### Page 2 of 22

C. Lewis, DP219775, 10/30/95 ). Based on the current use profile, exposures can be expected to occur via the die tary (food and drinking water) and occupational (handler and post

- ap plication) routes for prosulfuron

.

The toxicology database for prosulfuron is considered substantially complete for the purposes of registration review risk assessment

. An immunotoxicity study is the only remaining data requirement.

Prosulfuron has low toxicity by the oral, dermal, and inhalation routes of exposure and is

not considered a n eye or skin irritant. Acceptable Developmental, reproductive and neurotoxicity studies are available for prosulfuron. T here was no evidence from the developmental and reproductive studies of increased suscepti bility in rat or rabbit fetu ses. Evidence of neurotoxicity was observed in gavage but not dietary dosing studies with prosulfuron

. The neurological effects seen in the acute neurotoxicity study were consistent with transient neurotoxicity affecting primary s ensorimotor and gait fun ctions.
T here was also evidence of neurotoxicity and neuropathology in a developmental range

finding stud y in rabbits at all doses tested . Al so in the rabbit developmental range

finding study ataxia, hypoactivity

, and neuropathology were observed. Howev er, the 90

- day neurotoxicity study in rats did not result in any significant neurotoxicity; other dietary studies in the rat, mouse and dog also did not show evidence of neurotoxicity. Upon receipt of the required immuno toxicity stud y , HED will reevaluat e the points of departure and uncertainty factors for the dietary and occupational exposure assessments.

Under the old cancer guideline classification system, t he Agency classified prosulfuron as a Group D Chemical; ― Not Classifiable as to Human Carcinogenicity ‖ (1995). The Agency has since reaffirmed this classification in subsequesnt evaluations. In accordance with the 2005 Guidelines for Carcinogen Risk Assessment, prosulfuron is classified as

― Not Likely to Be Carcinogenic to Humans” based on the lack of evidence of carcinogenicity in mice and rats and no concern for mutagenicity.

The existing residue c hemistry database for prosulfuron is adequate for risk assessment

purposes. The qualitative nature of the residue(s) of prosulfuron in plan ts and animals has been adequately identified/characterized and is understood and adequate enforcement analytical methods are available

. The current tolerance expression as listed in the 40 CFR§180.481 has not been updated to reflect current HED policies and thus will need to be revised during the registration review process.

The dietary exposure database is also adequate to support the existing registrations. In the last dietary assessment, t he chronic and acute dietary exposure for food and water was not greater than 1% of the cPAD or the aPAD for all population groups. A c ancer dietary
risk assessment is not required for prosulfuron.

There are currently no residential uses for prosulfuron ; therefore

, a residential risk assessment was not required.

U pdated aggregate exposure and risk assessments may be required if the toxicological endpoints change or other new data are received by the Agency which impact dietary

### Page 3 of 22

exposure estimates . The assessments would include combining food and drinking water
onl y since there are no registere d residential uses of prosulfuron

.

The occupational exposure database is adequate to support the registrati on review process for prosulfuron

. In the 2005 exposure assessment s , a ll of the non

- cancer occupation al
handler risk estimates were below the Agency’s level of concern. No new occupational handler or post

- application worker studies are needed at this time. Revised occupational handler assessments would be based upon revisions to the Agency’s scenario

- specific surrogate handler exposure data ( http://www.epa.gov/pesticides/science/handler

exposure

- table.pdf

).

Introduction

Prosulfuro n is a selective herbicide used for weed control in sever al crops. HED has reviewed the most recent exposure and risk assessments for prosulfuron , as well as toxicity data, exposure and usage databases, and the latest Agency science policy and risk assessment methodologies to determine if sufficient data are av ailable and if updates are needed to support registration review. Additionally, the team conducted a screening

level literature search for any information that would aid in assessing human health risks

to prosulfuron

.

Chemical Identity

Prosulfuron

, 1

- (4

- methoxy

- 6

- methyl

- 1,3,5

- triazin

- 2

- yl)

- 3

- [2

- (3,3,3

- trifluoropropyl)

- P henyl sulfonyl]

- urea , is a selective herbicide used for weed control in or on field corn (grown for grain, silage, or seed), popcorn, grain sorghum (milo), wheat, barley, rye oats,

t riticale, proso millet, and following small grain harvest

. It is used for ground or aerial

spray treatment. In addition, pre

- emergence applications may be made in some areas for broadleaf weed control in sorghum.

The nomenclature and physicochemical prop erties of prosulfuron are presented in Tables
1 and 2

.

Hazard Identification/Toxicology

The toxicology database for prosulfuron is nearly complete at the present ti me with the exception of an immunotoxicity study (Table 3)

. The toxicity profile of prosu lfuron developed from acute, subchronic, chronic and other studi es is presented in Table s 4 and
5

.

Prosulfuron has low toxicity by the oral, dermal, and inhalation routes of exposure and is

not con sidered an eye or skin irritant. Chronic and subchronic studies with prosulfuron
indicated possible treatment

- related effects. T he most prevalent effect observed across studies was on body weight. In a subchronic oral toxicity study in rats, there were
reductions in mean body weight s . S ubchronic oral toxicity study in dogs showed that exposure to prosulfuron resulted in not only decreased body weight s but also hematological parameters and hepatic toxicity. Similar findings were also found in the 1

-

### Page 4 of 22

year chronic feeding study in dogs and t he 2

- year rat chronic toxicity/ carcin ogenicity study

.

HED classified prosulfuron as a Group D Chemical; ― Not Classifiable as to Human Carcinogenicity ‖, under the old cancer guideline classification system (1995) HED has since reaffirmed this classification in subsequent evaluations. This classification was based on the lack of evidence of carcinogenicity in male or female mice at the limit dose and equivocal evidence of carcinogenicity in female rats. In female rats, there was suggestive evidence of a possible treatment

- related increase in the incidence of adenocarcinomas of the mammary glands at the mid dose but not at the high
dose. This lack of dose

- response (i.e. the relatively limited response in the high dose group and a more pronounced response in the middle

- dose group) along with the lack of evidence of carcinogenicity in mice and the lack of evidence for in vivo or vitro mutagenicity lowered the concern for the carcinogenic potential of prosulfuron. Thus, in accordance with the 2005 Guidelines for Carcinogen Risk Assessment, prosulfuron is
classified as ―

Not Likely to Be Carcinogenic to Humans” based on the lack of evide nce of carcinogenicity in mice and rats and no concern for mutagenicity.

In the first of t wo rabbit developmental studies, there were no signs of maternal or developmental toxicity. However, in the rabbit range

- finding study that used higher doses, not only were there neurotoxicity effect s but there were also decreased body weights and increased skeletal malformations. The rat and the second rabbit (tested using higher doses than the first) developmental studies showed dose

- related increases in small
fe tuses and skeletal effects. In the reproductive study, d ecreases in body weights were
noted for both the adults of the P 0 

### and P 1 

### generations and for the F 1 

### and F 2 

### offspring as

pups. However, there was no evidence from the developmental and reproductive st udies of increased susceptibility in rat or rabbit fetuses.

Metabolism studies were conducted for prosulfuron in rats. In both of the rat studies, approximately 90% of the administered dose was excreted during the first 48 hours. At higher doses a greate r proportion of the administered dose was excreted in the feces compared to urine. Females usually excreted more of the dose in the urine than males in both instances. The major routes of metabolism occurred via hydroxylation at side chains and phenyl rin g positions, and O

- demethylation of the triazyl methoxy group or O

demethylation of the methoxy group, and hydroxylation of the triazinyl methyl group. Minor routes of metabolism included unsaturation of the trifluoropropyl side chain, hydrolysis of the p henyl

- sulfonylurea link, and oxidative/hydrolytic cleavage of the triazine ring system.

HED has fully evaluated the toxicity databa se of prosulfuron with respect to the potential for special sensitivi ty of infants and children. HED concludes that there is no concern for

pre

- and postnatal susceptibility for infants and children. The FQPA safety factor has
been reduced to 1X because (1) the lack of evidence of increased pre

- and/or postnatal sensitivity; (2) the evidence of neurotoxicity found only afte r gavage dosing at dose levels in excess of those where systemic toxicity occurred and at a dose at least 15

- fold higher than the NOAELs selected for risk assessment ; (3) no neurotoxicity was observed in the subchronic neurotoxicity study in rats; (4) the neuropathology observed in pregnant

### Page 5 of 22

rabbits only occurred at dose levels where mortality and abortions were observed; and (5) the lesions in the spinal cord and sciatic nerve showed no dose

- response.

Acceptable acute and subchronic neurotoxicity studies a re available for prosulfuron. Evidence of neurotoxicity was observed in gavage but not dietary dosing studies with prosulfuron

. Staggered gait, lacrimation, and hyposensitivity to touch and sound were seen in an acute oral study in rats. In addition, evi dence of neurotoxicity (transiently decreased motor activity, ataxia and abnormal gait, impaired righting reflex, decreased body temperature) was observed in the acute neurotoxicity acute study in rats. The neurological effects were consistent with transie nt neurotoxicity affecting primary

s ensorimotor and gait functions. At all doses tested, there is evidence of neurotoxicity and neuropathology in a developmental range

- finding stud y in rabbits . Al so in the rabbit developmental range

- finding study ataxia, hypoactivity

, and neuropathology were observed. However, the 90

- day neurotoxicity study in rats did not result in any significant neurotoxicity; other dietary studies in the rat, mouse and dog also did not show evidence of neurotoxicity.

An immunotoxici ty study is also required as a part of the new data requirements in the 40 CFR Part 158 for conventional pesticide registration. 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 lower 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.

The Po ints of Departures and toxicological endpoints of concern for the overall risk assessment (dietary and occupational) are presented in Table 6.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential
adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecol ogical hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision

, EPA reviewed these data and selected the m ost sensitive endpoints for relevant risk assessment scenarios from the existing hazard
database. However, as required by FFDCA section 408(p), prosulfuron 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

### Page 6 of 22

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 estr ogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which , if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a
dose

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

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

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 iner t ingredients.
Prosulfuron is not among the group of 58 pesticide 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 prosulfuron

. For further information 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/

.

Conclusions for Hazard Identification/Toxicology

The toxicology database for prosulfuron is complete at the present time with the exception of an immunotoxicity study. Upon receipt of the required toxicity stud y , HED may reevaluate the points of departure and uncertainty factors for the dietary and occupational exposure assessments.

Residue Chemistry

The existing residue chemistry database for prosulfuron is adequate for risk assessment purposes; no additional data are required at this time. The qualitative nature of the residue(s) of prosulfuron in plants is considered adequately understood ; based on acceptable metabolism studies and the most recently submitted rotat ional crop studies on root and leafy vegetables and small grains

. Outstanding deficiencies previously noted (DP Barcode: D242049 dated 04/04/2000, Case: 014396) were resolved with the submission and acceptance of the storage stability data. The qualitative nature of the residue(s) of prosulfuron in animals is adequately understood based on the metabolism studies in ruminants and poultry. Based on the cow and chicken feeding studies, meat, milk, poultry, and egg tolerances are not required. T here is no reaso nable expectation of residues in livestock commodities (40CFR§6(a)(3)). Adequate high

- performance liquid chromatography (HPLC) methods are available for enforcing tolerances for prosulfuron residues in plant commodities.

Conclusions for Residue Chemistry

The existing residue chemistry database for prosulfuron is complete and adequate for risk assessment purposes.

### Page 7 of 22

Dietary Exposure and Risks

An unrefined chronic dietary (food and water ) risk assessment and an acute dietary risk

assessment was completed for prosulfuron (B

. Hanson

, D 370557 , 10/ 20 /200 9 )

. These assessments were performed using the Dietary Exposure Evaluation Model (DEEM

FCID TM 

### , Version 2.03) which uses food consumption data from the U.S. Department of Agriculture’s Continuing S urveys of Food Intakes by Individuals (CSFII) from 1994

- 1996 and 1998. In th ese assessment s , HED concluded that there is a reasonable certainty that no harm will result to the general population, infants, and children from chronic and

acute dietary exposur e to prosulfuron

. The chronic and acute dietary exposure for food and water was no greater than 1% of the cPAD or the aPAD for all population groups.
C ancer dietary exposure estimates are not required for prosulfuron.

Drinking Water

The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED) and summarized in the following memorandum: ―Drinking Water Exposure Assessment for Prosulfuron Usage on Small
Grains and Co rn,‖ (DP Number : 326831

, Barrett, 11/20/2006) and incorporated directly into this dietary assessment. The Screening Concentration in Ground Water (SCI

GROW) model was used to estimate ground water concentrations and the Pesticide Root Zone Model (PRZM) and Exposure Analysis Modeling System (EXAMS) models were
used to estimate surface water concentrations.

Conclusions for Dietary Exposure and Risk Assessment

The dietary exposure database is adequate to support the existing registrations.

Residential Expo sure and Risks

There are no residential uses for prosulfuron , therefore, a residential exposure assessment will not be required.

Conclusions for Residential Exposure and Risk Assessment

Currently, t here are no uses for prosulfuron that would result in direct residential exposure. However, residential bystander inhalation exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of prosulfuron . The Agency is in the process of evaluating these types of exposures 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. The need for a bystander inhalati on risk a ssessment for prosulfuron will be examined during registration review.

Aggregate Risk Assessment

### Page 8 of 22

The aggregate risk assessment evaluates the combined risk from dietary exposure (food and water) and any non

- occupational (residential) uses. There are no registere d residential uses of prosulfuron ; therefore, the aggregate assessments only reflect potential food and drinking water exposure and are equivalent to the dietary assessments . The chronic dietary exposure risks were <1% cPAD; therefore, th ere are no aggregate risk

concerns.

Conclusions for Aggregate Exposure and Risk Assessment

Updated aggregate exposure and risk assessments may be required under registration
review if toxicological endpoints change or other new data are received by th e Agency which impact dietary exposure estimates

.

Occupational Exposure and Risks

Prosulfuron is a selective herbicide to be used for ground or aerial spray treatment for weed control in several crops. Prosulfuron may be applied to field corn (grown for grain, silage, or seed), popcorn, gra in sorghum (milo), wheat, barle y, rye oats, triticale, proso millet, and following small grain harvest. Prosulfuron is applied after emergence of both crop and weeds for the control of broadleaf weeds and post

- emergen ce to weeds following small grain harvest. In addition, pre

- emergence applications can be used in some areas for broadleaf weed control in sorghum. Prosulfuron is marketed as a water

dispersible granule and as a technical chemical used for formulation on ly.

Occupational Handlers

In 1995, HED conducted an occupational and residential exposure assessment for small grains. HED determined that the MOEs (ranged from 1,000 to 8,833) were not of
concern to mixers /loaders and applica tors (i.e., MOEs ≥100)

. (C. Lewis, DP 219775, 10/30/95).

In 1995, HED conducted an occupational and residential exposure assessment for corn. HED determined that the MOEs (ranged from 3,118 to 12,045) as a result of the mixing/loading and application of prosulfuron by workers d o not exceed HED’s level of concern (i.e., MOEs ≥100)

. ( B. Madden , 5/1/95).

Occupational Post

- application

An occupational post

- application exposure or risk estimate was not performed for prosulfuron because it is not required at this time. Based on the toxicity database, no appropriate dermal endpoint was identified

.

Since prosulfuron is classified as Toxicity Category III for acute oral and acute dermal, Toxicity Category IV for acute inhalation, primary eye irritation, and primary skin irritation, th e default Worker Protection Standard Restr icted Entry Interval (REI) is 12
hours.

### Page 9 of 22

Conclusions

The occupational exposure database is adequate to support the registration review process
for prosulfuron . No new handler or post

- application worker studies are needed at this time. Updated occupational handler exposure assessments may be required under registration review based upon revisions to the Agency’s scenario

- specific surrogate handler exposure data ( http://www.epa.gov/pesticides/science/handler

- exposure

table.pdf ). A r evised occupational handler and a post

- application assessment may also be needed if toxicological endpoints change or other new data are received by the Agency which impact exposure estimates.

Human Studies

Prosulfuron risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Studies such as the
Pest icide Handlers Exposure Database

, Outdoor Residential Exposure Task Force , and Agricultural Handler Exposure Task Force have been reviewed by the Agency and found on the basis of available evidence to have been neither fundamentally unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted. There is no barrier in EPA's "Protection of Human Subjects" regulation to reliance on these studies.

Public Health and Pesticide Epidemiology Data

An updat ed review of prosulfuron incident reports was recently prepared by HED (S. Recore, D 397848

, 1/3/2012 )

. For this evaluation, the OPP Incident Data System (IDS) was consulted for pesticide incident data on the active ingredient prosulfuron

.

The IDS includes reports of alleged human health incidents from various sources, including mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6 (a) (2) reports from registrants, other federal and state health and environmental agencies and individual con sumers. IDS contain s reports from across the U.S. and most incidents have all relevant product information recorded. Reports submitted to the IDS represent anecdotal cases or allegations only, unless otherwise stated. IDS records incidents resulting in high er severity outcomes in more detail, in a module called the
Main IDS module. This system stores incident data for death, major and moderate incidents, and it includes more details about the location, date and nature of the incident.

For the Main IDS, from January 1, 2006 to December 14, 2011 there are no case s reported that involve the active ingredient prosulfuron

. In the Aggregate IDS, from January 1, 2006 t o December 14, 2011, there is 1 incident reported for prosulfuron

. Because it falls within the categories reported as counts (which includes minor, unknown or no effects), there is no unique report that provides details about the incident and single chemical incidents are not distinguished from multiple chemical incidents; however, a high freque ncy of incidents indicates there is a high potential for exposur e and vice versa.

### Page 10 of 22

For prosulfuron , there appears to be a low pot ential for exposure. Prosulfuron is not included in the Agricultural Health Study (AHS), and therefore, does not provide
informa tion for this report.

Based on the low frequency and severity of incident cases, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to
monitor the incident information and if a concern is triggered, additional analysis will be included during registration review.

Tolerance Assessment and International Harmonization

Tolerances are established under 40 CFR §180. 481 for residues of the herbicide prosulfuron parent , in or on a variety of f ood and feed crops (see Table 10). These tolerances are based on the residue analysis of prosulfuron

. There are currently no established or proposed Codex, Canadian, or Mexican maximum residue limits (MRLs)
for prosulfuron

.

The current tolerance expression as listed in the 40 CFR §180. 481 has not been updated to reflect current HED policies. The tolerance expression will need to be revised during the registration review process. The revised tolerance expression should be as f ollows:

“Tolerances are established under 40 CFR §180.481 for residues of the herbicide prosulfuron, including its metabolites and degradates, in or on the following commodities. Compliance with the tolerance levels specified is to be determined by

meas uring only prosulfuron parent [1

- (4

- methoxy

- 6

- methyl

- 1, 3,5

- triazin

- 2

- yl)

- 3

- [2

- (3,3,3

- trifluoropropyl)

-

phenylsulfonyl]

- urea ] in or on the commodity”.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were c onsidered 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.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf . The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use of a pesticide when conducting human healt h risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvesting crops. Should these high exposures indicate p otential risks of concern, OPP will further
refine the risk assessments to ensure that the risk estimates are based on the best available
information.

Cumulative Risk Assessment

At this time, EPA does not have available data to determine whether prosulfuron has a common mechanism of toxicity with other substances. EPA has not made a common
mech anism of toxicity finding as to prosulfuron and any other substances, and prosulfuron does not appear to produce a toxic metabolite produced by other subst ances

### Page 11 of 22

which have tolerances in the U.S. Therefore, EPA has not assumed that prosulfuron has a common mechanism of toxicity with other substances.

Data Requirements

HED does not anticipate that additional residue chemistry, toxicology or occupational/re sidential exposure data will be required for the prosulfuron registration review process, with the exception of the following studies listed below:

Immunotoxicity Study (OPPTS 870.7800)

### Page 12 of 22

Table 1 . Prosulfuron Nomenclature. Compound

Common name Prosulfuron

IUPAC name 1

- (4

- methoxy

- 6

- methyl

- 1,3,5

- triazin

- 2

- yl)

- 3

- [2

- (3,3,3

- trifluoropropyl)

- phenylsulfonyl]

- urea CAS name Benzenesulfonamide, N

- [[(4

- methoxy

- 6

- methyl

- 1,3,5

- triazin

- 2

- yl)amino]carbonyl]

- 2

- (3,3,3

- trifluoropropyl)

- CAS registry number 94125

- 34

- 5

Table 2 . Physicochemical Properties of the Technical Grade Prosulfuron

Parameter Value Reference Melting point/range 155°C MSDS pH Not Applicable Bulk density (g ml - 1 )/Specific gravity 1.45 Water solubility (g/L) at 25 oC 4.0 at pH 6.8 Solvent solubility (g/L) at room temperature Acetone: 160 (purity: 95.1 %)
Toluene : 6.1
Dichloromethane : 180 Ethyl acetate : 56

n

- Hexane : 0.006
Ethanol : 8.4

n

- octanol :1.4 Vapor pressure < 3.5x10

- 6 Pa at 25 °C Dissociation constant, pK
a pKa = 3.76 Octanol/water partition coefficient (log Pow) pH5 : 1.5 at 25°C

UV/visible absorption L mol - 1 cm - 1 ε = 21645 l x mol - 1 x cm - 1 at λ max = 227.5 nm
shoulder at 250 nm No absorption >290 nm

### Page 13 of 22

Table 3

. Prosulfuron T oxicology Data Requirements

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

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

yes
yes
yes
yes
yes

870.3100 Oral Subchronic (rodent)

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

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

- 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

no
yes
yes
yes yes

- yes
yes
yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

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

yes
yes
870.6100a Acute Delayed Neurotox. (hen)

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

- Day Neurotoxicity (hen)

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

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

- Day Neuro. Screening Battery (rat)

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

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

no
yes
yes

no -

- yes
yes

-

870.7485 General Metabolism

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

................................ ........................ 870.7800 Immunotoxicity............................................... yes

no
yes yes

-

no

### Page 14 of 22 Table 4 Acute Toxicity of Prosulfuron Technical

Guideline No. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral 42685215 LD 50 = 986 mg/kg III

870.1200 Acute Dermal 42685216 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation 42685217 LC 50 = 5.467 mg/L IV

870.2400 Primary Eye

Irritation 42685218 Minimal irritant IV

870.2500 Primary Skin

Irritation 42685219 Non

- irritant IV

870.2600 Dermal

Sensitization 42685220 Non

- sensitizer N/A

Table 5. Prosulfuron Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/
Classification
/Doses Results

82

- 1 870.3100
90

- Day oral toxicity rats 42685232
D ietary levels of 0, 5, 50, 500, 4,000 or 8,000 ppm. Mean daily doses were 0, 0.31, 3.1, 31, 255, or
522 mg/kg/day for males and 0, 0.32, 3.4, 35, 268, or 512 mg/kg/day for . The L OA EL is 500 ppm for males, based

on reduced body weight and body weight gain (13%); and 4,000 ppm for females, based on reduced body weight, body weight gain, food consumption, and food efficiency. In addition, statistically significant reductions in 5'nucleotidase activity at > 4,000 ppm and reduced triglycerides at 8,000 were observed in males, although it was unclear whether these changes were related to treatment.
The NO A EL is 50 ppm (3.1 mg/kg/day) for males and 500 ppm (35 mg/kg/day) for
females.

870.3100
90

- Day feeding

- mouse. 42685234

D ietary levels of 0, 15, 500, 1750, 3500, or 7000 ppm. Mean daily doses were 0, 2.0, 69.3, 234, 504, 969 mg/kg/day for males and 0, 2.9, 91.3, 293, 606, and 1400 mg/kg/day for
females. At higher dose levels, degenerative

vacuolation of the heart was observed in males at > 3500 ppm and in females at 7000 ppm. The incidence of centrilobular hypertrophy observed in the liver was statistically significant at > 1750 in males
and > 3500 in females. The histopathological findings in the liver correlated with the statistically significant increased relative liver (to brain and/or body) weight observed in both sexes at > 1750 ppm. The L OA EL is 500 pp m (69.3 mg/kg/day) for males, based on

### Page 15 of 22

Table 5. Prosulfuron Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/
Classification
/Doses Results

statistically significant decreased albumin and total bilirubin and statistically significant increased absolute and relative liver (to brain and/or body) weights. The LEL is 1750 for females, based on statistically s ignificant increased relative liver (to brain and body) weights, statistically significant increased hematocrit and mean corpuscular volume, and decreased mean corpuscular hemoglobin concentration. The NO A EL is 15 ppm (2.0 mg/kg/day) for males; 500 ppm (91 .3 mg/kg/day) for females.

82

- 1 870.3100
90

- Day feeding

– dog. 42685230
via the diet at dose levels of 0, 15, 150, 1500, or 3000 ppm for 90 days. The equivalent average daily intake of test material was 0, 0.54, 5.3, 57, or 110 mg/kg/day (males) and 0, 0.59, 6.5, 54, or 120 mg/kg/day (females). At the highest dose tested, two males

displayed myocardial necrosis with fibrosis and dystrophic mineralization in the ventricular and papillary muscles and one female displayed myocardial degeneration. The NOAEL is 150 ppm (5.3 mg/kg/day) and the LOAEL is 1500 ppm (54 mg/kg/day) based on decreased bodyweight gain and feed efficiency as well as hematological and hepatic toxicity
in both males and females.

82

- 2 870.3200
21

- day dermal toxicity study

- rabbits 42685235

D oses of 0, 10, 100, 500 or 1,000 mg/kg/day CGA

152005 Technical, were applied to the clipped backs of
Chbb:NZW rabbits for 6 hours/day, 7 ays/week, for 3
weeks. There was increased absolute and relative

liver weights in both sexes at 500 and 1000 mg/kg/day. However, these findings
were not considered sufficient to esta blish a systemic toxicity LOAEL. The increased liver weights, however, were considered indicative of dermal absorption of CGA

152005. Based on the absence of any significant dermal or systemic effects at the highest dose tested (1000 mg/kg/day),
the NOAEL' s for dermal and systemic
effects are established at 1000 mg/kg/day.
An LOAEL was not determined.

870.3250 90

- Day dermal toxicity No study available and not required at this time.

870.3465 90

- Day inhalation toxicity No study available and not required at this time.

83

- 3 870.3700 Prenatal developmental

- rats. 1992. 43159317
42700001 Sprague Dawley rats received either 0, 5, 50, 200 or 400 mg
of CGA

152005/kg/day by gavage (technical, 96% a.i.), from There was a statistically significant

decrease in bodyweight gain at the high dose of 400 mg/kg/day during the treatment period. No other maternal toxicity was observed at any dose level in this study. The LOAEL for maternal

to xicity = 400 mg/kg/day (highest dose level tested), based on decrease body weight gain. The NOAEL for maternal

### Page 16 of 22

Table 5. Prosulfuron Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/
Classification
/Doses Results

gestation days 6 through 15,
inclusive toxicity = 200 mg/kg/day. The incidence

of skeletal alterations per litter, which
included the incidence of extra full and rudimentary ribs (incr ease in findings of 14th ribs) seen in the high dose group of 400 mg/kg/day versus controls, gives evidence of developmental toxicity. Thus, the LOAEL for developmental toxicity = 400 mg/kg/day based on skeletal findings (increase in findings of 14th ribs) . The NOAEL for developmental toxicity = 200 mg/kg/day.

83

- 3 870.3700 Prenatal developmental

- rabbits
1992 42685239
42685238
43159318
New Zealand White
rabbits receive either 0, 1, 10, or 100 mg
of CGA

152005/kg/day by gavage (96% a.i.), from gestation days 7 through 19,
inclusive. The LOAEL for maternal toxicity is > 100

mg/kg/day (highest dose level tested) and
the NOAEL for maternal toxicity > 100 mg/kg/day (HDT). A developmental toxicity LOAEL has not been determined in this study. Therefore, the LOAEL for developmental toxicity is > 100 mg/kg/day (highest dose level tested) and the NOAEL for developmental toxicity > 100 mg/kg/day ( HDT). No effects were noted at the highest dose level tested, 100 mg/kg/day, but this should not be
considered a definitive NOAEL since the maternal animals were not adequately challenged, and a limit dose was not utilized in this study.

83

- 3 870.3700
P renatal developmental

- rabbits
1996 43953506
New Zealand White
rabbits received dosages of CGA

152005 technical (96% a.i.) by gavage at dose levels of 0, 20, 100 and 200 mg/kg/day on gestation days 7 to
19 Available data support an LOAEL for

maternal tox icity of 100 mg/kg/day based on increases in abortion, decreases in food consumption, and in mean body weight gain. The NOAEL is 20 mg/kg/day. A
dose

- related increase in runts and small
fetuses was observed in the 100 and 200 mg/kg/day groups. Fetal weigh ts were reduced and skeletal anomalies/delayed
ossification increased. Based upon the
dose

- related increase in runts and small fetuses and the skeletal effects, an LOAEL for developmental toxicity can be established at 200 mg/kg/day. An NOAEL for developme ntal toxicity can be established at 100 mg/kg/day.

83

- 4 870.3800 Multigeneration Reproduction

- rat 1992 42700002 Sprague

- Dawley rats received either 0, 10, 200, 2000, or 4000 ppm (0, 0.67, 13.3, 136, and 278 mg/kg/day for P0 T he NOAEL for parental toxicity is 200

ppm (13.3 mg/kg/day for males and 15.3 mg/kg/day for females). The LOAEL for parental toxicity is 2000 ppm (136 mg/kg/day for males and 152 mg/kg/day for females), based upon decreased mean body weights and body weight gain

### Page 17 of 22

Table 5. Prosulfuron Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/
Classification
/Doses Results

males and 0, 0.76, 15.3, 152, and~3l1 mg/kg/day for P0 females during the premating growth periods, respectively) of
CGA

- 152005 (99.1% a.i.) mixed
in the feed.

. observed in the P0 and P1 generation

animals. Reproductive performance of the P1 generation to produce the F2 litters was slightly affected at the 4,000 ppm dose level with decreases noted in the Fertility, Gestation and Parturition Indices. On day 4 of lactation, mean litter size was reduced to a statistically significant level (p < 0.05)
with a mean of 13 pups per litter at 4000 ppm versus 14.7 in the controls. By day 14 of lactation, pups at both the 2000 and 4000 ppm levels had statistically significantly reduced mean pup weights. Therefore, in both generations, an effect during lactation was apparent.
T he NOAEL for reproductive toxicity is established at 200 ppm (13.3 mg/kg/day for males and 15.3 mg/kg/day for females). The LOAEL for reproductive toxicity is established at 2000 ppm (136 mg/kg/day for males and 152 mg/kg/day for females), based upon decre ased pup weights observed in both the Fl and F2 offspring.

83

- 1 870.4100 Chronic toxicity
rodents Refer to 870.4300 rat chronic feeding/carcinogenicity study below

83

- 1 870.4100 Chronic toxicity dogs. 43159314
43387705
D iet concentrations at 0, 10, 60, 600 or 1200 ppm (0.3, 2.0,
18.6 or 41.0 mg/kg/day, males and 0, 0.3, 1.8, 20.2 or 48.8 mg/kg/day, females). mg/kg/day The L OA EL is 600 ppm (18.6 mg/kg/day,

males), based on hematologic and clinical chemistry effects (females) and incidence of lipof uscin accumulation in liver (both sexes). The NO A EL is 60 ppm (1.8 mg/kg/day, females).

83

- 2 870.4200 Carcinogenicity mice.

1995

18

- months 43159316
43387706 (Crl:CD

- (ICR)BR),
mice were admin 0, 15, 700, 3500 or 7000 ppm of CGA

152005 technical in the diet. Compound consumption was: 0, 1.71, 81.4, 410 and 832 mg/kg/day in males; 0, 2.11, 100, 508, and 1062 mg/kg/day in The systemic toxicity LOAEL is 3500

ppm (410 mg/kg/day in males and 508 mg/kg/day in females), based on slightly
decreased body weight gain in females. The systemic toxicity NOAEL is 700 ppm (81.4 mg/kg/day in males and 100 mg/kg/day in females). There appeared to
be no increase in the incidence of neoplasia in treatment groups when compared to controls.

### Page 18 of 22

Table 5. Prosulfuron Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/
Classification
/Doses Results

females.

83

- 5 870.4300. Com

bined chronic feeding and carcinogenicity study

- rats 1994

2

- years 42700003
43159321
(CrL:CD(SD)BR),

rats were administered 0,10, 200, 2000 or 4000

ppm (0.4, 7.9, 79.9
and 160.9 mg/kg/day for males and 0.5, 9.2, 95.7
and 205.8 mg/kg/day for females, respectively) of
technical CGA

152005 (a.i. 99.1%)
in the diet

. The systemic NOAEL is 200 ppm (7.9

mg/kg/day, males and 9.2 mg/kg/day, females). The systemic LOAEL is 2000 ppm (79.9 mg/kg/day, males and 95.7 mg/kg/day, females), based on decreased body we ight and body weight gain during the first months to 1 year of the study, decreased food consumption (females), hematopoietic system effects (males), and possibly increased GGT with decreases in liver, kidney and adrenal weight (females). Increases in the incidence of mammary
adenocarcinomas in females was observed at 2000 ppm (31.9%; p < 0.5) and 4000 ppm (26.3%; NS) compared to controls (17.5%). Mammary gland adenomas were also slightly increased at 2000 ppm and 4000 ppm (4.3% and 2.5% v s. 0%, controls). Slight increases in the incidence of benign testicular interstitial cell tumors (significant trend only) were also observed at 2000 ppm (8.6%) and 4000 ppm (5.0%) compared to controls (1.6%).

81

- 8 870.6200 Acute neurotoxicity screening battery

F unctional observational battery and motor activity tests were conducted pretreatment, on the day of dosing (peak effect, 3 hr post

- dosing) and on Day 7 and 14 post

- dosing. Neural tissues from 5 control and high dose
animals/sex and brain levels 4 and 5
from all animals were examined microscopically. 43387703 Hsd:Sprague

Dawley rats received 0, 10, 250, 500 or 1000 mg CGA

152005 (technical, 99.1% a.i.)/kg body weight by gavage in aqueous 3% corn
starch/

- 0.5% Tween 80 (20 ml/kg). The LOAEL is 250 mg/kg/day, based on

reduced motor activity and body temperature in males and abnormal gait in females. The NOAEL is 10 mg/kg.

81

- 8 870.6200 Subchronic neurotoxicity screening battery

– 90 day 43387704
R ats were fed diets containing 0, 10,
2 00, 2500, 50 00 (high dose, females only) or 10,000 (high dose, males only) ppm p rosulf

uron technical. The equivalent average daily test material intakes were 0, 0.6, 12.1, 147 or 628 mg/kg/day, males; 0, 0.6, 12.5, 157 or 313 mg/kg/day, The L OA EL for system ic toxicity is 2500

ppm, based on slightly reduced body weight gain in males. The NO A EL is 200 ppm. The NO A EL for neurotoxicity is >10,000 ppm (males) or >5000 ppm (females).

### Page 19 of 22

Table 5. Prosulfuron Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/
Classification
/Doses Results

females).

85

- 1 870.7485 Metabolism and pharmacokinetics

- rat 43159326
R ats were administered [phenyl

- 14C] prosulfuron as a single oral dose of 0.5 mg/kg, a single
i.v. dose of 0.5 mg/kg, a single oral dose of 400 mg/kg and a single oral dose of [phenyl

14C] prosulfuron following 14 days of repeated dosing with 0.5 mg/kg of
nonlabeled compound. Approximately 90% of the administered

dose was excreted during the first 48 hours. At 400 mg/kg, a greater proportion
of the administered dose was excreted in the feces (33

- 36%) compared to urine (61

- 71%). Females usually excreted more of
the d ose in the urine (79

- 91%) than males (66

- 79%). The parent compound represented 8

- 27% of the total activity in
the urine of females and 5

- 9% in males,
whereas in the feces there was 10

- 16% of the parent compound in females and 5

- 6% in males. Fifteen urinary metabolites were
determined and 13 similar metabolites
were confirmed in feces. Tissue levels
were low. No measurable amount of radioactivity was found in most tissues 168 hours post

- dosing in animals at 0.5 mg/kg. The major routes of metabolism
occurred via hydroxylation at side chains and phenyl ring of the trifluoropropyl side chain, hydrolysis of the phenyl

sulfonylurea link and oxidative/hydrolytic cleavage of the triazine ring system. The major metabolite (47% to 60% of urinary radioactivity at 0.5 m g/kg) was formed by hydroxylation of the triazinyl methyl group. At the 0.5 mg/kg level, metabolism was not affected by route of administrationpositions and O

demethylation of the triazyl methoxy group. Minor routes of metabolism
included unsaturation

85

- 1 870.7485 Metabolism and pharmacokinetics

- rat 43159322
43159323

rats were administered [triazine

- 4

- 14C] prosulfuron as a single oral dose of 0.5 mg/kg, a single
i.v. dose of 0.5 mg/kg, a single oral dose of 400 mg/kg and a single oral dose of [triazine

- 4

- 14C] prosulfuron following 14 days of repeated dosing with
0.5 m g/kg of Approximately 90% of the administered

dose was excreted within 48 hours post

dosing. Tissue radioactivity was low, less
than 0.91% of the administered dose. The metabolite profile for each sex was similar regardless of the route of administration. However, females tended to excrete more radioactivity in the urine and less in the
feces than males. The metabolites in the greatest concentration in the urine were #2 (hydroxylation of triazinyl methyl group) and #11 (parent com

pound) along with #1 (O

- demethylated methoxy group) and #3 (hydroxylation of trifluoropropyl group). Females excreted more parent compound
than males. Males excreted more of the hydroxylated metabolites and more

### Page 20 of 22

Table 5. Prosulfuron Subchronic, Chronic and Other Toxicity Profile

Guideline No./ Study Type MRID No. (year)/
Classification
/Doses Results

nonradiolabeled compound. metabolites with a double bond on the

triflu oropropyl group. Urinary metabolite #3 was greater at 400 mg/kg than 0.5 mg/kg, especially in males. It is believed
that O

- demethylation of the methoxy group and hydroxylation of the triazinyl methyl group are the primary metabolic pathways; while hydroxyl ation at various sites of the trifluoropropylbenzene moiety is a slower process that increases in importance as the primary pathways approach saturation.

85

- 2 Dermal Absoprtion No study available and not required at this time.



### Table 6. Summary of Toxicological Doses and Endpoints for Prosulfuron for Use in Dietary and Occupational Human Health Risk Assessments

Summary of Toxicological Endpoints Prosulfuron for Use in Human Health Risk Assessment

Exposure
Scenario Dose Used in Risk

Assessment,
UF FQPA SF and Level of
Concern for Risk
Assessment Study and Toxicological Effects

Acute Dietary All populations NOAEL = 10

mg/kg
UF = 100
Acute RfD = 0.1 mg/kg/day FQPA SF = 1X

aPAD = 0.1 mg/kg/day Acute Neurotoxicity Study

- Rat
LOAEL = 250 mg/kg/day, based on abnormal gait in females.

Chronic Dietary All populations NOAEL= 5.3

mg/kg/day
UF = 100 Chronic RfD = 0.053 mg/kg/day FQPA SF = 1X

cPAD = 0.053 mg/kg/day Subchronic Oral Toxicity Study

- Dog LOAEL = 54 mg/kg/day, based on
decreased body

- weight gain and feed efficiency, hematological findings and hepatotoxicity in both sexes

.

Short

- (1

- 30 days)
Intermed

- Term (1

- 6 months) and Long

- Term (>6 months) Dermal Not required based on the fact that no hazard was identified in the dermal study at dose

levels as high as the limit dose (1000 mg/kg/day).

Short

- (1

- 30 days),
Intermed

- (1

- 6 months) and Long

Term (> 6 months)
Inhalation NOAEL = 5.3

mg/kg/day FQPA SF = 1X Subchronic Oral Toxicity Study

- Dog LOAEL = 54 mg/kg/day, based on decreased body

- weight gain and feed efficiency, hematological findings and hepatotoxicity in both sexes

.

### Page 21 of 22

Summary of Toxicological Endpoints Prosulfuron for Use in Human Health Risk Assessment

Exposure
Scenario Dose Used in Risk

Assessment,
UF FQPA SF and Level of
Concern for Risk
Assessment Study and Toxicological Effects

Cancer (oral, dermal, inhalation) Prosulfuron is classified as ― Not Likely to Be Carcinogenic to Humans” based on the lack

of evidence of carcinogenicity in mice and rats and no concern for mutagenicity.

1 UF = uncertainty factor, FQPA SF = Special FQPA SF, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic)
RfD = reference dose



### Table 7. Prosulfuron Tolerances 40 §180.481 Parts per million

Grain, cereal, forage, fodder, and straw, group 16, except rice, fodder 0.01

Grain, cereal, forage, fodder, and straw, group 16, except rice, forage 0.10

Grain, cereal, forage, fodder, and straw, group 16, except rice, hay 0.20

Grain, cereal, forage, fodder, and straw, group 16, except rice, straw 0.02

Grain, cereal, group 15, except rice 0.01

Table 8 : HED Memoranda Relevant to Registration Review
Author Barcode Date Title

B. Hanson D370557 10/20/2009 Prosulfuron: Human Health Risk Assessment (Revised)

B. Hanson D299767 12/19/2006 Prosulfuron: Acute and Chronic Dietary (Food and Drinking Water) Exposure
Assessment

L. Taylor HED Doc 0054301 08/16/2006 Health Effects Division Toxicology/Hazard Assessment Update for Prosulfuron Human
Health Risk Assessment

G. J.
Herndon D242049 04/04/2000 PP#5F4469. Prosulfuron in or on Cereal Grains (Excep t Rice)
and Animal Commodities

M. Bonner HED Doc 0013976 01/24/2000 Health Effects Division HIARC Report

### Page 22 of 22 Table 8 : HED Memoranda Relevant to Registration Review
Author Barcode Date Title

B. Madden No ne 05/01/1995 Health Effects Division Risk
Assessment for Use of
Prosulfuron in/on Corn

C. Lewis D219775 10/30/1995 Exposure Assessment for Use
of Prosulfuron on Small Grains