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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF PREVENTION, PESTICIDE

AND TOXIC SUBSTANCES

MEMORANDUM

Date: 27 October 2009

SUBJECT: Nicosulfuron. Human Health Risk Assessment for the Proposed Use on Grasses.

PC Code: 129008 DP Barcode: D360807

Decision No.: 404568 Registration No.: 352-IRO

Petition No.: 8F7501 Regulatory Action: Section 3 Registration

Risk Assessment Type:

 Single Chemical, Aggregate

Case No.: NA

TXR 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 860.1300 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.doc
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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 Physical 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 Literature 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 Analysis and Residual Uncertainties for Preand/or Postnatal Susceptibility.................................................................. 12

3.3.7 Recommendation for not requiring a Developmental Neurotoxicity Study12

3.4 FQPA Safety Factor for Infants and Children ........................................................... 12

3.5 Hazard Identification and Toxicity Endpoint Selection............................................. 12

3.5.1 Acute Reference 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 Level 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 Epidemiology 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............................................................................................. 18
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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 Characterization............................................ 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 ...................................................... 34
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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 the petition, they are 

requesting Section 3 Registration for a 56.2% dry flowable (DF) formulation of nicosulfuron 

(PastoraTM Herbicide; EPA File Symbol 352-IRO). 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 only 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. Despite 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 relatively 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 residential 

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 environmental 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 Low-Income Populations" 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 
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Extensive data on food consumption patterns are compiled 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 analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Whenever appropriate, nondietary 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 

postapplication are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary

patterns among specific subgroups.

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 Exposure 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 (ethically conducted) for use in risk assessments.

Prior to registration, HED recommends revised Sections B (directions for use) and F (proposed 

tolerances) and a revised analytical 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. Studies 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 additional concern at this time.

2.0 Ingredient Profile

2.1 Summary of Registered/Proposed Uses
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Table 2.1. Summary of Directions 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 

Limitations1

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 aerial 

(≥2 gal/A)

56.2% DF

[352-IRO]

0.035 2 0.070

(implied)

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 = nonionic surfactant; COC = crop oil concentrate.

2

 The label states that there are no grazing or haying restrictions.

Application through any type of irrigation system 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 Nomenclature.

Chemical structure

N

O

N

H3C CH3

S

NH NH

N

N O

O

CH3

CH3

O O

O

Common name Nicosulfuron

Company experimental name DPX-V9360
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Table 2.2. Nicosulfuron Nomenclature.

IUPAC name 2-(4,6-dimethoxypyrimidin-2-ylcarbamoylsulfamoyl)-N,N-dimethylnicotinamide;

1-(4,6-dimethoxypyrimidin-2-yl)-3-(3-dimethylcarbamoyl-2-pyridylsulfonyl)urea

CAS name 2-[[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]aminosulfonyl]-N,N-dimethyl3-pyridinecarboxamide

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/range 183.3 ± 0.3 °C MRID 47632204

pH 4.5 MRID 47632204

Density 1.441 ± 0.006 g/cm3relative 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

MRID 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 26

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/visible 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.
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3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

3.1.1.1 Sufficiency of studies/data

Based 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 chronic 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 well 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 10x 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 enzyme acetolactate synthase. 

Inhibition of this enzyme blocks branch-chain amino acid biosynthesis involved in plant growth 

processes which leads to death of the plant. Acetolactate synthase 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 hydrolytic cleavage/oxidation products of the 

parent. There were no significant sex- or dose-related differences 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.
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Developmental effects were not observed in the rat developmental toxicity study. In rabbits, 

maternal toxicity included clinical signs, decreased body weight gain during dosing and 

increased abortions. Developmental toxicity was observed at maternally toxic levels only

(postimplantation loss and decreases in fetal body weight). In the rat reproductive toxicity study, 

decreased live litter size and decreased pup weight at day 14 to 21 were observed in the F2a 

offspring at doses that were maternally toxic and exceeded the limit dose. In the available 

toxicity studies, there was no evidence of estrogen-, androgen- and/or thyroid-mediated toxicity.

Nicosulfuron is not likely to be carcinogenic based on negative bioassays 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 preand/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 developmental 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 LOAEL 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 

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 chronic dog 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 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 Safety Factor is 

discussed below in Section 3.3.
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Residential Exposure: Endpoints for residential exposure were not selected because there are 

presently 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.

Carcinogenicity: Nicosulfuron is classified as “not likely to be carcinogenic to humans” based 

on lack of tumorigenic effects in rodent (rats and mice) bioassays at the limit doses. 

Nicosulfuron was not mutagenic in in vitro and in vivo genotoxicity assays. 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 additional 

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 

assessment. Developmental toxicity studies in two species and a rat multigeneration 

reproductive toxicity study are available. Nicosulfuron is poorly absorbed and toxicity is 

generally low. Increased quantitative or qualitative pre- and/or postnatal susceptibility 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 only in the 

presence of maternal toxicity, which included abortions, 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 CO2

was negligible (<0.01% of dose). Radioactivity was not retained in tissues at significant levels 

(≤0.5% of dose). Minor metabolites of hydrolytic and oxidative metabolism were identified. In 

addition to unchanged parent compound, pyridinesulfonamide (N, N-dimethyl-2-sulfonamide 
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pyridine-3-carboxamine) was identified in the urine (1.1 to 5.7% of dose) and pyridine acid 

sulfonamide (2-sulfonamidepyridine-3-carboxylic acid) was tentatively identified as a minor 

metabolite in feces of orally dosed rats and urine of intravenously dosed rats. The poor oral 

absorption 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 Evidence 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, administered from 

gestation days 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 pregnant 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 days 7 

through 19. Maternal toxicity was observed at 500 mg/kg/day based 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 pup weights at 

postpartum day 14 through 21. 
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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

Increased quantitative or qualitative pre- and/or postnatal susceptibility was not observed in the 

developmental toxicity studies in rats or rabbits. Developmental effects were only observed at 

doses that caused maternal toxicity. 

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre- and/or Postnatal 

Susceptibility

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 immunotoxicity

study have not been submitted, there is no evidence for either type of toxicity in the available 

studies. The rat and rabbit developmental toxicity and rat reproductive toxicity studies 

adequately 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 qualitative 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 special FQPA SF to 1x is recommended, based on the following:

- The 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. 

- Increased 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. 

- There 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 Endpoint Selection

3.5.1 Acute Reference Dose (aRfD) – General Population
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No appropriate endpoint attributable 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 Assessment: 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

mg kg day = 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-year) for chronic oral 

exposure. The NOAEL of 125 mg/kg/day represents the most sensitive endpoint for this 

exposure duration. The endpoint is supported by the maternal toxicity NOAEL/LOAEL 

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 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 chronic endpoint was therefore selected as a 

more realistic endpoint. The selected endpoint is also protective 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 via 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 studies 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-Dog
Page 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 liver 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 studies 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/LOAEL of 

100/500 mg/kg/day). The rationale for selection of the chronic 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 NOAEL have been selected 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 

nicosulfuron. 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 Nicosulfuron for Use in Human 

Risk Assessments

Table 3.5.10.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

UFA= 10x

UFH= 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.

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) 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 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 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 

Human 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 (shortand 

intermediateterm)

NOAEL=125 

mg/kg/day

DAF = 100% 

(default)

UFA= 10x

UFH= 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 (LOAEL).

Supported by the NOAEL of 100 

mg/kg/day/LOAEL 500 mg/kg/day in 

the rabbit developmental toxicity 

study.

Inhalation 

(short- and 

intermediateterm)

NOAEL=125 

mg/kg/day

IAF = 100% 

(default)

UFA= 10x

UFH= 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 (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) 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 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable. DAF = dermal absorption factor. IAF = Inhalation absorption factor.

3.6 Endocrine 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 by a naturally 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 thyroid hormone systems, in addition to the estrogen hormone 

system. 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 systems 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 thyroid-mediated toxicity.

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 14C-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 14CO2 was negligible (<0.01 of the administered 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, pyridine sulfonamide 

(N, N-dimethyl-2-sulfonamide pyridine-3-carboxamide) was detected in the urine and accounted 

for 1.1 to 5.7% of the dose. Pyridine acid sulfonamide (2-sulfonamidepyridine-3-carboxylic 

acid) was tentatively identified as a minor metabolite in the feces of orally dosed rats, and in the 

urine of intravenously dosed rats. These metabolites represent 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 hydroxylation of nicosulfuron at the 5-

position of the pyrimidine amine followed by glucosidation (in early 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 the 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 that in rats and 

plants. The likely metabolic pathway for nicosulfuron in livestock is hydrolysis of the 

sulfonylurea bridge to yield pyridine sulfonamide and pyrimidine amine (both of which undergo 

additional metabolism), N-demethylation and subsequent loss of sulfur dioxide leading to an 
Page 18 of 35

unidentified cyclized compound; and oxidation and conjugation at the 5-position of the 

pyrimidine ring. 

Table 5.1. Summary of Metabolites and Degradates to be included in the 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 Applicable

5.2 Drinking Water Residue Profile

The Environmental Fate and Effects Division (EFED) has not provided HED with an updated 

analysis of nicosulfuron concentrations in drinking water. Estimated drinking 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 use on corn.

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 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. Summary of Estimated Surface and Ground Water Concentrations for Nicosulfuron.

Exposure Duration Concentration, ppb

Surface Water a Ground Water b

Acute 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 tentatively 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 

Spreadsheet) are summarized in Table 5.5.

Table 5.3. Summary of Residue Data from Crop Field Trials with Nicosulfuron.

Crop Matrix Treatment; 

Total Applic. Rate

(lb ai/A)

PHI1

(days)

Residue Levels (ppm)

n Min. Max. HAFT2 Median Mean Std. Dev.

Grass (proposed 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

(2nd cutting)

2 applications;

0.085-0.091

0 24 0.53 3.6 3.6 1.9 1.8 0.1

Grass hay

(2nd 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 analyzed for residues of nicosulfuron, the residue of concern, 

as well as for residues of metabolite IN-V9367 using 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 fat. 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 byproducts at 0.05 ppm. A tolerance is not needed for milk fat because 

residues did not concentrate in cream. A revised Section F should be submitted to the Agency.

5.4 International Residue Limits

Neither Codex Alimentarius Commission, Canada, nor Mexico have established maximum 

residue limits (MRLs) for residues of nicosulfuron in/on grasses. Tolerance harmonization is not 

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 tolerance 

enforcement of nicosulfuron residues in/on plants and livestock, respectively.
Page 21 of 35

Table 5.5. Tolerance Summary for Nicosulfuron.

Commodity Proposed Tolerance 

(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

Horse, 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

Sheep, 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 Surveys 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 conducted. The analysis assumes tolerance-level residues and 

100% crop treated for all foods (corn, meat, and milk commodities). Even with these highly 

conservative assumptions, the resulting risk estimates are less than 1% of the chronic populationadjusted dose (cPAD) for all population subgroups (Table 5.6). Generally 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. Summary of Dietary (Food + Drinking Water) Exposure and Risk for Nicosulfuron.

Population Subgroup

Acute (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) Information

The assessment assumes tolerance-level residues and 100% crop treated for all commodities.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no residential uses for nicosulfuron; therefore, residential exposure is not a concern for 

this chemical.

6.1 Other (Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method 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 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 registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 

off-target drift with specific products 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 estimates are equivalent to the dietary risk estimates 

presented in Section 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 any other substances, and nicosulfuron does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has assumed that nicosulfuron 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.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

Occupational 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 

significantly 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 Layer 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 Exposures & Risks for Occupational Handlers Applying Nicosulfuron to 

Bermudagrass.

Unit Exposure1

mg ai/lb handled

Applic. Rate2

lb ai/unit

Units 

Treated3

Avg. Daily Exposure4

mg ai/kg bw/day

MOE5

Mixer/Loader - Dry Flowable - Open Pour

Dermal: 0.066 (Single Layer, No Gloves)

Inhalation: 0.00077 

0.088 lb ai/A 350 A/day Dermal: 0.029

Inhalation: 0.0003

4,200

Applicator - Ground-boom - Open-cab

Dermal: 0.014 (Single Layer, No Gloves)

Inhalation: 0.00074 

0.088 lb ai/A 200 A/day Dermal: 0.0035

Inhalation: 0.00018

33,000

Aerial Applicator (Pilots not required to wear gloves)

Dermal: 0.005 (Single Layer, No Gloves)

Inhal. 0.000068

0.088 lb ai/A 350 A/day Dermal: 0.0022

Inhalation: 0.000030

56,000

Mixer/Loader/Applicator*– ATV low-pressure handwand (based on wettable powder)

Dermal: 8.6 (Single Layer, with Gloves)

Inhalation: 1.1

0.088 lb ai/A 5 A/day Dermal: 0.054

Inhalation: 0.0068

2,000

Mixer/Loader/Applicator**– Backpack sprayer

Dermal: 2.5

Inhalation: 0.03

0.088lb ai/A 2 A/day Dermal: 0.0063

Inhalation: 0.000075

19,000
Page 24 of 35

3. Units Treated are taken from “Standard Values 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 was assumed in 

the previous assessment (M. Dow, D361732, 1 April 2009).

4. Average Daily Exposure = Unit 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 handwand 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. There 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 10-30 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. It is possible for agricultural workers to have post-application exposure to 

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 post-application exposures to 

pesticide 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 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 cm2/hr for scouting. Since the requested applications of nicosulfuron are for early 

season (early 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 cm2/hr

for scouting. As a “screening” level assessment, the TC of 1,100 cm2/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-application exposure: 

Dislodgeable Foliar Residue (DFR) - Surrogate

= applic. rate * 20% * (1-D)t* 4.54 x 108μg/lb * 2.47 x 10-8 A/cm2 

= 0.088 lb ai/A * 0.20 * (1-0)0 * 4.54 x 108 μg/lb * 2.47 x10-8 A/cm2 

= 0.197 μg/cm2.

Average Daily Dose (ADD) (mg ai/kg bw/day) 

= DFR μg/cm2* TC cm2/hr * hr/day * 0.001 mg/μg * 1/70 kg bw 

= 0.197 μg/cm2* 1,100 cm2/hr * 8 hr/day * 0.001 mg/μg  70 kg bw

= 0.0248 mg/kg bw/day.
Page 25 of 35

MOE = NOAEL  ADD = 125.0 mg/kg bw/day  0.0248 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 level 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 Guideline 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 absorption 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.

• OPPTS 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 amend the proposed label to include a retreatment interval; the 

submitted field trial data will support a minimum retreatment interval of 16 days for 

grasses. 

860.1340 Residue Analytical 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 method developer relayed a 

number of minor revisions to the method. In addition, a number of questions 

concerning the method were forwarded by the ILV laboratory and addressed by the 
Page 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 typographical error in the second 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 phenylhexyl

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 % purity 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 by 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 DuPont-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 method 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).

 The 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 its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance 

levels specified below is to be determined by measuring only nicosulfuron [3-

pyridinecarboxamide, 2-((((4,6-dimethoxypyrimidin-2-yl)aminocarbonyl)-

aminosulfonyl))-N,N-dimethyl].”

HED recommends that conditional registration 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 should 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, respectively.

Livestock tissues:

 The petitioner should submit the outstanding 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 determine 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 

specified under OPPTS 860.1900 on representative crops of root and tuber 

vegetables, leafy vegetables or soybean, 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 Analytical Chemistry and Residue Data.

D369742 M. Doherty, 15 October 2009. Nicosulfuron – Dietary Exposure and Risk 

Analysis 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. NICOSULFURON – 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 new 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 Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction

Yes

Yes

Yes

Yes

Yes

Yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5300 Mutagenicity—Gene Mutation - mammalian

870.5385 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

Acute Oral (rat)

Subchronic Oral (rat)

Six-month 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 Acute Oral LD50, Rat (90.6% a.i.) 40924205 LD50 (M/F) >5000 mg/kg

Tox Category IV

870.1200 Acute Dermal LD50, Rabbit (90.6% a.i.) 40924207 LD50 (M/F) >2000 mg/kg

Tox Category III

870.1300 Acute Inhalation Toxicity, Rat (90.6% a.i.) 40924209 LC50 (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, Guinea 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 was 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 all 

treated males were also reported. However, 

none of these findings were considered 

biologically significant because a dose-response 

was not observed and they were not seen in the 

24-month study.

870.3100 90-Day Oral Toxicity 

(Diet)

Mouse [Crl:CD1(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

870.3250 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/guideline

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

Developmental NOAEL ≥ 6000 mg/kg/day

Developmental 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, decreased 

body weight gain during the dosing period, staining 

of hair in the rectal and vaginal areas and an 

apparent increase in % postimplantation loss.

Developmental NOAEL = 500 mg/kg/day

Developmental LOAEL = 1000 mg/kg/day, based 

on decreased fetal body weight

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

Parental 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 females
Page 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 neoplasms 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. typhimurium

41082612, 41360124

(1988)

Acceptable/guideline

TA 98, TA1535 at 0.1 to 

1 microgram/ plate. 

TA97A at 0.02 to 0.1 

microgram/ plate; 

TA100 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 

Hamster 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 aberrations 
Page 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 cytotoxicity (HED TXR 007963). 

870.6200a Acute 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/guideline

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 dose); excretion via urine was 9 

to 20% of the dose. Elimination via exhaled CO2

was 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 eliminated 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 compound, 

pyridinesulfonamide (N,N-dimethyl-2-sulfonamide 

pyridine-3-carboxylic acid) was tentatively 

identified 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 Available
Page 34 of 35

A.3 Rationale for Toxicology Data Requirements.

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 inhalation 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. The 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 absence 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% absorption 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 

scenarios 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 may 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 studies 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 

testing 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 the 
Page 35 of 35

effects of chemical exposures of nicosulfuron on neurologic parameters are limited and may be 

inadequate to characterize a pesticide’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 primary 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 conducting 

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 effects (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 and 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.