Page 1 of 35 UNITED STATES ENVIRONMENTA L PROTECTION A GENCY

WASHINGTON, D.C. 20460 OFFICE OF PREVENTION, PESTICIDE

AND TOXIC SUBSTANCES
MEMORANDUM Date: 27 October 2009 SUBJECT: Nicosulfuron. Human Health Risk Assessment for the P roposed Use on Grasses
.

PC Code: 129008 DP Barcode: D360807 Decision No.: 404568 Re gistration No. : 352
- IRO Petition No . : 8F7501 Regulatory Action: Section 3 Registration Risk A ss essment Type : Single Chemical, Aggregate Case No.: NA T XR No. : NA CAS No.: 111991
- 09
- 4 MRID No . : See Summary Table 40 CFR: 180.454 FROM: Michael A. Doherty, Ph.D., Chemist Linnea Hansen, Ph.D., Toxicologist William Drew, Chemist Risk Assessment Branch II Health Effects Division (7509P) THROUGH: Douglas Dotson, Ph.D., Chemist

Edward Scollon, Ph.D., Toxicologist Margarita Collantes, Biologist Richard A. Loranger, Ph.D., Senior Scientist Christina Swartz, Branch Chief Risk Assessment Branch II Health Effects Division (7509P) TO: Mindy

Ondish/Jim Tompkins (RM 25) Herbicide Branch Registration Division (7505 P) MRID Summary Table MRID No. Study Type Comments 47632210, 47632211 860. 1 300 Canola New DER; 47632210.der.doc 47632212 860.1300 Canola and corn justification paper No DER; MRID addressed herein 47632206, 47632209 860.1340 Plant method New DER; 47632206.der.doc 47632207, 47632208 860.1340 Livestock method New DER; 47632207.der.doc 47640501 860.1480 Cattle New DER; 47640501.der.doc 47632204 860.1500 Pasture grass New DER; 47632204.der.docPage 2 of 35 Table of Contents 1.0 Executive Summary
................................ ................................ ................................ .......... 4 2.0 Ingredient Profile
................................ ................................ ................................ .............. 5 2.1 Summary

of Registered/Proposed Uses
................................ ................................ .. 5 2.2 Structure and Nomenclature
................................ ................................ ................... 6 2.3 Phy sical and Chemical Properties
................................ ................................ ........... 7 3.0 Hazard Characterization/Assessment
................................ ................................ ............. 7 3.1 Hazard and Dose
- Response Characterization
................................ .............................. 8 3.1.1 Database Summary
................................ ................................ ....................... 8 3.1.1.1 Sufficiency

of studies/data
................................ ............................. 8 3.1.1.2 Mode of action, metabolism, toxicokinetic data
............................ 8 3.1.2 Toxicological Effects
................................ ................................ .................... 8 3.1.3 Dose
- response ................................ ................................ ............................... 9 3.1.4 FQPA
................................ ................................ ................................ .......... 10 3.2 Absorption, Distribution, Metabolism, Excretion (ADME)
................................ ...... 10 3.3 FQPA Considerations
................................ ................................ ................................ 11 3.3.1 Adequacy

of the Toxicity

Database
................................ ............................ 11 3.3.2 Evidence of Neurotoxicity
................................ ................................ .......... 11 3.3.3 Developmental Toxicity Studies
................................ ................................ . 11 3.3.4 Reproductive Toxicity Study
................................ ................................ ...... 11 3.3.5 Additional Information from L iterature Sources
................................ ........ 12 3.3.6 Pre
- and/or Postnatal Toxicity
................................ ................................ ..... 12 3. 3.6.1 Determination of Susceptibility
................................ ................... 12 3.3.6.2 Degree of Concern Anal ys is and Residual Uncertainties for Pre
and/or Postnatal Susceptibility
................................ ................................ .. 12 3.3.7 Recommendation for not requiring a Devel opmental Neurotoxicity Study 12 3.4 FQPA Safet y Factor for Infants and Children
................................ ........................... 12 3.5 Hazard Identification and Toxicity Endpoint Selection
................................ ............. 12 3.5.1 Acute Referen ce Dose (aRfD)

– General Population
................................ . 12 3.5.2 Acute Reference Dose (aRfD)
- Females age 13
- 49
................................ ... 13 3.5.3 Chronic Reference Dose (cRfD)
................................ ................................ . 13 3.5.4 Incidental Oral Exposure ................................ ................................ ............ 13 3.5.5 Dermal Absorption
................................ ................................ ...................... 13 3.5.6 Residential and Occupational Dermal Exposure
................................ ........ 13 3.5.8 L evel of Concern for Margin of Exposure
................................ .................. 14 3.5.9 Recommendation for Aggregate Exposure Risk Assessments
................... 14 3.5.9 Recommendation for Aggregate Exposure Risk Assessments
................. 14 3.5.10 Classification of Carcinogenic Potential
................................ ................... 14 3.5.11 Summary

of Toxicological Doses and Endpoints for Trifloxysulfuron for Use in Human Risk Assessments
................................ ................................ .......... 15 3.6 Endocrine disruption
................................ ................................ ................................ .. 16 4.0 Public Health and Pesticide Epidem iology Data
................................ .......................... 17 5.0 Dietary Exposure/Risk Characterization
................................ ................................ ..... 17 5.1 Pesticide Metabolism and Environmental Degradation
................................ ........ 17 5.2 Drinking Water Residue Profile
................................ ................................ ............ 18 5.3 Food Residue Profile
................................ ................................ ............................. 18Page 3 of 35

5.4 International Residue Limits
................................ ................................ ................. 20 5.5 Dietary

Exposure and Risk
................................ ................................ ................... 21 5.6 Anticipated Residue and Percent Crop Treated (%CT) Information
.................... 22 6.0 Residential (Non - Occupational) Exposure/Risk Characterization
............................ 22 6.1 Other (Spray

Drift, etc .)
................................ ................................ ........................ 22 7.0 Aggregate Risk Assessments and Risk Ch aracterization
................................ ............ 22 8.0 Cumulative Risk Characterization/Assessment
................................ ........................... 23 9.0 Occupational Exposure/Risk Pathway
................................ ................................ .......... 23 10.0 Data Needs and Label Recommendations
................................ ................................ .... 25 10.1 Toxicology
................................ ................................ ................................ ............ 25 10.2 Residue Chemistry
................................ ................................ ................................ 25 10.3 Occupational and Residential Exposure
................................ ............................... 27 References
................................ ................................ ................................ ................................ .... 27 Appendix A. Toxicology Database Summary
................................ ............................. 29 A.1 Toxicology

Data Requirements
................................ ................................ ............ 29 A.1 Toxicicty

Profile Table for Nicosulfuron
................................ ............................. 30 A.3 Rationale for Toxicology Data Requirements
................................ ...................... 34Page 4 of 35

1.0 Executive Summary DuPont is requesting establishment of permanent tolerances for residues of nicosulfuron in/on grass forage and hay , and in livestock commodities . In conjunction with th e petition, they are requesting Section 3 Registration for a 56.2% dry flowable (DF) formulation of nicosulfuron (PastoraTM Herbicide; EPA File Sy mbol 352
- IR O). This product is a multiple active ingredient (MAI) formulation which also contains metsulfuron
- methyl at 15%. Metsulfuron
- methyl is already registered for this use and has tolerances for grasses
. This document addresses the human health risks associated with nicosulfuron only
. A Section 18 emergency exemption for nicosulfuron on Bermuda grass was recently reviewed by

HED (W. Cutchin, D361732, 14 July 2009). Nicosulfuron shows low acute toxicity by all routes of exposure and showed only minimal toxicity in longer
- term studies. No neurotoxic or immunotoxic effects were seen in the available data, and developmental effects were seen onl y at high doses (and in the presence of significant maternal effects). In a chronic study with dogs, nicosulfuron affected body weight gain and relative organ weights. These effects are being used to assess nicosulfuron risks
. Toxicology studies are required in order for the toxicology database to be complete. D espite these data gaps, HED has sufficient information to evaluate the hazards associated with exposure to nicosulfuron and is recommending, based on the available data, that the FQPA factor remain at 1X as it has in previous assessments of this chemical. Adequate residue chemistry data are available to support tolerances for residues of nicosulfuron in/on grass commodities. The residue chemistry database is relativel y complete; however, HED is recommending that registration of the requested uses be made conditional, pending receipt and review of storage stability, residue decline, and rotational crop data. Furthermore, HED is recommending that revisions to the label , Section F, and the enforcement method be made prior to registration . A suitable method is available for tolerance enforcement , provided the recommended revisions are made
. Dietary risks from exposure to nicosulfuron are very low, even with highly

conservative assumptions regarding the degree and frequency of residue levels. As there are no r esidential uses of nicosulfuron, aggregate risk estimates are equivalent to the dietary risk estimates and are not of concern. Similarly , risk estimates associated with occupational exposure to nicosulfuron are not of concern. There are no risk issues that would preclude granting conditional registration for the requested uses or establishing permanent tolerances , with the tolerance expression specified in Section 10.2, on grass and livestock commodities as listed in Table 10
. Potential areas of enviro nmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations" htt p://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well
- established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.Page 5 of 35

Extensive data on food consumption patterns are compile d by the USDA under the Continuing Survey of Food Intakes by

Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . 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 postapplicat ion are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to b ys tanders and farm workers as well as lifestyl e and tradit ional dietary patterns among specific subgroups. This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These studies, which comprise the Pesticide Handlers Expo sure Database (PHED), have been determined to require a review of their ethical conduct, and have received that review. The studies in PHED are considered appropriate (ethicall y conducted) for use in risk assessments. Prior to registration, HED recommend s revised Sections B (directions for use) and F (proposed tolerances) and a revised anal yt ical method be submitted to OPP. As a condition of registration, residue chemistry data pertaining to storage stability , residue decline, and rotational crops should be submitted to the Agency
. S tudies to elucidate immunotoxicity , acute and subchronic neurotoxicity , inhalation toxicity , and dermal toxicity are also required
. Although these data are now required, the absence of these studies does not raise any additi onal concern at this time. 2.0 Ingredient Profile 2.1 Summary of Registered/Proposed UsesPage 6 of 35

Table 2.1. Summ ary of Directions for Use of Nicosulfuron . Applic. Timing, Ty pe , and Equip. Form

ulation [EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations 1 Bermuda grass Pastures and Hay Meadows Postemergence, Broadcast, Ground ( ≥10 gal/A) or aerial ( ≥2 gal/A) 56.2% DF

[352
- IRO ] 0.035
-

0.053 Not

specified (NS) 0.088 0 2 Application is to be made to Bermuda grass that has been established for at least one growing season, when broadleaf weeds are <4” tall or in diameter and grass weeds are <2” tall . Use of a spray adjuvant is required: NIS at 0.25%
- 0.5% v/v or COC at 1
- 2% v/v or a combination adjuvant containing NIS, COC, and/or ammonium nitrogen fertilizer. Switchgrass Grown in Tennessee Postemergence Broadcast, Ground ( ≥10 gal/A) or ae rial ( ≥2 gal/A) 56.2% DF

[352
- IRO ] 0.035 2 0.070 (im plied) 0.088 (general restriction) 0 2 Application is to be made

after the switchgrass has reached the 2
- leaf stage, when weeds are young and actively growing. Use of an NIS is required. 1 NIS = nonion ic surfactant; COC = crop oil concentrate. 2 The label states that there are no grazing or haying restrictions. Application through an y ty pe of irrigation s ys tem or to grasses grown for seed is prohibited. No retreatment intervals (RTIs) are specified. Use is prohibited in the following Colorado counties: Alamosa, Conejos, Costilla, Rio Grande, and Saquache. A 4
- hour re
- entry interval is specified. 2.2 Structure and Nomenclature Table 2.2 . Nicosulfuron Nom enclature
. Chemical structure

N O N C H 3 C H 3

S N H NH N N O

O C H 3 C H 3 O O O

Common name Nicosulfuron Com pany experimental name DPX
- V9360Page 7 of 35

Table 2.2 . Nicosulfuron Nom enclature
. IUPAC name 2
- (4,6
- dimethoxypyrimidin
- 2
- ylcarbamoylsulfamoyl)
- N,N
- dimethylnicotinamide; 1
- (4,6
- dimethoxypyrimidin
- 2
- yl)
- 3
- (3
- dimethylcarbamoyl
- 2
- py ridylsulfonyl )urea CAS name 2
- [[(4,6
- dimethoxypyrimidin
- 2
- yl)aminocarbonyl]aminosulfonyl]
-N,N
- dimethyl
3
- py ridinecarboxamide CAS registry number 111991
- 09
- 4 End
- use product (EP) 56.2% DF formulation (PastoraTM Herbicide; EPA File Symbol 352
- IRO) 2.3 Physical and Chemical Properties Table 2 .3 . Physicochemical Properties of Nicosulfuron . Parameter Value Reference Melting point/rang e 183.3 ± 0.3 °C MRID 47632204 pH 4.5 MRID 47632204 Density 1.441 ± 0.006 g/cm3 relative density MRID 47632204 Water solubility (25 °C) Anhydrous form (g/L) pH 5 = 0.36 pH 7 = 12.2 pH 9 = 39.1 Monohydrate form (g/L) pH 5 = 0.42 pH 7 = 7.4 pH 9 = 47.96 M RID 47632204
Solvent solubility (28 °C) Solubility g/L Acetone 18 Acetonitrile 23 Benzene 1.7 Chloroform 64 Dichloromethane 160 Dimethylformamide 64 Ethanol 4.5 Ethyl acetate 3.8 Hexane <0.02 Methanol 0.44 2
- Propanol 1.2 Tetrahydrofuran 2 6 Toluene 0.37 Xylenes 0.2 MRID 47632204

Vapor pressure (25 °C) 1.2 x 10 - 16 Torr MRID 47632204 Dissociation constant, pKa 4.22 MRID 47632204 Octanol/water partition coefficient, KOW at 25 °C pH 5 = 0.44 pH 7 = 0.02 pH 9 = 0.007 MRID 47632204 UV/vis ible absorption spectrum No absorbance maxima at or above 290 nm at 20 °C for acid, basic, and neutral solutions. MRID 47632204 3.0 Hazard Characterization/Assessment This hazard characterization updates the previous assessment of November 30, 2004, prepared for the HED Chapter of the Tolerance Reassessment Eligibility Decision Document (TRED; DP Barcode D302694). No additional toxicology data have been received since that time.Page 8 of 35

3.1 Hazard and Dose - Res ponse Characterization 3.1.1 Database Summary 3.1.1.1 Sufficiency of studies/data B ased on the proposed use patterns, the toxicology database for nicosulfuron is adequate for risk assessment. There are acceptable studies available for endpoint selection that include: 1) subchronic oral toxicity

studies in rats, mice and dogs; 2) a chron ic oral toxicity study in dogs and chronic/ carcinogenicity studies in rats and mice; and 3) developmental and reproduction studies in rats and a developmental study in rabbits; 4) a complete mutagenicity battery , and 5) a general metabolism study in the rat. As part of the new 40 CFR Part 158, additional studies are required to satisfy guideline data requirements for registration of nicosulfuron. These include a rat or rabbit 21/28 day dermal study , rat acute and subchronic neurotoxicity studies, as wel l as an immunotoxicity study in rats and/or mice. In addition, a rat 28
- day inhalation toxicity

study is required to assess risk from inhalation exposure. Although additional studies are required to satisfy current guideline requirements, an additional 1 0x database uncertainty factor is not needed at this time as the available studies indicated no potential immunotoxic or neurotoxic effects, nor concerns for increased pre
- and/or postnatal developmental susceptibility . Inhalation and dermal exposure may be assessed using oral studies and a default assumption of 100% absorption. The rationales for the additional studies are provided in Appendix A.3 of this assessment. 3.1.1.2 Mode of action, metabolism, toxicokinetic data Nicosulfuron is an herbicide belonging to the sulfonylurea class of chemicals. The pesticidal mode of action for nicosulfuron is through inhibition of the plant enzy me acetolactate s ynthase. Inhibition of thi s enzy

me blocks branch
- chain amino acid biosy nthesis involved in plant growth processes which leads to death of the plant. Acetolactate s ynthase is not found in humans or other mammals. In the rat, nicosulfuron shows poor oral absorption and limited metabolism, with most of the administered dose excreted in the feces as unchanged parent compound within 24 hrs. Minor metabolites were identified as h ydrolytic cleavage/oxidation products of the parent. There were no significant sex
- or dose
- related differe nces in metabolism. 3.1.2 Toxicological Effects Nicosulfuron is of low toxicity in animals by

all routes and durations of exposure. It is of minimal or low toxicity

(Category

III or IV) in the acute lethality and irritation studies and is not a dermal sensitizer. Consistent target organs were not identified in repeated dosing studies. Subchronic or chronic dietary administration of doses exceeding the limit dose did not produce adverse effects in rats or mice. Chronic dietary administration to dogs produced mild effects (decreased body weight gains in males; increased relative liver and kidney weights) at the limit dose. No findings were reported in dogs following subchronic dosing at comparable dietary levels. There were no indications of neurotoxic or immunotoxic effects. No dermal or inhalation studies have been submitted.Page 9 of 35

Developmental effects were not observed in the rat developmental toxicity study . In rabbits, maternal toxicity

included clin ical signs, decreased body weight gain during dosing and increased abortions. Developmental toxicity was observed at maternall y toxic levels only (postimplantation loss and decreases in fetal body weight). In the rat reproductive toxicity study , decrease d live litter size and decreased pup weight at day 14 to 21 were observed in the F2a offspring at doses that were maternall y toxic and exceeded the limit dose. In the available toxicity studies, there was no evidence of estrogen
- , androgen
- and/or th yro id
- mediated toxicity
. Nicosulfuron is not likely to be carcinogenic based on negative bioassay s in the rat and mouse and lack of effects in the in vitro and in vivo genotoxicity studies. Based on the hazard and exposure data available for nicosulfuron, there are low concerns for pre
and/or postnatal susceptibility and no residual uncertainties with regard to pre and/or postnatal toxicity . Therefore, HED recommends reduction of the FQPA Safety Factor to1x. 3.1.3 Dose - response Due to the lack of observed effects in the database as a whole, the studies suitable for selection of endpoints for risk assessment were limited to the rabbit developmental study and the dog chronic study. Maternal effects in the rabbit dev elopmental study consisted of vaginal discharge, staining of hair in the rectal and vaginal areas, decreased body weight gain during the dosing period, and late abortion. Developmental effects consisted of an increase in percentage postimplantation loss at 500 mg/kg/day and decreased fetal body weight at 1000 mg/kg/day . The maternal and developmental NOAELs were 100 mg/kg/day . Effects in the chronic dog study were limited to decreased body weight gain in males and increases in liver and kidney weight at the L OAEL of 500 mg/kg/day , with a NOAEL of 125 mg/kg/day
. Although these two oral studies were of different dosing durations (one year in the case of the chronic dog study, and gestation days 7
- 19 in the rabbit developmental study) , they had similar NO AELs and LOAELs. The slight difference in NOAELs (125 vs.100 mg/kg/day) is a result of dose
- spacing rather than actual differences in toxicity , and the LOAELs for each study (both 500 mg/kg/day) were significantly higher than the NOAEL s. The chronic dog study NOAE L of 125 mg/kg/day

was selected for all risk assessment scenarios of all exposure routes and durations as a more realistic NOAEL, supported b y the rabbit developmental toxicity study . It is considered protective of potential pre
- and/or postnatal toxicity based on observation of developmental effects in the rabbit at a much higher LOAEL (500 mg/kg/day). Each exposure scenario is discussed as follows: Acute Dietary Endpoint (all populations) : No effects were considered attributable to a single day ’s exposure; therefore, an assessment was not performed. Chronic Dietary

Endpoint (all populations): The NOAEL of 125 mg/kg/day from the chronic oral toxicity

study in the dog was selected, where decreased body weight gain in males and increased relative liver and kidney weights were observed at the LOAEL of 500 mg/kg/day . The study is of an appropriate route and duration for this assessment. The FQPA S afety F actor is discussed below in Section 3.3.Page 10 of 35

Residential Exposure : Endpoints for residential exposure were not selected because there are presentl y no residential uses. Short
- and Intermediate
- Term Occupational Dermal and Inhalation : The NOAEL of 125 mg/kg/day

from the dog chronic oral study was selected for all occupational exposure scenarios. The rationale for this selection is discussed above. For both dermal and inhalation exposure, a default absorption factor of 100% of oral absorption was applied since an oral study was selected and dermal/inhalation absorption data were not available. C arcinogenicity : Nicosu l furon is classified as “not likely to be carcinogenic to humans” based on lack of tumorigenic effects in rodent (rats and mice) bioassay s at the limit doses. Nicosulfuron was not mutagenic in in vitro and in vivo genotoxicity assay s. Therefore there is no cancer risk associated with the proposed new use. MOE for Occupational/Residential Risk Assessments : A MOE of 100 (10x for interspecies extrapolation and 10x for intraspecies variation) is adequate for this assessment. No addi tional safety factors were included to account for data gaps (subchronic dermal and inhalation toxicity, neurotoxicity , immunotoxicity ) because the database as a whole indicated low toxicity and there was no evidence of neurotoxicity or immunotoxicity

in the available studies. 3.1.4 FQPA Reduction of the FQPA SF to 1x is recommended. Although a number of studies now required under 40 CFR Part 158 are not available, the database is adequate for the purpose of this risk a ssessment. Developmental toxicity studies in two species and a rat multigeneration reproductive toxicity

study are available. Nicosulfuron is poorly absorbed and toxicity

is generall y low. Increased quantitative or qualitative pre
- and/or postnatal susc eptibility was not observed. There were no effects in the rat developmental toxicity study , and developmental toxicity in rabbits (postimplantation loss, decreased fetal body weight) was observed onl y in the presence of maternal toxicity , which included a bortions, clinical signs and decreased body weight gain. Reduced live litter size and pup weight during lactation was observed in the rat reproductive toxicity

study at the maternal LOAEL. There was no evidence of neurotoxicity or immunotoxicity

in the available studies. There are currently no residential uses and exposure assessments will not underestimate risks. 3.2 Absorption, Distribution, Metabolism, Excretion (ADME) Upon oral administration, nicosulfuron is poorly absorbed. In the rat, most of the administered dose was excreted as unmetabolized parent compound, primarily via the feces (total fecal excretion 80
- 95%) and a lower percentage was excreted in the urine ( total urinary excretion 9
- 20%). When administered intravenously , urinary excretion was higher (76 to 80% of administered dose) and fecal excretion was lower (9 to 20% of dose). Excretion via exhaled CO 2 was negligible (<0.01% of dose). Radioactivity was not retained in tissues at significant levels ( ≤0.5% of dose). Minor metabolites of hydroly tic and oxidative metabolism were identified. In addition to unchanged parent compound, p yridinesulfonamide (N, N
- dimethyl
- 2
- sulfonamidePage 11 of 35

py ridine
- 3
- carboxamine) w as identified in the urine (1.1 to 5.7% of dose) and py ridine acid sulfonamide (2
- sulfonamidepy ridine
- 3
- carbox yl ic acid) was tentativel y identified as a minor metabolite in feces of orally dosed rats and urine of intravenousl y dosed rats. The poor oral ab sorption is consistent with the low toxicity observed in available studies. 3.3 FQPA Considerations 3.3.1 Adequacy of the Toxicity Database The database is adequate to characterize potential pre
- and/or post
- natal risk for infants and children. Acceptable/guideline studies for developmental toxicity in rats and rabbits, and reproduction in rats are available for FQPA assessment. 3.3.2 Eviden ce of Neurotoxicity Acute and subchronic neurotoxicity screening studies have not been submitted. However, there was no evidence of neurotoxicity from exposure to nicosulfuron in the available studies. 3.3.3 Developmental Toxicity Studies In the rat developmental toxicity study (MRID 41082608, 41360122), no maternal or developmental toxicity

was observed at gavage doses up to 6000 mg/kg/day , a dministered from gestation day s 7 through 16 to 25 pregnant Crl:CD BR rats/dose group. Dose groups were 0, 200, 1000, 2500 or 6000 mg/kg/day (in 20 mL/kg 0.5% methylcellulose suspension). In the rabbit developmental study (MRID 41082609, 41360121), 20 pr egnant New Zealand White females/dose group were administered nicosulfuron at 0, 100, 500, 1000 or 2000 mg/kg/day

by gavage (10 mL/kg in 0.5% methylcellulose suspension) from gestation day s 7 through 19. Maternal toxicity was observed at 500 mg/kg/day bas ed on clinical signs, vaginal discharge, abortion, decreased body weight gain during dosing and an apparent increase in percent postimplantation loss. The NOAEL was 100 mg/kg/day . Developmental effects were seen at ≥500 mg/kg/day

as decreased mean fetal body weight and postimplantation loss. 3.3.4 Reproductive Toxicity Study In a two
- generation reproductive toxicity study (41360101), nicosulfuron was administered continuously

in the diet to Crl:CD BR rats (30/sex/dose) at 0, 250, 5000 or 20,000 ppm (equivalent to average daily doses of 0, 14.4
- 16.7, 289
- 338, 1203
- 1428 mg/kg/day in males and 0, 15.5
- 20.0, 287
- 390 or 1265
- 1604 mg/kg/day , females) throughout premating, gestation and lactation. Parental toxicity was observed at 1265 mg/kg/day as decreased body

weight gain in the F1 females during the last week of gestation. Offspring/reproductive toxicity was observed in F2a offspring at 1265 mg/kg/day as decreased litter size at birth and decreased pu p weights at postpartum day

14 through 21.Page 12 of 35

3.3.5 Additional Information from Literature Sources A literature search was not conducted for this risk assessment. 3.3.6 Pre - and /or Postnatal Toxicity 3.3.6.1 Determination of Susceptibility In creased quantitative or qualitative pre
- and/or postnatal susceptibili ty was not observed in the developmental toxicity

studies in rats or rabbits. Developmental effects were onl y observed at doses that caused maternal toxicity
. 3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre - and/or Postnatal Susc eptibility Considering the overall toxicity database and the doses selected for risk assessment, the degree of concern for quantitative or qualitative pre
- and/or postnatal susceptibility is low and there are no residual uncertainties. Absorption of nicosulfuron via the oral route is poor and toxicity overall is low. Although acute and subchronic neurotoxicity studies and an immunot oxicity study have not been submitted, there is no evidence for either ty pe of toxicity in the available studies. The rat and rabbit developmental toxicity and rat reproductive toxicity studies adequatel y characterized developmental/reproductive effects. 3.3.7 Recommendation for not requiring a Developmental Neurotoxicity Study Based on the lack of evidence of neurotoxicity or increased quantitative or qual itative pre
- and/or postnatal susceptibility , a developmental neurotoxicity study is not warranted at this time. 3.4 FQPA Safety Factor for Infants and Children Reduction of the specia l FQPA SF to 1x is recommended, based on the following:

- T he database is adequate for conducting this risk assessment, and includes acceptable developmental toxicity

studies in the rat and rabbit and a rat reproductive toxicity study
.

- Nicosulfuron is poorly absorbed and toxicity

is low in the available studies.

- In creased quantitative or qualitative pre
- and/or postnatal susceptibility was not observed in either rats or rabbits.

- There is no evidence of neurotoxicity or immunotoxicity in the submitted studies
.

- The re are no concerns and no residual uncertainties with regard to assessment of pre - and/or postnatal toxicity
.

- There are no residential uses and exposure assessments will not underestimate risks
. 3.5 Hazard Identification and Toxicity Endpoi nt Selection 3.5.1 Acute Reference Dose (aRfD)

– General PopulationPage 13 of 35

No appropriate endpoint attrib utable to a single dose was identified in the toxicity database. 3.5.2 Acute Reference Dose (aRfD) - Females age 13 - 49 No appropriate endpoint attributable to a single dose was identified in the toxicity database. 3.5.3 Chronic Reference Dose (cRfD ) - All Populations Studies Selected: Chronic Oral Toxicity
- Dog MRID No: 41360102 Dose and Endpoint for Risk Assessme nt : NOAEL= 125 mg/kg/day , based on decreased body weight gain in males and increased relative liver and kidney weights at 500 mg/kg/day
. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Chronic RfD = ) ( 100 / / 125 UF day

kg mg = 1.25 mg/kg/day Comments about Study/Endpoint/Uncertainty Factors: The study selected for this risk assessment is of the appropriate route (oral) and duration (one
- ye ar) for chronic oral exposure. The NOAEL of 125 mg/kg/day represents the mo st sensitive endpoint for this exposure duration. The endpoint is supported by the maternal toxicity

NOAEL/L OAEL of 100/500 mg/kg/day

from the rabbit developmental toxicity study . The slight difference in NOAELs (125 vs. 100 mg/kg/day) is a result of dos e - spacing rather than actual differences in toxicity and the LOAELs for each study (both 500 mg/kg/day) were significantl y higher than the NOAELs. The chronic endpoint was therefore selected as a more realistic endpoint. The selected endpoint is also pro te ctive of developmental effects, which were observed in the rabbit at ≥500 mg/kg/day
. 3.5.4 Incidental Oral Exposure There are no proposed or registered residential uses; therefore exposures and risks v ia this route are not of concern , and points of departure for residential exposure scenarios have not been selected at this time. 3.5.5 Dermal Absorption There are no dermal toxicity or dermal absorption stud ies available for nicosulfuron. Therefore, a default dermal absorption factor of 100% is assumed for risk assessment using endpoints derived from an oral study
. 3.5.6 Short - and Intermediate - Term Occupational Dermal and Inhalation Exposure Studies Selected: Chronic Oral Toxicity
- DogPage 14 of 35

MRID No: 41360102 Dose and Endpoint for Risk Assessment: NOAEL= 125 mg/kg/day , based on decreased body weight gain in males and increased relative li ver and kidney weights at 500 mg/kg/day
. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: Although the study is of chronic duration, it was selected because the stu dies suitable for endpoint selection for nicosulfuron were limited to the chronic dog study (NOAEL/LOAEL of 125/500 mg/kg/day) and the rabbit developmental toxicity study (maternal NOAEL/L OAEL of 100/500 mg/kg/day). The rationale for selection of the chro nic dog NOAEL is discussed in Section 3.5.3. 3.5.7 Level of Concern for Margin of Exposure Table 3. 5 . 7 . Summary of Levels of Concern for Risk Assessment. Route Short
- Term (1
- 30 Days) Intermediate
- Term (1
- 6 Months) Long
- Term (> 6 Months) Occupational (Worker) Exposure Dermal 100 100 N/A Inhalation 100 100 N/A Residential Exposure Dermal N/A N/A N/A Inhalation N/A N/A N/A Incidental Oral N/A N/A N/A N/A Not applicable (risk assessment not required due to use patterns) 3.5.8 Recommendation for Aggregate Exposure Risk Assessments As per FQPA, 1996, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. However, an aggregate risk assessment across the three routes of exposure is not required for nicosulfuron since there are no registered or proposed residential uses. For occupational risk assessments, dermal and inhalation exposures should be combined since the same endpoint and NOAELhave been sel ected for these exposure routes. 3.5.9 Classification of Carcinogenic Potential There were no treatment
- related increases in tumors in rat and mouse carcinogenicity studies on nicosulf uron. Nicosulfuron did not show genotoxic potential in a battery of genotoxicity

studies. Nicosulfuron is classified as “Not likely to be Carcinogenic to humans.”Page 15 of 35

3.5.10 Summary of Toxicological Doses and Endpoints for Nicosulf uron for Use in Human Risk Assessments Table 3. 5 . 10 . a Summ ary of Toxicological Doses and Endpoints for Nicosulfuron for Use in Dietary and Non Occupational Hum an Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects
Ac ute Dietary ( All p opulation s , including I nfants and Children and Females 13
- 49 years of age ) An endpoint of concern attributable to a single dose was not identified
.

Chronic Dietary (All Populations) N OAEL= 125

mg/kg/day UF A= 10x

UF H = 10x FQPA SF= 1 x Chronic RfD =

cPAD = 1.25 mg/kg/day Oral tox icity

– dog

NOAEL = 125 mg/kg/day based upon decreased body weight gain in males and the statistically significant increase in the relative liver and kidney weights of males at the LOAEL of 500 mg/kg/day
. Supported by the NOAEL of 100 mg/kg/day/LOAEL 500 m g/kg/day in the rabbit developmental toxicity study. Incidental Oral This risk assessment is not required. There are no residential uses of nicosulfuron. Dermal (all durations) This risk assessment is not required. There are no residential uses of ni cosulfuron. Inhalation (all durations) This risk assessment is not required. There are no residential uses of nicosulfuron. Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on lack of tumori genic effects

in rodent (rats and mice) bioassays at the limit doses and lack of mutagenic effects in the in vitro and in vivo genotoxicity assays. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose
- response data and us ed to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. LOC = level of concern. N/A = not applicable.Page 16 of 35

Table 3. 5 . 10 . b Summary of Toxicological Doses and Endpoints for Nicosulfuron for Use in Occupational Hum an Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD , Level

of Concern for Risk Assessment Study and Toxicological Effects

Dermal (short
and intermediate
term) NOAEL=125

mg/kg/day DAF = 100% (default) UF A= 10x

UF H = 10x Occupational

LOC for MOE < 100 Oral toxicity

– dog

NOAEL = 125 mg/kg/day based upon decreased body weight gain in males and the statistically significant increase in the relative liver and kidney weights of males administered 500 mg/kg/day (L OAEL)
. Supported by the NOAEL of 100 mg/kg/day/LOAEL 500 mg/kg/day in the rabbit developmental tox icity study.

Inhalation (short
- and intermediate
term) NOAEL=125

mg/kg/day IAF = 100% (default) UF A= 10x

UF H = 10x Occupational

LOC for MOE < 100 Oral toxicity

– dog

NOAEL = 125 mg/kg/day based upon decreased body weight gain in males and the statisticall y significant increase in the relative liver and kidney weights of males administered 500 mg/kg/day ( LOAEL for the test material )
. Supported by the NOAEL of 100 mg/kg/day/LOAEL 500 mg/kg/day in the rabbit developmental toxicity study. Cancer (oral, dermal , inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on lack of tumori genic effects

in rodent (rats and mice) bioassays at the limit doses and lack of mutagenic effects in the in vitro and in vivo genotoxicity assays. Point of D eparture (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 adv erse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). F QPA 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. DAF = dermal absorption factor. IA F = Inhalation absorption factor. 3.6 End ocrine disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) “may have an effect in humans that is similar to an effect produced b y a naturall y occurring estrogen, or other such endocrine effects as the Administrator may designate.” Following recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thy roid hormone s ys tems, in addition to the estrogen hormone sy stem. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may

help determine whether a substance may have an effect in humans,Page 17 of 35

FFDCA authority

to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone s ys tems may be added to the Endocrine Disruptor Screening Program (EDSP). When additional appropriate screening and/or testing protocols being considered under the Agency ’s EDSP have been developed, nicosulfuron may be subjected to further screening and/or testing to better characterize effects related to endocrine disruption. In the available toxicity studies, there was no evidence of estrogen
- , androgen
- , and/or th yroid
- mediated to xicity
. 4.0 Public Health and Pesticide Epidemiology Data No public health or pesticide epidemiological data were used in this risk assessment 5.0 Dietary Exposure/Risk Characterization 5.1 Pesticide Metabolism and Environmental Degradation The metabolism of 14 C
- nicosulfuron was studied in male and female rats. Following oral dosing, most of the radioactivity

was excreted unchanged within 24 hours. Elimination in the feces accounted for 80 to 95% of the dose, and elimination in the urine accounted for 9 to 20%. Elimination of 14 CO 2 was negligible (<0.01 of the administered do se). Following intravenous administration, approximately 76 to 80% of the dose was eliminated in the urine and 27 to 30% in the feces. Residues in tissues accounted for 0.05 to 0.5% of the dose. The major excretion product in urine and feces was unchang ed parent compound. In addition, py ridine sulfonamide (N, N
- dimethyl
- 2
- sulfonamide py ridine
- 3
- carboxamide) was detected in the urine and accounted for 1.1 to 5.7% of the dose. Py ridine acid sulfonamide (2
- sulfonamidep yri dine
- 3
- carbox yl ic acid) was tentat ivel y identified as a minor metabolite in the feces of orall y dosed rats , and in the urine of intravenousl y dosed rats. These metabolites represent h ydrol yt ic cleavage/oxidation of the parent molecule. The metabolic pathway

of nicosulfuron in plants is s imilar to its pathway in rats. Based upon the results of the nicosulfuron metabolism study in corn, the metabolism of nicosulfuron proceeds predominantl y via two mechanisms: the hydrol ys is of the sulfon ylurea bridge yi elding py ridine sulfonamide and py ri midine amine, and the hydroxylation of nicosulfuron at the 5
- position of the py

rimidine amine followed b y glucosidation (in earl y forage samples). The anal ys es show that nicosulfuron gradually decreases during the corn growing season and is present in very low levels at maturity . However, residues of the metabolite py ridine sulfonamide begin at day

0 and are detected in the whole plant and stalk at maturity (113 day PHI ) exceeding residues of nicosulfuron. Py rimidine amine is further metabolized to its 5
- hydrox y derivative and its glucoside, but is not detected in the whole plant (49 day PHI) or in fodder or stover (113 day PHI )
. The metabolic pathway

of nicosulfuron in livestock also appears to be similar to that in rat s and plant s . The likely

metaboli c pathway

for nicosulfuron in livestock is hydroly sis of the sulfonylurea bridge to yi eld py ridine sulfonamide and py rimidine amine (both of which undergo additional metabolism), N
- demeth yl ation and subsequent loss of sulfur dioxide leading to anPage 18 of 35

unidentif ied cyclized compound; and oxidation and conjugation at the 5
- position of the py rimidine ring. Table 5.1. Summary of Metabolites and Degradates to be included in th e Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Nicosulfuron Nicosulfuron Rotational Crop Nicosulfuron Nicosulfuron Livestock Ruminant Not Applicable Not Applicable Poultry Not Applicable Not Applicable Drinking Water Nicosulfuron Not A pplicable 5. 2 Drinking Water Residue Profile The Environmental Fate and Effects Division (EFED) has not provided HED with an updated anal ys is of nicosulfuron concentrations in drinking water. Estimated drinki ng water concentrations (EDWCs) based on the use pattern for corn were provided previously by EFED ( L
. Liu, D301842, 28 July 2004) and are summarized below. HED is assuming, based on the similarity of the use pattern, that EDWCs based on the requested use on grass will not exceed those derived from the u se on corn . EFED present ed the Tier I EECs for nicosulfuron, estimated using the models FIRST for surface water and SCIGROW for groundwater in the human health risk assessment. For nicosulfuron, the surf ace water chronic (average 56
- day) value is 0.685 ppb based on the application on corn. The groundwater screening concentration is 0.056 ppb for nicosulfuron. The highest result of the two models, surface water at 0.685 ppb, should be used for water, all sources (both indirect and direct). The water model estimates were placed in all water food forms, both indirect and direct, for the aggregate food + water assessment. Table 5 .2 . Summ ary of Estimated Surface and Ground Water Concentrations for Nicosul furon. Exposure Duration Concentration, ppb Surface Water a Ground Water b Ac ute N/A N/A Chronic (non
- cancer) 0.685 0.056 Chronic (cancer) N/A N/A a From the Tier I FIRST b From the SCI
- GROW model 5. 3 Food Residue Profile W. Drew , D360897.Page 19 of 35

The submitted residue data for grass forage and hay are tentativel y acceptable. The number and location of field trials are in accordance with OPPTS Guideline 860.1500 for grasses. The study reflects the maximum proposed use pattern for grass, and samples were analyzed for nicosulfuron, the residue of concern, as well as its metabolite IN
- V9367, using an acceptable method. However, additional storage stability and residue decline data are required to support the study . Per OPPTS 860.1500, residue decline data are required when a pesticide is applied when the edible portion of the crop has formed, and it is clear that residues may occur on the food or feed commodities at, or close to, the earliest harvest time. HED notes that IN
- V9367 is not a residue of concern. Pending submission of outstanding concurrent storage stability data (see section 860.1380) and a single residue decline trial conducted according to the maximum proposed use pattern, the available field trial data will support tolerances for residues of nicosulfuron only in/on grass forage at 9.0 ppm and grass hay at 25 ppm. The residues are summarized in Table 5.3, below , and the proposed and recommended tolerance levels (based on the NAFTA Harmonization Spreadsh eet) are summarized in Table 5.5
. Table 5.3 . Summ ary of Residue Data fromCrop Field Trials with Nicosulfuron. Crop Matrix Treatment;

Total Applic. Rate (lb ai/A) PHI 1

(days) Residue Levels (ppm)

n Min. Max. HAFT 2 Median Mean Std. Dev. G rass (pr oposed use =0.088 lb ai/A total application rate, 0 - day PHI Nicosulfuron (data for IN - V9367 are not shown) Grass forage 1 application;

0.056
- 0.061 0 24 0.032 5.7 5.0 3.7 3.5 1.3 Grass hay 0 (2
- 8) 24 0.11 10 9.3 6.2 5.5 3.2 Grass forage (2 nd cutting) 2 applications;

0.085
- 0.091 0 24 0.53 3.6 3.6 1.9 1.8 0.1 Grass hay (2 nd cutting) 0 (2
- 7) 24 1.6 7.3 5.9 3.0 3.4 1.5 Grass forage 1 application;

0.088
- 0.092 0 24 3.4 8.2 7.7 5.4 5.6 1.1 Grass hay 0 (2
- 8) 24 0.26 18 18 12 10 4.3 1 For hay, days dried in the field are reported in parentheses. 2 HAFT = Highest Average Field Trial. The submitted dairy

cow feeding study

is tentatively

acceptable, provided the outstanding storage stability

data confirm that residues of nicosulfuron and IN
- V9367 are stable in tissues stored frozen for up to 9.4 months. The petitioner has indicated that the storage stability study has been initiated. Samples were anal yz ed for residues of nicosulfuron, the residue of concern, as well as for residues of metabolite IN
- V9367 u sing an acceptable method. Dosing was done at levels of 20, 50, 150, and 500 ppm in the feed. The lowest dosing level corresponds to 1.2x the dietary burden for dairy

cattle, and the highest dosing level corresponds to 30x the dietary burden for dairy

cattle. Detectable residues of nicosulfuron were observed at feeding levels of 50, 150, and 500 ppm in milk, skim milk, and cream and in tissues at all feeding levels except in fat at the 20
- ppm feeding level. Residues did not concentrate in cream.Page 20 of 35

If the residues observed at the various dosing levels are adjusted to a 1x feeding level for dairy cattle, maximum expected residues of nicosulfuron would be 0.007 ppm for milk, 0.013 ppm for liver, 0.053 ppm for kidney , 0.008 ppm for muscle, and 0.008 ppm for f at. The data indicate that tolerances are needed for milk, and the meat and fat of cattle, goat, horse, and sheep at the LOQ of 0.01 ppm and for meat by products at 0.05 ppm. A tolerance is not needed for milk fat because residues did not concentrate in c ream. A revised Section F should be submitted to the Agency
. 5. 4 International Residue Limits Neither Codex Alimentarius Commission, Canada, n or Mexico have established maximum residue limits (MRL s) for residues of nicosulfuron in/on grasses. Tolerance harmonization is n ot an issue for this petition. 5.5 Recommended Tolerances Recommended tolerance levels (Table 5.5) are derived from the submitted residue data and the NAFTA Tolerance/MRL Harmonization Spreadsheet. Pending revisions recommended during the independent laboratory validation (ILV) and submission of supporting data for the validation of the method in egg , Methods DuPont
- 17928 and DuPont
- 17927 are acceptable for t olerance enforcement of nicosulfuron residues in/on plants and livestock, respectively
.Page 21 of 35

Table 5.5 . Tolerance Summary for Nicosulfuron. Commodity Proposed T olerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition Grass, forage 9 .0 9.0 Grass, hay 25.0 25 Cattle, fat 0.05 0.01 Cattle, meat byproducts 0.05 0.05 Cattle, meat 0.05 0.01 Goat, fat 0.05 0.01 Goat, meat byproducts 0.05 0.05 Goat, meat 0.05 0.01 Hog, fat 0.05 Not needed Tolerances are not needed for hog commodities because there are no swine feed items associated with the proposed use on grasses, and the dietary burden for swine (resulting from use on corn) is substantially lower than that for ruminants. Hog, meat byproducts 0.05 Hog, meat 0.05

Hors e, fat 0.05 0.01 Horse, meat byproducts 0.05 0.05 Horse, meat 0.05 0.01 Milk 0.05 0.01 Milk, fat 0.02 Not needed A tolerance is not needed because residues do not concentrate in cream. Sheep, fat 0.05 0.01 Sheep, meat byproducts 0.05 0.05 She ep, meat 0.05 0.01

5. 6 Dietary Exposure and Risk A chronic combined dietary (food + drinking water) exposure and risk assessment was conducted using the Dietary Exposure Evaluation Model DEEM
- FCIDTM, Version 2.03 which use food consumption data from the U.S. Department of Agriculture’s Continuing Survey s of Food Intakes by

Individuals (CSFII) from 1994
- 1996 and 1998. The analysis was completed to evaluate a requested use on grasses. Although the action does not affect any human foods directly , the use, if granted, will result in new tolerances for residues in meat and milk commodities. No hazards associated with acute dietary exposure were identified for nicosulfuron; therefore, only a chronic evaluation was con ducted. The analy sis assumes tolerance
- level residues and 100% crop treated for all foods (corn, meat, and milk commodities). Even with these highl y conservative assumptions, the resulting risk estimates are less than 1% of the chronic population
adjuste d dose (cPAD) for all population subgroups (Table 5. 6 ) . Generall y HED is concerned when risk estimates exceed 100% of the cPAD. Nicosulfuron is not a carcinogen; therefore,Page 22 of 35

there are no cancer concerns associated with this herbicide. There are no dietary exposure considerations that would preclude granting the requested use. Table 5. 6 . Summ ary of Dietary ( Food + Drinking Water ) Exposure and Risk for Nicosulfuron. Population Subgroup Ac ute ( 95th Percentile) Chronic Cancer Exposure (mg/kg/day) % aPAD Exposure (mg/kg/day) % cPAD Exposure (mg/kg/day) Risk General U.S. Population

N/A N/A 0.000300 <1

N/A N/A All Infants (< 1 year old) 0.000454 <1 Children 1 - 2 years old 0.000835 <1 Children 3
- 5 years old 0.000766 <1 Children 6
- 12 years old 0.000540 <1 Youth 13
- 19 years old 0.000362 <1 Adults 20
- 49 years old 0.000225 <1 Adults 50+ years old 0.000151 <1 Females 13
- 49 years old 0.000226 <1 N/A = Not Applicable 5. 6 .1 Anticipated Residue and Percent Crop Treated (%CT) I nformation The asse ssment assumes tolerance
- level residues and 100% crop treated for all commodities
. 6.0 Residential (Non - Occupational) Exposure/Risk Characterization There are no residential uses fo r nicosulfuron; therefore, residential exposure is not a concern for this chemical. 6. 1 Other (Spray Drift, etc. ) Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application metho d employed for nicosulfuron
. The Agency

has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical b y chemi cal basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply

the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy is in plac e, the Agency

may impose further refinements in spray drift management practices to reduce off
- target drift with specific products with significant risks associated with drift. 7.0 Aggregate Risk Assessments and Risk Characterization As there are no residential uses for nicosulfuron, the only source of exposure will be via dietary exposure. Therefore, the aggregate risk estimate s are equivalent to the dietary risk estimates presented in S ection 5.5.Page 23 of 35

8.0 Cumulative Risk Characterization/Assessment 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 nicosulfuron and an y other substances , and nicosulfuron does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has assumed that nic osulfuron does not have a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP 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.g ov/pesticides/cumulative/. 9.0 Occupational Exposure/Risk Pathway Occ upational exposure and risk were evaluated in conjunction with a Section 18 assessment for nicosulfuron (M. Dow, D361732, 1 April 2009)
. That assessment evaluated risks associated with the activities listed in Table 9 .0. Handlers
. The margins of exposure associated with handler/applicator activities are all significantl y greater than 100 and, therefore, represent risks that are below HED’s level of concern. The April assessment is based on an application rate of 0.0527 lb a.i./A rather than the maximum rate of 0.088 lb a.i./A. The MOEs in Table 9 reflect the risk estimates at the maximum application rate.

1. Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”, Estimates of Worker Exposure from The Pesticide Handler Exposure Database Version 1.1, August 1998. Dermal = Single L ayer Work Clothing No Gloves; Single Layer Work Clothing With Gloves; Inhal. = Inhalation. Units = mg ai/pound of active ingredient handled. 2. Applic. Rate. = maximum value from draft label. Table 9. Summary of Short - Term Exposure s & Risk s for Occupational Handlers Applying Nicosulfuron to Berm udagrass .

Unit Exposure 1 mg ai/lb handled Applic. Rate 2 lb ai/unit Units

Treated 3 Avg. Daily Exposure 4

mg ai/kg bw/day MOE 5 Mixer/Loader - Dry Flowable - Open Pour Dermal: 0 .066 ( S ingle L ayer, No Glove s) Inhalation: 0.00077 0.0 88 lb ai/A 350 A/day Dermal: 0.029 Inhal ation: 0.000 3 4 , 2 00 Applicator - Ground

-boom - Open - cab Dermal: 0.014 ( S ingle L ayer, No Glove s) Inhal ation: 0.00074 0.0 88 lb ai/A 200 A/day Dermal: 0. 0035 Inhal ation: 0.0001 8 33,000 Aerial Applicator (Pilots not required to wear gloves) Dermal: 0.005 ( S ingle L ayer, No Glove s) Inhal. 0.000068 0.0 88 lb ai/A 350 A/day Dermal: 0.0022 Inhalation: 0.0000 30 56,000 Mixer/Loader/Applicator *

– ATV low - pressure handwand (based on wettable powder) Dermal: 8.6 (Single Layer, with Gloves ) Inhal ation: 1.1 0.0 88 lb ai/A 5 A/day Dermal: 0.054 Inhal ation: 0.00 68 2,000 Mixer/Loader/Applicator **

– Backpack sprayer Dermal: 2.5 Inhal ation: 0.03 0.0 88 lb ai/A 2 A/day Dermal: 0.0063 Inhal ation: 0.0000 75 19,000Page 24 of 35

3. Units Treated are taken from “Standard Values for D aily Acres Treated in Agriculture” ; ExpoSAC SOP No. 9.1. Revised 5 July 2000; Area for backpack derived from HED SOP; Area for ATV mounted sprayer wa s assumed in the previous assessment (M. Dow , D361732, 1 April 2009)
. 4. Average Daily Exposure = Uni t Exposure * Applic. Rate * Units Treated *100 % dermal absorption  70 kg Body Weight 5. MOE = Margin of Exposure = NOAEL  (dermal + inhalation exposure) . NOAEL = 125 mg ai/kg bw/day. * The unit exposure for M/L/A using an ATV is taken from the PHED for a M/L/A using open pour loading of wettable powder and a low
- pressure hand
- wand sprayer. Typically, ATVs are fitted with a spray tank and hand
wand sprayer. “Mini” ground booms are also used. However, use of the hand
- wand is likely to result in the greatest exposure and, thus , contributes to the most conservative (protective) estimate of risk. 5 acres per day is selected as the units treated per day. ** The unit exposure for a M/L/A using a backpack is based on PHED for open loading of liquids. T here are no PHED M/L/A data reflecting backpack and dry flowable granules. The data for handlers loading liquids are considered to be conservative/protective. The units treated are based on the spray volumes recommended. Ground spray volumes vary from 1 0
- 30 gpa. Therefore, at a median of 20 gpa spray volume and an Agency default of 40 gallons/day using backpack , the number of units treated is 2 acres per day. Post
- Application
. Itis possible for agricultural workers to have post
- application exposure t o pesticide residues during the course of typical agricultural activities. HED , in conjunction with the Agricultural Re
- entry Task Force (ARTF) , has identified a number of post
- application agricultural activities that may occur and which may

result in pos t - application exposures to pesticide residues. HED has also identified transfer c oefficients (TC) (cm2/hr) relative to the various activities which express the amount of foliar contact over time, during each of the activities identified (HED SOP 003.1, Agricultural Transfer Coefficients, Revised August 2000). The HED SOP does not reflect post
- application agricultural activity data with regards to grasses, per se . The database does contain information regarding “forage plants.” The highest TC listed is 1 ,100 cm 2 /hr for scouting. Since the requested applications of nicosulfuron are for earl y season (earl y post - emergence), scouting is expected to be the most likely post - application activity
. The small grains crops are also grasses. The highest TC for the small grains is also 1,100 cm 2 /hr for scouting. As a “screening” level assessment, the TC of 1,100 cm 2 /hr for scouting to assess efficacy of the treatment has been used. As no compound
- specific dislodgeable foliar residue (DFR) data have been submitted for nicosulfuron , HED assumes 20% of the application rate is available as dislodgeable foliar residue on day zero after application. This is adapted from the ExpoSAC SOP No. 003 ( 5/ 7 / 98
- Revised 8/7/ 00). The following may

be used to estimate post
- appl ication exposure : D islodgeable Foliar Residue (DFR)
- Surrogate = applic. rate * 20% * (1
- D) t * 4.54 x 10 8 μg/lb * 2.47 x 10 - 8 A/cm2

= 0. 088 lb ai /A * 0.20 * (1
- 0) 0 * 4.54 x 10 8 μg/lb * 2.47 x10 - 8 A/cm2 = 0. 197 μg/cm 2

. Average Dail y Dose (ADD) (mg a i /kg bw/day) = DFR μg/cm 2 * TC cm 2/hr * hr/day * 0.001 mg/μg * 1/ 7 0 kg bw = 0. 1 97 μg/cm 2 * 1,100 cm 2 /hr * 8 hr/day * 0.001 mg/μg  7 0 kg bw = 0.0 24 8 mg/kg bw/day
.Page 25 of 35

MOE = NOAEL  ADD = 125.0 mg/kg bw/day  0.0 2 48 mg/kg bw/day ≈ 5000
. A MOE of 100 is adequate to protect agricultural workers from post
- application exposures . The most conservative estimate (i.e., highest exposure/risk) of post
- application exposure results in MOEs > 100. Therefore, risks associated with the proposed use do not exceed HED’s l evel of concern. 10.0 Data Needs and Label Recommendations 10.1 Toxicology As part of the revised 40 CFR Part 158, these additional studies are required for registration of a pesticide:
• OPPTS Guideli ne 870.3200
- 21/28 Day Dermal Study

(Note: This study

is now required for food use chemicals under the updated 40CFR §158 data requirements. The route specific study eliminates the uncertainties associated with the use of an oral study and dermal absorp tion factors)
• OPPTS Guideline 870. 3250

– Subchronic (28
- day) inhalation study
. (Note: This study is now required for food use chemicals under the updated 40CFR §158 data requirements. The route specific study eliminates the uncertainties associated with the use of an oral study and dermal absorption factors)
• OPPTS Guideline 870
- 6200
- Acute and subchronic neurotoxicity studies.
• O PPTS Guideline 870.7800

– Immunotoxicity study
. HED recommends that these data be required as a condition of registration for the proposed new uses of nicosulfuron. 10.2 Residue Chemistry HED recommends that the following issues be addressed prior to registration : 860.1200 Directions for Use

 The petitioner should amen d the proposed label to include a retreatment interval; the submitted field trial data will support a minimum retreatment interval of 16 day s for grasses. 860.1340 Residue Anal yt ical Methods Plant commodities:  For method DuPont
- 17928 to be suitable for enforcement purposes, the petitioner should modify

the method to incorporate the changes identified by the method developer and those recommended by the ILV laboratory , and submit an updated version of the method. Prior to initiation of the ILV, the meth od developer relayed a number of minor revisions to the method. In addition, a number of questions concerning the method were forwarded b y the ILV laboratory and addressed by

thePage 26 of 35 method developer. Most of these questions pertained to minor issues; however, the following important issues were resolved: (1) the need for a refrigerated centrifuge or a means of preventing heating of the pellet above 35 °C during extraction to avoid degradation of the samples; (2) resolution of a typ ographical error in the se cond ion transition monitored for determination of IN
- V9367; (3) a change in the organic component of the mobile phase from 0.1 mM formic acid in 0.1 mM ammonium formate to 0.01 M aqueous formic acid; and (4) the decision to use a phenylhex yl column rather than a C18 column for sample analysis. The following modifications, interpretations, and critical steps were identified by the ILV laboratory : (1) use of the % purit y of the primary standard as a correction factor for determining the amount of standard in the stock solution; (2) hydration of the fortified hay

sample with 0.1 M ammonium carbonate solution for ~30 minutes prior to extraction with acetone/0.1 M ammonium carbonate as described in the method; (3) keeping the sample and sample extract cold during homogenization and centrifugation b y conducting homogenization on a bed of dry ice; (4) a change in the centrifuge speed; and (5) replacing the C18 column with a phenylhexyl column and adjusting the mobile phase. Livestock commodities:  For method DuPo nt - 17927 to be suitable for enforcement purposes, supporting raw data for method validation with egg should be submitted. In addition, the petitioner should modify

the method to incorporate the changes made during the ILV. The ILV laboratory

included a m ethod review, stating that the method procedures were clear and did not need interpretation, but noting the following: (1) the method does not include information concerning how to prepare egg samples; (2) insufficient information was provided concerning how to prepare post
- fortification samples to investigate whether matrix effect influenced recovery of nicosulfuron and IN
- V9367; (3) the method was not clear concerning whether an additional aliquot of extraction solution needs to be added for fat, kidney , liver, and meat following the first decanting step of extraction. 860.1550 Proposed Tolerances

 The 40 CFR section referenced in Section F should be revised to reflect the correct section for nicosulfuron: §180.454.

 A revised Section F should be submitted (see Table 10).

 T he proposed tolerances for milk, and the meat and fat of cattle, goat, horse, and sheep should be revised from 0.05 ppm to 0.01 ppm.

 The proposed tolerances for milk fat and hog fat, meat byproducts, and meat should be removed
.Page 27 of 35

Note to PM: According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the tolerance expression for nicosulfuron should be revised to state: “Tolerances are established for residues of nicosulfuron, including i t s metabolites and degra dates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only nicosulfuron [3 - pyridinec a rboxamide, 2 - ((((4,6 - dim ethoxypyrimidin - 2 - yl)aminocarbonyl) - aminosulfonyl)) - N,N - dimeth yl].” HED recommends that conditiona l reg istration for the requested use on grasses be converted to unconditional registration upon submission of the following residue chemistry data: 860.1380 Storage Stability Grass forage and hay :  The petitioner shou ld submit the final concurrent storage stability report reflecting storage stability

of nicosulfuron and IN
- V9367 in/on grass forage and hay stored frozen for up to 9.6 and 12.4 months, respectivel y. Livestock tissues:  The petitioner should submit the out standing storage stability study reflecting storage stability

of nicosulfuron and IN
- V9367 in livestock tissues stored frozen for up to 9.4 months. 860.1500 Crop Field Trials

 A single residue decline trial should be submitted for grass. The trial should be conducted according to the maximum proposed use pattern for grasses. 860.1900 Field Accumulation in Rotational Crops

 In consideration of the expanded use of nicosulfuron on grasses, HED now requires submission of a limited rotational crop study to de termine whether residues of nicosulfuron will occur in rotational crops under actual field conditions, and to establish appropriate rotational crop restrictions based on the maximum use pattern. The limited rotational crop trials should be conducted as sp ecified under OPPTS 860.1900 on representative crops of root and tuber vegetables, leafy

vegetables or soy

bean, and small grains, and should reflect an application rate of 0.088 lb ai/A. 10.3 Occupational and Residential Exposure None. References:Page 28 of 35

D360897 W. Drew, in preparation . Nicosulfuron. Petition Request for New Uses on

Grasses. Summary

of Analy tical Chemistry

and Residue Data
. D369742 M. Dohert y, 15 October 2009
. Nicos ulfuron

– Dietary Exposure and Risk Analy sis to Evaluate a New Use Request for Grasses. D361732 W. Cutchin, 14 July 2009. Nicosulfuron: Human Health Risk Assessment for Proposed Section 18 Use on Bermudagrass. D362708 M. Dow, 1 April 2009. NI COSULFURON

– Human Occupational

Exposure/Risk Assessment for the Proposed FIFRA Section 18 Use of Nicosulfuron on Bermudagrass Pasture and Hayfields in Oklahoma and Texas
.Page 29 of 35

Appendix A. Toxicology Database Summary A .1 Toxicology Data Requirements The requirements (40 CFR 158.340) for food uses of nicosulfuron are in Table 1. Use of the new guideline numbers does not imply that the ne w guideline protocols were used. 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 28
- Day

Inhalation Yes Yes Yes No Yes Yes Yes No

- No 870.3700a Dev elopmental 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 Oncogen icity (mouse) 870.4300 Chronic/Oncogenicity Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 870.5100 Mutagenicity

—Gene Mutation
- bacterial 870.5300 Mutagenicity

—Gene Mutation
- mammalian 870.5385 Mutagenicity

—Mammalian Bone Marrow Chromosome Aberration Aberrations 870.5550 Mutagenicity

— Unscheduled DNA Synthesis Yes Yes Yes Yes Yes Yes Yes Yes 870.6200a Acute Neurotoxicity Screening Battery (rat) 870.6200b 90
- Day

Neurotoxicity Screening Battery (rat) 870.6300 Developmental Neurotoxicity Yes Yes No No No

- 870.7485 General Metabolism 870.7600 Dermal Penetration 870.7800 Immunotoxicity Yes No Yes Yes

- No Special Studies for Ocular Effects

Ac ute Oral (rat) Subchronic Oral (rat) Six
- mo nth Oral (dog) No No No -

-

-Page 30 of 35

A.2 Toxicity Profile Table for Nicosulfuron Table A.2a. Acute Toxicity Profile

– Nicosulfuron Type of Study/Guide line Study Title MRID Results 870.1000 A cute Oral LD 50 , Rat (90.6% a.i.) 40924205 LD 50 (M/F) >5000 mg/kg Tox Category IV 870.1200 Ac ute Dermal LD 50 , Rabbit (90.6% a.i.) 40924207 LD 50 (M/F) >2000 mg/kg Tox Category III 870.1300 Ac ute Inhalation Toxicity, Rat (90.6% a.i.) 40924209 LC 50 (M/F) 5.9 g/L Tox Category IV 870.2400 Primary Eye Irritation, Rabbit

(90.4% a.i.) 41082602 Moderate eye irritant Tox Category III 870.2500 Primary Dermal Irritation, Rabbit (90.6%

a.i.) 41082603 Not an irritant Tox Category IV 870.2600 Dermal Sensitization, G uinea Pig (90.4% a.i.) 41082604 Not a sensitizer Table A.2.b Subchronic, Chronic and Other Toxicity Profile for Nicosulfuron Type of Study/ Guideline Study Title MRID (year) Doses Results 870.3100 90
- Day

Oral Toxicity (Diet), Rat (Crl:CD BR) (10/sex/ dose) 41082607 (1988) Acceptable/guideline ppm : 0, 300, 1500, 7500 or 20,000 (94.9% a.i.) M: 0, 22.2, 107.0, 555.0, 1495.0 mg/kg/day F: 0, 26.0, 133.0, 685.0, 1830.0 mg/kg/day NOAEL (M/F) = 1495/1830 mg/kg/day LOAEL (M/F) ≥1495/1830 mg/kg/day. There wa s a statistically significant decrease (p<0.05) in platelets in females at all doses tested at 45 and 90
- day sacrifices. Decreased blood calcium and bilirubin at ≥1500 ppm in males and females and ketones in the urine of a ll treated males were also reported. However, none of these findings were considered biologically significant because a dose
- response wa s not observed and they were not seen in the 24
- mo nth study. 870.3100 90
- Day

Oral Toxicity (Diet) Mouse [Crl:CD
1(ICR) BR] 41082605, 41360119 (1988) Unacceptable/guideline ppm : 0, 300, 1500, 7500, 10,000 (90.4% a.i.) M: 0, 43.9, 234.0, 1164.0, 1509.0 mg/kg/day F: 0, 62.0, 323.0, 1537.0, 2016.0 mg/kg/day NOAEL (M/F) = 43.9/62.0 mg/kg/day LOAEL (M/F) = 234.0/323.0 mg/kg/day, based on decreased hematological parameters (especially neutrophils and other white blood cells). Tentative due to lack of gross necropsy data.

870.3150 90
- Day

Oral Toxicity (Diet) Beagle Dog 41082606 (1988) Acceptable/guideline ppm : 0, 250, 5000 or 20,000 NOAEL ( F) = 161 mg/kg/day. NOAEL (M) ≥710 mg/kg/day. LOAEL (F) = 683 mg/kg/day, based on hematologic changes (reduced neutrophils in females). A LOAEL was not identified in males.Page 31 of 35

Table A.2.b Subchronic, Chronic and Other Toxicity Profile for Nicosulfuron Type of Study/ Guideline Study Title MRID (year) Doses Results (94.5% a.i.) M: 0, 9.23, 172.0, 710.0 mg/kg/day F: 0, 9.14, 161.0, 683.0 mg/kg/day 870.3200 21
- Day

Dermal Toxicity, Rabbit No study available 870.32 50 90
- Day

Dermal Toxicity, Rat No study available 870.3465 90
- Day

Inhalation Toxicity, Rat No study available 870.3700a Developmental Toxicity

(Gavage), Rat (Crl:CD BR) 41082608 (1988) Acceptable/guide line 0, 200, 1000, 2500 or 6000 mg/kg/day on GD 7 through 16 (90.6% a.i.) Maternal NOAEL ≥ 6000 mg/kg/day. Maternal LOAEL > 6000 mg/kg/day Developm ental NOAEL ≥ 6000 mg/kg/day Developm ental LOAEL > 6000 mg/kg/day. No toxicity was observed at any dose. 870.3700b Developmental Toxicity

(Gavage), Rabbit (New

Zealand White SPF) 41082609 (1988) Acceptable/guideline 0, 100, 500, 1000 or 2000 mg/kg/day on GD 7 through 19 (90.6% a.i.) Maternal NOAEL = 100 mg/kg/day Maternal LOAEL = 500 mg/kg/day, based on increased incidence of diarrhea (100 mg/kg/day), possible vaginal discharge, abortion, decre ased body weight gain during the dosing period, staining of hair in the rectal and vaginal areas and an apparent increase in % postimplantation loss. Developm ental NOAEL = 500 mg/kg/day Developm ental LOAEL = 1000 mg/kg/day, based on decreased fetal body w eight 870.3800 Reproduction and

Fertility Effects (Diet) Rat (Crl:CD BR) 41360101 (1989) Acceptable/guideline ppm : 0, 250, 5000, 20,000 (90.6% a.i.) M: 0, 14.4
- 16.7, 289
- 338 or 1203
- 1428 mg/kg/day; F: 15.5
- 20.0, 287
- 390 or 1265
- 1604 mg/kg/day Parent al NOAEL = 287 mg/kg/day Parental LOAEL = 1265 mg/kg/day, based on significantly decreased body weight gains (F1 females during gestation; nonsignificantly decreased body weight gains in F0 females during gestation also observed). Reproductive NOAEL ≥ 1265 mg/kg/day Reproductive LOAEL > 1265 mg/kg/day Offspring NOAEL = 287 mg/kg/day Offspring LOAEL = 1265 mg/kg/day , based on F2a generation decreased litter size at birth and pup weight at postpartum days 14 through 21. 870.4100b Chronic Feeding, Dog (1

year) 41360102 (1989) Acceptable/guideline ppm : 0, 250, 5000, 20,000 (90.6% a.i.) NOAEL = 125 mg/kg/day LOAEL = 500 mg/kg/day, based on increased relative liver and kidney weights in males. No effects observed in femalesPage 32 of 35

Table A.2.b Subchronic, Chronic and Other Toxicity Profile for Nicosulfuron Type of Study/ Guideline Study Title MRID (year) Doses Results 0, 62.5, 125, 500 mg/kg/day 870.4200a Carcinogenicity, Rat Satisfied by Guideline 870.4300 (chronic toxicity/oncogenicity study) 870.4200b Carcinogenicity, 18
-

Month Feeding, Mouse 41360103 (1989) Acceptable/guideline ppm : 0, 25, 250, 2500 or 7500 (90.6% a.i.) M: 0, 3.2, 31. 4, 314, 953 mg/kg/day; F: 0, 4.2, 43.0, 420 or 1260 mg/kg/day NOAEL = 953/1260 mg/kg/day M/F (7500 ppm) LOAEL > 953/1260 mg/kg/day M/F. Although the MTD was not achieved, the material was tested at limit doses in both sexes. No treatment
- related neoplas ms observed.

870.4300 Chronic/Oncogenicity, 2
-

Year
- Rat 41360104 (1989) Acceptable/guideline ppm : 0, 50, 1500, 7500 or 20,000 (90.6%
- 92.8% a.i.) M: 0, 1.9, 58, 289, 786 mg/kg/day; F: 0, 2.6, 77, 382, 1098 mg/kg/day NOAEL = 786/1098 mg/kg/day M/F ( 20,000 ppm) LOAEL > 786/1098 mg/kg/day M/F . Although the MTD was not achieved, the material was tested at limit dose levels in both sexes. No treatment
- related neoplasms observed.

870.5100 Ames Bacterial

Mutagenicity Test, reverse gene mutation S. typh imurium 41082612, 41360124 (1988) Acceptable/guideline TA 98, TA1535 at 0.1 to 1 microgram/ plate. TA 97A at 0.02 to 0.1 microgram/ plate; TA 100 at 0.1 to 10 micrograms/plate with and without metabolic activation (90.6% a.i.) Negative
- not mutagenic in presence or absence of S9 activation

870.5300 In Vitro Mammalian

Gene Mutation
- Chinese Ham ster Ovary Cells/HPRT mutation 41082614, 41360124 (1988) Acceptable/guideline 4, 20, 40, 200 or 465 micrograms/mL with or without S9 metabolic activation (90.6% a.i.) Negative
- not mutagenic in the presence or absence of S
- 9 activation

870.5375 Mammalian Bone 41082616 (1988) Negative for induction of chromosome aberrationsPage 33 of 35

Table A.2.b Subchronic, Chronic and Other Toxicity Profile for Nicosulfuron Type of Study/ Guideline Study Title MRID (year) Doses Results Marrow Chromosome Aberration Assay

– Crl:CD
- 1(ICR)BR mouse Acceptable/guideline 0, 500, 2500 or 5000 mg/kg (90.6% a.i) in the bone marrow cells of male or female mice at 24, 48 or 72 hrs postexposure.

870.5550 Unscheduled DNA

Synthesis

– cultured rat hepatocyte 41082613, 42360125 (1988) Acceptable/guideline 0.04, 0.4, 1.2, 4.1, 12, 41 , 122, 409 or 470 micrograms/mL (90.6% a.i.) Negative for induction of DNA damage or inducible repair in the rat hepatocyte. The highest concentration selected in this study was 470 micrograms/mL, the limit of solubility in the test system without cytotox icity (HED TXR 007963).

870.6200a Ac ute neurotoxicity

screening battery
- rats No study Available 870.6200b Subchronic neurotoxicity

screening battery No study Available 870.7485 General Metabolism

–

Crl:CD(BR) rats 41082617 (1988) Acceptable/guide line 10 or 1000 mg/kg, single oral dose; 10 mg/kg/day for 14 days; 10 mg/kg intravenous single dose Total recovery of radioactivity was 90
- 109% of administered dose at 4 days postdosing, mostly excreted unchanged within 24 hrs. There were no apparent differences between males and females or dose groups, although a slightly higher percentage of the administered dose was detected in feces of high dose animals than low dose animals. Elimination following oral dosing was primarily via feces (80
- 95% of dos e); excretion via urine was 9 to 20% of the dose. Elimination via exhaled CO 2 wa s negligible (<0.01 of the dose). The average total cumulative excretion indicated half
- lives between 12
- 24 hrs. Following IV administration, about 76
- 80% of the dose was el iminated in the urine and 27
- 30% in the feces. Tissue residues were low (0.05 to 0.5% of dose). In addition to excretion of the unchanged parent com pound, pyridinesulfonamide (N ,N
- dimethyl
- 2
- sulfonamide pyridine
- 3
- carboxylic acid) was tentatively identif ied as a minor metabolite in the feces of orally dosed rats and urine of IV dosed rats. These metabolites represent hydrolytic cleavage/oxidation of the parent compound. 870.7800 Immunotoxicity No study AvailablePage 34 of 35

A .3 Rationale for Toxicology Data Requ irements
. Guideline Number: 870.3465 Study Title: 28 - or 90 - Day Inhalation Toxicity Rationale for Requiring the Data This study is required if there is the likelihood of significant repeated i nhalation exposure to the pesticide as a gas, vapor or aerosol. The Agency has determined that there are potential inhalation exposures to mixers, loaders and applicators, as well as potential postapplication exposures, associated with nicosulfuron applications. T he inhalation study may potentially be shortened (i.e., 28
- day exposure) as appropriate to exposures from current use patterns. Because toxicity via the inhalation route may differ from that observed following oral dosing, the study is required to better assess potential effects resulting from inhalation exposure and provide a refined assessment of risk from inhalation exposure. Practical Utility of the Data How did the Agency make its re - registration decision without these data? In the abse nce of inhalation toxicity studies on a pesticide , The Agency estimates occupational risk from inhalation exposure by using the most sensitive oral endpoint appropriate for a given exposure scenario. To account for route
- to - route extrapolation, 100% abso rption is assumed
. How will the data be used? An inhalation study may result in changes to the endpoints and how the risks are quantified. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenari os and are considered a primary data source for reliable reference dose calculation. How could the data impact the Agency’s future decision - making? The Agency does not have a full picture of the potential effects which could occur as a result of exposure via the inhalation route. In some cases, toxicity observed via the inhalation route is higher than toxicity observed via oral exposure, which means that route
- to - route extrapolation could result in an underestimation of risks from inhalation. The study m ay be used to confirm that no further mitigation is needed for uses where inhalation exposure occurs. Guideline Number: 870.6200 Study Title: Acute & Subchronic Neurotoxicity Rationale for Requiring the Data The acute and subchronic neurotoxicity stu dies are a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non
- food uses). The Neurotoxicity Test Guideline (OPPTS 870.6200) prescribes functional and structural neurotoxicity testin g and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects on the nervous system. Although some information on neurotoxicity may be obtained from standard guideline toxicity study data, studies not specifically conducted to assess neurotoxic endpoints may be inadequate to characterize a pesticide’s potential neurotoxicity. While data on clinical signs of toxicity or histopathology in routine chronic or subchronic toxicity studies may offer useful information on potential neurotoxic effects, these endpoints alone may be insufficient to detect more subtle neurological effects. Practical Utility of the Data How will the data be used? Neurotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the nervous system from pesticide exposure. Since epidemiologic data on thePage 35 of 35

effects of chemical exposures of nicosulfuron on neurologic parameters are limited and may be inadequate to characterize a pestic ide’s potential neurotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessment. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a p rimary data source for reliable reference dose calculation. How could the data impact the Agency's future decision - making? If the neurotoxicity studies show that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have these data, a 10X database uncertainty factor may be applied for c onducting a risk assessment from the available studies. Guideline Number: 870.7800 Study Title: Immunotoxicity Rationale for Requiring the Data The immunotoxicity study is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non
- food uses). The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effe cts (i.e., suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia . Because the immune system is highly complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s potential immunotoxicity. While data from hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies may offer useful information on potential immunotoxic effects, these endpoints alone are insufficient to predict immunotoxicity. Practical Utility of the Data How will the data be used? Immunotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the immune system from pesticide exposure. Since epidemiologic data on the effects of chemical exposures on immune parameters are limited an d are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessment. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8
- tetrachlorodibenzo -p - dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997). How could the data impact the Agency's future decision - making? If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have these data, a 10X database uncertainty factor may be applied for conducting a risk assessment from the available studies.