 12

- hr restricted entry interval (REI)

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

2.3.3 Recommendations for Residential Safety

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

3.0 Ingredient Profile

Flazasulfuron [N

- [[4,6

- dimethoxy

- 2

- pyrimidi nyl)amino]carbonyl]

- 3

- (trifluoromethyl)

- 2

- pyridinesulfonaminde] belongs to the pyrimidinylsulfonylurea class of herbicides. It is used to
control certain broadleaf weeds and grasses and acts by inhibiting the acetolactate synthase (ALS) biochemical process.

ISK has proposed the first food/feed uses for flazasulfuron on in citrus, grapes, and sugar cane, as well as, uses on Christmas trees and industrial vegetation management in nonagricultural areas.

Flazasulfuron is currently r egistered for use on golf courses and other non

- residential turf areas

.

The flazasulfuron end

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

formulated as a water dispersible granular (WDG/WG) formulation containing 25% act ive ingredient (ai). The product is proposed for use on citrus, grapes, and sugarcane at a maximum single application rate of 0.045 lb ai/A or a maximum seasonal application rate of 0.15 lb ai/A. The

use of a non

- ionic surfactant is recommended for post

- emergence applications to citrus and grapes.

The pre

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

3.1 Structure and Nomenclature

Table 3.1 Flazasulfuron 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)ureaFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 11 of 50 Table 3.1 Flazasulfuron N omenclature

CAS name N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (trifluoromethyl)

- 2

- pyridinesulfonamide
CAS registry number 104040

- 78

- 0

End

- use product (EP) ISK Flazasulfuron Herbicide, a WDG/WG formulation containing 25% active ingredient (ai) (EPA File Symbol 71512

- RI ) , for use on citrus, grapes, and sugarcane; Flazasulfuron 25WG (EPA Reg. No 71512

- 12), registered on turf

3.2 Physical/Chemical Characteristics

Table 3.2 Physico

- Chemical Properties of Flazasulfuron

Parameter Value Reference

Melting point 150°C MRID 46220905

pH 4.01 at 25°C (1% w/w)

Density 0.66 g/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 torr (<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

3.3 Summary of Existing/Proposed Uses

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

for flazasulfuron

. However, in the U.S.

, f lazasulfuron is currently registered to control annual and perennial grasses, sedges, and broadleaf weeds on golf courses and other non

- residential turf areas such as industrial parks, tank farms, sod farms, seed farms, and professio nally managed sports fields

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

25% flazasulfuron.

ISK Biosciences Corporation has proposed the first food/f eed uses for flazasulfuron on citrus, grapes, and sugarcane, as well as, uses on Christmas trees and industrial vegetation management in nonagricultural areas as summarized in Table 3.3 below . The flazasulfuron end

- use product rel evant for this petition is ISK Flazasulfuron Herbicide which is formulated as a water dispersible granular (WDG/WG) containing 25% active ingredient (ai).Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 12 of 50 The submitted label for ISK Flazasulfuron Herbicide ( EPA File Symbol 71512

- RI ) is adequate to allow evaluation of the residue data relative to the proposed uses. Refer to Section 2.3 for

recommended modi fications to the proposed label

.

Table 3.3 Summary of Directions for Use of Flazasulfuron

Applic. Timing, Type, and Equip. Application

Rate (lb ai/A) Max. No. Applications per Season Max. Seasonal Application

Rate (lb ai/A) Minimum

RTI (days) PHI (days) Use Directions and Limitations

Citrus

Pre

- emergence and

Post

- emergence; Soil application using ground spray equipment 0.045 Not reported 0.15 Not reported 1 1 Apply only as a directed spray to the

soil beneath the trees.

Use a non

- ionic surfactant at 0.25% v/v for post

- emergence applications.

Grapes

Pre

- emergence and

Post

- emergence; Soil application using ground spray equipment 0.045 Not reported 0.15 Not reported 1 75 Apply only as a directed spray to the

soil beneath the vines.

Use a non

- ionic surfactant at 0.25%

v/v.

Sugarcane

Over

- the

- Top or

Post

- directed 0.023 Not reported 0.15 14 180 Apply prior to spiking or on ratoon up to 24 inches tall at a 0.014 lb ai/A rate.

Use a non

- ionic surfactant at 0.25%

v/v.

Allow a 12 month interval between the last application and the planting of the rotational crop.

Post

- Directed 0.045 Not reported 0.15 14 180 Apply to sugarcane that is 18 inches tall up through layby. Applications should

minimize contact with the whorl of the

sugarcane.

Use a non

- ionic surfactant at 0.25%

v/v.

Allow a 12 month interval between the last application and the planting of the

rot ational crop.

Christmas TreesFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 13 of 50 Table 3.3 Summary of Directions for Use of Flazasulfuron

Applic. Timing, Type, and Equip. Application

Rate (lb ai/A) Max. No. Applications per Season Max. Seasonal Application

Rate (lb ai/A) Minimum

RTI (days) PHI (days) Use Directions and Limitations

Pre

- emergence and

Post

- emergence 0.045 Not reported Not reported Not reported NA Do not apply to conifer seedbeds. Do not apply to trees within 1 year of seeding. May be applied over

- the

- top to conifers prior to spring bud break or when conifers are sufficiently hardened off. Directed sprays must be made to conifers that have new gr owth or are not sufficiently hardened off. Directed sprays are preferred and recommended to reduce phytotoxicity potential

Use a non

- ionic surfactant at 0.25%

v/v.

Industrial Vegetation Management

Post

- emergence 0.047 Not reported Not reported 4 to 6

weeks NA Do not use near residential properties.

Use a non

- ionic surfactant at 0.25%

v/v.

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

General application information on the label states that pre

- emergence and post

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

- emergence sprays, a spray volume of 20 gallons or more per acre is recommended. Applications should be made using conventional low pressure ground spray equipment. Applications cannot be made aerially or through any irrigation system. The general label application restrictions also state that repeat applications may be made at 2 to 6 weeks after application. However, the label also states that split applications should be made at 4 to 6 weeks after the first application, and that sequential applications are made on a longer term interval such as spring followed by a fall applicatio n.

4.0 Hazard Characterization and Dose

- Response Assessment

Flazasulfuron belongs to the pyrimidinylsulfonylurea class of herbicides and controls weeds by inhibiting the acetolactate synthase (ALS) biochemical process. Since ALS is a component in synthesis of some essential amino acids, weed survival and growth are inhibited. A direct correlation of this mode of action in plants to a mode of action in mammals is not clear because ALS

is not present in mammals.

4.1 Toxicology Studies Available for Analysis

The existing database is deemed sufficient for characterizing the hazard of flazasulfuron. T he database contains studies evaluating toxicity following oral exposure in rats , mice, dogs and rabbits

and dermal exposure in rabbits , which help to characterize toxicity associated with oral, dermal, and inhalation exposure routes in humans.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 14 of 50 The available studies consist of an acute neurotoxicity study in the rat; 90

- day oral studies in the r at and dog and a 21

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

multi

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

vitro and in vivo mutagenicity studies; and a batte ry of metabolism and pharmacokinetics studies in

the rat.

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

Absorption. Differences in absorption rates were generally not noted between dose levels or between single versus repeated dose admi nistration, but were noted between males and females. The bile cannulation study, demonstrated that Flazasulfuron [ 14 C

- SL

- 160(P)] is rapidly absorbed following a single oral dose of 2 or 50 mg/kg. By 48 hours post exposure, males and females

absorbed 94% a nd 93% of the low dose, respectively, and 86% and 93% of the high dose, respectively. A similar pattern was observed when low

- and high

- dose animals were followed up to 168 hours with little differences being noted between a single or repeated exposure. T

max values of 30 minutes to 6 hours were dose and sex dependent, being shorter at low doses and in females. T 1/2 in blood ranged from 18.8 to 36 hours and was slightly shorter in females.

Distribution. At seven days, blood, liver, and muscle were the tissues with the highest concentrations (0.03

- 1.0 % of dose depending on tissue, dose regimen, and sex) while the carcass had up to 2.5% of the administered dose. These findings might be explained by binding of some of

the radiolabel to tissue macromolecu les such as proteins and/or DNA. In general, the pattern of radiolabel distribution in tissues seemed to be similar irrespective of the dosing regimen.

Metabolism. In the single and repeated dose studies, the parent compound was the primary component in the metabolite profiles for urine (males: 19

- 40%; females: 51

- 67% of administered dose), with lesser amounts in feces (males and females: 2

- 5% of administered dose), and bile (males

and females: 0.6

- 2% of administered dose). Including parent compound, up t o 11 fractions were detected among these matrices. The most prevalent metabolite (expressed as pe rcent of administered dose) was HDTG

- i

- TPPG (

— 6.5

- 12% in urine,

— 0.4

- 2% in feces, and

— 6.5

- 14% in bile), with minor amounts (<5%) of DTPU, HDPU, HTTP, TPSA, an d MTMG. Individually, unidentified fractions generally accounted for less than 2% of the administered dose in the urine and biliary metabolite profile. The fecal metabolite profile had up to 35% unidentified of the recovered fecal radiolabel. In aquatic and soil environmental simulation media, there were several hydrolysis products that were generated from SL

- 160 including DTPU, DTPP, HTPP, TPSA, and ADMP all of which were either identified as isolated rat metabolites or as an intermediate metabolite (DTP P).

Elimination. 14 C

- SL

- 160(P) is rapidly, though not completely, excreted from the animal; total body burdens at seven days post dosing were equal to or less than 4% and 1% of the administered radioactivity in males and females, respectively. Elimina tion via the urine was the major route of excretion, accounting for 74

- 80% and 90

- 94% in males and females, respectively, irrespective of dosing regimens with a significant portion of the radioactivity being excreted within 48

- 72 hrs.

Feces were the secon dary route of elimination, accounting for 21

- 24% and 9

- 10% in males and females, respectively, following both low

- and high

- dose and single and repeated dose

administration. The biliary excretion study determined that, relative to the administered dose, 9 .5%Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 15 of 50 of appeared in bile by 48 hours in low

- dose males and low

- and high

- dose females while 16.5% appeared in the high

- dose males.

4.2.1 Dermal Absorption

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

- day dermal toxicity study (rabbit) was submitted. In this study, no systemic toxicity occurred at the limit dose (1000 mg/kg/day) and the primary toxic effects of concern were adequately assessed in the study. In the absence of a dermal absorption study, a conservative dermal ab sorption factor (DAF) was estimated based on available oral and dermal toxicity data. HED estimated a DAF of no more than 45% based on the ratio of the LOAEL from the oral rabbit developmental study (450 mg/kg/day) and the

NOAEL from the 21

- day dermal tox icity study in rabbits (1000 mg/kg/day). This is a conservative

estimate because the 21

- day dermal study did not present an adverse effect at the highest dose tested in order to produce a LOAEL.

Dermal Absorption Factor (DAF) = 450 mg/kg/day (LOAEL) 1000 mg/kg/day (NOAEL) x 100 = 45%

4.3 Toxicological Effects

Chronic oral studies in the rat , mouse and dog indicate that the kidney and liver are the target organs for chronic oral exposure. Observe d effects include adv erse changes in kidney function ( chronic nephropathy) and kidney physiology (enlargement, dark color of kidney), increase s in liver weight

an d hepatocellular hypertrophy), increase s in i nflammatory cell infiltration, hepatocellular necrosis, hepatocellular swelling, and bile duct proliferation

. Subchronic oral studies indicated decreased body weight gain, slight anemia in rats and liver abnormalities in dogs. Dermal or systemic toxicity was not seen in a subchronic dermal study in ra bbits at dose levels up to the limit d ose.

Developmental t oxicity was observed in rats and rabbits. Reduced fetal weights and delays in ossification are the effects observed in a Sprague

- Dawley rat developm ental 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 developmental and reproductive studies occurred at dose levels which were toxic

to the parents.

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

- dosing) was observed at the mid

- dose of 1000 mg/kg in an acute neurotoxicity study

. This observation may be associated with a systemic effect and not be associated with neurotoxicity.

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.

Flazasulfuron exhibits low acute toxicity i n rats and rabbits. The oral LD 50 is greater than 5000 mg/kg, the acute inhalation LD 50 is greater than 4.0 mg/L, and the acute dermal LD 50 is greater thanFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 16 of 5 0 2000 mg/kg. All studies are in Toxicity Category III or IV. Flazasulfuron is not irritating to the skin or eyes and is not a sensitizer.

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

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

residual uncertainties.

4.4 .1 Completeness o f the Toxicology Database

The toxicit y database for flazasulfuron is complete except for an immunotoxicity study (OPPTS Guideline 870.7800), and a subchronic neurotoxicity study (OPPTS Guideline 870. 6200b). These

studies are now requirements under 40 CFR §158.5 00 for pesticide registration. In the absence of specific immunotoxicity and subchronic neurotoxicity studies, HED has evaluated the available flazasulfuron toxicity database to determine whether an additional database uncertainty factor is needed to account for potential immunotoxici ty or neurotoxicity.

With the exception of a transient decrease in motor activity at a high dose level (1000 mg/kg/day) in the acute neurotoxicity study, which may be associated with a systemic effect, there is no evidence of neurotoxicity. There is no evidence of immunotoxicity in the database, as indicated by hematology, lymphoid organ weights and histopathology in standard studies

.

Consequently, HED believes the existing data are sufficient for endpoint selection for exposure/risk

assessment scenar ios and for evaluation of the requirements under FQPA, and an additional database uncertainty factor does not need to be applied.

4.4.2 Evidence of N eurotoxicity

A guideline acute neurotoxicity study was conducted with flazasulfuron at dose levels up to 2 000 mg/kg. Mean motor activity measurements for 1000 and 2000 mg/kg males and females were statistically significantly different from the respective control groups five hours post

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

material

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

As previously mentioned, the acute neurotoxicity study demonstra ted reversible adverse effects at high dose levels, with no accompanying histopathologic changes, and these effects may be associated with systemic toxicity and not neurotoxicity. The available subchronic and chronic data did not show any adverse effects that could be considered as neurotoxicity.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young AnimalFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 17 of 50 The available data indicate that flazasulfuron produced developmental and reproductive effects only at maternally/parentally toxic dose levels. In addition, clear NOAELs and LOAELs have been

established for these effects . Therefore, HED has no concerns for quantitative susceptibility. A potential qualitative susceptibility concern from one rat developmental study (intraventricular septal defect seen at minimally toxic maternal dose levels) is addressed by the presence of clear NOAELs and LOAELs, and by the selection of regulatory endpoints that are protective of this effect.

4.4.4 Residual Uncertainty in the Exposure Database

Data have been requested to verify the reported storage intervals in the grape storage stability study. Also, a confined rotational crop study has been requested for a permanent registration. Although these data have been requested, there are no residual uncertainties in the exposure database for the following reasons:

Grape Storage Stability Study : Dates of sample spiking and analysis in the grape storage stability study are required only to confirm the reported storage intervals.

Confined Rotational Crop Study : The 12

- month plant

- back restriction on the sugarcane label will be adequate for a conditional registration.

Since the dietary and non

- dietary exposure estimates were based on several conservative assumptions, HED does not believe that the ex posure estimates are underestimated. The acute and

chro n ic dietary assessment s conducted with DEEM

- FCID were screening level analyse s. The

assessment s utilized tolerance values and default processing factors, and 100% crop treated was

assumed for all comm odities. 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 underestim ate risk from acute or chronic exposure to flazasulfuron. Similarly, HED does not believe that the non

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

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

treated/amount handled

.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

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

- dose effect and is appropriate for all populations. The endp oint 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.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 18 of 50 A separate acute d ietary endpoint for Females 13

- 49 was not selected from the available developmental toxicity studies because the NOAEL of 50 mg/kg /day from the acute n eurotoxicity 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 effect s is not considered necessary.

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

For short

- and intermediate

- term residential and occupational exposure scenarios (incidental oral and inhalation), the NOAEL of 2 mg/kg/day from the oral subchronic study in dogs wa s selected. The LOAEL of 10 mg/kg/day was based on changes in liver (increases in: deposition of brown pigments, glutamic pyruvic transaminase, creatine phosphokinase, inflammatory cell infiltration, and microgranulomas). The systemic NOAEL of 2 mg/kg/da y 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 avai lable and showed no local or systemic effects at dose levels of 250

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

route

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

Long

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

4.5.2 R ecommendation for Combining Routes of Exposures for Risk Assessment

Residential or occupational exposures from different routes (dermal, oral, and inhalation) can be combined if the toxicological effects are the same

. Because the same toxicity study (and same eff ect) was used to select the end point for the oral and inhalation routes, these routes of exposure can be combined to estimate aggregate risk.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Based on lack of carcinogenic effects in the rat and mouse carcinogenicity studies and lack of a mutagenicity concern, flazasulfuron can be classified as “No evidence of carcinogenicity to

humans”.

4. 5

. 4 Summary of Points of Departure and Toxicity Endpoin ts Used in Human Risk

Assessment

The selection of toxicity endpoints and points of departure is presented in the previous risk assessment ( D303573 , G. Burke, 11/16/2005) . The short

- term incidental oral and occupational,Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 19 of 50 and the dermal endpoints have been updated for this risk assessment and the rationales presented in

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

and b.

Table 4. 5.4 a. Summary of Toxicological Doses and Endpoints for Flazasulfuron for Use in Residential and

Non

- Occupational Human Health Risk Assessments

Exposure/

Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (all populations including

Females 13

- 49) NOAEL =50 mg/kg /day 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 /day 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 Residential:

LOC for MOE =

100 90

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

Dermal

Short

- Term (1

- 30 days)

and

Intermediate

Term (1

- 6 months) NOAEL =

N/A UF A = N/A

UF H = N/A Residential:

LOC for MOE =

N/A 21

- day Dermal study

NOAEL > 1000 mg/kg/day.

No hazard was identified at the limit dose following dermal exposure and there are no concerns for developmental or neurotoxicity; therefore, there is no risk potential for this exposure scenario.

Inhalation

Short

- Term (1

- 30 days)

And

Intermediate

Term (1

- 6 months) NOAEL = 2 mg/kg/day

(inhalation absorption

rate = 100%) UF A = 10x

UF H = 10x Residential:

LOC for MOE =

100 90

- Day oral toxicity in (dog) LOAEL = 10 mg/kg/day based on changes in liver (increase in: deposition of brown pigments, glutamic pyruvic transaminase, creatine phosphokinase, inflammatory cell in filtration, 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 concernFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 20 of 50 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 ad verse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies ). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4. 5.4 b. Summary of Toxicological Doses and Endpoints for F lazasulfuron for Use in Occupational

Human Health Risk Assessments

Exposure/

Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Dermal

Short

- Term (1

- 30 days)

Intermediate

Term (1

- 6 months) NOAEL =

N/A UF A = N/A

UF H = N/A Residential:

LOC for MOE =

N/A 21

- day Dermal study

NOAEL > 1000 mg/kg/day.

No hazard was identified at the limit dose following dermal exposure and there are no

concerns for developmental or neurotoxicity; therefore, there is no risk potential for this exposure scenario.

Inhalation

Short

- Term (1

- 30 days)

And

Intermediate

Term (1

- 6 months) NOAEL = 2 mg/kg/day (inhalation absorption rate = 100%) UF A = 10x

UF H = 10x Occupational:

LOC for MOE =

100 90

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

Cancer (oral, dermal, inhalation) Classification: No evidence of carcinogenicity to humans based on lack of carcinogenic effects in the rat and mouse carcinogenicity studies and lack of a mutagenicity concern

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lo west observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = po pulation adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

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

flazasu lfuron was assessed using an oral toxicity study. The Agency sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide , Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, reexamine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data. If any new polici es or procedures are developed, the Agency may revisit the need forFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 21 of 50 an inhalation toxicity study for flazasulfuron and/or a reexamination of the inhalation toxicity risk

assessment.

4.6 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen , or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical su bstance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the ED SP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and establish a dose

- response relationship

betwe en the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA has issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This

list of chemicals wa s selected based on the potential for human exposure through pathways such as food and water, residential activity, and certain post

- application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors.

Flazasulfuron is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test order s/data call

- ins for all pesticide active ingredients

.

For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

P RIMARY CROPS: A cceptable metabolism studies on grapes, sugarcane, and tomatoes are available. Residues of the parent (flazasulfuron) were not detected in the tomato study and were only detected as a trace or minor component in the grape and sugarcane studies. The major metabolites (>10% total radioactive res idues [TRR]) which were identified were DTPU in grape leaves and grape fruit, DTPP in grape leaves, and HTPP (primarily conjugated) and TPSA in tomato fruit. There were no major metabolites (>10% TRR) in sugarcane but the primary minor metabolites (<10% T RR) were HTPP, TPSA, and ADMP. (Refer to Appendix E for chemical names andFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 22 of 50 structures). The metabolic pathways for grapes, tom at oes, and sugarcane are similar. The pathways

involv e intramolecular rearrangement of the sulfonyl urea bridge to form DTPU , fo llowed by hydrolysis t o form DTPP and HTPP, and cleavage of the sulfonylurea bridge to form TPSA and

ADMP.

ROTATIONAL CROPS: There are no rotational crop data requirements associated with the use on citrus or grapes (OPPTS 860.1850). The rotational crop guidelines are applicable for sugarcane; however, rotational crop data have not been submitted. The proposed label for sugarcane specifies a 12

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

of rotation al crop data

.

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

in goat kidney were the parent (flazasulfuron), HTPP, and DTPU. HTPP was the major residue in goat liver and muscle. Parent was not found in go at liver and muscle. DTPP was identified as a minor metabolite only. Chromatographic analysis showed that the radioactivity extracted from a tissue type was consistent regardless of label position and yielded little evidence of cleavage of the parent mol ecule by the goat, elimination of the sulfonyl moiety and reconnection of the urea bridge notwithstanding.

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

, data requirements pertaining to poultry are not relevant to this petition.

5.1.2 Summary of Environmental Degradation

Several flazasulfuron degradates were detected in the env ironmental fate studies , including DTPU, DTPP, TPSA, ADMP, HTPP, 2,3

- GTP, bo und residues, and carbon dioxide (see appendix for names and structures)

.

The degradates of flazasulfuron are persistent in both aquatic and soil environments. Hydrolysis (abiotic; enzyme

- mediated) is the major route of transformation of flazasulfuron, but metabolic products were also observed in soil and water

- sediment systems. The abiotic hydrolysis study showed that the rates of hydrolysis and the mechanism of formation of products are pH

- dependent. Mobility is expected to increase with increasing pH

. However, the soils selected for the environmental fate studies had a narrow range of pH that do es not allow an adequate correlation of persistence and mobility with pH. Like all sulfonylurea herbicides, flazasulfuron can exhibit high mobility in soil. Direct photolysis in water is likely associated with hydrolytic products rather than with parent flazasulfuron. Flazasulfuron has low potential to volatilize from soil or water. Potentially, soil particulates containing flazasulfuron could be transported away from the treatment site by wind erosion or runoff.

5.1.3 Comparison of Metabolic Pathways

In plants flazasulfuron is degraded by cleavage of the sulfonylurea bridge to TPSA and ADMP and extrusion of sulfur dioxide by intramolecular rearrangement to DTPU. The degradation is very extensive since flazasulfuron is not detected in tomato and only traces of the parent compound are present in grape and sugarcane. No confined rotational crop study has been conducted.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 23 of 50 In the goat, flazasul furon appears mainly to be degraded by the intramolecular rearrangemen t pathway; however, the degradation is not as extensive as in plants since a substantial amount of flazasulfuron is present in the kidney. No metabolism data on poultry were submitted.

In both plants and goat, DTPU is further hydrolyzed and demethylated to HTTP. The latter is conjugated as the glucoside in tomato (HTPP conjugate) and it is postulated that HTTP forms the glucuronic acid conjugate in the goat (TPPG). It is also postulat ed that hydroxylation in the pyrimidine ring occurs in the goat to yield a conjugate with glucuronic acid (HDTG).

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

For drinking water, the residues of concern for risk assessment were parent, DTPU, DTPP, TPSA, ADMP, HTPP, and 2,3

- GTP.

5.1.4 Residues of Concern Summary and Rationale

Table 5.1.4. Summary of Metabolites and Degradates to be included in th e 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

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

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

2 S ee Appendix E for metabolite names and structures.

3 Rotational crop studies are not available at this time. Parent only is included as an interim recommendation pending submission of an adequate study.

Rationale:

Plants

Primary Crops : Metabolism studies were conducted on grape, sugarcane, and tomato while the proposed uses are citrus, grape, and sugarcane. Quantifiable residues of flazasulfuron parent were not found in the tomato metabolism study, but were observed in the grape and sug arcane metabolism studies as minor residues (<10% of the total radioactive residue (TRR)). Several metabolites were observed as major residues (>10% TRR ): HTPP: tomato; DTPP: grape leaves; DTPU: grape fruit and leaves; TPSA: tomato) . M inor residues (<10% TRR) were found as follows: HTPP: grape fruitFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 24 of 50 and leaves, sugarcane , tomato ; DTPP: grape fruit and leaves, sugarcane; DTPU: grape leaves,

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

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

0.15 lb ai/A is expected to result in residues of <LOQ (<0.01 ppm) for pare nt and <LOQ (<0.01 ppm) for DTPU in all raw agricultural commodities and processed commodities of citrus, grape s, and sugarcane

. No parent was detected in citrus, grape, or sugarcane field trials or processing studies. DTPU was not detected in citrus field trials or processing studies or in grape field trials and was not tested for in sugarcane. Although quantif iable residues of DTPU were observed in raisins (0.01 ppm), given the exaggerated use rate of the grape processing rate (~10X the proposed use rate) there is no expectation of finite residues under the proposed use pattern. Furthermore, the primary

metab olites DTPU, HTPP + conjugates, and TPSA + conjugates are not expected to be more toxic than parent flazasulfuron (ROCKS memo, D386767, E. Holman, 2/28/11 ). Therefore, the use of parent flazasulfuron only is an adequate measure for tolerance enforcement a nd risk assessment purposes in primary crops.

Rotational Crops : No confined rotational crop study has been conducted. Sugarcane, the only rotated crop, has a 12

- month crop rotation restriction on the proposed label; a confined rotational crop study wi ll be required for permanent registration. Parent only is considered to be the residue of concern pending submission of an adequate study.

Livestock

Ruminants: For the proposed use pattern associated with this petition, no secondary residues are expected to occur in livestock commodities. Based on the goat metabolism study and the low residues (0.0024 ppm) calculated to be in the ruminant diet from feeding dri ed citrus pulp and sugarcane molasses (the only ruminant feed items associated with citrus, grapes, and sugarcane), no residues are expected to occur in ruminant commodities from use on citrus, grapes, and sugarcane. Hence a 40 CFR 180.6(a)(3) situation ( no expectation of finite residues) exists.

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

no poultry or swine feed items associated with citrus, grapes, and sugarcane. However, this decision may also need to be revisited for future uses of flazasulfuron that involve significant livestock feed

items.

Drinking Water: The parent compound and all identified metabolites are included in the drinking water exposure assessment, which is consistent with the previous risk assessment (DP Barcode D303573, G.V. Burke, Ph.D., 11/16/05)

. The current assessment includes residues of the following compounds in drinking water: 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 inc luded 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 dat a available for GTF, the use of the total residue approach should account for any potential

contribution of GTF.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 25 of 50 5 .2 Food Residue Profile

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

assessment and tole rance assessment

. Residues of flazasulfuron were not detectable in any commodity at a limit of detection, indicating that there will be minimal exposure to flazasulfuron in food. Processing studies were conducted in oranges, grapes, and sugarcane; residu es of flazasulfuron did not concentration in any commodity. There is no reasonable expectation of finite

residues in livestock commodities based on the non

- detectable residues of flazasulfuron in/on animal

feed items and the results of the ruminant metabol ism study. The magnitude of residue and processing studies are supported by adequate storage stability data for flazasulfuron.

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

Commodity Analyte Total Applic.

Rate (lb ai /A) PHI (days) Residue Levels (ppm) 1

n Min. Max. HAFT 1 Median Mean Std.

Dev. Citrus (proposed use = 0.15 lb ai/A total application rate, 1

- day PHI)

Orange,

fruit Flazasulfuron (parent) 0.154

– 0.159 1 24 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

29

- 30 24 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

DTPU 0.154

– 0.159 1 24 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

29

- 30 24 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

Grapefruit,

fruit Flazasulfuron (parent) 0.153

– 0.161 1 12 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

28

- 30 12 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

DTPU 0.153

– 0.161 1 12 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

28

- 30 12 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

Lemon, fruit Flazasulfuron (parent) 0.154

– 0.156 1 8 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

30 8 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

DTPU 0.154

– 0.156 1 8 <LOQ (ND) <LOQ (ND) < LOQ (ND) <LOQ (ND) <LOQ (ND) --

30 8 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --
Grapes (proposed use = 0.15 lb ai/A total application rate, 75

- day PHI)

Grapes, fruit Flazasulfuron (parent) 0.149

- 0.158 74

- 77 24 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) -

DTPU 0.149

- 0.158 74

- 77 24 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) Sugarcane (proposed use = 0.15 lb ai/A total application rate, 180

- day PHI)

Sugarcane Flazasulfuron (parent) 0.152

- 0.164 179

- 180 16 <LOQ (ND) <LOQ (ND) < LOQ (ND) <LOQ (ND) <LOQ (ND) --

1 The LOQ is 0.010 ppm. The calculated LOD for fl azasulfuron is 0.003 ppm.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 26 of 50 5.3 Water Residue Profile

Estimated surface water and groundwater concent rations are shown in Table 5.3. The dietary exposure assessment used the peak concentration value of 102 ppb for acute and chronic

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

- GW)

simulations for all currently registered and proposed flazasulfur on uses.

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

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

flazasulfuron residues.

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

for Flazasulfuron c

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

Acute 26.9 102

Chronic (non

- cancer) 4.67 102

a From the Tier II PRZM

- EXAMS

- Index Reservoir model. 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 assuming a maximum use rate of 3 applications at 0.045 lb ai/A/application, a K

oc of

10 mL/g, and an aerobic soil metabolism half

- life of 10,398 days , applied to corn in the Delmarva Peninsula to represent uses on citrus, grapes, Christmas trees, and indu strial vegetation management.

c DP#3 72897

, Andrew Shelby, 4/4/2011

.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute and chronic dietary analysis for non

- cancer risk assessment assumed tolerance level residues for all proposed crops

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

. Therefore, processing factors were excluded from the dietary exposure assessment.

5.4.2 Percent Crop T reated 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 crops and 100% CT was assumed. A tier II (PRZM

- GW) EDWC derived through EFED modeling which is unlikely to underestimate the

concentration of flazasulfuron in drinking water was utilized. The ground water EDWC (102 μ g/L) was incorporated directly into the dietary assessment (A. Shelby, D372897, 4/4/11)

.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 27 of 50 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 acute dietary exposure estimates at the

95 th percentile are 1 .1% of the a PAD for the general U.S. population and 4.0% of the aPAD for all infants (<1 year old), the most highly exposed population subgroup.

5.4.4 Chronic Dietary Risk Assessment

A n unrefined chronic dietary assessment was conducted. Tolerance level r esidues

, 100 % CT , and

DEEM TM 7.81 default processing factors were used to determine the chronic dietary exposure and

risk estimates. A tier II EDWC derived through EFED modeling which is unlikely to underestimate

the concentration of flazasulfuron in drin king water was utilized. The ground water EDWC (102

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

.

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

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

. The chronic dietary exposure estimates are 17% of the c PAD for the general U.S. population and 54% of the cPAD for all infants (<1 year old), the m ost 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 carcino genicity

studies

.

5.4.6 Summary Table

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

for Flazasulfuron

Population Subgroup Acute Dietary ( 95th Percentile) Chronic Dietary

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

General U.S. Population 0.0054 1.1 0.0022 17

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

Children 1

- 2 years old 0.0084 1.7 0.0033 25

Children 3

- 5 years old 0.0077 1.5 0.0031 24

Children 6

- 12 years old 0.0053 1.1 0.0021 16

Youth 13

- 19 years old 0.0044 <1.0 0.0016 12

Adults 20

- 49 years old 0.0049 <1.0 0.0020 16Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 28 of 50 Table 5.4.6. Summary of Dietary ( Food and Drinking Water ) Exposure and Risk

for Flazasulfuron

Population Subgroup Acute Dietary ( 95th Percentile) Chronic Dietary

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

Adults 50+ years old 0.0045 <1.0 0.0020 16

Females 13

- 49 years old 0.0050 1.00 0.0020 16

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

This document only presents the assessment of the proposed new ag ricultural uses of flazasulfuron

. N o new residential uses are being reque sted at this time; therefore, a residential risk assessment has

not been conducted.

6.1 Residential Handler Exposure

Residential handler exposure was not assessed since flazasulfuron is only applied to use sites such as industrial parks, tank farms, sod farms, seed farms, and professionally managed spo rts fields which are not treated by residential handlers

.

6.2 Post

- Ap plication Exposure

F lazasulfuron is currently registered for use on golf courses and other non

- residential turf areas such as industrial parks, tank farms, sod farms, seed farms, and profe ssionally managed sports fields

. Post

- application s hort

- term dermal exposure was previously assessed for recreational golfers or players of various sports who use a golf course or athletic field after flazasulfuron has been applied (D316614, Burke, G. , 11/23/05). However, since a revised hazard assessment was perfo rmed for fluzazsulfruon, a dermal hazard was not identified and dermal exposures and risks are no longer required.

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

- application inhalation exposure

assessment was not performed for flazasulfuro n at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure ( < 1 x 10 - 7 torr ). However, volatilization of pesticides may be a source of post

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

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

- application inhalation ex posure assessment for flazasulfuron

.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 29 of 50 6.3 Combined Exposure

Residential post

- application pesticide exposure can occur within a scenario from multiple routes of exposure (e.g., dermal, inhalation, and oral). These exposures to pesticides do not occur as single, isolated events, but rather as a s eries 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 combined when it is likely that they can occur simultaneously based on the use pattern and when the toxicological effects across different routes of exposure are the same. If appropriate for an exposure scenario, the recommended routes of exposure for combining include dermal, inhalation, and hand

to

- mouth.

For the short

- and

– intermediate term scenarios , combined exposures were not necessary to assess for flazasulfuron since residential handler exposures do not occur , no dermal hazard was identified, and post

- application inhalation exposures were not quantitatively assessed.

6.4 Spray Dr ift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground applicatio n method employed for flazasulfuron . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labe ling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce

off

- target drift with specific products wi th significant risks associated with drift.

7.0 Aggregate Exposure/Risk Characterization

Under FQPA, HED must consider and aggregate pesticide exposures and risk from three major sources: food, drinking water, and residential exposures.

7.1 Acute Aggregate Risk

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

. Refer to

Section 5.4.

7.2 Short

- and Intermediate

- Term Aggregate Risk

There is potential short

- term exposure to flazasulfuron via the dietary pathway (which is consideredFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 30 of 50 background exposure) and the residential pathway (which is considered the primary pathway ). Since

intermediate

- term residential exposures are not likely to occur, intermediate

- term aggregate risks

were not assessed. T he short

- term ag gregate exposure assessment for adults include s dietary (food

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

was not identified. For children, exposure includes only food and drinking water since dermal a nd incidental oral exposure to children from treated golf and athletic field turf is considered to be negligible.

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 Aggregate 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 Chara cterization

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

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

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

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

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

9.0 Occupational Exposure/Risk Characterization

Occupational exposures are expected to occu r from the proposed flazasulfuron uses on citrus, grapes, sugarcane, Christmas trees, and industrial vegetation management areas . Short

- (1

- 30 consecutive days) and intermediate

- term (1

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

- and intermediate

- term dermal exposures are expected from post

- application activities. However, dermal risks were not assessed since a dermal

hazard was not identified.

9. 1 Short

- /Intermediate

- Term Handler Risk

Chemical

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

- specific monitoring data are not available, it is the policy of HED to use data fromFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 31 of 50 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 f lazasulfuron use patterns, HED assessed risks to occupational pesticide handlers in the following scenarios:

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

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

**•** appl ying sprays with groundboom equipment,

**•** applying sprays with right

- of

- way sprayer equipment,

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

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

Short

- and i ntermediate

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

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

exposures
, and therefore a re not of concern

.

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. 372903

Page 32 of 50 Table 9.1.1

. Summary Of Short

- and Intermediate

- Term Occupational Handler Exposures And Risks

Exposure Scenario Crop Grouping Application

Rate a (lb ai/A) Area Treated Daily b
(A/day) Baseline

Inhalation c Unit Exposure

(μg/lb ai) Baseline

Inhalation Dose

(mg/kg/day) Baseline Inhalation

ST/IT MOE d
(LOC ≥ 100)

Mixer/Loader

Mixing/Loading Dry

Flowable for

Groundboom Applications Citrus

0.045 80 0.77 0.000040 51,000 Grapes
Sugarcane

Christmas Trees

Non

- crop 0.047 80 0.77 0.000041 48,000

Mixing/Loading Dry

Flowable for Right

- of

Way Applications Non

- crop 0.047 40 0.77 0.000021 97,000

Applicator

Applying Sprays via

Groundboom Equipment (open cab) Citrus Grapes Sugarcane

Christmas Trees 0.045 80 0.74 0.000038 53,000

Non

- crop 0.047 80 0.74 0.000040 50,000

Applying Sprays via Right

- of

- Way Equipment Non

- crop 0.0024 (lb ai/gal) 1000 (gal/day) 3.9 0.00013 15,000

Mixer/Loader/Applicator

Backpack Christmas Trees 0.0023 40 30 0.000039 52,000

Non

- crop 0.0024 40 30 0.00004 0 50,000

(lb ai/gal) (gal/day)

Low Pressure

Handwand Christmas Trees 0.0023 40 1100 0.0014 1,400

Non

- crop 0.0024 40 1100 0.0015 1,400

(lb ai/gal) (gal/day)

a Application rates are the maximum application rates determined from p roposed labels for flazasulfuron

. b Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard Values for Daily Acres Treated in Agriculture,”

c Baseline Inhalation: no respirator.

d Inhalation ST/IT MOE = ST /IT NOAEL (2 mg/kg/day) / inhalation daily dose (mg/ kg/ day), where inhalation dose = daily unit exposure (μg/ lb ai) x applicatio n rate (lb ai/A) x area treated (A/day) x 100% inhalation absorption / body weight (70 kg adult). LOC = 100Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 33 of 50 9.2 Short

- /Intermediate

- Term Post

- Application Risk

There is a possibility for agricultural workers to have post

- application dermal exposure to

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

, therefore, post

- application dermal exposures were not assessed.

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

- application inhalation exposure

assessment was not performed for flazasulfuron at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure ( < 1 x 10 - 7 torr ). However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

app lication activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatiliza tion 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 A gency is in the process of evaluating the SAP report as well as available post

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

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

- application

inhal ation ex posure assessment for flazasulfuron

.

Although a quantitative occupational post

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

post

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

- application inhalation exp osure scenarios.

Restricted Entry Interval: Flazasulfuron elicits developmental effects

. Per the Worker Protection Standard (WPS), a 12

- hr restricted entry interval (REI) is required for chemicals that exhibit adverse

health effects

. T he ISK Flazasulfuron Herbicide label indicates an REI of 4 hrs, which is not in compliance with the WPS. The REI on the label needs to be corrected to 12 hours.

10.0 Environmental Justice Considerations

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

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

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on foo d consumption patterns are compiled by the USDA underFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 34 of 50 the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever ap propriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated.

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

11.0 Ref erences

Dodd, N., 2/16/11, DP# 372901

, Flazasulfuron: Summary of Analytical Chemistry and Residue Data for Use on Citrus, Grapes and Sugarcane.

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

Subcommittee (ROCKS)

.

Rury, K., 4/12/11, DP# 378629, Flazasulfuron: Acute & Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the first food use, Section 3 Registration Action (Citrus, Grapes and Sugarcane).

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

Shelby, A., 4/4/11, DP# 372897

, Flazasulfuron: Refined Drinking Water Assessment for First Food Uses on citrus, grapes and sugarcane and new outdoor non

- food uses on Christmas trees and industrial vegetation management

.

Walls, C., Ph.D., 3/19/11

, D P# 37 8633

, FL AZASULFURON : Occupational and Residential Exposure/Risk Assessment for Use on Citrus, Grapes, Sugarcane, Christmas Trees, and Industrial Vegetation Management

.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 35 of 50 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 the new (1998) gu ideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

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

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

- Day Dermal

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

- Day Dermal

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

- Day Inhalation

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

yes

yes

no

no yes

yes

yes

--

-- 870.3700a Developmental Toxicity (rodent)

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

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

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

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

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

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

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

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

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

yes

yes

yes

yes yes

yes

yes

yes

yes
870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

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

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

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

- Day Neurotoxicity (hen)

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

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

- Day Neuro. Screening Battery (rat)

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

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

no

yes

yes

no -

- yes

no

--

870.7485 General Metabolism

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

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

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

yes

yes yes

yes

no

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. 372903

Page 36 of 50 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) 4622092 2 (1994) 0, 250, 500, 1000 mg/kg/day Acceptable/Guideline NOAEL (M/F) = 1000/1000 mg/kg/day LOAEL (M/F) = No systemic toxicity was observed at the

limit dose. No localized dermal effects were observed.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 37 of 50 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./

Study Type MRID No. (year)/

Classification /Doses Results

870.3700a

Prenatal developmental in (rat):

Wistar 46220924 (1988) 0, 100, 300, 1000 mg/kg/day Acceptable/Guideline Maternal NOAEL = 100 mg/kg/day LOAEL = 300 mg/kg/day based on increase in maternal relative liver weight and decreased body weight gain and food consumption. Developmental NOAEL = 10 0 mg/kg/day LOAEL = 300 mg/kg/day based on increased incidence of visceral malformations (interventricular septal defect).

870.3700a

Prenatal developmental in (rat): Sprague

- Dawley 46220925 (1996)
0, 100, 300, 1000 mg/kg/day Acceptable/Guideline Maternal NOAEL = 300 mg/kg/day LOAEL =1000 mg/kg/day based on transient decreased body weight gain and food consumption. Developmental NOAEL = 300 mg/kg/day LOAEL = 1000 mg/kg/day based on reduced fetal weights

and retardation in ossification.

870.3700b

Prenatal developmental in (rabbit) 46220923 (1988) 0, 50, 150, 450 mg/kg/day Acceptable/Guideline 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.

Dev elopmental 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).

870.4300

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 icityFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 38 of 50 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./

Study Type MRID No. (year)/

Classification /Doses Results

870.4200 Carcinogenicity (mouse) 46220928 (1995) 0, 500, 3500, 7000 ppm M: 0, 77.3, 552.7, 1053.8 mg/kg/day
F: 0, 93.7, 659.8, 1208.2 mg/kg/day Acceptable/Guideline NOAEL (M/F) = 77.3/93.7 mg/kg/day LOAEL (M/F) = 552.7/659.8 mg/kg/day based on decrease in body weight, body weight gain, food consumption and an increase in liver effects (liver weight and hepatocellular hypertrophy).

no evidence of carcinogenicity

870.5500

Salmonella typhimurium and

Escherichia coli

Reverse Mutation Assay 46220933 (1987) 0, 20, 50, 100, 200, 500,

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

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

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

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

Negative

870.5300

in vitro Mouse Lymphoma Mutagenesis Assay 46220930 (1993) 0, 20, 30, 40, 50, 60, 70, 80, 90, 100, 500  g/ml in the presence and

absence of metabolic

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

of mutant colonies.

Negative

870.5375

in vitro Cytogenetics Test 46220931 (1988) 0, 3.3 x 10 - 4 , 1.7 x 10 - 4

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

, 2.1 x 10

- 5 M, with and

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

S9activation.

Negative

870.5395

in vivo Mammalian Erythrocyte

Micronucleus Test:

Mouse 46220932 (1995) 0, 1250, 2500, 5000 mg/kg Acceptable/Guideline There was no statistically significant increase in the frequency of micronucleated polychromatic erythrocytes in mouse bone marrow at any dose or collection time.

Negative

870.6200a Acute neurotoxicity screening battery (rat) 46220934 (2002) 0, 50, 1000, 2000 mg/kg/day Acceptable pending data

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

- dosing)Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 39 of 50 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No./

Study Type MRID No. (year)/

Classification /Doses Results

870.7485

Metabolism and pharmacokinetics (rat) 46220940 (1994), 46220941 (1995), 46220942 (1995), 46220943 (1995) single dose: 2, 50 mg/kg multiple dose: 2 mg/kg

Radiolabel: (first ring: Pyridine second ring: Pyrimidine) Acceptable/Guideline Radiolabeled flazasulfuron (Pyridine/Pyrimidine) was rapidly distributed and excreted in the urine and feces following multiple dosing. Urinary elimina tion, calculated from a total collection of 168 hours, occurred slower in males (74/73%) compared to females (90/91%). Fecal elimination, calculated from a total collection of 168 hours, was greater in males (23/23%) than in females (10/9%).

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

at 6 hours in both sexes.

A.3 Hazard Identification and Endpoint Selection

The Hazard Identification and Endpoint Selection sections are presented in the previous Risk Assessment document. Please refer to D303573, G.V. Burke, Ph.D., 11/16/05.

A.4 Executive Summaries

The executive summaries of the studies used in this risk assessment are presented in the previous Risk Assessment document. Please refer to D303573, G.V. Burke, Ph.D., 11/16/05.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 40 of 50 A.5 Endpoint Selection Worksheet: Flazasulfuron

Table A.5.1 Toxicity Endpoint Selection Worksheet Exposure

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

Acute Dietary, General Population Acute Neurotoxicity

— Rat

Developmental Toxicity

-- Rat

Developmental Toxicity

-- Rabbit The NOAEL was 50 m/k/d. The LOAEL was 1000 mg/kg based on a transient decrease in motor activity
observed 5 hours post

- dosing. SELECTED

Maternal NOAEL = 100 m/k/d. LOAEL= 300 m/k/d based on increased relative liver weight and decreased body weight gain and food consumption Developmental NOAEL = 100 m/k/d. LOAEL= 300 m/k/d based on increased incidence of visceral malformations (interventricular septal defect )

.

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.

Acute Neurotoxicity

— Rat was selected because it is a singl e

- dose effect and provides the lowest and most protective point of departure.

Both developmental toxicity studies qualify for candidacy because intraventular septal defect (rat) and abortion (rabbit) both can be a single

- dose effect. Acute Dietary,

Fem ales 13+ Acute Neurotoxicity

— Rat

Developmental Toxicity

-- Rat

Developmental Toxicity

-- Rabbit The NOAEL was 50 m/k/d. The LOAEL was 1000 mg/kg based on a transient decrease in motor activity
observed 5 hours post

- dosing. SELECTED

Maternal NOAEL = 100 m/k/d. LOAEL= 300 m/k/d based on increased relative liver weight and decreased body weight gain and food consumption Developmental NOAEL = 100 m/k/d. LOAEL= 300 m/k/d based on increased incidence of visceral malformations (interventricular septal defect )

.

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.

Acute Neurotoxicity

— Rat was selected because it is a single dose study and also is protective of the developmental effects seen at 300 m/k/d in the rat, and 450 m/k/d in the rabbit.

The two developmental toxicity studies qualify for candidacy because th e developmental effects observed, interventral septal defect in the rat and abortion in the rabbit, both qualify as single

- dose effects.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 41 of 50 Table A.5.1 Toxicity Endpoint Selection Worksheet Exposure

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

Chronic Dietary, General Population C hronic/Carcinogenicity study in rats

Chronic (1 year) Study in dogs

Carcinogenicity study in

mice

Multigeneration Reproduction study in rats NOAEL = 1.3 mg/kg/day. LOAEL = 13.3 mg/kg/day based on : Adverse change in kidney function
(chronic nephropathy) and kidney physiology (enlargement, dark color of kidney) SELEC TED

NOAEL = 2 mg/kg/day. LOAEL = 10 mg/kg/day based on changes in liver (increase in: inflammatory cell infiltration, hepatocellular necrosis, hepatocellular swelling, and bile duct proliferation).

NOAEL (M/F) = 77.3/93.7 mg/kg/day. LOAEL (M/F) = 552.7/659.8 mg/kg/day based on decrease in body weight, body weight gain, food consumption and an increase in liver effects (liver weight and hepatocellular hypertrophy).

Parental/Systemic NOAEL (M/F) = 8.7/124.5 mg/kg/day. LOAEL (M/F) = 87.5/613.7 mg/kg/day based on changes in kidney parameters (M/F: Bilateral discoloration, enlargement, mild nephropathy) Reproductive NOAEL (M/F) =473.0/613.7mg/kg/day. LOAEL (M/F) =not established. Offspring NOAEL (M/F) = 87.5/124.5 mg/kg/day. LOAEL (M/F) = 473.0/61 3.7 mg/kg/day based on reduction in lactational body weights of the F 1 and F 2 offspring.

Chronic/Oncogenicity Study

-- Rat was selected because its NOAEL was the lowest of the candidates, and provides the most protective point of departure.

The chronic d og and mouse carcinogenicity studies are candidates because their duration is long

- term and therefore appropriate. The mouse reproduction study is a candidate because its duration spans three generations.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 42 of 50 Table A.5.1 Toxicity Endpoint Selection Worksheet Exposure

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

Incidental Oral,

S hort

- term (1

- 30 days)

and

Inh alation

Short

- term (1

- 30 days) 90

- Day oral toxicity

-- dog

Multi

- generation reproduction

-- R at

Acute Neurotoxicity

— Rat

Developmental Toxicity

— Rabbit

Developmental Toxicity

— Rat NOAEL = 2 mg/kg/day. LOAEL= 10 mg/kg/day based on changes in liver (increase in: deposition of brown pigments, glutamic pyruvic transaminase, creatine phosphokinase, inflammatory cell infiltration,
microgranulomas). SELECTED

Parental NOAEL = 8.7 mg/kg/day. LOAEL = 87.5 mg/kg /day based on based on changes in kidney parameters (Bilateral discoloration, enlargement, mild nephropathy) and reductions in body weight in both generations (F 0 , F 1 ). Offspring NOAEL = 87.5 mg/kg/day. LOAEL = 430 mg/kg /day based on reduction in lactatio nal body weights in F 1 and F 2 offspring

.

The NOAEL was 50 m/k/d. The LOAEL was 1000 mg/kg based on a transient decrease in motor activity observed 5 hours post

- dosing.

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.

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

. Developmental NOAEL = 100 m/k/d. LOAEL= 300 m/k/d based on increased incidence of visceral malformations (interventricular septal defect )

.

90

- Day oral toxicity

— dog was selected because the NOAEL of 2 mg/kg/day is the lowest dose of any non

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

available non

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

T he acute neurotoxicity study is a candidate (incidental oral and inhalation) because it is short

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

- term effects seen in offspring in the developmental and reproductive studies. The multi

- generation study is a candidate (for incidental oral) because it shows short

- term effects in young animals which is a population of concern in humans for incidental oral exposure. The developmental (rat and rabbit) stud ies are candidates (for incidental oral and inhalation) because they show effects in adults over short

- term duration.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 43 of 50 Table A.5.1 Toxicity Endpoint Selection Worksheet Exposure

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

Incidental Oral,

Intermediate

- term (1

– 6 months)

and

Inhalation

Intermediate

- term (1

– 6 months) 90

- Day oral toxicity

-- dog

90

- Day oral toxicity

-- rat NOAEL = 2 mg/kg/day. LOAEL= 10 mg/kg/day based on changes in liver (increase in: deposition of brown pigments, glutamic pyruvic transaminase, creatine phosphokinase, inflammatory cell infiltration,
microgranulomas). SELECTED

NOAEL (M/F ) = 11.66/61.5 mg/kg/day. LOAEL (M/F) = 57.1/309 mg/kg/day based on depression of body weight gain (M/F) and slight anemia due to decrease in hemoglobin (F).

90

- Day oral toxicity

— dog was selected because it provided a lower NOAEL than the subchronic ra t study and therefore provides a more protective point of departure.

The 90

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

- term exposure duration. Dermal Absorption None The Dermal absorption factor is calculated < 45% , based on the ratio of the LOAEL from the oral rabbit developmental study (450 mg/kg/day) and the NOAEL from the 21

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

- day dermal study did not present an adverse effect at the highest dose tested in order to produce a LOAEL.

Dermal

, Short

- term

, (1

- 30 days)

and

Dermal

Intermediate

- term (1

- 6 months) 21

- day dermal

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

21

- day dermal

— rabbit is chosen because it is route

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

Dermal

, Long

- term ( > 6 months )

and Inhalation, Long

- term ( > 6 months ) None Long

- term dermal and inhalation exposures are not anticipated, therefore, endpoints were not selected.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 44 of 50 A ppendix B. Metabolism Summary Table

Table B1 . Tabular Summary of Metabolites and Degradates

Common

Name/Code

Name Matrix Percent TRR ( PPB ) 1

Structure Matrices

- Major

Residue (>10%TRR) Matrices

- Minor

Residue (<10%TRR)

Flazasulfuron /

SL

- 160 Grape (fruit)

-- 2.40 (0.1) Pm/F 1.10 (<0.05) P/GH 1.86 (<0.05) Pm/GH
Grape leaves

-- 0.22 (0.4) P/F 0.59 (0.3) Pm/F 2.04 (0.4) P/GH 1.16 (0.5) Pm/GH
Sugarcane

-- 1.53 (0.153) P/GH
1.02 (0.08) Pm/GH

Tomato

-- -- Rotational Crops N ot A vailable (NA) NA

Goat

Kidney 16.6 (0.028) P
59.7 (0.016) Pm --

Poultry Not Available ( NA ) NA

Rat 2

Water 3

HTPP Grape (fruit)

-- 1.11 (<0.05)Pm/F 2.56 (<0.05) P/GH

4.21 (0.1) Pm/GH
Grape leaves

-- 0.70 (1.1) P/F 0.82 (0.4) Pm/F 1.67 (0.3) P/GH 1.72 (0.8) Pm/GH
Sugarcane

-- 2.57 (0.26) P/GH
3.80 (0.29) Pm/GH

Tomato Conjugate:
33 (0.5) P/F
18.7 (0.2) Pm/F Free: 4.3 (<0.05) P/F
2.0 (<0.05) Pm/F

Rotational Crops NA NA

Goat

Liver

Kidney

Muscle 40.2 (0.142) P
31.5 (0.017) Pm
13.4 (0.022) P
89.6 (0.044) P --

Poultry NA NA

Rat 2

Water 3

DTPP Grape (fruit)

-- 7.10 (0.2 ) Pm/F 2.54 (<0.05) P/GH
2.25 (<0.05) Pm/GHFlazasulfuron Human Health Risk Assessment DP No. 372903

Page 45 of 50 Table B1 . Tabular Summary of Metabolites and Degradates

Common

Name/Code

Name Matrix Percent TRR ( PPB ) 1

Structure Matrices

- Major

Residue (>10%TRR) Matrices

- Minor

Residue (<10%TRR)

Grape leaves 10.21 (5.3) Pm/F 1.16 (1.9) P/F 4.00 (0.8) P/GH
7.16 (3.4) Pm/GH
Sugarcane

-- 0.22 (0.022) P/GH
0.67 (0.05 ) Pm/GH

Tomato

-- -- Rotational Crops NA NA

Goat

Kidney 4.5 (0.007 ) P
9.1 (0.002) Pm
Poultry NA NA

Rat 2

Water 3

DTPU Grape (fruit) 43.38 (1.1)Pm/F 10.96 (0.1) P/GH
19.64 (0.4) Pm/GH --

Grape leaves 50.90 (26.2)Pm/F 28.47 (5.4) P/GH
34.86 (16.4) P m/GH 5.78 (9.5) P/F

Sugarcane

-- 0.72 (0.072) P/GH

1.14 (0.09) Pm/GH

Tomato

-- 7.8 (0.1) P/F
7.8 (0.1) Pm/F
Rotational Crops NA NA

Goat

Kidney 50.2(0.083) P
17.6 (0.005) Pm --

Poultry NA NA

Rat 2

Water 3

TPSA Grape (fruit)

-- 1.42 (<0.05) P/GH

Grape leaves

-- 1.74 (2.9) P/F 2.36 (0.4) P/GH
Sugarcane

-- 5.91 (0.591) P/GH

Tomato 13.6 (0.2) P/F

--

Rotational Crops NA NA

Goat

-- --

Poultry NA NA

Rat 2

Water 3Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 46 of 50 Table B1 . Tabular Summary of Metabolites and Degradates

Common

Name/Code

Name Matrix Percent TRR ( PPB ) 1

Structure Matrices

- Major

Residue (>10%TRR) Matrices

- Minor

Residue (<10%TRR)

ADMP Grape (fruit)

-- -- Grape leaves

-- -- Sugarcane

-- 6.68 (0.51) Pm/GH

Tomato

-- 3.3 (0.0) Pm/F

Rotational Crops NA NA

Goat

-- -- Poultry NA NA

Rat 2

Water 3

Grape ; 47939905; 2 x 0.045 lb ai/A = 0.089 lb ai/A; 0.59x seasonal application label rate of 0.15 lb ai/A/season ; the first application was made at early bud break or at post bud break when vines were approximately 10 feet in height and the second application was made seven or eight weeks after the first ; 85

- day PHI in the field, 34

- day PHI in the greenhouse. Sugarcane ; 47939906 lb ai/A; 2 x 0.20 = 0.40 lb ai /A ; 2.7x seasonal application label rate of 0.15 lb ai/A/season ; the first application

was at the 2

- 3 leaf stage and the second application was 23

- 25 days later at the 5

- 6 leaf stage; 364

- 367

- day PHI.

Tomato ; 47939907; 1 application at 0.045 lb ai/A; there is no proposed use on tomato but the rate is 0.30x the seasonal rate of the proposed plants; the application was made to immature plants with no fruit, 40 days after the seed was planted; 83

- day PHI.

Goat ; 47939908; 11.4 ppm [ 14 C

- pyridyl] label; 14. 3 ppm 14 C

- pyrimidinyl] label; 4750x or 5958x MRBDB; 3 days; 23

- 24 hour PSI

. Rat Metabolism ; 46220940, 46220941, 46220938, 46220939 ; single dose: 2 mg/kg or 50 mg/kg; multiple dose: 2 mg/kg

1 P= pyridyl

14 C label; Pm = pyrimidinyl

14 C label; GH = greenhouse; F = field

2 Rat metabolites: The most prevalent metabolites (expressed as percent of administered dose) were HDTG+TPPG (~6.5

- 17.7% in urine, ~0.4

- 9.7% in feces, and ~6.5

- 14% in bile), with minor amounts (<5%) of other compounds. Individually, unidentified fractions generally accounted for less than 2% of the administered dose in the urine and biliary metabolite profile. The fecal metabol ite profile had up to 35% unidentified of the recovered dose.

3 Water metabolites: The previ ous risk assessment (DP Barcode D303573, G.V. Burke, Ph.D., 11/16/05) included residues of the following compounds in water for the risk assessment: Parent, DTPU, DTPP, HTPP, TSPA, and ADMP.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 47 of 50 Appendix C. Review of Human Research

This risk assessment rel ies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide expo sure databases such as PHED. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly d eficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barri er to continued reliance on these studies.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 48 of 50 Appendix D. International Residue Limits

Flazasulfuron ( PC Code 119011) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex 3

40 CFR 180. xxx : Plant / Livestock : N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (trifluoromethyl)

- 2

- pyridinesulfonamide None None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex

Fruit, citrus, group 10

- 10 0.01
Grape 0.01
Sugarcane 0.01

Completed: M. Negussie; 1/12/2010

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

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

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed ha ve not been finalized by the CCPR and the CAC.Flazasulfuron Human Health Risk Assessment DP No. 372903

Page 49 of 50 Appendix E. 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 struc ture

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. 372903

Page 50 of 50 2,3

- GTF 3

- trifluor o methyl

- 2

- pyridylguanidine