### Page 2 of 19

Executive Summary

The HED Registration Review Team has evaluated the most recent human health assessments

and database for the herbicide flazasulfuron to determine whether sufficient data are available and whether any updates are needed to support Registration Review. HED has considered the

most recent human

- health risk assessments for flazasulfuron, updates to the toxicity, exposure, and usage databas es, and current Agency science policy and risk assessment methodologies to determine the scope of work necessary to support Registration Review. In addition, HED conducted an open literature search to look for new literature relevant to the human health r isk

assessment. The results of the literature search showed that no new information relevant to the human health risk assessment has been published.

Flazasulfuron is a sulfonylurea herbicide used to control certain broad

- leaf weeds and grasses,

and acts by inhibiting the acetolactate synthase (ALS) biochemical process, a process not present in humans. Flazasulfuron has low acute toxicity. With repeated dosing, the kidney and liver were the primary target organs of flazasulfuron toxicity. Subchronic stu dies in animals indicated decreased body weight gain, slight anemia in rats and liver abnormalities in dogs. Flazasulfuron is classified as “no evidence of carcinogenicity to humans.” It is negative for mutagenicity in a battery of genotoxicity studies. The toxicity and exposure database supported the reduction of the FQPA Safety Factor to 1X.

Sufficient data are available to assess the toxicity of flazasulfuron, with the exception of an immunotoxicity study and a subchronic neurotoxicity study. Once these new studies have been received and reviewed, the flazasulfuron Registration Review Team recommends that the points of departure and safety factors used for risk assessment purposes for flazasulfuron be re

examined.

Flazasulfuron is currently registered for use on non

- residential turf such as golf courses, sod farms, athletic fields, commercial lawns and industrial vegetation management areas as well as,

on Christmas trees

. Additionally

, it is registered on agricultural food crop s including citrus, grapes and sugarcane

.

The residue chemistry database is sufficient to support current and pending registrations of

flazasulfuron

. The nature of the residue in plants and livestock has been defined. Adequate field trial, rotational cr op data, and storage stability data are available.

A new risk assessment may be needed depending on the results of the additional data which are required and the results of the reevaluation of databases using current policies. A dditional toxicology stu dies are required so endpoints may need to be reevaluated. O ccupational exposure

assessments for the turf use may need to be reassessed based on current Occupational and Residential Exposure ( ORE ) polic ies and exposure data

. In addition, the Agency may need to

consider off

- target movement of pesticides into residential settings.

### Page 3 of 19

Introduction

HED has evaluated the existing human health risk assessments for flazasulfuron to determine

whether sufficient data are available and whether a new hum an health risk assessment is needed to support Registration Review. HED has considered the most recent risk assessments for flazasulfuron, updates to its toxicity, exposure and usage databases, and current Agency science policies and risk assessment metho ds. The most recent risk assessment for flazasulfuron was conducted in 2011 (D372903, C. Walls, 6/12/11).

Hazard Identification/ Toxicology

Flazasulfuron belongs to the pyrimidinylsulfonylurea class of herbicides and controls weeds by inhibiting the ac etolactate synthase (ALS) biochemical process. Since ALS is a component in

the 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 cl ear because ALS is not present in mammals.

In c hronic oral studies in the rat , mouse and dog , the target organs were the kidney and liver.

Observe d effects include adv erse changes in kidney function ( chronic nephropathy) and kidney physiology (enlargemen t, dark color of kidney), increase s in liver weight (hepatocellular hypertrophy), and adverse effects on liver tissue ( increase s in inflammatory cell infiltration, hepatocellular necrosis, hepatocellular swelling, and bile duct proliferation ). Subchronic oral studies indicated decreased body weight gain, slight anemia in rats and liver abnormalities in dogs. Dermal or systemic toxicity was not seen in a subchronic dermal study in rabbits at dose levels up to the limit dose.

Developmental toxicity was observed in rats and rabbits at maternally toxic dose levels. Reduced fetal weights and delays in ossification are the effects observed in a Sprague

- Dawley rat developmental study. An earlier developmental rat study (Wistar rats) showed increased

inciden ce of visceral malformations (interventricular septal defect). The developmental study in

rabbits showed increased incidences of abortion at the highest dose tested (450 mg/kg/day). Decreases in body weight and chronic nephropathy were observed in offspr ing in a 2

- generation rat reproduction study, at dose levels that were toxic to the parental generation.

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 co nsidered sufficient and there are no residual uncertainties. Additionally, the available exposure data do not underestimate exposure.

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

- dosing) was observed at high dose levels ( > 1000 mg/kg ) in an acute neurotoxicity study. This observation was associated with a systemic effect and not with neurotoxicity.

### Page 4 of 19

Upon examination of the toxicity data base, the FQPA factor was reduced to 1X because : a) there were no qualitative or quantitative susce ptibility concerns based on the developmental and reproductive toxicity data and there are no residual concerns regarding prenatal or postnatal exposure; b) there is no conclusive evidence of neurotoxicity at dose levels up to the Limit Dose; c) there is no evidence of immunotoxicity, as indicated by hematology, lymphoid organ weights and histopathology in standard studies ; d) there are no residual uncertainties in the exposure

database.

I n vitro and in vivo mutagenicity studies showed no genotoxic potent ial . 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 in 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 than 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 sensiti zer.

In accordance with the revised 40 CFR Part 158 data requirements, studies that are now required but missing from the flazasulfuron toxicity data base are an immunotoxicity study (OPPTS

Guideline § 870.7800), and a subchronic neurotoxicity study (OPPTS Guideline § 870. 6200b). OPP is conducting an independent retrospective analysis of more than 120 immunotoxicity studies submitted to Agency. P reliminary findings of OPP’s retrospective analysis suggest that immunotoxicity studies have not yet provided l ower PoDs than are selected from other guideline experimental toxicology studies and thus, so far, immunotoxicity studies would not have impact ed the Agency’s risk assessment s . The OPP retrospective analysis is anticipated to be completed in the summer of 2012. In the interim, HED recommends that the immunotoxicity continue to be required for registration and registration review chemicals.

Toxicity endpoints, points of departure, and safety factors for flazasulfuron risk assessment were selected by HED in 2011 for the following exposure scenarios: acute and chronic dietary; short

and intermediate

- term incidental oraland short

- and intermediate

- term inhalation

. Quantification of dermal risk is not required. No dermal or systemic toxicity was seen followin g repeated dermal applications at the Limit Dose and there are no concerns for neuro

- , developmental, or reproductive toxicity. Long

- term dermal and inhalation endpoints were not identified because exposure is not anticipated for these scenarios. The to xicity endpoints are presented in

Attachment 3

.

Conclusions : No new toxicity data beyond the subchronic neurotoxicity and immunotoxicity studies are required to support the registration review of flazasulfuron . Once all data have been received and reviewed, the flazasulfuron Registration Review Team recommends that the points of departure and safety factors used for risk assessment purposes for flazasulfuron be re

examined.

Dietary Exposure

The residue chemistry data and drinking water data are adequate to assess dietary exposure. The

### Page 5 of 19

most recent dietary (food and drinking water) exposure assessment was conducted in 2011 (D 378629, K. Rury, 4/12/11) using the Dietary Exposure Evaluation Model DEEM

- FCID TM



### , Version 2.03. This assessment was conducted to support the pending 2012 PRIA action for first food uses on citrus, grapes, and sugarcane. The dietary exposure assessment relies on conservative inputs (tolerance level residues, 100% crop tr eated, DEEMTM default processing factors) to model exposure to flazasulfuron through food and drinking water.

The e stimated drinking water concentration (EDWC) of flazasulfuron was provided by the Environmental Fate and Effects Division (EFED) and incorp orated directly into the acute and

chronic assessments. The EDWC for ground water from the Tier II provisional groundwater model (PRZM

- GW) using the Delmarva corn scenario was used since it is higher than that for

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

The acute dietary exposure estimates for food and drinking water are well below HED’s level of

concern at the 95 th 

### percentile for the general U.S. population and all population subgroups (1.1%

o f the aPAD for the general U.S. population and 4.0% of the aPAD for all infants (<1 year old), the most highly exposed population subgroup).

The chronic dietary exposure estimates for food and drinking water are below HED’s level of concern for the gener al U.S. population and all population subgroups (17% of the cPAD for the general U.S. population and 54% of the cPAD for all infants (<1 year old), the most highly exposed population subgroup).

HED classified flazasulfuron as “ no evidence of carcinogenicity to humans ;” therefore, quantification of human cancer risk was not conducted.

The residue chemistry database is sufficient to support current and pending registrations. The nature of the residue in plants and livestock has been defined. No tolerances have been established for livestock commodities since there is no reasonable expectation that finite residues

will occur in these matric es

.

Adequate field trial and rotational crop data are available. The magnitude of the residue and processing studies are supported by adequate storage stability data for flazasulfuron. Residues are not expected to occur in rotational crops since citrus and grapes are not rotated and since the proposed sugarcane label contains a 12

- month p lant

- back restriction. The requirement of a confined rotational crop study to support the use on sugarcane (the only proposed/ registered crop which is rotated) has been waived since an adequate 12

- month plant

- back restriction was placed on the proposed la bel. (This waiver was based on low residues in metabolism studies, no detectable residues in field studies, and limited sugarcane acreage.) Adequate enforcement methods are available to support tolerances for plants.

Conclusions: Provided that EFED d rinking water estimates do not need revision , a new dietary assessment for flazasulfuron may not be required for the purpose of registration review. Furthermore, a lthough a new version of DEEM (Version 3.04) will be released, a new dietary

### Page 6 of 19

risk assessment may not be needed since it is anticipated that the changes in the model will not

affect the risk conclusion.

Residential Exposure

Residential Handlers

Flazasulfuron is currently registered for use on golf courses and other non

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

fields. However, a r esidential handler exposure assessment is not required because flazasulfuron is only appl ied to use sites that are not treated by residential handlers.

Residential Post

- A pplication

Based on the current use patterns, t here is only potential for post

- application dermal exposure for recreational golfers. Since a dermal end point was not selec ted due to lack of obser ved toxic effects, a residential post

- application assessment is not necessary. A new risk assessment is not

needed for the existing uses

.

Aggregate Risk Assessment

A ggregate assessments consider exposures from food, drinking water, and residential uses. In the most recent human health risk assessment (D372903, C. Walls, 6/12/11), aggregate risks were estimated for the acute (food and drinking water) and chronic (food and drinking water) exposure durations. As previously mentioned, these aggregate dietary risks were below HED’s

level of concern. The short

- and intermediate

- term aggregate risk assessments were not required

as no short or intermediate

- term dermal tox ic ity endpoints were identified

.

Conclusions: The a ggregate risk assessment s include only food and drinking water and will not
need to be reassessed provided that the drinking water estimates do not change

.

Occupational E xpos ure

Flazasulfuron registrat ion is pending for use on citrus, grapes, sugarcane, Christmas trees, and industrial vegetation management areas, and currently registered on golf course and other professionally managed turf areas . There is potential for short

- and intermediate

- term occupational exposure to flazasulfuron during handling (mixing, loading, and applying) and

post

- application activities.

Occupational Handlers

O ccupational handler exposure and risk assessments were conducted for the pending uses on

citrus , grapes, sugarcane, Christmas trees, and industr ial vegetation management areas and registered uses on golf course and other p rofessionally managed turf area . The resulting in risk

estimates are not of concern (MOEs ranging from 1,4 00 to 97 ,000). These assessments were based on PHED unit exposure values. However, HED policies have since changed yielding

### Page 7 of 19

updated acreage assumptions as well as updated unit exposure values. New occup ational handler assessments may be needed for all use patterns.

Occupational Post

- A pplication

There is a possibility for agricultural workers to have post

- application dermal exposure to

flazasulfuron following its 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 occupational post

- application inhalation

exposure assessment has not been performed for flazasulfuron at this time. However, there a re multiple potential sources of post

- application inhalation exposure to individuals performing post

application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particu lates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. 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 as well as available post

- application inhalation exposure data generated by the Agricultur al Reentry Task Force and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate occupational

post

- application inhalation exposure into the Agency's risk assessments. If new policies or

proc edures are put into place, the Agency may revisit the need for a quantitative occupational

post

- application inhalation exposure assessment for flazasulfuron

.

Conclusions: There is sufficient information available to assess occup ational exposure.
However, the occupational exposure scenarios were not assessed based on current ORE policies. An up

- to

- d ate occupational assessment may be needed , accounting for the changes in policies and unit exposures

.

Public Health and Pesticide Epidemiology Data

The eva luation of the OPP Incident Data System (IDS) indicated no incidents identified in the United States for flazasulfuron in either Main or Aggregate IDS, from January 1, 2006 to

December 14 , 2011 ( D 399369

, S. Recore, 02/14/12 ). Flazasulfuron is not included in the Agricultural Health Study (AHS), and therefore, does not provide information for this report. There does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the inci dent information and if a concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Currently, there are permanent US tolerances established for flazasulfuron are in/on citrus, grapes, and sugarcane. There are no Codex, Canadian, or Mexican maximum residue limits ( MRLs ) establish ed for residues of flazasulfuron on plant or livestock commodities. Therefore,

there are no harmonization issues.

### Page 8 of 19

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with US 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 accordin g 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

pe sticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesti cide. 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 perf ormed when conditions or circumstances warrant. Whenever appropriate, non

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

post

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

.

Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies inclu de acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including e ffects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and

chronic studi es that assess growth, developmental and reproductive effects in different taxonomic groups. As part of the most recent registration decision reviewed these data and selected the most sensitive endpoints for the relevant risk assessment scenarios from the existing

hazard database. However, as required by FFDCA section 408(p), flazasulfuron is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

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

- tiered approach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemical s that go through Tier 1 screening and are found to have the potential to

### Page 9 of 19

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pes ticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Flazasulfuron is not among the group of 58 pestici de active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data

call

- ins, requiring the submission of EDSP screening assays for flazasulfuron

. For further

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

.

Cumulative

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 action, therefore, EPA has not

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

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Human Studies

The previous risk assessment s rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the PHED, the Outdoor Residential Exposure Task Force (ORETF), and the Agricultural Reentry Task Force (ARTF) have been d etermined to require a review of their ethical conduct, and have

received that review.

Data Requirements / Outstanding Deficiencies

Toxicology

870.6200b Subchronic Neurotoxicity Screening Battery

● Under the data requirements as presented in 40 CFR Part 158, a subchronic

neurotoxicity screening study is required.

### Page 10 of 19

870.7800 Immunotoxicity

● Under the data requirements as presented in 40 CFR Part 158, an immunotoxicity

study is required.

References

As shown in Reference s below, only two human health risk assessment have been conducted for

flazasulfuron.

Memoranda Relevant to Registration Review of Flazasulfuron

Author Barcode

(DP#) Date Title

N. Dodd 394885 11/8/11 Flazasulfuron. Amendment to Review of Analytical Chemistry and Residue Data for Use on Citrus, Grapes and Sugarcane

C. Walls 372903 6/12/11 Flazasulfuron: Human Health Risk Assessment for Proposed Uses on Citrus, Grapes, Sugarcane, Christmas Trees, and Industrial Vegetation Manageme nt K. Rury 378629 4/12/11 Flazasulfuron: Acute & Chronic Aggregate Dietary (Food and Drinking Water) Exposu re and Risk Assessment for the

First Food U se, Section 3 Registration Action (Citrus, Grapes, and Sugarcane)

C. Walls 378633 3/19/11 FLAZASULFURON: Occupational and Residential Exposure/Risk Assessment for Use on Citrus, Grapes, Sugarcane, Christmas Trees, and Industrial Vegetation Management

E. Holman 386767 2/28/11 Flazasulfuron; Report of the Residues of Concern Knowledgebase Subcom mittee (ROCKS)

N. Dodd 372901 2/16/11 Flazasulfuron. Summary of Analytical Chemistry and Residue Data for Use on Citrus, Grapes, and Sugarcane

K.
O’Rourke 316614 11/23/05 Occupational and Residential Risk Assessment to Support Request for Registration of Flazasulfuron on Non

- Residential

Turf

G. Burke 303573,

309442 11/16/05 Flazasulfuron: Human Health Risk Assessment for the

Proposed Uses on Golf Courses, Sod Farms, Profes sionally Managed Athletic Fields (College and Professional), and

Commercial Lawns.

Attachment s 1. Chemical Identity Table

2. Tolerance Summary Table

3. Endpoint Selection Table

### Page 11 of 19 Attachment 1

Chemical Identity Table

Table 1 a

. Chemical Identity of Flazasulfuron

Common N ame f lazasulfuron

IUPAC N ame 1

- (4,6

- dimethoxypyrimidin

- 2

- yl)

- 3

- (3

- trifluoromethyl

- 2

- pyridylsulfonyl)urea

Chemical Abstracts Service (CAS) N ame N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (trifluoromethyl)

- 2

- pyridinesulfonamide

PC Code 119011
CAS registry number 104040

- 78

- 0

Chemical Class Sulfonylurea herbicide

Chemical Structure

Table 1b. Chemical Names and Structures for Flazasulfuron Metabolites /Degradates

Common name/code Chemical name Chemical structure

ADMP 2

- amino

- 4,6

- dimethoxypyrimidine

DTPU N

- (4,6

- dimethoxy

- 2

- pyrimidinyl)

- N

- [3

- (trifluoromethyl)

- 2

- pyridinyl]urea

DTPP 4,6

- dimethoxy

- N

- [3

- (trifluoromethyl)

- 2

- pyridinyl]

- 2

- pyrimidinamine

### Page 12 of 19

HTPP 6

- methoxy

- 2

- [[3

- (trifluoromethyl)

- 2

- pyridinyl]amino]

- 4

- pyrimidinol

TPSA 3

- (trifluoromethyl)

- 2

- pyridinesulfonamide

2,3

- GTF 3

- trifluoromethyl

- 2

- pyridylguanidine

### Page 13 of 19 Attachment 2

Tolerance/MRL Table

Table 2. Summary of US and International Tolerances and Maximum Residue Limits for

Flazasulfuron

Residue Definition:

US Canada Mexico 2 

### Codex

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; 02/23/2012

1 Includes only commodities registered in the US

.

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

### Page 14 of 19 Attachment 3

Summary of Flazasulfuron Endpoints Selected for Risk Assessment

Table 3

- 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, microgran ulomas).

Dermal

Short

- Term (1

- 30 days)

and

Intermediate

Term (1

- 6 months) Quantification of dermal risk is not required. No dermal or systemic toxicity was seen following repeated dermal applications at the Limit Dose

and there are no concerns for neuro

- , developmental, or reproductive toxicity

Inhalation

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).

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

### Page 15 of 19

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = ex trapolation 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 3

- B. Summary of Toxicological Doses and Endpoints for Flazasulfuron for Use in Occupational

Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Dermal

Short

- Term (1

- 30 days)

Interme diate

Term (1

- 6 months) Quantification of dermal risk is not required. No dermal or systemic toxicity was seen following repeated dermal applications at the Limit Dose

and there are no concerns for neuro

- , developmental, or reproductive toxicity

Inhalation

Short

- Term (1

- 30 days)

And

Intermediate

Term (1

- 6 months) NOAEL = 2

mg/kg/day 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 infiltratio n, 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 effe ct 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.

### Page 16 of 19

Toxicity Profiles

Table A.3 .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.3 .2 Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses Results

870.3100

90

- Day oral toxicity (rat) 46220920 (1988)

M/F: 0, 40, 200, 1000, 5000 ppm M: 0, 2.31, 11.66, 57.1, 287 mg/kg/day

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

870.3150

90

- Day oral toxicity (dog)

- capsule 46220921 (1994)

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

870.3200

21

- Day dermal toxicity (rabbit) 46220922 (1994)

0, 250, 500, 1000 mg/kg/day Acceptable/Guideline NOAEL (M/F) = 1000/1000 mg/kg/day

LOAEL (M/F) = No systemic toxicity was observed at the

limit dose. No localized dermal effects were observed.

### Page 17 of 19

Table A.3 .2 Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses Results

870.3700a

Prenatal developmental in (rat):

Wistar 46220924 (1988)

0, 100, 300, 1000 mg/kg/day Acceptable/Guideline Maternal NOAEL = 100 mg/kg/day LOAEL = 300 mg/kg/day based on increase in maternal relative liver weight and decreased body weight gain and food consumption. Developmental NOAEL = 100 mg/kg/day LOAEL = 300 mg/kg/day based on increased incidence of visceral malformations (interventricul ar 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. Developmental NOAEL = 150 mg/kg/day LOAEL = 450 mg/kg/day based on high incidences of

abortion.

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

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

870.4100b Chronic toxicity (dog)

- capsule 46220927 (1995)

M: 0, 0.4, 2, 10, 50 mg/kg/day F: 0, 2, 10, 50 mg/kg/day Acceptable/Guideline NOAEL = 2 mg/kg/day LOAEL = 10 mg/kg/day based on changes in liver (increase in: inflammatory cell infiltration, hepatocellular necrosis, hepatocellular swelling, and bile duct proliferation).

870.4300

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

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

no evidence of carcinogenicity

### Page 18 of 19

Table A.3 .2 Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses Results

870.4200 Carcinogenicity (mouse) 46220928 (1995)

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

no evidence of carcinogenicity

870.5500

Salmonella typhimurium and

Escherichia coli

Reverse Mutation Assay 46220933 (1987)

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

1000  g/ plate ( S. typhimurium ); 0, 100, 200, 500, 1000, 2000,

5000 ( E. coli ) in the presence and absence of

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

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

coli , and did not induce a genotoxic response in a ny 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)

### Page 19 of 19

Table A.3 .2 Subchronic, Chronic and Other Toxicity Profile

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

Classification /Doses Results

870.7485

Metabolism and pharmacokinetics (rat) 46220940 (1994),

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

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

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

at 6 hours in both sexes.