Nicosulfuron Health Risk Assessment DP No. D408756 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: June 26, 2014 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Nicosulfuron: Human Health Risk Assessment for Proposed Use on ALS 

Inhibitor Tolerant Sorghum. 

PC Code: 129008 

Decision No.: 473409 

Petition No.: 2F8132 

DP Ba rcode: 0408756 

Registration Nos.: 352-560, 352-8 16, 352-535 

Regulatory Action: Section 3Registration 

Risk Assessment Type: Single Chemical Aggregate Case No.: 7227 

Risk Assessment 

T XR No.: NA 

MRIDNo.: NA 

CAS No.: 111991-09-4 

40 CFR: § 180.454 

FROM: Kristin Rury, Risk Assessor ¥-~ /--; Minerva Mercado, Toxicologist !Jf/. # 

Meheret Negussie, Residue Che~1 Heitd:-c:/- ~~e.. Risk Assessment Branch III (RAB III) 

Health Effects Division (7509P) 

THROUGH: Christine Olinger, Branch Chief //// ./ -

Ri

Hea

sk 

lth 

Assessme

Effects Di

nt 

v

Branch 

ision (7

III 

50

(RA

9P) 

B III) ~/--~ 

TO: Kable Davis, Risk Manager 

Mindy Ondish, Risk Manager Reviewer 

Herbicide Branch 

Registration Division (7505P) 

Page 1 of3 1 
Nicosulfuron Health Risk Assessment DP No. D408756 

1.0 Executive Summary ........................................................................................................... 4 

2.0 HED Recommendations ............................................................................. ....................... 6 

2.1 Data Deficiencies ......... ......................................... .......................................................... 6 

2.2 Tolerance Considerations .............................................................................................. 6 

2.2.1 Enforcement Analytical Method ..................... ................... ....................................... 6 

2.2.2 Recommended Tolerances .... ................... .................................................................. 6 

2.2.3 Revisions to Petitioned-For Tolerances ............................ ............................. ........ ... 7 

2.2.4 International Harmonization ...................................... ............................................... 7 

2.3 Label Recommendations ............................................................................................. ... 7 

2.3.1 Recommendations from Residue Reviews ................. ............................................... 7 

3.0 Introduction ............................................................................................................ .... ........ 8 

3.1 Chemical Identity ........................................................................................................... 8 

3.2 PhysicaVChemical Characteristics ............................................................................... 8 

3.3 Pesticide Use Pattern ...................................................................................................... 8 

3.4 Anticipated Exposure Pathways ................................................................................... 9 

3.5 Consideration of Environmental Justice .................................................................... 10 

4.0 Hazard Characterization and Dose-Response Assessment.. ........................................ 10 

4.1 Summary of Toxicological Effects .............................................................................. 10 

4.2 Safety Factor for Infants and Children (FQPA Safety Factor) ............................ ... 11 

4.2.1 Completeness of the Toxicology Database .............................................................. 11 

4.2.2 Evidence of Neurotoxicity ........................................................................................ 11 

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.. ...... 11 

4.2.4 Residual Uncertainty in the Exposure Database ................................................... 12 

4.3 Toxicity Endpoint and Point of Departure Selections .. ........ .... ............ .................... 12 

4.3.1 Dose Response Assessment ...................................................................................... 12 

4.3.2 Recommendation for Combining Routes of Exposures for Risk Assessment.. ... 12 

4.3.3 Summary of Points of Departure and Toxicity Endpoints Used in Human Health 

Risk Assessment ........................................... ........................................................................... 12 

5.0 Dietary Exposure and Risk Assessment.. ................................................................... .... 14 

5.1 Residues of Concern Summary and Rationale .......................................................... 14 

5.2 Food Residue Profile ..................................... ... ................ ............................................ 15 

5.3 Water Residue Profile ....................................... ........................................................... 15 

5.4 Dietary Risk Assessment .............................................................................. .... ............ 16 

5.4.1 Description of Residue Data Used in Dietary Assessment. ................................ ... 16 

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 16 

5.4.3 Acute Dietary Risk Assessment ............................................... .... .... ................. ....... 16 

5.4.4 Chronic Dietary Risk Assessment ........................................................................... 17 

5.4.5 Cancer Dietary Risk Assessment ................................................. ................ ............ 17 

5.4.6 Summary Table ......................................................................................................... 17 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 18 

6.1 Residential Bystander Post-application Inhalation Exposure ................................. 18 

6.2 Spray Drift .................................................................................................................... 18 

7.0 Aggregate Exposure/Risk Characterization .................................................. ................ 18 

8.0 Cumulative Exposure/Risk Characterization ....... ........................................................ 19 

9.0 Occupational Exposure/Risk Characterization ..... ....................................................... 19 

9.1 Short-/Intermediate-Term Handler Risk. ....................................... .... ....................... 19 

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Nicosulfuron Health Risk Assessment DP No. D408756

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9.2.1 Dermal Post-Application Risk................................................................................. 22

9.2.2 Inhalation Post-Application Risk............................................................................ 22

10.0 References......................................................................................................................... 23

Appendix A. Toxicology Profile and Executive Summaries .................................................. 24

A.1 Toxicology Data Requirements................................................................................... 24

A.2 Toxicity Profiles............................................................................................................ 24

Appendix B. Physical/Chemical Properties............................................................................. 29

Appendix C. Review of Human Research................................................................................ 31
Nicosulfuron Health Risk Assessment DP No. D408756

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1.0 Executive Summary

Nicosulfuron is a sulfonylurea herbicide. It inhibits the action of an enzyme unique to plants, 

acetolactate synthase (ALS), leading to the disruption of cell division and plant growth. ALS is 

not found in humans or other mammals. Permanent tolerances are currently established in 40 

CFR §180.454 for nicosulfuron. Nicosulfuron is registered for use on field corn, sweet corn, and 

popcorn. It is also registered for use on sorghum plants in seed propagation fields, and on 

pastures, rangeland and non-crop areas. Additional time-limited tolerances (Section 18 

exemptions) of nicosulfuron on Bermuda grass forage and hay expired in December 2011. 

DuPont Crop Protection (DuPontTM) submitted a petition (PP#2F8132) to allow nicosulfuron use 

on sorghum tolerant to ALS herbicides. Nicosulfuron is currently registered for use on sorghum 

grown for seed and resistant to ALS herbicides, but the dietary and occupational exposure risk 

has not been previously evaluated. When applied to sorghum resistant to ALS-inhibitors, the 

surrounding weeds will be controlled. The resistant sorghum contains the trait “INZEN Z” 

which is a bred trait, not a genetically modified trait. However, when nicosulfuron is applied to 

sorghum that is not resistant to ALS-inhibitor herbicides, the plant itself will be eliminated. 

Nicosulfuron has no registered residential uses. 

Permanent tolerances are currently established in 40 CFR §180.454 for nicosulfuron. 

Use Profile

The end-use product (EP) formulations relevant to the sorghum use request are the technical 

product label (DuPontTM Nicosulfuron Technical, EPA Reg. No. 352-535), and the formulated 

end use product (EP) labels (DuPontTM Steadfast® XP herbicide, EPA Reg. No. 352-816, and 

DuPontTM Accent® herbicide, EPA Reg. No. 352-560). Both formulated end-use products are 

water dispersible granular (WG) formulations containing 30% and 75% nicosulfuron by weight, 

respectively. DuPontTM Steadfast® XP herbicide (EPA Reg. No. 352-816) also contains the 

active ingredient (ai) rimsulfuron. Exposure to rimsulfuron from the proposed use on sorghum 

will be evaluated in a separate document. The proposed labels require occupational handlers to 

wear long pants, long sleeved shirts, chemical resistant gloves, shoes, and socks. The restricted 

entry interval (REI) on the proposed labels is 4 hours.

Exposure Profile

There is a potential for occupational short- and intermediate-term inhalation and dermal exposure 

to nicosulfuron during mixing, loading, application, and post-application activities. There is also 

exposure expected through food and drinking water from the proposed and registered uses of 

nicosulfuron. There are no residential uses of nicosulfuron. 

Hazard Characterization

There is sufficient toxicology information for selecting doses and endpoints for nicosulfuron risk 

assessment. In repeated dose studies by the oral route, nicosulfuron is minimally toxic, and 

rodents are particularly insensitive to its effects. Dietary administration to rats for 24 months and

to mice for 18 months did not produce adverse effects. Dietary administration to dogs for one 

year produced only mild effects (increase in the relative liver and kidney weights of males) at the 

highest doses tested. Recently submitted acute and subchronic neurotoxicity studies and 
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immunotoxicity study did not change the points of departure (PODs) or endpoints from prior 

assessments. There were no concerns for developmental toxicity, and nicosulfuron is not 

genotoxic, neurotoxic, or carcinogenic. A subchronic inhalation toxicity study is not required for 

nicosulfuron at this time. Nicosulfuron is classified as Acute Toxicity Category IV for acute oral

and inhalation toxicity, Acute Toxicity Category III for acute dermal toxicity and eye irritation; 

nicosulfuron is not a dermal irritant, nor a dermal sensitizer. Based on the available hazard and 

exposure data, the Food Quality Protection Act (FQPA) Safety Factor (SF) is reduced to 1X for 

all population subgroups and exposure scenarios. 

Dietary Risk Estimates (Food and water)

No acute dietary toxicity endpoint was identified for nicosulfuron; therefore, an acute dietary risk 

assessment was not performed. 

The chronic dietary (food and drinking water) exposure assessment is considered conservative 

and assumed tolerance-level residues and that 100% of the proposed and registered crops were 

treated with nicosulfuron (100%CT). Dietary Exposure Evaluation Model software with the 

Food Commodity Intake Database (DEEM-FCID) default processing factors were assumed. 

Estimated drinking water concentrations (EDWCs) from ground water from the Environmental 

Fate and Effects Division (EFED) were also included. The results of the chronic analysis 

indicate that the chronic dietary (food and drinking water) risk estimates utilized <1% of the 

chronic population adjusted dose (cPAD) for the general U.S. population and all population 

subgroups. Therefore, the chronic dietary risk estimate is not of concern (i.e., <100% of the 

cPAD). 

Aggregate Risk

Short- and intermediate-term aggregate risk assessments were not performed because there are 

no registered residential uses of nicosulfuron. Therefore, the aggregate risk assessment for 

nicosulfuron only includes chronic exposures to residues in food and drinking water. The 

chronic dietary risk assessments for the U.S. population and all population subgroups are not of 

concern to HED (<100% cPAD).

Occupational Risk

A short- and intermediate-term occupational risk assessment was performed for nicosulfuron 

application using ground and aerial equipment to sorghum; chemigation is not permitted on the 

proposed labels. Because nicosulfuron is an herbicide, and the proposed label specifies 

broadcast, banded, and over-the-row applications to sorghum, the use of handheld equipment is 

not expected for nicosulfuron and exposure from mixing/loading/applying using handheld 

equipment was not assessed. There are no occupational handler risk estimates of concern for the 

proposed uses of nicosulfuron at baseline (no personal protective equipment; PPE). At baseline, 

all short- and intermediate-term occupational handler combined (dermal + inhalation) MOEs 

ranged from 490 to 56,000. The Restricted Entry Interval (REI) on the proposed label is 4 hours. 

The occupational short-term post-application risk estimates resulted in dermal MOEs of 30,000 

on the day of application and was not a risk of concern. Based on the Agency's current practices, 

a quantitative non-cancer occupational post-application inhalation exposure assessment was not 

performed for nicosulfuron at this time. If new policies or procedures are put into place, the 
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Agency may revisit the need for a quantitative occupational post-application inhalation exposure 

assessment for nicosulfuron. 

Environmental Justice

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).

2.0 HED Recommendations

HED has examined the residue chemistry, toxicity, and exposure databases for nicosulfuron and 

concluded that, provided a revised Section F is submitted, there are no residue chemistry 

deficiencies that would preclude granting a Section 3 registration on grain sorghum. 

The specific tolerance recommendations are discussed in Section 2.2.2. 

2.1 Data Deficiencies

There are no data deficiencies associated with the proposed uses of nicosulfuron.

860.1550 Proposed Tolerances

 The petitioner needs to submit a revised Section F to propose a tolerance of 0.3 ppm for 

sorghum forage and to reflect the correct commodity definitions presented in Table 2.2.3.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Acceptable high performance liquid chromatography methods with tandem mass spectroscopic 

detection (HPLC/MS/MS) are available for tolerance enforcement of grass and sorghum 

commodities (DuPont-17928 and DuPont-32277). An HPLC/UV (ultraviolet) method is 

available for tolerance enforcement of corn commodities. The methods have been adequately 

validated for the determination of residues of nicosulfuron in plants. 

DuPont has proposed an HPLC/MS/MS method (DuPont-32277) as an enforcement method for 

the determination of residues of nicosulfuron in sorghum forage, grain, and stover. The method 

determines residues of parent and metabolite IN-V9367 separately. (For chemical names and 

structures, refer to Appendix B). The method limit of quantitation (LOQ) is 0.010 ppm for each 

analyte in all matrices. The proposed enforcement method was used for data collection in the 

submitted crop field trials.

2.2.2 Recommended Tolerances

The current tolerance definition is found at 40 CFR §180.454. Compliance with the tolerance 

levels specified below is to be determined by measuring nicosulfuron only. Adequate data,
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reflecting the proposed use pattern, are available for purposes of establishing tolerances in 

sorghum forage, stover, and grain. The OECD statistical calculation procedure was utilized for

determining appropriate tolerance levels. The data indicate that the proposed tolerances of 0.05 

in sorghum stover and 0.8 ppm on sorghum grain are appropriate. The proposed tolerance of 0.4

ppm in sorghum forage needs to be revised; a tolerance of 0.3 ppm should be proposed based on 

the Organization for Economic Cooperation and Development (OECD) tolerance calculation 

spreadsheet. 

Table 2.2.3. Tolerance Summary for Nicosulfuron.

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Sorghum, grain 0.8 0.8 Sorghum, grain, grain

Sorghum, forage 0.4 0.3 Sorghum, grain, forage

Sorghum, stover 0.05 0.05 Sorghum, grain, stover

2.2.3 Revisions to Petitioned-For Tolerances

Note to PM: The tolerance expressions for nicosulfuron should be revised as follows:

Under 40 CFR §180.454(a): “Tolerances are established for residues of the herbicide 

nicosulfuron, including its metabolites and degradates, in or on the commodities in the 

table in this paragraph. Compliance with the tolerance levels specified in this 

paragraph is to be determined by measuring only nicosulfuron, 2-[[[[(4,6-dimethoxy-2-

pyrimidinyl)amino]carbonyl]amino]sulfonyl]-N,N-dimethyl-3-pyridinecarboxamide.

The proposed tolerance of 0.4 ppm in sorghum forage needs to be revised; a tolerance of 0.3 ppm 

should be proposed based on the OECD tolerance calculation spreadsheet. 

2.2.4 International Harmonization

No Codex or Mexican Maximum Residue Limits (MRLs) have been established for residues of 

nicosulfuron. There are no MRLs established in Canada for nicosulfuron use on sorghum. 

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

Subsequent to completion of the residue chemistry summary document, the registrant amended 

the preharvest intervals to plant height and growth stages. The proposed change is consistent 

with the residue data and HED has no objections to the proposed PHI. The PHI changes 

supersede those mentioned in the residue chemistry review (M. Negussie, D417854, 

02/14/2014).
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3.0 Introduction

Nicosulfuron is a sulfonylurea herbicide that inhibits the action of an enzyme unique to plants, 

acetolactate synthase (ALS), leading to the disruption of cell division and plant growth. ALS is 

not found in humans or mammals. 

3.1 Chemical Identity

Table 3.1. Nicosulfuron Nomenclature.

Chemical Structure

Common name Nicosulfuron

Company experimental name DPX-V9360

Molecular formula C15H18N6O6S

Molecular weight 410.40

IUPAC name 2-[(4,6-dimethoxypyrimidin-2-ylcarbamoyl)sulfamoyl]-N,Ndimethylnicotinamide;

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

pyridylsulfonyl)urea

CAS name 2-[[[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]-N,Ndimethyl-3-pyridinecarboxamide

CAS registry number 111991-09-4

End-use product (EP) DupontTM Accent® Herbicide; EPA File Symbol 352-560 and DupontTM 

STEADFAST® XP Herbicide; EPA File Symbol 352-816

3.2 Physical/Chemical Characteristics

The physical/chemical properties of nicosulfuron are summarized in Appendix B. Based on the 

molecular weight 410 g/mol, low vapor pressure (1.2 x 10-16 mm Hg at 25o C) and KOW (<0.44 at 

pH 4), nicosulfuron is not expected to volatilize, pass lipid barriers, or bioaccumulate.

Environmental fate data indicate nicosulfuron is moderately-persistent and mobile in terrestrial 

and aquatic environments. 

3.3 Pesticide Use Pattern

DuPont Crop Protection (DuPontTM) submitted a petition (PP#2F8132) to allow nicosulfuron use 

on sorghum tolerant to ALS herbicides. Nicosulfuron is currently registered for use on sorghum 

grown for seed and resistant to ALS herbicides, but the dietary and occupational exposure risk 

has not been previously evaluated. When applied to sorghum resistant to ALS-inhibitors, the 

N

O

N

H3C CH3

S

NH NH

N

N O

O

CH3

CH3

O O

O
Nicosulfuron Health Risk Assessment DP No. D408756

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surrounding weeds will be controlled. However, when applied to sorghum that is not resistant to 

ALS-inhibitor herbicides, the plant itself will be eliminated. Nicosulfuron has no registered 

residential uses. The end-use product (EP) formulations relevant to the sorghum use request are 

the technical product label (DuPontTM Nicosulfuron Technical, EPA Reg. No. 352-535), and the 

formulated EP labels (DuPontTM Steadfast® XP herbicide, EPA Reg. No. 352-816, and DuPontTM 

Accent® herbicide, EPA Reg. No. 352-560). DuPontTM Steadfast® XP herbicide (EPA Reg. No. 

352-816) also contains the ai rimsulfuron, also an ALS inhibiting herbicide. Exposure to 

rimsulfuron from the proposed use on sorghum will be evaluated in a separate document. Both 

formulated end-use products are water dispersible granular (WG) formulations containing 30% 

and 75% nicosulfuron by weight, respectively. The proposed use on sorghum is summarized in 

Table 3.3. 

Table 3.3. 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

Grain Sorghum Containing the DuPont INZEN Z Tolerance Trait

Post-Emergent, 

Aerial and 

Ground 

Equipment*

DuPontTM 

Accent 

Herbicide 

75% DF 

[352-560]

0.67-

1.33 

oz/A

(0.031-

0.062)

2

(7-days)

1.8 oz/A 

(0.084)

Mature 

Stage 

(forage, 

grain, 

stover)

Application is to be made 

to emerged grain sorghum 

that is up to 20 inches tall. 

Applications made to 4-20 

inch tall grain sorghum 

(V3-V7 stage) are 

recommended for best 

weed control and crop 

tolerance. Best results are 

obtained when applications 

are made to young actively 

growing weeds. Do not 

apply to grain sorghum 

taller than 20 inches. 

Use of a spray adjuvant is 

required (NIS at 0.25%-

0.5% v/v, or COC at 0.5%-

2% v/v, or a combination 

adjuvant containing NIS, 

COC, MSO and/or 

ammonium nitrogen 

fertilizer). 

DuPontTM 

Steadfast XP 

Herbicide 

30% 

[352-816]

1.25-

1.67 

oz/A

(0.023-

0.031)

1.67 oz/A

(0.031)

*Chemigation is not permitted on the proposed labels.

1. NIS = Nonionic Surfactant. COC = Crop Oil Concentrate. MSO = Methylated Seed oil

3.4 Anticipated Exposure Pathways

Humans may be exposed to nicosulfuron in food and drinking water, since nicosulfuron may be 

applied directly to growing crops and application may result in nicosulfuron reaching surface and 

ground water sources of drinking water. In an occupational setting, applicators may be exposed 

while handling the pesticide prior to application, as well as during application. There is a 

potential for post-application exposure for workers re-entering treated fields. This risk 

assessment considers all of the aforementioned exposure pathways based on the proposed new 
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use of nicosulfuron, but also considers the existing uses as well, particularly for the dietary 

assessment.

3.5 Consideration of Environmental Justice

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.epa.gov/environmentaljustice/resources/policy/exec_order_12898.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. Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, 

(NHANES/WWEIA) 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 and ethnic 

group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for children 1-2 years, youths, and adults entering or playing on treated 

areas post-application 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.

4.0 Hazard Characterization and Dose-Response Assessment

The most recent nicosulfuron risk assessment was conducted in 2009 (M. Doherty, D360807, 

10/27/2009). The toxicity endpoints and PoDs for risk assessment were selected for chronic 

dietary, and short- and intermediate-term dermal and inhalation scenarios. Recently submitted 

acute and subchronic neurotoxicity studies and an immunotoxicity study did not change 

endpoints from prior assessments.

4.1 Summary of Toxicological Effects

Nicosulfuron is a member of the sulfonylurea family of herbicides. Its herbicidal action is due to 

the inhibition of ALS leading to the disruption of cell division and elongation in the plant. This 

mode of herbicidal action is not relevant to human toxicity as ALS does not occur in animals. 

Upon oral administration, nicosulfuron appears to be incompletely absorbed. In rats, 

nicosulfuron is mostly excreted unchanged in feces (80-95%) and urine (9-20%) with trace 

residues in tissues. Minor metabolites of hydrolytic and oxidative metabolism were identified. 

A dermal absorption study is not available.
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In repeated dose studies by the oral route, nicosulfuron is minimally toxic, and rodents are 

particularly insensitive to its effects. Dietary administration of 786-1098 mg/kg/day to rats for 

24 months or 953-1262 mg/kg/day to mice for 18 months did not produce adverse effects.

Dietary administration to dogs for one year produced mild effects (increase in the relative liver 

and kidney weights of males) at the highest doses tested (500 mg/kg/day).

Nicosulfuron showed no developmental effects in rats, but produced abortions in rabbits at doses 

(500-2000 mg/kg/day) that also showed maternal toxicity. Decreased litter size was observed in 

a rat reproductive study from dams treated with the highest dose tested (1265 mg/kg/day). There 

are no indications of neurotoxic or immunotoxic effects elicited by nicosulfuron in animal 

studies; this includes recently submitted acute and subchronic neurotoxicity studies and an 

immunotoxicity study.

Nicosulfuron is not likely to be carcinogenic based on studies in the rat and mouse and lack of in 

vitro and in vivo mutagenic effects. 

4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

Based on the currently available toxicity and exposure data, the risk assessment team 

recommends the FQPA Safety Factor for nicosulfuron be reduced to 1X as supported by an 

essentially complete toxicological database. Nicosulfuron did not show neurotoxic or effects in 

any of the studies. Developmental toxicity occurred at the same or higher doses than maternal 

toxicity. 

4.2.1 Completeness of the Toxicology Database

The nicosulfuron toxicology database is adequate to characterize any potential for prenatal or 

postnatal risk for infants and children, and includes acceptable developmental toxicity studies in 

the rat and rabbit and a rat reproductive toxicity study, as well as acute and subchronic 

neurotoxicity studies. The Hazard and Science Policy Council (HASPOC) waived the required 

subchronic inhalation toxicity study based on nicosulfuron’s physical chemical properties, 

including low vapor pressure; low acute inhalation toxicity (Toxicity Category IV); and the use 

of a conservative, chronic oral POD that results in screening-level MOEs >30,000 

(TXR#0050011). 

4.2.2 Evidence of Neurotoxicity

Nicosulfuron did not show neurotoxic effects in acute, subchronic, and chronic testing in rats, 

mice and dogs. 

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The current database does not provide evidence of sensitivity/susceptibility in the developing or 

young animal. No treatment related effects were noted on maternal or developmental toxicity up 

to and including the highest dose tested in the rat prenatal developmental study. In the 2-
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generation reproductive study, lower gestational body weight gain in dams and lower pup weight 

on PND 14-21 were observed at the same dose (1265 mg/kg/day).

4.2.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties identified in the exposure databases. The chronic dietary 

assessment utilized tolerance-level residues for all crops and assumed 100% CT of the proposed 

and registered crops were treated with nicosulfuron. DEEM-FCID default processing factors 

were assumed. EPA made conservative (protective) assumptions in the ground and surface water 

modeling used to assess exposure to nicosulfuron in drinking water. These assessments will not 

underestimate the exposure and risks posed by nicosulfuron.

4.3 Toxicity Endpoint and Point of Departure Selections

4.3.1 Dose Response Assessment

With oral dosing, nicosulfuron is poorly absorbed. In the rat, most of the administered dose was 

excreted as un-metabolized parent compound, primarily via the feces (80-95%). The absorption, 

distribution, metabolism, and excretion (ADME) data are consistent with the low incidence of

effects observed throughout the database. Only two oral studies showed significant effects that 

could be used as PODs: the rabbit developmental toxicity study and the chronic dog study. Both

of these studies showed effects at a LOAEL of 500 mg/kg/day. The POD (125 mg/kg/day) 

selected from chronic dog study is more appropriate for a chronic exposure and should be 

protective of the effects seen in the rabbit developmental toxicity study. 

The toxicity endpoints and points of departures are presented in Tables 4.3.3.1 and 4.3.3.2, and a 

summary of the toxicological database used as the rationale for the selections is presented in 

Appendix A.

4.3.2 Recommendation for Combining Routes of Exposures for Risk Assessment

In accordance with the requirements of the FQPA (1996), HED has considered the potential for 

concurrent nicosulfuron exposure via oral, dermal, and inhalation routes. HED aggregates 

exposure from different routes for each population if the same toxic effects are seen for that 

duration of exposure by each route. There are no residential uses proposed for nicosulfuron, 

therefore, exposure from dermal, oral, and inhalation routes are not combined. However, for 

occupational uses of nicosulfuron, because the dermal and inhalation POD are the same, dermal 

and inhalation risk estimates have been combined.

4.3.3 Summary of Points of Departure and Toxicity Endpoints Used in Human Health 

Risk Assessment

As outlined in Tables 4.3.3.1 and 4.3.3.2 below, there have been no changes to the prior doseresponse assessment or recommendations for combining routes of exposure and/or cancer 

classification (M. Doherty, D360807, 10/27/2009). 
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For short and intermediate-term dermal and inhalation risk assessment, the POD is based on 

increased relative liver and kidney weights in males seen at the LOAEL of 500 mg/kg/day 

(NOAEL = 125 mg/kg/day) in the chronic oral toxicity study in dogs, and increased incidence of 

vaginal discharge, abortion, and staining of hair in the rectal and vaginal areas, as well as 

increase in post-implantation loss and decrease in body weight gain at the LOAEL of 500 

mg/kg/day (NOAEL = 100 mg/kg/day). The LOAELs in both studies are at the same dose level, 

and the NOAELs are similar; therefore these studies are co-critical to the POD selection. 

Because the effects seen in the rabbit developmental study are more severe (abortions), a body 

weight of 69 kg is recommended in the occupational risk assessment to be protective of 

developmental effects and female workers. 

Since no inhalation or dermal absorption data are available, toxicity by the dermal and inhalation 

routes is considered to be equivalent to the estimated toxicity by the oral route of exposure. 

Table 4.3.3.1 Summary of Toxicological Doses and Endpoints for Nicosulfuron for Use in Dietary and 

Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including Infants 

and Children)

No hazard was identified from appropriate oral toxicity studies including developmental 

toxicity studies in rats and rabbits. 

Acute Dietary

(Females 13-49 

years of age)

No hazard was identified from appropriate oral toxicity studies including developmental 

toxicity studies in rats and rabbits. 

Chronic Dietary 

(All 

Populations)

NOAEL= 

125

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD 

= 1.25

mg/kg/day

cPAD = 1.25

mg/kg/day

Chronic oral study in dogs. 

LOAEL = 500 mg/kg/day based on 

increased relative liver and kidney weights 

in males. Supported by rabbit 

developmental toxicity study (LOAEL =

500 mg/kg/day, NOAEL = 100 

mg/kg/day).

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. 
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Table 4.3.3.2 Summary of Toxicological Doses and Endpoints for Nicosulfuron for Use in Occupational 

Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal Short-

(1-30 days) and 

Intermediate-

(1-6 months)

Term 

NOAEL

=125

mg/kg/day

DAF = 

100%

UFA=10x

UFH=10x

Occupational 

LOC for MOE < 

100

Chronic oral study in dogs. 

LOAEL = 500 mg/kg/day based on 

increased relative liver and kidney 

weights in males. Supported by rabbit 

developmental toxicity study (NOAEL = 

100 mg/kg/day, LOAEL 500 mg/kg/day).

Inhalation 

Short- (1-30 

days) and 

Intermediateterm (1-6 

months)

Term 

NOAEL

=125

mg/kg/day

UFA=10x

UFH=10x

Occupational 

LOC for MOE < 

100

Chronic oral study in dogs. 

LOAEL = 500 mg/kg/day based on 

increased relative liver and kidney 

weights in males. Supported by rabbit 

developmental toxicity study (NOAEL = 

100 mg/kg/day, LOAEL 500 mg/kg/day).

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). MOE = margin of exposure. LOC = level of 

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

the inhalation route is assumed to be equivalent to the oral route.

5.0 Dietary Exposure and Risk Assessment 

5.1 Residues of Concern Summary and Rationale

The residue of concern for enforcement and risk assessment is the parent compound, 

nicosulfuron. The residues of concern for drinking water include parent nicosulfuron and all 

major degradates which maintain the sulfonylurea bridge which include degradates identified as 

IN-HYY21 and IN-37740 (structures listed in Appendix B). Therefore, the total residue method 

will be used to estimate exposure in drinking water sources.

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 Nicosulfuron Nicosulfuron

Poultry Nicosulfuron Nicosulfuron
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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

Drinking Water Nicosulfuron and IN-HYY21 

and IN-37740 Not Applicable

5.2 Food Residue Profile

Nicosulfuron is currently registered under 40 CFR §180.454(a) on corn and grass commodities, 

and ruminant commodities. Plant commodity tolerances are established at 0.1 ppm in corn 

(field, pop, sweet) commodities and at 9 to 25 ppm on grass commodities. Ruminant tolerance 

levels range from 0.01 ppm to 0.05 ppm which includes milk, and the meat, fat and meat 

byproducts of cattle, goats, horses, and sheep. 

Adequate crop field trial data have been submitted to support the requested use on ALS tolerant 

grain sorghum. The trials reflect the proposed use pattern and the number and locations of the 

trials are acceptable. Adequate storage stability data are available to support the storage 

durations and conditions of samples of sorghum commodities from the submitted crop field trial 

studies. Adequate confined and field rotational crop data are available.

The processing study on grain sorghum indicate that residues of nicosulfuron do not concentrate 

in aspirated grain fractions AGF (processing factor of ~0.6x).

The waiver request for poultry feeding study is acceptable. The proposed use on grain sorghum 

does not result in an increased dietary burden to ruminants and poultry. Therefore, no changes 

are needed to the existing tolerances on livestock commodities. There is no reasonable 

expectation of finite residues of nicosulfuron in swine and poultry commodities (40 CFR 

§180.6(a)(3)) based on the registered/proposed uses on swine and poultry feed items. HED notes 

that if additional uses of nicosulfuron with poultry feed items are proposed in the future, a 

poultry feeding study may be required.

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the 

Environmental Fate and Effects Division (EFED) (DP# 414505, G. Rothman, 01/07/2014) and 

incorporated directly into this dietary assessment. Water residues were incorporated in DEEMFCID into the food categories “water, direct, all sources” and “water, indirect, all sources.” 

Estimated drinking water concentrations (EDWCs) in surface waters are estimated using the Tier 

2 model PRZM/EXAMS (Pesticide Root Zone Model)/(Exposure Analysis Modeling System). 

Upper-bound Tier I modeling using PRZM/EXAMS predicts that the concentrations of 

nicosulfuron, IN-HYY21, and IN-37740 in surface drinking water sources are not likely to 

exceed 9.67 μg/L (9.67 ppb) for the acute peak concentration, 2.80 μg/L (2.80 ppb) for the 

chronic concentration, and 2.15 μg/L (2.15 ppb) for the cancer concentration. 
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Ground water estimates of concentrations are estimated using the PRZM-GW. PRZM-GW 

model estimates upper-bound concentrations of nicosulfuron, IN-HYY21, and IN-37740 in 

ground drinking water sources are not likely to exceed 26.3 g/L (26.3 ppb) for acute exposure 

and 19.2 g/L (19.2 ppb) for chronic and cancer exposure. The PRZM-GW estimate was higher 

compared to surface water estimated concentrations. Therefore, the chronic ground water 

estimate (19.2 ppb) was used in the assessment. The highest modeled value of 26.3 was not used 

because it represents acute exposures; and an acute dietary assessment is not required for 

nicosulfuron at this time because there were no effects seen in the database from a single 

exposure.

Estimates were derived based on the use on sorghum and are considered worst-case. 

The model and its description are available at the EPA internet site:

http://www.epa.gov/oppefed1/models/water/

Table 5.3. Comparison of PRZM-GW, SCI-GROW, and PRZM/EXAMS estimated upper bound 

concentrations for nicosulfuron and degradates of concern including IN-HYY21 and IN-37740.

Exposure Duration

PRZM-GW

(ppb)

SCI-GROW

(ppb)1 PRZM/EXAMS

Highest Daily Conc.

(Acute) 26.3

1.42

9.67

Post-Breakthrough Average 

Conc.

(Chronic and Cancer) 19.2

2.80

30-year Mean

(Cancer) 2.15

1 SCI-GROW modeling conservatively assumes that ground water concentrations are uniform over time and 

therefore, acute, chronic, and cancer concentration are the same.

The highest estimated concentration is bolded. 

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Existing and recommended tolerance-level residues [40 CFR §180.454] have been used for all 

food commodities in this assessment. The existing tolerances are 0.1 ppm for all corn 

commodities. The existing tolerances for livestock commodities (of cattle, horses, and sheep 

only) are 0.01 ppm for meat and fat, 0.05 ppm for meat byproducts, and 0.01 ppm for milk. For 

the proposed new use on sorghum, tolerance level (0.8 ppm) is recommended.

5.4.2 Percent Crop Treated Used in Dietary Assessment

It was assumed that 100% of foods in the assessment had residues of nicosulfuron (i.e., 100% 

crop treated). 

5.4.3 Acute Dietary Risk Assessment

No acute dietary toxicity endpoint could be identified based on the toxicology data currently 

available for nicosulfuron; therefore, an acute assessment was not performed. 
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5.4.4 Chronic Dietary Risk Assessment

Chronic aggregate dietary (food and drinking water) exposure and risk assessment was

conducted using the Dietary Exposure Evaluation Model software with the Food Commodity 

Intake Database (DEEM-FCID) Version 3.16. This software uses 2003-2008 food consumption 

data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition 

Examination Survey, What We Eat in America, (NHANES/WWEIA). The chronic dietary (food 

and drinking water) exposure assessment is considered conservative and unrefined. The results 

of the chronic analysis indicate that the chronic dietary (food and drinking water) risk estimates 

utilized <1% of the chronic population adjusted dose (cPAD) for the general U.S. population and 

all population subgroups. Therefore, the chronic dietary risk is not of concern (i.e., <100% of 

the cPAD). 

5.4.5 Cancer Dietary Risk Assessment

Nicosulfuron is classified as “Not Likely to be Carcinogenic to Humans”; therefore, a cancer 

dietary exposure assessment was not performed. 

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Nicosulfuron.

Population Subgroup

Acute Dietary Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

% cPAD*

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population

N/A N/A

0.000678 <1.0

N/A N/A

All Infants (< 1 year old) 0.001548 <1.0

Children 1-2 years old 0.001462 <1.0

Children 3-5 years old 0.001208 <1.0

Children 6-12 years old 0.000846 <1.0

Youth 13-19 years old 0.000603 <1.0

Adults 20-49 years old 0.000623 <1.0

Adults 50+ years old 0.000541 <1.0

Females 13-49 years old 0.000612 <1.0

*The values for the highest exposed population are bolded
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed or registered residential uses of nicosulfuron at this time; therefore, a 

residential exposure assessment has not been conducted. 

6.1 Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for nicosulfuron at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (1.2 x 10-16 mm Hg at 25oC), and 

the low proposed use rate (0.062 lb ai/A). However, volatilization of pesticides may be a source 

of post-application inhalation exposure to individuals nearby pesticide applications. The Agency 

sought expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, 

and received the SAP’s final report on March 2, 20101. The Agency is in the process of 

evaluating the SAP report and may, as appropriate, develop policies and procedures to identify 

the need for and, subsequently, the way to incorporate post-application inhalation exposure into 

the Agency's risk assessments. If new policies or procedures are developed, the Agency may 

revisit the need for a quantitative post-application inhalation exposure assessment for 

nicosulfuron. 

6.2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for nicosulfuron. The Agency has been working with the Spray Drift Task 

Force (a task force composed of various registrants which was developed as a result of a Data 

Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation 

and other parties to develop the best spray drift management practices (see the Agency’s Spray 

Drift website for more information). 2 The Agency is also taking means to qualitatively and 

qualitatively address spray drift as a potential source of exposure in risk assessments for 

pesticides through existing programs such as Ag Drift and chemical specific properties of 

pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during 

the Registration Review process which ensures that all uses for that pesticide will be considered 

concurrently. 

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

 

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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duration of exposure.

An acute aggregate risk assessment was not performed because no appropriate endpoint was 

available to determine the aRfD for the general U.S. population or any population subgroup. 

There are no residential uses of nicosulfuron. Therefore, the aggregate risk assessment for 

nicosulfuron only includes chronic exposures to residues in food and drinking water. The 

chronic dietary risk assessments for the U.S. population and all population subgroups are not of 

concern to HED (<100% cPAD). The results of the chronic analysis indicate that the chronic 

dietary (food and water) risk estimates utilized <1.0% of the cPAD for the general U.S. 

population all population subgroups. 

8.0 Cumulative Exposure/Risk Characterization

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 not assumed that nicosulfuron has 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 Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative. 

9.0 Occupational Exposure/Risk Characterization

There is potential for short- and intermediate-term occupational exposure to nicosulfuron during 

both handler [mixing, loading, and application (via the dermal and inhalation routes)] and postapplication activities (via the dermal route) based on the proposed uses. 

9.1 Short-/Intermediate-Term Handler Risk

HED has evaluated occupational exposure from the proposed uses of nicosulfuron. Application 

methods, maximum application rates, and use sites are summarized in Table 3.3. Chemigation 

application is prohibited on the proposed labels; however, nicosulfuron may be applied with 

aerial and ground equipment. Because nicosulfuron is an herbicide, and the proposed label 

specifies broadcast, banded, and over-the-row applications to sorghum, the use of handheld 

equipment is not expected for nicosulfuron and exposure from mixing/loading/applying using 

handheld equipment was not assessed. Based on application rate and label information, only 

short- and intermediate-term exposure is expected for occupational handlers. However, for both 

dermal and inhalation exposures, the PODs selected are considered protective of both durations. 

The proposed labels require occupational handlers to wear long pants, long sleeved shirts, 

chemical resistant gloves, shoes, and socks. 

HED’s LOC for the MOE is defined by the uncertainty factors that are applied to the assessment. 

HED applies a 10X factor to account for variability among species and a 10X factor to account 
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for variability within species. The total uncertainty factor that has been applied to the handler 

assessment of nicosulfuron is 100X for occupational exposure. Occupational exposure and risk 

resulting in MOEs greater than or equal to 100 will not be of concern to HED. Dermal and 

inhalation risk estimates were combined in this assessment, since the toxicological effects and 

PODs chosen for these exposure routes are the same. 

A summary of the short-term dermal inhalation risk estimates for occupational handlers applying 

nicosulfuron is provided in Table 9.1.1. There are no risk estimates of concern for the proposed 

uses of nicosulfuron at baseline (no Personal Protective Equipment; PPE). At baseline, all shortand intermediate-term occupational handler combined (dermal + inhalation) MOEs ranged from 

490 to 56,000. 
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Table 9.1.1. Occupational Handler Short- and Intermediate-Term Exposure and Risk Estimates for Nicosulfuron. 

Exposure Scenario Crop or 

Target

Dermal Unit 

Exposure (μg/lb 

ai)1

Inhalation Unit 

Exposure (μg/lb 

ai)1

Maximum 

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation Total

Baseline* Baseline* Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

Mixer/Loader

Mixing/Loading for Aerial 

Application Sorghum 227 8.96 0.062 1200 acres 0.25 510 0.0097 13,000 490

Mixing/Loading for 

Groundboom Application Sorghum 227 8.96 0.062 200 acres 0.047 3,100 0.0016 78,000 3,000

Applicator

Applying with Aerial 

Equipment Sorghum 2.08 0.0049 0.062 1200 acres 0.0023 56,000 0.0000053 24,000,000 56,000

Applying with 

Groundboom Equipment Sorghum 78.6 0.34 0.062 200 acres 0.014 8,900 0.000061 2,000,000 8,900

Flagger

Flagging for Aerial 

Application Sorghum 11 0.35 0.062 350 acres 0.0035 36,000 0.00011 1,100,000 35,000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013); Level of mitigation: Baseline. *Aerial Application is assessed assuming a closed cockpit 

(engineering controls).

2 Based on registered or proposed label (Reg. No. 352-560). This exposure assessment is protective of the DupontTM Steadfast® XP Herbicide label because the proposed application rate is lower than 

0.062 lb ai/A.

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF (100%) ÷ BW 

(69 kg).

5 Dermal MOE = Dermal NOAEL (125 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (69 kg).

7 Inhalation MOE = Inhalation NOAEL (125 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL (125 mg/kg/day) ÷ Dermal Dose + Inhalation Dose.
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9.2 Short-Term Post-Application Risk

9.2.1 Dermal Post-Application Risk

For nicosulfuron, both short- and intermediate-term exposure could occur for the proposed use 

on sorghum. However, because the POD is the same for dermal short- and intermediate-term 

exposures, one assessment is protective of both durations. Furthermore, only exposure from 

scouting was assessed because nicosulfuron is an herbicide. Hand weeding, the only other postapplication exposure scenario quantitatively considered associated with sorghum would not be 

necessary following application of an herbicide. While nicosulfuron is only applied early in the 

sorghum growth stage before the plant reaches 20” high, the assessment is also protective of 

exposure from scouting late in the crop season when foliage is full. Therefore, the assessment is 

considered a conservative estimate of post-application exposure to treated sorghum.

Chemical-specific dislodgeable foliar residue (DFR) data have not been submitted for

nicosulfuron. Therefore, this assessment uses HED’s default assumption that 25% of the 

application is available for transfer on day 0 following the application and the residues dissipate 

at a rate of 10% each following day.

A DFR study is not required for nicosulfuron at this time since the dermal MOEs are greater 

than 2 times the LOC based on default values for the fraction of application rate available for 

transfer after a foliar application.

The occupational short-term post-application risk assessment resulted in a dermal MOE of 

30,000 on the day of application. Therefore, there are no post-application risk estimates of 

concern for nicosulfuron. 

Table 9.2. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Nicosulfuron.

Crop/Site Activities Transfer Coefficient 

(cm2/hr) DFR1 Dermal Dose (mg/kg/day)2 MOE3

Short- and Intermediate-term

Sorghum Scouting 210 0.17 0.0042 30,000

1 DFR = Application Rate × F × (1-D)t × 4.54E8 μg/lb × 2.47E-8 acre/cm2; where F = 0.25 and D = 0.10 per day. 

2 Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (100%)]  BW (69 kg).

3 MOE = POD (125 mg/kg/day) / Daily Dermal Dose. 

9.2.2 Inhalation Post-Application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for nicosulfuron at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (1.2 x 10-16 mm Hg at 25oC), and 

the low proposed use rate (0.062 lb ai/A). However, there are multiple potential sources of postapplication inhalation exposure to individuals performing post-application activities in 

previously treated fields. These potential sources include volatilization of pesticides and 

resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and 
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received the SAP’s final report on March 2, 20103. The Agency is in the process of evaluating 

the SAP report as well as available post-application inhalation exposure data generated by the 

ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, 

subsequently, the way to incorporate occupational post-application inhalation exposure into the 

Agency's risk assessments. If new policies or procedures are put into place, the Agency may 

revisit the need for a quantitative occupational post-application inhalation exposure assessment 

for nicosulfuron.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

10.0 References

G. Rothman. 01/27/2014. D414505. Tier I Drinking Water Assessment for the proposed 

Section 3 ALS inhibition tolerant sorghum crops new use for the chemical Nicosulfuron.

J. VanAlstine. 08/02/2012. TXR#0050011. Nicosulfuron: Summary of Hazard and Science 

Policy Council (HASPOC) Meetings of March 29, 2012: Recommendations on the requirement 

of 90-day inhalation and 28-day dermal toxicity studies and neurotoxicity screening battery.

K. Rury. 12/18/2013. D416835. Nicosulfuron: Recommended Environmental Degradates to 

Include in Drinking Water Assessment. 

K. Rury. 05/14/2014. D417841. NICOSULFURON. Occupational and Residential Exposure 

Assessment for a Proposed Use on Sorghum.

M. Negussie. 02/14/2014. D417854. Nicosulfuron: Petition for the Establishment of 

Permanent Tolerances for Uses on Acetolactase Synthase (ALS) Tolerant Grain Sorghum. 

Summary of Analytical Chemistry and Residue Data. 

M. Negussie. 02/18/2014. D417840. Nicosulfuron: Chronic Aggregate Dietary (Food plus 

Drinking Water) Exposure and Risk Assessments in Support of a Section 3 Registration on 

Acetolactase Synthase (ALS) Tolerant Grain Sorghum.

 

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Nicosulfuron Human Health Risk Assessment DP No. D408756

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food uses of nicosulfuron are in the table below. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

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

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

870.2400 Acute Eye Irritation.......................................................

870.2500 Acute Dermal Irritation .................................................

870.2600 Skin Sensitization..........................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity in Rodents..................................

870.3150 90-Day Oral Toxicity in Nonrodents.............................

870.3200 21/28-Day Dermal Toxicity ..........................................

870.3250 90-Day Dermal Toxicity ...............................................

870.3465 90-Day Inhalation Toxicity ...........................................

yes

yes

yes

no

yes

yes

yes

waived 1

–

waived 1

870.3700a Prenatal Developmental Toxicity (rodent) ....................

870.3700b Prenatal Developmental Toxicity (nonrodent) ..............

870.3800 Reproduction and Fertility Effects ................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Carcinogenicity (rat)......................................................

870.4200b Carcinogenicity (mouse) ...............................................

870.4300 Combined Chronic Toxicity/Carcinogenicity ...............

yes

yes

yes

yes

no

2

yes

2

yes

yes

870.5100 Mutagenicity—Bacterial Reverse Mutation Test ..........

870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test..

870.5385 Mutagenicity—Structural Chromosomal Aberrations...

870.5550 Mutagenicity—Other Genotoxic Effects.......................

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

yes

yes

–

870.7485 Metabolism and Pharmacokinetics................................

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

870.7800 Immunotoxicity .............................................................

yes

no

yes

yes

–

yes

1 The requirement for this study has been waived (TXR 0050011).

2 A chronic/oncogenicity study is available for the rat, thus separate chronic and oncogenicity are not necessary.

A.2 Toxicity Profiles
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Table A.2.1 Acute Toxicity Profile of Nicosulfuron

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

870.1100 Acute oral – rat 40924205 LD50 > 5000 mg/kg IV

870.1200 Acute dermal – rabbit 40924207 LD50 ≥ 2000 mg/kg III

870.1300 Acute inhalation – rat 40924209 LC50 ≥ 5.9 mg/L IV

870.2400 Acute eye irritation – rabbit 41082602 Moderate eye irritant III

870.2500 Acute dermal irritation – rabbit 41082603 Not an irritant IV

870.2600 Skin sensitization – guinea pig 41082604 Not a sensitizer NA

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Nicosulfuron

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3100

90-Day Oral Toxicity in 

Rodents (rat)

41082607 (1988)

Acceptable/guideline

0, 300, 1500, 7500 or 

20,000 ppm

M: 0, 22, 107, 555, 1495; 

F: 0, 26, 133, 685, 1830

mg/kg/day

NOAEL = 1495/1830 mg/kg/day (M/F)

LOAEL = could not be established.

870.3150

90-Day Oral Toxicity in 

nonrodent (dog)

41082606 (1988)

Acceptable/guideline

0, 250, 5000, or 20,000 

ppm

M: 0, 9, 172, 710; F: 0, 

9, 171, 683 mg/kg/day

NOAEL = 171 mg/kg/day (F)

LOAEL = 683 mg/kg/day based on decreased 

neutrophils (F only).

870.3700a

Prenatal developmental in 

rodent (rat)

41082608 (1988)

Acceptable/guideline

0, 200, 1000 , 2500 or 

6000 mg/kg/day

Maternal NOAEL = 6000 mg/kg/day

LOAEL = could not be established.

Developmental NOAEL = 6000 mg/kg/day

LOAEL = could not be established.

870.3700b

Prenatal developmental in 

nonrodent (rabbit)

41082609 (1988)

Acceptable/guideline

0, 100, 500 , 1000 or 

2000 mg/kg/day

Maternal NOAEL = 100 mg/kg/day

LOAEL = 500 mg/kg/day based on increased incidence 

of vaginal discharge, abortion, and staining of hair in 

the rectal and vaginal areas, as well as increase in postimplantation loss and decrease in body weight gain. 

Increased incidence of diarrhea was observed at the 

next highest dose (1000 mg/kg/day).

Developmental NOAEL = 1000 mg/kg/day

LOAEL could not be determined.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Nicosulfuron

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3800

Reproduction and Fertility 

Effects (rat)

41360101 (1989)

Acceptable/guideline

0, 250, 5000 or 20,000 

ppm

M: 0, 15.6, 314, 1316; F: 

19.5, 380, 1588 

mg/kg/day 

Parental/Systemic NOAEL = 1203/1571 mg/kg/day

(M/F)

LOAEL could not be established..

Reproductive NOAEL = 289/370 mg/kg/day (M/F)

LOAEL = 1203/1571 mg/kg/day (M/F) based on 

decrease litter size from F1 dams.

Offspring NOAEL = 1203/1571 mg/kg/day (M/F)

LOAEL could not be established.

870.4100b

Chronic toxicity (dog)

41360102 (1989)

Acceptable/guideline

0, 250, 5000 or 20,000 

ppm

0, 6.25, 125, 500

mg/kg/day

NOAEL = 125 mg/kg/day

LOAEL = 500 mg/kg/day based on increased relative 

liver and kidney weights in males.

870.4200b

Carcinogenicity (mouse)

41360103 (1989)

Acceptable/guideline

0, 25, 250, 2500 or 7500 

ppm 

M: 3, 31, 314, 953; F: 4, 

43, 420, 1260 mg/kg/day

NOAEL = 953/1260 mg/kg/day (M/F)

LOAEL could not be established.

No evidence of carcinogenicity.

870.4300

Combined Chronic 

Toxicity/Carcinogenicity 

(rat)

41360104 (1989)

Acceptable/guideline

0, 50, 1500, 7500 or 

20,000 ppm

M: 2, 58, 289, 786; F: 3, 

77, 382, 1098 mg/kg/day

NOAEL = 786/1098 mg/kg/day (M/F)

LOAEL could not be established.

No evidence of carcinogenicity.

870.5100

Bacterial Reverse Mutation

Test (Salmonella 

typhimurium)

41082612, 41360124 

(1988)

Acceptable/guideline

0.02 -10 μg/plate 

(not all strains tested at 

the same concentrations)

Negative in strains TA97A, TA98, TA100 and TA1535 

at doses reaching cytotoxic levels in the presence or 

absence of metabolic activation.

870.5300 

In vitro Mammalian Cell 

Gene Mutation Test

(Chinese Hamster Ovary 

(CHO) cells)

41082614, 41360123 

(1988)

Acceptable/guideline

4, 20, 40, 200 or 465 

μg/mL

Negative at doses reaching the limit of solubility in the 

presence or absence of metabolic activation.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Nicosulfuron

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.5375 

In vitro Mammalian 

Chromosome Aberration 

Test (human lymphocytes)

41082615, 41368001 

(1988)

Acceptable/guideline

0, 200, 400 or 470 

μg/mL

Negative at doses reaching the limit of solubility in the 

presence or absence of metabolic activation.

870.5385

Mammalian Bone Marrow 

Chromosome Aberration 

Assay (mouse)

41082616, 41360126 

(1988) 

Acceptable/guideline 

0, 500, 2500 or 5000 

mg/kg

Negative for induction of chromosome aberrations in 

the bone marrow cells of male or female mice at 24, 48 

or 72 hrs post-exposure. 

870.5550 

Unscheduled DNA 

Synthesis in Mammalian 

Cells in Culture (rat 

hepatocytes)

41082613, 41360125 

(1998)

Acceptable/guideline

0.04, 0.4, 1.2, 4.1, 12, 

41, 122, 409 or 470 

μg/mL

Negative for DNA damage or inducible repair in the rat 

hepatocyte.

870.6200a

Acute Neurotoxicity 

Screening Battery (rat)

48790905 (2011)

Acceptable/guideline 

0, 200, 1000, or 2000 

mg/kg

NOAEL = 2000 mg/kg/day

LOAEL = could not be established.

870.6200b

Subchronic Neurotoxicity 

Screening Battery (rat)

48790903 (2011)

Acceptable/guideline 

0, 2500, 7500 or 18,000 

ppm

M: 0, 145, 449 or 1101; 

F: 0, 181, 532 or 1295 

mg/kg/day

NOAEL = 1101/1295 mg/kg/day (M/F)

LOAEL = could not be established.

870.7485

Metabolism and 

Pharmacokinetics (rat)

41082617 (1988)

Acceptable/guideline

Single dose oral: 10 or 

1000 mg/kg

Single dose iv: 10 mg/kg

Repeated dose oral: 10 

mg/kg/day for 14 days

Most of a single oral dose was excreted unchanged 

within 24 hours and 98-109% within 4 days; the oral 

half-life was 12-24 hours. 80-95% dose was eliminated 

in feces, 9-20% in urine and <0.01% in exhaled air. A 

slightly greater percent of the oral dose was detected in 

feces of high dose than low dose animals. After iv 

administration, 76-80% dose was eliminated in urine 

and 27-30% in the feces; the iv half-life was < 12 

hours. Residues in tissues were 0.05-0.5% dose; highest 

levels detected in the liver and kidneys. The major 

excretion product was unchanged parent compound. 

Pyridinesulfonamide was detected in urine (1.1-5.7% 

dose). Pyridine acid sulfonamide 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 

molecule. No differences were observed between sexes.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Nicosulfuron

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.7800

Immunotoxicity (female 

mice)

48790904 (2011)

Acceptable/guideline

0, 300, 900, 1800 or 

7000 ppm

0, 60, 181, 333 or

1207 mg/kg/day

NOAEL = 1207 mg/kg/day

LOAEL = could not be established.

M = males, F = females, PND = post natal day
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Appendix B. Physical/Chemical Properties

TABLE B.1. 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 (at 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 (at 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 (at 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 

(at 20°C)

No absorbance maxima at or above 290 nm for 

acidic, basic or neutral solutions. 

MRID #47632204

Appendix B - Chemical Name and Structure Table

APPENDIX B Chemical Names and Structures of Nicosulfuron and Metabolites. 

Company Code; 

Common Name

Chemical Name Chemical Structure

IN-V9367; pyridine 

sulfonamide

[2-aminosulfonyl]-N,N-dimethyl-3-

pyridinecarboxamide

N

O

N

H3C CH3

S

NH2

O

O
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APPENDIX B Chemical Names and Structures of Nicosulfuron and Metabolites. 

Company Code; 

Common Name

Chemical Name Chemical Structure

IN-HYY21 or AUSN

2-[[[[(Aminoiminomethyl) 

amino]carbonyl]amino]sulfonyl]-

N,N-dimethyl-3-

pyridinecarboxamide

IN-37740 2-[[(3,4-dihydro-6-methoxy-4-

oxopyrimidin-2-

yl]aminocarbonyl]aminosulfonyl]-N, 

N-dimethyl-3-pyridinecarboxamide
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Appendix C. Review of Human Research

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. 

Electronic Database. Task Force Members: Health Canada, U.S. EPA, and the National 

Agricultural Chemicals Associations, released February 1995. 

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit 

Exposure Surrogate Reference Table. U.S. EPA. Released June 21, 2011.