1 of 30 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES

MEMORANDUM

Date: 7/14/09

SUBJECT: Nicosulfuron : Human Health Risk Assessment for Proposed Section 18 Use on Bermudagrass.

PC Code: 129008 DP Num: D361732
Decision No.: 405771 Registration No.: NA
Petition No.: 09OK02 Regulatory Action: Section 18 Registration Risk Assessment Type: Single Chemical Aggregate Case No.: NA

TXR: NA CAS No.: 111991-09-4

MRID No.: NA 40 CFR: §180.454

FROM: W. Cutchin, Chemist Alternative Risk Integration Assessment (ARIA) Team Risk Integration, Minor Use, and Em ergency Response Branch (RIMUERB) Registration Division (RD; 7505P)

THROUGH: C. Swartz, Branch Chief L. Hansen, Ph.D., Biologist Registration Action Branch II (RAB II) Health Effects Division (HED; 7509P)

TO: B. Madden, Risk Manager RIMUERB/RD (7505P)2 of 30 Table of Contents
1.0 Executive Summary ............................................................................................................. 3
2.0 Ingredient Profile ................................................................................................................. 6
2.2 Structure and Nomenclature ...................................................................................... 7 2.3 Physical and Chemical Properties.............................................................................. 7
3.0 Hazard Characterization/Assessment ................................................................................ 8 3.1 Hazard and Dose-Response Characterization............................................................ 8 3.1.2 Toxicological Effects................................................................................... 10 3.5 Hazard Identification and Toxicity Endpoint Selection........................................... 10 3.5.5 Level of Concern for Margin of Exposure................................................... 10 3.5.6 Recommendation for Aggregate Exposure Risk Assessments .................... 10 3.5.8 Summary of Toxicological Doses and Endpoints for Nicosulfuron for Use in
Human Risk Assessments........................................................................................ 10
4.0 Public Health and Pesticide Epidemiology Data ............................................................. 12
5.0 Dietary Exposure/Risk Characterization ........................................................................ 12 5.1 Pesticide Metabolism and Environmental Degradation........................................... 12 5.1.1 Metabolism in Primary Crops...................................................................... 12 5.1.2 Metabolism in Rotational Crops .................................................................. 12
5.1.3 Metabolism in Livestock.............................................................................. 13 5.1.4 Analytical Methodology .............................................................................. 13 5.1.5 Environmental Degradation......................................................................... 14 5.1.6 Comparative Metabolic Profile.................................................................... 15
5.1.7 Pesticide Metabolites and De gradates of Concern....................................... 15 5.1.8 Drinking Water Residue Profile................................................................... 15
5.1.9 Food Residue Profile.................................................................................... 16
5.1.10 International Residue Limits...................................................................... 18 5.2 Dietary Exposure and Risk ........................................................................................... 18 5.2.1 Acute Dietary Exposure/Risk ........................................................................ 18 5.2.2 Chronic Dietary Exposure/Risk ..................................................................... 18 5.2.3 Cancer Dietary Risk....................................................................................... 19 5.3 Anticipated Residue and Percent Crop Treated (%CT) Information............................. 19
6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................... 19 6.1 Other (Spray Drift, etc.)........................................................................................... 19
7.0 Aggregate Risk Assessments and Risk Characterization ............................................... 20
8.0 Cumulative Risk Characterization/Assessment .............................................................. 20
9.0 Occupational Exposure/Risk Pathway ............................................................................. 20
9.1 Short-Term Handler Risk......................................................................................... 21 9.2 Short-/Intermediate-/Long-Te rm Postapplication Risk ........................................... 23
10.0 Data Needs and Label Recommendations ....................................................................... 24
References:

............................................................................................................................... ....... 24 Appendix A: Toxicology Assessment .......................................................................................... 26 Appendix B: International Residue Status ................................................................................. 303 of 30 1.0 Executive Summary

The Oklahoma Department of Agriculture, Food, and Forestry and the Texas Department of Agriculture have submitted a Section 18 pe tition proposing the use of nicosulfuron on Bermudagrass for control of sandbur. The proposed uses are for PastoraTM Herbicide (EPA Reg. No. not registered), a dry flowable (DF) formulation containing 3.19 lb ai/gal for multiple broadcast foliar applications at maximum seas onal rates of 0.0878 lb ai/A on Bermudagrass. Foliar applications may be made using ground or aerial equipment. The use of spray adjuvants is required. There are no feeding restrictions fo r the use of ni cosulfuron in Bermudagrass.

Nicosulfuron [3-pyridinecarboxamide, 2-((((4,6-dimethoxypyrimidin-2-yl)aminocarbonyl) aminosulfonyl))-N,N-dimethyl] is a member of the sulfonylurea family of herbicides which includes, among others, halosulfuron , pirimisulfuron and chlorsulfur on. Nicosulfuron is used for control of weeds such as Johnsongr ass, quackgrass, foxtails, shatte rcane, panicums, barnyardgrass, sandbur, pigweed, morning glory an d others. Nicosulfuron’s herb icidal action is due to the inhibition of the enzyme acetolactate synthetase l eading to the disruption of cell division and plant growth. The registered formul ations of nicosulfuron include water dispersible granules, an emulsifiable concentrate, and suspension concentrates.

Toxicology

Nicosulfuron is of low acute toxicity by all r outes of exposure (Category III or IV for acute lethality and irritation studies) and is not a skin sensitizer. In repeated dose studies by the oral route, nicosulfuron is minimally toxic. No eff ects were observed in rats or mice following either subchronic or chronic dietary admi nistration of doses exceeding the limit dose. Chronic dietary administration to dogs produced minimal toxicity (in males, decreased body weight and increased relative liver and kidney weights), also at high doses. Nicosulfur on is not likely to be carcinogenic based on lack of tumorigenicity in rodent bioassays and lack of mutagenic effects in the in vitro
and in vivo genotoxicity assays. Nicosu lfuron showed no developmental or reproductive effects in rats; in rabbits, developmental and maternal effects were obser ved at high doses. No effects indicating neurotoxicity or imm unotoxicity were observed in a ny study. The low toxicity of nicosulfuron is consistent with poor oral ab sorption as observed in the rat metabolism study.

Studies suitable for use in risk assessment were limited to the developmental study in rabbits and chronic study in dogs. An endpoint of concern attributable to a si ngle dose was not identified from the toxicity database. The chronic oral dog study was selected for all expos ure scenarios assessed for this proposed use, supported by the findings from the rabbit developmental toxicity study. This endpoint is protective of all populations including pre- and/or postnatal exposure. Uncertainty factors of 10X for intra- and 10X for interspecies variability, respectively, were applied to give a combined uncer tainty factor of 100X in determ ining the chronic reference dose (RfD) and calculation of the Margins of Expos ure (MOE) for Occupati onal/Residential Risk

Assessments.

The nicosulfuron HED team recommended reducti on of the Food Quality Protection Act (FQPA) Safety Factor (SF) to 1x because there are no concer ns and no residual uncertainties with regard to pre- and/or postnatal toxicity. The existing toxicology database for nicosulfuron is considered adequate for purposes of this risk assessment. Although there are several toxicology data gaps under the current (revised) 40 CF R Part 158 toxicology data re quirements (immunotoxicity, rat acute and subchronic neurotoxicity, and rat 28-day inhalation and 21- day dermal toxicity studies),
due to the lack of eviden ce of immunotoxicity or neurotoxicity in available studies, it is unlikely that these studies will identify a NOAEL belo w the dose currently selected for exposure assessments. Therefore, an additional safety factor (UF DB ) for database uncertainty is not needed.4 of 30 Residue Chemistry

The nature of the residue in plan ts and livestock is adequately understood for the purposes of this
action based on metabolism studies with corn and goats. The residue of concern for both risk
assessment and tolerance enfor cement purposes is nicosulfuron

. The primary degradation pathway, with regard to water, was aerobic soil metabolism. Degradation rate and the resulting degradates under aerobic soil metabolism conditions depended on the pH of the soil. Nicosulfuron is more persistent in alkaline soils.

CIBA-Geigy’s method, AG-499, a high performance liquid chromatography with ultra-violet detection (HPLC/UV) method, was found adequate for enforcement purposes. The procedure has a limit of detection (LOD) of 0.05 ppm. The me thod was recommended for inclusion in the Pesticide Analytical Manual Vol. II (PAM II). Gr ass forage and hay samples in the administrative materials submitted by DuPont in support of the Sec tion 18 request were analyzed for nicosulfuron using procedures described in DuPont-17928, an HPLC with electrospray mass spectrometry/mass spectrometry (ESI-MS/MS) method. The method LOD and limit of quantitation (LOQ) were 0.003 mg/kg and 0.010 mg/kg, respectively. A succe ssful Independent Laboratory Validation (ILV) has been conducted. The method is ad equate for data gathering purposes.

The registrant submitted a volume of administrative materials for an upcoming petition (for Section 3 Registration) in support of this Secti on 18 action. The registrant has conducted thirteen residue field trials on Bermudagrass, brome, a nd fescue. Nicosulfuron 75WG was applied either as a single foliar broadcas t application at the rate of 1.41 oz a i/A (0.088 lb ai/A), or as two foliar broadcast applications at the target rates of 0.938 oz ai/A (0.059 lb ai/A) and 0.469 oz ai/A (0.029 lb ai/A). Non-ionic surfactants or nitrogen were included in the sp ray mixture in all applications. Samples were harvested the same day as the la st application. Analysis of the samples was conducted using the method described in DuPont- 17928. The registrant repor ted that the LOQ of the analytical method was 0.010 ppm and the L OD was 0.003 ppm (1/3 the LOQ). Nicosulfuron residues in grass forage and hay were reporte d as ranging from 0.032 ppm to 7.7 ppm and from 0.11 ppm to 18.0 ppm, respectively. ARIA recomme nds for nicosulfuron time-limited tolerances on Bermudagrass, forage and hay at 10 ppm and 25 pp m, respectively, as a resu lt of this Section 18

use.

Grass forage and hay are feed items for beef and dairy cattle. A di etary burden for cattle using the
established tolerances for corn commodities as well as the pr oposed time-limited tolerances for Bermudagrass results in an exposur e of 3.0 ppm for both beef cattle and 5.8 ppm for dairy cattle. Previously submitted metabolism studies using lactat ing goats dosed with nicosulfuron at a daily feeding level of approximately 60 ppm showed that uptake of residues was low for all tissues and organs. The highest residue leve l found, 0.1 ppm (0.04% of total dose) , was in the liver. Using the dietary burden and the dosage and results of the metabolism study, residues would not be detectable in cattle commodities. Therefore, ARIA determines that as a result of this Section 18 use, there would be no detectable residues of ni cosulfuron in ruminants. There is no need for
nicosulfuron cattle tolera nces at this time.

Grass feed items are not used for swine and poultry. Since the addition of grass feed items will not affect the swine or poultry diets, there is no need for nicosulfur on swine or poultry tolerances at
this time.

Drinking Water5 of 30 The Ecological Fate and Effects Division (EFED) presented the Tier I Estimated Environmental Concentrations (EECs) for nicosulfuron, estima ted using the models FQPA Index Reservoir Screening Tool (FIRST) for surface water a nd Screening Concentration In GROund Water ( SCIGROW) for groundwater in the human health risk assessment. For nicosulfuron, the surface
water chronic value is 0.7 ppb and the groundwater sc reening concentration is 0.06 ppb based on the application on corn.

Dietary Exposure

Since no acute end point has been selected for nicosulfuron, an acute dietary exposure assessment was not required.

Chronic dietary exposure is based on potential residues in food and drinking water. In the case of this Section 18 request, there ar e no human food items of regulable interest for Bermudagrass.
ARIA has also determined that there will be no detectable nicosulfuron residues in livestock commodities. A previous chronic dietary (food + water) risk assessment was conducted for the general U.S. population and va rious population subgroups. Dri nking water was incorporated directly into the dietary assessment using the ch ronic (annual average) concentration for surface water. Tolerance level residues were used along with 100 percent crop treat ed (%CT), and a single point estimate for drinking water, resulting in a conservative chroni c exposure and risk assessment
for nicosulfuron. The results from the overall ch ronic dietary risks usin g DEEM-FCIDTM analyses
are below HED’s level of concern. The chronic population adjusted dose (cPAD) value for the general U.S. population is less than 1% and th e most highly exposed population subgroup, children 3-5, is also less than 1%.

Residential

There are no residential uses fo r nicosulfuron; therefore, incide ntal oral, dermal, and inhalation exposure assessments are not required.

Aggregate Risk

The acute aggregate risk assessment takes in to account exposure estimates from dietary consumption of nicosulfuron (food + drinking water). Since no acute endpoint has been identified for nicosulfuron an acute aggregate risk assessmen t is not required. Chroni c aggregate risk takes into account exposure estimates from dietary cons umption (food + drinking water), which is not of concern. Nicosulfuron is considered not likely to be carcinogenic, so there is no dietary or aggregate cancer risk associated with the proposed Section 18 use.

Occupational Exposure

ARIA/RD believes occupational hand lers will be exposed to short- term duration exposures (1-30 days). Multiple applications are generally not exp ected and treatment plots are expected be rather small by comparison to typical, large acreage ro w crops. Private (i.e., grower) applicators may perform all functions, that is, mix, load and apply the material. Standard HED practice directs that although the same individual may perform all those ta sks, they shall, in some cases, be assessed separately. The estimates of exposure to pestic ide handlers are based upon surrogate study data. For pesticide handlers, it is HED standard prac tice to present estimates of dermal exposure for “baseline” that is, for workers wearing appropriate work clothing. Since nicosulfuron dermal and
inhalation risks are based on an endpoint selected from an oral study, default 100% dermal and inhalation absorption factors were used in the occupational assessment Since the dermal and6 of 30 inhalation toxicological endpoints we re identified from the same study and effects, the dermal and inhalation exposures are summed prior to use in calculation of margins of exposure (MOE, where MOE = NOAEL ÷ Average Daily Exposure). The estimated MOEs are all > 100, with the most exposed occupational population MOE at 3,400. Th erefore the proposed Section 18 use does not
exceed ARIA/RD’s level of con cern for pesticide handlers.

It is possible for agricultural workers to have post-application exposure to pesticide residues during the course of typical agricultural activities. Since the requested appl ications of nicosulfuron are for early season (early post-emergen ce), scouting is expected to be the most likely post-application activity. The MOE from nicosulfuron during scouting was calculated using HED’s SOP for occupational exposure to be 8,445. Since an MOE of 100 is adequate to protect agricultural workers from post-application exposures, risks from the proposed Section 18 use do not exceed
ARIA/RDs level of concern.

Regulatory Decision

There are no data needs at this time for resi due chemistry, and occupational and residential exposure. However, there are other data requirements listed in Section 10 below.

To support the proposed Section 18 use on Bermudagrass, ARIA recommends for time-limited tolerances for nicosulfuron [3-pyridin ecarboxamide, 2-((((4,6-dimethoxypyrimidin-2- yl)aminocarbonyl) aminosulfonyl ))-N,N-dimethyl] in/on:

Bermudagrass, forage ............................................10 ppm Bermudagrass, hay.................................................25 ppm

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions
to Address Environmental Just ice in Minority Populations an d Low-Income Populations," http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf ).

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Thes e studies have been determined to require a review of their ethical cond uct, and have received that review.

2.0 Ingredient Profile

Nicosulfuron is a member of the sulfonylurea fam ily of herbicides which includes, among others, halosulfuron, pirimisulfuron and chlo rsulfuron. Nicosulfuron is used for control of weeds such as Johnsongrass, quackgrass, foxtails, shattercan e, panicums, barnyar dgrass, sandbur, pigweed, morning glory and others. Nicosulfuron’s herbicidal action is due to the in hibition of the enzyme acetolactate synthetase leading to the disruption of cell division and plant growth. The registered
formulations of nicosulfuron incl ude water dispersible granules, an emulsifiable concentrate, and suspension concentrates.

2.1 Summary of Proposed Uses

The registrant, DuPont Crop Protection, in supp ort of the Section 18 requests from Oklahoma Department of Agriculture, Food, and Forestry a nd the Texas Department of Agriculture provided a copy of a label for PastoraTM Herbicide (EPA Re g. No. not registered, 3.19 lb ai/gal DF). The proposed new use is summarized below in Table 2.1.7 of 30 Table 2.1. Summary of Direct ions for Use of Nicosulfuron.

Applic. Timing; Type; and Equip. Formulation [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

Bermudagrass

Broadcast foliar;
Ground or aerial

equipment 3.19 lb/gal

DF [not registered] 0.035-0.053 (1.0-1.5 oz formulation) 2 0.088 (2.5 oz formulation) 0 Use of a spray adjuvant is required. Apply only to established Bermudagrass that is at least one year old.

The proposed use directions are ad equate to allow evaluation of the residue data relative to the proposed use.

2.2 Structure and Nomenclature

The structure and nomenclature of nico sulfuron are summarized in Table 2.2.

Table 2.2 Nicosulfuron Nomenclature

Chemical structure

N N O

CH 3

CH 3

S N O

O H N O

H N N OMe

OMe

Empirical Formula C 15 H 18 N 6 O 6 S

Common name nicosulfuron

IUPAC name 2-(4,6-dimethoxypyrimidin-2-ylcarbamoylsulfamoyl)-N,Ndimethylnicotinamide; 1-(4,6-dimethoxypyrimidin-2-yl)-3-(3- dimethylcarbamoyl-2-pyridylsulfonyl)urea

CAS name 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-N,Ndimethyl-3-pyridinecarboxamide

CAS # 111991-09-4

End-use product/EP ACCENT, CELEBRITY, and STEADFAST

Chemical Class sulfonylureas

2.3 Physical and Chemical Properties

Nicosulfuron’s physical and chemical prope rties are summarized below in Table 2.3.

Table 2.3 Physicochemical Properties of Nicosulfuron

Parameter Value Reference

Molecular Weight 410.48 of 30 Table 2.3 Physicochemical Properties of Nicosulfuron

Parameter Value Reference

Melting point/range 141-144°C 40954501, 40924203

pH A slurry in HPLC water caused pH to decrease
from 6.6 to 4.5 40954501, 40924203

Density 0.313 g/mL 40954501, 40924203

Water solubility @ 25°C: 0.04 g/100g pH=5.0; 1.2 g/100g pH=7.0; 3.9 g/100g pH=9.0 40954501, 40924203

Solvent solubility 28oC: acetone, 0.018 ppm; acetonitrile, 0.023 ppm; benzene, 0.003; chloroform, 0.064 ppm; DMF, 0.064 ppm; ethanol, 0.004 ppm; methylene chloride, 0.160 ppm 40954501, 40924203

Vapor pressure 1.2 x 10 -16 torr at 25°C 40954501, 40924203

Dissociation constant, pK

a 4.3 (acid) 40954501, 40924203

Octanol/water partition coefficient, Log(K OW ) @ 25°C: 0.44 (pH 5); 0.017 (pH 7); 0.01 (pH 9) 40954501, 40924203

UV/visible absorption spectrum not available data outstanding

3.0 Hazard Characterization/Assessment

3.1 Hazard Characterization

For a more detailed characterization of the toxi city/dose response of ni cosulfuron, selection of endpoints and FQPA, please refer to the human health risk assessment conducted for the Reregistration Eligibility Decision Document (RED) (D301619, November 19, 2004). No new toxicity data have been submitted since the RED. Toxicity profile tables summarizing the database are provided in Appendix A. A lthough additional studies (rat acute and subchronic neurotoxicity; rat 21-day dermal; and immunotoxicity studies) ar e required under the cu rrent (revised) 40 CFR Part 158 toxicity data guidelines , the existing database is considered adequate for purposes of assessing human health risk from this emergency exemption use.

Nicosulfuron is a member of the sulfonylurea family of herbicides. Its herb icidal action is due to
the inhibition of acetolactate s ynthetase, leading to the disrupti on of cell division and elongation in the plant. This mode of herb icidal action is not relevant to human toxicity as acetolactate synthetase does not occur in humans or animals.

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 irrita tion studies and is not a dermal sensitizer. Subchronic or chronic dietary administration of doses exceeding the limit dose did not produce adverse effects in rats or mice. Chronic administration in the diet to dogs produced mild effects (decreased body weight gains in males and increase in the relative liver and kidney weights) at the limit dose. No findings were reported in dogs followi ng subchronic dosing at comparable dietary levels. No dermal or inhalation studies were submitted.

No developmental or reproductive effects were obser ved in rats, but in rabb its, maternal toxicity (clinical signs, decreased body weight gain duri ng dosing, increased abortions), postimplantation loss and decreases in fetal body weight were observe d. Toxicity to the fetus was only observed at maternally toxic doses. There were no indicatio ns of neurotoxic or im munotoxic effects.

Nicosulfuron is not likely to be carcinogenic ba sed on bioassays in the rat and mouse and lack of
effects in the in vitro and in vivo genotoxicity studies.9 of 30 Upon oral administration, nicosulfur on is poorly absorbed. In the ra t, 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%). Radioactivity was not retained in tissues at signi ficant levels. Minor metabolites of hydrolytic and oxidative metabolism were identified. The poor ab sorption is consistent with the low toxicity
observed in the available studies.

3.2 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 th e rabbit developmental study and the dog chronic study. Maternal effects in the ra bbit developmental study consisted of vaginal discharge, staining of hair in the rectal and vagi nal areas, decreased body weight gain during the dosing period and
late abortion. An increase in percentage postimplantation loss was observed at 500 mg/kg/day and decreased fetal body weight was observed at 100 0 mg/kg/day. The NOAEL was 100 mg/kg/day. Effects in the chronic dog study we re limited to decreased body weight gain in males and increases in liver and kidney weight at the LOAEL of 500 mg/kg/day w ith a NOAEL of 125 mg/kg/day.

Although these two oral studies we re of different dosing durations , they had similar NOAELs 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 NOAELs. The dog chronic study NOAEL of 125 mg/kg/day
was selected for all risk assessment scenarios of all exposure routes and durations as a more realistic NOAEL, supported by the rabbit developmenta l 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). E ach exposure scenario is discussed as follows:

Acute Dietary Endpoint : No effects were considered attri butable 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 dog study 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. Th e study is of an appropriate route and duration for this assessment. The FQPA safety factor is discussed below in Section 3.3.

Residential Exposure : Endpoints for residential exposure we re not selected because there are presently no residential uses.

Short- and Intermediate Term O ccupational Dermal and Inhalation : The NOAEL of 125 mg/kg/day from the dog chronic or al study was selected for all o ccupational exposure scenarios.
The rationale for this selection was discussed ab ove. For both dermal and inhalation exposure, a default absorption factor of 100% of oral absorption was applied si nce an oral study was selected and dermal/inhalation absorption data were not available.

Carcinogenicity : Nicosufuron is classified as “not lik ely to be carcinogenic to humans” based on lack of tumorigenic effects in rodent (rats a nd mice) bioassays at the limit doses and was not mutagenic in in vitro and in vivo genotoxicity assays. Therefore th ere is no cancer risk associated with the proposed Section 18 use.

MOE for Occupational/Residential Risk Assessments : A MOE of 100 (10 x for interspecies extrapolation and 10x for intraspecies variation) is adequate. No additional safety factors were included to account for lack of studies (neurotoxi city, immunotoxicity) becau se the database as a10 of 30 whole indicated low toxicity of nicosulfuron an d there was no evidence of neurotoxicity or immunotoxicity in the available st udies; therefore, it is considered unlikely that these studies would provide a lower NOAEL for risk assessment.

3.3 FQPA Considerations and Safety Factor Determination

Reduction of the special FQPA SF to 1x is reco mmended. The database is adequate for the purpose of this Section 18 risk assessment, and deve lopmental toxicity studies in two species and a rat multigeneration reproductive toxicity study are av ailable. Nicosulfuron is poorly absorbed and toxicity is low in the available studies. No developmental or re productive effects were observed in rats, and developmental toxicity in rabbits (p ostimplantation loss, decr eased fetal body weight) was observed only in the presence of maternal to xicity. Abortions and postimplantation loss were observed at the maternal toxicity LOAEL, along with clinical signs a nd decreased body weight gain. Increased pre- and/or pos tnatal susceptibility was not obser ved and there was no evidence of neurotoxicity or immunotoxicity. There are no re sidential uses and exposur e assessments will not
underestimate risks. There are no concerns and no re sidual uncertainties with regard to assessment of pre- and/or pos tnatal toxicity.

3.4 Hazard Identification and Toxicity Endpoint Selection

3.4.1 Level of Concern for Margin of Exposure

Table 3.4.1. 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)

3.4.2 Recommendation for Aggregat e Exposure Risk Assessments

The aggregate exposure assessments are only ch ronic food + drinking water (both surface and ground water model estimates).

3.4.3 Summary of Toxicological Doses and Endp oints for Nicosulfuron for Use in Human
Risk Assessments

Table 3.4.3.a Summary of Toxicological Doses and Endpoints for Nicosulfuron for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD, Level
of Concern for
Risk Assessment Study and Toxicological Effects11 of 30Table 3.4.3.a Summary of Toxicological Doses and Endpoints for Nicosulfuron for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD, Level
of Concern for
Risk Assessment Study and Toxicological Effects

Acute Dietary (All populations, including Infants
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) NOAEL=125 mg/kg/day UF A = 10x

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

cPAD = 1.25mg/kg/day 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 at the LOAEL of 500 mg/kg/day and
considered this dose to be the 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. 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 nicosulfuron.

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 tumorigenic effects in rodent (rats and mice) bioassay s 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 poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally 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). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short-term study for lo ng-term risk assessment. UF DB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted do se (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LO C = level of concern. N/A = not applicable.

Table 3.4.3.b Summary of Toxicological Doses and Endpoints for Nicosulfuron for Use in Occupational Human
Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD, Level
of Concern for
Risk Assessment Study and Toxicological Effects

Dermal (shortand intermediateterm) 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. Supported by the NOAEL of 100 mg/kg/day/LOAEL 500 mg/kg/day in the rabbit developmental toxicity study.12 of 30 Table 3.4.3.b Summary of Toxicological Doses and Endpoints for Nicosulfuron for Use in Occupational Human
Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD, Level
of Concern for
Risk Assessment Study and Toxicological Effects

Inhalation (shortand intermediateterm) 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 statistically significant increase in the relative liver and kidney weights of males administered 500 mg/kg/day and
considered this dose to be the 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 tumorigenic effects in rodent (rats and mice) bioassay s 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 poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally 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). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short-term study for lo ng-term risk assessment. UF DB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted do se (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. DAF = dermal absorption factor. IAH = Inhalation absorption factor.

4.0 Public Health and Pesticide Epidemiology Data

No data exists for nicosulfuron in NHANES or AG HEALTH studies.

5.0 Dietary Exposure/Risk Characterization

5.1 Pesticide Metabolism and Environmental Degradation

DP Num: 302694, D. Hrdy, 11/30/04

5.1.1 Metabolism in Primary Crops

Based upon the results of the nicosulfuron me tabolism study in corn, the metabolism of nicosulfuron proceeds predominantly via two me chanisms: the hydrolysis of the sulfonylurea bridge yielding pyridine sulfonamide and pyrimidin e amine, and the hydroxylation of nicosulfuron at the 5-position of the pyrimidine amine followed by glucosidation (in early forage samples). The glucose conjugate and its aglycone were present in the whole plant, but were not present in the fodder or stover (113 day PHI). The grain and co b were not analyzed since these contained <0.005 ppm total 14C-equivalents of nico sulfuron. Pyridine sulfonamide wa s present in the whole plant and in silage, and fodder and stover The analyses show that nicosulfur on gradually decreases during the corn growing season and is present in very low levels at maturity. However, residues of metabolite pyridine sulfonamide begin at day 0 an d are detected in the whole plant and stalk at maturity. These residues are higher than the de tected residues of the nicosulfuron. Pyrimidine amine is further metabolized to 5-OH pyrimidine amin e and its glucoside, but is not detected in the whole plant or in fodder or stover.

5.1.2 Metabolism in Rotational Crops13 of 30 The submitted confined rotationa l crop studies are acceptable. Based upon the data there is indication that metabolites /degradates containi ng the pyridine ring are more readily taken up by plants than those containing the py rimidine ring. Neither in soils no r in plants were the pyrimidine amine residues detected even though this me tabolite is a major metabolite/degradate of
nicosulfuron. Maximum total residues were obser ved in soybean forage/hay and seeds when the pyridine labeled material was used, but the amount of residues decreased w ith the aging period of the soil. The major metabolite detected was pyr idine sulfonamide. With the pyrimidine labeled material, total residues were lo wer and the only identified meta bolite/degradate was N-desmethyl nicosulfuron, which was higher in forage/hay than in seeds. Maximum total residues were also observed in wheat straw/chaff when the pyrid ine labeled nicosulfuron was used; pyridine sulfonamide was the major metabolite/degradate identi fied. The lowest residue s were identified in lettuce leaves and radish roots. (Ac cession #: 412004-044, E. Regelman, 6/1/90).

5.1.3 Metabolism in Livestock

In studies in which lactating goa ts were treated with radiolabel ed nicosulfuron for 3 consecutive days, residues continued to increase in the milk up to day 3 for the pyrimidinyl-labeled nicosulfuron and then apparently plateaued, wh ile the pyridinyl-labeled nicosulfuron gave no
detectable 14 C-residues on day 1, 2, or 3. The total 14 C activity measured in milk (pyrimidinyllabeled) was a maximum of 0.03 ppm (0.03% total radioactive residue, TRR). The administered

14 C-dosage was excreted in the urine at 46% and 17%, and in the feces at 62% and 32%, respectively for the pyridinyl- and pyrimidinyl-labeled nicosulfuron. Uptake of residues was low for all tissues and organs for either label. The highest level, 0.1 ppm (0.04% of total dose) was in the liver from the goat treated with the pyrid inyl label. All other tissues had TRR of approximately 0.07 ppm or less (nicosulfuron equiva lents). Radioactivity in the collected bile comprised 0.1% and 0.7% of the total dose, respec tively for the pyridinyl- and pyrimidinyl labeled
nicosulfuron.

The proposed metabolic pathway for nicosulfuron in the goat showed primar ily three mechanisms: 1) hydrolysis of the sulfonylurea bridge to yiel d pyridine sulfonamide and pyrimidine amine (both of which undergo additional metabolism); 2) N-de methylation and subse quent loss of sulfur dioxide leading to the cyclized compound was identified as a “cyclized ipso compound,”; and 3) oxidation and conjugation at the 5- position of the pyrimidine ring.

A poultry metabolism study was not required (R. Sc hmitt, 7/25/89) because at the proposed treatment rates the RACs used for feeding poul try, would contain no detectable residues of nicosulfuron (<0.05 ppm), or any significant me tabolites as evidenced by the plant metabolism study.

5.1.4 Analytical Methodology

90-TN-03, A. Akins, 1/11/90 PP#7G3564, F. Suhre, 1/30/89

CIBA-Geigy’s method, AG-499, an HPLC/UV met hod, was found adequate for enforcement purposes. The procedure has a LOD of 0.05 ppm. The method was recommended for inclusion in the Pesticide Analytical Manual Vol. II (PAM II). The method is adequate for enfocement of the
Section 18 time-limited tolerance.

Grass forage and hay samples in the administra tive materials submitted by DuPont in support of the Section 18 request were analyzed for nicosu lfuron using procedures described in DuPont17928, dated May 26, 2006, entitled "Analytical Met hod for the Determination of Nicosulfuron (DPX-V9360) and its Metabolite IN-V9367 in Pa sture Grass by HPLC/E SI-MS/MS" including14 of 30 modifications to the method dated December 20, 2007 and deviations to the method dated January 28, 2008, January 31, 2008, and March 14, 2008. Resi dues found in/on samples are reported as nicosulfuron, IN-V9367 (expressed as nicosulfuron parent equiva lents), and tota l nicosulfuron parent equivalents, based upon the molecu lar weight mathematical conversion.

Briefly, residues of nicosulfuron and IN-V9367 were extracted from fortified grass samples by homogenization in acetone: 0.1M ammonium carbona te (90:10, v/v) followed by shaking in 0.1 M ammonium carbonate. Aliquots of the sample ex tracts were purified by solid phase extraction (SPE). The compounds were eluted from the cartridges with methanol. The eluates were evaporated to dryness under a gentle stream of nitrogen gas at 35°C and then reconstituted in methanol: 10mM ammonium formate (5:95, v/v) so lution and filtered. The purified extracts were analyzed by reversed-phase HPLC with electro spray mass spectrometry/mass spectrometry (ESIMS/MS) for detection. The method L OD and LOQ were 0.003 mg/kg and 0.010 mg/kg, respectively.

Morse Laboratories, Inc. of Sacramento, Californi a, conducted a successful ILV of the Analytical Method “Analytical Method for the Determin ation of Nicosulfuron (DPX-V9360) and its Metabolite IN-V9367 in Pasture Grass by HPLC/E SI-MS/MS, DuPont-17928.” The study reports of this analytical method and validation (DuP ont-17928 and DuPont-18853) will be submitted with the tolerance petition.

The description of the method used for data gath ering is included for informational purposes. The adequacy of the method will be assessed when submitted with the tolerance petition.

5.1.5 Environmental Degradation

The primary degradation pathways were hydrolysis and oxidation. Nicosulfuron hydrolyzed to the major transformation product V9367 (pyridine su lfonamide) and to o-desmethyl nicosulfuron (37740), and then further degraded to the unide ntified major transformation product “metabolite A,” which has the sulfonylurea bridge intact.

The major transformation products detected in the soil were pyridine sulfonamide and the unidentified “metabolite A”. Pyridine sulfonamide was detected in the 0-6 inch soil depth at a maximum concentration of 0.004 ppm at 121 days and decreased to 0.001 ppm by 366-548 days posttreatment. Pyridine sulfonamide was not de tected in the 6-12 inch soil depth above 0.001 ppm. “Metabolite A” was detected in the 0-6 inch soil depth at a maximum concentration of 0.004 ppm at 250 days and decreased to 0.003 ppm by 366- 548 days posttreatment. “Metabolite A” was detected in the 6-12 inch soil depth at a maximum of 0.002 ppm at 366 days posttreatment.

The only major transformation product detected in the soil treated with [pyrimidine-2-

14 C]nicosulfuron was the unidentified “metabolite A”, which was detected in the 0-6 inch soil depth at a maximum concentra tion of 0.004 ppm at 121 and 250 da ys, and decreased to 0.003 ppm by 456-548 days posttreatment. “Metabolite A” was not detected in the 6-12 inch soil depth above 0.001 ppm.

In lysimeters treated with [pyridine-2- 14 C] nicosulfuron, material ba lances decreased from 84.6- 87.5% at 0-121 days to 72.9-75.6% by 250-548 days following treatment. In lysimeters treated with [pyrimidine-2- 14 C] nicosulfuron, material balances decreased from 76.7-92.2% at 0-121 days to 70.7-71.8% by 250-366 days and 53.6% by 548 days following treatment. The study authors attributed losses of radioactivity from lysimeters treated with both labels to the production of a volatile compound that was not captured. For the purposes of this Section 18, the residue of15 of 30 concern in drinking water is nicosulfuron only.

5.1.6 Comparative Metabolic Profile

The metabolism of 14 C-nicosulfuron was studied in male a nd female rats. Following oral dosing, most of the radioactivity was excreted unchange d within 24 hours. Elimination in the feces accounted for 80 to 95% of the dose, and elimin ation in the urine accounted for 9 to 20%.
Elimination of 14 CO 2 was negligible (<0.01 of the admini stered dose). 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 unchanged parent compound. In addition, pyridinesulfonamide (N, Ndimethyl-2-sulfonamide pyridine- 3-carboxamide) was detected in the urine and accounted for 1.1 to 5.7% of the dose. Pyridine acid sulfonami de (2-sulfonamidepyridin e-3-carboxylic acid) was tentatively identified as a minor metabolite in the feces of orally dos ed rats and urine of intravenously dosed rats. These metabolites repr esent hydrolytic cleavage/oxidation of the parent
molecule.

The metabolic pathway of nicosulfuron in plants is similar to its pathway in rats. Based upon the results of the nicosulfuron metabolism study in corn, the metabolism of nicosulfuron proceeds predominantly via two mechanisms: the hydrolysis of the sulfonylurea bridge yielding pyridine sulfonamide and pyrimidine amine, and the hydroxyl ation of nicosulfuron at the 5-position of the pyrimidine amine followed by glucosidation (in earl y forage samples). The analyses show that nicosulfuron gradually decreases during the corn growing season and is present in very low levels at maturity. However, residues of metabolite pyridine sulfonamide begin at day 0 and are detected in the whole plant and stalk at maturity ( 113 day PHI) exceeding residues of nicosulfuron. Pyrimidine amine is further metabolized to its 5-hydroxy 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 the rat and plant. The likely metabolic pathway for nicosulfuron in liv estock is hydrolysis of the sulfonylurea bridge to yield pyridine sulfonamide and pyrimidi ne amine (both of which undergo additional metabolism), N-demethylation and subsequent loss of sulfur dioxide leading to an unidentified cyclized compound; and oxidation and conjugati on at the 5-position of the pyrimidine ring.

5.1.7 Pesticide Metabolites and Degradates of Concern

Table 5.1.7. Summary of Metabolites and Degr adates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Primary Crop Nicosulfuron Nicosulfuron Plants

Rotational Crop Nicosulfuron Nicosulfuron

Ruminant Not Applicable Not Applicable Livestock

Poultry Not Applicable Not Applicable

Drinking Water Nicosulfuron Not Applicable

5.1.8 Drinking Water Residue Profile

DP Num: 301842, 302623, 302624, L. Liu, 7/28/04Page 16 of 30 EFED presented 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 surface water the chronic (average 56-day) value is 0.685 ppb based on the application on corn. The groundwat er screening concentration is 0.056 ppb for nicosulfuron. The highest result of the two models, surface wa ter 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 th e aggregate food + water assessment.

Table 5.1.8. Summary of Esti mated Surface and Ground Water Concentrations for Nicosulfuron.

Exposure Duration

Surface Water Conc., ppb a Ground Water Conc., ppb b

Chronic (non-cancer) 0.685 ppb 0.056 ppb

Chronic (cancer) N/A N/A

a From the Tier I FIRST

b From the SCI-GROW model

5.1.9 Food Residue Profile

In support of the proposed Section 18 use, th e Dept. of Agriculture has cited a volume of administrative materials for an upcoming petition entitled “Petition for Establishment of Tolerances for Nicosulfuron on Grass Forage, Grass Hay, Meat, Meat by-products, Milk and Milk, fat,” (R. Ashley, 12/2008). Thirteen residu e field trials were conducted on Bermudagrass, brome, and fescue in Regions 5 (Eastern ND and NE and Central MO and IA), 6 (Eastern TX and OK), 7 (Central SD), and 8 (Western TX and OK). Nicosulfuron 75WG was applied either as a single foliar broadcas t application at the rate of 1.41 oz a i/A (0.088 lb ai/A), or as two foliar broadcast applications at the target rates of 0.938 oz ai/A ( 0.059 lb ai/A) and 0.469 oz ai/A (0.029 lb ai/A). Non-ionic surfactants or nitrog en were included in the spray mixture in all applications.

Samples were harvested the same day as the last application (email, S. Groce, 3/31/09). Forage samples were cut at the same time as the hay samples, but were immediately frozen without drying. Analysis of the samples was conducte d using the method described in DuPont-17928. The registrant reported that the LOQ of the analytical method was 0.010 ppm and the LOD was 0.003 ppm (1/3 the LOQ). Nicosulfuron residue s in grass forage ranged from 0.032 ppm to 7.7 ppm. Nicosulfuron residues in grass hay ranged from 0.11 ppm to 18.0 ppm.

Table 5.1.9.a Summary of Crisis Exemption Use
Patterns

. State OK TX
Application Dates April 1,2009 Early February

2009

Counties Throughout statePage 17 of 30 Table 5.1.9.a Summary of Crisis Exemption Use

Patterns

. State OK TX Crop Bermudagrass

Pest Sand bur

Formulation PastoriaTM
# of Applications 2
Max. Appl. Rate 1.0-2.5 fl oz (0.035-0.088 lb ai) /A/yr
Acreage 200K 11,200K
Application Interval NA

Pre-harvest Interval Harvest or grazing may begin at any time.

Other Apply only to established Bermudagrass that is at least one year old.

These data indicate that a time-limited tolera nce for nicosulfuron residues on Bermudagrass, forage should be established at 10 pp m and on Bermudagrass, hay at 25 ppm.

Grass forage and hay are feed items for beef and dairy cattle. Table 5.1.9.b, below, shows a reasonably balanced dietary burden for cattle using the established tolerances for corn commodities as well as the proposed time-limited tolerances for Bermudagrass (e-mail, J. Stokes, 4/6/09). The diet results in an exposure of 3.0 ppm for bot h beef cattle and 5.8 ppm for dairy cattle. Previously submitted metabolism st udies using lactating goats dosed with either [pyrimidine 2- 14 C] nicosulfuron or [pyridine-2- 14 C] nicosulfuron at a daily feeding level of approximately 60 ppm showed uptake of residues was low for all tissues and organs for either label. The highest level found, 0.1 ppm (0.04% of total dose), was in the liver from the goat treated with the pyridinyl labe l. All other tissues had TRR of approximately 0.07 ppm or less (MRID 41082627). Using the dietary burden and the dosage and results of the metabolism study, residues would not be detectable in ca ttle commodities (0.1 ppm found in liver x 3.0 ppm beef cattle diet/ 60 ppm dose = 0.00 5 ppm in liver). Therefore, ARIA/RD has concluded that as
a result of this Section 18 use, there would be no detectab le residues of nicosulfuron in
ruminants.Page 18 of 30 Table 5.1.9.b Calculation of Reasonably Balanced Dietary Burdens of Nicosulfuron Residues for Livestock.

Feedstuff Type 1 % Dry

Matter 2 % Diet 2 Tolerance (ppm) Dietary Contribution (ppm) 3

Beef Cattle R 15%, CC 80%, PC 5%
Bermudagrass, hay R 88 10 25 2.84
Corn, forage/silage R 40 5 0.1 0.013
Corn, field, grain/milled byproducts CC 88 80 0.1 0.091

Untreated PC -- 5 -- --

TOTAL BURDEN 100 3.0
Dairy Cattle R 45%, CC 45%, PC 10%
Bermudagrass, hay R 88 20 25 5.68
Corn, forage/silage R 40 25 0.1 0.063
Corn, field, grain/milled byproducts CC 88 45 0.1 0.051

Untreated PC -- 5 -- --

TOTAL BURDEN 100 5.8

1 R: Roughage; CC: Carbohydrate concentrate; PC: Protein concentrate.

2 Table 1 Feedstuffs (June 2008).

3 Contribution = ([tolerance /% DM] X % diet).

Grass feed items are not used for swine and poultr y. Since the addition of grass feed items will not affect the swine or poultry diets, no change w ill be required in the associated tolerances (i.e.,
ARIA continues to conclude that livestock tolera nces are not needed for the existing use on corn or for the proposed Section 18 use on Bermudagrass..

5.1.10 International Residue Limits

Codex Alimentarius Commission, Canada, or Mexi co have not established maximum residue limits (MRLs) for residues of nicosulfuron in/ on grasses. Tolerance harmonization is not an issue for this petition.

5.2 Dietary Exposure and Risk

5.2.1 Acute Dietary Exposure/Risk

Since no acute end point has been selected for nicosulfuron, an acute dietary exposure
assessment was not conducted.

5.2.2 Chronic Dietary Exposure/Risk

Chronic dietary exposure is determined from food a nd drinking water. In the case of this Section 18 request, there are no human food items of regulable interest for Bermudagrass. ARIA has
also determined that there will be no detectable nicosulfuron residues in livestock commodities. A previous chronic dietary (food + water) risk assessment was conducted for the general U.S. population and various population su bgroups. Drinking water was incorporated directly into the dietary assessment using the chronic (annual av erage) concentration for surface water. ThePage 19 of 30 results of the chronic dietary exposure analysis are reported in Tabl e 5.2.3. Tolerance level residues were used, assuming 100 %CT, and a singl e point estimate for drinking water, resulting in a conservative analysis for this chronic e xposure and risk assessment on nicosulfuron. The
results indicate chronic dietar y risks are below HED’s level of concern (100% cPAD). The cPAD value for the general U.S. population is less than 1%, and the %cPAD for the most highly exposed population subgroup, children 3-5, is also less than 1% (DP Num: 302694, D. Hrdy,
11/30/04 ).

. 5.2.3 Cancer Dietary Risk

There is no cancer risk associated with the proposed Section 18 use b ecause nicosulfuron has been classified “not likely to be carcinogenic to humans.”

Table 5.2.3. Dietary (Food +Drinking Water) Exposure and Risk Estimates for Nicosulfuron.

Acute Chronic Cancer Population Subgroup

Exposure mg/kg/day %aPAD, Exposure mg/kg/day %cPAD Exposure mg/kg/day Risk

U.S. Population 0.000221 <1

All infants (< 1 yr) 0.000323 <1

Children 1-2 yrs 0.000443 <1

Children 3-5 yrs 0.000506 <1

Children 6-12 yrs 0.000384 <1

Youth 13-19 yrs 0.000292 <1

Adults 20-49 yrs 0.000181 <1

Adults 50+ yrs 0.000110 <1

Females 13-49 yrs NA NA

0.000181 <1 NA NA

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information

Tolerance level residues and 100%CT were assumed for all registered and proposed
commodities in the chronic assessment.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no residential uses of nicosulfuron; therefore a resi dential risk assessment was not
conducted.

6.1 Other (Spray Drift, etc.)

Spray drift is always a potential source of expos ure to residents nearby to spraying operations. This is particularly the case with aerial appl ication, but, to a lesser ex tent, could also be a potential source of exposure from the ground application method employed for nicosulfuron. The Agency has been working with the Spray Dr ift Task Force, EPA Regional Offices and StatePage 20 of 30 Lead Agencies for pesticide regulation and ot her parties to develop the best spray drift management practices. On a chem ical by chemical 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 regi strants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orch ard airblast and ground hydraulic me thods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant ri sks associated with drift.

7.0 Aggregate Risk Assessments and Risk Characterization

Since there are no residential us es of nicosulfuron, aggregate risk for all exposure durations consists only of food and drinking water. For ni cosulfuron, there is no en dpoint established for acute exposure and it has been determined to be a “not likely” carcinogen; therefore there is no acute or cancer aggregate risk. ARIA has dete rmined that chronic dietary exposure from food and drinking water does not exceed HED’s level of concern (see Section 5.2.2, above)

.

8.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has fo llowed 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 any other s ubstances and nicosulfuron does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore,
EPA has not assumed that nicosulfuron has a common mechanism of to xicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate th e cumulative effects of such chemicals, see the policy statements released by EPA’s OPP con cerning common mechanism determinations and procedures for cumulating effects from subs tances found to have a common mechanism on
EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

DP Num: 361732, M. Dow, 4/1/09

Based upon the proposed use pattern, ARIA/RD be lieves the most highly exposed occupational pesticide handlers will be 1) mixer/loaders us ing open-pour loading of dry flowables, 2) applicators using open-cab ground-boom sprayers, 3) aerial applicators, 4) applicators using ATVs (miniboom or “hand-wand”), 5) mixer/loader/applicators us ing backpack sprayers, and 6) mixer/loader/applicators using hand-held, pump-up spra yers. The latter is not assessed in that the assessment of a mixer/loader/applicator us ing an ATV mounted low-pressure hand-wand sprayer is adequate (protective) to describe a hand held sprayer. The spray wands are quite similar and the delivery pressures are similar (low pressure). The operator using an ATV mounted sprayer is likely more highly exposed th an a handler using a pump-up sprayer due to the increased area treated per day thus the increased volume handled per day.Page 21 of 30 9.1 Short-Term Handler Risk

ARIA/RD believes occupational hand lers will be exposed to short- term duration exposures (1 - 30 days). Multiple applications are generally not expected and treatment plots are expected be rather small by comparison to typical, large acreage row crops.

Private (i.e., grower) applicat ors may perform all functions, that is, mix, load and apply the material. Standard HED practice directs that although the same individual may perform all those tasks, they shall, in some cases, be assesse d separately. The avai lable exposure data for combined mixer/loader/applicator scenarios are li mited in comparison to the monitoring of these two activities separately. These exposure s cenarios are outlined in the Pesticide Handler Exposure Database (PHED) Surrogate Exposure Guide (August 1998).

HED has adopted a methodology to present the exposur e and risk estimates se parately for the job functions in some scenarios and to present them as combined in other cases. Most exposure scenarios for hand-held equipment (such as ha nd wands, backpack sprayers, and push-type granular spreaders) are assessed as a combined job function. With these types of hand held operations, all handling activities are assumed to be conducted by the same individual. The available PHED and other exposure data support this and HED presents them in this way. Conversely, for equipment types such as fixed- wing aircraft, ground-boom tr actors, or air-blast sprayers, the applicator exposures are assessed and presented separa tely from those of the mixers and loaders. By separating the two job func tions, HED/RD determine the most appropriate levels of personal protective equipment (PPE) fo r each aspect of the job without requiring an applicator to wear unnecessary PPE that might be required for a mixer/loader (e.g., chemical resistant gloves may only be necessary duri ng the pouring of a liquid formulation).

No chemical specific data were available with which to assess potential exposure to pesticide handlers. The estimates of exposure to pest icide handlers are based upon surrogate study data available in the PHED (v. 1.1, 1998). For pestic ide handlers, it is HED standard practice to present estimates of dermal exposure for “baselin e” that is, for workers wearing a single layer of work clothing consisting of a l ong-sleeved shirt, long pants, s hoes plus socks and no protective gloves as well as for “baseline” and the use of protective gloves or ot her PPE as might be necessary. The product label direct s applicators and other handlers to wear long-sleeved shirt, long pants, shoes plus socks and chemical-resist ant gloves in Category A (such as butyl rubber, natural rubber, neoprene rubbe r or nitrile rubber), all ≥ 14 mils.

Since an oral study was selected fo both dermal and inhalation exposure and risk assessment,
ARIA assumed default 100% dermal and inhala tion absorption factors (relative to oral absorption). Since the dermal and toxicologi cal endpoints were identified from the same study and effects, the dermal and inhalation exposures were summed prior to use in calculation of MOE (NOAEL ÷ Average Daily Exposure).

Nicosulfuron is not likely to be carcinogenic base d on lack of tumurogenic effects in bioassays at
the limit dose in the rat and mouse and lack of in vitro and in vivo mutagenic effects.Page 22 of 30 Since the adverse effects for all studies utilized in the nicosu lfuron risk assessments are not gender-specific, the average weight for an adult (i.e., 70 kg) was used to estimate exposure.

1. Unit Exposures are taken from “PHED SURROGATE EXPO SURE GUIDE”, Estimates of Worker Exposure from The Pesticide Handler Exposure Database Version 1.1, August 1998. Dermal = Single Layer Work Clothing No Gloves ; Single Layer Work Clothing With Gloves ; Inhal. = Inhalation. Units = mg ai/pound of active ingredient handled. 2. Applic. Rate. = Taken from OK and TX s ection 18 request and from draft label.
3. Units Treated are taken from “Standard Va lues for Daily 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 is assumed by ARIA/RD. 4. Average Daily Dose = Unit Exposur e * Applic. Rate * Units Treated *100 % dermal absorption ÷ 7 0 kg Body Weight 5. MOE = Margin of Exposure = NOAEL ÷ ADD. NOAEL = 125 mg ai/kg bw/day. ADD = dermal + inhalation exposure

* 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 a nd 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 greate st exposure thus cont ributes to the most conservative (protective) estimate of risk. 5 acres per day is select ed as the units treated per day. ** The unit exposure for a M/L/A using a bac kpack is based on PHED for open loading of liquids. There are no PHED M/L/A data reflectin g backpack and dry flowable granules. The data for handlers loading liquids are considered to be conservativ e/protective. The units treated are based on the spray volumes recommended. Ground spray volumes vary from 10-30 gpa. Table 9.1 Summary of Exposure & Risk to Occupa tional Handlers From Appl ying Nicosulfuron to Bermudagrass 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:
SLNoGlove 0.066
SLWithGlove 0.066
Inhal. 0.00077 0.0527
lb ai/A 350 A/day Dermal:
SLNoGlove 0.0174
SLWithGlove 0.0174
Inhal. 0.0002 No Glove 7,100
With Glove 7,100 Applicator - Ground-boom - Open-cab

Dermal:
SLNoGlove 0.014
SLWithGlove 0.014
Inhal. 0.00074 0.0527
lb ai/A 200 A/day Dermal:
SLNoGlove 0.0021
SLWithGlove 0.0021
Inhal. 0.00011 No Glove 57,000
With Glove 5,700 Aerial Applicator (Pilots not required to wear gloves)

Dermal:
SLNoGlove 0.005
Inhal. 0.000068 0.0527
lb ai/A 350 A/day Dermal:
SLNoGlove 0.00132
Inhal. 0.000018 No Glove 93,000

Mixer/Loader/Applicator * – ATV low-pressure handwand

Dermal:
SLNoGlove no data
SLWithGlove 8.6
Inhal. 1.1 0.0527
lb ai/A 5 A/day Dermal:
no data
SLWithGlove 0.0324
Inhal. 0.0041 With Glove 3,400

Mixer/Loader/Applicator **

– Backpack sprayer

Dermal:
SLNoGlove no data
SLWithGlove 2.5
Inhal. 0.03 0.0527
lb ai/A 2 A/day Dermal:
no data
SLWithGlove 0.00376
Inhal. 0.0000452 With Glove 33,000Page 23 of 30 Therefore, at a median of 20 gpa spray volume and an Agency default of 40 gallons/day using backpack = 2 acres per day.

A MOE of 100 is adequate to protect occupa tional pesticide handler s from exposures to
nicosulfuron. The estimated MO Es are all > 100. Th erefore the proposed Section 18 use does
not exceed ARIA/RD’s level of concern.

9.2 Short-/Intermediate-/Long -Term Postapplication Risk

It is possible for agricultural workers to have post-application exposur e to pesticide residues during the course of typi cal agricultural activities. HED in conjunction with the Agricultural Reentry Task Force (ARTF) has identified a number of post-application agricultural activities that may occur and which may result in post-applica tion exposures to pestic ide residues. HED has also identified transfer coefficients (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 Coeffici ents, Revised August 2000)..

The HED SOP does not reflect post-application agricultural activity data with regards to Bermudagrass. The database does contain inform ation regarding “forage plants.” The highest TC listed is 1,100 cm 2 /hr for scouting. Since the requested applications of nicosulfuron are for early season (early post-emergen ce), 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 assessm ent, ARIA/RD herein us es the TC of 1,100 cm 2 /hr for scouting to assess efficacy of the treatment.

The TCs used in this assessment are from an interim TC SOP developed by HED’s ExpoSAC using proprietary data from the ARTF database (SOP # 3.1). It is the intention of HED’s ExpoSAC that this SOP will be pe riodically updated to incorporat e additional information about agricultural practices in crops a nd new data on transfer coefficients. Much of this information will originate from exposure studies currently being conducted by the ARTF, from further analysis of studies already submitted to the Agen cy, and from studies in the published scientific
literature.

Lacking compound specific dislodgeable foliar re sidue (DFR) data, 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 convention may be used to estimate post-application exposure.

Average Daily Dose (ADD) (mg ai/kg bw/day) = DFR μg/cm 2 * TC cm 2 /hr * hr/day * 0.001 mg/μg * 1/70 kg bw

and where:Page 24 of 30 Surrogate Dislodgeable Foliar Residue (DFR) = app lication rate * 20% ava ilable as dislodgeable residue * (1-D) t * 4.54 x 10 8 μg/lb * 2.47 x 10 -8 A/cm 2

.

0.0527 lb ai/A * 0.20 * (1-0) 0 * 4.54 x 10 8 μg/lb * 2.47 x10 -8 A/cm2 = 0.118 μg/cm 2 , therefore,

0.118 μg/cm 2 * 1,100 cm 2 /hr * 8 hr/day * 0.001 mg/μg ÷ 70 kg bw = 0.0148 mg/kg bw/day.

MOE = NOAEL ÷ ADD then 125.0 mg/kg bw/day ÷ 0.0148 mg/kg bw/day = 8445.

A MOE of 100 is adequate to pr otect agricultural work ers from post-application exposures. The most conservative estimate (i.e ., highest exposure/risk) of post- application exposure results in MOEs > 100. Therefore, the proposed risk does not exceed ARIA/RDs level of concern.

10.0 Data Needs and Label Recommendations

ARIA/RD notes that a lthough there are no additional data needed to support the proposed Section 18 use on grasses, there are data gaps for toxicology studies wh ich result from the 2007 update of the Part 158 Data Requirements. The following studies should be submitted in support of future Section 3 registrations:

• Neurotoxicity studies (a cute and subchronic)

• Immunotoxicity study

• 21/28-day dermal study

References:

D. Hrdy, 11/30/04, “Nicosulfuron HED Chapter of the Reregistration Eligibility Decision Document (RED),” DP Num: 302694

A. Khasawinah, 11/19/04, “Nicosulfuron - H azard Characterization Assessment for the Reregistration eligivilig iy Decision Document (R ED). DP Num D302619.

D. Hrdy, 11/30/04, “Nicosulfuron Chronic Diet ary Exposure Assessment for the Tolerance Reassessment Eligibil ity Decision (TRED),” DP Num: 302621

Akins, 1/11/90,“90-TN-03. Section 18 Emergency Exemption for the use of Beacon on Field Corn to Contol Johnsongrass,” DEB# 6132

F. Suhre, 1/30/89, PP#7G3564

E. Regelman, 6/1/90, Accession #: 412004-044

R. Schmitt, 7/25/89Page 25 of 30 L. Liu, 7/28/04, “Tier I Estimated Environmental Concentrations of Nicosulfuron, for use in Human Health Risk Assessment,” DP Num: 301842, 302623, 302624

M. Dow, 4/1/09, “NICOSULFURON – Human Occ upational Exposure/Risk Assessment for the Proposed FIFRA Section 18 Use of Nicosulfuron on Bermudagrass Pasture and Hayfields in Oklahoma and Texas,” DP Num: 362708Page 26 of 30 Appendix A: Toxicology Assessment

Table A.1 Acute Toxicity Profile - Nicosulfuron

Guideline

No. Study Type MRID #(s) Results Toxicity Category

870.11 Acute Oral - Rats
90.6 % ai 409242054 LD 50 > 5000 mg/kg Acceptable/Guideline IV

870.12 Acute Dermal- Rabbits 90.6% ai 409242074 LD 50 = > 2000 mg/kg Acceptable/Guideline III

870.13 Acute Inhalation - Rats
90.6% ai 49242094 LC 50 = >5.9 mg/L Acceptable/Guideline IV

870.24 Acute eye irritation - Rabbits
90.4% ai 410826024 Moderate eye irritant Acceptable/Guideline III

870.25 Acute dermal irritation

- Rabbits, 90.6 % ai 410826034 Not irritant Supplement/Guideline IV

870.26 Skin Sensitization -guinea pigs
90.4% ai 410826044 Not a sensitizer Acceptable/Guideline NAPage 27 of 30 Table A.2 Subchronic, Chronic and Ot her Toxicity Profile: Nicosulfuron

Guideline No./

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

870.3100 90-Day oral toxicity ( CRL:CD BR rats ) 41082607 (1988) Acceptable/guideline (10/sex/dose) at 0, 300, 1500, 7500 or 20,000 ppm 94.9% purity 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 could not be derived from this study. There was a statistically significant decrease (p<0.05) but not in a dose dependent fashion in platelets in fe males at all doses tested both at the 45 and 90 day sacrifices. No other hematological parameters were significantly affected. Blood calcium and bilirubin were significantly depresse d (p<0.05) at dose levels of 1500 ppm and
above in males and fema les, but not in a dose-dependent fashion.Ketones were present in the urine of all treated males in a doserelated manner, but not in females. The hematological and urinary findings were not seen in the 24 month study in rats, thus the biological significance of these findi ngs in this subchronic test is questionable.

870.3150 90-Day oral toxicity Beagle dogs (4/sex/dose) 41082606 (1988) Acceptable/guideline 0, 250, 5000, or 20000 ppm 94.5% purity M: 0, 9.23, 172.0, 710.0 F: 0, 9.14, 171.0, 683.0 mg/kg/day NOAEL is 5000 ppm (172/ 171 mg/kg/day in males/females)
LOAEL = 20,000 ppm (710/ 683 mg/kg/day in males/females) based on the hematological findi ng (reduction of neutrophils in females)

870.3200 21/28-Day dermal toxicity (species) None

870.3250 90-Day dermal toxicity (species) None

870.3465 90-Day inhalation toxicity (species) None

870.3700a
Prenatal developmental in ( Crl:CD BR mated and presumed pregnant

rats ) 41082608 (1988) Acceptable/guideline 0, 200, 1000 , 2500 or 6000 mg/kg/day from days 7 through 16 of gestation. Maternal NOAEL = 6000 mg/kg/day or greater LOAEL = greater than 6000 mg/kg/day Developmental NOAEL = 6000 or greater mg/kg/day LOAEL = greater than 6000 mg/kg/day. No treatment-related
effects were noted on maternal or developmental toxicity up to and including the highest dose tested of 6 grams/kg (the limit of the suspension capability).

870.3700b
Prenatal developmental in ( New Zealand White

SPF Rabbits) 41082609 (1988) Acceptable/guideline 0, 100, 5000 , 1000 or 2000 mg/kg/day from days 7 through 19 of gestation Materna l NOAEL = 100 mg/kg/day LOAEL = 500 mg/kg/day based on an increase in the number of animals with diarrhea (1000 mg /kg/day), possible vaginal discharge, abortion, a decrease in body weight gain during the dosing period, staining of hair in the rectal and vaginal areas and an apparent increase in % postimplantation loss. Developmenta l NOAEL = 100] mg/kg/day LOAEL = 500 mg/kg/day based on an apparent increase in percent postimplantation loss
NOAEL for fetal toxicity is 500 mg/kg/day
LOAEL for fetal toxicity is 1000 mg/kg/day, based on reduced mean fetal body weight There were no external on visceral
anomalies in the fetuses.Page 28 of 30 870.3800 Reproduction and Fertility Effects (rats) 41360101 (1989) Acceptable/guideline 0, 250, 5000 or 20000 ppm M: 14.4-16.7, 289 - 338, Parental/Systemic NOAEL = 5000 ppm (287 mg/kg/day) LOAEL = 20,000 ppm (1265 mg/kg/day) based on lower body weight gain (p<0.05) in the F 1 (first mating) females
NOAEL for reproductive and fetal toxicity = 5000 ppm (287 mg/kg/day) LOAEL = 20,000 ppm (1265 mg/kg/da y) based on a statistically significant (p<0.05) decrease in litter size at birth and in pup weights at postpartum day 14 through 21 in the F 2a high dose group.

870.4300
Chronic/ Carcinogenicity (CR:CD-BR Rat) 41360104 (1989) Acceptable/guideline (90.6% - 92.8% ai) 0, 50, 1500, 7500 or 20000

ppm M: 1.9, 58, 289, 786 F: 2.6, 77, 382, 1098 mg/kg/day NOAEL = 20,000 ppm (786/ 1098 mg/kg/day in males/females, highest dose tested).
LOAEL = >20,000 ppm (786/ 1098 mg/kg/day in males/ females)
based on the lack of chronic toxic effects. Although, the MTD was not achieved, the material was tested at limit dose levels in both sexes. No tumors reported.

870.4100b Chronic toxicity (Beagle dog) 41360102 (1989) Acceptable/guideline (5/sex/dose/group) 0, 250, 5000 or 20000 ppm M & F : 0, 6.25, 125, 500 mg/kg/day LOAEL = 20,000 ppm (500 mg/kg/day) based upon the statistically significant increase in the relativ e liver and kidney weights of males
NOAEL = 5000 ppm (125 mg/kg/day)

870.4300 Carcinogenicity (CRL:CD-1(CR)BR mouse) 41360103 (1989) Acceptable/guideline (80/sex/dose/group) in the diet at 0, 25, 250, 2500 or 7500 ppm (3.2, 31.4, 314, 953/ 4.2, 43.0, 420, 1260 mg/kg/day for males/females, based on 90.6% purity) NOAEL = 7500 ppm= (953/1260 mg/kg/day in males/females, the highest dose tested).
LOAEL = >7500 ppm (953/1260 mg/ kg/day in males/females) based on the lack of systemic toxicity. (no) evidence of carcinogenicity

870.5100
Gene Mutation
Bacterial reverse
mutation
Salmonella typhimurium 41082612, 41360124 (1988) Acceptable/guideline TA98, TA1535 at 0.1 to 1 microgram /plate, TA97A at 0.02 to 0.1 microgram/ plate
and TA100 at 0.1 to 10 micrograms/plate with and
without metabolic activation INV-9360-7 was nonmutagenic to th ese strains at doses reaching cytotoxic levels in the presence or absence of metabolic activation.

870.5300 Cytogenetics

in vitro CHO/HPRT mutation assay 41082614, 41360123 (1988) Acceptable/guideline 4, 20, 40, 200 or 465 microgram/mL with or
without metabolic activation Nicosulfuron was non mutagenic. The maximum concentration tested 465 micrograms/mL was the limit of the test compound solubility in the test system (HED 007963).

870.8375 Cytogenetics 41082615, 41368001 (1988) Nicosulfuron was not clastogenic under the conditions of this test. 870.5395 Cytogenetics 41082616, 41360126 (1988) Acceptable/guideline 0, 500, 2500 or 5000 mg/kg. A positive control group received 40 mg/kg of cyclophospahmideIN V9360-27 did not induce a clastogenic or aneugenic effect in either sex at any dose or sacrifice time (24, 48 or 72 hours post-exposure)Page 29 of 30 870.5550
Other Effects Un
scheduled DNA synthesis in primary rat hepatocytes 41082613, 42360125 (1988) Acceptable/guideline 0.04, 0.4, 1.2, 4.1, 12, 41, 122, 409 or 470 micrograms/mL. 90.6% ai IN V9360-27 did not cause any DNA da mage or inducible repair in the rat hepatocytes. The highest concentration selected in this study was 470 micrograms/mL dose was the limit of solubility in the test system without cytotoxicity (HED 007963).

870.6200a Acute neurotoxicity screening battery NA

870.6200b
Subchronic neurotoxicity screening battery NA

870.6300 Developmental neurotoxicity NA

870.7485
Metabolism and pharmacokinetics (Rat) 41082617 (1988) Acceptable/guideline Pyridine-2-C 14 Accent orally at 10 mg/kg or 1000 mg/kg, or at 10 mg/kg following oral
administration of unlabeled Accent at 10 mg/kg/day for 14 days, and iv at 10 mg/kg. Pyrimidine-2-C 14 labeled Accent orally at 1000 mg/kg. Total recovery was 98-109% of AD after 4 days of dosing, mostly excreted unchanged within 24 hours. No apparent differences between sexes or dose groups, although a slightly greater % of the AD was detected in feces of animals receiving the high dose than in animals receiving the low dose. Following oral dosing, elimination in the feces was 80 to 95% of the dose, and in the urine was 9 to
20%. Elimination of 14 C-CO 2 was negligible (<0.01 of the AD). The average total cumulative excretion indicated half-lives between 12 and 24 hours. Following iv administration, ~ 76 to 80% of the
dose was eliminated in the urine and 27 to 30% in the feces. Residues in tissues were 0.05 to 0.5% of the dose. The major excretion product in urine and feces was unchanged parent compound. In addition, pyridinesulfonamide (n,N-dimethyl-2- sulfonamide pyridine-3-carboxamide) was detected in the urine (1.1 to 5.7% of the dose). Pyridine acid sulfonamide (2- sulfonamidepyridine-3-carboxylic ac id) was tentatively identified as
a minor metabolite in the feces of or ally dosed rats and urine of iv dosed rats. These metabolites represent hydrolytic cleavage/oxidation of the parent molecule.

870.7600 NA

Special studies NAPage 30 of 30 Appendix B: Internat ional Residue Status



## INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: [3- pyridinecarboxamide, 2- ((((4,6-dimethoxypyrimidin-2- yl)aminocarbonyl)aminosulfonyl))-N,Ndimethyl] Common Name:
Nicosulfuron ⁬ Proposed tolerance

⁬ Reevaluated tolerance

⁬ Other Date: 3/31/2009

Codex Status (Maximum Residue Limits) U. S. Tolerances √

No Codex proposal step 6 or above

⁬ No Codex proposal step 6 or above for the crops requested Petition Numbers : 09OK02
DP Number: 361732
Other Identifier:

Reviewer/Branch: W. Cutchin Residue definition (step 8/CXL): N/A

Residue definition: Nicosulfuron
Crop (s) MRL (mg/kg) Crop(s) Tolerance (ppm)
Bermudagrass, forage 10
Bermudagrass, hay 25

Limits for Canada Limits for Mexico

⁬ No Limits √ No Limits for the crops requested ⁬ No Limits √ No Limits for the crops requested

Residue definition:
2[[[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]- N,N

- dimethyl-3-pyridinecarboxamide Residue definition: nicosulfuron

Crop(s) MRL (mg/kg) Crop(s) MRL (mg/kg)

Notes/Special Instructions: S. Funk, 04/01/2009.

Rev. 1998